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Lung inflammation is a hallmark of Coronavirus disease 2019 (COVID-19) in patients who are severely ill, and the pathophysiology of disease is thought to be immune mediated. Mast cells (MCs) are polyfunctional immune cells present in the airways, where they respond to certain viruses and allergens and often promote inflammation. We observed widespread degranulation of MCs during acute and unresolved airway inflammation in SARS-CoV-2-infected mice and nonhuman primates. Using a mouse model of MC deficiency, MC-dependent interstitial pneumonitis, hemorrhaging, and edema in the lung were observed during SARS-CoV-2 infection. In humans, transcriptional changes in patients requiring oxygen supplementation also implicated cells with a MC phenotype in severe disease. MC activation in humans was confirmed through detection of MC-specific proteases, including chymase, the levels of which were significantly correlated with disease severity and with biomarkers of vascular dysregulation. These results support the involvement of MCs in lung tissue damage during SARS-CoV-2 infection in animal models and the association of MC activation with severe COVID-19 in humans, suggesting potential strategies for intervention.

Summary: LINC00116 encodes a microprotein first identified as Mitoregulin (MTLN), where it was reported to localize to the inner membrane of mitochondria to regulate fatty acid oxidation and oxidative phosphorylation. These initial discoveries were followed by reports with differing findings about its molecular functions and submitochondrial localization. To clarify the apparent discrepancies, we constructed multiple orthogonal methods of determining the localization of MTLN, including split GFP-based reporters that enable efficient and reliable topology analyses for microproteins. These methods unequivocally demonstrate MTLN primarily localizes to the outer membrane of mitochondria, where it interacts with enzymes of fatty acid metabolism including CPT1B and CYB5B. Loss of MTLN causes the accumulation of very long-chain fatty acids (VLCFAs), especially docosahexaenoic acid (DHA). Intriguingly, loss of MTLN protects mice against western diet/fructose-induced insulin-resistance, suggests a protective effect of VLCFAs in this context. MTLN thus serves as an attractive target to control the catabolism of VLCFAs.

Mito-SEPs are small peptides that can modulate oxidative metabolism in mitochondria. Here the authors show that C15ORF48 encodes a mito-SEP, MOCCI, capable of altering mitochondria respiration to suppress inflammation, while C15ORF48 3’ untranslated region also contains a miRNA, miR-147b, that synergizes with MOCCI to modulate host anti-viral responses.

Small open reading frame-encoded peptides (SEPs), shorter than 100 amino acids, are involved in many cell biological processes. Here the authors identify 16 nuclear-encoded mitochondrial SEPs, including BRAWNIN, an essential regulator of respiratory chain complex III assembly and ATP production.

The Apelin receptor (Aplnr) is essential for heart development, controlling the early migration of cardiac progenitors. Here we demonstrate that in zebrafish Aplnr modulates Nodal/TGFβ signaling, a key pathway essential for mesendoderm induction and migration. Loss of Aplnr function leads to a reduction in Nodal target gene expression whereas activation of Aplnr by a non-peptide agonist increases the expression of these same targets. Furthermore, loss of Aplnr results in a delay in the expression of the cardiogenic transcription factors mespaa/ab. Elevating Nodal levels in aplnra/b morphant and double mutant embryos is sufficient to rescue cardiac differentiation defects. We demonstrate that loss of Aplnr attenuates the activity of a point source of Nodal ligands Squint and Cyclops in a non-cell autonomous manner. Our results favour a model in which Aplnr is required to fine-tune Nodal output, acting as a specific rheostat for the Nodal/TGFβ pathway during the earliest stages of cardiogenesis.

Abstract Methane (CH4) emission reduction to limit warming to 1.5 °C can be tracked by analyzing CH4 concentration and its isotopic composition (δ 13C, δD) simultaneously. Based on reconstructions of the temporal trends, latitudinal, and vertical gradient of CH4 and δ13C from 1985 to 2020 using an atmospheric chemistry transport model, we show (1) emission reductions from oil and gas exploitation (ONG) since the 1990s stabilized the atmospheric CH4 growth rate in the late 1990s and early 2000s, and (2) emissions from farmed animals, waste management, and coal mining contributed to the increase in CH4 since 2006. Our findings support neither the increasing ONG emissions reported by the EDGARv6 inventory during 1990–2020 nor the large unconventional emissions increase reported by the GAINSv4 inventory since 2006. Total fossil fuel emissions remained stable from 2000 to 2020, most likely because the decrease in ONG emissions in some regions offset the increase in coal mining emissions in China.

Anthropogenic methane (CH4) emissions increases from the period 1850–1900 until 2019 are responsible for around 65% as much warming as carbon dioxide (CO2) has caused to date, and large reductions in methane emissions are required to limit global warming to 1.5°C or 2°C. However, methane emissions have been increasing rapidly since ~2006. This study shows that emissions are expected to continue to increase over the remainder of the 2020s if no greater action is taken and that increases in atmospheric methane are thus far outpacing projected growth rates. This increase has important implications for reaching net zero CO2 targets: every 50 Mt CH4 of the sustained large cuts envisioned under low-warming scenarios that are not realized would eliminate about 150 Gt of the remaining CO2 budget. Targeted methane reductions are therefore a critical component alongside decarbonization to minimize global warming. We describe additional linkages between methane mitigation options and CO2, especially via land use, as well as their respective climate impacts and associated metrics. We explain why a net zero target specifically for methane is neither necessary nor plausible. Analyses show where reductions are most feasible at the national and sectoral levels given limited resources, for example, to meet the Global Methane Pledge target, but they also reveal large uncertainties. Despite these uncertainties, many mitigation costs are clearly low relative to real-world financial instruments and very low compared with methane damage estimates, but legally binding regulations and methane pricing are needed to meet climate goals.

Abstract Increasing dorsolateral prefrontal cortex (DLPFC) activity by anodal transcranial direct current stimulation (tDCS) enhances cognitive control and might reduce aggression. The Val158Met polymorphism within the catechol-O-methyltransferase gene (rs4680) plays a pivotal role in prefrontal dopamine signaling, displaying associations with aggressive behavior, and potentially influencing the effects of tDCS. In a double-blind, sham-controlled study, we investigated the influence of rs4680 on tDCS effects on aggression. While undergoing functional magnetic resonance imaging, 89 healthy male participants performed the Taylor aggression paradigm before and immediately after tDCS. Actively stimulated participants (n = 45) received anodal tDCS (1.5 mA) for 20 min targeting the right DLPFC. Carriers of the val-allele (val+; n = 46; active tDCS n = 23) were compared to met-allele homozygotes (val−; n = 43; active tDCS n = 22). Analysis revealed decreased aggressive behavior in the val− group following active tDCS (p

Abstract Background Assessments, such as summative structured examinations, aim to verify whether students have acquired the necessary competencies. It is important to familiarize students with the examination format prior to the assessment to ensure that true competency is measured. However, it is unclear whether students can demonstrate their true potential or possibly perform less effectively due to the unfamiliar examination format. Hence, we questioned whether a 10-min active familiarization in the form of simulation improved medical students´ OSCE performance. Next, we wanted to elucidate whether the effect depends on whether the familiarization procedure is active or passive. Methods We implemented an intervention consisting of a 10-min active simulation to prepare the students for the OSCE setting. We compared the impact of this intervention on performance to no intervention in 5th-year medical students (n = 1284) from 2018 until 2022. Recently, a passive lecture, in which the OSCE setting is explained without active participation of the students, was introduced as a comparator group. Students who participated in neither the intervention nor the passive lecture group formed the control group. The OSCE performance between the groups and the impact of gender was assessed using X2, nonparametric tests and regression analysis (total n = 362). Results We found that active familiarization of students (n = 188) yields significantly better performance compared to the passive comparator (Cohen´s d = 0.857, p

The lysosome is central to the degradation of proteins, carbohydrates, and lipids and their salvage back to the cytosol for reutilization. Lysosomal transporters for amino acids, sugars, and cholesterol have been identified, and the metabolic fates of these molecules in the cytoplasm have been elucidated. Remarkably, it is not known whether lysosomal salvage exists for glycerophospholipids, the major constituents of cellular membranes. By using a transport assay screen against orphan lysosomal transporters, we identified the major facilitator superfamily protein Spns1 that is ubiquitously expressed in all tissues as a proton-dependent lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE) transporter, with LPC and LPE being the lysosomal breakdown products of the most abundant eukaryotic phospholipids, phosphatidylcholine and phosphatidylethanolamine, respectively. Spns1 deficiency in cells, zebrafish embryos, and mouse liver resulted in lysosomal accumulation of LPC and LPE species with pathological consequences on lysosomal function. Flux analysis using stable isotope-labeled phospholipid apolipoprotein E nanodiscs targeted to lysosomes showed that LPC was transported out of lysosomes in an Spns1-dependent manner and re-esterified back into the cytoplasmic pools of phosphatidylcholine. Our findings identify a phospholipid salvage pathway from lysosomes to the cytosol that is dependent on Spns1 and critical for maintaining normal lysosomal function. [ABSTRACT FROM AUTHOR]

BackgroundThe primary treatment for acute relapses in multiple sclerosis (MS) is the intravenous administration of high-dose methylprednisolone (IVMP). However, the mechanisms through which corticosteroid treatment impacts acute neuroinflammation in people with MS (pwMS) remain not fully understood. In particular, the changes induced by glucocorticoids (GCs) on cells of the innate immune system and the differences between patients with distinct immunotherapies have received little attention to date.MethodsWe conducted immunophenotyping using flow cytometry on peripheral blood mononuclear cells of pwMS who received IVMP treatment during a relapse. We compared the impact of an IVMP treatment on a broad variety of immune cell subsets within three groups: twelve patients who were treatment-naïve to disease modifying therapies (wDMT) to ten patients on platform therapies (PT) and eighteen patients on fingolimod therapy (FTY).ResultsWe observed pronounced interindividual short- and intermediate-term effects of IVMP on distinct immune cells subsets. In addition to the well-documented decrease in T-helper cells (Th cells), we detected significant alterations after the first IVMP infusion within the innate immune response among neutrophil, eosinophil and basophil granulocytes, monocytes and plasmacytoid dendritic cells (pDCs). When comparing patients wDMT to the PT and FTY cohorts, we found that IVMP had a similar impact on innate immune cells across all treatment groups. However, we did not observe a significant further decline in T lymphocyte counts during IVMP in patients with pre-existing lymphopenia under FTY treatment. Although T cell apoptosis is considered the main mechanism of action of GCs, patients with FTY still reported symptom improvement following IVMP treatment.ConclusionIn addition to T cell suppression, our data suggests that further immunoregulatory mechanisms of GC, particularly on cells of the innate immune response, are of greater significance than previously understood. Due to the regulation of the adaptive immune cells by DMTs, the impact of GC on these cells varies depending on the underlying DMT. Additional studies involving larger cohorts and cerebrospinal fluid samples are necessary to gain a deeper understanding of the immune response to GC in pwMS with different DMTs during relapse to define and explain differences in clinical response profiles.

Abstract In order to produce artificial silk fibers with properties that match the native spider silk we likely need to closely mimic the spinning process as well as fiber architecture and composition. To increase our understanding of the structure and function of the different silk glands of the orb weaver Larinioides sclopetarius, we used resin sections for detailed morphology, paraffin embedded sections for a variety of different histological stainings, and a histochemical method for localization of carbonic anhydrase activity. Our results show that all silk glands, except the tubuliform glands, are composed of two or more columnar epithelial cell types, some of which have not been described previously. We observed distinct regionalization of the cell types indicating sequential addition of secretory products during silk formation. This means that the major ampullate, minor ampullate, aciniform type II, and piriform silk fibers most likely are layered and that each layer has a specific composition. Furthermore, a substance that stains positive for polysaccharides may be added to the silk in all glands except in the type I aciniform glands. Active carbonic anhydrase was found in all silk glands and/or ducts except in the type I aciniform and tubuliform glands, with the strongest staining in aggregate glands and their ductal nodules. Carbonic anhydrase plays an important role in the generation of a pH gradient in the major ampullate glands, and our results suggest that some other glands may also harbor pH gradients.

Despite significant efforts toward improving therapy for septic shock, mortality remains high. Applying veno-arterial (V-A) extracorporeal membrane oxygenation (ECMO) in this context remains controversial. Since the cannulation of the femoral artery for V-A ECMO return leads to lower body hyperoxia, this study investigated the impact of V-A ECMO therapy on the intestinal and hepatic microcirculation during septic shock in a rodent model. Thirty male Lewis rats were randomly assigned to receive V-A ECMO therapy with low (60 mL/kg/min) or high (90 mL/kg/min) blood flow or a sham procedure. Hemodynamic data were collected through a pressure-volume catheter in the left ventricle and a catheter in the lateral tail artery. Septic shock was induced by intravenous administration of lipopolysaccharide (1 mg/kg). The rats received lung-protective ventilation during V-A ECMO therapy. The hepatic and intestinal microcirculation was measured by micro-lightguide spectrophotometry after median laparotomy for two hours. Systemic and pulmonary inflammation was detected via enzyme-linked immunosorbent assays (ELISA) of the plasma and bronchoalveolar lavage (BAL), respectively, measuring tumor necrosis factor-alpha (TNF-α), interleukins 6 (IL-6) and 10 (IL-10), and C-X-C motif ligands 2 (CXCL2) and 5 (CXCL5). Oxygen saturation and relative hemoglobin concentration were reduced in the hepatic and intestinal microcirculation during V-A ECMO therapy, independent of the blood flow rate. Further, rats treated with V-A ECMO therapy also presented elevated systolic, diastolic, and mean arterial blood pressure and increased stroke volume, cardiac output, and left ventricular end-diastolic volume. However, left ventricular end-diastolic pressure was only elevated during high-flow V-A ECMO therapy. Blood gas analysis revealed a dilutional anemia during V-A ECMO therapy. ELISA analysis showed an elevated plasma CXCL2 concentration only during high-flow V-A ECMO therapy and elevated BAL CXCL2 and CXCL5 concentrations only during low-flow V-A ECMO therapy. Rats undergoing V-A ECMO therapy exhibited impaired microcirculation of the intestine and liver during septic shock despite increased blood pressure and cardiac output. Increased pulmonary inflammation was detected only during low-flow V-A ECMO therapy in septic shock.

IntroductionConvenience foods are a double-edged sword in that they provide quick and easy nutrition but may promote non-communicable diseases related to excess intakes of sugar, fat, and salt. To inform the German national reduction and innovation strategy for less sugar, fat, and salt in processed foods, the present study sought to analyse the consumption frequency of selected convenience foods and to determine sociodemographic and behavioural factors that characterise frequent users.MethodsIn a representative computer-assisted telephone interview survey in the adult German population (N = 3,997) conducted in 2018, consumption frequency of 21 convenience foods was assessed. To characterise frequent in contrast to non-frequent users, data on sociodemographics and behavioural aspects were compared. Statistical analyses comprised chi-square tests with Bonferroni correction as well as Spearman’s rank correlation. Cramer’s V was used to determine the strength of an association.ResultsOverall and among frequent users (7.7% of the sample) sweet convenience foods and savoury cooking aids were consumed most frequently. Around 75% of the participants indicated little-to-no consumption of 19 of the 21 convenience foods. Male gender (p

ABSTRACTCytolethal distending toxins (CDTs) are released by Gram-negative pathogens into the extracellular medium as free toxin or associated with extracellular vesicles (EVs), commonly known as outer membrane vesicles (OMVs). CDT production by the gastrointestinal pathogen Campylobacter jejuni has been implicated in colorectal tumorigenesis. Despite CDT being a major virulence factor for C. jejuni, little is known about the EV-associated form of this toxin. To address this point, C. jejuni mutants lacking each of the three CDT subunits (A, B, and C) were generated. C. jejuni cdtA, cdtB, and cdtC bacteria released EVs in similar numbers and sizes to wild-type bacteria, ranging from 5 to 530 nm (mean ± SEM = 118 ±6.9 nm). As the CdtAC subunits mediate toxin binding to host cells, we performed “surface shearing” experiments, in which EVs were treated with proteinase K and incubated with host cells. These experiments indicated that CDT subunits are internal to EVs and that surface proteins are probably not involved in EV-host cell interactions. Furthermore, glycan array studies demonstrated that EVs bind complex host cell glycans and share receptor binding specificities with C. jejuni bacteria for fucosyl GM1 ganglioside, P1 blood group antigen, sialyl, and sulfated Lewisx. Finally, we show that EVs from C. jejuni WT but not mutant bacteria induce cell cycle arrest in epithelial cells. In conclusion, we propose that EVs are an important mechanism for CDT release by C. jejuni and are likely to play a significant role in toxin delivery to host cells.IMPORTANCECampylobacter jejuni is the leading cause of foodborne gastroenteritis in humans worldwide and a significant cause of childhood mortality due to diarrheal disease in developing countries. A major factor by which C. jejuni causes disease is a toxin, called cytolethal distending toxin (CDT). The biology of this toxin, however, is poorly understood. In this study, we report that C. jejuni CDT is protected within membrane blebs, known as extracellular vesicles (EVs), released by the bacterium. We showed that proteins on the surfaces of EVs are not required for EV uptake by host cells. Furthermore, we identified several sugar receptors that may be required for EV binding to host cells. By studying the EV-associated form of C. jejuni CDT, we will gain a greater understanding of how C. jejuni intoxicates host cells and how EV-associated CDT may be used in various therapeutic applications, including as anti-tumor therapies.

BackgroundDue to the declining prevalence of dental caries, noncarious tooth defects such as erosive tooth wear have gained increased attention over the past decades. While patients more frequently search the internet for health-related information, the quality of patient-centered, web-based health information on erosive tooth wear is currently unknown. ObjectiveThis study aimed to assess the quality of patient-centered, web-based health information (websites and YouTube videos) on erosive tooth wear. MethodsGerman-language websites were systematically identified through 3 electronic search engines (google.de, bing.de or yahoo.de, and duckduckgo.com) in September 2021. Eligible websites were independently assessed for (1) technical and functional aspects via the LIDA instrument, (2) readability via the Flesch reading-ease score, (3) comprehensiveness of information via a structured checklist, and (4) generic quality and risk of bias via the DISCERN instrument by 2 different reviewers. An overall quality score (ie, higher scores being favored) generated from all 4 domains was used as the primary outcome. Quality scores from each domain were separately analyzed as secondary outcomes and compared by the Friedman test. The effect of practice-specific variables on quality scores of websites from private dental offices was assessed using generalized linear modeling. Eligible YouTube videos were judged based on (1) the comprehensiveness of information, (2) viewers’ interaction, and (3) viewing rate. The comprehensiveness of information was compared between websites and YouTube videos using the Wilcoxon rank-sum test. ResultsOverall, 231 eligible websites and 7 YouTube videos were identified and assessed. The median overall quality of the websites was 33.6% (IQR 29.8%-39.2%). Secondary outcome scores amounted to 64.3% (IQR 59.8%-69.0%) for technical and functional aspects, 40.0% (IQR 34.0%-49.0%) for readability, 11.5% (IQR 3.9%-26.9%) for comprehensiveness of information, and 16.7% (IQR 8.3%-23.3%) for generic quality. While the comprehensiveness of information and generic quality received low scores, technical and functional aspects as well as readability resulted in higher scores (both Padjusted

Abstract Atmospheric methane is both a potent greenhouse gas and photochemically active, with approximately equal anthropogenic and natural sources. The addition of chlorine to the atmosphere has been proposed to mitigate global warming through methane reduction by increasing its chemical loss. However, the potential environmental impacts of such climate mitigation remain unexplored. Here, sensitivity studies are conducted to evaluate the possible effects of increasing reactive chlorine emissions on the methane budget, atmospheric composition and radiative forcing. Because of non-linear chemistry, in order to achieve a reduction in methane burden (instead of an increase), the chlorine atom burden needs to be a minimum of three times the estimated present-day burden. If the methane removal target is set to 20%, 45%, or 70% less global methane by 2050 compared to the levels in the Representative Concentration Pathway 8.5 scenario (RCP8.5), our modeling results suggest that additional chlorine fluxes of 630, 1250, and 1880 Tg Cl/year, respectively, are needed. The results show that increasing chlorine emissions also induces significant changes in other important climate forcers. Remarkably, the tropospheric ozone decrease is large enough that the magnitude of radiative forcing decrease is similar to that of methane. Adding 630, 1250, and 1880 Tg Cl/year to the RCP8.5 scenario, chosen to have the most consistent current-day trends of methane, will decrease the surface temperature by 0.2, 0.4, and 0.6 °C by 2050, respectively. The quantity and method in which the chlorine is added, its interactions with climate pathways, and the potential environmental impacts on air quality and ocean acidity, must be carefully considered before any action is taken.

Treatment of critically ill patients with venovenous (V-V) extracorporeal membrane oxygenation (ECMO) has gained wide acceptance in the last few decades. However, the use of V-V ECMO in septic shock remains controversial. The effect of ECMO-induced inflammation on the microcirculation of the intestine, liver, and critically damaged lungs is unknown. Therefore, the aim of this study was to measure the hepatic and intestinal microcirculation and pulmonary inflammatory response in a model of V-V ECMO and septic shock in the rat. Twenty male Lewis rats were randomly assigned to receive V-V ECMO therapy or a sham procedure. Hemodynamic data were measured by a pressure-volume catheter in the left ventricle and a catheter in the lateral tail artery. Septic shock was induced by the intravenous infusion of lipopolysaccharide (1 mg/kg). During V-V ECMO therapy, rats received lung-protective ventilation. The hepatic and intestinal microcirculation was assessed by micro-lightguide spectrophotometry after median laparotomy for 2 h. Systemic and pulmonary inflammation was measured by enzyme-linked immunosorbent assays of plasma and bronchoalveolar lavage (BAL), respectively, which included tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), IL-10, C-X-C motif ligand 2 (CXCL2), and CXCL5. Reduced oxygen saturation and relative hemoglobin concentration were measured in the hepatic and intestinal microcirculation during treatment with V-V ECMO. These animals also showed increased systolic, mean, and diastolic blood pressures. While no differences in left ventricular ejection fraction were observed, animals in the V-V ECMO group presented an increased heart rate, stroke volume, and cardiac output. Blood gas analysis showed dilutional anemia during V-V ECMO, whereas plasma analysis revealed a decreased concentration of IL-10 during V-V ECMO therapy, and BAL measurements showed increased concentrations of TNF-α, CXCL2, and CXCL5. Rats treated with V-V ECMO showed impaired microcirculation of the intestine and liver during septic shock despite increased blood pressure and cardiac output. Despite lung-protective ventilation, increased pulmonary inflammation was recognized during V-V ECMO therapy in septic shock.

Polyunsaturated fatty acids (PUFAs) can alter adipose tissue function; however, the relative effects of plant and marine n3-PUFAs are less clear. Our objective was to directly compare the n3-PUFAs, plant-based α-linolenic acid (ALA) in flaxseed oil, and marine-based eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) in high-purity oils versus n6-PUFA containing linoleic acid (LA) for their effects on the adipose tissue and oral glucose tolerance of obese rats. Male fa/fa Zucker rats were assigned to faALA, faEPA, faDHA, and faLA groups and compared to baseline fa/fa rats (faBASE) and lean Zucker rats (lnLA). After 8 weeks, faEPA and faDHA had 11–14% lower body weight than faLA. The oral glucose tolerance and total body fat were unchanged, but faEPA had less mesenteric fat. faEPA and faDHA had fewer large adipocytes compared to faLA and faALA. EPA reduced macrophages in the adipose tissue of fa/fa rats compared to ALA and DHA, while faLA had the greatest macrophage infiltration. DHA decreased (~10-fold) T-cell infiltration compared to faBASE and faEPA, whereas faALA and faLA had an ~40% increase. The n3-PUFA diets attenuated tumour necrosis factor-α in adipose tissue compared to faBASE, while it was increased by LA in both genotypes. In conclusion, EPA and DHA target different aspects of inflammation in adipose tissue.

Abstract Background In many low-and middle-income countries (LMICs), childhood overweight is increasing, while underweight remains a problem. This study aimed to investigate the association between socio-economic status (SES) and nutritional status among Nepalese school children. Methods This cross-sectional study used a multistage random cluster sampling method and included 868 students aged 9–17 years from both public and private schools located in a semi-urban area of Pokhara Metropolitan City, Nepal. SES was determined based on a self-reported questionnaire. Body weight and height were measured by health professionals and body mass index (BMI) was categorized based on the World Health Organization BMI-for-age cut-offs. The association between Lower and Upper SES and BMI was assessed using mixed-effects logistic regression model estimating the adjusted odds ratio (aOR) with a corresponding 95% confidence interval (CI) and compared to Middle SES. Results The proportion of obesity, overweight, underweight, and stunting among school children was 4%, 12%, 7%, and 17%, respectively. More girls were overweight/obese compared with boys (20% vs. 13%). The mixed-effects logistic regression model showed that both participants from Lower SES households and Upper SES households had a higher tendency to be overweight compared to participants from Middle SES; aOR = 1.4; 95% CI 0.7–3.1 and aOR = 1.1; 95% CI 0.6–2.1, respectively. Furthermore, stunting and overweight occurred simultaneously. Conclusions This study found that about one out of four children and adolescents in the study setting was malnourished. There was a tendency that both participants from Lower SES and Upper SES had higher odds of being overweight compared to participants from Middle SES. Furthermore, both stunting and overweight were present simultaneously in some individuals. This emphasizes the complexity and importance of awareness of childhood malnutrition in LMICs like Nepal.

Abstract Despite its projected crucial role in stringent, future global climate policy, non-CO2 greenhouse gas (NCGG) mitigation remains a large uncertain factor in climate research. A revision of the estimated mitigation potential has implications for the feasibility of global climate policy to reach the Paris Agreement climate goals. Here, we provide a systematic bottom-up estimate of the total uncertainty in NCGG mitigation, by developing ‘optimistic’, ‘default’ and ‘pessimistic’ long-term NCGG marginal abatement cost (MAC) curves, based on a comprehensive literature review of mitigation options. The global 1.5-degree climate target is found to be out of reach under pessimistic MAC assumptions, as is the 2-degree target under high emission assumptions. In a 2-degree scenario, MAC uncertainty translates into a large projected range in relative NCGG reduction (40–58%), carbon budget (±120 Gt CO2) and policy costs (±16%). Partly, the MAC uncertainty signifies a gap that could be bridged by human efforts, but largely it indicates uncertainty in technical limitations.

AbstractThis study proposes an integrated hydrometeorological modelling framework approach and methodology for flash flood Early Warning Systems in the Chugoku region of Japan. Unprecedented rainfall-induced hydrometeorological disasters and flash floods are increasingly occurring worldwide. Comprehensive efforts are conducted to simultaneously combine multiple disciplines into integrated modelling framework approaches to reduce disaster resilience. This enables more accurate hindcasts, reanalyses, real-time forecasts or nowcasts for flash floods. This study integrates proposed hydrological calibration approach with meteorological input. Two real-time rainfall forecasts by the Weather Research and Forecasting model forced by the Atmospheric Reanalysis v5 (ERA5) and the Japanese 55-year Reanalysis (JRA55) were used as input data to the hydrological model ensemble parameterized previously. This approach was applied to seven major rivers to evaluate river discharges real-time forecasts accuracy during the Heavy Rainfall Event of July 2018. Long lead-times of up to 29 h with a satisfactory reproducible range of Nash-Sutcliffe Efficiency were obtained using both meteorological forecast for all rivers cumulatively. This indicates that the proposed integrated hydrometeorological approach enables accurate flash flood real-time forecasting for this event. Similarly, the joint hydrometeorological approach enables framework for development of real-time flash food forecasting application in Japan and presumably worldwide.

Efforts to shape more sustainable and just land and water management practices are increasingly turning to the past for inspiration. However, what the past looked like exactly and what can be learned from it and applied to present-day challenges is not straightforward. Peru is one of those places where reviving ancestral land and water management practices and knowledge has become popular. This article starts with a project that aimed to recuperate ancestral water infiltration structures in the Peruvian highlands. Drawing on interviews conducted shortly after the project’s implementation, the author analyses how history and “the past” are imagined differently by various actors, according to their current worldviews, interests and values. The author unpacks the consequences of these diverse pasts for present-day relations and project implementation, calling attention to the importance of making explicit the “politics of the past,” including how the past is portrayed and by whom, and which past is to be recuperated or revalorized.

The European transition to renewable energy sources is increasingly reconfiguring land use in rural and peri-urban areas. These processes of change have diverse local social, ecological, and economic implications, and trigger divergent responses that range from outright contestation and protest, to welcoming and accommodating renewable energy projects. This paper analyses the dynamics and responses to the construction of large-scale solar plants in the peri-urban and rural landscape of Vall d’Albaida (Valencia, Spain). Through the analysis of grey literature, media reports and semi-structured interviews with diverse actors involved in, or affected by, photovoltaic power stations, this study dissects how processes of enclosure, encroachment, exclusion, and entrenchment take place simultaneously, conditioning a wide range of responses from stakeholders. While some activists openly challenge the projects, numerous local residents and farmers accommodate the construction. The reasons for the latter include economic motivations that relate to the wider context of the agricultural sector in the region; untransparent project trajectories and decision-making; a lack of resources to contest or a limited responsibility felt to openly contest. Through the analysis of both contestations and accommodations, as well as the underlying processes, the paper expands the current debate on local implications of the renewable energy transition in peri-urban areas.

Abstract Aim To explore the experiences of living with symptomatic atrial fibrillation. Design This study, with a descriptive qualitative design, was performed using semi‐structured individual interviews. Method Six women and nine men with symptomatic atrial fibrillation were included. The transcribed interviews were analysed using qualitative content analysis. The COREQ checklist was followed. Results The analysis resulted in a main theme, namely balancing life and included the themes striving for illness control, becoming a receiver or an active partner in care and dealing with changed self‐image. The participants strived to understand their illness, prevent attacks and manage anxiety. Some of the participants were not involved in decision‐making, were uninformed about self‐care measures, reported a lack of continuity in care and felt that the doctors focused on information about the medical part of care.

This paper analyses the discussions surrounding dam removal in Spain and, specifically, ongoing contestations around the Toranes Dam. Engaging with scholarship about the temporalities of infrastructure and imaginaries, I show how dam removal is a trend that comes forth from temporally situated and shifting relations in the sociopolitical, technical, financial and environmental networks in which dams are embedded. More than simply a consequence of material decay and expiring use licences, dam removal is also intrinsically related to changing imaginaries about dams, rivers and nature. However, dam removal is contested. Central to it are debates about the definition of, and relations between, nature, society and cultural heritage in the past, present and future. People’s subjectivities – shaped by the dam and its intended and unintended effects on the environment and hydrosocial relations – are also a source of anti-removal mobilisation. The paper demonstrates how dam removal is a fascinating topic that draws attention to the different temporalities dams hold, including the stage of material and potentially also ideological ruin. Dam removal, however, does not (yet?) represent a clear paradigm shift; rather, the reality is messy, with dam construction and removal at times being promoted simultaneously.

Immunogenicity has imposed a challenge to efficacy and safety evaluation of adeno-associated virus (AAV) vector-based gene therapies. Mild to severe adverse events observed in clinical development have been implicated with host immune responses against AAV gene therapies, resulting in comprehensive evaluation of immunogenicity during nonclinical and clinical studies mandated by health authorities. Immunogenicity of AAV gene therapies is complex due to the number of risk factors associated with product components and pre-existing immunity in human subjects. Different clinical mitigation strategies have been employed to alleviate treatment-induced or -boosted immunogenicity in order to achieve desired efficacy, reduce toxicity, or treat more patients who are seropositive to AAV vectors. In this review, the immunogenicity risk assessment, manifestation of immunogenicity and its impact in nonclinical and clinical studies, and various clinical mitigation strategies are summarized. Last, we present bioanalytical strategies, methodologies, and assay validation applied to appropriately monitor immunogenicity in AAV gene therapy-treated subjects.

Abstract Contaminants within cell culture media often co‐isolate with eukaryotic extracellular vesicles (EVs) thus affecting their biological properties. It has yet to be investigated if this is also true for bacterial EVs (BEVs), especially for organisms grown in complex culture media containing animal‐derived products. To address this question, we isolated BEVs from the fastidious bacterium Helicobacter pylori grown in either standard Brain Heart Infusion (BHI) medium or BHI depleted of animal‐derived products (D‐BHI). We show that BEVs prepared from bacteria grown in D‐BHI medium have similar morphologies, size ranges and yields to those prepared from standard medium. Similarly, no differences were found in the ability of H. pylori BEVs to induce IL‐8 responses in epithelial cells. However, H. pylori BEVs prepared from D‐BHI medium were of higher purity than those prepared from standard medium. Importantly, proteomic analyses detected 3.4‐fold more H. pylori proteins and 10‐fold fewer bovine‐derived proteins in BEV samples prepared from D‐BHI rather than the standard method. Fifty‐seven H. pylori proteins were uniquely detected in BEV samples prepared from D‐BHI. In conclusion, we have described an improved method for BEV isolation. Furthermore, we demonstrate how animal‐derived products in bacteriological culture media may adversely affect proteomic analyses of BEVs.

SwedAD, a Swedish nationwide registry for patients with atopic dermatitis receiving systemic pharmacotherapy, was launched on 1 September 2019. We describe here the establishment of a user-friendly registry to the benefit of patients with atopic dermatitis. By 5 November 2022, 38 clinics had recorded 931 treatment episodes in 850 patients with an approximate national coverage rate of 40%. Characteristics at enrolment included median Eczema Area and Severity Index (EASI) 10.2 (interquartile range 4.0, 19.4), Patient-Oriented Eczema Measure (POEM) 18.0 (10.0, 24.0), Dermatology Life Quality Index (DLQI) 11.0 (5.0, 19.0) and Peak Itch Numerical Rating Scale-11 (NRS-11) 6.0 (3.0, 8.0). At 3 months, median EASI was 3.2 (1.0, 7.3) and POEM, DLQI, and NRS-11 were improved. Regional coverage varied, reflecting the distribution of dermatologists, the ratio of public to private healthcare, and difficulties in recruiting certain clinics. This study highlights the importance of a nationwide registry when managing systemic pharmacotherapy of atopic dermatitis.