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Abstract Background Telemedicine provides specialized medical expertise in underserved areas where neurological expertise is frequently not available on a daily basis for hospitalized stroke patients. While tele-consultations are well established in acute stroke assessment, the value of telemedicine-based ward-rounds in the subsequent in-patient stroke management is unknown. Methods Four telemedicine stroke networks in Germany, implemented in eight out of 16 federal states, participate in this prospective observational multi-center study. We plan to enroll 523 patients hospitalized due to acute (suspected or confirmed) stroke or transient ischemic attack. Each recruited patient will receive both a tele-consultation and an on-site consultation at the same day within the first three days after hospital admission. We will test non-inferiority of telemedicine-based assessments in ward-rounds in terms of quality of medical assessment and recommendations for hospitalized stroke patients. The correctness of the medical assessment and recommendation is defined as positive evaluation (binary, correct vs. in-correct) of six out of six predefined quality indicators by at least two out of three blinded independent raters. The non-inferiority margin for the difference in proportions of correct assessments is set to 5%-points. Discussion If non-inferiority of telemedicine-based ward-rounds compared to on-site ward-rounds by a neurologist were demonstrated, telemedicine-based neurological consultation for post-acute stroke patients may contribute to deliver evidence-based high-quality stroke care more easily in underserved regions. Trial registration DRKS - DRKS00028671 ( https://drks.de/search/de/trial/DRKS00028671 ; registration date 09-27-2022).

Abstract Due to their potential impact on the host’s phenotype, organ-specific microbiotas are receiving increasing attention in several animal species, including cattle. Specifically, the vaginal microbiota of ruminants is attracting growing interest, due to its predicted critical role on cows’ reproductive functions in livestock contexts. Notably, fertility disorders represent a leading cause for culling, and additional research would help to fill relevant knowledge gaps. In the present study, we aimed to characterize the vaginal microbiota of a large cohort of 1171 female dairy cattle from 19 commercial herds in Northern France. Vaginal samples were collected using a swab and the composition of the microbiota was determined through 16S rRNA sequencing targeting the V3–V4 hypervariable regions. Initial analyses allowed us to define the core bacterial vaginal microbiota, comprising all the taxa observed in more than 90% of the animals. Consequently, four phyla, 16 families, 14 genera and a single amplicon sequence variant (ASV) met the criteria, suggesting a high diversity of bacterial vaginal microbiota within the studied population. This variability was partially attributed to various environmental factors such as the herd, sampling season, parity, and lactation stage. Next, we identified numerous significant associations between the diversity and composition of the vaginal microbiota and several traits related to host’s production and reproduction performance, as well as reproductive tract health. Specifically, 169 genera were associated with at least one trait, with 69% of them significantly associated with multiple traits. Among these, the abundances of Negativibacillus and Ruminobacter were positively correlated with the cows’ performances (i.e., longevity, production performances). Other genera showed mixed relationships with the phenotypes, such as Leptotrichia being overabundant in cows with improved fertility records and reproductive tract health, but also in cows with lower production levels. Overall, the numerous associations underscored the complex interactions between the vaginal microbiota and its host. Given the large number of samples collected from commercial farms and the diversity of the phenotypes considered, this study marks an initial step towards a better understanding of the intimate relationship between the vaginal microbiota and the dairy cow’s phenotypes.

Pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic cancer, is a deadly cancer, often diagnosed late and resistant to current therapies. PDAC patients are frequently affected by cachexia characterized by muscle mass and strength loss (sarcopenia) contributing to patient frailty and poor therapeutic response. This study assesses the mechanisms underlying mitochondrial remodeling in the cachectic skeletal muscle, through an integrative exploration combining functional, morphological, and omics-based evaluation of gastrocnemius muscle from KIC genetically engineered mice developing autochthonous pancreatic tumor and cachexia. Cachectic PDAC KIC mice exhibit severe sarcopenia with loss of muscle mass and strength associated with reduced muscle fiber’s size and induction of protein degradation processes. Mitochondria in PDAC atrophied muscles show reduced respiratory capacities and structural alterations, associated with deregulation of oxidative phosphorylation and mitochondrial dynamics pathways. Beyond the metabolic pathways known to be altered in sarcopenic muscle (carbohydrates, proteins, and redox), lipid and nucleic acid metabolisms are also affected. Although the number of mitochondria per cell is not altered, mitochondrial mass shows a twofold decrease and the mitochondrial DNA threefold, suggesting a defect in mitochondrial genome homeostasis. In conclusion, this work provides a framework to guide toward the most relevant targets in the clinic to limit PDAC-induced cachexia.

Abstract Background Stroke is a severe complication of infective endocarditis (IE), associated with high rates of mortality. Data on how IE patients with and without stroke differ may help to improve understanding contributing mechanisms. Methods All patients treated for IE between 2019 and 2021 with and without associated stroke were identified from the medical records of three academic tertiary care hospitals in Germany, all part of Charité – Universitätsmedizin Berlin, Germany. Multivariable logistic regression analyses were performed to identify variables associated with the occurrence of stroke. Results The study population consisted of 353 patients diagnosed with IE. Concomitant stroke occurred in 96/353 (27.2%) patients. Acute stroke was independently associated with co-occurring extracerebral arterial embolism [adjusted Odds ratio (aOR = 2.52; 95% confidence interval (CI) 1.35–4.71)], acute liver failure (aOR = 2.62; 95% CI 1.06–6.50), dental focus of infection (aOR = 3.14; 95% CI 1.21–8.12) and left-sided IE (aOR = 28.26; 95% CI 3.59-222.19). Stroke was found less often in IE patients with congenital heart disease (aOR = 0.20; 95% CI 0.04–0.99) and atypical pathogens isolated from blood culture (aOR = 0.31; 95% CI 0.14–0.72). Conclusions Stroke is more likely to occur in individuals with systemic complications affecting other organs, too. Special attention should be addressed to dental status. The low incidence of stroke in patients with congenital heart disease may reflect awareness and prophylactic measures.

Abstract Introduction Post-COVID-19 Syndrome (PCS) includes neurological manifestations, especially fatigue and cognitive deficits. Immune dysregulation, autoimmunity, endothelial dysfunction, viral persistence, and viral reactivation are discussed as potential pathophysiological mechanisms. The post-corona-virus immune treatment (PoCoVIT) trial is a phase 2a randomized, controlled, double-blind trial designed to evaluate the effect of methylprednisolone versus placebo on cognitive impairment in PCS. This trial is designed based on the hypothesised autoimmunological pathogenesis and positive aberrations, employing a series of off-label applications. Methods Recruitment criteria include a diagnosis of PCS, a minimum age of 18 years and self-reported cognitive deficits at screening. A total of 418 participants will be randomly assigned to either verum or placebo intervention in the first phase of the trial. The trial will consist of a first trial phase intervention with methylprednisolone versus placebo for six weeks, followed by a six-week treatment interruption period. Subsequently, an open second phase will offer methylprednisolone to all participants for six weeks. Outpatient follow-up visits will take place two weeks after each trial medication cessation. The third and final follow-up, at week 52, will be conducted through a telephone interview. The primary outcome measures an intra-patient change of 15 or more points in the memory satisfaction subscale of the Multifactorial Memory Questionnaire (MMQ) from baseline to follow-up 1 (week 8). Key secondary outcomes include long-term intra-patient changes in memory satisfaction from baseline to follow-up 2 (week 20), changes in other MMQ subscales (follow-up 1 and 2), and changes in neuropsychological and cognitive scores, along with assessments through questionnaires focusing on quality of life, fatigue, and mood over the same periods. Exploratory outcomes involve molecular biomarkers variations in serum and cerebrospinal fluid, as well as structural and functional brain magnetic resonance imaging (MRI) parameters changes related to cognition. Perspective This trial aims to contribute novel evidence for treating patients with PCS, with a primary focus on those manifesting cognitive deficits. By doing so, it may enhance comprehension of the underlying pathophysiological mechanisms, thereby facilitating biomarker research to advance our understanding and treatment of patients with PCS.

The performance of dairy cows is influenced by the microbial communities hosted within their digestive tract. While the rumen microbiota has long been associated with host phenotypes, the impact of the faecal microbiota remains elusive. In this study, we collected 697 faecal samples from commercial Holstein cows and analysed them with 16S rRNA gene analyses. For each animal, routinely recorded data, i.e., milk yield, fat yield, protein yield, fat content, protein content, and an aggregate production trait (pINEL) based on the French economic dairy index, were available to assess the links between the faecal microbiota and host production. Our findings revealed a strong and significant association between the structure of the bacterial and prokaryote community (β-diversity) and dairy production. In addition, differential abundance analyses identified 48 genera whose abundances were significantly associated with pINEL, milk, fat and protein yield. Among these genera, the increased abundance of Bifidobacterium, and particularly an amplicon sequence variant with a 16S rRNA V3-V4 gene region identical to B. globosum and B. pseudolongum, was found to be the most important for high-yielding animals. Bifidobacterium seemed to be a potential key member of the bovine faecal microbiota that should be further investigated. Conversely, the p-1088-a5 gut group genus was found more abundant in low-productive cows. In conclusion, this study demonstrates significant associations between the faecal microbiota and the performance of dairy cows at the whole lactation scale. A better understanding of the physiology of the gut microbiota could help to improve dairy cow production.

BackgroundOne of the first clinical observations of ibrutinib activity in the treatment of chronic lymphocytic leukemia (CLL) is a rapid decline in lymph nodes size. This phenomenon is accompanied by an hyperlymphocytosis, either transient or prolonged, which is associated with distinct clinical responses and thus has an impact on long-term outcomes. Understanding which factors determine distinct disease courses upon ibrutinib treatment remains a scientific challenge.Methods and findingsFrom 2016 to 2021, we conducted a longitudinal and observational study in 2 cohorts of patients with chronic lymphocytic leukemia (CLL) (cohort 1, n = 41; cohort 2, n = 81). These cohorts reflect the well-known clinical features of CLL patients, such as Male/Female sex ratio of 2/1, a median age of 70 years at diagnosis, and include patients in first-line therapy (27%) or relapsed/refractory patients (73%). Blood cell counts were followed for each patient during 2 years of ibrutinib treatment. In addition, immunophenotyping and whole-body magnetic resonance imaging (MRI) were assessed in patients from cohort 1. These data were integrated in a newly built mathematical model, inspired by previous mathematical works on CLL treatment and combining dynamical and statistical models, leading to the identification of biological mechanisms associated with the 2 types of clinical responses. This multidisciplinary approach allowed to identify baseline parameters that dictated lymphocytes kinetics upon ibrutinib treatment. Indeed, ibrutinib-induced lymphocytosis defined 2 CLL patient subgroups, transient hyperlymphocytosis (tHL) or prolonged hyperlymphocytosis (pHL), that can be discriminated, before the treatment, by absolute counts of CD4+ T lymphocytes (p = 0.026) and regulatory CD4 T cells (p = 0.007), programmed cell death protein 1 PD1 (p = 0.022) and CD69 (p = 0.03) expression on B leukemic cells, CD19/CD5high/CXCR4low level (p = 0.04), and lymph node cellularity. We also pinpointed that the group of patients identified by the transient hyperlymphocytosis has lower duration response and a poor clinical outcome. The mathematical approach led to the reproduction of patient-specific dynamics and the estimation of associated patient-specific biological parameters, and highlighted that the differences between the 2 groups were mainly due to the production of leukemic B cells in lymph node compartments, and to a lesser extent to T lymphocytes and leukemic B cell egress into bloodstream. Access to additional data, especially longitudinal MRI data, could strengthen the conclusions regarding leukemic B cell dynamics in lymph nodes and the relevance of 2 distinct groups of patients.ConclusionsAltogether, our multidisciplinary study provides a better understanding of ibrutinib response and highlights new pharmacodynamic parameters before and along ibrutinib treatment. Since our results highlight a reduced duration response and outcome in patients with transient hyperlymphocytosis, our approach provides support for managing ibrutinib therapy after 3 months of treatment.Trial registrationClinicalTrials.gov NCT02824159.

Background and Aims: Data on the prevalence and characteristics of so-called rare HCV genotypes (GTs) in larger cohorts is limited. This study investigates the frequency of rare GT and resistance-associated substitutions and the efficacy of retreatment in a European cohort. Methods: A total of 129 patients with rare GT1-6 were included from the European resistance database. NS3, NS5A, and NS5B were sequenced and clinical parameters and retreatment efficacies were collected retrospectively. Results: Overall 1.5% (69/4,656) of direct-acting antiviral (DAA)-naive and 4.4% (60/1,376) of DAA-failure patients were infected with rare GT. Although rare GTs were almost equally distributed throughout GT1-6 in DAA-naive patients, we detected mainly rare GT4 (47%, 28/60 GT4; of these n = 17, subtype 4r) and GT3 (25%, 15/60 GT3, of these n = 8, subtype 3b) among DAA-failures. A total of 62% (37/60) of DAA failures had not responded to first-generation regimes and the majority was infected with rare GT4 (57%, 21/37). In contrast, among patients with failure to pangenotypic DAA regimens (38%, 23/60), infections with rare GT3 were overrepresented (57%, 13/23). Although NS5A RASs were uncommon in rare GT2, GT5a, and GT6, we observed combined RASs in rare GT1, GT3, and GT4 at positions 28, 30, 31, which can be considered as inherent. DAA failures with completed follow-up of retreatment, achieved a high SVR rate (94%, 45/48 modified intention-to-treat analysis; 92%, 45/49 intention-to-treat). Three patients with GT4f, 4r, or 3b, respectively, had virological treatment failure. Conclusions: In this European cohort, rare HCV GT were uncommon. Accumulation of specific rare GT in DAA-failure patients suggests reduced antiviral activities of DAA regimens. The limited global availability of pangenotypic regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed. Impact and implications: Data on the prevalence and characteristics of rare HCV genotypes (GT) in larger cohorts are still scarce. This study found low rates of rare HCV GTs among European HCV-infected patients. In direct-acting antiviral (DAA)-failure patients, rare GT3 subtypes accumulated after pangenotypic DAA treatment and rare GT4 after first generation DAA failure and viral resistance was detected at NS5A positions 28, 30, and 31. The limited global availability of pangenotypic DAA regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed.

Abstract We find that NUPR1, a stress-associated intrinsically disordered protein, induced droplet formation via liquid–liquid phase separation (LLPS). NUPR1-driven LLPS was crucial for the creation of NUPR1-dependent stress granules (SGs) in pancreatic cancer cells since genetic or pharmacological inhibition by ZZW-115 of NUPR1 activity impeded SGs formation. The KrasG12D mutation induced oncogenic stress, NUPR1 overexpression, and promoted SGs development. Notably, enforced NUPR1 expression induced SGs formation independently of mutated KrasG12D. Mechanistically, KrasG12D expression strengthened sensitivity to NUPR1 inactivation, inducing cell death, activating caspase 3 and releasing LDH. Remarkably, ZZW-115-mediated SG-formation inhibition hampered the development of pancreatic intraepithelial neoplasia (PanINs) in Pdx1-cre;LSL-Kras G12D (KC) mice. ZZW-115-treatment of KC mice triggered caspase 3 activation, DNA fragmentation, and formation of the apoptotic bodies, leading to cell death, specifically in KrasG12D-expressing cells. We further demonstrated that, in developed PanINs, short-term ZZW-115 treatment prevented NUPR1-associated SGs presence. Lastly, a four-week ZZW-115 treatment significantly reduced the number and size of PanINs in KC mice. This study proposes that targeting NUPR1-dependent SGs formation could be a therapeutic approach to induce cell death in KrasG12D-dependent tumors.

Enhancing food security in the Sahel through nature-based solutions is urgent given population growth, resource scarcity and climate change. Traditional agroforestry parklands are a farmer- and nature-based widespread form of ecological intensification which randomly integrates trees into crop fields. While most studies estimating crop yields in agroforestry have been conducted in controlled experimental settings, few have addressed the inherent variability in such highly heterogeneous systems. Thus, the purpose of this study is to benefit from a UAV-based proxy-sensing and machine learning approach to address the variability of pearl millet grain yield, according to the distance to randomly distributed trees in a traditional agroforestry system dominated by Faidherbia albida (i.e. groundnut basin of Senegal). 21 vegetation indices (VIs), 32 normalized difference texture indices (NDTIs) derived from multispectral drone images, and normalization variables for radiative conditions were used with yield data collected in 15 plots (around 1 ha each) and subplots ( $15~m^{2} $ each) displayed at 3 distances from the tree over five cropping seasons (2018–2022). In this context, the optimal phenological stage was determined for predicting pearl millet grain yield, which proved to be the pre-heading period. This period was used as the basis for our machine learning model training dataset in the subplots. Two models, Random Forest (RF) and Gradient Boosting Machine (GBM) were compared by combining VIs, NDTIs and normalization variables. GBM was the best-performing model, explaining 78% of observed pearl millet yield variability over five years in the subplots, with a RMSE of 16 g. $m^{-2} $ . This study revealed that NDTIs calculated from red and green bands were more influential for yield estimation than those based on near-infrared. These results were subsequently used to predict yield in all plots, resulting in a mean relative error of 17.5% between yields estimated by the farmers and GBM-estimated yields. This approach represents a pathway to assessing the withinfield yield variability in highly heterogeneous agroforestry plots and to demonstrate, quantify and optimize tree benefits for ecological intensification.

In recent decades, remote sensing has been shown to be useful for crop cover monitoring over smallholder agricultural landscapes, such as agroforestry parklands. However, the fraction of green vegetation cover (FCover) has received little attention. Indeed, the collection of FCover ground data representative of the within-field heterogeneity is time-consuming. Thus, this article aims to bridge this gap by proposing an original methodological framework combining FCover data derived from unmanned aerial vehicle (UAV) and Sentinel-2 (S2) images for estimating millet FCover at the landscape scale in an agroforestry parkland of the groundnut basin of Senegal during the 2021 and 2022 cropping seasons. UAV-based FCover was computed over a 3 m × 3 m grid using a thresholding approach for six dates over the cropping seasons and then used as ground observation for the upscaling of millet FCover at the landscape scale with S2 data. Various spectral vegetation indices and textural features were derived from S2, and several modeling approaches based on machine learning algorithms were benchmarked. Our results showed that the modeling approach using the full-time series in combination with a random forest algorithm was able to explain 73% (root mean square error = 12.13%) of the UAV-FCover variability after validation in 2021 and 2022. In addition, UAV images are suitable for consistent monitoring of millet FCover over heterogeneous agricultural landscapes by training S2 satellite images. To further check its robustness, this approach should be tested for different crops and practices across a variety of agricultural landscapes in sub-Saharan Africa.

Background Sex differences in presentation, treatment, and prognosis of cardiovascular disorders are well recognized. Although an association between acute myocardial injury and mortality after ischemic stroke has been demonstrated, it is unclear whether prevalence and outcome of poststroke acute myocardial injury differ between women and men. Methods and Results We prospectively screened consecutive patients with acute ischemic stroke and serial high‐sensitivity cardiac troponin T measurements admitted to our center. Acute myocardial injury was defined as at least 1 high‐sensitivity cardiac troponin T value above the upper reference limit (14 ng/L) with a rise/fall of >20%. Rates of acute myocardial injury were also calculated using sex‐specific high‐sensitivity cardiac troponin T cutoffs (women upper reference limit, 9 ng/L; men upper reference limit, 16 ng/L). Logistic regression analyses were performed to evaluate the association between acute myocardial injury and outcomes. Of 1067 patients included, 494 were women (46%). Women were older, had a higher rate of known atrial fibrillation, were more likely to be functionally dependent before admission, had higher stroke severity, and more often had cardioembolic strokes (all P values

Pancreatic ductal adenocarcinoma (PDA) tumor cells are deprived of oxygen and nutrients and therefore must adapt their metabolism to ensure proliferation. In some physiological states, cells rely on ketone bodies to satisfy their metabolic needs, especially during nutrient stress. Here, we show that PDA cells can activate ketone body metabolism and that β-hydroxybutyrate (βOHB) is an alternative cell-intrinsic or systemic fuel that can promote PDA growth and progression. PDA cells activate enzymes required for ketogenesis, utilizing various nutrients as carbon sources for ketone body formation. By assessing metabolic gene expression from spontaneously arising PDA tumors in mice, we find HMG-CoA lyase (HMGCL), involved in ketogenesis, to be among the most deregulated metabolic enzymes in PDA compared to normal pancreas. In vitro depletion of HMGCL impedes migration, tumor cell invasiveness, and anchorage-independent tumor sphere compaction. Moreover, disrupting HMGCL drastically decreases PDA tumor growth in vivo, while βOHB stimulates metastatic dissemination to the liver. These findings suggest that βOHB increases PDA aggressiveness and identify HMGCL and ketogenesis as metabolic targets for limiting PDA progression.