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Postsecondary students with disabilities underutilize career services (CS) and report systemic barriers when trying to do so. Disability resource (DR) professionals rarely have the experience to advise students on employment issues such as internship opportunities, disclosure during interviews, and how to obtain workplace accommodations. Research recommends cross-training for professionals in both offices to facilitate more effective career development. The provision of accessible and disability-informed CS can strengthen students' preparation for workplace success, thereby improving persistent gaps in employment outcomes between college graduates with and without disabilities. This practice brief describes a virtual Community of Practice (CoP) involving CS and DR professionals from multiple Midwestern universities who shared strategies, challenges, and evaluation outcomes in a collaborative manner that can be replicated on other campuses.

This study examined the relationship between the accuracy of parental reporting of children's sleep duration compared to objectively measured child sleep and tested whether any discrepancies were related to childhood obesity prevalence in a sample of Latinx families (N = 119). A paired sample t-test revealed that parents significantly overestimated their child's sleep duration by 1.33 hours, t(86) = 6.69, p < 0.001. Using a one-way ANOVA, no significant differences were found in children's BMI percentile when grouped by the parent's accuracy of their child's sleep duration F(3, 83) = 0.76, p = 0.52. A potential, although non-significant, trend regarding parent accuracy and child BMI may merit further examination. Future research should seek to determine if the discrepancy in parent reported child sleep duration is indeed linked with increased child BMI and if this knowledge could be used in targeted intervention efforts to reduce childhood obesity.

Objective There is an established yet unexplained link between interferon (IFN) and systemic lupus erythematosus (SLE). The expression of sequences derived from transposable elements (TEs) may contribute to SLE phenotypes, specifically production of type I IFNs and generation of autoantibodies. Methods We profiled cell‐sorted RNA‐sequencing data (CD4+ T cells, CD14+ monocytes, CD19+ B cells, and natural killer cells) from peripheral blood mononuclear cells of 120 patients with SLE and quantified TE expression identifying 27,135 TEs. We tested for differential TE expression across 10 SLE phenotypes, including autoantibody production and disease activity. Results We found 731 differentially expressed (DE) TEs across all SLE phenotypes that were mostly cell specific and phenotype specific. DE TEs were enriched for specific families and open reading frames of viral genes encoded in TE sequences. Increased expression of DE TEs was associated with genes involved in antiviral activity, such as LY6E, ISG15, and TRIM22, and pathways such as IFN signaling. Conclusion These findings suggest that expression of TEs contributes to activation of SLE‐related mechanisms in a cell‐specific manner, which can impact disease diagnostics and therapeutics.

Abstract Denosumab is a monoclonal anti-RANKL antibody that inhibits bone resorption, increases bone mass, and reduces fracture risk. Denosumab discontinuation causes an extensive wave of rebound resorption, but the cellular mechanisms remain poorly characterized. We utilized in situ hybridization (ISH) as a direct approach to identify the cells that activate osteoclastogenesis through the RANKL/OPG pathway. ISH was performed across species, skeletal sites, and following recombinant OPG (OPG:Fc) and parathyroid hormone 1–34 (PTH) treatment of mice. OPG:Fc treatment in mice induced an increased expression of RANKL mRNA mainly in trabecular, but not endocortical bone surface cells. Additionally, a decreased expression of OPG mRNA was detected in bone surface cells and osteocytes of both compartments. A similar but more pronounced effect on RANKL and OPG expression was seen one hour after PTH treatment. These findings suggest that bone surface cells and osteocytes conjointly regulate the activation of osteoclastogenesis, and that OPG:Fc treatment induces a local accumulation of osteoclastogenic activation sites, ready to recruit and activate osteoclasts upon treatment discontinuation. Analysis of publicly available single-cell RNA sequencing (scRNAseq) data from murine bone marrow stromal cells revealed that Tnfsf11 + cells expressed high levels of Mmp13, Limch1, and Wif1, confirming their osteoprogenitor status. ISH confirmed co-expression of Mmp13 and Tnfsf11 in bone surface cells of both vehicle- and OPG:Fc-treated mice. Under physiological conditions of human/mouse bone, RANKL is expressed mainly by osteoprogenitors proximate to the osteoclasts, while OPG is expressed mainly by osteocytes and bone-forming osteoblasts.

Abstract Background Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) proteins are expressed on the surface of infected erythrocytes, mediating parasite sequestration in the vasculature. PfEMP1 is a major target of protective antibodies, but the features of the antibody response are poorly defined. Methods In Malawian children with cerebral or uncomplicated malaria, we characterized the antibody response to 39 recombinant PfEMP1 Duffy binding like (DBL) domains or cysteine-rich interdomain regions (CIDRs) in detail, including measures of antibody classes, subclasses, and engagement with Fcγ receptors and complement. Using elastic net regularized logistic regression, we identified a combination of seven antibody targets and Fc features that best distinguished between children with cerebral and uncomplicated malaria. To confirm the role of the selected targets and Fc features, we measured antibody-dependent neutrophil and THP-1 cell phagocytosis of intercellular adhesion molecule-1 (ICAM-1) and endothelial protein C (EPCR) co-binding infected erythrocytes. Results The selected features distinguished between children with cerebral and uncomplicated malaria with 87% accuracy (median, 80–96% interquartile range) and included antibody to well-characterized DBLβ3 domains and a less well-characterized CIDRγ12 domain. The abilities of antibodies to engage C1q and FcγRIIIb, rather than levels of IgG, correlated with protection. In line with a role of FcγRIIIb binding antibodies to DBLβ3 domains, antibody-dependent neutrophil phagocytosis of ICAM-1 and EPCR co-binding IE was higher in uncomplicated malaria (15% median, 8–38% interquartile range) compared to cerebral malaria (7%, 30–15%, p

Abstract Background Japanese knotweed (Reynoutria japonica var. japonica), a problematic invasive species, has a wide geographical distribution. We have previously shown the potential for attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy and chemometrics to segregate regional differentiation between Japanese knotweed plants. However, the contribution of environment to spectral differences remains unclear. Herein, the response of Japanese knotweed to varied environmental habitats has been studied. Eight unique growth environments were created by manipulation of the red: far-red light ratio (R: FR), water availability, nitrogen, and micronutrients. Their impacts on plant growth, photosynthetic parameters, and ATR-FTIR spectral profiles, were explored using chemometric techniques, including principal component analysis (PCA), linear discriminant analysis, support vector machines (SVM) and partial least squares regression. Key wavenumbers responsible for spectral differences were identified with PCA loadings, and molecular biomarkers were assigned. Partial least squared regression (PLSR) of spectral absorbance and root water potential (RWP) data was used to create a predictive model for RWP. Results Spectra from plants grown in different environments were differentiated using ATR-FTIR spectroscopy coupled with SVM. Biomarkers highlighted through PCA loadings corresponded to several molecules, most commonly cell wall carbohydrates, suggesting that these wavenumbers could be consistent indicators of plant stress across species. R: FR most affected the ATR-FTIR spectra of intact dried leaf material. PLSR prediction of root water potential achieved an R2 of 0.8, supporting the potential use of ATR-FTIR spectrometers as sensors for prediction of plant physiological parameters. Conclusions Japanese knotweed exhibits environmentally induced phenotypes, indicated by measurable differences in their ATR-FTIR spectra. This high environmental plasticity reflected by key biomolecular changes may contribute to its success as an invasive species. Light quality (R: FR) appears critical in defining the growth and spectral response to environment. Cross-species conservation of biomarkers suggest that they could function as indicators of plant-environment interactions including abiotic stress responses and plant health.

Abstract Purpose To determine the relationship between three postoperative physiotherapy activities (time to first postoperative walk, activity on the day after surgery, and physiotherapy frequency), and the outcomes of hospital length of stay (LOS) and discharge destination after hip fracture. Methods A cohort study was conducted on 437 hip fracture surgery patients aged ≥ 50 years across 36 participating hospitals from the Australian and New Zealand Hip Fracture Registry Acute Rehabilitation Sprint Audit during June 2022. Study outcomes included hospital LOS and discharge destination. Generalised linear and logistic regressions were used respectively, adjusted for potential confounders. Results Of 437 patients, 62% were female, 56% were aged ≥ 85 years, 23% were previously living in a residential aged care facility, 48% usually walked with a gait aid, and 38% were cognitively impaired prior to their injury. The median acute and total LOS were 8 (IQR 5–13) and 20 (IQR 8–38) days. Approximately 71% (n = 179/251) of patients originally living in private residence returned home and 29% (n = 72/251) were discharged to a residential aged care facility. Previously mobile patients had a higher total LOS if they walked day 2–3 (10.3 days; 95% CI 3.2, 17.4) or transferred with a mechanical lifter or did not get out of bed day 1 (7.6 days; 95% CI 0.6, 14.6) compared to those who walked day 1 postoperatively. Previously mobile patients from private residence had a reduced odds of return to private residence if they walked day 2–3 (OR 0.38; 95% CI 0.17, 0.87), day 4 + (OR 0.38; 95% CI 0.15, 0.96), or if they only sat, stood or stepped on the spot day 1 (OR 0.29; 95% CI 0.13, 0.62) when compared to those who walked day 1 postoperatively. Among patients from private residence, each additional physiotherapy session per day was associated with a -2.2 (95% CI -3.3, -1.0) day shorter acute LOS, and an increased log odds of return to private residence (OR 1.76; 95% CI 1.02, 3.02). Conclusion Hip fracture patients who walked earlier, were more active day 1 postoperatively, and/or received a higher number of physiotherapy sessions were more likely to return home after a shorter LOS.

BackgroundCommunity active case finding (ACF) for tuberculosis was widely implemented in Europe and North America between 1940 and 1970, when incidence was comparable to many present-day high-burden countries. Using an interrupted time series analysis, we analysed the effect of the 1957 Glasgow mass chest X-ray campaign to inform contemporary approaches to screening.Methods and findingsCase notifications for 1950 to 1963 were extracted from public health records and linked to demographic data. We fitted Bayesian multilevel regression models to estimate annual relative case notification rates (CNRs) during and after a mass screening intervention implemented over 5 weeks in 1957 compared to the counterfactual scenario where the intervention had not occurred. We additionally estimated case detection ratios and incidence. From 11 March 1957 to 12 April 1957, 714,915 people (622,349 of 819,301 [76.0%] resident adults ≥15 years) were screened with miniature chest X-ray; 2,369 (0.4%) were diagnosed with tuberculosis. Pre-intervention (1950 to 1956), pulmonary CNRs were declining at 2.3% per year from a CNR of 222/100,000 in 1950. With the intervention in 1957, there was a doubling in the pulmonary CNR (RR: 1.95, 95% uncertainty interval [UI] [1.81, 2.11]) and 35% decline in the year after (RR: 0.65, 95% UI [0.59, 0.71]). Post-intervention (1958 to 1963) annual rates of decline (5.4% per year) were greater (RR: 0.77, 95% UI [0.69, 0.85]), and there were an estimated 4,599 (95% UI [3,641, 5,683]) pulmonary case notifications averted due to the intervention. Effects were consistent across all city wards and notifications declined in young children (0 to 5 years) with the intervention. Limitations include the lack of data in historical reports on microbiological testing for tuberculosis, and uncertainty in contributory effects of other contemporaneous interventions including slum clearances, introduction of BCG vaccination programmes, and the ending of postwar food rationing.ConclusionsA single, rapid round of mass screening with chest X-ray (probably the largest ever conducted) likely resulted in a major and sustained reduction in tuberculosis case notifications. Synthesis of evidence from other historical tuberculosis screening programmes is needed to confirm findings from Glasgow and to provide insights into ongoing efforts to successfully implement ACF interventions in today's high tuberculosis burden countries and with new screening tools and technologies.

Abstract BackgroundNovel technologies, such as ecological momentary assessment (EMA) and wearable biosensor wristwatches, are increasingly being used to assess outcomes and mechanisms of change in psychological treatments. However, there is still a dearth of information on the feasibility and acceptability of these technologies and whether they can be reliably used to measure variables of interest. ObjectiveOur objectives were to assess the feasibility and acceptability of incorporating these technologies into dialectical behavior therapy and conduct a pilot evaluation of whether these technologies can be used to assess emotion regulation processes and associated problems over the course of treatment. MethodsA total of 20 adults with borderline personality disorder were enrolled in a 6-month course of dialectical behavior therapy. For 1 week out of every treatment month, participants were asked to complete EMA 6 times a day and to wear a biosensor watch. Each EMA assessment included measures of several negative affect and suicidal thinking, among other items. We used multilevel correlations to assess the contemporaneous association between electrodermal activity and 11 negative emotional states reported via EMA. A multilevel regression was conducted in which changes in composite ratings of suicidal thinking were regressed onto changes in negative affect. ResultsOn average, participants completed 54.39% (SD 33.1%) of all EMA (range 4.7%‐92.4%). They also wore the device for an average of 9.52 (SD 6.47) hours per day and for 92.6% of all days. Importantly, no associations were found between emotional state and electrodermal activity, whether examining a composite of all high-arousal negative emotions or individual emotional states (within-person r ConclusionsResults indicated moderate overall compliance with EMA and wearing the watch; however, there was no concurrence between EMA and wristwatch data on emotions. This pilot study raises questions about the reliability and validity of these technologies incorporated into treatment studies to evaluate emotion regulation mechanisms.

Optimizing warehouse layouts is crucial due to its significant impact on efficiency and productivity. We present an AI-driven framework for automated warehouse layout generation. This framework employs constrained beam search to derive optimal layouts within given spatial parameters, adhering to all functional requirements. The feasibility of the generated layouts is verified based on criteria such as item accessibility, required minimum clearances, and aisle connectivity. A scoring function is then used to evaluate the feasible layouts considering the number of storage locations, access points, and accessibility costs. We demonstrate our method's ability to produce feasible, optimal layouts for a variety of warehouse dimensions and shapes, diverse door placements, and interconnections. This approach, currently being prepared for deployment, will enable human designers to rapidly explore and confirm options, facilitating the selection of the most appropriate layout for their use-case.

Abstract Telomeres are repetitive nucleoprotein complexes at chromosomal termini essential for maintaining genome stability. Telomeric RNA, or TERRA, is a previously presumed long noncoding RNA of heterogeneous lengths that contributes to end-capping structure and function, and facilitates telomeric recombination in tumors that maintain telomere length via the telomerase-independent Alternative Lengthening of Telomeres (ALT) pathway. Here, we investigated TERRA in the radiation-induced DNA damage response (DDR) across astronauts, high-altitude climbers, healthy donors, and cellular models. Similar to astronauts in the space radiation environment and climbers of Mt. Everest, in vitro radiation exposure prompted increased transcription of TERRA, while simulated microgravity did not. Data suggest a specific TERRA DDR to telomeric double-strand breaks (DSBs), and provide direct demonstration of hybridized TERRA at telomere-specific DSB sites, indicative of protective TERRA:telomeric DNA hybrid formation. Targeted telomeric DSBs also resulted in accumulation of TERRA foci in G2-phase, supportive of TERRA’s role in facilitating recombination-mediated telomere elongation. Results have important implications for scenarios involving persistent telomeric DNA damage, such as those associated with chronic oxidative stress (e.g., aging, systemic inflammation, environmental and occupational radiation exposures), which can trigger transient ALT in normal human cells, as well as for targeting TERRA as a therapeutic strategy against ALT-positive tumors.

Abstract Hourly, year‐round flow cytometry has made it possible to relate seasonal environmental variability to the population dynamics of the smallest, most abundant phytoplankton on the Northeast US Shelf. To evaluate whether the insights from these data extend to Synechococcus farther from shore, we analyze flow cytometry measurements made continuously from the underway systems on 21 cruises traveling between the Martha's Vineyard Coastal Observatory (MVCO) and the continental shelf break. We describe how seasonal patterns in Synechococcus, which have been documented in detail at MVCO, occur across the region with subtle variation. We find that the underlying relationship between temperature and division rate is consistent across the shelf and can explain much of the observed spatial variability in concentration. Connecting individual cell properties to annual and regional patterns in environmental conditions, these results demonstrate the value of autonomous monitoring and create an improved picture of picophytoplankton dynamics within an economically important ecosystem.

Abstract Integrin trafficking to and from membrane adhesions is a crucial mechanism that dictates many aspects of a cell’s behaviour, including motility, polarisation, and invasion. In endothelial cells (ECs), the intracellular traffic of α5 integrin is regulated by both neuropilin 1 (NRP1) and neuropilin 2 (NRP2), yet the redundancies in function between these co-receptors remain unclear. Moreover, the endocytic complexes that participate in NRP-directed traffic remain poorly annotated. Here we identify an important role for the GTPase-activating protein p120RasGAP in ECs, promoting the recycling of α5 integrin from early endosomes. Mechanistically, p120RasGAP enables transit of endocytosed α5 integrin-NRP1-NRP2 complexes to Rab11+ recycling endosomes, promoting cell polarisation and fibronectin (FN) fibrillogenesis. Silencing of both NRP receptors, or p120RasGAP, resulted in the accumulation of α5 integrin in early endosomes, a loss of α5 integrin from surface adhesions, and attenuated EC polarisation. Endothelial-specific deletion of both NRP1 and NRP2 in the postnatal retina recapitulated our in vitro findings, severely impairing FN fibrillogenesis and polarised sprouting. Our data assign an essential role for p120RasGAP during integrin traffic in ECs and support a hypothesis that NRP receptors co-traffic internalised cargoes. Importantly, we utilise comparative proteomics analyses to isolate a comprehensive map of NRP1-dependent and NRP2-dependent α5 integrin interactions in ECs.

Systematic, routine, and comprehensive evaluation of Earth system models (ESMs) facilitates benchmarking improvement across model generations and identifying the strengths and weaknesses of different model configurations. By gauging the consistency between models and observations, this endeavor is becoming increasingly necessary to objectively synthesize the thousands of simulations contributed to the Coupled Model Intercomparison Project (CMIP) to date. The Program for Climate Model Diagnosis and Intercomparison (PCMDI) Metrics Package (PMP) is an open-source Python software package that provides quick-look objective comparisons of ESMs with one another and with observations. The comparisons include metrics of large- to global-scale climatologies, tropical inter-annual and intra-seasonal variability modes such as the El Niño–Southern Oscillation (ENSO) and Madden–Julian Oscillation (MJO), extratropical modes of variability, regional monsoons, cloud radiative feedbacks, and high-frequency characteristics of simulated precipitation, including its extremes. The PMP comparison results are produced using all model simulations contributed to CMIP6 and earlier CMIP phases. An important objective of the PMP is to document the performance of ESMs participating in the recent phases of CMIP, together with providing version-controlled information for all datasets, software packages, and analysis codes being used in the evaluation process. Among other purposes, this also enables modeling groups to assess performance changes during the ESM development cycle in the context of the error distribution of the multi-model ensemble. Quantitative model evaluation provided by the PMP can assist modelers in their development priorities. In this paper, we provide an overview of the PMP, including its latest capabilities, and discuss its future direction.

Abstract Background Obstructive sleep apnea (OSA) increases risk for cognitive decline and Alzheimer’s disease (AD). While the underlying mechanisms remain unclear, hypoxemia during OSA has been implicated in cognitive impairment. OSA during rapid eye movement (REM) sleep is usually more severe than in non-rapid eye movement (NREM) sleep, but the relative effect of oxyhemoglobin desaturation during REM versus NREM sleep on memory is not completely characterized. Here, we examined the impact of OSA, as well as the moderating effects of AD risk factors, on verbal memory in a sample of middle-aged and older adults with heightened AD risk. Methods Eighty-one adults (mean age:61.7 ± 6.0 years, 62% females, 32% apolipoprotein E ε4 allele (APOE4) carriers, and 70% with parental history of AD) underwent clinical polysomnography including assessment of OSA. OSA features were derived in total, NREM, and REM sleep. REM-NREM ratios of OSA features were also calculated. Verbal memory was assessed with the Rey Auditory Verbal Learning Test (RAVLT). Multiple regression models evaluated the relationships between OSA features and RAVLT scores while adjusting for sex, age, time between assessments, education years, body mass index (BMI), and APOE4 status or parental history of AD. The significant main effects of OSA features on RAVLT performance and the moderating effects of AD risk factors (i.e., sex, age, APOE4 status, and parental history of AD) were examined. Results Apnea–hypopnea index (AHI), respiratory disturbance index (RDI), and oxyhemoglobin desaturation index (ODI) during REM sleep were negatively associated with RAVLT total learning and long-delay recall. Further, greater REM-NREM ratios of AHI, RDI, and ODI (i.e., more events in REM than NREM) were related to worse total learning and recall. We found specifically that the negative association between REM ODI and total learning was driven by adults 60 + years old. In addition, the negative relationships between REM-NREM ODI ratio and total learning, and REM-NREM RDI ratio and long-delay recall were driven by APOE4 carriers. Conclusion Greater OSA severity, particularly during REM sleep, negatively affects verbal memory, especially for people with greater AD risk. These findings underscore the potential importance of proactive screening and treatment of REM OSA even if overall AHI appears low.

Abstract Due to population growth, climate change, and the urban heat island effect, heat exposure is becoming an important issue faced by urban built environments. Heat exposure assessment is a prerequisite for mitigation measures to reduce the impact of heat exposure. However, there is limited research on urban heat exposure assessment approaches that provides fine-scale spatiotemporal heat exposure information, integrated with meteorological status and human collective exposure as they move about in cities, to enable proactive heat exposure mitigation measures. Smart city digital twins (SCDTs) provide a new potential avenue for addressing this gap, enabling fine spatiotemporal scales, human-infrastructure interaction modeling, and predictive and decision support capabilities. This study aims to develop and test an SCDT for collective urban heat exposure assessment and forecasting. Meteorological sensors and computer vision techniques were implemented in Columbus, Georgia, to acquire temperature, humidity, and passersby count data. These data were then integrated into a collective temperature humidity index. A time-series prediction model and a crowd simulation were employed to predict future short-term heat exposures based on the data accumulated by this SCDT and to support heat exposure mitigation efforts. The results demonstrate the potential of SCDT to enhance public safety by providing city officials with a tool for discovering, predicting, and, ultimately, mitigating community exposure to extreme heat.

Abstract This paper introduces a methodology for characterizing the breadth of natural hazard types, hazard interrelationships, and risk scenarios in Global South urban areas, focusing on Nairobi, Kenya, and Istanbul, Türkiye. Our approach involves (a) a comprehensive characterization of multi‐hazards and their interrelationships in an urban setting, (b) collaborative development of relevant multi‐hazard scenarios with local disaster risk reduction (DRR) stakeholders, and (c) analysis of the potential for integrating these scenarios into urban DRR efforts. Using a critical review of 135 sources (academic and gray literature, databases, online, and social media), we identify 19 natural hazard types that might influence Nairobi and 23 in Istanbul. We further identified in Nairobi 88 and Istanbul 105 hazard interrelationship pairs (e.g., an earthquake triggering landslides) out of a possible 576 interrelationships. These findings are cataloged in an extensive database, which informs the creation of multi‐hazard risk scenario exemplars for each city. These exemplars are refined through stakeholder engagement, involving four workshops (47 participants) and nine semi‐structured interviews with local DRR stakeholders. Despite the identified benefits, this engagement reveals a significant gap in integrating multi‐hazards into current urban policy and practice. Governance challenges are highlighted as a key barrier, but opportunities for better integration are also identified, including evolving policies and growing awareness among urban actors. Our approach, particularly relevant in data‐scarce urban areas of low‐ and middle‐income countries, provides a framework for exploring multi‐hazard issues in various urban contexts.

Abstract The gold standard for enrollment and endpoint assessment in metabolic dysfunction‐associated steatosis clinical trials is histologic assessment of a liver biopsy performed on glass slides. However, obtaining the evaluations from several expert pathologists on glass is challenging, as shipping the slides around the country or around the world is time‐consuming and comes with the hazards of slide breakage. This study demonstrated that pathologic assessment of disease activity in steatohepatitis, performed using digital images on the AISight whole slide image management system, yields results that are comparable to those obtained using glass slides. The accuracy of scoring for steatohepatitis (nonalcoholic fatty liver disease activity score ≥4 with ≥1 for each feature and absence of atypical features suggestive of other liver disease) performed on the system was evaluated against scoring conducted on glass slides. Both methods were assessed for overall percent agreement with a consensus “ground truth” score (defined as the median score of a panel of three pathologists’ glass slides). Each case was also read by three different pathologists, once on glass and once digitally with a minimum 2‐week washout period between the modalities. It was demonstrated that the average agreement across three pathologists of digital scoring with ground truth was noninferior to the average agreement of glass scoring with ground truth [noninferiority margin: −0.05; difference: −0.001; 95% CI: (−0.027, 0.026); and p

IntroductionChronic low-grade inflammation might contribute to hyperandrogenemia and metabolic complications in polycystic ovary syndrome (PCOS). The proinflammatory cytokine interleukin (IL)-1 stimulates androgen production from ovarian cells, whereas blockade of the IL-1 pathway improves cardiometabolic health. We aimed to investigate whether blocking the IL-1 pathway ameliorates hyperandrogenemia in patients with PCOS.MethodsThis is a prospective, interventional, single-arm, proof-of-concept trial performed at a tertiary hospital in Switzerland (August 2018 to July 2020) in 18 premenopausal women with a diagnosis of PCOS according to the Rotterdam criteria, total testosterone levels ≥ 1.7 nmol/L, and C-reactive protein (CRP) ≥ 1.0 mg/L. Patients received 100 mg/day of the IL-1-receptor antagonist anakinra for 28 days and underwent weekly blood sampling until 1 week after the end of treatment. The primary endpoint was the change in serum androstenedione levels on day 7 of treatment, assessed with liquid chromatography–tandem mass spectrometry. Seven of these women participated in a subsequent observational sub-study (May 2021 to December 2021).ResultsMedian [interquartile range (IQR)] androstenedione increased by 0.5 [−0.1, 1.6] nmol/L (p = 0.048) with anakinra and by 1.3 [0.08, 2.4] nmol/L [p = 0.38] without anakinra between baseline and day 7. Anakinra reduced CRP levels on days 7, 21, and 28 (p < 0.001) but did not lead to an absolute reduction in androgens. However, four of six patients (67%) had smaller areas under the curves for androstenedione and/or testosterone during the 28-day intervention with anakinra as compared to 28 days without treatment.DiscussionOur findings suggest that anakinra suppresses IL-1-mediated chronic low-grade inflammation in PCOS and might attenuate biochemical hyperandrogenemia.

Summary: The study of pattern formation has benefited from our ability to reverse-engineer gene regulatory network (GRN) structure from spatiotemporal quantitative gene expression data. Traditional approaches have focused on systems where the timescales of pattern formation and morphogenesis can be separated. Unfortunately, this is not the case in most animal patterning systems, where pattern formation and morphogenesis are co-occurring and tightly linked. To elucidate patterning mechanisms in such systems we need to adapt our GRN inference methodologies to include cell movements. In this work, we fill this gap by integrating quantitative data from live and fixed embryos to approximate gene expression trajectories (AGETs) in single cells and use these to reverse-engineer GRNs. This framework generates candidate GRNs that recapitulate pattern at the tissue level, gene expression dynamics at the single cell level, recover known genetic interactions and recapitulate experimental perturbations while incorporating cell movements explicitly for the first time.

Computers have gone from being a workplace tool to something we carry in our pockets. This explosion of technological growth has been supported by HCI researchers and product designers as they strive to predict and meet user needs by studying user intentions toward, and experiences with, technology to improve usability. However, psychological research shows that device usage does not come without a psychological cost to the user, an impact apparently under-considered in HCI research. We surveyed users (n = 211) on their feelings about their experiences with different aspects and types of technology when the technology performed contrary to expectations. We found that technology that was frustrating to use or performed below expectations led to users reporting more negative feelings towards their use of the technology. Findings indicate that the user experience could be improved by considering user frustration and feelings towards technology in the design process.

Introduction Filipino Americans (FAs) are at high risk for developing type 2 diabetes despite other Asian phenotypes. Evidence suggests that pro-inflammatory interleukin-18 (IL-18) and anti-inflammatory adiponectin biomarkers associated with visceral adipose tissue (VAT) may explain this risk. Objectives This study aimed to quantify the biomarkers in relation to standard ranges of VAT or typical circulating concentration ranges reported in the literature of IL-18 and adiponectin, examine relationships of these markers, and determine if they were different among those participants without diabetes, prediabetes, and diabetes. Methods A cross-sectional study was used to enroll FAs without diabetes, prediabetes, or diabetes. VAT was measured using the InBody 570 © Body Composition Analyzer. Blood samples were obtained to assess plasma concentrations of IL-18 and adiponectin using enzyme-linked immunosorbent assay. All analyses were conducted using a 5% type I error rate. Mean ±SD and percentages were used to describe the sample and data where appropriate. Pearson's correlations (R) were calculated to determine the relationships between VAT and IL-18 in each group. Analysis of variance was used to determine differences in VAT, IL-18, and adiponectin among groups. Further, nonparametric procedures examined the differences in adiponectin among those within groups. Results Seventy-five participants were enrolled. Biomarkers above the typical concentration range were observed for VAT, IL-18, and adiponectin. Adiponectin significantly differed among groups with lower values in the diabetes group vs. the nondiabetes group. Conclusions The findings indicate that while inflammation-related biomarkers, such as adiponectin, correlate with VAT and may serve as indicators of increased risk of type 2 diabetes in FAs, correlation alone does not establish causality.

Fiber Reinforced Polymer (FRP) material is advocated for use in bridge structures to solve the corrosion and degradation problem of conventional steel reinforcements, thereby improving its durability and service life. Also, compared with ordinary concrete, self-compacting concrete (SCC) mixed with abundant industrial waste materials is expected to achieve sustainable development of concrete infrastructure. However, the research examining the performance of FRP reinforced SCC slabs in a real bridge is rather limited. This paper describes the application of basalt-FRP (BFRP) in a real bridge deck slab cast with low energy SCC. Since few studies have considered arching action on a real bridge deck slab, this paper aims at extending previous laboratory research using glass-FRP (GFRP) and BFRP reinforcement in in-plane restrained slabs to real bridge deck slabs. This study primarily investigates the serviceability behavior of real bridge deck slabs and utilizes the arching theory to predict their ultimate bearing capacity. The bearing capacities of real bridge deck slabs have been compared with the current specification requirements and the predictions considering arching theory. The test results indicate that a significantly low percentage of FRP reinforcement is possible in real bridge deck slabs due to the advantageous arching action.

Knowledge of surface pressure is essential for calculating column-averaged dry-air mole fractions of trace gases, such as CO2 (XCO2). In the NASA Orbiting Carbon Observatory 2 (OCO-2) Atmospheric Carbon Observations from Space (ACOS) retrieval algorithm, the retrieved surface pressures have been found to have unacceptable errors, warranting a parametric bias correction. This correction depends on the difference between retrieved and a priori surface pressures, which are derived from a meteorological model that is hypsometrically adjusted to the surface elevation using a digital elevation model (DEM). As a result, the effectiveness of the OCO-2 bias correction is contingent upon the accuracy of the referenced DEM. Here, we investigate several different DEM datasets for use in the OCO-2 ACOS retrieval algorithm: the OCODEM used in ACOS v10 and previous versions, the NASADEM+ (a composite of SRTMv4, ASTER GDEMv3, GIMP, and RAMPv2 DEMs) used in ACOS v11, the Copernicus GLO-90 DEM (GLO-90 DEM), and two polar regional DEMs (ArcticDEM and REMA). We find that the NASADEM+ (ASTER GDEMv3) has a persistent negative bias on the order of 10 to 20 m across most regions north of 60° N latitude, relative to all the other DEMs considered (OCODEM, ArcticDEM, and GLO-90 DEM). Variations of 10 m in DEM elevations lead to variations in XCO2 of approximately 0.4 ppm, meaning that the XCO2 from OCO-2 ACOS v11 retrievals tends to be 0.4 to 0.8 ppm lower across regions north of 60° N than XCO2 from OCO-2 ACOS v10. Our analysis also suggests that the GLO-90 DEM has superior global continuity and accuracy compared to the other DEMs, motivating a post-processing update from OCO-2 v11 Lite files (which used NASADEM+) to OCO-2 v11.1 by substituting the GLO-90 DEM globally. We find that OCO-2 v11.1 improves accuracy and spatial continuity in the bias-corrected XCO2 product relative to both v10 and v11 in high-latitude regions while resulting in marginal or no change in most regions within ± 60° latitude. In addition, OCO-2 v11.1 provides increased data throughput after quality control filtering in most regions, partly due to the change in DEM but mostly due to other corrections to quality control parameters. Given large-scale differences north of 60° N between the OCODEM and NASADEM+, we find that replacing the OCODEM with NASADEM+ yields a ∼ 100 TgC shift in inferred carbon uptake for the zones spanning 30 to 60° N and 60 to 90° N, which is on the order of 5 % to 7 % of the estimated pan-Arctic land sink. Changes in inferred fluxes from replacing the OCODEM with the GLO-90 DEM are smaller, and given the evidence for improved accuracies from this DEM, this suggests that large changes in inferred fluxes from the NASADEM+ are likely erroneous.

Abstract Background Self-reported adherence to direct-acting antivirals (DAAs) to treat hepatitis C virus (HCV) among persons who inject drugs (PWID) is often an overreport of objectively measured adherence. The association of such overreporting with sustained virologic response (SVR) is understudied. This study among PWID aimed to determine a threshold of overreporting adherence that optimally predicts lower SVR rates, and to explore correlates of the optimal overreporting threshold. Methods This study analyzed per-protocol data of participants with adherence data (N = 493) from the HERO (Hepatitis C Real Options) study. Self-reported and objective adherence to a 12-week DAA regimen were measured using visual analogue scales and electronic blister packs, respectively. The difference (Δ) between self-reported and objectively measured adherence was calculated. We used the Youden index based on receiver operating characteristic (ROC) curve analysis to identify an optimal threshold of overreporting for predicting lower SVR rates. Factors associated with the optimal threshold of overreporting were identified by comparing baseline characteristics between participants at/above versus those below the threshold. Results The self-reported, objective, and Δ adherence averages were 95.1% (SD = 8.9), 75.9% (SD = 16.3), and 19.2% (SD = 15.2), respectively. The ≥ 25% overreporting threshold was determined to be optimal. The SVR rate was lower for ≥ 25% vs.

Conservative mapping of data from one horizontal grid to another should preserve certain integral or mean properties of the original data. This may be essential in some model applications, including ensuring realistic exchange of energy and mass between coupled model components. It can also be essential for certain types of analysis, such as evaluating how far a system is from an equilibrium state. For some common grids, existing remapping algorithms may fail to perfectly represent the shapes and sizes of grid cells, which leads to errors in the remapped fields. A procedure is presented here that enables users to rely on the mapping weights generated by remapping algorithms but corrects for their deficiencies. With this procedure, for a given pair of source and destination grids, a single set of remapping weights can be applied to remap any variable, including those with grid cells that are partially or fully masked.

The latent viral reservoir represents one of the major barriers to curing HIV-1. Focus on the “kick and kill” (also called “shock and kill”) approach, in which virus expression is reactivated, and then cells producing virus are selectively depleted, has led to the discovery of many latency-reversing agents (LRAs) that have furthered our understanding of the mechanisms driving HIV-1 latency and latency reversal. Thus far, individual compounds have yet to be robust enough to work as a therapy, highlighting the importance of identifying new compounds that target novel pathways and synergize with known LRAs. In this study, we identified a promising LRA, NSC95397, from a screen of ~4250 compounds. We validated that NSC95397 reactivates latent viral transcription and protein expression from cells with unique integration events and across different latency models. Co-treating cells with NSC95397 and known LRAs demonstrated that NSC95397 synergizes with different drugs under both standard normoxic and physiological hypoxic conditions. NSC95397 does not globally increase open chromatin, and bulk RNA sequencing revealed that NSC95397 does not greatly increase cellular transcription. Instead, NSC95397 downregulates pathways key to metabolism, cell growth, and DNA repair—highlighting the potential of these pathways in regulating HIV-1 latency. Overall, we identified NSC95397 as a novel LRA that does not largely alter global transcription, shows potential for synergy with known LRAs, and may act through novel pathways not previously recognized for their ability to modulate HIV-1 latency.

In October 2020, the National Cancer Institute (NCI) Serological Sciences Network (SeroNet) was established to study the immune response to COVID-19, and "to develop, validate, improve, and implement serological testing and associated technologies" (https://www.cancer.gov/research/key-initiatives/covid-19/coronavirus-research-initiatives/serological-sciences-network). SeroNet is comprised of 25 participating research institutions partnering with the Frederick National Laboratory for Cancer Research (FNLCR) and the SeroNet Coordinating Center. Since its inception, SeroNet has supported collaborative development and sharing of COVID-19 serological assay procedures and has set forth plans for assay harmonization. To facilitate collaboration and procedure sharing, a detailed survey was sent to collate comprehensive assay details and performance metrics on COVID-19 serological assays within SeroNet. In addition, FNLCR established a protocol to calibrate SeroNet serological assays to reference standards, such as the U.S. severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serology standard reference material and first WHO international standard (IS) for anti-SARS-CoV-2 immunoglobulin (20/136), to facilitate harmonization of assay reporting units and cross-comparison of study data. SeroNet institutions reported development of a total of 27 enzyme-linked immunosorbent assay (ELISA) methods, 13 multiplex assays, and 9 neutralization assays and use of 12 different commercial serological methods. FNLCR developed a standardized protocol for SeroNet institutions to calibrate these diverse serological assays to reference standards. In conclusion, SeroNet institutions have established a diverse array of COVID-19 serological assays to study the immune response to SARS-CoV-2 and vaccines. Calibration of SeroNet serological assays to harmonize results reporting will facilitate future pooled data analyses and study cross-comparisons. IMPORTANCE SeroNet institutions have developed or implemented 61 diverse COVID-19 serological assays and are collaboratively working to harmonize these assays using reference materials to establish standardized reporting units. This will facilitate clinical interpretation of serology results and cross-comparison of research data.

To develop an equity-centered orientation in teacher education programs, it is essential to recognize what prospective teachers (PTs) attend to in classroom events and how they relate these events to mathematics instruction. We examined how race-gender intersections of a child (Black boy, Black girl, White boy, and White girl) in a written vignette shape PTs' noticing. Using an intersectional noticing lens, we analyzed PTs' responses with respect to race-gender intersections. The results indicated how racism and sexism can permeate PTs' implicit bias, positionality, and social expectations, which continue to oppress Blacks and girls within mathematics teaching and learning.

Objectives: We aimed to evaluate changes to measles-containing vaccine (MCV) provision and subsequent measles disease cases in low- and lower-middle income countries (LICs, LMICs) in relation to the COVID-19 pandemic.Methods: A systematic search was conducted of MEDLINE, OVID EMBASE and PubMed records. Primary quantitative and qualitative research studies published from January 2020 were included if they reported on COVID-19 impact on MCV provision and/or measles outbreak rates within LICs and LMICs.Results: 45 studies were included. The change in MCV1 vaccination coverage in national and international regions ranged −13% to +44.4% from pre-COVID time periods. In local regions, the median MCV1 and overall EPI rate changed by −23.3% and −28.5% respectively. Median MCV2 rate was disproportionally impacted in local areas during COVID-interruption time-periods (−48.2%) with ongoing disruption in early-recovery time-periods (−17.7%). 8.9% of studies reported on vaccination status of confirmed measles cases; from these, 71%–91% had received no MCV dose.Conclusion: MCV vaccination coverage experienced ongoing disruption during the recovery periods after initial COVID-19 disruption. Vaccination in local area datasets notably experienced longer-term disruption compared to nationally reported figures.

Fallopian tube pathology in patients with BRCA1 and BRCA2 mutations suggests a possible pathway to high grade serous ovarian carcinoma originates with a p53 signature, which is thought to represent a potential precursor to serous tubal intraepithelial carcinoma (STIC). The clinical implications of an isolated p53 signature in the average-risk population has not been well-established. This study aims to describe clinical outcomes in patients with incidentally noted p53 signature lesions.All patients diagnosed with a p53 signature lesion on final pathology from 2014 to 2022 were identified at a large academic institution. P53 signature is defined by our lab as morphologically normal to mildly atypical tubal epithelium with focal p53 over-expression on immunohistochemistry. Incidental p53 signature was defined as identification of a fallopian tube lesion excised for benign or unrelated indications in patients without a known hereditary disposition. Demographic, clinicopathologic, and genetic data were collected.A total of 127 patients with p53 signatures were identified. Thirty-six patients were excluded for established ovarian cancer or high-risk history leaving 91 total patients. Five patients (5.5%) developed a malignancy, none of which were ovarian or primary peritoneal, at the end of the eight and a half year follow up period. Twenty-four (26.4%) patients had salpingectomy without any form of oophorectomy at the time of initial surgery, while 67 (73.6%) patients had at least a unilateral oophorectomy at the time of their salpingectomy. Seven patients (7.7%) had additional surgery after p53 signature diagnosis; however, the final pathology yielded no evidence of malignancy in all these patients. After subsequent surgeries, 19 (20.9%) patients maintained their ovaries. The diagnosis of an incidental p53 signature was not associated with any primary peritoneal or ovarian cancer diagnoses during our follow up, and the majority of patients were managed conservatively by their providers with no further intervention after diagnosis.