Maternal One-Carbon Nutrient Intake and Risk of Being Overweight or Obese in Their Offspring-A Transgenerational Prospective Cohort Study.

We aimed to investigate the associations between maternal intake of folate, vitamin B12, B6, B2, methionine, choline, phosphatidylcholine and betaine during the period surrounding pregnancy and offspring weight outcomes from birth to early adulthood. These associations were examined among 2454 mother-child pairs from the Nurses' Health Study II and Growing Up Today Study. Maternal energy-adjusted nutrient intakes were derived from food frequency questionnaires. Birth weight, body size at age 5 and repeated BMI measurements were considered. Overweight/obesity was defined according to the International Obesity Task Force (<18 years) and World Health Organization guidelines (18+ years). Among other estimands, we report relative risks (RRs) for offspring ever being overweight with corresponding 95% confidence intervals across quintiles of dietary factors, with the lowest quintile as the reference. In multivariate-adjusted models, higher maternal intakes of phosphatidylcholine were associated with a higher risk of offspring ever being overweight (RRQ5vsQ1 = 1.16 [1.01-1.33] p-trend: 0.003). The association was stronger among offspring born to mothers with high red meat intake (high red meat RRQ5vsQ1 = 1.50 [1.14-1.98], p-trend: 0.001; low red meat RRQ5vsQ1 = 1.05 [0.87-1.27], p-trend: 0.46; p-interaction = 0.13). Future studies confirming the association between a higher maternal phosphatidylcholine intake during pregnancy and offspring risk of being overweight or obese are needed.

Bleb vessel density as a predictive factor for surgical revisions after Preserflo Microshunt implantation.

PURPOSE: Bleb failure is a common complication after glaucoma filtration surgery. Different bleb classification schemes incorporating filtration bleb vascularization have been proposed, but the reported correlation with intraocular pressure (IOP) has been variable, possibly because of subjective vascularization grading. The purpose of the present study was to evaluate bleb vascularization after Preserflo Microshunt (PM) implantation using anterior segment OCT-angiography (AS-OCTA) as a biomarker for bleb failure. METHODS: Twenty-three eyes of twenty-three patients underwent PM implantation. Up to 12 months after surgery PM scleral passage-centred AS-OCTA measurements (PLEX Elite 9000) for bleb-vessel density (BVD) determination were performed and IOP as well as necessity for surgical revisions (needling and open revision) were documented. After multi-step image analysis (region of interest definition, artefact removal, binarization, BVD calculation), the predictive value of early postoperative BVD for surgical revisions was assessed using logistic regression modelling. RESULTS: Baseline IOP (23.57 ± 7.75 mmHg) decreased significantly to 8.30 ± 2.12, 9.17 ± 2.33 and 11.70 ± 4.40 mmHg after 1, 2 and 4 week(s), and 13.48 ± 5.83, 11.87 ± 4.49, 12.30 ± 6.65, 11.87 ± 3.11 and 13.05 ± 4.12 mmHg after 2, 3, 6, 9 and 12 month(s), respectively (p < 0.001). Nine patients (39%) needed surgical revisions after a median time of 2 months. Bleb vessel densities at 2 and 4 weeks were significantly associated with future surgical revisions upon logistic regression analysis (2 W/4 W likelihood-ratio test p-value: 0.0244/0.0098; 2 W/4 W area under the receiver operating characteristics curve: 0.796/0.909). CONCLUSION: Filtration bleb vessel density can be determined using AS-OCTA in the early postoperative period and is predictive for bleb failure after PM implantation.

Timing and duration of dog walking and dog owner's chronotype in relation to incident depression risk among middle to older-aged female nurses.

BACKGROUND: We examined associations between dog ownership, morning dog walking and its timing and duration, and depression risk in female nurses, exploring effect modification by chronotype. We hypothesized that dog ownership and morning walking with the dog are associated with lower odds of depression, and that the latter is particularly beneficial for evening chronotypes by helping them to synchronize their biological clock with the solar system. METHODS: 26,169 depression-free US women aged 53-72 from the Nurses' Health Study 2 (NHS2) were prospectively followed from 2017-2019. We used age- and multivariable-adjusted logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (95%CIs) for depression according to dog ownership, and morning dog walking, duration, and timing. RESULTS: Overall, there was no association between owning a dog (ORvs_no_pets = 1.12, 95%CI = 0.91-1.37), morning dog walking (ORvs_not = 0.87, 95%CI = 0.64-1.18), or the duration (OR>30min vs. ≤15mins = 0.68, 95%CI = 0.35-1.29) or timing of morning dog walks (ORafter9am vs. before7am = 1.06, 95%CI = 0.54-2.05) and depression. Chronotype of dog owners appeared to modify these associations. Compared to women of the same chronotype but without pets, dog owners with evening chronotypes had a significantly increased odds of depression (OR = 1.60, 95%CI = 1.12-2.29), whereas morning chronotypes did not (OR = 0.94, 95%CI = 0.71-1.23). Further, our data suggested that evening chronotypes benefited more from walking their dog themselves in the morning (OR = 0.75, 95%CI = 0.46-1.23, Pintx = 0.064;) than morning chronotypes. CONCLUSIONS: Overall, dog ownership was not associated with depression risk though it was increased among evening chronotypes. Walking their dog in the morning might help evening chronotypes to lower their odds of depression, though more data are needed to confirm this finding.

The history of circadian rhythm research in Austria.

In view of the recent revival of interest in circadian biology and circadian epidemiology at the Medical University of Vienna, it seems appropriate to highlight the rich and pioneering history of circadian research in Austria. Among the forefathers of circadian research in Vienna are Otto Marburg (1874-1948), who discovered important elements of the pineal gland physiology, Robert Hofstätter (1883-1970), who used pineal gland extract in obstetrics/gynecology, and Paul Engel (1907-1997), who discovered that the pineal gland was controlled by light. More recently, Vera Lapin (1920-2007) showed that surgical removal of the pineal gland increased tumor growth, while Franz Waldhauser (*1946) investigated melatonin in conjunction with night work. Michael Kundi (*1950) and his team conducted among the first studies demonstrating differences in rhythms of night workers and early evidence for health impairments among them. Furthermore, Vienna-born Erhard Haus (1926-2013) pioneered the discovery of the role and importance of melatonin in relation to numerous diseases. This rich pioneering contribution of scientists in Vienna or with roots in Vienna is continued today by a new generation of chronobiologists, epidemiologists and clinicians in Vienna whose new insights contribute to the rapidly developing field of circadian rhythms research. Current topics and contributions relate to the impact of circadian rhythm disruption on health, and the application of chronotherapeutic approaches in clinical and preventive settings.

Eeny, meeny, miny, moe-Summer time and out are you? The working population in the EU would likely benefit from elimination of daylight saving time.

Daylight (saving) time (DST) is an over one century old practice to maximize the overlap between natural day light and individual active time (i.e., non-sleep time). Whether to abandon the practice is subject to an ongoing, twice a year intensifying debate. A request to abandon the practice is based on the lack of benefits in terms of energy savings and potential negative health effects. We present a tool that captures one key aspect of importance to the circadian system: maximizing the overlap of natural day light with human active time, focusing on early morning light exposure as the primary stimulus for our circadian system. Based on publicly available data we incorporated an approximation of the 27 European Union (EU) countries' spatial population distribution into a calculation of average exposure to morning sunlight under DST or no DST conditions for each EU27 country and the entire region. An online app offers visualization of these differences on the country level alongside a population-weighted average for the EU27. Our findings support that the majority of the EU's working population would likely benefit from the elimination of daylight saving time if maximizing an adequate morning stimulus is the primary goal and adjusting actual time zones or biennially changing the clock is not an option.

Rotating Night Shift Work, Sleep, and Thyroid Cancer Risk in the Nurses' Health Study 2.

Night shift work has been associated with breast, prostate, and colorectal cancer, but evidence on other types of cancer is limited. We prospectively evaluated the association of rotating night shift work, sleep duration, and sleep difficulty with thyroid cancer risk in the Nurses' Health Study 2 (NHS2). We assessed rotating night shift work duration (years) at baseline and throughout follow-up (1989-2015) and sleep characteristics in 2001. Cox proportional hazard models, adjusted for potential confounders, were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for (a) shift work duration, (b) sleep duration, and (c) difficulty falling or staying asleep. We stratified the analyses of night shift work by sleep duration and sleep difficulty. Over 26 years of follow-up, 588 incident cases were identified among 114,534 women in the NHS2 cohort. We observed no association between night shift work and the risk of thyroid cancer. Difficulty falling or staying asleep was suggestively associated with a higher incidence of thyroid cancer when reported sometimes (HR 1.26, 95% CI 0.95, 1.66) and all or most of the time (HR 1.35, 95% CI 1.00, 1.81). Night shift workers (10+ years) with sleep difficulty all or most of the time (HR 1.47; 0.58-3.73) or with >7 h of sleep duration (HR 2.17; 95% CI, 1.21-3.92) had a higher risk of thyroid cancer. We found modest evidence for an increased risk of thyroid cancer in relation to sleep difficulty, which was more pronounced among night shift workers.

Lack of Correlation Between Segmental Trabecular Meshwork Pigmentation and Angiographically Determined Outflow in Ex-Vivo Human Eyes.

PRECIS: Trabecular meshwork pigmentation is not correlated with angiographically determined aqueous humor outflow in an ex-vivo perfusion model using human eyes. PURPOSE: To evaluate whether segmental trabecular meshwork (TM) pigmentation is correlated to segmental aqueous humor outflow (AHO) in human eyes. METHODS: Post-mortem human eyes were acquired, and anterior segments were dissected. TM pigmentation was photographed 360-degrees around the eye. The anterior segments were then mounted onto a perfusion apparatus and perfused with DPBS until a stabile baseline outflow facility was achieved. Aqueous angiography (AHO angiography) was performed using fluorescein (2%), and segmental AHO was documented around the limbus using an angiographic camera (Spectralis HRA+OCT). Circumferential and nasal TM pigmentation were compared to respective angiographic outflow imaging using a Pearson's correlation analysis. RESULTS: Segmental TM pigment distribution and segmental AHO were seen. TM pigment was statistically greatest in the inferior quadrant. AHO angiographic outflow was numerically greatest in the nasal quadrant, but this was not statistically significant. No statistically significant correlation was observed (r=-0.083, P=0.06) between segmental TM pigmentation and segmental AHO angiographic signal. Analyzing just the nasal quadrant, a significant weak negative correlation was found (r=-0.296, P=0.001). DISCUSSION: Segmental TM pigmentation circumferentially around the eye is not a good proxy for segmental AHO circumferentially around the eye and should not be used to guide trabecular minimally invasive glaucoma surgeries.

Sleeping Difficulties, Sleep Duration, and Risk of Hypertension in Women.

BACKGROUND: Rates of poor sleep and hypertension are alarming worldwide. In this study, we investigate the association between sleeping difficulties and sleep duration with hypertension risk in women. METHODS: Sixty-six thousand one hundred twenty-two participants of the Nurses' Health Study 2, who were free of hypertension at baseline (2001), were followed prospectively for 16 years and incident hypertension assessed every 2 years. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for hypertension incidence associated with sleeping difficulties and sleep duration. RESULTS: During follow-up, we documented 25 987 incident cases of hypertension. After controlling for demographic and lifestyle risk factors, compared with women who slept 7 to 8 hours, women with shorter sleep duration had a significantly higher risk of hypertension (≤5 hours: HR, 1.10 [95% CI, 1.05-1.16]; 6 hours: HR, 1.07 [95% CI, 1.03-1.10]), whereas the risk for women with longer sleep duration was not statistically significant (9 hours: HR, 1.03 [95% CI, 0.97-1.10]; >9 hours: HR, 1.08 [95% CI, 0.94-1.23]). Compared with women rarely having difficulty falling or staying asleep, women sometimes or usually having these sleep difficulties had significantly higher risk of developing hypertension (HR, 1.14 [95% CI, 1.11-1.17] and 1.28 [95% CI, 1.22-1.35]; Ptrend<0.001). Early morning awakening was not associated with hypertension risk (Ptrend=0.722). There was no effect modification by night work or chronotype. CONCLUSIONS: Difficulty falling or staying asleep and short sleep duration were associated with higher risk of hypertension among women in our study. Screening for poor sleep could be useful in identifying people at higher risk for hypertension.

Sex differences in the survival benefit of kidney transplantation: a retrospective cohort study using target trial emulation.

BACKGROUND: Kidney transplantation is the preferred treatment for eligible patients with kidney failure who need renal replacement therapy. However, it remains unclear whether the anticipated survival benefit from kidney transplantation is different for women and men. METHODS: We included all dialysis patients recorded in the Austrian Dialysis and Transplant Registry who were waitlisted for their first kidney transplant between 2000 and 2018. In order to estimate the causal effect of kidney transplantation on 10-year restricted mean survival time, we mimicked a series of controlled clinical trials and applied inverse probability of treatment and censoring weighted sequential Cox models. RESULTS: This study included 4408 patients (33% female) with a mean age of 52 years. Glomerulonephritis was the most common primary renal disease both in women (27%) and men (28%). Kidney transplantation led to a gain of 2.22 years (95% CI 1.88 to 2.49) compared with dialysis over a 10-year follow-up. The effect was smaller in women (1.95 years, 95% CI 1.38 to 2.41) than in men (2.35 years, 95% CI 1.92 to 2.70) due to a better survival on dialysis. Across ages the survival benefit of transplantation over a follow-up of 10 years was smaller in younger women and men and increased with age, showing a peak for both women and men aged about 60 years. CONCLUSIONS: There were few differences in survival benefit by transplantation between females and males. Females had better survival than males on the waitlist receiving dialysis and similar survival to males after transplantation.

Time Spent Outdoors and Associations with Sleep, Optimism, Happiness and Health before and during the COVID-19 Pandemic in Austria.

Social restriction measures (SRM) implemented during the COVID-19 pandemic led to a reduction in time spent outdoors (TSO). The aim of this study was to describe TSO and evaluate its association with sleep outcomes, optimism, happiness and health-status before and during SRM. Two online surveys were conducted in 2017 (N = 1004) and 2020, during SRM (N = 1010), in samples representative of the age, sex and region of the Austrian population. Information on the duration of TSO, sleep, optimism, happiness and health-status was collected. Multivariable-adjusted logistic regression models were used to study the association of TSO with chronic insomnia, short sleep, late chronotype, optimism, happiness and self-rated health-status. The mean TSO was 3.6 h (SD: 2.18) in 2017 and 2.6 h (SD: 1.87) during times of SRM. Men and participants who were older, married or in a partnership and lived in a rural area reported longer TSO. Participants who spent less time outdoors were more likely to report short sleep or a late chronotype in both surveys and, in 2020, also chronic insomnia. Less TSO was associated with lower happiness and optimism levels and poor health-status. Our findings suggest that TSO may be a protective factor for sleep, mood and health, particularly during stressful and uncertain times.

Suicide mortality among physicians, dentists, veterinarians, and pharmacists as well as other high-skilled occupations in Austria from 1986 through 2020.

Some evidence puts health professionals at increased risk of suicide, especially females, whereas other research suggests a lower risk in high-skilled occupations. This study investigated the suicide risk of four health professions (physicians, dentists, veterinarians, pharmacists) and three other high-skilled occupations (notaries, lawyers, tax advisors/public accountants) in Austria compared to the general population, and analyzed suicide methods across occupations. Data was collected from professional associations and Austrian cause-of-death statistics to determine suicide cases. Gender-specific standardized mortality ratios (SMRs), crude and age-adjusted suicide rates and frequencies for suicide methods were calculated for each profession (maximum time span 1986-2020). Among males, only veterinarians had a significantly elevated suicide risk compared to the general population. Physicians and tax advisors/public accountants had a significantly lower suicide risk. Among females, the veterinarians, physicians, and pharmacists had a significantly elevated suicide risk; for dentists, it was also elevated, though non-significantly. Age-adjusted suicide rates showed a smaller gap between men and women in all professions compared to the general population. Poisoning was the predominant suicide method among health professions, except dentists. These findings are consistent with some of the prior literature and call for specific suicide prevention efforts in health professions, focusing on women.

The association between night shift work and breast cancer risk in the Finnish twins cohort.

Breast cancer is highly prevalent yet a more complete understanding of the interplay between genes and probable environmental risk factors, such as night work, remains lagging. Using a discordant twin pair design, we examined the association between night shift work and breast cancer risk, controlling for familial confounding. Shift work pattern was prospectively assessed by mailed questionnaires among 5,781 female twins from the Older Finnish Twin Cohort. Over the study period (1990-2018), 407 incident breast cancer cases were recorded using the Finnish Cancer Registry. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusting for potential confounders. Within-pair co-twin analyses were employed in 57 pairs to account for potential familial confounding. Compared to women who worked days only, women with shift work that included night shifts had a 1.58-fold higher risk of breast cancer (HR = 1.58; 95%CI, 1.16-2.15, highest among the youngest women i.e. born 1950-1957, HR = 2.08; 95%CI, 1.32-3.28), whereas 2-shift workers not including night shifts, did not (HR = 0.84; 95%CI, 0.59-1.21). Women with longer sleep (average sleep duration > 8 h/night) appeared at greatest risk of breast cancer if they worked night shifts (HR = 2.91; 95%CI, 1.55-5.46; Pintx=0.32). Results did not vary by chronotype (Pintx=0.74). Co-twin analyses, though with limited power, suggested that night work may be associated with breast cancer risk independent of early environmental and genetic factors. These results confirm a previously described association between night shift work and breast cancer risk. Genetic influences only partially explain these associations.

Rotating Night Shift Work and Bladder Cancer Risk in Women: Results of Two Prospective Cohort Studies.

Bladder cancer is the sixth most common cancer in the United States. Night shift work has previously been linked with cancer risk. Whether there is an association between rotating night shift work and bladder cancer in women has not been studied previously. Eligible participants in the Nurses' Health Study (NHS, n = 82,147, 1988-2016) and Nurses' Health Study II (NHSII, n = 113,630, 1989-2015) were prospectively followed and a total of 620 and 122 incident bladder cancer cases were documented during the follow-up of NHS and NHSII, respectively. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for bladder cancer incidence. We observed a significantly increased risk of bladder cancer among women with >5 years of night shift work history compared with women who never worked rotating night shifts in NHS (HR = 1.24; 95%CI = 1.01-1.54, p for trend = 0.06), but not in the pooled NHS and NHS II (HR = 1.18; 95%CI = 0.97-1.43, p for trend = 0.08). Secondary analyses stratified by smoking status showed no significant interaction (p = 0.89) between the duration of rotating night shift work and smoking status. In conclusion, our results did not provide strong evidence for an association between rotating night shift work and bladder cancer risk.

Relationship between pet ownership and risk of high depressive symptoms in adolescence and young adulthood.

BACKGROUND: Only few longitudinal studies with high risk of bias have examined relationship between pets and adolescents' mental health. METHODS: Our prospective cohort study followed depression-free US adolescents aged 12-18, enrolled in the Growing Up Today Study from pet ownership assessment in 1999 to possible occurrence of high depressive symptoms defined based on the McKnight Risk Factor Survey between 2001 and 2003. Propensity-score-adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) were estimated using generalized estimating equation models. RESULTS: Among 9631 adolescents [42.4 % male, mean age 14.9 years (SD 1.6)], we found no association between pet ownership and risk of high depressive symptoms (ORany_pet = 1.14; 95%CI, 0.95-1.38). Stratified analyses revealed no evidence of effect modification by sex, but effect modification by maternal history of depression (depressed mothers ORany_pet = 0.83; 95 % CI: 0.58-1.19, non-depressed mothers ORany_pet = 1.27; 95 % CI: 1.02-1.58; Pintx = 0.03), which differed further by children's sex. Effects were more pronounced among children with a history of childhood abuse (ORany_pet = 0.41 (0.14-1.15); Pintx ≤0.03). No major differences by type of pet owned were observed in any of these analyses. LIMITATIONS: Our sample is predominantly white and all are offspring of nurses with a similar academic background which could affect generalizability. CONCLUSIONS: Overall, we found no association between pet ownership and depression during adolescence, however subgroup analyses indicated some individuals may benefit from a pet. Future longitudinal studies with more detailed exposure assessments, including pet attachment are needed to further explore the potential of human-animal interaction on mental health.

Maternal adherence to healthy lifestyle and risk of depressive symptoms in the offspring: mediation by offspring lifestyle.

BACKGROUND: Adherence to healthy lifestyles can be beneficial for depression among adults, but the intergenerational impact of maternal healthy lifestyles on offspring depressive symptoms is unknown. METHODS: In total, 10 368 mothers in Nurses' Health Study II and 13 478 offspring in the Growing Up Today Study were paired. Maternal and offspring healthy lifestyles were defined as a composite score including a healthy diet, normal body mass index (BMI), never-smoking, light-to-moderate consumption of alcohol, and regular moderate-to-vigorous physical activity. Maternal lifestyles were assessed during their offspring's childhood. Offspring depressive symptoms were repeatedly assessed five times using the Center for Epidemiological Studies Depression Scale-10 (CESD-10); the offspring were between the ages of 14 and 30 when the first CESD-10 was assessed. Covariates included maternal variables (age at baseline, race/ethnicity, antidepressant use, pregnancy complications, etc.) and offspring age and sex. RESULTS: Children of mothers with the healthiest lifestyle had significantly fewer depressive symptoms (a 0.30 lower CESD-10 score, 95% confidence interval (CI) 0.09-0.50) in comparison with children of mothers with the least healthy lifestyle. The association was only found significant in female offspring but not in males. For individual maternal lifestyle factors, a normal BMI, never-smoking, and adherence to regular physical activity were independently associated with fewer depressive symptoms among the offspring. The association between maternal healthy lifestyles and offspring depressive symptoms was mediated by offspring's healthy lifestyles (mediation effect: 53.2%, 95% CI 15.8-87.3). CONCLUSIONS: Our finding indicates the potential mechanism of intergenerational transmission of healthy lifestyles to reduce the risk of depressive symptoms in offspring.

Survival Benefit of First Single-Organ Deceased Donor Kidney Transplantation Compared With Long-term Dialysis Across Ages in Transplant-Eligible Patients With Kidney Failure.

Importance: Kidney transplant is considered beneficial in terms of survival compared with continued dialysis for patients with kidney failure. However, randomized clinical trials are infeasible, and available evidence from cohort studies is at high risk of bias. Objective: To compare restricted mean survival times (RMSTs) between patients who underwent transplant and patients continuing dialysis across transplant candidate ages and depending on waiting time, applying target trial emulation methods. Design, Setting, and Participants: In this retrospective cohort study, patients aged 18 years or older appearing on the wait list for their first single-organ deceased donor kidney transplant between January 1, 2000, and December 31, 2018, in Austria were evaluated. Available data were obtained from the Austrian Dialysis and Transplant Registry and Eurotransplant and included repeated updates on wait-listing status and relevant covariates. Data were analyzed between August 1, 2019, and December 23, 2021. Exposures: A target trial was emulated in which patients were randomized to either receive the transplant immediately (treatment group) or to continue dialysis and never receive a transplant (control group) at each time an organ became available. Main Outcomes and Measures: The primary outcome was time from transplant allocation to death. Effect sizes in terms of RMSTs were obtained using a sequential Cox approach. Results: Among the 4445 included patients (2974 men [66.9%]; mean [SD] age, 52.2 [13.2] years), transplant was associated with increased survival time across all considered ages compared with continuing dialysis and remaining on the wait list within a 10-year follow-up. The estimated RMST differences were 0.57 years (95% CI, -0.14 to 1.84 years) at age 20 years, 3.01 years (95% CI, 2.50 to 3.54 years) at age 60 years, and 2.48 years (95% CI, 1.88 to 3.04 years) at age 70 years. The survival benefit for patients who underwent transplant across ages was independent of waiting time. Conclusions and Relevance: The findings of this study suggest that kidney transplant prolongs the survival time of persons with kidney failure across all candidate ages and waiting times.

A comparison of full model specification and backward elimination of potential confounders when estimating marginal and conditional causal effects on binary outcomes from observational data.

A common view in epidemiology is that automated confounder selection methods, such as backward elimination, should be avoided as they can lead to biased effect estimates and underestimation of their variance. Nevertheless, backward elimination remains regularly applied. We investigated if and under which conditions causal effect estimation in observational studies can improve by using backward elimination on a prespecified set of potential confounders. An expression was derived that quantifies how variable omission relates to bias and variance of effect estimators. Additionally, 3960 scenarios were defined and investigated by simulations comparing bias and mean squared error (MSE) of the conditional log odds ratio, log(cOR), and the marginal log risk ratio, log(mRR), between full models including all prespecified covariates and backward elimination of these covariates. Applying backward elimination resulted in a mean bias of 0.03 for log(cOR) and 0.02 for log(mRR), compared to 0.56 and 0.52 for log(cOR) and log(mRR), respectively, for a model without any covariate adjustment, and no bias for the full model. In less than 3% of the scenarios considered, the MSE of the log(cOR) or log(mRR) was slightly lower (max 3%) when backward elimination was used compared to the full model. When an initial set of potential confounders can be specified based on background knowledge, there is minimal added value of backward elimination. We advise not to use it and otherwise to provide ample arguments supporting its use.

Waiting Time for Second Kidney Transplantation and Mortality.

BACKGROUND AND OBJECTIVES: The median kidney transplant half-life is 10-15 years. Because of the scarcity of donor organs and immunologic sensitization of candidates for retransplantation, there is a need for quantitative information on if and when a second transplantation is no longer associated with a lower risk of mortality compared with waitlisted patients treated by dialysis. Therefore, we investigated the association of time on waiting list with patient survival in patients who received a second transplantation versus remaining on the waiting list. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this retrospective study using target trial emulation, we analyzed data of 2346 patients from the Austrian Dialysis and Transplant Registry and Eurotransplant with a failed first graft, aged over 18 years, and waitlisted for a second kidney transplantation in Austria during the years 1980-2019. The differences in restricted mean survival time and hazard ratios for all-cause mortality comparing the treatment strategies "retransplant" versus "remain waitlisted with maintenance dialysis" are reported for different waiting times after first graft loss. RESULTS: Second kidney transplantation showed a longer restricted mean survival time at 10 years of follow-up compared with remaining on the waiting list (5.8 life months gained; 95% confidence interval, 0.9 to 11.1). This survival difference was diminished in patients with longer waiting time after loss of the first allograft; restricted mean survival time differences at 10 years were 8.0 (95% confidence interval, 1.9 to 14.0) and 0.1 life months gained (95% confidence interval, -14.3 to 15.2) for patients with waiting time for retransplantation of <1 and 8 years, respectively. CONCLUSIONS: Second kidney transplant is associated with patient survival compared with remaining waitlisted and treatment by dialysis, but the survival difference diminishes with longer waiting time.

Mucosal Biofilms Are an Endoscopic Feature of Irritable Bowel Syndrome and Ulcerative Colitis.

BACKGROUND & AIMS: Irritable bowel syndrome (IBS) and inflammatory bowel diseases result in a substantial reduction in quality of life and a considerable socioeconomic impact. In IBS, diagnosis and treatment options are limited, but evidence for involvement of the gut microbiome in disease pathophysiology is emerging. Here we analyzed the prevalence of endoscopically visible mucosal biofilms in gastrointestinal disease and associated changes in microbiome composition and metabolism. METHODS: The presence of mucosal biofilms was assessed in 1426 patients at 2 European university-based endoscopy centers. One-hundred and seventeen patients were selected for in-depth molecular and microscopic analysis using 16S ribosomal RNA gene amplicon-sequencing of colonic biopsies and fecal samples, confocal microscopy with deep learning-based image analysis, scanning electron microscopy, metabolomics, and in vitro biofilm formation assays. RESULTS: Biofilms were present in 57% of patients with IBS and 34% of patients with ulcerative colitis compared with 6% of controls (P < .001). These yellow-green adherent layers of the ileum and right-sided colon were microscopically confirmed to be dense bacterial biofilms. 16S-sequencing links the presence of biofilms to a dysbiotic gut microbiome, including overgrowth of Escherichia coli and Ruminococcus gnavus. R. gnavus isolates cultivated from patient biofilms also formed biofilms in vitro. Metabolomic analysis found an accumulation of bile acids within biofilms that correlated with fecal bile acid excretion, linking this phenotype with a mechanism of diarrhea. CONCLUSIONS: The presence of mucosal biofilms is an endoscopic feature in a subgroup of IBS and ulcerative colitis with disrupted bile acid metabolism and bacterial dysbiosis. They provide novel insight into the pathophysiology of IBS and ulcerative colitis, illustrating that biofilm can be seen as a tipping point in the development of dysbiosis and disease.

Regression with Highly Correlated Predictors: Variable Omission Is Not the Solution.

Regression models have been in use for decades to explore and quantify the association between a dependent response and several independent variables in environmental sciences, epidemiology and public health. However, researchers often encounter situations in which some independent variables exhibit high bivariate correlation, or may even be collinear. Improper statistical handling of this situation will most certainly generate models of little or no practical use and misleading interpretations. By means of two example studies, we demonstrate how diagnostic tools for collinearity or near-collinearity may fail in guiding the analyst. Instead, the most appropriate way of handling collinearity should be driven by the research question at hand and, in particular, by the distinction between predictive or explanatory aims.