Differences in excess mortality by recipient sex after heart transplant: An individual patient data meta-analysis.

BACKGROUND: Identification of differences in mortality risk between female and male heart transplant recipients may prompt sex-specific management strategies. Because worldwide, males of all ages have higher absolute mortality rates than females, we aimed to compare the excess risk of mortality (risk above the general population) in female vs male heart transplant recipients. METHODS: We used relative survival models conducted separately in SRTR and CTS cohorts from 1988-2019, and subsequently combined using 2-stage individual patient data meta-analysis, to compare the excess risk of mortality in female vs male first heart transplant recipients, accounting for the modifying effects of donor sex and recipient current age. RESULTS: We analyzed 108,918 patients. When the donor was male, female recipients 0-12 years (Relative excess risk (RER) 1.13, 95% CI 1.00-1.26), 13-44 years (RER 1.17, 95% CI 1.10-1.25), and ≥45 years (RER 1.14, 95% CI 1.02-1.27) showed higher excess mortality risks than male recipients of the same age. When the donor was female, only female recipients 13-44 years showed higher excess risks of mortality than males (RER 1.09, 95% CI 1.00-1.20), though not significantly (p = 0.05). CONCLUSIONS: In the setting of a male donor, female recipients of all ages had significantly higher excess mortality than males. When the donor was female, female recipients of reproductive age had higher excess risks of mortality than male recipients of the same age, though this was not statistically significant. Further investigation is required to determine the reasons underlying these differences.

A Multinational Cohort Study Examining Sex Differences in Excess Risk of Death With Graft Function After Kidney Transplant.

BACKGROUND: Kidney transplant recipients show sex differences in excess overall mortality risk that vary by donor sex and recipient age. However, whether the excess risk of death with graft function (DWGF) differs by recipient sex is unknown. METHODS: In this study, we combined data from 3 of the largest transplant registries worldwide (Scientific Registry of Transplant Recipient, Australia and New Zealand Dialysis and Transplant Registry, and Collaborative Transplant Study) using individual patient data meta-analysis to compare the excess risk of DWGF between male and female recipients of a first deceased donor kidney transplant (1988-2019), conditional on donor sex and recipient age. RESULTS: Among 463 895 individuals examined, when the donor was male, female recipients aged 0 to 12 y experienced a higher excess risk of DWGF than male recipients (relative excess risk 1.68; 95% confidence interval, 1.24-2.29); there were no significant differences in other age intervals or at any age when the donor was female. There was no statistically significant between-cohort heterogeneity. CONCLUSIONS: Given the lack of sex differences in the excess risk of DWGF (other than in prepubertal recipients of a male donor kidney) and the known greater excess overall mortality risk for female recipients compared with male recipients in the setting of a male donor, future study is required to characterize potential sex-specific causes of death after graft loss.

School-based vaccination program against HPV and Hepatitis B: A longitudinal analysis of vaccine coverage between 2015 and 2021 in Quebec.

BACKGROUND: HPV vaccination prevents cancers, including 90% of cervical cancer. Since 2008, a school-based HPV vaccination program has been implemented in Quebec, but vaccine coverage is suboptimal. The COVID-19 pandemic disrupted school-based vaccination programs. This study aimed to assess variation in HPV vaccination coverage in the school-based program between 2015 and 2022 in Quebec and to identify sociodemographic characteristics associated with non-vaccination. METHODS: HPV vaccine coverage data were extracted from the Quebec Immunization Registry for students in Grade 4 and matched to the 2016 Canadian census sociodemographic data. Descriptive analysis was conducted to explore individual-level vaccine coverage according to sociodemographic data. A Generalized Estimating Equations model assessed the independent association between non-vaccination and students' sociodemographic characteristics. RESULTS: HPV vaccine coverage (at least one dose) was 84% in 2018-2019 and 85% in 2019-2020. A decrease was observed during the pandemic. In 2020-2021, the HPV vaccine coverage (at least one dose) was 52% (at the end of the school year) and rose to 84% with intense catch-up activities. In 2021-2022, the coverage was slightly lower than before the pandemic (81%). Factors in the dissemination area were statistically significantly associated with non-vaccination: material (p-value = 0.0001) and social deprivation index (p-value = 0.0048), the proportion of immigration (p-value < 0.0001), and the language spoken at home (English (p-value = 0.0318), other than French or English (p-value = 0.0001). CONCLUSION: School-based vaccination programs offer equitable access to vaccination, and our analysis showed that some groups have consistently lower vaccine acceptance and uptake. Strategies to improve HPV vaccine coverage should target children living in areas with a higher proportion of immigrants, non-French speakers, and people from underprivileged backgrounds. Although it is too early to assess the full impact of COVID-19 on school-based programs in Quebec, it remains important to ensure that catch-up strategies are implemented for missed doses.

Considering gestational diabetes and gestational hypertension history across two pregnancies in relationship to cardiovascular disease development: A retrospective cohort study.

AIMS: Gestational diabetes (GDM) and hypertension (GHTN) occurrences signal elevated cardiovascular disease (CVD) risk. There is little study of occurrence and recurrence of these conditions in relationship to CVD. Among women with two singleton pregnancies, we aimed to quantify CVD risk in relationship to the number of GDM/GHTN occurrences. METHODS: In this Quebec-based retrospective cohort study (n = 431,980), we ascertained the number of GDM/GHTN occurrences over two pregnancies and assessed for CVD over a median of 16.4 years (cohort inception 1990-2012, outcomes 1990-2019). We defined CVD as a composite of myocardial infarction, stroke, and angina, requiring hospitalization and/or causing death. We adjusted Cox proportional hazards models for offspring size, preterm/term birth status, maternal age group, time between deliveries, ethnicity, deprivation level, and co-morbid conditions. RESULTS: Compared to absence of GDM/GHTN in either pregnancy, one GDM/GHTN occurrence increased CVD hazards by 47% (hazard ratio [HR] = 1.47, 95% confidence interval [CI] 1.35-1.61), two occurrences nearly doubled hazards (HR = 1.91, 95% CI 1.68-2.17), and three or more approximately tripled CVD hazards (HR = 2.93, 95% CI 2.20-3.90). Individual components of the composite demonstrated similar findings. CONCLUSIONS: Health care providers and mothers should consider a complete history of GDM/GHTN occurrences to ascertain the importance and urgency of preventive action.

Influence of donor sex and age on graft outcome in kidney transplantation.

BACKGROUND AND HYPOTHESIS: There is a known recipient sex-dependent association between donor sex and kidney transplant survival. We hypothesized that donor age also modifies the association between donor sex and graft survival. METHODS: First deceased donor kidney transplant recipients (1988-2019, n = 461 364) recorded in the Scientific Registry of Transplant Recipients, Australia and New Zealand Dialysis and Transplant Registry, and the Collaborative Transplant Study were analyzed. We used multivariable Cox regression models to estimate the association between donor sex and death censored graft loss, accounting for the modifying effects of recipient sex and donor age; donor age was categorized as 5-19, 20-34, 35-49, 50-59, and ≥ 60 years. Results from cohort-specific Cox models were combined using individual patient data meta-analysis. RESULTS: Among female recipients of donors aged < 60 years, graft loss hazards did not differ by donor sex; recipients of female donors ≥ 60 years showed significantly lower graft loss hazards than recipients of male donors of the same age (combined adjusted hazard ratio, aHR 0.90, 95% CI 0.86-0.94). Among male recipients, female donors aged < 50 years were associated with significantly higher graft loss hazards than same-aged male donors (5-19 years: aHR 1.11, 95% CI 1.02-1.21; 20-34 years: aHR 1.08, 95% CI 1.02-1.15; 35-49 years: aHR 1.07, 95% CI 1.04-1.10). There were no significant differences in graft loss by donor sex among male recipients of donors aged ≥ 50 years. CONCLUSION: Donor age modifies the association between donor sex and graft survival. Older female donors were associated with similar or lower hazards of graft failure than older male donors in both male and female recipients, suggesting a better functional reserve of older female donor kidneys.

Associations of free sugars from solid and liquid sources with cardiovascular disease: a retrospective cohort analysis.

BACKGROUND: The World Health Organization recommends a 10% total energy (TE%) limit for free sugars (i.e., added sugars and naturally occurring sugars in fruit juice, honey, and syrups) based on evidence linking higher intakes with overweight and dental caries. Evidence for cardiovascular disease (CVD) is limited. Impacts may differ by sex, age group, and solid vs. liquid sources; liquids may stimulate more adverse CVD profiles (due to their rapid absorption in the body along along with triggering less satiety). We examined associations of consuming total free sugars ≥ 10 TE% with CVD within four sex and age-defined groups. Given roughly equal free sugar intakes from solid and liquid sources, we also evaluated source-specific associations of free sugars ≥ 5 TE% thresholds. METHODS: In this retrospective cohort study, we estimated free sugars from 24-h dietary recall (Canadian Community Health Survey, 2004-2005) in relationship to nonfatal and fatal CVD (Discharge Abstract and Canadian Mortality Databases, 2004-2017; International Disease Classification-10 codes for ischemic heart disease and stroke) through multivariable Cox proportional hazards models adjusted for overweight/obesity, health behaviours, dietary factors, and food insecurity. We conducted analyses in separate models for men 55 to 75 years, women 55 to 75 years, men 35 to 55 years, and women 35 to 55 years. We dichotomized total free sugars at 10 TE% and source-specific free sugars at 5 TE%. RESULTS: Men 55 to 75 years of age had 34% higher CVD hazards with intakes of free sugars from solid sources ≥ 5 TE% vs. below (adjusted HR 1.34, 95% CI 1.05- 1.70). The other three age and sex-specific groups did not demonstrate conclusive associations with CVD. CONCLUSIONS: Our findings suggest that from a CVD prevention standpoint in men 55 to 75 years of age, there may be benefits from consuming less than 5 TE% as free sugars from solid sources.

A multinational cohort study uncovered sex differences in excess mortality after kidney transplant.

Worldwide and at all ages, males have a higher mortality risk than females. This mortality bias should be preserved in kidney transplant recipients unless there are sex differences in the effects of transplantation. Here we compared the excess risk of mortality (risk above the general population) in female versus male recipients of all ages recorded in three large transplant databases. This included first deceased donor kidney transplant recipients and accounted for the modifying effects of donor sex and recipient age. After harmonization of variables across cohorts, relative survival models were fitted in each cohort separately and results were combined using individual patient data meta-analysis among 466,892 individuals (1988-2019). When the donor was male, female recipients 0-12 years (Relative Excess Risk 1.54, 95% Confidence Interval 1.20-1.99), 13-24 years (1.17, 1.01-1.34), 25-44 years (1.11, 1.05-1.18) and 60 years and older (1.05, 1.02-1.08) showed higher excess mortality risks than male recipients of the same age. When the donor was female, the Relative Excess Risk for those over 12 years were similar to those when the donor was male. There is a higher excess mortality risk in female than male recipients with differences larger at younger than older ages and only statistically significant when the donor was male. While these findings may be partly explained by the known sex differences in graft loss risks, sex differences in the risks of death with graft function may also contribute. Thus, higher risks in females than males suggest that management needs to be modified to optimize transplant outcomes among females.

Differences in medication adherence by sex and organ type among adolescent and young adult solid organ transplant recipients.

BACKGROUND: Identification of differences in medication adherence by sex or organ type may help in planning interventions to optimize outcomes. We compared immunosuppressive medication adherence between males and females, and between kidney, liver and heart transplant recipients. METHODS: This multicenter study of prevalent kidney, liver and heart transplant recipients 14-25 years assessed adherence 3 times (0, 3, 6 months post-enrollment) with the BAASIS self-report tool. At each visit, participants were classified as adherent if they missed no doses in the prior 4 weeks and non-adherent otherwise. Adherence was also assessed using the coefficient of variation (CV) of tacrolimus trough levels; CV < 30% was classified as adherent. We used multivariable mixed effects logistic regression models adjusted for potential confounders to compare adherence by sex and by organ. RESULTS: Across all visits, males (n = 150, median age 20.4 years, IQR 17.2-23.3) had lower odds of self-reported adherence than females (n = 120, median age 19.8 years, IQR 17.1-22.7) (OR 0.41, 95% CI 0.21-0.80) but higher odds of adherence by tacrolimus CV (OR 2.50, 95% CI 1.30-4.82). No significant differences in adherence (by self-report or tacrolimus CV) were noted between the 184 kidney, 58 liver, and 28 heart recipients. CONCLUSION: Females show better self-reported adherence than males but greater variability in tacrolimus levels. Social desirability bias, more common in females than males, may contribute to better self-reported adherence among females. Higher tacrolimus variability among females may reflect biologic differences in tacrolimus metabolism between males and females rather than sex differences in adherence. There were no significant differences in adherence by organ type.

Differences in medication adherence between preemptive and post-dialysis young kidney transplant recipients.

BACKGROUND: The mechanisms underlying the superior graft survival associated with preemptive kidney transplantation, compared with transplantation following a period of dialysis, are unknown. We aimed to compare medication adherence between preemptively transplanted young kidney transplant recipients and those who received a transplant after an interval of dialysis. METHODS: This was a secondary analysis of the Teen Adherence in Kidney transplant Effectiveness of Intervention Trial (TAKE-IT), in which adherence was assessed with electronic monitoring over 15 months among 11-24-year-old transplant recipients. Adherence scores were calculated for each day as 0%, 50%, or 100% (intake of none, half, or all prescribed doses). We used ordinal logistic regression, with generalized estimating equations to account for repeated measures within each participant, to estimate the association between preemptive transplantation and adherence. The model was adjusted for sex, age at transplant, time since transplant, primary kidney disease, race, donor source, medication insurer, household income, and adherence intervention. RESULTS: There were 43 preemptive transplant recipients and 103 who had been treated with dialysis. The median adherence score was 85.1% (IQR 81.3-88.9) for those preemptively transplanted, and 80.0% (IQR 76.7-83.4) for those transplanted after dialysis. Preemptively transplanted recipients had significantly higher odds of adherence than those dialyzed before transplantation (adjusted OR 1.76 95% CI 1.21-2.55; p = 0.003). CONCLUSIONS: Preemptively transplanted patients showed significantly better adherence than those treated with dialysis before transplantation. This suggests that the superior outcomes observed among preemptive kidney transplant recipients may reflect selection of patients more likely to adhere to therapy. A higher resolution version of the Graphical abstract is available as Supplementary information.

Age-dependent Sex Differences in Graft Loss After Kidney Transplantation.

BACKGROUND: Sex differences in kidney graft loss rates were reported in the United States. Whether these differences are present in other countries is unknown. METHODS: We estimated the association between recipient sex and death-censored graft loss in patients of all ages recorded in the Scientific Registry of Transplant Recipients, Australia and New Zealand Dialysis and Transplant Registry, and Collaborative Transplant Study registries who received a first deceased donor kidney transplant (1988-2019). We used multivariable Cox regression models, accounting for the modifying effects of donor sex and recipient age, in each registry separately; results were combined using individual patient data meta-analysis. RESULTS: We analyzed 438 585 patients. Young female patients 13-24 y old had the highest crude graft loss rates (female donor: 5.66; male donor: 5.50 per 100 person-years). Among young recipients of male donors, females showed higher graft loss risks than males (0-12 y: adjusted hazard ratio [aHR] 1.42, (95% confidence interval [CI], 1.17-1.73); 13-24 y: 1.24 (1.17-1.32); 25-44 y: 1.09 (1.06-1.13)). When the donor was female, there were no significant differences by recipient sex among those of age <45 y; however, the aHR for females was 0.93 (0.89-0.98) in 45-59 y-old and 0.89 (0.86-0.93) in ≥ 60 y-old recipients. Findings were similar for all 3 registries in most age intervals; statistically significant heterogeneity was seen only among 13-24-y-old recipients of a female donor (I2 = 71.5%, P = 0.03). CONCLUSIONS: There is an association between recipient sex and kidney transplantation survival that is modified by recipient age and donor sex.

Associations of overweight and gestational diabetes mellitus with free sugars from solid and liquid sources: cross-sectional and nested case-control analyses.

BACKGROUND: Sugar-sweetened beverages have obesogenic and diabetogenic effects ascribed to free sugars. These include added sugars and naturally occurring sugars in juices. A meta-analysis indicates that some foods with added sugars are associated with lower type 2 diabetes rates. To expand the evidence relevant to free sugars from solid sources, we examined a young to middle-aged population with respect to overweight and gestational diabetes (GDM) outcomes. METHODS: We studied female participants (12-50 years old) from the 2004-2005 Canadian Community Health Survey 2.2 (CCHS) with data linked to the hospital Discharge Abstract Database (DAD) until 2017, providing 13 years of follow-up. We estimated free sugars by solid and liquid sources from 24-h dietary recalls as percent total energy intake (TE%), and computed body mass index (BMI). We applied ICD-10 diagnostic codes for deliveries and GDM to DAD. We conducted multivariable logistic regression analyses to evaluate associations between free sugars with overweight at baseline (cross-sectional component) and, in those who delivered, with GDM during follow-up (nested case control component). We compared those with consumption above versus below various thresholds of intake for free sugars, considering solid and liquid sources separately (2.TE%, 5TE%, 10TE% and 15TE% thresholds). RESULTS: Among 6305 participants, 2505 (40%) were overweight, defined as BMI ≥ 85th percentile below 18 years and BMI ≥ 25 kg/m2 for adults. Free sugars from solid sources were associated with lower odds of overweight above versus below the 2.5TE% (adjusted odds ratio [adjOR] 0.80, 95%CI 0.70-0.92), 5TE% (adjOR 0.89, 95%CI 0.79-0.99), and 10TE% (adjOR 0.86, 95%CI 0.75-0.97) thresholds. Free sugars from liquid sources were associated with greater odds of overweight across the 2.5TE% (adjOR 1.20, 95%CI 1.07-1.36), 10TE% (adjOR 1.17, 95%CI 1.02-1.34), and 15TE% (adjOR 1.43, 95%CI 1.23-1.67) thresholds. There were 113 cases of GDM among the 1842 women who delivered (6.1%). Free sugars from solid sources were associated with lower odds of GDM above versus below the 5TE% threshold (adjOR 0.56, 95%CI 0.36-0.85). CONCLUSIONS: Our findings support limiting free sugars from liquid sources, given associations with overweight. We did not identify adverse associations of free sugars from solid sources across any of the thresholds examined.

Differences in Heart Graft Survival by Recipient Sex.

We aimed to characterize patterns of differences in heart graft failure rates by recipient sex, accounting for modifying effects of donor sex and recipient age. METHODS: We evaluated 69 246 first heart transplant recipients (1988-2019; Scientific Registry of Transplant Recipients). We used multivariable time-varying Cox models, considering recipient sex by donor sex by recipient age interaction and adjusting for potential confounders. Using the hazard ratio (HR) from the models and a fixed profile of recipient and donor characteristics, we also compared fitted absolute failure rates by recipient sex. RESULTS: Among recipients of male donors, female recipients of all ages had higher failure rates than males (0-12 y: HR 1.36 (95% confidence interval [CI], 1.03-1.81); 13-24 y: 1.43 [1.09-1.88]; 25-44 y: 1.22 [0.95-1.57]; ≥45 y: 1.16 [1.06-1.27]); differences were statistically significant in all age intervals except 25-44 y. When the donor was male, 13 to 24-y-olds showed the largest absolute difference in fitted absolute failure rates, with rates higher by 11.3 failures per 1000 person-y in female than male recipients. Among recipients of female donors, there were no statistically significant differences in graft failure rates between female and male heart recipients of any age. Although point estimates suggested higher failure rates in female than male recipients <25 y (0-12 y: HR 1.19 [95% CI, 0.85-1.66]; 13-24 y: 1.17 [0.84-1.63]), these were not statistically significant. CONCLUSIONS: Female recipients tended to have poorer outcomes than males, particularly at younger ages and when the donor was male, consistent with observations in kidney transplants.

Care processes and structures associated with higher medication adherence in adolescent and young adult transplant recipients.

BACKGROUND: We aimed to identify care processes and structures that were independently associated with higher medication adherence among young transplant recipients. METHODS: We conducted a prospective, observational cohort study of 270 prevalent kidney, liver, and heart transplant recipients 14-25 years old. Patients were ≥3 months post-transplant, ≥2 months post-discharge, and followed in one of 14 pediatric or 14 adult transplant programs in Canada. Patients were enrolled between June 2015 and March 2018 and followed for 6 months. Adherence was assessed at baseline, 3, and 6 months using the BAASIS© self-report tool. Patients were classified as adherent if no doses were missed in the prior 4 weeks. Transplant program directors and nurses completed questionnaires regarding care organization and processes. RESULTS: Of the 270 participants, 99 were followed in pediatric programs and 171 in adult programs. Median age was 20.3 years, and median time since transplant was 5 years. At baseline, 71.5% were adherent. Multivariable mixed effects logistic regression models with program as a random effect identified two program-level factors as independently associated with better adherence: minimum number of prescribed blood draws per year for those >3 years post-transplant (per 1 additional) (OR 1.12 [95% CI 1.00, 1.26]; p = .047), and average time nurses spend with patients in clinic (per 5 additional minutes) (OR 1.15 [1.03, 1.29]; p = .017). CONCLUSION: Program-level factors including protocols with a greater frequency of routine blood testing and more nurse time with patients were associated with better medication adherence. This suggests that interventions at the program level may support better adherence.

Differences in Liver Graft Survival by Recipient Sex.

We aimed to characterize patterns of differences in liver graft failure rates by recipient sex, accounting for the modifying effects of donor sex and recipient age. METHODS: We evaluated 144 212 first deceased donor liver transplant recipients [1988-2019; Scientific Registry of Transplant Recipients (SRTR)]. We used multivariable time-varying Cox models, considering a recipient sex by donor sex by recipient age (0-12, 13-24, 25-44, ≥45 y) interaction. RESULTS: Among recipients of male donors, females <45 y had higher graft failure rates than males of the same age, but none of these differences were statistically significant [0-12 y: adjusted hazard ratio (aHR) 1.17 (0.98, 1.40); 13-24 y: aHR 1.18 (0.96, 1.46); 25-44 y: aHR 1.11 (0.96, 1.28)]; there was no material or statistically significant difference between female and male recipients ≥45 y [aHR 1.01 (0.97, 1.06)]. When the donor was female, recipients <45 y showed no statistically significant differences in graft outcomes by recipient sex [0-12 y: aHR 0.91 (0.74, 1.11); 13-24 y: aHR 0.98 (0.77, 1.25); 25-44 y: aHR 0.86 (0.73, 1.01)], whereas female recipients ≥45 y had significantly lower graft failure rates [aHR 0.85 (0.81, 0.89)] than males of the same age. CONCLUSIONS: Among recipients of female donors, female recipients ≥45 y had significantly better outcomes than males of the same age; there were no clear differences by recipient sex in younger recipients. When the donor was male, there was no material or statistically significant difference in graft failure rates between males and females ≥45 y; among younger recipients point estimates suggested higher failure rates in females than males recipients, but confidence intervals were wide making firm conclusions impossible. Larger studies combining multiple datasets are needed.

Perinatal health among foreign versus native-born mothers in Canada: variations across outcomes and cohorts.

BACKGROUND: To examine perinatal health differences between foreign-born and native-born mothers in Canada across multiple outcomes and two cohorts 10 years apart. METHODS: Using 94 896 and 131 271 births in the 1996 and 2006 Canadian Census-Birth Cohort, respectively, we estimated risk ratios and risk differences of preterm birth (PTB), small-for-gestational age (SGA), large-for-gestational age (LGA), stillbirth and infant mortality between foreign-born and Canadian-born mothers. RESULTS: In the 1996 cohort, we observed no important differences in adverse outcomes between foreign-born and native-born mothers. In the 2006 cohort, however, foreign-born mothers had lower risks of PTB, LGA, stillbirth, and infant mortality and a higher risk of SGA on both the relative and absolute scales. Lowered risk of PTB among foreign-born mothers in the 2006 cohort was also observed within Caucasian, East Asian, Southeast Asian and South Asian mothers. Favourable outcomes associated with foreign-born status in the 2006 cohort were negatively graded by duration of residence in Canada among immigrant mothers. CONCLUSIONS: Differences in perinatal health by maternal foreign-born status varied across cohorts and a more pronounced 'healthy migrant' effect was observed among more recent migrants. The native-born mothers' perinatal health over time and a more restrictive/selective immigration policy in recent years would explain our results.

Associations of atopic dermatitis and asthma with child behaviour: Results from the PROBIT cohort.

BACKGROUND: Conflicting findings from studies evaluating associations of allergic disease with child behaviour require longitudinal studies to resolve. OBJECTIVE: To estimate the magnitude of associations of atopic dermatitis (AD) in infancy, and symptoms of asthma and AD at 6.5 years, with child behaviour at 6.5 years. METHODS: Secondary cohort analysis of the Promotion of Breastfeeding Intervention Trial (PROBIT). PROBIT enrolled 17 046 infants at birth and followed them up at 6.5 years (n = 13 889). Study paediatricians collected data on infantile AD at repeated follow-up examinations during the first year of life. At 6.5 years, paediatricians performed skin prick tests and parents reported asthma and AD symptoms during the prior year. In addition, parents and teachers completed the Strength and Difficulties Questionnaire, which includes scales on hyperactivity/inattention, emotional problems, conduct problems, peer problems and prosocial behaviours. RESULTS: Physician-diagnosed AD in the first year of life was not associated with increased risk for behavioural problems at 6.5 years. Emotional problems at 6.5 years were more common among children with AD symptoms (OR: 2.24, 95% CI: 1.62-3.12) and asthma symptoms (OR: 1.45; 95% CI: 1.07-1.96) during the past year at 6.5 years and ORs for children with symptoms of more severe AD and asthma were also higher. AD in the past year was also associated with probable hyperactivity/inattention disorder at 6.5 years (OR: 2.05; 95% CI: 1.09-3.84). Other subscales of the SDQ were not related to asthma or AD symptoms during the past year. CONCLUSIONS AND CLINICAL RELEVANCE: Children with AD symptoms were at higher risk for concomitant hyperactivity/inattention and emotional disorder, and children with asthma symptoms were at higher risk of having concomitant emotional problems. However, AD during infancy did not predict childhood behaviours.

Gestational diabetes associated with incident diabetes in childhood and youth: a retrospective cohort study.

BACKGROUND: Indicators of childhood- and youth-onset diabetes may be useful for early detection of diabetes; there is a known association between composite exposure of parental type 2 diabetes and gestational diabetes mellitus with childhood- and youth-onset diabetes. We examined associations between gestational diabetes mellitus and incidence of childhood- and youth-onset diabetes in offspring. METHODS: Using public health insurance administrative databases from Quebec, Canada, we randomly selected singleton live births with maternal gestational diabetes mellitus (1990-2007) and matched them 1:1 with singleton live births without gestational diabetes mellitus. Follow-up was to Mar. 31, 2012. We examined associations of diabetes in offspring with maternal gestational diabetes mellitus through unadjusted and adjusted Cox proportional hazards models. In secondary analyses, we separately considered age groups ranging from birth to age 12 years, and age 12 to 22 years. RESULTS: Incidence of pediatric diabetes (per 10 000 person-years) was higher in offspring born to mothers with gestational diabetes mellitus (4.52, 95% confidence interval [CI] 4.47-4.57) than in mothers without gestational diabetes mellitus (2.4, 95% CI 2.37-2.46). In an adjusted Cox proportional hazards model, maternal gestational diabetes mellitus was associated with development of pediatric diabetes overall (birth to age 22 yr: hazard ratio [HR] 1.77, 95% CI 1.41-2.22), during childhood (birth to age 12 yr: HR 1.43, 95% CI 1.09-1.89), and in youth (age 12 to 22 yr: HR 2.53, 95% CI 1.67-3.85). INTERPRETATION: Gestational diabetes mellitus is associated with incident diabetes in offspring during childhood and adolescence. Future studies are needed to examine longer-term outcomes in patients with pediatric diabetes with a maternal history of gestational diabetes mellitus, to ascertain how they compare with other patients with childhood- or youth-onset diabetes, in terms of disease severity and outcomes.

Infant feeding and growth: putting the horse before the cart.

Background: Previous observational studies have consistently shown slower weight and length gains in infants with prolonged breastfeeding than in those who were formula-fed from birth or breastfed for a shorter duration. These studies inferred that prolonged breastfeeding causes slower growth in infancy. Objective: We compared infant growth associated with ≥12 mo of breastfeeding with a shorter duration of breastfeeding on the basis of 3 different analytic approaches to the same data from a randomized trial: intention-to-treat (ITT; "as randomized"), observational ("as fed"), and instrumental variable (IV; by using randomization as an "instrument" to achieve ≥12 mo of breastfeeding). Design: This was a cluster-randomized trial of a breastfeeding-promotion intervention. Anthropometric measurements were obtained at birth and at 1, 2, 3, 6, 9, and 12 mo. Results: The 3 analytic approaches yielded different results. The ITT approach showed more rapid growth in the first 2 mo among infants randomly assigned to the breastfeeding-promotion intervention than among control infants, with a decreasing difference over the ensuing months and nearly identical weight, length, and body mass index by 12 mo. The observational analysis showed a different trend: higher weight and length in infants who were breastfed ≥12 mo than in those who were breastfed <12 mo during the first 3 mo and no difference by 6 mo, while infants who were breastfed <12 mo showed increasingly higher weight and length from 6 to 12 mo. The IV analysis showed a temporal pattern that was similar to that seen in the ITT analysis, but with larger (and less precise) differences between infants breastfed for ≥12 compared with <12 mo. Conclusions: We observed major differences in experimental (ITT and IV) compared with observational approaches to analyzing data obtained from the same children. These approaches lead to opposite causal inferences about the relation between infant feeding and growth and underline the importance of ensuring that the postulated cause (feeding) temporally precedes its hypothesized effect (growth). This trial is registered at http://www.isrctn.org/ as ISRCTN37687716.

Changes in Excess Mortality from End Stage Renal Disease in the United States from 1995 to 2013.

BACKGROUND AND OBJECTIVES: Individuals with ESRD have a very high risk of death. Although mortality rates have decreased over time in ESRD, it is unknown if improvements merely reflect parallel increases in general population survival. We, therefore, examined changes in the excess risk of all-cause mortality-over and above the risk in the general population-among people treated for ESRD in the United States from 1995 to 2013. We hypothesized that the magnitude of change in the excess risk of death would differ by age and RRT modality. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used time-dependent relative survival models including data from persons with incident ESRD as recorded in the US Renal Data System and age-, sex-, race-, and calendar year-specific general population mortality rates from the Centers for Disease Control and Prevention. We calculated relative excess risks (analogous to hazard ratios) to examine the association between advancing calendar time and the primary outcome of all-cause mortality. RESULTS: We included 1,938,148 children and adults with incident ESRD from 1995 to 2013. Adjusted relative excess risk per 5-year increment in calendar time ranged from 0.73 (95% confidence interval, 0.69 to 0.77) for 0-14 year olds to 0.88 (95% confidence interval, 0.88 to 0.88) for ≥65 year olds, meaning that the excess risk of ESRD-related death decreased by 12%-27% over any 5-year interval between 1995 and 2013. Decreases in excess mortality over time were observed for all ages and both during treatment with dialysis and during time with a functioning kidney transplant (year by age and year by renal replacement modality interactions were both P<0.001), with the largest relative improvements observed for the youngest persons with a functioning kidney transplant. Absolute decreases in excess ESRD-related mortality were greatest for the oldest persons. CONCLUSIONS: The excess risk of all-cause mortality among people with ESRD, over and above the risk in the general population, decreased significantly between 1995 and 2013 in the United States.

Association of Sex with Risk of Kidney Graft Failure Differs by Age.

Prior studies of sex differences in kidney graft survival showed conflicting results. We hypothesized that the association between recipient sex and kidney graft failure risk differs by recipient age and donor sex. We evaluated 159,417 patients recorded in the Scientific Registry of Transplant Recipients database who received a first deceased-donor kidney transplant (1995-2013). We used time-varying Cox models to estimate the association between recipient sex and death-censored graft failure. Models, stratified on donor sex and adjusted for potential confounders, included a recipient sex by current age interaction term. Among recipients of male donors, females of all ages had significantly higher graft failure risks than males (adjusted hazard ratios 0-14 years: 1.51 [95% confidence intervals 1.19 to 1.90]; 15-24 years: 1.37 [1.18 to 1.59]; 25-44 years: 1.14 [1.03 to 1.26]; 45 years: 1.05 [1.01 to 1.09]). Among recipients of female-donor grafts, only female recipients aged 15-24 years had a significantly higher graft failure risk than their male counterparts had (1.28 [1.06 to 1.53]). Indeed, female recipients aged ≥45 years had a significantly lower graft failure risk than their male counterparts had (0.95 [0.91 to 0.99]). These observations might be explained by the combined influence of several factors, including recognition of sex-determined minor histocompatibility antigens, influence of sex hormones on immune activation, sex- and age-related differences in medication adherence, and sex-related differences in body size. Additional studies should determine whether sex- and age-specific immunosuppression strategies are warranted for kidney graft recipients.