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ObjectiveOur objective was to investigate the overall and sex-specific relationships between the presence and severity of knee osteoarthritis (KOA) and muscle composition, power, and energetics in older adults.MethodsMale and female patients (n = 655, mean ± SD age 76.1 ± 4.9 years; 57% female) enrolled in the Study of Muscle, Mobility, and Aging completed standing knee radiographs and knee pain assessments. Participants were divided into three groups using Kellgren-Lawrence grade (KLG) of KOA severity (0-1, 2, or 3-4). Outcome measures included whole-body muscle mass, thigh fat-free muscle (FFM) volume and muscle fat infiltration (MFI), leg power, specific power (power normalized to muscle volume), and muscle mitochondrial energetics.ResultsOverall, the presence and severity of KOA is associated with greater MFI, lower leg power and specific power, and reduced oxidative phosphorylation (P trend < 0.036). Sex-specific analysis revealed reduced energetics only in female patients with KOA (P trend < 0.007) compared to female patients without KOA. In models adjusted for age, sex, race, nonsteroidal anti-inflammatory drug administration, site or technician, physical activity, height, and participants with abdominal adiposity with KLG 3 to 4 had greater MFI (mean 0.008%, 95% confidence interval [CI] 0.004%-0.011%) and lower leg power (mean -51.56 W, 95% CI -74.03 to -29.10 W) and specific power (mean -5.38 W/L, 95% CI -7.31 to -3.45 W/L) than those with KLG 0 to 1. No interactions were found between pain and KLG status. Among those with KOA, MFI and oxidative phosphorylation were associated with thigh FFM volume, leg power, and specific power.ConclusionMuscle health is associated with the presence and severity of KOA and differs by sex. Although muscle composition and power are lower in both male and female patients with KOA, regardless of pain status, mitochondrial energetics is reduced only in female patients.

Physical activity, including structured exercise, is associated with favorable health-related chronic disease outcomes. Although there is evidence of various molecular pathways that affect these responses, a comprehensive molecular map of these molecular responses to exercise has not been developed. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) is a multicenter study designed to isolate the effects of structured exercise training on the molecular mechanisms underlying the health benefits of exercise and physical activity. MoTrPAC contains both a preclinical and human component. The details of the human studies component of MoTrPAC that include the design and methods are presented here. The human studies contain both an adult and pediatric component. In the adult component, sedentary participants are randomized to 12 wk of Control, Endurance Exercise Training, or Resistance Exercise Training with outcomes measures completed before and following the 12 wk. The adult component also includes recruitment of highly active endurance-trained or resistance-trained participants who only complete measures once. A similar design is used for the pediatric component; however, only endurance exercise is examined. Phenotyping measures include weight, body composition, vital signs, cardiorespiratory fitness, muscular strength, physical activity and diet, and other questionnaires. Participants also complete an acute rest period (adults only) or exercise session (adults, pediatrics) with collection of biospecimens (blood only for pediatrics) to allow for examination of the molecular responses. The design and methods of MoTrPAC may inform other studies. Moreover, MoTrPAC will provide a repository of data that can be used broadly across the scientific community.NEW & NOTEWORTHY The Molecular Transducers of Physical Activity Consortium (MoTrPAC) will be the first large trial to isolate the effects of structured exercise training on the molecular mechanisms underlying the health benefits of exercise and physical activity. By generating a compendium of the molecular responses to exercise, MoTrPAC will lay the foundation for a new era of biomedical research on Precision Exercise Medicine. Presented here is the design, protocols, and procedures for the MoTrPAC human studies.

Intermuscular adipose tissue (IMAT) is a relatively understudied adipose depot located between muscle fibers. IMAT content increases with age and BMI and is associated with metabolic and muscle degenerative diseases; however, an understanding of the biological properties of IMAT and its interplay with the surrounding muscle fibers is severely lacking. In recent years, single-cell and nuclei RNA sequencing have provided us with cell type-specific atlases of several human tissues. However, the cellular composition of human IMAT remains largely unexplored due to the inherent challenges of its accessibility from biopsy collection in humans. In addition to the limited amount of tissue collected, the processing of human IMAT is complicated due to its proximity to skeletal muscle tissue and fascia. The lipid-laden nature of the adipocytes makes it incompatible with single-cell isolation. Hence, single nuclei RNA sequencing is optimal for obtaining high-dimensional transcriptomics at single-cell resolution and provides the potential to uncover the biology of this depot, including the exact cellular composition of IMAT. Here, we present a detailed protocol for nuclei isolation and library preparation of frozen human IMAT for single nuclei RNA sequencing. This protocol allows for the profiling of thousands of nuclei using a droplet-based approach, thus providing the capacity to detect rare and low-abundant cell types.

While there is increasing recognition that social processes in cities like gentrification have ecological consequences, we lack nuanced understanding of the ways gentrification affects urban biodiversity. We analyzed a large camera trap dataset of mammals (>500 g) to evaluate how gentrification impacts species richness and community composition across 23 US cities. After controlling for the negative effect of impervious cover, gentrified parts of cities had the highest mammal species richness. Change in community composition was associated with gentrification in a few cities, which were mostly located along the West Coast. At the species level, roughly half (11 of 21 mammals) had higher occupancy in gentrified parts of a city, especially when impervious cover was low. Our results indicate that the impacts of gentrification extend to nonhuman animals, which provides further evidence that some aspects of nature in cities, such as wildlife, are chronically inaccessible to marginalized human populations.

OBJECTIVES: Determine the incremental diagnostic yield of prenatal exome sequencing (pES) over chromosome microarray (CMA) or G-banding karyotype in fetuses with central nervous system (CNS) abnormalities. METHODS: Data were collected via electronic searches from January 2010 to April 2022 in MEDLINE, Cochrane, Web of Science and EMBASE. The NHS England prenatal exome cohort was also included. Incremental yield was calculated as a pooled value using a random-effects model. RESULTS: Thirty studies were included (n = 1583 cases). The incremental yield with pES for any CNS anomaly was 32% [95%CI 27%-36%; I2 = 72%]. Subgroup analysis revealed apparent incremental yields in; (a) isolated CNS anomalies; 27% [95%CI 19%-34%; I2 = 74%]; (b) single CNS anomaly; 16% [95% CI 10%-23%; I2 = 41%]; (c) more than one CNS anomaly; 31% [95% Cl 21%-40%; I2 = 56%]; and (d) the anatomical subtype with the most optimal yield was Type 1 malformation of cortical development, related to abnormal cell proliferation or apoptosis, incorporating microcephalies, megalencephalies and dysplasia; 40% (22%-57%; I2 = 68%). The commonest syndromes in isolated cases were Lissencephaly 3 and X-linked hydrocephalus. CONCLUSIONS: Prenatal exome sequencing provides a high incremental diagnostic yield in fetuses with CNS abnormalities with optimal yields in cases with multiple CNS anomalies, particularly those affecting the midline, posterior fossa and cortex.

Future climate change can cause more days with poor air quality. This could trigger more alerts telling people to stay inside to protect themselves, with potential consequences for health and health equity. Here, we study the change in US air quality alerts over this century due to fine particulate matter (PM2.5), who they may affect, and how they may respond. We find air quality alerts increase by over 1 mo per year in the eastern United States by 2100 and quadruple on average. They predominantly affect areas with high Black populations and leakier homes, exacerbating existing inequalities and impacting those less able to adapt. Reducing emissions can offer significant annual health benefits ($5,400 per person) by mitigating the effect of climate change on air pollution and its associated risks of early death. Relying on people to adapt, instead, would require them to stay inside, with doors and windows closed, for an extra 142 d per year, at an average cost of $11,000 per person. It appears likelier, however, that people will achieve minimal protection without policy to increase adaptation rates. Boosting adaptation can offer net benefits, even alongside deep emission cuts. New adaptation policies could, for example: reduce adaptation costs; reduce infiltration and improve indoor air quality; increase awareness of alerts and adaptation; and provide measures for those working or living outdoors. Reducing emissions, conversely, lowers everyones need to adapt, and protects those who cannot adapt. Equitably protecting human health from air pollution under climate change requires both mitigation and adaptation.

Inter-organ communication is a vital process to maintain physiologic homeostasis, and its dysregulation contributes to many human diseases. Given that circulating bioactive factors are stable in serum, occur naturally, and are easily assayed from blood, they present obvious focal molecules for therapeutic intervention and biomarker development. Recently, studies have shown that secreted proteins mediating inter-tissue signaling could be identified by 'brute force' surveys of all genes within RNA-sequencing measures across tissues within a population. Expanding on this intuition, we reasoned that parallel strategies could be used to understand how individual genes mediate signaling across metabolic tissues through correlative analyses of gene variation between individuals. Thus, comparison of quantitative levels of gene expression relationships between organs in a population could aid in understanding cross-organ signaling. Here, we surveyed gene-gene correlation structure across 18 metabolic tissues in 310 human individuals and 7 tissues in 103 diverse strains of mice fed a normal chow or high-fat/high-sucrose (HFHS) diet. Variation of genes such as FGF21, ADIPOQ, GCG, and IL6 showed enrichments which recapitulate experimental observations. Further, similar analyses were applied to explore both within-tissue signaling mechanisms (liver PCSK9) and genes encoding enzymes producing metabolites (adipose PNPLA2), where inter-individual correlation structure aligned with known roles for these critical metabolic pathways. Examination of sex hormone receptor correlations in mice highlighted the difference of tissue-specific variation in relationships with metabolic traits. We refer to this resource as gene-derived correlations across tissues (GD-CAT) where all tools and data are built into a web portal enabling users to perform these analyses without a single line of code (gdcat.org). This resource enables querying of any gene in any tissue to find correlated patterns of genes, cell types, pathways, and network architectures across metabolic organs.

BackgroundPhthalate exposures are ubiquitous during pregnancy and may contribute to racial and ethnic disparities in preterm birth.ObjectivesWe investigated race and ethnicity in the relationship between biomarkers of phthalate exposure and preterm birth by examining: a) how hypothetical reductions in racial and ethnic disparities in phthalate metabolites might reduce the probability of preterm birth; and b) exposure-response models stratified by race and ethnicity.MethodsWe pooled individual-level data on 6,045 pregnancies from 16 U.S. cohorts. We investigated covariate-adjusted differences in nine urinary phthalate metabolite concentrations by race and ethnicity [non-Hispanic White (White, 43%), non-Hispanic Black (Black, 13%), Hispanic/Latina (38%), and Asian/Pacific Islander (3%)]. Using g-computation, we estimated changes in the probability of preterm birth under hypothetical interventions to eliminate disparities in levels of urinary phthalate metabolites by proportionally lowering average concentrations in Black and Hispanic/Latina participants to be approximately equal to the averages in White participants. We also used race and ethnicity-stratified logistic regression to characterize associations between phthalate metabolites and preterm birth.ResultsIn comparison with concentrations among White participants, adjusted mean phthalate metabolite concentrations were consistently higher among Black and Hispanic/Latina participants by 23%-148% and 4%-94%, respectively. Asian/Pacific Islander participants had metabolite levels that were similar to those of White participants. Hypothetical interventions to reduce disparities in metabolite mixtures were associated with lower probabilities of preterm birth for Black [13% relative reduction; 95% confidence interval (CI): -34%, 8.6%] and Hispanic/Latina (9% relative reduction; 95% CI: -19%, 0.8%) participants. Odds ratios for preterm birth in association with phthalate metabolites demonstrated heterogeneity by race and ethnicity for two individual metabolites (mono-n-butyl and monoisobutyl phthalate), with positive associations that were larger in magnitude observed among Black or Hispanic/Latina participants.ConclusionsPhthalate metabolite concentrations differed substantially by race and ethnicity. Our results show hypothetical interventions to reduce population-level racial and ethnic disparities in biomarkers of phthalate exposure could potentially reduce the probability of preterm birth. https://doi.org/10.1289/EHP12831.

OBJECTIVE: There is increasing evidence supporting the clinical utility of next generation sequencing for identifying fetal genetic disorders. However, there are limited data on the demand for and accessibility of these tests, as well as payer coverage in the prenatal context. We sought to identify clinician perspectives on the utility of prenatal exome sequencing (ES) and on equitable access to genomic technologies for the care of pregnancies complicated by fetal structural anomalies. METHOD: We conducted two focus group discussions and six interviews with a total of 13 clinicians (11 genetic counselors; 2 Maternal Fetal Medicine/Geneticists) from U.S. academic centers and community clinics. RESULTS: Participants strongly supported ES for prenatal diagnostic testing in pregnancies with fetal structural anomalies. Participants emphasized the value of prenatal ES as an opportunity for a continuum of care before, during, and after a pregnancy, not solely as informing decisions about abortions. Cost and coverage of the test was the main access barrier, and research was the main pathway to access ES in academic centers. CONCLUSION: Further integrating the perspectives of additional key stakeholders are important for understanding clinical utility, developing policies and practices to address access barriers, and assuring equitable provision of prenatal diagnostic testing.

The Development and Behavior Access Clinic (DBAC) deploys a general pediatrician with brief/intensive training and proctoring by developmental-behavioral pediatricians (DBP) to provide developmental-behavioral (DB) care to children referred with mild/moderate complexity needs as determined by a team of clinical psychologists. This pilot study utilizes visit data, chart review, and surveys to assess wait times, need for subspecialty care, and referring clinician satisfaction. In its first 18 months, DBAC decreased the need for subspecialty DB care, providing initial services for 44% of patients referred for DB pediatric care from the study site; 89% did not require subsequent subspecialty evaluation. Among DBAC participants, average wait times for DB care decreased from a baseline of 218 to 41 calendar days. This pilot study provides a model for building DB clinical skills among interested general pediatricians, decreasing wait times, and building the capacity of primary care settings to address mild-to-moderate complexity DB concerns.

OBJECTIVE: To describe obstetric outcomes based on COVID-19 vaccination status, in women with rheumatic and musculoskeletal diseases (RMDs) who developed COVID-19 during pregnancy. METHODS: Data regarding pregnant women entered into the COVID-19 Global Rheumatology Alliance registry from 24 March 2020-25 February 2022 were analysed. Obstetric outcomes were stratified by number of COVID-19 vaccine doses received prior to COVID-19 infection in pregnancy. Descriptive differences between groups were tested using the chi-squared or Fishers exact test. RESULTS: There were 73 pregnancies in 73 women with RMD and COVID-19. Overall, 24.7% (18) of pregnancies were ongoing, while of the 55 completed pregnancies, 90.9% (50) of pregnancies resulted in livebirths. At the time of COVID-19 diagnosis, 60.3% (n = 44) of women were unvaccinated, 4.1% (n = 3) had received one vaccine dose while 35.6% (n = 26) had two or more doses. Although 83.6% (n = 61) of women required no treatment for COVID-19, 20.5% (n = 15) required hospital admission. COVID-19 resulted in delivery in 6.8% (n = 3) of unvaccinated women and 3.8% (n = 1) of fully vaccinated women. There was a greater number of preterm births (PTB) in unvaccinated women compared with fully vaccinated 29.5% (n = 13) vs 18.2% (n = 2). CONCLUSIONS: In this descriptive study, unvaccinated pregnant women with RMD and COVID-19 had a greater number of PTB compared with those fully vaccinated against COVID-19. Additionally, the need for COVID-19 pharmacological treatment was uncommon in pregnant women with RMD regardless of vaccination status. These results support active promotion of COVID-19 vaccination in women with RMD who are pregnant or planning a pregnancy.

People vary both in their embrace of their society's traditions, and in their perception of hazards as salient and necessitating a response. Over evolutionary time, traditions have offered avenues for addressing hazards, plausibly resulting in linkages between orientations toward tradition and orientations toward danger. Emerging research documents connections between traditionalism and threat responsivity, including pathogen-avoidance motivations. Additionally, because hazard-mitigating behaviors can conflict with competing priorities, associations between traditionalism and pathogen avoidance may hinge on contextually contingent tradeoffs. The COVID-19 pandemic provides a real-world test of the posited relationship between traditionalism and hazard avoidance. Across 27 societies (N = 7844), we find that, in a majority of countries, individuals' endorsement of tradition positively correlates with their adherence to costly COVID-19-avoidance behaviors; accounting for some of the conflicts that arise between public health precautions and other objectives further strengthens this evidence that traditionalism is associated with greater attention to hazards.

ObjectiveTo provide evidence-based recommendations on the use of vaccinations in children and adults with rheumatic and musculoskeletal diseases (RMDs).MethodsThis guideline follows American College of Rheumatology (ACR) policy guiding management of conflicts of interest and disclosures and the ACR guideline development process, which includes the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. It also adheres to the Appraisal of Guidelines for Research and Evaluation (AGREE) criteria. A core leadership team consisting of adult and pediatric rheumatologists and a guideline methodologist drafted clinical population, intervention, comparator, outcomes (PICO) questions. A review team performed a systematic literature review for the PICO questions, graded the quality of evidence, and produced an evidence report. An expert Voting Panel reviewed the evidence and formulated recommendations. The panel included adult and pediatric rheumatology providers, infectious diseases specialists, and patient representatives. Consensus required ≥70% agreement on both the direction and strength of each recommendation.ResultsThis guideline includes expanded indications for some vaccines in patients with RMDs, as well as guidance on whether to hold immunosuppressive medications or delay vaccination to maximize vaccine immunogenicity and efficacy. Safe approaches to the use of live attenuated vaccines in patients taking immunosuppressive medications are also addressed. Most recommendations are conditional and had low quality of supporting evidence.ConclusionApplication of these recommendations should consider patients' individual risk for vaccine-preventable illness and for disease flares, particularly if immunosuppressive medications are held for vaccination. Shared decision-making with patients is encouraged in clinical settings.

Over the past decade, abiraterone and enzalutamide have largely replaced ketoconazole as oral treatments for castration-resistant prostate cancer (CRPC). We investigated the differential adoption of abiraterone and enzalutamide across facilities in a national healthcare system to understand the impact a facility has on the receipt of these novel therapies. Using data from the VA Corporate Data Warehouse, we identified a cohort of men with CRPC who received the most common first-line therapies: abiraterone, enzalutamide, docetaxel, or ketoconazole between 2010 and 2017. We described variability in the adoption of abiraterone and enzalutamide across facilities by time period (2010-2013 or 2014-2017). We categorized facilities depending on the timing of adoption of abiraterone and enzalutamide relative to other facilities and described facility characteristics associated with early and late adoption. We identified 4998 men treated with ketoconazole, docetaxel, abiraterone, or enzalutamide as first-line CRPC therapy between 2010 and 2017 at 125 national facilities. When limiting the cohort to oral therapies, most patients treated earlier in the study period (2010-2013) received ketoconazole. A dramatic shift was seen by the second half of the study period (2014-2017) with most men treated with first-line abiraterone (61%). Despite this shift and a new standard of care, some facilities persisted in the widespread use of ketoconazole in the later period, so-called late adopting facilities. After multivariable adjustment, patients who received treatment at a late adopting facility were more likely receiving care at a lower complexity, rural facility, with less urology and hematology/oncology workforce (all p

We systematically delineated the prenatal phenotype, and obstetrical and neonatal outcomes of the RASopathy cardio-facio-cutaneous (CFC) syndrome. A comprehensive, retrospective medical history survey was distributed to parents of children with confirmed CFC in collaboration with CFC International, Inc. Data were collected on CFC gene variant, maternal characteristics, pregnancy course, delivery, and neonatal outcomes with the support of medical records. We identified 43 individuals with pathogenic variants in BRAF (81%), MEK1 (14%), or MEK2 (5%) genes. The median age was 8.5 years. Hyperemesis gravidarum, gestational diabetes, gestational hypertension, and preeclampsia occurred in 5/43 (12%), 4/43 (9%), 3/43 (7%), and 3/43 (7%) of pregnancies, respectively. Second and third trimester ultrasound abnormalities included polyhydramnios, macrocephaly, macrosomia, and renal and cardiac abnormalities. Delivery occurred via spontaneous vaginal, operative vaginal, or cesarean delivery in 15/42 (36%), 7/42 (16%), and 20/42 (48%), respectively. Median gestational age at delivery was 37 weeks and median birth weight was 3501 grams. Germline pathogenic vaiants had mutiple congenital consequences including polyhydramnios, renal and cardiac abnormalities, macrosomia, and macrocephaly on second and third trimester ultrasound. Elevated rates of operative delivery and neonatal complications were also noted. Understanding and defining a prenatal phenotype may improve prenatal prognostic counseling and outcomes.

Establishing the diagnosis of a fetal genetic disease in utero expands decision-making opportunities for individuals during pregnancy and enables providers to tailor prenatal care and surveillance to disease-specific risks. The selection of prenatal genetic tests is guided by key details from fetal imaging, family and obstetrical history, suspected diagnoses and mechanisms of disease, an accurate understanding of what abnormalities each test is designed to detect, and, at times, the gestational age at which testing is initiated. Pre- and posttest counseling, by or in conjunction with providers trained in genetics, ensure an accurate understanding of genetic tests, their potential results and limitations, estimated turnaround time for results, and the clinical implications of their findings. As prenatal diagnosis and testing options continue to expand rapidly, it is increasingly important for obstetrical providers to understand how to choose appropriate genetic testing and contextualize the clinical implications of their results.

We are living in a golden age of medicine in which the availability of prenatal diagnosis, fetal therapy, and gene therapy/editing make it theoretically possible to repair almost any defect in the genetic code. Furthermore, the ability to diagnose genetic disorders before birth and the presence of established surgical techniques enable these therapies to be delivered safely to the fetus. Prenatal therapies are generally used in the second or early third trimester for severe, life-threatening disorders for which there is a clear rationale for intervening before birth. While there has been promising work for prenatal gene therapy in preclinical models, the path to a clinical prenatal gene therapy approach is complex. We recently held a conference with the University of California, San Francisco-Stanford Center of Excellence in Regulatory Science and Innovation, researchers, patient advocates, regulatory (members of the Food and Drug Administration), and other stakeholders to review the scientific background and rationale for prenatal somatic cell gene therapy for severe monogenic diseases and initiate a dialogue toward a safe regulatory path for phase 1 clinical trials. This review represents a summary of the considerations and discussions from these conversations.

AimTo determine characteristics associated with more severe outcomes in a global registry of people with systemic lupus erythematosus (SLE) and COVID-19.MethodsPeople with SLE and COVID-19 reported in the COVID-19 Global Rheumatology Alliance registry from March 2020 to June 2021 were included. The ordinal outcome was defined as: (1) not hospitalised, (2) hospitalised with no oxygenation, (3) hospitalised with any ventilation or oxygenation and (4) death. A multivariable ordinal logistic regression model was constructed to assess the relationship between COVID-19 severity and demographic characteristics, comorbidities, medications and disease activity.ResultsA total of 1606 people with SLE were included. In the multivariable model, older age (OR 1.03, 95% CI 1.02 to 1.04), male sex (1.50, 1.01 to 2.23), prednisone dose (1-5 mg/day 1.86, 1.20 to 2.66, 6-9 mg/day 2.47, 1.24 to 4.86 and ≥10 mg/day 1.95, 1.27 to 2.99), no current treatment (1.80, 1.17 to 2.75), comorbidities (eg, kidney disease 3.51, 2.42 to 5.09, cardiovascular disease/hypertension 1.69, 1.25 to 2.29) and moderate or high SLE disease activity (vs remission; 1.61, 1.02 to 2.54 and 3.94, 2.11 to 7.34, respectively) were associated with more severe outcomes. In age-adjusted and sex-adjusted models, mycophenolate, rituximab and cyclophosphamide were associated with worse outcomes compared with hydroxychloroquine; outcomes were more favourable with methotrexate and belimumab.ConclusionsMore severe COVID-19 outcomes in individuals with SLE are largely driven by demographic factors, comorbidities and untreated or active SLE. Patients using glucocorticoids also experienced more severe outcomes.

Technological advances in both genome sequencing and prenatal imaging are increasing our ability to accurately recognize and diagnose Mendelian conditions prenatally. Phenotype-driven early genetic diagnosis of fetal genetic disease can help to strategize treatment options and clinical preventive measures during the perinatal period, to plan in utero therapies, and to inform parental decision-making. Fetal phenotypes of genetic diseases are often unique and at present are not well understood; more comprehensive knowledge about prenatal phenotypes and computational resources have an enormous potential to improve diagnostics and translational research. The Human Phenotype Ontology (HPO) has been widely used to support diagnostics and translational research in human genetics. To better support prenatal usage, the HPO consortium conducted a series of workshops with a group of domain experts in a variety of medical specialties, diagnostic techniques, as well as diseases and phenotypes related to prenatal medicine, including perinatal pathology, musculoskeletal anomalies, neurology, medical genetics, hydrops fetalis, craniofacial malformations, cardiology, neonatal-perinatal medicine, fetal medicine, placental pathology, prenatal imaging, and bioinformatics. We expanded the representation of prenatal phenotypes in HPO by adding 95 new phenotype terms under the Abnormality of prenatal development or birth (HP:0001197) grouping term, and revised definitions, synonyms, and disease annotations for most of the 152 terms that existed before the beginning of this effort. The expansion of prenatal phenotypes in HPO will support phenotype-driven prenatal exome and genome sequencing for precision genetic diagnostics of rare diseases to support prenatal care.

PurposePatients undergoing clinical exome sequencing (ES) are routinely offered the option to receive secondary findings (SF). However, little is known about the views of individuals from underrepresented minority pediatric or prenatal populations regarding SF.MethodsWe explored the preferences for receiving hypothetical categories of SF (H-SF) and reasons for accepting or declining actual SF through surveying (n = 149) and/or interviewing (n = 47) 190 families undergoing pediatric or prenatal ES.ResultsUnderrepresented minorities made up 75% of the probands. In total, 150 families (79%) accepted SF as part of their child/fetus's ES. Most families (63%) wanted all categories of H-SF. Those who declined SF as part of ES were less likely to want H-SF across all categories. Interview findings indicate that some families did not recall their SF decision. Preparing for the future was a major motivator for accepting SF, and concerns about privacy, discrimination, and psychological effect drove decliners.ConclusionA notable subset of families (37%) did not want at least 1 category of H-SF, suggesting more hesitancy about receiving all available results than previously reported. The lack of recollection of SF decisions suggests a need for alternative communication approaches. Results highlight the importance of the inclusion of diverse populations in genomic research.

ObjectiveWe aimed to determine the frequency of accepting secondary findings in families undergoing exome sequencing in prenatal and pediatric settings.MethodsThis was a secondary analysis of prospectively enrolled patients undergoing trio exome sequencing for congenital anomalies or developmental disorders in prenatal and pediatric settings, in which families were offered receiving secondary findings (initially assessed in the proband and, if identified, then in the parents). The primary outcome was frequency of accepting secondary findings. Secondary outcomes included frequency of acceptance in prenatal versus pediatric settings, and sociodemographic differences between those who accepted versus declined secondary findings.ResultsThere were 682 families included in the cohort (289 prenatal and 393 pediatric). Overall, 84% (576/682) of families accepted secondary findings: 86.2% (249/289) of families undergoing prenatal versus 83.2% (327/393) pediatric (p = 0.30) testing. Secondary findings were identified in 2.6% (15/576) of cases, with no difference between prenatal and pediatric settings. There were no differences in sociodemographics between families that accepted versus declined secondary findings.ConclusionThe majority of families undergoing exome sequencing accepted secondary findings; this did not differ in prenatal versus pediatric settings. This highlights the need for guidance surrounding the offer of secondary findings in the prenatal setting.

The ARID1A gene is an infrequent cause of Coffin-Siris syndrome (CSS) and has been associated with severe to profound developmental delays and hypotonia in addition to characteristic craniofacial and digital findings. We present three fetuses and a male neonate with ventriculomegaly/hydrocephalus, absence of the corpus callosum (ACC), cerebellar hypoplasia, retinal dysplasia, lung lobulation defects, renal dysplasia, imperforate or anteriorly placed anus, thymus hypoplasia and a single umbilical artery. Facial anomalies included downslanting palpebral fissures, wide-spaced eyes, low-set and posteriorly rotated ears, a small jaw, widely spaced nipples and hypoplastic nails. All fetuses had heterozygous variants predicting premature protein truncation in ARID1A (c.4886dup:p.Val1630Cysfs*18; c.4860dup:p.Pro1621Thrfs*27; and c.175G>T:p.Glu59*) and the baby's microarray demonstrated mosaicism for a deletion at chromosome 1p36.11 (arr[GRCh37] 1p36.11(26,797,508_27,052,080)×1∼2), that contained the first exon of ARID1A. Although malformations, in particular ACC, have been described with CSS caused by pathogenic variants in ARID1A, prenatal presentations associated with this gene are rare. Retinal dysplasia, lung lobulation defects and absent thymus were novel findings in association with ARID1A variants. Studies in cancer have demonstrated that pathogenic ARID1A variants hamper nuclear import of the protein and/or affect interaction with the subunits of SWI/SNF complex, resulting in dysregulation of the PI3K/AKT pathway and perturbed PTEN and PIKC3A signaling. As haploinsufficiency for PTEN and PIKC3A can be associated with ventriculomegaly/hydrocephalus, aberrant expression of these genes is a putative mechanism for the brain malformations demonstrated in patients with ARID1A variants.

BackgroundNext-generation sequencing is increasingly used in prenatal diagnosis. Targeted gene panels and exome sequencing are both available, but the comparative diagnostic yields of these approaches are not known.ObjectiveWe compared the diagnostic yield of exome sequencing with the simulated application of commercial targeted gene panels in a large cohort of fetuses with nonimmune hydrops fetalis.Study designThis was a secondary analysis of a cohort study of exome sequencing for nonimmune hydrops fetalis, in which recruitment, exome sequencing, and phenotype-driven variant analysis were completed in 127 pregnancies with features of nonimmune hydrops fetalis. An Internet search was performed to identify commercial laboratories that offer targeted gene panels for the prenatal evaluation of nonimmune hydrops fetalis or for specific disorders associated with nonimmune hydrops fetalis using the terms "non-immune hydrops fetalis," "fetal non-immune hydrops," "hydrops," "cystic hygroma," "lysosomal storage disease," "metabolic disorder," "inborn error of metabolism," "RASopathy," and "Noonan." Our primary outcome was the proportion of all genetic variants identified through exome sequencing that would have been identified if a targeted gene panel had instead been used. The secondary outcomes were the proportion of genetic variants that would have been identified by type of targeted gene panel (general nonimmune hydrops fetalis, RASopathy, or metabolic) and the percent of variants of uncertain significance that would have been identified on the panels, assuming 100% analytical sensitivity and specificity of panels for variants in the included genes.ResultsExome sequencing identified a pathogenic or likely pathogenic variant in 37 of 127 cases (29%) in a total of 29 genes. A variant of uncertain significance, strongly suspected to be associated with the phenotype, was identified in another 12 cases (9%). We identified 7 laboratories that offer 10 relevant targeted gene panels; 6 are described as RASopathy panels, 3 as nonimmune hydrops fetalis panels, and 1 as a metabolic panel. The median number of genes included on each of these panels is 22, ranging from 11 to 148. Had a nonimmune hydrops fetalis targeted gene panel been used instead of exome sequencing, 13 to 15 of the 29 genes (45%-52%) identified in our nonimmune hydrops fetalis cohort would have been sequenced, and 19 to 24 of the pathogenic variants (51%-62%) would have been detected. The yield was predicted to be the lowest with the metabolic panel (11%) and the highest with the largest nonimmune hydrops fetalis panel (62%). The largest nonimmune hydrops fetalis targeted gene panel would have had a diagnostic yield of 18% compared with 29% with exome sequencing. The exome sequencing platform used provided 30× or more coverage for all of the exons on the commercial targeted gene panels, supporting our assumption of 100% analytical sensitivity for exome sequencing.ConclusionThe broader coverage of exome sequencing for genetically heterogeneous disorders, such as nonimmune hydrops fetalis, made it a superior alternative to targeted gene panel testing.

SARS-CoV-2 infection causes diverse outcomes ranging from asymptomatic infection to respiratory distress and death. A major unresolved question is whether prior immunity to endemic, human common cold coronaviruses (hCCCoVs) impacts susceptibility to SARS-CoV-2 infection or immunity following infection and vaccination. Therefore, we analyzed samples from the same individuals before and after SARS-CoV-2 infection or vaccination. We found hCCCoV antibody levels increase after SARS-CoV-2 exposure, demonstrating cross-reactivity. However, a case-control study indicates that baseline hCCCoV antibody levels are not associated with protection against SARS-CoV-2 infection. Rather, higher magnitudes of pre-existing betacoronavirus antibodies correlate with more SARS-CoV-2 antibodies following infection, an indicator of greater disease severity. Additionally, immunization with hCCCoV spike proteins before SARS-CoV-2 immunization impedes the generation of SARS-CoV-2-neutralizing antibodies in mice. Together, these data suggest that pre-existing hCCCoV antibodies hinder SARS-CoV-2 antibody-based immunity following infection and provide insight on how pre-existing coronavirus immunity impacts SARS-CoV-2 infection, which is critical considering emerging variants.

BackgroundGastroschisis is often complicated by fetal growth restriction, preterm delivery, and prolonged neonatal hospitalization. Prenatal management and delivery decisions are often based on estimated fetal weight and interval growth; however, appropriate interval growth from week to week across gestation for these fetuses is poorly understood.ObjectiveThis study aimed to determine the median increase in overall estimated fetal weight and individual biometric measurements across each week of gestation in pregnancies with fetal gastroschisis and to assess whether lower in utero fetal weight gain is predictive of postnatal growth or adverse neonatal outcomes.Study designThis was a retrospective cohort study of pregnancies with gastroschisis evaluated at 5 institutions of the University of California Fetal-Maternal Consortium from December 2014 to December 2019. The inclusion criteria were prenatally diagnosed gastroschisis with at least 1 ultrasound performed at a University of California Fetal-Maternal Consortium institution. Estimated fetal weight and individual biometric measurements were recorded for each ultrasound performed at a University of California Fetal-Maternal Consortium institution from the time of gastroschisis diagnosis to delivery. Median estimated fetal weight and biometric measurements were calculated for each gestational age in 1-week increments. Neonatal outcomes collected were birthweight, length of stay, complications of gastroschisis (bowel atresia, bowel stricture, ischemic bowel before closure, or severe pulmonary hypoplasia), and growth failure at discharge.ResultsWe identified 95 pregnancies with fetal gastroschisis who, in aggregate, had 360 growth ultrasounds at a University of California Fetal-Maternal Consortium institution. The median interval growth was 130 g/wk. The median estimated fetal weight and abdominal circumference in fetal gastroschisis cases were approximately the tenth percentile on the Hadlock growth curve across gestation. Moreover, the median biparietal diameter, head circumference, and femur length measurements remained below the 50th percentile on the Hadlock growth curve across gestation. The median birthweight for neonates with less than the median weekly prenatal weight gain was less than for those with greater than the median weekly prenatal weight gain (2185 g vs 2780 g; P

BackgroundWe describe the early experiences of adults with systemic rheumatic disease who received the COVID-19 vaccine.MethodsFrom 2 April to 30 April 2021, we conducted an online, international survey of adults with systemic rheumatic disease who received COVID-19 vaccination. We collected patient-reported data on clinician communication, beliefs and intent about discontinuing disease-modifying antirheumatic drugs (DMARDs) around the time of vaccination, and patient-reported adverse events after vaccination.ResultsWe analysed 2860 adults with systemic rheumatic diseases who received COVID-19 vaccination (mean age 55.3 years, 86.7% female, 86.3% white). Types of COVID-19 vaccines were Pfizer-BioNTech (53.2%), Oxford/AstraZeneca (22.6%), Moderna (21.3%), Janssen/Johnson & Johnson (1.7%) and others (1.2%). The most common rheumatic disease was rheumatoid arthritis (42.3%), and 81.2% of respondents were on a DMARD. The majority (81.9%) reported communicating with clinicians about vaccination. Most (66.9%) were willing to temporarily discontinue DMARDs to improve vaccine efficacy, although many (44.3%) were concerned about rheumatic disease flares. After vaccination, the most reported patient-reported adverse events were fatigue/somnolence (33.4%), headache (27.7%), muscle/joint pains (22.8%) and fever/chills (19.9%). Rheumatic disease flares that required medication changes occurred in 4.6%.ConclusionAmong adults with systemic rheumatic disease who received COVID-19 vaccination, patient-reported adverse events were typical of those reported in the general population. Most patients were willing to temporarily discontinue DMARDs to improve vaccine efficacy. The relatively low frequency of rheumatic disease flare requiring medications was reassuring.

ObjectiveTo investigate baseline use of biologic or targeted synthetic (b/ts) disease-modifying antirheumatic drugs (DMARDs) and COVID-19 outcomes in rheumatoid arthritis (RA).MethodsWe analysed the COVID-19 Global Rheumatology Alliance physician registry (from 24 March 2020 to 12 April 2021). We investigated b/tsDMARD use for RA at the clinical onset of COVID-19 (baseline): abatacept (ABA), rituximab (RTX), Janus kinase inhibitors (JAKi), interleukin 6 inhibitors (IL-6i) or tumour necrosis factor inhibitors (TNFi, reference group). The ordinal COVID-19 severity outcome was (1) no hospitalisation, (2) hospitalisation without oxygen, (3) hospitalisation with oxygen/ventilation or (4) death. We used ordinal logistic regression to estimate the OR (odds of being one level higher on the ordinal outcome) for each drug class compared with TNFi, adjusting for potential baseline confounders.ResultsOf 2869 people with RA (mean age 56.7 years, 80.8% female) on b/tsDMARD at the onset of COVID-19, there were 237 on ABA, 364 on RTX, 317 on IL-6i, 563 on JAKi and 1388 on TNFi. Overall, 613 (21%) were hospitalised and 157 (5.5%) died. RTX (OR 4.15, 95% CI 3.16 to 5.44) and JAKi (OR 2.06, 95% CI 1.60 to 2.65) were each associated with worse COVID-19 severity compared with TNFi. There were no associations between ABA or IL6i and COVID-19 severity.ConclusionsPeople with RA treated with RTX or JAKi had worse COVID-19 severity than those on TNFi. The strong association of RTX and JAKi use with poor COVID-19 outcomes highlights prioritisation of risk mitigation strategies for these people.

To prevent congenital defects arising from maternal exposure, safety regulations require pre-market developmental toxicity screens for industrial chemicals and pharmaceuticals. Traditional embryotoxicity approaches depend heavily on the use of low-throughput animal models which may not adequately predict human risk. The validated embryonic stem cell test (EST) developed in murine embryonic stem cells addressed the former problem over 15 years ago. Here, we present a proof-of-concept study to address the latter challenge by updating all three endpoints of the classic mouse EST with endpoints derived from human induced pluripotent stem cells (hiPSCs) and human fibroblasts. Exposure of hiPSCs to selected test chemicals inhibited differentiation at lower concentrations than observed in the mouse EST. The hiPSC-EST also discerned adverse developmental outcomes driven by novel environmental toxicants. Evaluation of the early cardiac gene TBX5 yielded similar toxicity patterns as the full-length hiPSC-EST. Together, these findings support the further development of hiPSCs and early molecular endpoints as a biologically relevant embryotoxicity screening approach for individual chemicals and mixtures.

Disgust has long been viewed as a primary motivator of defensive responses to threats posed by both microscopic pathogens and macroscopic ectoparasites. Although disgust can defend effectively against pathogens encountered through ingestion or incidental contact, it offers limited protection against ectoparasites, which actively pursue a host and attach to its surface. Humans might, therefore, possess a distinct ectoparasite defence system-including cutaneous sensory mechanisms and grooming behaviours-functionally suited to guard the body's surface. In two US studies and one in China, participants (N = 1079) viewed a range of ectoparasite- and pathogen-relevant video stimuli and reported their feelings, physiological sensations, and behavioural motivations. Participants reported more surface-guarding responses towards ectoparasite stimuli than towards pathogen stimuli, and more ingestion/contamination-reduction responses towards pathogen stimuli than towards ectoparasite stimuli. Like other species, humans appear to possess evolved psychobehavioural ectoparasite defence mechanisms that are distinct from pathogen defence mechanisms.

ObjectivesTo determine factors associated with COVID-19-related death in people with rheumatic diseases.MethodsPhysician-reported registry of adults with rheumatic disease and confirmed or presumptive COVID-19 (from 24 March to 1 July 2020). The primary outcome was COVID-19-related death. Age, sex, smoking status, comorbidities, rheumatic disease diagnosis, disease activity and medications were included as covariates in multivariable logistic regression models. Analyses were further stratified according to rheumatic disease category.ResultsOf 3729 patients (mean age 57 years, 68% female), 390 (10.5%) died. Independent factors associated with COVID-19-related death were age (66-75 years: OR 3.00, 95% CI 2.13 to 4.22; >75 years: 6.18, 4.47 to 8.53; both vs ≤65 years), male sex (1.46, 1.11 to 1.91), hypertension combined with cardiovascular disease (1.89, 1.31 to 2.73), chronic lung disease (1.68, 1.26 to 2.25) and prednisolone-equivalent dosage >10 mg/day (1.69, 1.18 to 2.41; vs no glucocorticoid intake). Moderate/high disease activity (vs remission/low disease activity) was associated with higher odds of death (1.87, 1.27 to 2.77). Rituximab (4.04, 2.32 to 7.03), sulfasalazine (3.60, 1.66 to 7.78), immunosuppressants (azathioprine, cyclophosphamide, ciclosporin, mycophenolate or tacrolimus: 2.22, 1.43 to 3.46) and not receiving any disease-modifying anti-rheumatic drug (DMARD) (2.11, 1.48 to 3.01) were associated with higher odds of death, compared with methotrexate monotherapy. Other synthetic/biological DMARDs were not associated with COVID-19-related death.ConclusionAmong people with rheumatic disease, COVID-19-related death was associated with known general factors (older age, male sex and specific comorbidities) and disease-specific factors (disease activity and specific medications). The association with moderate/high disease activity highlights the importance of adequate disease control with DMARDs, preferably without increasing glucocorticoid dosages. Caution may be required with rituximab, sulfasalazine and some immunosuppressants.

ObjectiveTo develop updated guidelines for the pharmacologic management of rheumatoid arthritis.MethodsWe developed clinically relevant population, intervention, comparator, and outcomes (PICO) questions. After conducting a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the certainty of evidence. A voting panel comprising clinicians and patients achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations.ResultsThe guideline addresses treatment with disease-modifying antirheumatic drugs (DMARDs), including conventional synthetic DMARDs, biologic DMARDs, and targeted synthetic DMARDs, use of glucocorticoids, and use of DMARDs in certain high-risk populations (i.e., those with liver disease, heart failure, lymphoproliferative disorders, previous serious infections, and nontuberculous mycobacterial lung disease). The guideline includes 44 recommendations (7 strong and 37 conditional).ConclusionThis clinical practice guideline is intended to serve as a tool to support clinician and patient decision-making. Recommendations are not prescriptive, and individual treatment decisions should be made through a shared decision-making process based on patients' values, goals, preferences, and comorbidities.

ObjectiveMonochorionic, diamniotic (MCDA) twin pairs are predisposed to various pregnancy complications due to the unique placental angioarchitecture of monochorionicity. Few studies have evaluated the outcomes of weight-discordant MCDA pairs without selective fetal growth restriction (SFGR) or the risk factors for development of SFGR. This study aims to describe the natural history of expectant, noninvasive management of weight-discordant MCDA twins and to evaluate risk factors associated with progression to SFGR.Study designThis was a retrospective cohort study at a single, tertiary care center in the United States. All MCDA twins with isolated intertwin weight discordance (ITWD) ≥ 20% diagnosed before 26 weeks' gestational age (GA) were included. The primary outcome of descriptive analyses was overall pregnancy outcome, incorporating both survival to delivery and GA at delivery, as defined by the North American Fetal Therapy Network. The secondary outcome was SFGR in one twin (defined as estimated fetal weight

ObjectiveRacial/ethnic minorities experience more severe outcomes of coronavirus disease 2019 (COVID-19) in the general US population. This study was undertaken to examine the association between race/ethnicity and COVID-19 hospitalization, ventilation status, and mortality in people with rheumatic disease.MethodsUS patients with rheumatic disease and COVID-19 were entered into the COVID-19 Global Rheumatology Alliance physician registry between March 24, 2020 and August 26, 2020 were included. Race/ethnicity was defined as White, African American, Latinx, Asian, or other/mixed race. Outcome measures included hospitalization, requirement for ventilatory support, and death. Multivariable regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) adjusted for age, sex, smoking status, rheumatic disease diagnosis, comorbidities, medication use prior to infection, and rheumatic disease activity.ResultsA total of 1,324 patients were included, of whom 36% were hospitalized and 6% died; 26% of hospitalized patients required mechanical ventilation. In multivariable models, African American patients (OR 2.74 [95% CI 1.90-3.95]), Latinx patients (OR 1.71 [95% CI 1.18-2.49]), and Asian patients (OR 2.69 [95% CI 1.16-6.24]) had higher odds of hospitalization compared to White patients. Latinx patients also had 3-fold increased odds of requiring ventilatory support (OR 3.25 [95% CI 1.75-6.05]). No differences in mortality based on race/ethnicity were found, though power to detect associations may have been limited.ConclusionSimilar to findings in the general US population, racial/ethnic minorities with rheumatic disease and COVID-19 had increased odds of hospitalization and ventilatory support. These results illustrate significant health disparities related to COVID-19 in people with rheumatic diseases. The rheumatology community should proactively address the needs of patients currently experiencing inequitable health outcomes during the pandemic.

BackgroundThe cause of most fetal anomalies is not determined prenatally. Exome sequencing has transformed genetic diagnosis after birth, but its usefulness for prenatal diagnosis is still emerging. Nonimmune hydrops fetalis (NIHF), a fetal abnormality that is often lethal, has numerous genetic causes; the extent to which exome sequencing can aid in its diagnosis is unclear.MethodsWe evaluated a series of 127 consecutive unexplained cases of NIHF that were defined by the presence of fetal ascites, pleural or pericardial effusions, skin edema, cystic hygroma, increased nuchal translucency, or a combination of these conditions. The primary outcome was the diagnostic yield of exome sequencing for detecting genetic variants that were classified as either pathogenic or likely pathogenic according to the criteria of the American College of Medical Genetics and Genomics. Secondary outcomes were the percentage of cases associated with specific genetic disorders and the proportion of variants that were inherited.ResultsIn 37 of the 127 cases (29%), we identified diagnostic genetic variants, including those for disorders affecting the RAS-MAPK cell-signaling pathway (known as RASopathies) (30% of the genetic diagnoses); inborn errors of metabolism and musculoskeletal disorders (11% each); lymphatic, neurodevelopmental, cardiovascular, and hematologic disorders (8% each); and others. Prognoses ranged from a relatively mild outcome to death during the perinatal period. Overall, 68% of the cases (25 of 37) with diagnostic variants were autosomal dominant (of which 12% were inherited and 88% were de novo), 27% (10 of 37) were autosomal recessive (of which 95% were inherited and 5% were de novo), 1 was inherited X-linked recessive, and 1 was of uncertain inheritance. We identified potentially diagnostic variants in an additional 12 cases.ConclusionsIn this large case series of 127 fetuses with unexplained NIHF, we identified a diagnostic genetic variant in approximately one third of the cases. (Funded by the UCSF Center for Maternal-Fetal Precision Medicine and others; ClinicalTrials.gov number, NCT03412760.).

The primary goal of carrier screening is to identify asymptomatic individuals who carry variants associated with genetic diseases, to inform about the risk of having a child with a genetic disease. Carrier screening can be accomplished through different approaches including ethnicity-based screening, pan-ethnic screening, and expanded carrier screening (ECS), and the decision to pursue carrier screening is voluntary. ECS takes a broad approach by screening for a large number of genetic diseases irrespective of ethnic background, and ideally is performed prior to conception. ECS has many benefits, including that it does not depend on accuracy of reported ancestry, as well as its greater yield of information that can be used for reproductive decision-making. However, there are also many important limitations of ECS to consider, ranging from the yield of unexpected information, uncertainty about the phenotype of a particular disease for which an individual is a carrier, and greater downstream costs associated with further testing and genetic counseling. Detailed genetic counseling both prior to and after ECS is essential in order for patients to understand the breadth of this approach, potential and actual results, and limitations.

Individuals who identify as lesbian, gay, bisexual, transgender, queer, and otherwise nonstraight and/or non-cisgender (LGBTQ+) have often not felt welcome or represented in the biology community. Additionally, biology can present unique challenges for LGBTQ+ students because of the relationship between certain biology topics and their LGBTQ+ identities. Currently, there is no centralized set of guidelines to make biology learning environments more inclusive for LGBTQ+ individuals. Rooted in prior literature and the collective expertise of the authors who identify as members and allies of the LGBTQ+ community, we present a set of actionable recommendations to help biologists, biology educators, and biology education researchers be more inclusive of individuals with LGBTQ+ identities. These recommendations are intended to increase awareness of LGBTQ+ identities and spark conversations about transforming biology learning spaces and the broader academic biology community to become more inclusive of LGBTQ+ individuals.

Exercise provides a robust physiological stimulus that evokes cross-talk among multiple tissues that when repeated regularly (i.e., training) improves physiological capacity, benefits numerous organ systems, and decreases the risk for premature mortality. However, a gap remains in identifying the detailed molecular signals induced by exercise that benefits health and prevents disease. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to address this gap and generate a molecular map of exercise. Preclinical and clinical studies will examine the systemic effects of endurance and resistance exercise across a range of ages and fitness levels by molecular probing of multiple tissues before and after acute and chronic exercise. From this multi-omic and bioinformatic analysis, a molecular map of exercise will be established. Altogether, MoTrPAC will provide a public database that is expected to enhance our understanding of the health benefits of exercise and to provide insight into how physical activity mitigates disease.

OBJECTIVE:: To evaluate the utility of nuchal translucency (NT) screening in the detection of rare chromosomal aneuploidies in the setting of cell-free DNA (cfDNA). METHODS:: A retrospective cohort study of pregnancies screened through the California Prenatal Screening Program between March 2009 and December 2012. Karyotype analysis was the primary method of chromosomal evaluation during the study period and abnormal chromosomal karyotype results were classified by whether the abnormality would be detectable by cfDNA (non-mosaic trisomy 13, 18, 21 or sex-chromosomal aneuploidy (SCA)). For those rare aneuploidies detectable by karyotype but not cfDNA, the number of cases that had an increased NT and the detection rate and positive predictive value (PPV) of increased NT for rare aneuploidies were determined. RESULTS:: A total of 452,901 pregnant women had screening. There were 2,572 chromosomally abnormal fetuses, of which 1,922 (74.7%) had a common aneuploidy detectable by cfDNA, leaving 450,979 without T13, 18, 21. Of these, 4,181 (0.93%) had an NT ≥ 3.0mm. There were 649 rare aneuploidies not detectable by cfDNA. Of these, 108 (16.6%) had an NT ≥3.0mm. The PPV of an NT ≥3.0mm for rare aneuploidies was 2.6%. In all, 4,176 fetuses need to be screened with NT to detect a rare aneuploidy. CONCLUSIONS:: The addition of NT to cfDNA screening would detect 16.6% of rare aneuploidies. Increased NT has a low PPV for rare aneuploidies and a large number of women would need NT screening to detect each affected fetus.

IntroductionThe relationship between Parkinson Disease (PD) pathology, dopamine replacement therapy (DRT), and impulse control disorder (ICD) development is still incompletely understood. Given the sensorimotor-lateral substantia nigra (SN) selective degeneration associated with PD, we posit that a relative sparing of the limbic-medial SN in the context of DRT drives impulsive, reward-seeking behavior in PD patients with recent history of severe impulsivity.MethodsImpulsive and control participants were selected from a consecutive list of PD patients receiving pre-operative deep brain stimulation (DBS) planning scans including 3T structural MRI and 64 direction diffusion tensor imaging (DTI). Using previously identified substantia nigra (SN) subsegment network connectivity profiles to develop classification targets, split-hemisphere target-based SN segmentation with probabilistic tractography was performed. The relative subsegment volumes and strength of connectivity between the SN and the limbic, associative, and motor network targets were compared.ResultsOur results show that there is greater probability of connectivity between the SN and limbic network targets relative to motor and associative network targets in PD patients with recent history of severe impulsivity as compared to PD patients without impulsivity (P = 0.0075). We did not observe relative volumetric subsegment differences across groups.ConclusionFirstly, our results suggest that fine-grained, atlas-derived classification targets may be used in PD to parcellate and classify functionally distinct subsegments of the SN, with the apparent preservation of previously reported topographical limbic-medial SN, associative-ventral SN, and sensorimotor-lateral SN orientation. We suggest that relative, as opposed to absolute, degeneration amongst SN-associated dopaminergic networks relates to the impulsivity phenotype in PD.

PurposeTo characterize clinical characteristics and genotypes of patients in the ADVANCE study of 4000 L-scale alglucosidase alfa (NCT01526785), the largest prospective United States Pompe disease cohort to date.MethodsPatients aged ≥1 year with confirmed Pompe disease previously receiving 160 L alglucosidase alfa were eligible. GAA genotypes were determined before/at enrollment. Baseline assessments included histories/physical exams, Gross Motor Function Measure-88 (GMFM-88), pulmonary function tests, and cardiac assessments.ResultsOf 113 enrollees (60 male/53 female) aged 1-18 years, 87 had infantile-onset Pompe disease (IOPD) and 26 late-onset (LOPD). One hundred eight enrollees with GAA genotypes had 215 pathogenic variants (220 including combinations): 118 missense (4 combinations), 23 splice, 35 nonsense, 34 insertions/deletions, 9 duplications (1 combination), 6 other; c.2560C>T (n = 23), c.-32-13T>G (n = 13), and c.525delT (n = 12) were most common. Four patients had previously unpublished variants, and 14/83 (17%) genotyped IOPD patients were cross-reactive immunological material-negative. All IOPD and 6/26 LOPD patients had cardiac involvement, all without c.-32-13T>G. Thirty-two (26 IOPD, 6 LOPD) were invasively ventilated. GMFM-88 total %scores (mean ± SD, median, range): overall 46.3 ± 33.0% (47.9%, 0.0-100.0%), IOPD 41.6 ± 31.64% (38.9%, 0.0-99.7%), LOPD: 61.8 ± 33.2 (70.9%, 0.0-100.0%).ConclusionADVANCE, a uniformly assessed cohort comprising most US children and adolescents with treated Pompe disease, expands understanding of the phenotype and observed variants in the United States.

Niclosamide is an antihelminthic drug used worldwide for the treatment of tapeworm infections. Recent drug repurposing screens have highlighted the broad bioactivity of niclosamide across diverse mechanisms of action. As a result, niclosamide is being evaluated for a range of alternative drug-repurposing applications, including the treatment of cancer, bacterial infections, and Zika virus. As new applications of niclosamide will require non-oral delivery routes that may lead to exposure in utero, it is important to understand the mechanism of niclosamide toxicity during early stages of embryonic development. Previously, we showed that niclosamide induces a concentration-dependent delay in epiboly progression in the absence of effects on oxidative phosphorylation - a well-established target for niclosamide. Therefore, the overall objective of this study was to further examine the mechanism of niclosamide-induced epiboly delay during zebrafish embryogenesis. Based on this study, we found that (1) niclosamide exposure during early zebrafish embryogenesis resulted in a decrease in yolk sac integrity with a concomitant decrease in the presence of yolk sac actin networks and increase in cell size; (2) within whole embryos, niclosamide exposure did not alter non-polar metabolites and lipids, but significantly altered amino acids specific to aminoacyl-tRNA biosynthesis; (3) niclosamide significantly altered transcripts related to translation, transcription, and mRNA processing pathways; and (4) niclosamide did not significantly alter levels of rRNA and tRNA. Overall, our findings suggest that niclosamide may be causing a systemic delay in embryonic development by disrupting the translation of maternally-supplied mRNAs, an effect that may be mediated through disruption of aminoacyl-tRNA biosynthesis.

The study objective was to examine the effects of three days of sleep restriction on maximal jump performance and joint coordination. Eleven elite cyclists obtained a one-week baseline of habitual sleep then restricted sleep to 4 h/night (SR) for three nights assessed through self-report and actigraphy. Pre and post-intervention measures were a box drop maximal vertical jump with 3D motion capture to assess physical performance and biomechanical changes, and Psychomotor Vigilance Task (PVT) assessed changes in response time. Associations between biomechanical, physical, and cognitive performance measures were assessed. Participants restricted reported sleep from 7.4 ± 0.5 h/night at baseline to 4.0 ± 0.2 h/night and actigraphy indicated 6.7 ± 0.7 to 3.7 ± 0.2 h/night. Following SR, jump height decreased (0.44 ± 0.09 vs. 0.42 ± 0.10 m, p = 0.02, g = 0.21). Hip sagittal/knee frontal (Δ15.5°, p = 0.04, g = 0.40) and hip frontal/knee frontal (Δ11.0°, p < 0.01, g = 0.44) plane coordination variability increased after SR. Hip sagittal/knee frontal plane coordination variability after SR was associated with increasingly slower PVT response time (r = 0.63, p = 0.03). These findings suggest SR for three days decreased maximal jump performance. SR increased joint coordination variability and was associated with greater impairment in response time. SR leads to deviations from preferred movement patterns, which may have implications for decrements in athlete performance and increased injury risk.

A wide spectrum of genetic causes may lead to nonimmune hydrops fetalis (NIHF), and a thorough phenotypic and genetic evaluation are essential to determine the underlying etiology, optimally manage these pregnancies, and inform discussions about anticipated prognosis. In this review, we outline the known genetic etiologies of NIHF by fetal organ system affected, and provide a systematic approach to the evaluation of NIHF. Some of the underlying genetic disorders are associated with characteristic phenotypic features that may be seen on prenatal ultrasound, such as hepatomegaly with lysosomal storage disorders, hyperechoic kidneys with congenital nephrosis, or pulmonary valve stenosis with RASopathies. However, this is not always the case, and the approach to evaluation must include prenatal ultrasound findings as well as genetic testing and many other factors. Genetic testing that has been utilized for NIHF ranges from standard chromosomal microarray or karyotype to gene panels and broad approaches such as whole exome sequencing. Family and obstetric history, as well as pathology examination, can yield additional clues that are helpful in establishing a diagnosis. A systematic approach to evaluation can guide a more targeted approach to genetic evaluation, diagnosis, and management of NIHF.

A growing literature on reframing effects has identified a robust negativity bias: Under many circumstances, people's attitudes change less when framing switches from negative to positive (vs. positive to negative). Like other basic psychological biases, this one is often assumed to reflect a general human tendency, but there are theoretical reasons to expect boundary conditions on when and for whom it operates. In this article, we zero in on age as one important potential moderator, and test competing predictions from different perspectives. Using a large, highly powered data set that synthesizes across multiple past studies ( N = 2,452; aged 18-81 years), we fit multilevel models to test the moderating impact of age on reframing effects, as well as single-shot framing effects. We found that (consistent with socioemotional selectivity theory), the negativity bias in reframing attenuated as age increased. We discuss implications for the aging literature and for understanding valence biases more broadly.

PurposeNumerous etiologies may lead to nonimmune hydrops fetalis (NIHF), and the underlying cause often remains unclear. We aimed to determine the proportion of NIHF cases in which the etiology was clearly determined in a large, contemporary, and diverse cohort, as well as to describe the etiologies with a focus on genetic causes.MethodsRetrospective review of NIHF cases between 2015 and 2017 from the five University of California Fetal-Maternal Consortium sites. Singleton pregnancies with prenatally diagnosed NIHF were included, and cases with maternal alloimmunization were excluded. Cases were categorized as being of confirmed, suspected, or unknown etiology.ResultsSixty-five NIHF cases were identified. Forty-six percent (30/65) remained of unknown etiology, while 9.2% (6/65) had a suspected etiology and 44.6% (29/65) were of confirmed etiology. Among confirmed cases, 11 resulted from aneuploidy; 7 from fetal structural anomalies; 2 each from fetal arrhythmia, Noonan syndrome, and generalized lymphatic dysplasia; and 1 each from arthrogryposis, parvovirus, neonatal alloimmune thrombocytopenia, fetal goiter, and Kasabach-Merritt syndrome.ConclusionIn this contemporary, multicenter study, the cause of prenatally diagnosed NIHF was confirmed in only 44% of cases, and a genetic etiology was found in only 25% of those that received standard of care genetic testing.

ObjectiveTo examine the relationship between cardiomediastinal shift angle (CMSA) and adverse perinatal outcomes and hydrops in cases of congenital pulmonary airway malformation (CPAM).Study designThis retrospective study evaluated CPAM cases referred to our institution from 2008 to 2015. The primary outcome was a composite score for adverse perinatal outcome. CMSA was measured for each case and evaluated for its association with the primary outcome. The prediction accuracy of CMSA for adverse perinatal outcome was assessed using receiver operator characteristic (ROC) curves.ResultsEighteen (21.2%) of the 85 cases experienced an adverse perinatal outcome. Increases in CMSA were associated with adverse perinatal outcomes and hydrops in bivariate analyses. Adjusted analyses found each 10-degree increase in CMSA to be associated with increased odds of an adverse perinatal outcome (adjusted odds ratio [aOR] 2.2, 95% confidence interval [CI]: 1.4-3.3) and hydrops (aOR 3.0, 95% CI: 1.5-6.1). CMSA performed well and was comparable to CPAM volume ratio in predicting adverse perinatal outcomes (area under the curve 0.81 and 0.84, respectively).ConclusionWe describe a novel measurement of mediastinal shift in cases of CPAM and its relationship with adverse perinatal outcomes and hydrops. These findings may shape the evaluation and management of CPAMs, improve our understanding of their prognosis, and influence patient counseling.

Epidemiological studies suggest tobacco consumption as a probable environmental factor for a variety of congenital anomalies, including low bone mass and increased fracture risk. Despite intensive public health initiatives to publicize the detrimental effects of tobacco use during pregnancy, approximately 10-20% of women in the United States still consume tobacco during pregnancy, some opting for so-called harm-reduction tobacco. These include Snus, a type of orally-consumed yet spit-free chewing tobacco, which is purported to expose users to fewer harmful chemicals. Concerns remain from a developmental health perspective since Snus has not reduced overall health risk to consumers and virtually nothing is known about whether skeletal problems from intrauterine exposure arise in the embryo. Utilizing a newly developed video-based calcification assay we determined that extracts from Snus tobacco hindered calcification of osteoblasts derived from pluripotent stem cells early on in their differentiation. Nicotine, a major component of tobacco products, had no measurable effect in the tested concentration range. However, through the extraction of video data, we determined that the tobacco-specific nitrosamine N'-nitrosonornicotine caused a reduction in calcification with similar kinetics as the complete Snus extract. From measurements of actual nitrosamine concentrations in Snus tobacco extract we furthermore conclude that N'-nitrosonornicotine has the potential to be a major trigger of developmental osteotoxicity caused by Snus tobacco.

Substance abuse is one of the most prevalent and costly health problems in the world today. Standard medical therapy is often not curative, and relapse is common. Research over the past several decades on the neural underpinnings of addiction has implicated a network of structures within the brain shown to be altered in patients with substance abuse. The field of neuromodulation aims to utilize this knowledge to treat dysfunctional circuits by targeting and modulating specific brain circuits. While invasive neuromodulation such as DBS and VNS have proven to be effective in treating movement disorders, OCD and epilepsy, there is increasing interest and data with regards to its potential application for the treatment of severe, intractable addiction. Several neuromodulatory techniques and brain targets are currently under investigation in patients with various substance abuse disorders. This review aims to summarize the current state of evidence for neurosurgical neuromodulation as a therapy for substance abuse and addiction, and to provide additional expert opinions as to the obstacles and future directions of this endeavor.

The perceived support of supernatural agents has been historically, ethnographically, and theoretically linked with confidence in engaging in violent intergroup conflict. However, scant experimental investigations of such links have been reported to date, and the extant evidence derives largely from indirect laboratory methods of limited ecological validity. Here, we experimentally tested the hypothesis that perceived supernatural aid would heighten inclinations toward coalitional aggression using a realistic simulated coalitional combat paradigm: competitive team paintball. In a between-subjects design, US paintball players recruited for the study were experimentally primed with thoughts of supernatural support using a guided visualization exercise analogous to prayer, or with a control visualization of a nature scene. The participants then competed in a team paintball battle game modeled after "Capture the Flag." Immediately before and after the battle, participants completed surveys assessing confidence in their coalitional and personal battle performance. Participants assessed their coalition's prospects of victory and performance more positively after visualizing supernatural aid. Participants primed with supernatural support also reported inflated assessments of their own performance. Importantly, however, covarying increases in assessments of their overall coalition's performance accounted for the latter effect. This study provided support for the hypothesis that perceived supernatural support can heighten both prospective confidence in coalitional victory and retrospective confidence in the combat performance of one's team, while highlighting the role of competitive play in evoking the coalitional psychology of intergroup conflict. These results accord with and extend convergent prior findings derived from laboratory paradigms far removed from the experience of combat. Accordingly, the field study approach utilized here shows promise as a method for investigating coalitional battle dynamics in a realistic, experientially immersive manner.

ObjectiveThe significance of polyhydramnios of one twin in the absence of oligohydramnios of the cotwin in monochorionic diamniotic (MCDA) twin pregnancies (polyhydramnios affecting a recipient-like twin [PART]) is unknown. Our aim is to assess the risk of progression to twin-twin transfusion syndrome (TTTS) with PART, progression to ≥ stage II TTTS, and neonatal survival.Study designThis study was a retrospective cohort study of MCDA twin pregnancies with PART evaluated at a referral center from 2008 to 2015.ResultsSixty-four MCDA twin pregnancies with PART were identified. Fifteen (23.4%) progressed to TTTS, including 10 (15.6%) who progressed to ≥ stage II TTTS. Three pregnancies were terminated and one underwent selective reduction by radiofrequency ablation. Overall survival was 113 out of 128 (88.3%). Of those who remained stable, 91.8% (N = 45) had survival of both neonates. In multivariate analysis, the presence of arterioarterial (A-A) anastomosis by in utero Doppler ultrasound was associated with decreased risk of progression to TTTS (odds ratio: 0.12, p = 0.03, 95% confidence interval: 0.02-0.78).ConclusionMost MCDA twin pregnancies with PART do not progress to TTTS and have a favorable prognosis. Progression rates are higher than observed in uncomplicated MCDA twins; however, so close surveillance is warranted. The presence of an A-A anastomosis appears to confer decreased risk of progression to TTTS.