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Recurrent high-grade intracranial malignancies have a grim prognosis and uniform management guidelines are lacking. Re-irradiation is underused due to concerns about irreversible side effects. Pulsed-reduced dose rate radiotherapy (PRDR) aims to reduce toxicity while improving tumor control by exploiting dose-rate effects. We share our initial experience with temporally modulated pulsed proton re-irradiation (TMPPR), focusing on workflow, safety, feasibility, and outcomes for the first patient cohort. TMPPR was administered to patients with recurrent or progressive central nervous system malignancies using intensity modulated proton therapy with three fields. Patient and treatment data were collected, responses categorized using RANO assessment, and toxicities graded using CTCAE v5.0. Five patients received TMPPR between October 2022 and May 2023, with a median age of 54 years (Range: 32-72), and a median time from initial radiotherapy to re-RT of 23 months (Range 14-40). Treatment was completed without delay, with a median dose of 60 GyRBE in 30 fractions. Initial treatment response assessment showed complete (n = 1) or partial (n = 3) responses. Limited toxicity was observed, primarily grade 2 alopecia and one case of radiation necrosis graded at 2. This early experience demonstrates the feasibility of TMPPR delivery, highlighting the importance of prospective evaluations in the re-irradiation setting.

Human inborn errors of thymic T cell tolerance underlie the production of autoantibodies (auto-Abs) neutralizing type I IFNs, which predispose to severe viral diseases. We analyze 131 female patients with X-linked dominant incontinentia pigmenti (IP), heterozygous for loss-of-function (LOF) NEMO variants, from 99 kindreds in 10 countries. Forty-seven of these patients (36%) have auto-Abs neutralizing IFN-α and/or IFN-ω, a proportion 23 times higher than that for age-matched female controls. This proportion remains stable from the age of 6 years onward. On imaging, female patients with IP have a small, abnormally structured thymus. Auto-Abs against type I IFNs confer a predisposition to life-threatening viral diseases. By contrast, patients with IP lacking auto-Abs against type I IFNs are at no particular risk of viral disease. These results suggest that IP accelerates thymic involution, thereby underlying the production of auto-Abs neutralizing type I IFNs in at least a third of female patients with IP, predisposing them to life-threatening viral diseases.

BACKGROUND: Platelets are well known for their roles in hemostasis, but they also play a key role in thromboinflammatory pathways by regulating endothelial health, stimulating angiogenesis, and mediating host defense through both contact dependent and independent signaling. When activated, platelets degranulate releasing multiple active substances. We hypothesized that the soluble environment formed by trauma platelet releasates (TPR) attenuates thromboinflammation via mitigation of trauma induced endothelial permeability and metabolomic reprogramming. METHODS: Blood was collected from injured and healthy patients to generate platelet releasates and plasma in parallel. Permeability of endothelial cells when exposed to TPR and plasma (TP) was assessed via resistance measurement by electric cell-substrate impedance sensing (ECIS). Endothelial cells treated with TPR and TP were subjected to mass spectrometry-based metabolomics. RESULTS: TP increased endothelial permeability, whereas TPR decreased endothelial permeability when compared with untreated cells. When TP and TPR were mixed ex vivo, TPR mitigated TP-induced permeability, with significant increase in AUC compared with TP alone. Metabolomics of TPR and TP demonstrated disrupted redox reactions and anti-inflammatory mechanisms. CONCLUSION: Trauma platelet releasates provide endothelial barrier protection against TP-induced endothelial permeability. Our findings highlight a potential beneficial action of activated platelets on the endothelium in injured patients through disrupted redox reactions and increased antioxidants. Our findings support that soluble signaling from platelet degranulation may mitigate the endotheliopathy of trauma. The clinical implications of this are that activated platelets may prove a promising therapeutic target in the complex integration of thrombosis, endotheliopathy, and inflammation in trauma.

BACKGROUND: Rates of pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) for breast cancer have improved, especially among human epidermal growth factor 2-positive (HER2+) and triple-negative subtypes. The frequency and significance of biomarker profile change in residual disease are unclear. This study aimed to determine the rate of biomarker profile changes after NAC and the impact on clinical outcomes in a contemporary cohort. METHODS: Upon institutional review board approval, the study identified 634 consecutive patients treated with NAC between 2010 and 2022 at two academic institutions. The study cohort was focused on patients with residual disease who underwent biomarker profile retesting. Biomarker profile change for each subtype was compared across groups using Fisher-Irwin tests. Cox Proportional Hazards Model and Kaplan-Meier plots were performed to evaluate the association of changed versus unchanged biomarker profile with event-free survival. RESULTS: Biomarker retesting was performed for 259 (61.4 %) of 422 patients with residual disease. Biomarker profile change occurred in 18.1 % overall and was significantly higher among those with pre-NAC HER2+ disease (32.7 %, 17/52) than among those with HER2-disease (14.5 %, 30/207) (p = 0.004). Conversion of pre-NAC biomarker profiles of HR+HER2- and HR+HER2+ to triple-negative breast cancer (TNBC) post-NAC may be associated with worse event-free survival, hazard ratios of 2.23 (95 % confidence interval [CI], 0.90-5.53; p = 0.08), trending toward significance, and 36.7 (95 % CI, 2.2-610.8; p = 0.01), respectively. CONCLUSIONS: The results from one of the largest contemporary cohorts demonstrated that biomarker profile change in patients with residual disease after NAC was common. Furthermore, specific biomarker profile change in residual disease may have prognostic value. These findings strengthen the rationale for routine re-testing of biomarkers in residual disease after NAC.

OBJECTIVES: Up to a quarter of pregnant individuals with SLE have small for gestational age (SGA) infants. We aimed to characterize placental pathology associated with SGA infants in SLE. METHODS: We retrospectively analysed SLE deliveries with placental analysis at UCSD from November 2018 to October 2023, comparing SLE pregnancies resulting in SGA to those that did not, and additionally, to matched pregnancies with SGA but without SLE. RESULTS: Placental analysis was available only for 28/70 (40%) SLE deliveries, which had high rates of adverse outcomes (75%). All exhibited at least one histopathologic abnormality. Key findings distinguishing 12 SLE placentas resulting in SGA infants (vs.16 without) included small placental disc for gestational age (100% vs 56%, P = 0.01), placental disc infarct (50% vs 6%, P = 0.02) and increased perivillous fibrin deposition (PVFD, 58% vs 0%, P = 0.001). All seven SLE placentas with increased PVFD resulted in SGA infants. Compared with matched non-SLE pregnancies with SGA (n = 36), the only distinguishing placental lesion was a higher prevalence of increased PVFD in SLE-associated SGA (58% vs 22%, P = 0.03). CONCLUSION: The higher prevalence of increased PVFD in placentas of SLE-associated SGA may indicate a specific mechanism of placental injury leading to SGA in this context. Thus, its presence, particularly in context of SGA, should prompt providers to screen for an underlying autoimmune disease, including SLE. Systematic placental examination in context of SLE and associated autoimmune diseases could help evaluate responses to existing therapies, comparative studies of novel therapies and correlation to adverse outcomes.

Across four studies (N = 1544), we examined the relationship between individuals gender role mindsets, or beliefs about the malleability versus fixedness of traditional gender roles, and work-family conflict. We found that undergraduate women (but not men) business students holding a fixed, compared to growth, gender role mindset anticipated more work-family conflict. Next, we manipulated gender role mindset and demonstrated a causal link between womens growth mindsets (relative to fixed mindsets and control conditions) and reduced work-family conflict. We showed mechanistically that growth gender role mindsets unburden women from prescriptive gender roles, reducing work-family conflict. Finally, during COVID-19, we demonstrated a similar pattern among working women in high-achieving dual-career couples. We found an indirect effect of womens gender role mindset on job and relationship satisfaction, mediated through work-family conflict. Our preregistered studies suggest that holding the belief that gender roles can change mitigates womens work-family conflict.

Meningeal solitary fibrous tumors (SFT) are rare and have a high frequency of local recurrence and distant metastasis. In a cohort of 126 patients (57 female, 69 male; mean age at surgery 53.0 years) with pathologically confirmed meningeal SFTs with extended clinical follow-up (median 9.9 years; range 15 days-43 years), we performed extensive molecular characterization including genome-wide DNA methylation profiling (n = 80) and targeted TERT promoter mutation testing (n = 98). Associations were examined with NAB2::STAT6 fusion status (n = 101 cases; 51 = ex5-7::ex16-17, 26 = ex4::ex2-3; 12 = ex2-3::exANY/other and 12 = no fusion) and placed in the context of 2021 Central Nervous System (CNS) WHO grade. NAB2::STAT6 fusion breakpoints (fusion type) were significantly associated with metastasis-free survival (MFS) (p = 0.03) and, on multivariate analysis, disease-specific survival (DSS) when adjusting for CNS WHO grade (p = 0.03). DNA methylation profiling revealed three distinct clusters: Cluster 1 (n = 38), Cluster 2 (n = 22), and Cluster 3 (n = 20). Methylation clusters were significantly associated with fusion type (p

Pre-exposure prophylaxis (PrEP) is highly effective at reducing HIV acquisition. We aimed to estimate usage of oral-PrEP, and factors associated with adherence among female sex workers (FSWs) in Nairobi, Kenya, using a novel point-of-care urine tenofovir lateral flow assay (LFA). The Maisha Fiti study randomly selected FSWs from Sex Worker Outreach Program clinics in Nairobi. Data were collected from 1003 FSWs from June-October 2019, including surveys on self-reported oral-PrEP adherence. Adherence was also measured using the LFA for HIV-negative FSWs currently taking oral-PrEP. Informed by a social-ecological theoretical framework, we used hierarchical multivariable logistic regression models to estimate associations between individual, interpersonal/community, and structural/institutional-level factors and either self-reported or LFA-assessed adherence. Overall, 746 HIV-negative FSWs aged 18-40 participated in the study, of whom 180 (24.1%) self-reported currently taking oral-PrEP. Of these, 56 (31.1%) were adherent to oral-PrEP as measured by LFA. In the multivariable analyses, associations with currently taking oral-PrEP included having completed secondary education, high alcohol/substance use, feeling empowered to use PrEP, current intimate partner, no recent intimate partner violence, having support from sex worker organisations, experiencing sex work-related stigma, and seeking healthcare services despite stigma. Associations with oral-PrEP LFA-measured adherence measured included having only primary education, experience of childhood emotional violence, belonging to a higher wealth tertile, and being nulliparous. Oral-PrEP adherence, measured by self-report or objectively, is low among FSWs in Nairobi. Programs to improve oral-PrEP usage among FSWs should work to mitigate social and structural barriers and involve collaboration between FSWs, healthcare providers and policymakers.

INTRODUCTION: Decisions to prescribe opioids to patients depend on many factors, including illness severity, pain assessment, and patient age, race, ethnicity, and gender. Gender and sex disparities have been documented in many healthcare settings, but are understudied in inpatient general medicine hospital settings. OBJECTIVE: We assessed for differences in opioid administration and prescription patterns by legal sex in adult patient hospitalizations from the general medicine service at a large urban academic center. DESIGNS, SETTING, AND PARTICIPANTS: This study included all adult patient hospitalizations discharged from the acute care inpatient general medicine services at the University of California, San Francisco (UCSF) Helen Diller Medical Center at Parnassus Heights from 1/1/2013 to 9/30/2021. MAIN OUTCOME AND MEASURES: The primary outcomes were (1) average daily inpatient opioids received and (2) days of opioids prescribed on discharge. For both outcomes, we first performed logistic regression to assess differences in whether or not any opioids were administered or prescribed. Then, we performed negative binomial regression to assess differences in the amount of opioids given. We also performed all analyses on a subgroup of hospitalizations with pain-related diagnoses. RESULTS: Our study cohort included 48,745 hospitalizations involving 27,777 patients. Of these, 24,398 (50.1%) hospitalizations were female patients and 24,347 (49.9%) were male. Controlling for demographic, clinical, and hospitalization-level variables, female patients were less likely to receive inpatient opioids compared to male patents (adjusted OR 0.87; 95% CI 0.82, 0.92) and received 27.5 fewer morphine milligram equivalents per day on average (95% CI - 39.0, - 16.0). When considering discharge opioids, no significant differences were found between sexes. In the subgroup analysis of pain-related diagnoses, female patients received fewer inpatient opioids. CONCLUSIONS: Female patients were less likely to receive inpatient opioids and received fewer opioids when prescribed. Future work to promote equity should identify strategies to ensure all patients receive adequate pain management.

OBJECTIVE: The potential for choline metabolism to influence the development of diabetes has received increased attention. Previous studies on circulating choline metabolites and incident diabetes have been conducted in samples of older adults, often with a high prevalence of risk factors. RESEARCH DESIGN AND METHODS: Participants were from year 15 of follow-up (2000-2001) in the Coronary Artery Risk Development in Young Adults (CARDIA) Study (n = 3,133, aged 33-45 years) with plasma choline metabolite (choline, betaine, and trimethylamine N-oxide [TMAO]) data. We quantified associations between choline metabolites and 15-year risk of incident diabetes (n = 387) among participants free of diabetes at baseline using Cox proportional hazards regression models adjusted for sociodemographics, health behaviors, and clinical variables. RESULTS: Betaine was inversely associated with 15-year risk of incident diabetes (hazard ratio 0.76 [95% CI 0.67, 0.88] per 1-SD unit betaine), and TMAO was positively associated with 15-year risk of incident diabetes (1.11 [1.01, 1.22] per 1-SD unit). Choline was not significantly associated with 15-year risk of incident diabetes (1.05 [0.94, 1.16] per 1-SD). CONCLUSIONS: Our findings are consistent with other published literature supporting a role for choline metabolism in diabetes. Our study extends the current literature by analyzing a racially diverse population-based cohort of early middle-aged individuals in whom preventive activities may be most relevant.

ABSTRACTJustice-impacted persons may inconsistently access HIV testing. This cross-sectional secondary analysis investigates lifetime HIV testing prevalence among adults with prior histories of incarceration in Southern California, United States, participating in health-focused programming (n = 3 studies). Self-reported demographic and lifetime HIV testing data were collected between 2017-2023; descriptive analyses were conducted. Across the three samples, at least 74% of participants were male; Latino and African American individuals accounted for nearly two-thirds of participants. Lifetime HIV testing ranged from 72.8% to 84.2%. Males were significantly more likely than females to report never being tested in two samples and accounted for >95% of those never tested. No statistically significant differences in testing were observed by race/ethnicity. Single young adults (ages 18-26) were less likely than their partnered peers to report testing. HIV testing is critical for ensuring that individuals access prevention and treatment. HIV testing among justice-impacted adults in this study was higher than in the general population, potentially due to opt-out testing in correctional settings. Nevertheless, these findings underscore the importance of implementing targeted interventions to reduce structural (e.g., health insurance, access to self-testing kits) and social barriers (e.g., HIV stigma) to increase HIV testing among justice-impacted males and single young adults.

In this study, we employed a pre-interview survey and conducted interviews with nursing home staff members and residents/family members to understand their perceptions of whether the COVID-19 restrictions fulfilled obligations to nursing home residents under various principles, including autonomy, beneficence, nonmaleficence, justice, and privacy. We conducted 20 semi-structured interviews with staff members from 14 facilities, and 20 with residents and/or family members from 13 facilities. We used a qualitative descriptive study design and thematic analysis methodology to analyze the interviews. Findings from the pre-interview survey indicated that, compared to nursing home staff, residents and their families perceived lower adherence to bioethics principles during the pandemic. Qualitative analysis themes included specific restrictions, challenges, facility notifications, consequences, communication, and relationships between staff and residents/family members. Our study exposes the struggle to balance infection control with respecting bioethical principles in nursing homes, suggesting avenues for improving processes and policies during public health emergencies.

First-degree relatives of patients with multiple myeloma are at increased risk for the disease, but the contribution of pathogenic germline variants (PGV) in hereditary cancer genes to multiple myeloma risk and outcomes is not well characterized. To address this, we analyzed germline exomes in two independent cohorts of 895 and 786 patients with multiple myeloma. PGVs were identified in 8.6% of the Discovery cohort and 11.5% of the Replication cohort, with a notable presence of high- or moderate-penetrance PGVs (associated with autosomal dominant cancer predisposition) in DNA repair genes (3.6% and 4.1%, respectively). PGVs in BRCA1 (OR = 3.9, FDR < 0.01) and BRCA2 (OR = 7.0, FDR < 0.001) were significantly enriched in patients with multiple myeloma when compared with 134,187 healthy controls. Five of the eight BRCA2 PGV carriers exhibited tumor-specific copy number loss in BRCA2, suggesting somatic loss of heterozygosity. PGVs associated with autosomal dominant cancer predisposition were associated with younger age at diagnosis, personal or familial cancer history, and longer progression-free survival after upfront high-dose melphalan and autologous stem-cell transplantation (P < 0.01). Significance: Our findings suggest up to 10% of patients with multiple myeloma may have an unsuspected cancer predisposition syndrome. Given familial implications and favorable outcomes with high-dose melphalan and autologous stem-cell transplantation in high-penetrance PGV carriers, genetic testing should be considered for young or newly diagnosed patients with a personal or family cancer history. See related commentary by Walker, p. 375.

ObjectiveSexual and gender minority individuals are more likely to use tobacco and cannabis and have lower cigarette cessation. This study examined cannabis use associations with daily cigarettes smoked in sexual and gender minority individuals before and during a quit attempt.MethodParticipants included dual smoking same-sex/gender couples from California that were willing to make a quit attempt (individual n = 205, 68.3% female sex). Participants reported baseline past 30-day cannabis use and number of cigarettes smoked and cannabis use (yes/no) during 35 nightly surveys. Individuals with current cannabis use reported baseline cannabis use and/or nightly survey cannabis use. Multilevel linear models predicted number of cigarettes smoked by cannabis use.ResultsNumber of cigarettes decreased from before to during a quit attempt, but this decrease was smaller in individuals with current cannabis use compared to no current cannabis use (p < .001). In individuals with current cannabis use, number of cigarettes smoked was greater on days with cannabis use (p < .001). Furthermore, cannabis use that day increased overall number of cigarettes in those with relatively high overall cannabis use but only during a quit attempt in those with relatively low cannabis use (Within-Subject Cannabis Use × Between-Subject Cannabis Use × Quit Attempt interaction; p < .001).ConclusionsSexual and gender minority individuals with cannabis and cigarette use may have a harder time quitting smoking than those who do not use cannabis. For those with cannabis use, guidance on not using cannabis during a quit attempt may improve cigarette cessation outcomes. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

This paper proposes a smartphone-based method for measuring Blood Pressure (BP) using the oscillometric method. For oscillometry, it is necessary to measure (1) the pressure applied to the artery and (2) the local blood volume change. This is accomplished by performing an oscillometric measurement at the fingers digital artery, whereby a user presses down on the phones camera with steadily increasing force. The camera is used to capture the blood volume change using photoplethysmography. We devised a novel method for measuring the force applied of the finger without the use of specialized smartphone hardware with a technique called Vibrometric Force Estimation (VFE). The fundamental concept of VFE relies on a phenomenon where a vibrating object is dampened when an external force is applied on to it. This phenomenon can be recreated using the phones own vibration motor and measured using the phones Inertial Measurement Unit (IMU). A cross device reliability study with three smartphones of different manufacturers, shape, and prices results in similar force estimation performance across all smartphone models. In an N = 24 proof of concept study of the BP measurement, the smartphone technique achieves a mean absolute error of 9.21 mmHg and 7.77 mmHg of systolic and diastolic BP, respectively, compared to an FDA approved BP cuff. The vision for this technology is not necessarily to replace existing BP monitoring solutions, but rather to introduce a downloadable smartphone software application that could serve as a low-barrier hypertension screening measurement fit for widespread adoption.

C1q deficiency is a rare inborn error of immunity characterized by increased susceptibility to infections and autoimmune manifestations mimicking SLE, with an associated morbidity and mortality. Because C1q is synthesized by monocytes, to date, four patients treated with allogeneic HSCT have been reported, with a positive outcome in three. We conducted an international retrospective study to assess the outcome of HSCT in C1q deficiency. Eighteen patients, fourteen previously unreported, from eleven referral centres, were included. Two patients had two HSCTs, thus 20 HSCTs were performed in total, at a median age of 10 years (range 0.9-19). Indications for HSCT were autoimmune manifestations not controlled by ongoing treatment in seventeen, and early development of MALT lymphoma in one patient. Overall survival (OS) was 71% and event-free survival was 59% at two years (considering an event as acute GvHD ≥ grade III, disease recurrence and death). In eleven patients HSCT led to resolution of autoimmune features and discontinuation of immunosuppressive treatments (follow-up time range 3-84 months). Five patients died due to transplant-related complications. Patients with a severe autoimmune phenotype, defined as neurological and/or renal involvement, had the worst OS (40% vs 84%; p = 0.034). Reviewing data of 69 genetically confirmed C1q deficient patients, we found that anti-Ro antibodies are associated with neurologic involvement, and anti-RNP and anti-DNA antibodies with renal involvement. In conclusion, HSCT may be a valid curative option for C1q deficiency, but careful selection of patients, with an accurate assessment of risk and benefit, is mandatory.

BACKGROUND: Rezafungin is an echinocandin approved in the US and EU to treat candidaemia and/or invasive candidiasis. This post-hoc, pooled analysis of the Phase 2 STRIVE and Phase 3 ReSTORE trials assessed rezafungin versus caspofungin in patients with candidaemia and/or invasive candidiasis (IC) in the intensive care unit (ICU) at randomisation. METHODS: STRIVE and ReSTORE were randomised double-blind trials in adults with systemic signs and mycological confirmation of candidaemia and/or IC in blood or a normally sterile site ≤ 96 h before randomisation. Data were pooled for patients in the ICU at randomisation who received intravenous rezafungin (400 mg loading dose then 200 mg once weekly) or caspofungin (70 mg loading dose then 50 mg once daily) for ≤ 4 weeks. Outcomes were Day 30 all-cause mortality (primary outcome), Day 5 and 14 mycological eradication, time to negative blood culture, mortality attributable to candidaemia/invasive candidiasis, safety, and pharmacokinetics. RESULTS: Of 294 patients in STRIVE/ReSTORE, 113 were in the ICU at randomisation (rezafungin n = 46; caspofungin n = 67). At baseline, ~ 30% of patients in each group had impaired renal function and/or an Acute Physiologic Assessment and Chronic Health Evaluation II score ≥ 20. One patient (in the caspofungin group) was neutropenic at baseline. Day 30 all-cause mortality was 34.8% for rezafungin versus 25.4% for caspofungin. Day 5 and 14 mycological eradication was 78.3% and 71.7% for rezafungin versus 59.7% and 65.7% for caspofungin, respectively. Median time to negative blood culture was 18 (interquartile range, 12.6-43.0) versus 38 (interquartile range, 15.9-211.3) h for rezafungin versus caspofungin (stratified log-rank P = 0.001; nominal, not adjusted for multiplicity). Candidaemia/IC-attributable deaths occurred in two rezafungin patients versus one caspofungin patient. Safety profiles were similar between groups. Overall, 17.4% (rezafungin) versus 29.9% (caspofungin) of patients discontinued due to treatment-emergent adverse events. Rezafungin exposure following the initial 400-mg dose was comparable between patients in the ICU at randomisation (n = 50) and non-ICU patients (n = 117). CONCLUSIONS: Rezafungin was well tolerated and efficacious in critically ill, mainly non-neutropenic patients with candidaemia and/or IC. This analysis provides additional insights into the efficacy and safety of rezafungin in the ICU population.

OBJECTIVE: Paraoxonase-1 (PON1) is a high-density lipoprotein (HDL)-associated enzyme, that has been implicated as a biomarker of cardiovascular risk in patients with rheumatoid arthritis (RA). We aimed to investigate how different biologic therapies affect levels of PON1 and oxylipins. METHODS: 1213 adult patients with RA in the Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory CoNditions cohort study with moderate-to-high disease activity (Clinical Disease Activity Index (CDAI) >10) who initiated a new biologic (tocilizumab (TCZ), n=296; abatacept, n=374; tumour necrosis factor inhibitors, n=427; rituximab, n=116) were followed prospectively with serum specimens analysed for PON1 activity by arylesterase (ARYL), lactonase (LAC) and PON assays at baseline and after 6 months of biologic therapy. A targeted panel of oxylipins was evaluated by liquid chromatography-mass spectrometry/mass spectrometry in a subset of patients with the lowest and highest 6-month Disease Activity Score 28 (DAS28)-C reactive protein (CRP) responses in each treatment group. RESULTS: PON1 activity generally increased in the entire cohort after 6 months of new biologic therapy, showing the greatest, most consistent increases in the TCZ group. Increases in all three PON1 domains associated with significant decreases in disease activity in DAS28-CRP/CDAI (p

Subjective well-being (SWB) is often described as being U-shaped over adulthood, declining to a midlife slump and then improving thereafter. Improved SWB in later adulthood has been considered a paradox given age-related declines in health and social losses. While SWB has mostly been studied in high-income countries, it remains largely unexplored in rural subsistence populations lacking formal institutions that reliably promote social welfare. Here, we evaluate the age profile of SWB among three small-scale subsistence societies (n = 468; study 1), forest users from 23 low-income countries (n = 6987; study 2), and Tsimane horticulturalists (n = 1872; study 3). Across multiple specifications, we find variability in SWB age profiles. In some cases, we find no age-related differences in SWB or even inverted U-shapes. Adjusting for confounders reduces observed age effects. Our findings highlight variability in average well-being trajectories over the life course. Ensuring successful aging will require a greater focus on cultural and socioecological determinants of individual trajectories.

BACKGROUND: Antibiotic resistance of Enterobacterales poses a major challenge in the treatment of urinary tract infections (UTIs). In low- and middle-income countries (LMICs), standard microbiological (i.e. urine culture and simple disk diffusion test) methods are considered the gold standard for bacterial identification and drug susceptibility testing, while PCR and DNA sequencing are less commonly used. In this study, we aimed to re-identifying Enterobacterales as the primary bacterial agents responsible for urinary tract infections (UTIs) by comparing the sensitivity and specificity of traditional microbiological methods with advanced molecular techniques for the detection of uropathogens in indigenous women from Otavalo, Ecuador. METHODS: A facility-based cross-sectional study was conducted from October 2021 to February 2022 among Kichwa-Otavalo women. Pathogens from urine samples were identified using culture and biochemical typing. Morphological identification was doble-checked through PCR and DNA sequencing of 16S, recA, and rpoB molecular barcodes. The isolates were subjected to antimicrobial susceptibility-testing using disk diffusion test. RESULTS: This study highlighted a 32% misidentification rate between biochemical and molecular identification. Using traditional methods, E. coli was 26.19% underrepresented meanwhile Klebsiella oxytoca was overrepresented by 92.86%. Furthermore, the genera Pseudomonas, Proteus, and Serratia were confirmed to be E. coli and Klebsiella spp. by molecular method, and one Klebsiella spp. was reidentified as Enterobacter spp. The susceptibility profile showed that 59% of the isolates were multidrug resistant strains and 31% produced extended spectrum beta-lactamases (ESBLs). Co-trimoxazole was the least effective antibiotic with 61% of the isolates resistant. Compared to previous reports, resistance to nitrofurantoin and fosfomycin showed an increase in resistance by 25% and 15%, respectively. CONCLUSIONS: Community-acquired UTIs in indigenous women in Otavalo were primarily caused by E. coli and Klebsiella spp. Molecular identification (16S/rpoB/recA) revealed a high rate of misidentification by standard biochemical and microbiological techniques, which could lead to incorrect antibiotic prescriptions. UTI isolates in this population displayed higher levels of resistance to commonly used antibiotics compared with non-indigenous groups. Accurate identification of pathogens causing UTIs and their antibiotic susceptibility in local populations is important for local antibiotic prescribing guidelines.

BACKGROUND: The mechanism for recording International Classification of Diseases (ICD) and diagnosis related groups (DRG) codes in a patients chart is through a certified medical coder who manually reviews the medical record at the completion of an admission. High-acuity ICD codes justify DRG modifiers, indicating the need for escalated hospital resources. In this manuscript, we demonstrate that value of rules-based computer algorithms that audit for omission of administrative codes and quantifying the downstream effects with regard to financial impacts and demographic findings did not indicate significant disparities. METHODS: All study data were acquired via the UCLA Department of Anesthesiology and Perioperative Medicines Perioperative Data Warehouse. The DataMart is a structured reporting schema that contains all the relevant clinical data entered into the EPIC (EPIC Systems, Verona, WI) electronic health record. Computer algorithms were created for eighteen disease states that met criteria for DRG modifiers. Each algorithm was run against all hospital admissions with completed billing from 2019. The algorithms scanned for the existence of disease, appropriate ICD coding, and DRG modifier appropriateness. Secondarily, the potential financial impact of ICD omissions was estimated by payor class and an analysis of ICD miscoding was done by ethnicity, sex, age, and financial class. RESULTS: Data from 34,104 hospital admissions were analyzed from January 1, 2019, to December 31, 2019. 11,520 (32.9%) hospital admissions were algorithm positive for a disease state with no corresponding ICD code. 1,990 (5.8%) admissions were potentially eligible for DRG modification/upgrade with an estimated lost revenue of $22,680,584.50. ICD code omission rates compared against reference groups (private payors, Caucasians, middle-aged patients) demonstrated significant p-values

In this study, associations between prenatal exposure to fine particulate matter (PM2.5) from 9 sources and development of autism spectrum disorder (ASD) were assessed in a population-based retrospective pregnancy cohort in southern California. The cohort included 318,750 mother-child singleton pairs. ASD cases (N = 4559) were identified by ICD codes. Source-specific PM2.5 concentrations were estimated from a chemical transport model with a 4 × 4 km2 resolution and assigned to maternal pregnancy residential addresses. Cox proportional hazard models were used to estimate the hazard ratios (HR) of ASD development for each individual source. We also adjusted for total PM2.5 mass and in a separate model for all other sources simultaneously. Increased ASD risk was observed with on-road gasoline (HR [CI]: 1.18 [1.13, 1.24]), off-road gasoline (1.15 [1.12, 1.19]), off-road diesel (1.08 [1.05, 1.10]), food cooking (1.05 [1.02, 1.08]), aircraft (1.04 [1.01, 1.06]), and natural gas combustion (1.09 [1.06, 1.11]), each scaled to standard deviation increases in concentration. On-road gasoline and off-road gasoline were robust for other pollutant groups. PM2.5 emitted from different sources may have different impacts on ASD. The results also identify PM source mixtures for toxicological investigations that may provide evidence for future public health policies.

BACKGROUND: To prospectively evaluate ultrasound backscatter coefficients (BSCs) of the supraspinatus and infraspinatus muscles and compare with Goutallier classification on magnetic resonance imaging (MRI). METHODS: Fifty-six participants had shoulder MRI exams and ultrasound exams of the supraspinatus and infraspinatus muscles. Goutallier MRI grades were determined and BSCs were measured. Group means were compared and the strength of relationships between the measures were determined. Using binarized Goutallier groups (0-2 versus 3-4), areas under the receiver operating characteristic curves (AUROCs) were calculated. The nearest integer cutoff value was determined using Youdens index. RESULTS: BSC values were significantly different among most Goutallier grades for the supraspinatus and infraspinatus muscles (both p

BACKGROUND: Brain metastasis (BM) is a rare but severe complication of head and neck squamous cell carcinoma (HNSCC), with limited knowledge of molecular characteristics and immunogenicity. METHODS: We analyzed 61 cases of HNSCC-BM from three academic institutions (n = 24) and Foundation Medicine Inc (FMI, n = 37). A subset of cases underwent next-generation sequencing, multiple immunofluorescence, and proximity ligation sequencing. Gene enrichment analysis compared alterations in FMI BM samples (n = 37) with local samples (n = 4082). RESULTS: Demographics included: median age of 59 years, 75% male, 55% current/former smokers, 75% oropharyngeal primary, and 67% human papillomavirus (HPV) +. ATM (54%), KMT2A (54%), PTEN (46%), RB1 (46%), and TP53 (46%) were frequently altered in BM samples from academic centers (62% HPV/p16+). Structural rearrangements ranged from 9 to 90 variants by proximity ligation sequencing. BMs had low densities of CD8+, PD-1+, PD-L1+, and FOXP3 + cells, and 92% had PD-L1 combined positive scores

OBJECTIVE: Internally displaced persons (IDPs) can have limited access to HIV and hepatitis C Virus (HCV) treatment and prevention. IDPs comprise > 7% of Georgian population but prevalence and levels of HIV and HCV knowledge in this population remain unknown. We tested 100 IDPs in Georgia for HIV and HCV, many of whom had drug injecting experience, and interviewed them about their migration experience, sexual and drug injecting practices, and HIV/HCV transmission knowledge. RESULTS: The average age of participants was 37.5 years (range 18-63); 31% were women. Almost half (N = 48) of participants reported ever injecting drugs; 17% of those (N = 8) started injecting drugs within the last year. Anti-HCV and HIV prevalence was 11% and 0%, respectively. Fewer people without drug use experience compared to people who inject drugs correctly answered all questions on the HIV knowledge test (13% vs. 35%, p = 0.015) or knew where to get tested for HIV (67% vs 98%, p

BACKGROUND: The characteristics of electrocardiogram (ECG) abnormalities related to cardiac channelopathies potentially linked to sudden cardiac death (SCD) are not widely recognized in Iran. We examined the prevalence of such ECG patterns and their related factors among adult residents of Tehran, Iran. METHODS: The clinical characteristics and 12-lead ECGs of Tehran Cohort Study participants were examined. Long QT intervals, short QT intervals, Brugada syndrome (BrS) patterns, and early repolarization (ER) were evaluated using computer-based assessment software validated by cardiologists. Logistic regression models were employed to identify the factors associated with the prevalence of different ECG patterns. RESULTS: Out of 7678 available ECGs, 7350 were included in this analysis. Long QT interval, ER pattern, BrS patterns, and short QT interval were found in 3.08%, 1.43%, 0.31%, and 0.03% of participants, respectively. The prevalence of long QT interval increased with age, opium consumption, and presence of hypertension. Younger age, lower body mass index (BMI), alcohol use and male sex were independently linked to an elevated prevalence of ER pattern. Most individuals with BrS patterns were men (95%) and had lower BMI, high- and low-density lipoprotein, and total cholesterol compared to those without the BrS pattern. At a mean follow-up of 30.2 ± 5.5 months, all-cause mortality in the group exhibiting abnormal ECG patterns (6.3%) was approximately twice as high as that in the group without such patterns (2.96%). CONCLUSION: Abnormal ECG patterns corresponding to channelopathies were relatively rare among adult residents of the Tehran population, and their prevalence was influenced by various factors. CLINICAL TRIAL NUMBER: Not applicable.

BACKGROUND: Middle age is increasingly acknowledged as a critical window for prevention of Alzheimers disease and related dementia (ADRD) since research has shown that AD develops in the course of 20-30 years (1) but we know very little about middle-aged individuals perspectives on ADRD. Knowledge gaps are particularly large for Latinas living in regions typically underrepresented in ADRD research, such as rural and/or agricultural regions. This is important given that over the next 40 years Latinos are projected to have the largest increase in ADRD cases in the U.S. Therefore, this study aims to assess knowledge, perceptions, and feelings associated with ADRD among a sample of middle-age, Spanish-speaking Latina women. METHOD: Using qualitative methods involving semi-structured interviews, we examined knowledge, perceptions, and feelings associated with ADRD among a subsample of the Center for Health Assessment of Mothers and Children of Salinas (CHAMACOS) study. Participants are Latina women residing in an underserved agricultural community entering mid-life (mean = 46.5 years old). Interviews were conducted with 20 women and data was analyzed with inductive thematic content analysis. RESULTS: We identified themes regarding perceptions, knowledge, and feelings. First, participants perceive ADRD as involving (1) Loss of memory, (2) Getting lost; (3) Losing the person they once were. With regard to knowledge about ADRD, participants reported: (1) Some knowledge about protective and risk factors for ADRD, (2) No awareness of the links between cardiovascular risk factors and ADRD; (3) A desire to learn prevention methods alongside signs and symptoms of ADRD. Themes related to feelings about ADRD were: (1) Fear of developing ADRD and not being aware of reality or who they are; (2) Worry about losing relationships with loved ones and caretaking if diagnosed with ADRD; (3) Sadness about forgetting ones family and depending on others if diagnosed with ADRD. CONCLUSION: The knowledge gaps and negative feelings associated with ADRD highlighted in this study underscore the need for ADRD interventions to include CVD prevention, particularly for mid-life Latino populations residing in rural regions.

BIVV003 is a gene-edited autologous cell therapy in clinical development for the potential treatment of sickle cell disease (SCD). Hematopoietic stem cells (HSC) are genetically modified with mRNA encoding zinc finger nucleases (ZFN) that target and disrupt a specific regulatory GATAA motif in the BCL11A erythroid enhancer to reactivate fetal hemoglobin (HbF). We characterized ZFN-edited HSC from healthy donors and donors with SCD. Results of preclinical studies show that ZFN-mediated editing is highly efficient, with enriched biallelic editing and high frequency of on-target indels, producing HSC capable of long-term multilineage engraftment in vivo, and express HbF in erythroid progeny. Interim results from the Phase 1/2 PRECIZN-1 study demonstrated that BIVV003 was well-tolerated in seven participants with SCD, of whom five of the six with more than 3 months of follow-up displayed increased total hemoglobin and HbF, and no severe vaso-occlusive crises. Our data suggest BIVV003 represents a compelling and novel cell therapy for the potential treatment of SCD.

BACKGROUND: Little is known about penile high-risk human papillomavirus (hrHPV) among men who have sex with men (MSM) in low- and middle-income countries. We aimed to determine the incidence, clearance, and persistence of penile hrHPV among Rwandan MSM. METHODS: We enrolled 350 MSM (345 with valid human papillomavirus [HPV] results) aged ≥18 years. At each visit (6-12 months apart), we collected penile PreservCyt specimens and blood for HPV and HIV testing, as well as sociodemographic and behavioral variables. HPV testing was performed with the Ampfire assay. Penile hrHPV incidence and clearance per 1000 person-months of follow-up, as well as prevalent and incident persistence, were computed and compared by HIV status. RESULTS: The mean (SD) age was 27.7 (6.7) years and 19.4% were living with HIV. Penile hrHPV incidence was 34.8 (95% CI, 29.1-41.8) per 1000 person-months of follow-up. HPV-16 (11.7; 95% CI, 9.26-14.9) and HPV-59 (6.1; 95% CI, 4.52-8.39) had the highest incidence rates. Prevalent and incident persistence was 47.5% and 46.6%, respectively. HPV-66 (33.3%), HPV-52 (30.8%), and HPV-16 (29.2%) had the highest prevalent persistence and HPV-33 (53.8%), HPV-31 (46.7%), and HPV-16 (42.6%) the highest incident persistence. No differences were found by HIV status except for HPV-45 (higher in MSM with HIV). CONCLUSIONS: We found high incidence and prevalent/incident persistence of penile hrHPV among Rwandan MSM. This highlights the importance of preventive strategies for HPV-associated anogenital cancers.

BACKGROUND: The research community has historically failed to enroll diverse groups of participants in dementia clinical trials. A unique aspect of dementia care research is the requirement of a study partner, who can attest to the care recipients clinical and functional capacity. The aim of this study is to assess racial and ethnic differences and the importance of various trial considerations among dementia caregivers, in their decision to participate in clinical research as study partners. METHOD: We embedded a vignette about a hypothetical dementia clinical trial in a nationally representative survey of U.S. dementia caregivers, oversampling non-Hispanic Black and Hispanic caregivers. Dementia caregivers were asked about their willingness to participate in the trial with their care recipient and rated the importance of nine considerations in hypothetical decisions to participate. Caregiver demographic characteristics were analyzed as predictors of trial participation in a base demographic model. In a second reasons model caregiver demographic characteristics and the rated importance of the nine considerations were separately analyzed as predictors; both models used survey-weighted logistic regression. RESULT: The sample consisted of 610 dementia caregivers, including 156 non-Hispanic Black and 122 Hispanic caregiver participants. In the base demographic model, hypothetical trial participation was negatively associated with older caregiver age (OR (odds ratio) = 0.72, p =

Study designRetrospective cohort study of prospectively accrued data.ObjectiveTo evaluate a large, prospective, multicentre dataset of surgically treated degenerative cervical myelopathy (DCM) cases on the contemporary risk of C5 palsy with surgical approach.Summary of background dataThe influence of surgical technique on postoperative C5 palsy after decompression for DCM is intensely debated. Comprehensive, covariate-adjusted analyses are needed using contemporary data.MethodsPatients with moderate to severe DCM were prospectively enrolled in the multicenter, randomized, Phase III CSM-Protect clinical trial and underwent either anterior or posterior decompression between Jan 31, 2012 and May 16, 2017. The primary outcome was the incidence of postoperative C5 palsy, defined as the onset of muscle weakness by at least one grade in manual muscle test at the C5 myotome with slight or absent sensory disruption after cervical surgery. Two comparative cohorts were made based on the anterior or posterior surgical approach. Multivariate hierarchical mixed-effects logistic regression was used to estimate odds ratios (OR) with 95% confidence intervals (CI) for C5 palsy.ResultsA total of 283 patients were included, and 53.4% underwent posterior decompression. The total incidence of postoperative C5 palsy was 7.4% and was significantly higher in patients who underwent posterior decompression compared with anterior decompression (11.26% vs. 3.03%, P =0.008). After multivariable regression, the posterior approach was independently associated with greater than four times the likelihood of postoperative C5 palsy ( P =0.017). Rates of C5 palsy recovery were comparable between the two surgical approaches.ConclusionThe odds of postoperative C5 palsy are significantly higher after posterior decompression compared to anterior decompression for DCM. This may influence surgical decision-making when there is equipoise in deciding between anterior and posterior treatment options for DCM.Level of evidenceTherapeutic Level-II.

Enhancing the efficacy of immunotherapy in brain metastases (BrM) requires an improved understanding of the immune composition of BrM and how this is affected by radiation and dexamethasone. Our two-arm pilot study (NCT04895592) allocated 26 patients with BrM to either low (Arm A) or high (Arm B) dose peri-operative dexamethasone followed by pre-operative stereotactic radiosurgery (pSRS) and resection (n= 13 per arm). The primary endpoint, a safety analysis at 4 months, was met. The secondary clinical endpoints of overall survival, distant brain failure, leptomeningeal disease and local recurrence at 12-months were 66%, 37.3%, 6%, and 0% respectively and were not significantly different between arms (p= 0.7739, p= 0.3884, p= 0.3469). Immunological data from two large retrospective BrM datasets and confirmed by correlates from both arms of this pSRS prospective trial revealed that BrM CD8 T cells were composed of predominantly PD1+ TCF1+ stem-like and PD1+ TCF1-TIM3+ effector-like cells. Clustering of TCF1+ CD8 T cells with antigen presenting cells in immune niches was prognostic for local control, even without pSRS. Following pSRS, CD8 T cell and immune niche density were transiently reduced compared to untreated BrM, followed by a rebound 6+ days post pSRS with an increased frequency of TCF1- effector-like cells. In sum, pSRS is safe and therapeutically beneficial, and these data provide a framework for how pSRS may be leveraged to maximize intracranial CD8 T cell responses.

The effects of the COVID-19 pandemic on comprehensive maternal deaths in Brazil have not been fully explored. Using publicly available data from the Brazilian Mortality Information (SIM) and Information System on Live Births (SINASC) databases, we used two complementary forecasting models to predict estimates of maternal mortality ratios using maternal deaths (MMR) and comprehensive maternal deaths (MMRc) in the years 2020 and 2021 based on data from 2008 to 2019. We calculated national and regional standardized mortality ratio estimates for maternal deaths (SMR) and comprehensive maternal deaths (SMRc) for 2020 and 2021. The observed MMRc in 2021 was more than double the predicted MMRc based on the Holt-Winters and autoregressive integrated moving average models (127.12 versus 60.89 and 59.12 per 100,000 live births, respectively). We found persisting sub-national variation in comprehensive maternal mortality: SMRc ranged from 1.74 (95% confidence interval [CI] 1.64, 1.86) in the Northeast to 2.70 (95% CI 2.45, 2.96) in the South in 2021. The observed national estimates for comprehensive maternal deaths in 2021 were the highest in Brazil in the past three decades. Increased resources for prenatal care, maternal health, and postpartum care may be needed to reverse the national trend in comprehensive maternal deaths.

BACKGROUND: The Neuroform Atlas Stent System is an established treatment modality for unruptured anterior and posterior circulation intracranial aneurysms. Location-specific results are needed to guide treatment decision-making. However, it is unclear whether there are differences in safety and efficacy outcomes between carotid and more distal anterior circulation aneurysms. METHODS: The ATLAS IDE trial was a prospective, multicenter, single-arm, open-label interventional study that evaluated the safety and efficacy of the Neuroform Atlas Stent System. We compared differences in efficacy and safety outcomes of proximal internal carotid artery (ICA) versus distal and bifurcation anterior circulation aneurysms. RESULTS: Of 182 cases, there were 70 aneurysms in the ICA and 112 in the distal anterior circulation (including ICA terminus/bifurcation). There were no significant differences in the primary efficacy endpoint (85.5% vs 83.9%, p=0.78) and complete aneurysm occlusion rates (88.7% vs 87.9%, p=0.78) between proximal ICA aneurysms and distal aneurysms, respectively. Complications were more often encountered in distal and bifurcation aneurysms, but the overall rate of major safety events was low and comparable between the two groups (1.4% vs 6.3%, p=0.14). Recanalization and retreatment rates were also similar between the groups. CONCLUSION: The results of this study suggest that the Neuroform Atlas Stent System is a safe and efficacious treatment modality for unruptured anterior circulation intracranial aneurysms, regardless of aneurysm location. TRIAL REGISTRATION NUMBER: NCT02340585.

OBJECTIVES: This study aimed to evaluate pulmonary diffusing capacity for nitric oxide (DLNO) and pulmonary diffusing capacity for carbon monoxide (DLCO) in Mexican Hispanics born and raised at 2240 m altitude (midlanders) compared with those born and raised at sea level (lowlanders). It also aimed to assess the effectiveness of race-specific reference equations for pulmonary diffusing capacity (white people vs Mexican Hispanics) in minimising root mean square errors (RMSE) compared with race-neutral equations. METHODS: DLNO, DLCO, alveolar volume (VA) and gas transfer coefficients (KNO and KCO) were measured in 392 Mexican Hispanics (5 to 78 years) and compared with 1056 white subjects (5 to 95 years). Reference equations were developed using segmented linear regression (DLNO, DLCO and VA) and multiple linear regression (KNO and KCO) and validated with Least Absolute Shrinkage and Selection Operator. RMSE comparisons between race-specific and race-neutral models were conducted using repeated k-fold cross-validation and random forests. RESULTS: Midlanders exhibited higher DLCO (mean difference: +4 mL/min/mm Hg), DLNO (mean difference: +7 mL/min/mm Hg) and VA (mean difference: +0.17 L) compared with lowlanders. The Bayesian information criterion favoured race-specific models and excluding race as a covariate increased RMSE by 61% (DLNO), 18% (DLCO) and 4% (KNO). RMSE values for VA and KCO were comparable between race-specific and race-neutral models. For DLCO and DLNO, race-neutral equations resulted in 3% to 6% false positive rates (FPRs) in Mexican Hispanics and 20% to 49% false negative rates (FNRs) in white subjects compared with race-specific equations. CONCLUSIONS: Mexican Hispanics born and raised at 2240 m exhibit higher DLCO and DLNO compared with lowlanders. Including race as a covariate in reference equations lowers the RMSE for DLNO, DLCO and KNO and reduces FPR and FNR compared with race-neutral models. This study highlights the need for altitude-specific and race-specific reference equations to improve pulmonary function assessments across diverse populations.

To investigate how clinicians correct patient misconceptions, we analyzed 23 video recordings of primary care visits. Analysis focused on operationalizing, identifying, and characterizing clinician corrections, integrating two inductive approaches: microanalysis of clinical interaction and conversation analysis. According to our definition, patient misconception-clinician correction episodes met three essential criteria: (1) the clinician refuted something the patient had said, (2) which the patient had presented without uncertainty, and (3) which contained a proposition that was factually incorrect. We identified 59 such episodes; the patient misconceptions most commonly related to medication issues; fewer than half had foreseeable implications for patients' future actions. We identified seven clinician correction practices: Three direct practices (displaying surprise, marking disagreement, contradicting the patient) and four indirect practices (presenting the correct proposition, providing explanations, invoking an outside authority, demonstrating with evidence). We found an almost equal distribution of these direct and indirect practices.

BACKGROUND: Outcome measures are crucial to support a treat-to-target approach to rheumatoid arthritis (RA) care, yet their integration into clinical practice remains inconsistent. We developed an Electronic Heath Record-integrated, patient-facing side-car application to display RA outcomes (disease activity, functional status, pain scores), medications, and lab results during clinical visits (RA PRO Dashboard). The study aimed to evaluate patient perceptions and attitudes towards the implementation of a novel patient-facing dashboard during clinical visits using a mixed-methods approach. METHODS: RA patients whose clinicians used the dashboard at least once during their clinical visit were invited to complete a survey regarding its usefulness in care. We also conducted semi-structured interviews with a subset of patients to assess their perceptions of the dashboard. The interviews were transcribed verbatim and analyzed thematically using deductive and inductive techniques. Emerging themes and subthemes were organized into four domains of the Ecological Model of Health. RESULTS: Out of 173 survey respondents, 79% were interested in seeing the dashboard again at a future visit, 71% felt it improved their understanding of their disease, and 65% believed it helped with decision-making about their RA care. Many patients reported that the dashboard helped them discuss their RA symptoms (76%) and medications (72%) with their clinician. Interviews with 29 RA patients revealed 10 key themes: the dashboard was perceived as a valuable visual tool that improved patients understanding of RA outcome measures, enhanced their involvement in care, and increased their trust in clinicians and the clinic. Common reported limitations included concerns about reliability of RA outcome questionnaires for some RA patients and inconsistent collection and explanation of these measures by clinicians. CONCLUSIONS: In both the quantitative and qualitative components of the study, patients reported that the dashboard improved their understanding of their RA, enhanced patient-clinician communication, supported shared decision-making, and increased patient engagement in care. These findings support the use of dashboards or similar data visualization tools in RA care and can be used in future interventions to address challenges in data collection and patient education.

Behavioral speech tasks have been widely used to understand the mechanisms of speech motor control in typical speakers as well as in various clinical populations. However, determining which neural functions differ between typical speakers and clinical populations based on behavioral data alone is difficult because multiple mechanisms may lead to the same behavioral differences. For example, individuals with cerebellar ataxia (CA) produce atypically large compensatory responses to pitch perturbations in their auditory feedback, compared to typical speakers, but this pattern could have many explanations. Here, computational modeling techniques were used to address this challenge. Bayesian inference was used to fit a state feedback control (SFC) model of voice fundamental frequency (fo) control to the behavioral pitch perturbation responses of speakers with CA and typical speakers. This fitting process resulted in estimates of posterior likelihood distributions for five model parameters (sensory feedback delays, absolute and relative levels of auditory and somatosensory feedback noise, and controller gain), which were compared between the two groups. Results suggest that the speakers with CA may proportionally weight auditory and somatosensory feedback differently from typical speakers. Specifically, the CA group showed a greater relative sensitivity to auditory feedback than the control group. There were also large group differences in the controller gain parameter, suggesting increased motor output responses to target errors in the CA group. These modeling results generate hypotheses about how CA may affect the speech motor system, which could help guide future empirical investigations in CA. This study also demonstrates the overall proof-of-principle of using this Bayesian inference approach to understand behavioral speech data in terms of interpretable parameters of speech motor control models.

Recent research highlights the significant impact of the gut microbiota on health and disease. Thalassemia, a hereditary blood disorder, requires regular blood transfusions, leading to an accumulation of iron in the body. Such changes could potentially alter the intestinal microbiota, thereby increasing the susceptibility of thalassemic patients to infection. In this study, we analyzed the fecal microbiota of 70 non-transfusion-dependent (NTDT) β-thalassemia/HbE patients and 30 healthy controls. Our findings indicate that iron chelation intervention had no detectable effect on the microbiome profile of thalassemic patients. However, the cross-sectional analysis revealed that the bacterial diversity and community structure in patients were significantly less diverse and distinct compared to those of healthy subjects. Using reference frames, we were also able to demonstrate that bacterial taxa that are known to produce short chain fatty acids, from the genera Alistipes, Coprococcus, and Oscillospira, and those from the family Ruminococcaceae, were less prevalent in the patients. In contrast, bacterial taxa associated with an unhealthy gut, including the genus Clostridium and those from the families Fusobacteriaceae, Enterobacteriaceae, and Peptostrptococcaceae, were more prevalent in patients and found to be correlated with higher levels of ferritin. Collectively, these changes in the microbiota could be regarded as markers of raised ferritin levels, and therefore, awareness should be exercised as they could interfere, albeit indirectly, with the treatment of the co-morbidities of thalassemia.

BACKGROUND: Pre-diagnostic disturbances in the microbiome-derived metabolome have been associated with an increased risk of diabetes in non-pregnant populations. However, the roles of microbiome-derived metabolites, the end-products of microbial metabolism, in gestational diabetes (GDM) remain understudied. We examined the prospective association of microbiome-derived metabolites in early to mid-pregnancy with GDM risk in a diverse population. METHODS: We conducted a prospective discovery and validation study, including a case-control sample of 91 GDM and 180 non-GDM individuals within the multi-racial/ethnic The Pregnancy Environment and Lifestyle Study (PETALS) as the discovery set, a random sample from the PETALS (42 GDM, 372 non-GDM) as validation set 1, and a case-control sample (35 GDM, 70 non-GDM) from the Gestational Weight Gain and Optimal Wellness randomized controlled trial as validation set 2. We measured untargeted fasting serum metabolomics at gestational weeks (GW) 10-13 and 16-19 by gas chromatography/time-of-flight mass spectrometry (TOF-MS), liquid chromatography (LC)/quadrupole TOF-MS, and hydrophilic interaction LC/quadrupole TOF-MS. GDM was diagnosed using the 3-h, 100-g oral glucose tolerance test according to the Carpenter-Coustan criteria around GW 24-28. RESULTS: Among 1362 annotated compounds, we identified 140 of gut microbiome metabolism origin. Multivariate enrichment analysis illustrated that carbocyclic acids and branched-chain amino acid clusters at GW 10-13 and the unsaturated fatty acids cluster at GW 16-19 were positively associated with GDM risk (FDR

We investigate the emergence, mutation profile, and dissemination of SARS-CoV-2 lineage B.1.214.2, first identified in Belgium in January 2021. This variant, featuring a 3-amino acid insertion in the spike protein similar to the Omicron variant, was speculated to enhance transmissibility or immune evasion. Initially detected in international travelers, it substantially transmitted in Central Africa, Belgium, Switzerland, and France, peaking in April 2021. Our travel-aware phylogeographic analysis, incorporating travel history, estimated the origin to the Republic of the Congo, with primary European entry through France and Belgium, and multiple smaller introductions during the epidemic. We correlate its spread with human travel patterns and air passenger data. Further, upon reviewing national reports of SARS-CoV-2 outbreaks in Belgian nursing homes, we found this strain caused moderately severe outcomes (8.7% case fatality ratio). A distinct nasopharyngeal immune response was observed in elderly patients, characterized by 80% unique signatures, higher B- and T-cell activation, increased type I IFN signaling, and reduced NK, Th17, and complement system activation, compared to similar outbreaks. This unique immune response may explain the variants epidemiological behavior and underscores the need for nasal vaccine strategies against emerging variants.

INTRODUCTION: The Fear of Pain Questionnaire (FOPQ) is a self-report tool designed to measure an individuals fear of pain (FOP). While the Persian version of the FOPQ (FOPQ-P) has been developed, its validity and reliability have not yet been assessed in the Iranian context. This study aims to evaluate the psychometric properties of the FOPQ-P among Iranian patients after surgery. METHODS: A methodological study was conducted in 2023 involving 400 post-surgery patients selected with a convenience sampling. The FOPQ was translated into Persian, and its psychometric properties were analyzed using network analysis, exploratory factor analysis (EFA), confirmatory factor analysis (CFA), as well as assessments of convergent and discriminant validity. Internal consistency was measured using Cronbachs alpha, McDonalds Omega, average inter-item correlation coefficient, Composite Reliability, and Maximal Reliability. RESULTS: The EFA results with Promax and Kaiser Normalization rotation identified two factors that explained 54.32% of the variance, comprising seven items. The CFA confirmed the models validity. Both convergent and discriminant validity were established. The reliability analyses showed that Cronbachs alpha, McDonalds omega, composite reliability, and MaxR for all constructs were above 0.7. Additionally, the average inter-item correlation coefficient was greater than 0.5, indicating strong internal consistency and construct reliability. CONCLUSION: The findings suggest that the FOPQ-P possesses a valid structure and was acceptable reliability in patients cultural context of Iran post-surgery, making it a suitable instrument for measuring fear of pain in this population.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) that affects approximately 4% of males and 1% of females in the United States. While causes of ASD are multi-factorial, single rare genetic variants contribute to around 20% of cases. Here, we report a case series of seven unrelated probands (6 males, 1 female) with ASD or another variable NDD phenotype attributed to de novo heterozygous loss of function or missense variants in the gene LARP1 (La ribonucleoprotein 1). LARP1 encodes an RNA-binding protein that post-transcriptionally regulates the stability and translation of thousands of mRNAs, including those regulating cellular metabolism and metabolic plasticity. Using lymphocytes collected and immortalized from an index proband who carries a truncating variant in one allele of LARP1, we demonstrated that lower cellular levels of LARP1 protein cause reduced rates of aerobic respiration and glycolysis. As expression of LARP1 increases during neurodevelopment, with higher levels in neurons and astrocytes, we propose that LARP1 haploinsufficiency contributes to ASD or related NDDs through attenuated metabolic activity in the developing fetal brain.

PurposeTo evaluate functional and structural assessments as endpoints for clinical trials for USH2A-related retinal degeneration.MethodsPeople with biallelic disease-causing variants in USH2A, visual acuity ≥ 20/80, and visual field ≥ 10° diameter were enrolled in a 4-year, natural history study. Participants underwent static perimetry, microperimetry, visual acuity, fullfield stimulus testing (FST), and optical coherence tomography annually. Rates of change estimated from mixed-effects linear models and percentages of eyes with changes exceeding the coefficient of repeatability (CoR) or thresholds conforming with U.S. Food and Drug Administration (FDA) guidelines were evaluated.ResultsRates of change were generally more sensitive to change than proportions of eyes exceeding a threshold such as the CoR. Baseline ellipsoid zone area ≥ 3 mm2 was necessary to detect change. Mean sensitivity and volumetric hill of vision measures on static perimetry had similar properties and were the most sensitive to changes of the continuous measures. The highest 4-year proportions of eyes exceeding the CoR were from FST testing (47%) and microperimetry (32%). Specification of loci as functional transition points (FTPs) resulted in 45% (static perimetry) and 46% (microperimetry) at 4 years, meeting FDA guidelines for progression.ConclusionsRate of change of mean sensitivity on static perimetry was a sensitive perimetric continuous measure. Percentages of within-eye change were largest with FST testing and microperimetry. FTPs appear to be particularly sensitive to change. These results affect clinical trial design for USH2A-related retinal degeneration.Translational relevanceAnalyses of natural history data from the Rate of Progression in USH2A-Related Retinal Degeneration (RUSH2A) study can inform eligibility criteria and endpoints for clinical trials.

Rosacea is a chronic inflammatory skin disorder, whose underlying cellular and molecular mechanisms remain obscure. Here, we generate a single-cell atlas of facial skin from female rosacea patients and healthy individuals. Among keratinocytes, a subpopulation characterized by IFNγ-mediated barrier function damage is found to be unique to rosacea lesions. Blocking IFNγ signaling alleviates rosacea-like phenotypes and skin barrier damage in mice. The papulopustular rosacea is featured by expansion of pro-inflammatory fibroblasts, Schwann, endothelial and macrophage/dendritic cells. The frequencies of type 1/17 and skin-resident memory T cells are increased, and vascular mural cells are characterized by activation of inflammatory pathways and impaired muscle contraction function in rosacea. Most importantly, fibroblasts are identified as the leading cell type producing pro-inflammatory and vasodilative signals in rosacea. Depletion of fibroblasts or knockdown of PTGDS, a gene specifically upregulated in fibroblasts, blocks rosacea development in mice. Our study provides a comprehensive understanding of the aberrant alterations of skin-resident cell populations and identifies fibroblasts as a key determinant in rosacea development.

BACKGROUND AND OBJECTIVES: Traumatic brain injury (TBI) is frequently characterized by chronic motor deficits. Therefore, this clinical trial assessed whether intracranial implantation of allogeneic modified mesenchymal stromal (SB623) cells can improve chronic motor deficits after TBI. METHODS: Post hoc analysis of the double-blind, randomized, prospective, surgical sham-controlled, phase 2, STEMTRA clinical trial (June 2016 and March 2019) with 48 weeks of follow-up was conducted. In this international, multicenter clinical trial, eligible participants had moderate-to-severe TBI, were ≥12 months postinjury, and had chronic motor deficits. Participants were randomized in a 1:1:1:1 ratio to stereotactic surgical intracranial implantation of SB623 cells (2.5 × 106, 5.0 × 106, 10 × 106) or surgical sham-controlled procedure. The prespecified primary efficacy end point was significantly greater change from baseline of the Fugl-Meyer Motor Scale (FMMS) score, a measure of motor status, for the SB623 pooled vs control arm at 24 weeks. RESULTS: A total of 211 participants were screened, 148 were excluded, and 63 underwent randomization, of which 61 (97%; mean age, 34 [SD, 12] years; 43 men [70.5%]) completed the trial. Single participants in the SB623 2.5 × 106 and 5.0 × 106 cell dose groups discontinued before surgery. Safety and efficacy (modified intent-to-treat) were assessed in participants who underwent surgery (N = 61; SB623 = 46, controls = 15). The primary efficacy end point (FMMS) was achieved (least squares mean [SE] SB623: +8.3 [1.4]; 95% CI 5.5-11.2 vs control: +2.3 [2.5]; 95% CI -2.7 to 7.3; p = 0.04), with faster improvement of the FMMS score in SB623-treated groups than in controls at 24 weeks and sustained improvement at 48 weeks. At 48 weeks, improvement of function and activities of daily living (ADL) was greater, but not significantly different in SB623-treated groups vs controls. The incidence of adverse events was equivalent in SB623-treated groups and controls. There were no deaths or withdrawals due to adverse events. DISCUSSION: Intraparenchymal implantation of SB623 cells was safe and significantly improved motor status at 24 weeks in participants with chronic motor deficits after TBI, with continued improvement of function and ADL at 48 weeks. Cell therapy can modify chronic neurologic deficits after TBI. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02416492. Submitted to registry: April 15, 2015. First participant enrolled: July 6, 2016. Available at: classic.clinicaltrials.gov/ct2/show/NCT02416492. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that intracranial implantation of allogeneic stem (SB623) cells in adults with motor deficits from chronic TBI improves motor function at 24 weeks.

Identifying pan-tumor biomarkers that predict responses to immune checkpoint inhibitors (ICI) is critically needed. In the AMADEUS clinical trial (NCT03651271), patients with various advanced solid tumors were assessed for changes in intratumoral CD8 percentages and their response to ICI. Patients were grouped based on tumoral CD8 levels: those with CD8

BACKGROUND: 2-Fucosyllactose (2-FL) is an oligosaccharide contained in human milk and possesses prebiotic and anti-inflammatory effects, which may alleviate skeletal muscle atrophy under caloric restriction. This study evaluated the impacts of 12 weeks of 2-FL supplementation in conjunction with exercise (10,000 steps/day, 5 days/week) and energy-reduced (-300 kcals/day) dietary interventions on changes in body composition and health-related biomarkers. METHODS: A total of 41 overweight and sedentary female and male participants (38.0 ± 13 years, 90.1 ± 15 kg, 31.6 ± 6.6 kg/m2, 36.9 ± 7% fat) took part in a randomized, double-blind, and placebo-controlled study. The participants underwent baseline assessments and were then assigned to ingest 3 g/day of a placebo (PLA) or Momstamin 2-F while initiating the exercise and weight-loss program. Follow-up tests were performed after 6 and 12 weeks. Data were analyzed using general linear model statistics with repeated measures and mean changes from baseline values with 95% confidence intervals (CIs). RESULTS: No group × time × sex interaction effects were observed, so group × time effects are reported. Participants in both groups saw comparable reductions in weight. However, those with 2-FL demonstrated a significantly greater reduction in the percentage of body fat and less loss of the fat-free mass. Additionally, there was evidence that 2-FL supplementation promoted more favorable changes in resting fat oxidation, peak aerobic capacity, IL-4, and platelet aggregation, with some minimal effects on the fermentation of short-chain fatty acids and monosaccharides in fecal samples. Moreover, participants perceptions regarding some aspects of the functional capacity and ratings of the quality of life were improved, and the supplementation protocol was well tolerated, although a small, but significant, decrease in BMC was observed. CONCLUSIONS: The results support contentions that dietary supplementation of 2-FL (3 g/d) can promote fat loss and improve exercise- and diet-related markers of health and fitness in overweight sedentary individuals initiating an exercise and weight-loss program. Further research is needed to explore the potential health benefits of 2-FL supplementation in both healthy and elderly individuals (Registered clinical trial #NCT06547801).

BACKGROUND AND AIMS: Despite the inclusion of the Compulsive Sexual Behavior Disorder (CSBD) in the 11th edition of the International Classification of Diseases, emotional and cognitive impairments related to CSBD remains unclear. This study aimed to investigate the behavioral and neuronal effects of emotional interference on cognition among CSBD patients. METHODS: Thirty heterosexual males with CSBD and matched healthy controls (HC) were studied with the Emotional Stroop Task using 5 categories of emotionally arousing words (sex-related, positive, fear-related, negative, neutral) during functional magnetic imaging. RESULTS: At the behavioral level, we found the main effect of the condition: sex-related words evoked a stronger Stroop effect than other conditions. At the neural level, we found a significant group effect. Among CSBD patients processing of sex-related words was related to increased activity in the right putamen, right thalamus, hippocampi, and left pulvinar, when compared to HC. We also found a negative correlation between neuronal activation and time spent on sexual activity during the week preceding study and numerous group differences in brain regions connected to the emotional and motivational processing of sexually explicit material, correlating with CSBD symptoms. CONCLUSIONS: Behavioral results indicate a specific attentional bias toward sex-related stimuli in both groups, while neural data uncovered stronger reactivity to sex-related words in CSBD compared to HC. This reactivity is related to CSBD symptoms and provides evidence for the interference of sex-related stimuli with cognition. Such results are firmly in line with the Incentive Salience Theory and conceptualizing CSBD as a behavioral addiction.

BACKGROUND: Social integration (i.e., reciprocal interactions with peers and community members) is a notable challenge for many homeless-experienced adults with serious mental illness (SMI). In this study, we examine a range of housing services offered to homeless-experienced adults with SMI and identify the impacts of supportive services on participants social integration outcomes, with the goal of improving services in transitional and permanent housing settings for homeless-experienced adults with SMI. METHODS: Through semi-structured interviews with homeless-experienced adults with SMI (n = 30), we examine the impacts of housing and service settings on participants social integration. Participants received services in a variety of housing settings, including transitional housing with congregate/shared living (n = 10), transitional housing with individual quarters (n = 10), and permanent supportive housing (n = 10). RESULTS: Participants expressed caution in developing social relationships, as these could pose barriers to recovery goals (e.g., substance use recovery). For many, social integration was secondary to mental and physical health and/or housing stability goals. Individual quarters gave individuals a place of respite and a sense of control regarding when and with whom they socialized. Meeting recovery goals was strongly related to connecting to and receiving a range of supportive services; interviews suggest that proximity to services was critical for engagement in these resources. CONCLUSIONS: Programs serving homeless experienced adults with SMI should seek to understand how individuals conceptualize social integration, and how social relationships can either support or hinder participants recovery journey.