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Shared clinical decision-making (SCDM) about HPV vaccination has been recommended for U.S. mid-adults aged 27-45 since 2019. To explore barriers and facilitators to HPV vaccination in this population, we conducted 14 virtual focus groups with 86 unvaccinated mid-adults (34 men and 52 women) in Californias medically underserved Inland Empire between September 2020 and January 2021. We systematically analyzed the focus group data using the rigorous and accelerated data reduction (RADaR) technique to identify key themes. Identified barriers included: lack of awareness, vaccine hesitancy, and perceived unaffordability (cited in 14 groups); lack of healthcare provider communication and insufficient time (13 groups); fear of moral judgment (12 groups); lack of motivation and information needs (10 groups); and lack of reliable transportation and foregone care during the COVID-19 pandemic (3 groups). Proposed facilitators included: tailored HPV vaccine information for mid-adults, cost mitigation, and improved vaccine accessibility (12 groups); healthcare provider-initiated conversations (6 groups); and vaccine reminders (4 groups). These findings highlight challenges to HPV vaccination among U.S. mid-adults eligible for SCDM and point to actionable strategies for improvement. Specifically, tailored educational interventions, decision-making tools for pharmacists, and integrating HPV vaccination into other healthcare encounters may enhance vaccination efforts in areas with limited primary care resources.

BACKGROUND: Stroke remains a major health concern globally, with oral anticoagulants widely prescribed for stroke prevention. The efficacy and safety of mechanical thrombectomy (MT) in anticoagulated patients with distal medium vessel occlusions (DMVO) are not well understood. METHODS: This retrospective analysis involved 1282 acute ischemic stroke (AIS) patients who underwent MT in 37 centers across North America, Asia, and Europe from September 2017 to July 2023. Data on demographics, clinical presentation, treatment specifics, and outcomes were collected. The primary outcomes were functional outcomes at 90 days post-MT, measured by modified Rankin Scale (mRS) scores. Secondary outcomes included reperfusion rates, mortality, and hemorrhagic complications. RESULTS: Of the patients, 223 (34%) were on anticoagulation therapy. Anticoagulated patients were older (median age 78 vs 74 years; p

PURPOSE: Upper airway (UA) surgery is commonly employed in the treatment of patients with obstructive sleep apnea (OSA). The intricate pathophysiology of OSA, variability in sites and patterns of UA collapse, and the interaction between anatomical and non-anatomical factors in individual patients may contribute to possible surgical failures. This clinical consensus statement aims to identify areas of agreement among a development group comprising international experts in OSA surgery, regarding the appropriate definition, predictive factors in patients, and management of surgical failure in OSA treatment. METHODS: A clinical consensus statement (CCS) was developed using the Delphi method by a panel of 35 contributors from various countries. A systematic literature review adhering to PRISMA guidelines was conducted. A survey consisting of 60 statements was then formulated and presented to the experts. RESULTS: Following two rounds of the Delphi process, consensus or strong consensus was achieved on 36 items, while 24 items remained without consensus. Specifically, 5 out of 10 statements reached consensus regarding on the Definition of Surgical Success/Failure after OSA Surgery. Regarding the Predictive Factors of Surgical Failure in OSA Surgery, consensus was reached on 10 out of 13 statements. In the context of the Diagnostic Workup in OSA Surgery, consensus was achieved on 9 out of 13 statements. Lastly, in Treatment in Surgical Failure Cases, consensus was reached on 12 out of 24 statements. CONCLUSION: The management of OSA after surgical failure presents a significant clinical challenge for sleep specialists. This CCS provides valuable guidance for defining, preventing, and addressing surgical failures in the treatment of OSA syndrome.

OBJECTIVES: Implicit bias perpetuates health care inequities and manifests in patient-provider interactions, particularly nonverbal social cues like dominance. We investigated the use of artificial intelligence (AI) for automated communication assessment and feedback during primary care visits to raise clinician awareness of bias in patient interactions. MATERIALS AND METHODS: (1) Assessed the technical performance of our AI models by building a machine-learning pipeline that automatically detects social signals in patient-provider interactions from 145 primary care visits. (2) Engaged 24 clinicians to design usable AI-generated communication feedback for their workflow. (3) Evaluated the impact of our AI-based approach in a prospective cohort of 108 primary care visits. RESULTS: Findings demonstrate the feasibility of AI models to identify social signals, such as dominance, warmth, engagement, and interactivity, in nonverbal patient-provider communication. Although engaged clinicians preferred feedback delivered in personalized dashboards, they found nonverbal cues difficult to interpret, motivating social signals as an alternative feedback mechanism. Impact evaluation demonstrated fairness in all AI models with better generalizability of provider dominance, provider engagement, and patient warmth. Stronger clinician implicit race bias was associated with less provider dominance and warmth. Although clinicians expressed overall interest in our AI approach, they recommended improvements to enhance acceptability, feasibility, and implementation in telehealth and medical education contexts. DISCUSSION AND CONCLUSION: Findings demonstrate promise for AI-driven communication assessment and feedback systems focused on social signals. Future work should improve the performance of this approach, personalize models, and contextualize feedback, and investigate system implementation in educational workflows. This work exemplifies a systematic, multistage approach for evaluating AI tools designed to raise clinician awareness of implicit bias and promote patient-centered, equitable health care interactions.

ObjectiveWe examined the acceptability and feasibility of a multi-component digital health outreach intervention to promote uptake of guideline-recommended postpartum screening for type 2 diabetes among patients with gestational diabetes (GDM).MethodsWe conducted a 24 randomized factorial experiment as part of the Multiphase Optimization Strategy (MOST) preparation phase for developing behavioral interventions. Participants with current or recent GDM in an integrated healthcare system were randomized to receive an outreach message with up to four intervention components, designed to be self-administered in about 10 min and efficiently delivered online via REDCap: a streamlined values affirmation, personalized information on diabetes risk, an interactive motivational interviewing-based component, and an interactive action planning component. Patient-reported acceptability and feasibility outcomes were assessed via survey.ResultsAmong 162 participants, 72% self-identified with a racial/ethnic minority group. Across components, acceptability scores averaged 3.9/5; ≥91% of participants read most or all of the outreach message; ≥89% perceived the amount of information as "about right"; and ≥ 87% completed ≥1 interactive prompt.ConclusionEach intervention component was acceptable to diverse patients and feasible to deliver in a brief, self-directed, online format.InnovationThese novel components target unaddressed barriers to patient engagement in guideline-recommended postpartum diabetes screening and adapt theory-based behavior change techniques for large-scale use.

CT is crucial for diagnosing chest diseases, with image quality affected by spatial resolution. Thick-slice CT remains prevalent in practice due to cost considerations, yet its coarse spatial resolution may hinder accurate diagnoses. Our multicenter study develops a deep learning synthetic model with Convolutional-Transformer hybrid encoder-decoder architecture for generating thin-slice CT from thick-slice CT on a single center (1576 participants) and access the synthetic CT on three cross-regional centers (1228 participants). The qualitative image quality of synthetic and real thin-slice CT is comparable (p = 0.16). Four radiologists accuracy in diagnosing community-acquired pneumonia using synthetic thin-slice CT surpasses thick-slice CT (p  0.99). For lung nodule detection, sensitivity with thin-slice CT outperforms thick-slice CT (p  0.05). These findings indicate the potential of our model to generate high-quality synthetic thin-slice CT as a practical alternative when real thin-slice CT is preferred but unavailable.

BACKGROUND: The 24-h urine protein (24-hUP) excretion is the gold standard for evaluating proteinuria. This study aimed to evaluate the diagnostic efficacy of protein/creatinine ratio (PCR) for estimating 24-hUP at various levels of renal function and proteinuria levels. METHODS: A cross-sectional study was conducted between December 2021 and December 2023 in Salvador, Bahia-Brazil, as an extension of previously published data from the TUNARI study. The study included 217 samples from 152 patients with various levels of renal function and proteinuria. PCR in isolated samples and 24-hUP were determined conventionally within a 24-h timeframe. Patients were classified into three groups according to the level of renal function (Group 1 = 10 to  60 mL/min) and level of proteinuria ( 3.5 g/day). The data were analyzed using the Spearman correlation (rs), coefficient of determination (r2), Bland-Altman plots and receiver operating characteristic (ROC) curve. Likelihood ratios, positive (LR +), and negative (LR-) were derived from the sensitivity and specificity of PCR. RESULTS: Mean age was 41.5 ± 15.7 years, 61.8% were women, 36.8% Black and 52% Mixed-race. Glomerulopathies constituted 80.3%; 46.1% with lupus nephritis. Of the total urine samples, we observed a high correlation between PCR in the total sample of 24-hUP sample (rs = 0.86, p  0.3-3.5 g/day, the sensitivity was 64.1%, the specificity was 84.6%, and the AUC was 0.76 (95% CI = 0.67; 0.84), PCR detected all cases > 3.5 g/day. CONCLUSIONS: PCR is a suitable measure to be used as an indicator of 24-hUP at different levels of renal function, but may have limitations at higher levels of proteinuria. Analysis of PCR by proteinuria level found that agreement as well as sensitivity decreases at higher levels, but it maintains good specificity and is able to identify nephrotic range proteinuria.

Advancing the capabilities of earthquake nowcasting, the real-time forecasting of seismic activities, remains crucial for reducing casualties. This multifaceted challenge has recently gained attention within the deep learning domain, facilitated by the availability of extensive earthquake datasets. Despite significant advancements, the existing literature on earthquake nowcasting lacks comprehensive evaluations of pre-trained foundation models and modern deep learning architectures; each focuses on a different aspect of data, such as spatial relationships, temporal patterns, and multi-scale dependencies. This paper addresses the mentioned gap by analyzing different architectures and introducing two innovative approaches called Multi Foundation Quake and GNNCoder. We formulate earthquake nowcasting as a time series forecasting problem for the next 14 days within 0.1-degree spatial bins in Southern California. Earthquake time series are generated using the logarithm energy released by quakes, spanning 1986 to 2024. Our comprehensive evaluations demonstrate that our introduced models outperform other custom architectures by effectively capturing temporal-spatial relationships inherent in seismic data. The performance of existing foundation models varies significantly based on the pre-training datasets, emphasizing the need for careful dataset selection. However, we introduce a novel method, Multi Foundation Quake, that achieves the best overall performance by combining a bespoke pattern with Foundation model results handled as auxiliary streams.

The Zika virus (ZIKV) epidemic in Latin America (2015-2016) has primarily been studied in urban centers, with less understanding of its impact on smaller rural communities. To address this gap, we analyzed ZIKV seroepidemiology in 6 rural Ecuadorian communities (2018-2019) with varying access to a commercial hub. Seroprevalence ranged from 19% to 54%, measured by nonstructural protein 1 blockade of binding enzyme-linked immunosorbent assay. We observed a decline in ZIKV seroprevalence between 2018 and 2019 that was greater among younger populations, suggesting that the attack rates in the 2015-2016 epidemic were significantly higher than our 2018 observations. These data indicate that the 2015-2016 epidemic included significant transmission in rural and more remote settings. Our observations of high seroprevalence in our area of study highlights the importance of surveillance and research in rural areas lacking robust health systems to manage future Zika outbreaks and vaccine initiatives.

In Finland, the frequency of isolated cleft palate (CP) is higher than that of isolated cleft lip with or without cleft palate (CL/P). This trend contrasts to that in other European countries but its genetic underpinnings are unknown. We conducted a genome-wide association study in the Finnish population and identified rs570516915, a single nucleotide polymorphism highly enriched in Finns, as strongly associated with CP (P = 5.25 × 10-34, OR = 8.65, 95% CI 6.11-12.25), but not with CL/P (P = 7.2 × 10-5), with genome-wide significance. The risk allele frequency of rs570516915 parallels the regional variation of CP prevalence in Finland, and the association was replicated in independent cohorts of CP cases from Finland (P = 8.82 × 10-28) and Estonia (P = 1.25 × 10-5). The risk allele of rs570516915 alters a conserved binding site for the transcription factor IRF6 within an enhancer (MCS-9.7) upstream of the IRF6 gene and diminishes the enhancer activity. Oral epithelial cells derived from CRISPR-Cas9 edited induced pluripotent stem cells demonstrate that the CP-associated allele of rs570516915 concomitantly decreases the binding of IRF6 and the expression level of IRF6, suggesting impaired IRF6 autoregulation as a molecular mechanism underlying the risk for CP.

Mucopolysaccharidoses (MPSs) are childhood diseases caused by inherited deficiencies in glycosaminoglycan degradation. Most MPSs involve neurodegeneration, which to date is untreatable. Currently, most therapeutic strategies aim at correcting the primary genetic defect. Among these strategies, gene therapy has shown great potential, although its clinical application is challenging. We have shown previously in an MPS-IIIA mouse model that the molecular tweezer (MT) CLR01, a potent, broad-spectrum anti-amyloid small molecule, inhibits secondary amyloid storage, facilitates amyloid clearance, and protects against neurodegeneration. Here, we demonstrate that combining CLR01 with adeno-associated virus (AAV)-mediated gene therapy, targeting both the primary and secondary pathologic storage in MPS-IIIA mice, results in a synergistic effect that improves multiple therapeutic outcomes compared to each monotherapy. Moreover, we demonstrate that CLR01 is effective therapeutically in mouse models of other forms of neuronopathic MPS, MPS-I, and MPS-IIIC. These strongly support developing MTs as an effective treatment option for neuronopathic MPSs, both on their own and in combination with gene therapy, to improve therapeutic efficacy and translation into clinical application.

Durable and conductive interfaces that enable chronic and high-resolution recording of neural activity are essential for understanding and treating neurodegenerative disorders. These chronic implants require long-term stability and small contact areas. Consequently, they are often coated with a blend of conductive polymers and are crosslinked to enhance durability despite the potentially deleterious effect of crosslinking on the mechanical and electrical properties. Here the grafting of the poly(3,4 ethylenedioxythiophene) scaffold, poly(styrenesulfonate)-b-poly(poly(ethylene glycol) methyl ether methacrylate block copolymer brush to gold, in a controlled and tunable manner, by surface-initiated atom-transfer radical polymerization (SI-ATRP) is described. This "block-brush" provides high volumetric capacitance (120 F cm─3), strong adhesion to the metal (4 h ultrasonication), improved surface hydrophilicity, and stability against 10 000 charge-discharge voltage sweeps on a multiarray neural electrode. In addition, the block-brush film showed 33% improved stability against current pulsing. This approach can open numerous avenues for exploring specialized polymer brushes for bioelectronics research and application.

ObjectiveIndividuals with unhealthy alcohol use and comorbid depression or anxiety may be vulnerable to alcohol use escalation in times of stress such as the COVID-19 pandemic. Among a cohort of individuals with pre-pandemic unhealthy drinking, we compared changes in alcohol use by whether people had a depression or anxiety diagnosis and examined whether mental health treatment was related to these changes.MethodUsing electronic health record data from Kaiser Permanente Northern California, we analyzed drinking changes during the pandemic (3/1/2020-6/30/2022) among adults identified in primary care with unhealthy alcohol use (exceeding daily/weekly recommended limits) pre-pandemic (1/1/2019-2/29/2020). Outcomes were mean changes in number of heavy drinking days (prior 3 months), drinks/week, drinks/day, and drinking days/week. Multivariable linear regression models were fit to (a) compare outcomes of patients with depression or anxiety diagnoses to those without, and (b) among patients with depression or anxiety, estimate associations between mental health treatment and outcomes.ResultsThe sample included 62,924 adults with unhealthy alcohol use, of whom 12,281 (19.5%) had depression or anxiety. On average, alcohol use significantly decreased across all measures during the pandemic; however, patients with depression or anxiety had greater decreases in drinks/week (adjusted mean difference [aMD] [CI] = -0.34 [-0.55, -0.12]) and drinking days/week (-0.15 [-0.20, -0.10]). No associations were found between mental health treatment and changes in drinking.ConclusionsContrary to expectations, patients with unhealthy alcohol use and depression or anxiety decreased alcohol use more than those without depression or anxiety during COVID-19, regardless of whether they accessed mental health services.

BACKGROUND AND OBJECTIVES: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN pathogenic variant carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study was to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in patients with sporadic FTD. METHODS: Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic variant in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic nonpathogenic variant carriers, and noncarrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex, and CDR+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted. RESULTS: The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN pathogenic variant carriers under the recessive dosage model (N = 82, beta = 3.25, 95% CI [0.37-6.19], p = 0.034). This was most pronounced in the thalamus in the left hemisphere (beta = 0.03, 95% CI [0.01-0.06], p = 0.006), with a retained association when considering presymptomatic GRN pathogenic variant carriers only (N = 42, beta = 0.03, 95% CI [0.01-0.05], p = 0.003). The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 pathogenic variant carriers (N = 229, beta = 0.36, 95% CI [0.05-0.066], p = 0.021) and in presymptomatic C9orf72 pathogenic variant carriers (N = 106, beta = 0.33, 95% CI [0.03-0.63], p = 0.036), under the recessive dosage model. DISCUSSION: We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 pathogenic variants. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 pathogenic variant carriers could additionally reflect TMEM106Bs effect on divergent pathophysiologic changes before the appearance of clinical symptoms.

Mutations in GBA1 encoding the lysosomal enzyme β-glucocerebrosidase (GCase) are among the most prevalent genetic susceptibility factors for Parkinsons disease (PD), with 10-30% of carriers developing the disease. To identify genetic modifiers contributing to the incomplete penetrance, we examined the effect of 1634 human transcription factors (TFs) on GCase activity in lysates of an engineered human glioblastoma line homozygous for the pathogenic GBA1 L444P variant. Using an arrayed CRISPR activation library, we uncovered 11 TFs as regulators of GCase activity. Among these, activation of MITF and TFEC increased lysosomal GCase activity in live cells, while activation of ONECUT2 and USF2 decreased it. While MITF, TFEC, and USF2 affected GBA1 transcription, ONECUT2 might control GCase trafficking. The effects of MITF, TFEC, and USF2 on lysosomal GCase activity were reproducible in iPSC-derived neurons from PD patients. Our study provides a systematic approach to identifying modulators of GCase activity and deepens our understanding of the mechanisms regulating GCase.

BACKGROUND: Despite the proven effectiveness of endovascular therapy (EVT) in acute ischemic strokes (AIS) involving anterior circulation large vessel occlusions, isolated posterior cerebral artery (PCA) occlusions (iPCAo) remain underexplored in clinical trials. This study investigates the comparative effectiveness and safety of EVT against medical management (MM) in patients with iPCAo. METHODS: This multinational, multicenter propensity score-weighted study analyzed data from the Multicenter Analysis of primary Distal medium vessel occlusions: effect of Mechanical Thrombectomy (MAD-MT) registry, involving 37 centers across North America, Asia, and Europe. We included iPCAo patients treated with either EVT or MM. The primary outcome was the modified Rankin Scale (mRS) at 90 days, with secondary outcomes including functional independence, mortality, and safety profiles such as hemorrhagic complications. RESULTS: A total of 177 patients were analyzed (88 MM and 89 EVT). EVT showed a statistically significant improvement in 90-day mRS scores (OR = 0.55, 95% CI = 0.30-1.00, p = 0.048), functional independence (OR = 2.52, 95% CI = 1.02-6.20, p = 0.045), and a reduction in 90-day mortality (OR = 0.12, 95% CI = 0.03-0.54, p = 0.006) compared to MM. Hemorrhagic complications were not significantly different between the groups. CONCLUSION: EVT for iPCAo is associated with better neurological outcomes and lower mortality compared to MM, without an increased risk of hemorrhagic complications. Nevertheless, these results should be interpreted with caution due to the studys observational design. The findings are hypothesis-generating and highlight the need for future randomized controlled trials to confirm these observations and establish definitive treatment guidelines for this patient population.

For prostate cancer patients who experience biochemical progression during androgen deprivation therapy (ADT), prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) has not been prospectively compared to planar bone scan plus CT. This was a single-arm, head-to-head, prospective phase II trial (NCT04928820) designed to enroll 102 men with prostate cancer who experienced biochemical progression (rising prostate-specific antigen [PSA] ≥ 1 ng/mL) during ADT. All patients received 68Ga-PSMA-11 PET/CT and 99mTc-MDP planar bone scans. Each scan was interpreted by three central independent readers. The primary endpoint was the per-patient bone metastasis detection rate of PSMA PET/CT versus planar bone scan and CT. Secondary endpoints compared the number of bone metastases detected per patient and the inter-reader agreement of each imaging modality. Twenty-two men were enrolled between July 2021 and June 2022. Due to slow accrual following approval of PSMA PET radiotracers in the U.S. and a lack of a statistical signal between the two imaging modalities on interim analysis, this trial was closed early on October 2022. Median PSA was 8.5 ng/mL (interquartile range: 1.6-77.6). There was 100% agreement between the two scans. Six patients (27%) had negative findings and 16 patients (73%) had positive findings on both scans. PSMA PET/CT and bone scan plus CT detected an equal number of bone lesions for 14 patients (64%), PSMA PET/CT detected more bone lesions for six patients (27%), and bone scan plus CT detected more bone lesions for two patients (9.1%) (p = 0.092). The inter-reader agreement rates of PSMA PET/CT and bone scan plus CT were 96% and 82%, respectively (p = 0.25). In men with biochemical progression during ADT, 68Ga-PSMA-11 PET/CT and 99mTc-MDP planar bone scan plus CT had identical bone metastasis detection rates. Bone scan plus CT can continue to serve as a cost-effective and readily accessible restaging modality in patients with biochemical progression. ClinicalTrials.gov NCT04928820. Registered 16/06/2021.

BACKGROUND: Rib fractures are one of the most common traumatic injuries and may result in significant morbidity and mortality. Despite growing evidence, technological advances and increasing acceptance, surgical stabilization of rib fractures (SSRF) remains not uniformly considered in trauma centers. Indications, contraindications, appropriate timing, surgical approaches and utilized implants are part of an ongoing debate. The present position paper, which is endorsed by the World Society of Emergency Surgery (WSES), and supported by the Chest Wall Injury Society, aims to provide a review of the literature investigating the use of SSRF in rib fracture management to develop graded position statements, providing an updated guide and reference for SSRF. METHODS: This position paper was developed according to the WSES methodology. A steering committee performed the literature review and drafted the position paper. An international panel of experts then critically revised the manuscript and discussed it in detail, to develop a consensus on the position statements. RESULTS: A total of 287 studies (systematic reviews, randomized clinical trial, prospective and retrospective comparative studies, case series, original articles) have been selected from an initial pool of 9928 studies. Thirty-nine graded position statements were put forward to address eight crucial aspects of SSRF: surgical indications, contraindications, optimal timing of surgery, preoperative imaging evaluation, rib fracture sites for surgical fixation, management of concurrent thoracic injuries, surgical approach, stabilization methods and material selection. CONCLUSION: This consensus document addresses the key focus questions on surgical treatment of rib fractures. The expert recommendations clarify current evidences on SSRF indications, timing, operative planning, approaches and techniques, with the aim to guide clinicians in optimizing the management of rib fractures, to improve patient outcomes and direct future research.

Wildlife biodiversity is essential for healthy, resilient and sustainable ecosystems. For biologists, this diversity also represents a treasure trove of genetic, molecular and developmental mechanisms that deepen our understanding of the origins and rules of life. However, the rapid decline in biodiversity reported recently foreshadows a potentially catastrophic collapse of many important ecosystems and the associated irreversible loss of many forms of life on our planet. Immediate action by conservationists of all stripes is required to avert this disaster. In this Spotlight, we draw together insights and proposals discussed at a recent workshop hosted by Revive & Restore, which gathered experts to discuss how stem cell technologies can support traditional conservation techniques and help protect animal biodiversity. We discuss reprogramming, in vitro gametogenesis, disease modelling and embryo modelling, and we highlight the prospects for leveraging stem cell technologies beyond mammalian species.

The adoption of agriculture triggered a rapid shift towards starch-rich diets in human populations1. Amylase genes facilitate starch digestion, and increased amylase copy number has been observed in some modern human populations with high-starch intake2, although evidence of recent selection is lacking3,4. Here, using 94 long-read haplotype-resolved assemblies and short-read data from approximately 5,600 contemporary and ancient humans, we resolve the diversity and evolutionary history of structural variation at the amylase locus. We find that amylase genes have higher copy numbers in agricultural populations than in fishing, hunting and pastoral populations. We identify 28 distinct amylase structural architectures and demonstrate that nearly identical structures have arisen recurrently on different haplotype backgrounds throughout recent human history. AMY1 and AMY2A genes each underwent multiple duplication/deletion events with mutation rates up to more than 10,000-fold the single-nucleotide polymorphism mutation rate, whereas AMY2B gene duplications share a single origin. Using a pangenome-based approach, we infer structural haplotypes across thousands of humans identifying extensively duplicated haplotypes at higher frequency in modern agricultural populations. Leveraging 533 ancient human genomes, we find that duplication-containing haplotypes (with more gene copies than the ancestral haplotype) have rapidly increased in frequency over the past 12,000 years in West Eurasians, suggestive of positive selection. Together, our study highlights the potential effects of the agricultural revolution on human genomes and the importance of structural variation in human adaptation.

BACKGROUND: Supportive care to ensure optimal quality of life is an essential component of cancer care and symptom control across the lifespan. Ongoing advances in cancer treatment, increasing toxicity from many novel treatment regimes, and variations in access to care and cancer outcomes across the globe and resource settings present significant challenges for supportive care delivery. To date, no overarching framework has been developed to guide supportive care development worldwide. As an initial step of the Multinational Association of Supportive Care in Cancer (MASCC) Supportive Care 2030 Movement, we developed a targeted, unifying set of ambition statements to envision the future of supportive cancer care. METHODS: From September 2022 until June 2023, we used a modified Delphi methodology to develop and attain consensus about ambition statements related to supportive cancer care. Leaders of MASCC Study Groups were invited to participate in an Expert Panel for the first two Delphi rounds (and a preliminary round to suggest potential ambition statements). Patient Advocates then examined and provided input regarding the ambition statements. FINDINGS: Twenty-seven Expert Panelists and 11 Patient Advocates participated. Consensus was attained on 13 ambition statements, with two sub-statements. The ambition statements addressed global standards for guideline development and implementation, coordinated and individualized care, dedicated supportive oncology services, self-management, needs for screening and actions, patient education, behavioral support, financial impact minimization, comprehensive survivorship care, and timely palliative care, reflecting collaboration, coordination and team-based approach across all levels. INTERPRETATION: This study is the first to develop shared ambitions for the future of supportive cancer care on a global level. These ambition statements can facilitate a coordinated, resource-stratified, and person-centered approach and inform research, education, clinical services, and policy efforts. FUNDING: This project received funding support from Prof Raymond Chans NHMRC Investigator Grant (APP1194051).

IntroductionCardiovascular health is important for brain aging, yet its role in the clinical manifestation of autosomal dominant or atypical forms of dementia has not been fully elucidated. We examined relationships between Life's Simple 7 (LS7) and clinical trajectories in individuals with autosomal dominant frontotemporal lobar degeneration (FTLD).MethodsTwo hundred forty-seven adults carrying FTLD pathogenic genetic variants (53% asymptomatic) and 189 non-carrier controls completed baseline LS7, and longitudinal neuroimaging and neuropsychological testing.ResultsAmong variant carriers, higher baseline LS7 is associated with slower accumulation of frontal white matter hyperintensities (WMHs), as well as slower memory and language declines. Higher baseline LS7 associated with larger baseline frontotemporal volume, but not frontotemporal volume trajectories.DiscussionBetter baseline cardiovascular health related to slower cognitive decline and accumulation of frontal WMHs in autosomal dominant FTLD. Optimizing cardiovascular health may be an important modifiable approach to bolster cognitive health and brain integrity in FTLD.HighlightsBetter cardiovascular health associates with slower cognitive decline in frontotemporal lobar degeneration (FTLD). Lifestyle relates to the accumulation of frontal white matter hyperintensities in FTLD. More optimal cardiovascular health associates with greater baseline frontotemporal lobe volume. Optimized cardiovascular health relates to more favorable outcomes in genetic dementia.

PurposeWe aimed to estimate health state utility values (HSUVs) for the key health states found in opioid use disorder (OUD) cost-effectiveness models in the published literature.MethodsData obtained from six trials representing 1,777 individuals with OUD. We implemented mapping algorithms to harmonize data from different measures of quality of life (the SF-12 Versions 1 and 2 and the EQ-5D-3 L). We performed a regression analysis to quantify the relationship between HSUVs and the following variables: days of extra-medical opioid use in the past 30 days, injecting behaviors, treatment with medications for OUD, HIV status, and age. A secondary analysis explored the impact of opioid withdrawal symptoms.ResultsThere were statistically significant reductions in HSUVs associated with extra-medical opioid use (-0.002 (95% CI [-0.003,-0.0001]) to -0.003 (95% CI [-0.005,-0.002]) per additional day of heroin or other opiate use, respectively), drug injecting compared to not injecting (-0.043 (95% CI [-0.079,-0.006])), HIV-positive diagnosis compared to no diagnosis (-0.074 (95% CI [-0.143,-0.005])), and age (-0.001 per year (95% CI [-0.003,-0.0002])). Parameters associated with medications for OUD treatment were not statistically significant after controlling for extra-medical opioid use (0.0131 (95% CI [-0.0479,0.0769])), in line with prior studies. The secondary analysis revealed that withdrawal symptoms are a fundamental driver of HSUVs, with predictions of 0.817 (95% CI [0.768, 0.858]), 0.705 (95% CI [0.607, 0.786]), and 0.367 (95% CI [0.180, 0.575]) for moderate, severe, and worst level of symptoms, respectively.ConclusionWe observed HSUVs for OUD that were higher than those from previous studies that had been conducted without input from people living with the condition.

Adoption of high-content omic technologies in clinical studies, coupled with computational methods, has yielded an abundance of candidate biomarkers. However, translating such findings into bona fide clinical biomarkers remains challenging. To facilitate this process, we introduce Stabl, a general machine learning method that identifies a sparse, reliable set of biomarkers by integrating noise injection and a data-driven signal-to-noise threshold into multivariable predictive modeling. Evaluation of Stabl on synthetic datasets and five independent clinical studies demonstrates improved biomarker sparsity and reliability compared to commonly used sparsity-promoting regularization methods while maintaining predictive performance; it distills datasets containing 1,400-35,000 features down to 4-34 candidate biomarkers. Stabl extends to multi-omic integration tasks, enabling biological interpretation of complex predictive models, as it hones in on a shortlist of proteomic, metabolomic and cytometric events predicting labor onset, microbial biomarkers of pre-term birth and a pre-operative immune signature of post-surgical infections. Stabl is available at https://github.com/gregbellan/Stabl .

Background: In the United States, Black and Latino children with asthma are more likely than White children with asthma to require emergency department visits or hospitalizations because of an asthma exacerbation. Although many cite patient-level socioeconomic status and access to health care as primary drivers of disparities, there is an emerging focus on a major root cause of disparities-systemic racism. Current conceptual models of asthma disparities depict the historical and current effects of systemic racism as the foundation for unequal exposures to social determinants of health, environmental exposures, epigenetic factors, and differential healthcare access and quality. These ultimately lead to biologic changes over the life course resulting in asthma morbidity and mortality. Methods: At the 2022 American Thoracic Society International Conference, a diverse panel of experts was assembled to identify gaps and opportunities to address systemic racism in childhood asthma research. Panelists found that to examine and address the impacts of systemic racism on children with asthma, researchers and medical systems that support biomedical research will need to 1) address the current gaps in our understanding of how to conceptualize and characterize the impacts of systemic racism on child health, 2) design research studies that leverage diverse disciplines and engage the communities affected by systemic racism in identifying and designing studies to evaluate interventions that address the racialized system that contributes to disparities in asthma health outcomes, and 3) address funding mechanisms and institutional research practices that will be needed to promote antiracism practices in research and its dissemination. Results: A thorough literature review and expert opinion discussion demonstrated that there are few studies in childhood asthma that identify systemic racism as a root cause of many of the disparities seen in children with asthma. Community engagement and participation in research studies is essential to design interventions to address the racialized system in which patients and families live. Dissemination and implementation studies with an equity lens will provide the multilevel evaluations required to understand the impacts of interventions to address systemic racism and the downstream impacts. To address the impacts of systemic racism and childhood asthma, there needs to be increased training for research teams, funding for studies addressing research that evaluates the impacts of racism, funding for diverse and multidisciplinary research teams including community members, and institutional and financial support of advocating for policy changes based on study findings. Conclusions: Innovative study design, new tools to identify the impacts of systemic racism, community engagement, and improved infrastructure and funding are all needed to support research that will address impacts of systemic racism on childhood asthma outcomes.

SIGNIFICANCE: Microcirculation and neurovascular coupling are important parameters to study in neurological and neuro-ophthalmic conditions. As the retina shares many similarities with the cerebral cortex and is optically accessible, a special focus is directed to assessing the chorioretinal structure, microvasculature, and hemodynamics of mice, a vital animal model for vision and neuroscience research. AIM: We aim to introduce an optical imaging tool enabling in vivo volumetric mouse retinal monitoring of vascular hemodynamics with high temporal resolution. APPROACH: We translated the spatio-temporal optical coherence tomography (STOC-T) technique into the field of small animal imaging by designing a new optical system that could compensate for the mouse eye refractive error. We also developed post-processing algorithms, notably for the assessment of (i) localized hemodynamics from the analysis of pulse wave-induced Doppler artifact modulation and (ii) retinal tissue displacement from phase-sensitive measurements. RESULTS: We acquired high-quality, in vivo volumetric mouse retina images at a rate of 113 Hz over a lateral field of view of ∼ 500    μ m . We presented high-resolution en face images of the retinal and choroidal structure and microvasculature from various layers, after digital aberration correction. We were able to measure the pulse wave velocity in capillaries of the outer plexiform layer with a mean speed of 0.35 mm/s and identified venous and arterial pulsation frequency and phase delay. We quantified the modulation amplitudes of tissue displacement near major vessels (with peaks of 150 nm), potentially carrying information about the biomechanical properties of the retinal layers involved. Last, we identified the delays between retinal displacements due to the passing of venous and arterial pulse waves. CONCLUSIONS: The developed STOC-T system provides insights into the hemodynamics of the mouse retina and choroid that could be beneficial in the study of neurovascular coupling and vasculature and flow speed anomalies in neurological and neuro-ophthalmic conditions.

BACKGROUND: Co-administration of inactivated influenza vaccine (IIV) and SARS-CoV-2 vaccine may impact SARS-CoV-2 vaccine induced humoral immune responses. We aimed to compare IIV and SARS-CoV-2 vaccine induced cellular and humoral immune responses in those receiving concomitant vaccination to those receiving these vaccines separately. METHODS: We conducted a cohort study between 29th September 2021 and 5th August 2022 in healthcare workers who worked at the local NHS trust and in the surrounding area that were vaccinated with a mRNA SARS-CoV-2 booster and cell-based IIV. We measured haemagglutination inhibition assay (HAI) titres, SARS-CoV-2 anti-spike antibody and SARS-CoV-2 ELISpot count pre-vaccination, 1-month and 6-months post-vaccination and evaluated differences by vaccine strategy. FINDINGS: We recruited 420 participants, 234/420 (56%) were vaccinated concomitantly and 186/420 (44%) separately. The 1-month post-vaccination mean fold rise (MFR) in SARS-CoV-2 anti-spike antibodies was lower in those vaccinated concomitantly compared to separately (MFR [95% confidence interval (CI)] 9.7 [8.3, 11.4] vs 12.8 [10.3, 15.9], p = 0.04). After adjustment for age and sex, the adjusted geometric mean ratio (aGMR) remained lower for those vaccinated concomitantly compared to separately (aGMR [95% CI] 0.80 [0.70, 0.92], p = 0.001). At 6-months post-vaccination, we found no statistically significant difference in SARS-CoV-2 anti-spike antibody titres (aGMR [95% CI] 1.09 [0.87, 1.35], p = 0.45). We found no statistically significant correlation between vaccine strategy with SARS-CoV-2 ELISpot count and influenza HAI titres at 1-month and 6-months post-vaccination. INTERPRETATION: Our study found that concomitant vaccination with SARS-CoV-2 and IIV has no statistically significant impacts on long-term immunogenicity. Further research is required to understand the underlying mechanisms and assess the clinical significance of reduced anti-spike antibodies in those vaccinated concomitantly. FUNDING: Research and Innovation (UKRI) through the COVID-19 National Core Studies Immunity (NCSi) programme (MC_PC_20060).

While regular physical activity is a cornerstone of health, wellness, and vitality, the impact of endurance exercise training on molecular signaling within and across tissues remains to be delineated. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to characterize molecular networks underlying the adaptive response to exercise. Here, we describe the endurance exercise training studies undertaken by the Preclinical Animal Sites Studies component of MoTrPAC, in which we sought to develop and implement a standardized endurance exercise protocol in a large cohort of rats. To this end, Adult (6-mo) and Aged (18-mo) female (n = 151) and male (n = 143) Fischer 344 rats were subjected to progressive treadmill training (5 d/wk, ∼70%-75% VO2max) for 1, 2, 4, or 8 wk; sedentary rats were studied as the control group. A total of 18 solid tissues, as well as blood, plasma, and feces, were collected to establish a publicly accessible biorepository and for extensive omics-based analyses by MoTrPAC. Treadmill training was highly effective, with robust improvements in skeletal muscle citrate synthase activity in as little as 1-2 wk and improvements in maximum run speed and maximal oxygen uptake by 4-8 wk. For body mass and composition, notable age- and sex-dependent responses were observed. This work in mature, treadmill-trained rats represents the most comprehensive and publicly accessible tissue biorepository, to date, and provides an unprecedented resource for studying temporal-, sex-, and age-specific responses to endurance exercise training in a preclinical rat model.

INTRODUCTION: South Asian adults are at high risk for atherosclerotic cardiovascular disease, for which coronary artery calcification is an early predictor. Adherence to the Dietary Approaches to Stop Hypertension diet is a modifiable risk factor that may mitigate the progression of coronary artery calcification and atherosclerotic cardiovascular disease. METHODS: Using data from the Mediators of Atherosclerosis in South Asians Living in America cohort, the authors calculated a Dietary Approaches to Stop Hypertension dietary score (categorized as low, moderate, and high) to examine the associations of Dietary Approaches to Stop Hypertension diet adherence with coronary artery calcification after a 5-year follow up. RESULTS: The authors found that participants in the high Dietary Approaches to Stop Hypertension category were 41% less likely to have coronary artery calcification score >100 (age-adjusted incidence rate ratio=0.59; 95% CI=0.36, 0.95) than those in the low category; this association was attenuated in multivariable models. Differences were observed by sex. Men in the high Dietary Approaches to Stop Hypertension category were 51% less likely to have coronary artery calcification score >100 (adjusted incidence rate ratio=0.49; 95% CI=0.26, 0.95) and experienced 0.46-fold coronary artery calcification change (fold change=0.46; 95% CI=0.18, 0.90) in multivariable models. CONCLUSIONS: The findings indicate a relationship between Dietary Approaches to Stop Hypertension diet and early predictors of atherosclerotic cardiovascular disease risk among South Asians living in the U.S., particularly men.

Maternal mental health is a critical component of overall well-being for mothers and their families, yet it is often influenced by a complex array of factors beyond biological and psychological considerations. Among these, sociocultural influences play a significant role in shaping maternal mental health outcomes. This paper explores the impact of sociocultural factors on maternal mental health, with a focus on how cultural values, societal expectations, and access to support systems shape the mental well-being of mothers. By examining these influences, this study aims to better understand the diverse experiences of motherhood and to identify culturally sensitive interventions that can improve maternal mental health outcomes across different populations.

BACKGROUND: Medium vessel occlusion (MeVO) strokes, particularly affecting the M2 segment of the middle cerebral artery, represent a critical proportion of acute ischemic strokes, posing significant challenges in management and outcome prediction. The efficacy of mechanical thrombectomy (MT) in MeVO stroke may warrant reliable predictors of functional outcomes. This study aimed to investigate the prognostic value of follow-up infarct volume (FIV) for predicting 90-day functional outcomes in MeVO stroke patients undergoing MT. METHODS: This multicenter, retrospective cohort study analyzed data from the Multicenter Analysis of primary Distal medium vessel occlusions: effect of Mechanical Thrombectomy (MAD-MT) registry, covering patients with acute ischemic stroke due to M2 segment occlusion treated with MT. We examined the relationship between 90-day functional outcomes, measured by the modified Rankin Scale (mRS), and follow-up infarct volume (FIV), assessed through CT or MRI within 12-36 h post-MT. RESULTS: Among 130 participants, specific FIV thresholds were identified with high specificity and sensitivity for predicting outcomes. A FIV ⩽5 ml was highly specific for predicting favorable and excellent outcomes. The optimal cut-off for both prognostications was identified at ⩽15 ml by the Youden Index, with significant reductions in the likelihood of favorable outcomes observed above a 40 ml threshold. Receiver Operator Curve (ROC) analyses confirmed FIV as a superior predictor of functional outcomes compared to traditional recanalization scores, such as final modified thrombolysis in cerebral infarction score (mTICI). Multivariable analysis further highlighted the inverse relationship between FIV and positive functional outcomes. CONCLUSIONS: FIV within 36 h post-MT serves as a potent predictor of 90-day functional outcomes in patients with M2 segment MeVO strokes. Establishing FIV thresholds may aid in the prognostication of stroke outcomes, suggesting a role for FIV in guiding post intervention treatment decisions and informing clinical practice. Future research should focus on validating these findings across diverse patient populations and exploring the integration of FIV measurements with other clinical and imaging markers to enhance outcome prediction accuracy.

Immune checkpoint blockade (ICB) has revolutionized cancer treatment; however, the mechanisms determining patient response remain poorly understood. Here, we used machine learning to predict ICB response from germline and somatic biomarkers and interpreted the learned model to uncover putative mechanisms driving superior outcomes. Patients with higher infiltration of T-follicular helper cells had responses even in the presence of defects in the MHC class-I (MHC-I). Further investigation uncovered different ICB responses in tumors when responses were reliant on MHC-I versus MHC-II neoantigens. Despite similar response rates, MHC II-reliant responses were associated with significantly longer durable clinical benefits (discovery: median overall survival of 63.6 vs. 34.5 months; P = 0.0074; validation: median overall survival of 37.5 vs. 33.1 months; P = 0.040). Characteristics of the tumor immune microenvironment reflected MHC neoantigen reliance, and analysis of immune checkpoints revealed LAG3 as a potential target in MHC II-reliant but not MHC I-reliant responses. This study highlights the value of interpretable machine learning models in elucidating the biological basis of therapy responses.

Veteran access to sleep medicine is of paramount importance to the Veterans Health Administration (VA). To increase access, VA has created community referral policies and programs, as well as telehealth programs. In 2017, the Office of Rural Health (ORH) funded a TeleSleep initiative focused on reaching rural Veterans with unmet sleep needs. ORH provided 3-6 years of funding to help 19 hubs support 98 spoke sites serving rural Veterans. As ORH funding concluded, each hub identified its path to sustainment. This case study follows one TeleSleep hub in VAs western geographic region as it transitioned from ORH funding sustainment as a regional Sleep Clinical Resource Hub. This case study describes the real-world process of adaptation in care delivery strategies. One key area of adaptation revolved around whether to deliver care via the patients home facility or the providers home facility. In early 2021, the TeleSleep team implemented an innovative provider transfer model, where temporary reinforcements from the TeleSleep hub increased the workforce capacity of spoke sites, similar to the concept of locum tenens. In this provider transfer model, TeleSleep clinicians scheduled, documented, and billed for each encounter at the Veterans home facility. Positioning TeleSleep clinicians as local providers facilitated communication and referrals and promoted continuity and quality of care for Veterans in their home facility. This provider transfer model reduced the administrative burden of providers and schedulers and supported patient-side-only documentation of care. While this mirrors current locum tenens practice, transferring providers did not fit VAs financial model as implemented by the western regions Sleep Clinical Resource Hub. Therefore, in December 2021, VA aligned TeleSleep with VAs preferred practice of patient rather than provider transfers. In the patient transfer model, providers schedule and document in both the provider and patient electronic health records, and bill in the providers facility. However, reflecting on this period of innovation, TeleSleep team members concluded that the provider transfer model could improve patient safety and care coordination while reducing the administrative burden of frontline clinicians. Further research and development are needed to align the provider transfer model with VAs financial model.

The reaction of 4 equiv. of Li(N[double bond, length as m-dash]C( t Bu)Ph) with FeIICl2 results in isolation of [Li(Et2O)]2[FeII(N[double bond, length as m-dash]C( t Bu)Ph)4] (1), in good yields. The reaction of 1 with 1 equiv. of I2 leads to formation of [FeIV(N[double bond, length as m-dash]C( t Bu)Ph)4] (2), in moderate yields. 57Fe Mössbauer spectroscopy confirms the Fe(iv) oxidation state of 2, and X-ray crystallography reveals that 2 has a square planar coordination geometry along with several intramolecular H⋯C interactions. Furthermore, SQUID magnetometry indicates a small magnetic moment at room temperature, suggestive of an accessible S = 1 state. Both density functional theory and multiconfigurational calculations were done to elucidate the nature of the ground state. Consistent with the experimental results, the ground state was found to be an S = 0 state with an S = 1 excited state close in energy.

BACKGROUND: Fragile X syndrome (FXS) and autism spectrum disorder (ASD) are neurodevelopmental conditions that often have a substantial impact on daily functioning and quality of life. FXS is the most common cause of inherited intellectual disability (ID) and the most common monogenetic cause of ASD. Previous literature has shown that electrophysiological activity measured by electroencephalogram (EEG) during resting state is perturbated in FXS and ASD. However, whether electrophysiological profiles of participants with FXS and ASD are similar remains unclear. The aim of this study was to compare EEG alterations found in these two clinical populations presenting varying degrees of cognitive and behavioral impairments. METHODS: Resting state EEG signal complexity, alpha peak frequency (APF) and power spectral density (PSD) were compared between 47 participants with FXS (aged between 5-20), 49 participants with ASD (aged between 6-17), and 52 neurotypical (NT) controls with a similar age distribution using MANCOVAs with age as covariate when appropriate. MANCOVAs controlling for age, when appropriate, and nonverbal intelligence quotient (NVIQ) score were subsequently performed to determine the impact of cognitive functioning on EEG alterations. RESULTS: Our results showed that FXS participants manifested decreased signal complexity and APF compared to ASD participants and NT controls, as well as altered power in the theta, alpha and low gamma frequency bands. ASD participants showed exaggerated beta power compared to FXS participants and NT controls, as well as enhanced low and high gamma power compared to NT controls. However, ASD participants did not manifest altered signal complexity or APF. Furthermore, when controlling for NVIQ, results of decreased complexity in higher scales and lower APF in FXS participants compared to NT controls and ASD participants were not replicated. CONCLUSIONS: These findings suggest that signal complexity and APF might reflect cognitive functioning, while altered power in the low gamma frequency band might be associated with neurodevelopmental conditions, particularly FXS and ASD.

Epistasis is caused by genetic interactions among mutations that affect fitness. To characterize properties and potential mechanisms of epistasis, we engineered eight double mutants that combined mutations from the rho and rpoB genes of Escherichia coli. The two genes encode essential functions for transcription, and the mutations in each gene were chosen because they were beneficial for adaptation to thermal stress (42.2 °C). The double mutants exhibited patterns of fitness epistasis that included diminishing returns epistasis at 42.2 °C, stronger diminishing returns between mutations with larger beneficial effects and both negative and positive (sign) epistasis across environments (20.0 °C and 37.0 °C). By assessing gene expression between single and double mutants, we detected hundreds of genes with gene expression epistasis. Previous work postulated that highly connected hub genes in coexpression networks have low epistasis, but we found the opposite: hub genes had high epistasis values in both coexpression and protein-protein interaction networks. We hypothesized that elevated epistasis in hub genes reflected that they were enriched for targets of Rho termination but that was not the case. Altogether, gene expression and coexpression analyses revealed that thermal adaptation occurred in modules, through modulation of ribonucleotide biosynthetic processes and ribosome assembly, the attenuation of expression in genes related to heat shock and stress responses, and with an overall trend toward restoring gene expression toward the unstressed state.

Cortical processing of auditory information can be affected by interspecies differences as well as brain states. Here we compare multifeature spectro-temporal receptive fields (STRFs) and associated input/output functions or nonlinearities (NLs) of neurons in primary auditory cortex (AC) of four mammalian species. Single-unit recordings were performed in awake animals (female squirrel monkeys, female, and male mice) and anesthetized animals (female squirrel monkeys, rats, and cats). Neuronal responses were modeled as consisting of two STRFs and their associated NLs. The NLs for the STRF with the highest information content show a broad distribution between linear and quadratic forms. In awake animals, we find a higher percentage of quadratic-like NLs as opposed to more linear NLs in anesthetized animals. Moderate sex differences of the shape of NLs were observed between male and female unanesthetized mice. This indicates that the core AC possesses a rich variety of potential computations, particularly in awake animals, suggesting that multiple computational algorithms are at play to enable the auditory systems robust recognition of auditory events.

Metal halide perovskites (MHPs) are low-temperature processable hybrid semiconductor materials with exceptional performances that are revolutionizing the field of optoelectronic devices. Despite their great potential, commercial deployment is hindered by MHPs lack of stability and durability, mainly attributed to ion migration and chemical interactions with the electrodes. To address these issues, 2D layered MHPs are investigated as possible device interlayers or active material substitutes. Here, the 2D perovskite (PEA)2PbBr4 is considered that is recently discussed as promising candidate for X-ray direct detection. While the increased resilience of (PEA)2PbBr4 radiation detectors has already been reported, the physical mechanisms responsible for such improvement compared to 3D perovskites are not still fully understood. To unravel the charge transport process in (PEA)2PbBr4 crystals thought to underly the device better performance, an investigation technique is adapted previously used on highly resistive inorganic semiconductors, called photo induced current transient spectroscopy (PICTS). It is demonstrated that PICTS can reliably detect three trap states (T1, T2, and T3), and that their evolution upon X-ray exposure can explain (PEA)2PbBr4 superior radiation tolerance and reduced aging effects. Overall, the results provide essential insights into the electrical characteristics of 2D perovskites and their potential application as reliable direct X-ray detectors.

Mindfulness witnessed a substantial popularity surge in the past decade, especially as digitally self-administered interventions became available at relatively low costs. Yet, it is uncertain whether they effectively help reduce stress. In a preregistered (OSF https://doi.org/10.17605/OSF.IO/UF4JZ ; retrospective registration at ClinicalTrials.gov NCT06308744 ) multi-site study (nsites = 37, nparticipants = 2,239, 70.4% women, Mage = 22.4, s.d.age = 10.1, all fluent English speakers), we experimentally tested whether four single, standalone mindfulness exercises effectively reduced stress, using Bayesian mixed-effects models. All exercises proved to be more efficacious than the active control. We observed a mean difference of 0.27 (d = -0.56; 95% confidence interval, -0.43 to -0.69) between the control condition (M = 1.95, s.d. = 0.50) and the condition with the largest stress reduction (body scan: M = 1.68, s.d. = 0.46). Our findings suggest that mindfulness may be beneficial for reducing self-reported short-term stress for English speakers from higher-income countries.

INTRODUCTION: The apolipoprotein E gene (APOE) is an established central player in the pathogenesis of Alzheimers disease (AD), with distinct apoE isoforms exerting diverse effects. apoE influences not only amyloid-beta and tau pathologies but also lipid and energy metabolism, neuroinflammation, cerebral vascular health, and sex-dependent disease manifestations. Furthermore, ancestral background may significantly impact the link between APOE and AD, underscoring the need for more inclusive research. METHODS: In 2023, the Alzheimers Association convened multidisciplinary researchers at the AAIC Advancements: APOE conference to discuss various topics, including apoE isoforms and their roles in AD pathogenesis, progress in apoE-targeted therapeutic strategies, updates on disease models and interventions that modulate apoE expression and function. RESULTS: This manuscript presents highlights from the conference and provides an overview of opportunities for further research in the field. DISCUSSION: Understanding apoEs multifaceted roles in AD pathogenesis will help develop targeted interventions for AD and advance the field of AD precision medicine. HIGHLIGHTS: APOE is a central player in the pathogenesis of Alzheimers disease. APOE exerts a numerous effects throughout the brain on amyloid-beta, tau, and other pathways. The AAIC Advancements: APOE conference encouraged discussions and collaborations on understanding the role of APOE.

BACKGROUND: Education influences brain health and dementia. However, its impact across regions, specifically Latin America (LA) and the United States (US), is unknown. METHODS: A total of 1412 participants comprising controls, patients with Alzheimers disease (AD), and frontotemporal lobar degeneration (FTLD) from LA and the US were included. We studied the association of education with brain volume and functional connectivity while controlling for imaging quality and variability, age, sex, total intracranial volume (TIV), and recording type. RESULTS: Education influenced brain measures, explaining 24%-98% of the geographical differences. The educational disparities between LA and the US were associated with gray matter volume and connectivity variations, especially in LA and AD patients. Education emerged as a critical factor in classifying aging and dementia across regions. DISCUSSION: The results underscore the impact of education on brain structure and function in LA, highlighting the importance of incorporating educational factors into diagnosing, care, and prevention, and emphasizing the need for global diversity in research. HIGHLIGHTS: Lower education was linked to reduced brain volume and connectivity in healthy controls (HCs), Alzheimers disease (AD), and frontotemporal lobar degeneration (FTLD). Latin American cohorts have lower educational levels compared to the those in the United States. Educational disparities majorly drive brain health differences between regions. Educational differences were significant in both conditions, but more in AD than FTLD. Education stands as a critical factor in classifying aging and dementia across regions.

Multiple myeloma is a treatable, but currently incurable, hematological malignancy of plasma cells characterized by diverse and complex tumor genetics for which precision medicine approaches to treatment are lacking. The Multiple Myeloma Research Foundations Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study ( NCT01454297 ) is a longitudinal, observational clinical study of newly diagnosed patients with multiple myeloma (n = 1,143) where tumor samples are characterized using whole-genome sequencing, whole-exome sequencing and RNA sequencing at diagnosis and progression, and clinical data are collected every 3 months. Analyses of the baseline cohort identified genes that are the target of recurrent gain-of-function and loss-of-function events. Consensus clustering identified 8 and 12 unique copy number and expression subtypes of myeloma, respectively, identifying high-risk genetic subtypes and elucidating many of the molecular underpinnings of these unique biological groups. Analysis of serial samples showed that 25.5% of patients transition to a high-risk expression subtype at progression. We observed robust expression of immunotherapy targets in this subtype, suggesting a potential therapeutic option.

The fundamental trade-off between current and future reproduction has long been considered to result in a tendency for species that can grow large to begin reproduction at a larger size. Due to the prolonged time required to reach maturity, estimates of tree maturation size remain very rare and we lack a global view on the generality and the shape of this trade-off. Using seed production from five continents, we estimate tree maturation sizes for 486 tree species spanning tropical to boreal climates. Results show that a species' maturation size increases with maximum size, but in a non-proportional way: the largest species begin reproduction at smaller sizes than would be expected if maturation were simply proportional to maximum size. Furthermore, the decrease in relative maturation size is steepest in cold climates. These findings on maturation size drivers are key to accurately represent forests' responses to disturbance and climate change.

We report the identification of 15 galaxy candidates at z ≥ 9 using the initial COSMOS-Web JWST observations over 77 arcmin2 through four Near Infrared Camera filters (F115W, F150W, F277W, and F444W) with an overlap with the Mid-Infrared Imager (F770W) of 8.7 arcmin2. We fit the sample using several publicly available spectral energy distribution (SED) fitting and photometric redshift codes and determine their redshifts between z = 9.3 and z = 10.9 (〈z〉 = 10.0), UV magnitudes between M UV = −21.2 and −19.5 (with 〈M UV〉 = −20.2), and rest-frame UV slopes (〈β〉 = −2.4). These galaxies are, on average, more luminous than most z ≥ 9 candidates discovered by JWST so far in the literature, while exhibiting similar blue colors in their rest-frame UV. The rest-frame UV slopes derived from SED fitting are blue (β ∼ [−2.0, −2.7]) without reaching extremely blue values as reported in other recent studies at these redshifts. The blue color is consistent with models that suggest the underlying stellar population is not yet fully enriched in metals like similarly luminous galaxies in the lower-redshift Universe. The derived stellar masses with 〈 log 10 ( M ⋆/M ⊙)〉 ≈ 8-9 are not in tension with the standard Lambda cold dark matter (ΛCDM) model, and our measurement of the volume density of such UV-luminous galaxies aligns well with previously measured values presented in the literature at z ∼ 9-10. Our sample of galaxies, although compact, is significantly resolved.

IHMCIF (github.com/ihmwg/IHMCIF) is a data information framework that supports archiving and disseminating macromolecular structures determined by integrative or hybrid modeling (IHM), and making them Findable, Accessible, Interoperable, and Reusable (FAIR). IHMCIF is an extension of the Protein Data Bank Exchange/macromolecular Crystallographic Information Framework (PDBx/mmCIF) that serves as the framework for the Protein Data Bank (PDB) to archive experimentally determined atomic structures of biological macromolecules and their complexes with one another and small molecule ligands (e.g., enzyme cofactors and drugs). IHMCIF serves as the foundational data standard for the PDB-Dev prototype system, developed for archiving and disseminating integrative structures. It utilizes a flexible data representation to describe integrative structures that span multiple spatiotemporal scales and structural states with definitions for restraints from a variety of experimental methods contributing to integrative structural biology. The IHMCIF extension was created with the benefit of considerable community input and recommendations gathered by the Worldwide Protein Data Bank (wwPDB) Task Force for Integrative or Hybrid Methods (wwpdb.org/task/hybrid). Herein, we describe the development of IHMCIF to support evolving methodologies and ongoing advancements in integrative structural biology. Ultimately, IHMCIF will facilitate the unification of PDB-Dev data and tools with the PDB archive so that integrative structures can be archived and disseminated through PDB.

BackgroundIt is unknown if early COVID-19 monoclonal antibody (mAb) therapy can reduce risk of Long COVID. The mAbs amubarvimab/romlusevimab were previously demonstrated to reduce risk of hospitalization/death by 79%. This study assessed the impact of amubarvimab/romlusevimab on late outcomes, including Long COVID.MethodsNon-hospitalized high-risk adults within 10 days of COVID-19 symptom onset enrolled in a randomized, double-blind, placebo-controlled phase 2/3 trial of amubarvimab/romlusevimab for COVID-19 treatment. Late symptoms, assessed using a participant-completed symptom diary, were a pre-specified exploratory endpoint. The primary outcome for this analysis was the composite of Long COVID by participant self-report (presence of COVID-19 symptoms as recorded in the diary at week 36) or hospitalization or death by week 36. Inverse probability weighting (IPW) was used to address incomplete outcome ascertainment, giving weighted risk ratios (wRR) comparing amubarvimab/romlusevimab to placebo.FindingsParticipants received amubarvimab/romlusevimab (n = 390) or placebo (n = 390) between January and July 2021. Median age was 49 years, 52% were female, 18% Black/African American, 49% Hispanic/Latino, and 9% COVID-19-vaccinated at entry. At week 36, 103 (13%) had incomplete outcome ascertainment, and 66 (17%) on amubarvimab/romlusevimab and 92 (24%) on placebo met the primary outcome (wRR = 0.70, 95% confidence interval (CI) 0.53-0.93). The difference was driven by fewer hospitalizations/deaths with amubarvimab/romlusevimab (4%) than placebo (13%). Among 652 participants with available diary responses, 53 (16%) on amubarvimab/romlusevimab and 44 (14%) on placebo reported presence of Long COVID.InterpretationAmubarvimab/romlusevimab treatment, while highly effective in preventing hospitalizations/deaths, did not reduce risk of Long COVID. Additional interventions are needed to prevent Long COVID.FundingNational Institute of Allergy and Infectious Diseases of the National Institutes of Health. Amubarvimab and romlusevimab supplied by Brii Biosciences.

BACKGROUND AND AIMS: Home treatment is considered safe in acute pulmonary embolism (PE) patients selected by a validated triage tool (e.g. simplified PE severity index score or Hestia rule), but there is uncertainty regarding the applicability in underrepresented subgroups. The aim was to evaluate the safety of home treatment by performing an individual patient-level data meta-analysis. METHODS: Ten prospective cohort studies or randomized controlled trials were identified in a systematic search, totalling 2694 PE patients treated at home (discharged within 24 h) and identified by a predefined triage tool. The 14- and 30-day incidences of all-cause mortality and adverse events (combined endpoint of recurrent venous thromboembolism, major bleeding, and/or all-cause mortality) were evaluated. The relative risk (RR) for 14- and 30-day mortalities and adverse events is calculated in subgroups using a random effects model. RESULTS: The 14- and 30-day mortalities were 0.11% [95% confidence interval (CI) 0.0-0.24, I2 = 0) and 0.30% (95% CI 0.09-0.51, I2 = 0). The 14- and 30-day incidences of adverse events were 0.56% (95% CI 0.28-0.84, I2 = 0) and 1.2% (95% CI 0.79-1.6, I2 = 0). Cancer was associated with increased 30-day mortality [RR 4.9; 95% prediction interval (PI) 2.7-9.1; I2 = 0]. Pre-existing cardiopulmonary disease, abnormal troponin, and abnormal (N-terminal pro-)B-type natriuretic peptide [(NT-pro)BNP] at presentation were associated with an increased incidence of 14-day adverse events [RR 3.5 (95% PI 1.5-7.9, I2 = 0), 2.5 (95% PI 1.3-4.9, I2 = 0), and 3.9 (95% PI 1.6-9.8, I2 = 0), respectively], but not mortality. At 30 days, cancer, abnormal troponin, and abnormal (NT-pro)BNP were associated with an increased incidence of adverse events [RR 2.7 (95% PI 1.4-5.2, I2 = 0), 2.9 (95% PI 1.5-5.7, I2 = 0), and 3.3 (95% PI 1.6-7.1, I2 = 0), respectively]. CONCLUSIONS: The incidence of adverse events in home-treated PE patients, selected by a validated triage tool, was very low. Patients with cancer had a three- to five-fold higher incidence of adverse events and death. Patients with increased troponin or (NT-pro)BNP had a three-fold higher risk of adverse events, driven by recurrent venous thromboembolism and bleeding.