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A vapor-phase ZIF-8 MOF deposition procedure for seamless high-aspect-ratio interconnect gap fill has been developed with a short process time (15 min) at a 160 °C process temperature. This is the most rapid documented vapor technique to produce a MOF film and is made possible by a higher process temperature and a low background H 2 O environment. The process consists of ALD of a thin (<5 nm) ZnO film followed by conversion to ZIF-8 in an organic linker (ALD + soak cycle). This method exhibited complete ZnO to MOF conversion, as well as MOFs with low-k ( k ∼ 2.6). Dielectric gap fill was investigated utilizing patterned samples with widths ranging from 40 to 400 nm. Both high aspect ratio gap fill and multiple aspect ratio gap fills were shown with no residual ZnO. The MOF gap-fill process could be attributed to the reflow behavior of 2-methylimidazole-ZnO reaction intermediates or nascent product. The MOF was found to be stable at 400 °C under vacuum (1 × 10 -2 Torr), which is comparable to other low-k dielectrics. Fluorine plasma etch resistance was tested for the ZIF-8 MOF in comparison to bare Si, SiCOH, and SiO 2 ; the MOF was proven to be the best in resisting plasma etch. This work demonstrated that ALD + soak cycle conversion low-k ZIF-8 MOF films have the potential to be a plasma-free vapor-phase seamless gap fill for high aspect ratio features to be employed in logic and memory device fabrication, as well as three-dimensional heterogeneous integration (3DHI).

Over the last 80 years, chlorine (Cl) has been the primary promoter of the ethylene epoxidation reaction valued at ~40 billion USD per year, providing a ~25% selectivity increase over unpromoted silver (Ag) (~55%). Promoters such as cesium, rhenium, and molybdenum each add a few percent of selectivity enhancements to achieve 90% overall, but their codependence on Cl makes optimizing and understanding their function complex. We took a theory-guided, single-atom alloy approach to identify nickel (Ni) as a dopant in Ag that can facilitate selective oxidation by activating molecular oxygen (O 2 ) without binding oxygen (O) too strongly. Surface science experiments confirmed the facile adsorption/desorption of O 2 on NiAg, as well as demonstrating that Ni serves to stabilize unselective nucleophilic oxygen. Supported Ag catalyst studies revealed that the addition of Ni in a 1:200 Ni to Ag atomic ratio provides a ~25% selectivity increase without the need for Cl co-flow and acts cooperatively with Cl, resulting in a further 10% initial increase in selectivity.

Study Design: Prospective observational cohort., Objectives: To report on the role of a single wearable sensor in the evaluation of patients with Cervical Spondylotic Myelopathy (CSM)., Summary of Background Data: Clinical evaluation of CSM is limited, as Hoffmann's sign, Romberg testing and Tandem Gait are largely subjective and binary, making deterioration or improvement difficult to document accurately., Methods: Patients scheduled for surgical treatment of CSM underwent in-office and 24-hour continuous at-home data collection using a single wearable sensor. In-office testing consisted of Standing, Romberg testing, Tandem Gait and Timed Up & Go (TUG). Testing was repeated 6-months post-operatively., Results: Statistically significant improvements were seen following surgical treatment in the Romberg test eyes-open maximum antero-posterior sway (P=0.010), eyes-open total path traveled (P=0.048); in Tandem Gait speed (P=0.021), duration (P=0.002), antero-posterior sway (P=0.046) and initial peak acceleration (P=0.001). There was no statistically significant difference in TUG testing. At-home gait pattern revealed a trend toward decreased lateral sway post-operatively (P=0.062) and fewer sleep turns (P=0.078)., Conclusion: Wearable sensor data effectively quantifies standard exam findings and identifies new metrics with the potential to assess more accurately pre-operative and post-operative function in patients with CSM. Previously unreported pre-operative to 6-month post-operative changes were seen in speed of gait and ground impact force during Tandem Gait. These metrics were more sensitive as compared to the normal antero-posterior and lateral sway assessment. 24-hour sensor data showed decreased number of turns during sleep post-operatively. This study suggests that wearable sensor data will be a viable source for quantifiable data with the potential to guide treatment for patients with CSM. This capability is based partly on better quantification of existing binary measures, but also on identification of unanticipated patterns within the data., Competing Interests: The authors report no conflicts of interest., (Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose/objective: Individuals with spinal cord injuries and disorders (SCI/D) may exhibit cues that tell a story about their loneliness. Health care providers must recognize loneliness cues in order to take action. This study identified and described loneliness cues exhibited by persons with SCI/D from health provider perspectives., Research Method/design: Descriptive qualitative design using in-depth interviews with health providers and analyzed using thematic analysis., Results: Multidisciplinary SCI/D health providers from 10 nationwide Veterans Health Administration facilities. Ten themes described loneliness cues exhibited by persons with SCI/D: (a) direct or indirect verbal expression; (b) physical health symptoms/conditions; (c) mental health indicators; (d) withdrawal/lack of engagement; (e) "severe" voluntary seclusion, for example, not leaving house, not getting out of bed, sitting in the dark; (f) poor lifestyle behaviors, for example, substance use, poor nutrition; (g) neglecting personal self-care, for example, poor hygiene; (h) neglecting ones' internal environment, for example, dirty home, hoarding; (i) avoiding health care and health care management needs, for example, missing medical appointments, neglecting bowel care; and (j) fixating on health care to meet social health needs., Conclusions/implications: Health care providers identified several loneliness cues commonly exhibited by individuals with SCI/D. These cues, whether verbal or nonverbal, may represent a signal that alerts the provider of a concern around loneliness. The value of such cues depends on the health provider's ability to identify them in order to decide on next steps, which may involve formal screening or validated measurement followed by collaborative patient engagement to identify potential sources contributing to loneliness and areas patients wish to address. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

Lung bacterial infections, including hospital-acquired pneumonia, remain a serious problem for public health. Endothelial cell (EC) exposure to heat-killed Staphylococcus aureus (HKSA) represents a clinical scenario of high titers of killed bacterial particles present in the host after antibiotic therapy, which triggers inflammatory cascades, cytokine storms, and EC dysfunction leading to acute lung injury (ALI). GPR68 is a member of the proton-sensing G protein-coupled receptor family. Acting as a pH sensor, GPR68 becomes activated upon pH reduction and contributes to pathologic cell responses by activating ER stress and unfolded protein response. This study investigated the role of GPR68 in HKSA-induced EC dysfunction and HKSA-induced ALI. HKSA robustly increased GPR68 mRNA levels in human pulmonary EC and directly stimulated GPR68 activity. A selective GPR68 small molecule inhibitor, OGM-8345, attenuated HKSA-induced EC permeability and protected cell junction integrity. OGM-8345 inhibited HKSA-induced activation of inflammatory genes TNF-α, IL-6, IL-8, IL-1β, and CXCL5 and decreased cytokine secretion by HKSA-challenged EC. Co-treatment with the GPR68 activator Ogerin or medium acidification to pH 6.5 augmented HKSA-induced EC dysfunction, which was rescued by OGM-8345. Intratracheal HKSA injection increased vascular leak and lung inflammation in mice which were monitored by lung Evans blue extravasation, increased cell and protein count in bronchoalveolar lavage, and mRNA expression of inflammatory genes. ALI and barrier dysfunction was attenuated by OGM-8345. We show for the first time the role of GPR68 in mediating HKSA-induced lung injury and the strong potential for OGM-8345 as a therapeutic treatment of bacterial pathogen-induced ALI associated with tissue acidification., (© 2025 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Sperm cryopreservation is important for many individuals across the globe. Recent studies show that vitrification is a valuable approach for maintaining sperm quality after freeze-thawing processes and requires sub-microliter to microliter volumes. A major challenge for the adoption of vitrification in fertility laboratories is the ability to pipet small volumes of sample. Here, we present an open droplet generator that leverages open-channel microfluidics to passively generate sub-microliter to microliter volumes of purified human sperm samples and preserves sperm kinematics. We conclude that our platform is compatible with human sperm, an important foundation for future implementation of vitrification in fertility laboratories.

For many countries in the Global South traditional poverty estimates are available only infrequently and at coarse spatial resolutions, if at all. This limits decision-makers' and analysts' ability to target humanitarian and development interventions and makes it difficult to study relationships between poverty and other natural and human phenomena at finer spatial scales. Advances in Earth observation and machine learning-based methods have proven capable of generating more granular estimates of relative asset wealth indices. They have been less successful in predicting the consumption-based poverty measures most commonly used by decision-makers, those tied to national and international poverty lines. For a study area including four countries in southern and eastern Africa, we pilot a two-step approach that combines Earth observation, accessible machine learning methods, and asset-based structural poverty measurement to address this gap. This structural poverty approach to machine learning-based poverty estimation preserves the interpretability and policy-relevance of consumption-based poverty measures, while allowing us to explain 72 to 78% of cluster-level variation in a pooled model and 40 to 54% even when predicting out-of-country., Competing Interests: Competing interests statement:The authors declare no competing interest.

Popliteal artery rupture is a rare but life-threatening complication of total knee arthroplasty. In order to prevent dangerous outcomes, such as amputation or death, immediate vascular intervention is needed. This case highlights the importance of intraoperative vigilance and prompt action to mitigate these risks., Competing Interests: Professor Hennekens also declares that he serves as an independent scientist in an advisory role to investigators and sponsors as chair of two Data Monitoring Committees for Amgen (evolocumab and erenumab); to the United States Food and Drug Administration, and UpToDate; receives royalties for authorship or editorship of three textbooks; has an investment management relationship with the West‐Bacon Group within Truist Investment Services, which has discretionary investment authority; and does not own any common or preferred stock in any pharmaceutical or medical device company. None of the other authors declares any conflicts of interest., (© 2025 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.)

Objective: Persistent post-concussive symptoms (PPCS) are common and disruptive, particularly in military service members (SM), yet there are no approved therapies targeting underlying physiological processes. This study was designed to compare acoustic neuromodulation using Cereset Research™ Standard Operating Procedures (CR-SOP), with Cereset Research Cranial Electrical Stimulation (CR-CES), on PPCS., Methods: SM, veterans, or dependents with PPCS (Neurobehavioral Symptom Inventory [NSI] Score ≥23) were randomized to receive 10 sessions of engineered tones linked to brainwaves (CR-SOP) or 5 sessions of CR-CES, which adds intermittent low voltage transcranial alternating current stimulation (tACS) to CR-SOP. Designed to assess non-inferiority between varied doses of CR-SOP and CR-CES, the primary outcome was a change in post-concussive symptoms on the NSI, with secondary outcomes of heart rate variability (HRV) and self-report measures of PTSD, sleep, headaches, and depression., Results: Among study participants ( n  = 80, 21.3% female, mean age 40.2 [SD 13.2], 4.8 deployments, 3.2 TBIs), mean NSI declined from 45.6 to 29.5 after intervention ( p  < 0.0001), with gains sustained at 3 months (29.7). No significant between group differences for NSI (CR-SOP: baseline 43.9, post-intervention 26.0, 3-month 27.2, and CR-CES 46.4, 30.7, and 31.1, respectively), and no evidence of inferiority between the groups with respect to NSI. Similar improvements were seen on PCL-5, ISI, HIT-6, and PHQ-9, with no HRV differences between groups., Conclusion: Both acoustic neuromodulation alone (CR-SOP) and a lower dose of CR-SOP, with tACS added (CR-CES), significantly improved PPCS out to 3 months., Registration: ClinicalTrials.gov - NCT03649958.

Radioresistance is thought to be a major consequence of tumor milieu acidification resulting from the Warburg effect. Previously, using ogremorphin (OGM), a small molecule inhibitor of GPR68, an extracellular proton sensing receptor, we demonstrated that GPR68 is a key pro-survival pathway in glioblastoma cells. Here, we demonstrate that GPR68 inhibition also induces ferroptosis in lung cell carcinoma (A549) and pancreatic ductal adenocarcinoma (Panc02) cells. Moreover, OGM synergized with ionizing radiation to induce lipid peroxidation, a hallmark of ferroptosis, as well as reduce colony size in 2D and 3D cell culture. GPR68 inhibition is not acutely detrimental but increases intracellular free ferrous iron, which is known to trigger reactive oxygen species (ROS) generation. In summary, GPR68 inhibition induces lipid peroxidation in cancer cells and sensitizes them to ionizing radiation in part through the mobilization of intracellular free ferrous iron. Our results suggest that GPR68 is a key mediator of cancer cell radioresistance activated by acidic tumor microenvironment., Competing Interests: Declarations. Competing interests: LRN, JC, SR, CHW and CCH are inventors on a patent application related to this manuscript. DTF and CdAF declare no conflicts of interest., (© 2025. The Author(s).)

Introduction: As a result of improving survival rates, the adverse consequences of rectal cancer surgery are becoming increasingly recognised. Low anterior resection syndrome (LARS) is one such consequence and describes a constellation of bowel symptoms after rectal cancer surgery which includes urgency, faecal incontinence, stool clustering and incomplete evacuation. LARS has a significant adverse impact on quality of life (QoL) and symptoms are present in up to 75% of patients in the first year after surgery. Despite this, little is known about the natural history and there is poor evidence to support current treatment options., Methods and Analysis: The objectives of POLARiS are to explore the natural history of LARS and to evaluate the clinical and cost-effectiveness of transanal irrigation (TAI) or sacral neuromodulation (SNM) compared with optimised conservative management (OCM) for people with major LARS.POLARiS is a prospective, international, open-label, multi-arm, phase 3 randomised superiority trial within a cohort design, with internal pilot phase, qualitative sub-study, process evaluation and economic evaluation. Approximately 1500 adult participants from UK hospitals and 500 from Australian hospitals who have undergone a high or low anterior resection for colorectal cancer in the last 10 years will be recruited into the cohort. Six-hundred participants from the UK and 200 participants from Australia, with major LARS symptoms, defined as a LARS score of ≥30, will be recruited to the randomised controlled trial (RCT) element. Participants entering the RCT will be randomised between OCM, TAI or SNM, all with equal allocation ratios.Cohort and RCT participants will be followed up for a 24-month period, completing a series of questionnaires measuring LARS symptoms and QoL, as well as clinical review for those in the RCT. A process evaluation, qualitative sub-study and economic evaluation will also be conducted.The primary outcome measure of the POLARiS cohort and RCT is the LARS score up to 24 months post-registration/randomisation. Analyses of the RCT will be conducted on an intention-to-treat basis. Comparative effectiveness analyses for each endpoint will consist of two pairwise treatment comparisons: TAI versus OCM and SNM versus OCM. Secondary outcomes include health-related QoL, adverse events, treatment compliance and cost-effectiveness (up to 24 months post-registration/randomisation)., Ethics and Dissemination: Ethical approval has been granted by Wales REC 4 (reference: 23/WA/0171) in the UK and Sydney Local Health District HREC (reference: 2023/ETH00749) in Australia. The results of this trial will be disseminated to participants on request and published on completion of the trial in a peer-reviewed journal and at international conferences., Trial Registration Number: ISRCTN12834598; ACTRN12623001166662., Competing Interests: Competing interests: All authors were required to provide ICMJE COI disclosure form, the following disclosures were made: DDS is fully funded through the NIHR as a Research Professor and is an NIHR Efficacy and Mechanism Evaluation Funding Committee member. CHK has carried out speaker and consultancy work for Medtronic and consultancy work for Exero Medical. He is Chief Medical Officer and co-founder of Amber Therapeutics, and CMO and shareholder at Enterika LTD. AQ is a member of ACPGBI Advanced Cancer sub-committee and has received a ZR MedTech Honoraria for lecturing at the Chinese Colorectal Society. JCo has received an educational grant from BD & Medtronic and is Clinical Director of Everywoman Festival. All other authors made no declarations., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY. Published by BMJ Group.)

Objectives: To evaluate the association between cardiorespiratory fitness (CRF) and cognition in a large sample of older adults, and to examine clinical and demographic factors that might moderate these associations., Methods: CRF was measured with a graded exercise test performed on a motorised treadmill. A confirmatory factor analysis was conducted using data from a comprehensive neuropsychological battery to obtain latent factors reflecting core cognitive domains. Linear regression models evaluated the association between CRF and each of the cognitive composites, and potential moderators including demographic factors (age, sex, education), apolipoprotein E ε4 ( APOE4 ) carriage, beta-blocker use and components of maximal effort criteria during CRF testing., Results: The sample consisted of 648 adults (mean (SD) age 69.88 (3.75)), including 461 women (71.1%). The highest oxygen consumption obtained during testing (VO 2max ) was mean (SD) = 21.68 (5.06) mL/kg/min. We derived a five-factor model composed of episodic memory, processing speed, working memory, executive function/attentional control and visuospatial function. Higher CRF was associated with better performance across all five cognitive domains after controlling for covariates. Age and APOE4 carriage did not moderate observed associations. The relationship between CRF and cognitive performance was greater in women, those with fewer years of education and those taking beta-blockers in the domains of processing speed (sex: β=-0.447; p=0.015; education: β=-0.863; p=0.018) and executive function/attentional control (sex: β=-0.417; p=0.022; education β=-0.759; p=0.034; beta-blocker use: β=0.305; p=0.047)., Conclusion: Higher CRF in older adulthood is associated with better cognitive performance across multiple domains susceptible to age-related cognitive decline. Sex, education and use of beta-blockers moderated observed associations within select cognitive domains., Competing Interests: Competing interests: The authors declare no conflicts of interest relevant to this article. KIE consults for MedRhythms, Inc., and Neo Auvra, Inc. JMJ is on the Scientific Advisory Board for Wondr Health, Inc., and was the site principal investigator for a research study supported by Epitomee Medical, Inc., awarded to the University of Kansas Medical Center., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY. Published by BMJ Group.)

Introduction: POINTER Neurovascular (POINTER-NV) is an ancillary study that leverages the rich infrastructure and design of the U.S. Study to Protect Brain Health through Lifestyle Intervention to Reduce Risk (U.S. POINTER) to investigate neurovascular mechanisms that may underlie intervention effects on key brain outcomes., Methods: A comprehensive neurovascular assessment is conducted at baseline, Month 12, and Month 24 using a variety of complementary non-invasive techniques including transcranial Doppler ultrasound, carotid ultrasound, echocardiography, tonometry, and continuous blood pressure and heart rate monitoring. Measurements are acquired at rest and during orthostatic challenges, hyperventilation, and carbon dioxide inhalation., Results: The primary outcomes are baroreflex sensitivity and cerebral autoregulation. Secondary outcomes include aortic, carotid, and cerebral hemodynamics and various measures of autonomic function and vascular structure and function., Discussion: POINTER-NV will provide critical insight into neurovascular mechanisms that may change with intensive lifestyle modification and promote improvements in cognition and overall brain health., Highlights: This study takes advantage of U.S. Study to Protect Brain Health through Lifestyle Intervention to Reduce Risk (U.S. POINTER) to address key gaps in the field. POINTER Neurovascular (POINTER-NV) will provide insight into neurovascular mechanisms underlying dementia. POINTER-NV may help shed light on modifiable vascular contributions to dementia., (© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

During the past decade, growing recidivism has threatened the enormous beneficial impacts of vaccinations in the United States. The barriers are multifactorial and include increasing vaccine hesitancy. The continuing dedicated efforts of all healthcare professionals, along with advancements in vaccine technology and the resilience of public health systems, offers promise for the future. The ultimate goals of eradication and elimination of infectious diseases are within reach. The sustained commitments and collaborations of dedicated and conscientious individual healthcare providers and public health officials are important components. Healthcare providers and public health officials should remain cognizant that increasing vaccination rates are essential but not sufficient. Surveillance containment entails rapid detection and reporting of cases with prompt immunization of household members and close contacts of confirmed cases, combined with judicious use of isolation, prompt antiviral or antibiotic medications, social distancing, respiratory etiquette, home or large-scale quarantines, and masking. The continuing and expanded efforts of US healthcare providers are vital to these successes., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The pea aphid, Acyrthosiphon pisum, is an emerging model system in functional and comparative genomics, in part due to the availability of new genomic approaches and the different sequencing and annotation efforts that the community has dedicated to this important crop pest insect. The pea aphid is also used as a model to study fascinating biological traits of aphids, such as their extensive polyphenisms, their bacteriocyte-confined nutritional symbiosis, or their adaptation to the highly unbalanced diet represented by phloem sap. To get insights into the molecular basis of all these processes, it is important to have an appropriate annotation of transcription factors (TFs), which would enable the reconstruction/inference of gene regulatory networks in aphids. Using the latest version of the A. pisum genome assembly and annotation, which represents the first chromosome-level pea aphid genome, we annotated the complete repertoire of A. pisum TFs and complemented this information by annotating genes encoding chromatin-associated and basal transcription machinery proteins. These annotations were done combining information from the model Drosophila melanogaster, for which we also provide a revisited list of these proteins, and de novo prediction. The comparison between the two model systems allowed the identification of major losses or expansions in each genome, while a deeper analysis was made of ZNF TFs (with certain families expanded in the pea aphid), and the Hox gene cluster (showing reorganization in gene position in the pea aphid compared to D. melanogaster). All annotations are available to the community through the Aphid Transcription Factors database (ATFdb), consolidating the various annotations we generated. ATFdb serves as a valuable resource for gene regulation studies in aphids., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Blood-based biomarkers (BBMs) can enable early detection of brain amyloid beta (Aβ) pathology in cognitively unimpaired individuals. However, the extent to which common medical conditions affect biomarker performance remains unclear., Methods: Participants (n = 348) included individuals without cognitive impairment. We studied how brain Aβ associated with BBMs (Aβ42/40, phosphorylated tau [p-tau] 181 and 217, p-tau217/Aβ42, glial fibrillary acidic protein [GFAP], and neurofilament light [NfL]) and optimal BBM thresholds for predicting brain Aβ positivity and whether they are obscured by the presence of common medical conditions., Results: Plasma Aβ42/40, p-tau181, p-tau217, and GFAP, but not NfL, were significantly associated with brain Aβ. P-tau217/Aβ42 showed the best discriminative performance (area under the curve: 0.91). The strength of p-tau217-brain Aβ associations were obscured by diabetes and cardiovascular conditions., Discussion: These results suggest BBMs may help detect early Aβ pathology but suggest caution in their use due to common medical conditions that could affect accuracy., Highlights: Plasma Aβ42/40, p-tau181, p-tau217, and GFAP but not NfL showed significant associations with brain Aβ. BBMs were more strongly associated with the level of brain Aβ in those without diabetes and cardiovascular conditions. P-tau217/Aβ42 showed the best performance (AUC = 0.91) in discriminating Aβ presence with an optimal cut-off of >1.2, followed by p-tau217 at >0.46 pg/mL, with performance slightly improving when excluding participants with cardiovascular conditions., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Previous results from the KEYNOTE-716 trial demonstrated significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) with adjuvant pembrolizumab versus placebo in patients with resected stage IIB or IIC melanoma. We present a post hoc analysis of efficacy according to primary tumor location., Methods: KEYNOTE-716 (NCT03553836) is a randomized, multicenter, double-blind, phase III study. Patients aged ≥ 12 years with newly diagnosed, resected stage IIB or IIC melanoma (sentinel node-negative) were randomly assigned (1:1) to pembrolizumab 200 mg every 3 weeks (2 mg/kg up to 200 mg for pediatric patients) or placebo. This post hoc analysis evaluated RFS and DMFS by primary tumor location of the head/neck, trunk, or extremities., Results: Overall, 976 patients were assigned to pembrolizumab (n = 487) or placebo (n = 489). Median follow-up was 39.4 months (range 26.0-51.4). The hazard ratios {HRs (95% confidence interval [CI])} for RFS were 0.60 (0.38-0.93) for the head/neck subgroup, 0.57 (0.38-0.84) for the trunk subgroup, and 0.69 (0.47-1.02) for the extremities subgroup. The HRs (95% CI) for DMFS were 0.65 (0.37-1.14) for the head/neck subgroup, 0.59 (0.38-0.92) for the trunk subgroup, and 0.53 (0.31-0.90) for the extremities subgroup., Conclusion: RFS and DMFS consistently favored adjuvant pembrolizumab over placebo in most subgroups analyzed in this post hoc analysis from the KEYNOTE-716 trial. These results support the benefit of adjuvant pembrolizumab on RFS and DMFS in patients with resected high-risk stage II melanoma, irrespective of primary tumor location., Competing Interests: Disclosure: Charles H. Yoon has no conflicts of interest to declare. Merrick I. Ross has received consulting fees from, support for travel from, and participated on advisory boards for Merck & Co., Inc., Rahway, NJ, USA. Brian R. Gastman conducted an investigator-initiated trial unrelated to this work and has received honorarium from and participated in an advisory board meeting for Merck & Co., Inc., Rahway, NJ, USA. Jason J. Luke has received grants or contracts from AbbVie, Astellas, AstraZeneca, Bristol Myers Squibb, Corvus, Day One, EMD Serono, Fstar, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Merck & Co., Inc., Rahway, NJ, USA, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimmune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, and Xencor; consulting fees from 7 Hills, Bright Peak, Exo, Fstar, Inzen, RefleXion, Xilio, Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, Pyxis, Saros, Stipe, Tempest, AbbVie, Alnylam, Atomwise, Bayer, Bristol Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Eisai, EMD Serono, Endeavor, Flame, G1 Therapeutics, Genentech, Gilead, Glenmark, HotSpot, Kadmon, KSQ, Janssen, Ikena, Inzen, Immatics, Immunocore, Incyte, Instil, IO Biotech, Macrogenics, Merck & Co., Inc., Rahway, NJ, USA, Mersana, Nektar, Novartis, Partner, Pfizer, Pioneering Medicines, PsiOxus, Regeneron, Ribon, Roivant, Servier, STINGthera, Synlogic, and Synthekine; has the following patents (both provisional): Serial #15/612,657 (Cancer Immunotherapy) and PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof); participated on a data monitoring committee or advisory board for AbbVie, Immutep, Evaxion; had a leadership role in the Society for Immunotherapy of Cancer; and has stock ownership in Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, Pyxis, Saros, Stipe, and Tempest. Paolo A. Ascierto has received grants from or contracts with Bristol Myers Squibb, Roche-Genentech, Pfizer/Array, and Sanofi; has received consulting fees from Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre Fabre, AstraZeneca, Sun Pharma, Sanofi, Sandoz, Immunocore, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos, Medicenna, Bio-Al Health, ValoTX, Replimmune, Bayer, and Erasca; has received honoraria from Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre Fabre, AstraZeneca, Sun Pharma, Sanofi, Sandoz, Immunocore, Italfarmaco, and Pfizer; has received support for attending meetings from Pfizer, Bio-AI Health, and RepImmune; and has participated on a data safety monitoring board or advisory board for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre Fabre, AstraZeneca, Sun Pharma, Sanofi, Sandoz, Immunocore, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos, Medicenna, Bio-Al Health, ValoTX, Replimmune, Bayer, and Erasca. Georgina V. Long is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Bayer, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, GI Innovation, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Immunocore, Innovent Biologics USA, IOBiotech, Iovance Biotherapeutics, MSD, Novartis, PHMR Ltd, Pierre Fabre, Regeneron, Scancell, SkylineDX B.V. Piotr Rutkowski has received consulting fees from Bristol Myers Squibb, Merck & Co., Inc., Rahway, NJ, USA, Novartis, Pierre Fabre, Philogen, Pfizer, Genesis, and Madison Pharma; has received honoraria from Bristol Myers Squibb, Merck & Co., Inc., Rahway, NJ, USA, Novartis, Pfizer, Pierre Fabre, Sanofi, AstraZeneca, Pfizer, Novartis, Pierre Fabre, Merck & Co., Inc., Rahway, NJ, USA, and BMS; has received support for attending meetings and/or for travel from Orphan Europe and Pierre Fabre; and has received research funding (Inst) from Novartis, Pfizer, Roche, and Bristol Myers Squibb. Muhammad Khattak has received honoraria from and participated on an advisory board meeting for Merck & Co., Inc., Rahway, NJ, USA. Michele Del Vecchio has received consulting fees from Bristol Myers Squibb, Immunocore, Merck & Co., Inc., Rahway, NJ, USA, Novartis, and Pierre Fabre, and has received honoraria from Bristol Myers Squibb, Pierre Fabre, Merck & Co., Inc., Rahway, NJ, USA, Immunocore, and Novartis. Lius de la Cruz Merino has received consulting fees from BMS, Merck & Co., Inc., Rahway, NJ, USA, Roche, AstraZeneca, and Gilead; has received honoraria from AstraZeneca, Merck & Co., Inc., Rahway, NJ, USA, and BMS; and has received support for attending meetings and/or for travel from Gilead. Jacek Mackiewicz has received honoraria from Bristol Myers Squibb, Merck & Co., Inc., Rahway, NJ, USA, Pierre Fabre, and Novartis; has participated on advisory boards for Bristol Myers Squibb, and Merck & Co., Inc., Rahway, NJ, USA; and has received travel grants from Bristol Myers Squibb, Merck & Co., Inc., Rahway, NJ, USA, Pierre Fabre, and Novartis. Vanna Chiarion-Sileni has received honoraria from Immunocore, support for attending meetings and/or travel from Pierre Fabre and Sanofi, and has participated on a data monitoring committee for Pierre Fabre and Merck Sharp & Dohme. Dirk Schadendorf has received grants or contract (Inst) from BMS, Amgen, and Merck & Co., Inc., Rahway, NJ, USA; has received consulting fees from Anaveaon, Agenus, BMS, Novartis, Merck & Co., Inc., Rahway, NJ, USA, Merck-Serono, Sanofi, Regenereon, Pierre Fabre, Pfizer, 4SC, InFlarX, Seagen, Replimune, Sunpharma, Philogen, Neracare, BioAlta, Daiichi Sanyo, AstraZeneca, Immatics, PamGene, BioNTech, CureVac, Ersaca, Formycon, NoviGenix, Haystack, IOBioTech, Immunocore, Nektar, and OncoSec; has received honoraria from BMS, Novartis, Merck & Co., Inc., Rahway, NJ, USA, Merck-Serono, Sanofi, Pierre Fabre, Pfizer, and Sun Pharma; has participated on advisory boards for BioAlta, 4SC, InFlarX, Daiichi Sanyo, AstraZeneca, and Immunocore; and has a leadership role in Dermatologic Cooperative Group (DeCOG), EuMelaREg, NVKH, and Hiege-Stiftung. Matteo S. Carlino has received consulting fees from Amgen, Bristol Myers Squibb, Eisai, Ideaya, Merck & Co., Inc., Rahway, NJ, USA, Nektar, Novartis, Oncosec, Pierre Fabre, Qbiotics, Regeneron, Roche, and Sanofi; and honoraria from BMS and Merck & Co., Inc., Rahway, NJ, USA. Yujie Zhao, Mizuho Fukunaga-Kalabis, and Clemens Krepler are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and own stock in Merck & Co., Inc., Rahway, NJ, USA. Alexander M.M. Eggermont has received support for the present manuscript from Merck & Co., Inc., Rahway, NJ, USA; has received consulting fees from Agenus, Boehringer Ingelheim, BioInvent, BioNTech, Brenus, CatalYm, Eurobio, Galecto, GenOway, ImCheck, IO Biotech, Ipsen, IQVIA, ISA Pharmeuticals, Merck & Co., Inc., Rahway, NJ, USA, Pfizer, Pierre Fabre, Scancell, Scorpion, TigaTx, and Trained Immunity Discovery; has received honoraria from Merck & Co., Inc., Rahway, NJ, USA, and BMS; has participated on advisory boards for Agenus, Boehringer Ingelheim, BioInvent, BioNTech, Brenus, CatalYm, Eurobio, Galecto, GenOway, ImCheck, IO Biotech, Ipsen, IQVIA, ISA Pharmeuticals, Merck & Co., Inc., Rahway, NJ, USA, Pfizer, Pierre Fabre, Scancell, Scorpion, TigaTx, and Trained Immunity Discovery; and has stock ownership in IO Biotech, Sairopa B.V., and SkylineDX B.V. Jeffrey E. Gershenwald has received royalties from UpToDate, consulting fees and advisory board participation fees from Merck & Co., Inc., Rahway, NJ, USA, and is Vice Chair of the American Joint Committee on Cancer. Vernon K. Sondak has received grants or contracts from Neogene Therapeutics, SkylineDx, and Turnstone Biologics; and has received consulting fees from Bristol Myers Squibb, Genesis Drug Discovery & Development, Iovance, Merck & Co., Inc., Rahway, NJ, USA, Mural Oncology, Novartis, and Sun Pharmaceuticals., (© 2025. Merck & Co., Inc., Rahway, NJ, USA and its Affiliates & The Authors.)

Spinal cord epidural stimulation (scES) is a therapeutic option that promotes functional improvements in sensory, motor, and autonomic functions following spinal cord injury (SCI). Previous scES mapping studies targeting the lower urinary tract (LUT) in rats demonstrated functional response variability based upon lumbosacral level, parameters used, extent of injury (spinally intact vs. chronic anatomically complete spinal transections), and sex. In the current study, female rats with clinically relevant graded incomplete T9 contusion injuries were mapped with scES at 60 days post-injury at three spinal levels (T13, L3, L6) with a novel miniature 15-electrode array designed to deliver optimal specificity. The results obtained during bladder fill and void cycles conducted under urethane anesthesia indicate frequency dependent sub-motor threshold effects on LUT function with a single row of electrodes positioned across the full medio-lateral extent of the dorsal cord. The findings of improved storage and emptying, represented by significantly longer inter-contractile intervals with T13 scES and L3 scES and by a significantly increased estimated void efficiency with L6 scES, respectively, are consistent with previous studies using intact and chronic complete transected male and female rats. The data support the efficacy of selective spinal network stimulation to drive functionally relevant networks for storage versus emptying phases of the urinary cycle. The current findings further demonstrate the translational promise of scES for SCI individuals with LUT dysfunctions, regardless of injury severity.

Background: Idiopathic rapid eye movement sleep behavior disorder (RBD) is a strong known predictor of a final clinicopathological diagnosis of a Lewy type α-synucleinopathy (LTS). Olfactory dysfunction is an early symptom of synucleinopathies and has been repeatedly associated with the presence of post-mortem LTS., Objective: To assess the combined value of a clinician diagnosis of probable RBD (PRBD) and hyposmia in predicting the post-mortem presence of LTS in a broader, less-selected, volunteer elderly population., Methods: We studied 652 autopsied subjects from the Arizona Study of Aging and Neurodegenerative Disorders, which were evaluated for PRBD, had completed annual movement and cognitive assessments, and had at least one the University of Pennsylvania Smell Identification Test (UPSIT) olfactory test., Results: Histological evidence of LTS was significantly more frequent in those who had PRBD (112/152: 73.7%) than those without (177/494: 35.8%) (P < 0.001). LTS was more frequent in cases with PRBD and a low UPSIT score (90.8%) compared to cases with PRBD only (73.7%) (P < 0.001) or cases with a low UPSIT score only (69.4%) (P < 0.001). Sensitivity of PRBD diagnosis for predicting LTS was 38.8% and specificity 88.8%, whereas sensitivity of a low UPSIT score was 74.4% and specificity 73.4% (Youden's index = 0.276 for PRBD, 0.478 for UPSIT). When combining both measures, sensitivity was 34.3% and specificity increased to 97.2%., Conclusion: PRBD, diagnosed without sleep study confirmation, combined with a reduced olfactory performance is highly specific for predicting post-mortem presence of LTS. The combination of both measures may provide a cost-effective means of predicting LTS in a broader community., (© 2024 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: PATHFINDER was a prospective cohort study of multicancer early detection (MCED) testing in an outpatient ambulatory population. The aim of this study is to report the patient-reported outcomes (PROs) collected as secondary and exploratory measures in the PATHFINDER study., Methods: PATHFINDER is a prospective, multicentre, cohort study that enrolled existing healthy ambulatory outpatients at seven health networks in the USA, including hospitals, academic medical centres, and integrated health systems. Enrolled adults were aged 50 years or older without clinical suspicion of cancer, with or without additional cancer risk factors (smoking history, genetic predisposition, or previous cancer diagnosis). The primary objective was time to diagnostic resolution after an MCED cancer signal detected (CSD) result and extent of testing pursued. The objectives of the 12-month PATHFINDER study reported here were assessment of patient-reported outcomes and perceptions with MCED testing (the effect of the MCED test result disclosure, general anxiety symptoms, health-related quality of life, and satisfaction with the MCED test). PRO instruments used included an adapted Multidimensional Impact of Cancer Risk Assessment (MICRA) for distress, uncertainty, and positive experience at MCED test result disclosure; PRO Measurement Information System (PROMIS) Anxiety short-form for anxiety symptoms; and Short Form 12-Item Health Survey (SF-12v2) for health-related quality of life. Intentions towards adherence to guideline recommended screening was also assessed as an exploratory objective. This study is registered at ClinicalTrials.gov, NCT04241796, and is complete., Findings: Between Dec 12, 2019, and Dec 4, 2020, 6662 participants were recruited and 6621 eligible participants had analysable MCED test results (n=92 CSD and n=6529 no CSD [NCSD]). The majority of participants were women (4204 [63·5%] of 6621) and White (6071 [91·7%] of 6621). For participants who completed the MICRA at results disclosure, the mean total MICRA score was 28·4 (SD 14·9) for the 50 patients with a CSD result and 8·8 (7·2) for those with an NCSD result (n=5864 completed the full questionnaire). Mean general anxiety scores increased in true-positive and false-positive groups at results disclosure. The PROMIS anxiety true-positive group baseline score of 46·2 (SD 6·5; n=35) increased to 48·4 (7·3; n=19) and the scores in the false-positive group increased from 47·3 (7·3; n=52) to 49·7 (7·7; n=30). Mean scores in both groups returned towards baseline by end of study (true positive 46·8, SD 8·0; n=28; false positive 46·9, 8·1; n=41). Mean SF-12v2 mental component summary and scale scores were within the average general population range at all timepoints. A high proportion of participants (5749 [97·1%] of 5920) responded they were "satisfied", "very satisfied", or "extremely satisfied" with the MCED test, with this proportion highest in those with NCSD (5698 [97·2%] of 5861), followed by those with a true-positive MCED result (23 [92·0%] of 25) and those with a false-positive result (28 [82·4%] of 34). Most participants indicated they were likely or very likely to adhere to health-care providers' future cancer screening recommendations at end of study (5182 [95·6%] of 5418)., Interpretation: The negative patient-reported effects associated with a CSD result from MCED testing were small and returned to baseline within 12 months for participants with or without a cancer diagnosis. PATHFINDER results indicate potential clinical benefit of early cancer detection and minimal patient distress associated with MCED testing., Funding: GRAIL., Competing Interests: Declaration of interests CHM reports a consultant agreement with GRAIL. CRM reports an advisory role with Exact Sciences and a consulting agreement with Natera. KCC reports stock ownership in and is a former employee of GRAIL. ETF and ML report stock ownership in and are employees of GRAIL. EAK is an employee of GRAIL. DS reports an uncompensated advisory role and serving as a study investigator with research funding to Dana Farber Cancer Institute (GRAIL) and personal fees for editorial service (Journal of the American Medical Association). DLP reports payment of consulting fees and meeting and travel support from GRAIL. All other authors declare no competing interests., (Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

The development of a biological notion of "population" over the first century of the theory of evolution has been commented upon by a number of historians and philosophers of biology. Somewhat less commonly discussed, however, is the parallel development of the statistical concept of a population over precisely the same period, in some cases driven by the same historical actors (such as Francis Galton and R. A. Fisher). We explore here these parallel developments, first from the perspective of a reconstruction of the historical development of each concept, then with the aid of a digital analysis of a corpus of literature drawn from the journals Biometrika and JournalofGenetics, between 1900 and 1960. These twin analyses show both points of interesting overlap between these two historical trends as well as points of important divergence. The biological and statistical notions of "population" seem to be relatively clearly distinguishable over these six decades, in spite of the fact that a number of authors contributed clearly to both traditions. The complex interplay of continuity and discontinuity across these two notions of "population" makes them a particularly interesting case study of scientific conceptual change., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Recent studies have validated the efficacy of point-of-care ultrasound (POCUS) as an alternative diagnostic imaging approach to computed tomography (CT) for patients with suspected acute diverticulitis. This study aimed to quantify the national impact of this approach in cost savings, ED length-of-stay (LOS), and radiation risk mitigation using a POCUS-first approach for acute diverticulitis in the emergency department (ED)., Methods: Using published data, we constructed a Monte Carlo simulation model to compare two POCUS-first strategies (nonselective and selective approaches) for evaluating patients with suspected acute diverticulitis in the ED. Primary outcomes were cost savings, reduction in ED LOS, and radiation risk mitigation., Results: In our simulation model, both nonselective and selective POCUS-first strategies showed substantial potential reductions in the annual number of CTs. Notably, the selective approach led to significantly fewer estimated POCUS examinations (433,847 ± 45,103 exams vs 720,048 ± 55,815 exams, p < 0.001) resulting in greater cost savings ($94,620,235 ± $10,090,807 vs $70,017,473 ± $11,583,911, p < 0.001) and greater reductions in ED LOS (508,569 ± 640,048 bed-hours vs 332,518 ± 774,485 bed-hours, p < 0.001). Reduction in radiation exposure was comparable between the two approaches (8,779,414 ± 2,389,982 mSv vs 8,846,058 ± 2,420,185 mSv, p = 0.536)., Conclusion: Both POCUS-first models can achieve substantial national annual cost savings, ED LOS reduction, and decreases in radiation exposure compared to the traditional CT-first approach. POCUS should be strongly considered as a first-line imaging modality for acute diverticulitis especially among low-risk patients., Competing Interests: Declaration of competing interest Andrew Goldsmith reports a relationship with Ultrasight LLC. that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background Context: The North American Spine Society's (NASS) Evidence-Based Clinical Guideline for the Diagnosis and Treatment of Adults with Osteoporotic Vertebral Compression Fractures features evidence-based recommendations for diagnosing and treating adult patients with osteoporotic vertebral compression fractures. The guideline is intended to reflect contemporary treatment concepts for osteoporotic vertebral compression fractures as reflected in the highest quality clinical literature available on this subject as of September 2020., Purpose: The purpose of the guideline is to provide an evidence-based educational tool to assist spine specialists when making clinical decisions for adult patients with osteoporotic vertebral compression fractures. This article provides a brief summary of the evidence-based guideline recommendations for diagnosing and treating patients with this condition., Study Design: This is a guideline summary review., Methods: This guideline is the product of NASS' Clinical Practice Guidelines Committee. The methods used to develop this guideline are detailed in the complete guideline and technical report available on the NASS website. In brief, a multidisciplinary work group of spine care specialists convened to identify clinical questions to address in the guideline. The literature search strategy was developed in consultation with a medical librarian. Upon completion of the systematic literature search, evidence relevant to the clinical questions posed in the guideline was reviewed. Work group members utilized NASS evidentiary table templates to summarize study conclusions, identify study strengths and weaknesses, and assign levels of evidence. Work group members participated in recommendation meetings to update and formulate evidence-based recommendations and incorporate expert opinion when necessary. The draft guideline was submitted to an internal and external peer review process and ultimately approved by the NASS Board of Directors., Results: Twenty-nine clinical questions were addressed, and the answers are summarized in this article. The respective recommendations were graded according to the levels of evidence of the supporting literature., Conclusions: The evidence-based clinical guideline has been created using techniques of evidence-based medicine and best available evidence to aid practitioners in the diagnosis and treatment of adult patients with osteoporotic vertebral compression fractures. The entire guideline document, including the evidentiary tables, literature search parameters, literature attrition flowchart, suggestions for future research, and all of the references, is available electronically on the NASS website at http://www.spine.org/guidelines., (Copyright © 2025. Published by Elsevier Inc.)

Extracellular vesicles (EVs), particularly exosomes (EXOs) of various skeletal and stem cells, were shown to delay osteoarthritis (OA) progression, and apoptotic bodies (ABs), another EV subtype, of osteoclasts showed osteoanabolic actions and were involved in the osteoclastic-regulation of local bone formation. Moreover, this study demonstrates that microvesicles (MVs) released by osteoclasts displayed potent pro-chondrogenic, pro-osteogenic, and anti-inflammatory activities. These activities were unique to osteoclastic MVs and were not shared by osteoclastic ABs and EXOs or MVs of other cell types. Because chronic synovial inflammation, progressive articular cartilage erosion, abnormal subchondral bone remodeling, and inability to regenerate articular cartilage are key etiologies of OA, we postulate that the foregoing activities of osteoclastic MVs could simultaneously target multiple etiologies of OA and could thereby be an effective therapy for OA. Accordingly, this study sought to assess the feasibility of an osteoclastic MV-based strategy for OA with a mouse tibial plateau injury model of OA. Briefly, tibial plateau injuries were created on the right knees of adult C57BL/6J mice, MVs were intraarticularly injected into the injured joints biweekly, and the OA progression was monitored histologically at five weeks post-injury. The MV treatment reduced the OA-induced losses of articular cartilage area and thickness, decreased irregularity in the articular cartilage surface, reduced loss of gliding/intermediate zone of articular cartilage, reduced osteophyte formation, suppressed synovial inflammation, and decreased the OARSI OA score. In summary, treatment with osteoclastic MVs delayed or reversed OA progression. Thus, this study supports the feasibility of an osteoclastic MV-based therapy for OA.

Treated municipal wastewater effluent is an important pathway for Contaminants of Emerging Concern (CEC) to enter aquatic ecosystems. As the aging wastewater infrastructure in many industrialized countries requires upgrades or replacement, assessing new treatment technologies in the context of CEC effects may provide additional support for science-based resource management. Here, we used three lines of evidence, analytical chemistry, fish exposure experiments, and fish and water microbiome analysis, to assess the effectiveness of membrane bioreactor treatment (MBR) to replace traditional activated sludge treatment. To do this, we sampled a municipal wastewater treatment plant with a split wastewater stream, a portion of which was treated with an MBR and another via an oxidation ditch (OXI). The OXI and MBR treatments substantially reduced most measured CECs compared to the primary effluent (PRI). Only pesticides and some pharmaceuticals were recalcitrant to both secondary treatment methods. While ammonia toxicity of PRI prevented its inclusion in fish exposure experiments, exposure of fish with waters from the OXI or MBR treated wastewater produced only subtle biological differences with no adverse apical outcomes. These findings were consistent with low chemically derived exposure: activity ratios (EARs) for OXI and MBR. Microbiome analysis of fish and wastewater highlighted the significant reduction of microbial abundance and diversity in the MBR treatment compared to all other treatments. The comparable removal efficacy of CECs in MBR makes it an attractive alternative to traditional OXI, especially when MBR may eliminate the need for tertiary treatment for wastewater disinfection., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Society of Environmental Toxicology and Chemistry. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The Shab family voltage-gated K + channels (i.e., Kv2.1, Kv2.2) are widely expressed in mammalian brain and regulate neuronal action-potential firing. In addition to their canonical functions, the Kv2 proteins help establish direct attachments between plasma membrane and endoplasmic reticulum (ER), also known as ER-plasma membrane junctions. However, the biochemical properties and molecular organization of these ion channels have not yet been described in human neurons. Here, we have performed a systematic analysis of endogenous expression, post-translational modification, and subcellular distribution of the major components of Kv2 complex in neurons derived from human stem cells. We found that both Kv2.1, Kv2.2, and their auxiliary subunit AMIGO1 are significantly upregulated during early neurogenesis, localize at the cell surface, and already begin to assemble with each other. Human Kv2.1 and AMIGO1, but not Kv2.2, undergo substantial post-translational modification including phosphorylation and/or N-linked glycosylation. Acute pharmacological inhibition with Kv2 blockers also revealed their functional activation in human neurons. These proteins formed prominent clusters at cell bodies, dendritic branches, and axon initial segments. Interestingly, a large fraction of them also exhibited considerable accumulation at human presynaptic terminals, where they aggregated with the local ER network. This synaptic localization of Kv2 subunits was primarily restricted to presynaptic regions, as they demonstrated limited enrichment at postsynaptic densities. These results were highly reproducible in multiple stem cell lines used and alternative differentiation protocols tested, confirming that human presynaptic compartments can actively recruit the Shab family K + ion channels., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Exposure to repetitive head impacts (RHI), such as those experienced in American football, is linked to cognitive dysfunction later in life. Traumatic encephalopathy syndrome (TES) is a proposed clinical syndrome thought to be linked to neuropath-ology of chronic traumatic encephalopathy (CTE), a condition associated with RHI from football. Cognitive intra-individual variability (d-CIIV) measures test-score dispersion, indicating cognitive dysfunction. This study examined d-CIIV in former football players and its associations with TES diagnosis, RHI exposure, and DTI and CSF biomarkers. Methods: Data included 237 males (45-74 years) from DIAGNOSE CTE Research Project, including former professional and college football players (COL) ( n  = 173) and asymptomatic men without RHI or TBI ( n  = 55). Participants completed neuropsychological tests. TES diagnosis was based on 2021 NINDS TES criteria. Years of football play and a cumulative head impact index (CHII) measured RHI exposure. Lumipulse technology was used for CSF assays. DTI fractional anisotropy assessed white matter integrity. Coefficient of variation (CoV) measured d-CIIV. ANCOVA compared d-CIIV among groups (football versus control; TES-status). Pearson correlations and linear regressions tested associations between d-CIIV, RHI exposure, and CSF and DTI biomarkers. Results: Former professional players had higher d-CIIV than controls (F(7, 194) = 2.87, p  = .007). d-CIIV was associated with TES diagnosis (F(8, 146) = 9.063, p  < .001), with highest d-CIIV in TES Possible/Probable-CTE. Higher d-CIIV correlated with higher CHII scores ( r  = 0.19), reduced CSF Aβ 1-42 ( β  = -0.302), increased p-tau 181 ( β   = 0.374), and reduced DTI FA ( β  = -0.202). Conclusion: d-CIIV is linked to RHI exposure and TES diagnosis in former football players, with associated changes in CSF biomarkers and white matter integrity.

Background: For growing healthcare organisations, anchored resources-assets that are not easily movable-may complicate expansion and distort workflow patterns. We examine work patterns at a radiation oncology department of a major Canadian hospital. As this department doubled its size, healthcare providers remained bound to treatment planning rooms and radiation machines at the original site. This study examines workplace communication and interactions before and after the expansion., Methods: We conducted regression analyses using a unique dataset merging email communications, badge swipes, office locations and organisation charts for individuals that routinely use the treatment planning room (n=232). We use a difference-in-differences framework to compare individuals' behaviours before and after the expansion. Our dependent variables were how often individuals accessed the treatment planning room and email volumes between two individuals., Findings: We find an overall decrease in the use of the treatment planning room, though the effect was larger for those that moved away from it. Further, we find an increase in email communication for dyads of individuals separated in the move, but only if they belonged to different departments., Practical Implications: Our research points to complex interdependencies among healthcare providers, shedding light on how hospital expansion may have unintended consequences. Healthcare leaders should acknowledge that interaction patterns will be affected when healthcare providers are separated from each other or from anchored resources. Shifting to remote interactions may be adequate in some instances; in others, it may negatively affect work outcomes as well as the engagement and satisfaction of providers and patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Hyperpolarized- 13 C magnetic resonance imaging (HP- 13 C MRI) was used to image changes in 13 C-lactate signal during a visual stimulus condition in comparison to an eyes-closed control condition. Whole-brain 13 C-pyruvate, 13 C-lactate and 13 C-bicarbonate production was imaged in healthy volunteers (N = 6, ages 24-33) for the two conditions using two separate hyperpolarized 13 C-pyruvate injections. BOLD-fMRI scans were used to delineate regions of functional activation. 13 C-metabolite signal was normalized by 13 C-metabolite signal from the brainstem and the percentage change in 13 C-metabolite signal conditions was calculated. A one-way Wilcoxon signed-rank test showed a significant increase in 13 C-lactate in regions of activation when compared to the remainder of the brain ( p = 0.02 ). No significant increase was observed in 13 C-pyruvate signal ( p = 0.11 ) or 13 C-bicarbonate signal ( p = 0.95 ). The results show an increase in 13 C-lactate production in activated regions that is measurable with HP- 13 C MRI., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.P.C. is employed by GE Healthcare, the manufacturer of the SPINLab polarizer. K.R.K. is co-founder of Atish Technologies and serves on the Scientific Advisory Boards of NVision Imaging Technologies and Imaginostics. He holds patents related to imaging and leveraging cellular metabolism.

Many essential proteins require pyridoxal 5'-phosphate, the active form of vitamin B6, as a cofactor for their activity. These include enzymes important for amino acid metabolism, one-carbon metabolism, polyamine synthesis, erythropoiesis, and neurotransmitter metabolism. A third of all mammalian pyridoxal 5'-phosphate-dependent enzymes are localized in the mitochondria; however, the molecular machinery involved in the regulation of mitochondrial pyridoxal 5'-phosphate levels in mammals remains unknown. In this study, we used a genome-wide CRISPR interference screen in erythroleukemia cells and organellar metabolomics to identify the mitochondrial inner membrane protein SLC25A38 as a regulator of mitochondrial pyridoxal 5'-phosphate. Loss of SLC25A38 causes depletion of mitochondrial, but not cellular, pyridoxal 5'-phosphate, and impairs cellular proliferation under both physiological and low vitamin B6 conditions. Metabolic changes associated with SLC25A38 loss suggest impaired mitochondrial pyridoxal 5'-phosphate-dependent enzymatic reactions, including serine to glycine conversion catalyzed by serine hydroxymethyltransferase-2 as well as ornithine aminotransferase. The proliferation defect of SLC25A38-null K562 cells in physiological and low vitamin B6 media can be explained by the loss of serine hydroxymethyltransferase-2-dependent production of one-carbon units and downstream de novo nucleotide synthesis. Our work points to a role for SLC25A38 in mitochondrial pyridoxal 5'-phosphate accumulation and provides insights into the pathology of congenital sideroblastic anemia., Competing Interests: Competing interests: M.G.V.H. discloses that he is an advisor for Agios Pharmaceuticals, iTeos Therapeutics, Sage Therapeutics, Pretzel Therapeutics, Droia Ventures, MPM Capital, and Auron Therapeutics. G.S. is currently an employee and shareholder of AstraZeneca. All other authors declare that they have no competing interests., (© 2025. The Author(s).)

There are considerable data documenting the importance of early experiences for healthy human development. Though widely accepted amongst mental health clinicians, developmental researchers and early childhood policymakers, this information is not well known by much of the public. We describe a specialized program designed for established and emerging leaders in Louisiana, United States of America, to help them become better informed to take action to support young children and their families and to facilitate connections across sectors for greater impact. Conducted annually for 6 years, the program drew leaders from a variety of professional sectors working in every region of the state. To evaluate the effectiveness of the program, we conducted semi-structured interviews of program graduates and tabulated responses by thematic analysis. We conclude that translation efforts delivered in this kind of format can lead to gains in knowledge among leaders and action to support early childhood development and well-being., (© 2025 The Author(s). Infant Mental Health Journal published by Wiley Periodicals LLC on behalf of Michigan Association for Infant Mental Health.)

Disruption of extracellular pH and proton-sensing can profoundly impact cellular and protein functions, leading to developmental defects. To visualize changes in extracellular pH in the developing embryo, we generated a zebrafish transgenic line that ubiquitously expresses the ratiometric pH-sensitive fluorescent protein pHluorin2, tethered to the extracellular face of the plasma membrane using a glycosylphosphatidylinositol (GPI) anchor. Monitoring of pHluorin2 with ratiometric fluorescence revealed dynamic and discrete domains of extracellular acidification over the first 72 h of embryonic development. These included acidification of the notochord intercalations, transient acidification of the otic placode, and persistent acidification of the extracellular space of the myotome at distinctly different pH from that within the T-tubules. Knockdown of centronuclear myopathy genes Bin1b (OMIM: 255200) and MTM1 (OMIM: 310400), which disrupt T-tubule formation, also disrupted myotome acidification. In this study we visualize extracellular acidic microdomains in the tissues of whole live animals. This real-time reporter line for directly measuring changes in extracellular pH can be used to illuminate the role of extracellular pH in normal physiological development and disease states., (© 2025 The Author(s). Developmental Dynamics published by Wiley Periodicals LLC on behalf of American Association for Anatomy.)

Objective:  Cognitive impairment is a core feature of traumatic encephalopathy syndrome (TES), the putative clinical syndrome of chronic traumatic encephalopathy-a neuropathological disease associated with repetitive head impacts (RHI). Careful operationalization of cognitive impairment is essential to improving the diagnostic specificity and accuracy of TES criteria. We compared single- versus two-test criteria for cognitive impairment in their associations with CSF and imaging biomarkers in male former American football players. Method:  169 participants from the DIAGNOSE CTE Research Project completed neuropsychological tests of memory and executive functioning. Cognitive impairment was identified by single-test criteria ( z ≤-1.5 on one test) and two-test criteria ( z <-1 on two tests within a domain). ANCOVAs adjusting for age, race, education, body mass index, word-reading score, and APOE ε4 status assessed whether single- or two-test criteria predicted CSF markers (Aβ 1-42 , p-tau 181 , p-tau 181 /Aβ 1-42 , total tau, neurofilament light [NfL], glial fibrillary acidic protein [GFAP]) and MRI markers (hippocampal volume, cortical thickness, white matter hyperintensities). Results: Ninety-nine participants met single-test criteria for cognitive impairment. Sixty-six met two-test criteria. Participants who met two-test criteria had greater exposure to RHI than those who did not ( p =.04). Two-test criteria were -associated with higher CSF p-tau 181 /Aβ 1-42 ( q =.02) and CSF NfL ( q =.02). The association between two-test criteria and CSF NfL remained after excluding amyloid-positive participants ( q =.04). Single-test criteria were not associated with any biomarkers ( q 's>.05). Conclusions:  Two-test but not single-test criteria for cognitive impairment were associated with markers of neurodegeneration. Future clinical research in TES may benefit from applying two-test criteria to operationalize cognitive impairment.

Introduction: The London classification provides standardization for characterization of disorders of anorectal function, although prevalences and clinical impact of these disorders are unclear., Methods: An international research consortium was established, including five specialist centers. Prospective data were collected in consecutive adults referred for refractory chronic constipation (CC), fecal incontinence (FI) or coexistent CC/FI over 18 months. Patients completed a standardized clinical questionnaire and underwent anorectal physiology tests which were performed and interpreted using uniform methodology. The prevalence of the London classification was compared between symptom groups (CC, FI and coexistent CC/FI), equipment types, and sites. Clinical impact was assessed using Cleveland Clinic constipation and St. Marks incontinence scores., Results: Of 1,012 included patients (85.6% women), 30.5% had self-reported CC, 33.2% had FI, and 36.3% had coexistent CC/FI. Rectoanal areflexia was uncommon (3.1%). Disorders of anal tone/contractility (CC: 45.0%; FI: 68.5%; coexistent CC/FI: 63.8%; p<0.0001), and disorders of rectal sensation (major findings: rectal hyposensitivity, CC: 10.0%; FI: 5.0%; coexistent CC/FI: 11.1%; p=0.018; rectal hypersensitivity, CC: 3.8%; FI: 9.0%; coexistent CC/FI: 4.9%; p=0.025) varied between symptom groups and were associated with symptom severity. Most disorders of rectoanal coordination were found in similar proportions across symptom groups and were not associated with severity of CC (median Cleveland Clinic constipation score 10-14 in all groups). Prevalences of some disorders differed between equipment types (specifically balloon expulsion test)., Discussion: This prospective multicenter study provides information on the prevalence and clinical impact of the London classification, and will guide refinement of the current London classification., (Copyright © 2025 by The American College of Gastroenterology.)

Introduction: Published data investigating a time-dependent effect of initiation of antiarrhythmic therapy for shockable in-hospital cardiac arrest (IHCA) is lacking. We aimed to evaluate the association between time of intravenous amiodarone or lidocaine administration and return of spontaneous circulation (ROSC) in patients with IHCA caused by ventricular fibrillation (VF) or pulseless ventricular tachycardia (pVT)., Methods: This was a retrospective, multi-center, single health system, observational cohort study of patients with an IHCA caused by VF/pVT and who received amiodarone or lidocaine during 2014-2024. The primary outcome was ROSC, and the secondary outcome was survival to hospital discharge. A multivariable logistic regression model was constructed to evaluate the association between (1) time to drug administration and (2) drug administration prior to the second defibrillator shock on both survival outcomes., Results: A total of 88 patients with a shockable IHCA were identified. Longer time to amiodarone or lidocaine administration was associated with lower likelihood of ROSC (adjusted odds ratio [aOR] 0.91; 95% CI: 0.83-0.99, P = 0.04) but not with survival to discharge (aOR 0.99; CI 0.90-1.10P = 0.90). Administration of antiarrhythmic therapy prior to the second defibrillator shock was associated with higher likelihood of ROSC (aOR 6.48; CI 2.08-20.21, P = 0.001) and survival to discharge (aOR 2.82; CI 1.03-7.77, P = 0.04)., Conclusion: Early administration of amiodarone or lidocaine, particularly prior to the second defibrillator shock, was associated with an increased odds of survival outcomes in IHCA with shockable rhythms., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2025 The Author(s).)

Background: Patients with early psychosis (EP) (within 3 years after psychosis onset) show significant variability, which makes predicting outcomes challenging. Currently, little evidence exists for stable relationships between neural microstructural properties and symptom profiles across EP diagnoses, which limits the development of early interventions., Methods: A data-driven approach, partial least squares correlation, was used across 2 independent datasets to examine multivariate relationships between white matter properties and symptomatology and to identify stable and generalizable signatures in EP. The primary cohort included patients with EP from the Human Connectome Project for Early Psychosis (n = 124). The replication cohort included patients with EP from the Feinstein Institute for Medical Research (n = 78) as part of the MEND (Multimodal Evaluation of Neural Disorders) Project. Both samples included individuals with schizophrenia, schizoaffective disorder, and psychotic mood disorders., Results: In both cohorts, a significant latent component corresponded to a symptom profile that combined negative symptoms, primarily diminished expression, with specific somatic symptoms. Both latent components captured comprehensive features of white matter disruption, primarily a combination of subcortical and frontal association fibers. Strikingly, the partial least squares model trained on the primary cohort accurately predicted microstructural features and symptoms in the replication cohort. Findings were not driven by diagnosis, medication, or substance use., Conclusions: This data-driven transdiagnostic approach revealed a stable and replicable neurobiological signature of microstructural white matter alterations in EP across diagnoses and datasets, showing strong covariance of these alterations with a unique profile of negative and somatic symptoms. These findings suggest the clinical utility of applying data-driven approaches to reveal symptom domains that share neurobiological underpinnings., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Co-existing neuropathological comorbidities have been repeatedly reported to be extremely common in subjects dying with dementia due to Alzheimer disease. As these are likely to be additive to cognitive impairment, and may not be affected by molecularly-specific AD therapeutics, they may cause significant inter-individual response heterogeneity amongst subjects in AD clinical trials. Furthermore, while originally noted for the oldest old, recent reports have now documented high neuropathological comorbidity prevalences in younger old AD subjects, who are more likely to be included in clinical trials. Comorbid neuropathologies in subjects with Parkinson disease have received much less attention. As with AD, comorbidities may interfere with the evaluation of PD clinical trials. We have here examined the decadal-wise presence of multiple co-pathologies, and their clinical effects, in a series of autopsies of PD and control subjects from the Arizona Study of Aging and Neurodegenerative Disorders. Amyloid plaques were present in more than 40% of PD patients in their 60s, and in 85% of those in their 90s. Neurofibrillary tangles were present in PD, as in all elderly humans, from the 60s onwards, while Braak tangle stages of IV or greater, which are strongly associated with severe cognitive impairment, reached 40%, 50% and 60% in those subjects in their 70s, 80s and 90s, respectively. Both plaques and tangles were significant predictors of a lower MMSE score while greater CAA scores had borderline significance. None of these, however, were independently associated with a higher UPDRS score. The ApoE4 allele, while a known predictor of AD pathology, especially amyloid plaques, was not an independent predictor of function with either of these clinical measures, suggesting that its influence is largely mediated by the neuropathologies that it predisposes to. Non-AD tauopathies, including the major conditions of progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), as well as the microscopic changes of argyrophilic grains (ARG) and aging-related tau astrogliopathy (ARTAG), also co-existed with PD, especially ARG and ARTAG, which ranged between 20% and 40% across decades for the former and up to 80% for the latter; we did not find significant associations of either with final MMSE or UPDRS scores. We failed to find a significant association of limbic TDP-43 histopathology with either final MMSE score or final UPDRS motor score but our subjects were more heavily weighted with PD than those in prior studies and our cognitive correlate, limited to MMSE score, may have missed associations with cognitive domain subsets. We found several cerebrovascular pathologies to be predictors of both cognitive and motor impairment, including brain infarcts, circle of Willis atherosclerosis, and higher white matter rarefaction score. All of the investigated pathology types were common in the non-demented, non-parkinsonian control subjects, and all increased with age in parallel with those co-existing with PD, while with generally lower prevalences. The high concurrence rate of the neurodegenerative protein aggregate diseases is suggestive of either a synergistic co-pathogenesis, where one aggregate type may instigate or accelerate another type, or of one or more underlying predisposing physiological or molecular mechanisms.

Background: 22q11.2 deletion syndrome (22qDel) is a copy number variant that is associated with psychosis and other neurodevelopmental disorders. Adolescents who are at clinical high risk for psychosis (CHR) are identified based on the presence of subthreshold psychosis symptoms. Whether common neural substrates underlie these distinct high-risk populations is unknown. We compared functional brain measures in 22qDel and CHR cohorts and mapped the results to biological pathways., Methods: We analyzed 2 large multisite cohorts with resting-state functional magnetic resonance imaging data: 1) a 22qDel cohort (n = 164, 47% female) and typically developing (TD) control participants (n = 134, 56% female); and 2) a cohort of CHR individuals (n = 240, 41% female) and TD control participants (n = 149, 46% female) from the NAPLS-2 (North American Prodrome Longitudinal Study-2). We computed global brain connectivity (GBC), local connectivity (LC), and brain signal variability (BSV) across cortical regions and tested case-control differences for 22qDel and CHR separately. Group difference maps were related to published brain maps using autocorrelation-preserving permutation., Results: BSV, LC, and GBC were significantly disrupted in individuals with 22qDel compared with TD control participants (false discovery rate-corrected q < .05). Spatial maps of BSV and LC differences were highly correlated with each other, unlike GBC. In the CHR group, only LC was significantly altered versus the control group, with a different spatial pattern than the 22qDel group. Group differences mapped onto biological gradients, with 22qDel effects being strongest in regions with high predicted blood flow and metabolism., Conclusions: 22qDel carriers and CHR individuals exhibited different effects on functional magnetic resonance imaging temporal variability and multiscale functional connectivity. In 22qDel carriers, strong and convergent disruptions in BSV and LC that were not seen in CHR individuals suggest distinct functional brain alterations., (Copyright © 2024. Published by Elsevier Inc.)

Background Context: Clinical outcomes are directly related to patient selection and treatment indications for improved quality of life. With emphasis on quality and value, it is essential that treatment recommendations are optimized., Purpose: The purpose of the North American Spine Society (NASS) Appropriate Use Criteria (AUC) is to determine the appropriate (ie, reasonable) multidisciplinary treatment recommendations for patients with metastatic neoplastic vertebral fractures across a spectrum of more common clinical scenarios., Study Design: A Modified Delphi process., Patient Sample: Systematic Review OUTCOME MEASURES: Final rating for cervical fusion recommendation as either "Appropriate," "Uncertain," or "Rarely Appropriate" based on the median final rating among the raters., Methods: The methodology was based on the AUC development process established by the Research AND Development (RAND) Corporation. The topic of neoplastic vertebral fracture was selected by NASS for its Clinical Practice Guideline development (CPG). In conjunction, the AUC work group determined key modifiers and adopted the standard definitions developed by CPG, with minimal modifications. A literature search and evidence analysis performed by the CPG were reviewed by the AUC work group. A separate multidisciplinary rating group was assembled. Based on the literature, provider experience, and group discussion, each scenario was scored on a 9-point scale on 2 separate occasions, once without discussion and then a second time following discussion based on the initial responses. The median rating for each scenario was then used to determine if indications were rarely appropriate (1-3), uncertain / maybe appropriate (4-6), or appropriate (7-9). Consensus was not mandatory., Results: Medical management was essentially always appropriate. Radiation therapy was appropriate 50% of the time and uncertain otherwise, and directly related to radiosensitivity of the tumor. Ablation was never rated appropriate with agreement, and about 50% of the time was rated as uncertain. For cement augmentation, the scenarios without stenosis or neurological changes, stable fractures with less than 80% height loss and intact posterior wall, and higher VAS pain scores accounted for 88% probability of an appropriate rating. Otherwise, cement augmentation was uncertain 68% of the time. Surgery was rated as appropriate with agreement in 35%, and uncertain or appropriate with disagreement in 59% of scenarios. The most important variables determining final rating for surgery (in order) were stability, spinal stenosis, and prognosis., Conclusions: Multidisciplinary appropriate treatment criteria were generated based on the RAND methodology. Recommendations were made for medical treatment, ablation, radiation, cement augmentation, and surgery based on 432 practical clinical scenarios. This document provides comprehensive evidence-based recommendations for evaluation and treatment of metastatic neoplastic vertebral fractures. The document in its entirety will be found on the NASS website (https://www.spine.org/Research-Clinical-Care/Quality-Improvement/Appropriate-Use-Criteria)., Competing Interests: Declaration of competing interest One or more of the authors declare financial or professional relationships on ICMJE-TSJ disclosure forms., (Copyright © 2025 Elsevier Inc. All rights reserved.)

The TEAD family of transcription factors are best known as the DNA-binding factor in the Hippo pathway, where they act by interacting with transcriptional coactivators YAP and TAZ (YAP/TAZ). Despite the importance of the Hippo pathway, the in vivo functions of TEAD in mammals have not been well established. By comparing mouse mutants lacking TEAD1 and TEAD2 (TEAD1/2) to those lacking YAP/TAZ, we found that TEAD1/2 have both YAP/TAZ-dependent and -independent functions during ventral telencephalon development. TEAD1/2 loss and YAP/TAZ loss similarly disrupt neuroepithelial apical junctions. However, the impacts of their losses on progenitor lineage progression are essentially opposite: Whereas YAP/TAZ loss depletes early progenitors and increases later progenitors-consistent with their established function in promoting progenitor self-renewal and proliferation, TEAD1/2 loss expands early progenitors and reduces late progenitors, indicating that TEAD1/2 promote lineage progression. We further show that TEAD1/2 promote neural progenitor lineage progression by, at least in part, inhibiting Notch signaling and by cooperating with Insulinoma-associated 1 (INSM1). Orthologs of TEAD and INSM1 have been shown to cooperatively regulate neuronal cell fate decisions in worms and flies. Our study reveals a remarkable evolutionary conservation of the function of this transcription factor complex during metazoan neural development., Competing Interests: Competing Interest Statement The authors declare no competing interests.

Objective: To engage U.S. end users to (1) gather information on facilitators and barriers to awareness and adoption of the Canadian Spinal Cord Injury (SCI) Physical Activity (PA) guidelines; (2) inform potential adaptations to the presentation and messaging of the guidelines; and (3) develop recommendations for targeted dissemination strategies to promote awareness in the United States., Design: Multi-method., Setting: Working groups conducted remotely via Zoom and online surveys., Participants: Individuals with lived SCI experience ( n  = 5), providers/clinical researchers ( n  = 7), and members of SCI professional or community organisations ( n  = 6)., Interventions: N/A., Outcome Measures: N/A., Results: Participants highlighted the need for centralised, credible sources of information on PA. While participants generally viewed the guidelines as appropriate, useable, and acceptable, some questioned their credibility, as they were developed explicitly for Canadians with SCI rather than Americans. To enhance reach and effectiveness, participants suggested dissemination strategies that target specific audiences (i.e. level of functioning, level of injury, current level of PA). They also recommended collaborations with existing trusted community SCI organisations., Conclusion: Findings underscore the need for accessible, centralised, and credible information sources on PA tailored to the needs of the SCI community. Findings also suggest that while the guidelines do not require redevelopment for a U.S. context, they do need customised presentation, such as removing Canadian symbols from the materials, to better suit U.S. audiences. Effective dissemination will benefit from targeted strategies that leverage trusted organisations to reach and engage specific groups, ultimately supporting greater guideline awareness, acceptance, and application across the SCI population.

The Super-Kamiokande and T2K Collaborations present a joint measurement of neutrino oscillation parameters from their atmospheric and beam neutrino data. It uses a common interaction model for events overlapping in neutrino energy and correlated detector systematic uncertainties between the two datasets, which are found to be compatible. Using 3244.4 days of atmospheric data and a beam exposure of 19.7(16.3)×10^{20} protons on target in (anti)neutrino mode, the analysis finds a 1.9σ exclusion of CP conservation (defined as J&#95;{CP}=0) and a 1.2σ exclusion of the inverted mass ordering.

This study assessed the novel concept that osteoclast-derived Grem1 has regulatory functions in the skeletal response to calcium stress using an osteoclastic Grem1 conditional knockout (cKO) mouse model. The calcium stress was initiated by feeding cKO mutants and wildtype (WT) littermates a calcium-deficient diet for 2 weeks. Deletion of Grem1 in mature osteoclasts did not affect developmental bone growth nor basal bone turnover. In response to calcium depletion, male cKO mutants showed greater increases in osteoclastic resorption and trabecular bone loss than male WT littermates, indicating an enhanced skeletal sensitivity to calcium depletion in male mutants. The enhanced sensitivity to calcium depletion was sex-dependent, as female cKO mutants showed lower increases in osteoclastic resorption and bone loss than female WT littermates as well as male cKO mutants. The sex disparity in osteoclastic resorption response to calcium stress was intrinsic to osteoclasts since osteoclasts of male but not female cKO mutants showed greater in vitro bone resorption activity than osteoclasts of WT littermates of respective sex. Male cKO mutants displayed smaller bone formation response to calcium depletion than male WT littermates, while female mutants showed bigger bone formation response than female WT littermates, indicating that cKO mutants also displayed sex disparity in bone formation response. The sex disparity in bone formation response was not caused by intrinsic differences in osteoblasts but might be due to sex-dependent differential osteoclastic release of osteogenic factors. In summary, osteoclast-derived gremlin-1 has complicated and sex-dependent regulatory roles in skeletal response to calcium stress., Competing Interests: Declarations. Conflict of Interest: All authors (Matilda H.-C. Sheng, Charles H. Rundle, David J. Baylink, and Kin-Hing William Lau) state that they have no conflicts of interest.                                                           Human and Animal Rights and Informed Consent: The animal protocol (protocol #1298) was reviewed and approved by the Animal Care and Use Committee (IACUC) of VA Loma Linda Healthcare System as well as by the IACUC of the Loma Linda University and the Animal Care and Use Review Office (ACURO) of the US Army Medical Research and Materiel Command of the Department of Defense. In conducting research using animals, the investigators adhered to the Animal Welfare Act Regulations and other federal statures relating to animals and animal experimentation and the principles set forth in the current version of the National Institutes of Health (NIH) Guidelines for Research Involving Recombinant DNA Molecules. Disclaimers: The views, opinions and/or findings contained in this report are those of the authors and should not be construed as an official position, policy or decision of the US Army or the United States government, unless so designated by other documentation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., (© 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Competing Interests: Declarations of interest None.

Background: 95% of men with spinal cord injuries exhibit difficulties with sexual function, including erectile dysfunction, anejaculation, retrograde ejaculation, poor ejaculatory force, and poor sperm quality., Aim: The primary goal is to determine if well-established interventions, such as spinal cord epidural stimulation, are a feasible treatment for sexual dysfunction and if locomotor recovery training can be used to improve ejaculatory function in a rodent model of spinal cord injury (SCI)., Methods: Male Wistar rats underwent thoracic laminectomies (shams), spinal cord transections, or moderate spinal cord contusion injuries. In urethane-anesthetized rodents, terminal spinal cord epidural stimulation was performed to target the mid-lumbar level spinal generator for ejaculation (SGE) in animals with transection spinal cord injuries at 3-, 14-, or 70-days post-injury and in animals with sham surgeries and spinal cord contusions at 70 days post-injury. The impact of locomotor training frequency was examined in two groups of rats with spinal cord contusion, which underwent 1-hr of assisted plantar stepping on a treadmill, training two or five times weekly for 6 weeks. Terminal experiments in all groups were followed by measures of sperm concentration and post-mortem testicular weight and morphology., Outcomes: Spinal cord epidural stimulation consistently induced the expulsion phase of ejaculation, and occasionally the emission phase of ejaculation in rats with chronic SCI., Results: All animals were most responsive to spinal cord epidural stimulation combined with manual stimulation to induce ejaculation, with chronic injury resulting in the most consistent responses. Locomotor training improved response rates to spinal cord epidural stimulation, with intermittent training resulting in the most consistent induction of both the emission and expulsion phases of ejaculation. Sperm concentration was impacted by injury completeness and time-post injury, which was lowest in the chronic complete transection group of rats. Locomotor training resulted in an overall increase in sperm concentration, with 2 days per week of training resulting in a significant improvement of sperm motility., Clinical Implications: Spinal cord epidural stimulation combined with locomotor training is a feasible intervention for individuals with SCI who seek to regain sexual function., Strengths and Limitations: Although we have anecdotal reports of non-targeted L3 spinal cord epidural stimulation inducing ejaculation in humans having spinal cord injuries, the current outcomes may be underestimated as stimulation was carried out in anesthetized animals., Conclusion: Spinal cord epidural stimulation to target the SGE is a feasible intervention for sexual dysfunction following SCI., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society for Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background/objectives: Suicide in the United States (US) adolescents is a major clinical and public health problem. In this original investigation, we explored trends in suicidal behaviors (ideation, planning, and attempts) among US adolescents from 2011 to 2021., Methods: The study sample included 90,306 adolescents from the 2011-2021 Youth Risk Behavior Surveillance System. Descriptive statistics and the chi-squared test were used to assess differences in suicidal behaviors across gender, race/ethnicity, and grade between 2011 and 2021., Results: The overall percentage of female adolescents reporting suicidal behaviors increased significantly between 2011 and 2021, and it was higher than males. In 2021, females exhibited significantly higher rates of considering suicide (30.0% vs. 14.3%), planning (23.6% vs. 11.6%), and attempts (13.3% vs. 6.6%) compared to their male counterparts. Whites were more likely to report suicidal ideation (22.7%) while Black non-Hispanic youth had a higher likelihood of making a suicide plan (17.7%), attempting suicide (14.5%), or making a suicide attempt requiring medical treatment (4.4%) relative to other racial/ethnic groups. Overall, ninth graders were more likely to report suicide attempts (11.6%) compared to 12th graders (8.6%)., Conclusions: The results demonstrate significant increases in suicidal behavior among US adolescents, particularly in females. They suggest the need for gender-sensitive approaches in mental health support and prevention strategies. Overall, given the significant increase in suicidal behaviors, healthcare providers as well as public health professionals should prioritize mental health initiatives, promote awareness, and ensure access to mental health resources for adolescents.

Balanced mating type polymorphisms offer a distinct window into the forces shaping sexual reproduction strategies. Multiple hermaphroditic genera in Juglandaceae, including walnuts ( Juglans ) and hickories ( Carya ), show a 1:1 genetic dimorphism for male versus female flowering order (heterodichogamy). We map two distinct Mendelian inheritance mechanisms to ancient (>37 million years old) genus-wide structural DNA polymorphisms. The dominant haplotype for female-first flowering in Juglans contains tandem repeats of the 3' untranslated region of a gene putatively involved in trehalose-6-phosphate metabolism and is associated with increased cis gene expression in developing male flowers, possibly mediated by small RNAs. The Carya locus contains ~20 syntenic genes and shows molecular signatures of sex chromosome-like evolution. Inheritance mechanisms for heterodichogamy are deeply conserved, yet may occasionally turn over, as in sex determination.

This study assessed the feasibility of miR17 ~ 92-based antiresorptive strategy by determining the effects of conditional transgenic (cTG) overexpression of miR17 ~ 92 in myeloid cells on bone and osteoclasts. Osteoclasts of male and female cTG mutant mice each showed 3- to fivefold overexpression of miR17 ~ 92 cluster genes compared to those of age- and sex-matched wildtype (WT) littermates. Male but not female cTG mutant mice had more trabecular and cortical bones as well as lower bone resorption reflected by reduction in osteoclast number and resorbing surface. Osteoclasts of male but not female cTG mutants showed decreased bone resorption activity. Consistent with suppression of osteoclast maturation, osteoclasts of male cTG mutants were smaller, contained less nuclei, showed reduced levels of mRNA of genes associated with osteoclast differentiation and fusion, and formed more diffused actin ring. Osteoclastic overexpression of miR17 ~ 92 also increased bone formation, but the increase was much larger in males than in females. The increase in male mutants was due to higher mineral apposition rate, and conversely, it was caused by increasing bone-forming surface in female mutants. In summary, osteoclastic overexpression of miR17 ~ 92 increased bone mass through reduction in bone resorption along with coupled increase in bone formation in male-specific manner. Although the osteoclastic overexpression of miR17 ~ 92-induced suppression of bone resorption and increases in bone formation support the feasibility of miR17 ~ 92-based antiresorptive strategies, the male-specific sexual disparity in skeletal responses to osteoclastic overexpression of miR17 ~ 92 could limit its clinical utility as it may not be used in women with postmenopausal osteoporosis., Competing Interests: Declarations. Competing Interest: All authors state that they have no conflicts of interest. Human and Animal Rights and Informed Consent: All animal protocols (protocol #0047/1160) were reviewed and approved by the Animal Care and Use Committee of VA Loma Linda Healthcare System. In conducting research using animals, the investigators adhered to the Animal Welfare Act Regulations and other federal statures relating to animals and animal experimentation and the principles set forth in the current version of the National Institutes of Health (NIH) Guidelines for Research Involving Recombinant DNA Molecules., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)