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ObjectivesTo find the optimal treatment duration with antibiotics for community-acquired pneumonia (CAP) in adults.DesignSystematic review and duration-effect meta-analysis.Data sourcesMEDLINE, Embase and CENTRAL through 25 August 2021.Eligibility criteriaAll randomised controlled trials comparing the same antibiotics used at the same daily dosage but for different durations for CAP in adults. Both outpatients and inpatients were included but not those admitted to intensive care units. We imposed no date, language or publication status restriction.Data extraction and synthesisData extraction by two independent reviewers. We conducted a random-effects, one-stage duration-effect meta-analysis with restricted cubic splines. We tested the non-inferiority with the prespecified non-inferiority margin of 10% examined against 10 days . The primary outcome was clinical improvement on day 15 (range 7–45 days). Secondary outcomes: all-cause mortality, serious adverse events and clinical improvement on day 30 (15–60 days).ResultsWe included nine trials (2399 patients with a mean (SD) age of 61.2 (22.1); 39% women). The duration-effect curve was monotonic with longer duration leading to a lower probability of improvement, and shorter treatment duration (3–9 days) was likely to be non-inferior to 10-day treatment. Harmful outcome curves indicated no association. The weighted average percentage of the primary outcome in the 10-day treatment arms was 68%. Using that average, the absolute clinical improvement rates of the following durations were: 3-day treatment 75% (95% CI: 68% to 81%), 5-day treatment 72% (95% CI: 66% to 78%) and 7-day treatment 69% (95% CI: 61% to 76%).ConclusionsShorter treatment duration (3–5 days) probably offers the optimal balance between efficacy and treatment burden for treating CAP in adults if they achieved clinical stability. However, the small number of included studies and the overall moderate-to-high risk of bias may compromise the certainty of the results. Further research on the shorter duration range is required.PROSPERO registration numberCRD 42021273357.…

ObjectiveThis study aimed to assess the knowledge and acceptability of the human papillomavirus (HPV) vaccine and associated factors among female adolescent students in Debre Tabor Town, Ethiopia, 2021.DesignCross-sectional study was done from 9 December 2020 to 28 February 2021.AnalysisThe data were entered into EpiData V.4.2 and analysed with SPSS V.23 software. The OR, 95% CI and p<0.05 were used to determine the bivariable and multivariable statistical association.SettingThree high schools (grades 9 and 10) and six primary schools (grades 7 and 8) were included in the study.ParticipantsAdolescent female students in Debre Tabor Town.ResultsThe overall knowledge score in the questionnaire was six, and it was divided into two groups based on scoring level: poor (score <3) and good (score ≥3). More than half respondents (59.2%) scored good knowledge. The proportion of acceptability of the HPV vaccine was 61.9%. Age (adjusted OR, AOR 1.70, 95% CI 1.17 to 3.88), and having a source of information (AOR 1.94, 95% CI 1.06 to 3.22) were significantly associated with the knowledge of the HPV vaccine. Place of birth (AOR 1.55, 95% CI 1.15 to 1.95), fathers’ educational status (AOR 2.80, 95% CI 1.18 to 5.65), having a source of information (AOR 2.14, 95% CI 1.05 to 4.32) and knowledge about the HPV vaccine (AOR 6.41, 95% CI 3.45 to 11.90) were significantly associated with the acceptance of the female adolescent HPV vaccine.ConclusionIn this study, the knowledge and acceptability of students of the HPV vaccine were low. Health authorities, through the mass media, should strengthen HPV vaccine promotion in schools, religious institutions and health facilities.…

IntroductionThe effectiveness of psychotherapy in depression is subject of an ongoing debate. The mechanisms of change are still underexplored. Research tries to find influencing factors fostering the effect of psychotherapy. In that context, the dose–response relationship should receive more attention. Increasing the frequency from one to two sessions per week seems to be a promising start. Moreover, the concept of expectations and its influence in depression can be another auspicious approach. Dysfunctional expectations and the lack of their modification are central in symptom maintenance. Expectation focused psychological interventions (EFPI) have been investigated, primarily in the field of depression. The aim of this study is to compare cognitive behavioural therapy (CBT) once a week with an intensified version of CBT (two times a week) in depression as well as to include a third proof-of-principle intervention group receiving a condensed expectation focused CBT.Methods and analysisParticipants are recruited through an outpatient clinic in Germany. A current major depressive episode, diagnosed via structured clinical interviews should present as the main diagnosis. The planned randomised-controlled trial will allow comparisons between the following treatment conditions: CBT (one session/week), condensed CBT (two sessions/week) and EFPI (two sessions/week). All treatment arms include a total dose of 24 sessions. Depression severity applies as the outcome variable (Beck Depression Inventory II, Montgomery Asberg Depression Rating Scale). A sample size of n=150 is intended.Ethics and disseminationThe local ethics committee of the Department of Psychology, Philipps-University Marburg approved the study (reference number 2020-68 v). The final research article including the study results is intended to be published in international peer-reviewed journals.Trial registration numberGerman Clinical Trials Registry (DRKS00023203).…

ObjectivesThe non-transfusion-dependent beta-thalassaemia-patient-reported outcome (NTDT-PRO) questionnaire was developed for assessing anaemia-related tiredness/weakness (T/W) and shortness of breath (SoB) among patients with NTDT. Psychometric properties were evaluated using blinded data from the BEYOND trial (NCT03342404).DesignAnalysis of a phase 2, double-blind, randomised, placebo-controlled trial.SettingUSA, Greece, Italy, Lebanon, Thailand and the UK.ParticipantsAdults (≥18 years) (N=145) with NTDT who had not received a red blood cell transfusion within 8 weeks prior to randomisation, with mean baseline haemoglobin level ≤100 g/L.MeasuresNTDT-PRO daily scores from baseline until week 24, and scores at select time points for the 36-Item Short Form Health Survey version 2 (SF-36v2), Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) and Patient Global Impression of Severity (PGI-S).ResultsCronbach’s alpha at weeks 13–24 was 0.95 and 0.84 for the T/W and SoB domains, respectively, indicating acceptable internal consistency reliability. Among participants self-reporting no change in thalassaemia symptoms via the PGI-S between baseline and week 1, intraclass correlation coefficients were 0.94 and 0.92 for the T/W and SoB domains, respectively, indicating excellent test–retest reliability. In a known-groups validity analysis, least-squares mean T/W and SoB scores at weeks 13–24 were worse in participants with worse scores for the FACIT-F Fatigue Subscale (FS), SF-36v2 vitality or PGI-S. Indicating responsiveness, changes in T/W and SoB domain scores were moderately correlated with changes in haemoglobin levels, and strongly correlated with changes in SF-36v2 vitality, FACIT-F FS, select FACIT-F items and the PGI-S. Improvements in least-squares mean T/W and SoB scores were higher in participants with greater improvements in scores on other PROs measuring similar constructs.ConclusionsThe NTDT-PRO demonstrated adequate psychometric properties to assess anaemia-related symptoms in adults with NTDT and can be used to evaluate treatment efficacy in clinical trials.…

IntroductionPeople with disabilities have a higher prevalence of cigarette smoking than people without disabilities. However, little information exists on smoking cessation interventions tailored to address the unique needs of people with disabilities. This paper describes a systematic review protocol to identify and evaluate tobacco smoking cessation interventions designed to improve outcomes for people with disabilities.Methods and analysisWe will conduct a systematic review of the literature using the procedures outlined by Cochrane. We will search four electronic databases (CINAHL Plus (EBSCO), Embase (Ovid), Medline (Ovid) and PsycINFO (Ovid)) with no date restriction to identify tobacco cessation interventions tailored to meet the needs of people with disabilities. We will extract data and assess risk of bias using the RoB2 and ROBINS-I for included studies using Covidence systematic review software. Quantitative and qualitative syntheses will summarise key study characteristics and outcomes with text, tables and forest plots; a meta-analysis will be conducted, if appropriate.Ethics and disseminationEthical approval is not required as there are no primary data associated with the study. Data will be disseminated through a peer-reviewed articles and conference presentations.PROSPERO registration numberCRD42022337434.…

ObjectivesIncreasingly attention of the COVID-19 pandemic is directed towards its long-term effects, also known as Long-COVID. So far, Long-COVID was examined mainly from a medical perspective, leaving psychosocial effects of Long-COVID understudied. The present study advances the current literature by examining social support in the context of Long-COVID. The study not only examines received support reported by individuals with Long-COVID, but also provided support reported by relatives of individuals with Long-COVID.DesignCross-sectional study.SettingThe study was conducted from June to October 2021 in Austria, Germany and the German-speaking part of Switzerland.ParticipantsWe examined 256 individuals with Long-COVID (MAge=45.05 years, 90.2% women) and 50 relatives of individuals with Long-COVID (MAge=48.34 years, 66.1% female) in two separate online surveys, assessing social support, well-being and distress.Primary outcome measuresPrimary outcomes were positive and negative affect, anxiety and depressive symptoms and perceived stress.ResultsFor individuals with Long-COVID, receiving emotional support was related to higher well-being (positive affect: b=0.29, p<0.01; negative affect: b=–0.31, p<0.05) and less distress (anxiety: b=–1.45, p<0.01; depressive symptoms: b=–1.04, p<0.05; perceived stress: b=–0.21, p<0.05) but no effects emerged for receiving practical support. For relatives of individuals with Long-COVID, providing emotional support was only related to lower depressive symptoms (b=–2.57, p<0.05). Again, provided practical support was unrelated to the outcomes considered.ConclusionsEmotional support is likely to play an important role in well-being and distress of patients and relatives, whereas practical support does not seem to make a difference. Future research should clarify under what conditions different kinds of support unfold their positive effects on well-being and distress in the context of Long-COVID.…

Healthcare staff have been facing particular mental health challenges during the COVID-19-pandemic. Building on a first study at the beginning of the pandemic in March 2020, we aimed to investigate among healthcare professionals in Germany and Austria (1) how mental health may have changed in professionals over the course of the ongoing pandemic, (2) whether there are differences between different professional groups regarding mental health, (3) which stress factors may explain these mental health outcomes and (4) whether help-seeking behaviour is related to caretaker self-image or team climate. Between March and June 2021, N=639 healthcare professionals completed an online survey including the ICD-10 Symptom Rating checklist, event-sampling questions on pandemic-related stressors and self-formulated questions on help-seeking behaviour and team climate. Findings were analysed using t-tests, regressions and comparisons to a sample of healthcare professionals assessed in 2020 as well as to norm samples. Results show that mental health symptoms, particularly for depression and anxiety, persist among healthcare staff in the second pandemic year, that symptom prevalence rates are higher among nursing staff compared with physicians and paramedics and that team climate is associated with mental health outcomes. Implications of these findings in relation to the persisting pandemic and its aftermath are discussed.…

ObjectiveTo assess the prevalence, treatment outcomes and determinants of tuberculosis (TB)–HIV coinfection in Ghana.Study designA retrospective review of TB case register for Kwabre East Municipality was conducted for the period 2010–2020 to identify TB–HIV coinfections.Setting462 patients with TB from four sub-municipal treatment centres were included in the study.Primary outcome measureA logistic regression model was used to investigate the relationship between clinico-demographic factors (age, sex, type of patient, disease classification, treatment category and sputum smear microscopy) and TB–HIV coinfection.ResultsOf the 462 individual TB cases found in the TB register from 2010 to 2020, 286 (61.9%) were screened for HIV and the results showed that 18% had TB–HIV coinfection. TB–HIV coinfection was highest in 2015 with a prevalence of 40% among all registered TB cases. The likelihood of TB–HIV coinfection was highest among patients with TB aged 40–49 years (AOR=3.99, CI=1.3, 12.7). Those who tested negative for TB at the end of their treatment period had lower odds of HIV coinfection (AOR=0.27, CI=0.10, 0.72).ConclusionNearly one out of every five (18%) patients with TB in the municipality were found to be coinfected with HIV. TB–HIV coinfection was significantly associated with patients' age and their TB treatment outcomes. Urgent interventions are needed to address these risk factors to promote optimal health for patients with TB in the municipality.…

Science Advances, Volume 9, Issue 12, March 2023.

Science Advances, Volume 9, Issue 12, March 2023.

Antimicrobial Agents and Chemotherapy, Ahead of Print.

Publication date: Available online 21 March 2023Source: ImmunityAuthor(s): Michaela Seeling, Matthias Pöhnl, Sibel Kara, Nathalie Horstmann, Carolina Riemer, Miriam Wöhner, Chunguang Liang, Christin Brückner, Patrick Eiring, Anja Werner, Markus Biburger, Leon Altmann, Martin Schneider, Lukas Amon, Christian H.K. Lehmann, Sooyeon Lee, Meik Kunz, Diana Dudziak, Georg Schett, Tobias Bäuerle…

Publication date: Available online 21 March 2023Source: ImmunityAuthor(s): Conor M. Finlay, James E. Parkinson, Lili Zhang, Brian H.K. Chan, Jesuthas Ajendra, Alistair Chenery, Anya Morrison, Irem Kaymak, Emma L. Houlder, Syed Murtuza Baker, Ben R. Dickie, Louis Boon, Joanne E. Konkel, Matthew R. Hepworth, Andrew S. MacDonald, Gwendalyn J. Randolph, Dominik Rückerl, Judith E. Allen…

Objectives: Extracorporeal carbon dioxide removal (ECCO2R) devices are effective in reducing hypercapnia and mechanical ventilation support but have not been shown to reduce mortality. This may be due to case selection, device performance, familiarity, or the management. The objective of this study is to investigate the effectiveness and safety of a single ECCO2R device (Hemolung) in patients with acute respiratory failure and identify variables associated with survival that could help case selection in clinical practice as well as future research.Design: Multicenter, multinational, retrospective review.Setting: Data from the Hemolung Registry between April 2013 and June 2021, where 57 ICUs contributed deidentified data.Patients: Patients with acute respiratory failure treated with the Hemolung. The characteristics of patients who survived to ICU discharge were compared with those who died. Multivariable logistical regression analysis was used to identify variables associated with ICU survival.Interventions: None.Measurements and Main Results: Of the 159 patients included, 65 (41%) survived to ICU discharge. The survival was highest in status asthmaticus (86%), followed by acute respiratory distress syndrome (ARDS) (52%) and COVID-19 ARDS (31%). All patients had a significant reduction in Paco2 and improvement in pH with reduction in mechanical ventilation support. Patients who died were older, had a lower Pao2:Fio2 (P/F) and higher use of adjunctive therapies. There was no difference in the complications between patients who survived to those who died. Multivariable regression analysis showed non-COVID-19 ARDS, age less than 65 years, and P/F at initiation of ECCO2R to be independently associated with survival to ICU discharge (P/F 100–200 vs…

by Katriina Willgert, Susie da Silva, Ruoran Li, Premanshu Dandapat, Maroudam Veerasami, Hindol Maity, Mohan Papanna, Sreenidhi Srinivasan, James L. N. Wood, Vivek Kapur, Andrew J. K. ConlanZoonotic tuberculosis in humans is caused by infection with bacteria of the Mycobacterium tuberculosis complex acquired from animals, most commonly cattle. India has the highest burden of human tuberculosis in the world and any zoonotic risk posed by tuberculosis in bovines needs to be managed at the source of infection as a part of efforts to end human tuberculosis. Zoonotic tuberculosis in humans can be severe and is clinically indistinguishable from non-zoonotic tuberculosis. As a consequence, zoonotic tuberculosis remains under-recognised and the significance of its contribution to human tuberculosis is poorly understood. This study aimed to explore any association between bovine density, bovine ownership, and human tuberculosis reporting in India using self-reported tuberculosis data in households and officially reported tuberculosis cases while controlling for common confounders for human tuberculosis. We find an association between human tuberculosis reporting, bovine density and bovine ownership in India. Buffalo density was significantly associated with an increased risk of self-reported tuberculosis in households (odds ratio (OR) = 1.23 (95% credible interval (CI): 1.10–1.39) at household level; incidence rate ratio (IRR) = 1.17 (95% CI: 1.04–1.33) at district level), while cattle density (OR = 0.80, 95% CI: 0.71–0.89; IRR = 0.78, 95% CI: 0.70–0.87) and ownership of bovines in households (OR = 0.94, 95% CI: 0.9–0.99; IRR = 0.67, 95% CI: 0.57–0.79) had a protective association with tuberculosis reporting. It is unclear whether this relates to differences in tuberculosis transmission dynamics, or perhaps an association between bovines and other unexplored confounders for tuberculosis reporting in humans. Our study highlights a need for structured surveillance to estimate the prevalence of tuberculosis in cattle and buffaloes, characterisation of Mycobacterium tuberculosis complex species present in bovines and transmission analyses at the human-animal interface to better assess the burden and risk pathways of zoonotic tuberculosis in India.

by Laura Kananen, Xu Hong, Martin Annetorp, Jonathan K. L. Mak, Juulia Jylhävä, Maria Eriksdotter, Sara Hägg, Dorota ReligaObjective To analyse if the health progression of geriatric Covid-19 survivors three months after an acute Covid-19 infection was worse than in other geriatric patients. Specifically, we wanted to see if we could see distinct health profiles in the flow of re-admitted Covid-19 patients compared to re-admitted non-Covid-19 controls. Design Matched cohort study. Setting and participants Electronic medical records of geriatric patients hospitalised in geriatric clinics in Stockholm, Sweden, between March 2020 and January 2022. Patients readmitted three months after initial admission were selected for the analysis and Covid-19 survivors (n = 895) were compared to age-sex-Charlson comorbidity index (CCI)-matched non-Covid-19 controls (n = 2685). Methods We assessed using binary logistic and Cox regression if a previous Covid-19 infection could be a risk factor for worse health progression indicated by the CCI, hospital frailty risk score (HFRS), mortality and specific comorbidities. Results The patients were mostly older than 75 years and, already at baseline, had typically multiple comorbidities. The Covid-19 patients with readmission had mostly had their acute-phase infection in the 1st or 2nd pandemic waves before the vaccinations. The Covid-19 patients did not have worse health after three months compared to the matched controls according to the CCI (odds ratio, OR[95% confidence interval, CI] = 1.12[0.94–1.34]), HFRS (OR[95%CI] = 1.05[0.87–1.26]), 6-months (hazard ratio, HR[95%CI] = 1.04[0.70–1.52]) and 1-year-mortality risk (HR[95%CI] = 0.89[0.71–1.10]), adjusted for age, sex and health at baseline (the CCI and HFRS). Conclusions and implications The overall health progression of re-hospitalized geriatric Covid-19 survivors did not differ dramatically from other re-hospitalized geriatric patients with similar age, sex and health at baseline. Our results emphasize that Covid-19 was especially detrimental for geriatric patients in the acute-phase, but not in the later phase. Further studies including post-vaccination samples are needed.…

by Cristhian David Perdomo-Gómez, Nancy E. Ruiz-Uribe, John Mario González, Manu Forero-SheltonTrypanosoma cruzi is the etiological agent of Chagas disease, an important cause of infectious chronic myocardiopathy in Latin America. The life cycle of the parasite involves two main hosts: a triatomine (arthropod hematophagous vector) and a mammal. Epimastigotes are flagellated forms inside the triatomine gut; they mature in its intestine into metacyclic trypomastigotes, the infective form for humans. Parasites attach despite the shear stress generated by fluid flow in the intestines of the host, but little is known about the mechanisms that stabilize attachment in these conditions. Here, we describe the effect of varying levels of shear stress on attached T. cruzi epimastigotes using a parallel plate flow chamber. When flow is applied, parasites are partially dragged but maintain a connection to the surface via ~40 nm wide filaments (nanotubules) and the activity of flagella is reduced. When flow stops, parasites return near their original position and flagellar motion resumes. Nanotubule elongation increases with increasing shear stress and is consistent with a model of membrane tether extension under force. Fluorescent probes used to confirm membrane composition also show micron-wide anchoring pads at the distal end of the nanotubules. Multiple tethering accounts for more resistance to large shear stresses and for reduced flagellar movement when flow is stopped. The formation of membrane nanotubules is a possible mechanism to enhance adherence to host cells under shear stress, favoring the continuity of the parasite´s life cycle.

by Soraya C. Trindade, Mabel P. P. Lopes, Tatiane T. M. C. Oliveira, Milca J. Silva, Gerson A. Queiroz, Talita S. Jesus, Ellen K. N. Santos, Paulo C. Carvalho-Filho, Michelle M. L. Falcão, Patrícia M. Miranda, Rebeca P. B. Santos, Camila A. Figueiredo, Álvaro A. Cruz, Gregory J. Seymour, Isaac S. Gomes-FilhoThe Interleukin (IL)-33 is important in several inflammatory diseases and its cellular receptor is the Interleukin 1 receptor-like 1 (IL1RL1), also called suppression of tumorigenicity 2 ligand (ST2L). This study investigated associations between single nucleotide variants (SNVs) in the IL33 gene and in the IL1RL1 (ST2) gene with periodontitis. Additionally, aimed to determine the role of Aggregatibacter actinomycetemcomitans (Aa) relative amount in the subgingival biofilm in these associations. A cross-sectional study was carried out with 506 individuals that answered a structured questionnaire used to collect their health status, socioeconomic-demographic, and behavioral characteristics. Periodontal examination was performed to determine the presence and severity of periodontitis, and subgingival biofilm samples were collected to quantify the relative amount of Aa by real time polymerase chain reaction. Human genomic DNA was extracted from whole blood cells and SNV genotyping was performed. Logistic regression estimated the association measurements, odds ratio (OR), and 95% confidence interval (95%CI), between the IL33 and ST2 genes with periodontitis, and subgroup analyses assessed the relative amount of Aa in these associations. 23% of individuals had periodontitis. Adjusted measurements showed a statistically significant inverse association between two SNVs of the ST2; rs148548829 (C allele) and rs10206753 (G allele). These two alleles together with a third SNV, the rs11693204 (A allele), were inversely associated with moderate periodontitis. One SNV of the IL33 gene also showed a statistically significant inverse association with moderate periodontitis. Nine SNVs of the ST2 gene were inversely associated with the relative amount of Aa. In the high Aa subgroup, there was a direct association between 11 SNVs of the ST2 gene and moderate periodontitis and two SNVs of the ST2 gene and severe periodontitis, and eight SNVs of the ST2 gene and periodontitis. These exploratory findings of genetic variants in IL-33/ST2 axis support the concept that the different tissue responses among individuals with periodontitis may be modulated by the host’s genetics, influencing the physiopathology of the disease.

by Shantanu Dutta, Ashok Kumar, Pushpesh Pant, Caolan Walsh, Moumita DuttaDuring the pandemic era, COVID-related disclosure has become quite critical for shareholders and other market participants to understand the uncertainties and challenges associated with a firm’s operation. However, there is no well-grounded and systematic measure to gauge the intensity of COVID-related disclosure and its plausible impact. Therefore, this study develops and validates various COVID-related disclosure measures. More specifically, using a sample of publicly listed U.S. firms and applying natural language processing (NLP) on 10-K reports, we have developed two types of COVID dictionaries (or COVID-related disclosure measurement tools): (a) overall COVID dictionary (count of all COVID-related words/phrases) and (b) contextual COVID-dictionary (count of COVID related words/phrases preceded or followed by positive, negative tones, or financial constraints words). Subsequently, we have validated both types of COVID dictionaries by investigating their association with corporate liquidity events (e.g., dividend payment, dividend change). We confirm that the overall COVID dictionary effectively predicts a firm’s liquidity event. We find similar results for contextual COVID dictionaries with a negative spin (i.e., COVID disclosures with a negative tone or an indication of financial constraints). Our results further show that better-governed firms (e.g., greater board independence, and more female directors) tend to have more COVID-related disclosures, despite the fact that more COVID-related disclosures suppress a firm’s market-based stock performance (e.g. Tobin’s Q). Our results suggest that better-governed firms prefer greater transparency, even if it may hurt their market performance in the short run.

by María Dolores Cima Cabal, Felipe Molina, José Ignacio López-Sánchez, Efrén Pérez-Santín, María del Mar García-SuárezBackground This systematic review evaluates pneumolysin (PLY) as a target for new treatments against pneumococcal infections. Pneumolysin is one of the main virulence factors produced by all types of pneumococci. This toxin (53 kDa) is a highly conserved protein that binds to cholesterol in eukaryotic cells, forming pores that lead to cell destruction. Methods The databases consulted were MEDLINE, Web of Science, and Scopus. Articles were independently screened by title, abstract, and full text by two researchers, and using consensus to resolve any disagreements that occurred. Articles in other languages different from English, patents, cases report, notes, chapter books and reviews were excluded. Searches were restricted to the years 2000 to 2021. Methodological quality was evaluated using OHAT framework. Results Forty-one articles describing the effects of different molecules that inhibit PLY were reviewed. Briefly, the inhibitory molecules found were classified into three main groups: those exerting a direct effect by binding and/or blocking PLY, those acting indirectly by preventing its effects on host cells, and those whose mechanisms are unknown. Although many molecules are proposed as toxin blockers, only some of them, such as antibiotics, peptides, sterols, and statins, have the probability of being implemented as clinical treatment. In contrast, for other molecules, there are limited studies that demonstrate efficacy in animal models with sufficient reliability. Discussion Most of the studies reviewed has a good level of confidence. However, one of the limitations of this systematic review is the lack of homogeneity of the studies, what prevented to carry out a statistical comparison of the results or meta-analysis. Conclusion A panel of molecules blocking PLY activity are associated with the improvement of the inflammatory process triggered by the pneumococcal infection. Some molecules have already been used in humans for other purposes, so they could be safe for use in patients with pneumococcal infections. These patients might benefit from a second line treatment during the initial stages of the infection preventing acute respiratory distress syndrome and invasive pneumococcal diseases. Additional research using the presented set of compounds might further improve the clinical management of these patients.…

by Ineke R. van Herwijnen, Joanne A. M. van der Borg, Chantal M. Kapteijn, Saskia S. Arndt, Claudia M. VinkeTo examine the dog ownership factors characteristic to a population of dogs confiscated after a human and/ or animal-directed biting incident, we compared bite risk assessment reports of 159 confiscated dogs in the time frame 2008, 2009, 2010 (tf1) and of 215 confiscated dogs in the time frame 2020, 2021, 2022 (until mid-May; tf2). The reports were compiled by the same institute in a standardized format. We studied frequencies and chi-square pairwise comparisons (P…

by Sarah K. Highlander, Jason M. Wood, John D. Gillece, Megan Folkerts, Viacheslav Fofanov, Tara Furstenau, Nitin K. Singh, Lisa Guan, Arman Seuylemezian, James N. Benardini, David M. Engelthaler, Kasthuri Venkateswaran, Paul S. KeimThe National Aeronautics and Space Administration (NASA) has been monitoring the microbial burden of spacecraft since the 1970’s Viking missions. Originally culture-based and then focused 16S sequencing techniques were used, but we have now applied whole metagenomic sequencing to a variety of cleanroom samples at the Jet Propulsion Lab (JPL), including the Spacecraft Assembly Facility (SAF) with the goals of taxonomic identification and for functional assignment. Our samples included facility pre-filters, cleanroom vacuum debris, and surface wipes. The taxonomic composition was carried out by three different analysis tools to contrast marker, k-mer, and true alignment approaches. Hierarchical clustering analysis of the data separated vacuum particles from other SAF DNA samples. Vacuum particle samples were the most diverse while DNA samples from the ISO (International Standards Organization) compliant facilities and the SAF were the least diverse; all three were dominated by Proteobacteria. Wipe samples had higher diversity and were predominated by Actinobacteria, including human commensals Cutibacterium acnes and Corynebacterium spp. Taxa identified by the three methods were not identical, supporting the use of multiple methods for metagenome characterization. Likewise, functional annotation was performed using multiple methods. Vacuum particles and SAF samples contained strong signals of the tricarboxylic acid cycle and of amino acid biosynthesis, suggesting that many of the identified microorganisms have the ability to grow in nutrient-limited environments. In total, 18 samples generated high quality metagenome assembled genomes (MAG), which were dominated by Moraxella osloensis or Malassezia restricta. One M. osloensis MAG was assembled into a single circular scaffold and gene annotated. This study includes a rigorous quantitative determination of microbial loads and a qualitative dissection of microbial composition. Assembly of multiple specimens led to greater confidence for the identification of particular species and their predicted functional roles.

Abstract Background Cytomegalovirus (CMV) is a common virus. In pregnant women, CMV infection is usually mildly symptomatic or asymptomatic but can lead to fetal infection. Here we present a rare case of severe CMV pneumonitis and acute respiratory distress syndrome in a healthy immunocompetent pregnant woman. Case presentation A previous healthy 28-year-old woman with spontaneous conception, was admitted to the General University Hospital of Patras at 29 weeks of gestation with a day history of fever, fatigue, pharyngitis, and cough. She was diagnosed with acute CMV infection and CMV pneumonitis. During her hospitalization she developed acute distress syndrome (ARDS). The patient was intubated and underwent emergency caesarean delivery. She was admitted to the intensive care unit and received intravenous ganciclovir. She was discharged at 20th day postpartum in a good clinical condition. Conclusions This case highlights the infrequent yet potential complexity of CMV infection in immunocompetent patients and in pregnancy. …

Abstract Background Echinococcosis, also known as hydatid disease, is a zoonotic parasitic disease prevalent in pastoral areas, mainly involving the liver and lungs, and less frequently the bones and surrounding soft tissues. Diagnosis and treatment of bone hydatid disease is a challenge, and because of the insidious course of the disease, the lesions are often widely disseminated by the time patients seek medical attention. Case presentation A 29-year-old woman presented with a painless mass that was gradually increasing in size in the cervical thorax. Imaging revealed an enlarged clavicle with multiple bone cortical defects and the existence of cysts in the soft tissues surrounding the clavicle, for which complete excision of the clavicle and the attached cysts was performed. There was no recurrence of the cyst within one year after the operation, and the patient felt well and had normal shoulder joint movement. Conclusions Bone hydatid may appear in bones throughout the body, and cysts that leak from the bone into the surrounding soft tissues may spread at a relatively rapid rate. Prompt surgical removal of the affected bone and surrounding cysts is necessary for treatment. …

Abstract Background Human adenovirus (HAdV) infection outbreak causes community-acquired pneumonia. Cellular immune dysfunction and hypercytokinemia play important roles in the pathogenesis of adenovirus respiratory infection. Some soluble factors in peripheral blood can assist in judging the virus-induced disease severity. The expression levels of inflammatory cytokines differ among patients with different disease severity. However, whether and how HAdV-7 infection influences the composition of blood immune cells and serum cytokine levels in patients at different disease stages, as well as the diagnosis values of these parameters, have rarely been intensively studied. We aimed to investigate lymphocytes profiles and cytokines levels in blood of patients at different disease stages upon human adenovirus type 7 (HAdV-7) infections, and explored the diagnosis values of the investigated parameters. Methods Patients from two outbreaks of HAdV-7 in military of China were categorized into upper respiratory infection (URI) group, common pneumonia (CP) group and severe pneumonia (SP) group according to disease severity. Peripheral blood samples were subjected to routine laboratory tests, while flow cytometry and ELISA were used to measure the lymphocyte subsets and cytokines in blood, respectively. The receiver operating characteristic (ROC) curves were performed to examine the diagnostic of these blood parameters. Results Signs of imbalanced lymphocytes composition and hypercytokinemia were observed in HAdV-7-infected patients. The percentages of CD3+ T cells and NK cells were significantly decreased along with the aggravation of the disease, particularly for NK cells and CD4+ T cells. The neutrophil to lymphocyte ratio (NLR) increased significantly in patients with more severe disease. In addition, the levels of serum CXCL10, IL-2 and TNF-α were positively correlated with disease severity, while reduced levels of IFN-γ and IL-10 were found in SP patients. Furthermore, analysis of ROC showed that multiple parameters including the percentage of blood CD3+ cells and serum CXCL10 level could predict the progression of HAdV-7 infection. Conclusion Imbalance of immune state with hypercytokinemia occurred during HAdV-7 infection. The percentages of blood immune cells such as CD3+ T cells and the levels of serum cytokines such as CXCL10 showed potential diagnosis values in HAdV-7 infection. …

Abstract Background This study aimed to evaluate the socio-demographic, clinical, and laboratory risk factors in hospitalized COVID-19 patients during the first 6 months of the SARS-CoV-2 epidemic. Method This retrospective hospital-based cross-sectional study included all laboratory-confirmed cases of the COVID-19 virus that were admitted to the Shohadaye-Khalije-Fars Hospital in Bushehr, Iran, from February 22, 2020 to September 21, 2020. The patients' records were reviewed during the hospitalization period. The global COVID-19 clinical platform, i.e., the World Health Organization Rapid Case Report Form was used as the data collection tool. We conducted the survival analysis using the Kaplan–Meier and the Stepwise Cox regression analyses. Results The analysis included 2108 confirmed cases of COVID-19 with a mean age of 47.81 years (SD 17.78); 56.8% men, 43.2% women and 6.3% (n = 133) deaths. After adjustment, it was found that factors associated with an increased risk of death consisted of chronic kidney disease, intensive care unit admission, cancer, and hemoptysis. The 7-day survival rate was 95.8%, which decreased to 95.1%, 94.0%, and 93.8% on days 14, 21, and 28 of hospitalization, respectively. Discussion and conclusion Older COVID-19 patients with manifestation of hemoptysis and a past medical history of chronic kidney disease and cancer, should be closely monitored to prevent disease deterioration and death, and also should be admitted to the intensive care unit. …

Abstract Background The severity and distribution of dengue virus (DENV) infections have been attributed to a complex interaction among viral, host and environmental factors. Herein, we investigated the influence of chikungunya (CHIKV) and Zika (ZIKV) viruses on the epidemiological profile of dengue cases, using Recife, Pernambuco state, Brazil, as a study model. In addition, we described and compared the epidemiological profile related to each arbovirus (DENV vs. CHIKV vs. ZIKV). Methods All cases of dengue, chikungunya and Zika reported to the Pernambuco Health Department in 2011–2013 (DENV circulation) and 2016–2018 (DENV, CHIKV and ZIKV co-circulation) were included in our study. The cases were classified by sex, age and race/color and their distribution was analyzed by the χ2 test. Furthermore, the data were also analyzed for co-infections. Temperature, humidity and rainfall data were analyzed using one-way ANOVA and paired t-test. Results During 2011–2013, 15,315 dengue cases were diagnosed, most of them female, brown and 20–29 age group. Between 2016 and 2018, 15,870 dengue cases were described, which presented the same profile described above. In the two triennia, the female/male dengue ratio fluctuated significantly, ranging from 1.07 to 1.52. Regarding chikungunya, 7076 cases were reported, most of them female and brown. The female/male ratio also fluctuated significantly, ranging from 1.62 to 2.1. Two main age groups were observed in chikungunya: ≤ 19 years (minority of diagnoses) and ≥ 20 years (majority of diagnoses). In the same triennium, 266 Zika cases were reported to the Pernambuco Health Department, mainly in females and in the 0–9 and 20–39 age groups. In general, 119 co-infections were identified: 117 DENV-CHIKV, 1 CHIKV-ZIKV and 1 DENV-CHIKV-ZIKV. Concerning climate data, only the humidity in 2011 was significantly different from the other years. Conclusion The epidemiological profile of dengue cases did not change after the introduction of CHIKV and ZIKV. Females were the most diagnosed with dengue, chikungunya or Zika, however we found important differences in the age profile of these arboviruses, which should be considered by public health policies, as well as investigated in future studies of virus-host interaction. …

Abstract Background In countries with mature generalized HIV epidemics such as Uganda, there are still groups of individuals that are disproportionately affected. Among the key populations in Uganda are fishing communities, which make up about 10% of the population. Compared to the general population, HIV prevalence and incidence among individuals living in these communities is high. This high HIV burden has been attributed to several factors including limited access to prevention and treatment services as well as ongoing high-risk sexual behaviour. Methods We investigated the impact of combined HIV prevention interventions on HIV transmission dynamics in high-risk fishing communities in Uganda using a deterministic compartmental model. The model was calibrated to seroprevalence data from a census performed in 2014. To account for remaining uncertainty in the calibrated model parameters, 50 000 simulated scenarios were modelled to investigate the impact of combined prevention interventions. Results The projected HIV incidence decreased from 1.87 per 100 PY without intervention scale-up to 0.25 per 100 PY after 15 years (2014–2029) of intervention scale-up. A potential combination achieving this 87% reduction in incidence over 15 years in Ugandan FCs included condom use in about 60% of sexual acts, 23% of susceptible men circumcised, 87% of people living with HIV aware of their status, 75% of those on ART, and about 3% of susceptible individuals on oral PrEP. Uncertainty analysis revealed relative reductions in incidence ranging from 30.9 to 86.8%. Sensitivity analyses suggested that condom use and early ART were the most important interventions. Conclusion Reducing HIV incidence, as well as prevalence and AIDS-related mortality, in these high-risk fishing communities in Uganda is attainable over 15 years with a combination prevention package. Our projected intervention coverage levels are well within the national targets set by the Uganda government and enable coming close to reaching the UNAIDS 95-95-95 targets to end AIDS as a public health threat by 2030. …

Tropical Medicine &International Health, Accepted Article.

Infection and Immunity, Ahead of Print.

Scedosporium species are environmental fungi often found in soil and polluted waters that usually cause opportunistic infections in immunocompromised patients after near drowning or a penetrating trauma[1-2]. The two medically relevant species in humans are Scedosporium apiospermum and S. prolificans, the latter of which has recently been reclassified as Lomentospora prolificans[2]. However, there have been few case reports about pulmonary scedosporiosis caused by L. prolificans in immunocompetent patients.

With the emergence of highly transmissible SARS-CoV-2 variants and widespread use of at-home tests, the COVID-19 pandemic continues to challenge public health surveillance efforts and limit the precision in disease occurrence estimates. In the absence of reliable data on rates of infection, seroprevalence studies remain important in estimating the prevalence of infected individuals, particularly among young and healthy populations who are more likely to experience mild or asymptomatic infection although contributing to disease transmission.

Since the emergence of SARS-CoV2 in China in late 2019, over 671 million confirmed cases have been reported. While this statistic is staggering, equally threatening on a global scale is tuberculosis (TB). TB is an airborne disease that can be spread through coughing and sneezing (1). The World Health Organization estimates that 1.8 billion people – close to one-quarter of the world's population - are infected with M.tb. In 2022, TB regained its position as the leading infectious cause of death worldwide, ranking above COVID-19 and HIV/AIDS.

Cytomegalovirus is an opportunistic pathogen responsible for substantial morbidity after solid organ transplantation and hematopoietic stem cell transplantation. Treatment of CMV disease involves a two-pronged approach with antiviral drug treatment coupled with strategies to minimize the intensity of immune suppression.

Managing the COVID-19 pandemic has required the implementation of public health mitigation measures to limit the transmission of SARS-CoV-2. Airborne transmission via particles of different sizes, generally called droplets and aerosols, was recognized very late by Public Health organizations in part due to limited direct evidence of infectious virus in air samples. SARS-CoV-2 RNA has been detected in indoor air samples in various settings (1), but to this day only a few studies reported infectious virus particles in bioaerosols (2-5).

New England Journal of Medicine, Ahead of Print.

Life expectancy in the US is now the lowest it has been since 1996, with young- and middle-aged adults seeing the most rapid declines. These declines began in 2014 and have accelerated over the past 3 years of the pandemic. While COVID-19 represents a significant proportion, increases in heart disease between 2020 and 2021 explain more than 4% of the most recent shortening in life expectancy. These increases in cardiovascular mortality reflect recent disturbing trends in cardiovascular risk determinants and events in younger adults. Although overall cardiovascular disease mortality declined until 2020, hospitalization and death rates flattened or in some cases increased among specific racial and ethnic subgroups of young adults during this time. In particular, hypertensive heart disease, heart failure, and endocarditis have increased in young adults, particularly among Black individuals, through 2018. Consequently, young adults make up a growing proportion of cardiovascular disease events, with the proportion of premature myocardial infarction among adults younger than 40 years increasing by 2% every year. The increasing event rates observed among younger adults can be attributed to the increasing prevalence and onset of risk factors such as obesity and hypertension at younger ages, which exacerbate cumulative exposure and cardiovascular disease risk over near- and long-term time horizons.

Immunity generated by COVID-19 infection protects against hospitalization and death, according to a meta-analysis of 65 studies representing data from 19 countries. Protection against severe disease remained high after 40 weeks, at 90.2% for ancestral, Alpha, and Delta variants and 88.9% for Omicron BA.1 after 40 weeks.

More than one-third of patients hospitalized with COVID-19 had lung abnormalities including scarring and thickening 2 years later, according to an analysis of chest computed tomographic (CT) scans from 144 participants aged 27 to 80 years.

A normal gastrointestinal (GI) tract biopsy result might not eliminate an inflammatory bowel disease (IBD) diagnosis, according to a population-based, sibling-controlled study published in PLOS Medicine.

A Cochrane meta-analysis of 11 eligible trials examining the efficacy of ivermectin for the treatment of COVID-19 published through April 2022 concluded that ivermectin has no beneficial effect for people with COVID-19. Since May 2022, an additional 3 large randomized clinical trials including several thousand participants have been published, each reaching a similar conclusion.

This platform randomized clinical trial examines the effectiveness of ivermectin at a targeted dose of 600 μg/kg daily compared with placebo for the treatment of early mild to moderate COVID-19.

Microbiology and Molecular Biology Reviews, Volume 87, Issue 1, March 2023.

ObjectiveThis study used 2010–2018 Health Insurance Review and Assessment Service National Patient Sample data to analyse the distribution and healthcare utilisation of patients with migraine in South Korea.DesignRetrospective, observational study using serial cross-sectional data.ParticipantsPatients with primary diagnosis of G43, a Korean Standard Classification of Diseases-10 code for migraine, were included in the analysis. The exclusion criteria were missing code information; code for dental, health centre or psychiatry; institution type specified as nursing hospital, psychiatric hospital, dental hospital, midwifery centre or health centre; blank entries for total cost or days of care. 453 246 records of patients and 117 157 patients corresponding to those records were identified.Outcome measuresPrimary outcome measures were medical service utilisation status, treatment methods and drug use status associated with migraine.ResultsCases and patients of migraine increased from 48 846 and 19 468 (2010) to 52 729 and 20 802 (2018), respectively, increases of 7.95% and 6.85%, respectively, compared with 2010. Total cost of care increased from $921 857.88 (2010) to $1 711 219.60 (2018). The most common age range of patients was 45–54 years, with 2.69 times more female than male patients. In Western medicine hospitals, subcutaneous or intramuscular injection therapy was used frequently, while in Korean medicine hospitals, acupuncture therapy was used. Among Western medicine outpatients, more than 50% of the therapeutics prescribed for acute migraine were simple analgesics or non-steroidal anti-inflammatory drugs. The number of prescriptions for the prevention of episodic migraine increased from 13 600 cases (2010) to 20 546 cases (2018), representing the steepest increase in drug utilisation.ConclusionsTreatments frequently used in Western and Korean medicine hospitals and their frequency of use and costs were identified. The findings of this study can be used as a basis for relevant health policy decisions.…

ObjectivesCOVID-19, which is caused by SARS-CoV-2, is a severe threat to human health and the economy globally. This study aimed to investigate the prevalence of taste and/or smell dysfunction and associated risk factors in mild and asymptomatic patients with Omicron infection in Shanghai, China.DesignThis was a questionnaire-based cross-sectional study.SettingCOVID-19 patients at the makeshift hospital in the Shanghai World Expo Exhibition and Convention Centre were recruited from March to April 2022.ParticipantsIn total, 686 COVID-19-infected patients who were defined as mild or asymptomatic cases according to the diagnostic criteria of New Coronavirus Pneumonia Prevention and Control Programme ninth edition (National Health Commission of China, 2022) were enrolled.MeasuresData to investigate taste and smell loss and to characterise other symptoms were collected by the modified Chemotherapy-induced Taste Alteration Scale and Sino-Nasal Outcome Test-22 questionnaires. The risk factors for the severity of taste/smell dysfunction were analysed by binary logistic regression models.Results379 males (379/686, 55.2%) and 307 females (307/686, 44.8%) completed the questionnaires to record recent changes in taste and smell ability. A total of 302 patients (44%) had chemosensory dysfunction with Omicron infection, of which 22.7% (156/686) suffered from both taste and smell dysfunction. In addition, cough (60.2%), expectoration (40.5%), fever (33.2%) and sore throat (32.5%) were common symptoms during Omicron infection. The quality-of-life-related indicators were negatively associated with participants’ self-reported taste and smell dysfunction.ConclusionsThe prevalence of taste or/and smell dysfunction in patients with Omicron infections was 44%. Individuals with chemosensory dysfunction had significantly higher rates of various upper respiratory influenza-like symptoms, xerostomia and bad breath. Moreover, smell dysfunction was a risk factor for the prevalence of taste dysfunction in patients with Omicron infection.Trial registration numberChiCTR 2200059097.…

IntroductionOrthopaedic trauma and fracture care commonly cause perioperative anaemia and associated functional iron deficiency due to a systemic inflammatory state. Modern, strict transfusion thresholds leave many patients anaemic; managing this perioperative anaemia is an opportunity to impact outcomes in orthopaedic trauma surgery. The primary outcome of this pilot study is feasibility for a large randomised controlled trial (RCT) to evaluate intravenous iron therapy (IVIT) to improve patient well-being following orthopaedic injury. Measurements will include rate of participant enrolment, screening failure, follow-up, missing data, adverse events and protocol deviation.Methods and analysisThis single-centre, pilot, double-blind RCT investigates the use of IVIT for acute blood loss anaemia in traumatically injured orthopaedic patients. Patients are randomised to receive either a single dose infusion of low-molecular weight iron dextran (1000 mg) or placebo (normal saline) postoperatively during their hospital stay for trauma management. Eligible subjects include adult patients admitted for lower extremity or pelvis operative fracture care with a haemoglobin of 7–11 g/dL within 7 days postoperatively during inpatient care. Exclusion criteria include history of intolerance to intravenous iron supplementation, active haemorrhage requiring ongoing blood product resuscitation, multiple planned procedures, pre-existing haematologic disorders or chronic inflammatory states, iron overload on screening or vulnerable populations. We follow patients for 3 months to measure the effect of iron supplementation on clinical outcomes (resolution of anaemia and functional iron deficiency), patient-reported outcomes (fatigue, physical function, depression and quality of life) and translational measures of immune cell function.Ethics and disseminationThis study has ethics approval (Oregon Health & Science University Institutional Review Board, STUDY00022441). We will disseminate the findings through peer-reviewed publications and conference presentations.Trial registration numberNCT05292001; ClinicalTrials.gov.…

IntroductionOutcomes of traumatic brain injury (TBI) are highly variable, with cognitive and psychiatric problems often present in survivors, including an increased dementia risk in the long term. Military personnel are at an increased occupational risk of TBI, with high rates of complex polytrauma including TBI characterising the UK campaign in Afghanistan. The ArmeD SerVices TrAuma and RehabilitatioN OutComE (ADVANCE)-TBI substudy will describe the patterns, associations and long-term outcomes of TBI in the established ADVANCE cohort.Methods and analysisThe ADVANCE cohort comprises 579 military personnel exposed to major battlefield trauma requiring medical evacuation, and 566 matched military personnel without major trauma. TBI exposure has been captured at baseline using a standardised interview and registry data, and will be refined at first follow-up visit with the Ohio State Method TBI interview (a National Institute of Neurological Disorders and Stroke TBI common data element). Participants will undergo blood sampling, MRI and detailed neuropsychological assessment longitudinally as part of their follow-up visits every 3–5 years over a 20-year period. Biomarkers of injury, neuroinflammation and degeneration will be quantified in blood, and polygenic risk scores calculated for neurodegeneration. Age-matched healthy volunteers will be recruited as controls for MRI analyses. We will describe TBI exposure across the cohort, and consider any relationship with advanced biomarkers of injury and clinical outcomes including cognitive performance, neuropsychiatric symptom burden and function. The influence of genotype will be assessed. This research will explore the relationship between military head injury exposure and long-term outcomes, providing insights into underlying disease mechanisms and informing prevention interventions.Ethics and disseminationThe ADVANCE-TBI substudy has received a favourable opinion from the Ministry of Defence Research Ethics Committee (ref: 2126/MODREC/22). Findings will be disseminated via publications in peer-reviewed journals and presentations at conferences.…

IntroductionThe efficacy of taurolidine containing lock solutions for the prevention of central line-associated bloodstream infections (CLABSI) in paediatric oncology patients is still unknown. If the taurolidine-citrate-heparin lock appears to decrease the incidence of CLABSIs, we hope to increase the quality of life of children with cancer by subsequently reducing the central venous access device (CVAD)-removal rates, dispense of antibiotics, hospital admissions and incidence of severe sepsis resulting in intensive care unit admission.Methods and analysisThis assessor-blinded randomised controlled trial including 462 patients was designed to compare the taurolidine-citrate-heparin lock to the heparin-only lock for the prevention of CLABSIs in paediatric oncology patients. Patients receiving their first CVAD at the Princess Máxima Centre for Paediatric Oncology, Utrecht, the Netherlands, are eligible for inclusion. The primary outcome of this study is the incidence of first CLABSIs from CVAD insertion until the end of the study, maximum follow-up of 90 days. An intention-to-treat and a per-protocol analysis will be performed. An interim analysis will be performed after the inclusion of 50% of the patients. The results of the interim analysis and overall conduct of the trial will be discussed by a data safety monitoring board.Ethics and disseminationThe medical ethics committee NedMec, Utrecht, the Netherlands, has approved this research (number 20/370). Written informed consent for participation in this trial and publication of the trial data is obtained from all patients and/or their parents/guardians. The results of this trial will be published in a peer-reviewed journal and the data will be made available on reasonable request after publication of the main results manuscript.Trial registration numbersNTR6688; NCT05740150.…