Search

Abstract Rod and cone photoreceptor cells are specialized neurons responsible for transforming the information reaching the eyes in the form of photons into the language of neuronal activity. Rods are the most prevalent photoreceptor type, primarily responsible for light detection under conditions of limited illumination. Here we demonstrate that human rods have a morphological organization unique among all described species, whereby the cell soma extends alongside the light-sensitive outer segment compartment to form a structure we have termed the “accessory inner segment.” These structures have two striking features: they are reinforced by a massive microtubular cytoskeleton and contain electron-dense adhesions that mediate their attachment to outer segments. Given that the spacing of human rod photoreceptors is sparser than in most other species, the accessory inner segment likely provides mechanical support to the closely apposed outer segment. This discovery expands our understanding of the human retina and directs future studies of human photoreceptor function in health and disease.

Abstract Aims Heart failure (HF) is a highly prevalent and progressive condition associated with significant morbidity and mortality rates. Acute decompensated HF precipitates millions of hospitalizations each year. Despite therapeutic advances, the overall prognosis of HF is poor. The varying clinical courses and outcomes of patients with this disease may be due to region‐specific gaps and since most HF studies are conducted in developed countries, the participation of Latin American and Caribbean countries is low. Considering this, the American Registry of Ambulatory and Acute Decompensated Heart Failure (AMERICCAASS) aims to characterize the population with ambulatory and acute decompensated HF in the American continent and to determine rehospitalization and survival outcomes during the 12 months of follow‐up. Methods and results AMERICCAASS Registry is an observational, prospective, and hospital‐based registry recruiting patients with ambulatory or acute decompensated HF. The registry plans to include between two and four institutions per country from at least 20 countries in the Americas, and at least 60 patients recruited from each participant institution regardless of their ambulatory or acutely decompensated condition. Ambulatory patients with confirmed HF diagnosis or inpatients presenting with acute decompensated HF will be included. Follow‐up will be performed at 12 months in ambulatory patients or 1, 6, and 12 months after hospital discharge in acutely decompensated HF patients. This ongoing study began on 1 April 2022, with recruitment scheduled to end on 30 November 2023, and follow‐up on 31 January 2025. Ethics approval was obtained from the Biomedical Research Ethics Committee of Fundación Valle del Lili. Data collected in the AMERICCAASS registry is being stored on the electronic platform REDCap (Research Electronic Data Capture), which allows different forms for patient groups to enable unbiased analyses. For quantitative variables comparison, we will use the Student's t‐test or non‐parametric tests accordingly. Categorical variables will be presented as proportions, and groups will be compared with Fisher's exact test. The significance level will be

Ground freeze‒thaw processes have significant impacts on infiltration, runoff and evapotranspiration. However, there are still critical knowledge gaps in understanding of hydrological processes in permafrost regions, especially of the interactions among permafrost, ecology, and hydrology. In this study, an alpine permafrost basin on the northeastern Qinghai‒Tibet Plateau was selected to conduct hydrological and meteorological observations. We analyzed the annual variations in runoff, precipitation, evapotranspiration, and changes in water storage, as well as the mechanisms for runoff generation in the basin from May 2014 to December 2015. The annual flow curve in the basin exhibited peaks both in spring and autumn floods. The high ratio of evapotranspiration to annual precipitation (>1.0) in the investigated wetland is mainly due to the considerably underestimated ‘observed’ precipitation caused by the wind-induced instrumental error and the neglect of snow sublimation. The stream flow from early May to late October probably came from the lateral discharge of subsurface flow in alpine wetlands. This study can provide data support and validation for hydrological model simulation and prediction, as well as water resource assessment, in the upper Yellow River Basin, especially for the headwater area. The results also provide case support for permafrost hydrology modeling in ungauged or poorly gauged watersheds in the High Mountain Asia.

Abstract Background Children with Neurofibromatosis 1 (NF1) show cognitive, behavioural and social differences compared to their peers. However, the age and sequence at which these differences begin to emerge is not fully understood. This prospective cohort study examines the cognitive, behavioural, ADHD trait and autism symptom development in infant and pre-school children with NF1 compared with typically developing (TD) children without a family history of neurodevelopmental conditions. Methods Data from standardised tests was gathered at 5, 10, 14, 24 and 36 months of age (NF1 n = 35, TD n = 29). Developmental trajectories of cognitive (Mullen Scales of Early Learning, MSEL) and adaptive behavioural (Vineland Adaptive Behavior Scales, VABS) development from 5 to 36 months were analysed using linear mixed modelling. Measures of ADHD (Child Behavior Checklist) and autism traits (ADOS-2, BOSA-MV and ADI-R) were assessed at 24 and 36 months. Results The developmental trajectory of cognitive skills (all domains of the MSEL) and behavioural skills (four domains of the VABS) differed significantly between NF1 and TD groups. Post-hoc tests demonstrated that the NF1 participants scored significantly lower than TD participants at 24 months on all MSEL and VABS domains. The NF1 cohort demonstrated higher mean autism and ADHD traits at 24 months and 14% of the NF1 cohort met a research diagnostic classification for autism at 36 months. Limitations The study has a relatively small sample size due to variable retention and rolling recruitment. Due to limitations imposed by the COVID-19 pandemic, we utilised the Brief Observation of Symptoms of Autism for Minimally Verbal children (BOSA-MV) for some participants, which was administered online and may not gather as accurate a picture of traits as ADOS-2. The BOSA-MV was utilised for 41% of participants with NF1 at 36 months compared to 11% at 24 months. This may explain the reduction in the percentage of children with NF1 that met autism criteria at 36 months. Conclusions By 24 months of age, the NF1 cohort show lower cognitive skills and adaptive behaviour and higher levels of autism and ADHD traits as compared to TD children. This has implications for developmental monitoring and referral for early interventions. Trial registration Not applicable.

Abstract Background Sleep and mental health are intimately related and shown to impact graduate students enrolled in health sciences programs, including physical therapy education. Doctorate of Physical Therapy (DPT) students’ attitudes and behaviors surrounding sleep and whether these factors are associated with mental health are unknown. This study aimed to describe sleep behaviors and attitudes of entry-level DPT students and to explore the relationship between subjectively reported sleep quality and self-reported symptoms of anxiety in these students. Methods A cross-sectional online survey consisting of the Sleep Practices and Attitudes Questionnaire (SPAQ), the Generalized Anxiety Disorder-7 (GAD-7) questionnaire, and demographic questions were used. Analyses investigated sleep behaviors and attitudes, along with the relationship (unadjusted odds ratio) between restless sleep and anxiety in DPT students in hybrid and traditional DPT programs across the United States (US). Results A total of 271 DPT students completed the survey. A majority of students reported feeling tired during most days (80.8%, n = 219), a quarter of participants (24.7%) reported having a history of trouble sleeping and four (1.5%) reported being diagnosed with a sleep disorder. Of those who reported their sleep duration, participants slept an average of 6.86 h. The mean GAD-7 score was 7.68 (SD = 4.90), suggestive of mild anxiety. Sixty-seven (24.7%) reported having a diagnosed anxiety disorder, with generalized anxiety being the most common diagnosis. Those who reported having restless sleep were 4.09 times more likely to have moderate to severe anxiety [unadjusted odds ratio = 4.09 (95% CI 2.27,7.35; p

Abstract Background Recent changes in anatomy curricula in undergraduate medical education (UME), including pedagogical changes and reduced time, pose challenges for foundational learning. Consequently, it is important to ask clinicians what anatomical content is important for their clinical specialty, which when taken collectively, can inform curricular development. Methods This study surveyed 55 non-primary care residents in anesthesiology (AN; N = 6), emergency medicine (EM; N = 15), obstetrics and gynecology (OB; N = 13), and orthopedics (OR; N = 21) to assess the importance of 907 anatomical structures across all anatomical regions. Survey ratings by participants were converted into a post-hoc classification system to provide end-users of this data with an intuitive and useful classification system for categorizing individual anatomical structures (i.e., essential, more important, less important, not important). Results Significant variability was observed in the classifications of essential anatomy: 29.1% of all structures were considered essential by OB residents, 37.6% for AN residents, 41.6% for EM residents, and 72.0% for OR residents. Significant differences (with large effect sizes) were also observed between residency groups: OR residents rated anatomy of the back, limbs, and pelvis and perineum anatomy common to both sexes significantly higher, whereas OB residents rated the pelvis and perineum anatomy common to both sexes and anatomy for individuals assigned female at birth highest. Agreement in classifications of importance among residents was observed for selected anatomical structures in the thorax, abdomen, pelvis and perineum (assigned male at birth-specific anatomy), and head and neck. As with the ratings of anatomical structures, OR residents had the highest classification across all nine tissue types (p

Abstract Background Venous thromboembolism (VTE) in pregnancy is a major cause of maternal morbidity and mortality, and the use of preventive low-molecular-weight heparin (LMWH) can be challenging. Clinical guidelines recommend eliciting pregnant individuals’ preferences towards the use of daily injections of LMWH and discussing the best option through a shared decision-making (SDM) approach. Our aim was to identify individuals’ preferences concerning each of the main clinical outcomes, and categorize attributes influencing the use of LMWH during pregnancy. Methods Design: Convergent mixed-methods. Participants: Pregnant women or those planning a pregnancy with VTE recurrence risk. Intervention: A SDM intervention about thromboprophylaxis with LMWH in pregnancy. Analysis: Quantitatively, we report preference scores assigned to each of the health states. Qualitatively, we categorized preference attributes using Burke’s pentad of motives framework: act (what needs to be done), scene (patient’s context), agent (perspectives and influence of people involved in the decision), agency (aspects of the medication), and purpose (patient’s goals). We use mixed-method convergent analysis to report findings using side-by-side comparison of concordance/discordance. Results We comprehensively determined preferences for using LMWH by pregnant individuals at risk of VTE: through value elicitation exercises we found that the least valued health state was to experience a pulmonary embolism (PE), followed by major obstetrical bleeding (MOB), deep vein thrombosis (DVT), and using daily injections of LMWH (valued as closest to a ‘healthy pregnancy’); through interviews we found that: previous experiences, access to care (scene) and shared decision-making (agent) affected preferences. LMWH's benefits were noted, but substantial drawbacks were described (agency). For participants, the main goal of using LMWH was avoiding any risks in pregnancy (purpose). Side-by-side comparisons revealed concordance and discordance between health states and motives. Conclusions Mixed-methods provide a nuanced understanding of LMWH preferences, by quantifying health states preferences and exploring attributes qualitatively. Incorporating both methods may improve patient-centered care around preference-sensitive decisions in thromboprophylaxis during pregnancy.

The Flow Country blanket bogs in the counties of Caithness and Sutherland (northern Scotland, UK) harbour internationally important populations of specialist open-bog breeding bird species. However, commercial afforestation carried out in the 1980s, involving the non-native tree species lodgepole pine (Pinus contorta) and sitka spruce (Picea sitchensis) covering over 67,000 hectares (ca. 17 %) of the peatland, has significantly affected bird assemblages within and around the plantations. We conducted a literature review to identify the avian winners and losers resulting from this transformation. Our synthesis of existing findings confirms that afforestation has led to changes in the availability of breeding and foraging habitat, alterations in inter- and intra-specific competition dynamics, and the creation of forest edge effects. Crucially, the open-bog bird assemblages have been largely replaced by woodland specialists and generalists. While 33 species (including five Red-listed Birds of Conservation Concern) are observed to benefit from afforestation, these gains are arguably of lower conservation value than the original open-bog assemblages (27 species including 11 Red-listed species). As a mean proportion of the British population range, the Flow Country has a significantly higher proportion of Amber and Green-listed loser species than winners. Understanding the changes in assemblages is crucial for informing future decisions regarding forest planting and re-planting, particularly in the context of the ongoing dual challenges of climate change and biodiversity loss. Further research is necessary to comprehend the effects of afforestation on populations of waterfowl associated with open water features present in the blanket bog landscape. Given the need for woodland creation, bird conservation would benefit from leaving naturally open habitats intact and siting new woodland in areas that were formerly naturally forested.

Abstract Microglia-driven neuroinflammation plays an important role in the development of Alzheimer’s disease. Microglia activation is accompanied by the formation and chronic expression of TLR4 inflammarafts, defined as enlarged and cholesterol-rich lipid rafts serving as an assembly platform for TLR4 dimers and complexes of other inflammatory receptors. The secreted apoA-I binding protein (APOA1BP or AIBP) binds TLR4 and selectively targets cholesterol depletion machinery to TLR4 inflammaraft-expressing inflammatory, but not homeostatic microglia. Here we demonstrated that amyloid-beta (Aβ) induced formation of TLR4 inflammarafts in microglia in vitro and in the brain of APP/PS1 mice. Mitochondria in Apoa1bp −/− APP/PS1 microglia were hyperbranched and cupped, which was accompanied by increased reactive oxygen species and the dilated endoplasmic reticulum. The size and number of Aβ plaques and neuronal cell death were significantly increased, and the animal survival was decreased in Apoa1bp −/− APP/PS1 compared to APP/PS1 female mice. These results suggest that AIBP exerts control of TLR4 inflammarafts and mitochondrial dynamics in microglia and plays a protective role in Alzheimer’s disease associated oxidative stress and neurodegeneration.

Abstract Background Stigma is a complex social phenomenon that leads to marginalization and influences the course of illness. In the context of hepatitis C virus (HCV), stigma is a well-documented barrier to accessing care, treatment, and cure. In recent years, HCV rates among women have increased, resulting in an urgent need to address stigma and its harmful effects. The purpose of this concept analysis was to investigate stigma in the context of women living with HCV using Rodgers’ evolutionary method. Methods PubMed, CINAHL, Scopus, Medline, PsycINFO, and Nursing and Allied Health were used to identify articles describing HCV stigma among women. Articles from peer-reviewed journals and geographic locations, published between 2002–2023, were included in the analysis. As specified in Rodgers’ evolutionary method, articles were analyzed with a focus on the concept’s context, surrogate and related terms, antecedents, attributes, examples, and consequences. Results Following screening, 33 articles were selected for inclusion in the analysis. Discrimination and marginalization were identified as surrogate and related terms to stigma; and antecedents of stigma were identified as limited knowledge, fear of diagnosis, and disclosure. Prevalent attributes of stigma in the literature were described as feelings of decreased self-worth, negative stereotyping, and fear of transmission. Importantly, HCV stigma among women is unique in comparison to other forms of infectious disease-related stigma, primarily due its impact on women’s identity as mothers and caregivers. Stigmatization of women living with HCV resulted in negative consequences to personal relationships and healthcare access due to decreased health-seeking behaviours. Although access to HCV treatment has changed considerably over time, a temporal analysis could not be completed due to the limited number of articles. Conclusions Stigma in the context of women living with HCV has its own unique antecedents, attributes, and consequences. This enhanced understanding of stigma among women living with HCV has the potential to inform improved and more effective approaches to care, which will be required to reach HCV elimination. Furthermore, this analysis identifies stigma layering and stigma in the direct-acting antiviral treatment era as areas for more in-depth future inquiry.

Abstract Introduction To investigate the impact of posterior vitreous detachment (PVD) on the risk of developing neovascular glaucoma (NVG) in eyes with occlusions of the retinal artery (RAO) or retinal vein (RVO). Methods Single-center retrospective case-control study of adults with a history of RVO/RAO. Cases (N = 101) who developed NVG were age and sex matched 1:2 to controls who did not develop NVG (N = 202). Multivariable logistic regression was used to estimate the association between history of PVD and risk of NVG while controlling for other related demographic or clinical factors. Results In initial bivariate analyses, there was no difference in risk of NVG based on eye, lens status, hypertension, history of panretinal photocoagulation (PRP), or retinal surgery (all p > 0.10), a borderline difference based on diabetic retinopathy (DR) (p = 0.06) and prior anti-vascular endothelial growth factor (anti-VEGF) treatment (p = 0.08), and a significant difference based on race/ethnicity, type of vascular event, and PVD status (all p

BackgroundCervical cancer disparities persist among minoritized women due to infrequent screening and poor follow-up. Structural and psychosocial barriers to following up with colposcopy are problematic for minoritized women. Evidence-based interventions using patient navigation and tailored telephone counseling, including the Tailored Communication for Cervical Cancer Risk (TC3), have modestly improved colposcopy attendance. However, the efficacious TC3 intervention is human resource-intense and could have greater reach if adapted for mobile health, which increases convenience and access to health information. ObjectiveThis study aimed to describe feedback from clinic staff members involved in colposcopy processes and patients referred for colposcopy regarding adaptions to the TC3 phone-based intervention to text messaging, which addresses barriers among those referred for colposcopy after abnormal screening results. MethodsSemistructured depth qualitative interviews were conducted over Zoom [Zoom Communications, Inc] or telephone with a purposive sample of 22 clinic staff members (including clinicians and support staff members) and 34 patients referred for colposcopy from 3 academic obstetrics and gynecology (OB-GYN) clinics that serve predominantly low-income, minoritized patients in different urban locations in New Jersey and Pennsylvania. Participants were asked about colposcopy attendance barriers and perspectives on a proposed text message intervention to provide tailored education and support in the time between abnormal cervical screening and colposcopy. The analytic team discussed interviews, wrote summaries, and consensus-coded transcripts, analyzing output for emergent findings and crystallizing themes. ResultsClinic staff members and patients had mixed feelings about a text-only intervention. They overwhelmingly perceived a need to provide patients with appointment reminders and information about abnormal cervical screening results and colposcopy purpose and procedure. Both groups also thought messages emphasizing that human papillomavirus is common and cervical cancer can be prevented with follow-up could enhance attendance. However, some had concerns about the privacy of text messages and text fatigue. Both groups thought that talking to clinic staff members was needed in certain instances; they proposed connecting patients experiencing complex psychosocial or structural barriers to staff members for additional information, psychological support, and help with scheduling around work and finding childcare and transportation solutions. They also identified inadequate scheduling and reminder systems as barriers. From this feedback, we revised our text message content and intervention design, adding a health coaching component to support patients with complex barriers and concerns. ConclusionsClinic staff members and patient perspectives are critical for designing appropriate and relevant interventions. These groups conveyed that text message-only interventions may be useful for patients with lesser barriers who may benefit from reminders, basic educational information, and scheduling support. However, multimodal interventions may be necessary for patients with complex barriers to colposcopy attendance, which we intend to evaluate in a subsequent trial.

Borrelia (or Borreliella) burgdorferi, the causative agent of Lyme disease, is a motile and invasive zoonotic pathogen adept at navigating between its arthropod vector and mammalian host. While motility and chemotaxis are well known to be essential for its enzootic cycle, the role of each methyl-accepting chemotaxis proteins (MCPs) in the infectious cycle of B. burgdorferi remains unclear. In this study, we show that mcp5, a gene encoding one of the most abundant MCPs in B. burgdorferi, is differentially expressed in response to environmental signals and at distinct stages of the pathogen's enzootic cycle. Notably, mcp5 expression is regulated by the Hk1-Rrp1 and Rrp2-RpoN-RpoS pathways, two key regulatory pathways that are critical for the spirochete's colonization of the tick vector and mammalian host, respectively. Infection experiments with an mcp5 mutant revealed that spirochetes lacking MCP5 were unable to establish infections in either C3H/HeN mice or Severe Combined Immunodeficiency (SCID) mice, which are deficient in adaptive immunity, underscoring MCP5's critical role in mammalian infection. However, the mcp5 mutant was able to establish infection and disseminate in NOD SCID Gamma (NSG) mice, which are deficient in both adaptive and most innate immune responses, suggesting that MCP5 plays an important role in evading host innate immunity. Moreover, NK cell depletion in C3H and SCID mice restored the infectivity of the mcp5 mutant, further highlighting MCP5's role in evading NK cell-associated immunity. Co-culture assays with NK cells and macrophages revealed that the mcp5 mutant enhanced interferon-gamma production by NK cells. In the tick vector, the mcp5 mutants survived feeding but failed to transmit to mice. These findings reveal that MCP5, regulated by both the Rrp1 and Rrp2 pathways, is critical for establishing infection in mammalian hosts by evading NK cell-mediated host innate immunity and is important for the transmission of spirochetes from ticks to mammalian hosts. This work provides a foundation for further elucidation of chemotactic signals sensed by MCP5 that facilitate B. burgdorferi in evading host defenses.

Background The use of low titer group O whole blood (LTOWB) for resuscitation of patients with traumatic hemorrhage is becoming increasingly common. Practices regarding the administration of RhD-positive LTOWB to childbearing age females (CBAFs) vary between institutions due to concerns about RhD alloimmunization. This study examined practices related to LTOWB transfusion as they pertain to age and sex.Methods This was a secondary analysis of the Shock, Whole blood, and Assessment of TBI (traumatic brain injury) trial, a prospective, multicenter observational cohort study where outcomes following LTOWB transfusion were analyzed at seven level 1 trauma centers between 2018 and 2021, as well as a survey on transfusion practices at these centers conducted in 2023. The proportion of patients who received LTOWB or components was examined over the course of the study and grouped by age and sex, and the RhD group of injured CBAFs was documented.Results A total of 1046 patients were evaluated: 130 females aged

Background: Little is known about the extent of impairments in work and activities of daily life (ADL) in patients with psoriasis, and the influence of contextual factors such as disease-related characteristics and treatment. Therefore, this study aimed to assess these impairments in patients with psoriasis who started using biologicals/small molecule inhibitors.Methods: Using data from the prospective BioCAPTURE registry, we collected patient, disease, and treatment parameters, as well as work/ADL impairments at baseline, 6 and 12 months. Changes in impairment parameters and correlations between impairment and patient/disease characteristics were assessed using generalized estimating equations.Results: We included 194 patients in our analysis. After biological initiation, disease activity decreased significantly (PASI 11.2 at baseline versus 3.9 at 12 months, p

Triple-negative breast cancer (TNBC) lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC tumors are not sensitive to endocrine therapy, and standardized TNBC treatment regimens are lacking. TNBC is a more immunogenic subtype of breast cancer, making it more responsive to immunotherapy intervention. Tumor-associated macrophages (TAMs) constitute one of the most abundant immune cell populations in TNBC tumors and contribute to cancer metastasis. This study examines the role of the protein kinase HUNK in tumor immunity. Gene expression analysis using NanoString’s nCounter PanCancer Immune Profiling panel identified that targeting HUNK is associated with changes in the IL-4/IL-4 R cytokine signaling pathway. Experimental analysis shows that HUNK kinase activity regulates IL-4 production in mammary tumor cells, and this regulation is dependent on STAT3. In addition, HUNK-dependent regulation of IL-4 secreted from tumor cells induces polarization of macrophages into an M2-like phenotype associated with TAMs. In return, IL-4 induces cancer metastasis and macrophages to produce epidermal growth factor. These findings delineate a paracrine signaling exchange between tumor cells and TAMs regulated by HUNK and dependent on IL-4/IL-4 R. This highlights the potential of HUNK as a target for reducing TNBC metastasis through modulation of the TAM population.

Scientific literacy is foundational for many young learners in primary school grades when they have mastered the ability to comprehend vocabulary terms and the science concepts behind them. Text with engaging visual imagery can improve students' comprehension, enhance retrieval, and increase retention when it is integrated into either or both reading and science instruction. Integrating multimedia experiences into science content reading to enhance text through mixed reality (MR) has the potential to supplement both understanding of science concepts and reading ability. This study examined whether reading elementary science text, heavy in science vocabulary, through MR enhanced students’ reading fluency and/or science content learning. A quasi-experimental convergent mixed methods one group pretest-posttest design was employed with 24 grade 5 students in a rural area of the United States Mid-Atlantic region. Data sources included a reading fluency and retelling test, physical and chemical changes end of unit test, and post-interviews. Wilcoxon Signed Rank Tests suggested reading fluency and comprehension gains were statistically significant (p

Abstract Bistability enables adaptive designs with tunable deflections for applications including morphing wings, robotic grippers, and consumer products. Composite laminates may be designed to exhibit bistability due to pre-strains that develop during the processing of the polymer matrix, enabling fast reconfiguration between two stable shapes. Unfortunately, designing bistable laminates is challenging because of their highly nonlinear behavior. Here, we propose the Switching Tunneling Method to address this challenge by alternating between gradient-based local minimization and tunneling search phases, with the enhancement of objective expression switching to improve numerical conditioning. Results demonstrate high effectiveness compared to existing optimizers; the Switching Tunneling Method achieves a 99% success rate in finding all energy minima across general composite layups. Additionally, our method facilitates the inverse design of variable pre-strain fields, enabling bioinspired, positive Gaussian curvatures, which are not possible with conventional pre-strain laminates. Validations through both finite element analysis and 3D printed samples confirm the optimal designs.

Abstract Intermediate-length repeat expansions in ATAXIN-2 (ATXN2) are the strongest genetic risk factor for amyotrophic lateral sclerosis (ALS). At the molecular level, ATXN2 intermediate expansions enhance TDP-43 toxicity and pathology. However, whether this triggers ALS pathogenesis at the cellular and functional level remains unknown. Here, we combine patient-derived and mouse models to dissect the effects of ATXN2 intermediate expansions in an ALS background. iPSC-derived motor neurons from ATXN2-ALS patients show altered stress granules, neurite damage and abnormal electrophysiological properties compared to healthy control and other familial ALS mutations. In TDP-43 Tg -ALS mice, ATXN2-Q33 causes reduced motor function, NMJ alterations, neuron degeneration and altered in vitro stress granule dynamics. Furthermore, gene expression changes related to mitochondrial function and inflammatory response are detected and confirmed at the cellular level in mice and human neuron and organoid models. Together, these results define pathogenic defects underlying ATXN2-ALS and provide a framework for future research into ATXN2-dependent pathogenesis and therapy.

Abstract Background Fecal microbiota transplantation (FMT) is a therapeutic intervention used to treat diseases associated with the gut microbiome. In the human gut microbiome, phages have been implicated in influencing human health, with successful engraftment of donor phages correlated with FMT treatment efficacy. The impact that gastrointestinal phages exert on human health has primarily been connected to their ability to modulate the bacterial communities in the gut. Nonetheless, how FMT affects recipients’ phage populations, and in turn, how this influences the gut environment, is not yet fully understood. In this study, we investigated the effects of FMT on the phageome composition of participants within the Gut Bugs Trial (GBT), a double-blind, randomized, placebo-controlled trial that investigated the efficacy of FMT in treating obesity and comorbidities in adolescents. Stool samples collected from donors at the time of treatment and recipients at four time points (i.e., baseline and 6 weeks, 12 weeks, and 26 weeks post-intervention), underwent shotgun metagenomic sequencing. Phage sequences were identified and characterized in silico to examine evidence of phage engraftment and to assess the extent of FMT-induced alterations in the recipients’ phageome composition. Results Donor phages engrafted stably in recipients following FMT, composing a significant proportion of their phageome for the entire course of the study (33.8 ± 1.2% in females and 33.9 ± 3.7% in males). Phage engraftment varied between donors and donor engraftment efficacy was positively correlated with their phageome alpha diversity. FMT caused a shift in recipients’ phageome toward the donors’ composition and increased phageome alpha diversity and variability over time. Conclusions FMT significantly altered recipients' phage and, overall, microbial populations. The increase in microbial diversity and variability is consistent with a shift in microbial population dynamics. This proposes that phages play a critical role in modulating the gut environment and suggests novel approaches to understanding the efficacy of FMT in altering the recipient’s microbiome. Trial registration The Gut Bugs Trial was registered with the Australian New Zealand Clinical Trials Registry (ACTR N12615001351505). Trial protocol: the trial protocol is available at https://bmjopen.bmj.com/content/9/4/e026174 . Video Abstract

Abstract Respiratory infections caused by the human fungal pathogen Aspergillus fumigatus are a major cause of mortality for immunocompromised patients. Exposure to these pathogens occurs through inhalation, although the role of the respiratory epithelium in disease pathogenesis has not been fully defined. Employing a primary human airway epithelial model, we demonstrate that fungal melanins potently block the post-translational secretion of the chemokines CXCL1 and CXCL8 independent of transcription or the requirement of melanin to be phagocytosed, leading to a significant reduction in neutrophil recruitment to the apical airway both in vitro and in vivo. Aspergillus-derived melanin, a major constituent of the fungal cell wall, dampened airway epithelial chemokine secretion in response to fungi, bacteria, and exogenous cytokines. Furthermore, melanin muted pathogen-mediated calcium fluxing and hindered actin filamentation. Taken together, our results reveal a critical role for melanin interaction with airway epithelium in shaping the host response to fungal and bacterial pathogens.

Abstract While high circulating tumor DNA (ctDNA) levels are associated with poor survival for multiple cancers, variant-specific differences in the association of ctDNA levels and survival have not been examined. Here we investigate KRAS ctDNA (ctKRAS) variant-specific associations with overall and progression-free survival (OS/PFS) in first-line metastatic pancreatic ductal adenocarcinoma (mPDAC) for patients receiving chemoimmunotherapy (“PRINCE”, NCT03214250), and an independent cohort receiving standard of care (SOC) chemotherapy. For PRINCE, higher baseline plasma levels are associated with worse OS for ctKRAS G12D (log-rank p = 0.0010) but not G12V (p = 0.7101), even with adjustment for clinical covariates. Early, on-therapy clearance of G12D (p = 0.0002), but not G12V (p = 0.4058), strongly associates with OS for PRINCE. Similar results are obtained for the SOC cohort, and for PFS in both cohorts. These results suggest ctKRAS G12D but not G12V as a promising prognostic biomarker for mPDAC and that G12D clearance could also serve as an early biomarker of response.

Abstract Introduction Most European infant national immunization programs (NIPs) recommend pneumococcal conjugate vaccines (PCVs), which currently cover 10–15 serotypes administered in a three-dose schedule (two primary plus one booster). Recently, a PCV covering 20 serotypes that is administered in a four-dose schedule (three primary plus one booster) was licensed. Methods An online survey was administered to collect data from health care providers (HCPs) and caregivers of children aged 0–5 (including expectant mothers) in four European countries (Germany, France, Spain, and Greece). All caregiver respondents had a shared or full responsibility to make health decisions for their child. Data on opinions, perceptions, and openness to a change in childhood vaccination dosing schedules were collected, along with demographic information for HCPs as well as caregivers. Results A total of 601 HCPs and 1954 caregivers were recruited across the four countries. Nearly all HCPs (93%) agreed that broader serotype coverage against pneumococcal disease for children is a significant unmet need, and 92% had a “sense of urgency” to vaccinate children. Both HCPs and caregivers were supportive of an additional PCV dose and doctor visit, assuming it provided at least 20% more serotype coverage than what is currently available. Caregivers strongly agreed on the importance of full vaccination for pneumococcal disease, even if an extra dose and visit to the doctor was required. Conclusions HCPs and caregivers were virtually unanimous in their support for a PCV with broader serotype coverage and showed a subsequent willingness to include an extra infant dose/visit. These results can help guide broader discussions regarding public health policy and vaccine administration in the context of important efforts to reduce the global disease burden associated with pneumococcal disease.

In this study, we use a dataset collected from eBay to analyze buyers’ negative feedback ratings and associated textual comments. By using text mining and sentiment analysis, we identify seven key reasons why buyers post negative ratings: communication problems, shipping issues, product defects, payment refund problems, customer service issues, fraud, and product packaging. These seven reasons can be classified into three categories: (1) sellers’ malicious fraudulence toward buyers, (2) factors likely under the control of sellers, and (3) factors not likely under the control of sellers. Drawing on these categories, we discuss how sellers can effectively reduce the likelihood that buyers post negative ratings. The most important things sellers can do to avoid negative ratings are to improve communications with buyers and to handle product shipping issues properly. In addition to posting the reasons for their negative ratings of sellers, the textual comments associated with negative feedback ratings may also include direct denouncements of sellers, such as buyers explicitly claiming a seller is a liar and warning other buyers to be cautious of the seller. We collectively call these actions buyers’ denouncements against sellers. These denouncements have significant negative impacts on sellers’ reputations. In this study, we use correlation analysis and logistic regression to investigate the factors that motivate buyers to denounce sellers. We find that, of the three categories of reasons why buyers post negative ratings, sellers’ malicious fraudulence toward buyers and factors likely under the control of sellers are more likely to lead to buyers’ denouncements of sellers, while factors not likely under the control of sellers are not likely to lead to buyers’ denouncements of sellers. In addition, buyers’ strong negative sentiment is also more likely to lead to their denouncement of sellers. Managerial implications of these findings are discussed.

Abstract Face-processing timing differences may underlie visual social attention differences between autistic and non-autistic people, and males and females. This study investigates the timing of the effects of neurotype and sex on face-processing, and their dependence on age. We analysed EEG data during upright and inverted photographs of faces from 492 participants from the Longitudinal European Autism Project (141 neurotypical males, 76 neurotypical females, 202 autistic males, 73 autistic females; age 6–30 years). We detected timings of sex/diagnosis effects on event-related potential amplitudes at the posterior–temporal channel P8 with Bootstrapped Cluster-based Permutation Analysis and conducted Growth Curve Analysis (GCA) to investigate the timecourse and dependence on age of neural signals. The periods of influence of neurotype and sex overlapped but differed in onset (respectively, 260 and 310 ms post-stimulus), with sex effects lasting longer. GCA revealed a smaller and later amplitude peak in autistic female children compared to non-autistic female children; this difference decreased in adolescence and was not significant in adulthood. No age-dependent neurotype difference was significant in males. These findings indicate that sex and neurotype influence longer latency face processing and implicates cognitive rather than perceptual processing. Sex may have more overarching effects than neurotype on configural face processing.

Abstract HPV infections are associated with a fraction of vulvar cancers. Through hybridization capture and DNA sequencing, HPV DNA was detected in five of thirteen vulvar cancers. HPV16 DNA was integrated into human DNA in three of the five. The insertions were in introns of human NCKAP1, C5orf67, and LRP1B. Integrations in NCKAP1 and C5orf67 were flanked by short direct repeats in the human DNA, consistent with HPV DNA insertions at sites of abortive, staggered, endonucleolytic incisions. The insertion in C5orf67 was present as a 36 kbp, human-HPV-hetero-catemeric DNA as either an extrachromosomal circle or a tandem repeat within the human genome. The human circularization/repeat junction was defined at single nucleotide resolution. The integrated viral DNA segments all retained an intact upstream regulatory region and the adjacent viral E6 and E7 oncogenes. RNA sequencing revealed that the only HPV genes consistently transcribed from the integrated viral DNAs were E7 and E6*I. The other two HPV DNA+ tumors had coinfections, but no evidence for integration. HPV-positive and HPV-negative vulvar cancers exhibited contrasting human, global gene expression patterns partially overlapping with previously observed differences between HPV-positive and HPV-negative cervical and oropharyngeal cancers. A substantial fraction of the differentially expressed genes involved immune system function. Thus, transcription and HPV DNA integration in vulvar cancers resemble those in other HPV-positive cancers. This study emphasizes the power of hybridization capture coupled with DNA and RNA sequencing to identify a broad spectrum of HPV types, determine human genome integration status of viral DNAs, and elucidate their structures.

Background: The objective of this study is to examine magnocellular and parvocellular pathways differentiation based on checkerboard spatial frequency stimulation between normal and visually impaired individuals from athletes with mild traumatic brain injury. Purpose: Athletes who exhibited photophobia, and blurriness were subjected to 5 spatial frequency stimuli presented to the left and right eye, and both eyes simultaneously to determine the type of receptive field loss deprecation based on sports-related brain trauma. Methods: Checkerboard stimulation enables the measurement between 2 visual processing pathways and enables the determination of the integrity of visual processing through visual evoked potentials (VEPs). Conclusion: The principal results reflect P1 responses demonstrated distinct changes in amplitude from mTBI (>5 µV) from normal cohorts concluding higher P1 amplitude of the VEP in mTBI cohorts had increased after injury. Latency in P1 was not as distinct as amplitude changes. Our major conclusion is that most of the mTBI cohort exhibited receptive field loss across all the patients appears to be magnocellular process deprecation due to frequent instances of 8 × 8 and 16 × 16 spatial frequencies input as it relates to amplitude and latency output.

Non-invasive brain stimulation (NIBS) technologies, such as repetitive transcranial magnetic stimulation (rTMS), offer significant therapeutic potential for a growing number of neuropsychiatric conditions. Concurrent with the expansion of this field is the swift evolution of rTMS methodologies, including approaches to optimize stimulation site planning. Traditional targeting methods, foundational to early successes in the field and still widely employed today, include using scalp-based heuristics or integrating structural MRI co-registration to align the transcranial magnetic stimulation (TMS) coil with anatomical landmarks. Recent evidence, however, supports refining and personalizing stimulation sites based on the target's structural and/or functional connectivity profile. These connectomic approaches harness the network-wide neuromodulatory effects of rTMS to reach deeper brain structures while also enabling a greater degree of personalization by accounting for heterogenous network topology. In this study, we acquired baseline multimodal magnetic resonance (MRI) at two time points to evaluate the reliability and reproducibility of distinct connectome-based strategies for stimulation site planning. Specifically, we compared the intra-individual difference between the optimal stimulation sites generated at each time point for (1) functional connectivity (FC) guided targets derived from resting-state functional MRI and (2) structural connectivity (SC) guided targets derived from diffusion tensor imaging. Our findings suggest superior reproducibility of SC-guided targets. We emphasize the necessity for further research to validate these findings across diverse patient populations, thereby advancing the personalization of rTMS treatments.

Abstract Background Congenital Heart Disease (CHD) is the most common congenital abnormality. Survival rates are over 90%, however infants with CHD remain at high risk of attention and executive function impairments. These abilities are difficult to assess in toddlers because clinical assessments rely on language abilities which are commonly delayed in CHD. Our aim was to characterise visual attention in toddlers with CHD compared to controls and identify associations with parent‐rated effortful control. Methods Thirty toddlers with CHD (19 male, median (IQR) age at assessment 22.2 (22–23.1) months) and 66 controls from the developing human connectome project (36 male, age at assessment 22 (21.5–23.8) months) using eye‐tracking tasks designed to assess multiple components of visual attention. Analyses of co‐variance and regressions were used to identify differences between groups and relationships between gaze behaviours and parent‐rated effortful control. Results Toddlers with CHD were less accurate when switching behaviours (set‐shifting) [median (IQR) 79%, (28–100)] compared to controls [100% (86–100), pFDR = 0.032], with worse accuracy associated with lower parent‐rated effortful control in CHD but not controls (interaction pFDR = 0.028). Reaction times were slower during selective [CHD 1243 ms (986–1786), controls 1065 ms (0851–1397), pFDR

Abstract Background Prior to September 2021, 55,000–90,000 hospital inpatients in England were identified as having a potentially nosocomial SARS-CoV-2 infection. This includes cases that were likely missed due to pauci- or asymptomatic infection. Further, high numbers of healthcare workers (HCWs) are thought to have been infected, and there is evidence that some of these cases may also have been nosocomially linked, with both HCW to HCW and patient to HCW transmission being reported. From the start of the SARS-CoV-2 pandemic interventions in hospitals such as testing patients on admission and universal mask wearing were introduced to stop spread within and between patient and HCW populations, the effectiveness of which are largely unknown. Materials/methods Using an individual-based model of within-hospital transmission, we estimated the contribution of individual interventions (together and in combination) to the effectiveness of the overall package of interventions implemented in English hospitals during the COVID-19 pandemic. A panel of experts in infection prevention and control informed intervention choice and helped ensure the model reflected implementation in practice. Model parameters and associated uncertainty were derived using national and local data, literature review and formal elicitation of expert opinion. We simulated scenarios to explore how many nosocomial infections might have been seen in patients and HCWs if interventions had not been implemented. We simulated the time period from March-2020 to July-2022 encompassing different strains and multiple doses of vaccination. Results Modelling results suggest that in a scenario without inpatient testing, infection prevention and control measures, and reductions in occupancy and visitors, the number of patients developing a nosocomial SARS-CoV-2 infection could have been twice as high over the course of the pandemic, and over 600,000 HCWs could have been infected in the first wave alone. Isolation of symptomatic HCWs and universal masking by HCWs were the most effective interventions for preventing infections in both patient and HCW populations. Model findings suggest that collectively the interventions introduced over the SARS-CoV-2 pandemic in England averted 400,000 (240,000 – 500,000) infections in inpatients and 410,000 (370,000 – 450,000) HCW infections. Conclusions Interventions to reduce the spread of nosocomial infections have varying impact, but the package of interventions implemented in England significantly reduced nosocomial transmission to both patients and HCWs over the SARS-CoV-2 pandemic.

Abstract Finding evidence of non-trivial pairing states is one of the greatest experimental challenges in the field of unconventional superconductivity. Such evidence requires phase-sensitive probes susceptible to the internal structure of the order parameter. We report the measurement of the Little-Parks effect in the unconventional superconductor candidate 4Hb-TaS2. In half of our rings, which are fabricated from single-crystals, we find a π-shift in the transition-temperature oscillations. According to theory, such a π-shift is only possible if the order parameter is non-s-wave. In the absence of crystallographic defects, the shift provides evidence of a multi-component order parameter. Thus, this observation increases the likelihood of the two-component order parameter scenario in 4Hb-TaS2. Furthermore, we show that T c is enhanced as a function of the out-of-plane field when a constant in-plane field is applied, which we explain using a two-component order-parameter.

Abstract Introduction A 20-valent pneumococcal conjugate vaccine (PCV20) was recently recommended for use among US children. We evaluated the cost-effectiveness of PCV20 among children aged 6 years with chronic medical conditions (CMC+) and children aged 6 years with immunocompromising conditions (IC) versus one and two doses of 23-valent pneumococcal polysaccharide vaccine (PPSV23), respectively. Methods A probabilistic model was employed to depict 10-year risk of clinical outcomes and economic costs of pneumococcal disease, reduction in life years from premature death, and expected impact of vaccination among one cohort of children with CMC+ and IC aged 6 years. Vaccine uptake was assumed to be 20% for both PCV20 and PPSV23. Cost per quality-adjusted life year (QALY) gained was evaluated from the US societal and healthcare system perspectives; deterministic and probabilistic sensitivity analyses (DSA/PSA) were also conducted. Results Among the 226,817 children with CMC+ aged 6 years in the US, use of PCV20 (in lieu of PPSV23) was projected to reduce the number cases of pneumococcal disease by 5203 cases, medical costs by US$8.7 million, and nonmedical costs by US$6.2 million. PCV20 was the dominant strategy versus PPSV23 from both the healthcare and societal perspectives. In the PSA, 99.9% of the 1000 simulations yielded a finding of dominance for PCV20. Findings in analyses of children with IC aged 6 years in the USA were comparable (i.e., PCV20 was the dominant vaccination strategy). Scenario analyses showed that increasing PCV20 uptake to 100% could potentially prevent > 22,000 additional cases of pneumococcal disease and further reduce medical and nonmedical costs by US$70.0 million among children with CMC+ and IC. Conclusions Use of PCV20 among young children with CMC+ and IC in the USA would reduce the clinical burden of pneumococcal disease and yield overall cost savings from both the US healthcare system and societal perspectives. Higher PCV20 uptake could further reduce the number of pneumococcal disease cases in this population.

Elementary school curricular standards in the United States emphasize mathematics and literacy, while social studies and science are often left behind. Integrating science instruction with either mathematics or literacy is a strategy some teachers use to teach skills and concepts in both disciplines. Understanding science at a young age is reliant on grasping vocabulary that is new to the learner. Integrating visual imagery into reading instruction improves students’ comprehension, enhances retrieval, and increases retention. The media-based reading enhancement of text through spatial computing has begun to show promise for the integration of science vocabulary and reading comprehension, especially for low-proficiency readers. This paper provides a literary rationale for technology-enhanced intervention, provides examples of a study conducted to test the efficacy of such an intervention, presents the implications of the study’s findings, and discusses future avenues for how spatial computing might be used in science and literacy instruction in the future.

Glucagon-like peptide-1 agonists are effective weight loss treatments, yet few data are available regarding their use in patients with durable left ventricular assist devices. We report our single-center experience with glucagon-like peptide-1 agonist use in 21 patients with World Health Organization class I to III obesity on durable left ventricular assist device support. During therapy, patients experienced a median weight change of −12.4 (−20.0 to −2.9) kg and a −7.4% (−16.3 to −2.1) change in body weight with a median time on glucagon-like peptide-1 agonist therapy of 12 (6-22) months. Of these, 17 of 21 patients lost weight (median change −14.0kg [−21.8 to −5.3], −9.5% [−18.0 to −4.0] body weight) and 9 of 21 had a speed reduction. No major adverse events were attributed to glucagon-like peptide-1 agonist therapy. At our center, glucagon-like peptide-1 agonists use was well tolerated, safe, and associated with weight loss in patients with durable left ventricular assist devices.

Abstract Sodium layered oxide with anion redox activity (SLO‐A) stands out as a promising cathode material for sodium‐ion batteries due to its impressive capacity and high voltage resulting from Mn‐ and O‐redox processes. However, the SLO‐A faces significant challenges in cycling stability and rate performance, primarily due to the poor reversibility and sluggish kinetics of the O‐redox. In this study,a novel Ti‐doped material, Na2/3Li2/9Mn53/72Ti1/24O2 (NLMTO), exhibiting remarkable characteristics such as a notable rate capacity (130 mAh g−1 at 3C, where 1C equals 200 mA g−1) and excellent cycling retention (85.4% after 100 cycles at 0.5C) is introduced. Employing electrochemical differential analyses, the contributions to the superior performance arising from the Mn‐ and O‐redox processes are quantitatively delineated. The optimized performance of NLMTO is attributed, in part, to the enhanced stability of both bulk and interface structures. The introduction of Ti through substitution not only contributes to this stability but also allows for the fine‐tuning of the material's electron configurations. This is achieved by augmenting the density of states near the Fermi energy level, as well as elevating the O 2p and Mn 3d orbits. This research advances sodium‐ion battery technology.

Epistemic reflection involves the creation of qualitatively new knowledge. Different models have been proposed to account for new knowing through reflection that have typically been grounded in an information-processing framework. However, there are in-principle arguments that information-processing approaches preclude the emergence of new representation altogether. Accordingly, any information-processing account of knowing through reflection is plagued by emergence issues. After discussing some of these emergence issues for four prominent models in the cognitive science literature, an alternative action-based model of representation and reflection is presented called interactivism. Interactivism's model of representation, as grounded in action anticipations, serves as the foundational emergence needed to account for subsequent knowing through reflection. After introducing the interactivist models of representation and reflection through knowing levels, some of the implications for consciousness, enculturation, language, and developmental methodology are discussed.

ABSTRACT Although antibiotics remain a cornerstone of modern medicine, the issues of widespread antibiotic resistance and collateral damage to the microbiome from antibiotic use are driving a need for drug developers to consider more tailored, patient-directed products to avoid antibiotic-induced perturbations of the structure and function of the indigenous microbiota. This perspective summarizes a cascade of microbiome health effects that is initiated by antibiotic-mediated microbiome disruption at an individual level and ultimately leads to infection and transmission of multidrug-resistant pathogens across patient populations. The scientific evidence behind each of the key steps of this cascade is presented. The interruption of this cascade through the use of highly targeted, microbiome-sparing antibiotics aiming to improve health outcomes is discussed. Further, this perspective reflects on some key clinical trial design and reimbursement considerations to be addressed as part of the drug development path.

ABSTRACT Quantitative microbial risk assessment (QMRA) is a growing interdisciplinary field addressing exposures to microbial pathogens and infectious disease processes. Risk science is inherently interdisciplinary, but few of the contributing disciplinary programs offer courses and training specifically in QMRA. To develop multidisciplinary training in QMRA, an annual 10-day long intensive workshop was conducted from 2015 to 2019—the Quantitative Microbial Risk Assessment Interdisciplinary Instructional Institute (QMRA III). National leaders in the fields of public health, engineering, microbiology, epidemiology, communications, public policy, and QMRA served as instructors and mentors over the course of the program. To provide cross-training, multidisciplinary teams of 5–6 trainees were created from the approximately 30 trainees each year. A formal assessment of the program was performed based on observations and surveys containing Likert-type scales and open-ended prompts. In addition, a longitudinal alumni survey was also disseminated to facilitate the future redevelopment of QMRA institutes and determine the impact of the program. Across all years, trainees experienced statistically significant increases (P < 0.05) in their perceptions of their QMRA abilities (e.g., use of specific computer programs) and knowledge of QMRA constructs (e.g., risk management). In addition, 12 publications, three conference presentations, and two research grants were derived from the QMRA III institute projects or tangential research. The success of QMRA III indicates that a short course format can effectively address many multidisciplinary training needs. Key features of QMRA III, including the inter-disciplinary training approach, hands-on exercises, real-world institute projects, and interaction through a mentoring process, were vital for training multidisciplinary teams housing multiple forms of expertise. Future QMRA institutes are being redeveloped to leverage hybrid learning formats that can further the multidisciplinary training and mentoring objectives.

Abstract Flexible electronics has emerged as a continuously growing field of study. Two‐dimensional (2D) materials often act as conductors and electrodes in electronic devices, holding significant promise in the design of high‐performance, flexible electronics. Numerous studies have focused on harnessing the potential of these materials for the development of such devices. However, to date, the incorporation of 2D materials in flexible electronics has rarely been summarized or reviewed. Consequently, there is an urgent need to develop comprehensive reviews for rapid updates on this evolving landscape. This review covers progress in complex material architectures based on 2D materials, including interfaces, heterostructures, and 2D/polymer composites. Additionally, it explores flexible and wearable energy storage and conversion, display and touch technologies, and biomedical applications, together with integrated design solutions. Although the pursuit of high‐performance and high‐sensitivity instruments remains a primary objective, the integrated design of flexible electronics with 2D materials also warrants consideration. By combining multiple functionalities into a singular device, augmented by machine learning and algorithms, we can potentially surpass the performance of existing wearable technologies. Finally, we briefly discuss the future trajectory of this burgeoning field. This review discusses the recent advancements in flexible sensors made from 2D materials and their applications in integrated architecture and device design.

Abstract INTRODUCTION We examined the relationship between sedentary behavior (SB), moderate‐to‐vigorous physical activity (MVPA), and white matter hyperintensity (WMH) volumes, a common magnetic resonance imaging (MRI) marker associated with risk of neurodegenerative disease in middle‐aged to older adults. METHODS We used data from the UK Biobank (n = 14,415; 45 to 81 years) that included accelerometer‐derived measures of SB and MVPA, and WMH volumes from MRI. RESULTS Both MVPA and SB were associated with WMH volumes (βMVPA = −0.03 [−0.04, −0.01], p

Summary: Umbilical cord blood (CB) is a donor source for hematopoietic cell therapies. Understanding what drives hematopoietic stem and progenitor cell function is critical to our understanding of the usage of CB in hematopoietic cell therapies. Here, we describe how to isolate and analyze the function of human hematopoietic cells from umbilical CB. This protocol demonstrates assays that measure phenotypic properties and hematopoietic cell potency.For complete details on the use and execution of this protocol, please refer to Broxmeyer et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

California is the largest agricultural economy in the United States; however, its current and projected climate risks pose significant challenges. Farmers will need to adapt to climate change in their farming practices. The goal of this needs assessment was to understand farmers' perceptions and experiences with climate change exposures; the risk management practices they currently use; and what tools and resources would assist them in making strategic decisions. A statewide survey was conducted through Qualtrics with farmers (n = 341). Results showed that 67% of the farmers agree (agree + strongly agree) that climate change is happening, and 53.1% agreed that actions are required. Moreover, historically underrepresented farmers were very concerned about climate change-related impacts related to water, temperatures, and natural disasters. Farmers are currently implementing adaptation practices related to water management, soil health, and renewable energy and are also seeking insurance and government assistance programs to increase agricultural resilience. They also expressed interest and a high need for information on those adaptation practices to acquire skills and knowledge to manage various challenges of farming in variable climates. Also, the assessment established that farmers (47.5%) use decision-support tools, mostly weather stations (22.4%); and 51.9% indicated their interest in using online tools designed to translate climate information into forms that support production decision-making. Farmers (60.8%) responded that they would or may attend workshops to learn about adaptation practices. The findings of this needs assessment will inform the development of extension education programs on climate-smart agriculture for farmers in California and elsewhere.

Introduction Early childhood development forms the foundations for functioning later in life. Thus, accurate monitoring of developmental trajectories is critical. However, such monitoring often relies on time-intensive assessments which necessitate administration by skilled professionals. This difficulty is exacerbated in low-resource settings where such professionals are predominantly concentrated in urban and often private clinics, making them inaccessible to many. This geographic and economic inaccessibility contributes to a significant ‘detection gap’ where many children who might benefit from support remain undetected. The Scalable Transdiagnostic Early Assessment of Mental Health (STREAM) project aims to bridge this gap by developing an open-source, scalable, tablet-based platform administered by non-specialist workers to assess motor, social and cognitive developmental status. The goal is to deploy STREAM through public health initiatives, maximising opportunities for effective early interventions.Methods and analysis The STREAM project will enrol and assess 4000 children aged 0–6 years from Malawi (n=2000) and India (n=2000). It integrates three established developmental assessment tools measuring motor, social and cognitive functioning using gamified tasks, observation checklists, parent-report and audio-video recordings. Domain scores for motor, social and cognitive functioning will be developed and assessed for their validity and reliability. These domain scores will then be used to construct age-adjusted developmental reference curves.Ethics and dissemination Ethical approval has been obtained from local review boards at each site (India: Sangath Institutional Review Board; All India Institute of Medical Science (AIIMS) Ethics Committee; Indian Council of Medical Research—Health Ministry Screening Committee; Malawi: College of Medicine Research and Ethics Committee; Malawi Ministry of Health—Blantyre District Health Office). The study adheres to Good Clinical Practice standards and the ethical guidelines of the 6th (2008) Declaration of Helsinki. Findings from STREAM will be disseminated to participating families, healthcare professionals, policymakers, educators and researchers, at local, national and international levels through meetings, academic journals and conferences.