A Prospective Cohort Study of Persistent Endocrine Disrupting Chemicals and Perceived Stress.

Persistent endocrine disrupting chemicals (EDCs) can dysregulate the stress response. We evaluated associations between persistent EDCs and perceived stress among participants from the Study of Environment, Lifestyle and Fibroids (n=1,394), a prospective cohort study of Black women. Participants completed the Perceived Stress Scale (PSS-4) at baseline, and every 20 months through 60 months (range of scores: 0-16); higher scores indicated higher stress. EDCs, including per- and polyfluoroalkyl substances (PFAS), polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and organochlorine pesticides, were quantified in plasma samples at baseline. We fit Bayesian Kernel Machine Regression (BKMR) and linear mixed effects models to estimate associations of EDCs (as a mixture and individually) with PSS-4 scores at baseline and at each follow-up visit, respectively. Increasing percentiles of the mixture were not strongly associated with PSS-4 scores at baseline, and no interactions were observed among EDCs. Several individual EDCs (e.g., PFDA, PCB 118, PBDE 99) were associated with higher PSS-4 scores at baseline or follow-up, while other EDCs (e.g., PCB 138/158) were associated with lower PSS-4 scores at baseline or follow-up. The directionality of associations for individual EDCs was inconsistent across follow-up visits. In conclusion, specific EDCs may be associated with perceived stress in Black women.

Aduhelm, the Newly Approved Medication for Alzheimer Disease: What Epidemiologists Can Learn and What Epidemiology Can Offer.

Alzheimer disease (AD) is a progressive disorder common among older adults and culminating in profound cognitive impairments and high mortality risk. The US Food and Drug Administration (FDA) recently provided accelerated approval for Aduhelm, a medication for AD treatment. Aduhelm (Biogen Inc., Cambridge, Massachusetts) has been described as the first disease-modifying treatment for AD but has not been demonstrated to improve patients' cognitive or functional outcomes. In this commentary, we describe why Aduhelm approval was controversial and aspects of the current evidence of special pertinence to epidemiologists. The FDA decision was based primarily on 2 randomized controlled trials (RCTs), both terminated early, with conflicting findings about the cognitive benefits of Aduhelm. Both RCTs showed important adverse effects of the medication. The FDA cited the documented reduction in brain amyloid, an AD biomarker hypothesized as a surrogate outcome, to justify accelerated approval. Despite lack of racial/ethnic diversity in the RCT participants, concerns about health disparities have been invoked to argue for public funding of this expensive medication. The Centers for Medicare and Medicaid Services recently made a "Coverage with Evidence Development" determination for Aduhelm and similar medications. We end by describing how innovative study designs could accelerate postapproval research and evaluate the proposed surrogate outcomes.

Relationship Between Level of American Football Playing and Diagnosis of Chronic Traumatic Encephalopathy in a Selection Bias Analysis.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts such as those from American football. Our understanding of this association is based on research in autopsied brains, since CTE can only be diagnosed postmortem. Such studies are susceptible to selection bias, which needs to be accounted for to ensure a generalizable estimate of the association between repetitive head impacts and CTE. We evaluated the relationship between level of American football playing and CTE diagnosis after adjusting for selection bias. The sample included 290 deceased male former American football players who donated their brains to the Veterans Affairs-Boston University-Concussion Legacy Foundation (VA-BU-CLF) Brain Bank between 2008 and 2019. After adjustment for selection bias, college-level and professional football players had 2.38 (95% simulation interval (SI): 1.16, 5.94) and 2.47 (95% SI: 1.46, 4.79) times the risk of being diagnosed with CTE as high-school-level players, respectively; these estimates are larger than estimates with no selection bias adjustment. Since CTE is currently diagnosed only postmortem, we additionally provide plausible scenarios for CTE risk ratios for each level of play during the former players' lifetime. This study provides further evidence to support a dose-response relationship between American football playing and CTE.

A Prospective Ultrasound Study of Plasma Polychlorinated Biphenyl Concentrations and Incidence of Uterine Leiomyomata.

BACKGROUND: Uterine leiomyomata, or fibroids, are hormone-dependent neoplasms of the myometrium that can cause severe gynecologic morbidity. In previous studies, incidence of these lesions has been positively associated with exposure to polychlorinated biphenyls (PCBs), a class of persistent endocrine-disrupting chemicals. However, previous studies have been retrospective in design and none has used ultrasound to reduce disease misclassification. METHODS: The Study of Environment, Lifestyle, and Fibroids is a prospective cohort of 1,693 reproductive-aged Black women residing in Detroit, Michigan (enrolled during 2010-2012). At baseline and every 20 months for 5 years, women completed questionnaires, provided blood samples, and underwent transvaginal ultrasound to detect incident fibroids. We analyzed 754 baseline plasma samples for concentrations of 24 PCB congeners using a case-cohort study design. We used multivariable Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals for the association between plasma PCB concentrations and ultrasound-detected fibroid incidence over a 5-year period. RESULTS: We observed little association between PCB congener concentrations and fibroid incidence. The HR for a one-standard deviation increase in log-transformed total PCBs was 0.94 (95% CI = 0.78, 1.1). The PCB congener with the largest effect estimate was PCB 187 (HR for a one-standard deviation increase in log-transformed exposure = 0.88, 95% CI = 0.73, 1.1). Associations did not seem to vary strongly across PCB groupings based on hormonal activity. CONCLUSIONS: In this cohort of reproductive-aged Black women, plasma PCB concentrations typical of the contemporary general population were not appreciably associated with higher risk of fibroids.

Remote Blood Biomarkers of Longitudinal Cognitive Outcomes in a Population Study.

OBJECTIVE: The longitudinal association of the blood biomarkers total tau (t-tau), neurofilament light (Nf-L), and glial fibrillary acidic protein (GFAP) with common sporadic Alzheimer disease (AD) and cognitive decline is not established. METHODS: Using a single molecule array technology, ultrasensitive immunoassays for serum concentrations of t-tau, Nf-L, and GFAP were measured in a population sample of 1,327 participants (60% African Americans and women) who had a clinical evaluation for AD, had completed in-home cognitive assessments, and had undergone 1.5T structural magnetic resonance imaging. RESULTS: Higher concentrations of serum biomarkers were associated with the development of clinical AD; especially, the time-specific associations were notable: t-tau 8 to 16 years, and Nf-L and GFAP 4 to 8 years prior to clinical AD. Serum biomarkers were associated with faster cognitive decline over 16 years; baseline t-tau > 0.40pg/ml had 30% faster decline, Nf-L > 25.5pg/ml had 110% faster decline, and GFAP > 232pg/ml had 130% faster decline compared to those in the lowest quartile. Participants with baseline GFAP > 232pg/ml showed 160% faster decline in hippocampal volume compared to those with values < 160pg/ml. Additionally, higher baseline t-tau was associated with faster increase in 3rd ventricular volume, and baseline Nf-L and GFAP were associated with faster decline in cortical thickness. INTERPRETATION: Serum t-tau, Nf-L, and GFAP predict the development of sporadic AD and cognitive decline, and changes in structural brain characteristics, suggesting their usefulness not only as screening and predictive biomarkers, but also in capturing the pathogenesis of Alzheimer dementia. ANN NEUROL 2020;88:1065-1076.

Duration of American Football Play and Chronic Traumatic Encephalopathy.

OBJECTIVE: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to contact and collision sports, including American football. We hypothesized a dose-response relationship between duration of football played and CTE risk and severity. METHODS: In a convenience sample of 266 deceased American football players from the Veterans Affairs-Boston University-Concussion Legacy Foundation and Framingham Heart Study Brain Banks, we estimated the association of years of football played with CTE pathological status and severity. We evaluated the ability of years played to classify CTE status using receiver operating characteristic curve analysis. Simulation analyses quantified conditions that might lead to selection bias. RESULTS: In total, 223 of 266 participants met neuropathological diagnostic criteria for CTE. More years of football played were associated with having CTE (odds ratio [OR] = 1.30 per year played, 95% confidence interval [CI] = 1.19-1.41; p = 3.8 × 10-9 ) and with CTE severity (severe vs mild; OR = 1.14 per year played, 95% CI = 1.07-1.22; p = 3.1 × 10-4 ). Participants with CTE were 1/10th as likely to have played <4.5 years (negative likelihood ratio [LR] = 0.102, 95% CI = 0.100-0.105) and were 10 times as likely to have played >14.5 years (positive LR = 10.2, 95% CI = 9.8-10.7) compared with participants without CTE. Sensitivity and specificity were maximized at 11 years played. Simulation demonstrated that years played remained adversely associated with CTE status when years played and CTE status were both related to brain bank selection across widely ranging scenarios. INTERPRETATION: The odds of CTE double every 2.6 years of football played. After accounting for brain bank selection, the magnitude of the relationship between years played and CTE status remained consistent. ANN NEUROL 2020;87:116-131.

Correlates of Persistent Endocrine-Disrupting Chemical Mixtures among Reproductive-Aged Black Women.

Black women are exposed to multiple endocrine-disrupting chemicals (EDCs), but few studies have examined their profiles of exposure to EDC mixtures. We identified biomarker profiles and correlates of exposure to EDC mixtures in a cross-sectional analysis of data from a prospective cohort study of 749 Black women aged 23-35 years. We quantified plasma concentrations of polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), organochlorine pesticides (OCPs), and per- and polyfluoroalkyl substances (PFAS) in nonfasting samples collected at baseline. Demographic, behavioral, dietary, and reproductive covariates were also collected at baseline. We used k-means clustering and principal component analysis (PCA) to describe concentration profiles of EDC mixtures (17 PCBs, 6 PBDEs, 4 OCPs, 6 PFAS), followed by multinomial logistic and multivariable linear regression to estimate mean differences in PCA scores (ß) and odds ratios (ORs) of cluster membership with their respective 95% confidence intervals (CIs). Older age (per 1 year increase: ß = 0.47, CI = 0.39, 0.54; OR = 1.27, CI = 1.20, 1.35), lower body mass index (per 1 kg/m2 increase: ß = -0.14, CI = -0.17, -0.12; OR = 0.91, CI = 0.89, 0.94), and current smoking (≥10 cigarettes/day vs never smokers: ß = 1.37, CI = 0.20, 2.55; OR = 2.63, CI = 1.07, 6.50) were associated with profiles characterized by higher concentrations of all EDCs. Other behaviors and traits, including dietary factors and years since last birth, were also associated with EDC mixtures.

Population estimate of people with clinical Alzheimer's disease and mild cognitive impairment in the United States (2020-2060).

INTRODUCTION: The estimate of people with clinical Alzheimer's disease (AD) and mild cognitive impairment provides an understanding of the disease burden. METHODS: We estimated people with cognitive impairment using a quasibinomial regression model in 10,342 participants with cognitive test scores. RESULTS: The 2020 US Census-adjusted prevalence of clinical AD was 11.3% (95% confidence interval [CI] = 10.7-11.9): 10.0% among non-Hispanic Whites, 14.0% among Hispanics, and 18.6% among non-Hispanic Blacks. We estimate that in 2020, 6.07 (95% CI = 5.75-6.38) million people were living with clinical AD, which increases to 13.85 (95% CI = 12.98-14.74) million in 2060, 423% higher among Hispanics, 192% higher among Blacks, and 63% higher among Whites. However, there are predicted to be more significant increases in later years among those over 85 and women compared to men. DISCUSSION: The number of people with clinical AD will increase as the "baby boom" generation reaches older ages, exerting a strong upward influence on disease burden.

Long-term community noise exposure in relation to dementia, cognition, and cognitive decline in older adults.

INTRODUCTION: Exposure to noise might influence risk of Alzheimer's disease (AD) dementia. METHODS: Participants of the Chicago Health and Aging Project (≥65 years) underwent triennial cognitive assessments. For the 5 years preceding each assessment, we estimated 5227 participants' residential level of noise from the community using a spatial prediction model, and estimated associations of noise level with prevalent mild cognitive impairment (MCI) and AD, cognitive performance, and rate of cognitive decline. RESULTS: Among these participants, an increment of 10 A-weighted decibels (dBA) in noise corresponded to 36% and 29% higher odds of prevalent MCI (odds ratio [OR] = 1.36; 95% confidence interval [CI], 1.15 to 1.62) and AD (OR = 1.29, 95% CI, 1.08 to 1.55). Noise level was associated with worse global cognitive performance, principally in perceptual speed (-0.09 standard deviation per 10 dBA, 95% CI: -0.16 to -0.03), but not consistently associated with cognitive decline. DISCUSSION: These results join emerging evidence suggesting that noise may influence late-life cognition and risk of dementia.

The Society for Epidemiologic Research and the Future of Diversity and Inclusion in Epidemiology.

"The mission of the Diversity and Inclusion Committee (D&I) in the Society for Epidemiologic Research is to foster the diversity of our membership and work towards the engagement of all members, from diverse backgrounds at all stages of their careers, in the Society's activities, with the intent of enhancing discovery in public health." As a foundational step in implementing our mission, the D&I Committee conducted a survey of SER membership. Here we report on the efforts we have undertaken to expand the diversity and inclusiveness of our Society and our aspirations for future efforts in support of D&I. Early on, we established the SERvisits program to conduct outreach to institutions and students that have historically been underrepresented at SER; we hope this program continues to grow in its reach and impact. We have also taken steps to increase the inclusiveness of SER activities, for example, by engaging members on issues of D&I through symposia and workshops at SER annual meetings and through social media. DeVilbiss et al. (Am J Epidemiol. 2020;189(10):998-1010) have demonstrated that there is substantial room for improvement with regards to diversity and inclusion within SER. We invite SER members to become involved and collaborate on this long-term goal.

Assessing Representation and Perceived Inclusion among Members in the Society for Epidemiologic Research.

Using web-based survey data collected June - August 2018 from the Society for Epidemiologic Research (SER) members, we characterized numerous dimensions of social identity and lived experience, and assessed relationships between these characteristics and perceptions of inclusion and society participation. We quantified associations between characteristics, feeling very welcomed, high (top 25th percentile) self-initiated participation, and any (top 10th percentile) society-initiated participation. Racial/ethnic and religious minority categories were blinded to preserve anonymity and we accounted for missing data. Most 2018 SER members (n = 1631) were white (62%) or female (66%). Females with racial/ethnic non-response were least likely, while white males were most likely to report feeling very welcomed. Members who did not report race, identified with a specific racial/ethnic minority, or were politically conservative/right-leaning were less likely than white or liberal/left-leaning members to have high self-initiated participation. Women and individuals of a specific racial/ethnic minority or minority religious affiliations were less likely to participate in events initiated by the society. These data represent a baseline for assessing trends and the impact of future initiatives aimed at improving diversity, inclusion, representation and participation within SER.

Changes in Behavior with Increasing Pregnancy Attempt Time: A Prospective Cohort Study.

BACKGROUND: The extent to which couples change their behaviors with increasing pregnancy attempt time is not well documented. METHODS: We examined change in selected behaviors over pregnancy attempt time in a North American preconception cohort study. Eligible females were ages 21-45 years and not using fertility treatment. Participants completed baseline and bimonthly follow-up questionnaires for up to 12 months or until pregnancy. RESULTS: Among 3,339 females attempting pregnancy for 0-1 cycles at enrollment, 250 contributed 12 months of follow-up without conceiving. Comparing behaviors at 12 months versus baseline, weighted for loss-to-follow-up, we observed small-to-moderate reductions in mean caffeine intake (-19.5 mg/day, CI = -32.7, -6.37), alcohol intake (-0.85 drinks/week, CI = -1.28, -0.43), marijuana use (-3.89 percentage points, CI = -7.33, 0.46), and vigorous exercise (-0.68 hours/week, CI = -1.05, -0.31), and a large increase in activities to improve conception chances (e.g., ovulation testing) (21.7 percentage points, CI = 14.8, 28.6). There was little change in mean cigarette smoking (-0.27 percentage points, CI = -1.58, 1.04), perceived stress scale score (-0.04 units, CI = -0.77, 0.69), or other factors (e.g., sugar-sweetened soda intake, moderate exercise, intercourse frequency, and multivitamin use), but some heterogeneity within subgroups (e.g., 31% increased and 32% decreased their perceived stress scores by ≥2 units; 14% reduced their smoking but none increased their smoking by ≥5 cigarettes/day). CONCLUSIONS: Although many behaviors changed with increasing pregnancy attempt time, mean changes tended to be modest for most variables. The largest differences were observed for the use of caffeine, alcohol, and marijuana, and methods to improve conception chances.

Tissue Specific Fate of Nanomaterials by Advanced Analytical Imaging Techniques - A Review.

A variety of imaging and analytical methods have been developed to study nanoparticles in cells. Each has its benefits, limitations, and varying degrees of expense and difficulties in implementation. High-resolution analytical scanning transmission electron microscopy (HRSTEM) has the unique ability to image local cellular environments adjacent to a nanoparticle at near atomic resolution and apply analytical tools to these environments such as energy dispersive spectroscopy and electron energy loss spectroscopy. These tools can be used to analyze particle location, translocation and potential reformation, ion dispersion, and in vivo synthesis of second-generation nanoparticles. Such analyses can provide in depth understanding of tissue-particle interactions and effects that are caused by the environmental "invader" nanoparticles. Analytical imaging can also distinguish phases that form due to the transformation of "invader" nanoparticles in contrast to those that are triggered by a response mechanism, including the commonly observed iron biomineralization in the form of ferritin nanoparticles. The analyses can distinguish ion species, crystal phases, and valence of parent nanoparticles and reformed or in vivo synthesized phases throughout the tissue. This article will briefly review the plethora of methods that have been developed over the last 20 years with an emphasis on the state-of-the-art techniques used to image and analyze nanoparticles in cells and highlight the sample preparation necessary for biological thin section observation in a HRSTEM. Specific applications that provide visual and chemical mapping of the local cellular environments surrounding parent nanoparticles and second-generation phases are demonstrated, which will help to identify novel nanoparticle-produced adverse effects and their associated mechanisms.

Blood pressure and risk of incident Alzheimer's disease dementia by antihypertensive medications and APOE ε4 allele.

OBJECTIVE: To examine the association of blood pressure (BP) with incident Alzheimer's disease (AD) dementia. METHODS: This work is based on a longitudinal, cohort study of 18 years, the Chicago Health and Aging Project (CHAP) performed in 2,137 participants (55% black) with systolic BP measured around 8.1 years before incident AD dementia. RESULTS: The association of BP with risk of AD dementia was U-shaped, with the lowest risks of AD dementia near the center of the systolic BP (SBP) and diastolic BP (DBP) distributions, and modestly elevated risk at lower BPs, and greater risk at higher BPs. The degree of U-shape and the range of lowest risk (threshold ranges) varied with antihypertensive medication use and presence of the APOE ε4 allele. The U-shape was most prominent for the subgroup not taking antihypertensive medications and having an APOE ε4 allele. At higher BPs, those having the APOE ε4 allele and not receiving antihypertensive medication were at greater risk of AD dementia than other groups: The risk of incident AD dementia increased by 100% (relative risk [RR] = 2.00; 95% confidence interval [CI] = 1.70, 2.31) for every 10 mm Hg increase in SBP above 140 mm Hg. For DBP, the risk of incident of AD dementia increased by 57% (RR = 1.57; 95% CI = 1.33, 1.86) for every 5 mm Hg increase in DBP above 76 mm Hg. INTERPRETATION: The BP risk of AD dementia association is U-shaped, with elevated risk at lower and higher BPs. People having the APOE ε4 allele and not receiving antihypertensive medication with higher BPs have notably elevated risk of AD dementia. Ann Neurol 2018;83:935-944.

Prevalence and incidence of clinically diagnosed Alzheimer's disease dementia from 1994 to 2012 in a population study.

INTRODUCTION: The trends in prevalence and incidence of Alzheimer's disease (AD) dementia remain uncertain. METHODS: A sample of 2794 participants with a clinical diagnosis for AD dementia were included. RESULTS: The 2010 census standardized prevalence of AD dementia was 14.5% (95% CI = 13.7-15.3), and annual incidence was 2.3% (1.7-2.9). Both prevalence and incidence showed substantial variation over time, but no secular trends. The prevalence of AD dementia did not change significantly from 14.6% (95% CI = 13.0, 16.2) in 1994-1997 to 14.7% (95% CI = 13.2, 16.2) in 2010-2012 (P = .84). The annual incidence of AD dementia was 2.8% (95% CI = 2.2, 3.2) in 1998-2000 and 2.2% (95% CI = 1.6, 2.8) in 2004-2006 (P = .20) and remained steady in 2010-2012. The prevalence and incidence among African Americans were approximately twice than those among European Americans. CONCLUSIONS: The prevalence and incidence of AD dementia showed substantial variation between 1994 and 2012, but no secular trend.

Perceived Stress and Fecundability: A Preconception Cohort Study of North American Couples.

While some epidemiologic studies support the hypothesis that stress can adversely affect fertility, few prospective studies have assessed the association in couples from the general population. We used data from Pregnancy Study Online, a web-based preconception cohort study of pregnancy planners from the United States and Canada (2013-2018), to examine the association between women's and men's perceived stress levels prior to conception and fecundability. Women (aged 21-45 years) and their male partners (aged ≥21 years) who were attempting conception without fertility treatment were eligible. We measured perceived stress using the 10-item Perceived Stress Scale (PSS). We ascertained pregnancy information using bimonthly follow-up questionnaires of female participants. We followed 4,769 couples until self-reported pregnancy, initiation of fertility treatment, loss to follow-up, or 12 menstrual cycles of attempt time, whichever came first. We used proportional probabilities regression models to estimate fecundability ratios and 95% confidence intervals, adjusting for potential confounders. Higher PSS scores among the women were associated with slight reductions in fecundability (comparing PSS scores of ≥25 vs. <10, fecundability ratio = 0.87, 95% confidence interval: 0.74, 1.02). PSS scores among the men were not substantially associated with fecundability.

Cognitive Aging in Black and White Americans: Cognition, Cognitive Decline, and Incidence of Alzheimer Disease Dementia.

BACKGROUND: US-based studies have reported that older blacks perform worse than older whites on cognitive tests and have higher risk of Alzheimer disease dementia (AD). It is unclear whether these findings reflect differences in cognitive decline. METHODS: The Chicago Health and Aging Project followed individuals, 65+ years old (64% black, 36% white), for up to 18 years. Participants underwent triennial cognitive assessments; stratified randomized samples underwent assessments for AD. We compared black and white participants' cognitive performance, cognitive decline rate (N = 7,735), and AD incidence (N = 2,144), adjusting for age and sex. RESULTS: Black participants performed worse than white participants on the cognitive tests; 441 participants developed AD. Black participants' incident AD risk was twice that of whites (RR = 1.9; 95% CI, 1.4, 2.7), with 58 excess cases/1,000 occurring among blacks (95% CI, 28, 88). Among noncarriers of APOE ε4, blacks had 2.3 times the AD risk (95% CI, 1.5, 3.6), but among carriers, race was not associated with risk (RR = 1.1; 95% CI, 0.6, 2.0; Pinteraction = 0.05). However, cognitive decline was not faster among blacks: the black-white difference in 5-year change in global cognitive score was 0.007 standard unit (95% CI, -0.034, 0.047). Years of education accounted for a sizable portion of racial disparities in cognitive level and AD risk, in analyses using a counterfactual approach. CONCLUSIONS: The higher risk of AD among blacks may stem from lower level of cognitive test performance persisting throughout the observation period rather than faster rate of late-life cognitive decline. Disparities in educational attainment may contribute to these performance disparities. See video abstract at, http://links.lww.com/EDE/B299.

IVF success corrected for drop-out: use of inverse probability weighting.

STUDY QUESTION: Does inverse probability weighting (IPW) provide a more valid estimate of the cumulative incidence of live birth after multiple cycles of IVF? SUMMARY ANSWER: IPW can provide a more accurate estimate of treatment success for counseling and decision-making regarding IVF. WHAT IS KNOWN ALREADY: Different approaches have been used to define and calculate IVF success; however, many of these approaches have limitations and potentially violate statistical assumptions. IPW can address potential selection bias that arises when people do not continue IVF treatment after a failed cycle. STUDY DESIGN, SIZE, DURATION: Data were derived from a cohort study of women undergoing their first fresh embryo transfer IVF cycle at our institution between 1 January 1995 and 31 December 2014. All autologous cycles (fresh and frozen) were included, up to six total cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: We identified 20 015 women who underwent 47 079 IVF cycles and had 10 031 live births during the study period. The cumulative incidence of live birth was calculated using three approaches. First, we used a standard Kaplan-Meier approach, 'the optimistic approach', censoring women when they dropped out of treatment. Second, we used a 'conservative' Kaplan-Meier approach that assumed women who dropped out of treatment did not achieve a live birth. Finally, we used IPW to calculate the probability of remaining in treatment, while accounting for differences in treatment drop out. IPW up-weights the data of those remaining under observation who resembled the women who dropped out of treatment, thereby decreasing the potential selection bias resulting from loss to follow-up. The IPW was incorporated into a Kaplan-Meier approach. MAIN RESULTS AND THE ROLE OF CHANCE: The cumulative incidence of live birth was 72.1% (95% CI: 71.0-73.1%) for the optimistic approach, 50.1% (49.4-50.8%) for the conservative approach and 66.8% (65.5-68.1%) for the IPW approach. Among women < 38 years of age, the cumulative incidence of live birth calculated by the IPW was slightly higher than that calculated by the optimistic approach. For women 41-42 years of age, the IPW cumulative incidence of live birth was slightly lower. The IPW was similar to the optimistic approach for the other age groups. The conservative estimate was lowest for all age groups. LIMITATIONS, REASONS FOR CAUTION: Only clinical data recorded by the providers during an IVF cycle were used to generate weights for IPW. Covariates included: age, gravidity and year at the start of the cycle; primary infertility diagnosis; procedure type (i.e. whether a fresh or frozen embryo was transferred); number of mature oocytes retrieved; number of embryos transferred; cycle cancellation; pregnancy loss in the cycle; and insurance status. We were unable to determine exact reasons for treatment drop out (e.g. cessation of IVF treatment, transfer to another institution or spontaneous pregnancy). Our IPW model was moderately predictive based on the c-statistic from the calculation of the denominator of the weight; however, residual selection bias may remain due to the limited range of covariate data. WIDER IMPLICATIONS OF THE FINDINGS: IPW can be used in a variety of settings to address selection bias introduced by differential loss to follow up or treatment drop out. STUDY FUNDING/COMPETING INTEREST(S): AMM was supported by National Institutes of Health (NIH) T32 HD052458-Boston University Reproductive, Perinatal and Pediatric Epidemiology Training Program. The authors report no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Quantification of manganese and mercury in toenail in vivo using portable X-ray fluorescence (XRF).

BACKGROUND AND OBJECTIVE: Toenail is an advantageous biomarker to assess exposure to metals such as manganese and mercury. Toenail Mn and Hg are in general analyzed by chemical methods such as inductively coupled plasma mass spectrometry and atomic absorption spectrophotometry. In this project, a practical and convenient technology-portable X-ray florescence (XRF)-is studied for the noninvasive in vivo quantification of manganese and mercury in toenail. MATERIAL AND METHODS: The portable XRF method has advantages in that it does not require toenail clipping and it can be done in 3 min, which will greatly benefit human studies involving the assessment of manganese and mercury exposures. This study mainly focused on the methodology development and validation which includes spectral analysis, system calibration, the effect of toenail thickness, and the detection limit of the system. Manganese- and mercury-doped toenail phantoms were made. Calibration lines were established for these measurements. RESULTS: The results show that the detection limit for manganese is 3.65 µg/g (ppm) and for mercury is 0.55 µg/g (ppm) using 1 mm thick nail phantoms with 10 mm soft tissue underneath. DISCUSSION AND CONCLUSION: We conclude that portable XRF is a valuable and sensitive technology to quantify toenail manganese and mercury in vivo.

Clinicopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football.

Importance: Players of American football may be at increased risk of long-term neurological conditions, particularly chronic traumatic encephalopathy (CTE). Objective: To determine the neuropathological and clinical features of deceased football players with CTE. Design, Setting, and Participants: Case series of 202 football players whose brains were donated for research. Neuropathological evaluations and retrospective telephone clinical assessments (including head trauma history) with informants were performed blinded. Online questionnaires ascertained athletic and military history. Exposures: Participation in American football at any level of play. Main Outcomes and Measures: Neuropathological diagnoses of neurodegenerative diseases, including CTE, based on defined diagnostic criteria; CTE neuropathological severity (stages I to IV or dichotomized into mild [stages I and II] and severe [stages III and IV]); informant-reported athletic history and, for players who died in 2014 or later, clinical presentation, including behavior, mood, and cognitive symptoms and dementia. Results: Among 202 deceased former football players (median age at death, 66 years [interquartile range, 47-76 years]), CTE was neuropathologically diagnosed in 177 players (87%; median age at death, 67 years [interquartile range, 52-77 years]; mean years of football participation, 15.1 [SD, 5.2]), including 0 of 2 pre-high school, 3 of 14 high school (21%), 48 of 53 college (91%), 9 of 14 semiprofessional (64%), 7 of 8 Canadian Football League (88%), and 110 of 111 National Football League (99%) players. Neuropathological severity of CTE was distributed across the highest level of play, with all 3 former high school players having mild pathology and the majority of former college (27 [56%]), semiprofessional (5 [56%]), and professional (101 [86%]) players having severe pathology. Among 27 participants with mild CTE pathology, 26 (96%) had behavioral or mood symptoms or both, 23 (85%) had cognitive symptoms, and 9 (33%) had signs of dementia. Among 84 participants with severe CTE pathology, 75 (89%) had behavioral or mood symptoms or both, 80 (95%) had cognitive symptoms, and 71 (85%) had signs of dementia. Conclusions and Relevance: In a convenience sample of deceased football players who donated their brains for research, a high proportion had neuropathological evidence of CTE, suggesting that CTE may be related to prior participation in football.