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The risks, benefits, and utilities of multiplex panels for breast cancer susceptibility are unknown, and new counseling and informed consent models are needed. We sought to obtain patient feedback and early outcome data with a novel tiered-binned model for multiplex testing. BRCA1/2-negative and untested patients completed pre- and posttest counseling and surveys evaluating testing experiences and cognitive and affective responses to multiplex testing. Of 73 patients, 49 (67%) completed pretest counseling. BRCA1/2-negative patients were more likely to proceed with multiplex testing (86%) than those untested for BRCA1/2 (43%; P < 0.01). Many patients declining testing reported concern for uncertainty and distress. Most patients would not change anything about their pre- (76%) or posttest (89%) counseling sessions. Thirty-three patients (72%) were classified as making an informed choice, including 81% of those who proceeded with multiplex testing. Knowledge increased significantly. Anxiety, depression, uncertainty, and cancer worry did not significantly increase with multiplex testing. Some patients, particularly those without prior BRCA1/2 testing, decline multiplex testing. Most patients who proceeded with testing did not experience negative psychological responses, but larger studies are needed. The tiered-binned approach is an innovative genetic counseling and informed consent model for further study in the era of multiplex testing.

Estrogen receptors (ERs) are believed to be ligand-activated transcription factors belonging to the nuclear receptor superfamily, which on ligand binding translocate into the nucleus and activate gene transcription. To date, two ERs have been identified: ERα and ERβ. ERα plays major role in the estrogen-mediated genomic actions in both reproductive and nonreproductive tissue, whereas the function of ERβ is still unclear. In this study, we used immunocytochemistry, immunoblotting, and proteomics to demonstrate that ERβ localizes to the mitochondria. In immunocytochemistry studies, ERβ was detected with two ERβ antibodies and found to colocalize almost exclusively with a mitochondrial marker in rat primary neuron, primary cardiomyocyte, and a murine hippocampal cell line. The colocalization of ERβ and mitochondrial markers was identified by both fluorescence and confocal microscopy. No translocation of ERβ into the nucleus on 17β-estradiol treatment was seen by using immunocytochemistry. Immunoblotting of purified human heart mitochondria showed an intense signal of ERβ, whereas no signals for nuclear and other organelle markers were found. Finally, purified human heart mitochondrial proteins were separated by SDS/PAGE. The 50,000-65,000 Mrband was digested with trypsin and subjected to matrix-assisted laser desorption/ionization mass spectrometric analysis, which revealed seven tryptic fragments that matched with those of ERβ. In summary, this study demonstrated that ERβ is localized to mitochondria, suggesting a role for mitochondrial ERβ in estrogen effects on this important organelle.

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3–50, P  < 2.14 × 10 −6 ) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA ( N -methyl- d -aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders 1 , epilepsy and severe neurodevelopmental disorders 2 , although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk 3 , suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach. Whole-exome sequencing identifies ten risk genes for schizophrenia implicated by rare protein-coding variants, a subset of which overlap with risk genes in other neurodevelopmental disorders.

Purpose of Review Increasing wildfire size and severity across the western United States has created an environmental and social crisis that must be approached from a transdisciplinary perspective. Climate change and more than a century of fire exclusion and wildfire suppression have led to contemporary wildfires with more severe environmental impacts and human smoke exposure. Wildfires increase smoke exposure for broad swaths of the US population, though outdoor workers and socially disadvantaged groups with limited adaptive capacity can be disproportionally exposed. Exposure to wildfire smoke is associated with a range of health impacts in children and adults, including exacerbation of existing respiratory diseases such as asthma and chronic obstructive pulmonary disease, worse birth outcomes, and cardiovascular events. Seasonally dry forests in Washington, Oregon, and California can benefit from ecological restoration as a way to adapt forests to climate change and reduce smoke impacts on affected communities. Recent Findings Each wildfire season, large smoke events, and their adverse impacts on human health receive considerable attention from both the public and policymakers. The severity of recent wildfire seasons has state and federal governments outlining budgets and prioritizing policies to combat the worsening crisis. This surging attention provides an opportunity to outline the actions needed now to advance research and practice on conservation, economic, environmental justice, and public health interests, as well as the trade-offs that must be considered. Summary Scientists, planners, foresters and fire managers, fire safety, air quality, and public health practitioners must collaboratively work together. This article is the result of a series of transdisciplinary conversations to find common ground and subsequently provide a holistic view of how forest and fire management intersect with human health through the impacts of smoke and articulate the need for an integrated approach to both planning and practice.

Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers.

Parkinson's disease (PD), a progressive neurodegenerative disorder, manifests with motor and non-motor symptoms. Despite similar incidence, in the US, disease management of Hispanic patients with PD is poorer than that of White non-Hispanics, and their participation in clinical trials does not reflect expected values (well below 5% vs. expected values around 20%). Together with other evidence, these observations are expressions of poor healthcare in Hispanic patients with PD, suggesting underutilization of proper healthcare, social and economic disadvantage, and other factors. The scant participation of Hispanic patients in clinical trials further exacerbates care inadequacy. In this paper, after reviewing evidence of healthcare gaps in Hispanic patients with PD and their low participation in research, we present a comprehensive model for reaching these patients and their caregivers, educating them on PD, and engaging them in research. This model is based on the work and experience of the Parkinson's Foundation, which over the years, has worked to increase PD awareness in Hispanic communities. This model is based on the training of promotores de salud (community health workers) inside Hispanic communities, the identification of needs and priorities of patients and caregivers with surveys and focus groups within Hispanic communities, and the patients' feedback about their participation in research. The development of this model could achieve sustainable partnerships with community-based organizations to promote better care and enhance participation in research of Hispanic patients. In turn, this could lead to a better quality of life for all patients with PD and their caregivers.

The new airborne thermal infrared (TIR) imager VELOX (Video airbornE Longwave Observations within siX channels) is introduced. VELOX is a commercially available TIR camera system that has been adapted extensively for atmospheric applications, which are introduced in this paper. The system covers six spectral bands with centre wavelengths between 7.7 and 12 µm. Currently, VELOX is installed on board the German High Altitude and Long Range Research Aircraft (HALO) to observe cloud and surface properties. It provides observations of two-dimensional (2D) fields of upward terrestrial spectral radiance with a horizontal resolution of approximately 10 m×10 m at a target distance of 10 km. Atmospheric temperature values are rather low compared to the originally intended commercial applications of VELOX and range close to the detection limit of the sensor. This challenge requires additional calibration efforts to enable atmospheric applications of VELOX. Therefore, required sophisticated calibration and correction procedures, including radiometric calibrations, non-uniformity corrections, bad-pixel replacements, and window corrections, are presented. Furthermore, first observations of cloud properties acquired by VELOX during the EUREC4A (ElUcidating the RolE of Cloud-Circulation Coupling in ClimAte) campaign are discussed, including an analysis of the cloud top brightness temperature, cloud mask/fraction, and cloud top altitude data. The data reveal the potential of VELOX to resolve the cloud top temperature with a resolution of better than 0.1 K, which translates into a resolution of approximately 40 m in cloud top altitude.

No diagnostic biomarkers are available for obsessive-compulsive disorder (OCD). Here, we aimed to identify magnetic resonance imaging (MRI) biomarkers for OCD, using 46 data sets with 2304 OCD patients and 2068 healthy controls from the ENIGMA consortium. We performed machine learning analysis of regional measures of cortical thickness, surface area and subcortical volume and tested classification performance using cross-validation. Classification performance for OCD vs. controls using the complete sample with different classifiers and cross-validation strategies was poor. When models were validated on data from other sites, model performance did not exceed chance-level. In contrast, fair classification performance was achieved when patients were grouped according to their medication status. These results indicate that medication use is associated with substantial differences in brain anatomy that are widely distributed, and indicate that clinical heterogeneity contributes to the poor performance of structural MRI as a disease marker.

Larger thalamic volume has been found in children with obsessive-compulsive disorder (OCD) and children with clinical-level symptoms within the general population. Particular thalamic subregions may drive these differences. The ENIGMA-OCD working group conducted mega- and meta-analyses to study thalamic subregional volume in OCD across the lifespan. Structural T 1 -weighted brain magnetic resonance imaging (MRI) scans from 2649 OCD patients and 2774 healthy controls across 29 sites (50 datasets) were processed using the FreeSurfer built-in ThalamicNuclei pipeline to extract five thalamic subregions. Volume measures were harmonized for site effects using ComBat before running separate multiple linear regression models for children, adolescents, and adults to estimate volumetric group differences. All analyses were pre-registered ( https://osf.io/73dvy ) and adjusted for age, sex and intracranial volume. Unmedicated pediatric OCD patients (<12 years) had larger lateral ( d  = 0.46), pulvinar ( d  = 0.33 ) , ventral ( d  = 0.35) and whole thalamus ( d  = 0.40) volumes at unadjusted p -values <0.05. Adolescent patients showed no volumetric differences. Adult OCD patients compared with controls had smaller volumes across all subregions (anterior, lateral, pulvinar, medial, and ventral) and smaller whole thalamic volume ( d  =  − 0.15 to −0.07) after multiple comparisons correction, mostly driven by medicated patients and associated with symptom severity. The anterior thalamus was also significantly smaller in patients after adjusting for thalamus size. Our results suggest that OCD-related thalamic volume differences are global and not driven by particular subregions and that the direction of effects are driven by both age and medication status.

Background: In Part 1 of the phase III RUBY trial (NCT03981796) in patients with primary advanced or recurrent endometrial cancer (EC), dostarlimab plus carboplatin–paclitaxel (CP) significantly improved progression-free survival and overall survival compared with CP alone. Limited safety data have been reported for the combination of immunotherapies plus chemotherapy in this setting. Objectives: The objective of this analysis was to identify the occurrence of treatment-related adverse events (TRAEs) and immune-related adverse events (irAEs) and to describe irAE management in Part 1 of the RUBY trial. Design: RUBY is a phase III, randomized, double-blind, multicenter study of dostarlimab plus CP compared with CP alone in patients with primary advanced or recurrent EC. Methods: Patients were randomized 1:1 to dostarlimab 500 mg, or placebo, plus CP every 3 weeks for 6 cycles, followed by dostarlimab 1000 mg, or placebo, every 6 weeks for up to 3 years. Adverse events (AEs) were assessed according to Common Terminology Criteria for Adverse Events, version 4.03. Results: The safety population included 487 patients who received ⩾1 dose of treatment (241 dostarlimab plus CP; 246 placebo plus CP). Treatment-emergent AEs were experienced by 100% of patients in both arms. TRAEs occurred in 97.9% of the dostarlimab arm and 98.8% of the placebo arm. The most common TRAEs occurred at similar rates between arms and were mostly low grade. IrAEs occurred in 58.5% of patients in the dostarlimab arm and 37.0% of patients in the placebo arm. Dostarlimab- or placebo-related irAEs were reported in 40.7% of patients in the dostarlimab arm and 16.3% of the placebo arm. Conclusion: The safety profile of dostarlimab plus CP was generally consistent with that of the individual components. Dostarlimab plus CP has a favorable benefit–risk profile and is a new standard of care for patients with primary advanced or recurrent EC. Trial registration: NCT03981796. Plain language summary Safety of dostarlimab plus carboplatin-paclitaxel compared with carboplatin-paclitaxel in primary advanced or recurrent endometrial cancer For many years, patients with primary advanced or recurrent endometrial cancer were treated with chemotherapy, specifically with a combination of carboplatin and paclitaxel. Recently, new treatments called immune checkpoint inhibitors have been used to treat endometrial cancer. Dostarlimab, an immune checkpoint inhibitor, is being tested to treat many types of cancer, including endometrial cancer. In the RUBY trial, a combination of dostarlimab plus chemotherapy was compared with chemotherapy alone as treatment for primary advanced or recurrent endometrial cancer. Results showed that patients treated with dostarlimab plus chemotherapy had a lower risk of their cancer becoming worse and a lower risk of dying. Results in this article describe the safety of dostarlimab plus chemotherapy compared with chemotherapy alone. All patients in the RUBY trial experienced at least one adverse event (an undesired effect that happens while receiving treatment or shortly after stopping treatment); most were determined to be caused by the cancer treatments. No differences in the frequency of the overall cancer treatment-related adverse events were seen in patients who received dostarlimab plus chemotherapy compared with those patients who received chemotherapy alone. Some patients experienced an immune-related adverse event. These are a specific type of undesired effect that can occur when patients are treated with immune checkpoint inhibitors. Immune-related adverse events occurred more frequently in patients who received dostarlimab plus chemotherapy than in those who received chemotherapy alone. Physicians were generally able to treat the immune-related adverse events, and only a low percentage of patients discontinued treatment because they experienced an immune-related adverse event. The types of adverse events seen were similar to a combination of those seen in patients who received dostarlimab alone or patients who received chemotherapy alone as treatment for endometrial cancer. Dostarlimab plus chemotherapy is a new standard of care for patients with primary advanced or recurrent endometrial cancer.