Uganda Genome Resource Enables Insights into Population History and Genomic Discovery in Africa.

Genomic studies in African populations provide unique opportunities to understand disease etiology, human diversity, and population history. In the largest study of its kind, comprising genome-wide data from 6,400 individuals and whole-genome sequences from 1,978 individuals from rural Uganda, we find evidence of geographically correlated fine-scale population substructure. Historically, the ancestry of modern Ugandans was best represented by a mixture of ancient East African pastoralists. We demonstrate the value of the largest sequence panel from Africa to date as an imputation resource. Examining 34 cardiometabolic traits, we show systematic differences in trait heritability between European and African populations, probably reflecting the differential impact of genes and environment. In a multi-trait pan-African GWAS of up to 14,126 individuals, we identify novel loci associated with anthropometric, hematological, lipid, and glycemic traits. We find that several functionally important signals are driven by Africa-specific variants, highlighting the value of studying diverse populations across the region.

Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease.

RIPK1 is a key regulator of innate immune signalling pathways. To ensure an optimal inflammatory response, RIPK1 is regulated post-translationally by well-characterized ubiquitylation and phosphorylation events, as well as by caspase-8-mediated cleavage1-7. The physiological relevance of this cleavage event remains unclear, although it is thought to inhibit activation of RIPK3 and necroptosis8. Here we show that the heterozygous missense mutations D324N, D324H and D324Y prevent caspase cleavage of RIPK1 in humans and result in an early-onset periodic fever syndrome and severe intermittent lymphadenopathy-a condition we term 'cleavage-resistant RIPK1-induced autoinflammatory syndrome'. To define the mechanism for this disease, we generated a cleavage-resistant Ripk1D325A mutant mouse strain. Whereas Ripk1-/- mice died postnatally from systemic inflammation, Ripk1D325A/D325A mice died during embryogenesis. Embryonic lethality was completely prevented by the combined loss of Casp8 and Ripk3, but not by loss of Ripk3 or Mlkl alone. Loss of RIPK1 kinase activity also prevented Ripk1D325A/D325A embryonic lethality, although the mice died before weaning from multi-organ inflammation in a RIPK3-dependent manner. Consistently, Ripk1D325A/D325A and Ripk1D325A/+ cells were hypersensitive to RIPK3-dependent TNF-induced apoptosis and necroptosis. Heterozygous Ripk1D325A/+ mice were viable and grossly normal, but were hyper-responsive to inflammatory stimuli in vivo. Our results demonstrate the importance of caspase-mediated RIPK1 cleavage during embryonic development and show that caspase cleavage of RIPK1 not only inhibits necroptosis but also maintains inflammatory homeostasis throughout life.

Improving spatial exposure data for everyone - lifecourse social context and ascertaining residential history.

Measuring age-specific, contextual exposures is crucial for lifecourse epidemiology research. Longitudinal residential data offers a "golden ticket" to cumulative exposure metrics and can enhance our understanding of health disparities. Residential history can be linked to myriad spatiotemporal databases to characterize environmental, socioeconomic, and policy contexts that a person experienced throughout life. However, obtaining accurate residential history is challenging in the United States due to the limitations of administrative registries and self-reports. Xu et al. (Am J Epidemiol. 2024; 193(2):348-359) detail an approach to linking residential history sourced from LexisNexis ® Accurint ® to a Wisconsin-based research cohort, offering insights into challenges with residential history collection. Researchers must analyze the magnitude of selection and misclassification biases inherent to ascertaining residential history from cohort data. A lifecourse framework can provide insights into why the frequency and distance of moves is patterned by age, birth cohort, racial/ethnic identity, socioeconomic status, and urbanicity. Historic and contemporary migration patterns of marginalized people seeking economic and political opportunities must guide interpretations of residential history data. We outline methodologic priorities for use of residential history in health disparities research, including contextualizing residential history data with determinants of residential moves, triangulating spatial exposure assessment methods, and transparently quantifying measurement error.

High Traffic Roads and Adverse Birth Outcomes: Comparing Births Upwind and Downwind of the Same Road.

Traffic related air pollution is a major concern for perinatal health. Determining causal associations, however, is difficult since high-traffic areas tend to correspond with lower socioeconomic neighborhoods and other environmental exposures. To overcome confounding, we compared pregnant individuals living downwind and upwind of the same high-traffic road. We leveraged vital statistics data for Texas from 2007-2016 (n=3,570,272 births) and computed hourly wind estimates for residential addresses within 500 m of high-traffic roads (i.e., annual average daily traffic greater than 25,000) (10.9% of births). We matched pregnant individuals predominantly upwind to pregnant neighbors downwind of the same road segment (n=37,631 pairs). Living downwind was associated with an 11.6 gram (95% CI: -18.01, -5.21) decrease in term birth weight. No associations were observed with low term birth weight, preterm birth, or very preterm birth. In distance-stratified models, living downwind within 50 m was associated with a -36.3 gram (95% CI: -67.74, -4.93) decrease in term birth weight and living 51-100m downwind was associated with an odds ratio of 3.68 (95% CI: 1.71, 7.90) for very preterm birth. These results suggest traffic air pollution is associated with adverse birth outcomes, with steep distance decay gradients around major roads.

Financial Toxicity: Unveiling the Burden of Cancer Care on Patients in Rwanda.

INTRODUCTION: Cancer is a major public health problem in Rwanda and other low- and middle-income countries (LMICs). While there have been some improvements in access to cancer treatment, the cost of care has increased, leading to financial toxicity and treatment barriers for many patients. This study explores the financial toxicity of cancer care in Rwanda. METHODS: This prospective cross-sectional study was conducted at 3 referral hospitals in Rwanda, which deliver most of the country's cancer care. Data were collected over 6 months from June 1 to December 1, 2022 by trained research assistants (RAs) using a modified validated data collection tool. RAs interviewed consecutive eligible patients with breast cancer, cervical cancer, colorectal cancer, Hodgkin's and non-Hodgkin's lymphoma who were on active systemic therapy. The study aimed to identify sources of financial burden. Data were analyzed using descriptive statistics. RESULTS: 239 patients were included; 75% (n = 180/239) were female and mean age was 51 years. Breast, cervix, and colorectal cancers were the most common diagnoses (42%, 100/239; 24%, 58/239; and 24%, 57/239, respectively) and 54% (n = 129/239) were diagnosed with advanced stage (stages III-IV). Financial burden was high; 44% (n = 106/239) of respondents sold property, 29% (n = 70/239) asked for charity from public, family, or friends, and 16% (n = 37/239) took loans with interest to fund cancer treatment. CONCLUSION: Despite health insurance which covers many elements of cancer care, a substantial proportion of patients on anti-cancer treatment in Rwanda experience major financial toxicity. Novel health financing solutions are needed to ensure accessible and affordable cancer care.

Recombinant vesicular stomatitis vaccine against Nipah virus has a favorable safety profile: Model for assessment of live vaccines with neurotropic potential.

Nipah virus (NiV) disease is a bat-borne zoonosis responsible for outbreaks with high lethality and is a priority for vaccine development. With funding from the Coalition of Epidemic Preparedness Innovations (CEPI), we are developing a chimeric vaccine (PHV02) composed of recombinant vesicular stomatitis virus (VSV) expressing the envelope glycoproteins of both Ebola virus (EBOV) and NiV. The EBOV glycoprotein (GP) mediates fusion and viral entry and the NiV attachment glycoprotein (G) is a ligand for cell receptors, and stimulates neutralizing antibody, the putative mediator of protection against NiV. PHV02 is identical in construction to the registered Ebola vaccine (Ervebo) with the addition of the NiV G gene. NiV ephrin B2 and B3 receptors are expressed on neural cells and the wild-type NiV is neurotropic and causes encephalitis in affected patients. It was therefore important to assess whether the NiV G alters tropism of the rVSV vector and serves as a virulence factor. PHV02 was fully attenuated in adult hamsters inoculated by the intramuscular (IM) route, whereas parental wild-type VSV was 100% lethal. Two rodent models (mice, hamsters) were infected by the intracerebral (IC) route with graded doses of PHV02. Comparator active controls in various experiments included rVSV-EBOV (representative of Ebola vaccine) and yellow fever (YF) 17DD commercial vaccine. These studies showed PHV02 to be more neurovirulent than both rVSV-EBOV and YF 17DD in infant animals. PHV02 was lethal for adult hamsters inoculated IC but not for adult mice. In contrast YF 17DD retained virulence for adult mice inoculated IC but was not virulent for adult hamsters. Because of the inconsistency of neurovirulence patterns in the rodent models, a monkey neurovirulence test (MNVT) was performed, using YF 17DD as the active comparator because it has a well-established profile of quantifiable microscopic changes in brain centers and a known reporting rate of neurotropic adverse events in humans. In the MNVT PHV02 was significantly less neurovirulent than the YF 17DD vaccine reference control, indicating that the vaccine will have an acceptable safety profile for humans. The findings are important because they illustrate the complexities of phenotypic assessment of novel viral vectors with tissue tropisms determined by transgenic proteins, and because it is unprecedented to use a heterologous comparator virus (YF vaccine) in a regulatory-enabling study. This approach may have value in future studies of other novel viral vectors.

EXPOSURE TO AMBIENT HEAT AND RISK OF SPONTANEOUS ABORTION: A CASE-CROSSOVER STUDY.

BACKGROUND: Few epidemiologic studies have examined the association of ambient heat with spontaneous abortion, a common and devastating pregnancy outcome. METHODS: We conducted a case-crossover study nested within Pregnancy Study Online, a preconception cohort study (2013-2022). We included all participants reporting spontaneous abortion (n=1,524). We defined the case window as the 7 days preceding the event and used time-stratified referent selection to select control windows matched on calendar month and day of week. Within each 7-day case and control window, we measured mean, maximum, and minimum of daily maximum outdoor air temperatures. We fit splines to examine non-linear relationships across the entire year and conditional logistic regression to estimate odds ratios (OR) and 95% CI of spontaneous abortion with increases in temperature during the warm season (May-September) and decreases during the cool season (November-March). RESULTS: We found evidence of a U-shaped association between outdoor air temperature and spontaneous abortion risk based on year-round data. When restricting to warm season events (n=657), the OR for a 10-percentile increase in the mean of lag 0-6 daily maximum temperatures was 1.1 (95% CI: 0.96, 1.2) and, for the maximum, 1.1 (95% CI: 0.99, 1.2). The OR associated with any extreme heat days (>95th county-specific percentile) in the preceding week was 1.2 (95% CI: 0.95, 1.5). Among cool season events (n=615), there was no appreciable association between lower temperatures and spontaneous abortion risk. CONCLUSION: Our study provides evidence of an association between high outdoor temperatures and incidence of spontaneous abortion.

Treating new-onset cognitive complaints after risk-reducing salpingo-oophorectomy: A randomized controlled crossover trial of lisdexamfetamine.

OBJECTIVE: To determine whether the psychostimulant lisdexamfetamine improves subjective and objective measures of cognitive functioning among women genetically at-risk for cancer who have undergone risk-reducing salpingo-oophorectomy and report new-onset executive functioning difficulties. METHODS: 69 participants were assigned to a randomized controlled crossover trial with 6-week trials of active medication (lisdexamfetamine) and placebo, separated by a minimum 2-week washout in an intent-to-treat framework (clinical trial registration number: NCT03187353). At trial baseline, midpoint, and endpoint, participants completed a self-report measure of executive functioning (Brown Attention Deficit Disorder Scale). At study baseline and trial endpoint, participants completed sustained attention, attention/working memory, and verbal learning/memory cognitive tasks. Side effects were assessed at 2, 3, 4, and 6 weeks for each trial. RESULTS: From trial baseline to trial endpoint, lisdexamfetamine - relative to placebo - significantly improved total scores on the self-report Brown Attention Deficit Disorder Scale (and scores on four of five subdomains) as well as attention and working memory performance. Significantly more participants endorsed side effects across the lisdexamfetamine trial versus placebo; however, trial completion rates were similar, indicating that lisdexamfetamine was nonetheless well-tolerated. CONCLUSIONS: Lisdexamfetamine improved both subjective and objective measures of attention and working memory and could offer women experiencing cognitive difficulties post-risk-reducing salpingo-oophorectomy an alternative therapeutic option.

Placental differences between severe fetal growth restriction and hypertensive disorders of pregnancy requiring early preterm delivery: morphometric analysis of the villous tree supported by artificial intelligence.

BACKGROUND: The great obstetrical syndromes of fetal growth restriction and hypertensive disorders of pregnancy can occur individually or be interrelated. Placental pathologic findings often overlap between these conditions, regardless of whether 1 or both diagnoses are present. Quantification of placental villous structures in each of these settings may identify distinct differences in developmental pathways. OBJECTIVE: This study aimed to determine how the quantity and surface area of placental villi and vessels differ between severe, early-onset fetal growth restriction with absent or reversed umbilical artery Doppler indices and hypertensive disorders of pregnancy or the 2 conditions combined among subjects with disease severity that warrant early preterm delivery. We hypothesized that the trajectories of placental morphogenesis diverge after a common initiating insult of deep defective placentation. Specifically, we postulated that only villi are affected in pregnancy-related hypertension, whereas both villous and vascular structures are proportionally diminished in severe fetal growth restriction with no additional effect when hypertension is concomitantly present. STUDY DESIGN: In this retrospective cohort study, paraffin-embedded placental tissue was obtained from 4 groups, namely (1) patients with severe fetal growth restriction with absent or reversed umbilical artery end-diastolic velocities and hypertensive disorders of pregnancy, (2) patients with severe fetal growth restriction with absent or reversed umbilical artery Doppler indices and no hypertension, (3) gestational age-matched, appropriately grown pregnancies with hypertensive disease, and (4) gestational age-matched, appropriately grown pregnancies without hypertension. Dual immunohistochemistry for cytokeratin-7 (trophoblast) and CD34 (endothelial cells) was performed, followed by artificial intelligence-driven morphometric analyses. The number of villi, total villous area, number of fetoplacental vessels, and total vascular area across villi within a uniform region of interest were quantified. Quantitative analyses of placental structures were modeled using linear regression. RESULTS: Placentas from pregnancies complicated by hypertensive disorders of pregnancy exhibited significantly fewer stem villi (-282 stem villi; 95% confidence interval, -467 to -98; P<.01), a smaller stem villous area (-4.3 mm2; 95% confidence interval, -7.3 to -1.2; P<.01), and fewer stem villous vessels (-4967 stem villous vessels; 95% confidence interval, -8501 to -1433; P<.01) with no difference in the total vascular area. In contrast, placental abnormalities in cases with severe growth restriction were limited to terminal villi with global decreases in the number of villi (-873 terminal villi; 95% confidence interval, -1501 to -246; P<.01), the villous area (-1.5 mm2; 95% confidence interval, -2.7 to -0.4; P<.01), the number of blood vessels (-5165 terminal villous vessels; 95% confidence interval, -8201 to -2128; P<.01), and the vascular area (-0.6 mm2; 95% confidence interval, -1.1 to -0.1; P=.02). The combination of hypertension and growth restriction had no additional effect beyond the individual impact of each state. CONCLUSION: Pregnancies complicated by hypertensive disorders of pregnancy exhibited defects in the stem villi only, whereas placental abnormalities in severely growth restricted pregnancies with absent or reversed umbilical artery end-diastolic velocities were limited to the terminal villi. There were no significant statistical interactions in the combination of growth restriction and hypertension, suggesting that distinct pathophysiological pathways downstream of the initial insult of defective placentation are involved in each entity and do not synergize to lead to more severe pathologic consequences. Delineating mechanisms that underly the divergence in placental development after a common inciting event of defective deep placentation may shed light on new targets for prevention or treatment.

Residential Proximity to Oil and Gas Development and Mental Health in a North American Preconception Cohort Study: 2013-2023.

Objectives. To evaluate associations between oil and gas development (OGD) and mental health using cross-sectional data from a preconception cohort study, Pregnancy Study Online. Methods. We analyzed baseline data from a prospective cohort of US and Canadian women aged 21 to 45 years who were attempting conception without fertility treatment (2013-2023). We developed residential proximity measures for active OGD during preconception, including distance from nearest site. At baseline, participants completed validated scales for perceived stress (10-item Perceived Stress Scale, PSS) and depressive symptoms (Major Depression Inventory, MDI) and reported psychotropic medication use. We used log-binomial regression and restricted cubic splines to estimate prevalence ratios (PRs) and 95% confidence intervals (CIs). Results. Among 5725 participants across 37 states and provinces, residence at 2 km versus 20 to 50 km of active OGD was associated with moderate to high perceived stress (PSS ≥ 20 vs < 20: PR = 1.08; 95% CI = 0.98, 1.18), moderate to severe depressive symptoms (MDI ≥ 20 vs < 20: PR = 1.27; 95% CI = 1.11, 1.45), and psychotropic medication use (PR = 1.11; 95% CI = 0.97, 1.28). Conclusions. Among North American pregnancy planners, closer proximity to OGD was associated with adverse preconception mental health symptomatology. (Am J Public Health. 2024;114(9):923-934. https://doi.org/10.2105/AJPH.2024.307730).

Evaluating participant engagement in a preconception cohort study in relation to the Dobbs decision.

BACKGROUND: On June 24th, 2022, the United States (US) Supreme Court's ruling in Dobbs v. Jackson, et al. (hereafter, the Dobbs decision) removed federal-level protections for induced abortion, sparking concerns about reproductive rights and health privacy. Although other pregnancy outcomes (e.g. spontaneous abortion, ectopic pregnancy) are not explicit targets of post-Dobbs abortion bans, study participants may be worried about how their reproductive health data are used by researchers in the post-Dobbs era. OBJECTIVE: To evaluate the extent to which the Dobbs decision influenced participant's engagement in a preconception cohort study. METHODS: We leveraged data spanning 20 weeks before and after the Dobbs decision (4 February 2022, to 11 November 2022) from US participants in Pregnancy Study Online (PRESTO), an internet-based prospective preconception cohort study of couples attempting conception. We categorised participants' state-level abortion access by residential location: banned or restricted rights; limited access; and protected rights. We evaluated three participant engagement outcomes: follow-up questionnaire completion; report of a pregnancy; and clicking on the invitation link for a fertility-tracking app. We fit separate linear regression models and restricted cubic splines to compare outcome prevalence before and after the Dobbs decision by state-level abortion category. RESULTS: A total of 585 newly enrolled participants and 1247 already-enrolled participants received 2802 invitations to complete a follow-up questionnaire. In states with limited or protected abortion rights, we observed little change in participant engagement. In states with banned or restricted abortion rights, however, we observed a 27.12 percentage point reduction (95% confidence interval -43.68, -10.51) in the prevalence of clicking on the invitation link for the fertility-tracking app comparing the post- versus pre-Dobbs periods. CONCLUSIONS: There was some evidence of reduced participant engagement after the Dobbs decision in states with banned or restricted abortion rights, indicating potentially deleterious effects on the conduct of reproductive health studies.

A comparison of population-level exposure and equity tradeoffs across strategies to reduce fine particulate matter emissions from transportation sources in the northeastern US.

BACKGROUND: Many climate mitigation policies to reduce transportation emissions have public health benefits related to ambient air pollution. However, few health analyses consider the equity implications of alternative policies. Equity can be conceptualized in many different ways that may be relevant to communities, decision-makers, and other stakeholders. OBJECTIVES: To evaluate alternative transportation emissions reduction scenarios across the northeastern United States considering population exposure reductions and multiple equity constructs. METHODS: We developed four quantitative indicators reflecting equity constructs that aligned with stakeholder perspectives, including racial/ethnic exposure inequities, proportion of benefits in environmental justice communities, distribution of benefits among participating states, and rural/urban share of benefits. We analyzed numerous transportation emissions reduction scenarios for directly emitted fine particulate matter (primary PM2.5) covering 12 Northeast states and the District of Columbia. We used the Community Multiscale Air Quality model with the decoupled direct method to estimate the reduction in population-weighted primary PM2.5 exposure and the impact on equity for each scenario. RESULTS: Scenarios that yielded greater reductions in population-weighted primary PM2.5 exposure generally emphasized emissions reductions in urban areas or states with large urban centers, with a more than threefold difference in benefits across scenarios. The higher exposure-benefit scenarios typically also had greater reductions in racial/ethnic exposure inequities but led to higher between-state or rural/urban inequality. Scenarios that targeted uniform percentage emission reductions from light or heavy-duty trucks best addressed rural/urban inequalities but led to the smallest reductions in racial/ethnic inequity. CONCLUSION: There are intrinsic tradeoffs among equity constructs, where focusing resources on distributing benefits across states or between urban and rural populations could come at the expense of less reduction in racial/ethnic exposure inequities or in environmental justice communities. Future health benefits analyses should incorporate multiple equity indicators that reflect different stakeholder perspectives and articulate the underlying constructs and tradeoffs.

Exposure to residential greenness, perceived stress, and depressive symptoms in a North American preconception cohort.

BACKGROUND: Studies suggest that greater exposure to natural vegetation (i.e., greenness) is associated with better mental health. However, there is limited research on greenness and mental health in the preconception period, a critical window of exposure in the life course. We investigated the associations of residential greenness with perceived stress and depressive symptoms using cross-sectional data from a cohort of pregnancy planners. METHODS: From 2013 to 2019, we enrolled female-identified participants aged 21-45 years who were trying to conceive without the use of fertility treatment into a North American preconception cohort study (Pregnancy Study Online [PRESTO]). On the baseline questionnaire, participants completed the 10-item Perceived Stress Scale (PSS) and the Major Depression Inventory (MDI). Using geocoded addresses, we estimated residential greenness exposure via satellite imagery (Normalized Difference Vegetation Index [NDVI]) in a 100m buffer. We estimated mean differences and 95% confidence intervals for the association of greenness with perceived stress and depression scores using linear regression models, adjusting for individual and neighborhood sociodemographic characteristics. We also evaluated the extent to which associations were modified by urbanicity and neighborhood socioeconomic status (SES). RESULTS: Among 9718 participants, mean age was 29.9 years, 81.5% identified as non-Hispanic White, 25% had household incomes <$50,000, and mean neighborhood income was $61,932. In adjusted models, higher greenness was associated with lower stress and depression scores (mean difference per interquartile range in greenness: -0.20, 95% CI: -0.39, -0.01; and -0.19, 95% CI: -0.48, 0.10, respectively). The association was stronger among residents of lower SES neighborhoods in urban areas (PSS: -0.57, 95% CI: -1.00, -0.15; MDI: -0.72, 95% CI: -1.40, -0.04). CONCLUSIONS: Higher greenness exposure was associated with lower stress and depressive symptoms among pregnancy planners, particularly in lower-SES neighborhoods.

Ambient air pollution and rate of spontaneous abortion.

Spontaneous abortion (SAB), defined as a pregnancy loss before 20 weeks of gestation, affects up to 30% of conceptions, yet few modifiable risk factors have been identified. We estimated the effect of ambient air pollution exposure on SAB incidence in Pregnancy Study Online (PRESTO), a preconception cohort study of North American couples who were trying to conceive. Participants completed questionnaires at baseline, every 8 weeks during preconception follow-up, and in early and late pregnancy. We analyzed data on 4643 United States (U.S.) participants and 851 Canadian participants who enrolled during 2013-2019 and conceived during 12 months of follow-up. We used country-specific national spatiotemporal models to estimate concentrations of particulate matter <2.5 µm (PM2.5), nitrogen dioxide (NO2), and ozone (O3) during the preconception and prenatal periods at each participant's residential address. On follow-up and pregnancy questionnaires, participants reported information on pregnancy status, including SAB incidence and timing. We fit Cox proportional hazards regression models with gestational weeks as the time scale to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of time-varying prenatal concentrations of PM2.5, NO2, and O3 with rate of SAB, adjusting for individual- and neighborhood-level factors. Nineteen percent of pregnancies ended in SAB. Greater PM2.5 concentrations were associated with a higher incidence of SAB in Canada, but not in the U.S. (HRs for a 5 µg/m3 increase = 1.29, 95% CI: 0.99, 1.68 and 0.94, 95% CI: 0.83, 1.08, respectively). NO2 and O3 concentrations were not appreciably associated with SAB incidence. Results did not vary substantially by gestational weeks or season at risk. In summary, we found little evidence for an effect of residential ambient PM2.5, NO2, and O3 concentrations on SAB incidence in the U.S., but a moderate positive association of PM2.5 with SAB incidence in Canada.

Predictors at 6 and 12 Months for Social Participation Outcome at 24 Months in the Adult Burn Injury Population: A Burn Model System National Database Study.

OBJECTIVE: To identify clinical factors (physical and psychological symptoms and post-traumatic growth) that predict social participation outcome at 24-month after burn injury. DESIGN: A prospective cohort study based on Burn Model System National Database. SETTING: Burn Model System centers. PARTICIPANTS: 181 adult participants less than 2 years after burn injury (N=181). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Demographic and injury variables were collected at discharge. Predictor variables were assessed at 6 and 12 months: Post-Traumatic Growth Inventory Short Form (PTGI-SF), Post-Traumatic Stress Disorder Checklist Civilian Version (PCL-C), Patient-Reported Outcomes Measurement Information System (PROMIS-29) Depression, Anxiety, Sleep Disturbance, Fatigue, and Pain Interference short forms, and self-reported Heat Intolerance. Social participation was measured at 24 months using the Life Impact Burn Recovery Evaluation (LIBRE) Social Interactions and Social Activities short forms. RESULTS: Linear and multivariable regression models were used to examine predictor variables for social participation outcomes, controlling for demographic and injury variables. For LIBRE Social Interactions, significant predictors included the PCL-C total score at 6 months (ß=-0.27, P<.001) and 12 months (ß=-0.39, P<.001), and PROMIS-29 Pain Interference at 6 months (ß=-0.20, P<.01). For LIBRE Social Activities, significant predictors consisted of the PROMIS-29 Depression at 6 months (ß=-0.37, P<.001) and 12 months (ß=-0.37, P<.001), PROMIS-29 Pain Interference at 6 months (ß=-0.40, P<.001) and 12 months (ß=-0.37, P<.001), and Heat Intolerance at 12 months (ß=-4.55, P<.01). CONCLUSIONS: Post-traumatic stress and pain predicted social interactions outcomes, while depression, pain and heat intolerance predicted social activities outcomes in people with burn injury.

Moderation Effects of Daily Behavior on Associations Between Symptoms and Social Participation Outcomes After Burn Injury: A 6-Month Digital Phenotyping Study.

OBJECTIVE: To examine the moderation effects of daily behavior on the associations between symptoms and social participation outcomes after burn injury. DESIGN: A 6-month prospective cohort study. SETTING: Community. PARTICIPANTS: Twenty-four adult burn survivors. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Symptoms and social participation outcomes were assessed weekly using smartphone surveys, including symptoms of pain (Patient-Reported Outcomes Measurement Information System [PROMIS] Pain Intensity and Pain Interference), anxiety (PROMIS Anxiety), and depression (Patient Health Questionnaire), as well as outcomes of social interactions and social activities (Life Impact Burn Recovery Evaluation [LIBRE] Social Interactions and Social Activities). Daily behaviors were automatically recorded by a smartphone application and smartphone logs, including physical activity (steps, travel miles, and activity minutes), sleep (sleep hours), and social contact (number of phone calls and message contacts). RESULTS: Multilevel models controlling for demographic and burn injury variables examined the associations between symptoms and social participation outcomes and the moderation effects of daily behaviors. Lower (worse) LIBRE Social Interactions and LIBRE Social Activities scores were significantly associated with higher (worse) PROMIS Pain Intensity, PROMIS Pain Interference, PROMIS Anxiety, and Patient Health Questionnaire-8 scores (P<.05). Additionally, daily steps and activity minutes were associated with LIBRE Social Interactions and LIBRE Social Activities (P<.05), and significantly moderated the association between PROMIS Anxiety and LIBRE Social Activities (P<.001). CONCLUSIONS: Social participation outcomes are associated with pain, anxiety, and depression symptoms after burn injury, and are buffered by daily physical activity. Future intervention studies should examine physical activity promotion to improve social recovery after burns.

Proteasomal conformation controls unfolding ability.

The 26S proteasome is the macromolecular machine responsible for the bulk of protein degradation in eukaryotic cells. As it degrades a ubiquitinated protein, the proteasome transitions from a substrate-accepting conformation (s1) to a set of substrate-processing conformations (s3 like), each stabilized by different intramolecular contacts. Tools to study these conformational changes remain limited, and although several interactions have been proposed to be important for stabilizing the proteasome's various conformations, it has been difficult to test these directly under equilibrium conditions. Here, we describe a conformationally sensitive Förster resonance energy transfer assay, in which fluorescent proteins are fused to Sem1 and Rpn6, which are nearer each other in substrate-processing conformations than in the substrate-accepting conformation. Using this assay, we find that two sets of interactions, one involving Rpn5 and another involving Rpn2, are both important for stabilizing substrate-processing conformations. Mutations that disrupt these interactions both destabilize substrate-processing conformations relative to the substrate-accepting conformation and diminish the proteasome's ability to successfully unfold and degrade hard-to-unfold substrates, providing a link between the proteasome's conformational state and its unfolding ability.

High estradiol levels in fresh embryo transfer cycles are not associated with detrimental impact on birth outcomes.

PURPOSE: There is an unclear relationship between estradiol levels and fresh embryo transfer (ET) outcomes. We determined the relationship between estradiol on the day of trigger, in fresh ET cycles without premature progesterone elevation, and good birth outcomes (GBO). METHODS: We identified autologous fresh ET cycles from 2015 to 2021 at multiple clinics in the USA. Patients with recurrent pregnancy loss, uterine factor, and elevated progesterone on the day of trigger (progesterone > 2 ng/mL or 3-day area under the curve > 4.5 ng/mL) were excluded. The primary outcome was GBO (singleton, term, live birth with appropriate weight). Log-binomial generalized estimating equations determined the likelihood of outcomes. RESULTS: Of 17,608 fresh ET cycles, 5025 (29%) yielded GBO. Cycles with estradiol ≥ 4000 pg/mL had a greater likelihood of GBO compared to cycles < 1000 pg/mL (aRR = 1.32, 95% CI 1.13-1.54). Pairwise comparisons of estradiol between < 1000 pg/mL versus 1000-1999 pg/mL and 1000-1999 pg/mL versus 2000-2999 pg/mL revealed a higher likelihood of GBO with higher estradiol (aRR 0.83, 95% CI 0.73-0.95; aRR 0.91, 95% CI 0.85-0.97, respectively). Comparisons amongst more elevated estradiol levels revealed that the likelihood of GBO remained similar between groups (2000-2999 pg/mL versus 3000-3999 pg/mL, aRR 1.04, 95% CI 0.97-1.11; 3000-3999 pg/mL versus ≥ 4000 pg/mL, aRR 0.96, 95% CI 0.9-1.04). CONCLUSION: In fresh ET cycles, higher estradiol levels were associated with an increased prevalence of GBO until estradiol 2000-2999 pg/mL, thereafter plateauing. In fresh ET candidates, elevated estradiol levels should not preclude eligibility though premature progesterone rise, and risk of ovarian hyperstimulation syndrome must still be considered.

Preventing metastatic recurrence in low-risk ER/PR + breast cancer patients-a retrospective clinical study exploring the evolving challenge of persistence with adjuvant endocrine therapy.

PURPOSE: In the genomic era, more women with low-risk breast cancer will forego chemotherapy and rely on adjuvant endocrine therapy (AET) to prevent metastatic recurrence. However, some of these patients will unfortunately relapse. We sought to understand this outcome. Preliminary work suggested that early discontinuation of AET, also known as non-persistence, may play an important role. A retrospective analysis exploring factors related to our breast cancer patients' non-persistence with AET was performed. METHODS: Women who underwent Oncotype-DX® testing between 2011 and 2014 with minimum 5 years follow-up were included. 'Low risk' was defined as Oncotype score < 26. Outcomes of recurrence and persistence were determined by chart review. Patient, tumor and treatment factors were collected, and persistent versus non-persistent groups compared using multivariable ANOVA and Fisher Chi square exact test. RESULTS: We identified six cases of distant recurrence among low-risk patients with a median follow-up of 7.7 years. Among them, five of six patients (83%) were non-persistent with AET. The non-persistence rate in our cohort regardless of recurrence was 57/228 (25%). Non-persistent patients reported more severe side effects compared with persistent patients (p = 0.002) and were more likely to be offered a switch in endocrine therapy, rather than symptom-relief (p = 0.006). In contrast, persistent patients were 10.3 times more likely to have been offered symptom-alleviating medications compared with non-persistent patients (p < 0.001). A subset analysis revealed that patients who persisted with therapy had a higher Oncotype-DX® score than patients who discontinued early (p = 0.028). CONCLUSION: Metastatic recurrence in low-risk breast cancer patients may be primarily due to non-persistence with endocrine therapy. Further work is needed to optimize care for patients who struggle with side effects. To our knowledge, these are the first published data suggesting that Oncotype-DX® score may influence persistence with AET.

Identification and verification of plasma protein biomarkers that accurately identify an ectopic pregnancy.

BACKGROUND: Differentiating between a normal intrauterine pregnancy (IUP) and abnormal conditions including early pregnancy loss (EPL) or ectopic pregnancy (EP) is a major clinical challenge in early pregnancy. Currently, serial ß-human chorionic gonadotropin (ß-hCG) and progesterone are the most commonly used plasma biomarkers for evaluating pregnancy prognosis when ultrasound is inconclusive. However, neither biomarker can predict an EP with sufficient and reproducible accuracy. Hence, identification of new plasma biomarkers that can accurately diagnose EP would have great clinical value. METHODS: Plasma was collected from a discovery cohort of 48 consenting women having an IUP, EPL, or EP. Samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) followed by a label-free proteomics analysis to identify significant changes between pregnancy outcomes. A panel of 14 candidate biomarkers were then verified in an independent cohort of 74 women using absolute quantitation by targeted parallel reaction monitoring mass spectrometry (PRM-MS) which provided the capacity to distinguish between closely related protein isoforms. Logistic regression and Lasso feature selection were used to evaluate the performance of individual biomarkers and panels of multiple biomarkers to predict EP. RESULTS: A total of 1391 proteins were identified in an unbiased plasma proteome discovery. A number of significant changes (FDR ≤ 5%) were identified when comparing EP vs. non-EP (IUP + EPL). Next, 14 candidate biomarkers (ADAM12, CGA, CGB, ISM2, NOTUM, PAEP, PAPPA, PSG1, PSG2, PSG3, PSG9, PSG11, PSG6/9, and PSG8/1) were verified as being significantly different between EP and non-EP in an independent cohort (FDR ≤ 5%). Using logistic regression models, a risk score for EP was calculated for each subject, and four multiple biomarker logistic models were identified that performed similarly and had higher AUCs than models with single predictors. CONCLUSIONS: Overall, four multivariable logistic models were identified that had significantly better prediction of having EP than those logistic models with single biomarkers. Model 4 (NOTUM, PAEP, PAPPA, ADAM12) had the highest AUC (0.987) and accuracy (96%). However, because the models are statistically similar, all markers in the four models and other highly correlated markers should be considered in further validation studies.