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Prerequisites for effective interventions against severe anaemia and malaria among infants are economic evaluations to aid the setting of priorities and the making of health policy. In the present study we analysed the cost and effectiveness of three control strategies hypothetically delivered through the Expanded Programme on Immunization (EPI). For the prevention of severe anaemia and from the perspective of the health provider, the cost-effectiveness ratios were, respectively, US$ 8, US$ 9, and US$ 21 per disability-adjusted life year (DALY) for malaria chemoprophylaxis with Deltaprim (a combination of 3.125 mg pyrimethamine and 25 mg dapsone) + iron, Deltaprim alone, or iron supplementation alone. For malaria prevention, Deltaprim + iron cost US$ 9.7 per DALY and Deltaprim alone cost US$ 10.2 per DALY. From a sociocultural perspective the cost-effectiveness ratios ranged from US$ 9 to US$ 26 for severe anaemia prevention and from US$ 11 to US$ 12 for the prevention of clinical malaria. These ratios were highly cost-effective, as defined by the World Bank’s proposed threshold of less than US$ 25 per DALY for comparative assessments. Furthermore, all the preventive interventions were less costly than the current malaria and anaemia control strategies that rely on clinical case management. This economic analysis supports the inclusion of both malaria chemoprophylaxis and iron supplementation delivered through EPI as part of the control strategies for these major killers of infants in parts of sub-Saharan Africa.

The United Nations General Assembly has convened a Summit on non-communicable diseases (NCDs), an historic moment in the global combat of these disorders. Lifestyles in increasingly urban and globalised environments have led to a steep surge in NCD incidence in low and middle income countries, where two thirds of all NCD deaths occur (most importantly from cancer, cardiovascular and respiratory disease as well as diabetes). Treatment of NCDs is usually long term and expensive, thus threatening patients’ and nations’ budgets and putting them at high risk for poverty. The NCD Summit offers an opportunity for strengthening and shaping primary prevention, the most cost-effective instrument to fight major risk factors such as tobacco smoking, alcohol abuse, physical inactivity and unhealthy diet. From a Swiss perspective, we also emphasised the efforts for new laws on prevention and diagnosis registration, in accordance with the recommendations of the NCD summit in order to strengthen primary prevention and disease monitoring. In addition, the need for structural prevention across all policy sectors with leadership in environmental policy making to prevent NCDs as well as the need to adapt and strengthen primary health care are equally relevant for Switzerland. To compliment efforts in primary prevention, the field of NCDs requires special R&D platforms for affordable NCD drugs and diagnostics for neglected population segments in both Switzerland and low and middle income countries. Switzerland has a track record in research and development against diseases of poverty on a global scale that now needs to be applied to NCDs.

The collocation of software development teams is common, specially in agile software development environments. However little is known about the impact of collocation on the team’s effectiveness. This paper explores the impact of collocating agile software development teams on a number of team effectiveness factors. The study focused on South African software development teams and gathered data through the use of questionnaires and interviews. The key finding was that collocation has a positive impact on a number of team effectiveness factors which can be categorised under team composition, team support, team management and structure and team communication. Some of the negative impact collocation had on team effectiveness relate to the fact that team members perceived that less emphasis was placed on roles, that morale of the group was influenced by individuals, and that collocation was invasive, reduced level of privacy and increased frequency of interruptions. Overall through it is proposed that companies should consider collocating their agile software development teams, as collocation might leverage overall team effectiveness.

Background: The Single-Incision Power Optimizing Cost-Effective Repair (SPOC) method reattaches the distal biceps tendon to its original posterior anatomic footprint and utilizes the anterior cortex of the supinated radius for fixation. The purpose of the study was to define the long-term complications and durability of the SPOC method. Methods: Two hundred and eighteen patients underwent the SPOC repair of distal biceps ruptures from 2008 to 2020, with 185 having at least 1-year follow-up data. The average follow-up was 50.1 months. Information regarding smoking, body mass index, interval between injury and surgery, peripheral nerve injury, heterotopic ossification, vascular injury, re-rupture, chronic regional pain syndrome, fracture of the radius, loss of motion, pain with use, and deformity were acquired. Results: No complication occurred beyond the third postoperative month. No patient complained of severe lateral antebrachial cutaneous nerve-related symptoms. Major complications exclusive of re-rupture occurred include 1 case of heterotopic ossification and 1 deep infection. Major complications with re-ruptures occurred in 9 patients (4.8%). Seven of the re-ruptures (78%) were associated with an unexpected forceful contraction within the first 4 weeks postop. All complications aside from 1 minor complication occurred in the chronic group. Long term follow-up revealed no re-ruptures and high satisfaction rate with return of strength, motion, and biceps profile. Conclusion: The safety profile of the SPOC repair is consistent with those of other published repairs. Major complications were associated with prolonged intervals between injury and reconstruction. Re-ruptures were associated with worker’s compensation status and patient noncompliance with postoperative protocols.

Abstract Little is known about electrocardiogram (ECG) markers of Parkinson’s disease (PD) during the prodromal stage. The aim of the study was to build a generalizable ECG-based fully automatic artificial intelligence (AI) model to predict PD risk during the prodromal stage, up to 5 years before disease diagnosis. This case–control study included samples from Loyola University Chicago (LUC) and University of Tennessee-Methodist Le Bonheur Healthcare (MLH). Cases and controls were matched according to specific characteristics (date, age, sex and race). Clinical data were available from May, 2014 onward at LUC and from January, 2015 onward at MLH, while the ECG data were available as early as 1990 in both institutes. PD was denoted by at least two primary diagnostic codes (ICD9 332.0; ICD10 G20) at least 30 days apart. PD incidence date was defined as the earliest of first PD diagnostic code or PD-related medication prescription. ECGs obtained at least 6 months before PD incidence date were modeled to predict a subsequent diagnosis of PD within three time windows: 6 months–1 year, 6 months–3 years, and 6 months–5 years. We applied a novel deep neural network using standard 10-s 12-lead ECGs to predict PD risk at the prodromal phase. This model was compared to multiple feature engineering-based models. Subgroup analyses for sex, race and age were also performed. Our primary prediction model was a one-dimensional convolutional neural network (1D-CNN) that was built using 131 cases and 1058 controls from MLH, and externally validated on 29 cases and 165 controls from LUC. The model was trained on 90% of the MLH data, internally validated on the remaining 10% and externally validated on LUC data. The best performing model resulted in an external validation AUC of 0.67 when predicting future PD at any time between 6 months and 5 years after the ECG. Accuracy increased when restricted to ECGs obtained within 6 months to 3 years before PD diagnosis (AUC 0.69) and was highest when predicting future PD within 6 months to 1 year (AUC 0.74). The 1D-CNN model based on raw ECG data outperformed multiple models built using more standard ECG feature engineering approaches. These results demonstrate that a predictive model developed in one cohort using only raw 10-s ECGs can effectively classify individuals with prodromal PD in an independent cohort, particularly closer to disease diagnosis. Standard ECGs may help identify individuals with prodromal PD for cost-effective population-level early detection and inclusion in disease-modifying therapeutic trials.

Abstract Background Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with antipsychotic use. Data from RE-KINECT, a real-world study of antipsychotic-treated outpatients, were analyzed to assess the effects of possible TD on patient health and social functioning. Methods Analyses were conducted in Cohort 1 (patients with no abnormal involuntary movements) and Cohort 2 (patients with possible TD per clinician judgment). Assessments included: EuroQoL’s EQ-5D-5L utility (health); Sheehan Disability Scale (SDS) total score (social functioning); patient- and clinician-rated severity of possible TD (“none”, “some”, “a lot”); and patient-rated impact of possible TD (“none”, “some”, “a lot”). Regression models were used to analyze the following: associations between higher (worse) severity/impact scores and lower (worse) EQ-5D-5L utility (indicated by negative regression coefficients); and associations between higher (worse) severity/impact scores and higher (worse) SDS total score (indicated by positive regression coefficients). Results In Cohort 2 patients who were aware of their abnormal movements, patient-rated TD impact was highly and significantly associated with EQ-5D-5L utility (regression coefficient: − 0.023, P

Sympatry is a common consequence of niche differentiation and can exist as broad sympatry (shared geographical region) or direct sympatry (i.e., syntopy [shared resource patch]). Syntopy may be highly dynamic, particularly in environments that experience stochastic events that increase variability in abiotic conditions and vegetation. We examined how estimates of syntopy varied across space and time in a rangeland system within the Southern Great Plains, USA over a three-year period (2013–2015). We modeled annual estimates of syntopy between three functionally similar (ground-foraging Galliformes) species (northern bobwhite [Colinus virginianus], scaled quail [Callipepla squamata], and lesser prairie-chicken [Tympanuchus pallidicinctus]. Niche similarity representing increased syntopy was greatest during years with increased drought conditions (2013–2014). Niche differentiation was greatest in 2015 in which rangelands experienced the greatest amount of precipitation. Syntopy estimates were driven by variability in vegetation cover estimates, representing changes in rangeland conditions related to abiotic conditions. Our results suggest that syntopy can be highly dynamic across space and time and can be driven by variability in abiotic conditions (i.e., precipitation). Furthermore, these results suggest that habitat is in a state of non-equilibrium. Finally, we highlight that climate refuges that promote demographic resiliency through intraspecific changes in resource use are fundamental drivers of spatio-temporal patterns in community dynamics, particularly across similar functional species.

Protease-activated receptor 4 (PAR4) (gene F2RL3) harbors a functional dimorphism, rs773902 A/G (encoding Thr120/Ala120, respectively) and is associated with greater platelet aggregation. The A allele frequency is more common in Black individuals, and Black individuals have a higher incidence of ischemic stroke than White individuals. However, it is not known whether the A allele is responsible for worse stroke outcomes. To directly test the in vivo effect of this variant on stroke, we generated mice in which F2rl3 was replaced by F2RL3, thereby expressing human PAR4 (hPAR4) with either Thr120 or Ala120. Compared with hPAR4 Ala120 mice, hPAR4 Thr120 mice had worse stroke outcomes, mediated in part by enhanced platelet activation and platelet-neutrophil interactions. Analyses of 7,620 Black subjects with 487 incident ischemic strokes demonstrated the AA genotype was a risk for incident ischemic stroke and worse functional outcomes. In humanized mice, ticagrelor with or without aspirin improved stroke outcomes in hPAR4 Ala120 mice, but not in hPAR4 Thr120 mice. P selectin blockade improved stroke outcomes and reduced platelet-neutrophil interactions in hPAR4 Thr120 mice. Our results may explain some of the racial disparity in stroke and support the need for studies of nonstandard antiplatelet therapies for patients expressing PAR4 Thr120.

Abstract Regulatory T cells (Treg) are vital to the maintenance of immune homeostasis. The genetic background of an inbred mouse strain can have a profound effect on the immune response in the animal, including Treg responses. Most Treg studies focus on animals created on the C57BL/6 or BALB/c background. Recent studies have demonstrated a difference in the phenotype and behavior of C57BL/6 and BALB/c Tregs. In this study, we have investigated the function of FVB/N Tregs compared to C57BL/6 and BALB/c. We observed that while FVB/N Tregs appear to suppress normally in a cell contact‐dependent system, FVB/N Tregs are less capable of suppressing when regulation depends on the secretion of a soluble factor. FVB/N Tregs produce IL‐10; however, TGF‐β was not detected in any culture from C57BL/6 or FVB/N. C57BL/6 Foxp3+ Tregs expressed more of the TGF‐β‐related proteins glycoprotein‐A repetitions predominant (GARP) and latency‐associated peptide (LAP) on the cell surface than both FVB/N and BALB/c, but C57BL/6 Tregs expressed significantly less Ctse (Cathepsin E) mRNA. Each strain displayed different abilities of thymic Tregs (tTreg) to maintain Foxp3 expression and had a varying generation of induced Tregs (iTregs). In vitro generated FVB/N iTregs expressed significantly less GARP and LAP. These results suggest Tregs of different strains have varying phenotypes and dominant mechanisms of action for the suppression of an immune response. This information should be taken into consideration when Tregs are examined in future studies, particularly for therapeutic purposes in a genetically diverse population.

Abstract Background To date, no medication has slowed the progression of Parkinson’s disease (PD). Preclinical, epidemiological, and experimental data on humans all support many benefits of endurance exercise among persons with PD. The key question is whether there is a definitive additional benefit of exercising at high intensity, in terms of slowing disease progression, beyond the well-documented benefit of endurance training on a treadmill for fitness, gait, and functional mobility. This study will determine the efficacy of high-intensity endurance exercise as first-line therapy for persons diagnosed with PD within 3 years, and untreated with symptomatic therapy at baseline. Methods This is a multicenter, randomized, evaluator-blinded study of endurance exercise training. The exercise intervention will be delivered by treadmill at 2 doses over 18 months: moderate intensity (4 days/week for 30 min per session at 60–65% maximum heart rate) and high intensity (4 days/week for 30 min per session at 80–85% maximum heart rate). We will randomize 370 participants and follow them at multiple time points for 24 months. The primary outcome is the Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) motor score (Part III) with the primary analysis assessing the change in MDS-UPDRS motor score (Part III) over 12 months, or until initiation of symptomatic antiparkinsonian treatment if before 12 months. Secondary outcomes are striatal dopamine transporter binding, 6-min walk distance, number of daily steps, cognitive function, physical fitness, quality of life, time to initiate dopaminergic medication, circulating levels of C-reactive protein (CRP), and brain-derived neurotrophic factor (BDNF). Tertiary outcomes are walking stride length and turning velocity. Discussion SPARX3 is a Phase 3 clinical trial designed to determine the efficacy of high-intensity, endurance treadmill exercise to slow the progression of PD as measured by the MDS-UPDRS motor score. Establishing whether high-intensity endurance treadmill exercise can slow the progression of PD would mark a significant breakthrough in treating PD. It would have a meaningful impact on the quality of life of people with PD, their caregivers and public health. Trial registration ClinicalTrials.gov NCT04284436 . Registered on February 25, 2020.

BackgroundThe Unified Dyskinesia Rating Scale (UDysRS) evaluates dyskinesia in patients with Parkinson's disease (PD). A minimal clinically important change (MCIC)—the smallest change in a treatment outcome that a patient considers important—remains undefined for the UDysRS.ObjectiveTo utilize pivotal amantadine delayed-release/extended-release (DR/ER) trial data to derive MCICs for the UDysRS total score in patients with PD experiencing dyskinesia.MethodsPivotal trials included PD patients with ≥1 h daily ON time with troublesome dyskinesia and baseline scores ≥2 on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part IV, item 4.2. Patients randomized to amantadine DR/ER or placebo completed two consecutive 24-h diaries before each clinic visit and were evaluated during ON time with dyskinesia using the UDysRS, MDS-UPDRS, and Clinician Global Impression of Change (CGI-C). The UDysRS changes from baseline to week 12 were anchored to corresponding changes in MDS-UPDRS item 4.2 scores. A minimal clinically important improvement in the CGI-C and diary-reported ON time with troublesome dyskinesia (≥0.5 h) were supportive anchors. Receiver operating characteristic curves determined the UDysRS change values optimizing sensitivity and specificity to at least minimal improvement on each anchor.ResultsThe analyses included 196 patients. Week 12 UDysRS total score reduction of ≥8 points corresponded to at least minimal MDS-UPDRS item 4.2 improvement. UDysRS reduction of ≥9 points corresponded to decreased ON time with troublesome dyskinesia of ≥0.5 h per patient diaries, and UDysRS reduction of ≥10 points corresponded to at least minimal improvement on the CGI-C.ConclusionAnchored to the MDS-UPDRS Part IV, item 4.2, an 8-point reduction in the UDysRS total score can be considered an MCIC for PD patients with dyskinesia.

Paediatric cancers commonly harbour quiet mutational landscapes and are instead characterized by single driver events such as the mutation of critical chromatin regulators, expression of oncohistones, or expression of oncogenic fusion proteins. These events ultimately promote malignancy through disruption of normal gene regulation and development. The driver protein in Ewing sarcoma, EWS/FLI, is an oncogenic fusion and transcription factor that reshapes the enhancer landscape, resulting in widespread transcriptional dysregulation. Lysine-specific demethylase 1 (LSD1) is a critical functional partner for EWS/FLI as inhibition of LSD1 reverses the transcriptional activity of EWS/FLI. However, how LSD1 participates in fusion-directed epigenomic regulation and aberrant gene activation is unknown. We now show EWS/FLI causes dynamic rearrangement of LSD1 and we uncover a role for LSD1 in gene activation through colocalization at EWS/FLI binding sites throughout the genome. LSD1 is integral to the establishment of Ewing sarcoma super-enhancers at GGAA-microsatellites, which ubiquitously overlap non-microsatellite loci bound by EWS/FLI. Together, we show that EWS/FLI induces widespread changes to LSD1 distribution in a process that impacts the enhancer landscape throughout the genome.

Abstract The Trial of Parkinson’s And Zoledronic acid (TOPAZ, https://clinicaltrials.gov/ct2/show/NCT03924414 ) is a unique collaboration between experts in movement disorders and osteoporosis to test the efficacy of zoledronic acid, an FDA-approved parenteral treatment for osteoporosis, for fracture prevention in people with neurodegenerative parkinsonism. Aiming to enroll 3,500 participants age 65 years or older, TOPAZ is one of the largest randomized, placebo-controlled clinical trials ever attempted in parkinsonism. The feasibility of TOPAZ is enhanced by its design as a U.S.- wide home-based trial without geographical limits. Participants receive information from multiple sources, including specialty practices, support groups and websites. Conducting TOPAZ in participants’ homes takes advantage of online consent technology, the capacity to confirm diagnosis using telemedicine and the availability of research nursing to provide screening and parenteral therapy in homes. Home-based clinical research may provide an efficient, convenient, less expensive method that opens participation in clinical trials to almost anyone with parkinsonism.

BackgroundPeople with Parkinson disease (PD) have a variety of complex medical problems that require detailed review at each clinical encounter for appropriate management. Care of other complex conditions has benefited from digital health solutions that efficiently integrate disparate clinical information. Although various digital approaches have been developed for research and care in PD, no digital solution to personalize and improve communication in a clinical encounter is readily available. ObjectiveWe intend to improve the efficacy and efficiency of clinical encounters with people with PD through the development of a platform (PD-BRIDGE) with personalized clinical information from the electronic health record (EHR) and patient-reported outcome (PRO) data. MethodsUsing human-centered design (HCD) processes, we engaged clinician and patient stakeholders in developing PD-BRIDGE through three phases: an inspiration phase involving focus groups and discussions with people having PD, an ideation phase generating preliminary mock-ups for feedback, and an implementation phase testing the platform. To qualitatively evaluate the platform, movement disorders neurologists and people with PD were sent questionnaires asking about the technical validity, usability, and clinical relevance of PD-BRIDGE after their encounter. ResultsThe HCD process led to a platform with 4 modules. Among these, 3 modules that pulled data from the EHR include a longitudinal module showing motor ratings over time, a display module showing the most recently collected clinical rating scales, and another display module showing relevant laboratory values and diagnoses; the fourth module displays motor symptom fluctuation based on an at-home diary. In the implementation phase, PD-BRIDGE was used in 17 clinical encounters for patients cared for by 1 of 11 movement disorders neurologists. Most patients felt that PD-BRIDGE facilitated communication with their clinician (n=14, 83%) and helped them understand their disease trajectory (n=11, 65%) and their clinician’s recommendations (n=11, 65%). Neurologists felt that PD-BRIDGE improved their ability to understand the patients’ disease course (n=13, 75% of encounters), supported clinical care recommendations (n=15, 87%), and helped them communicate with their patients (n=14, 81%). In terms of improvements, neurologists noted that data in PD-BRIDGE were not exhaustive in 62% (n=11) of the encounters. ConclusionsIntegrating clinically relevant information from EHR and PRO data into a visually efficient platform (PD-BRIDGE) can facilitate clinical encounters with people with PD. Developing new modules with more disparate information could improve these complex encounters even further.

All animals must select sites to rest and may spend a large portion of their lives doing so. Despite the importance of this period in their daily activity budget, we lack information about rest/roost ecology for most animals, including the imperiled lesser prairie-chicken (Tympanuchus pallidicinctus; hereafter “LEPC”). Therefore, we sought to identify how landcover, anthropogenic features, and human policy (i.e., presence of the Conservation Reserve Program [CRP]) influenced roost site selection and movement patterns of the LEPC. From March to May 2013–2015, we captured and fitted GPS transmitters to 106 LEPCs (n = 72 males; n = 34 females) within Beaver County, Oklahoma and recorded two nocturnal locations per 24-hour period, annually. We used discrete choice models and generalized linear mixed effects models to determine how vegetation cover, CRP patches, and anthropogenic features influenced roost site selection and movements to roosting sites, respectively. We found that roost sites were closer to CRP, leks, and croplands than would be expected at random. Conversely, roost sites were located farther away from shortgrass prairie, roads, and transmission lines than expected. The probability of a LEPC roosting in a location increased by 15% and 4.5% for every 36-meter decrease in distance to a CRP patch and distance to their lek of capture, respectively. Similarly, individuals roosting in CRP patches would travel shorter distances to get to roost sites if their last diurnal location was near CRP. Bird’s movements to roosts in CRP were 1.4 times shorter for every meter decrease in the distance of their last diurnal location to a CRP patch, indicating that individuals modify their movement based on CRP presence. Our results indicate that CRP is influential to roosting ecology of the LEPC within this region and may be meeting critical cover requirements.

AU Mic is a young (22 Myr), nearby exoplanetary system that exhibits excess transit timing variations (TTVs) that cannot be accounted for by the two known transiting planets nor stellar activity. We present the statistical “validation” of the tentative planet AU Mic d (even though there are examples of “confirmed” planets with ambiguous orbital periods). We add 18 new transits and nine midpoint times in an updated TTV analysis to prior work. We perform the joint modeling of transit light curves using EXOFASTv2 and extract the transit midpoint times. Next, we construct an O − C diagram and use Exo-Striker to model the TTVs. We generate TTV log-likelihood periodograms to explore possible solutions for d’s period, then follow those up with detailed TTV and radial velocity Markov Chain Monte Carlo modeling and stability tests. We find several candidate periods for AU Mic d, all of which are near resonances with AU Mic b and c of varying order. Based on our model comparisons, the most-favored orbital period of AU Mic d is 12.73596 ± 0.00793 days ( T _C _,d = 2458340.55781 ± 0.11641 BJD), which puts the three planets near 4:6:9 mean-motion resonance. The mass for d is 1.053 ± 0.511 M _⊕ , making this planet Earth-like in mass. If confirmed, AU Mic d would be the first known Earth-mass planet orbiting a young star and would provide a valuable opportunity in probing a young terrestrial planet’s atmosphere. Additional TTV observations of the AU Mic system are needed to further constrain the planetary masses, search for possible transits of AU Mic d, and detect possible additional planets beyond AU Mic c.

Abstract Spatially distributed populations often rely on large‐scale processes for long‐term population stability. These processes are driven by individuals moving across the landscape through long‐distance dispersal movements. However, as landscapes are continually altered by anthropogenic development, increased fragmentation and avoidance behavior can affect landscape permeability and limit dispersal. Lesser prairie‐chickens (Tympanuchus pallidicinctus) are a species of concern that have lost significant portions (>90%) of their historic distribution in the Southern Great Plains of the United States and are currently being impacted by continued anthropogenic development. Using GPS telemetry locations of 346 lesser prairie‐chickens across their entire geographic distribution, we identified 184 different long‐distance movements that drive population connectivity. We used empirical cumulative distribution functions to create a selection–avoidance–neutral curve and estimated the spatial scale of response to anthropogenic features (i.e., towers and windmills, large transmission and smaller distribution powerlines, oil wells, roads, and fences) during these movements. In addition, we tested for behavioral differences between movement types (e.g., exploratory loops vs. long‐distance movements between home ranges) and for regional differences in response among study areas. We found that during long‐distance movements, lesser prairie‐chickens generally avoided all anthropogenic feature types we tested despite some variation in the reported response distance among study areas. However, they avoided the tallest features (i.e., towers and windmills and transmission powerlines) at much greater distances in comparison with the shorter features in our analysis. Our results show that long‐distance movements are likely affected by responses to functional landscape fragmentation through increased development of anthropogenic features in important connectivity zones. As our estimated response distances during long‐distance movements varied in comparison with previously reported response distances during other behavioral states (e.g., breeding or nesting), using long‐distance or dispersal specific movement data may be more appropriate when asking questions related to connectivity across the landscape.

Weighted Quantile Sum (WQS) regression is a method commonly used in environmental epidemiology to assess the impact of chemical mixtures in relation to a health outcome of interest. Data are partitioned into a single training and test set to reduce sample-specific chemical weights. However, in typical epidemiology sample sizes, this may produce unstable chemical weights and WQS index estimates, and investigators may resort to training and testing on the same data. To solve this problem, we propose repeated holdout validation whereby data are randomly partitioned 100 times, producing a distribution of validated results. Taking the mean as the final estimate, confidence estimates may also be calculated for inference. Further, this method helps characterize the variability in chemical weights, aiding in the identification of chemicals of concern. This is important since it may direct future research into specific chemicals.Using data from 718 mother-child pairs in the Swedish Environmental Longitudinal, Mother and Child, Asthma and Allergy (SELMA) study, we assessed the association between prenatal exposure to 26 endocrine disrupting chemicals and child Intelligence Quotient (IQ). Results using a single partition were unstable, varying by random seed. The WQS index estimate was significant when all data was used (e.g. no partition) (β = −2.2 CI = −3.43, −0.98), but attenuated and nonsignificant using repeated holdout validation (β = −0.82 CI = −2.11, 0.45). When implementing WQS in epidemiologic studies with limited sample sizes, repeated holdout validation is a viable alternative to using a single, or no partitioning. Repeated holdout can both stabilize results and help characterize the uncertainty in identifying chemicals of concern, while maintaining some of the the rigor of holdout validation. • Repeated holdout validation improves the stability of WQS estimates in finite study samples • Uncertainty in identifying toxic chemicals of concern is acknowledged and characterized Method name: Repeated holdout validation for weighted quantile sum regression, Keywords: Environmental epidemiology, Chemical mixtures, Cross-validation, Bootstrap, Uncertainty plot, Chemical of concern

Background Left ventricular hypertrophy (LVH) is associated with an increased risk for cardiovascular disease (CVD) events and all‐cause mortality. Many individuals without LVH have a left ventricular mass that exceeds the level predicted by their sex, body size, and cardiac workload, a condition called inappropriate left ventricular mass (iLVM). We investigated the association of iLVM with CVD events and all‐cause mortality among blacks. Methods and Results We analyzed data from the Jackson Heart Study, a community‐based cohort of blacks. The current analysis included 4424 participants without CVD and with an echocardiogram at baseline. Among this cohort, the prevalence of iLVM was 13.8%. There were 262 CVD events and 419 deaths over a median follow‐up of 9.7 years (maximum, 12 years). Compared with participants without iLVM, participants with iLVM had a higher rate of CVD events and all‐cause mortality. After multivariable adjustment, including for the presence of LVH, iLVM was associated with an increased risk of CVD events (hazard ratio, 1.87; 95% CI, 1.33–2.62). The multivariable‐adjusted hazard ratio for all‐cause mortality was 1.29 (95% CI, 0.98–1.70). Among participants without and with LVH, the multivariable‐adjusted hazard ratios of iLVM for CVD events were 2.53 (95% CI, 1.68–3.81) and 1.21 (95% CI, 0.74–2.00), respectively (Pinteraction=0.029); and for all‐cause mortality, the hazard ratios were 1.24 (95% CI, 0.81–1.89) and 1.26 (95% CI, 0.86–1.85), respectively (Pinteraction=0.664). Conclusions iLVM is associated with an increased risk for CVD events among blacks without LVH.