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Abstract Dysarthria, a motor speech disorder that impacts articulation and speech clarity, presents significant challenges for Automatic Speech Recognition (ASR) systems. This study proposes a groundbreaking approach to enhance the accuracy of Dysarthric Speech Recognition (DSR). A primary innovation lies in the integration of the SepFormer-Speech Enhancement Generative Adversarial Network (S-SEGAN), an advanced generative adversarial network tailored for Dysarthric Speech Enhancement (DSE), as a front-end processing stage for DSR systems. The S-SEGAN integrates SEGAN’s adversarial learning with SepFormer speech separation capabilities, demonstrating significant improvements in performance. Furthermore, a multistage transfer learning approach is employed to assess the DSR models for both word-level and sentence-level DSR. These DSR models are first trained on a large speech dataset (LibriSpeech) and then fine-tuned on dysarthric speech data (both isolated and augmented). Evaluations demonstrate significant DSR accuracy improvements in DSE integration. The Dysarthric Speech (DS)-baseline models (without DSE), Transformer and Conformer achieved Word Recognition Accuracy (WRA) percentages of 68.60% and 69.87%, respectively. The introduction of Hierarchical Attention Network (HAN) with the Transformer and Conformer architectures resulted in improved performance, with T-HAN achieving a WRA of 71.07% and C-HAN reaching 73%. The Transformer model with DSE + DSR for isolated words achieves a WRA of 73.40%, while that of the Conformer model reaches 74.33%. Notably, the T-HAN and C-HAN models with DSE + DSR demonstrate even more substantial enhancements, with WRAs of 75.73% and 76.87%, respectively. Augmenting words further boosts model performance, with the Transformer and Conformer models achieving WRAs of 76.47% and 79.20%, respectively. Remarkably, the T-HAN and C-HAN models with DSE + DSR and augmented words exhibit WRAs of 82.13% and 84.07%, respectively, with C-HAN displaying the highest performance among all proposed models.

Abstract Background Despite great advances in proliferative diabetic retinopathy (PDR) therapy over the last decades, one third of treated patients continue to lose vision. While resident vitreous macrophages called hyalocytes have been implicated in the pathophysiology of vitreoretinal proliferative disease previously, little is known about their exact role in PDR. In this study, we address molecular and cellular alterations in the vitreous of PDR patients as a means towards assessing the potential contribution of hyalocytes to disease pathogenesis. Results A total of 55 patients were included in this study encompassing RNA-Sequencing analysis of hyalocytes isolated from the vitreous of PDR and control patients, multiplex immunoassay and ELISA analyses of vitreous samples from PDR and control patients, as well as isolation and immunohistochemical staining of cultured porcine hyalocytes. Transcriptional analysis revealed an enhanced inflammatory response of hyalocytes contributing to the cytokine pool within the vitreous of PDR patients by expressing interleukin-6, among others. Further, increased angiopoietin-2 expression indicated that hyalocytes from PDR patients undergo a proangiogenic shift and may thus mediate the formation of retinal neovascularizations, the hallmark of PDR. Finally, RNA-Sequencing revealed an upregulation of factors known from hemoglobin catabolism in hyalocytes from PDR patients. By immunohistochemistry, cultured porcine hyalocytes exposed to red blood cells were shown to engulf and phagocytose these, which reveals hyalocytes’ potential to dispose of erythrocytes. Thus, our data suggest a potential role for vitreous macrophages in erythrophagocytosis and, thereby, clearance of vitreous hemorrhage, a severe complication of PDR. Conclusion Our results strongly indicate a critical role for vitreous hyalocytes in key pathophysiological processes of proliferative diabetic retinopathy: inflammation, angiomodulation and erythrophagocytosis. Immunomodulation of hyalocytes may thus prove an essential novel therapeutic approach in diabetic vitreoretinal disease.

Abstract Diabetes mellitus is considered one of the main causes of death worldwide. If diabetes fails to be treated and diagnosed earlier, it can cause several other health problems, such as kidney disease, nerve disease, vision problems, and brain issues. Early detection of diabetes reduces healthcare costs and minimizes the chance of serious complications. In this work, we propose an e-diagnostic model for diabetes classification via a machine learning algorithm that can be executed on the Internet of Medical Things (IoMT). The study uses and analyses two benchmarking datasets, the PIMA Indian Diabetes Dataset (PIDD) and the Behavioral Risk Factor Surveillance System (BRFSS) diabetes dataset, to classify diabetes. The proposed model consists of the random oversampling method to balance the range of classes, the interquartile range technique-based outlier detection to eliminate outlier data, and the Boruta algorithm for selecting the optimal features from the datasets. The proposed approach considers ML algorithms such as random forest, gradient boosting models, light gradient boosting classifiers, and decision trees, as they are widely used classification algorithms for diabetes prediction. We evaluated all four ML algorithms via performance indicators such as accuracy, F1 score, recall, precision, and AUC-ROC. Comparative analysis of this model suggests that the random forest algorithm outperforms all the remaining classifiers, with the greatest accuracy of 92% on the BRFSS diabetes dataset and 94% accuracy on the PIDD dataset, which is greater than the 3% accuracy reported in existing research. This research is helpful for assisting diabetologists in developing accurate treatment regimens for patients who are diabetic.

Background There is growing interest in the use of nutrition and dietary supplements to optimize training and time-trial (TT) performance in cyclists. Separately, quercetin (QCT) and citrulline (CIT) have been used as ergogenic aids to improve oxygen (VO2) kinetics, perceived effort, and cycling TT performance. However, whether the combination of QCT and CIT can provide additive benefits and further enhance cycling performance production is currently unknown.Methods We examined 28-days of QCT + CIT supplementation on TT performance and several performance measures (i.e. mean power, VO2, respiratory exchange ratio (RER), and rate of perceived exertion (RPE)). Forty-eight highly trained cyclists were assigned to one of four supplementation groups: (1) QCT + CIT (QCT: 500 mg, CIT: 3000 g), (2) QCT (500 mg), (3) CIT (3000 mg), or (4) placebo (3500 mg of a zero-calorie flavored crystal light package). Supplements were consumed two times per day for 28 consecutive days. Participants performed a 20-km cycling time-trial race, pre- and post-supplementation to determine the impact of the combined effects of QCT + CIT.Results There were no potential benefits of QCT +CIT supplementation on TT performance and several performance measures. However, there was an improvement in VO2 from pre-to-post-supplementation in QCT (p = 0.05) and CIT (p = 0.04) groups, but not in the QCT+CIT and PL groups.Conclusions QCT + CIT does not seem beneficial for 20-km TT performance; further exploration with a focus on an increase in cycling duration or QCT+CIT combined with additional polyphenols may amplify any perceived bioactive or metabolic effects on cycling performance. The efficacy of QCT + CIT supplementation to improve cycling performance remains ambiguous.

Steel production is a critical economic activity and amongst the largest industrial consumers of energy. The industry faces a complex and costly task to decarbonise in line with global climate targets. This paper evaluates the performance of environmental and emissions scores within leading Environmental, Social and Governance (ESG) ratings products in capturing carbon emissions outcomes and investment in low-carbon production amongst major steel producers. We assess data for 75 steel producers, representing 65% of global production. We find no strong evidence that environmental or emissions scores reflect either levels of, or changes in, firms’ total greenhouse gas emissions or emissions intensity in the period 2013–2022. Overall, ‘good’ scores are not explained by available emissions or investment data. These findings for a critical industry emphasise the need for methodological transparency from all ratings providers, more research into ratings’ performance in reflecting outcomes and investments, and further policies to enhance disclosures from firms and rating agencies.

With the exponential proliferation of digital documents, there arises a pressing need for automated document summarization (ADS). Summarization, a compression technique, condenses a source document into concise sentences that encapsulate its salient information for summary generation. A primary challenge lies in crafting a dependable summary, contingent upon both extracted features and human-established parameters. This article introduces an intelligent methodology that seamlessly integrates extractive and abstractive techniques to ensure heightened relevance between the input document and its summary. Initially, input sentences undergo transformation into representations utilizing BERT, subsequently transposed into a symmetric matrix based on their similarity. Semantically congruent sentences are then extracted from this matrix to construct an extractive summary. The transformer model integrates an objective function highly symmetric and invariant under unitary transformation for language generation. This model refines the extracted informative sentences and generates an abstractive summary akin to manually crafted summaries. Employing this hybrid summarization technique on the CNN/DailyMail dataset and DUC2004, we evaluate its efficacy using ROUGE metrics. Results demonstrate the superiority of our proposed technique over conventional summarization methods.

ABSTRACT Cellular responses to external stress allow microorganisms to adapt to a vast array of environmental conditions, including infection sites. The molecular mechanisms behind these responses are studied to gain insight into microbial pathogenesis, which could lead to new antimicrobial therapies. Here, we explore a role for arrestin protein-mediated ubiquitination in stress response and pathogenesis in the pathogenic fungus Cryptococcus neoformans. In a previous study, we identified four arrestin-like proteins in C. neoformans and found that one of these is required for efficient membrane synthesis, likely by directing interaction between fatty acid synthases and the Rsp5 E3 ubiquitin ligase. Here, we further explore Cn Rsp5 function and determine that this single Ub ligase is absolutely required for pathogenesis and survival in the presence of cellular stress. Additionally, we show that a second arrestin-like protein, Ali2, similarly facilitates interaction between Rsp5 and some of its protein targets. Of the four postulated C. neoformans arrestin-like proteins, Ali2 appears to contribute the most to C. neoformans pathogenesis, likely by directing Rsp5 to pathogenesis-related ubiquitination targets. A proteomics-based differential ubiquitination screen revealed that several known cell surface proteins are ubiquitinated by Rsp5 and a subset also requires Ali2 for their ubiquitination. Rsp5-mediated ubiquitination alters the stability and the localization of these proteins. A loss of Rsp5-mediated ubiquitination results in cell wall defects that increase susceptibility to external stresses. These findings support a model in which arrestin-like proteins guide Rsp5 to ubiquitinate specific target proteins, some of which are required for survival during stress.IMPORTANCEMicrobial proteins involved in human infectious diseases often need to be modified by specific chemical additions to be fully functional. Here, we explore the role of a particular protein modification, ubiquitination, in infections due to the human fungal pathogen Cryptococcus neoformans. We identified a complex of proteins responsible for adding ubiquitin groups to fungal proteins, and this complex is required for virulence. These proteins are fungal specific and might be targets for novel anti-infection therapy.

ABSTRACT During mammalian colonization and infection, microorganisms must be able to rapidly sense and adapt to changing environmental conditions including alterations in extracellular pH. The fungus-specific Rim/Pal signaling pathway is one process that supports microbial adaptation to alkaline pH. This cascading series of interacting proteins terminates in the proteolytic activation of the highly conserved Rim101/PacC protein, a transcription factor that mediates microbial responses that favor survival in neutral/alkaline pH growth conditions, including many mammalian tissues. We identified the putative Rim pathway proteins Rim101 and Rra1 in the human skin colonizing fungus Malassezia sympodialis. Gene deletion by transconjugation and homologous recombination revealed that Rim101 and Rra1 are required for M. sympodialis growth at higher pH. In addition, comparative transcriptional analysis of the mutant strains compared to wild-type suggested mechanisms for fungal adaptation to alkaline conditions. These pH-sensing signaling proteins are required for optimal growth in a murine model of atopic dermatitis, a pathological condition associated with increased skin pH. Together, these data elucidate both conserved and phylum-specific features of microbial adaptation to extracellular stresses.IMPORTANCEThe ability to adapt to host pH has been previously associated with microbial virulence in several pathogenic fungal species. Here we demonstrate that a fungal-specific alkaline response pathway is conserved in the human skin commensal fungus Malassezia sympodialis (Ms). This pathway is characterized by the pH-dependent activation of the Rim101/PacC transcription factor that controls cell surface adaptations to changing environmental conditions. By disrupting genes encoding two predicted components of this pathway, we demonstrated that the Rim/Pal pathway is conserved in this fungal species as a facilitator of alkaline pH growth. Moreover, targeted gene mutation and comparative transcriptional analysis support the role of the Ms Rra1 protein as a cell surface pH sensor conserved within the basidiomycete fungi, a group including plant and human pathogens. Using an animal model of atopic dermatitis, we demonstrate the importance of Ms Rim/Pal signaling in this common inflammatory condition characterized by increased skin pH.

The Arabian leopard Panthera pardus nimr is categorized as Critically Endangered, with < 200 individuals estimated to remain in the wild. Historically the species ranged over an extensive area of western Saudi Arabia but, with no confirmed sightings since 2014, investigating potential continued presence and distribution is of critical conservation importance. We present the results of a comprehensive survey designed to detect any remaining Arabian leopard populations in Saudi Arabia. We conducted 14 surveys, deploying 586 camera-trap stations at 13 sites, totalling 82,075 trap-nights. Questionnaire surveys were conducted with 843 members of local communities across the Arabian leopard's historical range to assess the presence of leopards, other predators and prey species. Predator scats were collected ad hoc by field teams and we used mitochondrial DNA analysis to identify the originating species. We obtained 62,948 independent photographs of animals and people, but none were of Arabian leopards. Other carnivores appeared widespread and domestic animals were numerous, but wild prey were comparatively scarce. Three questionnaire respondents reported sightings of leopards within the previous year, but targeted camera-trap surveys in these areas did not yield evidence of leopards. Of the 143 scats sent for analysis, no DNA was conclusively identified as that of the leopard. From this extensive study, we conclude there are probably no surviving, sustainable populations of Arabian leopards in Saudi Arabia. Individual leopards might be present but were not confirmed. Any future Arabian leopard conservation in Saudi Arabia will probably require reintroduction of captive-bred leopards.

Transparent amorphous germanium (a‐Ge) has emerged as a promising material for engineering nanostructures and metasurfaces, offering significant potential for enhancing the performance of photonic devices in the short‐wavelength infrared (SWIR) spectrum. Herein, the successful application of a‐Ge metasurfaces with a truncated pyramid profile to enhance the external quantum efficiency (EQE) of a digital alloy Al0.3InAsSb p–i–n photodiode across a broad‐wavelength range in the SWIR is presented. The experimental findings demonstrate a broadband enhancement in EQE. Two metasurface samples are designed to emphasize different‐wavelength ranges. Notably, 51% improvement in EQE at 1550 nm and 125% enhancement at 2000 nm is achieved. Finite‐difference time domain simulations show that the observed EQE improvement originates from the reduction of reflection and electromagnetic field enhancement. This study underscores the promising role of a‐Ge metasurfaces in advancing the capabilities of SWIR photodetectors. It lays the groundwork for further exploration in optoelectronic device enhancements.

ABSTRACT Many international, national, state, and local organizations prioritize the ranking of threatened and endangered species to help direct conservation efforts. For example, the International Union for Conservation of Nature (IUCN) assesses the Green Status of species and publishes the influential Red List of threatened species. Unfortunately, such conservation yardsticks do not explicitly consider genetic or genomic diversity (GD), even though GD is positively associated with contemporary evolutionary fitness, individual viability, and with future evolutionary potential. To test whether populations of genome sequences could help improve conservation assessments, we estimated GD metrics from 82 publicly available mammalian datasets and examined their statistical association with attributes related to conservation. We also considered intrinsic biological factors, including trophic level and body mass, that could impact GD and quantified their relative influences. Our results identify key population GD metrics that are both reflective and predictive of IUCN conservation categories. Specifically, our analyses revealed that Watterson's theta (the population mutation rate) and autozygosity (a product of inbreeding) are associated with the current Red List categorization, likely because demographic declines that lead to “listing” decisions also reduce levels of standing genetic variation. We argue that by virtue of this relationship, conservation organizations like IUCN could leverage emerging genome sequence data to help categorize Red List threat rankings (especially in otherwise data‐deficient species) and/or enhance Green Status assessments to establish a baseline for future population monitoring. Thus, our paper (1) outlines the theoretical and empirical justification for a new GD‐based assessment criterion, (2) provides a bioinformatic pipeline for estimating GD from population genomic data, and (3) suggests an analytical framework that can be used to measure baseline GD while providing quantitative GD context for consideration by conservation authorities.

IntroductionHIV-1 envelope (Env) is the key target for antibodies (Abs) against the virus and thus an important HIV-1 vaccine component. Env is synthesized from a gp160 precursor with a signal peptide (SP) at its N-terminus. This study investigated the influence of the SP on Env antigenicity and immunogenicity.MethodsEnv proteins from two HIV-1 isolates, AA05 and AC02, were analyzed as gp120 and gp160 in their native wild-type (WT) forms and as chimeras with swapped SPs (AA05-02 and AC02-05). The WT and chimeric Env were assessed for antigenicity and glycosylation using monoclonal antibodies (mAbs) and glycan probes. Immunogenicity was tested in mice using three vaccine types: gp120 protein, gp120 DNA+gp120 protein, and gp120 DNA+gp160 DNA.ResultsThe recombinant AC02 gp120 protein was antigenically superior to AA05 as indicated by higher reactivity with most mAbs tested. When SPs were swapped, the antigenicity of the chimeric gp120s (AA05-02 and AC02-05) resembled that of the gp120s from which the SPs were derived; AA05-02 was similar to AC02 and vice versa. Glycan probe reactivity followed a similar pattern: AA05-02 and AC02 showed similar affinity to high-mannose specific mAbs and lectins. Interestingly, the antigenicity of gp160s showed an opposite pattern; membrane-bound gp160 expressed with the AA05 SP (AA05 and AC02-05) showed greater mAb binding than gp160 with the AC02 SP (AC02 and AA05-02). Mice immunized with gp120 protein showed that AA05-02 induced stronger cross-reactive binding Ab responses than AA05 WT, and AC02 elicited stronger responses than AC02-05, indicating AC02 SP enhanced gp120 immunogenicity. However, when DNA vaccines were included (gp120 DNA+gp120 protein and gp120 DNA+gp160 DNA), the use of heterologous SPs diminished the immunogenicity of the WT immunogens. Among the three vaccine regimens tested, only gp120 DNA+gp160 DNA immunization elicited low-level Tier 2 neutralizing Abs, with AA05 WT inducing Abs with greater neutralization capabilities than AA05-02.ConclusionThese data demonstrate that the SP can significantly impact the antigenicity and immunogenicity of HIV-1 Env proteins. Hence, while SP swapping is a common practice in constructing Env immunogens, this study highlights the importance of careful consideration of the effects of replacing native SPs on the immunogenicity of Env vaccines.

The detection of landmines, namely anti-tank mines, explosive devices, and unexploded ordnance, is a formidable obstacle for the global community. The visible consequences of unobserved explosives in communities affected by war are characterized by significant devastation and human suffering. In order to effectively tackle this matter, it is imperative to use proactive strategies that focus on the identification and mitigation of these perilous substances prior to their potential infliction of harm. Nevertheless, the majority of current solutions exhibit significant deficiencies, such as exorbitant expenses, inefficiencies, and apprehensions over accuracy. These drawbacks are further compounded by the inherent trade-offs that exist between these elements, where improvements in one area often come at the expense of another. Contrarily, recent breakthroughs in the areas of deep learning, unmanned aerial vehicles, and sensor technologies are being recognized as potentially transformative elements in the domain of landmine identification and removal. This paper presents a thorough examination of recent scholarly investigations that integrate computerized technology in the field of landmine detection. To the extent of our current understanding, there has been no prior investigation that has thoroughly examined this particular domain. The main aim of this study is to investigate the incorporation of machine learning based regression methods in the field of landmine detection. The study specifically emphasizes the identification and resolution of existing issues that hinder the development of efficient automated solutions, hence enhancing performance optimization. The Sum of Sine Curve Fit Regression Model is proposed and proved a powerful and adaptable tool for extracting relevant information from this hyperspectral images.

The emerging 5G network has been revolutionizing the data transfer across the networks. Recently, advanced technologies transform the healthcare industry. With the emergence of 5G technology, smart and ubiquitous healthcare systems are interconnected with high speed and low latency. As ubiquitous healthcare applications require stringent network requirements, managing network traffic and resources becomes difficult. Internet of Medical Things (IoMT) devices generates a large volume and variety of data, including physiological signals, images, and videos. As many medical applications require real-time communication and data transfer, this puts high demands on the network, which needs handle low latency, high availability, and high reliability. Achieving consistent QoS is challenging due to the inherent limitations of conventional methods which are susceptible to network congestion and latency issues. The next generation of Software Defined Networking (SDN) in IoMT can play a vital role in supporting traffic management. Reliable classification and forecasting will enable the SDN controller to make optimal routing decisions dynamically. Therefore in this paper, a novel Medical Traffic Forecasting framework based on Weighted Multivariate Singular Spectrum Analysis (MTF-WMSSA) is proposed for an SDN-enabled IoMT healthcare network to analyze and forecast network traffic and ensure accurate real-time medical data transfer. The evaluation was conducted on the EHMS dataset to study the performance of the proposed method. The comparison of the proposed MTF-WMSSA is made with classical methods such as SVR and LSTM. The result shows that the proposed MTF-WMSSA exhibits improved classification accuracy of 93%. The network parameters that are forecasted are average traffic load, average packet arrival rate and average jitter. The MAPE of the multi-step ahead forecast is 13.64 and 11.41 for short and long intervals respectively. The forecasting algorithm proposed in this paper can efficiently determine future flow parameters which help to implement adaptive traffic engineering. The evaluation was conducted on the dataset to study the performance of the proposed method. The result shows that the proposed MTF-WMSSA exhibits better accuracy for multi-step ahead forecast and outperforms the classical methods.

Background Psilocybin and related tryptamines have come into the spotlight in recent years as potential therapeutics for depression. Research on the mechanisms of these effects has historically focused on the direct effects of these drugs on neural processes. However, in addition to such neural effects, alterations in peripheral physiology may also contribute to their therapeutic effects. In particular, substantial support exists for a gut microbiome-mediated pathway for the antidepressant efficacy of other drug classes, but no prior studies have determined the effects of tryptamines on microbiota. Methods To address this gap, in this preliminary study, male Long Evans rats were treated with varying dosages of oral psilocybin (0.2 or 2 mg/kg), norbaeocystin (0.25 or 2.52 mg/kg), or vehicle and their fecal samples were collected 1 week and 3 weeks after exposure for microbiome analysis using integrated 16S ribosomal DNA sequencing to determine gut microbiome composition. Results We found that although treatment with neither psilocybin nor norbaeocystin significantly affected overall microbiome diversity, it did cause significant dose- and time-dependent changes in bacterial abundance at the phylum level, including increases in Verrucomicrobia and Actinobacteria, and decreases in Proteobacteria. Conclusion and Implications These preliminary findings support the idea that psilocybin and other tryptamines may act on the gut microbiome in a dose- and time-dependent manner, potentially identifying a novel peripheral mechanism for their antidepressant activity. The results from this preliminary study also suggest that norbaeocystin may warrant further investigation as a potential antidepressant, given the similarity of its effects to psilocybin.

Abstract. Objectives:. Limb amputation is a possible outcome of acute compartment syndrome. We undertook this study to investigate the occurrence of fasciotomy and amputation in patients with tibial fractures in the Ontario adult population, aiming to evaluate variables that may be associated with each of these outcomes. Design:. Retrospective, population-based cohort study (April 1, 2003–March 31, 2016). Setting:. Canadian province of Ontario. Participants:. Patients with tibial fracture, aged 14 years and older. Intervention(s):. Fasciotomy after tibial fracture. Main Outcome(s) and Measure(s):. The primary outcomes were fasciotomy and amputation within 1 year of fasciotomy. Secondary outcomes included repeat surgery, new-onset renal failure, and mortality, all within 30 days of fasciotomy. Results:. We identified 76,299 patients with tibial fracture; the mean (SD) age was 47 (21) years. Fasciotomy was performed in 1303 patients (1.7%); of these, 76% were male and 24% female. Patients who were younger, male, or experienced polytrauma were significantly more likely to undergo fasciotomy. Limb amputation occurred in 4.3% of patients undergoing fasciotomy, as compared with 0.5% in those without fasciotomy; older age, male sex, presence of polytrauma, and fasciotomy were associated with an increased risk of amputation (age odds ratio [OR] of 1.03 [95% CI, 1.02–1.03], P < 0.0001; sex OR of 2.04 [95% CI, 1.63–2.55], P < 0.0001; polytrauma OR of 9.37 [95% CI, 7.64–11.50], P < 0.0001; fasciotomy OR of 4.35 [95% CI, 3.21–5.90], P < 0.0001), as well as repeat surgery within 30 days (sex OR of 1.54 [95% CI, 1.14–2.07], P = 0.0053; polytrauma OR of 4.24 [95% CI, 3.33–5.38], P < 0.0001). Conclusions:. Among tibial fracture patients, those who were male and who experienced polytrauma were at significantly higher risk of undergoing fasciotomy and subsequent amputation. Fasciotomy was also significantly associated with risk of amputation, a finding that is likely reflective of the severity of the initial injury.

Abstract Background Early skeletal muscle loss has been observed in adolescent and young adult (AYA) sarcoma patients undergoing treatment. Identification of individuals within the AYA populace that are at greatest risk of anthracycline‐induced skeletal muscle loss is unknown. Moreover, investigations which seek out underlying causes of skeletal muscle degradation during chemotherapy are critical for understanding, preventing, and reducing chronic health conditions associated with poor skeletal muscle status. Methods Computed tomography (CT) scans were used to investigate changes in skeletal muscle of 153 AYA sarcoma and Hodgkin lymphoma patients at thoracic vertebra 4 after anthracycline treatment. Images were examined at three time points during the first year of treatment. In parallel, we used translational juvenile mouse models to assess the impact of doxorubicin (DOX) in the soleus and gastrocnemius on muscle wasting. Results Significant reductions in total skeletal muscle index and density were seen after chemotherapy in AYA cancer patients (p

Abstract Globally, we are facing an emerging climate crisis, with impacts to be notably felt in semiarid regions across the world. Cultivation of drought‐adapted succulent plants has been suggested as a nature‐based solution that could: (i) reduce land degradation, (ii) increase agricultural diversification and provide both economic and environmentally sustainable income through derived bioproducts and bioenergy, (iii) help mitigate atmospheric CO2 emissions and (iv) increase soil sequestration of CO2. Identifying where succulents can grow and thrive is an important prerequisite for the advent of a sustainable alternative ‘bioeconomy’. Here, we first explore the viability of succulent cultivation in Africa under future climate projections to 2100 using species distribution modelling to identify climatic parameters of greatest importance and regions of environmental suitability. Minimum temperatures and temperature variability are shown to be key controls in defining the theoretical distribution of three succulent species explored, and under both current and future SSP5 8.5 projections, the conditions required for the growth of at least one of the species are met in most parts of sub‐Saharan Africa. These results are supplemented with an analysis of potentially available land for alternative succulent crop cultivation. In total, up to 1.5 billion ha could be considered ecophysiologically suitable and available for succulent cultivation due to projected declines in rangeland biomass and yields of traditional crops. These findings may serve to highlight new opportunities for farmers, governments and key stakeholders in the agriculture and energy sectors to invest in sustainable bioeconomic alternatives that deliver on environmental, social and economic goals.

Coastal environments are complex systems that are influenced by a combination of natural processes and human activities. Scientific interest in the effects of coastal erosion/accretion and climatic change-related processes has greatly increased in recent decades due to the growing human development along coastal areas. This paper investigates the state and evolution of beach–dune systems for the 1977–2001 and 2001–2019 periods of the Mediterranean coast of Andalusia (Spain) using two different proxies: the dune toe line, which was used to track foredunes evolution, and the high-water line, which was used to assess shoreline evolution. Results showed a general erosional behavior of the studied beach–dune systems and identified cases where the main trend was altered through human interventions. During the 1977–2001 period, foredunes essentially showed erosion (54%), accretion (24%), and stability (22%) and shorelines showed accretion (40%) and erosion and stability (34% each). During the 2001–2019 period, foredunes essentially showed erosion (42%), stability (30%), and accretion (28%), and shorelines showed erosion (40%), accretion (34%), and stability (26%). Combining the evolution classes of each proxy (dune toe/shoreline) allows the behavior of both shoreline proxies to be assessed together and provides insights additional to those derived from the use of a single proxy. In this regard, Erosion/erosion (EE) and Accretion/accretion (AA) were the most frequent behaviors in the first and second periods. The results obtained provide additional insights on the nature and drivers of coastal change that aid local coastal managers and administrations in understanding erosion processes. The method can be applied to other areas around the world where a similar database is available.

Abstract The emergence of large language models has led to the development of powerful tools such as ChatGPT that can produce text indistinguishable from human-generated work. With the increasing accessibility of such technology, students across the globe may utilize it to help with their school work—a possibility that has sparked ample discussion on the integrity of student evaluation processes in the age of artificial intelligence (AI). To date, it is unclear how such tools perform compared to students on university-level courses across various disciplines. Further, students’ perspectives regarding the use of such tools in school work, and educators’ perspectives on treating their use as plagiarism, remain unknown. Here, we compare the performance of the state-of-the-art tool, ChatGPT, against that of students on 32 university-level courses. We also assess the degree to which its use can be detected by two classifiers designed specifically for this purpose. Additionally, we conduct a global survey across five countries, as well as a more in-depth survey at the authors’ institution, to discern students’ and educators’ perceptions of ChatGPT’s use in school work. We find that ChatGPT’s performance is comparable, if not superior, to that of students in a multitude of courses. Moreover, current AI-text classifiers cannot reliably detect ChatGPT’s use in school work, due to both their propensity to classify human-written answers as AI-generated, as well as the relative ease with which AI-generated text can be edited to evade detection. Finally, there seems to be an emerging consensus among students to use the tool, and among educators to treat its use as plagiarism. Our findings offer insights that could guide policy discussions addressing the integration of artificial intelligence into educational frameworks.

Background: Plasma refill rates can be estimated by combining measurements of urine output with relative blood volume profiles. Change in plasma refill rates could guide decongestive loop diuretic therapy in acute heart failure. The objective of the study was to assess average relative blood volume profiles generated from 2 or 3 follow-up measurements obtained hours after loop diuretic administration in subjects with vs without baseline congestion. Methods: A systematic review was conducted of articles written in English, French, Spanish, and German, using MEDLINE (1964 to 2019), Cochrane Reviews (1996 to 2019), and Embase (1974 to 2019). Search terms included the following: diuretics, hemoconcentration, plasma volume, and blood volume. We included studies of adults given a loop diuretic with at least one baseline and one follow-up measurement. A single author extracted subject- or group-level blood volume measurements, aggregated them when needed, and converted them to relative changes. Results: Across all 16 studies that met the prespecified inclusion criteria, relative blood volume maximally decreased 9.2% (6.6% to 12.0%) and returned to baseline after 3 or more hours. Compared to subjects without congestion, those with congestion experienced smaller decreases in relative blood volume across all follow-up periods (P = 0.001) and returned to baseline within the final follow-up period. Conclusions: Single doses of loop diuretics produce measurable changes in relative blood volume that follow distinct profiles for subjects with vs without congestion. Measured alongside urine output, these profiles may be used to estimate plasma refill rates—potential patient-specific targets for decongestive therapy across serial diuretic doses. Résumé: Contexte: Le taux de remplissage plasmatique peut être estimé en combinant les mesures de la diurèse et les profils volémiques relatifs. Chez les personnes atteintes d’insuffisance cardiaque aiguë, une variation du taux de remplissage plasmatique pourrait guider un traitement décongestif par un diurétique de l’anse. L’étude avait pour objectif d’évaluer les profils volémiques relatifs moyens obtenus dans le cadre de deux ou trois mesures de suivi réalisées quelques heures après l’administration d’un diurétique de l’anse à des sujets présentant ou non une congestion initiale. Méthodologie: Une revue systématique d’articles rédigés en anglais, en français, en espagnol et en allemand a été effectuée au moyen des bases de données MEDLINE (1964 à 2019), Cochrane Reviews (1996 à 2019) et Embase (1974 à 2019). Les termes de recherche comprenaient : diurétiques, hémoconcentration, volume plasmatique et volume sanguin. Nous avons inclus des études portant sur des adultes ayant reçu un diurétique de l’anse chez qui au moins une mesure initiale et une mesure de suivi avaient été effectuées. Un seul auteur a recueilli des mesures du volume sanguin individuelles ou de groupe, les a regroupées, au besoin, et converties en variations relatives. Résultats: Parmi les 16 études qui répondaient aux critères d’inclusion prédéfinis, le volume sanguin relatif a diminué de 9,2 % (de 6,6 % à 12,0 %) et est revenu aux valeurs initiales après trois heures ou plus. Les sujets qui présentaient une congestion ont connu des diminutions du volume sanguin relatif inférieures à celles de ceux n’en présentant pas lors de toutes les périodes de suivi (p = 0,001); le volume sanguin relatif est revenu aux valeurs initiales durant la période finale de suivi. Conclusions: Des doses uniques de diurétique de l’anse produisent des changements mesurables du volume sanguin relatif selon des profils distincts chez les sujets présentant une congestion, comparativement à ceux n’en présentant pas. Utilisés en association avec les mesures de la diurèse, ces profils peuvent servir à estimer le taux de remplissage plasmatique, qui constitue potentiellement une cible particulière au patient qui reçoit une série de doses d’un diurétique comme traitement décongestif.

Abstract Psychostimulants target the dopamine transporter (DAT) to elicit their psychomotor actions. Bile acids (BAs) can also bind to DAT and reduce behavioral responses to cocaine, suggesting a potential therapeutic application of BAs in psychostimulant use disorder. Here, we investigate the potential of BAs to decrease drug-primed reinstatement when administered during an abstinence phase. To do this, after successful development of cocaine-associated contextual place preference (cocaine CPP), cocaine administration was terminated, and animals treated with vehicle or obeticholic acid (OCA). When preference for the cocaine-associated context was extinguished, mice were challenged with a single priming dose of cocaine, and reinstatement of cocaine-associated contextual preference was measured. Animals treated with OCA demonstrate a significantly lower reinstatement for cocaine CPP. OCA also impairs the ability of cocaine to reduce the clearance rate of electrically stimulated dopamine release and diminishes the area under the curve (AUC) observed with amperometry. Furthermore, the AUC of the amperometric signal positively correlates with the reinstatement index. Using operant feeding devices, we demonstrate that OCA has no effect on contextual learning or motivation for natural rewards. These data highlight OCA as a potential therapeutic for cocaine use disorder.

Abstract Obesity is a chronic, multifactorial disease which is linked to a number of adverse endocrinological and metabolic conditions. Currently, bariatric surgery is one of the most effective treatments for individuals diagnosed with severe obesity. However, the current indications for bariatric surgery are based on inadequate metrics (i.e., BMI) which do not account for the complexity of the disease, nor the heterogeneity among the patient population. Moreover, there is a lack of understanding with respect to the biological underpinnings that influence successful and sustained weight loss post-bariatric surgery. Studies have implicated age and pre-surgery body weight as two factors that are associated with favorable patient outcomes. Still, there is an urgent medical need to identify other potential factors that could improve the specificity of candidate selection and better inform the treatment plan of patients with obesity. In this report, we present and describe the cohort of the DECON pilot project, a multicenter study which aims to identify predictive biomarkers of successful weight loss after bariatric surgery.

Abstract Background Radiation therapy (RT) is a common treatment for adolescents and young adults (AYAs, 15–39 years old) with cancer; however, it may cause toxicities that affect health‐related quality‐of‐life (HRQOL). Thus, we assessed HRQOL in AYAs before, during, and after RT. Methods We identified 265 AYAs who completed HRQOL PROMIS® surveys before (n = 87), during (n = 84), or after (n = 94) RT. Higher PROMIS® score represents more of the concept. Mean scores were compared to the general US population and minimally important differences (MIDs) were used to evaluate the impact of cancer on HRQOL. Linear regression modeling was used to evaluate the effect of clinical and demographic factors on PROMIS scores. Results Median [IQR] age was 26 [20–31] years. Cancer types varied; most had sarcoma (26%) or CNS malignancy (23%). Compared to the general US population, the before RT cohort had worse anxiety (mean score 55.2 vs. 50, MID 3, p

In electroreceptive jawed vertebrates, embryonic lateral line placodes give rise to electrosensory ampullary organs as well as mechanosensory neuromasts. Previous reports of shared gene expression suggest that conserved mechanisms underlie electroreceptor and mechanosensory hair cell development and that electroreceptors evolved as a transcriptionally related “sister cell type” to hair cells. We previously identified only one transcription factor gene, Neurod4, as ampullary organ-restricted in the developing lateral line system of a chondrostean ray-finned fish, the Mississippi paddlefish (Polyodon spathula). The other 16 transcription factor genes we previously validated in paddlefish were expressed in both ampullary organs and neuromasts. Here, we used our published lateral line organ-enriched gene-set (arising from differential bulk RNA-seq in late-larval paddlefish), together with a candidate gene approach, to identify 25 transcription factor genes expressed in the developing lateral line system of a more experimentally tractable chondrostean, the sterlet (Acipenser ruthenus, a small sturgeon), and/or that of paddlefish. Thirteen are expressed in both ampullary organs and neuromasts, consistent with conservation of molecular mechanisms. Seven are electrosensory-restricted on the head (Irx5, Irx3, Insm1, Sp5, Satb2, Mafa and Rorc), and five are the first-reported mechanosensory-restricted transcription factor genes (Foxg1, Sox8, Isl1, Hmx2 and Rorb). However, as previously reported, Sox8 is expressed in ampullary organs as well as neuromasts in a catshark (Scyliorhinus canicula), suggesting the existence of lineage-specific differences between cartilaginous and ray-finned fishes. Overall, our results support the hypothesis that ampullary organs and neuromasts develop via largely conserved transcriptional mechanisms, and identify multiple transcription factors potentially involved in the formation of electrosensory versus mechanosensory lateral line organs.

Aquaponic production of fresh produce is a sustainable agricultural method becoming widely adopted, though few studies have investigated potential food safety hazards within commercial systems. A longitudinal study was conducted to isolate and quantify several foodborne pathogens from a commercial, aquaponic farm, and to elucidate their distribution throughout. The survey was conducted over 2 years on a controlled-environment farm containing Nile tilapia (Oreochromis niloticus) and lettuce (Lactuca sativa). Samples (N = 1,047) were collected bimonthly from three identical, independent systems, and included lettuce leaves, roots, fingerlings (7–126 d old), feces from mature fish (>126 d old), water, and sponge swabs collected from the tank interior surface. Most probable number of generic Escherichia coli were determined using IDEXX Colilert Quanti-Tray. Enumeration and enrichment were used to detect Shiga toxin-producing E. coli (STEC), Salmonella enterica, Listeria monocytogenes, Aeromonas spp., Aeromonas hydrophilia, and Pseudomonas aeruginosa. Generic E. coli, STEC, L. monocytogenes, and S. enterica were not detected in collected samples. P. aeruginosa was isolated from water (7/351; 1.99%), swabs (3/351; 0.85%), feces (2/108; 1.85%), and lettuce leaves (2/99; 2.02%). A. hydrophila was isolated from all sample types (623/1047; 59.50%). The incidence of A. hydrophila in water (X2 = 23.234, p

Abstract Heterogeneous chemical cycles of pyrogenic nitrogen and halides influence tropospheric ozone and affect the stratosphere during extreme Pyrocumulonimbus (PyroCB) events. We report field‐derived N2O5 uptake coefficients, γ(N2O5), and ClNO2 yields, φ(ClNO2), from two aircraft campaigns observing fresh smoke in the lower and mid troposphere and processed/aged smoke in the upper troposphere and lower stratosphere (UTLS). Derived φ(ClNO2) varied across the full 0–1 range but was typically

Abstract Archimedean spirals are common in various fields such as biology, engineering, astronomy, and space physics. Here we report the discovery of patterns resembling the general Archimedean spirals in particle distributions in the Earth radiation belt. Our analytic theory and numerical simulations demonstrate that electrons with initially asymmetric spatial distributions form such spirals in the inner magnetosphere, where particles at smaller radial distances move more slowly in angular velocity. These spirals result in time‐varying peaks and valleys in particle fluxes, referred to as “zebra stripes,” which are well consistent with Van Allen Probes measurements. Although the initial asymmetric distribution may be seeded by the electric field in the magnetosphere, the spiral formation does not require them. Furthermore, we show that, due to the same fundamental motion of charged particles in regions dominated by dipole fields, this spiral phenomenon may also appear in the proton distributions, as well as in planetary magnetospheres.

Recently we found compelling evidence for a gravitational-wave background with Hellings and Downs (HD) correlations in our 15 yr data set. These correlations describe gravitational waves as predicted by general relativity, which has two transverse polarization modes. However, more general metric theories of gravity can have additional polarization modes, which produce different interpulsar correlations. In this work, we search the NANOGrav 15 yr data set for evidence of a gravitational-wave background with quadrupolar HD and scalar-transverse (ST) correlations. We find that HD correlations are the best fit to the data and no significant evidence in favor of ST correlations. While Bayes factors show strong evidence for a correlated signal, the data does not strongly prefer either correlation signature, with Bayes factors ∼2 when comparing HD to ST correlations, and ∼1 for HD plus ST correlations to HD correlations alone. However, when modeled alongside HD correlations, the amplitude and spectral index posteriors for ST correlations are uninformative, with the HD process accounting for the vast majority of the total signal. Using the optimal statistic, a frequentist technique that focuses on the pulsar-pair cross-correlations, we find median signal-to-noise ratios of 5.0 for HD and 4.6 for ST correlations when fit for separately, and median signal-to-noise ratios of 3.5 for HD and 3.0 for ST correlations when fit for simultaneously. While the signal-to-noise ratios for each of the correlations are comparable, the estimated amplitude and spectral index for HD are a significantly better fit to the total signal, in agreement with our Bayesian analysis.

ABSTRACTThe coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has led to over 770 million cases and >6.9 million deaths worldwide. We identified a panel of human neutralizing monoclonal antibodies (mAbs) targeting the SARS-CoV-2 Spike protein using Harbour H2L2 transgenic mice immunized with Spike receptor-binding domain (RBD) (J. A. Duty, T. Kraus, H. Zhou, Y. Zhang, et al., Med 3:705–721, 2022, https://doi.org/10.1016/j.medj.2022.08.002). Representative antibodies from genetically distinct families were evaluated for the inhibition of replication-competent VSV expressing SARS-CoV-2 Spike (rcVSV-S) in the place of VSV-G. One mAb clone denoted FG-10A3 and its therapeutically modified version STI-9167 effectively inhibited infection and in vivo proliferation of early variants of SARS-CoV-2 including Omicron BA.1 and BA.2 and corresponding pseudoviruses and rcVSV-S variants (Duty et al.). To define the epitope of the broadly reactive FG-10A3 mAb, we generated mAb-resistant rcVSV-S virions and performed structural analysis of the antibody/antigen complex using cryo-electron microscopy (EM). FG-10A3/STI-9167 is a Class 1 antibody that prevents Spike-ACE2 binding by engaging a region within the Spike receptor binding motif. Sequencing of mAb-resistant rcVSV-S virions identified F486 as a critical residue for mAb neutralization, with structural analysis revealing that both the variable heavy and light chains of STI-9167 bound the disulfide-stabilized 470–490 loop at the Spike RBD tip. Furthermore, neutralization studies using rcVSV-S F486 point mutants and currently-circulating variants Omicron BA.5, XBB.1.5, and BQ.1.1 that contain a V or P at position 486 further supported the model in which residue 486 is an important residue for FG-10A3 inhibition. This work provides an experimental strategy to define the neutralizing capacity and limitations of mAb therapeutics against emerging SARS-CoV-2 variants.IMPORTANCEThe COVID-19 pandemic remains a significant public health concern for the global population; the development and characterization of therapeutics, especially ones that are broadly effective, will continue to be essential as severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) variants emerge. Neutralizing monoclonal antibodies remain an effective therapeutic strategy to prevent virus infection and spread so long as they recognize and interact with circulating variants. The epitope and binding specificity of a neutralizing anti-SARS-CoV-2 Spike receptor-binding domain antibody clone against many SARS-CoV-2 variants of concern were characterized by generating antibody-resistant virions coupled with cryo-EM structural analysis and VSV-spike neutralization studies. This workflow can serve to predict the efficacy of antibody therapeutics against emerging variants and inform the design of therapeutics and vaccines.

Abstract Species distribution models (SDMs) are widely applied to understand the processes governing spatial and temporal variation in species abundance and distribution but often do not account for measurement errors such as false negatives and false positives. We describe unmarked, a package for the freely available and open‐source R software that provides a complete workflow for modelling species distribution and abundance while explicitly accounting for measurement errors. Here we focus on recent advances in unmarked functionality to support multi‐species, multi‐state, and multi‐season data, as well as support for fitting models with random effects. For illustration, we present an analysis of Acadian Flycatcher Empidonax virescens abundance on Roanoke River National Wildlife Refuge, North Carolina, USA, over 18 years. We found that Acadian Flycatcher abundance was initially greater in hardwood plantation habitat relative to bottomland hardwood forest along river levees but that abundance declined over time in both habitats. We plan for unmarked development to keep pace with advances in hierarchical modelling in ecology, including better handling of continuous‐time data from camera trap and automated recording units and integrated models for multiple data streams.

Abstract Background Single-cell RNA-seq has emerged as an innovative technology used to study complex tissues and characterize cell types, states, and lineages at a single-cell level. Classification of bulk tumors by their individual cellular constituents has also created new opportunities to generate single-cell atlases for many organs, cancers, and developmental models. Despite the tremendous promise of this technology, recent evidence studying epithelial tissues and diverse carcinomas suggests the methods used for tissue processing, cell disaggregation, and preservation can significantly bias gene expression and alter the observed cell types. To determine whether sarcomas – tumors of mesenchymal origin – are subject to the same technical artifacts, we profiled patient-derived tumor explants (PDXs) propagated from three aggressive subtypes: osteosarcoma (OS), Ewing sarcoma (ES), desmoplastic small round cell tumor (DSRCT). Given the rarity of these sarcoma subtypes, we explored whether single-nuclei RNA-seq from more widely available archival frozen specimens could accurately be identified by gene expression signatures linked to tissue phenotype or pathognomonic fusion proteins. Results We systematically assessed dissociation methods across different sarcoma subtypes. We compared gene expression from single-cell and single-nucleus RNA-sequencing of 125,831 whole-cells and nuclei from ES, DSRCT, and OS PDXs. We detected warm dissociation artifacts in single-cell samples and gene length bias in single-nucleus samples. Classic sarcoma gene signatures were observed regardless of the dissociation method. In addition, we showed that dissociation method biases could be computationally corrected. Conclusions We highlighted transcriptional biases, including warm dissociation and gene-length biases, introduced by the dissociation method for various sarcoma subtypes. This work is the first to characterize how the dissociation methods used for sc/snRNA-seq may affect the interpretation of the molecular features in sarcoma PDXs.

In the sixth generation (6G) era, intelligent machine network (IMN) applications, such as intelligent transportation, require collaborative machines with communication, sensing, and computation (CSC) capabilities. This article proposes an integrated communication, sensing, and computation (ICSAC) framework for 6G to achieve the reciprocity among CSC functions to enhance the reliability and latency of communication, accuracy and timeliness of sensing information acquisition, and privacy and security of computing to realize the IMN applications. Specifically, the sensing and communication functions can merge into unified platforms using the same transmit signals, and the acquired real-time sensing information can be exploited as prior information for intelligent algorithms to enhance the performance of communication networks. This is called the computing-empowered integrated sensing and communications (ISAC) reciprocity. Such reciprocity can further improve the performance of distributed computation with the assistance of networked sensing capability, which is named the sensing-empowered integrated communications and computation (ICAC) reciprocity. The above ISAC and ICAC reciprocities can enhance each other iteratively and finally lead to the ICSAC reciprocity. To achieve these reciprocities, we explore the potential enabling technologies for the ICSAC framework. Finally, we present the evaluation results of crucial enabling technologies to show the feasibility of the ICSAC framework.

Introduction: The traditional ligament reconstruction and tendon interposition (LRTI) procedure requires a trapeziectomy with the reconstruction of the palmar oblique ligament. Introduction of an interference screw (IS) during the tendon interposition is intended to improve tensioning of the beak ligament reconstruction and limit subsidence which may increase stability for the patient postoperatively. Material and methods: Non-inferiority, clinical, blinded, and randomized trial was performed. Twenty patients were randomized to one of the two treatment groups (Standard LRTI vs LRTI + IS). Four patients did not receive surgery during the allotted time. Finally, 16 patients (8 per group) had completed follow-up data at the end of the designated 2-year follow up. Results: Equivalent functional and radiographic outcomes were found. Trapezial height at 2 years was 4.44 mm for standard LRTI and 3.83 mm for LRTI with screw. At the end of the follow up period both groups had comparable grip strength. Mean improvement of DASH score, VAS and EQ5D was similar in both groups, showing good outcomes for both procedures. Conclusion: Ligament reconstruction and tendon interposition with and without interference screw has shown equivalent results in a 2-year follow-up related to stability and functional outcomes. Interference screw is a safe and reliable technique with no difference in pain or complication rates. Level of evidence: Therapeutic II.

BackgroundUrinary stone disease (USD) historically has affected older men, but studies suggest recent increases in women, leading to a near identical sex incidence ratio. USD incidence has doubled every 10 years, with disproportionate increases amongst children, adolescent, and young adult (AYA) women. USD stone composition in women is frequently apatite (calcium phosphate), which forms in a higher urine pH, low urinary citrate, and an abundance of urinary uric acid, while men produce more calcium oxalate stones. The reasons for this epidemiological trend are unknown.MethodsThis perspective presents the extent of USD with data from a Canadian Province and a North American institution, explanations for these findings and offers potential solutions to decrease this trend. We describe the economic impact of USD.FindingsThere was a significant increase of 46% in overall surgical interventions for USD in Ontario. The incidence rose from 47.0/100,000 in 2002 to 68.7/100,000 population in 2016. In a single United States institution, the overall USD annual unique patient count rose from 10,612 to 17,706 from 2015 to 2019, and the proportion of women with USD was much higher than expected. In the 10–17-year-old patients, 50.1% were girls; with 57.5% in the 18–34 age group and 53.6% in the 35–44 age group. The roles of obesity, diet, hormones, environmental factors, infections, and antibiotics, as well as the economic impact, are discussed.InterpretationWe confirm the significant increase in USD among women. We offer potential explanations for this sex disparity, including microbiological and pathophysiological aspects. We also outline innovative solutions – that may require steps beyond typical preventive and treatment recommendations.

Over 1 million Americans are currently living with T1D and improvements in diabetes management have increased the number of adults with T1D living into later decades of life. This growing population of older adults with diabetes is more susceptible to aging comorbidities, including both vascular disease and osteoporosis. Indeed, adults with T1D have a 2- to 3- fold higher risk of any fracture and up to 7-fold higher risk of hip fracture compared to those without diabetes. Recently, diabetes-related vascular deficits have emerged as potential risks factors for impaired bone blood flow and poor bone health and it has been hypothesized that there is a direct pathophysiologic link between vascular disease and skeletal outcomes in T1D. Indeed, microvascular disease (MVD), one of the most serious consequences of diabetes, has been linked to worse bone microarchitecture in older adults with T1D compared to their counterparts without MVD. The association between the presence of microvascular complications and compromised bone microarchitecture indicates the potential direct deleterious effect of vascular compromise, leading to abnormal skeletal blood flow, altered bone remodeling, and deficits in bone structure. In addition, vascular diabetic complications are characterized by increased vascular calcification, decreased arterial distensibility, and vascular remodeling with increased arterial stiffness and thickness of the vessel walls. These extensive alterations in vascular structure lead to impaired myogenic control and reduced nitric-oxide mediated vasodilation, compromising regulation of blood flow across almost all vascular beds and significantly restricting skeletal muscle blood flow seen in those with T1D. Vascular deficits in T1D may very well extend to bone, compromising skeletal blood flow control, and resulting in reduced blood flow to bone, thus negatively impacting bone health. Indeed, several animal and ex vivo human studies report that diabetes induces microvascular damage within bone are strongly correlated with diabetes disease severity and duration. In this review article, we will discuss the contribution of diabetes-induced vascular deficits to bone density, bone microarchitecture, and bone blood flow regulation, and review the potential contribution of vascular disease to skeletal fragility in T1D.

The vast production of resource-constrained wireless communication devices and the development of various techniques in recent years opens room for security concerns to overcome potential attacks. However, efficient methods are needed to reduce the trade-off between communication and computation complexities in resource-constrained wireless device communication. In this paper, we propose a lightweight fault-tolerant secure data communication framework that consists of Elliptic Curve Diffie-Hellman (ECDH) secure communication scheme, Elliptic Curve Cryptography (ECC) based secure communication scheme and Elliptic Curve Integrated Encryption Scheme (ECIES) based authentication scheme for wireless sensor network communication using Message Passing Interface (MPI) parallel program platform. Further, we have implemented the proposed framework for a single sink node (scenario-1) and all sink nodes (scenario-2) scenarios with parallel threads using Linux Pthreads to improve the total execution time. It is observed that the overall execution time performance of ECC is better in scenario-2 whereas the performance of ECDH is better in scenario-1 when the number of sensors is greater than 200. It is also observed that enabling Linux Pthreads in ECC implementation guarantees the parallel execution of decryption process and the reduction in the overall execution time in both scenarios. The results demonstrate the superiority of the proposed framework in terms of execution time and memory use over simulated wireless network environments, making the proposed framework suitable for fault-tolerant wireless sensor communication applications.

Background: Few studies have addressed whether anticholinergic (AC) medications for overactive bladder (OAB) cause cognitive decline in individuals with existing cognitive impairment, and whether the APOE ε4 gene increases this risk. Objective: To determine whether OAB AC use is associated with a clinically relevant change in cognitive measures among adults with normal and abnormal cognition. Design, setting, and participants: This was a retrospective cohort study using data from the National Alzheimer’s Coordinating Center. Patients were enrolled at specialized centers in the USA between 2005 and 2019. Patients with existing OAB AC use, missing APOE ε4 status, and confounding neurologic diagnoses were excluded. New users of an OAB AC were matched 1:1 to patients not taking an OAB AC using propensity scores. Intervention: New use of oxybutynin, tolterodine, solifenacin, trospium, darifenacin, or fesoterodine. Outcome measurements and statistical analysis: The outcome was a change in cognitive function, measured as a ≥1-point increase on the Clinical Dementia Rating (CDR) instrument or a ≥3-point decrease on the Mini-Mental State Examination (MMSE). Conditional logistic regression with odds ratios (ORs) was conducted. We also tested for APOE ε4 effect modification. Results and limitations: Among 18 835 eligible patients, 782 matched pairs were identified. The most common OAB ACs were oxybutynin (38%) and tolterodine (23%). There was no significant increase in the risk of a clinically relevant cognitive decline among OAB AC users (CDR: OR 1.38, 95% confidence interval [CI] 0.93–2.05; p = 0.11, MMSE: OR 1.06, 95% CI 0.79–1.43; p = 0.70). There was no significant interaction between APOE ε4 status and OAB AC use for the CDR (p = 0.38) or MMSE (p = 0.95) outcomes. Users of oxybutynin or tolterodine had numerically higher odds of a change on the CDR test (OR 1.65, 95% CI 0.98–2.77) that was close to statistical significance (p = 0.06). Limitations include the inability to determine medication dose or duration, and residual confounding. Conclusions: OAB AC use was not associated with a significant change in cognitive function among individuals with normal and abnormal cognition. Further research is necessary to determine if oxybutynin and tolterodine are significantly more likely to cause cognitive decline. Patient summary: Use of a specific class of overactive bladder medication was not associated with negative changes in brain function among patients with either normal or abnormal function. A genetic risk factor for Alzheimer’s disease did not predispose individuals to cognitive decline when taking these drugs. Two of the drugs (oxybutynin and tolterodine) may lead to a higher risk of cognitive decline in comparison to other drugs, and this needs further research.

Background: Oral immunotherapy containing peanut (Arachis hypogaea) allergen powder-dnfp (PTAH) (Palforzia [Aimmune Therapeutics, Brisbane, Calif]) for 9 to 12 months resulted in higher tolerated amounts of peanut protein in PTAH-treated individuals aged 4 to 17 years with peanut allergy than in placebo-treated participants. Objective: We aimed to describe additional long-term pooled safety data and changes in peanut sensitization markers from baseline through approximately 5 years of treatment. Methods: The results from 6 clinical trials of PTAH (3 controlled and 3 open-label extension studies [N = 1227]) were pooled, and analysis of safety outcomes and immunologic data was performed. The PTAH doses were administered sequentially as follows: initial dose escalation (dose increased to 6 mg over 2 days), updosing (dose increased every 2 weeks to 300 mg for a minimum of 6 months), and maintenance dosing (300 mg per day). Results: There was a trend toward decreased adverse events (AEs) at years 1 and 2 that was maintained up to 5 years, with 94% of patients experiencing mild or moderate AEs and only 13% discontinuing PTAH use because of AEs overall. Gastrointestinal symptoms were the most commonly reported treatment-related AEs. A downward trend in systemic allergic reactions was also reported. PTAH treatment resulted in reduced levels of peanut-specific IgE after the first year and increased levels of peanut-specific IgG4, with a lowered peanut-specific IgE:IgG4 ratio. A reduction in median peanut skin prick test wheal diameter was observed (11.50 mm at baseline vs 5.75 mm at year 5). Conclusion: Long-term immunomodulation without any new safety signals was reported with PTAH immunotherapy in the largest safety data set and longest treatment duration for oral immunotherapy published to date.

Myotonic dystrophy type 1 (DM1), the most common form of adult-onset muscular dystrophy, is caused by a CTG expansion resulting in significant transcriptomic dysregulation that leads to muscle weakness and wasting. While strength training is clinically beneficial in DM1, molecular effects had not been studied. To determine whether training rescued transcriptomic defects, RNA-Seq was performed on vastus lateralis samples from 9 male patients with DM1 before and after a 12-week strength-training program and 6 male controls who did not undergo training. Differential gene expression and alternative splicing analysis were correlated with the one-repetition maximum strength evaluation method (leg extension, leg press, hip abduction, and squat). While training program–induced improvements in splicing were similar among most individuals, rescued splicing events varied considerably between individuals. Gene expression improvements were highly varied between individuals, and the percentage of differentially expressed genes rescued after training were strongly correlated with strength improvements. Evaluating transcriptome changes individually revealed responses to the training not evident from grouped analysis, likely due to disease heterogeneity and individual exercise response differences. Our analyses indicate that transcriptomic changes are associated with clinical outcomes in patients with DM1 undergoing training and that these changes are often specific to the individual and should be analyzed accordingly.

Group management is practiced to deploy access control and to ease multicast and broadcast communication. However, the devices that constitute the Internet of Things (IoT) are resource-constrained, and the network of IoT is heterogeneous with variable topologies interconnected. Hence, to tackle heterogeneity, SDN-aided centralized group management as a service framework is proposed to provide a global network perspective and administration. Group management as a service includes a group key management function, which can be either centralized or decentralized. Decentralized approaches use complex cryptographic primitives, making centralized techniques the optimal option for the IoT ecosystem. It is also necessary to use a safe, scalable approach that addresses dynamic membership changes with minimal overhead to provide a centralized group key management service. A group key management strategy called a one-way Function Tree (OFT) was put forth to lower communication costs in sizable dynamic groups. The technique, however, is vulnerable to collusion attacks in which an appending and withdrawing device colludes and conspires to obtain unauthorized keys for an unauthorized timeline. Several collusion-deprived improvements to the OFT method are suggested; however, they come at an increased cost for both communication and computation. The Modified One-Way Function Tree (MOFT), a novel technique, is suggested in this proposed work. The collusion resistance of the proposed MOFT system was demonstrated via security analysis. According to performance studies, MOFT lowers communication costs when compared to the original OFT scheme. In comparison to the OFT’s collusion-deprived upgrades, the computation cost is smaller.

Periodic signatures in time-domain observations of quasars have been used to search for binary supermassive black holes (SMBHs). These searches, across existing time-domain surveys, have produced several hundred candidates. The general stochastic variability of quasars, however, can masquerade as a false-positive periodic signal, especially when monitoring cadence and duration are limited. In this work, we predict the detectability of binary SMBHs in the upcoming Rubin Observatory Legacy Survey of Space and Time (LSST). We apply computationally inexpensive sinusoidal curve fits to millions of simulated LSST Deep Drilling Field light curves of both single, isolated quasars and binary quasars. The period and phase of simulated binary signals can generally be disentangled from quasar variability. Binary amplitude is overestimated and poorly recovered for two-thirds of potential binaries due to quasar accretion variability. Quasars with strong intrinsic variability can obscure a binary signal too much for recovery. We also find that the most luminous quasars mimic current binary candidate light curves and their properties: The false-positive rates are 60% for these quasars. The reliable recovery of binary period and phase for a wide range of input binary LSST light curves is promising for multi-messenger characterization of binary SMBHs. However, pure electromagnetic detections of binaries using photometric periodicity with amplitude greater than 0.1 mag will result in samples that are overwhelmed by false positives. This paper represents an important and computationally inexpensive way forward for understanding the true and false-positive rates for binary candidates identified by Rubin.

The radio galaxy 3C 66B has been hypothesized to host a supermassive black hole binary (SMBHB) at its center based on electromagnetic observations. Its apparent 1.05 yr period and low redshift (∼0.02) make it an interesting testbed to search for low-frequency gravitational waves (GWs) using pulsar timing array (PTA) experiments. This source has been subjected to multiple searches for continuous GWs from a circular SMBHB, resulting in progressively more stringent constraints on its GW amplitude and chirp mass. In this paper, we develop a pipeline for performing Bayesian targeted searches for eccentric SMBHBs in PTA data sets, and test its efficacy by applying it to simulated data sets with varying injected signal strengths. We also search for a realistic eccentric SMBHB source in 3C 66B using the NANOGrav 12.5 yr data set employing PTA signal models containing Earth term-only as well as Earth+pulsar term contributions using this pipeline. Due to limitations in our PTA signal model, we get meaningful results only when the initial eccentricity e _0 < 0.5 and the symmetric mass ratio η > 0.1. We find no evidence for an eccentric SMBHB signal in our data, and therefore place 95% upper limits on the PTA signal amplitude of 88.1 ± 3.7 ns for the Earth term-only and 81.74 ± 0.86 ns for the Earth+pulsar term searches for e _0 < 0.5 and η > 0.1. Similar 95% upper limits on the chirp mass are (1.98 ± 0.05) × 10 ^9 and (1.81 ± 0.01) × 10 ^9 M _☉ . These upper limits, while less stringent than those calculated from a circular binary search in the NANOGrav 12.5 yr data set, are consistent with the SMBHB model of 3C 66B developed from electromagnetic observations.

We present the results of a Bayesian search for gravitational wave (GW) memory in the NANOGrav 12.5 yr data set. We find no convincing evidence for any gravitational wave memory signals in this data set. We find a Bayes factor of 2.8 in favor of a model that includes a memory signal and common spatially uncorrelated red noise (CURN) compared to a model including only a CURN. However, further investigation shows that a disproportionate amount of support for the memory signal comes from three dubious pulsars. Using a more flexible red-noise model in these pulsars reduces the Bayes factor to 1.3. Having found no compelling evidence, we go on to place upper limits on the strain amplitude of GW memory events as a function of sky location and event epoch. These upper limits are computed using a signal model that assumes the existence of a common, spatially uncorrelated red noise in addition to a GW memory signal. The median strain upper limit as a function of sky position is approximately 3.3 × 10 ^−14 . We also find that there are some differences in the upper limits as a function of sky position centered around PSR J0613−0200. This suggests that this pulsar has some excess noise that can be confounded with GW memory. Finally, the upper limits as a function of burst epoch continue to improve at later epochs. This improvement is attributable to the continued growth of the pulsar timing array.

The critical human resources deficit in the healthcare sector in low-resource settings (LRS) has an overwhelming impact on health outcomes and disparities in growth and development of the global healthcare workforce. There is a lack of qualified trainers and mentors and this makes it challenging to connect existing capacity gaps with existing expertise and established programs. Through global health partnerships, training programs, and mentorship, individuals and institutions from around the globe can connect to share training resources and strengthen clinical and research capacity in LRSs. Global health partnerships focused on capacity building face many challenges including; unequal access to information about potential partners and training opportunities, a lack of transparency regarding each institutions training priorities, and inequity and absent reciprocity within global health partnerships that have disproportionate power division between high-resource and LRSs. This initiative, the Consortium of Universities for Global Health Capacity Strengthening Platform (CUGH-CPS) (CUGHCapacityBuilding.org), aims to empower institutions and individuals in LRSs to address these challenges and drive partnership engagement through avenues that are beneficial to the LRS agent needs and context by leading the prioritization of training capacity development across clinical and research domains. The CUGH-CPS helps to identify and create a platform for the dissemination of training and mentorship needs from LRS institutions and share this information with the global community. This manuscript describes this new initiative officially launched to a global audience at the April 2023 CUGH meeting.

IntroductionMyocardial ischemia disrupts the cardio-spinal neural network that controls the cardiac sympathetic preganglionic neurons, leading to sympathoexcitation and ventricular tachyarrhythmias (VTs). Spinal cord stimulation (SCS) is capable of suppressing the sympathoexcitation caused by myocardial ischemia. However, how SCS modulates the spinal neural network is not fully known.MethodsIn this pre-clinical study, we investigated the impact of SCS on the spinal neural network in mitigating myocardial ischemia-induced sympathoexcitation and arrhythmogenicity. Ten Yorkshire pigs with left circumflex coronary artery (LCX) occlusion-induced chronic myocardial infarction (MI) were anesthetized and underwent laminectomy and a sternotomy at 4−5 weeks post-MI. The activation recovery interval (ARI) and dispersion of repolarization (DOR) were analyzed to evaluate the extent of sympathoexcitation and arrhythmogenicity during the left anterior descending coronary artery (LAD) ischemia. Extracellular in vivo and in situ spinal dorsal horn (DH) and intermediolateral column (IML) neural recordings were performed using a multichannel microelectrode array inserted at the T2-T3 segment of the spinal cord. SCS was performed for 30 min at 1 kHz, 0.03 ms, 90% motor threshold. LAD ischemia was induced pre- and 1 min post-SCS to investigate how SCS modulates spinal neural network processing of myocardial ischemia. DH and IML neural interactions, including neuronal synchrony as well as cardiac sympathoexcitation and arrhythmogenicity markers were evaluated during myocardial ischemia pre- vs. post-SCS.ResultsARI shortening in the ischemic region and global DOR augmentation due to LAD ischemia was mitigated by SCS. Neural firing response of ischemia-sensitive neurons during LAD ischemia and reperfusion was blunted by SCS. Further, SCS showed a similar effect in suppressing the firing response of IML and DH neurons during LAD ischemia. SCS exhibited a similar suppressive impact on the mechanical, nociceptive and multimodal ischemia sensitive neurons. The LAD ischemia and reperfusion-induced augmentation in neuronal synchrony between DH-DH and DH-IML pairs of neurons were mitigated by the SCS.DiscussionThese results suggest that SCS is decreasing the sympathoexcitation and arrhythmogenicity by suppressing the interactions between the spinal DH and IML neurons and activity of IML preganglionic sympathetic neurons.

Androgen receptor can promote tumour progression in desmoplastic small round cell tumour (DSRCT), an aggressive paediatric malignancy that predominantly affects young males. Here, the authors show that DSRCT is an AR-driven malignancy and sensitive to androgen deprivation therapy

A panel of neutralizing human monoclonal antibodies targeting human cytomegalovirus offers a combination approach geared toward virus entry and replication to prevent viral dissemination.