Mary Ann Moon

The immediate isolation of children with acute Escherichia coli O157 infection could potentially decrease the number of secondary cases by half, according to results of a retrospective study of 89 primary cases in a 2005 outbreak.

In particular, the researchers estimated that by quarantining patients who are at the highest risk of transmitting the infection (those aged 10 years and younger who have a sibling), the number needed to be isolated to prevent one case of life-threatening hemolytic uremic syndrome (HUS) is only 47.

In comparison, the number of household contacts needed to be treated with prophylaxis to prevent one secondary case of meningococcal disease is 218, and the secondary attack rate for that disease is 10 times lower than the secondary attack rate for HUS (4%), Dr. Dirk Werber and his associates reported (Clin. Infect. Dis. 2008;46:1189–96).

In an editorial comment accompanying this report, Dr. Christina K. Ahn and her associates said that if these findings are confirmed in further studies, “we should carefully consider the compelling empirical data from Werber et al. in favor of the commonsense practice of quarantine … of all patients with plausible or definite E. coli O157:H7 infection during acute illness.”

Dr. Werber of the National Public Health Service of Wales, Cardiff, and his associates observed that in a 2005 outbreak of E. coli O157 infection primarily involving Welsh children who ate tainted meat in school meals, the source of infection was rapidly identified and removed. Yet many secondary infections occurred among household contacts of infected children.

Because the prevention of household transmission of this infection has not yet been investigated, the researchers conducted a retrospective cohort study to assess whether the immediate isolation of primary case patients would have prevented transmission.

There were 89 primary case patients in the study. All 25 cases of secondary infection developed in family members of the primary cases, the majority of them in younger siblings. HUS developed in four of these siblings, one of whom died.

A risk analysis showed that the presence of a sibling and young age (younger than 5 years) in the primary case patient were independent predictors that a secondary case would develop. Children aged 5–10 years also were liable to transmit the infection to family members.

Complete information was available for only 15 secondary cases. Seven of these were deemed to have been preventable, if the primary case patient had been isolated when diagnosed. All four secondary cases in which HUS developed were among these preventable cases.

Dr. Werber and his associates estimated that in future outbreaks, the isolation of all primary case patients as soon as they are diagnosed would cut the rate of secondary cases by half. And in at-risk households, only 47 primary cases patients would need to be quarantined to prevent one case of HUS from developing in a family member.

The researchers added that hospitalizing these patients would be the easiest and most effective means of isolating them. A substantial portion of patients with E. coli O157 (20% in this outbreak) will require hospitalization anyway, and quicker access to IV fluids may mitigate the risk of HUS.

In their editorial comment, Dr. Ahn and her associates agreed that hospitalization is the best method of quarantine because medical professionals are better able to manage infection control than are parents (Clin. Infect. Dis. 2008;46:1197–9).

“It is unreasonable to expect families to implement measures that even begin to approximate [a hospital's] hygienic standards at home. … [Also,] caregiver fatigue must be considered, because infected children are often awake for much of the night, because they are in pain. Exhausted parents might be less able to adhere to sanitary practice,” Dr. Ahn and her associates said.

Moreover, preventing even one case of secondary infection leading to HUS “justifies hospitalizing many additional infected children while they are acutely ill. … The vascular injury that presumably precedes and leads to renal injury following E. coli O157:H7 infection is already well underway by the time such patients present for medical attention,” they added.

The immediate isolation of children with acute Escherichia coli O157 infection could potentially decrease the number of secondary cases by half, according to results of a retrospective study of 89 primary cases in a 2005 outbreak.

In particular, the researchers estimated that by quarantining patients who are at the highest risk of transmitting the infection (those aged 10 years and younger who have a sibling), the number needed to be isolated to prevent one case of life-threatening hemolytic uremic syndrome (HUS) is only 47.

In comparison, the number of household contacts needed to be treated with prophylaxis to prevent one secondary case of meningococcal disease is 218, and the secondary attack rate for that disease is 10 times lower than the secondary attack rate for HUS (4%), Dr. Dirk Werber and his associates reported (Clin. Infect. Dis. 2008;46:1189–96).

In an editorial comment accompanying this report, Dr. Christina K. Ahn and her associates said that if these findings are confirmed in further studies, “we should carefully consider the compelling empirical data from Werber et al. in favor of the commonsense practice of quarantine … of all patients with plausible or definite E. coli O157:H7 infection during acute illness.”

Dr. Werber of the National Public Health Service of Wales, Cardiff, and his associates observed that in a 2005 outbreak of E. coli O157 infection primarily involving Welsh children who ate tainted meat in school meals, the source of infection was rapidly identified and removed. Yet many secondary infections occurred among household contacts of infected children.

Because the prevention of household transmission of this infection has not yet been investigated, the researchers conducted a retrospective cohort study to assess whether the immediate isolation of primary case patients would have prevented transmission.

There were 89 primary case patients in the study. All 25 cases of secondary infection developed in family members of the primary cases, the majority of them in younger siblings. HUS developed in four of these siblings, one of whom died.

A risk analysis showed that the presence of a sibling and young age (younger than 5 years) in the primary case patient were independent predictors that a secondary case would develop. Children aged 5–10 years also were liable to transmit the infection to family members.

Complete information was available for only 15 secondary cases. Seven of these were deemed to have been preventable, if the primary case patient had been isolated when diagnosed. All four secondary cases in which HUS developed were among these preventable cases.

Dr. Werber and his associates estimated that in future outbreaks, the isolation of all primary case patients as soon as they are diagnosed would cut the rate of secondary cases by half. And in at-risk households, only 47 primary cases patients would need to be quarantined to prevent one case of HUS from developing in a family member.

The researchers added that hospitalizing these patients would be the easiest and most effective means of isolating them. A substantial portion of patients with E. coli O157 (20% in this outbreak) will require hospitalization anyway, and quicker access to IV fluids may mitigate the risk of HUS.

In their editorial comment, Dr. Ahn and her associates agreed that hospitalization is the best method of quarantine because medical professionals are better able to manage infection control than are parents (Clin. Infect. Dis. 2008;46:1197–9).

“It is unreasonable to expect families to implement measures that even begin to approximate [a hospital's] hygienic standards at home. … [Also,] caregiver fatigue must be considered, because infected children are often awake for much of the night, because they are in pain. Exhausted parents might be less able to adhere to sanitary practice,” Dr. Ahn and her associates said.

Moreover, preventing even one case of secondary infection leading to HUS “justifies hospitalizing many additional infected children while they are acutely ill. … The vascular injury that presumably precedes and leads to renal injury following E. coli O157:H7 infection is already well underway by the time such patients present for medical attention,” they added.

The immediate isolation of children with acute Escherichia coli O157 infection could potentially decrease the number of secondary cases by half, according to results of a retrospective study of 89 primary cases in a 2005 outbreak.

In particular, the researchers estimated that by quarantining patients who are at the highest risk of transmitting the infection (those aged 10 years and younger who have a sibling), the number needed to be isolated to prevent one case of life-threatening hemolytic uremic syndrome (HUS) is only 47.

In comparison, the number of household contacts needed to be treated with prophylaxis to prevent one secondary case of meningococcal disease is 218, and the secondary attack rate for that disease is 10 times lower than the secondary attack rate for HUS (4%), Dr. Dirk Werber and his associates reported (Clin. Infect. Dis. 2008;46:1189–96).

In an editorial comment accompanying this report, Dr. Christina K. Ahn and her associates said that if these findings are confirmed in further studies, “we should carefully consider the compelling empirical data from Werber et al. in favor of the commonsense practice of quarantine … of all patients with plausible or definite E. coli O157:H7 infection during acute illness.”

Dr. Werber of the National Public Health Service of Wales, Cardiff, and his associates observed that in a 2005 outbreak of E. coli O157 infection primarily involving Welsh children who ate tainted meat in school meals, the source of infection was rapidly identified and removed. Yet many secondary infections occurred among household contacts of infected children.

Because the prevention of household transmission of this infection has not yet been investigated, the researchers conducted a retrospective cohort study to assess whether the immediate isolation of primary case patients would have prevented transmission.

There were 89 primary case patients in the study. All 25 cases of secondary infection developed in family members of the primary cases, the majority of them in younger siblings. HUS developed in four of these siblings, one of whom died.

A risk analysis showed that the presence of a sibling and young age (younger than 5 years) in the primary case patient were independent predictors that a secondary case would develop. Children aged 5–10 years also were liable to transmit the infection to family members.

Complete information was available for only 15 secondary cases. Seven of these were deemed to have been preventable, if the primary case patient had been isolated when diagnosed. All four secondary cases in which HUS developed were among these preventable cases.

Dr. Werber and his associates estimated that in future outbreaks, the isolation of all primary case patients as soon as they are diagnosed would cut the rate of secondary cases by half. And in at-risk households, only 47 primary cases patients would need to be quarantined to prevent one case of HUS from developing in a family member.

The researchers added that hospitalizing these patients would be the easiest and most effective means of isolating them. A substantial portion of patients with E. coli O157 (20% in this outbreak) will require hospitalization anyway, and quicker access to IV fluids may mitigate the risk of HUS.

In their editorial comment, Dr. Ahn and her associates agreed that hospitalization is the best method of quarantine because medical professionals are better able to manage infection control than are parents (Clin. Infect. Dis. 2008;46:1197–9).

“It is unreasonable to expect families to implement measures that even begin to approximate [a hospital's] hygienic standards at home. … [Also,] caregiver fatigue must be considered, because infected children are often awake for much of the night, because they are in pain. Exhausted parents might be less able to adhere to sanitary practice,” Dr. Ahn and her associates said.

Moreover, preventing even one case of secondary infection leading to HUS “justifies hospitalizing many additional infected children while they are acutely ill. … The vascular injury that presumably precedes and leads to renal injury following E. coli O157:H7 infection is already well underway by the time such patients present for medical attention,” they added.

Sleep duration of less than 12 hours per day during infancy may predict childhood overweight, researchers reported.

In a prospective study of 915 mother-child pairs, sleep curtailment at age 6 months to 2 years doubled the odds that, at age 3 years, a child would show increased adiposity, as measured by both body mass index and skinfold thickness, according to Dr. Elsie M. Taveras and her associates at Harvard Medical School, Boston.

They described this study as the first to report a link between infant sleep duration and childhood overweight. The findings are consistent with data from previous studies involving older children and adolescents, they noted.

They analyzed data from a cohort study of gestational factors and offspring health in Massachusetts residents. The children's sleep duration was assessed at ages 6 months, 1 year, and 2 years. Adiposity was assessed at age 3 years, at which time 9% of the children were overweight (defined as a BMI for age and sex at the 95th percentile or greater).

In the first analysis of the data, “[we] observed an approximately twofold higher prevalence of overweight in children who slept less than 12 hours in a 24-hour period.” But short sleep duration was also associated with having a single parent, lower household income, lower maternal education status, nonwhite ethnicity, and longer durations of television viewing.

Further analysis adjusted for these potentially confounding factors, as well as for maternal BMI and smoking status, and for infant birth weight and activity level, but the association changed only minimally after the adjustments.

The combination of short sleep duration and extended durations (2 hours or more per day) of television viewing appeared to be synergistic and “was associated with markedly higher” adiposity, the investigators said (Arch. Ped. Adolesc. Med. 2008;162:305–11).

The mechanism by which infant sleep curtailment affects later adiposity is not yet clear. In adults, sleep restriction can reduce leptin levels and elevate ghrelin levels, both of which are likely to increase appetite.

Increased time awake also allows more time for eating. And it may increase daytime sleepiness, which in turn may reduce physical activity and promote overweight, the authors wrote.

ELSEVIER GLOBAL MEDICAL NEWS

Sleep duration of less than 12 hours per day during infancy may predict childhood overweight, researchers reported.

In a prospective study of 915 mother-child pairs, sleep curtailment at age 6 months to 2 years doubled the odds that, at age 3 years, a child would show increased adiposity, as measured by both body mass index and skinfold thickness, according to Dr. Elsie M. Taveras and her associates at Harvard Medical School, Boston.

They described this study as the first to report a link between infant sleep duration and childhood overweight. The findings are consistent with data from previous studies involving older children and adolescents, they noted.

They analyzed data from a cohort study of gestational factors and offspring health in Massachusetts residents. The children's sleep duration was assessed at ages 6 months, 1 year, and 2 years. Adiposity was assessed at age 3 years, at which time 9% of the children were overweight (defined as a BMI for age and sex at the 95th percentile or greater).

In the first analysis of the data, “[we] observed an approximately twofold higher prevalence of overweight in children who slept less than 12 hours in a 24-hour period.” But short sleep duration was also associated with having a single parent, lower household income, lower maternal education status, nonwhite ethnicity, and longer durations of television viewing.

Further analysis adjusted for these potentially confounding factors, as well as for maternal BMI and smoking status, and for infant birth weight and activity level, but the association changed only minimally after the adjustments.

The combination of short sleep duration and extended durations (2 hours or more per day) of television viewing appeared to be synergistic and “was associated with markedly higher” adiposity, the investigators said (Arch. Ped. Adolesc. Med. 2008;162:305–11).

The mechanism by which infant sleep curtailment affects later adiposity is not yet clear. In adults, sleep restriction can reduce leptin levels and elevate ghrelin levels, both of which are likely to increase appetite.

Increased time awake also allows more time for eating. And it may increase daytime sleepiness, which in turn may reduce physical activity and promote overweight, the authors wrote.

ELSEVIER GLOBAL MEDICAL NEWS

Sleep duration of less than 12 hours per day during infancy may predict childhood overweight, researchers reported.

In a prospective study of 915 mother-child pairs, sleep curtailment at age 6 months to 2 years doubled the odds that, at age 3 years, a child would show increased adiposity, as measured by both body mass index and skinfold thickness, according to Dr. Elsie M. Taveras and her associates at Harvard Medical School, Boston.

They described this study as the first to report a link between infant sleep duration and childhood overweight. The findings are consistent with data from previous studies involving older children and adolescents, they noted.

They analyzed data from a cohort study of gestational factors and offspring health in Massachusetts residents. The children's sleep duration was assessed at ages 6 months, 1 year, and 2 years. Adiposity was assessed at age 3 years, at which time 9% of the children were overweight (defined as a BMI for age and sex at the 95th percentile or greater).

In the first analysis of the data, “[we] observed an approximately twofold higher prevalence of overweight in children who slept less than 12 hours in a 24-hour period.” But short sleep duration was also associated with having a single parent, lower household income, lower maternal education status, nonwhite ethnicity, and longer durations of television viewing.

Further analysis adjusted for these potentially confounding factors, as well as for maternal BMI and smoking status, and for infant birth weight and activity level, but the association changed only minimally after the adjustments.

The combination of short sleep duration and extended durations (2 hours or more per day) of television viewing appeared to be synergistic and “was associated with markedly higher” adiposity, the investigators said (Arch. Ped. Adolesc. Med. 2008;162:305–11).

The mechanism by which infant sleep curtailment affects later adiposity is not yet clear. In adults, sleep restriction can reduce leptin levels and elevate ghrelin levels, both of which are likely to increase appetite.

Increased time awake also allows more time for eating. And it may increase daytime sleepiness, which in turn may reduce physical activity and promote overweight, the authors wrote.

ELSEVIER GLOBAL MEDICAL NEWS

The use of sigmoidoscopy or colonoscopy to screen for colorectal cancer has increased in recent years, according to Dr. D.A. Joseph and his associates at the Centers for Disease Control and Prevention.

“Although this increase is encouraging, disparities persist in colorectal cancer test use,” they said.

The researchers used data from the Behavioral Risk Factor Surveillance System to compare rates of colorectal cancer testing in 2002, 2004, and 2006. The BRFSS conducts telephone surveys of adults in all 50 states except Hawaii, and sampled between 100,000 and 200,000 adults in the 3 years included in this report.

The proportion of respondents aged 50 years and older who reported that they had undergone “lower endoscopy” within the preceding decade rose from 45% in 2002 to 50% in 2004 and to 56% in 2006.

However, the proportion that reported they had undergone fecal occult blood testing within the preceding year declined during the same period, from 22% in 2002, to 18% in 2004, and to 16% in 2006, the investigators said (MMWR 2008;57:253–8).

Taking these colorectal cancer screens together, there was a net gain in the proportion of people aged 50 and older who underwent some form of screening.

Although the percentages increased for all races, the proportion of whites who underwent screening remained higher than that of all the other races. In addition, the proportions of people who underwent screening also increased with increasing education level and increasing household income.

In an editorial note accompanying this report, the CDC said that several factors might have contributed to the increase in colorectal cancer screening, including Medicare coverage of screening colonoscopy and increased coverage by private insurers.

“Previous studies have documented a greater prevalence of colorectal cancer screening among men than women. Data in this report suggest that the gap in prevalence between men and women is closing,” the CDC said.

The use of sigmoidoscopy or colonoscopy to screen for colorectal cancer has increased in recent years, according to Dr. D.A. Joseph and his associates at the Centers for Disease Control and Prevention.

“Although this increase is encouraging, disparities persist in colorectal cancer test use,” they said.

The researchers used data from the Behavioral Risk Factor Surveillance System to compare rates of colorectal cancer testing in 2002, 2004, and 2006. The BRFSS conducts telephone surveys of adults in all 50 states except Hawaii, and sampled between 100,000 and 200,000 adults in the 3 years included in this report.

The proportion of respondents aged 50 years and older who reported that they had undergone “lower endoscopy” within the preceding decade rose from 45% in 2002 to 50% in 2004 and to 56% in 2006.

However, the proportion that reported they had undergone fecal occult blood testing within the preceding year declined during the same period, from 22% in 2002, to 18% in 2004, and to 16% in 2006, the investigators said (MMWR 2008;57:253–8).

Taking these colorectal cancer screens together, there was a net gain in the proportion of people aged 50 and older who underwent some form of screening.

Although the percentages increased for all races, the proportion of whites who underwent screening remained higher than that of all the other races. In addition, the proportions of people who underwent screening also increased with increasing education level and increasing household income.

In an editorial note accompanying this report, the CDC said that several factors might have contributed to the increase in colorectal cancer screening, including Medicare coverage of screening colonoscopy and increased coverage by private insurers.

“Previous studies have documented a greater prevalence of colorectal cancer screening among men than women. Data in this report suggest that the gap in prevalence between men and women is closing,” the CDC said.

The use of sigmoidoscopy or colonoscopy to screen for colorectal cancer has increased in recent years, according to Dr. D.A. Joseph and his associates at the Centers for Disease Control and Prevention.

“Although this increase is encouraging, disparities persist in colorectal cancer test use,” they said.

The researchers used data from the Behavioral Risk Factor Surveillance System to compare rates of colorectal cancer testing in 2002, 2004, and 2006. The BRFSS conducts telephone surveys of adults in all 50 states except Hawaii, and sampled between 100,000 and 200,000 adults in the 3 years included in this report.

The proportion of respondents aged 50 years and older who reported that they had undergone “lower endoscopy” within the preceding decade rose from 45% in 2002 to 50% in 2004 and to 56% in 2006.

However, the proportion that reported they had undergone fecal occult blood testing within the preceding year declined during the same period, from 22% in 2002, to 18% in 2004, and to 16% in 2006, the investigators said (MMWR 2008;57:253–8).

Taking these colorectal cancer screens together, there was a net gain in the proportion of people aged 50 and older who underwent some form of screening.

Although the percentages increased for all races, the proportion of whites who underwent screening remained higher than that of all the other races. In addition, the proportions of people who underwent screening also increased with increasing education level and increasing household income.

In an editorial note accompanying this report, the CDC said that several factors might have contributed to the increase in colorectal cancer screening, including Medicare coverage of screening colonoscopy and increased coverage by private insurers.

“Previous studies have documented a greater prevalence of colorectal cancer screening among men than women. Data in this report suggest that the gap in prevalence between men and women is closing,” the CDC said.

African Americans who had multiple first-degree relatives with colon cancer were much less likely to undergo the recommended screening colonoscopy than their white counterparts, according to the findings of a large cohort study.

“Physicians and other health care providers need to elicit family history information for all patients and ensure that African Americans with affected relatives appropriately receive colon cancer screening,” concluded Dr. Harvey J. Murff of Vanderbilt University, Nashville, Tenn., and his associates.

The investigators assessed colonoscopy screening rates in the Southern Community Cohort Study, an ongoing prospective observational study of disparities in cancer incidence and mortality across racial and geographic groups treated at 48 community health centers throughout 12 southeastern states. Their assessment included 41,830 subjects aged 40–79 years.

A total of 538 African Americans and 255 whites reported having multiple affected first-degree relatives or at least one first-degree relative diagnosed before age 50, putting them at increased risk for the disease.

Only 34% of these African Americans aged 50 and older reported that they had undergone colonoscopy within the preceding 5 years, compared with 50% of whites. Similarly, 21% of high-risk African Americans in their 40s had undergone colonoscopy, compared with 34% of high-risk whites in that age group.

This racial disparity persisted after the data were adjusted to account for participants' education status, income level, and insurance status, Dr. Murff and his associates said (Arch. Intern. Med. 2008;168:625–31).

For subjects of both races, the most often cited reason for not undergoing colonoscopy was that their health care providers never recommended the procedure. African Americans were much more likely to cite this reason than were whites. “However, it is unlikely that this difference completely explains the [racial] variation in the rate of colonoscopy procedures,” the investigators said.

African Americans who had multiple first-degree relatives with colon cancer were much less likely to undergo the recommended screening colonoscopy than their white counterparts, according to the findings of a large cohort study.

“Physicians and other health care providers need to elicit family history information for all patients and ensure that African Americans with affected relatives appropriately receive colon cancer screening,” concluded Dr. Harvey J. Murff of Vanderbilt University, Nashville, Tenn., and his associates.

The investigators assessed colonoscopy screening rates in the Southern Community Cohort Study, an ongoing prospective observational study of disparities in cancer incidence and mortality across racial and geographic groups treated at 48 community health centers throughout 12 southeastern states. Their assessment included 41,830 subjects aged 40–79 years.

A total of 538 African Americans and 255 whites reported having multiple affected first-degree relatives or at least one first-degree relative diagnosed before age 50, putting them at increased risk for the disease.

Only 34% of these African Americans aged 50 and older reported that they had undergone colonoscopy within the preceding 5 years, compared with 50% of whites. Similarly, 21% of high-risk African Americans in their 40s had undergone colonoscopy, compared with 34% of high-risk whites in that age group.

This racial disparity persisted after the data were adjusted to account for participants' education status, income level, and insurance status, Dr. Murff and his associates said (Arch. Intern. Med. 2008;168:625–31).

For subjects of both races, the most often cited reason for not undergoing colonoscopy was that their health care providers never recommended the procedure. African Americans were much more likely to cite this reason than were whites. “However, it is unlikely that this difference completely explains the [racial] variation in the rate of colonoscopy procedures,” the investigators said.

African Americans who had multiple first-degree relatives with colon cancer were much less likely to undergo the recommended screening colonoscopy than their white counterparts, according to the findings of a large cohort study.

“Physicians and other health care providers need to elicit family history information for all patients and ensure that African Americans with affected relatives appropriately receive colon cancer screening,” concluded Dr. Harvey J. Murff of Vanderbilt University, Nashville, Tenn., and his associates.

The investigators assessed colonoscopy screening rates in the Southern Community Cohort Study, an ongoing prospective observational study of disparities in cancer incidence and mortality across racial and geographic groups treated at 48 community health centers throughout 12 southeastern states. Their assessment included 41,830 subjects aged 40–79 years.

A total of 538 African Americans and 255 whites reported having multiple affected first-degree relatives or at least one first-degree relative diagnosed before age 50, putting them at increased risk for the disease.

Only 34% of these African Americans aged 50 and older reported that they had undergone colonoscopy within the preceding 5 years, compared with 50% of whites. Similarly, 21% of high-risk African Americans in their 40s had undergone colonoscopy, compared with 34% of high-risk whites in that age group.

This racial disparity persisted after the data were adjusted to account for participants' education status, income level, and insurance status, Dr. Murff and his associates said (Arch. Intern. Med. 2008;168:625–31).

For subjects of both races, the most often cited reason for not undergoing colonoscopy was that their health care providers never recommended the procedure. African Americans were much more likely to cite this reason than were whites. “However, it is unlikely that this difference completely explains the [racial] variation in the rate of colonoscopy procedures,” the investigators said.

Certain parental behaviors in response to their toddlers' nighttime awakenings may pave the way for the children to have sleep problems at ages 4–6 years, so these behaviors should be considered maladaptive, according to results from a Canadian study of nearly 1,000 infants and children.

When a child aged 2–3 years awakens in the night, bringing him into the parents' bed, removing him from his own bed to provide comfort, giving him something to eat or drink, or leaving him to “cry it out” all were associated with later sleep difficulties.

Children treated in this way were more likely to have bad dreams, shorter sleep duration, and a harder time falling asleep when they reached 4–6 years of age, Valérie Simard, a psychologist at the University of Montreal, and her associates reported (Arch. Ped. Adoles. Med. 2008;162:360–7).

It appears that some parents first adopt these responses when the children have sleep problems as babies. But what often are adaptive responses during infancy “may later become inappropriate to the child's age and needs,” Ms. Simard and her coauthors said.

They assessed sleep problems using data from a longitudinal study of child development in which 987 Quebec children were evaluated every year from ages 5 months through 6 years.

Most parents (64%) responded to their child's nocturnal awakenings at age 29 months by comforting the child briefly in his or her own bed. But a minority of parents responded by bringing the child into their bed (17%), giving him or her something to eat or drink (8%), or leaving him or her to cry (2%).

Similarly, when children aged 41 months awakened at night, most parents (70%) responded by comforting the child in his or her own bed. But a minority responded by bringing the child into their bed (18%), giving him or her something to eat or drink (5%), or leaving him or her to cry (1%).

These “maladaptive” responses were associated with negative sleep outcomes–bad dreams, shortened sleep duration, and longer sleep-onset latency–when the children reached 4–6 years of age, the investigators said.

Factors such as the mother's feelings of efficacy in parenting, the mother's depressive feelings, and the child's overall level of anxiety were not predictive of sleep outcomes.

The researchers said their findings “suggest that early sleep problems are more predictive of future sleep disturbances than are intervening parental behaviors.” Further, they wrote, “When controlling for early sleep factors, most parental behaviors no longer predict future sleep disturbances or remain predictors only in interaction with prior [sleep-onset] difficulties.

The investigators also found that children deemed to have “a difficult temperament” in infancy and toddlerhood were much more likely to have sleep problems from early in infancy through their sixth year.

This “support[s] the suggestion that difficult temperament is the original context within which sleep disturbances arise,” Ms. Simard and her associates said.

“In fact, the working definition of temperament as a specific pattern of emotive/physiological self-regulation implicating central nervous system activity suggests that sleep difficulties likely are part of the difficult temperament profile,” they added. Future research on this relationship is needed, they said.

The investigators did not report any financial conflicts of interest.

Bringing a child into the parents' bed during a wakeful night may not be best. Stanford W. Carpenter

Certain parental behaviors in response to their toddlers' nighttime awakenings may pave the way for the children to have sleep problems at ages 4–6 years, so these behaviors should be considered maladaptive, according to results from a Canadian study of nearly 1,000 infants and children.

When a child aged 2–3 years awakens in the night, bringing him into the parents' bed, removing him from his own bed to provide comfort, giving him something to eat or drink, or leaving him to “cry it out” all were associated with later sleep difficulties.

Children treated in this way were more likely to have bad dreams, shorter sleep duration, and a harder time falling asleep when they reached 4–6 years of age, Valérie Simard, a psychologist at the University of Montreal, and her associates reported (Arch. Ped. Adoles. Med. 2008;162:360–7).

It appears that some parents first adopt these responses when the children have sleep problems as babies. But what often are adaptive responses during infancy “may later become inappropriate to the child's age and needs,” Ms. Simard and her coauthors said.

They assessed sleep problems using data from a longitudinal study of child development in which 987 Quebec children were evaluated every year from ages 5 months through 6 years.

Most parents (64%) responded to their child's nocturnal awakenings at age 29 months by comforting the child briefly in his or her own bed. But a minority of parents responded by bringing the child into their bed (17%), giving him or her something to eat or drink (8%), or leaving him or her to cry (2%).

Similarly, when children aged 41 months awakened at night, most parents (70%) responded by comforting the child in his or her own bed. But a minority responded by bringing the child into their bed (18%), giving him or her something to eat or drink (5%), or leaving him or her to cry (1%).

These “maladaptive” responses were associated with negative sleep outcomes–bad dreams, shortened sleep duration, and longer sleep-onset latency–when the children reached 4–6 years of age, the investigators said.

Factors such as the mother's feelings of efficacy in parenting, the mother's depressive feelings, and the child's overall level of anxiety were not predictive of sleep outcomes.

The researchers said their findings “suggest that early sleep problems are more predictive of future sleep disturbances than are intervening parental behaviors.” Further, they wrote, “When controlling for early sleep factors, most parental behaviors no longer predict future sleep disturbances or remain predictors only in interaction with prior [sleep-onset] difficulties.

The investigators also found that children deemed to have “a difficult temperament” in infancy and toddlerhood were much more likely to have sleep problems from early in infancy through their sixth year.

This “support[s] the suggestion that difficult temperament is the original context within which sleep disturbances arise,” Ms. Simard and her associates said.

“In fact, the working definition of temperament as a specific pattern of emotive/physiological self-regulation implicating central nervous system activity suggests that sleep difficulties likely are part of the difficult temperament profile,” they added. Future research on this relationship is needed, they said.

The investigators did not report any financial conflicts of interest.

Bringing a child into the parents' bed during a wakeful night may not be best. Stanford W. Carpenter

Certain parental behaviors in response to their toddlers' nighttime awakenings may pave the way for the children to have sleep problems at ages 4–6 years, so these behaviors should be considered maladaptive, according to results from a Canadian study of nearly 1,000 infants and children.

When a child aged 2–3 years awakens in the night, bringing him into the parents' bed, removing him from his own bed to provide comfort, giving him something to eat or drink, or leaving him to “cry it out” all were associated with later sleep difficulties.

Children treated in this way were more likely to have bad dreams, shorter sleep duration, and a harder time falling asleep when they reached 4–6 years of age, Valérie Simard, a psychologist at the University of Montreal, and her associates reported (Arch. Ped. Adoles. Med. 2008;162:360–7).

It appears that some parents first adopt these responses when the children have sleep problems as babies. But what often are adaptive responses during infancy “may later become inappropriate to the child's age and needs,” Ms. Simard and her coauthors said.

They assessed sleep problems using data from a longitudinal study of child development in which 987 Quebec children were evaluated every year from ages 5 months through 6 years.

Most parents (64%) responded to their child's nocturnal awakenings at age 29 months by comforting the child briefly in his or her own bed. But a minority of parents responded by bringing the child into their bed (17%), giving him or her something to eat or drink (8%), or leaving him or her to cry (2%).

Similarly, when children aged 41 months awakened at night, most parents (70%) responded by comforting the child in his or her own bed. But a minority responded by bringing the child into their bed (18%), giving him or her something to eat or drink (5%), or leaving him or her to cry (1%).

These “maladaptive” responses were associated with negative sleep outcomes–bad dreams, shortened sleep duration, and longer sleep-onset latency–when the children reached 4–6 years of age, the investigators said.

Factors such as the mother's feelings of efficacy in parenting, the mother's depressive feelings, and the child's overall level of anxiety were not predictive of sleep outcomes.

The researchers said their findings “suggest that early sleep problems are more predictive of future sleep disturbances than are intervening parental behaviors.” Further, they wrote, “When controlling for early sleep factors, most parental behaviors no longer predict future sleep disturbances or remain predictors only in interaction with prior [sleep-onset] difficulties.

The investigators also found that children deemed to have “a difficult temperament” in infancy and toddlerhood were much more likely to have sleep problems from early in infancy through their sixth year.

This “support[s] the suggestion that difficult temperament is the original context within which sleep disturbances arise,” Ms. Simard and her associates said.

“In fact, the working definition of temperament as a specific pattern of emotive/physiological self-regulation implicating central nervous system activity suggests that sleep difficulties likely are part of the difficult temperament profile,” they added. Future research on this relationship is needed, they said.

The investigators did not report any financial conflicts of interest.

Bringing a child into the parents' bed during a wakeful night may not be best. Stanford W. Carpenter

Variants in the LRP5 gene are associated with both bone mineral density and fracture risk, researchers reported in JAMA.

Two LRP5 variants were found to have “modest” effects that were very consistent across different populations and independent of subject sex or age. Based on these findings, carriers of these polymorphisms may have a fracture risk that is 15%–20% higher than that for noncarriers, wrote Joyce van Meurs, Ph.D., of Erasmus Medical Center, Rotterdam, the Netherlands, and her associates in the Genetic Markers for Osteoporosis (GENOMOS) consortium.

The study involved 37,534 subjects who underwent genotyping and assessment of bone mineral density. A total of 8,932 subjects had fractures, including 2,146 vertebral fractures (JAMA 2008;299:1277–90).

Members of the GENOMOS consortium—18 research teams in Europe and North America—performed prospective genotyping for several polymorphisms of the LRP5 gene that are thought to be related to osteoporosis. “Some scattered studies have tested this association, but results have not been conclusive due to limited sample size,” the researchers wrote.

“The current collaborative study has the potential to answer this question more definitively because of its large sample size and therefore large power to observe the expected modest associations,” Dr. van Meurs and her associates explained.

“Although any single marker explains only a small portion of the phenotype risk, identification of several such osteoporosis risk variants may eventually help in improving clinical prediction,” they wrote. “Single genetic risk variants may also offer useful insights about mechanisms and pathways that may be useful in drug development.”

The investigators cautioned that their results may not apply to Asian or African populations, since the study subjects were predominantly whites of European descent.

Variants in the LRP5 gene are associated with both bone mineral density and fracture risk, researchers reported in JAMA.

Two LRP5 variants were found to have “modest” effects that were very consistent across different populations and independent of subject sex or age. Based on these findings, carriers of these polymorphisms may have a fracture risk that is 15%–20% higher than that for noncarriers, wrote Joyce van Meurs, Ph.D., of Erasmus Medical Center, Rotterdam, the Netherlands, and her associates in the Genetic Markers for Osteoporosis (GENOMOS) consortium.

The study involved 37,534 subjects who underwent genotyping and assessment of bone mineral density. A total of 8,932 subjects had fractures, including 2,146 vertebral fractures (JAMA 2008;299:1277–90).

Members of the GENOMOS consortium—18 research teams in Europe and North America—performed prospective genotyping for several polymorphisms of the LRP5 gene that are thought to be related to osteoporosis. “Some scattered studies have tested this association, but results have not been conclusive due to limited sample size,” the researchers wrote.

“The current collaborative study has the potential to answer this question more definitively because of its large sample size and therefore large power to observe the expected modest associations,” Dr. van Meurs and her associates explained.

“Although any single marker explains only a small portion of the phenotype risk, identification of several such osteoporosis risk variants may eventually help in improving clinical prediction,” they wrote. “Single genetic risk variants may also offer useful insights about mechanisms and pathways that may be useful in drug development.”

The investigators cautioned that their results may not apply to Asian or African populations, since the study subjects were predominantly whites of European descent.

Variants in the LRP5 gene are associated with both bone mineral density and fracture risk, researchers reported in JAMA.

Two LRP5 variants were found to have “modest” effects that were very consistent across different populations and independent of subject sex or age. Based on these findings, carriers of these polymorphisms may have a fracture risk that is 15%–20% higher than that for noncarriers, wrote Joyce van Meurs, Ph.D., of Erasmus Medical Center, Rotterdam, the Netherlands, and her associates in the Genetic Markers for Osteoporosis (GENOMOS) consortium.

The study involved 37,534 subjects who underwent genotyping and assessment of bone mineral density. A total of 8,932 subjects had fractures, including 2,146 vertebral fractures (JAMA 2008;299:1277–90).

Members of the GENOMOS consortium—18 research teams in Europe and North America—performed prospective genotyping for several polymorphisms of the LRP5 gene that are thought to be related to osteoporosis. “Some scattered studies have tested this association, but results have not been conclusive due to limited sample size,” the researchers wrote.

“The current collaborative study has the potential to answer this question more definitively because of its large sample size and therefore large power to observe the expected modest associations,” Dr. van Meurs and her associates explained.

“Although any single marker explains only a small portion of the phenotype risk, identification of several such osteoporosis risk variants may eventually help in improving clinical prediction,” they wrote. “Single genetic risk variants may also offer useful insights about mechanisms and pathways that may be useful in drug development.”

The investigators cautioned that their results may not apply to Asian or African populations, since the study subjects were predominantly whites of European descent.

Imiquimod cream, a topical immune-response modifier, cleared vulvar intraepithelial neoplasia lesions and eliminated human papillomavirus DNA expression in a small randomized trial comparing it with placebo.

“As a convenient, self-administered treatment, imiquimod is well tolerated, is less invasive than surgery, relieves itching and pain, and does not influence health-related quality of life, body image, or sexuality. Therefore, we consider imiquimod the first-choice treatment for vulvar intraepithelial neoplasia,” said Dr. Manon van Seters of Erasmus University Medical Center, Rotterdam, the Netherlands, and her associates.

The agent has previously been reported as efficacious against vulvar intraepithelial neoplasia (VIN), but “only in small, uncontrolled studies.”

Dr. van Seters and her associates conducted a double-blind, placebo-controlled clinical trial in 52 women with multifocal, grade 2 or 3 VIN. The subjects had had the condition for a mean of 5 years, and many had undergone repeated surgeries.

The women were randomly assigned to receive 250 mg of imiquimod 5% or a placebo cream, and were instructed to apply a thin layer to their lesions twice a week for 16 weeks. The cream remained in place overnight, uncovered. Subjects also were advised to use sulfur precipitate in 5% zinc oxide ointment the day after using the cream, to avoid superinfection.

The women recorded adverse effects in a diary and were evaluated every 4 weeks for symptoms and side effects. They underwent pretreatment and posttreatment biopsy of lesions, as well as long-term assessments at 7 months and 12 months after entering the trial.

At 20 weeks, lesion size was reduced by more than 25% in 21 of 26 patients using imiquimod (81%) but in none of the patients using placebo cream. Nine of the women in the imiquimod group had complete clearance of lesions, and they remained free of disease at 1-year follow-up. Another five women had a “strong partial” response, with reductions of 75% in lesion size, at 20 weeks.

In 18 of the 26 women using imiquimod (69%), biopsies showed histologic regression from grade 2 or 3, compared with one woman who used placebo cream (4%).

At baseline, 25 patients in each group had lesions that were positive for HPV DNA. After treatment, HPV was no longer detected in 15 of those who had received imiquimod (58%), compared with 2 of those who had received placebo (8%).

Compared with placebo, imiquimod reduced pruritus and pain at 20 weeks, a difference that persisted through 1-year follow-up. There were no differences between the two groups in health-related quality of life, body image, or sexuality, the investigators said (N. Engl. J. Med. 2008;358:1465–73).

The drug's exact mechanism of action is not yet known, nor was it evident why some patients responded better to treatment than did others, Dr. van Seters and her associates added.

Imiquimod cream, a topical immune-response modifier, cleared vulvar intraepithelial neoplasia lesions and eliminated human papillomavirus DNA expression in a small randomized trial comparing it with placebo.

“As a convenient, self-administered treatment, imiquimod is well tolerated, is less invasive than surgery, relieves itching and pain, and does not influence health-related quality of life, body image, or sexuality. Therefore, we consider imiquimod the first-choice treatment for vulvar intraepithelial neoplasia,” said Dr. Manon van Seters of Erasmus University Medical Center, Rotterdam, the Netherlands, and her associates.

The agent has previously been reported as efficacious against vulvar intraepithelial neoplasia (VIN), but “only in small, uncontrolled studies.”

Dr. van Seters and her associates conducted a double-blind, placebo-controlled clinical trial in 52 women with multifocal, grade 2 or 3 VIN. The subjects had had the condition for a mean of 5 years, and many had undergone repeated surgeries.

The women were randomly assigned to receive 250 mg of imiquimod 5% or a placebo cream, and were instructed to apply a thin layer to their lesions twice a week for 16 weeks. The cream remained in place overnight, uncovered. Subjects also were advised to use sulfur precipitate in 5% zinc oxide ointment the day after using the cream, to avoid superinfection.

The women recorded adverse effects in a diary and were evaluated every 4 weeks for symptoms and side effects. They underwent pretreatment and posttreatment biopsy of lesions, as well as long-term assessments at 7 months and 12 months after entering the trial.

At 20 weeks, lesion size was reduced by more than 25% in 21 of 26 patients using imiquimod (81%) but in none of the patients using placebo cream. Nine of the women in the imiquimod group had complete clearance of lesions, and they remained free of disease at 1-year follow-up. Another five women had a “strong partial” response, with reductions of 75% in lesion size, at 20 weeks.

In 18 of the 26 women using imiquimod (69%), biopsies showed histologic regression from grade 2 or 3, compared with one woman who used placebo cream (4%).

At baseline, 25 patients in each group had lesions that were positive for HPV DNA. After treatment, HPV was no longer detected in 15 of those who had received imiquimod (58%), compared with 2 of those who had received placebo (8%).

Compared with placebo, imiquimod reduced pruritus and pain at 20 weeks, a difference that persisted through 1-year follow-up. There were no differences between the two groups in health-related quality of life, body image, or sexuality, the investigators said (N. Engl. J. Med. 2008;358:1465–73).

The drug's exact mechanism of action is not yet known, nor was it evident why some patients responded better to treatment than did others, Dr. van Seters and her associates added.

Imiquimod cream, a topical immune-response modifier, cleared vulvar intraepithelial neoplasia lesions and eliminated human papillomavirus DNA expression in a small randomized trial comparing it with placebo.

“As a convenient, self-administered treatment, imiquimod is well tolerated, is less invasive than surgery, relieves itching and pain, and does not influence health-related quality of life, body image, or sexuality. Therefore, we consider imiquimod the first-choice treatment for vulvar intraepithelial neoplasia,” said Dr. Manon van Seters of Erasmus University Medical Center, Rotterdam, the Netherlands, and her associates.

The agent has previously been reported as efficacious against vulvar intraepithelial neoplasia (VIN), but “only in small, uncontrolled studies.”

Dr. van Seters and her associates conducted a double-blind, placebo-controlled clinical trial in 52 women with multifocal, grade 2 or 3 VIN. The subjects had had the condition for a mean of 5 years, and many had undergone repeated surgeries.

The women were randomly assigned to receive 250 mg of imiquimod 5% or a placebo cream, and were instructed to apply a thin layer to their lesions twice a week for 16 weeks. The cream remained in place overnight, uncovered. Subjects also were advised to use sulfur precipitate in 5% zinc oxide ointment the day after using the cream, to avoid superinfection.

The women recorded adverse effects in a diary and were evaluated every 4 weeks for symptoms and side effects. They underwent pretreatment and posttreatment biopsy of lesions, as well as long-term assessments at 7 months and 12 months after entering the trial.

At 20 weeks, lesion size was reduced by more than 25% in 21 of 26 patients using imiquimod (81%) but in none of the patients using placebo cream. Nine of the women in the imiquimod group had complete clearance of lesions, and they remained free of disease at 1-year follow-up. Another five women had a “strong partial” response, with reductions of 75% in lesion size, at 20 weeks.

In 18 of the 26 women using imiquimod (69%), biopsies showed histologic regression from grade 2 or 3, compared with one woman who used placebo cream (4%).

At baseline, 25 patients in each group had lesions that were positive for HPV DNA. After treatment, HPV was no longer detected in 15 of those who had received imiquimod (58%), compared with 2 of those who had received placebo (8%).

Compared with placebo, imiquimod reduced pruritus and pain at 20 weeks, a difference that persisted through 1-year follow-up. There were no differences between the two groups in health-related quality of life, body image, or sexuality, the investigators said (N. Engl. J. Med. 2008;358:1465–73).

The drug's exact mechanism of action is not yet known, nor was it evident why some patients responded better to treatment than did others, Dr. van Seters and her associates added.

In the 3 years after the Women's Health Initiative clinical trial was halted early, risks and benefits related to hormone therapy changed rapidly among the subjects who stopped taking the medication, investigators with the long-term trial reported in JAMA.

Despite these alterations, the overall assessment of health risks and benefits associated with combined HT (conjugated equine estrogens plus medroxyprogesterone acetate) “continues to be weighted toward risk,” said Dr. Gerardo Heiss of the University of North Carolina, Chapel Hill, and his associates in the Women's Health Initiative (WHI) study (JAMA 2008;299:1036–45).

But according to representatives of Wyeth Pharmaceuticals who spoke during a company-sponsored March 4 press teleconference, the study does not reflect the current, much lower HT dosages doctors are recommending for typical HT users, who are younger, newly menopausal women. Wyeth manufactures Prempro, the combination HT product used in the WHI study.

“This isn't how we practice today; we've decreased dosages; we are using the lowest effective dose,” said Dr. Hugh S. Taylor, an associate chief for research at the Center for Research in Reproductive Biology at Yale University, New Haven, Conn.

Dr. Gary Stiles, executive vice president and chief medical officer for Wyeth Pharmaceuticals, said the company continues to encourage doctors to provide lower dosages of HT drugs for the shortest time possible.

Describing the findings as an “ad hoc analysis without providing the full context,” Dr. Stiles said today's patients, in comparison to those in the study, were “more than a decade” younger than the study participants, who had a mean age of 63 years at baseline.

The portion of the WHI trial that dealt with combined hormone therapy (HT) was stopped in 2002 at a mean of 5.6 years of follow-up because an interim analysis showed the therapy increased the risk of invasive breast cancer and failed to yield any overall health benefit.

Analysis of the results accumulated to that date showed that women who took HT (0.625 mg of conjugated equine estrogens and 2.5 mg of medroxyprogesterone acetate daily) for menopausal symptoms also had higher risks of cardiovascular disease, coronary heart disease, stroke, and venous thromboembolism, along with lower risks of fracture and of colorectal cancer, compared with women who did not take HT.

Most of the subjects continued to be followed through the planned 8-year duration of the WHI. Results are now available on 15,730 of these women for a further 2.4 years of follow-up after the HT intervention was stopped (see bar chart).

The increased risk of cardiovascular disease-related events noted in the interim analysis did not persist after stopping HT, and the risk of deep vein thrombosis and pulmonary embolism also “disappeared,” the investigators said.

In contrast, the risk of all malignancies increased. This was attributed to a rise in the rate of cancers other than breast and colorectal malignancies, primarily lung cancers.

The increased risk of breast cancer noted at the interim analysis did not persist after discontinuing HT. But at the same time, the decreased risk of colorectal cancer also did not persist after discontinuing HT.

HT's protective effect against fractures also dissipated after the treatment was discontinued. Women who had taken and then stopped HT showed the same risk of hip, vertebral, and other osteoporotic fractures as did women who had taken placebo.

In reference to the risks and benefits reported in the study, Dr. Taylor said the differences between the HT and placebo groups were not statistically significant. He added that the study did not show “important” age breakdown information nor did it distinguish the difference between the effects of combination HT and estrogen-only therapies.

During the intervention phase of the WHI, all-cause mortality was virtually identical between subjects taking HT and those taking placebo. In contrast, during the postintervention phase, mortality was 15% higher among women who had taken and then discontinued HT. Although this difference did not reach statistical significance because of the small number of deaths in the study, it suggests that all-cause mortality did increase after HT, the researchers said.

Overall, the findings show that the risks of HT continue to outweigh benefits. “The global index of risk versus benefit remained essentially unchanged in the postintervention period, maintaining a nominally significant overall 12% increase from baseline” through extended follow-up in the women who had taken HT, Dr. Heiss and his associates said.

The results also indicate that maintaining clinical vigilance for malignancies, particularly lung cancer, is warranted in women who have taken HT, they added.

Dr. Taylor disclosed that he receives honoraria for speaking engagements but was not compensated for speaking at Wyeth's teleconference.

Associate editor Lorinda Bullock contributed to this article.

ELSEVIER GLOBAL MEDICAL NEWS

In the 3 years after the Women's Health Initiative clinical trial was halted early, risks and benefits related to hormone therapy changed rapidly among the subjects who stopped taking the medication, investigators with the long-term trial reported in JAMA.

Despite these alterations, the overall assessment of health risks and benefits associated with combined HT (conjugated equine estrogens plus medroxyprogesterone acetate) “continues to be weighted toward risk,” said Dr. Gerardo Heiss of the University of North Carolina, Chapel Hill, and his associates in the Women's Health Initiative (WHI) study (JAMA 2008;299:1036–45).

But according to representatives of Wyeth Pharmaceuticals who spoke during a company-sponsored March 4 press teleconference, the study does not reflect the current, much lower HT dosages doctors are recommending for typical HT users, who are younger, newly menopausal women. Wyeth manufactures Prempro, the combination HT product used in the WHI study.

“This isn't how we practice today; we've decreased dosages; we are using the lowest effective dose,” said Dr. Hugh S. Taylor, an associate chief for research at the Center for Research in Reproductive Biology at Yale University, New Haven, Conn.

Dr. Gary Stiles, executive vice president and chief medical officer for Wyeth Pharmaceuticals, said the company continues to encourage doctors to provide lower dosages of HT drugs for the shortest time possible.

Describing the findings as an “ad hoc analysis without providing the full context,” Dr. Stiles said today's patients, in comparison to those in the study, were “more than a decade” younger than the study participants, who had a mean age of 63 years at baseline.

The portion of the WHI trial that dealt with combined hormone therapy (HT) was stopped in 2002 at a mean of 5.6 years of follow-up because an interim analysis showed the therapy increased the risk of invasive breast cancer and failed to yield any overall health benefit.

Analysis of the results accumulated to that date showed that women who took HT (0.625 mg of conjugated equine estrogens and 2.5 mg of medroxyprogesterone acetate daily) for menopausal symptoms also had higher risks of cardiovascular disease, coronary heart disease, stroke, and venous thromboembolism, along with lower risks of fracture and of colorectal cancer, compared with women who did not take HT.

Most of the subjects continued to be followed through the planned 8-year duration of the WHI. Results are now available on 15,730 of these women for a further 2.4 years of follow-up after the HT intervention was stopped (see bar chart).

The increased risk of cardiovascular disease-related events noted in the interim analysis did not persist after stopping HT, and the risk of deep vein thrombosis and pulmonary embolism also “disappeared,” the investigators said.

In contrast, the risk of all malignancies increased. This was attributed to a rise in the rate of cancers other than breast and colorectal malignancies, primarily lung cancers.

The increased risk of breast cancer noted at the interim analysis did not persist after discontinuing HT. But at the same time, the decreased risk of colorectal cancer also did not persist after discontinuing HT.

HT's protective effect against fractures also dissipated after the treatment was discontinued. Women who had taken and then stopped HT showed the same risk of hip, vertebral, and other osteoporotic fractures as did women who had taken placebo.

In reference to the risks and benefits reported in the study, Dr. Taylor said the differences between the HT and placebo groups were not statistically significant. He added that the study did not show “important” age breakdown information nor did it distinguish the difference between the effects of combination HT and estrogen-only therapies.

During the intervention phase of the WHI, all-cause mortality was virtually identical between subjects taking HT and those taking placebo. In contrast, during the postintervention phase, mortality was 15% higher among women who had taken and then discontinued HT. Although this difference did not reach statistical significance because of the small number of deaths in the study, it suggests that all-cause mortality did increase after HT, the researchers said.

Overall, the findings show that the risks of HT continue to outweigh benefits. “The global index of risk versus benefit remained essentially unchanged in the postintervention period, maintaining a nominally significant overall 12% increase from baseline” through extended follow-up in the women who had taken HT, Dr. Heiss and his associates said.

The results also indicate that maintaining clinical vigilance for malignancies, particularly lung cancer, is warranted in women who have taken HT, they added.

Dr. Taylor disclosed that he receives honoraria for speaking engagements but was not compensated for speaking at Wyeth's teleconference.

Associate editor Lorinda Bullock contributed to this article.

ELSEVIER GLOBAL MEDICAL NEWS

In the 3 years after the Women's Health Initiative clinical trial was halted early, risks and benefits related to hormone therapy changed rapidly among the subjects who stopped taking the medication, investigators with the long-term trial reported in JAMA.

Despite these alterations, the overall assessment of health risks and benefits associated with combined HT (conjugated equine estrogens plus medroxyprogesterone acetate) “continues to be weighted toward risk,” said Dr. Gerardo Heiss of the University of North Carolina, Chapel Hill, and his associates in the Women's Health Initiative (WHI) study (JAMA 2008;299:1036–45).

But according to representatives of Wyeth Pharmaceuticals who spoke during a company-sponsored March 4 press teleconference, the study does not reflect the current, much lower HT dosages doctors are recommending for typical HT users, who are younger, newly menopausal women. Wyeth manufactures Prempro, the combination HT product used in the WHI study.

“This isn't how we practice today; we've decreased dosages; we are using the lowest effective dose,” said Dr. Hugh S. Taylor, an associate chief for research at the Center for Research in Reproductive Biology at Yale University, New Haven, Conn.

Dr. Gary Stiles, executive vice president and chief medical officer for Wyeth Pharmaceuticals, said the company continues to encourage doctors to provide lower dosages of HT drugs for the shortest time possible.

Describing the findings as an “ad hoc analysis without providing the full context,” Dr. Stiles said today's patients, in comparison to those in the study, were “more than a decade” younger than the study participants, who had a mean age of 63 years at baseline.

The portion of the WHI trial that dealt with combined hormone therapy (HT) was stopped in 2002 at a mean of 5.6 years of follow-up because an interim analysis showed the therapy increased the risk of invasive breast cancer and failed to yield any overall health benefit.

Analysis of the results accumulated to that date showed that women who took HT (0.625 mg of conjugated equine estrogens and 2.5 mg of medroxyprogesterone acetate daily) for menopausal symptoms also had higher risks of cardiovascular disease, coronary heart disease, stroke, and venous thromboembolism, along with lower risks of fracture and of colorectal cancer, compared with women who did not take HT.

Most of the subjects continued to be followed through the planned 8-year duration of the WHI. Results are now available on 15,730 of these women for a further 2.4 years of follow-up after the HT intervention was stopped (see bar chart).

The increased risk of cardiovascular disease-related events noted in the interim analysis did not persist after stopping HT, and the risk of deep vein thrombosis and pulmonary embolism also “disappeared,” the investigators said.

In contrast, the risk of all malignancies increased. This was attributed to a rise in the rate of cancers other than breast and colorectal malignancies, primarily lung cancers.

The increased risk of breast cancer noted at the interim analysis did not persist after discontinuing HT. But at the same time, the decreased risk of colorectal cancer also did not persist after discontinuing HT.

HT's protective effect against fractures also dissipated after the treatment was discontinued. Women who had taken and then stopped HT showed the same risk of hip, vertebral, and other osteoporotic fractures as did women who had taken placebo.

In reference to the risks and benefits reported in the study, Dr. Taylor said the differences between the HT and placebo groups were not statistically significant. He added that the study did not show “important” age breakdown information nor did it distinguish the difference between the effects of combination HT and estrogen-only therapies.

During the intervention phase of the WHI, all-cause mortality was virtually identical between subjects taking HT and those taking placebo. In contrast, during the postintervention phase, mortality was 15% higher among women who had taken and then discontinued HT. Although this difference did not reach statistical significance because of the small number of deaths in the study, it suggests that all-cause mortality did increase after HT, the researchers said.

Overall, the findings show that the risks of HT continue to outweigh benefits. “The global index of risk versus benefit remained essentially unchanged in the postintervention period, maintaining a nominally significant overall 12% increase from baseline” through extended follow-up in the women who had taken HT, Dr. Heiss and his associates said.

The results also indicate that maintaining clinical vigilance for malignancies, particularly lung cancer, is warranted in women who have taken HT, they added.

Dr. Taylor disclosed that he receives honoraria for speaking engagements but was not compensated for speaking at Wyeth's teleconference.

Associate editor Lorinda Bullock contributed to this article.

ELSEVIER GLOBAL MEDICAL NEWS

In primiparous women, cervical length at 22–24 weeks' gestation predicts the need for emergency cesarean delivery during labor at term, according to a study of data from more than 27,000 women at hospitals in England.

A long cervix (40–67 mm) at mid-pregnancy was associated with a high risk of intrapartum cesarean delivery at term because of failure of labor to progress, and this risk declined with a decreasing length of the cervix.

“We hypothesize that poor progress during labor at term is determined by the development of the uterus at much earlier stages of pregnancy,” Dr. Gordon C. S. Smith of Cambridge University (U.K.) and his associates wrote in the New England Journal of Medicine.

Animal studies have suggested that preparation of the uterus for labor begins at relatively early stages of gestation.

To explore this issue in humans, Dr. Smith and his coinvestigators conducted a secondary analysis of data collected in a large multicenter study of pregnancy interventions.

That study, which was conducted at eight hospitals in and around London between 1998 and 2006, had included data from transvaginal ultrasound assessment of cervical length at a median of 23 weeks' gestation in 27,472 primiparous women.

A total of 5,542 of the women went on to require cesarean section, almost always because their labor failed to progress.

The rate of caesarean delivery was lowest (16%) among women with a cervical length in the lowest quartile at mid-pregnancy.

The rate of cesarean delivery rose significantly among women in the second quartile (18%), rose significantly again among women in the third quartile (22%), and rose significantly again among women in the highest quartile (26%) of cervical length.

“Rates of cesarean delivery started to rise at a cervical length of 25 mm and plateaued at a cervical length of 50 mm, approximately doubling across the range of observed values,” Dr. Smith and his associates reported (N. Engl. J. Med. 2008;358:1346–53).

“Adjustment for a range of characteristics (maternal age, body mass index, smoking status, race or ethnic group, gestational age at birth, spontaneous or induced labor, birth weight percentile, and hospital of delivery) slightly attenuated but did not eliminate the significant association between cervical length and risk of cesarean delivery at term,” the researchers concluded.

Further study is needed to investigate the possibility that a long cervix in mid-pregnancy may signal dysfunctional development of the uterus, “which is ultimately manifested in the need for cesarean delivery at term,” Dr. Smith and his associates said.

In primiparous women, cervical length at 22–24 weeks' gestation predicts the need for emergency cesarean delivery during labor at term, according to a study of data from more than 27,000 women at hospitals in England.

A long cervix (40–67 mm) at mid-pregnancy was associated with a high risk of intrapartum cesarean delivery at term because of failure of labor to progress, and this risk declined with a decreasing length of the cervix.

“We hypothesize that poor progress during labor at term is determined by the development of the uterus at much earlier stages of pregnancy,” Dr. Gordon C. S. Smith of Cambridge University (U.K.) and his associates wrote in the New England Journal of Medicine.

Animal studies have suggested that preparation of the uterus for labor begins at relatively early stages of gestation.

To explore this issue in humans, Dr. Smith and his coinvestigators conducted a secondary analysis of data collected in a large multicenter study of pregnancy interventions.

That study, which was conducted at eight hospitals in and around London between 1998 and 2006, had included data from transvaginal ultrasound assessment of cervical length at a median of 23 weeks' gestation in 27,472 primiparous women.

A total of 5,542 of the women went on to require cesarean section, almost always because their labor failed to progress.

The rate of caesarean delivery was lowest (16%) among women with a cervical length in the lowest quartile at mid-pregnancy.

The rate of cesarean delivery rose significantly among women in the second quartile (18%), rose significantly again among women in the third quartile (22%), and rose significantly again among women in the highest quartile (26%) of cervical length.

“Rates of cesarean delivery started to rise at a cervical length of 25 mm and plateaued at a cervical length of 50 mm, approximately doubling across the range of observed values,” Dr. Smith and his associates reported (N. Engl. J. Med. 2008;358:1346–53).

“Adjustment for a range of characteristics (maternal age, body mass index, smoking status, race or ethnic group, gestational age at birth, spontaneous or induced labor, birth weight percentile, and hospital of delivery) slightly attenuated but did not eliminate the significant association between cervical length and risk of cesarean delivery at term,” the researchers concluded.

Further study is needed to investigate the possibility that a long cervix in mid-pregnancy may signal dysfunctional development of the uterus, “which is ultimately manifested in the need for cesarean delivery at term,” Dr. Smith and his associates said.

In primiparous women, cervical length at 22–24 weeks' gestation predicts the need for emergency cesarean delivery during labor at term, according to a study of data from more than 27,000 women at hospitals in England.

A long cervix (40–67 mm) at mid-pregnancy was associated with a high risk of intrapartum cesarean delivery at term because of failure of labor to progress, and this risk declined with a decreasing length of the cervix.

“We hypothesize that poor progress during labor at term is determined by the development of the uterus at much earlier stages of pregnancy,” Dr. Gordon C. S. Smith of Cambridge University (U.K.) and his associates wrote in the New England Journal of Medicine.

Animal studies have suggested that preparation of the uterus for labor begins at relatively early stages of gestation.

To explore this issue in humans, Dr. Smith and his coinvestigators conducted a secondary analysis of data collected in a large multicenter study of pregnancy interventions.

That study, which was conducted at eight hospitals in and around London between 1998 and 2006, had included data from transvaginal ultrasound assessment of cervical length at a median of 23 weeks' gestation in 27,472 primiparous women.

A total of 5,542 of the women went on to require cesarean section, almost always because their labor failed to progress.

The rate of caesarean delivery was lowest (16%) among women with a cervical length in the lowest quartile at mid-pregnancy.

The rate of cesarean delivery rose significantly among women in the second quartile (18%), rose significantly again among women in the third quartile (22%), and rose significantly again among women in the highest quartile (26%) of cervical length.

“Rates of cesarean delivery started to rise at a cervical length of 25 mm and plateaued at a cervical length of 50 mm, approximately doubling across the range of observed values,” Dr. Smith and his associates reported (N. Engl. J. Med. 2008;358:1346–53).

“Adjustment for a range of characteristics (maternal age, body mass index, smoking status, race or ethnic group, gestational age at birth, spontaneous or induced labor, birth weight percentile, and hospital of delivery) slightly attenuated but did not eliminate the significant association between cervical length and risk of cesarean delivery at term,” the researchers concluded.

Further study is needed to investigate the possibility that a long cervix in mid-pregnancy may signal dysfunctional development of the uterus, “which is ultimately manifested in the need for cesarean delivery at term,” Dr. Smith and his associates said.

Use of the aromatase inhibitor letrozole was linked to a significant 63% reduction in disease recurrence in women with early-stage breast cancer who completed 5 years of tamoxifen therapy 1–7 years earlier, results of a phase III study suggest.

“It appears that most cancers remain estrogen dependent for long periods in follow-up and that their clinical courses can be improved by the judicious use of aromatase inhibitors, even very late in follow-up,” study investigators reported online in the Journal of Clinical Oncology.

Until now clinicians, regulatory agencies, and health care funders have restricted the use of letrozole to women who were within 3 months of discontinuing tamoxifen, because the evidence supported its use only in these cases. But many, if not most, breast cancer survivors have been off tamoxifen for more than 3 months. They have never been offered letrozole even though they might benefit from it, wrote Dr. Paul E. Goss of Massachusetts General Hospital Cancer Center, Boston, and his associates in the National Cancer Institute of Canada (NCIC) Clinical Trials Group MA.17 study.

Ideally, the question would be settled by a randomized clinical trial. Such a study is under consideration, but even if it proves feasible, the results will not be available for years. In the meantime, assessing outcomes in a subgroup of women in the NCIC MA.17 trial “provides a unique opportunity to determine whether a later intervention with the aromatase inhibitor” is beneficial. These findings “provide the only available information that can be used to inform the decision these women and their physicians face,” Dr. Goss and his associates said.

In the MA.17 trial, more than 5,000 postmenopausal women within 3 months of completing approximately 5 years of adjuvant tamoxifen therapy were randomly assigned to receive letrozole or placebo and were to be followed for another 5 years. But an interim analysis after a median of 2.4 years showed a distinct advantage with letrozole, so the trial was unblinded and the placebo group was offered letrozole for the remaining 2.6 years of the trial.

A total of 1,579 women switched to letrozole, while 804 elected no further treatment after unblinding. Thirty-one women (2%) who switched to letrozole developed recurrences, compared with 39 (5%) who did not take letrozole. The drug was associated with an adjusted hazard ratio of 0.37, corresponding to a 63% reduction in disease recurrence (J. Clin. Oncol. 2008;26 [doi: 10.1200/jco.2007.11.6798]).

Distant metastases occurred in 1% of women who switched to letrozole, compared with 2.4% of those who didn't take letrozole; a significant 61% reduction in the risk of developing distant metastases was reported. Similarly, mortality was lower with letrozole than without it (1.3% vs. 4.5%).

Interpreting these results is complicated by the fact that these study subjects self-selected for letrozole therapy or no further therapy. The patients who chose letrozole were at greater risk of recurrence because of tumor characteristics, however.

In addition to the NCIC's funding, this study was supported by the Pharmacia Corp, a Pfizer company, and Novartis Pharmaceuticals Canada Inc.

Use of the aromatase inhibitor letrozole was linked to a significant 63% reduction in disease recurrence in women with early-stage breast cancer who completed 5 years of tamoxifen therapy 1–7 years earlier, results of a phase III study suggest.

“It appears that most cancers remain estrogen dependent for long periods in follow-up and that their clinical courses can be improved by the judicious use of aromatase inhibitors, even very late in follow-up,” study investigators reported online in the Journal of Clinical Oncology.

Until now clinicians, regulatory agencies, and health care funders have restricted the use of letrozole to women who were within 3 months of discontinuing tamoxifen, because the evidence supported its use only in these cases. But many, if not most, breast cancer survivors have been off tamoxifen for more than 3 months. They have never been offered letrozole even though they might benefit from it, wrote Dr. Paul E. Goss of Massachusetts General Hospital Cancer Center, Boston, and his associates in the National Cancer Institute of Canada (NCIC) Clinical Trials Group MA.17 study.

Ideally, the question would be settled by a randomized clinical trial. Such a study is under consideration, but even if it proves feasible, the results will not be available for years. In the meantime, assessing outcomes in a subgroup of women in the NCIC MA.17 trial “provides a unique opportunity to determine whether a later intervention with the aromatase inhibitor” is beneficial. These findings “provide the only available information that can be used to inform the decision these women and their physicians face,” Dr. Goss and his associates said.

In the MA.17 trial, more than 5,000 postmenopausal women within 3 months of completing approximately 5 years of adjuvant tamoxifen therapy were randomly assigned to receive letrozole or placebo and were to be followed for another 5 years. But an interim analysis after a median of 2.4 years showed a distinct advantage with letrozole, so the trial was unblinded and the placebo group was offered letrozole for the remaining 2.6 years of the trial.

A total of 1,579 women switched to letrozole, while 804 elected no further treatment after unblinding. Thirty-one women (2%) who switched to letrozole developed recurrences, compared with 39 (5%) who did not take letrozole. The drug was associated with an adjusted hazard ratio of 0.37, corresponding to a 63% reduction in disease recurrence (J. Clin. Oncol. 2008;26 [doi: 10.1200/jco.2007.11.6798]).

Distant metastases occurred in 1% of women who switched to letrozole, compared with 2.4% of those who didn't take letrozole; a significant 61% reduction in the risk of developing distant metastases was reported. Similarly, mortality was lower with letrozole than without it (1.3% vs. 4.5%).

Interpreting these results is complicated by the fact that these study subjects self-selected for letrozole therapy or no further therapy. The patients who chose letrozole were at greater risk of recurrence because of tumor characteristics, however.

In addition to the NCIC's funding, this study was supported by the Pharmacia Corp, a Pfizer company, and Novartis Pharmaceuticals Canada Inc.

Use of the aromatase inhibitor letrozole was linked to a significant 63% reduction in disease recurrence in women with early-stage breast cancer who completed 5 years of tamoxifen therapy 1–7 years earlier, results of a phase III study suggest.

“It appears that most cancers remain estrogen dependent for long periods in follow-up and that their clinical courses can be improved by the judicious use of aromatase inhibitors, even very late in follow-up,” study investigators reported online in the Journal of Clinical Oncology.

Until now clinicians, regulatory agencies, and health care funders have restricted the use of letrozole to women who were within 3 months of discontinuing tamoxifen, because the evidence supported its use only in these cases. But many, if not most, breast cancer survivors have been off tamoxifen for more than 3 months. They have never been offered letrozole even though they might benefit from it, wrote Dr. Paul E. Goss of Massachusetts General Hospital Cancer Center, Boston, and his associates in the National Cancer Institute of Canada (NCIC) Clinical Trials Group MA.17 study.

Ideally, the question would be settled by a randomized clinical trial. Such a study is under consideration, but even if it proves feasible, the results will not be available for years. In the meantime, assessing outcomes in a subgroup of women in the NCIC MA.17 trial “provides a unique opportunity to determine whether a later intervention with the aromatase inhibitor” is beneficial. These findings “provide the only available information that can be used to inform the decision these women and their physicians face,” Dr. Goss and his associates said.

In the MA.17 trial, more than 5,000 postmenopausal women within 3 months of completing approximately 5 years of adjuvant tamoxifen therapy were randomly assigned to receive letrozole or placebo and were to be followed for another 5 years. But an interim analysis after a median of 2.4 years showed a distinct advantage with letrozole, so the trial was unblinded and the placebo group was offered letrozole for the remaining 2.6 years of the trial.

A total of 1,579 women switched to letrozole, while 804 elected no further treatment after unblinding. Thirty-one women (2%) who switched to letrozole developed recurrences, compared with 39 (5%) who did not take letrozole. The drug was associated with an adjusted hazard ratio of 0.37, corresponding to a 63% reduction in disease recurrence (J. Clin. Oncol. 2008;26 [doi: 10.1200/jco.2007.11.6798]).

Distant metastases occurred in 1% of women who switched to letrozole, compared with 2.4% of those who didn't take letrozole; a significant 61% reduction in the risk of developing distant metastases was reported. Similarly, mortality was lower with letrozole than without it (1.3% vs. 4.5%).

Interpreting these results is complicated by the fact that these study subjects self-selected for letrozole therapy or no further therapy. The patients who chose letrozole were at greater risk of recurrence because of tumor characteristics, however.

In addition to the NCIC's funding, this study was supported by the Pharmacia Corp, a Pfizer company, and Novartis Pharmaceuticals Canada Inc.