Association between iron deficiency anemia and severe maternal morbidity: A retrospective cohort study.

PURPOSE: We examined the association between iron deficiency anemia (IDA) and severe maternal morbidity (SMM) during delivery and up to 1-year postpartum. METHODS: In a retrospective cohort study across 3 states, we computed adjusted relative risks (aRR) for SMM comparing individuals with IDA versus those without, using modified Poisson regression models. RESULTS: Among 2459,106 individuals, 10.3 % (n = 252,240) had IDA. Individuals with IDA experienced higher rates of blood transfusion and non-transfusion SMM (329 and 122 per 10,000 deliveries, respectively) than those without IDA (33 and 46 per 10,000 deliveries, respectively). The risk of blood transfusion (aRR: 8.2; 95 % CI 7.9-8.5) and non-transfusion SMM (aRR: 1.9; 95 % CI: 1.8-2.0) were higher among individuals with IDA. The attributable risk per 10,000 deliveries due to IDA for blood transfusion and non-transfusion SMM during delivery were 29.5 (95 % CI: 28.9-30.0) and 5.7 (95 % CI: 5.3-6.2), respectively. Within 1-year postpartum, the relative risk of non-transfusion SMM (aRR:1.3; 95 % CI: 1.2-1.3) was 30 % higher among individuals with IDA. CONCLUSION: IDA is associated with increased SMM risk. Addressing IDA in pregnant individuals may reduce SMM rates.

Inclusive Soundscapes: How Race, Socioeconomic Status and Maternal Age Influence the Pediatric Cochlear Implant Journey.

OBJECTIVE: This study aimed to assess how race, social vulnerability, and maternal age influence pediatric cochlear implant access and usage. STUDY DESIGN: Retrospective cohort. SETTING: Tertiary Pediatric University Hospital. METHODS: This study included individuals aged 0 to 18 who received a cochlear implant at our center between the years 2000 and 2022. Social vulnerability data from 2020 was obtained from the Centers for Disease Control and Prevention. RESULTS: Of the 302 patients included in our study, 43% were black and 50% were white. Patients from the highest to lowest social vulnerability quintiles comprised 31%, 25%, 18%, 10%, and 14% of our sample, respectively. Race was associated with social vulnerability index (SVI) (P < .001), with a mean score of 0.70 (±0.26) and 0.49 (±0.27) for black and white patients, respectively. Later age at hearing loss (HL) diagnosis and cochlear implantation (CI) were associated with more and most vulnerable SVI (P < .05). Delayed diagnosis was also associated with black and other racial groups (P = .041), and adolescent maternal age (P = .03). Greater SVI was associated with less daily cochlear implant usage (P = .004). The most vulnerable patients were more likely to be lost to follow-up (P = .03) despite no difference based on maternal age (P = .59) and insurance status (P = .47). CONCLUSION: This study underscores the significance of mitigating disparities in timely diagnosis of HL, consistent CI usage, and appropriate follow-up care. This is a first step toward the formulation of novel strategies aimed at overcoming barriers and developing appropriate intervention programs.

Sustained hair regrowth with continued ritlecitinib treatment through Week 48 in patients with alopecia areata with or without early target responses: post hoc analysis of the ALLEGRO phase 2b/3 trial.

BACKGROUND: Few treatments for alopecia areata (AA) have demonstrated sustained efficacy. OBJECTIVE: Evaluate the efficacy and safety of continued ritlecitinib treatment to Week 48 in patients with AA with or without target efficacy responses at Week 24. METHODS: Patients aged ≥12 years received daily ritlecitinib (± 4-week loading dose): 200/50 mg, 200/30 mg, 50 mg, or 30 mg. Patients with clinical response at Week 24, based on a Severity of Alopecia Tool (SALT) score ≤20 and ≤10 were evaluated for sustained response through Week 48. Nonresponders at Week 24 were assessed for response through Week 48. RESULTS: Among ritlecitinib-treated patients with SALT score ≤20 and ≤10 responses at Week 24, ≥85% and ≥68%, respectively, sustained these responses through Week 48. Of those with SALT score >20 at Week 24, 22%-34% achieved SALT score ≤20 at Week 48. Of those with a SALT score >10 at Week 24, 20%-26% achieved SALT score ≤10 at Week 48. Safety was similar across subgroups. LIMITATIONS: Small sample size. CONCLUSION: Hair regrowth was sustained through Week 48 in patients with response at Week 24. Up to one-third of patients who did not meet target efficacy at Week 24 achieved response with continued ritlecitinib treatment.

Gut Bacteria Metabolize Natural and Synthetic Steroid Hormones via the Reductive OsrABC Pathway.

Steroid hormone metabolism by the gut microbiome has multiple implications for mammalian physiology, but the underlying mechanisms and broader significance of this activity remains largely unknown. Here, we isolate a novel human gut bacterium, Clostridium steroidoreducens T strain HCS.1, that reduces cortisol, progesterone, testosterone, and related steroid hormones to 3ß,5ß-tetrahydrosteroid products. Through transcriptomics and heterologous enzyme profiling, we identify and biochemically characterize the C. steroidoreducens OsrABC reductive steroid hormone pathway. OsrA is a 3-oxo-Δ1-steroid hormone reductase that selectively targets the Δ1-bond present in synthetic steroid hormones, including the anti-inflammatory corticosteroids prednisolone and dexamethasone. OsrB is a promiscuous 3-oxo-Δ4-steroid hormone reductase that converts steroid hormones to 5ß-dihydrosteroid intermediates. OsrC is a 3-oxo-5ß-steroid hormone oxidoreductase that reduces 5ß-intermediates to 3ß,5ß-tetrahydro products. We find that osrA and osrB homologs predict steroid hormone reductase activity in diverse gut bacteria and are enriched in Crohn's disease fecal metagenomes. These studies thus identify the basis of reductive steroid hormone metabolism in the gut and establish a link between inflammatory disease and microbial enzymes that deplete anti-inflammatory corticosteroids.

Human parainfluenza virus 3 field strains undergo extracellular fusion protein cleavage to activate entry.

Human parainfluenza virus 3 (HPIV3) infection is driven by the coordinated action of viral surface glycoproteins hemagglutinin-neuraminidase (HN) and fusion protein (F). Receptor-engaged HN activates F to insert into the target cell membrane and drive virion-cell membrane fusion. For F to mediate entry, its precursor (F0) must first be cleaved by host proteases. F0 cleavage has been thought to be executed during viral glycoprotein transit through the trans-Golgi network by the ubiquitously expressed furin because F0 proteins of laboratory-adapted viruses contain a furin recognition dibasic cleavage motif RXKR around residue 108. Here, we show that the F proteins of field strains have a different cleavage motif from laboratory-adapted strains and are cleaved by unidentified proteases expressed in only a narrow subset of cell types. We demonstrate that extracellular serine protease inhibitors block HPIV3 F0 cleavage for field strains, suggesting F0 cleavage occurs at the cell surface facilitated by transmembrane proteases. Candidate proteases that may process HPIV3 F in vivo were identified by a genome-wide CRISPRa screen in HEK293/dCas9-VP64 + MPH cells. The lung-expressed extracellular serine proteases TMPRSS2 and TMPRSS13 are both sufficient to cleave HPIV3 F and enable infectious virus release by otherwise non-permissive cells. Our findings support an alternative mechanism of F activation in vivo, reliant on extracellular membrane-bound serine proteases expressed in a narrow subset of cells. The proportion of HPIV3 F proteins cleaved and infectious virus release is determined by host cell expression of requisite proteases, allowing just-in-time activation of F and positioning F cleavage as another key regulator of HPIV3 spread. IMPORTANCE: Enveloped viruses cause a wide range of diseases in humans. At the first step of infection, these viruses must fuse their envelope with a cell membrane to initiate infection. This fusion is mediated by viral proteins that require a critical activating cleavage event. It was previously thought that for parainfluenza virus 3, an important cause of respiratory disease and a representative of a group of important pathogens, this cleavage event was mediated by furin in the cell secretory pathways prior to formation of the virions. We show that this is only true for laboratory strain viruses, and that clinical viruses that infect humans utilize extracellular proteases that are only made by a small subset of cells. These results highlight the importance of studying authentic clinical viruses that infect human tissues for understanding natural infection.

Single cell spatial profiling of FFPE splenic tissue from a humanized mouse model of HIV infection.

BACKGROUND: Latency remains a major obstacle to finding a cure for HIV despite the availability of antiretroviral therapy. Due to virus dormancy, limited biomarkers are available to identify latent HIV-infected cells. Profiling of individual HIV-infected cells is needed to explore potential latency biomarkers and to study the mechanisms of persistence that maintain the HIV reservoir. METHODS: Single cell spatial transcriptomic characterization using the CosMx Spatial Molecular Imager platform was conducted to analyze HIV-infected cells in formalin-fixed paraffin-embedded sections of splenic tissue surgically obtained from an HIV-infected humanized mouse model. Regulation of over a thousand human genes was quantified in both viremic and aviremic specimens. In addition, in situ hybridization and immunohistochemistry were performed in parallel to identify HIV viral RNA- and p24-containing cells, respectively. Finally, initial findings from CosMx gene profiling were confirmed by isolating RNA from CD4 + T cells obtained from a person living with HIV on antiretroviral therapy following either PMA/Ionomycin or DMSO treatment. RNA was quantified using qPCR for a panel of targeted human host genes. RESULTS: Supervised cell typing revealed that most of the HIV-infected cells in the mouse spleen sections were differentiated CD4 + T cells. A significantly higher number of infected cells, 2781 (1.61%) in comparison to 112 (0.06%), and total HIV transcripts per infected cell were observed in viremic samples compared to aviremic samples, respectively, which was consistent with the data obtained from ISH and IHC. Notably, the expression of 55 genes was different in infected cells within tissue from aviremic animals compared to viremic. In particular, both spleen tyrosine kinase (SYK) and CXCL17, were expressed approximately 100-fold higher. This data was further evaluated against bulk RNA isolated from HIV-infected human primary CD4 + T cells. A nearly 6-fold higher expression of SYK mRNA was observed in DMSO-treated CD4 + T cells compared to those stimulated with PMA/Ionomycin. CONCLUSION: This study found that the CosMx SMI platform is valuable for assessing HIV infection and providing insights into host biomarkers associated with HIV reservoirs. Higher relative expression of the SYK gene in aviremic-infected cells from the humanized mouse HIV model was consistent with levels found in CD4 + T cells of aviremic donors.

Effect of endoscopic ultrasound guided celiac plexus block on the palliation of pain in chronic pancreatitis (EPOCH Trial): study protocol for a randomized multicenter sham-controlled trial {1}.

BACKGROUND: Celiac plexus block has been commonly utilized for the treatment of chronic pancreatitis-associated abdominal pain. Prospective studies suggest efficacy in 30 to 50% of patients, although no randomized sham-controlled trials have been performed. The objective of this study is to assess the effect of endoscopic ultrasound (EUS)-guided celiac plexus block on abdominal pain in patients with documented chronic pancreatitis. METHODS: This is a two-arm randomized sham-controlled trial with blinded evaluators. The study will be conducted at multiple academic sites in the United States who are members of the United States Pancreatic Disease Study Group (USPG). Patients referred for EUS to exclude chronic pancreatitis as a cause of abdominal pain as well as those with established painful chronic pancreatitis undergoing EUS for another indication will be eligible. At the time of EUS with confirmation of chronic pancreatitis by standard EUS diagnostic criteria, patients will be randomized to either celiac plexus block or sham whereby an anesthetic and steroid combination will be injected into the celiac plexus or saline will be injected into the gastric lumen with the same type of needle as used for celiac plexus block, respectively. The main outcome measure will be a 50% reduction in abdominal pain using the Brief Pain Inventory Short Form (BPI-SF) at 1 month post-intervention. A number of secondary outcomes will be measured including visual analog scale (VAS), Comprehensive Pain Assessment Tool Short Form (COMPAT-SF) pain scores, and quality of life using a pancreas-specific validated measure (PANQOLI). DISCUSSION: In this study, the effect of celiac plexus block on abdominal pain in patients with chronic pancreatitis will be compared to a sham intervention. This randomized trial will offer a definitive assessment of the role of celiac plexus block for the treatment of abdominal pain in this setting. TRIAL REGISTRATION {2}: ClinicalTrials.gov NCT06178315. Registered on December 21, 2023.

Reoperation Rates and Risk Factors after Spinal Cord Stimulation Revision Surgery.

INTRODUCTION: Spinal cord stimulation (SCS) is an effective treatment for patients with refractory chronic pain. Despite its efficacy, rates of reoperation after initial implantation of SCS remain high. While revision rates after index SCS surgeries are well reported, less is known about rates and risk factors associated with repeat reoperations. We sought to evaluate patient, clinical, and surgical characteristics associated with repeat reoperation among patients who underwent an initial SCS revision procedure. METHODS: We performed a retrospective review of patients who underwent SCS revision surgery performed at a single institution between 2008 and 2022. Patients were stratified by whether they underwent a single revision (SR) or multiple revision (MR) surgeries. Multivariate logistic regression was performed to determine risk factors associated with repeat SCS revision. Kaplan-Meier survival analysis was used to compare rates of devices requiring revision across groups. RESULTS: A total of 54 patients underwent an initial SCS revision. Of these, 15 (28%) underwent a second revision. The most common indication for revision surgery was lead migration (65%). No significant differences were observed in age, body mass index, comorbidities, lead type, and revision indication among the SR and MR groups. On multivariate adjusted analysis, only cervical lead position was significantly associated with repeat reoperation (OR 7.10, 95% CI [1.14, 44.3], p = 0.036). Time to reoperation after a single and MR SCS surgeries did not differ. CONCLUSIONS: Among patients who undergo SCS reoperation, a substantial portion requires additional revisions. Cervical lead placement may be associated with a higher risk of repeat revision surgery compared to thoracic lead positioning. Consideration of lead positioning in the decision to perform and undergo reoperation may therefore result in lower revision rates and improved clinical outcomes among SCS patients with MRs.

Out of sight, into mind: a socioecological model-informed qualitative study on barriers and facilitators to hepatitis B care among West African immigrants in the Bronx, New York.

BACKGROUND: There is a high burden of hepatitis B virus (HBV) in West Africa. Over the past 20 years, West African immigration to the United States (U.S.) has been increasing. Prevalence of HBV infection in West Africa has been reported to be as high as 5-10%. METHODS: We sought to understand knowledge and attitudes of and barriers and facilitators to HBV screening, vaccination, and treatment in a cohort of West African immigrants in the Bronx living with or at risk for HBV through a series of one-on-one qualitative interviews. We interviewed 23 West African immigrants and analyzed transcripts for recurring themes using Applied Thematic Analysis. We situated our analysis in the socioecological model (SEM) and adhered to the consolidated criteria for reporting qualitative research (COREQ). RESULTS: Multiple themes emerged, most prominently themes relating to HBV knowledge/awareness, trust in U.S. healthcare providers and the U.S. healthcare system, positive social support improving healthcare access, knowledge sharing, stigma towards those with HBV, issues concerning immigration status, insurance status, and access to healthcare services. CONCLUSION: Raising awareness of HBV, addressing social and structural barriers such as stigma and health insurance, and improving access to culturally sensitive programs among West African communities are needed to increase HBV screening, vaccination, and linkage to care.

Tensions on the actin cytoskeleton and apical cell junctions in the C. elegans spermatheca are influenced by spermathecal anatomy, ovulation state and activation of myosin.

Introduction: Cells generate mechanical forces mainly through myosin motor activity on the actin cytoskeleton. In C. elegans, actomyosin stress fibers drive contractility of the smooth muscle-like cells of the spermatheca, a distensible, tube-shaped tissue in the hermaphrodite reproductive system and the site of oocyte fertilization. Stretching of the spermathecal cells by oocyte entry triggers activation of the small GTPase Rho. In this study, we asked how forces are distributed in vivo, and explored how spermathecal tissue responds to alterations in myosin activity. Methods: In animals expressing GFP labeled actin or apical membrane complexes, we severed these structures using femtosecond laser ablation and quantified retractions. RNA interference was used to deplete key contractility regulators. Results: We show that the basal actomyosin fibers are under tension in the occupied spermatheca. Reducing actomyosin contractility by depletion of the phospholipase C-ε/PLC-1 or non-muscle myosin II/NMY-1, leads to distended spermathecae occupied by one or more embryos, but does not alter tension on the basal actomyosin fibers. However, activating myosin through depletion of the Rho GAP SPV-1 increases tension on the actomyosin fibers, consistent with earlier studies showing Rho drives spermathecal contractility. On the inner surface of the spermathecal tube, tension on the apical junctions is decreased by depletion of PLC-1 and NMY-1. Surprisingly, when basal contractility is increased through SPV-1 depletion, the tension on apical junctions also decreases, with the most significant effect on the junctions aligned in perpendicular to the axis of the spermatheca. Discussion: Our results suggest that much of the tension on the basal actin fibers in the occupied spermatheca is due to the presence of the embryo. Additionally, increased tension on the outer basal surface may compress the apical side, leading to lower tensions apically. The three dimensional shape of the spermatheca plays a role in force distribution and contractility during ovulation.

Structure-guided engineering of type I-F CASTs for targeted gene insertion in human cells.

Conventional genome editing tools rely on DNA double-strand breaks (DSBs) and host recombination proteins to achieve large insertions, resulting in a heterogeneous mixture of undesirable editing outcomes. We recently leveraged a type I-F CRISPR-associated transposase (CAST) from the Pseudoalteromonas Tn7016 transposon (PseCAST) for DSB-free, RNA-guided DNA integration in human cells, taking advantage of its programmability and large payload capacity. PseCAST is the only characterized CAST system that has achieved human genomic DNA insertions, but multiple lines of evidence suggest that DNA binding may be a critical bottleneck that limits high-efficiency activity. Here we report structural determinants of target DNA recognition by the PseCAST QCascade complex using single-particle cryogenic electron microscopy (cryoEM), which revealed novel subtype-specific interactions and RNA-DNA heteroduplex features. By combining our structural data with target DNA library screens and rationally engineered protein mutations, we uncovered CAST variants that exhibit increased integration efficiency and modified PAM stringency. Structure predictions of key interfaces in the transpososome holoenzyme also revealed opportunities for the design of hybrid CASTs, which we leveraged to build chimeric systems that combine high-activity DNA binding and DNA integration modules. Collectively, our work provides unique structural insights into type I-F CAST systems while showcasing multiple diverse strategies to investigate and engineer new RNA-guided transposase architectures for human genome editing applications.

Regulation of immune responses to food by commensal microbes.

The increasing prevalence of immune-mediated non-communicable chronic diseases, such as food allergies, has prompted a deeper investigation into the role of the gut microbiome in modulating immune responses. Here, we explore the complex interactions between commensal microbes and the host immune system, highlighting the critical role of gut bacteria in maintaining immune homeostasis. We examine how modern lifestyle practices and environmental factors have disrupted co-evolved host-microbe interactions and discuss how changes in microbiome composition impact epithelial barrier function, responses to food allergens, and susceptibility to allergic diseases. Finally, we examine the potential of bioengineered microbiome-based therapies, and live biotherapeutic products, for reestablishing immune homeostasis to prevent or treat food allergies.

Tensions on the actin cytoskeleton and apical cell junctions in the C. elegans spermatheca are influenced by spermathecal anatomy, ovulation state and activation of myosin.

Cells generate mechanical forces mainly through myosin motor activity on the actin cytoskeleton. In C. elegans, actomyosin stress fibers drive contractility of the smooth muscle-like cells of the spermatheca, a distensible, tube-shaped tissue in the hermaphrodite reproductive system and the site of oocyte fertilization. Stretching of the spermathecal cells by oocyte entry triggers activation of the small GTPase Rho. In this study, we asked how forces are distributed in vivo using the spermatheca, and explored how this tissue responds to alterations in myosin activity. Using laser ablation, we show that the basal actomyosin fibers are under tension in the occupied spermatheca. Reducing actomyosin contractility by depletion of the phospholipase C-ε/PLC-1 or non-muscle myosin II/NMY-1, leads to distended spermathecae occupied by one or more embryos, but does not alter tension on the basal actomyosin fibers. This suggests that much of the tension on the basal actin fibers in the occupied spermatheca is due to the presence of the embryo. However, activating myosin through depletion of the Rho GAP SPV-1 increases tension on the actomyosin fibers, consistent with earlier studies showing Rho drives spermathecal contractility. On the inner surface of the spermathecal tube, tension on the apical junctions is decreased by depletion of PLC-1 and NMY-1. Surprisingly, when basal contractility is increased through SPV-1 depletion, the tension on apical junctions also decreases, with the most significant effect on the junctions aligned in perpendicular to the axis of the spermatheca. This suggests tension on the outer basal surface may compress the apical side, and suggests the three-dimensional shape of the spermatheca plays a role in force distribution and contractility during ovulation.

Functional mapping of epigenetic regulators uncovers coordinated tumor suppression by the HBO1 and MLL1 complexes.

Epigenetic dysregulation is widespread in cancer. However, the specific epigenetic regulators and the processes they control to drive cancer phenotypes are poorly understood. Here, we employed a novel, scalable and high-throughput in vivo method to perform iterative functional screens of over 250 epigenetic regulatory genes within autochthonous oncogenic KRAS-driven lung tumors. We identified multiple novel epigenetic tumor suppressor and tumor dependency genes. We show that a specific HBO1 complex and the MLL1 complex are among the most impactful tumor suppressive epigenetic regulators in lung. The histone modifications generated by the HBO1 complex are frequently absent or reduced in human lung adenocarcinomas. The HBO1 and MLL1 complexes regulate chromatin accessibility of shared genomic regions, lineage fidelity and the expression of canonical tumor suppressor genes. The HBO1 and MLL1 complexes are epistatic during lung tumorigenesis, and their functional correlation is conserved in human cancer cell lines. Together, these results demonstrate the value of quantitative methods to generate a phenotypic roadmap of epigenetic regulatory genes in tumorigenesis in vivo .

CD4 + T cells recruit, then engage macrophages in cognate interactions to clear Mycobacterium tuberculosis from the lungs.

IFN-γ-producing CD4 + T cells are required for protection against lethal Mycobacterium tuberculosis ( Mtb ) infections. However, the ability of CD4 + T cells to suppress Mtb growth cannot be fully explained by IFN-γ or other known T cell products. In this study, we show that CD4 + T cell-derived IFN-γ promoted the recruitment of monocyte-derived macrophages (MDMs) to the lungs of Mtb -infected mice. Although the recruited MDMs became quickly and preferentially infected with Mtb , CD4 + T cells rapidly disinfected the MDMs. Clearance of Mtb from MDMs was not explained by IFN-γ, but rather by MHCII-mediated cognate interactions with CD4 + T cells. These interactions promoted MDM expression of glycolysis genes essential for Mtb control. Thus, by recruiting MDMs, CD4 + T cells initiate a cycle of bacterial phagocytosis, Mtb antigen presentation and disinfection in an attempt to clear the bacteria from the lungs.

A New Mechanism for Formation of Glycine from Glyoxylic acid: the Aza-Cannizzaro Reaction.

Glyoxylic acid and glycine are widely considered to have been important prebiotic building blocks. Several mechanistic routes have been previously examined for conversion of glyoxylic acid to glycine. Here we provide evidence for a new mechanistic path. Glycine is spontaneously formed from glyoxylic acid in ammonium-rich aqueous solutions at neutral pH; oxamic acid is generated as well. Hydride transfer from the glyoxylate-derived hemiaminal to the corresponding iminium ion appears to underlie this transformation. This proposed mechanism parallels the well-known Cannizzaro reaction mechanism, which leads us to suggest the designation "aza-Cannizzaro reaction." This discovery offers a new perspective on prebiotic nitrogen incorporation because glycine can be a source of nitrogen for more complex molecules, including other α-amino acids.

Streamlining LC-MS Characterization of Pharmaceutical Polymers by Fourier-Transform-Based Deconvolution and Macromolecular Mass Defect Analysis.

Polymer conjugation has risen in importance over the past three decades as a means of increasing the in vivo half-life of biotherapeutics, with benefits including better stability, greater drug efficacy, and lower toxicity. However, the intrinsic variability of polymer synthesis results in products with broad distributions in chain length and branching structure, complicating quality control for successful functionalization and downstream conjugation. Frequently, a combination of several analytical techniques is required for comprehensive characterization. While liquid chromatography-mass spectrometry (LC-MS) is a powerful platform that can provide detailed molecular features of polymers, the mass spectra are inherently challenging to interpret due to high mass polydispersity and overlapping charge distributions. Here, by leveraging Fourier transform-based deconvolution and macromolecular mass defect analysis, we demonstrate a new way to streamline pharmaceutical polymer analysis, shedding light on polymer size, composition, branching, and end-group functionalization with the capability for reaction monitoring.

An international study presenting a federated learning AI platform for pediatric brain tumors.

While multiple factors impact disease, artificial intelligence (AI) studies in medicine often use small, non-diverse patient cohorts due to data sharing and privacy issues. Federated learning (FL) has emerged as a solution, enabling training across hospitals without direct data sharing. Here, we present FL-PedBrain, an FL platform for pediatric posterior fossa brain tumors, and evaluate its performance on a diverse, realistic, multi-center cohort. Pediatric brain tumors were targeted due to the scarcity of such datasets, even in tertiary care hospitals. Our platform orchestrates federated training for joint tumor classification and segmentation across 19 international sites. FL-PedBrain exhibits less than a 1.5% decrease in classification and a 3% reduction in segmentation performance compared to centralized data training. FL boosts segmentation performance by 20 to 30% on three external, out-of-network sites. Finally, we explore the sources of data heterogeneity and examine FL robustness in real-world scenarios with data imbalances.

"They're not my daughter, and yet they're also not my son": Parents negotiating their adult child's nonbinary gender identity.

Scholars are increasingly recognizing that substantial gender heterogeneity exists among transgender populations; that is, gender identities that defy the ubiquitous binary categories of male and female. However, the developing research base on the families of transgender adults focuses almost exclusively on the family members of transgender persons with binary gender identities, a noteworthy shortcoming considering the prevalence of nonbinary gender identities among transgender populations and the pervasive assumption that only two genders exist. To address this gap, the current study sought to uncover how the parents of transgender adults with nonbinary gender identities come to understand, make sense of, and negotiate nonbinary gender identities in their families. Fourteen parents-12 mothers and 2 fathers-completed in-depth, semi-structured interviews, and the collected data were analyzed using reflexive thematic analysis. Analyses generated three broad themes that best-described these parents' experience with their child's gender, which was heavily shaped by the pervasiveness of cisnormativity: (a) varied attempts to understand nonbinary gender; (b) a nonbinary "double-edged sword"; and (c) familial resilience. Directions for future research, clinical practice, and policy change are discussed, including the therapeutic benefit of dialectical thinking and the need for legislation that legally affirms and protects nonbinary persons.