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Abstract Background Chronic overlapping pain conditions (COPCs), pain-related conditions that frequently occur together, may occur in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and could impact illness severity. This study aimed to identify comorbid COPCs in patients with ME/CFS and evaluate their impact on illness severity. Methods We used data from 923 participants in the Multi-Site Clinical Assessment of ME/CFS study, conducted in seven U.S. specialty clinics between 2012 and 2020, who completed the baseline assessment (595 ME/CFS and 328 healthy controls (HC)). COPCs included chronic low back pain (cLBP), chronic migraine/headache (cMHA), fibromyalgia (FM), interstitial cystitis/irritable bladder (IC/IB), irritable bowel syndrome (IBS), temporomandibular disorder (TMD). Illness severity was assessed through questionnaires measuring symptoms and functioning. Multivariate analysis of variance and analysis of covariance models were used for analyses. Log-binomial regression analyses were used to compute prevalence of COPCs and prevalence ratios (PR) between groups with 95% confidence intervals. Both unadjusted and adjusted results with age and sex are presented. Results 76% of participants with ME/CFS had at least one COPCs compared to 17.4% of HC. Among ME/CFS participants, cMHA was most prevalent (48.1%), followed by FM (45.0%), cLBP (33.1%), and IBS (31.6%). All individual COPCs, except TMD, were significantly more frequent in females than males. The unadjusted PR (ME/CFS compared to HC) was highest for FM [147.74 (95% confidence interval (CI) = 20.83-1047.75], followed by cLBP [39.45 (12.73-122.27)], and IC/IB [13.78 (1.88-101.24)]. The significance and order did not change after age and sex adjustment. The COPC comorbidities of cLBP and FM each had a significant impact on most health measures, particularly in pain attributes (Cohen’s d effect size 0.8 or larger). While the impact of COPC comorbidities on non-pain attributes and quality of life measures was less pronounced than that on pain, statistically significant differences between ME/CFS participants with and without COPCs were still evident. Conclusions More than 75% of ME/CFS participants had one or more COPCs. Multiple COPCs further exacerbated illness severity, especially among females with ME/CFS. Assessment and management of COPCs may help improve the health and quality of life for patients with ME/CFS.

Abstract Microbial communities can self-assemble into highly diverse states with predictable statistical properties. However, these initial states can be disrupted by rapid evolution of the resident strains. When a new mutation arises, it competes for resources with its parent strain and with the other species in the community. This interplay between ecology and evolution is difficult to capture with existing community assembly theory. Here, we introduce a mathematical framework for predicting the first steps of evolution in large randomly assembled communities that compete for substitutable resources. We show how the fitness effects of new mutations and the probability that they coexist with their parent depends on the size of the community, the saturation of its niches, and the metabolic overlap between its members. We find that successful mutations are often able to coexist with their parent strains, even in saturated communities with low niche availability. At the same time, these invading mutants often cause extinctions of metabolically distant species. Our results suggest that even small amounts of evolution can produce distinct genetic signatures in natural microbial communities.

Abstract The use of compounds produced by hosts or symbionts for defence against antagonists has been identified in many organisms, including in fungus-farming termites (Macrotermitinae). The obligate mutualistic fungus Termitomyces plays a pivotal role in plant biomass decomposition and as the primary food source for these termites. Despite the isolation of various specialized metabolites from different Termitomyces species, our grasp of their natural product repertoire remains incomplete. To address this knowledge gap, we conducted a comprehensive analysis of 39 Termitomyces genomes, representing 21 species associated with members of five termite host genera. We identified 754 biosynthetic gene clusters (BGCs) coding for specialized metabolites and categorized 660 BGCs into 61 biosynthetic gene cluster families (GCFs) spanning five compound classes. Seven GCFs were shared by all 21 Termitomyces species and 21 GCFs were present in all genomes of subsets of species. Evolutionary constraint analyses on the 25 most abundant GCFs revealed distinctive evolutionary histories, signifying that millions of years of termite-fungus symbiosis have influenced diverse biosynthetic pathways. This study unveils a wealth of non-random and largely undiscovered chemical potential within Termitomyces and contributes to our understanding of the intricate evolutionary trajectories of biosynthetic gene clusters in the context of long-standing symbiosis.

Aim: Prostate biopsy can be prone to complications and thus should be avoided when unnecessary. Although the combination of magnetic resonance imaging (MRI), the prostate health index (PHI), and PHI density (PHID) has been shown to improve detection of clinically significant prostate cancer (csPCa), there is limited information available assessing its clinical utility. We sought to determine whether using PHID could enhance the detection of PCa on MRI ultrasound fusion-targeted biopsy (MRF-TB) compared to other biomarker cutoffs. Methods: Between June 2015 and December 2020, 302 men obtained PHI testing before MRF-TB at a single institution. We used descriptive statistics, multivariable logistic regression, and receiver operating characteristic curves to determine the predictive accuracy of PHID and PHI to detect ≥ Gleason grade group (GGG) 2 PCa and identify cutoff values. Results: Any cancer grade was identified in 75.5% of patients and ≥ GGG2 PCa was identified in 45% of patients. The median PHID was 1.05 [interquartile range (IQR) 0.59–1.64]. A PHID cutoff of 0.91 had a higher discriminatory ability to predict ≥ GGG2 PCa compared to PHI > 27, PHI > 36, and prostate specific-antigen (PSA) density > 0.15 (AUC: 0.707 vs. 0.549 vs. 0.620 vs. 0.601), particularly in men with Prostate Imaging Reporting and Data System (PI-RADS) 1–2 lesions on MRI (AUC: 0.817 vs. 0.563 vs. 0.621 vs. 0.678). At this cutoff, 35.0% of all the original biopsies could be safely avoided (PHID < 0.91 and no ≥ GGG2 PCa) and csPCa would be missed in 9.67% of patients who would have been biopsied. In patients with PI-RADS 1–2 lesions using a PHID cutoff of 0.91, 56.8% of biopsies could be safely avoided while missing 0 csPCa. Conclusions: These findings suggest that a PHID cutoff of 0.91 improves the selection of patients with elevated prostate-specific antigen who are referred for prostate biopsy, and potentially in patients with PI-RADS 1–2 lesions.

Abstract Metabolic comorbidities, such as obesity and diabetes, are associated with subclinical alterations in both cardiac structure/function and natriuretic peptides prior to the onset of heart failure (HF). Despite this, the exact metabolic pathways of cardiac dysfunction which precede HF are not well-defined. Among older individuals without HF in the Multi-Ethnic Study of Atherosclerosis (MESA), we evaluated the associations of 47 circulating metabolites measured by 1H-NMR with echocardiographic measures of cardiac structure and function. We then evaluated associations of significant metabolites with circulating N-terminal pro-B-type natriuretic peptide (NT-proBNP). In a separate cohort, we evaluated differences between top metabolites in patients with HF with preserved ejection fraction (HFpEF) and comorbidity-matched controls. Genetic variants associated with top metabolites (mQTLs) were then related to echocardiographic measures and NT-proBNP. Among 3440 individuals with metabolic and echocardiographic data in MESA (62 ± 10 years, 52% female, 38% White), 10 metabolites broadly reflective of glucose and amino acid metabolism were associated with at least 1 measure of cardiac structure or function. Of these 10 metabolites, 4 (myo-inositol, glucose, dimethylsulfone, carnitine) were associated with higher NT-proBNP and 2 (d-mannose, acetone) were associated with lower NT-proBNP. In a separate cohort, patients with HFpEF had higher circulating myo-inositol levels compared with comorbidity-matched controls. Genetic analyses revealed that 1 of 6 known myo-inositol mQTLs conferred risk of higher NT-proBNP. In conclusion, metabolomic profiling identifies several novel metabolites associated with cardiac dysfunction in a cohort at high risk for HF, revealing pathways potentially relevant to future HF risk.

Abstract Background Higher cruciferous vegetable intake is associated with lower cardiovascular disease risk in observational studies. The pathways involved remain uncertain. We aimed to determine whether cruciferous vegetable intake (active) lowers 24-h brachial systolic blood pressure (SBP; primary outcome) compared to root and squash vegetables (control) in Australian adults with mildly elevated BP (SBP 120–160 mmHg inclusive). Methods In this randomized, controlled, crossover trial, participants completed two 2-week dietary interventions separated by a 2-week washout. Cruciferous vegetables were compared to root and squash vegetables (~ 300 g/day) consumed with lunch and dinner meals. Participants were blinded to which interventions were the active and control. Adherence was assessed using food diaries and biomarkers (S-methyl cysteine sulfoxide (SMCSO, active) and carotenoids (control)). Twenty-four-hour brachial ambulatory SBP and secondary outcomes were assessed pre- and post each intervention. Differences were tested using linear mixed effects regression. Results Eighteen participants were recruited (median (IQR) age: 68 (66–70); female: n = 16/18; mean ± SD clinic SBP: 135.9 ± 10.0 mmHg). For both interventions, 72% participants had 100% adherence (IQR: 96.4–100%). SMCSO and carotenoids were significantly different between interventions (mean difference active vs. control SMCSO: 22.93 mg/mL, 95%CI 15.62, 30.23, P

Abstract Background Emerging randomized data, mostly from phase II trials, have suggested that patients with oligometastatic cancers may benefit from ablative treatments such as stereotactic ablative radiotherapy (SABR). However, phase III data testing this paradigm are lacking, and many studies have examined SABR in the setting of metachronous oligometastatic disease. The goal of the SABR-SYNC trial is to assess the effect of SABR in patients with oligometastatic cancers and a synchronous primary tumor. Methods One hundred and eighty patients will be randomized in a 1:2 ratio between standard of care (SOC) palliative-intent treatments vs. SOC + ablative therapy (SABR preferred) to all sites of known disease. Randomization will be stratified based on histology and number of metastases at enrollment. SABR may be delivered in 1-, 3- and 5-fraction regimens, with recommended doses of 20 Gy, 30 Gy, and 35 Gy, respectively. Non-SABR local modalities (e.g. surgery, thermal ablation, conventional radiation) may be used for treatment of the primary or metastases at the discretion of the treating physicians, if those modalities are clinically preferred. The primary endpoint is overall survival, and secondary endpoints include progression-free survival, time to development of new metastatic lesions, time to initiation of next systemic therapy, quality of life, and toxicity. Translational endpoints include assessment of circulating tumor DNA and immunological predictors of outcomes. Discussion SABR-SYNC will provide phase III data to assess the impact of SABR on overall survival in a population of patients with synchronous oligometastases. The translational component will attempt to identify novel prognostic and predictive biomarkers to aid in clinical decision making. Trial registration Clinicaltrials.gov NCT05717166 (registration date: Feb. 8, 2023).

Abstract Racism is a pervasive threat to health with differential impact based on race and ethnicity. Considering the continued perpetration and visibility of racism online and in the news, vicarious racism, or “secondhand” racism when hearing about or witnessing racism being committed against members of one’s ethnic or racial group, is a particularly urgent threat in the context of such disparities and their subsequent health consequences. The current study examines if frequency of exposure to vicarious racism and the emotional impact of those experiences are linked to psychoactive substance use, and explores the role of ethnic identity in moderating these relationships. In a cross-sectional survey, 504 adult participants aged 18–78 (M age = 30.15, SD = 11.52, 52.6% female) identifying as Black/African American or Latine reported on their experiences with vicarious racism and alcohol, marijuana, and tobacco use over the past 30 days. Logistic regression was utilized to test hypotheses. Primary findings indicate that greater emotional impact of vicarious racism was associated with a 50% increase in odds of alcohol consumption and that ethnic identity moderated the association between vicarious racism and marijuana use. Greater emotional impact of vicarious racism was related to more marijuana use for those lower on ethnic identity, whereas there was no association for those higher on ethnic identity. Vicarious racism was not related to tobacco use. Results suggest that ethnic identity might be protective in the association of vicarious racism on substance use. Further research on this topic is needed as vicarious racism becomes an increasingly common experience among marginalized populations.

Abstract Investigating the gut microbiome and metabolome frequently requires faecal samples, which can be difficult to obtain. Previous studies have shown that rectal swabs are comparable to faecal samples for analysing gut microbiota composition and key metabolites. In this study, 3D printed rectal swabs were compared with conventional flocked swabs and faecal samples, due to the potential advantages 3D printing as a technique offers for swab production and development. 16S rRNA gene sequencing, qPCR and metabolite profiling (using 1H-NMR spectroscopy) were performed on swab and faecal samples from healthy participants. Faecal calprotectin and total protein analysis were performed on samples from inflammatory bowel disease (IBD) patients. There were no significant differences between both swab types and faecal samples when assessing key measures of alpha and beta diversity, and differences in the abundance of major phyla. There was a strong correlation between both swab types and faecal samples for all combined metabolites detected by NMR. In IBD patients, there was no significant difference in faecal calprotectin and total protein levels between both swab types and faecal samples. These data lead us to conclude that 3D printed swabs are equivalent to flocked swabs for the analysis of the gut microbiome, metabolome and inflammation.

Abstract One Health is a recognition of the shared environment inhabited by humans, animals and plants, and the impact of their interactions on the health of all organisms. The COVID-19 pandemic highlighted the need for a framework of pathogen surveillance in a tractable One Health paradigm to allow timely detection and response to threats to human and animal health. We present case studies centered around the recent global approach to tackle antimicrobial resistance and the current interest in wastewater testing, with the concept of “one sample many analyses” to be further explored as the most appropriate means of initiating this endeavor.

Abstract This study on severe malarial anemia (SMA: Hb < 6.0 g/dL), a leading global cause of childhood morbidity and mortality, compares the entire expressed whole blood host transcriptome between Kenyan children (3-48 mos.) with non-SMA (Hb ≥ 6.0 g/dL, n = 39) and SMA (n = 18). Differential expression analyses reveal 1403 up-regulated and 279 down-regulated transcripts in SMA, signifying impairments in host inflammasome activation, cell death, and innate immune and cellular stress responses. Immune cell profiling shows decreased memory responses, antigen presentation, and immediate pathogen clearance, suggesting an immature/improperly regulated immune response in SMA. Module repertoire analysis of blood-specific gene signatures identifies up-regulation of erythroid genes, enhanced neutrophil activation, and impaired inflammatory responses in SMA. Enrichment analyses converge on disruptions in cellular homeostasis and regulatory pathways for the ubiquitin-proteasome system, autophagy, and heme metabolism. Pathway analyses highlight activation in response to hypoxic conditions [Hypoxia Inducible Factor (HIF)−1 target and Reactive Oxygen Species (ROS) signaling] as a central theme in SMA. These signaling pathways are also top-ranking in protein abundance measures and a Ugandan SMA cohort with available transcriptomic data. Targeted RNA-Seq validation shows strong concordance with our entire expressed transcriptome data. These findings identify key molecular themes in SMA pathogenesis, offering potential targets for new malaria therapies.

Abstract Background Radiotherapy is a core treatment modality for oropharyngeal cancer (OPC), where the primary gross tumor volume (GTVp) is manually segmented with high interobserver variability. This calls for reliable and trustworthy automated tools in clinician workflow. Therefore, accurate uncertainty quantification and its downstream utilization is critical. Methods Here we propose uncertainty-aware deep learning for OPC GTVp segmentation, and illustrate the utility of uncertainty in multiple applications. We examine two Bayesian deep learning (BDL) models and eight uncertainty measures, and utilize a large multi-institute dataset of 292 PET/CT scans to systematically analyze our approach. Results We show that our uncertainty-based approach accurately predicts the quality of the deep learning segmentation in 86.6% of cases, identifies low performance cases for semi-automated correction, and visualizes regions of the scans where the segmentations likely fail. Conclusions Our BDL-based analysis provides a first-step towards more widespread implementation of uncertainty quantification in OPC GTVp segmentation.

ABSTRACT Background The cumulative, health system‐wide survival benefit of immune checkpoint inhibitors (ICIs) is unclear, particularly among real‐world patients with limited life expectancies and among subgroups poorly represented on clinical trials. We sought to determine the health system‐wide survival impact of ICIs. Methods We identified all patients receiving PD‐1/PD‐L1 or CTLA‐4 inhibitors from 2010 to 2023 in the national Veterans Health Administration (VHA) system (ICI cohort) and all patients who received non‐ICI systemic therapy in the years before ICI approval (historical control). ICI and historical control cohorts were matched on multiple cancer‐related prognostic factors, comorbidities, and demographics. The effect of ICI on overall survival was quantified with Cox regression incorporating matching weights. Cumulative life‐years gained system‐wide were calculated from the difference in adjusted 5‐year restricted mean survival times. Results There were 27,322 patients in the ICI cohort and 69,801 patients in the historical control cohort. Among ICI patients, the most common cancer types were NSCLC (46%) and melanoma (10%). ICI demonstrated a large OS benefit in most cancer types with heterogeneity across cancer types (NSCLC: adjusted HR [aHR] 0.56, 95% confidence interval [CI] 0.54–0.58, p

IntroductionPatients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) experience cognitive problems with attention, information processing speed, working memory, learning efficiency, and executive function. Commonly, patients report worsening of cognitive symptoms over time after physical and/or cognitive challenges. To determine, monitor, and manage longitudinal decrements in cognitive function after such exposures, it is important to be able to screen for cognitive dysfunction and changes over time in clinic and also remotely at home. The primary objectives of this paper were: (1) to determine whether a brief computerized cognitive screening battery will detect differences in cognitive function between ME/CFS and Healthy Controls (HC), (2) to monitor the impact of a full-day study visit on cognitive function over time, and (3) to evaluate the impact of exercise testing on cognitive dysfunction.MethodsThis cognitive sub-study was conducted between 2013 and 2019 across seven U.S. ME/CFS clinics as part of the Multi-Site Clinical Assessment of ME/CFS (MCAM) study. The analysis included 426 participants (261 ME/CFS and 165 HC), who completed cognitive assessments including a computerized CogState Brief Screening Battery (CBSB) administered across five timepoints (T0-T4) at the start of and following a full day in-clinic visit that included exercise testing for a subset of participants (182 ME/CFS and 160 HC). Exercise testing consisted of ramped cycle ergometry to volitional exhaustion. The primary outcomes are performance accuracy and latency (performance speed) on the computerized CBSB administered online in clinic (T0 and T1) and at home (T2-T4).ResultsNo difference was found in performance accuracy between ME/CFS and HCs whereas information processing speed was significantly slower for ME/CFS at most timepoints with Cohen’s d effect sizes ranging from 0.3–0.5 (p < 0.01). The cognitive decline over time on all CBSB tasks was similar for patients with ME/CFS independent of whether exercise testing was included in the clinic visit.ConclusionThe challenges of a clinic visit (including cognitive testing) can lead to further cognitive deficits. A single short session of intense exercise does not further reduce speed of performance on any CBSB tasks.

Summary: Background: Patients with small cell lung cancer (SCLC) have historically been characterised by poor overall survival (OS) and high risk for brain metastasis (BM), but large-scale real-world evidence on clinical presentation and treatment in this population is lacking. Our aim was to describe the clinical characteristics and outcomes of patients with SCLC and BM in Ontario, Canada. Methods: This population-based, retrospective cohort study included all patients in Ontario, Canada, who were diagnosed with SCLC between April 1, 2010, and March 31, 2018. Data were analysed between June 2, 2022, and December 20, 2023. Patients with second cancer diagnosis were excluded. Patients were identified and data retrieved from the Institute for Clinical Evaluative Sciences (ICES) databases. Kaplan–Meier and multivariable Cox regression analyses were performed to compare OS between patient cohorts stratified by disease stage, BM diagnosis, and intracranial treatment modality. Propensity score-matching based on age, disease stage, time to BM, and receipt of chemotherapy was performed to compare OS between intracranial treatment modalities. Findings: 8705 patients were included (male: 4433, female: 4272). Median age at diagnosis was 68 years (interquartile range, IQR, 61–75). Median OS of all patients was 7.46 months (95% confidence interval, CI, 7.23–7.69). 32% (n = 2686) of patients developed BM (synchronous, 43.7%; asynchronous, 56.3%) with median OS of 9.76 months (95% CI, 9.36–10.22). 102 (4%), 1654 (62%), and 930 (35%) patients received stereotactic radiosurgery (SRS), whole brain radiation therapy (WBRT), or no treatment, respectively, for their BM in the first-line setting or after prophylactic cranial irradiation (PCI). In propensity score-matched analyses, OS from time of BM diagnosis was non-inferior between SRS- and WBRT-treated cohorts among patients who did not receive PCI (hazard ratio, HR, 0.68, 95% CI, 0.44–1.06, p = 0.091, n = 86) and in favour of SRS for those who received PCI prior to BM development (HR, 0.47, 95% CI, 0.31–0.72, p = 0.0042, n = 112). Interpretation: OS for patients with SCLC remains poor, and many patients present with BM. With careful selection, patients with SCLC and BM may benefit from SRS treatment. Future research should incorporate information on burden of intracranial disease and novel immunotherapies. Funding: None.

IntroductionPregnant and breastfeeding women at substantial risk for HIV infection in sub-Saharan Africa can benefit from biomedical interventions such as pre-exposure prophylaxis (PrEP). We estimated the benefit that pregnant and breastfeeding women may derive from PrEP service delivery in order to guide PrEP roll-out in the target population in Zambia.MethodsBetween September and December 2021, we conducted a discrete choice experiment (DCE) among a convenient sample of 389 pregnant and breastfeeding women not living with HIV in Lusaka, Zambia. Women aged 18 years or older, with a documented negative HIV result in their antenatal card responded to a structured questionnaire containing 12 choice sets on service delivery attributes of PrEP: waiting time at the facility, travel time to the facility dispensing PrEP, location for PrEP pick-up, health care provider attitude and PrEP supply at each refill. Mixed logit regression analysis was used to determine the participant's willingness to trade off one attribute of PrEP for the other at a 5% significance level. Willingness to wait (WTW) was used to determine the relative utility derived from each attribute against waiting time.ResultsWaiting time at the facility, travel time to the facility, health care provider attitude and amount of PrEP supply at each refill were important attributes of PrEP service delivery (all p

Objective: Intermittent Preventive Treatment of schoolchildren (IPTsc) is recommended by WHO as a strategy to protect against malaria; to explore whether IPTsc with dihydroartemisinin-piperaquine (DP) or artesunate-amodiaquine (ASAQ) cause a selection of molecular markers in Plasmodium falciparum genes associated with resistance in children in seven schools in Tanga region, Tanzania. Methods: SNPs in P. falciparum genes Pfmdr1, Pfexo, Pfkelch13, and Pfcrt and copy number variations in Pfplasmepsin-2 and Pfmdr1 were assessed in samples collected at 12 months (visit 4, n=74) and 20 months (visit 6, n=364) after initiation of IPTsc and compared with the baseline prevalence (n=379). Results: The prevalence of Pfmdr1 N86 and Pfexo 415G was >99% and 0%, respectively without any temporal differences observed. The prevalence of Pfmdr1 184F changed significantly from baseline (52.2%) to visit 6 (64.6%) (χ2=6.11, P=0.013), but no differences were observed between the treatment arms (χ2=0.05, P=0.98). Finally, only minor differences in the amplification of Pfmdr1 were observed; from 10.2% at baseline to 16.7% at visit 6 (χ2=0.98, P=0.32). Conclusions: The IPTsc strategy does not seem to pose a risk for the selection of markers associated with DP or ASAQ resistance. Continuously and timely surveillance of markers of antimalarial drug resistance is recommended.

We systematically reviewed the literature on the effects of the coronavirus disease 2019 (COVID-19) pandemic on the progression, prevalence, and incidence of myopia. A comprehensive literature search was performed on PubMed, Cochrane Central Register of Controlled Trials, and Scopus databases. Studies included in the review assessed myopia progression, prevalence, and/or incidence as the primary outcome. Of 523 articles yielded in the initial search, 23 studies (6 cross-sectional and 17 cohort) were eligible for inclusion. Sixteen of these were conducted in China and one each in Hong Kong, Turkey, Spain, Israel, India, Korea, and Tibet. Quality appraisals were conducted with the Joanna Briggs Institute Critical Appraisal Checklists. Of the included studies, a large majority reported a greater myopic shift and increase in myopia prevalence during the COVID-19 pandemic compared to the pre-COVID-19 years. All three studies on myopia incidence showed increased incidence during the COVID-19 pandemic. Myopia progression accelerated during the COVID-19 pandemic, even in individuals using low-concentration atropine eye drops in two studies but not in those using orthokeratology treatment in one study. Overall, the studies found that the COVID-19 pandemic and its associated home confinement measures generally increased myopia progression, prevalence, and incidence, even in individuals using low-concentration atropine eye drops.

Abstract Aim To examine the associations of a diet high in flavonoid-rich foods, as reflected by a “Flavodiet Score” (FDS), the major individual food contributors to flavonoid intake, and flavonoid subclasses with type 2 diabetes (T2D) risk in the UK Biobank cohort. Materials and methods Flavonoid intakes were estimated from ≥2 dietary assessments among 113,097 study participants [age at enrolment: 56 ± 8 years; 57% female] using the U.S Department of Agriculture (USDA) databases. Multivariable Cox proportional hazards models were used to investigate associations between dietary exposures and T2D. Results During 12 years of follow-up, 2628 incident cases of T2D were identified. A higher FDS (compared to lower [Q4 vs. Q1]), characterised by an average of 6 servings of flavonoid-rich foods per day, was associated with a 26% lower T2D risk [HR: 0.74 (95% CI: 0.66–0.84), ptrend =

Abstract Cancer risk is associated with the widely debated measure body mass index (BMI). Fat mass and fat-free mass measurements from bioelectrical impedance may further clarify this association. The UK Biobank is a rare resource in which bioelectrical impedance and BMI data was collected on ~ 500,000 individuals. Using this dataset, a comprehensive analysis using regression, principal component and genome-wide genetic association, provided multiple levels of evidence that increasing whole body fat (WBFM) and fat-free mass (WBFFM) are both associated with increased post-menopausal breast cancer risk, and colorectal cancer risk in men. WBFM was inversely associated with prostate cancer. We also identified rs615029[T] and rs1485995[G] as associated in independent analyses with both PMBC (p = 1.56E–17 and 1.78E–11) and WBFFM (p = 2.88E–08 and 8.24E–12), highlighting splice variants of the intriguing long non-coding RNA CUPID1 (LINC01488) as a potential link between PMBC risk and fat-free mass.

Abstract The Malagasy Summer Monsoon is an important part of the larger Indian Ocean and tropical monsoon region. As the effects of global warming play out, changes to precipitation in Madagascar will have important ramifications for the Malagasy people. To help understand how precipitation responds to climate changes we present a long-term Holocene speleothem record from Anjohibe, part of the Andranoboka cave system in northwestern Madagascar. To date, it is the most complete Holocene record from this region and sheds light on the nature of millennial and centennial precipitation changes in this region. We find that over the Holocene, precipitation in northwestern Madagascar is actually in phase with the Northern Hemisphere Asian monsoon on multi-millennial scales, but that during some shorter centennial-scale events such as the 8.2 ka event, Anjohibe exhibits an antiphase precipitation signal to the Northern Hemisphere. The ultimate driver of precipitation changes across the Holocene does not appear to be the meridional migration of the monsoon. Instead, zonal sea surface temperature gradients in the Indian Ocean seem to play a primary role in precipitation changes in northwestern Madagascar.

Abstract Trial‐based economic value of prevention programs for diabetes is inexplicit. We aimed to review the cost‐effectiveness of nonpharmacological interventions to prevent type‐2 diabetes mellitus (T2DM) for high‐risk people. Six electronic databases were searched up to March 2022. Studies assessing both the cost and health outcomes of nonpharmacological interventions for people at high‐risk of T2DM were included. The quality of the study was assessed by the Consolidated Health Economic Evaluation Reporting Standards 2022 checklist. The primary outcome for synthesis was incremental cost‐effectiveness ratios (ICER) for quality‐adjusted life years (QALYs), and costs were standardized in 2022 US dollars. Narrative synthesis was performed, considering different types and delivery methods of interventions. Sixteen studies included five based on the US diabetes prevention program (DPP), six on non‐DPP‐based lifestyle interventions, four on health education, and one on screening plus lifestyle intervention. Compared with usual care, lifestyle interventions showed higher potential of cost‐effectiveness than educational interventions. Among lifestyle interventions, DPP‐based programs were less cost‐effective (median of ICERs: $27,077/QALY) than non‐DPP‐based programs (median of ICERs: $1395/QALY) from healthcare perspectives, but with larger decreases in diabetes incidence. Besides, the cost‐effectiveness of interventions was more possibly realized through the combination of different delivery methods. Different interventions to prevent T2DM in high‐risk populations are both cost‐effective and feasible in various settings. Nevertheless, economic evidence from low‐ and middle‐income countries is still lacking, and interventions delivered by trained laypersons and combined with peer support sessions or mobile technologies could be potentially a cost‐effective solution in such settings with limited resources.

Introduction: SCLC has traditionally been considered to arise from toxic exposure factors, such as smoking. Recent evidence has revealed that germline mutations may also affect the development of SCLC; however, these alterations remain understudied. We sought to identify novel germline mutations in SCLC including germline copy number variations (CNVs) in our cohort of patients. Methods: We designed a custom hybrid-capture gene panel to evaluate germline alterations in 192 cancer-predisposition and frequently mutated genes in SCLC. We applied this panel to germline analysis of a treatment-naive cohort of 67 patients with SCLC at our institution. Subsequently, we annotated the variants using the American College of Medical Genetics criteria and further classified variants of uncertain significance using a set of in silico tools, including DeepMind AlphaMissense, MutationTaster, SIFT, and Polyphen2. Results: We identified American College of Medical Genetics pathogenic or likely pathogenic alterations in seven of 67 patients. Five (71%) were novel alterations (BCORL1, FANCC, ATR, and BBC3) and a novel CNV (SLFN11) with two (29%) previously described mutations (CHEK1 and BRIP1). We also identified 191 variants of uncertain significance in 60 of 67 patients, of which, depending on the in silico tool, 5% to 14% were predicted to be pathogenic. Patients with SCLC with the seven pathogenic alterations were observed to have a numerically longer overall survival (hazard ratio = 0.50) and progression-free survival (hazard ratio = 0.45) though not statistically significant compared with the remaining cohort. Conclusions: Our study identifies novel germline alterations, including a CNV, and provides additional evidence that germline factors could be important contributing factors to the development of SCLC.

Faecal/intestinal microbiota transplant (FMT/IMT) is an efficacious treatment option for recurrent Clostridioides difficile infection, which has prompted substantial interest in FMT’s potential role in the management of a much broader range of diseases associated with the gut microbiome. Despite its promise, the success rates of FMT in these other settings have been variable. This review critically evaluates the current evidence on the impact of clinical, biological, and procedural factors upon the therapeutic efficacy of FMT, and identifies areas that remain nebulous. Due to some of these factors, the optimal therapeutic approach remains unclear; for example, the preferred timing of FMT administration in a heavily antibiotic-exposed hematopoietic cell transplant recipient is not standardized, with arguments that can be made in alternate directions. We explore how these factors may impact upon more informed selection of donors, potential matching of donors to recipients, and aspects of clinical care of FMT recipients. This includes consideration of how gut microbiome composition and functionality may strategically inform donor selection criteria. Furthermore, we review how the most productive advances within the FMT space are those where clinical and translational outcomes are assessed together, and where this model has been used productively in recent years to better understand the contribution of the gut microbiome to human disease, and start the process toward development of more targeted microbiome therapeutics.

**Background:** The use of androgen receptor signaling inhibitors, including apalutamide, in combination with androgen deprivation therapy is recommended for the treatment of metastatic castration-sensitive prostate cancer (mCSPC) and non-metastatic castration-resistant prostate cancer (nmCRPC). **Objective:** To describe real-world treatment patterns and clinical outcomes among patients with mCSPC or nmCRPC who initiated apalutamide in the United States. **Methods:** A retrospective cohort study of patients with mCSPC or nmCRPC who initiated apalutamide was conducted using electronic medical record data from US community-based urology practices (Feb. 1, 2017–April 1, 2022). Persistence with apalutamide was reported at 6-, 12-, and 18-months post treatment initiation. Clinical outcomes described up to 24 months after apalutamide initiation using Kaplan-Meier analyses included progression to castration resistance, castration resistance-free survival (CRFS), and metastasis-free survival (MFS). Outcomes were reported separately based on mCSPC or nmCRPC status and race (ie, Black or non-Black). **Results:** This study included 589 patients with mCSPC (mean age, 75.9 years) and 406 patients with nmCRPC (mean age, 78.8 years). Using a treatment gap of >90 days, persistence with apalutamide at 12 months remained high for both the mCSPC (94.9%) and nmCRPC (92.7%) cohorts, and results were descriptively similar among Black and non-Black patients, and when a treatment gap of >60 days was considered. In patients with mCSPC, overall progression to castration resistance rates at 12 and 24 months were 20.9% and 33.5%, and overall CRFS rates were 76.2% and 62.0%, respectively. In patients with nmCRPC, overall MFS rates at 12 and 24 months were 89.7% and 75.4%, respectively. Rates of these clinical outcomes were descriptively similar between Black and non-Black patients. **Discussion:** While clinical trials have demonstrated the efficacy and safety of apalutamide, there is limited real-world data describing treatment persistence and clinical outcomes among patients with mCSPC and nmCRPC who initiated apalutamide. **Conclusions:** In this real-world study of patients with mCSPC or nmCRPC initiated on apalutamide, treatment persistence was high and apalutamide demonstrated robust real-world effectiveness with respect to progression to castration resistance, CRFS, and MFS, overall and among Black and non-Black patients.

ABSTRACT Certain members of the family Sulfolobaceae represent the only archaea known to oxidize elemental sulfur, and their evolutionary history provides a framework to understand the development of chemolithotrophic growth by sulfur oxidation. Here, we evaluate the sulfur oxidation phenotype of Sulfolobaceae species and leverage comparative genomic and transcriptomic analysis to identify the key genes linked to sulfur oxidation. Metabolic engineering of the obligate heterotroph Sulfolobus acidocaldarius revealed that the known cytoplasmic components of sulfur oxidation alone are not sufficient to drive prolific sulfur oxidation. Imaging analysis showed that Sulfolobaceae species maintain proximity to the sulfur surface but do not necessarily contact the substrate directly. This indicates that a soluble form of sulfur must be transported to initiate cytoplasmic sulfur oxidation. Conservation patterns and transcriptomic response implicate an extracellular tetrathionate hydrolase and putative thiosulfate transporter in a newly proposed mechanism of sulfur acquisition in the Sulfolobaceae.IMPORTANCESulfur is one of the most abundant elements on earth (2.9% by mass), so it makes sense that the earliest biology found a way to use sulfur to create and sustain life. However, beyond evolutionary significance, sulfur and the molecules it comprises have important technological significance, not only in chemicals such as sulfuric acid and in pyritic ores containing critical metals but also as a waste product from oil and gas production. The thermoacidophilic Sulfolobaceae are unique among the archaea as sulfur oxidizers. The trajectory for how sulfur biooxidation arose and evolved can be traced using experimental and bioinformatic analyses of the available genomic data set. Such analysis can also inform the process by which extracellular sulfur is acquired and transported by thermoacidophilic archaea, a phenomenon that is critical to these microorganisms but has yet to be elucidated.

Purpose: 18F-Flotufolastat (18F-rhPSMA-7.3) is a newly approved prostate-specific membrane antigen targeting radiopharmaceutical for diagnostic imaging of prostate cancer (PCa). SPOTLIGHT (National Clinical Trials 04186845) evaluated 18F-flotufolastat in men with suspected PCa recurrence. Here, we present results of predefined exploratory endpoints from SPOTLIGHT to evaluate the impact of clinical factors on 18F-flotufolastat detection rates (DR). Methods and Materials: The impact of baseline prostate-specific antigen (PSA), PSA doubling time (PSAdt), and International Society of Urologic Pathology Grade Group (GG) on 18F-flotufolastat DR was evaluated among all SPOTLIGHT patients with an evaluable scan, with DR stratified according to the patients’ prior treatment (radical prostatectomy ± radiation therapy [RP] or radiation therapy only [RT]). The patients underwent positron emission tomography 50 to 70 minutes after receiving 18F-flotufolastat (296 MBq IV), and scans were read by 3 blinded central readers, with the majority read representing agreement between ≥2 readers. Results: In total, 389 men (median PSA: 1.10 ng/mL) were evaluable. By majority read, 18F-flotufolastat identified distant lesions in 39% and 43% of patients treated with prior RP or RT, respectively. The overall DR broadly increased with increasing PSA (

Background and purpose: Lung cancer is a leading cause of cancer-related mortality, and stereotactic body radiotherapy (SBRT) has become a standard treatment for early-stage lung cancer. However, the heterogeneous response to radiation at the tumor level poses challenges. Currently, standardized dosage regimens lack adaptation based on individual patient or tumor characteristics. Thus, we explore the potential of delta radiomics from on-treatment magnetic resonance (MR) imaging to track radiation dose response, inform personalized radiotherapy dosing, and predict outcomes. Materials and methods: A retrospective study of 47 MR-guided lung SBRT treatments for 39 patients was conducted. Radiomic features were extracted using Pyradiomics, and stability was evaluated temporally and spatially. Delta radiomics were correlated with radiation dose delivery and assessed for associations with tumor control and survival with Cox regressions. Results: Among 107 features, 49 demonstrated temporal stability, and 57 showed spatial stability. Fifteen stable and non-collinear features were analyzed. Median Skewness and surface to volume ratio decreased with radiation dose fraction delivery, while coarseness and 90th percentile values increased. Skewness had the largest relative median absolute changes (22 %–45 %) per fraction from baseline and was associated with locoregional failure (p = 0.012) by analysis of covariance. Skewness, Elongation, and Flatness were significantly associated with local recurrence-free survival, while tumor diameter and volume were not. Conclusions: Our study establishes the feasibility and stability of delta radiomics analysis for MR-guided lung SBRT. Findings suggest that MR delta radiomics can capture short-term radiographic manifestations of the intra-tumoral radiation effect.

Orientation: The changing demands employees experience because of the turbulent and competitive world of work has increased their workload, necessitating a focus on their well-being to ensure their contribution to the effectiveness of organisations. Research purpose: The purpose of this study was to investigate the relationship between employee well-being (EWB) and organisational effectiveness (OE) in a South African bond origination company. Motivation for the study: Organisations need to improve their effectiveness to remain competitive and are dependent on the well-being of their employees to achieve this. Understanding the effect of EWB on OE can assist organisations in managing this relationship. Research design/approach and method: A quantitative cross-sectional approach was used in which a convenient sample of 203 employees completed five questionnaires to measure OE and the four underlying contructs of EWB. A correlation analysis was conducted to determine the statistical relationship between the four EWB constructs and OE. Main findings: Results indicated a statistically significant positive relationship between job satisfaction, work engagement and OE and a statistically significant negative relationship between Burnout and OE, while no relationship was found between workaholism and OE. Practical/managerial implications: Managers should implement interventions to increase job satisfaction and work engagement and decrease burnout to increase the performance of their organisations. Contributions/value-add: This study provides managers with an understanding of how the performance of their organisations can be improved by managing the well-being of their employees.

Culture of Pacific white shrimp (Litopenaeus vannamei) and red swamp crayfish (Procambarus clarkii), using an intercropping production strategy, is being used by one shrimp farmer in Alabama. A concern is that crayfish feed on invertebrates. This raises the question of whether crayfish would feed on shrimp, negatively impacting survival and production. Two trials were conducted using different systems to investigate the cohabitation of these species. Trial 1 consisted of a 24-tank clear water system. Treatment 1 served as an experimental control and consisted of 20 shrimp fed a daily ration of shrimp feed. Treatment 2 comprised of 20 shrimp and one adult crayfish per tank, each receiving a calculated daily ration of shrimp feed. Treatment 3 had the same number of shrimp and crayfish as above, but no additional shrimp feed was added to account for the crayfish in the tank. Trial 2 used a green water on-levee flow-through tank system, stocked at an initial mean shrimp stocking weight of 0.15 ± 0.01 g with four replicates and similar treatments as Trial 1. Shrimp survival was 91.9 % when they were reared in a clear water system without crayfish. Adding crayfish significantly decreased shrimp survival, with no difference in survival between crayfish treatments fed a daily crayfish ration (58.8 %) and those not receiving a daily crayfish ration (40.6 %). Shrimp weight gain did not differ between treatments. However, when shrimp were in the presence of crayfish not receiving a daily crayfish ration, tank-to-tank variability in weight gain by >50 % compared to other treatments increased. Shrimp survival was 92.0–97.3% across treatments when reared in a green water system (Trial 2) without crayfish. Results indicate that cohabitation of crayfish and shrimp is feasible.

To investigate how host and pathogen diversity govern immunity against Mycobacterium tuberculosis (Mtb), we performed a large-scale screen of vaccine-mediated protection against aerosol Mtb infection using three inbred mouse strains [C57BL/6 (B6), C3HeB/FeJ (C3H), Balb/c x 129/SvJ (C129F1)] and three Mtb strains (H37Rv, CDC1551, SA161) representing two lineages and distinct virulence properties. We compared three protective modalities, all of which involve inoculation with live mycobacteria: Bacillus Calmette-Guérin (BCG), the only approved TB vaccine, delivered either subcutaneously or intravenously, and concomitant Mtb infection (CoMtb), a model of pre-existing immunity in which a low-level Mtb infection is established in the cervical lymph node following intradermal inoculation. We examined lung bacterial burdens at early (Day 28) and late (Day 98) time points after aerosol Mtb challenge and histopathology at Day 98. We observed substantial heterogeneity in the reduction of bacterial load afforded by these modalities at Day 28 across the combinations and noted a strong positive correlation between bacterial burden in unvaccinated mice and the degree of protection afforded by vaccination. Although we observed variation in the degree of reduction in bacterial burdens across the nine mouse/bacterium strain combinations, virtually all protective modalities performed similarly for a given strain-strain combination. We also noted dramatic variation in histopathology changes driven by both host and bacterial genetic backgrounds. Vaccination improved pathology scores for all infections except CDC1551. However, the most dramatic impact of vaccination on lesion development occurred for the C3H-SA161 combination, where vaccination entirely abrogated the development of the large necrotic lesions that arise in unvaccinated mice. In conclusion, we find that substantial TB heterogeneity can be recapitulated by introducing variability in both host and bacterial genetics, resulting in changes in vaccine-mediated protection as measured both by bacterial burden as well as histopathology. These differences can be harnessed in future studies to identify immune correlates of vaccine efficacy.

ABSTRACT Sindbis virus (SINV) infection of mice provides a model system for studying the pathogenesis of alphaviruses that infect the central nervous system (CNS) to cause encephalomyelitis. While studies of human viral infections typically focus on accessible cells from the blood, this compartment is rarely evaluated in mice. To bridge this gap, single-cell RNA sequencing (scRNAseq) was combined with flow cytometry to characterize the transcriptional and phenotypic changes of peripheral blood mononuclear cells (PBMCs) from SINV-infected mice. Twenty-one clusters were identified by scRNAseq at 7 days after infection, with a unique cluster and overall increase in naive B cells for infected mice. Uninfected mice had fewer immature T cells and CCR9+ CD4 T cells and a unique immature T cell cluster. Gene expression was most altered in the Ki67+ CD8 T cell cluster, with chemotaxis and proliferation-related genes upregulated. Global analysis indicated metabolic changes in myeloid cells and increased expression of Ccl5 by NK cells. Phenotypes of PBMCs and cells infiltrating the CNS were analyzed by flow cytometry over 14 days after infection. In PBMCs, CD8 and Th1 CD4 T cells increased in representation, while B cells showed a transient decrease at day 5 in total, Ly6a+, and naive cells, and an increase in activated B cells. In the brain, CD8 T cells increased for the first 7 days, while Th1 CD4 T cells and naive and Ly6a+ B cells continued to accumulate for 14 days. Therefore, dynamic immune cell changes can be identified in the blood as well as the CNS during viral encephalomyelitis.IMPORTANCEThe outcome of viral encephalomyelitis is dependent on the host immune response, with clearance and resolution of infection mediated by the adaptive immune response. These processes are frequently studied in mouse models of infection, where infected tissues are examined to understand the mechanisms of clearance and recovery. However, studies of human infection typically focus on the analysis of cells from the blood, a compartment rarely examined in mice, rather than inaccessible tissue. To close this gap, we used single-cell RNA sequencing and flow cytometry to profile the transcriptomic and phenotypic changes of peripheral blood mononuclear cells (PBMCs) before and after central nervous system (CNS) infection in mice. Changes to T and B cell gene expression and cell composition occurred in PBMC and during entry into the CNS, with CCL5 being a differentially expressed chemokine. Therefore, dynamic changes occur in the blood as well as the CNS during the response of mice to virus infection, which will inform the analysis of human studies.

Abstract Background Polycystic ovary syndrome (PCOS) is a complex multifactorial disorder with a substantial genetic component. However, the clinical manifestations of PCOS are heterogeneous with notable differences between lean and obese women, implying a different pathophysiology manifesting in differential body mass index (BMI). We performed a meta-analysis of genome-wide association study (GWAS) data from six well-characterised cohorts, using a case–control study design stratified by BMI, aiming to identify genetic variants associated with lean and overweight/obese PCOS subtypes. Results The study comprised 254,588 women (5,937 cases and 248,651 controls) from individual studies performed in Australia, Estonia, Finland, the Netherlands and United States of America, and separated according to three BMI stratifications (lean, overweight and obese). Genome-wide association analyses were performed for each stratification within each cohort, with the data for each BMI group meta-analysed using METAL software. Almost half of the total study population (47%, n = 119,584) were of lean BMI (≤ 25 kg/m2). Two genome-wide significant loci were identified for lean PCOS, led by rs12000707 within DENND1A (P = 1.55 × 10–12) and rs2228260 within XBP1 (P = 3.68 × 10–8). One additional locus, LINC02905, was highlighted as significantly associated with lean PCOS through gene-based analyses (P = 1.76 × 10–6). There were no significant loci observed for the overweight or obese sub-strata when analysed separately, however, when these strata were combined, an association signal led by rs569675099 within DENND1A reached genome-wide significance (P = 3.22 × 10–9) and a gene-based association was identified with ERBB4 (P = 1.59 × 10–6). Nineteen of 28 signals identified in previous GWAS, were replicated with consistent allelic effect in the lean stratum. There were less replicated signals in the overweight and obese groups, and only 4 SNPs were replicated in each of the three BMI strata. Conclusions Genetic variation at the XBP1, LINC02905 and ERBB4 loci were associated with PCOS within unique BMI strata, while DENND1A demonstrated associations across multiple strata, providing evidence of both distinct and shared genetic features between lean and overweight/obese PCOS-affected women. This study demonstrated that PCOS-affected women with contrasting body weight are not only phenotypically distinct but also show variation in genetic architecture; lean PCOS women typically display elevated gonadotrophin ratios, lower insulin resistance, higher androgen levels, including adrenal androgens, and more favourable lipid profiles. Overall, these findings add to the growing body of evidence supporting a genetic basis for PCOS as well as differences in genetic patterns relevant to PCOS BMI-subtype.

Abstract Gut microbiota can adapt to their host environment by rapidly acquiring new mutations. However, the dynamics of this process are difficult to characterize in dominant gut species in their complex in vivo environment. Here we show that the fine-scale dynamics of genome-wide transposon libraries can enable quantitative inferences of these in vivo evolutionary forces. By analyzing >400,000 lineages across four human Bacteroides strains in gnotobiotic mice, we observed positive selection on thousands of cryptic variants — most of which were unrelated to their original gene knockouts. The spectrum of fitness benefits varied between species, and displayed diverse tradeoffs over time and in different dietary conditions, enabling inferences of their underlying function. These results suggest that within-host adaptations arise from an intense competition between numerous contending variants, which can strongly influence their emergent evolutionary tradeoffs.

Abstract Manual segmentation of tumors and organs-at-risk (OAR) in 3D imaging for radiation-therapy planning is time-consuming and subject to variation between different observers. Artificial intelligence (AI) can assist with segmentation, but challenges exist in ensuring high-quality segmentation, especially for small, variable structures, such as the esophagus. We investigated the effect of variation in segmentation quality and style of physicians for training deep-learning models for esophagus segmentation and proposed a new metric, edge roughness, for evaluating/quantifying slice-to-slice inconsistency. This study includes a real-world cohort of 394 patients who each received radiation therapy (mainly for lung cancer). Segmentation of the esophagus was performed by 8 physicians as part of routine clinical care. We evaluated manual segmentation by comparing the length and edge roughness of segmentations among physicians to analyze inconsistencies. We trained eight multiple- and individual-physician segmentation models in total, based on U-Net architectures and residual backbones. We used the volumetric Dice coefficient to measure the performance for each model. We proposed a metric, edge roughness, to quantify the shift of segmentation among adjacent slices by calculating the curvature of edges of the 2D sagittal- and coronal-view projections. The auto-segmentation model trained on multiple physicians (MD1-7) achieved the highest mean Dice of 73.7 ± 14.8%. The individual-physician model (MD7) with the highest edge roughness (mean ± SD: 0.106 ± 0.016) demonstrated significantly lower volumetric Dice for test cases compared with other individual models (MD7: 58.5 ± 15.8%, MD6: 67.1 ± 16.8%, p

Abstract Hyperglycemia and rash are expected but challenging adverse events of phosphatidylinositol-3-kinase inhibition (such as with alpelisib). Two modified Delphi panels were conducted to provide consensus recommendations for managing hyperglycemia and rash in patients taking alpelisib. Experts rated the appropriateness of interventions on a 1-to-9 scale; median scores and dispersion were used to classify the levels of agreement. Per the hyperglycemia panel, it is appropriate to start alpelisib in patients with HbA1c 6.5% (diabetes) to

DNA methylation is a fundamental mechanism of epigenetic control in cells and its dysregulation is strongly implicated in cancer development. Cancers possess an extensively hypomethylated genome with focal regions of hypermethylation at CPG islands. Due to the highly conserved nature of cancer-specific methylation, its detection in cell-free DNA in plasma using liquid biopsies constitutes an area of interest in biomarker research. The advent of next-generation sequencing and newer computational technologies have allowed for the development of diagnostic and prognostic biomarkers that utilize methylation profiling to diagnose disease and stratify risk. Methylome-based predictive biomarkers can determine the response to anti-cancer therapy. An additional emerging application of these biomarkers is in minimal residual disease monitoring. Several key challenges need to be addressed before cfDNA-based methylation biomarkers become fully integrated into practice. The first relates to the biology and stability of cfDNA. The second concerns the clinical validity and generalizability of methylation-based assays, many of which are cancer type-specific. The third involves their practicability, which is a stumbling block for translating technologies from bench to clinic. Future work on developing pan-cancer assays with their respective validities confirmed using well-designed, prospective clinical trials is crucial in pushing for the greater use of these tools in oncology.

Abstract We present an ensemble transfer learning method to predict suicide from Veterans Affairs (VA) electronic medical records (EMR). A diverse set of base models was trained to predict a binary outcome constructed from reported suicide, suicide attempt, and overdose diagnoses with varying choices of study design and prediction methodology. Each model used twenty cross-sectional and 190 longitudinal variables observed in eight time intervals covering 7.5 years prior to the time of prediction. Ensembles of seven base models were created and fine-tuned with ten variables expected to change with study design and outcome definition in order to predict suicide and combined outcome in a prospective cohort. The ensemble models achieved c-statistics of 0.73 on 2-year suicide risk and 0.83 on the combined outcome when predicting on a prospective cohort of $$\sim$$ ∼ 4.2 M veterans. The ensembles rely on nonlinear base models trained using a matched retrospective nested case-control (Rcc) study cohort and show good calibration across a diversity of subgroups, including risk strata, age, sex, race, and level of healthcare utilization. In addition, a linear Rcc base model provided a rich set of biological predictors, including indicators of suicide, substance use disorder, mental health diagnoses and treatments, hypoxia and vascular damage, and demographics.

Abstract Social determinants of health (SDoH) play a critical role in patient outcomes, yet their documentation is often missing or incomplete in the structured data of electronic health records (EHRs). Large language models (LLMs) could enable high-throughput extraction of SDoH from the EHR to support research and clinical care. However, class imbalance and data limitations present challenges for this sparsely documented yet critical information. Here, we investigated the optimal methods for using LLMs to extract six SDoH categories from narrative text in the EHR: employment, housing, transportation, parental status, relationship, and social support. The best-performing models were fine-tuned Flan-T5 XL for any SDoH mentions (macro-F1 0.71), and Flan-T5 XXL for adverse SDoH mentions (macro-F1 0.70). Adding LLM-generated synthetic data to training varied across models and architecture, but improved the performance of smaller Flan-T5 models (delta F1 + 0.12 to +0.23). Our best-fine-tuned models outperformed zero- and few-shot performance of ChatGPT-family models in the zero- and few-shot setting, except GPT4 with 10-shot prompting for adverse SDoH. Fine-tuned models were less likely than ChatGPT to change their prediction when race/ethnicity and gender descriptors were added to the text, suggesting less algorithmic bias (p

Abstract Objectives Osteoarthritis (OA) is a joint disease with a heritable component. Genetic loci identified via genome-wide association studies (GWAS) account for an estimated 26.3% of the disease trait variance in humans. Currently, there is no method for predicting the onset or progression of OA. We describe the first use of the Collaborative Cross (CC), a powerful genetic resource, to investigate knee OA in mice, with follow-up targeted multi-omics analysis of homologous regions of the human genome. Methods We histologically screened 275 mice for knee OA and conducted quantitative trait locus (QTL) mapping in the complete cohort (> 8 months) and the younger onset sub-cohort (8–12 months). Multi-omic analysis of human genetic datasets was conducted to investigate significant loci. Results We observed a range of OA phenotypes. QTL mapping identified a genome-wide significant locus on mouse chromosome 19 containing Glis3, the human equivalent of which has been identified as associated with OA in recent GWAS. Mapping the younger onset sub-cohort identified a genome-wide significant locus on chromosome 17. Multi-omic analysis of the homologous region of the human genome (6p21.32) indicated the presence of pleiotropic effects on the expression of the HLA − DPB2 gene and knee OA development risk, potentially mediated through the effects on DNA methylation. Conclusions The significant associations at the 6p21.32 locus in human datasets highlight the value of the CC model of spontaneous OA that we have developed and lend support for an immune role in the disease. Our results in mice also add to the accumulating evidence of a role for Glis3 in OA.

Severe malarial anemia (SMA, Hb < 6.0 g/dL) is a leading cause of childhood morbidity and mortality in holoendemic Plasmodium falciparum transmission zones. This study explored the entire expressed human transcriptome in whole blood from 66 Kenyan children with non-SMA (Hb ≥ 6.0 g/dL, n = 41) and SMA (n = 25), focusing on host immune response networks. RNA-seq analysis revealed 6862 differentially expressed genes, with equally distributed up-and down-regulated genes, indicating a complex host immune response. Deconvolution analyses uncovered leukocytic immune profiles indicative of a diminished antigenic response, reduced immune priming, and polarization toward cellular repair in SMA. Weighted gene co-expression network analysis revealed that immune-regulated processes are central molecular distinctions between non-SMA and SMA. A top dysregulated immune response signaling network in SMA was the HSP60-HSP70-TLR2/4 signaling pathway, indicating altered pathogen recognition, innate immune activation, stress responses, and antigen recognition. Validation with high-throughput gene expression from a separate cohort of Kenyan children (n = 50) with varying severities of malarial anemia (n = 38 non-SMA and n = 12 SMA) confirmed the RNA-seq findings. Proteomic analyses in 35 children with matched transcript and protein abundance (n = 19 non-SMA and n = 16 SMA) confirmed dysregulation in the HSP60-HSP70-TLR2/4 signaling pathway. Additionally, glutamine transporter and glutamine synthetase genes were differentially expressed, indicating altered glutamine metabolism in SMA. This comprehensive analysis underscores complex immune dysregulation and novel pathogenic features in SMA.

Not available.

Summary: Horizontal basal cells (HBCs) mediate olfactory epithelium (OE) regeneration following severe tissue injury. The dynamism of the post-injury environment is well illustrated by in silico modeling of RNA sequencing data that demonstrate an evolving HBC transcriptome. Unfortunately, spatiotemporally dynamic processes occurring within HBCs in situ remain poorly understood. Here, we show that HBCs at 24 h post-OE injury spatially redistribute a constellation of proteins, which, in turn, helped to nominate Rac1 as a regulator of HBC differentiation during OE regeneration. Using our primary culture model to activate HBCs pharmacologically, we demonstrate that concurrent Rac1 inhibition attenuates HBC differentiation potential. This in vitro functional impairment manifested in vivo as decreased HBC differentiation into olfactory sensory neurons following HBC-specific Rac1 conditional knockout. Taken together, our data potentiate the design of hyposmia-alleviating therapies and highlight aspects of in situ HBC spatiotemporal dynamics that deserve further investigation.

Background:. Venous thromboembolism (VTE) is a dangerous postoperative complication after abdominal wall reconstruction (AWR). Intraoperative core body temperature has been associated with thrombotic events in other surgical contexts. This study examines the effects of intraoperative temperature on VTE rate after AWR. Methods:. A retrospective study was performed on AWR patients. Cohorts were defined by postoperative 30-day VTE. Intraoperative core body temperature was recorded as the minimum, maximum, and mean intraoperative temperatures. Study variables were analyzed with logistic regression and cutoff analysis to assess for association with VTE. Results:. In total, 344 patients met inclusion criteria. Fourteen patients were diagnosed with 30-day VTE for an incidence of 4.1%. The VTE cohort had a longer median inpatient stay (8 days versus 5 days, P < 0.001) and greater intraoperative change in peak inspiratory pressure (3 mm H2O versus 1 mm H2O, P = 0.01) than the non-VTE cohort. Operative duration [odds ratio (OR) = 1.32, P = 0.01], length of stay (OR = 1.07, P = 0.001), and intraoperative PIP difference (OR = 1.18, P = 0.045) were significantly associated with 30-day VTE on univariable regression. Immunocompromised status (OR = 4.1, P = 0.023; OR = 4.0, P = 0.025) and length of stay (OR = 1.1, P < 0.001; OR = 1.1, P < 0.001) were significant predictors of 30-day VTE on two multivariable regression models. No significant associations were found between temperature metrics and 30-day VTE on cutoff point or regression analysis. Conclusions:. Intraoperative core body temperature did not associate with 30-day VTE after AWR, though operative duration, length of stay, immunocompromised status, and intraoperative PIP difference did. Surgeons should remain mindful of VTE risk after AWR, and future research is warranted to elucidate all contributing factors.

Abstract Introduction In recent years, the expansion of HIV treatment eligibility has resulted in an increase in people with antiretroviral therapy (ART) experience prior to pregnancy but little is known about postpartum engagement in care in this population. We examined differences in disengagement from HIV care after delivery by maternal ART history before conception. Methods We analysed data from people living with HIV (aged 15–49) in Khayelitsha, South Africa, with ≥1 live birth between April 2013 and March 2019. We described trends over time in ART history prior to estimated conception, classifying ART history groups as: (A) on ART with no disengagement (>270 days with no evidence of HIV care); (B) returned before pregnancy following disengagement; (C) restarted ART in pregnancy after disengagement; and (D) ART new start in pregnancy. We used Kaplan–Meier curves and proportional‐hazards models (adjusted for maternal age, number of pregnancy records and year of delivery) to examine the time to disengagement from delivery to 2 years postpartum. Results Among 7309 pregnancies (in 6680 individuals), the proportion on ART (A) increased from 19% in 2013 to 41% in 2019. The proportions of those who returned (B) and restarted (C) increased from 2% to 13% and from 2% to 10%, respectively. There was a corresponding decline in the proportion of new starts (D) from 77% in 2013 to 36% in 2019. In the first recorded pregnancy per person in the study period, 26% (95% CI 25–27%) had disengaged from care by 1 year and 34% (95% CI 33–36%) by 2 years postpartum. Individuals who returned (B: aHR 2.10, 95% CI 1.70–2.60), restarted (C: aHR 3.32, 95% CI 2.70–4.09) and newly started ART (D: aHR 2.41, 95% CI 2.12–2.74) had increased hazards of postpartum disengagement compared to those on ART (A). Conclusions There is a growing population of people with ART experience prior to conception and postpartum disengagement varies substantially by ART history. Antenatal care presents an important opportunity to understand prior ART experiences and an entry into interventions for strengthened engagement in HIV care.

Abstract Objectives The relationship between COVID‐19‐related telehealth calls could be used to predict emergency department visits and hospital surges 3 days later potentially facilitating staffing adjustments in advance of patient arrivals. The purpose of this research was to study the temporal association between frequencies of on demand telehealth calls and emergency department surges during the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic. Methods This cohort study examined patients who self‐initiated synchronous audio‐video on‐demand telehealth calls between January 1, 2020 and June 30, 2022, and compared these to emergency department arrivals. The exposure in question was a synchronous audio‐video on‐demand telehealth visit. Our main outcome measured was frequency of emergency department visits. After autocorrelation, a multivariate linear regression model was utilized to determine temporal relationships between the two variables. Results This cohort study examined 42,429 synchronous audio‐video on‐demand telehealth calls, of which 43.6% were COVID‐19 related, and 540,686 emergency department visits, of which 3.9% were diagnosed with COVID‐19. COVID‐19‐related telehealth calls 3 days prior were predictive of emergency department encounters (r2 = 0.85, p