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Abstract Community-acquired pneumonia (CAP) in chronic obstructive pulmonary disease (COPD) often result in sudden and persistent reduction in health-related quality of life (HRQoL), which may be alleviated with palliative care. Among individuals with COPD, we aimed to investigate potential associations between HRQoL at admission with CAP and the risk of re-hospitalization and mortality and potential associations between specific HRQoL domains and CAP treatment outcomes. HRQoL was assessed at admission and the participants were grouped into tertiles based on the HRQoL utility index and specific domains. The results revealed that participants in the middle and highest tertiles of HRQoL had a lower 90-day re-hospitalization risk compared to those in the lowest tertile, whereas no differences in re-hospitalization risk were observed 30 and 180 days after discharge. Almost one in four had severe pain or discomfort at admission and the domain pain or discomfort emerged as a predictor of re-hospitalization. In addition, participants in the middle and highest tertiles had lower risk of 180-day mortality compared to those in the lowest, while no differences were observed in 30-day or 90-day mortality risk. An increased focus on in-hospital palliative care could alleviate the pain and discomfort reported by many participants with potential to reduce re-hospitalization rates.

Objective: This review examines the evidence for psychosocial influences in asthma and behavioral medicine approaches to its treatment. Method: We conducted a systematic review of the literature on psychosocial influences and the evidence for behavioral interventions in asthma with a focus on research in the past 10 years and clinical trials. Additional attention was directed at promising new developments in the field. Results: Psychosocial factors can influence the pathogenesis and pathophysiology of asthma, either directly through autonomic, endocrine, immunological, and central nervous system mechanisms or indirectly through lifestyle factors, health behaviors, illness cognitions, and disease management, including medication adherence and trigger avoidance. The recent decade has witnessed surging interest in behavioral interventions that target the various pathways of influence. Among these, self-management training, breathing training, and exercise or physical activation programs have proved particularly useful, whereas other essential or promising interventions, such as smoking cessation, dietary programs, perception and biofeedback training, and suggestive or expressive psychotherapy, require further, more rigorous evaluation. Given the high comorbidity with anxiety and mood disorders, further evaluation of illness-specific cognitive behavior therapy is of particular importance. Progress has also been made in devising community-based and culturally tailored intervention programs. Conclusion: In concert with an essential medication treatment, behavioral medicine treatment of asthma is moving closer toward an integrated biopsychosocial approach to disease management. (Contains 1 table and 1 footnote.)

Background People living with cystic fibrosis in Denmark had early, universal access to triple modulator treatment with elexacaftor/tezacaftor/ivacaftor. Close monitoring allowed us to assess the impact of treatment on lung function and progression of lung disease in an unselected nationwide cystic fibrosis population from 6 years of age. Methods Data were analysed using linear mixed-effect models to assess changes in levels and annual rates of change (slopes) in percent predicted (pp) forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and forced expiratory flow at 25–75% of FVC (ppFEF25–75%) between the 12 months pre-treatment and treatment periods. Subgroup analyses assessed the impact of elexacaftor/tezacaftor/ivacaftor among those with/without previous modulator treatment, normal/mild/moderate/severe lung disease at treatment initiation, children/adults and birth cohorts. Results We included 392 people living with cystic fibrosis with a median (interquartile range) 12 (nine to 15) spirometry measurements per person. The mean (95% CI) improvement in ppFEV1 was 13.0 (11.3–14.6) 12 months after initiation of elexacaftor/tezacaftor/ivacaftor treatment. The annual rate of change improved from −1.4 (−2.1 – −0.6) ppFEV1 in the pre-treatment year to 2.7 (1.8–3.5) ppFEV1 per year during treatment. Similarly, ppFVC increased by 8.0 (7.1–8.9) and FEF25–­75% by 19.5 (17.0–21.9). Conclusions Using high-resolution data from a nationwide real-world setting, our study documents the impact of elexacaftor/tezacaftor/ivacaftor on lung function across subgroups based on age, disease severity and treatment history. These findings point towards a new period of consistent lung function improvement among people living with cystic fibrosis on elexacaftor/tezacaftor/ivacaftor.

Many people suffer from chronic diseases and problems due to injury from accidents or ailments. Some problems, such as measles and cancer, can be cured or put into remission with time, medicine, or treatments. Other ailments, such as high blood pressure, failing kidneys, and cystic fibrosis, cannot be cured and require continuous use of medications or organ transplants. Many people are in need of organ transplants (113,075 in the U.S., with only about 1,000 donors per month giving organs or tissues to transplant) (UNOS, 2012). In addition, for those who receive transplants, there is a need to continuously receive antirejection medications to keep their bodies from rejecting the new organs. It seems that, for many, there is no cure to failing health conditions. In this article, the author explores the possible uses of stem cells to aid in mending the human body, and analyzes the ethics associated with this technology. The medical community is using the term regenerative medicine and tissue engineering more and more because of the negativism some attach to stem cell research. (Contains 5 figures.)

Abstract Alterations in thyroid hormones (TH) and thyroid-stimulating hormone levels are frequently found following exposure to chemicals of concern. Dysregulation of TH levels can severely perturb physiological growth, metabolism, differentiation, homeostasis in the adult and developmental processes in utero. A frequently identified mode of action for this interaction is the induction of hepatic detoxification mechanisms (e.g. SULTs and UGTs), which lead to TH conjugation and elimination and therefore interfere with hormonal homeostasis, fulfilling the endocrine disruptors (EDs) definition. A short-term study in rats with dietary exposure to cyproconazole, epoxiconazole and prochloraz was conducted and hepatocyte hypertrophy, hepatic UGT activity and Phase 1/2 gene expression inductions were observed together with changes in TH levels and thyroid follicular hypertrophy and hyperplasia. To test for specific interaction with the thyroid hormone system, in vitro assays were conducted covering thyroidal I-uptake (NIS), TH transmembranal transport via MCT8 and thyroid peroxidase (TPO) function. Assays for iodothyronine deiodinases (DIO1–DIO3) and iodotyrosine deiodinase (DEHAL1) were included, and from the animal experiment, Dio1 and Dehal1 activities were measured in kidney and liver as relevant local indicators and endpoints. The fungicides did not affect any TH-specific KEs, in vitro and in vivo, thereby suggesting hepatic conjugation as the dominant MoA.

Glioblastoma (GBM) harbors a highly immunosuppressive tumor microenvironment (TME) which influences glioma growth. Major efforts have been undertaken to describe the TME on a single-cell level. However, human data on regional differences within the TME remain scarce. Here, we performed high-depth single-cell RNA sequencing (scRNAseq) on paired biopsies from the tumor center, peripheral infiltration zone and blood of five primary GBM patients. Through analysis of >45,000 cells, we revealed a regionally distinct transcription profile of microglia (MG) and monocyte-derived macrophages (MdMs) and an impaired activation signature in the tumor-peripheral cytotoxic-cell compartment. Comparing tumor-infiltrating CD8+ T cells with circulating cells identified CX3CR1high and CX3CR1int CD8+ T cells with effector and memory phenotype, respectively, enriched in blood but absent in the TME. Tumor CD8+ T cells displayed a tissue-resident memory phenotype with dysfunctional features. Our analysis provides a regionally resolved mapping of transcriptional states in GBM-associated leukocytes, serving as an additional asset in the effort towards novel therapeutic strategies to combat this fatal disease.

Abstract Here, the comparison of two different semiconductor materials is demonstrated, TiO2 and melem/g-C3N4 composites—modified with balls of approximately 5 nm Ag nanoparticles (NPs) as photocatalysts for the degradation of the model dye acid orange 7 (AO7). The melem molecule synthesized here is one of a series of organic compounds consisting of triazine ring compounds with a structure similar to that of melam and melamine. The photodegradation process of AO7 was carried out to examine all powder materials as a potential photocatalyst. Additionally, two different lamps of wavelengths 368 nm (UV light) and 420 nm (VIS light) were applied to compare the photodegradation tests. A new synthesis route for the acquisition of Ag NPs (Ag content 0.5, 1.0 and 2.5 wt%), based on a wet and low temperature method without the use of reducing reagents was proposed. The best photocatalytic performances under UV and VIS light were obtained for both, TiO2 and melem/g-C3N4 materials (new synthesis route) modified with a very low Ag content—0.5 wt%. The photodegradation activities using UV lamp (3 h, 368 nm irradiation) for samples with 0.5 wt% of Ag: TiO2 and melem/g-C3N4, in excess of 95 and 94%, respectively, were achieved. The highest photoactive materials melem/g-C3N4 with 0.5 and 1 wt% Ag revealed 98% of activity under the VIS lamp after 3 h long irradiation. Our work demonstrates a novel, environmentally acceptable, and cost-effective chemical strategy for preparation of photocatalysts suitable for degradation of organic contaminants in wastewater treatment.

BACKGROUND: Paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) may occur 4 to 8 weeks after SARS-CoV-2 infection. The acute presentation of PIMS-TS has been well described, but data on longer-term outcomes, particularly cardiac, is scarce. METHODS: This prospective nationwide surveillance study included children and adolescents less than 18 years of age who were hospitalised with PIMS-TS in Switzerland between March 2020 and March 2022. Data was collected from all 29 paediatric hospitals through the Swiss Paediatric Surveillance Unit (SPSU) during hospitalisation and approximately six weeks after discharge. The data was analysed after categorising the participants into three groups based on their admission status to the intensive care unit (ICU) (non-ICU, ICU-moderate) and the requirement for invasive ventilatory and/or inotropic support (ICU-severe). RESULTS: Overall, 204 children were included of whom 194 (95.1%) had follow-up data recorded. Median age was 9.0 years (interquartile range [IQR] 6.0–11.5) and 142 (69.6%) were male. In total, 105/204 (51.5%) required ICU admission, of whom 55/105 (52.4%) received inotropic support and 14/105 (13.3%) mechanical ventilation (ICU-severe group). Echocardiography was performed in 201/204 (98.5%) children; 132 (64.7%) had a cardiac abnormality including left ventricular systolic dysfunction (73 [36.3%]), a coronary artery abnormality (45 [22.4%]), pericardial effusion (50 [24.9%]) and mitral valve regurgitation (60 [29.9%]). Left ventricular systolic dysfunction was present at admission in 62/201 (30.8%) children and appeared during hospitalisation in 11 (5.5%) children. A coronary artery abnormality was detected at admission in 29/201 (14.2%) children and developed during hospitalisation or at follow-up in 13 (6.5%) and 3 (1.5%) children, respectively. None of the children had left ventricular systolic dysfunction at follow-up, but a coronary abnormality and pericardial effusion were found in 12 (6.6%) and 3 (1.7%) children, respectively. School absenteeism at the time of follow-up was more frequent in children who had been admitted to the ICU (2.5% in the non-ICU group compared to 10.4% and 17.6% in the ICU-moderate and ICU-severe group, respectively) (p = 0.011). CONCLUSION: Cardiac complications in children presenting with PIMS-TS are common and may worsen during the hospitalisation. Irrespective of initial severity, resolution of left ventricular systolic dysfunction is observed, often occurring rapidly during the hospitalisation. Most of the coronary artery abnormalities regress; however, some are still present at follow-up, emphasising the need for prolonged cardiac evaluation after PIMS-TS.

Abstract In this work, the electrochemical properties of the leached sludge, magnetite and zinc ferrite were studied. Acetic acid was used as a leaching reagent because, in recent years, there has been a surge of interest in using zinc-containing materials as photocatalysts, with acetic acid finding application in their preparation. Various methodological approaches were used, but the best results were achieved with a combination of 1–3 h leaching in 0.01 M acetic acid with a solid/liquid ratio of 500. In this arrangement, zincite was almost completely removed from the sludge, while zinc ferrite and magnetite remained in the solid residue. Ex situ analyses of the main leaching products were performed by X-ray diffraction, infrared spectroscopy, and thermogravimetry. The electrochemical behaviour of solid residue and model systems, that are micromagnetite and zinc ferrite, was studied in alkaline media by means of modified carbon paste electrodes, cyclic voltammetry, and chronocoulometry, with a suitable potential window ranging from 0 to 1.5 V. In summary, a linear dependence of the anodic and cathodic peak height on the square root of the scan rate was found. The position of the anodic and cathodic peaks shifted slightly with scan rate, only at low rates, up to 25 mV/s, the individual peaks coincided. The electrochemical response suggested a quasireversible process.

Abstract Human saliva is a complex fluid containing proteins such as salivary cytokines, which can be used for diagnostic purposes, particularly among the pediatric population. This study aimed to assess the concentrations of salivary cytokines in healthy children and adolescents and determine their associations with age, sex, and oral and dental findings. Healthy children and adolescents aged 4–18 years were enrolled in this cross-sectional study. The concentrations of the following salivary cytokines were measured by Luminex technology: IFN-γ, IL-1α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, IP-10, TNF-α, and VEGF-A. Additionally, oral and dental parameters were recorded using a standardized protocol. A total of 128 participants (mean age, 10.7 years; males, 50.8%) were enrolled. The levels of 1β, IL-6, IL-8, and IL-10 were significantly higher in those with gingivitis. Increased salivary flow rates were negatively correlated with IL-1α, IL-1β, IL-6, IL-8, IL-10, TNF-α, and VEGF-A concentrations. The findings of this study showed that the concentrations of most of the salivary cytokines were positively correlated with age and the presence of oral pathologies (such as gingivitis and caries) and negatively correlated with salivary flow rate.

Treating patients in an intensive care unit (ICU) isolation room is full of challenges for the caregivers and the patients. While this is known for years, the COVID-19 pandemic has highlighted these challenges as if under a burning glass - intensified by a high number of patients at the same time. The risk of infection for the caregivers is very high inside the isolation room and the time spent for putting on and taking off personal protective equipment (PPE) is enormous. Thus, every treatment that can be performed from the anteroom of the isolation room at the same quality level as if being inside the isolation room is a potential building block for solving the challenges. However, data like vital signs have to be provided to the anteroom, alarms have to be transferred to the right caregiver at the right place, and controlling medical device parameters from the anteroom are prerequisites. The new IEEE 11073 Service-oriented Device Connectivity (SDC) series of standards is a key technology to realize this. Therefore, this paper presents an example implementation of IEEE 11073 SDC-based ICU isolation rooms by means of a demonstrator. Such systems can significantly reduce the amount of time the caregivers have to spend in the isolation room and reduce the number of clothing (PPE) changes while providing care at a level of a non-isolation room. As a midterm goal these are steps for the vision of a “silent/quiet ICU”.

Background Despite possible benefits for growth, milk is costly to include in foods for undernourished children. Furthermore, the relative effects of different milk components, milk protein (MP), and whey permeate (WP) are unclear. We aimed to assess the effects of MP and WP in lipid-based nutrient supplement (LNS), and of LNS itself, on linear growth and body composition among stunted children. Methods and findings We performed a randomized, double-blind, 2 × 2 factorial trial among 12 to 59 months old stunted children in Uganda. Children were randomized to 4 formulations of LNS with MP or soy protein isolate and WP or maltodextrin (100 g/day for 12 weeks) or no supplementation. Investigators and outcome assessors were blinded; however, participants were only blinded to the ingredients in LNS. Data were analyzed based on intention-to-treat (ITT) using linear mixed-effects models adjusted for age, sex, season, and site. Primary outcomes were change in height and knee-heel length, and secondary outcomes included body composition by bioimpedance analysis (ISRCTN13093195). Between February and September 2020, we enrolled 750 children with a median age of 30 (interquartile range 23 to 41) months, with mean (± standard deviation) height-for-age z-score (HAZ) −3.02 ± 0.74 and 12.7% (95) were breastfed. The 750 children were randomized to LNS (n = 600) with or without MP (n = 299 versus n = 301) and WP (n = 301 versus n = 299), or no supplementation (n = 150); 736 (98.1%), evenly distributed between groups, completed 12-week follow-up. Eleven serious adverse events occurred in 10 (1.3%) children, mainly hospitalization with malaria and anemia, all deemed unrelated to the intervention. Unsupplemented children had 0.06 (95% confidence interval, CI [0.02, 0.10]; p = 0.015) decline in HAZ, accompanied by 0.29 (95% CI [0.20, 0.39]; p < 0.001) kg/m2 increase in fat mass index (FMI), but 0.06 (95% CI [−0.002; 0.12]; p = 0.057) kg/m2 decline in fat-free mass index (FFMI). There were no interactions between MP and WP. The main effects of MP were 0.03 (95% CI [−0.10, 0.16]; p = 0.662) cm in height and 0.2 (95% CI [−0.3, 0.7]; p = 0.389) mm in knee-heel length. The main effects of WP were −0.08 (95% CI [−0.21, 0.05]; p = 220) cm and −0.2 (95% CI [−0.7; 0.3]; p = 403) mm, respectively. Interactions were found between WP and breastfeeding with respect to linear growth (p < 0.02), due to positive effects among breastfed and negative effects among non-breastfed children. Overall, LNS resulted in 0.56 (95% CI [0.42, 0.70]; p < 0.001) cm height increase, corresponding to 0.17 (95% CI [0.13, 0.21]; p < 0.001) HAZ increase, and 0.21 (95% CI [0.14, 0.28]; p < 0.001) kg weight increase, of which 76.5% (95% CI [61.9; 91.1]) was fat-free mass. Using height-adjusted indicators, LNS increased FFMI (0.07 kg/m2, 95% CI [0.0001; 0.13]; p = 0.049), but not FMI (0.01 kg/m2, 95% CI [−0.10, 0.12]; p = 0.800). Main limitations were lack of blinding of caregivers and short study duration. Conclusions Adding dairy to LNS has no additional effects on linear growth or body composition in stunted children aged 12 to 59 months. However, supplementation with LNS, irrespective of milk, supports linear catch-up growth and accretion of fat-free mass, but not fat mass. If left untreated, children already on a stunting trajectory gain fat at the expense of fat-free mass, thus nutrition programs to treat such children should be considered. Trial registration ISRCTN13093195 In a randomized trial Benedikte Grenov and colleagues investigate the effects of milk protein and whey permeate on catch-up growth among 1-5 year-old Ugandan children affected by growth stunting. Author summary Why was this study done? Stunting affects 149 million children below 5 years and is associated with increased morbidity and mortality, delayed cognitive development and later risk of chronic diseases. There are concerns that catch-up growth beyond 2 years may not be possible and that supplementation of already stunted children may lead to fat mass accretion. But no trials have evaluated the effect of lipid-based nutrient supplement (LNS) among children already stunted. Milk may support growth and fat-free mass accretion. However, it is expensive and individual effects of milk protein (MP) and whey permeate (WP) are unknown. We aimed to assess the effects of MP and WP in large quantity LNS among 1- to 5-year-old children that were already stunted. What did the researchers do and find? MAGNUS was a randomized 2 × 2 factorial trial with an unsupplemented control group among 750 stunted 1- to 5-year-old children. The effect of large quantity LNS with MP and/or WP on linear growth (primary outcome) and body composition (secondary outcome) was assessed. There were no effects of MP or WP on linear growth or body composition. During the 12-week study, height-for-age z-score (HAZ) declined in unsupplemented children, and relative to their height, these children accumulated fat mass and lost fat-free mass. In contrast, children receiving LNS—irrespective of milk ingredients—increased in HAZ and fat-free mass, however, not fat mass. There was no difference in catch-up growth between children below and above 2 years. What do these findings mean? Since children on a growth-faltering trajectory gain fat at the expense of fat-free mass, programs using LNS to treat stunting should be considered.

Abstract Non-alcoholic fatty liver disease is a continuum of disorders among which non-alcoholic steatohepatitis (NASH) is particularly associated with a negative prognosis. Hepatocyte lipotoxicity is one of the main pathogenic factors of liver fibrosis and NASH. However, the molecular mechanisms regulating this process are poorly understood. The main aim of this study was to dissect transcriptional mechanisms regulated by lipotoxicity in hepatocytes. We achieved this aim by combining transcriptomic, proteomic and chromatin accessibility analyses from human liver and mouse hepatocytes. This integrative approach revealed several transcription factor networks deregulated by NASH and lipotoxicity. To validate these predictions, genetic deletion of the transcription factors MAFK and TCF4 was performed, resulting in hepatocytes that were better protected against saturated fatty acid oversupply. MAFK- and TCF4-regulated gene expression profiles suggest a mitigating effect against cell stress, while promoting cell survival and growth. Moreover, in the context of lipotoxicity, some MAFK and TCF4 target genes were to the corresponding differentially regulated transcripts in human liver fibrosis. Collectively, our findings comprehensively profile the transcriptional response to lipotoxicity in hepatocytes, revealing new molecular insights and providing a valuable resource for future endeavours to tackle the molecular mechanisms of NASH.

Abstract Background Many aspiring physicians perceive research experience as a way to support their medical school applications; however, the importance of research experiences as articulated in medical school admission policies is unclear. This is significant since policies and other discursive signals about selection processes can influence the behaviour of aspiring physicians. The purpose of this study is to describe the ways through which Canadian medical schools articulate the importance of research experiences in publicly available policy documents. Methods From January to June 2021, the authors reviewed publicly available selection criteria, application materials, institutional and research-related web pages associated with the 17 Canadian medical schools alongside high-level Canadian articulations of important competencies for physicians. These materials were analyzed using a qualitative descriptive approach. The authors considered concordance and/or discordance within each school’s stance on the importance of research experiences in their selection criteria and application materials. Results Research experiences are typically not explicitly required for entry into a Canadian Doctor of Medicine (MD) program; however, there are expectations that graduating physicians should understand research. All 17 Canadian medical schools signal an appreciation for the value of research on an institutional level. Review of selection criteria and application materials show that five Canadian medical schools suggest to aspiring physicians that research experiences are important for admission and four do not suggest that research experiences are important for admission. There were both intra-institution and inter-institution discordance concerning the importance of research experiences for medical school applicant selection in one and seven medical schools respectively. Conclusions Given the significant variance among the 17 Canadian medical schools, it is worthwhile for medical schools to evaluate their front-facing admission policies with consideration of the potential impact it might have on the behaviour of aspiring physicians, to ensure best selection of future physicians.

Chronically high blood glucose (hyperglycemia) leads to diabetes and fatty liver disease. Obesity is a major risk factor for hyperglycemia, but the underlying mechanism is unknown. Here, we show that a high-fat diet (HFD) in mice causes early loss of expression of the glycolytic enzyme Hexokinase 2 (HK2) specifically in adipose tissue. Adipose-specific knockout of Hk2 reduced glucose disposal and lipogenesis and enhanced fatty acid release in adipose tissue. In a non-cell-autonomous manner, Hk2 knockout also promoted glucose production in liver. Furthermore, we observed reduced hexokinase activity in adipose tissue of obese and diabetic patients, and identified a loss-of-function mutation in the hk2 gene of naturally hyperglycemic Mexican cavefish. Mechanistically, HFD in mice led to loss of HK2 by inhibiting translation of Hk2 mRNA. Our findings identify adipose HK2 as a critical mediator of local and systemic glucose homeostasis, and suggest that obesity-induced loss of adipose HK2 is an evolutionarily conserved mechanism for the development of selective insulin resistance and thereby hyperglycemia.

Abstract Lack of rapid and comprehensive microbiological diagnosis in patients with community acquired pneumonia (CAP) hampers appropriate antimicrobial therapy. This study evaluates the real-world performance of the BioFire FilmArray Pneumonia panel plus (FAP plus) and explores the feasibility of evaluation in a randomised controlled trial. Patients presenting to hospital with suspected CAP were recruited in a prospective feasibility study. An induced sputum or an endotracheal aspirate was obtained from all participants. The FAP plus turnaround time (TAT) and microbiological yield were compared with standard diagnostic methods (SDs). 96/104 (92%) enrolled patients had a respiratory tract infection (RTI); 72 CAP and 24 other RTIs. Median TAT was shorter for the FAP plus, compared with in-house PCR (2.6 vs 24.1 h, p

Despite the widespread use of SARS-CoV-2–specific monoclonal antibody (mAb) therapy for the treatment of acute COVID-19, the impact of this therapy on the development of SARS-CoV-2–specific T cell responses has been unknown, resulting in uncertainty as to whether anti–SARS-CoV-2 mAb administration may result in failure to generate immune memory. Alternatively, it has been suggested that SARS-CoV-2–specific mAb may enhance adaptive immunity to SARS-CoV-2 via a “vaccinal effect.” Bamlanivimab (Eli Lilly and Company) is a recombinant human IgG1 that was granted FDA emergency use authorization for the treatment of mild to moderate COVID-19 in those at high risk for progression to severe disease. Here, we compared SARS-CoV-2–specific CD4+ and CD8+ T cell responses of 95 individuals from the ACTIV-2/A5401 clinical trial 28 days after treatment with bamlanivimab versus placebo. SARS-CoV-2–specific T cell responses were evaluated using activation-induced marker assays in conjunction with intracellular cytokine staining. We demonstrate that most individuals with acute COVID-19 developed SARS-CoV-2–specific T cell responses. Overall, our findings suggest that the quantity and quality of SARS-CoV-2–specific T cell memory were not diminished in individuals who received bamlanivimab for acute COVID-19. Receipt of bamlanivimab during acute COVID-19 neither diminished nor enhanced SARS-CoV-2–specific cellular immunity.

Abstract The notion that T cell insulitis increases as type 1 diabetes (T1D) develops is unsurprising, however, the quantitative analysis of CD4+ and CD8+ T cells within the islet mass is complex and limited with standard approaches. Optical microscopy is an important and widely used method to evaluate immune cell infiltration into pancreatic islets of Langerhans for the study of disease progression or therapeutic efficacy in murine T1D. However, the accuracy of this approach is often limited by subjective and potentially biased qualitative assessment of immune cell subsets. In addition, attempts at quantitative measurements require significant time for manual analysis and often involve sophisticated and expensive imaging software. In this study, we developed and illustrate here a streamlined analytical strategy for the rapid, automated and unbiased investigation of islet area and immune cell infiltration within (insulitis) and around (peri-insulitis) pancreatic islets. To this end, we demonstrate swift and accurate detection of islet borders by modeling cross-sectional islet areas with convex polygons (convex hulls) surrounding islet-associated insulin-producing β cell and glucagon-producing α cell fluorescent signals. To accomplish this, we used a macro produced with the freeware software ImageJ equipped with the Fiji Is Just ImageJ (FIJI) image processing package. Our image analysis procedure allows for direct quantification and statistical determination of islet area and infiltration in a reproducible manner, with location-specific data that more accurately reflect islet areas as insulitis proceeds throughout T1D. Using this approach, we quantified the islet area infiltrated with CD4+ and CD8+ T cells allowing statistical comparison between different age groups of non-obese diabetic (NOD) mice progressing towards T1D. We found significantly more CD4+ and CD8+ T cells infiltrating the convex hull-defined islet mass of 13-week-old non-diabetic and 17-week-old diabetic NOD mice compared to 4-week-old NOD mice. We also determined a significant and measurable loss of islet mass in mice that developed T1D. This approach will be helpful for the location-dependent quantitative calculation of islet mass and cellular infiltration during T1D pathogenesis and can be combined with other markers of inflammation or activation in future studies.

Background Responses to conventional donor lymphocyte infusion for postallogeneic hematopoietic cell transplantation (HCT) relapse are typically poor. Natural killer (NK) cell–based therapy is a promising modality to treat post-HCT relapse.Methods We initiated this ongoing phase I trial of adoptively transferred cytokine-induced memory-like (CIML) NK cells in patients with myeloid malignancies who relapsed after haploidentical HCT. All patients received a donor-derived NK cell dose of 5 to 10 million cells/kg after lymphodepleting chemotherapy, followed by systemic IL-2 for 7 doses. High-resolution profiling with mass cytometry and single-cell RNA sequencing characterized the expanding and persistent NK cell subpopulations in a longitudinal manner after infusion.Results In the first 6 enrolled patients on the trial, infusion of CIML NK cells led to a rapid 10- to 50-fold in vivo expansion that was sustained over months. The infusion was well tolerated, with fever and pancytopenia as the most common adverse events. Expansion of NK cells was distinct from IL-2 effects on endogenous post-HCT NK cells, and not dependent on CMV viremia. Immunophenotypic and transcriptional profiling revealed a dynamic evolution of the activated CIML NK cell phenotype, superimposed on the natural variation in donor NK cell repertoires.Conclusion Given their rapid expansion and long-term persistence in an immune-compatible environment, CIML NK cells serve as a promising platform for the treatment of posttransplant relapse of myeloid disease. Further characterization of their unique in vivo biology and interaction with both T cells and tumor targets will lead to improvements in cell-based immunotherapies.Trial Registration ClinicalTrials.gov NCT04024761.Funding Dunkin’ Donuts, NIH/National Cancer Institute, and the Leukemia and Lymphoma Society.

BACKGROUND: Coronavirus disease 2019 (COVID-19) can be more severe in infants than in older children. To date, only a few case series have reported data on neonates with COVID-19, including mostly asymptomatic neonates who were tested because of exposure to maternal SARS-CoV-2 infection. This study summarises nationwide epidemiological data, clinical characteristics, treatment and outcomes of neonates presenting with symptomatic SARS-CoV-2 infection. METHODS: Data were prospectively collected through the Swiss Paediatric Surveillance Unit from hospitalised neonates with laboratory-confirmed SARS-CoV-2 infection (positive polymerase chain reaction on a respiratory sample) from 1 March 2020 to 31 September 2021. All 29 paediatric hospitals in Switzerland reported cases. RESULTS: In total, 73 neonates were included; 7 (10%) were preterm. The median age at presentation was 17 days (interquartile range [IQR] 11–23); 40 (55%) were female. The majority of neonates (64, 88%) were admitted from home. Nine (12%) had a pre-existing medical condition. Overall, the most common symptom recorded was fever in 52 (71%), followed by rhinorrhoea or nasal congestion in 32 (44%) and respiratory distress in 19 (26%). Twenty (27%) neonates presented with fever without a source. Seven (10%) neonates were admitted to an intensive care unit (5 for respiratory failure and 2 for monitoring). One (1%) neonate required inotropic support. The median length of hospital stay in term neonates was 4 days (IQR 3–5). Two (3%) were treated with corticosteroids and 1 (1%) with remdesivir. In total, 60 (82%) neonates had contact with a known or suspected SARS-CoV-2 index case. All of the 71 neonates for whom data were available were discharged to their homes without symptoms. CONCLUSION: In neonates, COVID-19 mainly presents with fever, and symptoms of upper and lower respiratory tract infection. The clinical course is mostly mild, requiring a short period of hospitalisation. COVID-19 needs to be added as a differential diagnosis in neonates who present with fever without a source. However, the presence of SARS-CoV-2 should not deter from the search for a serious bacterial infection. Further data from surveillance studies are needed to better understand COVID-19 in neonates, guide therapy and to evaluate whether the clinical spectrum is changing with new SARS-CoV-2 variants.

BACKGROUND: With the invasion of Ukraine by the Russian Army in February 2022, refugees, the majority of whom are women and children, started fleeing the war to neighbouring countries. Even before the current escalation, the conflict in the eastern part of Ukraine has led to the internal displacement of more than 200,000 children, and many others have experienced attacks, e.g. on schools. This inevitably leads to limitations in health care delivery. During transit, overcrowding, poor shelter and vulnerability may further put refugees at increased risk for infectious diseases. This consensus document aims to provide information and guidance regarding health issues that paediatricians and general practitioners may face when caring for Ukrainian children. METHODS: Members of the Migrant Health Reference Group of Paediatrics Switzerland and the Paediatric Infectious Disease Group in Switzerland developed this recommendation between March and April 2022 in a modified Delphi process. RESULTS: A total of 50 recommendations were agreed on with a ≥80% consensus. These include the following topics: i) general aspects, including interpreter services, urgent health needs, personal history and general check-ups; ii) mental health, including how to search for signs of psychological distress without going into traumatic details; iii) vaccinations, including recommendations for evaluation and catch-up; iv) screening for tuberculosis, human immunodeficiency virus, and hepatitis B and C; and v) providing age-appropriate preventive and health service information. CONCLUSION: This document provides current evidence and guidance when caring for paediatric refugees from Ukraine. The recommendations focus on Switzerland but may well be used in other countries. These are based on current evidence and may need to be adapted to individual situations and once further evidence becomes available.

Abstract Background Primary care physicians are at the very heart of managing patients suffering from multimorbidity. However, several studies have highlighted that some physicians feel ill-equipped to manage these kinds of complex clinical situations. Few studies are available on the clinical reasoning processes at play during the long-term management and follow-up of patients suffering from multimorbidity. This study aims to contribute to a better understanding on how the clinical reasoning of primary care physicians is affected during follow-up consultations with these patients. Methods A qualitative research project based on semi-structured interviews with primary care physicians in an ambulatory setting will be carried out, using the video stimulated recall interview method. Participants will be filmed in their work environment during a standard consultation with a patient suffering from multimorbidity using a “button camera” (small camera) which will be pinned to their white coat. The recording will be used in a following semi-structured interview with physicians and the research team to instigate a stimulated recall. Stimulated recall is a research method that allows the investigation of cognitive processes by inviting participants to recall their concurrent thinking during an event when prompted by a video sequence recall. During this interview, participants will be prompted by different video sequence and asked to discuss them; the aim will be to encourage them to make their clinical reasoning processes explicit. Fifteen to twenty interviews are planned to reach data saturation. The interviews will be transcribed verbatim and data will be analysed according to a standard content analysis, using deductive and inductive approaches. Conclusion Study results will contribute to the scientific community’s overall understanding of clinical reasoning. This will subsequently allow future generation of primary care physicians to have access to more adequate trainings to manage patients suffering from multimorbidity in their practice. As a result, this will improve the quality of the patient’s care and treatments.

Abstract Background The Wnt/β-catenin signaling pathway is a prolific regulator of cell-to-cell communication and gene expression. Canonical Wnt/β-catenin signaling involves partnering of β-catenin with members of the TCF/LEF family of transcription factors (TCF1, TCF3, TCF4, LEF1) to regulate gene expression. IL-6 is a key cytokine involved in inflammation and is particularly a hallmark of inflammation in the brain. Astrocytes, specialized glial cells in the brain, secrete IL-6. How astrocytes regulate IL-6 expression is not entirely clear, although in other cells NFκB and C/EBP pathways play a role. We evaluated here the interface between β-catenin, TCFs/LEF and C/EBP and NF-κB in relation to IL-6 gene regulation in astrocytes. Methods We performed molecular loss and/or gain of function studies of β-catenin, TCF/LEF, NFκB, and C/EBP to assess IL-6 regulation in human astrocytes. Specifically, siRNA mediated target gene knockdown, cDNA over expression of target gene, and pharmacological agents for regulation of target proteins were used. IL-6 levels was evaluated by real time quantitative PCR and ELISA. We also cloned the IL-6 promoter under a firefly luciferase reporter and used bioinformatics, site directed mutagenesis, and chromatin immunoprecipitation to probe the interaction between β-catenin/TCFs/LEFs and IL-6 promoter activity. Results β-catenin binds to TCF/LEF to inhibits IL-6 while TCFs/LEF induce IL-6 transcription through interaction with ATF-2/SMADs. β-catenin independent of TCFs/LEF positively regulates C/EBP and NF-κB, which in turn activate IL-6 expression. The IL-6 promoter has two putative regions for TCFs/LEF binding, a proximal site located at -91 nt and a distal site at -948 nt from the transcription start site, both required for TCF/LEF induction of IL-6 independent of β-catenin. Conclusion IL-6 regulation in human astrocytes engages a discordant interaction between β-catenin and TCF/LEF. These findings are intriguing given that no role for β-catenin nor TCFs/LEF to date is associated with IL-6 regulation and suggest that β-catenin expression in astrocytes is a critical regulator of anti-inflammatory responses and its disruption can potentially mediate persistent neuroinflammation. Video Abstract Graphical abstract

BACKGROUND Gut decontamination (GD) can decrease the incidence and severity of acute graft-versus-host disease (aGVHD) in murine models of allogeneic hematopoietic cell transplantation (HCT). In this pilot study, we examined the impact of GD on gut microbiome composition and the incidence of aGVHD in HCT patients.METHODS We randomized 20 patients undergoing allogeneic HCT to receive (GD) or not receive (no-GD) oral vancomycin-polymyxin B from day –5 through neutrophil engraftment. We evaluated shotgun metagenomic sequencing of serial stool samples to compare the composition and diversity of the gut microbiome between study arms. We assessed clinical outcomes in the 2 arms and performed strain-specific analyses of pathogens that caused bloodstream infections (BSI).RESULTS The 2 arms did not differ in the predefined primary outcome of Shannon diversity of the gut microbiome at 2 weeks post-HCT (genus, P = 0.8; species, P = 0.44) or aGVHD incidence (P = 0.58). Immune reconstitution of T cell and B cell subsets was similar between groups. Five patients in the no-GD arm had 8 BSI episodes versus 1 episode in the GD arm (P = 0.09). The BSI-causing pathogens were traceable to the gut in 7 of 8 BSI episodes in the no-GD arm, including Staphylococcus species.CONCLUSION While GD did not differentially affect Shannon diversity or clinical outcomes, our findings suggest that GD may protect against gut-derived BSI in HCT patients by decreasing the prevalence or abundance of gut pathogens.TRIAL REGISTRATION ClinicalTrials.gov NCT02641236.FUNDING NIH, Damon Runyon Cancer Research Foundation, V Foundation, Sloan Foundation, Emerson Collective, and Stanford Maternal & Child Health Research Institute.

Background Among children with moderate acute malnutrition (MAM) the level of serum cobalamin (SC) and effect of food supplements are unknown. We aimed to assess prevalence and correlates of low SC in children with MAM, associations with hemoglobin and development, and effects of food supplements on SC. Methods and findings A randomized 2 × 2 × 3 factorial trial was conducted in Burkina Faso. Children aged 6 to 23 months with MAM received 500 kcal/d as lipid-based nutrient supplement (LNS) or corn–soy blend (CSB), containing dehulled soy (DS) or soy isolate (SI) and 0%, 20%, or 50% of total protein from milk for 3 months. Randomization resulted in baseline equivalence between intervention groups. Data on hemoglobin and development were available at baseline. SC was available at baseline and after 3 and 6 months. SC was available from 1,192 (74.1%) of 1,609 children at baseline. The mean (±SD) age was 12.6 (±5.0) months, and 54% were females. Low mid-upper arm circumference (MUAC; Conclusions Low SC is prevalent among children with MAM and may contribute to impaired erythropoiesis and child development. The SC increase during supplementation was inadequate. The bioavailability and adequacy of cobalamin in food supplements should be reconsidered. Trial registration ISRCTN Registry ISRCTN42569496. Henrik Friis and colleagues, investigate the prevalence and correlates of low serum cobalamin, associations with hemoglobin and child development, and associations of serum cobalamin levels with food supplementation in children moderate acute malnutrition in Burkina Faso. Author summary Why was this study done? We searched PubMed since 2000 using the terms (severe malnutrition OR acute malnutrition OR marasmus OR kwashiorkor OR wasting) AND (cobalamin OR B12) AND child*). We found no studies among children with moderate acute malnutrition (MAM) or severe acute malnutrition (SAM) treated with recommended food aid products and with data on serum cobalamin (SC) before and after treatment. What did the researchers do and find? We found that two-thirds of children with MAM had marginal or low SC, which were associated with deficits in hemoglobin and child development scores. The content of cobalamin in the food aid products was in accordance with the World Health Organization (WHO)’s recommendation and the duration of supplementation, 3 months, much longer than in programs. Despite this, one-third still had marginal or low SC at the end of supplementation, and mean levels declined considerable in the subsequent 3 months. While the study showed that supplementation was inadequate in terms of normalizing cobalamin status, it showed that lipid-based nutrient supplement (LNS) based on soy isolate (SI) was the best. What do these findings mean? Cobalamin is important for erythropoiesis and brain development. It is also likely to be of pivotal importance in the development of malnutrition, given its role in enterocyte turnover and, hence, absorption. Millions of children are treated for acute malnutrition every year. It is important that these children not only survive, but also get enough cobalamin to support key functions and long-term development.

Eidolon helvum bats are reservoir hosts for highly pathogenic lyssaviruses often showing limited disease upon natural infection. An enhanced antiviral interferon (IFN) response combined with reduced inflammation might be linked to the apparent virus tolerance in bats. Lyssavirus phosphoproteins inhibit the IFN response with virus strain-specific efficiency. To date, little is known regarding the lyssavirus P-dependent anti-IFN countermeasures in bats, mainly due to a lack of in vitro tools. By using E. helvum bat cell cultures in a newly established bat-specific IFN-promoter activation assay, we analyzed the IFN-ß inhibitory activity of multiple lyssavirus P in E. helvum compared to human cells. Initial virus infection studies with a recently isolated E. helvum-borne Lagos bat virus street strain from Ghana showed enhanced LBV propagation in an E. helvum lung cell line compared to human A549 lung cells at later time points suggesting effective viral countermeasures against cellular defense mechanisms. A direct comparison of the IFN-ß inhibitory activity of the LBV-GH P protein with other lyssavirus P proteins showed that LBV-GH P and RVP both strongly inhibited the bat IFN-β promotor activation (range 75–90%) in EidLu/20.2 and an E. helvum kidney cell line. Conversely, LBV-GH P blocked the activation of the human IFN-β promoter less efficiently compared to a prototypic Rabies virus P protein (range LBV P 52–68% vs RVP 71–95%) in two different human cell lines (HEK-293T, A549). The same pattern was seen for two prototypic LBV P variants suggesting an overall reduced LBV P IFN-ß inhibitory activity in human cells as compared to E. helvum bat cells. Increased IFN-ß inhibition by lyssavirus P in reservoir host cells might be a result of host-specific adaptation processes towards an enhanced IFN response in bat cells.

Background Every year, over 4 million children are treated for severe acute malnutrition with varying program performance. This study sought to explore the predictors of time to recovery from and non-response to outpatient treatment of SAM. Methods Children with weight-for-height z-score (WHZ) Results Fifty-five percent of children recovered and mean time to recovery was eight weeks while 13% ended as non-response to treatment. Independent predictors of longer time to recovery or non-response included low age, being admitted with WHZ Conclusions Both longer time to recovery and higher non-response to treatment seem most strongly associated with illness episodes and missed visits during treatment. This indicates that prevention of illnesses would be key to shortening the treatment duration and that there is a need to seek ways to facilitate adherence.

Background Kinetics of copeptin and mid regional proadrenomedullin (MR-proADM) during febrile pediatric lower respiratory tract infections (LRTI) are unknown. We aimed to analyze kinetic profiles of copeptin and MR-proADM and the impact of clinical and laboratory factors on those biomarkers. Methods This is a retrospective post-hoc analysis of a randomized controlled trial, evaluating procalcitonin guidance for antibiotic treatment of LRTI (ProPAED-study). In 175 pediatric patients presenting to the emergency department plasma copeptin and MR-proADM concentrations were determined on day 1, 3, and 5. Their association with clinical characteristics and other inflammatory biomarkers were tested by non-linear mixed effect modelling. Results Median copeptin and MR-proADM values were elevated on day 1 and decreased during on day 3 and 5 (-26%; -34%, respectively). The initial concentrations of MR-proADM at inclusion were higher in patients receiving antibiotics intravenously compared to oral administration (difference 0.62 pmol/L, 95%CI 0.44;1.42, pConclusion Elevated MR-proADM and increases thereof were associated with ICU admission suggesting the potential as a prognostic factor for severe pediatric LRTI. MR-proADM might only bear limited value for decision making on stopping antibiotics due to its slow decrease. Copeptin had no added value in our setting.

Modelo do estudo: Estudo transversal. Objetivo: avaliar a sensibilidade e especificidade de sistemas de rastreamento de acesso aberto para interações medicamentosas potenciais (IMp) em comparação com o DRUG-REAX® system e analisar o impacto clínico potencial das IMp de gravidades “Contraindicada” e “Maior” não detectadas. Métodos: amostra composta por 140 pacientes em acompanhamento em um ambulatório especializado no atendimento a pessoas com doenças crônicas não transmissíveis (DCNT) de um hospital universitário. As IMp foram identificadas e classificadas no DRUG-REAX® System e em oito sistemas de rastreamento de acesso aberto. As IMp de gravidade “Contraindicada” e “Maior” foram analisadas segundo o impacto clínico. Utilizou-se estatística descritiva e calculou-se sensibilidade e especificidade dos sistemas de rastreamento na identificação das IMp. Resultados: Os sistemas de acesso aberto pertencentes as bases Drugs.com, UCLA School of Health e CVC Caremark apresentaram sensibilidade e especificidade > 70%. A totalidade dos sistemas de acesso aberto não detectou os pares ciprofibrato + estatinas e metformina + sitagliptina, cujos impactos clínicos incluíram risco de miopatia e rabdomiólise e hipoglicemia, respectivamente. Cerca de um terço (37,5%) dos sistemas de acesso aberto não detectou a IMp ácido acetilsalicílico + hidroclorotiazida, capaz de ocasionar nefrotoxicidade. Conclusão: A maioria dos pares de IMp integra o rol terapêutico de pacientes com DCNT e cujos impactos clínicos são tempo-dependentes. A combinação de julgamento clínico, revisão periódica do plano terapêutico e os atributos de precisão (sensibilidade e especificidade) são fundamentais para garantir a segurança do paciente, sobretudo no contexto ambulatorial.

AIMS OF THE STUDY: Apparent life threatening events (ALTEs) are highly stressful situations for the caregiver and commonly result in presentation of the child to an emergency department. As the events are usually brief and resolve in a short period of time, the entity is now called a brief resolved unexplained event (BRUE). Updated recommendations have been published in recent years on the management of BRUE, including a risk stratification to identify those at lower risk for subsequent events or severe underlying disorders. The aim of this study was to describe the epidemiology of ALTE and BRUE at our hospital and detail clinical practice of management in this population in a tertiary care children’s hospital in Switzerland. METHODS: We retrospectively analysed all cases of children with an ALTE or BRUE admitted to the University Children’s Hospital Basel between September 2009 and April 2018, identified using ICD-10GM coding. Electronic health records were used to extract data on diagnostic procedures, duration of admission and outcome. Infants with a lower-risk BRUE (defined as age >60 days and

Patients with COPD often have reduced physical activity, which can impair health status. Real-world data can provide valuable information on the health and functional status of patients with COPD treated with tiotropium/olodaterol. AERIAL® (ClinicalTrials.gov NCT03165045) was a German, non-interventional study of patients with COPD receiving treatment with tiotropium/olodaterol under real-world conditions for ∼6 weeks. The primary end-point was the proportion of patients achieving a decrease of ≥0.4 points in Clinical COPD Questionnaire (CCQ) score. The CCQ-4 subdomain was used to assess functional status, and the Physician's Global Evaluation (PGE) scale was used to assess the patients’ general condition. Safety was assessed, as well as patient satisfaction and willingness to continue treatment. Out of 1351 screened patients, 1322 were treated and 1140 comprised the full analysis set. The primary end-point was met: 66.3% of patients achieved a ≥0.4-point decrease in overall CCQ score (mean±sd decrease 0.78±0.95). Mean±sd decreases in CCQ symptoms and functional state subdomains were 0.84±1.06 and 0.75±1.05 points, respectively. PGE scores improved. One fatality (not treatment-related) and 23 drug-related adverse events were recorded, most commonly nausea and vertigo. >85% of patients were satisfied/very satisfied with tiotropium/olodaterol overall and with the Respimat® device, both in terms of inhalation and handling. Most patients (95.2%) expressed willingness to continue treatment. Patients with COPD treated with tiotropium/olodaterol via Respimat® in routine clinical practice had clinically relevant improvements in health and functional status compared with baseline.

In anticipation of an interseasonal respiratory syncytial virus (RSV) epidemic, a clinician-led reporting system was rapidly established to capture RSV infections in Swiss hospitals, starting in January 2021. Here, we present details of the reporting system and first results to June 2021. An unusual epidemiology was observed with an interseasonal surge of RSV infections associated with COVID-19-related non-pharmacological interventions. These data allowed real-time adjustment of RSV prophylaxis guidelines and consequently underscore the need for and continuation of systematic nationwide RSV surveillance.

Background: Gliomas are the most frequent and aggressive malignancies of the central nervous system. Decades of molecular analyses have demonstrated that gliomas accumulate genetic alterations that culminate in enhanced activity of receptor tyrosine kinases and downstream mediators. While the genetic alterations, like gene amplification or loss, have been well characterized, little information exists about changes in the proteome of gliomas of different grades. Methods: We performed unbiased quantitative proteomics of human glioma biopsies by mass spectrometry followed by bioinformatic analysis. Findings: Various pathways were found to be up- or downregulated. In particular, endocytosis as pathway was affected by a vast and concomitant reduction of multiple machinery components involved in initiation, formation, and scission of endocytic carriers. Both clathrin-dependent and -independent endocytosis were changed, since not only clathrin, AP-2 adaptins, and endophilins were downregulated, but also dynamin that is shared by both pathways. The reduction of endocytic machinery components caused increased receptor cell surface levels, a prominent phenotype of defective endocytosis. Analysis of additional biopsies revealed that depletion of endocytic machinery components was a common trait of various glioma grades and subclasses. Interpretation: We propose that impaired endocytosis creates a selective advantage in glioma tumor progression due to prolonged receptor tyrosine kinase signaling from the cell surface. Fund: This work was supported by Grants 316030-164105 (to P. Jenö), 31003A-162643 (to M. Spiess) and PP00P3-176974 (to G. Hutter) from the Swiss National Science Foundation. Further funding was received by the Department of Surgery from the University Hospital Basel. Keywords: Glioma, Endocytosis, RTK, Dynamin, Clathrin, AP-2

Abstract Background Estimation of the dietary requirements for vitamin D is crucial from a public health perspective in providing a framework for the prevention of vitamin D deficiency. It has been shown that pooling individual participant-level data (IPD) from selected randomised controlled trials (RCTs) of white children and adults facilitated the generation of more accurate estimates of the vitamin D requirement. Recent RCT data suggest the vitamin D requirement of dark-skinned, particularly black, individuals, an at-risk group of vitamin D deficiency, is greater than those of white counterparts. Thus, we wished to develop a study protocol for the conduct of an IPD-level meta-analysis of vitamin D requirements using data from appropriate vitamin D RCTs in dark-skinned population subgroups. Methods The study protocol details the steps needed within such an IPD meta-analysis which will include its registration, constituent systematic review to identify all appropriate RCTs on the basis of pre-specified eligibility criteria, the associated data collection, handling, and synthesis, as well as checking the integrity of the IPD, followed by implementation of a one/two-stage IPD meta-analysis and derivation of vitamin D requirement estimates. Discussion As dark-skinned population subgroups are at increased risk of vitamin D deficiency, further investigation of dietary recommendations for vitamin D in these subgroups is needed. We strongly believe that application of an IPD-based meta-analysis is a highly strategic approach by which to undertake some of this further investigation. Such IPD-based analysis, however, will need collaboration across the principal investigators of the identified RCTs meeting with the eligibility criteria, and the availability of this study protocol will be important to highlight the potential of IPD-based analysis for estimation of the dietary requirement for vitamin D for this particular population subgroup as well as for other at-risk target populations. Systematic review registration PROSPERO International Prospective Register of Systematic Reviews (registration number: CRD42018092343).

BackgroundDuring the early phase of the Covid-19 pandemic, reductions of hospital admissions with a focus on emergencies have been observed for several medical and surgical conditions, while trend data during later stages of the pandemic are scarce. Consequently, this study aims to provide up-to-date hospitalization trends for several conditions including cardiovascular, psychiatry, oncology and surgery cases in both the in- and outpatient setting.Methods and findingsUsing claims data of 86 Helios hospitals in Germany, consecutive cases with an in- or outpatient hospital admission between March 13, 2020 (the begin of the "protection" stage of the German pandemic plan) and December 10, 2020 (end of study period) were analyzed and compared to a corresponding period covering the same weeks in 2019. Cause-specific hospitalizations were defined based on the primary discharge diagnosis according to International Statistical Classification of Diseases and Related Health Problems (ICD-10) or German procedure classification codes for cardiovascular, oncology, psychiatry and surgery cases. Cumulative hospitalization deficit was computed as the difference between the expected and observed cumulative admission number for every week in the study period, expressed as a percentage of the cumulative expected number. The expected admission number was defined as the weekly average during the control period. A total of 1,493,915 hospital admissions (723,364 during the study and 770,551 during the control period) were included. At the end of the study period, total cumulative hospitalization deficit was -10% [95% confidence interval -10; -10] for cardiovascular and -9% [-10; -9] for surgical cases, higher than -4% [-4; -3] in psychiatry and 4% [4; 4] in oncology cases. The utilization of inpatient care and subsequent hospitalization deficit was similar in trend with some variation in magnitude between cardiovascular (-12% [-13; -12]), psychiatry (-18% [-19; -17]), oncology (-7% [-8; -7]) and surgery cases (-11% [-11; -11]). Similarly, cardiovascular and surgical outpatient cases had a deficit of -5% [-6; -5] and -3% [-4; -3], respectively. This was in contrast to psychiatry (2% [1; 2]) and oncology cases (21% [20; 21]) that had a surplus in the outpatient sector. While in-hospital mortality, was higher during the Covid-19 pandemic in cardiovascular (3.9 vs. 3.5%, OR 1.10 [95% CI 1.06-1.15], PConclusionsThere have been varying changes in care pathways and in-hospital mortality in different disciplines during the Covid-19 pandemic in Germany. Despite all the inherent and well-known limitations of claims data use, this data may be used for health care surveillance as the pandemic continues worldwide. While this study provides an up-to-date analysis of utilization of hospital care in the largest German hospital network, short- and long-term consequences are unknown and deserve further studies.

BackgroundMajority of active tuberculosis (TB) cases in children in low-incidence countries are due to rapid progression of infection (latent TB infection (LTBI)) to disease. We aimed to assess common practice for managing paediatric LTBI in Austria, Germany and Switzerland prior to the publication of the first joint national guideline for paediatric TB in 2017.MethodsOnline-based survey amongst pediatricians, practitioners and staff working in the public health sector between July and November 2017. Data analysis was conducted using IBM SPSS.ResultsA total of 191 individuals participated in the survey with 173 questionnaires included for final analysis. Twelve percent of respondents were from Austria, 60% from Germany and 28% from Switzerland. Proportion of children with LTBI and migrant background was estimated by the respondents to be >50% by 58%. Tuberculin skin test (TST) and interferon-γ-release-assay (IGRA), particularly Quantiferon-gold-test, were reported to be used in 86% and 88%, respectively. In children > 5 years with a positive TST or IGRA a chest x-ray was commonly reported to be performed (28%). Fifty-three percent reported to take a different diagnostic approach in children ≤ 5 years, mainly combining TST, IGRA and chest x-ray for initial testing (31%). Sixty-eight percent reported to prescribe isoniazid-monotherapy: for 9 (62%), or 6 months (6%), 31% reported to prescribe combination therapy of isoniazid and rifampicin. Dosing of isoniazid and rifampicin below current recommendations was reported by up to 22% of respondents. Blood-sampling before/during LTBI treatment was reported in >90% of respondents, performing a chest-X-ray at the end of treatment by 51%.ConclusionThis survey showed reported heterogeneity in the management of paediatric LTBI. Thus, regular and easily accessible educational activities and national up-to-date guidelines are key to ensure awareness and quality of care for children and adolescents with LTBI in low-incidence countries.

BackgroundThe prevalence of latent tuberculosis infection (LTBI) is vastly higher than that of tuberculosis (TB) disease and this enormous reservoir of individuals with LTBI impacts the global TB control strategy. Adolescents are at greatest risk of TB infection and are thus an ideal target population for a potential effective TB vaccine to be added to the current BCG programme as it could reduce the number of latent infections and consequently the number of adults with TB disease. However, LTBI rates are often unknown for this population. This study aims to estimate the magnitude of LTBI and to determine if Tanzanian adolescents would be a good population for a prevention of TB infection trial.MethodsThis was a descriptive cross-sectional study that recruited 193 adolescents aged 12 and 16 years from government schools and directly from the community in Mwanza Region, Tanzania. Socio-demographic characteristics were collected for all enrolled participants. Blood was drawn and tested using QuantiFERON-TB Gold In-Tube (QFT-GIT), and Early Secretory Antigenic Target-6-Free Interferon-gamma Release Assay (ESAT-6 free IGRA). Concordance between QFT-GIT and ESAT-6 free IGRA was evaluated using the McNemar's test.ResultsOverall estimates of LTBI prevalence were 19.2% [95%CI, 14.1; 25.2] and 18.6% [95%CI, 13.6; 24.6] as measured by QFT-GIT IGRA and ESAT-6 free IGRA, respectively. The 16-year-old cohort had a higher LTBI prevalence (23.7% [95%CI, 16.1; 32.9]) as compared to 12-year-old cohort (14.6% [95%CI, 8.6; 22.7]) as measured by QFT-GIT IGRA. When measured by ESAT-6 Free IGRA, LTBI prevalence was 24.7% (95%CI, 16.9; 34.0) for the 16-year-old cohort and 12.5% (95%CI, 7.0; 20.3) among the 12-year-old cohort. According to both tests the prevalence of TB infection and the corresponding annual risk of tuberculosis infection (ARTI) and force of infection were high and increased with age. Of all enrolled participants, 97.4% had concordant results for QFT-GIT IGRA and ESAT-6 free IGRA (p = 0.65).ConclusionsThe prevalence of LTBI and the associated ARTI and force of infection among adolescents is high and increases with age in Mwanza Region. There was a high concordance between the QFT-GIT and the novel ESAT-6 free IGRA assays. These findings suggest Mwanza is a promising area to conduct novel TB vaccine research prevention of infection (POI) studies targeting adolescents.

Personalised nutrition (PN) is an emerging field that bears great promise. Several definitions of PN have been proposed and different modelling approaches have been used to claim PN effects. We tentatively propose to group these approaches into two categories, which we term outcome-based and population reference approaches, respectively. Understanding the fundamental differences between these two types of modelling approaches may allow a more realistic appreciation of what to expect from PN interventions presently and may be helpful for designing and planning future studies investigating PN interventions.

BackgroundLipid-based nutrient supplements (LNS) and corn-soy blends (CSBs) with varying soy and milk content are used in treatment of moderate acute malnutrition (MAM). We assessed the impact of these supplements on child development.Methods and findingsWe conducted a randomised 2 × 2 × 3 factorial trial to assess the effectiveness of 12 weeks' supplementation with LNS or CSB, with either soy isolate or dehulled soy, and either 0%, 20%, or 50% of protein from milk, on child development among 6-23-month-old children with MAM. Recruitment took place at 5 health centres in Province du Passoré, Burkina Faso between September 2013 and August 2014. The study was fully blinded with respect to soy quality and milk content, while study participants were not blinded with respect to matrix. This analysis presents secondary trial outcomes: Gross motor, fine motor, and language development were assessed using the Malawi Development Assessment Tool (MDAT). Of 1,609 children enrolled, 54.7% were girls, and median age was 11.3 months (interquartile range [IQR] 8.2-16.0). Twelve weeks follow-up was completed by 1,548 (96.2%), and 24 weeks follow-up was completed by 1,503 (93.4%); follow-up was similar between randomised groups. During the study, 4 children died, and 102 children developed severe acute malnutrition (SAM). There was no difference in adverse events between randomised groups. At 12 weeks, the mean MDAT z-scores in the whole cohort had increased by 0.33 (95% CI: 0.28, 0.37), p < 0.001 for gross motor; 0.26 (0.20, 0.31), p < 0.001 for fine motor; and 0.14 (0.09, 0.20), p < 0.001 for language development. Children had larger improvement in language z-scores if receiving supplements with milk (20%: 0.09 [-0.01, 0.19], p = 0.08 and 50%: 0.11 [0.01, 0.21], p = 0.02), although the difference only reached statistical significance for 50% milk. Post hoc analyses suggested that this effect was specific to boys (interaction p = 0.02). The fine motor z-scores were also improved in children receiving milk, but only when 20% milk was added to CSB (0.18 [0.03, 0.33], p = 0.02). Soy isolate over dehulled soy increased language z-scores by 0.07 (-0.01, 0.15), p = 0.10, although not statistically significant. Post hoc analyses suggested that LNS benefited gross motor development among boys more than did CSB (interaction p = 0.04). Differences between supplement groups did not persist at 24 weeks, but MDAT z-scores continued to increase post-supplementation. The lack of an unsupplemented control group limits us from determining the overall effects of nutritional supplementation for children with MAM.ConclusionsIn this study, we found that child development improved during and after supplementation for treatment of MAM. Milk protein was beneficial for language and fine motor development, while suggested benefits related to soy quality and supplement matrix merit further investigation. Supplement-specific effects were not found post-intervention, but z-scores continued to improve, suggesting a sustained overall effect of supplementation.Trial registrationISRCTN42569496.

The extracellular matrix (ECM) plays critical roles in tumor progression and metastasis. However, the contribution of ECM proteins to early metastatic onset in the peritoneal cavity remains unexplored. Here, we suggest a new route of metastasis through the interaction of integrin alpha 2 (ITGA2) with collagens enriched in the tumor coinciding with poor outcome in patients with ovarian cancer. Using multiple gene-edited cell lines and patient-derived samples, we demonstrate that ITGA2 triggers cancer cell adhesion to collagen, promotes cell migration, anoikis resistance, mesothelial clearance, and peritoneal metastasis in vitro and in vivo. Mechanistically, phosphoproteomics identify an ITGA2-dependent phosphorylation of focal adhesion kinase and mitogen-activated protein kinase pathway leading to enhanced oncogenic properties. Consequently, specific inhibition of ITGA2-mediated cancer cell-collagen interaction or targeting focal adhesion signaling may present an opportunity for therapeutic intervention of metastatic spread in ovarian cancer.

BACKGROUND In the last decade an increasing number of asylum-seeking children arrived in Europe and local healthcare systems have been challenged to adapt to their health needs. The aim of this study was to compare the spectrum of disease and management of asylum-seeking and non-asylum-seeking children requiring hospital admission. METHODS This was a retrospective cohort study including health data from recently arrived asylum-seeking and non-asylum-seeking children admitted between January 2016 and December 2017. Data were collected using electronic administrative and medical records. RESULTS Of 11,794 admissions of 9407 patients, 149 (1%) were asylum-seeking and 11,645 (99%) from non-asylum-seeking children. In asylum-seeking children the median age was 4 years (interquartile range [IQR] 0–13) with 61% males and in non-asylum-seeking children 4 years (IQR 0–11) years with 56% males. Respiratory infections accounted for 17–19% of admissions in both groups. Rare infectious diseases were more frequent in asylum-seeking children (15 vs 7%; difference in proportions 0.08, 95% confidence interval [CI] 0.02–0.14; p

In childhood tuberculosis (TB), with an estimated 69% of missed cases in children under 5 years of age, the case detection gap is larger than in other age groups, mainly due to its paucibacillary nature and children’s difficulties in delivering sputum specimens. Accurate and accessible point-of-care tests (POCTs) are needed to detect TB disease in children and, in turn, reduce TB-related morbidity and mortality in this vulnerable population. In recent years, several POCTs for TB have been developed. These include new tools to improve the detection of TB in respiratory and gastric samples, such as molecular detection of Mycobacterium tuberculosis using loop-mediated isothermal amplification (LAMP) and portable polymerase chain reaction (PCR)-based GeneXpert. In addition, the urine-based detection of lipoarabinomannan (LAM), as well as imaging modalities through point-of-care ultrasonography (POCUS), are currently the POCTs in use. Further to this, artificial intelligence-based interpretation of ultrasound imaging and radiography is now integrated into computer-aided detection products. In the future, portable radiography may become more widely available, and robotics-supported ultrasound imaging is currently being trialed. Finally, novel blood-based tests evaluating the immune response using “omic-“techniques are underway. This approach, including transcriptomics, metabolomic, proteomics, lipidomics and genomics, is still distant from being translated into POCT formats, but the digital development may rapidly enhance innovation in this field. Despite these significant advances, TB-POCT development and implementation remains challenged by the lack of standard ways to access non-sputum-based samples, the need to differentiate TB infection from disease and to gain acceptance for novel testing strategies specific to the conditions and settings of use.

In low tuberculosis-burden countries, children and adolescents with the highest incidence of tuberculosis (TB) infection or disease are usually those who have immigrated from high-burden countries. It is, therefore, essential that low-burden countries provide healthcare services to immigrant and refugee families, to assure that their children can receive proper testing, evaluation, and treatment for TB. Active case-finding through contact tracing is a critical element of TB prevention in children and in finding TB disease at an early, easily treated stage. Passive case-finding by evaluating an ill child is often delayed, as other, more common infections and conditions are suspected initially. While high-quality laboratory services to detect Mycobacterium tuberculosis are generally available, they are often underutilized in the diagnosis of childhood TB, further delaying diagnosis in some cases. Performing research on TB disease is difficult because of the low number of cases that are spread over many locales, but critical research on the evaluation and treatment of TB infection has been an important legacy of low-burden countries. The continued education of medical providers and the involvement of educational, professional, and non-governmental organizations is a key element of maintaining awareness of the presence of TB. This article provides the perspective from North America and Western Europe but is relevant to many low-endemic settings. TB in children and adolescents will persist in low-burden countries as long as it persists throughout the rest of the world, and these wealthy countries must increase their financial commitment to end TB everywhere.

Abstract Background Several articles suggest that DNA methylation levels in blood relate to Parkinson’s disease (PD) but there is a need for a large-scale study that involves suitable population based controls. The purposes of the study were: (1) to study whether PD status is associated with DNA methylation levels in blood/saliva; (2) to study whether observed associations relate to blood cell types; and (3) to characterize genome-wide significant markers (“CpGs”) and clusters of CpGs (co-methylation modules) in terms of biological pathways. Methods In a population-based case control study of PD, we studied blood samples from 335 PD cases and 237 controls and saliva samples from another 128 cases and 131 controls. DNA methylation data were generated from over 486,000 CpGs using the Illumina Infinium array. We identified modules of CpGs (clusters) using weighted correlation network analysis (WGCNA). Results Our cross-sectional analysis of blood identified 82 genome-wide significant CpGs (including cg02489202 in LARS2 p = 8.3 × 10–11 and cg04772575 in ABCB9 p = 4.3 × 10–10). Three out of six PD related co-methylation modules in blood were significantly enriched with immune system related genes. Our analysis of saliva identified five significant CpGs. PD-related CpGs are located near genes that relate to mitochondrial function, neuronal projection, cytoskeleton organization, systemic immune response, and iron handling. Conclusions This study demonstrates that: (1) PD status has a profound association with DNA methylation levels in blood and saliva; and (2) the most significant PD-related changes reflect changes in blood cell composition. Overall, this study highlights the role of the immune system in PD etiology but future research will need to address the causal structure of these relationships.

Abstract Pediatric tuberculosis (TB) is challenging to diagnose, confirmed by growth of Mycobacterium tuberculosis at best in 40% of cases. The WHO has assigned high priority to the development of non-sputum diagnostic tools. We therefore sought to identify transcriptional signatures in whole blood of Indian children, capable of discriminating intra-thoracic TB disease from other symptomatic illnesses. We investigated the expression of 198 genes in a training set, comprising 47 TB cases (19 definite/28 probable) and 36 asymptomatic household controls, and identified a 7- and a 10-transcript signature, both including NOD2, GBP5, IFITM1/3, KIF1B and TNIP1. The discriminatory abilities of the signatures were evaluated in a test set comprising 24 TB cases (17 definite/7 probable) and 26 symptomatic non-TB cases. In separating TB-cases from symptomatic non-TB cases, both signatures provided an AUC of 0.94 (95%CI, 0.88–1.00), a sensitivity of 91.7% (95%CI, 71.5–98.5) regardless of culture status, and 100% sensitivity for definite TB. The 7-transcript signature provided a specificity of 80.8% (95%CI, 60.0–92.7), and the 10-transcript signature a specificity of 88.5% (95%CI, 68.7–96.9%). Although warranting exploration and validation in other populations, our findings are promising and potentially relevant for future non-sputum based POC diagnostic tools for pediatric TB.

Abstract All over the world, different types of nanomaterials with a diversified spectrum of applications are designed and developed, especially in the field of nanomedicine. The great variety of nanoparticles (NPs), in vitro test systems and cell lines led to a vast amount of publications with conflicting data. To identify the decisive principles of these variabilities, we conducted an intercomparison study of collaborating laboratories within the German DFG Priority Program SPP1313, using well-defined experimental parameters and well-characterized NPs. The participants analyzed the in vitro biocompatibility of silica and polymer NPs on human hepatoma HepG2 cells. Nanoparticle mediated effects on cell metabolism, internalization, and inflammation were measured. All laboratories showed that both nanoparticle formulations were internalized and had a low cytotoxicity profile. Interestingly, small variations in nanoparticle preparation, cell handling and the type of culture slide influenced the nanoparticle stability and the outcomes of cell assays. The round robin test demonstrated the importance of the use of clearly defined and characterized NPs and parameters for reproducible results across laboratories. Comparative analyses of in vitro screening methods performed in multiple laboratories are absolutely essential to establish robust standard operation procedure as a prerequisite for sound hazard assessment of nanomaterials.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.