MDedge ObGyn

Postmenopausal women not only have larger brain volume than women who are premenopausal, but they also experience larger reductions in brain volume over time, reported Ananthan Ambikairajah of the Centre for Research on Ageing, Health and Wellbeing, Australian National University, Canberra, and associates. Their report was published in Menopause.

In this large population-based cohort of 5,072 women aged 37-73 years, the goal of the study was to look at links between brain volume and measures of menstruation history, such as menopausal status, age at menopause, age at menarche, and the duration of a woman’s reproductive stage, but to do so within the context of how it relates to dementia prevalence. Citing a study in The Lancet Neurology, the authors noted that the age-standardized prevalence for dementia is 17% higher in women than in men, and they speculated that it may be important to look beyond age for answers.
 

What about menstrual history and Alzheimer’s disease?

According to the Framingham Study in Neurology, the remaining lifetime risk of Alzheimer’s disease (AD) is nearly double for a 65-year-old woman (12%) compared with a 65-year-old man (6.3%), leading Mr. Ambikairajah and associates to conclude that “menstruation history may also be particularly relevant, given that it is unique to female aging.” They further speculated, citing several related studies, that because AD pathology is initiated decades prior to the onset of clinical signs, menstruation history and its effects on brain health may, in fact, be reflected in brain volume.

Postmenopausal women had 0.82% and 1.33% larger total brain and hippocampal volume, respectively, compared with premenopausal women. Postmenopausal women had a 23% greater decrease in total brain volume but not in hippocampal volume over time, compared with premenopausal women.

As Braak and Braak illustrated in Acta Neuropathologica, chronic inflammation has been linked to brain shrinkage “consistent with the pattern of results in the present study,” Mr. Ambikairajah and colleagues noted, adding that longitudinal neuroimaging/biomarker studies are needed to explore this further.

What made this study unique was its ability to match pre- and postmenopausal women for age, a critically important attribute “given that aging and menopause both progress concurrently, which can make it difficult to determine the individual contribution of each for measures of brain health,” the authors explained.

In an interview, Constance Bohon, MD, an ob.gyn. in private practice and assistant clinical professor, George Washington University, Washington, observed: “The conclusion [in this study] is that an early age of menarche, delayed age of menopause and increased duration of the reproductive stage is negatively associated with brain volume.”
 

What of the neuroprotective effects of endogenous estrogen?

“Their findings are not consistent with a neuroprotective effect of endogenous estrogen exposure on brain volume,” she noted, adding that the study “did not assess the effect of exogenous estrogen on brain volume. Neither was the effect of exogenous or endogenous estrogen on cerebral blood flow assessed. In a study published in Obstetrics & Gynecology, the conclusion was that oophorectomy before the age of natural menopause is associated with a decrease in cognitive impairment and dementia. There was no assessment of brain volume or cerebral blood flow. Likewise in a report published in Neurobiology of Aging, Maki P and Resnick S M. concluded that estrogen helps maintain hippocampal and prefrontal function as women age,” observed Dr. Bohon, noting that the study did not assess brain volume.

“It is unclear whether the most predictive assessment for worsening cognition and dementia is the finding of decreased total brain volume, decreased hippocampal volume, or decreased cerebral blood flow. The effect of both endogenous and exogenous estrogen on the risk for dementia needs further evaluation,” she cautioned.

Mr. Ambikairajah cited one financial disclosure; the remaining contributors had no relevant disclosures.

Postmenopausal women not only have larger brain volume than women who are premenopausal, but they also experience larger reductions in brain volume over time, reported Ananthan Ambikairajah of the Centre for Research on Ageing, Health and Wellbeing, Australian National University, Canberra, and associates. Their report was published in Menopause.

In this large population-based cohort of 5,072 women aged 37-73 years, the goal of the study was to look at links between brain volume and measures of menstruation history, such as menopausal status, age at menopause, age at menarche, and the duration of a woman’s reproductive stage, but to do so within the context of how it relates to dementia prevalence. Citing a study in The Lancet Neurology, the authors noted that the age-standardized prevalence for dementia is 17% higher in women than in men, and they speculated that it may be important to look beyond age for answers.
 

What about menstrual history and Alzheimer’s disease?

According to the Framingham Study in Neurology, the remaining lifetime risk of Alzheimer’s disease (AD) is nearly double for a 65-year-old woman (12%) compared with a 65-year-old man (6.3%), leading Mr. Ambikairajah and associates to conclude that “menstruation history may also be particularly relevant, given that it is unique to female aging.” They further speculated, citing several related studies, that because AD pathology is initiated decades prior to the onset of clinical signs, menstruation history and its effects on brain health may, in fact, be reflected in brain volume.

Postmenopausal women had 0.82% and 1.33% larger total brain and hippocampal volume, respectively, compared with premenopausal women. Postmenopausal women had a 23% greater decrease in total brain volume but not in hippocampal volume over time, compared with premenopausal women.

As Braak and Braak illustrated in Acta Neuropathologica, chronic inflammation has been linked to brain shrinkage “consistent with the pattern of results in the present study,” Mr. Ambikairajah and colleagues noted, adding that longitudinal neuroimaging/biomarker studies are needed to explore this further.

What made this study unique was its ability to match pre- and postmenopausal women for age, a critically important attribute “given that aging and menopause both progress concurrently, which can make it difficult to determine the individual contribution of each for measures of brain health,” the authors explained.

In an interview, Constance Bohon, MD, an ob.gyn. in private practice and assistant clinical professor, George Washington University, Washington, observed: “The conclusion [in this study] is that an early age of menarche, delayed age of menopause and increased duration of the reproductive stage is negatively associated with brain volume.”
 

What of the neuroprotective effects of endogenous estrogen?

“Their findings are not consistent with a neuroprotective effect of endogenous estrogen exposure on brain volume,” she noted, adding that the study “did not assess the effect of exogenous estrogen on brain volume. Neither was the effect of exogenous or endogenous estrogen on cerebral blood flow assessed. In a study published in Obstetrics & Gynecology, the conclusion was that oophorectomy before the age of natural menopause is associated with a decrease in cognitive impairment and dementia. There was no assessment of brain volume or cerebral blood flow. Likewise in a report published in Neurobiology of Aging, Maki P and Resnick S M. concluded that estrogen helps maintain hippocampal and prefrontal function as women age,” observed Dr. Bohon, noting that the study did not assess brain volume.

“It is unclear whether the most predictive assessment for worsening cognition and dementia is the finding of decreased total brain volume, decreased hippocampal volume, or decreased cerebral blood flow. The effect of both endogenous and exogenous estrogen on the risk for dementia needs further evaluation,” she cautioned.

Mr. Ambikairajah cited one financial disclosure; the remaining contributors had no relevant disclosures.

Postmenopausal women not only have larger brain volume than women who are premenopausal, but they also experience larger reductions in brain volume over time, reported Ananthan Ambikairajah of the Centre for Research on Ageing, Health and Wellbeing, Australian National University, Canberra, and associates. Their report was published in Menopause.

In this large population-based cohort of 5,072 women aged 37-73 years, the goal of the study was to look at links between brain volume and measures of menstruation history, such as menopausal status, age at menopause, age at menarche, and the duration of a woman’s reproductive stage, but to do so within the context of how it relates to dementia prevalence. Citing a study in The Lancet Neurology, the authors noted that the age-standardized prevalence for dementia is 17% higher in women than in men, and they speculated that it may be important to look beyond age for answers.
 

What about menstrual history and Alzheimer’s disease?

According to the Framingham Study in Neurology, the remaining lifetime risk of Alzheimer’s disease (AD) is nearly double for a 65-year-old woman (12%) compared with a 65-year-old man (6.3%), leading Mr. Ambikairajah and associates to conclude that “menstruation history may also be particularly relevant, given that it is unique to female aging.” They further speculated, citing several related studies, that because AD pathology is initiated decades prior to the onset of clinical signs, menstruation history and its effects on brain health may, in fact, be reflected in brain volume.

Postmenopausal women had 0.82% and 1.33% larger total brain and hippocampal volume, respectively, compared with premenopausal women. Postmenopausal women had a 23% greater decrease in total brain volume but not in hippocampal volume over time, compared with premenopausal women.

As Braak and Braak illustrated in Acta Neuropathologica, chronic inflammation has been linked to brain shrinkage “consistent with the pattern of results in the present study,” Mr. Ambikairajah and colleagues noted, adding that longitudinal neuroimaging/biomarker studies are needed to explore this further.

What made this study unique was its ability to match pre- and postmenopausal women for age, a critically important attribute “given that aging and menopause both progress concurrently, which can make it difficult to determine the individual contribution of each for measures of brain health,” the authors explained.

In an interview, Constance Bohon, MD, an ob.gyn. in private practice and assistant clinical professor, George Washington University, Washington, observed: “The conclusion [in this study] is that an early age of menarche, delayed age of menopause and increased duration of the reproductive stage is negatively associated with brain volume.”
 

What of the neuroprotective effects of endogenous estrogen?

“Their findings are not consistent with a neuroprotective effect of endogenous estrogen exposure on brain volume,” she noted, adding that the study “did not assess the effect of exogenous estrogen on brain volume. Neither was the effect of exogenous or endogenous estrogen on cerebral blood flow assessed. In a study published in Obstetrics & Gynecology, the conclusion was that oophorectomy before the age of natural menopause is associated with a decrease in cognitive impairment and dementia. There was no assessment of brain volume or cerebral blood flow. Likewise in a report published in Neurobiology of Aging, Maki P and Resnick S M. concluded that estrogen helps maintain hippocampal and prefrontal function as women age,” observed Dr. Bohon, noting that the study did not assess brain volume.

“It is unclear whether the most predictive assessment for worsening cognition and dementia is the finding of decreased total brain volume, decreased hippocampal volume, or decreased cerebral blood flow. The effect of both endogenous and exogenous estrogen on the risk for dementia needs further evaluation,” she cautioned.

Mr. Ambikairajah cited one financial disclosure; the remaining contributors had no relevant disclosures.

Among the more than 320 million people in the United States, there was a prevalence estimate of 67.6 million sexually transmitted infections at the time of assessment in 2018, according to the results of an epidemiologic study using multiple data sources, including the National Health and Nutrition Examination Survey (NHANES).

In addition, almost half of the incident STIs occurred in the 15- to 24-year age bracket, according to a report published online in Sexually Transmitted Diseases. Researchers estimated the combined number of prevalent and incident infections of eight STIs in the United States in 2018: chlamydia, gonorrhea, trichomoniasis, syphilis, genital herpes (caused by herpes simplex virus type 2 [HSV-2]), human papillomavirus (HPV), sexually transmitted hepatitis B virus (HBV), and sexually transmitted HIV.

The estimated incidences of these STIs in this update, the first since 2008, were made using more recent data and improved estimation methods to provide updated STI prevalence and incidence estimates for 2018, both overall and by disease. “Having a combined estimate is crucial for policy purposes to illustrate the importance of STIs in the United States,” according to Kristen M. Kreisel, PhD, an epidemiologist at the Centers for Disease Control and Prevention, division of STD prevention, and colleagues.

The number of prevalent and incident infections were obtained by multiplying each STI’s updated per capita estimates by the 2018 full resident population estimates from the American Community Survey.
 

Detailed results

Chlamydia. The prevalence of chlamydia was estimated using 2015-2018 NHANES data, which was then used to create a modeled prevalence in 2018, according to the authors. There were an estimated 2.4 million prevalent urogenital chlamydial infections among persons aged 15-39 years in 2018; 1.1 and 1.3 million infections among men and women, respectively. Individuals aged 15-24 years comprised 56.7% and 75.8% of all infections in men and women respectively.

Gonorrhea. The prevalence of gonorrhea was estimated using ordinary differential equation based modeling. The number of prevalent urogenital gonococcal infections in 2018 among 15- to 39-year-olds was 209,000 overall; 50,000 in men and 155,000 in women. Of these, 113,000 (54.1%) occurred in 15- to 24-year-olds.

Trichomoniasis. The prevalence of trichomoniasis was estimated using 2015-2018 NHANES data, which was then used to create a modeled prevalence in 2018, according to the authors. The number of prevalent Trichomonas infections among 15- to 59-year-olds was 2.6 million, with 470,000 in men and 2.1 million in women. Persons aged 15-24 years comprised 15.6% of all prevalent infections, according to the authors.

Syphilis. The number of estimated prevalent syphilitic infections (all stages) among 14- to 49-year-old persons in 2018 was 156,000, with infections in men comprising 71.8% of all infections. Infections in both men and women aged 14-24 years accounted for about 25% of all infections, with 36,000 total prevalent syphilitic infections among 14- to 24-year-olds in 2018.

Genital herpes. The prevalence of genital herpes (caused by HSV-2) was estimated using 2015-2018 NHANES data, according to the authors. In persons aged 15-49 years in 2018, there were 18.6 million prevalent HSV-2 infections; 6.4 million among men and 12.2 million among women. Infections in 15- to 24-year-olds comprised 7.1% of all prevalent HSV-2 infections.

HPV. The prevalence of HPV was estimated using 2013-2016 NHANES data, which was assumed to reflect stable prevalence in 2018, according to the authors. Among 15- to 59-year-olds, the estimated number of persons, men, and women infected with one or more disease-associated HPV types in 2018 was 42.5, 23.4, and 19.2 million, respectively, with an estimated 9.0 million (21%) 15- to 24-year-olds infected,

HBV. NHANES 2013-2018 data were used to estimate the prevalence of sexually transmitted chronic HBV infections in 2018, according to the authors. The estimated number of infections among persons aged 15 years and older in 2018 was 103,000 (51,000 men and 52,000 women). There small sample size of individuals aged 15-24 years in the NHANES database made it impossible to obtain an accurate estimate for this group, according to the authors.

HIV. Data from the National HIV Surveillance System were used to estimate the prevalence and incidence of sexually transmitted HIV infections for persons aged 13 years and older in 2018. A total of 984,000 individuals aged 13 years and older were estimated to be living with sexually transmitted HIV at the end of 2018, according to the authors. Nearly 80% were men. In the 13- to 24-year-old age bracket, there were an estimated 45,400 living with sexually transmitted HIV.

Billions in costs

Commenting on the study by the CDC researchers, Raul Romaguera, acting director for CDC’s division of STD prevention, stated in a press release: “There are significant human and financial costs associated with these infections, and we know from other studies that cuts in STI prevention efforts result in higher costs down the road. Preventing STIs could save billions in medical costs, but more importantly, prevention would improve the health and lives of millions of people.”

“About 20% of the total U.S. population had an STI at a given point in 2018, while nearly half of all incident infections occurred in people aged 15-24 years. Focusing STI prevention efforts on the 15- to 24-year-old population may be key to lowering the STI burden in the U.S.,” the researchers concluded.

The authors reported that they had no disclosures.

mlesney@mdedge.com

Among the more than 320 million people in the United States, there was a prevalence estimate of 67.6 million sexually transmitted infections at the time of assessment in 2018, according to the results of an epidemiologic study using multiple data sources, including the National Health and Nutrition Examination Survey (NHANES).

In addition, almost half of the incident STIs occurred in the 15- to 24-year age bracket, according to a report published online in Sexually Transmitted Diseases. Researchers estimated the combined number of prevalent and incident infections of eight STIs in the United States in 2018: chlamydia, gonorrhea, trichomoniasis, syphilis, genital herpes (caused by herpes simplex virus type 2 [HSV-2]), human papillomavirus (HPV), sexually transmitted hepatitis B virus (HBV), and sexually transmitted HIV.

The estimated incidences of these STIs in this update, the first since 2008, were made using more recent data and improved estimation methods to provide updated STI prevalence and incidence estimates for 2018, both overall and by disease. “Having a combined estimate is crucial for policy purposes to illustrate the importance of STIs in the United States,” according to Kristen M. Kreisel, PhD, an epidemiologist at the Centers for Disease Control and Prevention, division of STD prevention, and colleagues.

The number of prevalent and incident infections were obtained by multiplying each STI’s updated per capita estimates by the 2018 full resident population estimates from the American Community Survey.
 

Detailed results

Chlamydia. The prevalence of chlamydia was estimated using 2015-2018 NHANES data, which was then used to create a modeled prevalence in 2018, according to the authors. There were an estimated 2.4 million prevalent urogenital chlamydial infections among persons aged 15-39 years in 2018; 1.1 and 1.3 million infections among men and women, respectively. Individuals aged 15-24 years comprised 56.7% and 75.8% of all infections in men and women respectively.

Gonorrhea. The prevalence of gonorrhea was estimated using ordinary differential equation based modeling. The number of prevalent urogenital gonococcal infections in 2018 among 15- to 39-year-olds was 209,000 overall; 50,000 in men and 155,000 in women. Of these, 113,000 (54.1%) occurred in 15- to 24-year-olds.

Trichomoniasis. The prevalence of trichomoniasis was estimated using 2015-2018 NHANES data, which was then used to create a modeled prevalence in 2018, according to the authors. The number of prevalent Trichomonas infections among 15- to 59-year-olds was 2.6 million, with 470,000 in men and 2.1 million in women. Persons aged 15-24 years comprised 15.6% of all prevalent infections, according to the authors.

Syphilis. The number of estimated prevalent syphilitic infections (all stages) among 14- to 49-year-old persons in 2018 was 156,000, with infections in men comprising 71.8% of all infections. Infections in both men and women aged 14-24 years accounted for about 25% of all infections, with 36,000 total prevalent syphilitic infections among 14- to 24-year-olds in 2018.

Genital herpes. The prevalence of genital herpes (caused by HSV-2) was estimated using 2015-2018 NHANES data, according to the authors. In persons aged 15-49 years in 2018, there were 18.6 million prevalent HSV-2 infections; 6.4 million among men and 12.2 million among women. Infections in 15- to 24-year-olds comprised 7.1% of all prevalent HSV-2 infections.

HPV. The prevalence of HPV was estimated using 2013-2016 NHANES data, which was assumed to reflect stable prevalence in 2018, according to the authors. Among 15- to 59-year-olds, the estimated number of persons, men, and women infected with one or more disease-associated HPV types in 2018 was 42.5, 23.4, and 19.2 million, respectively, with an estimated 9.0 million (21%) 15- to 24-year-olds infected,

HBV. NHANES 2013-2018 data were used to estimate the prevalence of sexually transmitted chronic HBV infections in 2018, according to the authors. The estimated number of infections among persons aged 15 years and older in 2018 was 103,000 (51,000 men and 52,000 women). There small sample size of individuals aged 15-24 years in the NHANES database made it impossible to obtain an accurate estimate for this group, according to the authors.

HIV. Data from the National HIV Surveillance System were used to estimate the prevalence and incidence of sexually transmitted HIV infections for persons aged 13 years and older in 2018. A total of 984,000 individuals aged 13 years and older were estimated to be living with sexually transmitted HIV at the end of 2018, according to the authors. Nearly 80% were men. In the 13- to 24-year-old age bracket, there were an estimated 45,400 living with sexually transmitted HIV.

Billions in costs

Commenting on the study by the CDC researchers, Raul Romaguera, acting director for CDC’s division of STD prevention, stated in a press release: “There are significant human and financial costs associated with these infections, and we know from other studies that cuts in STI prevention efforts result in higher costs down the road. Preventing STIs could save billions in medical costs, but more importantly, prevention would improve the health and lives of millions of people.”

“About 20% of the total U.S. population had an STI at a given point in 2018, while nearly half of all incident infections occurred in people aged 15-24 years. Focusing STI prevention efforts on the 15- to 24-year-old population may be key to lowering the STI burden in the U.S.,” the researchers concluded.

The authors reported that they had no disclosures.

mlesney@mdedge.com

Among the more than 320 million people in the United States, there was a prevalence estimate of 67.6 million sexually transmitted infections at the time of assessment in 2018, according to the results of an epidemiologic study using multiple data sources, including the National Health and Nutrition Examination Survey (NHANES).

In addition, almost half of the incident STIs occurred in the 15- to 24-year age bracket, according to a report published online in Sexually Transmitted Diseases. Researchers estimated the combined number of prevalent and incident infections of eight STIs in the United States in 2018: chlamydia, gonorrhea, trichomoniasis, syphilis, genital herpes (caused by herpes simplex virus type 2 [HSV-2]), human papillomavirus (HPV), sexually transmitted hepatitis B virus (HBV), and sexually transmitted HIV.

The estimated incidences of these STIs in this update, the first since 2008, were made using more recent data and improved estimation methods to provide updated STI prevalence and incidence estimates for 2018, both overall and by disease. “Having a combined estimate is crucial for policy purposes to illustrate the importance of STIs in the United States,” according to Kristen M. Kreisel, PhD, an epidemiologist at the Centers for Disease Control and Prevention, division of STD prevention, and colleagues.

The number of prevalent and incident infections were obtained by multiplying each STI’s updated per capita estimates by the 2018 full resident population estimates from the American Community Survey.
 

Detailed results

Chlamydia. The prevalence of chlamydia was estimated using 2015-2018 NHANES data, which was then used to create a modeled prevalence in 2018, according to the authors. There were an estimated 2.4 million prevalent urogenital chlamydial infections among persons aged 15-39 years in 2018; 1.1 and 1.3 million infections among men and women, respectively. Individuals aged 15-24 years comprised 56.7% and 75.8% of all infections in men and women respectively.

Gonorrhea. The prevalence of gonorrhea was estimated using ordinary differential equation based modeling. The number of prevalent urogenital gonococcal infections in 2018 among 15- to 39-year-olds was 209,000 overall; 50,000 in men and 155,000 in women. Of these, 113,000 (54.1%) occurred in 15- to 24-year-olds.

Trichomoniasis. The prevalence of trichomoniasis was estimated using 2015-2018 NHANES data, which was then used to create a modeled prevalence in 2018, according to the authors. The number of prevalent Trichomonas infections among 15- to 59-year-olds was 2.6 million, with 470,000 in men and 2.1 million in women. Persons aged 15-24 years comprised 15.6% of all prevalent infections, according to the authors.

Syphilis. The number of estimated prevalent syphilitic infections (all stages) among 14- to 49-year-old persons in 2018 was 156,000, with infections in men comprising 71.8% of all infections. Infections in both men and women aged 14-24 years accounted for about 25% of all infections, with 36,000 total prevalent syphilitic infections among 14- to 24-year-olds in 2018.

Genital herpes. The prevalence of genital herpes (caused by HSV-2) was estimated using 2015-2018 NHANES data, according to the authors. In persons aged 15-49 years in 2018, there were 18.6 million prevalent HSV-2 infections; 6.4 million among men and 12.2 million among women. Infections in 15- to 24-year-olds comprised 7.1% of all prevalent HSV-2 infections.

HPV. The prevalence of HPV was estimated using 2013-2016 NHANES data, which was assumed to reflect stable prevalence in 2018, according to the authors. Among 15- to 59-year-olds, the estimated number of persons, men, and women infected with one or more disease-associated HPV types in 2018 was 42.5, 23.4, and 19.2 million, respectively, with an estimated 9.0 million (21%) 15- to 24-year-olds infected,

HBV. NHANES 2013-2018 data were used to estimate the prevalence of sexually transmitted chronic HBV infections in 2018, according to the authors. The estimated number of infections among persons aged 15 years and older in 2018 was 103,000 (51,000 men and 52,000 women). There small sample size of individuals aged 15-24 years in the NHANES database made it impossible to obtain an accurate estimate for this group, according to the authors.

HIV. Data from the National HIV Surveillance System were used to estimate the prevalence and incidence of sexually transmitted HIV infections for persons aged 13 years and older in 2018. A total of 984,000 individuals aged 13 years and older were estimated to be living with sexually transmitted HIV at the end of 2018, according to the authors. Nearly 80% were men. In the 13- to 24-year-old age bracket, there were an estimated 45,400 living with sexually transmitted HIV.

Billions in costs

Commenting on the study by the CDC researchers, Raul Romaguera, acting director for CDC’s division of STD prevention, stated in a press release: “There are significant human and financial costs associated with these infections, and we know from other studies that cuts in STI prevention efforts result in higher costs down the road. Preventing STIs could save billions in medical costs, but more importantly, prevention would improve the health and lives of millions of people.”

“About 20% of the total U.S. population had an STI at a given point in 2018, while nearly half of all incident infections occurred in people aged 15-24 years. Focusing STI prevention efforts on the 15- to 24-year-old population may be key to lowering the STI burden in the U.S.,” the researchers concluded.

The authors reported that they had no disclosures.

mlesney@mdedge.com

Intact removal of an ovarian cyst is a well-established gynecologic surgical principle because ovarian cancer is definitively diagnosed only in retrospect (after ovarian extraction) and intraoperative cyst rupture upstages an otherwise nonmetastatic cancer to stage IC. This lumps cancers that are ruptured during surgical extraction together with those that have spontaneously ruptured or have surface excrescences. The theoretical rationale for this “lumping” is that contact between malignant cells from the ruptured cyst may take hold on peritoneal surfaces resulting in development of metastases. To offset this theoretical risk, it has been recommended that all stage IC ovarian cancer is treated with chemotherapy, whereas low-grade stage IA and IB cancers generally are not. No conscientious surgeon wants their surgical intervention to be the cause of a patient needing toxic chemotherapy. But is the contact between malignant cyst fluid and the peritoneum truly as bad as a spontaneous breach of the surface of the tumor? Or is cyst rupture a confounder for other adverse prognostic features, such as histologic cell type and dense pelvic attachments? If ovarian cyst rupture is an independent risk factor for patients with stage I ovarian cancer, strategies should be employed to avoid this occurrence, and we should understand how to counsel and treat patients in whom this has occurred.

In 2017 the International Federation of Gynecology and Obstetrics (FIGO) staging of epithelial ovarian cancer subcategorized stage IC. This group encompasses women with contact between malignant cells and the peritoneum in the absence of other extraovarian disease. The table includes these distinct groupings. Stage IC1 includes patients in whom intraoperative spill occurred. Stage IC2 includes women with preoperative cyst rupture, and or microscopic or macroscopic surface involvement because the data support that these cases carry a poorer prognosis, compared with those with intraoperative rupture (IC1).¹ The final subcategory, IC3, includes women who have washings (obtained at the onset of surgery, prior to manipulation of the tumor) that were positive for malignant cells, denoting preexisting contact between the tumor and peritoneum and a phenotypically more aggressive tumor.

The clinical significance of ovarian cancer capsule rupture has been evaluated in multiple studies with some mixed results.¹ Consistently, it is reported that preoperative rupture, surface or capsular involvement, and preexisting peritoneal circulation of metastatic cells all portend a poorer prognosis; however, it is less clear that iatrogenic surgical rupture has the same deleterious association. In a large retrospective series from Japan, the authors evaluated 15,163 cases of stage I ovarian cancer and identified 7,227 cases of iatrogenic (intraoperative) cyst rupture.² These cases were significantly more likely to occur among clear cell cancers, and were more likely to occur in younger patients. Worse prognosis was associated with cell type (clear cell cancers), but non–clear cell cancers (such as serous, mucinous, and endometrioid) did not have a higher hazard ratio for death when intraoperative rupture occurred. But why would intraoperative cyst rupture result in worse prognosis for only one histologic cell type? The authors hypothesized that perhaps rupture was more likely to occur during extraction of these clear cell tumors because they were associated with dense adhesions from associated endometriosis, and perhaps an adverse biologic phenomenon associated with infiltrative endometriosis is driving the behavior of this cancer.

The Japanese study also looked at the effect of chemotherapy on these same patients’ outcomes. Interestingly, the addition of chemotherapy did not improve survival for the patients with stage IC1 cancers, which was in contrast to the improved survival seen when chemotherapy was given to those with spontaneous rupture or ovarian surface involvement (IC2, IC3). These data support differentiating the subgroups of stage IC cancer in treatment decision-making, and suggest that adjuvant chemotherapy might be avoided for patients with nonclear cell stage IC1 ovarian cancer. While the outcomes are worse for patients with ruptured clear cell cancers, current therapeutic options for clear cell cancers are limited because of their known resistance to traditional agents, and outcomes for women with clear cell cancer can be worse across all stages.

While cyst rupture may not always negatively affect prognosis, the goal of surgery remains an intact removal, which influences decisions regarding surgical approach. Most adnexal masses are removed via minimally invasive surgery (MIS). MIS is associated with benefits of morbidity and cost, and therefore should be considered wherever feasible. However, MIS is associated with an increased risk of ovarian cyst rupture, likely because of the rigid instrumentation used when approaching a curved structure, in addition to the disparity in size of the pathology, compared with the extraction site incision.³ When weighing the benefits and risks of different surgical approaches, it is important to gauge the probability of malignancy. Not all complex ovarian masses associated with elevations in tumor markers are malignant, and certainly most that are associated with normal tumor markers are not. If the preoperative clinical data suggest that the mass is more likely to be malignant (e.g., mostly solid, vascular tumors with very elevated tumor markers), consideration might be made to abandoning a purely minimally invasive approach to a hand-assisted MIS or laparotomy approach. However, it would seem that abandoning an MIS approach to remove every ovarian cyst is unwise given that there is clear patient benefit with MIS and, as discussed above, most cases of iatrogenic malignant cyst rupture are unavoidable even with laparotomy, and do not necessarily independently portend poorer survival or mandate chemotherapy.

Surgeons should be both nuanced and flexible and apply some basic rules of thumb when approaching the diagnostically uncertain adnexal mass. Peritoneal washings should be obtained at the commencement of the case to discriminate those cases of true stage IC3. The peritoneum parallel to the ovarian vessel should be extensively opened to a level above the pelvic brim. In order to do this, the physiological attachments between the sigmoid colon or cecum and the suspensory ligament of the ovary may need to be carefully mobilized. This allows for retroperitoneal identification of the ureter and skeletonization of the ovarian vessels at least 2 cm proximal to their insertion into the ovary and avoidance of contact with the ovary itself (which may have a fragile capsule) or incomplete ovarian resection. If the ovary remains invested close to the sidewall or colonic structures and the appropriate peritoneal and retroperitoneal mobilization has not occurred, the surgeon may unavoidably rupture the ovarian cyst as they try to “hug” the ovary with their bites of tissue in an attempt to avoid visceral injury. There is little role for an ovarian cystectomy in a postmenopausal woman undergoing surgery for a complex adnexal mass, particularly if she has elevated tumor markers, because the process of performing ovarian cystectomy commonly invokes cyst rupture or fragmentation. Ovarian cystectomy should be reserved for premenopausal women with adnexal masses at low suspicion for malignancy. If the adnexa appears densely adherent to adjacent structures – for example, associated with infiltrative endometriosis – consideration for laparotomy or a hand-assisted approach may be necessary; in such cases, even open surgery can result in cyst rupture, and the morbidity of conversion to laparotomy should be weighed for individual cases.

Finally, retrieval of the ovarian specimen should occur intact without morcellation. There should be no uncontained morcellation of adnexal structures during retrieval of even normal-appearing ovaries. The preferred retrieval method is to place the adnexa in an appropriately sized retrieval bag, after which contained morcellation or drainage can occur to facilitate removal through a laparoscopic incision. Contained morcellation is very difficult for large solid masses through a laparoscopic port site; in these cases, extension of the incision may be necessary.

While operative spill of an ovarian cancer does upstage nonmetastatic ovarian cancer, it is unclear that, in most cases, this is independently associated with worse prognosis, and chemotherapy may not always be of added value. However, best surgical practice should always include strategies to minimize the chance of rupture when approaching adnexal masses, particularly those at highest likelihood of malignancy.

 

References

1. Kim HS et al. Eur J Surg Oncol. 2013 Mar 39(3):279-89.

2. Matsuo K et al. Obstet Gynecol. 2019 Nov;134(5):1017-26.

3. Matsuo K et al. JAMA Oncol. 2020 Jul 1;6(7):1110-3.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.

Intact removal of an ovarian cyst is a well-established gynecologic surgical principle because ovarian cancer is definitively diagnosed only in retrospect (after ovarian extraction) and intraoperative cyst rupture upstages an otherwise nonmetastatic cancer to stage IC. This lumps cancers that are ruptured during surgical extraction together with those that have spontaneously ruptured or have surface excrescences. The theoretical rationale for this “lumping” is that contact between malignant cells from the ruptured cyst may take hold on peritoneal surfaces resulting in development of metastases. To offset this theoretical risk, it has been recommended that all stage IC ovarian cancer is treated with chemotherapy, whereas low-grade stage IA and IB cancers generally are not. No conscientious surgeon wants their surgical intervention to be the cause of a patient needing toxic chemotherapy. But is the contact between malignant cyst fluid and the peritoneum truly as bad as a spontaneous breach of the surface of the tumor? Or is cyst rupture a confounder for other adverse prognostic features, such as histologic cell type and dense pelvic attachments? If ovarian cyst rupture is an independent risk factor for patients with stage I ovarian cancer, strategies should be employed to avoid this occurrence, and we should understand how to counsel and treat patients in whom this has occurred.

In 2017 the International Federation of Gynecology and Obstetrics (FIGO) staging of epithelial ovarian cancer subcategorized stage IC. This group encompasses women with contact between malignant cells and the peritoneum in the absence of other extraovarian disease. The table includes these distinct groupings. Stage IC1 includes patients in whom intraoperative spill occurred. Stage IC2 includes women with preoperative cyst rupture, and or microscopic or macroscopic surface involvement because the data support that these cases carry a poorer prognosis, compared with those with intraoperative rupture (IC1).¹ The final subcategory, IC3, includes women who have washings (obtained at the onset of surgery, prior to manipulation of the tumor) that were positive for malignant cells, denoting preexisting contact between the tumor and peritoneum and a phenotypically more aggressive tumor.

The clinical significance of ovarian cancer capsule rupture has been evaluated in multiple studies with some mixed results.¹ Consistently, it is reported that preoperative rupture, surface or capsular involvement, and preexisting peritoneal circulation of metastatic cells all portend a poorer prognosis; however, it is less clear that iatrogenic surgical rupture has the same deleterious association. In a large retrospective series from Japan, the authors evaluated 15,163 cases of stage I ovarian cancer and identified 7,227 cases of iatrogenic (intraoperative) cyst rupture.² These cases were significantly more likely to occur among clear cell cancers, and were more likely to occur in younger patients. Worse prognosis was associated with cell type (clear cell cancers), but non–clear cell cancers (such as serous, mucinous, and endometrioid) did not have a higher hazard ratio for death when intraoperative rupture occurred. But why would intraoperative cyst rupture result in worse prognosis for only one histologic cell type? The authors hypothesized that perhaps rupture was more likely to occur during extraction of these clear cell tumors because they were associated with dense adhesions from associated endometriosis, and perhaps an adverse biologic phenomenon associated with infiltrative endometriosis is driving the behavior of this cancer.

The Japanese study also looked at the effect of chemotherapy on these same patients’ outcomes. Interestingly, the addition of chemotherapy did not improve survival for the patients with stage IC1 cancers, which was in contrast to the improved survival seen when chemotherapy was given to those with spontaneous rupture or ovarian surface involvement (IC2, IC3). These data support differentiating the subgroups of stage IC cancer in treatment decision-making, and suggest that adjuvant chemotherapy might be avoided for patients with nonclear cell stage IC1 ovarian cancer. While the outcomes are worse for patients with ruptured clear cell cancers, current therapeutic options for clear cell cancers are limited because of their known resistance to traditional agents, and outcomes for women with clear cell cancer can be worse across all stages.

While cyst rupture may not always negatively affect prognosis, the goal of surgery remains an intact removal, which influences decisions regarding surgical approach. Most adnexal masses are removed via minimally invasive surgery (MIS). MIS is associated with benefits of morbidity and cost, and therefore should be considered wherever feasible. However, MIS is associated with an increased risk of ovarian cyst rupture, likely because of the rigid instrumentation used when approaching a curved structure, in addition to the disparity in size of the pathology, compared with the extraction site incision.³ When weighing the benefits and risks of different surgical approaches, it is important to gauge the probability of malignancy. Not all complex ovarian masses associated with elevations in tumor markers are malignant, and certainly most that are associated with normal tumor markers are not. If the preoperative clinical data suggest that the mass is more likely to be malignant (e.g., mostly solid, vascular tumors with very elevated tumor markers), consideration might be made to abandoning a purely minimally invasive approach to a hand-assisted MIS or laparotomy approach. However, it would seem that abandoning an MIS approach to remove every ovarian cyst is unwise given that there is clear patient benefit with MIS and, as discussed above, most cases of iatrogenic malignant cyst rupture are unavoidable even with laparotomy, and do not necessarily independently portend poorer survival or mandate chemotherapy.

Surgeons should be both nuanced and flexible and apply some basic rules of thumb when approaching the diagnostically uncertain adnexal mass. Peritoneal washings should be obtained at the commencement of the case to discriminate those cases of true stage IC3. The peritoneum parallel to the ovarian vessel should be extensively opened to a level above the pelvic brim. In order to do this, the physiological attachments between the sigmoid colon or cecum and the suspensory ligament of the ovary may need to be carefully mobilized. This allows for retroperitoneal identification of the ureter and skeletonization of the ovarian vessels at least 2 cm proximal to their insertion into the ovary and avoidance of contact with the ovary itself (which may have a fragile capsule) or incomplete ovarian resection. If the ovary remains invested close to the sidewall or colonic structures and the appropriate peritoneal and retroperitoneal mobilization has not occurred, the surgeon may unavoidably rupture the ovarian cyst as they try to “hug” the ovary with their bites of tissue in an attempt to avoid visceral injury. There is little role for an ovarian cystectomy in a postmenopausal woman undergoing surgery for a complex adnexal mass, particularly if she has elevated tumor markers, because the process of performing ovarian cystectomy commonly invokes cyst rupture or fragmentation. Ovarian cystectomy should be reserved for premenopausal women with adnexal masses at low suspicion for malignancy. If the adnexa appears densely adherent to adjacent structures – for example, associated with infiltrative endometriosis – consideration for laparotomy or a hand-assisted approach may be necessary; in such cases, even open surgery can result in cyst rupture, and the morbidity of conversion to laparotomy should be weighed for individual cases.

Finally, retrieval of the ovarian specimen should occur intact without morcellation. There should be no uncontained morcellation of adnexal structures during retrieval of even normal-appearing ovaries. The preferred retrieval method is to place the adnexa in an appropriately sized retrieval bag, after which contained morcellation or drainage can occur to facilitate removal through a laparoscopic incision. Contained morcellation is very difficult for large solid masses through a laparoscopic port site; in these cases, extension of the incision may be necessary.

While operative spill of an ovarian cancer does upstage nonmetastatic ovarian cancer, it is unclear that, in most cases, this is independently associated with worse prognosis, and chemotherapy may not always be of added value. However, best surgical practice should always include strategies to minimize the chance of rupture when approaching adnexal masses, particularly those at highest likelihood of malignancy.

 

References

1. Kim HS et al. Eur J Surg Oncol. 2013 Mar 39(3):279-89.

2. Matsuo K et al. Obstet Gynecol. 2019 Nov;134(5):1017-26.

3. Matsuo K et al. JAMA Oncol. 2020 Jul 1;6(7):1110-3.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.

Intact removal of an ovarian cyst is a well-established gynecologic surgical principle because ovarian cancer is definitively diagnosed only in retrospect (after ovarian extraction) and intraoperative cyst rupture upstages an otherwise nonmetastatic cancer to stage IC. This lumps cancers that are ruptured during surgical extraction together with those that have spontaneously ruptured or have surface excrescences. The theoretical rationale for this “lumping” is that contact between malignant cells from the ruptured cyst may take hold on peritoneal surfaces resulting in development of metastases. To offset this theoretical risk, it has been recommended that all stage IC ovarian cancer is treated with chemotherapy, whereas low-grade stage IA and IB cancers generally are not. No conscientious surgeon wants their surgical intervention to be the cause of a patient needing toxic chemotherapy. But is the contact between malignant cyst fluid and the peritoneum truly as bad as a spontaneous breach of the surface of the tumor? Or is cyst rupture a confounder for other adverse prognostic features, such as histologic cell type and dense pelvic attachments? If ovarian cyst rupture is an independent risk factor for patients with stage I ovarian cancer, strategies should be employed to avoid this occurrence, and we should understand how to counsel and treat patients in whom this has occurred.

In 2017 the International Federation of Gynecology and Obstetrics (FIGO) staging of epithelial ovarian cancer subcategorized stage IC. This group encompasses women with contact between malignant cells and the peritoneum in the absence of other extraovarian disease. The table includes these distinct groupings. Stage IC1 includes patients in whom intraoperative spill occurred. Stage IC2 includes women with preoperative cyst rupture, and or microscopic or macroscopic surface involvement because the data support that these cases carry a poorer prognosis, compared with those with intraoperative rupture (IC1).¹ The final subcategory, IC3, includes women who have washings (obtained at the onset of surgery, prior to manipulation of the tumor) that were positive for malignant cells, denoting preexisting contact between the tumor and peritoneum and a phenotypically more aggressive tumor.

The clinical significance of ovarian cancer capsule rupture has been evaluated in multiple studies with some mixed results.¹ Consistently, it is reported that preoperative rupture, surface or capsular involvement, and preexisting peritoneal circulation of metastatic cells all portend a poorer prognosis; however, it is less clear that iatrogenic surgical rupture has the same deleterious association. In a large retrospective series from Japan, the authors evaluated 15,163 cases of stage I ovarian cancer and identified 7,227 cases of iatrogenic (intraoperative) cyst rupture.² These cases were significantly more likely to occur among clear cell cancers, and were more likely to occur in younger patients. Worse prognosis was associated with cell type (clear cell cancers), but non–clear cell cancers (such as serous, mucinous, and endometrioid) did not have a higher hazard ratio for death when intraoperative rupture occurred. But why would intraoperative cyst rupture result in worse prognosis for only one histologic cell type? The authors hypothesized that perhaps rupture was more likely to occur during extraction of these clear cell tumors because they were associated with dense adhesions from associated endometriosis, and perhaps an adverse biologic phenomenon associated with infiltrative endometriosis is driving the behavior of this cancer.

The Japanese study also looked at the effect of chemotherapy on these same patients’ outcomes. Interestingly, the addition of chemotherapy did not improve survival for the patients with stage IC1 cancers, which was in contrast to the improved survival seen when chemotherapy was given to those with spontaneous rupture or ovarian surface involvement (IC2, IC3). These data support differentiating the subgroups of stage IC cancer in treatment decision-making, and suggest that adjuvant chemotherapy might be avoided for patients with nonclear cell stage IC1 ovarian cancer. While the outcomes are worse for patients with ruptured clear cell cancers, current therapeutic options for clear cell cancers are limited because of their known resistance to traditional agents, and outcomes for women with clear cell cancer can be worse across all stages.

While cyst rupture may not always negatively affect prognosis, the goal of surgery remains an intact removal, which influences decisions regarding surgical approach. Most adnexal masses are removed via minimally invasive surgery (MIS). MIS is associated with benefits of morbidity and cost, and therefore should be considered wherever feasible. However, MIS is associated with an increased risk of ovarian cyst rupture, likely because of the rigid instrumentation used when approaching a curved structure, in addition to the disparity in size of the pathology, compared with the extraction site incision.³ When weighing the benefits and risks of different surgical approaches, it is important to gauge the probability of malignancy. Not all complex ovarian masses associated with elevations in tumor markers are malignant, and certainly most that are associated with normal tumor markers are not. If the preoperative clinical data suggest that the mass is more likely to be malignant (e.g., mostly solid, vascular tumors with very elevated tumor markers), consideration might be made to abandoning a purely minimally invasive approach to a hand-assisted MIS or laparotomy approach. However, it would seem that abandoning an MIS approach to remove every ovarian cyst is unwise given that there is clear patient benefit with MIS and, as discussed above, most cases of iatrogenic malignant cyst rupture are unavoidable even with laparotomy, and do not necessarily independently portend poorer survival or mandate chemotherapy.

Surgeons should be both nuanced and flexible and apply some basic rules of thumb when approaching the diagnostically uncertain adnexal mass. Peritoneal washings should be obtained at the commencement of the case to discriminate those cases of true stage IC3. The peritoneum parallel to the ovarian vessel should be extensively opened to a level above the pelvic brim. In order to do this, the physiological attachments between the sigmoid colon or cecum and the suspensory ligament of the ovary may need to be carefully mobilized. This allows for retroperitoneal identification of the ureter and skeletonization of the ovarian vessels at least 2 cm proximal to their insertion into the ovary and avoidance of contact with the ovary itself (which may have a fragile capsule) or incomplete ovarian resection. If the ovary remains invested close to the sidewall or colonic structures and the appropriate peritoneal and retroperitoneal mobilization has not occurred, the surgeon may unavoidably rupture the ovarian cyst as they try to “hug” the ovary with their bites of tissue in an attempt to avoid visceral injury. There is little role for an ovarian cystectomy in a postmenopausal woman undergoing surgery for a complex adnexal mass, particularly if she has elevated tumor markers, because the process of performing ovarian cystectomy commonly invokes cyst rupture or fragmentation. Ovarian cystectomy should be reserved for premenopausal women with adnexal masses at low suspicion for malignancy. If the adnexa appears densely adherent to adjacent structures – for example, associated with infiltrative endometriosis – consideration for laparotomy or a hand-assisted approach may be necessary; in such cases, even open surgery can result in cyst rupture, and the morbidity of conversion to laparotomy should be weighed for individual cases.

Finally, retrieval of the ovarian specimen should occur intact without morcellation. There should be no uncontained morcellation of adnexal structures during retrieval of even normal-appearing ovaries. The preferred retrieval method is to place the adnexa in an appropriately sized retrieval bag, after which contained morcellation or drainage can occur to facilitate removal through a laparoscopic incision. Contained morcellation is very difficult for large solid masses through a laparoscopic port site; in these cases, extension of the incision may be necessary.

While operative spill of an ovarian cancer does upstage nonmetastatic ovarian cancer, it is unclear that, in most cases, this is independently associated with worse prognosis, and chemotherapy may not always be of added value. However, best surgical practice should always include strategies to minimize the chance of rupture when approaching adnexal masses, particularly those at highest likelihood of malignancy.

 

References

1. Kim HS et al. Eur J Surg Oncol. 2013 Mar 39(3):279-89.

2. Matsuo K et al. Obstet Gynecol. 2019 Nov;134(5):1017-26.

3. Matsuo K et al. JAMA Oncol. 2020 Jul 1;6(7):1110-3.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.

The Step 2 Clinical Skills (CS) test for medical school students and graduates has been permanently canceled, cosponsors of the U.S. Medical Licensing Examination (USMLE) announced in a press release this afternoon.

As previously reported by this news organization, the USMLE cosponsors, the Federation of State Medical Boards and the National Board of Medical Examiners, had announced in May that they would take the following 12-18 months to revamp the required test.

COVID-19 had forced a suspension of the all-day test, which requires test takers to have physical contact with standardized patients. It’s designed to gauge how soon-to-be doctors gather information from patients, perform physical exams, and communicate their findings to patients and colleagues.

However, the cosponsors said today, “we have no plans to bring back Step 2 CS, but we intend to take this opportunity to focus on working with our colleagues in medical education and at the state medical boards to determine innovative ways to assess clinical skills.”

David Johnson, FSMB’s chief assessment officer, said in an interview that, after months of study, “it became clear that the relaunch of a modified Step 2 CS exam would not meet our expectations to be appreciably better than the prior exam.”
 

Only weeks ago, NBME was hiring for the revamp

The news came as a huge surprise. Just weeks earlier, NBME was advertising for a position key to modifying the exam. The description for the position read: “This role will focus on operational planning and coordination both within the NBME and with ECFMG [Educational Commission for Foreign Medical Graduates] to effectively deliver a modified Step 2 Clinical Skills exam.”

Bryan Carmody, MD, MPH, an assistant professor at Eastern Virginia Medical School, Norfolk, noted in a Jan. 15 tweet that the position requires extensive information technology experience, “suggesting plans for a virtual test remain intact.”

Dr. Johnson said that, although the opportunities for helping lead the revamp of the test were posted until the announcement, no one had been hired for the position.

Today’s announcement stated that the USMLE still believes independent standardized tests for medical knowledge and clinical skills are important; however, it now feels clinical reasoning and communication skills will be able to be assessed in other steps.

“Computer-based case simulations in Step 3 and communication content recently bolstered in Step 1 are examples of these efforts that will continue,” the press release stated. “While not a replacement for Step 2 CS, these formats continue to contribute positively, e.g., measuring critical knowledge of medical communication.”

Critics ‘thrilled’ by test termination

Lydia Flier, MD, from the department of internal medicine at Harvard Medical School, Boston – who wrote an editorial for this news organization in August 2020 advocating that Step 2 CS be changed completely or ended entirely – said in an interview that she was “surprised and thrilled” by the announcement.

She said the cosponsors hadn’t initially appeared to agree with the growing sentiment that disruption from the pandemic had “proven the test was unnecessary and it looked like they really were going to try and keep it.”

“I’m thrilled for future generations,” she said. “It is proof of what many people have known all along, which is that the test is a no-value-add proposition that did not actually help determine people’s clinical skills.”

The test “met a breaking point” during the pandemic, she said, “from which CS could not recover.”

She noted in her editorial that the test costs $1,300 plus travel fees, as the test had been offered at only five sites. She agreed that the skills assessed by the Step 2 CS are already covered in medical school and through other Steps.

“It seems as though they could not justify it anymore. It’s the obvious right answer,” said Dr. Flier, who in 2016 cofounded #EndStep2CS, a nationwide movement demanding an end to the exam.

Another cofounder in that movement, Christopher Henderson, MD, a staff physician with Kaiser Permanente in Seattle, said in an interview that “this decision represents tremendous progress in the fight to reduce unnecessary costs in medical education, and is a win for future students. Credit goes to the many women and men who organized and voiced their desire for change.” He added that his views are his own and “do not reflect or imply the views of my organization.”

For the FSMB’s part, Dr. Johnson acknowledged that “the consideration of cost and value were two of many important factors for the Step 2 CS revitalization work.”

Dr. Johnson, Dr. Flier, and Dr. Henderson have declared no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The Step 2 Clinical Skills (CS) test for medical school students and graduates has been permanently canceled, cosponsors of the U.S. Medical Licensing Examination (USMLE) announced in a press release this afternoon.

As previously reported by this news organization, the USMLE cosponsors, the Federation of State Medical Boards and the National Board of Medical Examiners, had announced in May that they would take the following 12-18 months to revamp the required test.

COVID-19 had forced a suspension of the all-day test, which requires test takers to have physical contact with standardized patients. It’s designed to gauge how soon-to-be doctors gather information from patients, perform physical exams, and communicate their findings to patients and colleagues.

However, the cosponsors said today, “we have no plans to bring back Step 2 CS, but we intend to take this opportunity to focus on working with our colleagues in medical education and at the state medical boards to determine innovative ways to assess clinical skills.”

David Johnson, FSMB’s chief assessment officer, said in an interview that, after months of study, “it became clear that the relaunch of a modified Step 2 CS exam would not meet our expectations to be appreciably better than the prior exam.”
 

Only weeks ago, NBME was hiring for the revamp

The news came as a huge surprise. Just weeks earlier, NBME was advertising for a position key to modifying the exam. The description for the position read: “This role will focus on operational planning and coordination both within the NBME and with ECFMG [Educational Commission for Foreign Medical Graduates] to effectively deliver a modified Step 2 Clinical Skills exam.”

Bryan Carmody, MD, MPH, an assistant professor at Eastern Virginia Medical School, Norfolk, noted in a Jan. 15 tweet that the position requires extensive information technology experience, “suggesting plans for a virtual test remain intact.”

Dr. Johnson said that, although the opportunities for helping lead the revamp of the test were posted until the announcement, no one had been hired for the position.

Today’s announcement stated that the USMLE still believes independent standardized tests for medical knowledge and clinical skills are important; however, it now feels clinical reasoning and communication skills will be able to be assessed in other steps.

“Computer-based case simulations in Step 3 and communication content recently bolstered in Step 1 are examples of these efforts that will continue,” the press release stated. “While not a replacement for Step 2 CS, these formats continue to contribute positively, e.g., measuring critical knowledge of medical communication.”

Critics ‘thrilled’ by test termination

Lydia Flier, MD, from the department of internal medicine at Harvard Medical School, Boston – who wrote an editorial for this news organization in August 2020 advocating that Step 2 CS be changed completely or ended entirely – said in an interview that she was “surprised and thrilled” by the announcement.

She said the cosponsors hadn’t initially appeared to agree with the growing sentiment that disruption from the pandemic had “proven the test was unnecessary and it looked like they really were going to try and keep it.”

“I’m thrilled for future generations,” she said. “It is proof of what many people have known all along, which is that the test is a no-value-add proposition that did not actually help determine people’s clinical skills.”

The test “met a breaking point” during the pandemic, she said, “from which CS could not recover.”

She noted in her editorial that the test costs $1,300 plus travel fees, as the test had been offered at only five sites. She agreed that the skills assessed by the Step 2 CS are already covered in medical school and through other Steps.

“It seems as though they could not justify it anymore. It’s the obvious right answer,” said Dr. Flier, who in 2016 cofounded #EndStep2CS, a nationwide movement demanding an end to the exam.

Another cofounder in that movement, Christopher Henderson, MD, a staff physician with Kaiser Permanente in Seattle, said in an interview that “this decision represents tremendous progress in the fight to reduce unnecessary costs in medical education, and is a win for future students. Credit goes to the many women and men who organized and voiced their desire for change.” He added that his views are his own and “do not reflect or imply the views of my organization.”

For the FSMB’s part, Dr. Johnson acknowledged that “the consideration of cost and value were two of many important factors for the Step 2 CS revitalization work.”

Dr. Johnson, Dr. Flier, and Dr. Henderson have declared no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The Step 2 Clinical Skills (CS) test for medical school students and graduates has been permanently canceled, cosponsors of the U.S. Medical Licensing Examination (USMLE) announced in a press release this afternoon.

As previously reported by this news organization, the USMLE cosponsors, the Federation of State Medical Boards and the National Board of Medical Examiners, had announced in May that they would take the following 12-18 months to revamp the required test.

COVID-19 had forced a suspension of the all-day test, which requires test takers to have physical contact with standardized patients. It’s designed to gauge how soon-to-be doctors gather information from patients, perform physical exams, and communicate their findings to patients and colleagues.

However, the cosponsors said today, “we have no plans to bring back Step 2 CS, but we intend to take this opportunity to focus on working with our colleagues in medical education and at the state medical boards to determine innovative ways to assess clinical skills.”

David Johnson, FSMB’s chief assessment officer, said in an interview that, after months of study, “it became clear that the relaunch of a modified Step 2 CS exam would not meet our expectations to be appreciably better than the prior exam.”
 

Only weeks ago, NBME was hiring for the revamp

The news came as a huge surprise. Just weeks earlier, NBME was advertising for a position key to modifying the exam. The description for the position read: “This role will focus on operational planning and coordination both within the NBME and with ECFMG [Educational Commission for Foreign Medical Graduates] to effectively deliver a modified Step 2 Clinical Skills exam.”

Bryan Carmody, MD, MPH, an assistant professor at Eastern Virginia Medical School, Norfolk, noted in a Jan. 15 tweet that the position requires extensive information technology experience, “suggesting plans for a virtual test remain intact.”

Dr. Johnson said that, although the opportunities for helping lead the revamp of the test were posted until the announcement, no one had been hired for the position.

Today’s announcement stated that the USMLE still believes independent standardized tests for medical knowledge and clinical skills are important; however, it now feels clinical reasoning and communication skills will be able to be assessed in other steps.

“Computer-based case simulations in Step 3 and communication content recently bolstered in Step 1 are examples of these efforts that will continue,” the press release stated. “While not a replacement for Step 2 CS, these formats continue to contribute positively, e.g., measuring critical knowledge of medical communication.”

Critics ‘thrilled’ by test termination

Lydia Flier, MD, from the department of internal medicine at Harvard Medical School, Boston – who wrote an editorial for this news organization in August 2020 advocating that Step 2 CS be changed completely or ended entirely – said in an interview that she was “surprised and thrilled” by the announcement.

She said the cosponsors hadn’t initially appeared to agree with the growing sentiment that disruption from the pandemic had “proven the test was unnecessary and it looked like they really were going to try and keep it.”

“I’m thrilled for future generations,” she said. “It is proof of what many people have known all along, which is that the test is a no-value-add proposition that did not actually help determine people’s clinical skills.”

The test “met a breaking point” during the pandemic, she said, “from which CS could not recover.”

She noted in her editorial that the test costs $1,300 plus travel fees, as the test had been offered at only five sites. She agreed that the skills assessed by the Step 2 CS are already covered in medical school and through other Steps.

“It seems as though they could not justify it anymore. It’s the obvious right answer,” said Dr. Flier, who in 2016 cofounded #EndStep2CS, a nationwide movement demanding an end to the exam.

Another cofounder in that movement, Christopher Henderson, MD, a staff physician with Kaiser Permanente in Seattle, said in an interview that “this decision represents tremendous progress in the fight to reduce unnecessary costs in medical education, and is a win for future students. Credit goes to the many women and men who organized and voiced their desire for change.” He added that his views are his own and “do not reflect or imply the views of my organization.”

For the FSMB’s part, Dr. Johnson acknowledged that “the consideration of cost and value were two of many important factors for the Step 2 CS revitalization work.”

Dr. Johnson, Dr. Flier, and Dr. Henderson have declared no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The U.K.’s B117 variant is circulating in at least 24 states, according to new data from the Centers for Disease Control and Prevention COVID-19 variant surveillance. The CDC projects that the U.K. variant will become the dominant strain in the United States by March.

From any vantage point, the United Kingdom appears to be in the crosshairs of COVID-19: Weeks after a new, highly contagious variant emerged that fueled a surge in cases and fresh lockdowns, the United Kingdom was revealed to have the world’s highest coronavirus death rate.

But the United Kingdom also has a not-so-secret weapon of its own: A genomic sequencing program widely believed to be the most coordinated and advanced any nation has forged. In the vise grip of the virus, the Brits have gleaned key insights into the behavior and consequences of SARS-CoV-2.

But B117 is also notable for what it is missing: In this case, producing a negative result on certain polymerase chain reaction (PCR) tests in the spike protein, or S-gene.

One of the S-gene mutations specific to the variant deletes two amino acids, causing that portion of the PCR test to show up negative. The coincidental finding known as an S-gene target failure has become an integral proxy to help track where and when the variant is spreading in the United Kingdom, where about 5% of samples from COVID-19–infected patients are sequenced, said Sharon Peacock, PhD, executive director and chair of the COVID-19 Genomics U.K. Consortium.

That same tactic could prove valuable to clinicians similarly overwhelmed with cases and deaths but lacking high-level sequencing information on the virus, Dr. Peacock said in an interview. A British report released Friday stated that there is a “realistic possibility” that the variant has a higher death rate than other cases of SARS-CoV-2.

“In this particular variant, a deletion in the genome leads to one part of the diagnostic test failing,” Dr. Peacock explained. “Several targets are positive, but this is negative. In the U.K., this has been used as a surrogate marker.”
 

Targeting an invisible adversary

B117 is not the only variant that produces this result, Dr. Peacock cautioned, “but in screening for it, you can have this in mind.”

“Since the U.K. is sequencing about 5% of the cases they detect, this gives them really important clues about what’s happening there,” said Anderson Brito, PhD, a virologist and postdoctoral researcher at Yale University, New Haven, Conn., where investigators are creating custom PCR tests to detect the B117 variant.

Dr. Brito, who lived in the United Kingdom for 4 years while studying for his doctorate at Imperial College London, said a “major advantage” is the more unified process to collect and sequence samples. Crucial information – including the date and place of collection – comes with each sample, which fuels not only sequencing, but an epidemiologic perspective.

“They’re not in the dark at all,” Dr. Brito said in an interview. “I think no other country in the world knows better which virus lineages are circulating.”

The CDC launched the SPHERES consortium in May 2020 to coordinate the sequencing of SARS-CoV-2 genomes across the United States.

But American genomic efforts are “not as centralized,” said Dr. Brito, whose lab detected the first two cases of the U.K. variant in Connecticut on Jan. 6. “We struggle to get samples, because they’re decentralized to a level where there’s little coordination between hospitals and research centers. They’re not as connected as in the U.K. If we just get a sample and it has no date of collection and no origin information, for example, it’s basically useless.”

Global genomic collaborations include GISAID, an international database where researchers share new genomes from various coronaviruses. As of mid-January, the United States had submitted about 68,000 sequences to GISAID, adding about 3,000 new samples every week and expecting even more from commercial labs in coming days, according to the CDC.

“The U.K. is definitely much more on top of looking for variants as they pop up,” said Gigi Gronvall, PhD, an immunologist and senior scholar at Johns Hopkins Center for Health Security in Baltimore. “The U.S. has now turned that up.”
 

Warning from British scientists to the world

Despite these genomic accomplishments, some British scientists said they have regrets too, wishing they’d known just how rapidly SARS-CoV-2 was actually spreading a year ago, when it hit western Europe.

That information was crucial not only for preventive efforts, but because viruses inevitably mutate faster the more people who are infected, said Igor Rudan, MD, PhD, director of the Center for Global Health Research at University of Edinburgh.

“Italy showed us just how fast it was spreading and how deadly it is for the very old and people with multiple comorbidities,” said Dr. Rudan, who also editor in chief of the Journal of Global Health. “We wish we knew it was spreading so fast, and we wish we knew the threshold of cases we could allow to be infected before the virus would mutate.”

More mutations mean more new strains of SARS-CoV-2, Dr. Rudan said in an interview. “We’ve reached that threshold now and will see more of these mutations.”

Despite its current struggles, the United Kingdom is reaching beyond tracking its new variant’s spread and trying to identify new mutations that might change the way the virus behaves.

Three features of any emerging variant are particularly important, Dr. Peacock explained: Is it more transmissible? Is it more lethal? And does it cut the ability of natural- or vaccine-induced immunity to protect people from infection?

“We need to sequence people coming to the hospital who are sicker,” said Dr. Peacock, also a professor of public health and microbiology at the University of Cambridge (England). “Also, if anyone has the infection after they’ve already been sick or had the vaccine, we really want to know what that looks like” genomically.

SARS-CoV-2 has already logged more than 4,000 mutations, Dr. Peacock said. But “knowing that viruses mutate all the time is not sufficient reason not to look. We really want to know if mutations lead to changes in amino acids, and if that can lead to changes in functionality.”

For the moment, however, experts say they’re relieved that the U.K. strain doesn’t seem able to evade COVID-19 vaccines or render them less effective.

“Even though mutations are common, those able to change the viral coding are rare,” Dr. Brito explained. If necessary, vaccines could be tweaked to replace the spike gene sequence “within a matter of weeks. We already do this for flu vaccines. Every year, we have to monitor variants of the virus circulating to develop a vaccine that covers most of them. If we end up having to do it for SARS-CoV-2, I would not be surprised.”

But variant-fueled increases in infections will require more people to be vaccinated before herd immunity can be achieved, Dr. Rudan warned. “If it spreads faster, we’ll need to vaccinate probably 85% of people versus 70% to reach herd immunity.”

One lesson the COVID-19 pandemic has driven home “is to always be on your guard about what happens next,” Dr. Peacock said. Although confident about the genomic efforts in the United Kingdom to date, she and her colleagues feel they’re still reaching for a complete understanding of the evolutionary changes of the virus.

“We’re ahead of the curve right now, but we want to get in front of the curve,” Dr. Peacock said. “It’s essential to get ahead of what might be around the corner because we don’t know how the virus is going to evolve.”

A version of this article first appeared on Medscape.com.

The U.K.’s B117 variant is circulating in at least 24 states, according to new data from the Centers for Disease Control and Prevention COVID-19 variant surveillance. The CDC projects that the U.K. variant will become the dominant strain in the United States by March.

From any vantage point, the United Kingdom appears to be in the crosshairs of COVID-19: Weeks after a new, highly contagious variant emerged that fueled a surge in cases and fresh lockdowns, the United Kingdom was revealed to have the world’s highest coronavirus death rate.

But the United Kingdom also has a not-so-secret weapon of its own: A genomic sequencing program widely believed to be the most coordinated and advanced any nation has forged. In the vise grip of the virus, the Brits have gleaned key insights into the behavior and consequences of SARS-CoV-2.

But B117 is also notable for what it is missing: In this case, producing a negative result on certain polymerase chain reaction (PCR) tests in the spike protein, or S-gene.

One of the S-gene mutations specific to the variant deletes two amino acids, causing that portion of the PCR test to show up negative. The coincidental finding known as an S-gene target failure has become an integral proxy to help track where and when the variant is spreading in the United Kingdom, where about 5% of samples from COVID-19–infected patients are sequenced, said Sharon Peacock, PhD, executive director and chair of the COVID-19 Genomics U.K. Consortium.

That same tactic could prove valuable to clinicians similarly overwhelmed with cases and deaths but lacking high-level sequencing information on the virus, Dr. Peacock said in an interview. A British report released Friday stated that there is a “realistic possibility” that the variant has a higher death rate than other cases of SARS-CoV-2.

“In this particular variant, a deletion in the genome leads to one part of the diagnostic test failing,” Dr. Peacock explained. “Several targets are positive, but this is negative. In the U.K., this has been used as a surrogate marker.”
 

Targeting an invisible adversary

B117 is not the only variant that produces this result, Dr. Peacock cautioned, “but in screening for it, you can have this in mind.”

“Since the U.K. is sequencing about 5% of the cases they detect, this gives them really important clues about what’s happening there,” said Anderson Brito, PhD, a virologist and postdoctoral researcher at Yale University, New Haven, Conn., where investigators are creating custom PCR tests to detect the B117 variant.

Dr. Brito, who lived in the United Kingdom for 4 years while studying for his doctorate at Imperial College London, said a “major advantage” is the more unified process to collect and sequence samples. Crucial information – including the date and place of collection – comes with each sample, which fuels not only sequencing, but an epidemiologic perspective.

“They’re not in the dark at all,” Dr. Brito said in an interview. “I think no other country in the world knows better which virus lineages are circulating.”

The CDC launched the SPHERES consortium in May 2020 to coordinate the sequencing of SARS-CoV-2 genomes across the United States.

But American genomic efforts are “not as centralized,” said Dr. Brito, whose lab detected the first two cases of the U.K. variant in Connecticut on Jan. 6. “We struggle to get samples, because they’re decentralized to a level where there’s little coordination between hospitals and research centers. They’re not as connected as in the U.K. If we just get a sample and it has no date of collection and no origin information, for example, it’s basically useless.”

Global genomic collaborations include GISAID, an international database where researchers share new genomes from various coronaviruses. As of mid-January, the United States had submitted about 68,000 sequences to GISAID, adding about 3,000 new samples every week and expecting even more from commercial labs in coming days, according to the CDC.

“The U.K. is definitely much more on top of looking for variants as they pop up,” said Gigi Gronvall, PhD, an immunologist and senior scholar at Johns Hopkins Center for Health Security in Baltimore. “The U.S. has now turned that up.”
 

Warning from British scientists to the world

Despite these genomic accomplishments, some British scientists said they have regrets too, wishing they’d known just how rapidly SARS-CoV-2 was actually spreading a year ago, when it hit western Europe.

That information was crucial not only for preventive efforts, but because viruses inevitably mutate faster the more people who are infected, said Igor Rudan, MD, PhD, director of the Center for Global Health Research at University of Edinburgh.

“Italy showed us just how fast it was spreading and how deadly it is for the very old and people with multiple comorbidities,” said Dr. Rudan, who also editor in chief of the Journal of Global Health. “We wish we knew it was spreading so fast, and we wish we knew the threshold of cases we could allow to be infected before the virus would mutate.”

More mutations mean more new strains of SARS-CoV-2, Dr. Rudan said in an interview. “We’ve reached that threshold now and will see more of these mutations.”

Despite its current struggles, the United Kingdom is reaching beyond tracking its new variant’s spread and trying to identify new mutations that might change the way the virus behaves.

Three features of any emerging variant are particularly important, Dr. Peacock explained: Is it more transmissible? Is it more lethal? And does it cut the ability of natural- or vaccine-induced immunity to protect people from infection?

“We need to sequence people coming to the hospital who are sicker,” said Dr. Peacock, also a professor of public health and microbiology at the University of Cambridge (England). “Also, if anyone has the infection after they’ve already been sick or had the vaccine, we really want to know what that looks like” genomically.

SARS-CoV-2 has already logged more than 4,000 mutations, Dr. Peacock said. But “knowing that viruses mutate all the time is not sufficient reason not to look. We really want to know if mutations lead to changes in amino acids, and if that can lead to changes in functionality.”

For the moment, however, experts say they’re relieved that the U.K. strain doesn’t seem able to evade COVID-19 vaccines or render them less effective.

“Even though mutations are common, those able to change the viral coding are rare,” Dr. Brito explained. If necessary, vaccines could be tweaked to replace the spike gene sequence “within a matter of weeks. We already do this for flu vaccines. Every year, we have to monitor variants of the virus circulating to develop a vaccine that covers most of them. If we end up having to do it for SARS-CoV-2, I would not be surprised.”

But variant-fueled increases in infections will require more people to be vaccinated before herd immunity can be achieved, Dr. Rudan warned. “If it spreads faster, we’ll need to vaccinate probably 85% of people versus 70% to reach herd immunity.”

One lesson the COVID-19 pandemic has driven home “is to always be on your guard about what happens next,” Dr. Peacock said. Although confident about the genomic efforts in the United Kingdom to date, she and her colleagues feel they’re still reaching for a complete understanding of the evolutionary changes of the virus.

“We’re ahead of the curve right now, but we want to get in front of the curve,” Dr. Peacock said. “It’s essential to get ahead of what might be around the corner because we don’t know how the virus is going to evolve.”

A version of this article first appeared on Medscape.com.

The U.K.’s B117 variant is circulating in at least 24 states, according to new data from the Centers for Disease Control and Prevention COVID-19 variant surveillance. The CDC projects that the U.K. variant will become the dominant strain in the United States by March.

From any vantage point, the United Kingdom appears to be in the crosshairs of COVID-19: Weeks after a new, highly contagious variant emerged that fueled a surge in cases and fresh lockdowns, the United Kingdom was revealed to have the world’s highest coronavirus death rate.

But the United Kingdom also has a not-so-secret weapon of its own: A genomic sequencing program widely believed to be the most coordinated and advanced any nation has forged. In the vise grip of the virus, the Brits have gleaned key insights into the behavior and consequences of SARS-CoV-2.

But B117 is also notable for what it is missing: In this case, producing a negative result on certain polymerase chain reaction (PCR) tests in the spike protein, or S-gene.

One of the S-gene mutations specific to the variant deletes two amino acids, causing that portion of the PCR test to show up negative. The coincidental finding known as an S-gene target failure has become an integral proxy to help track where and when the variant is spreading in the United Kingdom, where about 5% of samples from COVID-19–infected patients are sequenced, said Sharon Peacock, PhD, executive director and chair of the COVID-19 Genomics U.K. Consortium.

That same tactic could prove valuable to clinicians similarly overwhelmed with cases and deaths but lacking high-level sequencing information on the virus, Dr. Peacock said in an interview. A British report released Friday stated that there is a “realistic possibility” that the variant has a higher death rate than other cases of SARS-CoV-2.

“In this particular variant, a deletion in the genome leads to one part of the diagnostic test failing,” Dr. Peacock explained. “Several targets are positive, but this is negative. In the U.K., this has been used as a surrogate marker.”
 

Targeting an invisible adversary

B117 is not the only variant that produces this result, Dr. Peacock cautioned, “but in screening for it, you can have this in mind.”

“Since the U.K. is sequencing about 5% of the cases they detect, this gives them really important clues about what’s happening there,” said Anderson Brito, PhD, a virologist and postdoctoral researcher at Yale University, New Haven, Conn., where investigators are creating custom PCR tests to detect the B117 variant.

Dr. Brito, who lived in the United Kingdom for 4 years while studying for his doctorate at Imperial College London, said a “major advantage” is the more unified process to collect and sequence samples. Crucial information – including the date and place of collection – comes with each sample, which fuels not only sequencing, but an epidemiologic perspective.

“They’re not in the dark at all,” Dr. Brito said in an interview. “I think no other country in the world knows better which virus lineages are circulating.”

The CDC launched the SPHERES consortium in May 2020 to coordinate the sequencing of SARS-CoV-2 genomes across the United States.

But American genomic efforts are “not as centralized,” said Dr. Brito, whose lab detected the first two cases of the U.K. variant in Connecticut on Jan. 6. “We struggle to get samples, because they’re decentralized to a level where there’s little coordination between hospitals and research centers. They’re not as connected as in the U.K. If we just get a sample and it has no date of collection and no origin information, for example, it’s basically useless.”

Global genomic collaborations include GISAID, an international database where researchers share new genomes from various coronaviruses. As of mid-January, the United States had submitted about 68,000 sequences to GISAID, adding about 3,000 new samples every week and expecting even more from commercial labs in coming days, according to the CDC.

“The U.K. is definitely much more on top of looking for variants as they pop up,” said Gigi Gronvall, PhD, an immunologist and senior scholar at Johns Hopkins Center for Health Security in Baltimore. “The U.S. has now turned that up.”
 

Warning from British scientists to the world

Despite these genomic accomplishments, some British scientists said they have regrets too, wishing they’d known just how rapidly SARS-CoV-2 was actually spreading a year ago, when it hit western Europe.

That information was crucial not only for preventive efforts, but because viruses inevitably mutate faster the more people who are infected, said Igor Rudan, MD, PhD, director of the Center for Global Health Research at University of Edinburgh.

“Italy showed us just how fast it was spreading and how deadly it is for the very old and people with multiple comorbidities,” said Dr. Rudan, who also editor in chief of the Journal of Global Health. “We wish we knew it was spreading so fast, and we wish we knew the threshold of cases we could allow to be infected before the virus would mutate.”

More mutations mean more new strains of SARS-CoV-2, Dr. Rudan said in an interview. “We’ve reached that threshold now and will see more of these mutations.”

Despite its current struggles, the United Kingdom is reaching beyond tracking its new variant’s spread and trying to identify new mutations that might change the way the virus behaves.

Three features of any emerging variant are particularly important, Dr. Peacock explained: Is it more transmissible? Is it more lethal? And does it cut the ability of natural- or vaccine-induced immunity to protect people from infection?

“We need to sequence people coming to the hospital who are sicker,” said Dr. Peacock, also a professor of public health and microbiology at the University of Cambridge (England). “Also, if anyone has the infection after they’ve already been sick or had the vaccine, we really want to know what that looks like” genomically.

SARS-CoV-2 has already logged more than 4,000 mutations, Dr. Peacock said. But “knowing that viruses mutate all the time is not sufficient reason not to look. We really want to know if mutations lead to changes in amino acids, and if that can lead to changes in functionality.”

For the moment, however, experts say they’re relieved that the U.K. strain doesn’t seem able to evade COVID-19 vaccines or render them less effective.

“Even though mutations are common, those able to change the viral coding are rare,” Dr. Brito explained. If necessary, vaccines could be tweaked to replace the spike gene sequence “within a matter of weeks. We already do this for flu vaccines. Every year, we have to monitor variants of the virus circulating to develop a vaccine that covers most of them. If we end up having to do it for SARS-CoV-2, I would not be surprised.”

But variant-fueled increases in infections will require more people to be vaccinated before herd immunity can be achieved, Dr. Rudan warned. “If it spreads faster, we’ll need to vaccinate probably 85% of people versus 70% to reach herd immunity.”

One lesson the COVID-19 pandemic has driven home “is to always be on your guard about what happens next,” Dr. Peacock said. Although confident about the genomic efforts in the United Kingdom to date, she and her colleagues feel they’re still reaching for a complete understanding of the evolutionary changes of the virus.

“We’re ahead of the curve right now, but we want to get in front of the curve,” Dr. Peacock said. “It’s essential to get ahead of what might be around the corner because we don’t know how the virus is going to evolve.”

A version of this article first appeared on Medscape.com.

Just as Brazil surpassed 200,000 deaths from COVID-19 on Jan. 7, news from Bahia added another layer of concern: A platform case report in a preprint detailed the first case of reinfection in that state, apparently caused by a new strain, one having the E484K mutation.

That variant, now called Brazil P.1, has migrated to the United States. The Minnesota Department of Health announced on Jan. 25 the nation’s first known COVID-19 case associated with it.

The mutation is located in the protein gene of the virus’ spike, which forms the crown structure of coronaviruses and is responsible for the virus’ binding to human cells. The E484K mutation is now the focus because it’s associated with mutations that escape the immune system’s neutralizing antibodies.

“This mutation is at the center of worldwide concern, and it is the first time that it has appeared in a reinfection,” the study’s first author, Bruno Solano de Freitas Souza, MD, a researcher at the Salvador regional unit of Instituto D’Or of Teaching and Research, based at Hospital São Rafael, Salvador, Brazil, explained in an interview.

“We will wait for the sample from Bahia to confirm the case from the perspective of the Ministry of Health’s surveillance network,” said Fernando Motta, PhD, deputy head of the Laboratory for Respiratory Virus and Measles at the Oswaldo Cruz Institute in Rio de Janeiro, which acts as a national reference center for respiratory viruses with the Brazilian Ministry of Health (MS) and as a reference for the World Health Organization.
 

A case of reinfection

The case patient that led to the alarm was a 45-year-old woman who is a health care executive. She had no comorbidities. The team had been following health care professionals and patients who had tested positive on reverse transcription–polymerase chain reaction (RT-PCR) testing more than once to understand whether they represented cases of prolonged viral persistence or new infections.

The woman had symptoms of viral infection on two occasions (May 26 and Oct. 26). On both occasions, results of RT-PCR testing for SARS-CoV-2 on nasopharyngeal samples were positive. In the first episode, the patient had diarrhea, myalgia, asthenia, and odynophagia for about 7 days. She returned to activities 21 days later. In the second episode, she had more severe symptoms that lasted longer, but she still did not require hospitalization.

“It was the first confirmed case of reinfection in Bahia, and in the second episode, we observed a mutation that could have an impact on the ability of antibodies to neutralize the virus,” Dr. Souza said. “The research continues with the investigation of cases in which the patient has a positive SARS-CoV-2 RT-PCR more than once in an interval greater than 45 days, to have a higher level of evidence.”

He stressed that “it is very important to reinforce measures to control the pandemic, social distance, use of masks, and speed up vaccination to be able to control the circulation of the virus, while monitoring the evolution of it.”
 

On alert for more cases

A person who twice tests positive for SARS-CoV-2 on real-time RT-PCR is suspected of having been reinfected, provided 90 or more days have elapsed between the two episodes, regardless of the condition observed. To confirm the suspected case, the samples must be sent to reference laboratories according to a plan established by the Ministry of Health in Brazil.

A health professional living in the Brazilian city of Natal represented the first confirmed case of reinfection by the new coronavirus in Brazil. That case was announced on Dec. 10, 2020.

“We communicated this case of reinfection to the MS in early December 2020. And the second sample already had the E484K mutation on the spike, as in the case of Bahia,” said Dr. Motta.

The first step in differentiating reinfection from persistence is to observe differences in the genotyping of the virus. For the technique to be successful, Dr. Souza said, researchers need a large amount of viral genetic material, which usually cannot be obtained.

“That is why there are many more suspected than confirmed cases,” Dr. Souza explained. He admitted that, although there are few cases, “it is increasingly clear that reinfection is a reality.”
 

Markers of mutations

What worried the researchers most was not only the possibility of reinfection but also the fact that preliminary analyses showed a specific mutation.

“The E484K mutation is present in a group of variants identified in South Africa that have been associated with increased infectivity and has been observed in a strain recently described in Brazil,” Dr. Souza said.

Mutations are expected, appear spontaneously, and in most cases have no effects on transmission or clinical outcome – they are simply used as markers and are useful for contact tracing or studying transmission routes. But some mutations can last because they provide an advantage for the pathogen, even if only momentary. In the case of SARS-CoV-2, mutations in the protein spike gene (S) are relevant because they may give clues to that advantage – as well as to changes in infectivity, transmission potential, antibodies, and response to vaccines.

A variant of the virus that has eight changes that affect the protein S gene – and several others in different genes – is behind the increase in the number of cases in London and southeastern England. Researchers from the University of São Paulo identified one of the factors that made this new variant – classified as B.1.1.7 – more infectious.

With bioinformatics tools, they found that the protein S gene in the new viral strain has a stronger molecular interaction with the ACE2 receptor, which is on the surface of human cells and to which the virus binds, making infection possible. The variant has already spread to the rest of the world, and the first two cases have been confirmed in Brazil by the Adolf Lutz Institute.

The alert for a new variant in Africa – similar to B.1.1.7 in the United Kingdom in that it carries nine changes in protein S at position 501 – was made by the Brazilian virologist Tulio de Oliveira, PhD.

“We found that this strain seems to be spreading much faster,” Dr. Oliveira, who is with the University of KwaZulu Natal, told the journal Science. His work first alerted British scientists to the importance of the position N501Y.

“The new variants just described in the United Kingdom and South Africa are slightly more transmissible and have already been identified in cases imported into Brazil,” Dr. Motta said. “Unfortunately, we believe it is only a matter of time before it becomes indigenous.”
 

The viral family grows

Viruses such as SARS-CoV-2 are classified into strains on the basis of small differences in their genetic material. Since Dec. 26, 2020, in addition to the British and South African variants, it appears the Carioca lineage also is a player.

In a preprint article, researchers analyzed the evolution of the epidemic in Rio de Janeiro from April 2020 until just before the new increase in incidence in December. They compared the complete sequences of the viral genome of 180 patients from different municipalities. The study, which is being jointly conducted by members of the Federal University of Rio de Janeiro and the National Laboratory for Scientific Computing, identified a new variant of SARS-CoV-2 that has five unique mutations (from one of the predominant strains). Concern arose because, in addition to those five genetic changes, many of the samples had a sixth – the well-known E484K mutation.

“The three lines – the U.K., South Africa, and Brazil – were almost synchronous publications, but there is no clear evidence that they have any kind of common ancestry,” Carolina M. Voloch, PhD, the article’s first author and a biologist and researcher at the Molecular Virology Laboratory and associate professor in the department of genetics at the Federal University of Rio de Janeiro, said in an interview.

Dr. Voloch’s research focuses on the use of bioinformatics tools to study the molecular, phylogenetic, and genomic evolution of viruses.

“The emergence of new strains is common for viruses,” she said. “It can be happening anywhere in the world at any time.”

She stressed that identifying when mutations emerge will help to define the new Brazilian lineage. Researchers are working to determine whether the neutralizing antibodies of patients who have been infected with other strains respond to this Rio de Janeiro strain.

“We hope to soon be sharing these results,” Dr. Voloch said.

The article’s authors estimated that the new strain likely appeared in early July. They say more analysis is needed to predict whether the changes have a major effect on viral infectivity, the host’s immune response, or the severity of the disease. Asked about the lineage that caused the reinfection in Bahia, Dr. Voloch said she hadn’t yet contacted the authors to conduct a joint analysis but added that the data disclosed in the preprint would not represent the same variant.

“There are only two of the five mutations that characterize the Rio de Janeiro lineage. However, it has the E484K mutation that is present in more than 94% of the samples of the new variant of Rio,” she said.

She added that there’s a possibility of reinfection by the lineage that’s circulating in Rio de Janeiro and in other states, as well as countries such as the United States, the United Kingdom, and Japan.

“The Carioca virus is being exported to the rest of the world,” Dr. Voloch said.
 

Virus’ diversity still unknown

Researchers now know that SARS-CoV-2 probably circulated silently in Brazil as early as February 2020 and reached all the nation’s regions before air travel was restricted. Since the first half of 2020, there have been two predominant strains.

“More than a dozen strains have been identified in Brazil, but more important than counting strains to identify the speed with which they arise – which is directly associated with the rate of infection, which is very high in the country,” said Dr. Motta.

The so-called variant of Rio de Janeiro, he said, has also been detected in other states in four regions of Brazil. The key to documenting variants is to get a more representative sample with genomes from other parts of the country.

As of Jan. 10, a total of 347,000 complete genome sequences had been shared globally through open databases since SARS-CoV-2 was first identified, but the contribution of countries is uneven. Although the cost and complexity of genetic sequencing has dropped significantly over time, effective sequencing programs still require substantial investments in personnel, equipment, reagents, and bioinformatics infrastructure.

According to Dr. Voloch, it will only be possible to combat the new coronavirus by knowing its diversity and understanding how it evolves. The Fiocruz Genomic Network has made an infographic available so researchers can track the strains circulating in Brazil. It›s the result of collaboration between researchers from Fiocruz and the GISAID Initiative, an international partnership that promotes rapid data sharing.

As of Jan. 5, researchers in Brazil had studied 1,897 genomes – not nearly enough.

“In Brazil, there is little testing and even less sequencing,” lamented Dr. Souza.

“In the U.K., 1 in 600 cases is sequenced. In Brazil it is less than 1 in 10 million cases,” Dr. Voloch added.

So far, no decisive factors for public health, such as greater virulence or greater transmissibility, have been identified in any of the strains established in Brazil. The million-dollar question is whether the emergence of new strains could have an impact on the effectiveness of vaccines being administered today.

“In one way or another, the vaccine is our best bet ever, even if in the future we identify escapist mutants and have to modify it,” Dr. Motta said. “It is what we do annually with influenza.”

Dr. Voloch, Dr. Motta, and Dr. Souza disclosed no relevant financial relationships.

A version of this article first appeared on the Portuguese edition of Medscape.com.

Just as Brazil surpassed 200,000 deaths from COVID-19 on Jan. 7, news from Bahia added another layer of concern: A platform case report in a preprint detailed the first case of reinfection in that state, apparently caused by a new strain, one having the E484K mutation.

That variant, now called Brazil P.1, has migrated to the United States. The Minnesota Department of Health announced on Jan. 25 the nation’s first known COVID-19 case associated with it.

The mutation is located in the protein gene of the virus’ spike, which forms the crown structure of coronaviruses and is responsible for the virus’ binding to human cells. The E484K mutation is now the focus because it’s associated with mutations that escape the immune system’s neutralizing antibodies.

“This mutation is at the center of worldwide concern, and it is the first time that it has appeared in a reinfection,” the study’s first author, Bruno Solano de Freitas Souza, MD, a researcher at the Salvador regional unit of Instituto D’Or of Teaching and Research, based at Hospital São Rafael, Salvador, Brazil, explained in an interview.

“We will wait for the sample from Bahia to confirm the case from the perspective of the Ministry of Health’s surveillance network,” said Fernando Motta, PhD, deputy head of the Laboratory for Respiratory Virus and Measles at the Oswaldo Cruz Institute in Rio de Janeiro, which acts as a national reference center for respiratory viruses with the Brazilian Ministry of Health (MS) and as a reference for the World Health Organization.
 

A case of reinfection

The case patient that led to the alarm was a 45-year-old woman who is a health care executive. She had no comorbidities. The team had been following health care professionals and patients who had tested positive on reverse transcription–polymerase chain reaction (RT-PCR) testing more than once to understand whether they represented cases of prolonged viral persistence or new infections.

The woman had symptoms of viral infection on two occasions (May 26 and Oct. 26). On both occasions, results of RT-PCR testing for SARS-CoV-2 on nasopharyngeal samples were positive. In the first episode, the patient had diarrhea, myalgia, asthenia, and odynophagia for about 7 days. She returned to activities 21 days later. In the second episode, she had more severe symptoms that lasted longer, but she still did not require hospitalization.

“It was the first confirmed case of reinfection in Bahia, and in the second episode, we observed a mutation that could have an impact on the ability of antibodies to neutralize the virus,” Dr. Souza said. “The research continues with the investigation of cases in which the patient has a positive SARS-CoV-2 RT-PCR more than once in an interval greater than 45 days, to have a higher level of evidence.”

He stressed that “it is very important to reinforce measures to control the pandemic, social distance, use of masks, and speed up vaccination to be able to control the circulation of the virus, while monitoring the evolution of it.”
 

On alert for more cases

A person who twice tests positive for SARS-CoV-2 on real-time RT-PCR is suspected of having been reinfected, provided 90 or more days have elapsed between the two episodes, regardless of the condition observed. To confirm the suspected case, the samples must be sent to reference laboratories according to a plan established by the Ministry of Health in Brazil.

A health professional living in the Brazilian city of Natal represented the first confirmed case of reinfection by the new coronavirus in Brazil. That case was announced on Dec. 10, 2020.

“We communicated this case of reinfection to the MS in early December 2020. And the second sample already had the E484K mutation on the spike, as in the case of Bahia,” said Dr. Motta.

The first step in differentiating reinfection from persistence is to observe differences in the genotyping of the virus. For the technique to be successful, Dr. Souza said, researchers need a large amount of viral genetic material, which usually cannot be obtained.

“That is why there are many more suspected than confirmed cases,” Dr. Souza explained. He admitted that, although there are few cases, “it is increasingly clear that reinfection is a reality.”
 

Markers of mutations

What worried the researchers most was not only the possibility of reinfection but also the fact that preliminary analyses showed a specific mutation.

“The E484K mutation is present in a group of variants identified in South Africa that have been associated with increased infectivity and has been observed in a strain recently described in Brazil,” Dr. Souza said.

Mutations are expected, appear spontaneously, and in most cases have no effects on transmission or clinical outcome – they are simply used as markers and are useful for contact tracing or studying transmission routes. But some mutations can last because they provide an advantage for the pathogen, even if only momentary. In the case of SARS-CoV-2, mutations in the protein spike gene (S) are relevant because they may give clues to that advantage – as well as to changes in infectivity, transmission potential, antibodies, and response to vaccines.

A variant of the virus that has eight changes that affect the protein S gene – and several others in different genes – is behind the increase in the number of cases in London and southeastern England. Researchers from the University of São Paulo identified one of the factors that made this new variant – classified as B.1.1.7 – more infectious.

With bioinformatics tools, they found that the protein S gene in the new viral strain has a stronger molecular interaction with the ACE2 receptor, which is on the surface of human cells and to which the virus binds, making infection possible. The variant has already spread to the rest of the world, and the first two cases have been confirmed in Brazil by the Adolf Lutz Institute.

The alert for a new variant in Africa – similar to B.1.1.7 in the United Kingdom in that it carries nine changes in protein S at position 501 – was made by the Brazilian virologist Tulio de Oliveira, PhD.

“We found that this strain seems to be spreading much faster,” Dr. Oliveira, who is with the University of KwaZulu Natal, told the journal Science. His work first alerted British scientists to the importance of the position N501Y.

“The new variants just described in the United Kingdom and South Africa are slightly more transmissible and have already been identified in cases imported into Brazil,” Dr. Motta said. “Unfortunately, we believe it is only a matter of time before it becomes indigenous.”
 

The viral family grows

Viruses such as SARS-CoV-2 are classified into strains on the basis of small differences in their genetic material. Since Dec. 26, 2020, in addition to the British and South African variants, it appears the Carioca lineage also is a player.

In a preprint article, researchers analyzed the evolution of the epidemic in Rio de Janeiro from April 2020 until just before the new increase in incidence in December. They compared the complete sequences of the viral genome of 180 patients from different municipalities. The study, which is being jointly conducted by members of the Federal University of Rio de Janeiro and the National Laboratory for Scientific Computing, identified a new variant of SARS-CoV-2 that has five unique mutations (from one of the predominant strains). Concern arose because, in addition to those five genetic changes, many of the samples had a sixth – the well-known E484K mutation.

“The three lines – the U.K., South Africa, and Brazil – were almost synchronous publications, but there is no clear evidence that they have any kind of common ancestry,” Carolina M. Voloch, PhD, the article’s first author and a biologist and researcher at the Molecular Virology Laboratory and associate professor in the department of genetics at the Federal University of Rio de Janeiro, said in an interview.

Dr. Voloch’s research focuses on the use of bioinformatics tools to study the molecular, phylogenetic, and genomic evolution of viruses.

“The emergence of new strains is common for viruses,” she said. “It can be happening anywhere in the world at any time.”

She stressed that identifying when mutations emerge will help to define the new Brazilian lineage. Researchers are working to determine whether the neutralizing antibodies of patients who have been infected with other strains respond to this Rio de Janeiro strain.

“We hope to soon be sharing these results,” Dr. Voloch said.

The article’s authors estimated that the new strain likely appeared in early July. They say more analysis is needed to predict whether the changes have a major effect on viral infectivity, the host’s immune response, or the severity of the disease. Asked about the lineage that caused the reinfection in Bahia, Dr. Voloch said she hadn’t yet contacted the authors to conduct a joint analysis but added that the data disclosed in the preprint would not represent the same variant.

“There are only two of the five mutations that characterize the Rio de Janeiro lineage. However, it has the E484K mutation that is present in more than 94% of the samples of the new variant of Rio,” she said.

She added that there’s a possibility of reinfection by the lineage that’s circulating in Rio de Janeiro and in other states, as well as countries such as the United States, the United Kingdom, and Japan.

“The Carioca virus is being exported to the rest of the world,” Dr. Voloch said.
 

Virus’ diversity still unknown

Researchers now know that SARS-CoV-2 probably circulated silently in Brazil as early as February 2020 and reached all the nation’s regions before air travel was restricted. Since the first half of 2020, there have been two predominant strains.

“More than a dozen strains have been identified in Brazil, but more important than counting strains to identify the speed with which they arise – which is directly associated with the rate of infection, which is very high in the country,” said Dr. Motta.

The so-called variant of Rio de Janeiro, he said, has also been detected in other states in four regions of Brazil. The key to documenting variants is to get a more representative sample with genomes from other parts of the country.

As of Jan. 10, a total of 347,000 complete genome sequences had been shared globally through open databases since SARS-CoV-2 was first identified, but the contribution of countries is uneven. Although the cost and complexity of genetic sequencing has dropped significantly over time, effective sequencing programs still require substantial investments in personnel, equipment, reagents, and bioinformatics infrastructure.

According to Dr. Voloch, it will only be possible to combat the new coronavirus by knowing its diversity and understanding how it evolves. The Fiocruz Genomic Network has made an infographic available so researchers can track the strains circulating in Brazil. It›s the result of collaboration between researchers from Fiocruz and the GISAID Initiative, an international partnership that promotes rapid data sharing.

As of Jan. 5, researchers in Brazil had studied 1,897 genomes – not nearly enough.

“In Brazil, there is little testing and even less sequencing,” lamented Dr. Souza.

“In the U.K., 1 in 600 cases is sequenced. In Brazil it is less than 1 in 10 million cases,” Dr. Voloch added.

So far, no decisive factors for public health, such as greater virulence or greater transmissibility, have been identified in any of the strains established in Brazil. The million-dollar question is whether the emergence of new strains could have an impact on the effectiveness of vaccines being administered today.

“In one way or another, the vaccine is our best bet ever, even if in the future we identify escapist mutants and have to modify it,” Dr. Motta said. “It is what we do annually with influenza.”

Dr. Voloch, Dr. Motta, and Dr. Souza disclosed no relevant financial relationships.

A version of this article first appeared on the Portuguese edition of Medscape.com.

Just as Brazil surpassed 200,000 deaths from COVID-19 on Jan. 7, news from Bahia added another layer of concern: A platform case report in a preprint detailed the first case of reinfection in that state, apparently caused by a new strain, one having the E484K mutation.

That variant, now called Brazil P.1, has migrated to the United States. The Minnesota Department of Health announced on Jan. 25 the nation’s first known COVID-19 case associated with it.

The mutation is located in the protein gene of the virus’ spike, which forms the crown structure of coronaviruses and is responsible for the virus’ binding to human cells. The E484K mutation is now the focus because it’s associated with mutations that escape the immune system’s neutralizing antibodies.

“This mutation is at the center of worldwide concern, and it is the first time that it has appeared in a reinfection,” the study’s first author, Bruno Solano de Freitas Souza, MD, a researcher at the Salvador regional unit of Instituto D’Or of Teaching and Research, based at Hospital São Rafael, Salvador, Brazil, explained in an interview.

“We will wait for the sample from Bahia to confirm the case from the perspective of the Ministry of Health’s surveillance network,” said Fernando Motta, PhD, deputy head of the Laboratory for Respiratory Virus and Measles at the Oswaldo Cruz Institute in Rio de Janeiro, which acts as a national reference center for respiratory viruses with the Brazilian Ministry of Health (MS) and as a reference for the World Health Organization.
 

A case of reinfection

The case patient that led to the alarm was a 45-year-old woman who is a health care executive. She had no comorbidities. The team had been following health care professionals and patients who had tested positive on reverse transcription–polymerase chain reaction (RT-PCR) testing more than once to understand whether they represented cases of prolonged viral persistence or new infections.

The woman had symptoms of viral infection on two occasions (May 26 and Oct. 26). On both occasions, results of RT-PCR testing for SARS-CoV-2 on nasopharyngeal samples were positive. In the first episode, the patient had diarrhea, myalgia, asthenia, and odynophagia for about 7 days. She returned to activities 21 days later. In the second episode, she had more severe symptoms that lasted longer, but she still did not require hospitalization.

“It was the first confirmed case of reinfection in Bahia, and in the second episode, we observed a mutation that could have an impact on the ability of antibodies to neutralize the virus,” Dr. Souza said. “The research continues with the investigation of cases in which the patient has a positive SARS-CoV-2 RT-PCR more than once in an interval greater than 45 days, to have a higher level of evidence.”

He stressed that “it is very important to reinforce measures to control the pandemic, social distance, use of masks, and speed up vaccination to be able to control the circulation of the virus, while monitoring the evolution of it.”
 

On alert for more cases

A person who twice tests positive for SARS-CoV-2 on real-time RT-PCR is suspected of having been reinfected, provided 90 or more days have elapsed between the two episodes, regardless of the condition observed. To confirm the suspected case, the samples must be sent to reference laboratories according to a plan established by the Ministry of Health in Brazil.

A health professional living in the Brazilian city of Natal represented the first confirmed case of reinfection by the new coronavirus in Brazil. That case was announced on Dec. 10, 2020.

“We communicated this case of reinfection to the MS in early December 2020. And the second sample already had the E484K mutation on the spike, as in the case of Bahia,” said Dr. Motta.

The first step in differentiating reinfection from persistence is to observe differences in the genotyping of the virus. For the technique to be successful, Dr. Souza said, researchers need a large amount of viral genetic material, which usually cannot be obtained.

“That is why there are many more suspected than confirmed cases,” Dr. Souza explained. He admitted that, although there are few cases, “it is increasingly clear that reinfection is a reality.”
 

Markers of mutations

What worried the researchers most was not only the possibility of reinfection but also the fact that preliminary analyses showed a specific mutation.

“The E484K mutation is present in a group of variants identified in South Africa that have been associated with increased infectivity and has been observed in a strain recently described in Brazil,” Dr. Souza said.

Mutations are expected, appear spontaneously, and in most cases have no effects on transmission or clinical outcome – they are simply used as markers and are useful for contact tracing or studying transmission routes. But some mutations can last because they provide an advantage for the pathogen, even if only momentary. In the case of SARS-CoV-2, mutations in the protein spike gene (S) are relevant because they may give clues to that advantage – as well as to changes in infectivity, transmission potential, antibodies, and response to vaccines.

A variant of the virus that has eight changes that affect the protein S gene – and several others in different genes – is behind the increase in the number of cases in London and southeastern England. Researchers from the University of São Paulo identified one of the factors that made this new variant – classified as B.1.1.7 – more infectious.

With bioinformatics tools, they found that the protein S gene in the new viral strain has a stronger molecular interaction with the ACE2 receptor, which is on the surface of human cells and to which the virus binds, making infection possible. The variant has already spread to the rest of the world, and the first two cases have been confirmed in Brazil by the Adolf Lutz Institute.

The alert for a new variant in Africa – similar to B.1.1.7 in the United Kingdom in that it carries nine changes in protein S at position 501 – was made by the Brazilian virologist Tulio de Oliveira, PhD.

“We found that this strain seems to be spreading much faster,” Dr. Oliveira, who is with the University of KwaZulu Natal, told the journal Science. His work first alerted British scientists to the importance of the position N501Y.

“The new variants just described in the United Kingdom and South Africa are slightly more transmissible and have already been identified in cases imported into Brazil,” Dr. Motta said. “Unfortunately, we believe it is only a matter of time before it becomes indigenous.”
 

The viral family grows

Viruses such as SARS-CoV-2 are classified into strains on the basis of small differences in their genetic material. Since Dec. 26, 2020, in addition to the British and South African variants, it appears the Carioca lineage also is a player.

In a preprint article, researchers analyzed the evolution of the epidemic in Rio de Janeiro from April 2020 until just before the new increase in incidence in December. They compared the complete sequences of the viral genome of 180 patients from different municipalities. The study, which is being jointly conducted by members of the Federal University of Rio de Janeiro and the National Laboratory for Scientific Computing, identified a new variant of SARS-CoV-2 that has five unique mutations (from one of the predominant strains). Concern arose because, in addition to those five genetic changes, many of the samples had a sixth – the well-known E484K mutation.

“The three lines – the U.K., South Africa, and Brazil – were almost synchronous publications, but there is no clear evidence that they have any kind of common ancestry,” Carolina M. Voloch, PhD, the article’s first author and a biologist and researcher at the Molecular Virology Laboratory and associate professor in the department of genetics at the Federal University of Rio de Janeiro, said in an interview.

Dr. Voloch’s research focuses on the use of bioinformatics tools to study the molecular, phylogenetic, and genomic evolution of viruses.

“The emergence of new strains is common for viruses,” she said. “It can be happening anywhere in the world at any time.”

She stressed that identifying when mutations emerge will help to define the new Brazilian lineage. Researchers are working to determine whether the neutralizing antibodies of patients who have been infected with other strains respond to this Rio de Janeiro strain.

“We hope to soon be sharing these results,” Dr. Voloch said.

The article’s authors estimated that the new strain likely appeared in early July. They say more analysis is needed to predict whether the changes have a major effect on viral infectivity, the host’s immune response, or the severity of the disease. Asked about the lineage that caused the reinfection in Bahia, Dr. Voloch said she hadn’t yet contacted the authors to conduct a joint analysis but added that the data disclosed in the preprint would not represent the same variant.

“There are only two of the five mutations that characterize the Rio de Janeiro lineage. However, it has the E484K mutation that is present in more than 94% of the samples of the new variant of Rio,” she said.

She added that there’s a possibility of reinfection by the lineage that’s circulating in Rio de Janeiro and in other states, as well as countries such as the United States, the United Kingdom, and Japan.

“The Carioca virus is being exported to the rest of the world,” Dr. Voloch said.
 

Virus’ diversity still unknown

Researchers now know that SARS-CoV-2 probably circulated silently in Brazil as early as February 2020 and reached all the nation’s regions before air travel was restricted. Since the first half of 2020, there have been two predominant strains.

“More than a dozen strains have been identified in Brazil, but more important than counting strains to identify the speed with which they arise – which is directly associated with the rate of infection, which is very high in the country,” said Dr. Motta.

The so-called variant of Rio de Janeiro, he said, has also been detected in other states in four regions of Brazil. The key to documenting variants is to get a more representative sample with genomes from other parts of the country.

As of Jan. 10, a total of 347,000 complete genome sequences had been shared globally through open databases since SARS-CoV-2 was first identified, but the contribution of countries is uneven. Although the cost and complexity of genetic sequencing has dropped significantly over time, effective sequencing programs still require substantial investments in personnel, equipment, reagents, and bioinformatics infrastructure.

According to Dr. Voloch, it will only be possible to combat the new coronavirus by knowing its diversity and understanding how it evolves. The Fiocruz Genomic Network has made an infographic available so researchers can track the strains circulating in Brazil. It›s the result of collaboration between researchers from Fiocruz and the GISAID Initiative, an international partnership that promotes rapid data sharing.

As of Jan. 5, researchers in Brazil had studied 1,897 genomes – not nearly enough.

“In Brazil, there is little testing and even less sequencing,” lamented Dr. Souza.

“In the U.K., 1 in 600 cases is sequenced. In Brazil it is less than 1 in 10 million cases,” Dr. Voloch added.

So far, no decisive factors for public health, such as greater virulence or greater transmissibility, have been identified in any of the strains established in Brazil. The million-dollar question is whether the emergence of new strains could have an impact on the effectiveness of vaccines being administered today.

“In one way or another, the vaccine is our best bet ever, even if in the future we identify escapist mutants and have to modify it,” Dr. Motta said. “It is what we do annually with influenza.”

Dr. Voloch, Dr. Motta, and Dr. Souza disclosed no relevant financial relationships.

A version of this article first appeared on the Portuguese edition of Medscape.com.

Seven days into his presidency, Joe Biden announced that he is taking new steps to speed vaccines to Americans.

The president said he would increase the supply of vaccines to states from 8.6 million doses to 10 million doses per week, a 16% increase, for at least the next 3 weeks.

He said he was working to give states more advanced notice of their allotments so they could better plan their campaigns. He also said doses would be doled out based on population.

“We will both increase the supply and give our state and local partners more certainty about when doses will arrive,” he said Tuesday.

Finally, Mr. Biden announced that the United States would “soon be able to confirm” the purchase of 200 million more doses of the Pfizer and Moderna vaccines – 100 million of each – to effectively double the nation’s supply by “early summer.” That would increase the nation’s supply enough to fully vaccinate 300 million Americans by fall.

Mr. Biden said he was also working to shift the focus to getting more doses to economically disadvantaged communities and rural areas, which have fallen further behind as the vaccine rollout has faltered.

Even with these steps, Mr. Biden stressed that it would take months for vaccines to curb infections and deaths. He said, for the time being, masks, not vaccines, are the best way to save lives.

“The brutal truth is its going to take months before we get the majority of Americans vaccinated. Months,” he said, adding that wearing masks until at least April could save to save 50,000 lives.

“Let me be clear,” Mr. Biden said, “Things are going to get worse before they get better.

“We didn’t get into this mess overnight. It’s going to take months for us to turn things around. But let me be equally clear we’re going to get through this. We will defeat this pandemic,” he said.

A version of this article first appeared on WebMD.com.

Seven days into his presidency, Joe Biden announced that he is taking new steps to speed vaccines to Americans.

The president said he would increase the supply of vaccines to states from 8.6 million doses to 10 million doses per week, a 16% increase, for at least the next 3 weeks.

He said he was working to give states more advanced notice of their allotments so they could better plan their campaigns. He also said doses would be doled out based on population.

“We will both increase the supply and give our state and local partners more certainty about when doses will arrive,” he said Tuesday.

Finally, Mr. Biden announced that the United States would “soon be able to confirm” the purchase of 200 million more doses of the Pfizer and Moderna vaccines – 100 million of each – to effectively double the nation’s supply by “early summer.” That would increase the nation’s supply enough to fully vaccinate 300 million Americans by fall.

Mr. Biden said he was also working to shift the focus to getting more doses to economically disadvantaged communities and rural areas, which have fallen further behind as the vaccine rollout has faltered.

Even with these steps, Mr. Biden stressed that it would take months for vaccines to curb infections and deaths. He said, for the time being, masks, not vaccines, are the best way to save lives.

“The brutal truth is its going to take months before we get the majority of Americans vaccinated. Months,” he said, adding that wearing masks until at least April could save to save 50,000 lives.

“Let me be clear,” Mr. Biden said, “Things are going to get worse before they get better.

“We didn’t get into this mess overnight. It’s going to take months for us to turn things around. But let me be equally clear we’re going to get through this. We will defeat this pandemic,” he said.

A version of this article first appeared on WebMD.com.

Seven days into his presidency, Joe Biden announced that he is taking new steps to speed vaccines to Americans.

The president said he would increase the supply of vaccines to states from 8.6 million doses to 10 million doses per week, a 16% increase, for at least the next 3 weeks.

He said he was working to give states more advanced notice of their allotments so they could better plan their campaigns. He also said doses would be doled out based on population.

“We will both increase the supply and give our state and local partners more certainty about when doses will arrive,” he said Tuesday.

Finally, Mr. Biden announced that the United States would “soon be able to confirm” the purchase of 200 million more doses of the Pfizer and Moderna vaccines – 100 million of each – to effectively double the nation’s supply by “early summer.” That would increase the nation’s supply enough to fully vaccinate 300 million Americans by fall.

Mr. Biden said he was also working to shift the focus to getting more doses to economically disadvantaged communities and rural areas, which have fallen further behind as the vaccine rollout has faltered.

Even with these steps, Mr. Biden stressed that it would take months for vaccines to curb infections and deaths. He said, for the time being, masks, not vaccines, are the best way to save lives.

“The brutal truth is its going to take months before we get the majority of Americans vaccinated. Months,” he said, adding that wearing masks until at least April could save to save 50,000 lives.

“Let me be clear,” Mr. Biden said, “Things are going to get worse before they get better.

“We didn’t get into this mess overnight. It’s going to take months for us to turn things around. But let me be equally clear we’re going to get through this. We will defeat this pandemic,” he said.

A version of this article first appeared on WebMD.com.

Since the first baby was born after a uterus transplantation in Sweden in 2014, uterus transplantation has been rapidly transitioning toward clinical reality.¹ Several teams in the United States and multiple teams worldwide have performed the procedure, with the total number of worldwide surgeries performed nearing 100.

Uterus transplantation is the first and only true treatment for women with absolute uterine factor infertility – estimated to affect 1 in 500 women – and is filling an unmet need for this population of women. Women who have sought participation in uterus transplantation research have had complex and meaningful reasons and motivations for doing so.² Combined with an accumulation of successful pregnancies, this makes continued research and technical improvement a worthy endeavor.

Most of the births thus far have occurred through the living-donor model; the initial Swedish trial involved nine women, seven of whom completed the procedure with viable transplants from living donors, and gave birth to eight healthy children. (Two required hysterectomy prior to attempted embryo transfer.³)

The Cleveland Clinic opted to build its first – and still ongoing – trial focusing on deceased-donor uterus transplants on the premise that such an approach obviates any risk to the donor and presents the fewest ethical challenges at the current time. Of eight uterus transplants performed thus far at the Cleveland Clinic, there have been three live births and two graft failures. As of early 2021, there was one ongoing pregnancy and two patients in preparation for embryo transfer.

Thus far, neither the living- nor deceased-donor model of uterus transplantation has been demonstrated to be superior. However, as data accrues from deceased donor studies, we will be able to more directly compare outcomes.

In the meantime, alongside a rapid ascent of clinical landmarks – the first live birth in the United States from living-donor uterus transplantation in 2017 at Baylor University Medical Center in Houston,⁴ for instance, and the first live birth in the United States from deceased-donor uterus transplantation in 2019 at the Cleveland Clinic ^– there have been significant improvements in surgical retrieval of the uterus and in the optimization of graft performance.⁵

Most notably, the utero-ovarian vein has been used successfully in living donors to achieve venous drainage of the graft. This has lessened the risks of deep pelvic dissection in the living donor and made the transition to laparoscopic and robotic approaches in the living donor much easier.
 

Donor procurement, venous drainage

Adequate circulatory inflow and outflow for the transplanted uterus are essential both for the prevention of ischemia and thrombosis, which have been major causes of graft failure, and for meeting the increased demands of blood flow during pregnancy. Of the two, the outflow is the more challenging component.

Courtesy Cleveland Clinic

Venous drainage traditionally has been accomplished through the use of the uterine veins, which drain into the internal iliac veins; often the vascular graft will include a portion of the internal iliac vessel which can be connected via anastomoses to the external iliac vein classically in deceased donors. Typically, the gynecologic surgeon on the team performs the vaginal anastomosis and suspension of the uterus, while the transplant surgeons perform the venous and arterial anastomoses.

In the living-donor model, procurement and dissection of these often unpredictable and tortuous complexes in the deep pelvis – particularly the branching uterine veins that lie in close proximity to the ureter, bladder, other blood vessels, and rectum – can be risky. The anatomic variants in the uterine vein are numerous, and even in one patient, a comprehensive dissection on one side cannot be expected to be mirrored on the contralateral side.

Courtesy Cleveland Clinic

In addition to the risk of injury to the donor, the anastomosis may be unsuccessful as the veins are thinly walled and challenging to suture. As such, multiple modifications have been developed, often adapted to the donor’s anatomy and the caliber and accessibility of vessels. Preoperative vascular imaging with CT and/or MRI may help to identify suitable candidates and also may facilitate presurgical planning of which vessels may be selected for use.

Recently, surgeons performing living-donor transplantations have successfully used the more accessible and less risky ovarian and/or utero-ovarian veins for venous anastomosis. In 2019, for instance, a team in Pune, India, reported laparoscopically dissecting the donor ovarian veins and a portion of the internal iliac artery, and completing anastomosis with bilateral donor internal iliac arteries to recipient internal iliac arteries, and bilateral donor ovarian veins to recipient external iliac veins.⁶ It is significant that these smaller-caliber vessels were found to able to support the uterus through pregnancy.

Courtesy Cleveland Clinic

We must be cautious, however, to avoid removing donors’ ovaries. Oophorectomy for women in their 40s can result in significant long-term medical sequelae. Surgeons at Baylor have achieved at least one live birth after harvesting the donor’s utero-ovarian veins while conserving the ovaries – a significant advancement for the living-donor model.⁴

There is tremendous interest in developing minimally invasive approaches to further reduce living-donor risk. The Swedish team has completed a series of eight robotic hysterectomies in living-donor uterus transplantations as part of a second trial. Addressing the reality of a learning curve, their study was designed around a step-wise approach, mastering initial steps first – e.g., dissections of the uterovaginal fossa, arteries, and ureters – and ultimately converting to laparotomy.⁷ In the United States, Baylor University has now completed at least five completely robotic living-donor hysterectomies with complete vaginal extraction.

Published data on robotic surgery suggests that surgical access and perioperative visualization of the vessels may be improved. And as minimally invasive approaches are adopted and improved, the length of donor surgery – 10-13 hours of operating room time in the original Swedish series – should diminish, as should the morbidity associated with laparotomy.

Courtesy Cleveland Clinic

Surgical acquisition of a uterine graft from a deceased donor diminishes concerns for injury to nearby structures. Therefore, although it is a technically similar procedure, a deceased-donor model allows more flexibility with the length, caliber, and number of vessels that can be used for anastomosis. The internal iliac vessels and even portions of the external iliac vessels and ovarian vessels can be used to allow maximum flexibility.⁸

Surgical technique for uterus recipients

For the recipient surgery, entry is achieved via a midline, vertical laparotomy. The external iliac vessels are exposed, and the sites of vascular anastomoses are identified. The peritoneal reflection of the bladder is identified and dissected away to expose the anterior vagina, and the vagina is opened to a diameter that matches the donor, typically using a monopolar electrosurgical cutting instrument.

Courtesy Cleveland Clinic

The vault of the donor vagina will be attached to the recipient’s existing vagina or vaginal pouch. It is important to identify recipient vaginal mucosa and incorporate it into the vaginal anastomosis to reduce the risk of vaginal stricture. We recommend that the vaginal mucosa be tagged with PDS II sutures or grasped with allis clamps to prevent retraction.

Surgical teams have taken multiple approaches to vaginal anastomosis. The Cleveland Clinic has used both a running suture as well as a horizontal mattress stitch for closure. For the latter, a 30-inch double-armed 2.0 Vicryl allows for complete suturing of the recipient vagina – with eight stitches placed circumferentially – before the uterus is placed. Both ends of the suture are passed intra-abdominal to intravaginal in the recipient.⁹

Once the donor uterus is suspended, attention focuses on vascular anastomosis, with bilateral end-to-side anastomosis between the donor anterior division of the internal iliac arteries and the external iliac vessels of the recipient, and with venous drainage commonly achieved through the uterine veins draining into the internal or external iliac vein of the recipient. As mentioned, recent cases involving living donors have also demonstrated success with the use of ovarian and/or utero-ovarian veins. Care should be taken to avoid having tension or twisting across the anastomosis.

Courtesy Cleveland Clinic

After adequate graft perfusion is confirmed, with the uterus turning from a dusky color to a pink and well-perfused organ, the vaginal anastomosis is completed, with the arms of the double-armed suture passed through the donor vagina, from intravaginal to intra-abdominal. Tension should be evenly spread along the recipient and donor vagina in order to reduce the formation of granulation tissue and the severity of future vaginal stricturing.

For uterine fixation, polypropylene sutures are placed between the graft uterosacral ligaments and recipient uterine rudiments, and between the graft round ligaments and the recipient pelvic side wall at the level of the deep inguinal ring.

Current uterus transplantation protocols require removal of the uterus after one or two live births are achieved, so that recipients will not be exposed to long-term immunosuppression.
 

Complications and controversies

Postoperative vaginal strictures can make embryo transfer difficult and are a common complication in both living- and deceased-donor models. The Cleveland Clinic team has applied techniques from vaginal reconstructive surgery to try to reduce the occurrence of postoperative strictures – mainly increasing attention paid to anastomosis tissue–site preparation and closure of the anastomosis using a tension-free interrupted suture technique, as described above.⁹ The jury is out on whether such changes are sufficient, and a more complete understanding of the causes of vaginal stricture is needed.

Other perioperative complications include infection and graft thrombosis, both of which typically result in urgent graft hysterectomy. During pregnancy, one of our patients experienced abnormal placentation, though this was not thought to be related to uterus transplantation.⁵

The U.S. Uterus Transplant Consortium (USUTC) is a group of active programs that are sharing ideas and outcomes and advocating for continued research in this rapidly developing field. Uterine transplants require collaboration with transplant surgery, transplant medicine, infectious disease, gynecologic surgery, high-risk obstetrics, and other specialties. While significant progress has been made in a short period of time, uterine transplantation is still in its early stages, and transplants should be done in institutions that have the capacity for mentorship, bioethical oversight, and long-term follow-up of donors, recipients, and offspring.

The USUTC has recently proposed guidelines for nomenclature related to operative technique, vascular anatomy, and uterine transplantation outcomes.¹⁰ It proposes standardizing the names for the four veins originating from the uterus (to eliminate current inconsistency), which will be important as optimal strategies for vascular anastomoses are discussed and determined.

In addition, the consortium is creating a registry for the rigorous collection of data on procedures and outcomes (from menstruation and pregnancy through delivery, graft removal, and long-term follow-up). A registry has also been proposed by the International Society for Uterine Transplantation.

A major question remains in our field: Is the living-donor or deceased-donor uterus transplant the best approach? Knowledge of the quality of the uterus is greater preoperatively within a living-donor model, but no matter how minimally invasive the technique, the donor still assumes some risk of prolonged surgery and extensive pelvic dissection for a transplant that is not lifesaving.

On the other hand, deceased-donor transplants require additional layers of organization and coordination, and the availability of suitable deceased-donor uteri will likely not be sufficient to meet the current demand. Many of us in the field believe that the future of uterine transplantation will involve some combination of living- and deceased-donor transplants – similar to other solid organ transplant programs.

Dr. Flyckt and Dr. Richards reported that they have no relevant financial disclosures.

Correction, 2/2/21: An earlier version of this article misstated Dr. Richards' name in the photo caption.
 

References

1. Lancet. 2015;14:385:607-16.

2. AJOB Empir Bioeth. 2019;10(1):23-5.

3. Transplantation. 2020;104(7):1312-5.

4. Am J Transplant. 2018;18(5):1270-4.

5. Am J Obstet Gynecol. 2020;223(2):143-51.

6. J Minimally Invasive Gynecol. 2019;26:628-35.

7. Acta Obstet Gynecol Scand. 2020;99(9):1222-9.

8. Fertil Steril. 2018;110(1):183.

9. Fertil Steril. 2020 Jul 16. doi: 10.1016/j.fertnstert.2020.05.017

10 Am J Transplant. 2020;20(12):3319-25.

Since the first baby was born after a uterus transplantation in Sweden in 2014, uterus transplantation has been rapidly transitioning toward clinical reality.¹ Several teams in the United States and multiple teams worldwide have performed the procedure, with the total number of worldwide surgeries performed nearing 100.

Uterus transplantation is the first and only true treatment for women with absolute uterine factor infertility – estimated to affect 1 in 500 women – and is filling an unmet need for this population of women. Women who have sought participation in uterus transplantation research have had complex and meaningful reasons and motivations for doing so.² Combined with an accumulation of successful pregnancies, this makes continued research and technical improvement a worthy endeavor.

Most of the births thus far have occurred through the living-donor model; the initial Swedish trial involved nine women, seven of whom completed the procedure with viable transplants from living donors, and gave birth to eight healthy children. (Two required hysterectomy prior to attempted embryo transfer.³)

The Cleveland Clinic opted to build its first – and still ongoing – trial focusing on deceased-donor uterus transplants on the premise that such an approach obviates any risk to the donor and presents the fewest ethical challenges at the current time. Of eight uterus transplants performed thus far at the Cleveland Clinic, there have been three live births and two graft failures. As of early 2021, there was one ongoing pregnancy and two patients in preparation for embryo transfer.

Thus far, neither the living- nor deceased-donor model of uterus transplantation has been demonstrated to be superior. However, as data accrues from deceased donor studies, we will be able to more directly compare outcomes.

In the meantime, alongside a rapid ascent of clinical landmarks – the first live birth in the United States from living-donor uterus transplantation in 2017 at Baylor University Medical Center in Houston,⁴ for instance, and the first live birth in the United States from deceased-donor uterus transplantation in 2019 at the Cleveland Clinic ^– there have been significant improvements in surgical retrieval of the uterus and in the optimization of graft performance.⁵

Most notably, the utero-ovarian vein has been used successfully in living donors to achieve venous drainage of the graft. This has lessened the risks of deep pelvic dissection in the living donor and made the transition to laparoscopic and robotic approaches in the living donor much easier.
 

Donor procurement, venous drainage

Adequate circulatory inflow and outflow for the transplanted uterus are essential both for the prevention of ischemia and thrombosis, which have been major causes of graft failure, and for meeting the increased demands of blood flow during pregnancy. Of the two, the outflow is the more challenging component.

Courtesy Cleveland Clinic

Venous drainage traditionally has been accomplished through the use of the uterine veins, which drain into the internal iliac veins; often the vascular graft will include a portion of the internal iliac vessel which can be connected via anastomoses to the external iliac vein classically in deceased donors. Typically, the gynecologic surgeon on the team performs the vaginal anastomosis and suspension of the uterus, while the transplant surgeons perform the venous and arterial anastomoses.

In the living-donor model, procurement and dissection of these often unpredictable and tortuous complexes in the deep pelvis – particularly the branching uterine veins that lie in close proximity to the ureter, bladder, other blood vessels, and rectum – can be risky. The anatomic variants in the uterine vein are numerous, and even in one patient, a comprehensive dissection on one side cannot be expected to be mirrored on the contralateral side.

Courtesy Cleveland Clinic

In addition to the risk of injury to the donor, the anastomosis may be unsuccessful as the veins are thinly walled and challenging to suture. As such, multiple modifications have been developed, often adapted to the donor’s anatomy and the caliber and accessibility of vessels. Preoperative vascular imaging with CT and/or MRI may help to identify suitable candidates and also may facilitate presurgical planning of which vessels may be selected for use.

Recently, surgeons performing living-donor transplantations have successfully used the more accessible and less risky ovarian and/or utero-ovarian veins for venous anastomosis. In 2019, for instance, a team in Pune, India, reported laparoscopically dissecting the donor ovarian veins and a portion of the internal iliac artery, and completing anastomosis with bilateral donor internal iliac arteries to recipient internal iliac arteries, and bilateral donor ovarian veins to recipient external iliac veins.⁶ It is significant that these smaller-caliber vessels were found to able to support the uterus through pregnancy.

Courtesy Cleveland Clinic

We must be cautious, however, to avoid removing donors’ ovaries. Oophorectomy for women in their 40s can result in significant long-term medical sequelae. Surgeons at Baylor have achieved at least one live birth after harvesting the donor’s utero-ovarian veins while conserving the ovaries – a significant advancement for the living-donor model.⁴

There is tremendous interest in developing minimally invasive approaches to further reduce living-donor risk. The Swedish team has completed a series of eight robotic hysterectomies in living-donor uterus transplantations as part of a second trial. Addressing the reality of a learning curve, their study was designed around a step-wise approach, mastering initial steps first – e.g., dissections of the uterovaginal fossa, arteries, and ureters – and ultimately converting to laparotomy.⁷ In the United States, Baylor University has now completed at least five completely robotic living-donor hysterectomies with complete vaginal extraction.

Published data on robotic surgery suggests that surgical access and perioperative visualization of the vessels may be improved. And as minimally invasive approaches are adopted and improved, the length of donor surgery – 10-13 hours of operating room time in the original Swedish series – should diminish, as should the morbidity associated with laparotomy.

Courtesy Cleveland Clinic

Surgical acquisition of a uterine graft from a deceased donor diminishes concerns for injury to nearby structures. Therefore, although it is a technically similar procedure, a deceased-donor model allows more flexibility with the length, caliber, and number of vessels that can be used for anastomosis. The internal iliac vessels and even portions of the external iliac vessels and ovarian vessels can be used to allow maximum flexibility.⁸

Surgical technique for uterus recipients

For the recipient surgery, entry is achieved via a midline, vertical laparotomy. The external iliac vessels are exposed, and the sites of vascular anastomoses are identified. The peritoneal reflection of the bladder is identified and dissected away to expose the anterior vagina, and the vagina is opened to a diameter that matches the donor, typically using a monopolar electrosurgical cutting instrument.

Courtesy Cleveland Clinic

The vault of the donor vagina will be attached to the recipient’s existing vagina or vaginal pouch. It is important to identify recipient vaginal mucosa and incorporate it into the vaginal anastomosis to reduce the risk of vaginal stricture. We recommend that the vaginal mucosa be tagged with PDS II sutures or grasped with allis clamps to prevent retraction.

Surgical teams have taken multiple approaches to vaginal anastomosis. The Cleveland Clinic has used both a running suture as well as a horizontal mattress stitch for closure. For the latter, a 30-inch double-armed 2.0 Vicryl allows for complete suturing of the recipient vagina – with eight stitches placed circumferentially – before the uterus is placed. Both ends of the suture are passed intra-abdominal to intravaginal in the recipient.⁹

Once the donor uterus is suspended, attention focuses on vascular anastomosis, with bilateral end-to-side anastomosis between the donor anterior division of the internal iliac arteries and the external iliac vessels of the recipient, and with venous drainage commonly achieved through the uterine veins draining into the internal or external iliac vein of the recipient. As mentioned, recent cases involving living donors have also demonstrated success with the use of ovarian and/or utero-ovarian veins. Care should be taken to avoid having tension or twisting across the anastomosis.

Courtesy Cleveland Clinic

After adequate graft perfusion is confirmed, with the uterus turning from a dusky color to a pink and well-perfused organ, the vaginal anastomosis is completed, with the arms of the double-armed suture passed through the donor vagina, from intravaginal to intra-abdominal. Tension should be evenly spread along the recipient and donor vagina in order to reduce the formation of granulation tissue and the severity of future vaginal stricturing.

For uterine fixation, polypropylene sutures are placed between the graft uterosacral ligaments and recipient uterine rudiments, and between the graft round ligaments and the recipient pelvic side wall at the level of the deep inguinal ring.

Current uterus transplantation protocols require removal of the uterus after one or two live births are achieved, so that recipients will not be exposed to long-term immunosuppression.
 

Complications and controversies

Postoperative vaginal strictures can make embryo transfer difficult and are a common complication in both living- and deceased-donor models. The Cleveland Clinic team has applied techniques from vaginal reconstructive surgery to try to reduce the occurrence of postoperative strictures – mainly increasing attention paid to anastomosis tissue–site preparation and closure of the anastomosis using a tension-free interrupted suture technique, as described above.⁹ The jury is out on whether such changes are sufficient, and a more complete understanding of the causes of vaginal stricture is needed.

Other perioperative complications include infection and graft thrombosis, both of which typically result in urgent graft hysterectomy. During pregnancy, one of our patients experienced abnormal placentation, though this was not thought to be related to uterus transplantation.⁵

The U.S. Uterus Transplant Consortium (USUTC) is a group of active programs that are sharing ideas and outcomes and advocating for continued research in this rapidly developing field. Uterine transplants require collaboration with transplant surgery, transplant medicine, infectious disease, gynecologic surgery, high-risk obstetrics, and other specialties. While significant progress has been made in a short period of time, uterine transplantation is still in its early stages, and transplants should be done in institutions that have the capacity for mentorship, bioethical oversight, and long-term follow-up of donors, recipients, and offspring.

The USUTC has recently proposed guidelines for nomenclature related to operative technique, vascular anatomy, and uterine transplantation outcomes.¹⁰ It proposes standardizing the names for the four veins originating from the uterus (to eliminate current inconsistency), which will be important as optimal strategies for vascular anastomoses are discussed and determined.

In addition, the consortium is creating a registry for the rigorous collection of data on procedures and outcomes (from menstruation and pregnancy through delivery, graft removal, and long-term follow-up). A registry has also been proposed by the International Society for Uterine Transplantation.

A major question remains in our field: Is the living-donor or deceased-donor uterus transplant the best approach? Knowledge of the quality of the uterus is greater preoperatively within a living-donor model, but no matter how minimally invasive the technique, the donor still assumes some risk of prolonged surgery and extensive pelvic dissection for a transplant that is not lifesaving.

On the other hand, deceased-donor transplants require additional layers of organization and coordination, and the availability of suitable deceased-donor uteri will likely not be sufficient to meet the current demand. Many of us in the field believe that the future of uterine transplantation will involve some combination of living- and deceased-donor transplants – similar to other solid organ transplant programs.

Dr. Flyckt and Dr. Richards reported that they have no relevant financial disclosures.

Correction, 2/2/21: An earlier version of this article misstated Dr. Richards' name in the photo caption.
 

References

1. Lancet. 2015;14:385:607-16.

2. AJOB Empir Bioeth. 2019;10(1):23-5.

3. Transplantation. 2020;104(7):1312-5.

4. Am J Transplant. 2018;18(5):1270-4.

5. Am J Obstet Gynecol. 2020;223(2):143-51.

6. J Minimally Invasive Gynecol. 2019;26:628-35.

7. Acta Obstet Gynecol Scand. 2020;99(9):1222-9.

8. Fertil Steril. 2018;110(1):183.

9. Fertil Steril. 2020 Jul 16. doi: 10.1016/j.fertnstert.2020.05.017

10 Am J Transplant. 2020;20(12):3319-25.

Since the first baby was born after a uterus transplantation in Sweden in 2014, uterus transplantation has been rapidly transitioning toward clinical reality.¹ Several teams in the United States and multiple teams worldwide have performed the procedure, with the total number of worldwide surgeries performed nearing 100.

Uterus transplantation is the first and only true treatment for women with absolute uterine factor infertility – estimated to affect 1 in 500 women – and is filling an unmet need for this population of women. Women who have sought participation in uterus transplantation research have had complex and meaningful reasons and motivations for doing so.² Combined with an accumulation of successful pregnancies, this makes continued research and technical improvement a worthy endeavor.

Most of the births thus far have occurred through the living-donor model; the initial Swedish trial involved nine women, seven of whom completed the procedure with viable transplants from living donors, and gave birth to eight healthy children. (Two required hysterectomy prior to attempted embryo transfer.³)

The Cleveland Clinic opted to build its first – and still ongoing – trial focusing on deceased-donor uterus transplants on the premise that such an approach obviates any risk to the donor and presents the fewest ethical challenges at the current time. Of eight uterus transplants performed thus far at the Cleveland Clinic, there have been three live births and two graft failures. As of early 2021, there was one ongoing pregnancy and two patients in preparation for embryo transfer.

Thus far, neither the living- nor deceased-donor model of uterus transplantation has been demonstrated to be superior. However, as data accrues from deceased donor studies, we will be able to more directly compare outcomes.

In the meantime, alongside a rapid ascent of clinical landmarks – the first live birth in the United States from living-donor uterus transplantation in 2017 at Baylor University Medical Center in Houston,⁴ for instance, and the first live birth in the United States from deceased-donor uterus transplantation in 2019 at the Cleveland Clinic ^– there have been significant improvements in surgical retrieval of the uterus and in the optimization of graft performance.⁵

Most notably, the utero-ovarian vein has been used successfully in living donors to achieve venous drainage of the graft. This has lessened the risks of deep pelvic dissection in the living donor and made the transition to laparoscopic and robotic approaches in the living donor much easier.
 

Donor procurement, venous drainage

Adequate circulatory inflow and outflow for the transplanted uterus are essential both for the prevention of ischemia and thrombosis, which have been major causes of graft failure, and for meeting the increased demands of blood flow during pregnancy. Of the two, the outflow is the more challenging component.

Courtesy Cleveland Clinic

Venous drainage traditionally has been accomplished through the use of the uterine veins, which drain into the internal iliac veins; often the vascular graft will include a portion of the internal iliac vessel which can be connected via anastomoses to the external iliac vein classically in deceased donors. Typically, the gynecologic surgeon on the team performs the vaginal anastomosis and suspension of the uterus, while the transplant surgeons perform the venous and arterial anastomoses.

In the living-donor model, procurement and dissection of these often unpredictable and tortuous complexes in the deep pelvis – particularly the branching uterine veins that lie in close proximity to the ureter, bladder, other blood vessels, and rectum – can be risky. The anatomic variants in the uterine vein are numerous, and even in one patient, a comprehensive dissection on one side cannot be expected to be mirrored on the contralateral side.

Courtesy Cleveland Clinic

In addition to the risk of injury to the donor, the anastomosis may be unsuccessful as the veins are thinly walled and challenging to suture. As such, multiple modifications have been developed, often adapted to the donor’s anatomy and the caliber and accessibility of vessels. Preoperative vascular imaging with CT and/or MRI may help to identify suitable candidates and also may facilitate presurgical planning of which vessels may be selected for use.

Recently, surgeons performing living-donor transplantations have successfully used the more accessible and less risky ovarian and/or utero-ovarian veins for venous anastomosis. In 2019, for instance, a team in Pune, India, reported laparoscopically dissecting the donor ovarian veins and a portion of the internal iliac artery, and completing anastomosis with bilateral donor internal iliac arteries to recipient internal iliac arteries, and bilateral donor ovarian veins to recipient external iliac veins.⁶ It is significant that these smaller-caliber vessels were found to able to support the uterus through pregnancy.

Courtesy Cleveland Clinic

We must be cautious, however, to avoid removing donors’ ovaries. Oophorectomy for women in their 40s can result in significant long-term medical sequelae. Surgeons at Baylor have achieved at least one live birth after harvesting the donor’s utero-ovarian veins while conserving the ovaries – a significant advancement for the living-donor model.⁴

There is tremendous interest in developing minimally invasive approaches to further reduce living-donor risk. The Swedish team has completed a series of eight robotic hysterectomies in living-donor uterus transplantations as part of a second trial. Addressing the reality of a learning curve, their study was designed around a step-wise approach, mastering initial steps first – e.g., dissections of the uterovaginal fossa, arteries, and ureters – and ultimately converting to laparotomy.⁷ In the United States, Baylor University has now completed at least five completely robotic living-donor hysterectomies with complete vaginal extraction.

Published data on robotic surgery suggests that surgical access and perioperative visualization of the vessels may be improved. And as minimally invasive approaches are adopted and improved, the length of donor surgery – 10-13 hours of operating room time in the original Swedish series – should diminish, as should the morbidity associated with laparotomy.

Courtesy Cleveland Clinic

Surgical acquisition of a uterine graft from a deceased donor diminishes concerns for injury to nearby structures. Therefore, although it is a technically similar procedure, a deceased-donor model allows more flexibility with the length, caliber, and number of vessels that can be used for anastomosis. The internal iliac vessels and even portions of the external iliac vessels and ovarian vessels can be used to allow maximum flexibility.⁸

Surgical technique for uterus recipients

For the recipient surgery, entry is achieved via a midline, vertical laparotomy. The external iliac vessels are exposed, and the sites of vascular anastomoses are identified. The peritoneal reflection of the bladder is identified and dissected away to expose the anterior vagina, and the vagina is opened to a diameter that matches the donor, typically using a monopolar electrosurgical cutting instrument.

Courtesy Cleveland Clinic

The vault of the donor vagina will be attached to the recipient’s existing vagina or vaginal pouch. It is important to identify recipient vaginal mucosa and incorporate it into the vaginal anastomosis to reduce the risk of vaginal stricture. We recommend that the vaginal mucosa be tagged with PDS II sutures or grasped with allis clamps to prevent retraction.

Surgical teams have taken multiple approaches to vaginal anastomosis. The Cleveland Clinic has used both a running suture as well as a horizontal mattress stitch for closure. For the latter, a 30-inch double-armed 2.0 Vicryl allows for complete suturing of the recipient vagina – with eight stitches placed circumferentially – before the uterus is placed. Both ends of the suture are passed intra-abdominal to intravaginal in the recipient.⁹

Once the donor uterus is suspended, attention focuses on vascular anastomosis, with bilateral end-to-side anastomosis between the donor anterior division of the internal iliac arteries and the external iliac vessels of the recipient, and with venous drainage commonly achieved through the uterine veins draining into the internal or external iliac vein of the recipient. As mentioned, recent cases involving living donors have also demonstrated success with the use of ovarian and/or utero-ovarian veins. Care should be taken to avoid having tension or twisting across the anastomosis.

Courtesy Cleveland Clinic

After adequate graft perfusion is confirmed, with the uterus turning from a dusky color to a pink and well-perfused organ, the vaginal anastomosis is completed, with the arms of the double-armed suture passed through the donor vagina, from intravaginal to intra-abdominal. Tension should be evenly spread along the recipient and donor vagina in order to reduce the formation of granulation tissue and the severity of future vaginal stricturing.

For uterine fixation, polypropylene sutures are placed between the graft uterosacral ligaments and recipient uterine rudiments, and between the graft round ligaments and the recipient pelvic side wall at the level of the deep inguinal ring.

Current uterus transplantation protocols require removal of the uterus after one or two live births are achieved, so that recipients will not be exposed to long-term immunosuppression.
 

Complications and controversies

Postoperative vaginal strictures can make embryo transfer difficult and are a common complication in both living- and deceased-donor models. The Cleveland Clinic team has applied techniques from vaginal reconstructive surgery to try to reduce the occurrence of postoperative strictures – mainly increasing attention paid to anastomosis tissue–site preparation and closure of the anastomosis using a tension-free interrupted suture technique, as described above.⁹ The jury is out on whether such changes are sufficient, and a more complete understanding of the causes of vaginal stricture is needed.

Other perioperative complications include infection and graft thrombosis, both of which typically result in urgent graft hysterectomy. During pregnancy, one of our patients experienced abnormal placentation, though this was not thought to be related to uterus transplantation.⁵

The U.S. Uterus Transplant Consortium (USUTC) is a group of active programs that are sharing ideas and outcomes and advocating for continued research in this rapidly developing field. Uterine transplants require collaboration with transplant surgery, transplant medicine, infectious disease, gynecologic surgery, high-risk obstetrics, and other specialties. While significant progress has been made in a short period of time, uterine transplantation is still in its early stages, and transplants should be done in institutions that have the capacity for mentorship, bioethical oversight, and long-term follow-up of donors, recipients, and offspring.

The USUTC has recently proposed guidelines for nomenclature related to operative technique, vascular anatomy, and uterine transplantation outcomes.¹⁰ It proposes standardizing the names for the four veins originating from the uterus (to eliminate current inconsistency), which will be important as optimal strategies for vascular anastomoses are discussed and determined.

In addition, the consortium is creating a registry for the rigorous collection of data on procedures and outcomes (from menstruation and pregnancy through delivery, graft removal, and long-term follow-up). A registry has also been proposed by the International Society for Uterine Transplantation.

A major question remains in our field: Is the living-donor or deceased-donor uterus transplant the best approach? Knowledge of the quality of the uterus is greater preoperatively within a living-donor model, but no matter how minimally invasive the technique, the donor still assumes some risk of prolonged surgery and extensive pelvic dissection for a transplant that is not lifesaving.

On the other hand, deceased-donor transplants require additional layers of organization and coordination, and the availability of suitable deceased-donor uteri will likely not be sufficient to meet the current demand. Many of us in the field believe that the future of uterine transplantation will involve some combination of living- and deceased-donor transplants – similar to other solid organ transplant programs.

Dr. Flyckt and Dr. Richards reported that they have no relevant financial disclosures.

Correction, 2/2/21: An earlier version of this article misstated Dr. Richards' name in the photo caption.
 

References

1. Lancet. 2015;14:385:607-16.

2. AJOB Empir Bioeth. 2019;10(1):23-5.

3. Transplantation. 2020;104(7):1312-5.

4. Am J Transplant. 2018;18(5):1270-4.

5. Am J Obstet Gynecol. 2020;223(2):143-51.

6. J Minimally Invasive Gynecol. 2019;26:628-35.

7. Acta Obstet Gynecol Scand. 2020;99(9):1222-9.

8. Fertil Steril. 2018;110(1):183.

9. Fertil Steril. 2020 Jul 16. doi: 10.1016/j.fertnstert.2020.05.017

10 Am J Transplant. 2020;20(12):3319-25.

Until the advent of uterus transplantation, there was no restorative procedure available to a woman presenting with an absent uterus or nonfunctioning uterus; that is, absolute uterine factor infertility (AUFI). It is estimated that 1 in 500 women of childbearing age are affected by AUFI.^1,2 An absent uterus may be secondary to uterine agenesis or Mayer-Rokitansky-Küster-Hauser syndrome (MRKH), which occurs in 1 in 4,500 women.^3,4 (Because women with MRKH have a normal karyotype, their children can be normal, without urogenital malformations.⁵)

Given the fact that roughly 240,000 hysterectomies are performed in the United States each year for women aged under 44 years, hysterectomy is the most common cause of acquired AUFI.⁶AUFI may also be secondary to a uterus that will not support a viable pregnancy; that is, a nonfunctional uterus. In this case, medical or surgical treatment is impossible to enable normal physiological uterine function to produce a successful pregnancy. Causal factors include Müllerian anomalies, severe intrauterine adhesions/Asherman syndrome, uterine fibroids not amendable to surgical therapy, and radiation injury not responsive to medical therapy.

Prior to uterus transplantation, parenthood could only be achieved via adoption, foster parenting, or gestational carrier. While utilizing a gestational carrier is legal in most U.S. states, most countries of western Europe as well as Brazil and Japan, to name a few, do not allow the use of gestational carriers. For some women, moreover, the desire is not only to have a baby, but to carry a child as well.

For this edition of the Master Class in Gynecologic Surgery, I have enlisted the assistance of Rebecca Flyckt, MD, division chief of reproductive endocrinology and infertility at University Hospitals Cleveland Medical Center and associate professor at Case Western Reserve University, Cleveland, and Elliott G. Richards, MD, director of reproductive endocrinology and infertility research at the Cleveland Clinic, to discuss the current and future state of uterus transplantation.

Dr. Flyckt and Dr. Richards have both contributed to the uterus transplantation team at the Cleveland Clinic and are founding members of the U.S. Uterus Transplant Consortium. They are well published in the field of minimally invasive gynecology and reproductive endocrinology and infertility. It is truly a pleasure to welcome them both to this edition of the Master Class in Gynecologic Surgery.

References

1. Fertil Steril. 2014 May;101(5):1228-36.

2. Acta Biomater. 2014 Dec;10(12):5034-42.

3. Hum Reprod Update. Mar-Apr 2001;7(2):161-74.

4. Obstet Gynecol Surv. 2000 Oct;55(10):644-9.

5. Fertil Steril. 1997 Feb;67(2):387-9

6. Am J Public Health. 2003 Feb;93(2):307-12.
 

Dr. Miller is professor of obstetrics & gynecology in the department of clinical sciences, Rosalind Franklin University, North Chicago, and director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill. Dr. Miller reported that he has no disclosures relevant to this Master Class. Email him at obnews@mdedge.com.

Until the advent of uterus transplantation, there was no restorative procedure available to a woman presenting with an absent uterus or nonfunctioning uterus; that is, absolute uterine factor infertility (AUFI). It is estimated that 1 in 500 women of childbearing age are affected by AUFI.^1,2 An absent uterus may be secondary to uterine agenesis or Mayer-Rokitansky-Küster-Hauser syndrome (MRKH), which occurs in 1 in 4,500 women.^3,4 (Because women with MRKH have a normal karyotype, their children can be normal, without urogenital malformations.⁵)

Given the fact that roughly 240,000 hysterectomies are performed in the United States each year for women aged under 44 years, hysterectomy is the most common cause of acquired AUFI.⁶AUFI may also be secondary to a uterus that will not support a viable pregnancy; that is, a nonfunctional uterus. In this case, medical or surgical treatment is impossible to enable normal physiological uterine function to produce a successful pregnancy. Causal factors include Müllerian anomalies, severe intrauterine adhesions/Asherman syndrome, uterine fibroids not amendable to surgical therapy, and radiation injury not responsive to medical therapy.

Prior to uterus transplantation, parenthood could only be achieved via adoption, foster parenting, or gestational carrier. While utilizing a gestational carrier is legal in most U.S. states, most countries of western Europe as well as Brazil and Japan, to name a few, do not allow the use of gestational carriers. For some women, moreover, the desire is not only to have a baby, but to carry a child as well.

For this edition of the Master Class in Gynecologic Surgery, I have enlisted the assistance of Rebecca Flyckt, MD, division chief of reproductive endocrinology and infertility at University Hospitals Cleveland Medical Center and associate professor at Case Western Reserve University, Cleveland, and Elliott G. Richards, MD, director of reproductive endocrinology and infertility research at the Cleveland Clinic, to discuss the current and future state of uterus transplantation.

Dr. Flyckt and Dr. Richards have both contributed to the uterus transplantation team at the Cleveland Clinic and are founding members of the U.S. Uterus Transplant Consortium. They are well published in the field of minimally invasive gynecology and reproductive endocrinology and infertility. It is truly a pleasure to welcome them both to this edition of the Master Class in Gynecologic Surgery.

References

1. Fertil Steril. 2014 May;101(5):1228-36.

2. Acta Biomater. 2014 Dec;10(12):5034-42.

3. Hum Reprod Update. Mar-Apr 2001;7(2):161-74.

4. Obstet Gynecol Surv. 2000 Oct;55(10):644-9.

5. Fertil Steril. 1997 Feb;67(2):387-9

6. Am J Public Health. 2003 Feb;93(2):307-12.
 

Dr. Miller is professor of obstetrics & gynecology in the department of clinical sciences, Rosalind Franklin University, North Chicago, and director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill. Dr. Miller reported that he has no disclosures relevant to this Master Class. Email him at obnews@mdedge.com.

Until the advent of uterus transplantation, there was no restorative procedure available to a woman presenting with an absent uterus or nonfunctioning uterus; that is, absolute uterine factor infertility (AUFI). It is estimated that 1 in 500 women of childbearing age are affected by AUFI.^1,2 An absent uterus may be secondary to uterine agenesis or Mayer-Rokitansky-Küster-Hauser syndrome (MRKH), which occurs in 1 in 4,500 women.^3,4 (Because women with MRKH have a normal karyotype, their children can be normal, without urogenital malformations.⁵)

Given the fact that roughly 240,000 hysterectomies are performed in the United States each year for women aged under 44 years, hysterectomy is the most common cause of acquired AUFI.⁶AUFI may also be secondary to a uterus that will not support a viable pregnancy; that is, a nonfunctional uterus. In this case, medical or surgical treatment is impossible to enable normal physiological uterine function to produce a successful pregnancy. Causal factors include Müllerian anomalies, severe intrauterine adhesions/Asherman syndrome, uterine fibroids not amendable to surgical therapy, and radiation injury not responsive to medical therapy.

Prior to uterus transplantation, parenthood could only be achieved via adoption, foster parenting, or gestational carrier. While utilizing a gestational carrier is legal in most U.S. states, most countries of western Europe as well as Brazil and Japan, to name a few, do not allow the use of gestational carriers. For some women, moreover, the desire is not only to have a baby, but to carry a child as well.

For this edition of the Master Class in Gynecologic Surgery, I have enlisted the assistance of Rebecca Flyckt, MD, division chief of reproductive endocrinology and infertility at University Hospitals Cleveland Medical Center and associate professor at Case Western Reserve University, Cleveland, and Elliott G. Richards, MD, director of reproductive endocrinology and infertility research at the Cleveland Clinic, to discuss the current and future state of uterus transplantation.

Dr. Flyckt and Dr. Richards have both contributed to the uterus transplantation team at the Cleveland Clinic and are founding members of the U.S. Uterus Transplant Consortium. They are well published in the field of minimally invasive gynecology and reproductive endocrinology and infertility. It is truly a pleasure to welcome them both to this edition of the Master Class in Gynecologic Surgery.

References

1. Fertil Steril. 2014 May;101(5):1228-36.

2. Acta Biomater. 2014 Dec;10(12):5034-42.

3. Hum Reprod Update. Mar-Apr 2001;7(2):161-74.

4. Obstet Gynecol Surv. 2000 Oct;55(10):644-9.

5. Fertil Steril. 1997 Feb;67(2):387-9

6. Am J Public Health. 2003 Feb;93(2):307-12.
 

Dr. Miller is professor of obstetrics & gynecology in the department of clinical sciences, Rosalind Franklin University, North Chicago, and director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill. Dr. Miller reported that he has no disclosures relevant to this Master Class. Email him at obnews@mdedge.com.

A systematic review suggests at least one-third of SARS-CoV-2 infections occur in people who never develop symptoms, providing strong evidence for the prevalence of asymptomatic infections.

The finding that nearly one in three infected people remain symptom free suggests testing should be changed, the investigators noted.

“To reduce transmission from people who are presymptomatic or asymptomatic, we need to shift our testing focus to at-home screening,” lead author Daniel Oran, AM, said in an interview. “Inexpensive rapid antigen tests, provided to millions of people for frequent use, could help us significantly reduce the spread of the virus.”

The systematic review was published online Jan. 22 in Annals of Internal Medicine.

The findings come at a dire time when the official number of COVID-19 cases in the United States exceeds 25 million for the first time. Public health officials have raised concerns about more transmissible, and possibly more deadly, variants of SARS-CoV-2, while a new presidential administration tries to meet the challenge of improving vaccine distribution and acceptance rates.

The results also build on earlier findings from the same research team – Mr. Oran and senior author Eric Topol, MD – that published a review article looking at asymptomatic COVID-19 cases. Even though initial data were more limited, they likewise suggested a broader scope of testing is warranted, pointing out that asymptomatic individuals can transmit SARS-CoV-2 for up to 14 days. Dr. Topol is also editor in chief of Medscape.

In the current systematic review, the highest-quality evidence comes from large studies in England and Spain. The nationally representative evidence included serologic surveys from more than 365,000 people in England and more than 61,000 in Spain. When analyzed separately, about the same proportion of asymptomatic cases emerged: 32.4% in England and 33% in Spain.

“It was really remarkable to find that nationwide antibody testing studies in England and Spain – including hundreds of thousands of people – produced nearly identical results: About one-third of the SARS-CoV-2 infections were completely asymptomatic,” said Mr. Oran, a researcher at Scripps Research Translational Institute in La Jolla, Calif.

The systematic review included 43 studies with PCR testing for active SARS-CoV-2 infection and another 18 with antibody results that indicated present or previous infection. The studies were published up until Nov. 17, 2020.

An appreciation for asymptomatic transmission of SARS-CoV-2 infection has come a long way from initial dismissals about its importance, Dr. Topol noted via Twitter. “When Dr. @camilla_rothe reported an asymptomatic transmission a year ago, the @NEJM report was refuted and disparaged. She was later named a TIME 100 Person of the Year.”
 

Not symptomatic vs. never symptomatic

The term “asymptomatic” could be misleading because some people in this group do progress to develop signs of infection. This “presymptomatic” group of patients is likely a minority, the authors noted. Longitudinal studies indicate that about three-quarters of people who are asymptomatic with SARS-CoV-2 remain so.

Dr. Topol anticipated the one-third asymptomatic finding could draw some feedback about distinguishing asymptomatic from presymptomatic individuals. He tweeted, “Some will argue that there is admixture with presymptomatic cases, but review of all the data supports this estimate as being a conservative one.”

The heterogeneity of the settings, populations and other features of the studies prevented the authors from performing a meta-analysis of the findings.
 

Home is where the test is

Based on their findings, Mr. Oran and Dr. Topol believe “that COVID-19 control strategies must be altered, taking into account the prevalence and transmission risk of asymptomatic SARS-CoV-2 infection.” They suggested frequent use of inexpensive, rapid home tests to identify people who are asymptomatic or presymptomatic, along with programs and housing provided by the government to offer financial assistance and allow this group of people to isolate themselves.

Further research is warranted to determine if and how well vaccines for SARS-CoV-2 prevent asymptomatic infection.

Dr. Topol and Mr. Oran created a short video to highlight the findings from their systematic review.

The study was supported by a grant from the National Institutes of Health.

A version of this article first appeared on Medscape.com.

A systematic review suggests at least one-third of SARS-CoV-2 infections occur in people who never develop symptoms, providing strong evidence for the prevalence of asymptomatic infections.

The finding that nearly one in three infected people remain symptom free suggests testing should be changed, the investigators noted.

“To reduce transmission from people who are presymptomatic or asymptomatic, we need to shift our testing focus to at-home screening,” lead author Daniel Oran, AM, said in an interview. “Inexpensive rapid antigen tests, provided to millions of people for frequent use, could help us significantly reduce the spread of the virus.”

The systematic review was published online Jan. 22 in Annals of Internal Medicine.

The findings come at a dire time when the official number of COVID-19 cases in the United States exceeds 25 million for the first time. Public health officials have raised concerns about more transmissible, and possibly more deadly, variants of SARS-CoV-2, while a new presidential administration tries to meet the challenge of improving vaccine distribution and acceptance rates.

The results also build on earlier findings from the same research team – Mr. Oran and senior author Eric Topol, MD – that published a review article looking at asymptomatic COVID-19 cases. Even though initial data were more limited, they likewise suggested a broader scope of testing is warranted, pointing out that asymptomatic individuals can transmit SARS-CoV-2 for up to 14 days. Dr. Topol is also editor in chief of Medscape.

In the current systematic review, the highest-quality evidence comes from large studies in England and Spain. The nationally representative evidence included serologic surveys from more than 365,000 people in England and more than 61,000 in Spain. When analyzed separately, about the same proportion of asymptomatic cases emerged: 32.4% in England and 33% in Spain.

“It was really remarkable to find that nationwide antibody testing studies in England and Spain – including hundreds of thousands of people – produced nearly identical results: About one-third of the SARS-CoV-2 infections were completely asymptomatic,” said Mr. Oran, a researcher at Scripps Research Translational Institute in La Jolla, Calif.

The systematic review included 43 studies with PCR testing for active SARS-CoV-2 infection and another 18 with antibody results that indicated present or previous infection. The studies were published up until Nov. 17, 2020.

An appreciation for asymptomatic transmission of SARS-CoV-2 infection has come a long way from initial dismissals about its importance, Dr. Topol noted via Twitter. “When Dr. @camilla_rothe reported an asymptomatic transmission a year ago, the @NEJM report was refuted and disparaged. She was later named a TIME 100 Person of the Year.”
 

Not symptomatic vs. never symptomatic

The term “asymptomatic” could be misleading because some people in this group do progress to develop signs of infection. This “presymptomatic” group of patients is likely a minority, the authors noted. Longitudinal studies indicate that about three-quarters of people who are asymptomatic with SARS-CoV-2 remain so.

Dr. Topol anticipated the one-third asymptomatic finding could draw some feedback about distinguishing asymptomatic from presymptomatic individuals. He tweeted, “Some will argue that there is admixture with presymptomatic cases, but review of all the data supports this estimate as being a conservative one.”

The heterogeneity of the settings, populations and other features of the studies prevented the authors from performing a meta-analysis of the findings.
 

Home is where the test is

Based on their findings, Mr. Oran and Dr. Topol believe “that COVID-19 control strategies must be altered, taking into account the prevalence and transmission risk of asymptomatic SARS-CoV-2 infection.” They suggested frequent use of inexpensive, rapid home tests to identify people who are asymptomatic or presymptomatic, along with programs and housing provided by the government to offer financial assistance and allow this group of people to isolate themselves.

Further research is warranted to determine if and how well vaccines for SARS-CoV-2 prevent asymptomatic infection.

Dr. Topol and Mr. Oran created a short video to highlight the findings from their systematic review.

The study was supported by a grant from the National Institutes of Health.

A version of this article first appeared on Medscape.com.

A systematic review suggests at least one-third of SARS-CoV-2 infections occur in people who never develop symptoms, providing strong evidence for the prevalence of asymptomatic infections.

The finding that nearly one in three infected people remain symptom free suggests testing should be changed, the investigators noted.

“To reduce transmission from people who are presymptomatic or asymptomatic, we need to shift our testing focus to at-home screening,” lead author Daniel Oran, AM, said in an interview. “Inexpensive rapid antigen tests, provided to millions of people for frequent use, could help us significantly reduce the spread of the virus.”

The systematic review was published online Jan. 22 in Annals of Internal Medicine.

The findings come at a dire time when the official number of COVID-19 cases in the United States exceeds 25 million for the first time. Public health officials have raised concerns about more transmissible, and possibly more deadly, variants of SARS-CoV-2, while a new presidential administration tries to meet the challenge of improving vaccine distribution and acceptance rates.

The results also build on earlier findings from the same research team – Mr. Oran and senior author Eric Topol, MD – that published a review article looking at asymptomatic COVID-19 cases. Even though initial data were more limited, they likewise suggested a broader scope of testing is warranted, pointing out that asymptomatic individuals can transmit SARS-CoV-2 for up to 14 days. Dr. Topol is also editor in chief of Medscape.

In the current systematic review, the highest-quality evidence comes from large studies in England and Spain. The nationally representative evidence included serologic surveys from more than 365,000 people in England and more than 61,000 in Spain. When analyzed separately, about the same proportion of asymptomatic cases emerged: 32.4% in England and 33% in Spain.

“It was really remarkable to find that nationwide antibody testing studies in England and Spain – including hundreds of thousands of people – produced nearly identical results: About one-third of the SARS-CoV-2 infections were completely asymptomatic,” said Mr. Oran, a researcher at Scripps Research Translational Institute in La Jolla, Calif.

The systematic review included 43 studies with PCR testing for active SARS-CoV-2 infection and another 18 with antibody results that indicated present or previous infection. The studies were published up until Nov. 17, 2020.

An appreciation for asymptomatic transmission of SARS-CoV-2 infection has come a long way from initial dismissals about its importance, Dr. Topol noted via Twitter. “When Dr. @camilla_rothe reported an asymptomatic transmission a year ago, the @NEJM report was refuted and disparaged. She was later named a TIME 100 Person of the Year.”
 

Not symptomatic vs. never symptomatic

The term “asymptomatic” could be misleading because some people in this group do progress to develop signs of infection. This “presymptomatic” group of patients is likely a minority, the authors noted. Longitudinal studies indicate that about three-quarters of people who are asymptomatic with SARS-CoV-2 remain so.

Dr. Topol anticipated the one-third asymptomatic finding could draw some feedback about distinguishing asymptomatic from presymptomatic individuals. He tweeted, “Some will argue that there is admixture with presymptomatic cases, but review of all the data supports this estimate as being a conservative one.”

The heterogeneity of the settings, populations and other features of the studies prevented the authors from performing a meta-analysis of the findings.
 

Home is where the test is

Based on their findings, Mr. Oran and Dr. Topol believe “that COVID-19 control strategies must be altered, taking into account the prevalence and transmission risk of asymptomatic SARS-CoV-2 infection.” They suggested frequent use of inexpensive, rapid home tests to identify people who are asymptomatic or presymptomatic, along with programs and housing provided by the government to offer financial assistance and allow this group of people to isolate themselves.

Further research is warranted to determine if and how well vaccines for SARS-CoV-2 prevent asymptomatic infection.

Dr. Topol and Mr. Oran created a short video to highlight the findings from their systematic review.

The study was supported by a grant from the National Institutes of Health.

A version of this article first appeared on Medscape.com.