Search

Adverse drug events (ADEs) occur frequently and are a common cause of suffering, hospitalizations, or death, and can be caused by harmful combinations of medications. One method used to prevent ADEs is by using clinical decision support systems (CDSSs). Janusmed Risk Profile is a CDSS evaluating the risk for nine common or serious ADEs resulting from combined pharmacodynamic effects. The aim of this study was to examine the prevalence of potential ADEs identified using CDSS algorithms from Janusmed Risk Profile. This retrospective, cross-sectional study covered the population of a Swedish region (n = 246,010 inhabitants in year 2020) using data on all medications dispensed and administered. More than 20% of patients had an increased risk of bleeding, constipation, orthostatism, or renal toxicity based on their medications. The proportion of patients with an increased risk varied from 3.5% to almost 30% across the nine categories of ADEs. A higher age was associated with an increased risk of potential ADEs and there were gender differences. A cluster analysis identified groups of patients with an increased risk for several categories of ADEs. This study shows that combinations of medications that could increase the risk of ADEs are common. Future studies should examine how this correlates with observed ADEs.

Acute respiratory distress syndrome (ARDS) is a potential life-threatening, heterogenous, inflammatory lung disease. There are no data available on potential drug–drug interactions (pDDIs) in critically ill patients with ARDS. This study analyzed pDDIs in this specific cohort and aimed to investigate possible associations of coronavirus disease 2019 (COVID-19) as an underlying cause of ARDS and treatment with extracorporeal membrane oxygenation (ECMO) with the occurrence of pDDIs. This retrospective study included patients ≥18 years of age diagnosed with ARDS between January 2010 and September 2021. The Janusmed database was used for the identification of pDDIs. A total of 2694 pDDIs were identified in 189 patients with a median treatment duration of 22 days. These included 323 (12%) clinically relevant drug combinations that are best avoided, corresponding to a median rate of 0.05 per day. There was no difference in the number of pDDIs between COVID-19- and non-COVID-19-associated ARDS. In patients treated with ECMO, the rate of the most severely graded pDDIs per day was significantly higher compared with those who did not require ECMO. PDDIs occur frequently in patients with ARDS. On average, each patient may encounter at least one clinically relevant drug combination that should be avoided during their intensive care unit stay.

Abstract Background PHARAO is a decision support system developed to evaluate the risk for a set of either common or serious side-effects resulting from a combination of pharmacodynamic effects from a patient’s medications. The objective of this study was to investigate the validity of the risk scores for the common side-effects generated by PHARAO in older patients. Methods Side-effects included were sedation, constipation, orthostatic symptoms, anticholinergic and serotonergic effects. The alerts generated by PHARAO were tested in 745 persons ≥65 years old. Dispensed prescriptions retrieved from the Swedish prescribed drug register were used to generate the pharmacological risk scores of patients’ medications. Symptoms possibly related to side-effects were extracted from medical records data. Results The PHARAO system generated 776 alerts, most often for the risk of anticholinergic symptoms. The total specificity estimates of the PHARAO system were 0.95, 0.89 and 0.78 for high, intermediate and low risk alerts, respectively. The corresponding sensitivity estimates were between 0.12 and 0.37. The negative predictive value was 0.90 and the positive predictive value ranged between 0.20–0.25. Conclusions The PHARAO system had a high specificity and negative predictive value to detect symptoms possibly associated with the of patients’ medications, while the sensitivity and positive predictive value were low. The PHARAO system has the potential to minimise the risk of over-alerts in combination with a drug-drug interaction alert system, but should be used in connection with a medical evaluation of the patient.

Psycho-emotional state of youth in the COVID-19 pandemic can become an indicator of various positive or negative social transformations and trends. The purpose of the study is to determine the influence of socio-demographic factors (gender, age, year of study, the direction of professional training at university, combining study and work, living in a rural area or a city, in a private house or an apartment, with parents or independently) in conditions of self-isolation on assessment of the main components of the psycho-emotional state of the students: well-being, activity, and mood. We used the method of rapid well-being, activity, and mood assessment. The test was conducted online; the relevant materials were posted on eCampus of North Caucasus Federal University educational portal. The research results analysis was based on Kruskal Wallice H-test, the primary frequency analysis, analysis of average scale values and standard deviations for the comparison groups. The study was conducted from April 13 to May 22, 2020, and involved 1,173 students aged 17 to 36 years, enrolled in 1-5 years. The study suggests that the psycho-emotional state of students in the self-isolation period depends on their age: the younger the students are, the more likely they are to experience fatigue and decline in well-being, activity, mood. The study provided new data on the features of integrated assessments of students’ well-being, activity, and mood in conditions of forced self-isolation due to the COVID-19 pandemic.

Objective: Maintenance of glucose homeostasis requires the precise regulation of hormone secretion from the endocrine pancreas. Free fatty acid receptor 4 (FFAR4/GPR120) is a G protein-coupled receptor whose activation in islets of Langerhans promotes insulin and glucagon secretion and inhibits somatostatin secretion. However, the contribution of individual islet cell types (α, β, and δ cells) to the insulinotropic and glucagonotropic effects of GPR120 remains unclear. As gpr120 mRNA is enriched in somatostatin-secreting δ cells, we hypothesized that GPR120 activation stimulates insulin and glucagon secretion via inhibition of somatostatin release. Methods: Glucose tolerance tests were performed in mice after administration of selective GPR120 agonist Compound A. Insulin, glucagon, and somatostatin secretion were measured in static incubations of isolated mouse islets in response to endogenous (ω-3 polyunsaturated fatty acids) and/or pharmacological (Compound A and AZ-13581837) GPR120 agonists. The effect of Compound A on hormone secretion was tested further in islets isolated from mice with global or somatostatin cell-specific knock-out of gpr120. Gpr120 expression was assessed in pancreatic sections by RNA in situ hybridization. Cyclic AMP (cAMP) and calcium dynamics in response to pharmacological GPR120 agonists were measured specifically in α, β, and δ cells in intact islets using cAMPER and GCaMP6 reporter mice, respectively. Results: Acute exposure to Compound A increased glucose tolerance, circulating insulin, and glucagon levels in vivo. Endogenous and/or pharmacological GPR120 agonists reduced somatostatin secretion in isolated islets and concomitantly demonstrated dose-dependent potentiation of glucose-stimulated insulin secretion and arginine-stimulated glucagon secretion. Gpr120 was enriched in δ cells. Pharmacological GPR120 agonists reduced cAMP and calcium levels in δ cells but increased these signals in α and β cells. Compound A-mediated inhibition of somatostatin secretion was insensitive to pertussis toxin. The effect of Compound A on hormone secretion was completely absent in islets from mice with either global or somatostatin cell-specific deletion of gpr120 and partially reduced upon blockade of somatostatin receptor signaling by cyclosomatostatin. Conclusions: Inhibitory GPR120 signaling in δ cells contributes to both insulin and glucagon secretion in part by mitigating somatostatin release.

Innate immunity is critical in the early containment of influenza A virus (IAV) infection and surfactant protein D (SP-D) plays a crucial role in innate defense against IAV in the lungs. Multivalent lectin-mediated interactions of SP-D with IAVs result in viral aggregation, reduced epithelial infection, and enhanced IAV clearance by phagocytic cells. Previous studies showed that porcine SP-D (pSP-D) exhibits distinct antiviral activity against IAV as compared to human SP-D (hSP-D), mainly due to key residues in the lectin domain of pSP-D that contribute to its profound neutralizing activity. These observations provided the basis for the design of a full-length recombinant mutant form of hSP-D, designated as “improved SP-D” (iSP-D). Inspired by pSP-D, the lectin domain of iSP-D has 5 amino acids replaced (Asp324Asn, Asp330Asn, Val251Glu, Lys287Gln, Glu289Lys) and 3 amino acids inserted (326Gly-Ser-Ser). Characterization of iSP-D revealed no major differences in protein assembly and saccharide binding selectivity as compared to hSP-D. However, hemagglutination inhibition measurements showed that iSP-D expressed strongly enhanced activity compared to hSP-D against 31 different IAV strains tested, including (pandemic) IAVs that were resistant for neutralization by hSP-D. Furthermore, iSP-D showed increased viral aggregation and enhanced protection of MDCK cells against infection by IAV. Importantly, prophylactic or therapeutic application of iSP-D decreased weight loss and reduced viral lung titers in a murine model of IAV infection using a clinical isolate of H1N1pdm09 virus. These studies demonstrate the potential of iSP-D as a novel human-based antiviral inhalation drug that may provide immediate protection against or recovery from respiratory (pandemic) IAV infections in humans.

Janusmed interactions is a drug-drug interactions (DDI) database available online for healthcare professionals (HCP) at all levels of the healthcare system including pharmacies. The database is aimed at HCP but is also open to the public for free, for those individuals who register for a personal account. The aim of this study was to investigate why and how patients use the database Janusmed interactions, how they perceive content and usability, and how they would react if they found an interaction. A web-based questionnaire was sent by email to all users who had registered for Janusmed interactions as a “patient” (n = 3219). A total of 406 patients completed the survey (response rate 12.6%). The study shows that there is an interest among patients to use a DDI database to check their own or a relative’s medication. The respondents found the database easy to use and perceive they understand the information aimed at HCP. Most patients stated they would talk to their HCP if they found an interaction and not adjust their treatment by themselves. However, the respondents in this study are actively searching for information and seem to have high health literacy. Thus, the findings are not generalizable for the general population.

AimsTramadol, a widely used analgesic drug, inhibits the reuptake of noradrenaline and serotonin impairing the aggregation function of thrombocytes. However, the risk for severe bleeding has previously not been studied. The aim of the present study is to investigate the association between tramadol and bleeding peptic ulcer in the Swedish population.MethodsIn this register based case-control study based on the Swedish national patient registry and prescription drug registry, we included 18 306 patients hospitalized with a first-time diagnosis of bleeding peptic ulcer. For every case, 4 matched controls were included. To investigate the temporal aspects of tramadol induced bleeding ulcer, exposure was divided into patients with newly initiated and ongoing treatment. To explore a possible confounding by indication, the effect of codeine, a drug also prescribed for the treatment of moderate pain, but not known to affect thrombocyte function, was investigated. Univariable and multivariable logistic regression was used to analyse the association between tramadol use and bleeding ulcer.ResultsTramadol was associated with an increased risk of bleeding ulcer (adjusted odds ratio (aOR) 2.1, 95% confidence interval: (2.0-2.3). The association was stronger for newly initiated treatment with tramadol 2.8 (2.5-3.2) and weaker for ongoing treatment 1.7 (1.6-1.9). Codeine was also associated with an increased risk of bleeding ulcer 1.9 (1.7-2.1) and this association was also stronger for newly initiated treatment with codeine 2.3 (2.0-2.6) and weaker for ongoing treatment 1.7 (1.5-1.9).ConclusionTreatment with tramadol was associated with an increased risk of bleeding peptic ulcer. Most of this association may be mediated by factors related to the pain condition rather than the pharmacologic effect per se.

Dengue virus (DENV) is the leading cause of mosquito-borne viral illness and death in humans. Like many viruses, DENV has evolved potent mechanisms that abolish the antiviral response within infected cells. Nevertheless, several in vivo studies have demonstrated a key role of the innate immune response in controlling DENV infection and disease progression. Here, we report that sensing of DENV infected cells by plasmacytoid dendritic cells (pDCs) triggers a robust TLR7-dependent production of IFNα, concomitant with additional antiviral responses, including inflammatory cytokine secretion and pDC maturation. We demonstrate that unlike the efficient cell-free transmission of viral infectivity, pDC activation depends on cell-to-cell contact, a feature observed for various cell types and primary cells infected by DENV, as well as West Nile virus, another member of the Flavivirus genus. We show that the sensing of DENV infected cells by pDCs requires viral envelope protein-dependent secretion and transmission of viral RNA. Consistently with the cell-to-cell sensing-dependent pDC activation, we found that DENV structural components are clustered at the interface between pDCs and infected cells. The actin cytoskeleton is pivotal for both this clustering at the contacts and pDC activation, suggesting that this structural network likely contributes to the transmission of viral components to the pDCs. Due to an evolutionarily conserved suboptimal cleavage of the precursor membrane protein (prM), DENV infected cells release uncleaved prM containing-immature particles, which are deficient for membrane fusion function. We demonstrate that cells releasing immature particles trigger pDC IFN response more potently than cells producing fusion-competent mature virus. Altogether, our results imply that immature particles, as a carrier to endolysosome-localized TLR7 sensor, may contribute to regulate the progression of dengue disease by eliciting a strong innate response.

PURPOSE: To investigate the extent to which clinicians avoid well-established drug-drug interactions associated with warfarin. We hypothesised that clinicians would avoid combining non-steroidal anti-inflammatory drugs (NSAIDs), tramadol and sulfamethoxazole with warfarin. METHODS: A cross-sectional analysis of nationwide dispensing data was performed in Swedish individuals 18 years or older (n = 7,563,649). Odds ratios of interacting NSAIDs, tramadol and sulfamethoxazole versus respective prevalence of comparator drugs codeine, and ciprofloxacin in patients co-dispensed interacting warfarin versus patients unexposed was calculated. RESULTS: The odds of receiving an interacting NSAID versus the comparator codeine was markedly lower in patients with warfarin than in the remaining population (adjusted OR 0.21; 95% CI 0.20 - 0.22). Also, the interacting drugs tramadol and sulfamethoxazole were less common among patients dispensed warfarin as compared to the remaining population, although the decrease was much more modest (adjusted OR 0.83; CI 0.80-0.87 and 0.81; CI 0.73 - 0.90). CONCLUSIONS: In conclusion, Swedish doctors in the vast majority of cases refrain from prescribing NSAIDs to patients already on warfarin. Tramadol and sulfamethoxazole are however rarely avoided.

Zinc-α2-glycoprotein (ZAG), a potent cachectic factor, is increased in patients undergoing maintenance dialysis. However, there is no data for patients before initiation of renal replacement therapy. The purpose of the present study was to assess the relationship between plasma ZAG concentration and renal function in patients with a large range of glomerular filtration rate (GFR). Plasma ZAG concentration and its relationship to GFR were investigated in 71 patients with a chronic kidney disease (CKD) stage 1 to 5, 17 chronic hemodialysis (HD), 8 peritoneal dialysis (PD) and 18 non-CKD patients. Plasma ZAG concentration was 2.3-fold higher in CKD stage 5 patients and 3-fold higher in HD and PD patients compared to non-CKD controls (P

Dendritic cells express lectins receptors, like DC-SIGN, which allow these cells to sense glycans that are present on various bacterial and viral pathogens. Interaction of DC-SIGN with carbohydrate moieties induces maturation of dendritic cells and promotes endocytosis of pathogens which is an important property of these professional antigen presenting cells. Uptake of pathogens by dendritic cells may lead to cross-presentation of antigens or infection of these cells, which ultimately results in activation of virus-specific T cells in draining lymph nodes. Little is known about the interaction of DC-SIGN with influenza A viruses. Here we show that a virus with a non-functional receptor binding site in its hemagglutinin, can replicate in cells expressing DC-SIGN. Also in the absence of sialic acids, which is the receptor for influenza A viruses, these viruses replicate in DC-SIGN expressing cells including human dendritic cells. Furthermore, the efficiency of DC-SIGN mediated infection is dependent on the extent of glycosylation of the viral hemagglutinin.

The emergence of influenza viruses resistant to existing classes of antiviral drugs raises concern and there is a need for novel antiviral agents that could be used therapeutically or prophylacticaly. Surfactant protein D (SP-D) belongs to the family of C-type lectins which are important effector molecules of the innate immune system with activity against bacteria and viruses, including influenza viruses. In the present study we evaluated the potential of recombinant porcine SP-D as an antiviral agent against influenza A viruses (IAVs) in vitro. To determine the range of antiviral activity, thirty IAVs of the subtypes H1N1, H3N2 and H5N1 that originated from birds, pigs and humans were selected and tested for their sensitivity to recombinant SP-D. Using these viruses it was shown by hemagglutination inhibition assay, that recombinant porcine SP-D was more potent than recombinant human SP-D and that especially higher order oligomeric forms of SP-D had the strongest antiviral activity. Porcine SP-D was active against a broad range of IAV strains and neutralized a variety of H1N1 and H3N2 IAVs, including 2009 pandemic H1N1 viruses. Using tissue sections of ferret and human trachea, we demonstrated that recombinant porcine SP-D prevented attachment of human seasonal H1N1 and H3N2 virus to receptors on epithelial cells of the upper respiratory tract. It was concluded that recombinant porcine SP-D holds promise as a novel antiviral agent against influenza and further development and evaluation in vivo seems warranted.

ObjectiveMaintenance of glucose homeostasis requires the precise regulation of hormone secretion from the endocrine pancreas. Free fatty acid receptor 4 (FFAR4/GPR120) is a G protein-coupled receptor whose activation in islets of Langerhans promotes insulin and glucagon secretion and inhibits somatostatin secretion. However, the contribution of individual islet cell types (α, β, and δ cells) to the insulinotropic and glucagonotropic effects of GPR120 remains unclear. As gpr120 mRNA is enriched in somatostatin-secreting δ cells, we hypothesized that GPR120 activation stimulates insulin and glucagon secretion via inhibition of somatostatin release.MethodsGlucose tolerance tests were performed in mice after administration of selective GPR120 agonist Compound A. Insulin, glucagon, and somatostatin secretion were measured in static incubations of isolated mouse islets in response to endogenous (ω-3 polyunsaturated fatty acids) and/or pharmacological (Compound A and AZ-13581837) GPR120 agonists. The effect of Compound A on hormone secretion was tested further in islets isolated from mice with global or somatostatin cell-specific knock-out of gpr120. Gpr120 expression was assessed in pancreatic sections by RNA in situ hybridization. Cyclic AMP (cAMP) and calcium dynamics in response to pharmacological GPR120 agonists were measured specifically in α, β, and δ cells in intact islets using cAMPER and GCaMP6 reporter mice, respectively.ResultsAcute exposure to Compound A increased glucose tolerance, circulating insulin, and glucagon levels in vivo. Endogenous and/or pharmacological GPR120 agonists reduced somatostatin secretion in isolated islets and concomitantly demonstrated dose-dependent potentiation of glucose-stimulated insulin secretion and arginine-stimulated glucagon secretion. Gpr120 was enriched in δ cells. Pharmacological GPR120 agonists reduced cAMP and calcium levels in δ cells but increased these signals in α and β cells. Compound A-mediated inhibition of somatostatin secretion was insensitive to pertussis toxin. The effect of Compound A on hormone secretion was completely absent in islets from mice with either global or somatostatin cell-specific deletion of gpr120 and partially reduced upon blockade of somatostatin receptor signaling by cyclosomatostatin.ConclusionsInhibitory GPR120 signaling in δ cells contributes to both insulin and glucagon secretion in part by mitigating somatostatin release.

Adverse drug events (ADEs) occur frequently and are a common cause of suffering, hospitalizations, or death, and can be caused by harmful combinations of medications. One method used to prevent ADEs is by using clinical decision support systems (CDSSs). Janusmed Risk Profile is a CDSS evaluating the risk for nine common or serious ADEs resulting from combined pharmacodynamic effects. The aim of this study was to examine the prevalence of potential ADEs identified using CDSS algorithms from Janusmed Risk Profile. This retrospective, cross-sectional study covered the population of a Swedish region (n = 246,010 inhabitants in year 2020) using data on all medications dispensed and administered. More than 20% of patients had an increased risk of bleeding, constipation, orthostatism, or renal toxicity based on their medications. The proportion of patients with an increased risk varied from 3.5% to almost 30% across the nine categories of ADEs. A higher age was associated with an increased risk of potential ADEs and there were gender differences. A cluster analysis identified groups of patients with an increased risk for several categories of ADEs. This study shows that combinations of medications that could increase the risk of ADEs are common. Future studies should examine how this correlates with observed ADEs. [ABSTRACT FROM AUTHOR]

Abstract Primary antiphospholipid syndrome (PAPS) is a life-threatening clotting disorder mediated by pathogenic autoantibodies. Here we dissect the origin of self-reactive B cells in human PAPS using peripheral blood and bone marrow of patients with triple-positive PAPS via combined single-cell RNA sequencing, B cell receptors (BCR) repertoire profiling, CITEseq analysis and single cell immortalization. We find that antiphospholipid (aPL)-specific B cells are present in the naive compartment, polyreactive, and derived from the natural repertoire. Furthermore, B cells with aPL specificities are not eliminated in patients with PAPS, persist until the memory and long-lived plasma cell stages, likely after defective germinal center selection, while becoming less polyreactive. Lastly, compared with the non-PAPS cells, PAPS B cells exhibit distinct IFN and APRIL signature as well as dysregulated mTORC1 and MYC pathways. Our findings may thus elucidate the survival mechanisms of these autoreactive B cells and suggest potential therapeutic targets for the treatment of PAPS.

Abstract Summer 2022 was exceptionally hot and dry in Europe and especially in Southwest France, where the most important wildfires since 1949 had serious environmental and socio-economic impacts. Here we conduct an impact-oriented climate change attribution study by first investigating which climate indices are the most correlated with the burnt area between 2003 and 2022. We find that an index combining soil moisture integrated over 6 months and temperature and vapour pressure deficit integrated over 3 months is correlated with large burnt areas. Using the index developed, we estimate that anthropogenic climate change made climate conditions propitious for wildfire development, such as the ones of July 2022, two times more likely, with a return period of 13 years in the current climate. Our study raises the question of the sustainability of the Landes Forest and stresses the urgent need to mitigate greenhouse gas emissions and adapt to climate change.

Abstract The aim of this work was to develop an experimental protocol that takes into account the influence of experimental conditions on these perineal tissues, before determining their mechanical properties. Samples of each perineal tissue layer were obtained from the skin, the vagina, the external anal sphincter (EAS), the internal anal sphincter (IAS) and anal mucosa of freshly dead sows. They were tested in quasi-static uniaxial tension using the Mach-1 testing machine. Stress-strain curves of each perineal tissue layer before the first damage for each sow were obtained and modeled by hyperelastic laws described by three coefficients: C1, C2, and C3 (Yeoh model). The influence of sample preparation conditions such as tissue freezing, hygrometry and sample orientation were evaluated, and the conditions under which the tests were performed such as the displacement velocity during testing were also evaluated by analysing C1-coefficient. This study suggested that sample preparation conditions such as tissue freezing for 24 h, storage in cellophane paper for two hours and the strain rate did not statistically affect the C1-hyperelastic coefficient for each perineal layer (p > 0.05). Samples should not be stored in saline for 2 h (p 0.05). This experimental protocol could be used to study in vitro biomechanical properties of perineal tissues in order to better understand perineal tears during delivery.

Abstract Background Effective physician-patient communication is crucial to compassionate healthcare, particularly when conveying life-altering diagnoses such as those associated with congenital heart diseases. Despite its importance, medical practitioners often face challenges in communicating effectively. Because of these gaps, we aim to introduce a simulation-based training protocol to improve pediatric cardiology trainee’s communication skills. This study will be conducted in collaboration with associations supporting caregivers of children with congenital heart disease. It strives to demonstrate how specific training programs can efficiently foster humanistic, patient-centered care in standard medical practice. Methods This multicenter, open-label randomized controlled trial will be conducted in pediatric cardiac units and simulation centers of across 10 universities in France. The study population comprises pediatric cardiologists in training (including pediatric cardiac fellows or specialist assistants). The SIMUL-CHD intervention will consist of simulation-based training with standardized patients, focusing on improving communication skills for pediatric cardiology trainees during diagnostic counselling. Patients and caregivers have been recruited from a National Patient Association named “Petit Cœur de Beurre”. The primary outcome is the quality of physicians’ communication skills. The evaluation committee, which will review video recordings of the sessions, will be blinded to which participants received simulation-based training (group of interest) and which received theory-based training (control group). Secondary outcomes are the effect of SIMUL-CHD on empathy and anxiety levels in young pediatric cardiologists. Baseline scores pre and post-intervention will be compared, and skill improvement resulting from the intervention measured. Discussion Simulation-based training has proven efficacy in teaching technical skills in various scenarios however its application to communication skills in pediatric cardiology remains unexplored. The involvement of experienced parents provides a unique perspective, incorporating their profound understanding of the emotional challenges and specific hurdles faced by families dealing with congenital heart disease. Trial registration This trial is registered with the OSF registry (registered https://osf.io/ed78q ).

Nitrous oxide (N2O) emissions from soil are partly controlled by aeration and gas transfer in soil, and thus by soil structure. The intensity of N2O emissions is usually expressed according to the water filled pore space (WFPS), calculated using the soil bulk density. These factors, even if they describe the soil structure and the water proportion in the porous network, do not inform about porous network characteristics among scales and their connectivity. The aim of this work was therefore to determine (1) to what extent the soil structure of an agricultural soil controlled N2O emissions during a snap-shot campaign and (2) which metric of gas transfer or soil structure was the most appropriate to describe the N2O emission variability at field scale. N2O emissions were measured with a mobile chamber on a maize crop after fertilization with several soil management practices resulting in four soil states (strip-till versus tillage, compacted soil versus uncompacted) with contrasting soil structure. Soil cylinders and bulk soil were sampled from 24 plots exhibiting a strong gradient in N2O emissions. Classical soil physical and chemical properties were measured, including soil bulk density and water filled pore space. Soil structure also was characterized quantitatively by X-ray tomography at meso and macro scales, and indirectly by gas transfer parameters. Clear differences were observed between low and high emission plots in terms of soil structure, soil temperature and nitrate concentration. However, soil structure appeared more strongly connected to N2O emissions, and some thresholds on soil structural indicators were relevant to disentangle high and low N2O fluxes. Some structural indicators at both scales (e.g. porosity, surface density) and gas transfer parameters (relative gas diffusivity, air permeability) were good descriptors of the observed N2O fluxes. Nevertheless, the gas transfer parameters can be easily measured over a short period of time, whereas the soil structure indicators determined from 3D images require an acquisition and a processing phase that can be time consuming. A good compromise to evaluate the field N2O flux potential from an easy measure would be to evaluate the relative gas diffusivity, which directly controls the diffusion of oxygen in soil and thereby the microbial processes of N2O production.

Bone regeneration is mediated by skeletal stem/progenitor cells (SSPCs) that are mainly recruited from the periosteum after bone injury. The composition of the periosteum and the steps of SSPC activation and differentiation remain poorly understood. Here, we generated a single-nucleus atlas of the periosteum at steady state and of the fracture site during the early stages of bone repair (https://fracture-repair-atlas.cells.ucsc.edu). We identified periosteal SSPCs expressing stemness markers (Pi16 and Ly6a/SCA1) and responding to fracture by adopting an injury-induced fibrogenic cell (IIFC) fate, prior to undergoing osteogenesis or chondrogenesis. We identified distinct gene cores associated with IIFCs and their engagement into osteogenesis and chondrogenesis involving Notch, Wnt, and the circadian clock signaling, respectively. Finally, we show that IIFCs are the main source of paracrine signals in the fracture environment, suggesting a crucial paracrine role of this transient IIFC population during fracture healing. Overall, our study provides a complete temporal topography of the early stages of fracture healing and the dynamic response of periosteal SSPCs to injury, redefining our knowledge of bone regeneration.

# Background Forty-nine percent of overhead athletes suffer from shoulder pain. Throwing movements require the participation of all components of the kinetic chain to reduce risk for shoulder overuse. Thus, limited lower limb range of motion or weakness has been identified as a risk factor for shoulder pain in overhead athletes. # Purpose This systematic review aims to evaluate the association between shoulder, trunk, and lower limb pain in overhead athletes. # Study Design Systematic Review and Meta-analysis # Methods A systematic review was conducted in the PubMed/MEDLINE, Science Direct and CENTRAL/Cochrane databases for observational studies. Search terms included sports-related terms (e.g., 'overhead', 'baseball', 'volleyball', 'handball') and injury-related terms (e.g., 'injury history', 'shoulder pain', 'lower limb pain', 'hip pain', 'knee pain', 'ankle pain', 'foot pain', 'trunk pain'). Studies were considered for review if they met the following criteria: inclusion of overhead athletes, investigation of injury or pain in shoulder and lower limb or trunk, had data related to or could calculate the calculation of odds ratio (OR) or relative risk (RR), available in French or English. The ROBINS-E tool was used to assess the methodological quality of each article. The data were pooled in a random-effects meta-analysis, using odds ratios to estimate the strength of the association between shoulder pain and pain at other locations. # Results Seven articles were included. Five of them were at moderate risk of bias and two were at high risk of bias. Shoulder pain was associated with low back pain (OR=5.51), hip pain (OR=4.32), knee pain (OR=3.03) and ankle/foot pain (OR=2.84). # Conclusion This systematic review highlighted, with very low to low certainty, a significant association between shoulder pain and trunk/lower limb pain or injuries. # Level of Evidence Level 3

Summary: Background: In industrialized countries, the incidence of inflammatory bowel disease (IBD) appears stabilized. This study examined the incidence and phenotype of IBD in Northern France over a 30-year period. Methods: Including all IBD patients recorded in the EPIMAD population-based registry from 1988 to 2017 in Northern France, we described the incidence and clinical presentation of IBD according to age, sex and time. Findings: A total of 22,879 incident IBD cases were documented (59% (n = 13,445) of Crohn’s disease (CD), 38% (n = 8803) of ulcerative colitis (UC), 3% (n = 631) of IBD unclassified (IBDU)). Over the study period, incidence of IBD, CD and UC was 12.7, 7.2 and 5.1 per 105 person-years, respectively. The incidence of CD increased from 5.1/105 in 1988–1990 to 7.9/105 in 2015–2017 (annual percent change (APC): +1.9%, p

Abstract Background Incidence of complications following obstetrical anal sphincter injury (OASI) during vaginal delivery are poorly defined. They are only studied in high level maternities, small cohorts, all stages of perineal tear or in low-income countries. The aim of our study was to describe complications after primary OASI repair following a vaginal delivery in all French maternity wards at short and midterm and to assess factors associated with complication occurrence. Methods We conducted a historical cohort study using the French nationwide claim database (PMSI) from January 2013 to December 2021. All women who sustained an OASI repair following a vaginal delivery were included and virtually followed-up for 2 years. Then, we searched for OASIS complications. Finally, we evaluated factors associated with OASIS complication repaired or not and OASIS complication repairs. Results Among the 61,833 included women, 2015 (2.8%) had an OASI complication and 842 (1.16%) underwent an OASI complication repair. Women were mainly primiparous (71.6%) and 44.3% underwent an instrumental delivery. During a follow-up of 2 years, 0.6% (n = 463), 0.3% (n = 240), 0.2% (n = 176), 0.1% (n = 84), 0.06% (n = 43) and 0.01% (n = 5) of patients underwent second surgery for a perineal repair, a fistula repair, a sphincteroplasty, a perineal infection, a colostomy and a sacral nervous anal stimulation, respectively. Only one case of artificial anal sphincter was noticed. Instrumental deliveries (OR = 1.56 CI95%[1.29;1.9]), private for-profit hospitals (OR = 1.42 [1.11;1.82], reference group “public hospital”), obesity (OR = 1.36 [1;1.84]), stage IV OASIS (OR = 2.98 [2.4;3.72]), perineal wound breakdown (OR = 2.8 [1.4;5.48]), ages between 25 and 29 years old (OR = 1.59 [1.17;2.18], refence group “age between 13 and 24 years old”) and 30 and 34 years old (OR = 1.57 [1.14; 2.16], refence group “age between 13 and 24 years old”) were factors associated with OASIS complication repairs. Conclusions Maternal age, stage IV OASIS, obesity, instrumental deliveries and private for-profit hospitals seemed to predict OASIS complications. Understanding factors associated with OASIS complications could be beneficial for the patient to inform them and to influence the patient’s follow-up in order to prevent complications, repairs and maternal distress.

Abstract Cognitive reserve is the ability to actively cope with brain deterioration and delay cognitive decline in neurodegenerative diseases. It operates by optimizing performance through differential recruitment of brain networks or alternative cognitive strategies. We investigated cognitive reserve using Huntington’s disease (HD) as a genetic model of neurodegeneration to compare premanifest HD, manifest HD, and controls. Contrary to manifest HD, premanifest HD behave as controls despite neurodegeneration. By decomposing the cognitive processes underlying decision making, drift diffusion models revealed a response profile that differs progressively from controls to premanifest and manifest HD. Here, we show that cognitive reserve in premanifest HD is supported by an increased rate of evidence accumulation compensating for the abnormal increase in the amount of evidence needed to make a decision. This higher rate is associated with left superior parietal and hippocampal hypertrophy, and exhibits a bell shape over the course of disease progression, characteristic of compensation.

ABSTRACT Candida auris is a yeast pathogen causing nosocomial outbreaks of candidemia. Its ability to adhere to inert surfaces and to be transmitted from one patient to another via medical devices is of particular concern. Like other Candida spp., C. auris has the ability to transition from the yeast form to pseudohyphae and to build biofilms. Moreover, some isolates have a unique capacity to form aggregates. These morphogenetic changes may impact virulence. In this study, we demonstrated the role of the transcription factor Ume6 in C. auris morphogenesis. Genetic hyperactivation of Ume6 induced filamentation and aggregation. The Ume6-hyperactivated strain (UME6HA) also exhibited increased adhesion to inert surface and formed biofilms of higher biomass compared to the parental strain. Transcriptomic analyses of UME6HA revealed enrichment of genes encoding for adhesins, proteins involved in cell wall organization, sterol biosynthesis, and aspartic protease activities. The three most upregulated genes compared to wild-type were those encoding for the agglutin-like sequence adhesin Als4498, the C. auris-specific adhesin Scf1, and the hypha-specific G1 cyclin-related protein Hgc1. The deletion of these genes in the UME6HA background showed that Ume6 controls filamentation via Hgc1 and aggregation via Als4498 and Scf1. Adhesion to inert surface was essentially triggered by Scf1. However, Als4498 and Hgc1 were also crucial for biofilm formation. Our data show that Ume6 is a universal regulator of C. auris morphogenesis via distinct modulators.IMPORTANCEC. auris represents a public health threat because of its ability to cause difficult-to-treat infections and hospital outbreaks. The morphogenetic plasticity of C. auris, including its ability to filament, to form aggregates or biofilms on inert surfaces, is important to the fungus for interhuman transmission, skin or catheter colonization, tissue invasion, antifungal resistance, and escape of the host immune system. This work deciphered the importance of Ume6 in the control of distinct pathways involved in filamentation, aggregation, adhesion, and biofilm formation of C. auris. A better understanding of the mechanisms of C. auris morphogenesis may help identify novel antifungal targets.

Can books be treated as mere decorative items ? From the 19th Century, when books started to beceome everyday consomer products, to nowadays, when social media tend to promote books by associating them with vintage and comforting values, books have found their place in the field of decorative arts and have been present in interior decoration manuals. Indeed, books can be at the center of several scenographies that contribute to expose them at home ; as such, they become part of our daily environment. Beyond their aesthetic interest, however, books are also part of a self-dramaturgy that takes place at home as well on the Bookoverse, according to new patterns. Nevertheless, the decorative uses of books tend to conflict with the dominant axiology that subordinate books to reading. Contrary to the temptation of opposing reading and non-reading as to celebrate the first one and condamn the latest, this paper aims at showing that decorative uses of books can be seen as a prolongation of our relation towards texts by making them immediately visible in our day-to-day environment.

Background Limited data are available on long-term respiratory disabilities in patients following acute COVID-19. Patients and methods This prospective, monocentric, observational cohort study included patients admitted to our hospital with acute COVID-19 between 12 March and 24 April 2020. Clinical, functional and radiological data were collected up to 28 months after hospital discharge. Results Among 715 patients hospitalised for COVID-19, 493 (69.0%) were discharged alive. We could access complete medical records for 268 out of 493 patients (54.4%); 138 out of 268 (51.5%) exhibited persistent respiratory symptoms and agreed with the data collection and follow-up. Patients were predominantly male (64.5%), with a mean±sd age of 58.9±15.3 years. At the last follow-up, the leading symptoms were asthenia (31.5%), dyspnoea (29.8%) and neuropsychological symptoms (17.7%). Lung function improved up to the last visit. Mean diffusing capacity of the lung for carbon monoxide (DLCO) was 77.8% of predicted value, total lung capacity (TLC) was 83.5% and O2 desaturation during exercise (O2 desaturation) was 2.3%. While DLCO improved over the entire period, TLC improved in the early phase and O2 desaturation in the late phase. Except for those with lung comorbidities, only one patient presented with minor functional and chest radiological alterations at 28 months. Conclusion Patients with acute COVID-19 discharged alive showed improved clinical symptoms, lung function parameters and radiological signs up to 28 months post-infection. Persistent symptoms consisted mainly of asthenia and dyspnoea, with lung function returning to normal. One patient without prior respiratory issues exhibited moderate pulmonary fibrosis.

Introduction A proportion of people develop Long Covid after acute COVID-19, but with most studies concentrated in high-income countries (HICs), the global burden is largely unknown. Our study aims to characterise long-term COVID-19 sequelae in populations globally and compare the prevalence of reported symptoms in HICs and low-income and middle-income countries (LMICs).Methods A prospective, observational study in 17 countries in Africa, Asia, Europe and South America, including adults with confirmed COVID-19 assessed at 2 to

Abstract Regulatory T cells (Tregs) are plastic cells playing a pivotal role in the maintenance of immune homeostasis. Tregs actively adapt to the microenvironment where they reside; as a consequence, their molecular and functional profiles differ among tissues and pathologies. In tumors, the features acquired by Tregs remains poorly characterized. Here, we observe that human tumor-infiltrating Tregs selectively overexpress CD74, the MHC class II invariant chain. CD74 has been previously described as a regulator of antigen-presenting cell biology, however its function in Tregs remains unknown. CD74 genetic deletion in human primary Tregs reveals that CD74KO Tregs exhibit major defects in the organization of their actin cytoskeleton and intracellular organelles. Additionally, intratumoral CD74KO Tregs show a decreased activation, a drop in Foxp3 expression, a low accumulation in the tumor, and consistently, they are associated with accelerated tumor rejection in preclinical models in female mice. These observations are unique to tumor conditions as, at steady state, CD74KO-Treg phenotype, survival, and suppressive capacity are unaffected in vitro and in vivo. CD74 therefore emerges as a specific regulator of tumor-infiltrating Tregs and as a target to interfere with Treg anti-tumor activity.

Abstract We have previously introduced the first generation of C3P3, an artificial system that allows the autonomous in-vivo production of mRNA with m7GpppN-cap. While C3P3-G1 synthesized much larger amounts of capped mRNA in human cells than conventional nuclear expression systems, it produced a proportionately much smaller amount of the corresponding proteins, indicating a clear defect of mRNA translatability. A possible mechanism for this poor translatability could be the rudimentary polyadenylation of the mRNA produced by the C3P3-G1 system. We therefore sought to develop the C3P3-G2 system using an artificial enzyme to post-transcriptionally lengthen the poly(A) tail. This system is based on the mutant mouse poly(A) polymerase alpha fused at its N terminus with an N peptide from the λ virus, which binds to BoxBr sequences placed in the 3′UTR region of the mRNA of interest. The resulting system selectively brings mPAPαm7 to the target mRNA to elongate its poly(A)-tail to a length of few hundred adenosine. Such elongation of the poly(A) tail leads to an increase in protein expression levels of about 2.5–3 times in cultured human cells compared to the C3P3-G1 system. Finally, the coding sequence of the tethered mutant poly(A) polymerase can be efficiently fused to that of the C3P3-G1 enzyme via an F2A sequence, thus constituting the single-ORF C3P3-G2 enzyme. These technical developments constitute an important milestone in improving the performance of the C3P3 system, paving the way for its applications in bioproduction and non-viral human gene therapy.