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Teresa A Simon,1 John H Simon,1 Erin G Heaning,1 Andres Gomez-Caminero,1 Jahan P Marcu1,2 1Physicians Research Center, LLC, Toms River, NJ, USA; 2Marcu Enterprises, Jersey City, NJ, USACorrespondence: Teresa A Simon, Physicians Research Center, LLC, Toms River, NJ, 08753, USA, Tel +732 818-7900, Fax +732 557-0217, Email prctrials@gmail.comPurpose: The aim of this study was to characterize the frequency of adverse effects where delta-8 tetrahydrocannabinol (D8-THC) was identified as a possible suspect drug in the FDA Adverse Event Reporting System (FAERS) database.Methods: A case-series design was used.Results: A total of 183 cases listed D8-THC as a suspect drug in FAERS as of June 30, 2021. The most common events included dyspnea, respiratory disorder, and seizure. The reporting odds ratios were consistently and significantly greater than 2, a 2-fold increase from 2019 to 2021, indicating a potential safety signal.Conclusion: The first report of D8-THC, in the FAERS database, as a suspect drug appears to be in 2011. Overall, there are 183 total cases listing D8-THC as a suspect drug in the FAERS database as of June 30, 2021. Of the 183 cases, most were respiratory in nature.Keywords: cannabis, hemp-derived, safety, adverse effects, public health, cannabinoid, delta-8 tetrahydrocannabinol, hemp, adverse event

Teresa A Simon,1 Marlene S Khouri,2 Tzuyung D Kou,3 Andres Gomez-Caminero3 1Physicians Research Center, LLC, Toms River, NJ, USA; 2Innovation Law, Bristol Myers Squibb, Princeton, NJ, USA; 3Worldwide Patient Safety, Bristol Myers Squibb, Princeton, NJ, USACorrespondence: Teresa A SimonPhysicians Research Center, LLC, Toms River, NJ 08755, USATel +1 732 818-7900Email prctrials@gmail.comAbstract: Assessing a patient’s perspective on their treatment is part of an increasingly integrated approach to pharmacovigilance and treatment optimization. New tools and methods developed in partnership with patients can capture and quantify cognitive and behavioral aspects of the treatment experience. These treatment insights have the potential to shape the drug development process, as well as supplement patient-reported outcome data in a way that is meaningful to the patient. We highlight examples of tools developed to assess the impact of treatment on the aspects of disease that are of utmost concern to the patient in their daily life.Keywords: drug development, patient engagement, patient perspective, patient-reported outcome

Edward Ewen,1 Zugui Zhang,1 Teresa A Simon,2 Paul Kolm,1 Xianchen Liu,3,4 William S Weintraub11Christiana Care Health System, Newark, DE, USA; 2Bristol-Myers Squibb, Princeton, NJ, USA; 3Indiana University School of Medicine, Indianapolis, IN, USA; 4Pfizer, Groton, CT, USABackground: Warfarin is recommended for stroke prevention in high-risk patients with atrial fibrillation. However, it is often underutilized and inadequately managed in actual clinical practice.Objectives: To examine the patterns of warfarin use and their relationship with stroke and bleeding in atrial fibrillation patients in community-based primary care practices.Design: Retrospective longitudinal cohort study.Participants: A total of 1141 atrial fibrillation patients were selected from 17 primary care practices with a shared electronic medical record and characterized by stroke risk, potential barriers to anticoagulation, and comorbid conditions.Main measures: Duration and number of warfarin exposures, interruptions in warfarin exposure > 45 days, stroke, and bleeding events.Results: Among 1141 patients with a mean age of 70 years (standard deviation 13.3) and mean follow-up of 3.4 years (standard deviation 3.0), 764 (67%) were treated with warfarin. Warfarin was discontinued within 1 year in 194 (25.4%), and 349 (45.7%) remained on warfarin at the end of follow-up. Interruptions in warfarin use were common, occurring in 32.6% (249 of 764) of patients. Those with two or more interruptions were younger and at lower baseline stroke risk when compared to those with no interruptions. There were 76 first strokes and 73 first-bleeding events in the follow-up period. When adjusted for baseline stroke risk, time to warfarin start, and total exposure time, two or more interruptions in warfarin use was associated with an increased risk of stroke (relative risk, 2.29; 95% confidence interval: 1.29–4.07). There was no significant association between warfarin interruptions and bleeding events.Conclusion: Warfarin was underutilized in a substantial portion of eligible atrial fibrillation patients in these community-based practices. In addition, prolonged interruptions in anticoagulation were common in this population, and multiple interruptions were associated with over twice the risk of stroke when compared to those treated continuously.Keywords: cardiovascular disease, primary care, quality assessment, outcomes

Abstract Background and objectives Accurate classification of lymphadenopathy is essential for determining the pathological nature of lymph nodes (LNs), which plays a crucial role in treatment selection. The biopsy method is invasive and carries the risk of sampling failure, while the utilization of non-invasive approaches such as ultrasound can minimize the probability of iatrogenic injury and infection. With the advancement of artificial intelligence (AI) and machine learning, the diagnostic efficiency of LNs is further enhanced. This study evaluates the performance of ultrasound-based AI applications in the classification of benign and malignant LNs. Methods The literature research was conducted using the PubMed, EMBASE, and Cochrane Library databases as of June 2024. The quality of the included studies was evaluated using the QUADAS-2 tool. The pooled sensitivity, specificity, and diagnostic odds ratio (DOR) were calculated to assess the diagnostic efficacy of ultrasound-based AI in classifying benign and malignant LNs. Subgroup analyses were also conducted to identify potential sources of heterogeneity. Results A total of 1,355 studies were identified and reviewed. Among these studies, 19 studies met the inclusion criteria, and 2,354 cases were included in the analysis. The pooled sensitivity, specificity, and DOR of ultrasound-based machine learning in classifying benign and malignant LNs were 0.836 (95% CI [0.805, 0.863]), 0.850 (95% CI [0.805, 0.886]), and 33.331 (95% CI [22.873, 48.57]), respectively, indicating no publication bias (p = 0.12). Subgroup analyses may suggest that the location of lymph nodes, validation methods, and type of primary tumor are the sources of heterogeneity. Conclusion AI can accurately differentiate benign from malignant LNs. Given the widespread use of ultrasonography in diagnosing malignant LNs in cancer patients, there is significant potential for integrating AI-based decision support systems into clinical practice to enhance the diagnostic accuracy.

Background: In the Sahel, one of the largest semi-arid areas in the world, pastoral livestock is the main source of protein for the local population. The quantification of herbaceous biomass in the Sahelian rangelands is of major importance since it provides food for the livestock. The main method used to monitor the biomass consists of cutting, drying, and weighting it. However, indirect methods are available and allow a reliable biomass estimation. Methods: In this study, we developed a non-destructive method for estimating herbaceous biomass for the Sahelian rangelands based on measurements of its height and coverage. Results: Results show that the fit is better in the fenced area. The volume index (height × coverage) provides a better biomass prediction with relative differences between measured and predicted biomass of 11% in 2017 and 8% in 2019. Conclusions: Monitoring herbaceous biomass without destroying it is possible by measuring only its height and coverage.

Abstract Multiple respiratory viruses lead to high morbidity and mortality, yet global surveillance platforms focus primarily on seasonal influenza viruses. The COVID-19 pandemic and new RSV vaccines highlight the importance of a broader approach. Upper respiratory tract swabs from children aged 24–59 months presenting with influenza-like illness in The Gambia were collected during follow-up of a live-attenuated influenza vaccine randomised controlled trial in 2017–18. A microfluidic quantitative polymerase chain reaction (qPCR) assay was established and used to detect 21 respiratory viruses. 76.6% of samples had one or more viruses detected (n = 121/158). The viruses detected most frequently were rhinovirus (n = 37/158, 23.4%) and adenovirus (n = 34/158, 21.5%), followed by parainfluenza virus 3, influenza B and human metapneumovirus B. A third of positive samples had multiple viruses detected (two n = 31/121, 25.6%; three n = 9/121, 7.4%). Our data demonstrates how microfluidic qPCR is a useful tool for high-throughput, comprehensive detection of multiple respiratory viruses in surveillance platforms. Rapidly changing epidemiology exemplifies the need for new, broader approaches to virus surveillance in low-resource settings to respond to future epidemics and to guide the need for and use of new prevention and therapeutic measures.

Abstract Objectives Insertional Achilles tendinopathy is a common and disabling condition. This trial aimed to determine the feasibility of conducting a parallel group randomised trial to evaluate the efficacy of heel lifts compared to a sham intervention for reducing pain intensity associated with insertional Achilles tendinopathy. Methods Twenty‐six people with insertional Achilles tendinopathy were randomised to either the heel lift group or sham intervention group. Outcome measures were obtained at baseline, 4, 8 and 12 weeks. The primary outcome was feasibility, evaluated according to demand (recruitment rate and conversion rate), acceptability, adherence, adverse events and retention. Limited efficacy testing was conducted on secondary outcome measures including pain intensity, function, physical activity, health‐related quality of life, use of co‐interventions and global rating of change. Results Between August 25, 2023, and April 7, 2024, we recruited and tested 26 participants (aged 28–65 years, mean [SD] 51 [8]). The pre‐determined thresholds were met for demand, acceptability, adherence, retention, pain intensity, function, quality of life and global rating of change and partly met for adverse events, physical activity and use of co‐interventions. Between 47 and 241, participants will be needed for a fully powered randomised trial. Conclusion In its current form, a randomised trial of heel lifts compared to a sham intervention is feasible. However, future triallists may need to consider strategies to manage the risk of adverse events and plan to adjust the analyses to account for the use of co‐interventions. Trial registration: ACTRN12623000721606.

BackgroundInternational health care students encounter unique hurdles as they pursue education in foreign countries. These challenges, stemming from adjustment to new cultural environments and stressful academic programs, significantly impact their well-being. Understanding the barriers and facilitators experienced by international health care students is crucial for ensuring their successful integration into academic and professional spheres. Most existing reviews focus on specific populations or disciplines, thus limiting their generalizability. ObjectiveThis systematic integrative review aims to provide a comprehensive understanding of barriers and facilitators of international health care students’ well-being in higher education. MethodsThe protocol follows the Joanna Briggs Institute’s guidance for a mixed methods systematic review. The main information sources will include PubMed, Scopus, Web of Science, and EBSCOhost, supplemented with manual reference search and citation tracking using Google Scholar. The study selection will be done independently by 2 reviewers based on predetermined eligibility criteria. The study population will consist of international higher education students enrolled in human health–related disciplines including medicine, pharmacy, nursing, and allied health care fields. Qualitative and quantitative data relating to barriers and facilitators of international health care students’ well-being will be extracted using a customized data extraction template in Covidence review management software. Quantitative data will be “qualitized” and integrated with qualitative data using a convergent integrated approach, as described in the Joanna Briggs Institute’s guidance. The integrated data will then be synthesized using a thematic analysis approach to provide a comprehensive understanding of barriers and facilitators of international health care students’ well-being. ResultsThe initial literature search yielded 2408 papers from the selected databases. The findings of this review will be presented in a narrative format, supported by visualizations such as tables and diagrams. The review is expected to be completed by December 2024. ConclusionsThis systematic integrative review will identify barriers and facilitators of international health care students’ well-being in higher education. The findings could inform the development of targeted interventions and support initiatives in higher education institutions globally, with the ultimate goal of enhancing the well-being as well as the academic and professional success of international health care students. Trial RegistrationPROSPERO CRD42024372785; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024372785 International Registered Report Identifier (IRRID)PRR1-10.2196/59927

Immunotherapy-based systemic treatment (ST) is the standard of care for most patients diagnosed with metastatic renal cell carcinoma (mRCC). Cytoreductive nephrectomy (CN) has historically shown benefit for select patients with mRCC, but its role and timing are not well understood in the era of immunotherapy. The primary objective of this study is to assess outcomes in patients who received ST only, CN followed by ST (CN-ST), and ST followed by CN (ST-CN). The Canadian Kidney Cancer information system (CKCis) database was queried to identify patients with de novo mRCC who received immunotherapy-based ST between January 2014 and June 2023. These patients were classified into three categories as described above. Cox proportional hazards models were used to assess the impact of the timing of ST and CN on overall survival (OS) and progression-free survival (PFS), after adjusting for the International Metastatic RCC Database Consortium (IMDC) risk group, age, and comorbidities. Best overall response and complications of ST and CN for these cohorts were collected. A total of 588 patients were included in this study: 331 patients received ST only, 215 patients received CN-ST, and 42 patients received ST-CN. Patient and disease characteristics including age, gender, performance status, IMDC risk category, comorbidity, histology, type of ST, and metastatic sites are reported. OS analysis favored patients who received ST-CN (hazard ratio [HR] 0.30, 95% confidence interval [CI] 0.13–0.68) and CN-ST (HR 0.68, CI 0.47–0.97) over patients who received ST only. PFS analysis showed a similar trend for ST-CN (HR 0.45, CI 0.26–0.77) and CN-ST (HR 0.9, CI 0.68–1.17). This study examined baseline features and outcomes associated with the use and timing of CN and ST using real-world data via a large Canadian real-world cohort. Patients selected to receive CN after ST demonstrated improved outcomes. There were no appreciable differences in perioperative complications across groups. Limitations include the small number of patients in the ST-CN group and residual confounding and selection biases that may influence the outcomes in patients undergoing CN.

Contexte: Le climat et la fauche influencent la production fourragère au Sahel. Cependant, l’effet combiné de ces paramètres reste à évaluer. Objectif: Cette étude vise à évaluer l’effet conjoint de la pluviométrie et des pratiques de fauche sur la quantité et la qualité des fourrages. Méthodes: Des échantillons de phytomasse ont été prélevés au cours et à la fin de la saison des pluies 2021 par coupe intégrale sur 68 parcelles : 20 parcelles avec différents régimes hydriques et 48 parcelles avec différentes quantités d’eau combinées à différentes hauteurs et périodes de fauche. Résultats: Les valeurs de la phytomasse sèche étaient respectivement comprise entre 2 932,2 ± 1 672,1 et 6 383,6 ± 2 962,6 kg/ha, 2 397,7 ± 6 263,4 et 15 059,2 ± 9 782,9 kg/ha pour les traitements de régime hydrique et du cumul de phytomasse fauchée. Le taux de cellulose brute (en % de Matière sèche) était compris entre 5,5 ± 0,9 % et 6,4 ± 1,2 %. La matière azotée digestible a varié entre 21,8 ± 67,96 et 67,2 ± 15,8 %. Quelle que soit la quantité d’eau reçue, des quantités et qualités équivalentes de fourrages ont été produites par les parcelles non fauchées et celles fauchées au début du cycle de développement des espèces. Pour une fauche à 0 ou 5 cm au-dessus du sol, la quantité de phytomasse était la même. Les parcelles fauchées au stade de fructification des espèces ont produit des fourrages composés de jeunes plantes en quantités plus faibles et de bonne qualité. Conclusions: La quantité et la qualité de fourrage herbacé en fin de saison des pluies ont surtout été influencées par le stade phénologique. Les programmes de gestion des ressources fourragères devront privilégier des périodes et hauteurs de coupe permettant une couverture optimale du sol afin de réduire les risques d’érosion.

Abstract Background Mid-portion Achilles tendinopathy is a common condition, characterised by localised Achilles tendon load-related pain and dysfunction. Numerous non-surgical treatments have been proposed for the treatment of this condition, but many of these treatments have a poor or non-existent evidence base. Heel lifts have also been advocated as a treatment for Achilles tendinopathy, but the efficacy and mechanism of action of this intervention is unclear. This proposal describes a randomised controlled trial comparing the effectiveness of heel lifts versus sham heel lifts for reducing pain associated with mid-portion Achilles tendinopathy, with an embedded biomechanical analysis. Methods One hundred and eight men and women aged 18 to 65 years with mid-portion Achilles tendinopathy (who satisfy the inclusion and exclusion criteria) will be recruited. Participants will be randomised, using the website Sealed Envelope, to either a control group (sham heel lifts) or an experimental group (heel lifts). Both groups will be provided with education regarding acceptable pain levels to ensure all participants receive some form of treatment. The participants will be instructed to use their allocated intervention for at least 8 h every day for 12 weeks. The primary outcome measure will be pain intensity (numerical rating scale) at its worst over the previous week. The secondary outcome measures will be additional measures of Achilles tendon pain and disability, participant-perceived global ratings of change, function, level of physical activity and health-related quality of life. Data will be collected at baseline and the primary endpoint (week 12). Data will be analysed using the intention-to-treat principle. In addition, the acute kinetic and kinematic effects of the interventions will be examined at baseline in a subpopulation of the participants (n = 40) while walking and running using three-dimensional motion analysis. Discussion The LIFT trial (efficacy of heeL lIfts For mid-portion Achilles Tendinopathy) will be the first randomised trial to compare the efficacy of heel lifts to a sham intervention in reducing pain and disability in people with Achilles tendinopathy. The biomechanical analysis will provide useful insights into the mechanism of action of heel lifts. Trial registration Australian New Zealand Clinical Trials Registry, ACTRN12623000627651 . Registered 7 June 2023.

Abstract Esophageal adenocarcinoma is a prominent example of cancer characterized by frequent amplifications in oncogenes. However, the mechanisms leading to amplicons that involve breakage-fusion-bridge cycles and extrachromosomal DNA are poorly understood. Here, we use 710 esophageal adenocarcinoma cases with matched samples and patient-derived organoids to disentangle complex amplicons and their associated mechanisms. Short-read sequencing identifies ERBB2, MYC, MDM2, and HMGA2 as the most frequent oncogenes amplified in extrachromosomal DNAs. We resolve complex extrachromosomal DNA and breakage-fusion-bridge cycles amplicons by integrating of de-novo assemblies and DNA methylation in nine long-read sequenced cases. Complex amplicons shared between precancerous biopsy and late-stage tumor, an enrichment of putative enhancer elements and mobile element insertions are potential drivers of complex amplicons’ origin. We find that patient-derived organoids recapitulate extrachromosomal DNA observed in the primary tumors and single-cell DNA sequencing capture extrachromosomal DNA-driven clonal dynamics across passages. Prospectively, long-read and single-cell DNA sequencing technologies can lead to better prediction of clonal evolution in esophageal adenocarcinoma.

Abstract A combination of improved body armor, medical transportation, and treatment has led to the increased survival of warfighters from combat extremity injuries predominantly caused by blasts in modern conflicts. Despite advances, a high rate of complications such as wound infections, wound failure, amputations, and a decreased quality of life exist. To study the molecular underpinnings of wound failure, wound tissue biopsies from combat extremity injuries had RNA extracted and sequenced. Wounds were classified by colonization (colonized vs. non-colonized) and outcome (healed vs. failed) status. Differences in gene expression were investigated between timepoints at a gene level, and longitudinally by multi-gene networks, inferred proportions of immune cells, and expression of healing-related functions. Differences between wound outcomes in colonized wounds were more apparent than in non-colonized wounds. Colonized/healed wounds appeared able to mount an adaptive immune response to infection and progress beyond the inflammatory stage of healing, while colonized/failed wounds did not. Although, both colonized and non-colonized failed wounds showed increasing inferred immune and inflammatory programs, non-colonized/failed wounds progressed beyond the inflammatory stage, suggesting different mechanisms of failure dependent on colonization status. Overall, these data reveal gene expression profile differences in healing wounds that may be utilized to improve clinical treatment paradigms.

Abstract Background Grasslands provide a wide range of ecosystem services (ESs). However, there is currently no method for easily diagnosing the level of ESs produced. Our aim was to develop ES indicators based on botanical surveys, which are readily available data and integrative of grassland spatiotemporal variability. Methods Based on academic knowledge and expertise, we identified several simple vegetation criteria that we aggregated using a multicriteria analysis tool to construct indicators of the level of ESs provided by grasslands. In this study, the indicators were calculated from over 2000 botanical surveys spread over a wide biogeographical gradient. Results Analyses of correlation between the various indicators show that “forage supply” and “diversity conservation” were not correlated. “Forage availability” and “nitrogen availability for the vegetation” were positively linked together and negatively linked to the robustness of the plant community to extreme events. A temporal approach highlights that the “biodiversity conservation” score decreased from 1970 to 2010 and that “nitrogen availability for the vegetation” was lower in 1970 and 1980 than in 2000 and 2010. Conclusions These results show that our aggregation method based on a large data set of botanical surveys could be appropriate for studying temporal dynamics of ESs.

The Great Green Wall (GGW) is an international initiative to combat land degradation and restore native plant life in the Sahel, but due to a lack of monitoring tools, it remains unknown to be considered as success or failure. Here, we quantify the impact of GGW plantations and Corporate plantations (privately owned) in Sahelian Senegal based on remote sensing data and deep learning by mapping individual trees and their biomass across the Sahel region. Tree features (cover, density and above-ground biomass) have been computed in every hectare of 42 plantations (of both, corporate and GGW) and their surrounding non-planted areas, subsequently used for a comparative analysis of tree features. Results showed that gains in tree features varied substantially between plantations. At plot scale, among Corporate plantations, the average gain in tree density was 61.16±42.12 trees/ha while it was 5.7 ± 5.8 trees/ha for GGW plantations. In regards to tree cover, the average gain was 618.5 ± 588.5 m2/ha for Corporate plantations and 71.72±108.89 m2/ha for GGW plantations. For the above-ground biomass, the average gain was 3.36±3.29 tons/ha in the Corporate plantations and 0.46±0.67 tons/ha in the GGW plantations. The average gain in foliar biomass in the Corporate plantations was 0.15±0.13 tons/ha and in the GGW plantations, it was 0.02±0.03 tons/ha. The average gain in wood biomass was 3.21±3.12 tons/ha among the Corporate plantations and was 0.43±0.64 tons/ha among the GGW plantations. Notably, regarding the relative benefit in terms of ecosystem services per unit of density, each tree in GGW plantations contribute more to ecosystem services per unit of density compared to Corporate plantations. In GGW, each gained tree contributes 18 m2 of cover, 116.1 kg of above-ground biomass, 5.6 kg of foliar biomass, and 114.2 kg of woody biomass, while in corporate plantations, on the other hand, each gained tree adds 9 m2 of cover, 48.4 kg of above-ground biomass, 2.3 kg of foliar biomass, and 46.3 kg of woody biomass. These findings are opposed to conventional paradigms, suggesting that the Great Green Wall, while perhaps missing its tree density targets, has succeeded in its mission to produce ecosystem services per tree. This raises important questions about the redefinition of objectives in reforestation projects, focusing on quality rather than quantity, a perspective that could transform our understanding of the successes and failures of these essential ecological restoration initiatives. However, the assessment primarily relies on indicators such as cover and biomass, potentially overlooking other crucial ecosystem services. Therefore, while our conclusions underscore the effectiveness of reforestation initiatives, future research should aim to establish a more comprehensive understanding of ecosystem services by incorporating additional indicators beyond cover and biomass, such as species diversity, soil health, water retention, and habitat quality.

Abstract Introduction The objective of this systematic review is to determine the benefits and harms of heel lifts to any comparator for lower limb musculoskeletal conditions. Methods Ovid MEDLINE, Ovid AMED, Ovid EMCARE, CINAHL Plus and SPORTDiscus were searched from inception to the end of May 2024. Randomised, quasi‐randomised or non‐randomised trials comparing heel lifts to any other intervention or no‐treatment were eligible for inclusion. Data was extracted for the outcomes of pain, disability/function, participation, participant rating of overall condition, quality of life, composite measures and adverse events. Two authors independently assessed risk of bias and certainty of evidence using the GRADE approach at the primary time point 12 weeks (or next closest). Results Eight trials (n = 903), investigating mid‐portion Achilles tendinopathy, calcaneal apophysitis and plantar heel pain were included. Heel lifts were compared to exercise, ultrasound, cryotherapy orthotics, stretching, footwear, activity modification, felt pads and analgesic medication. No outcome was at low risk of bias and few effects (2 out of 47) were clinically important. Low‐certainty evidence (1 trial, n = 199) indicates improved pain relief (55.7 points [95% CI: 50.3–61.1], on a 100 mm visual analogue scale) with custom orthotics compared to heel lifts at 12 weeks for calcaneal apophysitis. Very low‐certainty evidence (1 trial, n = 62) indicates improved pain and function with heel lifts over indomethacin (35.5 points [95% CI: 21.1–49.9], Foot Function Index) at 12 months for plantar heel pain. Conclusions Few trials have assessed the benefits and harms of heel lifts for lower limb musculoskeletal conditions. Only two outcomes out of 47 showed clinically meaningful between group differences. However, due to very low to low certainty evidence we are unable to be confident in the results and the true effect may be substantially different. Registration PROSPERO registration number CRD42022309644.

Abstract Poor bone quality is a major factor in skeletal fragility in elderly individuals. The molecular mechanisms that establish and maintain bone quality, independent of bone mass, are unknown but are thought to be primarily determined by osteocytes. We hypothesize that the age-related decline in bone quality results from the suppression of osteocyte perilacunar/canalicular remodeling (PLR), which maintains bone material properties. We examined bones from young and aged mice with osteocyte-intrinsic repression of TGFβ signaling (TβRII ocy−/− ) that suppresses PLR. The control aged bone displayed decreased TGFβ signaling and PLR, but aging did not worsen the existing PLR suppression in male TβRII ocy−/− bone. This relationship impacted the behavior of collagen material at the nanoscale and tissue scale in macromechanical tests. The effects of age on bone mass, density, and mineral material behavior were independent of osteocytic TGFβ. We determined that the decline in bone quality with age arises from the loss of osteocyte function and the loss of TGFβ-dependent maintenance of collagen integrity.

Abstract The number of genome-level resources for non-model species continues to rapidly expand. However, frog species remain underrepresented, with up to 90% of frog genera having no genomic or transcriptomic data. Here, we assemble the first genomic and transcriptomic resources for the recently described southern stuttering frog (Mixophyes australis). The southern stuttering frog is ground-dwelling, inhabiting naturally vegetated riverbanks in south-eastern Australia. Using PacBio HiFi long-read sequencing and Hi-C scaffolding, we generated a high-quality genome assembly, with a scaffold N50 of 369.3 Mb and 95.1% of the genome contained in twelve scaffolds. Using this assembly, we identified the mitochondrial genome, and assembled six tissue-specific transcriptomes. We also bioinformatically characterised novel sequences of two families of antimicrobial peptides (AMPs) in the southern stuttering frog, the cathelicidins and β-defensins. While traditional peptidomic approaches to peptide discovery have typically identified one or two AMPs in a frog species from skin secretions, our bioinformatic approach discovered 12 cathelicidins and two β-defensins that were expressed in a range of tissues. We investigated the novelty of the peptides and found diverse predicted activities. Our bioinformatic approach highlights the benefits of multi-omics resources in peptide discovery and contributes valuable genomic resources in an under-represented taxon.

Abstract Background The savannah ecosystems of Sahel have experienced continuous and heavy grazing of livestock for centuries but still, their vegetation response to grazing pressure remains poorly understood. In this study, we analysed the herbaceous plant dynamics, measured by species diversity, composition, cover, and biomass in response to grazing pressure in the savannah ecosystems of Sahel. In Senegal, we selected four savannah sites represented with high, moderate, light and no grazing intensity levels. Transect survey methods were used for sampling the vegetation data within each of the sites. Species richness and composition were analysed using species accumulation curve and multivariate analyses. Furthermore, we used General Linear Models and a piecewise Structural Equation Model (pSEM) to examine the relationships between grazing intensity, vegetation cover, diversity and biomass. Results The herbaceous species diversity and composition varied significantly among the different grazing intensity levels (p

Objectives The study aims to (1) report the process of recruiting young adults into a secondary knee osteoarthritis prevention randomised controlled trial (RCT) after anterior cruciate ligament reconstruction (ACLR); (2) determine the number of individuals needed to be screened to include one participant (NNS) and (3) report baseline characteristics of randomised participants.Methods The SUpervised exercise-therapy and Patient Education Rehabilitation (SUPER)-Knee RCT compares SUPER and minimal intervention for young adults (aged 18–40 years) with ongoing symptoms (ie, mean score of

Background:. Facial cancer surgery involving the midface (comprising the lower eyelids, nose, cheeks, and upper lip) can have debilitating life-changing functional, social, and psychological impacts on the patient. Midface symptoms are inadequately captured by existing patient-reported outcome measures (PROMs). PROMs are increasingly used for individual patient care, quality improvement, and standardized reporting of treatment outcomes. This study aimed to present our findings from the first phase of the development of a midface, specifically periocular and nasal, PROM. Methods:. After international guidance for PROM development, the first phase comprised identification of salient issues and item generation. Fifteen patients who had midface surgery and 10 clinicians from various specialties with more than 5 years’ experience treating these patients were recruited. Semi-structured interviews explored aesthetic, functional, social, and psychological outcomes, with specific attention to deficiencies in current PROMs. Thematic analysis was used to develop an item pool, and group interviews with clinicians were carried out to create and refine PROM scales. Results:. Qualitative data from patient interviews were grouped into aesthetic, functional, and psychosocial domains for the eyelids and nose. Ninety-nine draft items were generated across these domains. Following focus group discussions, the final version of the midface-specific PROM contained 31 items (13 eye-specific, 10-nose-specific, eight general midface items). Conclusions:. This midface-specific PROM is valuable in assessing and comparing patient-reported outcomes in those who have undergone complex resection and reconstruction of the midface. This PROM is currently undergoing field testing.

Background: Small and medium social enterprises (SMSEs) in developing countries, particularly in South Africa, play a crucial role in a country’s economy. With an entrepreneurial mindset, they respond innovatively to social, economic and environmental societal problems. However, SMSEs in emerging economies experience critical survival and performance challenges, including financial sustainability. Thus, investigating the funding model is important to overcome those challenges. Aim: The study aims to investigate the funding model of SMSEs in KwaZulu-Natal (KZN), South Africa, to identify the initial and primary funding source, and to explore the revenue-generating activities and revenue growth. Setting: The research was conducted in KZN with SMSEs participated in the champions’ programme of local economic development (LED) project at the University of KwaZulu-Natal (UKZN). Methods: A qualitative research design of 10 purposively selected case studies were conducted using an in-depth interview. The data were analysed using NVivo software. Results: The study found that self-funding followed by revenue generated from a commercial business is the most common funding model SMSEs adopt. A lack of access to different funding sources to secure success and sustainability hindered the development and growth of SMSEs. Conclusion: Diversifying funding might help SMSEs avoid the challenge of sustainability and will enable them to focus on improving their activities towards achieving their social mission. Contribution: The study brings a new theoretical approach to the funding model of SMSEs. Furthermore, the study contributes to the enterprises’ management.

Abstract Background Studies have suggested a positive association between bladder cancer (BC) outcome and comedication use, including nonsteroidal anti-inflammatory drugs (NSAID), metformin, and prednisone use. To validate these associations, we evaluated whether these medications were associated with clinical outcome in a Canadian cohort of BC patients. Methods This is a retrospective cohort study on BC patients undergoing radical cystectomy (RC) in Québec province in 2000–2015, as registered in the provincial health administration databases. Medication use was considered chronic when prescribed for ≥ 1 year. Overall (OS), disease-specific (DSS) and recurrence-free (RFS) survival were compared using multivariable Cox proportional hazards models. Covariates included age, Charlson’s comorbidity index, region of residence, year of RC, distance to hospital, hospital type, hospital and surgeon annual RC volume, neoadjuvant chemotherapy use, and type of bladder diversion, as well as mutual adjustment for concomitant comedication use (statins, NSAIDs, metformin, and prednisone). Results Of 3742 patients included, 293, 420, and 1503 patients chronically used prednisone, metformin, and NSAIDs before surgery, respectively. In multivariable analyses, preoperative prednisone use was associated with improved OS (HR 0.67, 95%CI 0.55–0.82), DSS (HR 0.58, 95%CI 0.45–0.76), and RFS (HR 0.61, 95%CI 0.47–0.78). Patients who chronically used metformin preoperatively had a worse OS (HR 1.29, 95%CI 1.07–1.55), DSS (HR 1.38, 95%CI 1.10–1.72), and RFS (HR 1.41, 95%CI 1.13–1.74). Preoperative, chronic NSAID use was not significantly associated with all clinical outcomes, with adjusted HRs for OS, DSS, and RFS of 1.10 (95%CI 0.95–1.27), 1.24 (95%CI 1.03–1.48), and 1.22 (95%CI 1.03–1.45), respectively. Directionality of findings was similar when stratifying by comedication use in the year following surgery. Results were similar after propensity-score matching too. Conclusions In our Canadian cohort of BC undergoing RC, chronic prednisone use was associated with improved clinical outcomes, while metformin and NSAID were not.

Abstract Background In sub-Saharan Africa (SSA), malaria remains a public health problem despite recent reports of declining incidence. Severe malaria is a multiorgan disease with wide-ranging clinical spectra and outcomes that have been reported to vary by age, geographical location, transmission intensity over time. There are reports of recent malaria epidemics or resurgences, but few data, if any, focus on the clinical spectrum of severe malaria during epidemics. This describes the clinical spectrum and outcomes of childhood severe malaria during the disease epidemic in Eastern Uganda. Methods This prospective cohort study from October 1, 2021, to September 7, 2022, was nested within the ‘Malaria Epidemiological, Pathophysiological and Intervention studies in Highly Endemic Eastern Uganda’ (TMA2016SF-1514-MEPIE Study) at Mbale Regional Referral Hospital, Uganda. Children aged 60 days to 12 years who at admission tested positive for malaria and fulfilled the clinical WHO criteria for surveillance of severe malaria were enrolled on the study. Follow-up was performed until day 28. Data were collected using a customized proforma on social demographic characteristics, clinical presentation, treatment, and outcomes. Laboratory analyses included complete blood counts, malaria RDT (SD BIOLINE Malaria Ag P.f/Pan, Ref. 05FK60-40-1) and blood slide, lactate, glucose, blood gases and electrolytes. In addition, urinalysis using dipsticks (Multistix® 10 SG, SIEMENS, Ref.2300) at the bedside was done. Data were analysed using STATA V15.0. The study had prior ethical approval. Results A total of 300 participants were recruited. The median age was 4.6 years, mean of 57.2 months and IQR of 44.5 months. Many children, 164/300 (54.7%) were under 5 years, and 171/300 (57.0%) were males. The common clinical features were prostration 236/300 (78.7%), jaundice in 205/300 (68.3%), severe malarial anaemia in 158/300 (52.7%), black water fever 158/300 (52.7%) and multiple convulsions 51/300 (17.0%), impaired consciousness 50/300(16.0%), acidosis 41/300(13.7%), respiratory distress 26/300(6.7%) and coma in 18/300(6.0%). Prolonged hospitalization was found in 56/251 (22.3%) and was associated with acidosis, P = 0.041. The overall mortality was 19/300 (6.3%). Day 28 follow-up was achieved in 247/300 (82.3%). Conclusion During the malaria epidemic in Eastern Uganda, severe malaria affected much older children and the spectrum had more of prostration, jaundice severe malarial anaemia, black water fever and multiple convulsions with less of earlier reported respiratory distress and cerebral malaria.

BackgroundPodcasts have proven to be a successful alternative source of educational material for students. Given the ability to listen to podcasts 24/7 and while on the go, this technology has the potential to provide informative and educational material to a large number of people at any given time. Podcasts are usually freely available on commonly used mobile devices, such as smartphones, laptops, and tablets. ObjectiveThis paper describes the impact of health-related podcasts as an intervention tool to support the knowledge and awareness of nursing students on a given topic. MethodsPre- and postpodcast questionnaires will gather data regarding the participants’ knowledge and awareness of two topics—gestational diabetes and mental health. This intervention will be tested on general nursing undergraduate students. The total number of students (N=2395) from the participating universities are broken down as follows: (1) University College Cork (n=850) and the University of Galway (n=450) in Ireland, (2) Mzuzu University in Malawi (n=719), and (3) University of Fort Hare in South Africa (n=376). ResultsThe study received ethical approval from the University College Cork Ethics Committee (2022-027A1). The approval obtained from University College Cork sufficed as ethics coverage for the University of Galway in Ireland. Ethics approval was also received from the Mzuzu University Research Ethics Committee (ID MZUNIREC/DOR/23/28) and the Inter-Faculty Research Ethics Committee of the University of Fort Hare (ID CIL002-21). Data collection is currently underway and will continue until the end of February 2024. The quantitative and qualitative data are expected to be analyzed in March 2024. ConclusionsResults from this study will allow for an investigation into the impact of podcasts in different settings: a high-income country (Ireland), an upper-middle–income country (South Africa), and a low-to-middle–income country (Malawi). The data gathered from this feasibility study will provide more clarity on the potential utility of podcasts as an intervention tool. We will gather data regarding listener demographics (eg, country of residence, age, gender, and year of study). International Registered Report Identifier (IRRID)DERR1-10.2196/50735

Artificial intelligence (AI) and machine learning are central components of today's medical environment. The fairness of AI, i.e. the ability of AI to be free from bias, has repeatedly come into question. This study investigates the diversity of members of academia whose scholarship poses questions about the fairness of AI. The articles that combine the topics of fairness, artificial intelligence, and medicine were selected from Pubmed, Google Scholar, and Embase using keywords. Eligibility and data extraction from the articles were done manually and cross-checked by another author for accuracy. Articles were selected for further analysis, cleaned, and organized in Microsoft Excel; spatial diagrams were generated using Public Tableau. Additional graphs were generated using Matplotlib and Seaborn. Linear and logistic regressions were conducted using Python to measure the relationship between funding status, number of citations, and the gender demographics of the authorship team. We identified 375 eligible publications, including research and review articles concerning AI and fairness in healthcare. Analysis of the bibliographic data revealed that there is an overrepresentation of authors that are white, male, and are from high-income countries, especially in the roles of first and last author. Additionally, analysis showed that papers whose authors are based in higher-income countries were more likely to be cited more often and published in higher impact journals. These findings highlight the lack of diversity among the authors in the AI fairness community whose work gains the largest readership, potentially compromising the very impartiality that the AI fairness community is working towards.

Abstract The consistent monitoring of trees both inside and outside of forests is key to sustainable land management. Current monitoring systems either ignore trees outside forests or are too expensive to be applied consistently across countries on a repeated basis. Here we use the PlanetScope nanosatellite constellation, which delivers global very high-resolution daily imagery, to map both forest and non-forest tree cover for continental Africa using images from a single year. Our prototype map of 2019 (RMSE = 9.57%, bias = −6.9%). demonstrates that a precise assessment of all tree-based ecosystems is possible at continental scale, and reveals that 29% of tree cover is found outside areas previously classified as tree cover in state-of-the-art maps, such as in croplands and grassland. Such accurate mapping of tree cover down to the level of individual trees and consistent among countries has the potential to redefine land use impacts in non-forest landscapes, move beyond the need for forest definitions, and build the basis for natural climate solutions and tree-related studies.

Purpose Carotid vessel wall volume (VWV) measurement on three-dimensional ultrasonography (3DUS) outperforms conventional two-dimensional ultrasonography for carotid atherosclerosis evaluation. Although time-saving semi-automated algorithms have been introduced, their clinical availability remains limited due to a lack of validation, particularly an extensive reliability analysis. This study compared inter-observer and intra-observer reliability between manual segmentation and semi-automated segmentation for carotid VWV measurements on 3DUS. Methods Thirty-one 3DUS volume datasets were prospectively acquired from 20 healthy subjects, aged >18 years, without previous stroke, transient ischemic attack, or cardiovascular disease. Five observers segmented all volume datasets both manually and semi-automatically. The process was repeated five times. Reliability was expressed by the intraclass correlation coefficient, supplemented by the coefficient of variation. Results Carotid VWV measurements using the common carotid artery (CCA) were more reliable than those using the internal carotid artery (ICA) or external carotid artery (ECA) for both manual and semiautomated segmentation (manual segmentation, CCA: inter-observer, 0.935; intra-observer, 0.934 to 0.966; ICA: inter-observer, 0.784; intra-observer, 0.756 to 0.878; ECA: inter-observer, 0.732; intraobserver, 0.919 to 0.962; semi-automated segmentation, CCA: inter-observer, 0.986; intra-observer, 0.954 to 0.993; ICA: inter-observer, 0.977; intra-observer, 0.958 to 0.978; ECA: inter-observer, 0.966; intra-observer, 0.884 to 0.937). Total carotid VWV measurements by manual (inter-observer, 0.922; intra-observer, 0.927 to 0.961) and semi-automated segmentation (inter-observer, 0.987; intra-observer, 0.968 to 0.989) were highly reliable. Semi-automated segmentation showed higher reliability than manual segmentation for both individual and total carotid VWV measurements. Conclusion 3DUS carotid VWV measurements of the CCA are more reliable than measurements of the ICA and ECA. Total carotid VWV measurements are highly reliable. Semi-automated segmentation has higher reliability than manual segmentation.

L’effet de la pâture sur l’évolution de la masse herbacée et sa digestibilité au cours de l’année a été étudié à Dahra, dans le Sahel sénégalais. Dans cette zone d’élevage la strate herbacée, base de l’alimentation du bétail, a une croissance brève pendant la saison des pluies. L’étude a été conduite pendant la saison des pluies et la saison sèche sur deux années consécutives, de juillet 2018 à juin 2020. Les mesures de phytomasse et de qualité fourragère (digestibilité in vitro de la matière organique, DMO) ont démarré dix jours après la première pluie et ont été répétées avec une fréquence de dix jours en saison des pluies et trente en saison sèche. La dynamique des herbacées annuelles se fait en trois étapes : une première de faible croissance, une deuxième de croissance rapide et une troisième de sénescence. La quantité maximale de masse sur pied sous pâture était de 1 992 ± 755 kg MS.ha-1 en 2018 et de 1 801 ± 601 kg MS.ha-1 en 2019 alors que, dans la mise en défens, elle était de 2022 ± 375 kg MS.ha-1 en 2018 et de 2357 ± 664 kg MS.ha-1 en 2019. La DMO a fortement décru au cours de la saison de végétation : de 70 % en début de saison des pluies, elle était en moyenne de 52 % en pleine saison des pluies et 30 % en saison sèche. La matière organique du fourrage a été plus digestible sous pâture que sous mise en défens. La pâture n’a pas systématiquement diminué la masse sur pied disponible de façon significative, mais en revanche elle en a amélioré la digestibilité.

Easter is one of the significant moments for Christians and Catholics. The purpose of this study is to understand the texts containing ideology by the Indonesian Communion of Churches (PGI) and the Archdiocese of Jakarta of 2023. The method applied was qualitative descriptive with data collection techniques, namely documentation by downloading written texts from PGI and the Archdiocese of Jakarta. Then downloaded data was followed by data reduction and displayed processes. The results of this process were analyzed using a Critical Discourse Analysis approach with Fairclough's model, which includes Textual, discursive, and socio-cultural analysis. The results of this study show that the textual dimension reveals linguistic features such as fundamentalist and contextual interpretation, cause-and-effect features, and connotative words that undergo expanded meanings. In addition to these features, the use of the pronoun “we” emphasizes the equal positions, indicating strategy of emphasis persuasive meaning. The discursive practices show the variety of language features such as repetition and borrowing texts, Meanwhile, the socio-cultural dimension reveals the concerns and anticipatory attitudes toward potential threats such as the Covid-19 pandemic, global recession, political wars, political issues in 2024, social justice and welfare system, and the consumptive attitude.

[This corrects the article DOI: 10.1371/journal.pgen.1010965.].

Revue Sciences Eaux & Territoires - Vient de paraître en ligneLa fragmentation du paysage se matérialise par une rupture de connexion au sein des réseaux écologiques. Le concept de trame verte et bleue est apparu comme un outil de protection et de restauration des continuités écologiques dans les territoires. De nouvelles trames écologiques ont récemment été proposées pour identifier d’autres discontinuités écologiques effectives. C’est notamment le cas de la trame turquoise associant la trame bleue et la partie de la trame verte en interaction fonctionnelle. La trame turquoise regroupe ainsi différents types d’habitats aquatiques et terrestres dont dépendent de nombreuses espèces d’amphibiens, d’odonates et autres invertébrés ou encore de chiroptères. Cette nouvelle trame bénéficie d’une attention croissante dans le monde opérationnel, alors même que sa définition et les méthodes de caractérisation ne sont pas encore stabilisées. Cet article propose de contribuer à une meilleure définition et compréhension de la trame turquoise. S’appuyant sur la méthode des graphes paysagers, aujourd’hui largement utilisée pour modéliser les réseaux écologiques et mesurer leur connectivité, le projet INTERFACE a permis le développement d’un protocole innovant de réseau multi-habitats pour tenir compte de l’hétérogénéité des habitats dans l’évaluation de la connectivité de la trame turquoise. Il permet ainsi d’aller au-delà de la délimitation d’une zone tampon autour des cours d’eau et d'identifier les zones fonctionnelles à préserver, les zones vulnérables et les points de conflits où il serait intéressant de restaurer des habitats aquatiques et/ou terrestres pour améliorer les connectivités.

Since the 1960s, droughts have caused significant degradation of Sahelian ecosystems, particularly resulting in a reduction in tree cover. Despite the challenges posed by climate change, the rural Sahelian population continues to depend on natural resources for pastoral livestock farming, which remains a critical source of livelihood. To address this issue of land degradation, Sahelian states and international coalitions are prioritizing efforts to restore pastoral land through reforestation programs. These initiatives aim to enhance ecosystem services, generate new income for the population, and safeguard biodiversity.In practice, however, reforestation has often led to a depletion of resources for communities due to enclosure policies. This paper explores various land management models for reforestation within a pastoral context through provisioning ecosystem services (PES) modeling.This study quantifies the economic potential of PES offered by reforestation programs in Senegal. It employs a quantitative methodology to assess the profitability of these operations from the perspective of pastoral economies. The analysis reveals that the PES benefits of reforestation can significantly enhance the economic potential of sylvo-pastoral productions if resource access is negotiated collaboratively between pastoralists and forestry extension services during reforestation activities and after. From an investment perspective, the economic viability of reforestation operations in drylands is questionable. The findings suggest that when evaluated solely in terms of PES profitability, these programs may not be financially sustainable. The sustainability of these investments would require taking into account supporting and regulating ecosystem services.

PURPOSEStandard-of-care therapies for metastatic renal cell carcinoma (mRCC) have greatly evolved. However, the availability of emerging options in global health care systems can vary. We sought to describe the integration and usage of systemic therapies for mRCC in Canada since 2011.METHODSWe included patients with mRCC enrolled in the Canadian Kidney Cancer Information System, a prospective cohort of patients from 14 Canadian academic centers, who received systemic therapy from January 1, 2011, to December 31, 2021. Patients were stratified by treatment era (cohort 1: 2011-2015, cohort 2: 2016-2021). Stacked bar charts were used to present treatment proportions; Sankey diagrams were used to show the evolution of treatment sequencing between the two cohorts.RESULTSFour thousand one hundred seven patients were diagnosed with mRCC, of whom 2,752 (67%) received systemic therapy. Among these patients, mean age was 64 years, 74% were male, 75% had clear cell histology, and International Metastatic RCC Database Consortium risk classification was favorable, intermediate, and poor in 16%, 56%, and 28%, respectively. Utilization of immune checkpoint inhibition (ICI)–based treatments has increased in Canada and reflects global and local patterns of approval and adoption. The use of therapies after doublet ICI has mostly shifted toward vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKIs) that were previously used in first line with subsequent treatments reflecting approved and available agents after previous VEGF-TKI. Clinical trial participation among patients who received systemic therapy was 18% in first, 21% in second, and 24% in third line.CONCLUSIONIn Canada's publicly funded health care system, availability of standard mRCC therapies broadly reflects access from government-funded clinical trials and compassionate access program sources. In an evolving therapeutic landscape, ongoing advocacy is required to continue to facilitate patient access to efficacious therapies.

Drosophila ovarian Follicle Stem Cells (FSCs) present a favorable paradigm for understanding how stem cell division and differentiation are balanced in communities where those activities are independent. FSCs also allow exploration of how this balance is integrated with spatial stem cell heterogeneity. Posterior FSCs become proliferative Follicle Cells (FCs), while anterior FSCs become quiescent Escort Cells (ECs) at about one fourth the frequency. A single stem cell can nevertheless produce both FCs and ECs because it can move between anterior and posterior locations. Studies based on EdU incorporation to approximate division rates suggested that posterior FSCs divide faster than anterior FSCs. However, direct measures of cell cycle times are required to ascertain whether FC output requires a net flow of FSCs from anterior to posterior. Here, by using live imaging and FUCCI cell-cycle reporters, we measured absolute division rates. We found that posterior FSCs cycle more than three times faster than anterior FSCs and produced sufficient new cells to match FC production. H2B-RFP dilution studies supported different cycling rates according to A/P location and facilitated live imaging, showing A/P exchange of FSCs in both directions, consistent with the dynamic equilibrium inferred from division rate measurements. Inversely graded Wnt and JAK-STAT pathway signals regulate FSC differentiation to ECs and FCs. JAK-STAT promotes both differentiation to FCs and FSC cycling, affording some coordination of these activities. When JAK-STAT signaling was manipulated to be spatially uniform, the ratio of posterior to anterior division rates was reduced but remained substantial, showing that graded JAK-STAT signaling only partly explains the graded cycling of FSCs. By using FUCCI markers, we found a prominent G2/M cycling restriction of posterior FSCs together with an A/P graded G1/S restriction, that JAK-STAT signaling promotes both G1/S and G2/M transitions, and that PI3 kinase signaling principally stimulates the G2/M transition.

Summary: Background: Currently, melatonin is used to treat children and adolescents with insomnia without knowing the full extent of the short-term and long-term consequences. Our aim was to provide clinicians and guideline panels with a systematic assessment of serious—and non-serious adverse events seen in continuation of melatonin treatment and the impact on pubertal development and bone health following long-term administration in children and adolescents with chronic insomnia. Methods: We searched PubMed, Embase, Cinahl and PsycINFO via Ovid, up to March 17, 2023, for studies on melatonin treatment among children and adolescents (aged 5–20 years) with chronic insomnia. The language was restricted to English, Danish, Norwegian, and Swedish. Outcomes were non-serious adverse events and serious adverse events assessed 2–4 weeks after initiating treatment and pubertal development and bone health, with no restriction on definition or time of measurement. Observational studies were included for the assessment of long-term outcomes, and serious and non-serious adverse events were assessed via randomised studies. The certainty of the evidence was assessed using Grades of Recommendation, Assessment, Development and Evaluation (GRADE). The protocol is registered with the Danish Health Authority. Findings: We identified 22 randomised studies with 1350 patients reporting on serious—and non-serious adverse events and four observational studies with a total of 105 patients reporting on pubertal development. Melatonin was not associated with serious adverse events, yet the number of patients experiencing non-serious adverse events was increased (Relative risk 1.56, 95% CI 1.01–2.43, 17 studies, I2 = 47%). Three studies reported little or no influence on pubertal development following 2–4 years of treatment, whereas one study registered a potential delay following longer treatment durations (>7 years). These findings need further evaluation due to several methodological limitations. Interpretation: Children who use melatonin are likely to experience non-serious adverse events, yet the actual extent to which melatonin leads to non-serious adverse events and the long-term consequences remain uncertain. This major gap of knowledge on safety calls for caution against complacent use of melatonin in children and adolescents with chronic insomnia and for more research to inform clinicians and guideline panels on this key issue. Funding: The Danish Health Authority. The Parker Institute, Bispebjerg and Frederiksberg Hospital, supported by the Oak Foundation.

Summary: Background: Melatonin prescriptions for children and adolescents have increased substantially during the last decade. Existing clinical recommendations focus on melatonin as a treatment for insomnia related to neurodevelopmental disorders. To help guide clinical decision-making, we aimed to construct a recommendation on the use of melatonin in children and adolescents aged 5–20 years with idiopathic chronic insomnia. Methods: A systematic search for guidelines, systematic reviews and randomised controlled trials (RCT) were performed in Medline, Embase, Cochrane Library, PsycInfo, Cinahl, Guidelines International Network, Trip Database, Canadian Agency for Drugs and Technologies in Health, American Academy of Sleep Medicine, European Sleep Research Society and Scandinavian Health Authorities databases. A search for adverse events in otherwise healthy children and adolescents was also performed. The latest search for guidelines, systematic reviews, and adverse events was performed on March 18, 2023. The latest search for RCTs was performed on to February 6, 2023. The language was restricted to English, Danish, Norwegian, and Swedish. Eligible participants were children and adolescents (5–20 years of age) with idiopathic chronic insomnia, in whom sleep hygiene practices have been inadequate and melatonin was tested. There were no restrictions on dosage, duration of treatment, time of consumption, or release formula. Primary outcomes were quality of sleep, daytime functioning and serious adverse events. Secondary outcomes included total sleep time, sleep latency, awakenings, drowsiness, quality of life, all-cause dropouts, and non-serious adverse events. Outcomes were assessed at different time points to assess short-term and long-term effects. Meta-analysis was performed using inverse variance random-effects model and risk of bias was assessed using Cochrane risk of bias tool. If possible, funnel plots would be constructed to investigate publication bias. Heterogeneity was calculated via I2 statistics. A multidisciplinary guideline panel formulated the recommendation according to Grading of Recommendations Assessment, Development and Evaluation (GRADE). The certainty of evidence was considered either high, moderate, low or very low depending on the extent of risk of bias, inconsistency, imprecision, indirectness, or publication bias. The evidence-to-decision framework was subsequently used to discuss the feasibility and acceptance of the constructed recommendation alongside the impact on resources and equity. The protocol is registered with the Danish Health Authority. Findings: We included eight RCTs with 419 children and adolescents with idiopathic chronic insomnia. Melatonin led to a moderate increase in total sleep time by 30.33 min (95% confidence interval (CI) 18.96–41.70, 4 studies, I2 = 0%) and a moderate reduction in sleep latency by 18.03 min (95% CI −26.61 to −9.44, 3 studies, I2 = 0%), both as assessed by sleep diary. No other beneficial effects were found. None of the studies provided information on serious adverse events, yet the number of participants experiencing non-serious adverse events was increased (Relative risk 3.44, 95% CI 1.25–9.42, 4 studies, I2 = 0%). Funnel plots were not constructed due to the low number of studies. The certainty of evidence was very low on the quality of sleep and low for daytime functioning. Interpretation: Evidence of very low certainty shows that benefits are limited and unwanted events are likely when melatonin is used to treat otherwise healthy children and adolescents with chronic insomnia. Melatonin should never be the first choice of treatment for this particular population, yet carefully monitored short-term use may be considered if sleep hygiene practices and non-pharmacological interventions have proven inadequate, and only if daytime function is compromised. Funding: The Danish Health Authority and the Parker Institute, Bispebjerg and Frederiksberg Hospital supported by the Oak Foundation.

Summary: Background: Melatonin has become a widely used sleeping aid for young individuals currently not included in existing guidelines. The aim was to develop a recommendation on the use of melatonin in children and adolescents aged 2–20 years, with chronic insomnia due to disorders beyond indication. Methods: We performed a systematic search for guidelines, systematic reviews, and randomised trials (RCTs) in Medline, Embase, Cochrane Library, PsycInfo, Cinahl, Guidelines International Network, Trip Database, Canadian Agency for Drugs and Technologies in Health, American Academy of Sleep Medicine, European Sleep Research Society and Scandinavian Health Authorities databases. A separate search for adverse events was also performed. The latest search for guidelines, systematic reviews, and adverse events was performed on March 17, 2023. The latest search for RCTs was performed on to February 6, 2023. The language was restricted to English, Danish, Norwegian, and Swedish. Eligible participants were children and adolescents (2–20 years of age) with chronic insomnia due to underlying disorders, in whom sleep hygiene practices have been inadequate and melatonin was tested. Studies exclusively on autism spectrum disorders or attention deficit hyperactive disorder were excluded. There were no restrictions on dosage, duration of treatment, time of consumption or release formula. Primary outcomes were quality of sleep, daytime functioning and serious adverse events, assessed at 2–4 weeks post-treatment. Secondary outcomes included total sleep time, sleep latency, awakenings, drowsiness, quality of life, non-serious adverse events, and all-cause dropouts (assessed at 2–4 weeks post-treatment), plus quality of sleep and daytime functioning (assessed at 3–6 months post-treatment). Pooled estimates were calculated using inverse variance random effects model. Statistical heterogeneity was calculated using I2 statistics. Risk of bias was assessed using Cochrane risk of bias tool. Publication bias was assessed using funnel plots. A multidisciplinary guideline panel constructed the recommendation using Grades of Recommendation, Assessment, Development and Evaluation (GRADE). The certainty of evidence was considered either high, moderate, low or very low depending on the extent of risk of bias, inconsistency, imprecision, indirectness, or publication bias. The evidence-to-decision framework was used to discuss the feasibility and acceptance of the constructed recommendation and its impact on resources and equity. The protocol is registered with the Danish Health Authority. Findings: We identified 13 RCTs, including 403 patients with a wide range of conditions. Melatonin reduced sleep latency by 14.88 min (95% CI 23.42–6.34, 9 studies, I2 = 60%) and increased total sleep time by 18.97 min (95% CI 0.37–37.57, 10 studies, I2 = 57%). The funnel plot for total sleep time showed no apparent indication of publication bias. No other clinical benefits were found. The number of patients experiencing adverse events was not statistically increased however, safety data was scarce. Certainty of evidence was low. Interpretation: Low certainty evidence supports a moderate effect of melatonin in treating sleep continuity parameters in children and adolescents with chronic insomnia due to primarily medical disorders beyond indication. The off-label use of melatonin for these patients should never be the first choice of treatment, but may be considered by medical specialists with knowledge of the underlying disorder and if non-pharmacological interventions are inadequate. If treatment with melatonin is initiated, adequate follow-up to evaluate treatment effect and adverse events is essential. Funding: The Danish Health Authority. The Parker Institute, Bispebjerg and Frederiksberg Hospital, supported by the Oak Foundation.

Objective To explore the comparative effectiveness of pharmacological interventions for hand osteoarthritis (OA).Methods We systematically searched Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials from inception until 26 December 2021, for randomised trials of pharmacological interventions for people with hand OA. Two reviewers independently extracted study data and assessed the risk of bias. We calculated the effect sizes for pain (standardised mean differences) using Bayesian random effects models for network meta-analysis (NMA) and pairwise meta-analysis. Based on a pre-specified protocol, we prospectively registered the study at PROSPERO, CRD42021215393.Results We included 72 trials with 7609 participants. 65 trials (n=5957) were eligible for the quantitative synthesis, investigating 29 pharmacological interventions. Oral non-steroidal anti-inflammatory drugs (NSAIDs) and oral glucocorticoids’ NMA effect sizes were −0.18 (95% credible interval −0.36 to 0.02) and −0.54 (−0.83 to −0.24), respectively, compared with placebo, and the result was consistent when limiting evidence to the pairwise meta-analysis of trials without high risk of bias. Intra-articular hyaluronate, intra-articular glucocorticoids, hydroxychloroquine, and topical NSAIDs’ NMA effect sizes were 0.22 (−0.08 to 0.51), 0.25 (0.00 to 0.51), −0.01 (−0.19 to 0.18), and −0.14 (−0.33 to 0.08), respectively, compared with placebo. Oral NSAIDs were inferior to oral glucocorticoids with an NMA effect size of 0.36 (0.01 to 0.72). No intervention was superior to placebo when stratifying for thumb and finger OA.Conclusion Oral NSAIDs and glucocorticoids are apparently effective pharmacological interventions in hand OA. Intra-articular therapies and topical NSAIDs were not superior to placebo.

Cerebrovascular disease (CVD) poses a major public health and socio-economic burden worldwide due to its high morbidity and mortality rates. Accurate assessment of cerebral arteries’ haemodynamic plays a crucial role in the diagnosis and treatment management of CVD. The study compared a non-imaging transcranial Doppler ultrasound (TCD) and transcranial color-coded Doppler ultrasound (with (cTCCD) and without (ncTCCD)) angle correction in quantifying middle cerebral arteries (MCAs) haemodynamic parameters. A cross-sectional study involving 50 healthy adults aged ≥ 18 years was conducted. The bilateral MCAs were insonated via three trans-temporal windows (TTWs—anterior, middle, and posterior) using TCD, cTCCD, and ncTCCD techniques. The MCA peak systolic velocity (PSV) and mean flow velocity (MFV) were recorded at proximal and distal imaging depths that could be visualised on TCCD with a detectable spectral waveform. A total of 152 measurements were recorded in 41 (82%) subjects with at least one-sided open TTW across the three techniques. The mean PSVs measured using TCD, ncTCCD, and cTCCD were 83 ± 18 cm/s, 81 ± 19 cm/s, and 93 ± 21 cm/s, respectively. There was no significant difference in PSV between TCD and ncTCCD (bias = 2 cm/s, p = 1.000), whereas cTCCD yielded a significantly higher PSV than TCD and ncTCCD (bias = −10 cm/s, p < 0.001; bias = −12 cm/s, p ≤ 0.001, respectively). The bias in MFV between TCD and ncTCCD techniques was (bias = −0.5 cm/s; p = 1.000), whereas cTCCD demonstrated a higher MFV compared to TCD and ncTCCD (bias = −8 cm/s, p < 0.001; bias = −8 cm/s, p ≤ 0.001, respectively). TCCD is a practically applicable imaging technique in assessing MCA blood flow velocities. cTCCD is more accurate and tends to give higher MCA blood flow velocities than non-imaging TCD and ncTCCD techniques. ncTCCD is comparable to non-imaging TCD and should be considered in clinical cases where using both TCD and TCCD measurements is needed.

High-strength, high-conductivity copper/silver-alloyed materials were prepared by cold-spray (CS) manufacturing. For DC high-field application at room temperature, bulk Cu/Ag (5% vol. Ag) alloys with high mechanical properties and high electrical conductivity can be obtained by CS and post-heat treatments. For pulsed-field application at liquid nitrogen temperature, bulk Cu/Ag (5% vol. Ag) alloys serve as precursors for room-temperature wire drawing. The Cu/Ag-alloyed bulk CS deposit presents a high yield strength of about 510 MPa with a corresponding electrical resistivity of 1.92 µΩ·cm (at 293 K). The Cu/Ag-alloyed wires show a very high ultimate tensile strength (1660 MPa at 77 K or 1370 MPa at 293 K) and low electrical resistivity (1.05 µΩ·cm at 77 K or 2.56 µΩ·cm at 293 K). Microstructural studies via STEM allow us to understand this very high level of mechanical strength. The results evidence that materials developed by CS exhibit very high mechanical properties compared to materials prepared by other routes, due to the high velocity of the deposited particles, which leads to high initial deformation rates and specific microstructural features.

Genomic structural variants (SVs) in cancer are notoriously difficult to identify, despite the impact they have on cancer progression and treatment efficacy. This study applies state-of-the-art computational methods to catalogue SVs in 383 cases of oesophageal cancer, uncovering mutational patterns and new disease drivers.

Almost half of all jobs in the San Francisco Bay Area are “remote-eligible” – more than any other metropolitan area in the United States, due to the high concentration of employees in the technology sector who were early to embrace teleworking at the start of the COVID-19 pandemic in early 2020. Any significant share of these tech workers staying remote may have profound long-term impacts on aggregate travel patterns in the region. This research seeks to predict the magnitude of these impacts and derive insights about the newly learned behaviors of tech workers, as indicative of remote-eligible workers in general.A survey of over 660 tech workers ran from November 2021 to March 2022, asking about participants’ employers and remote work policies, commute details and mode preferences, non-work trips, and interest in relocation.Respondents expected employer-driven hybrid arrangements of 2–3 days per week in the office after the pandemic, which in turn dictated the number of predicted future commuting trips and suppressed interest in relocation. Though almost half of respondents expressed interest in moving, they only planned to move a median of 20.93 miles – staying within the region but shifting away from their offices and towards less dense and more automobile-oriented suburban neighborhoods.Additionally, those moving more than ten miles from their office are likely to switch to less sustainable travel modes. On the other hand, robust observed retention of online shopping habits for groceries and food delivery may mitigate the added vehicle trips caused by rebound effects.

Digital interventions can increase physical activity (PA) levels in adults. However, the COVID-19 pandemic highlighted the complexities faced when guiding people to start or return to PA following illness or inactivity. A digital tool, Movement Foundations, was developed to provide remote guidance on building strength and capacity across functional movement patterns, with graduated progression based on user responses and input. This qualitative study aimed to explore the perceived impacts of using the tool. Nine participants aged over 35 years from the healthcare and academic healthcare sectors were recruited to use it and were subsequently interviewed. Thematic analysis identified three themes falling under the overarching concept of ‘Capability, Opportunity and Motivation—Behaviour (COM-B) Plus’, encompassing: skills and capacity for movement; opportunities, motivations and barriers for movement; and a personalised, safe space in which to develop. Participants felt that the digital tool increased their capacity and confidence in movement and positively impacted their daily activities. External factors such as illness and stress clouded perceptions of the impacts of PA. Time, work pressures and needing equipment were still considered significant barriers to PA. Still, participants appreciated the flexibility and non-prescriptive nature of the tool and felt that it helped movement to become opportunistic and habitual. Increased capacity for PA and feeling the subsequent physical and mental effects positively influenced motivation. Structure and guidance, with graduated progress, were seen as protective. Guided self-reflection helped participants understand their capacity and limitations with regard to movement and promoted motivation. Although acquiring technical skills to guide movement may be important for those recovering from illness, participants found that a structure promoting individualised guidance, graduated progression and guided self-reflection were important motivational factors for continuing use. Digital interventions should consider these aspects when seeking to promote habitual PA.