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Abstract Background Safe and accurate execution of surgeries to date mainly rely on preoperative plans generated based on preoperative imaging. Frequent intraoperative interaction with such patient images during the intervention is needed, which is currently a cumbersome process given that such images are generally displayed on peripheral two-dimensional (2D) monitors and controlled through interface devices that are outside the sterile filed. This study proposes a new medical image control concept based on a Brain Computer Interface (BCI) that allows for hands-free and direct image manipulation without relying on gesture recognition methods or voice commands. Method A software environment was designed for displaying three-dimensional (3D) patient images onto external monitors, with the functionality of hands-free image manipulation based on the user’s brain signals detected by the BCI device (i.e., visually evoked signals). In a user study, ten orthopedic surgeons completed a series of standardized image manipulation tasks to navigate and locate predefined 3D points in a Computer Tomography (CT) image using the developed interface. Accuracy was assessed as the mean error between the predefined locations (ground truth) and the navigated locations by the surgeons. All surgeons rated the performance and potential intraoperative usability in a standardized survey using a five-point Likert scale (1 = strongly disagree to 5 = strongly agree). Results When using the developed interface, the mean image control error was 15.51 mm (SD: 9.57). The user's acceptance was rated with a Likert score of 4.07 (SD: 0.96) while the overall impressions of the interface was rated as 3.77 (SD: 1.02) by the users. We observed a significant correlation between the users' overall impression and the calibration score they achieved. Conclusions The use of the developed BCI, that allowed for a purely brain-guided medical image control, yielded promising results, and showed its potential for future intraoperative applications. The major limitation to overcome was noted as the interaction delay.

Abstract Background The helicopter emergency services (HEMS) Benefit Score (HBS) is a nine-level scoring system developed to evaluate the benefits of HEMS missions. The HBS has been in clinical use for two decades in its original form. Advances in prehospital care, however, have produced demand for a revision of the HBS. Therefore, we developed the emergency medical services (EMS) Benefit Score (EBS) based on the former HBS. As reflected by its name, the aim of the EBS is to measure the benefits produced by the whole EMS systems to patients. Methods This is a four-round, web-based, international Delphi consensus study with a consensus definition made by experts from seven countries. Participants reviewed items of the revised HBS on a 5-point Likert scale. A content validity index (CVI) was calculated, and agreement was defined as a 70% CVI. Study included experts from seven European countries. Of these, 18 were prehospital expert panellists and 11 were in-hospital commentary board members. Results The first Delphi round resulted in 1248 intervention examples divided into ten diagnostic categories. After removing overlapping examples, 413 interventions were included in the second Delphi round, which resulted in 38 examples divided into HBS categories 3–8. In the third Delphi round, these resulted in 37 prehospital interventions, examples of which were given revised version of the score. In the fourth and final Delphi round, the expert panel was given an opportunity to accept or comment on the revised scoring system. Conclusions The former HBS was revised by a Delphi methodology and EBS developed to represent its structural purpose better. The EBS includes 37 exemplar prehospital interventions to guide its clinical use. Trial registration The study permission was requested and granted by Turku University Hospital (decision number TP2/010/18).

Abstract Background Exposure to hypothermia is somehow unavoidable when a baby comes to life. This is the reason why any possible effort should be made by every caregiver involved during birth, from labour to transfer into the maternity ward, to reduce it. Hypothermia has widely shown to be related to several neonatal problems, and the risks are more relevant when the babies are born prematurely. Method An observational study was conducted in April 2016 to assess the current practises to avoid hypothermia at birth in 20 Italian neonatal units. Each unit introduced local improvements in clinical practice and the same observational study was repeated 1 year later. Results A total of 4722 babies were analysed. An overall increase in adherence to local and international recommendations emerged from our study. Significant differences between 2016 and 2017 were found in regard to neonatal temperature at nursery entry (36.3 °C vs 36.5 °C, respectively, p 60″ (48.1% vs 68.1%, respectively, p 60′ (56.3% vs 60.9, respectively, p = 0.03). Statistical correlations with the risk of hypothermia were found for delivery room (OR 0.88 (CI 95%0.83–0.94), p

Abstract Background Non-specific neck pain and headache are major economic and individual burden in office-workers. The aim of this study is to investigate the effect of a multi-component intervention combining workstation ergonomics, health promotion information group workshops, neck exercises, and an app to enhance intervention adherence to assess possible reductions in the economic and individual burden of prevalent and incident neck pain and headache in office workers. Methods/design This study is a stepped wedge cluster-randomized controlled trial. Eligible participants will be any office-worker aged 18–65 years from two Swiss organisations in the Cantons of Zurich and Aargau, working more than 25 h a week in predominantly sedentary office work and without serious health conditions of the neck. One hundred twenty voluntary participants will be assigned to 15 clusters which, at randomly selected time steps, switch from the control to the intervention group. The intervention will last 12 weeks and comprises workstation ergonomics, health promotion information group workshops, neck exercises and an adherence app. The primary outcome will be health-related productivity losses (presenteeism, absenteeism) using the Work Productivity and Activity Impairment Questionnaire. Secondary outcomes are neck disability and pain (measured by the Neck Disability Index, and muscle strength and endurance measures), headache (measured by the short-form headache impact test), psychosocial outcomes (e.g. job-stress index, Fear-Avoidance Beliefs Questionnaire), workplace outcomes (e.g. workstation ergonomics), adherence to intervention, and additional measures (e.g. care-seeking). Measurements will take place at baseline, 4 months, 8 months, and 12 months after commencement. Data will be analysed on an intention to treat basis and per protocol. Primary and secondary outcomes will be examined using linear mixed-effects models. Discussion To the authors’ knowledge, this study is the first that investigates the impact of a multi-component intervention combining current evidence of effective interventions with an adherence app to assess the potential benefits on productivity, prevalent and incident neck pain, and headache. The outcomes will impact the individual, their workplace, as well as private and public policy by offering evidence for treatment and prevention of neck pain and headache in office-workers. Trial registration ClinicalTrials.gov, NCT04169646 . Registered 15 November 2019 - Retrospectively registered.

Abstract Background Eating disorders are serious conditions which are increasing in prevalence internationally. The causes of these conditions are complex and incompletely understood, and clinical presentations can vary over time. The complexity of these conditions can also complicate treatment. Therefore, stepped care treatment comprising a hierarchy of interventions, including access to day treatment programs (DTPs), is recommended. While studies have examined patient outcomes and provided narrative accounts of these programs, no published studies describe DTP development. This study aims to address this gap by examining development and implementation of a DTP from service providers and patients’ perspectives. Methods This study utilised a mixed-methods design to examine the design and implementation of a publicly funded, closed group DTP in Australia. Data from service records and documents were analysed, alongside interviews with patients and interview and focus groups with service providers conducted between June 2016 and July 2017. Quantitative data were analysed using descriptive statistics. Qualitative data were analysed using the Framework Approach. Results Seventeen service providers (n = 4 in managerial and n = 13 clinical positions, with clinical experience of 3 months to 20 years) and 11 patients (100% F, 17-33 years) were interviewed. The service providers reported that implementation was a stressful undertaking due to tight timeframes to achieve multiple tasks. Patients had diverse opinions regarding the DTP content and the group treatment experience. Despite this, all patients reported benefits from attending the DTP, varying from improvements in mood, weight gain, development of personal skills and strengths, to living independently. For further benefit, patients suggested that programs could be shaped and targets towards differing patient groups, with fewer breaks throughout treatment. Conclusions Designing and implementing a DTP is a challenge and can be a time-intensive undertaking, however the result can be beneficial for both service providers and patients. The closed group format was beneficial in creating a supportive environment, though may have led to increases in additional eating disordered behaviours. While the current structure of this DTP may require reconsideration, organisations considering implementing a new DTP may find usefulness in the overall design described in this study, alongside learning from the issues experienced.

Abstract Background Perioperative anaemia leads to impaired oxygen supply with a risk of vital organ ischaemia. In healthy and fit individuals, anaemia can be compensated by several mechanisms. Elderly patients, however, have less compensatory mechanisms because of multiple co-morbidities and age-related decline of functional reserves. The purpose of the study is to evaluate whether elderly surgical patients may benefit from a liberal red blood cell (RBC) transfusion strategy compared to a restrictive transfusion strategy. Methods The LIBERAL Trial is a prospective, randomized, multicentre, controlled clinical phase IV trial randomising 2470 elderly (≥ 70 years) patients undergoing intermediate- or high-risk non-cardiac surgery. Registered patients will be randomised only if Haemoglobin (Hb) reaches ≤9 g/dl during surgery or within 3 days after surgery either to the LIBERAL group (transfusion of a single RBC unit when Hb ≤ 9 g/dl with a target range for the post-transfusion Hb level of 9–10.5 g/dl) or the RESTRICTIVE group (transfusion of a single RBC unit when Hb ≤ 7.5 g/dl with a target range for the post-transfusion Hb level of 7.5–9 g/dl). The intervention per patient will be followed until hospital discharge or up to 30 days after surgery, whichever occurs first. The primary efficacy outcome is defined as a composite of all-cause mortality, acute myocardial infarction, acute ischaemic stroke, acute kidney injury (stage III), acute mesenteric ischaemia and acute peripheral vascular ischaemia within 90 days after surgery. Infections requiring iv antibiotics with re-hospitalisation are assessed as important secondary endpoint. The primary endpoint will be analysed by logistic regression adjusting for age, cancer surgery (y/n), type of surgery (intermediate- or high-risk), and incorporating centres as random effect. Discussion The LIBERAL-Trial will evaluate whether a liberal transfusion strategy reduces the occurrence of major adverse events after non-cardiac surgery in the geriatric population compared to a restrictive strategy within 90 days after surgery. Trial registration ClinicalTrials.gov (identifier: NCT03369210).

Abstract Background Despite the positive outcomes of the use of noninvasive positive pressure ventilation (NPPV) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD), NPPV fails in approximately 15% of patients with AECOPD, possibly because the inspiratory pressure delivered by conventional low-intensity NPPV is insufficient to improve ventilatory status for these patients. High-intensity NPPV, a novel form that delivers high inspiratory pressure, is believed to more efficiently augment alveolar ventilation than low-intensity NPPV, and it has been shown to improve ventilatory status more than low-intensity NPPV in stable AECOPD patients. Whether the application of high-intensity NPPV has therapeutic advantages over low-intensity NPPV in patients with AECOPD remains to be determined. The high-intensity versus low-intensity NPPV in patients with AECOPD (HAPPEN) study will examine whether high-intensity NPPV is more effective for correcting hypercapnia than low-intensity NPPV, hence reducing the need for intubation and improving survival. Methods/design The HAPPEN study is a multicenter, two-arm, single-blind, prospective, randomized controlled trial. In total, 600 AECOPD patients with low to moderate hypercapnic respiratory failure will be included and randomized to receive high-intensity or low-intensity NPPV, with randomization stratified by study center. The primary endpoint is NPPV failure rate, defined as the need for endotracheal intubation and invasive ventilation. Secondary endpoints include the decrement of arterial carbon dioxide tension from baseline to 2 h after randomization, in-hospital and 28-day mortality, and 90-day survival. Patients will be followed up for 90 days after randomization. Discussion The HAPPEN study will be the first randomized controlled study to investigate whether high-intensity NPPV better corrects hypercapnia and reduces the need for intubation and mortality in AECOPD patients than low-intensity NPPV. The results will help critical care physicians decide the intensity of NPPV delivery to patients with AECOPD. Trial registration ClinicalTrials.gov, NCT02985918. Registered on 7 December 2016.

Abstract Background Obstetric haemorrhage, sepsis and pregnancy hypertension account for more than 50% of maternal deaths worldwide. Early detection and effective management of these conditions relies on vital signs. The Microlife® CRADLE Vital Sign Alert (VSA) is an easy-to-use, accurate device that measures blood pressure and pulse. It incorporates a traffic-light early warning system that alerts all levels of healthcare provider to the need for escalation of care in women with obstetric haemorrhage, sepsis or pregnancy hypertension, thereby aiding early recognition of haemodynamic instability and preventing maternal mortality and morbidity. The aim of the trial was to determine whether implementation of the CRADLE intervention (the Microlife® CRADLE VSA device and CRADLE training package) into routine maternity care in place of existing equipment will reduce a composite outcome of maternal mortality and morbidity in low- and middle-income country populations. Methods The CRADLE-3 trial was a stepped-wedge cluster-randomised controlled trial of the CRADLE intervention compared to routine maternity care. Each cluster crossed from routine maternity care to the intervention at 2-monthly intervals over the course of 20 months (April 2016 to November 2017). All women identified as pregnant or within 6 weeks postpartum, presenting for maternity care in cluster catchment areas were eligible to participate. Primary outcome data (composite of maternal death, eclampsia and emergency hysterectomy per 10,000 deliveries) were collected at 10 clusters (Gokak, Belgaum, India; Harare, Zimbabwe; Ndola, Zambia; Lusaka, Zambia; Free Town, Sierra Leone; Mbale, Uganda; Kampala, Uganda; Cap Haitien, Haiti; South West, Malawi; Addis Ababa, Ethiopia). This trial was informed by the Medical Research Council guidance for complex interventions. A process evaluation was undertaken to evaluate implementation in each site and a cost-effectiveness evaluation will be undertaken. Discussion All aspects of this protocol have been evaluated in a feasibility study, with subsequent optimisation of the intervention. This trial will demonstrate the potential impact of the CRADLE intervention on reducing maternal mortality and morbidity in low-resource settings. It is anticipated that the relatively low cost of the intervention and ease of integration into existing health systems will be of significant interest to local, national and international health policy-makers. Trial registration ISCRTN41244132. Registered on 2 February 2016. Prospective protocol modifications have been recorded and were communicated to the Ethics Committees and Trials Committees. The adapted Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Checklist and the SPIRIT Checklist are attached as Additional file 1.

Abstract Background Countdown to 2015 was a multi-institution consortium tracking progress towards Millennium Development Goals (MDGs) 4 and 5. Case studies to explore factors contributing to progress (or lack of progress) in reproductive, maternal, newborn and child health (RMNCH) were undertaken in: Afghanistan, Bangladesh, China, Ethiopia, Kenya, Malawi, Niger, Pakistan, Peru, and Tanzania. This paper aims to identify cross-cutting themes on how and why these countries achieved or did not achieve MDG progress. Methods Applying a standard evaluation framework, analyses of impact, coverage and equity were undertaken, including a mixed methods analysis of how these were influenced by national context and coverage determinants (including health systems, policies and financing). Results The majority (7/10) of case study countries met MDG-4 with over two-thirds reduction in child mortality, but none met MDG-5a for 75 % reduction in maternal mortality, although six countries achieved >75 % of this target. None achieved MDG-5b regarding reproductive health. Rates of reduction in neonatal mortality were half or less that for post-neonatal child mortality. Coverage increased most for interventions administered at lower levels of the health system (e.g., immunisation, insecticide treated nets), and these experienced substantial political and financial support. These interventions were associated with ~30–40 % of child lives saved in 2012 compared to 2000, in Ethiopia, Malawi, Peru and Tanzania. Intrapartum care for mothers and newborns -- which require higher-level health workers, more infrastructure, and increased community engagement -- showed variable increases in coverage, and persistent equity gaps. Countries have explored different approaches to address these problems, including shifting interventions to the community setting and tasks to lower-level health workers. Conclusions These Countdown case studies underline the importance of consistent national investment and global attention for achieving improvements in RMNCH. Interventions with major global investments achieved higher levels of coverage, reduced equity gaps and improvements in associated health outcomes. Given many competing priorities for the Sustainable Development Goals era, it is essential to maintain attention to the unfinished RMNCH agenda, particularly health systems improvements for maternal and neonatal outcomes where progress has been slower, and to invest in data collection for monitoring progress and for rigorous analyses of how progress is achieved in different contexts.

An amendment to this paper has been published and can be accessed via the original article.

An amendment to this paper has been published and can be accessed via the original article.

Abstract Background Patients with central lines face an increased risk of developing bacteremia. Preventing late-onset catheter-related infections relies on implementing various measures during manipulations of the catheter hub of central lines (e.g., during connections, disconnections, blood withdrawals, pulsed rinses, or injections performed at the first connection after the central catheter). French guidelines include, among these measures, the requirement to put on sterile gloves immediately before proximal manipulation to help prevent contamination of the catheter hub during preparation. To our knowledge, no study has reported compliance with wearing sterile gloves during these manipulations, nor the impact of not wearing sterile gloves on the cleanliness of the fingers of healthcare workers (HCWs) just before manipulating the connectors. Methods We conducted a two-part study to assess compliance with sterile gloving and to provide direct microbiological evidence of bacterial contamination on HCWs’ hands immediately before the manipulation of central lines when sterile gloving is not used. First, the use of sterile gloves was observed during proximal manipulations of central lines using a standardized grid. Second, we examined the microbial flora present on the fingers of each observed HCW just before proximal manipulation. Results A total of 260 HCWs from 35 healthcare institutions were observed during proximal manipulation. The HCWs were distributed into three groups: 188 used sterile gloves (72%), 23 used nonsterile gloves (9%), and 49 did not wear gloves (19%). The swabbing of the fingertips revealed microbial cultures from 72 samples (28%). A total of 97 microorganisms were identified, all of which are well-recognized agents responsible for catheter-related bacteremia, predominantly coagulase-negative staphylococci (n = 36) and Bacillus sp. (n = 31). Fingertip contamination was lower for HCWs wearing sterile gloves (27/188; 14%) than for those wearing nonsterile gloves (12/23; 52%) or not wearing gloves (33/49; 67%) (p

Abstract Background Patient experiences with COVID-19 aftercare remain largely unknown. We evaluated COVID-19 aftercare from a patient perspective one year after hospitalization, assessing satisfaction and its associated factors, and unmet needs. Methods The Satisfaction with COVID-19 Aftercare Questionnaire (SCAQ) was developed as part of a multicenter prospective cohort study and administered one year after hospital discharge. The SCAQ assesses (1) patient satisfaction, comprising information provision, rehabilitation, follow-up by hospitals and general practitioners (GPs), the most important aftercare topics, and overall satisfaction, and (2) unmet needs. Results 487/561 (87%) COVID-19 patients completed the SCAQ, all had been discharged from the hospital between March 2020 and May 2021. Among responders, the median age of patients was 60 (IQR 54–67) years, 338 (69%) were male, and the median length of stay in the hospital was 13 (6–27) days. Patients were least satisfied with information on who could be contacted with questions when health problems arise (59% satisfied or very satisfied). Many patients (75%) received rehabilitation, most frequently community-based (70%). Across the different community-based therapies, ≥ 60% of patients were satisfied with shared-decision making and ≥ 70% with the received therapy; a majority (≥ 79%) indicated a preference for receiving the same therapy again if needed. Regarding follow-up by hospitals, 86% of patients received this follow-up, most frequently visiting a pulmonologist (96%), being generally satisfied with the received aftercare. Aftercare from GPs was received by 39% of patients, with 88% being satisfied with the GP’s availability and 79% with referral to appropriate aftercare providers. Patients (> 50%) considered information-related items most important in aftercare. Overall, patients rated their satisfaction with aftercare 8/10 (7–9) points. Those who received medical rehabilitation (versus no rehabilitation, adjusted beta 0.61 [95%CI 0.11 to 1.11], p = 0.02) or aftercare by a hospital medical specialist (1.1 [0.46 to 1.64], p

Abstract Background Health professionals are increasingly called upon and willing to engage in planetary health care and management. However, so far, this topic is rarely covered in medical curricula. As the need for professional communication is particularly high in this subject area, this study aimed to evaluate whether the objective structured clinical examination (OSCE) could be used as an accompanying teaching tool. Methods During the winter semester 2022/2023, 20 third- and fifth-year medical students voluntarily participated in a self-directed online course, three workshops, and a formal eight-station OSCE on planetary health care and management. Each examinee was also charged alternatingly as a shadower with the role of providing feedback. Experienced examiners rated students’ performance using a scoring system supported by tablet computers. Examiners and shadowers provided timely feedback on candidates` performance in the OSCE. Immediately after the OSCE, students were asked about their experience using a nine-point Likert-scale survey and a videotaped group interview. Quantitative analysis included the presentation of the proportional distribution of student responses to the survey and of box plots showing percentages of maximum scores for the OSCE performance. The student group interview was analyzed qualitatively. Results Depending on the sub-theme, 60% -100% of students rated the subject of planetary health as likely to be useful in their professional lives. Similar proportions (57%-100%) were in favour of integrating planetary health into required courses. Students perceived learning success from OSCE experience and feedback as higher compared to that from online courses and workshops. Even shadowers learned from observation and feedback discussions. Examiners assessed students’ OSCE performance at a median of 80% (interquartile range: 83%-77%) of the maximum score. Conclusions OSCE can be used as an accompanying teaching tool for advanced students on the topic of planetary health care and management. It supports learning outcomes, particularly in terms of communication skills to sensitise and empower dialogue partners, and to initiate adaptation steps at the level of individual patients and local communities.

Abstract Background Treatment-resistant depression (TRD) is defined by the European Medicines Agency as a lack of clinically meaningful improvement after treatment, with at least two different antidepressants. Individual, familiar, and socio-economic burden of TRD is huge. Given the lack of clear guidelines, the large variability of TRD approaches across different countries and the availability of new medications to meet the need of effective and rapid acting therapeutic strategies, it is important to understand the consensus regarding the clinical characteristics and treatment pathways of patients with TRD in Italian routine clinical practice, particularly in view of the recent availability of esketamine nasal spray. Methods A Delphi questionnaire with 17 statements (with a 7 points Likert scale for agreement) was administered via a customized web-based platform to Italian psychiatrists with at least 5 years of experience and specific expertise in the field of depression. In the second-round physicians were asked to answer the same statements considering the interquartile range of each question as an index of their colleagues’ responses. Stata 16.1 software was used for the analyses. Results Sixty panellists, representative of the Italian territory, answered the questionnaire at the first round. For 8/17 statements more than 75% of panellists reached agreement and a high consensus as they assigned similar scores; for 4 statements the panellists assigned similar scores but in the middle of the Likert scale showing a moderate agreement with the statement, while for 5 statements there was indecision in the agreement and low consensus with the statement. Conclusions This Delphi Panel showed that there is a wide heterogeneity in Italy in the management of TRD patients, and a compelling need of standardised strategies and treatments specifically approved for TRD. A high level of consensus and agreement was obtained about the importance of adding lithium and/or antipsychotics as augmentation therapies and in the meantime about the need for long-term maintenance therapy. A high level of consensus and agreement was equally reached for the identification of esketamine nasal spray as the best option for TRD patients and for the possibility to administrate without difficulties esketamine in a community outpatient setting, highlighting the benefit of an appropriate educational support for patients.

Abstract Background Central catheters expose ICU patients at risk of catheter-related bloodstream infections. A mechanism by which these infections occur is the contamination of the catheter during its insertion if aseptic techniques are not strictly applied. Recent studies suggest that the use of ultrasound guidance (USG) may increase the risk of catheter contamination during insertion. We assessed current practices regarding the use of USG during catheter insertion, with a focus on identifying breaches of the surgical asepsis required for this invasive procedure. Methods In 26 intensive care units, we evaluated the use of USG during catheter insertion, using a questionnaire addressed to intensivists and direct observation of their practices. Results We analyzed 111 questionnaires and 36 observations of intensivists placing catheters. The questionnaires revealed that 88% of intensivists used USG for catheter insertion. Among those using USG, 56% had received specific training, 17% benefited from specific recommendations, 76% marked the insertion site before skin antisepsis, and during catheter insertion, 96% used sterile gel and 100% used a sterile sheath and sterile gloves. We identified potential deviations from strict aseptic technique, including contact between the sheath and the needle (19.4%), handling of the US system during catheter insertion (2.8%), and use of sterile devices, where they were not yet necessary (during the marking site or skin antisepsis), resulting in their contamination at the time of catheter insertion. Conclusions Interventions aimed at ensuring compliance with measures to prevent CRBs should be organized to prevent an increase in infections associated with US-guided catheter insertion.

Abstract Background The role of inflammation in the aetiology of schizophrenia has gained wide attention and research on the association shows an exponential growth in the last 15 years. Autoimmune diseases and severe infections are risk factors for the later development of schizophrenia, elevated inflammatory markers in childhood or adolescence are associated with a greater risk of schizophrenia in adulthood, individuals with schizophrenia have increased levels of pro-inflammatory cytokines compared to healthy controls, and autoimmune diseases are overrepresented in schizophrenia. However, treatments with anti-inflammatory agents are so far of doubtful clinical relevance. The primary objective of this study is to test whether the monoclonal antibody rituximab, directed against the B-cell antigen CD20 ameliorates psychotic symptoms in adults with schizophrenia or schizoaffective disorder and to examine potential mechanisms. A secondary objective is to examine characteristics of inflammation-associated psychosis and to identify pre-treatment biochemical characteristics of rituximab responders. A third objective is to interview a subset of patients and informants on their experiences of the trial to obtain insights that rating scales may not capture. Methods A proof-of-concept study employing a randomised, parallel-group, double-blind, placebo-controlled design testing the effect of B-cell depletion in patients with psychosis. 120 participants with a diagnosis of schizophrenia spectrum disorders (SSD) (ICD-10 codes F20, F25) will receive either one intravenous infusion of rituximab (1000 mg) or saline. Psychiatric measures and blood samples will be collected at baseline, week 12, and week 24 post-infusion. Brief assessments will also be made in weeks 2 and 7. Neuroimaging and lumbar puncture, both optional, will be performed at baseline and endpoints. Approximately 40 of the patients and their informants will be interviewed for qualitative analyses on the perceived changes in well-being and emotional qualities, in addition to their views on the research. Discussion This is the first RCT investigating add-on treatment with rituximab in unselected SSD patients. If the treatment is helpful, it may transform the treatment of patients with psychotic disorders. It may also heighten the awareness of immune-psychiatric disorders and reduce stigma. Trial registration NCT05622201, EudraCT-nr 2022–000220-37 version 2.1. registered 14th of October 2022.

Abstract Background Patients who have short peripheral venous catheters (PVC) face an elevated risk of developing bloodstream infections. Preventing catheter-related infections relies on implementing multiple measures, including practicing proper hand hygiene (HH) during catheter placement. Methods We conducted a four-part study: (1) an evaluation of HH practices through direct observation of PVC placements, coupled with the study of the microbial flora of the HCWs fingers just before the placement; (2) the development of an educational tool based on the collected observational and microbiological data; (3) the training to the HCWs observed during the first part, using this tool; and (4) the subsequent observation of the trained HCWs to measure the impact of the training on practice improvement. Results Compliant HH was observed in 23.5% of the 647 HCWs observed during PVC placement before training. The microbiological study revealed fewer pathogens on the fingertips of the HCWs practicing compliant HH compared other HCWs (2.6 vs 11,7%; p = 0.003). The comparison of practices before and after training, assessed among 180 HCWs, showed an increase in the proportion of HCWs performing compliant HH (25.0 vs 63.2%; p

Abstract Background Currently, evidence about the long-term consequences of COVID-19 on return to work and health-related quality of life (HRQoL) is limited. We evaluated return to work and its associations with baseline characteristics and physical and mental recovery over time in patients up to 1 year after hospitalization for COVID-19. Secondly, we aimed to evaluate the association between return to work and health-related quality of life (HRQoL). Methods CO-FLOW, a multicenter prospective cohort study, enrolled adult participants hospitalized for COVID-19, aged ≥ 18 years within 6 months after hospital discharge. Return to work and HRQoL were collected at 3, 6, and 12 months after hospital discharge using the iMTA Productivity Cost Questionnaire and the 36-Item Short Form Health Survey, respectively. Data were collected between July 1, 2020, and September 1, 2022. Generalized estimating equations with repeated measurements were used to assess outcomes over time. Results In the CO-FLOW study, 371 participants were employed pre-hospitalization. At 3, 6, and 12 months post-discharge, 50% (170/342), 29% (92/317), and 15% (44/295) of participants had not returned to work, and 21% (71/342), 21% (65/317), and 16% (48/295) only partially, respectively. ICU admission (adjusted odds ratio (95% confidence interval): 0.17 (0.10 to 0.30), p

Abstract Background Motor neuron disease (MND) is a fatal, progressive neurodegenerative disease that causes progressive weakening and wasting of limb, bulbar, thoracic and abdominal muscles. Clear evidence-based guidance on how psychological distress should be managed in people living with MND (plwMND) is lacking. Acceptance and Commitment Therapy (ACT) is a form of psychological therapy that may be particularly suitable for this population. However, to the authors' knowledge, no study to date has evaluated ACT for plwMND. Consequently, the primary aim of this uncontrolled feasibility study was to examine the feasibility and acceptability of ACT for improving the psychological health of plwMND. Methods PlwMND aged ≥ 18 years were recruited from 10 UK MND Care Centres/Clinics. Participants received up to 8 one-to-one ACT sessions, developed specifically for plwMND, plus usual care. Co-primary feasibility and acceptability outcomes were uptake (≥ 80% of the target sample [N = 28] recruited) and initial engagement with the intervention (≥ 70% completing ≥ 2 sessions). Secondary outcomes included measures of quality of life, anxiety, depression, disease-related functioning, health status and psychological flexibility in plwMND and quality of life and burden in caregivers. Outcomes were assessed at baseline and 6 months. Results Both a priori indicators of success were met: 29 plwMND (104%) were recruited and 76% (22/29) attended ≥ 2 sessions. Attrition at 6-months was higher than anticipated (8/29, 28%), but only two dropouts were due to lack of acceptability of the intervention. Acceptability was further supported by good satisfaction with therapy and session attendance. Data were possibly suggestive of small improvements in anxiety and psychological quality of life from baseline to 6 months in plwMND, despite a small but expected deterioration in disease-related functioning and health status. Conclusions There was good evidence of acceptability and feasibility. Limitations included the lack of a control group and small sample size, which complicate interpretation of findings. A fully powered RCT to evaluate the clinical and cost-effectiveness of ACT for plwMND is underway. Trial registration The study was pre-registered with the ISRCTN Registry (ISRCTN12655391).

Abstract Background Despite progress, stillbirth rates in many high- and upper-middle income countries remain high, and the majority of these deaths are preventable. We introduce the Ending Preventable Stillbirths (EPS) Scorecard for High- and Upper Middle-Income Countries, a tool to track progress against the Lancet’s 2016 EPS Series Call to Action, fostering transparency, consistency and accountability. Methods The Scorecard for EPS in High- and Upper-Middle Income Countries was adapted from the Scorecard for EPS in Low-Income Countries, which includes 20 indicators to track progress against the eight Call to Action targets. The Scorecard for High- and Upper-Middle Income Countries includes 23 indicators tracking progress against these same Call to Action targets. For this inaugural version of the Scorecard, 13 high- and upper-middle income countries supplied data. Data were collated and compared between and within countries. Results Data were complete for 15 of 23 indicators (65%). Five key issues were identified: (1) there is wide variation in stillbirth rates and related perinatal outcomes, (2) definitions of stillbirth and related perinatal outcomes vary widely across countries, (3) data on key risk factors for stillbirth are often missing and equity is not consistently tracked, (4) most countries lack guidelines and targets for critical areas for stillbirth prevention and care after stillbirth and have not set a national stillbirth rate target, and (5) most countries do not have mechanisms in place for reduction of stigma or guidelines around bereavement care. Conclusions This inaugural version of the Scorecard for High- and Upper-Middle Income Countries highlights important gaps in performance indicators for stillbirth both between and within countries. The Scorecard provides a basis for future assessment of progress and can be used to help hold individual countries accountable, especially for reducing stillbirth inequities in disadvantaged groups.

Abstract Objectives Although a growing share of the population in many countries has been vaccinated against the SARS-CoV-2 virus to different degrees, social distancing and hygienic non-pharmaceutical interventions still play a substantial role in containing the pandemic. The goal of this study was to investigate which factors are correlated with a higher compliance with these regulations in the context of a cohort study in the city of Munich, southern Germany, during the summer of 2020, i.e. after the first lockdown phase. Methods Using self-reported compliance with six regulations and personal hygiene rules (washing hands, avoiding touching face, wearing a mask, keeping distance, avoiding social gatherings, avoiding public spaces) we extracted two compliance factor scores, namely compliance with personal hygiene measures and compliance with social distancing regulations. Using linear and logistic regressions, we estimated the correlation of several socio-demographic and risk perception variables with both compliance scores. Results Risk aversion proved to be a consistent and significant driver of compliance across all compliance behaviors. Furthermore, being female, being retired and having a migration background were positively associated with compliance with personal hygiene regulations, whereas older age was related with a higher compliance with social distancing regulations. Generally, socioeconomic characteristics were not related with compliance, except for education, which was negatively related with compliance with personal hygiene measures. Conclusions Our results suggest that for a targeted approach to improve compliance with measures to prevent SARS-CoV-2 infection, special attention should be given to younger, male and risk-prone individuals.

Abstract Background In contrast to adults, the situation for pediatric trauma care from an international point of view and the global management of severely injured children remain rather unclear. The current study investigates structural management of pediatric trauma in centers of different trauma levels as well as experiences with pediatric trauma management around the world. Methods A web-survey had been distributed to the global mailing list of the World Society of Emergency Surgery from 10/2021–03/2022, investigating characteristics of respondents and affiliated hospitals, case-load of pediatric trauma patients, capacities and infrastructure for critical care in children, trauma team composition, clinical work-up and individual experiences with pediatric trauma management in response to patients´ age. The collaboration group was subdivided regarding sizes of affiliated hospitals to allow comparisons concerning hospital volumes. Comparable results were conducted to statistical analysis. Results A total of 133 participants from 34 countries, i.e. 5 continents responded to the survey. They were most commonly affiliated with larger hospitals (> 500 beds in 72.9%) and with level I or II trauma centers (82.0%), respectively. 74.4% of hospitals offer unrestricted pediatric medical care, but only 63.2% and 42.9% of the participants had sufficient experiences with trauma care in children ≤ 10 and ≤ 5 years of age (p = 0.0014). This situation is aggravated in participants from smaller hospitals (p 500 in-hospital beds), larger hospitals were more likely affiliated with advanced trauma centers, more elaborated pediatric intensive care infrastructure (p

Abstract Background More than 2.7 million hospitalizations of COVID-19-infected patients have occurred in Europe alone since the outbreak of the coronavirus in 2020. Interventions against SARS-CoV-2 are still in high need to prevent admissions to ICUs worldwide. FX06, a naturally occurring peptide in humans and other mammals, has the potential to reduce capillary leak by improving endothelial dysfunction and thus preventing the deterioration of patients. With IXION, we want to investigate the potential of FX06 to prevent disease progression in hospitalized, non-intubated COVID-19 patients. Methods IXION is an EU-wide, multicentre, placebo-controlled, double-blinded, parallel, randomized (2:1) phase II clinical study. Patient recruitment will start in September 2022 (to Q2/2023) in Germany, Italy, Lithuania, Spain, Romania, Portugal, and France. A total of 306 hospitalized patients (≥ 18 years and < 75 years) with a positive SARS-CoV-2 PCR test and a COVID-19 severity of 4–6 according to the WHO scale will be enrolled. After randomization to FX06 or placebo, patients will be assessed until day 28 (and followed up until day 60). FX06 (2 × 200 mg per day) or placebo will be administered intravenously for 5 consecutive days. The primary endpoint is to demonstrate a difference in the proportion of patients with progressed/worsened disease state in patients receiving FX06 compared to patients receiving placebo. Secondary endpoints are lung function, oxygen saturation and breathing rate, systemic inflammation, survival, capillary refill time, duration of hospital stay, and drug accountability. Discussion With IXION, the multidisciplinary consortium aims to deliver a new therapy in addition to standard care against SARS-CoV-2 for the clinical management of COVID-19 during mild and moderate stages. Potential limitations might refer to a lack of recruiting and drop-out due to various possible protocol violations. While we controlled for drop-outs in the same size estimation, recruitment problems may be subject to external problems difficult to control for. Trial registration EudraCT 2021-005059-35 . Registered on 12 December 2021. Study Code TMP-2204-2021-47.

Abstract Background The SARS-CoV-2 pandemic is still ongoing and a major challenge for health care services worldwide. In the first WSES COVID-19 emergency surgery survey, a strong negative impact on emergency surgery (ES) had been described already early in the pandemic situation. However, the knowledge is limited about current effects of the pandemic on patient flow through emergency rooms, daily routine and decision making in ES as well as their changes over time during the last two pandemic years. This second WSES COVID-19 emergency surgery survey investigates the impact of the SARS-CoV-2 pandemic on ES during the course of the pandemic. Methods A web survey had been distributed to medical specialists in ES during a four-week period from January 2022, investigating the impact of the pandemic on patients and septic diseases both requiring ES, structural problems due to the pandemic and time-to-intervention in ES routine. Results 367 collaborators from 59 countries responded to the survey. The majority indicated that the pandemic still significantly impacts on treatment and outcome of surgical emergency patients (83.1% and 78.5%, respectively). As reasons, the collaborators reported decreased case load in ES (44.7%), but patients presenting with more prolonged and severe diseases, especially concerning perforated appendicitis (62.1%) and diverticulitis (57.5%). Otherwise, approximately 50% of the participants still observe a delay in time-to-intervention in ES compared with the situation before the pandemic. Relevant causes leading to enlarged time-to-intervention in ES during the pandemic are persistent problems with in-hospital logistics, lacks in medical staff as well as operating room and intensive care capacities during the pandemic. This leads not only to the need for triage or transferring of ES patients to other hospitals, reported by 64.0% and 48.8% of the collaborators, respectively, but also to paradigm shifts in treatment modalities to non-operative approaches reported by 67.3% of the participants, especially in uncomplicated appendicitis, cholecystitis and multiple-recurrent diverticulitis. Conclusions The SARS-CoV-2 pandemic still significantly impacts on care and outcome of patients in ES. Well-known problems with in-hospital logistics are not sufficiently resolved by now; however, medical staff shortages and reduced capacities have been dramatically aggravated over last two pandemic years.

Abstract Introduction The WHO estimates that each year 5 million people are left permanently disabled after stroke. Adjuvant treatments to promote the effects of rehabilitation are urgently needed. Cortical excitability and neuroplasticity can be enhanced by non-invasive brain stimulation but evidence from sufficiently powered, randomized controlled multi-center clinical trials is absent. Methods Neuroregeneration enhanced by transcranial direct current stimulation (tDCS) in stroke (NETS) tested efficacy and safety of anodal tDCS to the primary motor cortex of the lesioned hemisphere in the subacute phase (day 5–45) after cerebral ischemia. Stimulation was combined with standardized rehabilitative training and repeatedly applied in 10 sessions over a period of 2 weeks in a planned sample of 120 patients. Primary outcome parameter was upper-extremity function at the end of the 2-weeks intervention period of active treatment or placebo (1:1 randomization), measured by the upper-extremity Fugl-Meyer assessment. Sustainability of the treatment effect was evaluated by additional follow-up visits after 30 and 90 days. Further secondary endpoints included metrics of arm and hand function, stroke impact scale, and the depression module of the patient health questionnaire. Perspective NETS was aimed at providing evidence for an effective and safe adjuvant treatment for patients after stroke. Trial registration: ClinicalTrials.gov Identifier NCT00909714. Registered May 28, 2009.

Abstract Background Facioscapulohumeral muscular dystrophy (FSHD) is among the most prevalent muscular dystrophies and currently has no treatment. Clinical and genetic heterogeneity are the main challenges to a full comprehension of the physiopathological mechanism. Improving our knowledge of FSHD is crucial to the development of future therapeutic trials and standards of care. National FSHD registries have been set up to this end. The French National Registry of FSHD combines a clinical evaluation form (CEF) and a self-report questionnaire (SRQ), filled out by a physician with expertise in neuromuscular dystrophies and by the patient, respectively. Aside from favoring recruitment, our strategy was devised to improve data quality. Indeed, the pairwise comparison of data from 281 patients for 39 items allowed for evaluating data accuracy. Kappa or intra-class coefficient (ICC) values were calculated to determine the correlation between answers provided in both the CEF and SRQ. Results Patients and physicians agreed on a majority of questions common to the SRQ and CEF (24 out of 39). Demographic, diagnosis- and care-related questions were generally answered consistently by the patient and the medical practitioner (kappa or ICC values of most items in these groups were greater than 0.8). Muscle function-related items, i.e. FSHD-specific signs, showed an overall medium to poor correlation between data provided in the two forms; the distribution of agreements in this section was markedly spread out and ranged from poor to good. In particular, there was very little agreement regarding the assessment of facial motricity and the presence of a winged scapula. However, patients and physicians agreed very well on the Vignos and Brooke scores. The report of symptoms not specific to FSHD showed general poor consistency. Conclusions Patient and physician answers are largely concordant when addressing quantitative and objective items. Consequently, we updated collection forms by relying more on patient-reported data where appropriate. We hope the revised forms will reduce data collection time while ensuring the same quality standard. With the advent of artificial intelligence and automated decision-making, high-quality and reliable data are critical to develop top-performing algorithms to improve diagnosis, care, and evaluate the efficiency of upcoming treatments.

Abstract Background Health technology assessment (HTA) brings together evidence from various disciplines while using explicit methods to assess the value of health technologies. In resource-constrained settings, there is a growing demand to measure and develop specialist skills, including those for HTA, to aid the implementation of Universal Healthcare Coverage. The purpose of this study was twofold: a) to find validated tools for the assessment of the technical capacity to conduct a HTA, and if none were found, to develop a tool, and b) to describe experiences of its pilot. Methods First, a mapping review identified tools to assess the skills to conduct a HTA. A medical librarian conducted a comprehensive search in four databases (MEDLINE, Embase, Web of Science, ERIC). Then, incorporating results from the mapping and following an iterative process involving stakeholders and experts, we developed a HTA skills assessment tool. Finally, using an online platform to gather and analyse responses, in collaboration with our institutional partner, we piloted the tool in Ghana, and sought feedback on their experiences. Results The database search yielded 3871 records; fifteen those were selected based on a priori criteria. These records were published between 2003 and 2018, but none covered all technical skills to conduct a HTA. In the absence of an instrument meeting our needs, we developed a HTA skill assessment tool containing four sections (general information, core and soft skills, and future needs). The tool was designed to be administered to a broad range of individuals who would potentially contribute to the planning, delivery and evaluation of HTA. The tool was piloted with twenty-three individuals who completed the skills assessment and shared their initial impressions of the tool. Conclusions To our knowledge, this is the first comprehensive tool enabling the assessment of technical skills to conduct a HTA. This tool allows teams to understand where their individual strengths and weakness lie. The tool is in the early validation phases and further testing is needed. Trial registration Not applicable.

Abstract Background To estimate the short term (5 years) and long term (30 years) economic burden of stroke among younger adults (18–64 years), and to calculate the loss of health-related quality of life in these individuals, in Australia. Methods A Markov microsimulation model was built to simulate incidence of stroke among younger adults in Australia. Younger adults with stroke commenced in the model via health states defined by the modified Rankin Scale at 12 months from the AVERT study (A Very Early Rehabilitation Trial), and transitioned through these health states. Costs in Australian dollars (AUD) were measured from a societal perspective for a 2018 reference year and categorised into medical, non-medical and indirect costs. Probabilistic sensitivity analyses were performed to test the robustness around the cost of illness estimates. The loss of health-related quality of life due to stroke among younger adults was calculated by determining the difference in estimated quality-adjusted life years (QALYs) between the stroke population and the general population. This was determined by multiplying the predicted remaining life years for the modelled stroke cohort and the age-matched general population, by their corresponding age-dependent utilities. Results The economic burden of stroke among younger adults was estimated to be AUD2.0 billion over 5 years, corresponding to a mean of $149,180 per stroke patient. Over 30 years, the economic impact was AUD3.4 billion, equating to a mean of $249,780 per case. Probabilistic sensitivity analyses revealed a mean cost per patient of $153,410 in the short term, and a mean cost per patient of $273,496 in the long term. Compared to the age-matched general population, younger adults with stroke experienced a loss of 4.58 life years and 9.21 QALYs. Conclusions The results of our study suggests high economic and health burden of stroke among younger adults and highlights the need for preventive interventions targeting this age group. Trial registration ACTRN12606000185561 , retrospectively registered.

Abstract Background In spite of the global implementation of standardized surgical safety checklists and evidence-based practices, general surgery remains associated with a high residual risk of preventable perioperative complications and adverse events. This study was designed to validate the hypothesis that a new “Trigger Tool” represents a sensitive predictor of adverse events in general surgery. Methods An observational multicenter validation study was performed among 31 hospitals in Spain. The previously described “Trigger Tool” based on 40 specific triggers was applied to validate the predictive power of predicting adverse events in the perioperative care of surgical patients. A prediction model was used by means of a binary logistic regression analysis. Results The prevalence of adverse events among a total of 1,132 surgical cases included in this study was 31.53%. The “Trigger Tool” had a sensitivity and specificity of 86.27% and 79.55% respectively for predicting these adverse events. A total of 12 selected triggers of overall 40 triggers were identified for optimizing the predictive power of the “Trigger Tool”. Conclusions The “Trigger Tool” has a high predictive capacity for predicting adverse events in surgical procedures. We recommend a revision of the original 40 triggers to 12 selected triggers to optimize the predictive power of this tool, which will have to be validated in future studies.

Abstract Background Gestational diabetes (GDM) impacts 8–18% of pregnancies and greatly increases both maternal and child risk of developing non-communicable diseases such as type 2 diabetes and obesity. Whilst lifestyle interventions in pregnancy and postpartum reduce this risk, a research translation gap remains around delivering implementable interventions with adequate population penetration and participation. Impact Diabetes Bump2Baby is an implementation project of an evidence-based system of care for the prevention of overweight and obesity. Bump2Baby and Me is the multicentre randomised controlled trial investigating the effectiveness of a mHealth coaching programme in pregnancy and postpartum for women at high risk of developing GDM. Methods Eight hundred women will be recruited in early pregnancy from 4 clinical sites within Ireland, the UK, Spain, and Australia. Women will be screened for eligibility using the validated Monash GDM screening tool. Participants will be enrolled from 12 to 24 weeks’ gestation and randomised on a 1:1 basis into the intervention or control arm. Alongside usual care, the intervention involves mHealth coaching via a smartphone application, which uses a combination of synchronous and asynchronous video and text messaging, and allows for personalised support and goal setting with a trained health coach. The control arm receives usual care. All women and their children will be followed from early pregnancy until 12 months postpartum. The primary outcome will be a difference in maternal body mass index (BMI) of 0.8 kg/m2 at 12 months postpartum. Secondary maternal and infant outcomes include the development of GDM, gestational weight gain, pregnancy outcomes, improvements in diet, physical activity, sleep, and neonatal weight and infant growth patterns. The 5-year project is funded by the EU Commission Horizon 2020 and the Australian National Health and Medical Research Council. Ethical approval has been received. Discussion Previous interventions have not moved beyond tightly controlled efficacy trials into routine service delivery. This project aims to provide evidence-based, sustainable support that could be incorporated into usual care for women during pregnancy and postpartum. This study will contribute evidence to inform the early prevention of non-communicable diseases like obesity and diabetes in mothers and the next generation. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12620001240932 . Registered on 19 November 2020

Abstract Background First studies indicate that up to 6 months after hospital discharge, coronavirus disease 2019 (COVID-19) causes severe physical, cognitive, and psychological impairments, which may affect participation and health-related quality of life (HRQoL). After hospitalization for COVID-19, a number of patients are referred to medical rehabilitation centers or skilled nursing facilities for further treatment, while others go home with or without aftercare. The aftercare paths include 1] community-based rehabilitation; 2] in- and outpatient medical rehabilitation; 3] inpatient rehabilitation in skilled nursing facilities; and 4] sheltered care (inpatient). These aftercare paths and the trajectories of recovery after COVID-19 urgently need long-term in-depth evaluation to optimize and personalize treatment. CO-FLOW aims, by following the outcomes and aftercare paths of all COVID-19 patients after hospital discharge, to systematically study over a 2-year period: 1] trajectories of physical, cognitive, and psychological recovery; 2] patient flows, healthcare utilization, patient satisfaction with aftercare, and barriers/facilitators regarding aftercare as experienced by healthcare professionals; 3] effects of physical, cognitive, and psychological outcomes on participation and HRQoL; and 4] predictors for long-term recovery, health care utilization, and patient satisfaction with aftercare. Methods CO-FLOW is a multicenter prospective cohort study in the mid-west of the Netherlands with a 2-year follow-up period. Measurements comprise non-invasive clinical tests and patient reported outcome measures from a combined rehabilitation, pulmonary, and intensive care perspective. Measurements are performed at 3, 6, 12, and 24 months after hospital discharge and, if applicable, at rehabilitation discharge. CO-FLOW aims to include at least 500 patients who survived hospitalization for COVID-19, aged ≥18 years. Discussion CO-FLOW will provide in-depth knowledge on the long-term sequelae of COVID-19 and the quality of current aftercare paths for patients who survived hospitalization. This knowledge is a prerequisite to facilitate the right care in the right place for COVID-19 and comparable future infectious diseases. Trial registration The Netherlands Trial Register (NTR), https://www.trialregister.nl . Registered: 12-06-2020, CO-FLOW trialregister no. NL8710.

Abstract Background Most post-licensure vaccine pharmacovigilance in low- and middle-income countries (LMICs) are passive reporting systems. These have limited utility for maternal immunization pharmacovigilance in LMIC settings and need to be supplemented with active surveillance. Our study’s main objective was to identify existing perinatal data collection systems in LMICs that collect individual information on maternal and neonatal health outcomes and could be developed to inform active safety surveillance of novel vaccines for use during pregnancy. Methods A scoping review was performed following the Arksey and O’Malley six-stage approach. We included studies describing electronic or mixed paper-electronic data collection systems in LMICs, including research networks, electronic medical records, and custom software platforms for health information systems. Medline PubMed, EMBASE, Global Health, Cochrane Library, LILACS, Bibliography of Asian Studies (BAS), and CINAHL were searched through August 2019. We also searched grey literature including through Google and websites of existing relevant perinatal data collection systems, as well as contacted authors of key studies and experts in the field to validate the information and identify additional sources of relevant unpublished information. Results A total of 11,817 records were identified. The full texts of 264 records describing 96 data collection systems were assessed for eligibility. Eight perinatal data collection systems met our inclusion criteria: Global Network’s Maternal Newborn Health Registry, International Network for the Demographic Evaluation of Populations and their Health; Perinatal Informatic System; Pregnancy Exposure Registry & Birth Defects Surveillance; SmartCare; Open Medical Record System; Open Smart Register Platform and District Health Information Software 2. These selected systems were qualitatively characterized according to seven different domains: governance; system design; system management; data management; data sources, outcomes and data quality. Conclusion This review provides a list of active maternal and neonatal data collection systems in LMICs and their characteristics as well as their outreach, strengths, and limitations. Findings could potentially help further understand where to obtain population-based high-quality information on outcomes to inform the conduct of maternal immunization active vaccine safety surveillance activities and research in LMICs.

Abstract Background A two-stage prosthesis exchange procedure has been the gold standard in surgical treatment of the chronically infected knee arthroplasty so far. This includes 2 surgeries/hospitalizations and an interim period of 2–3 months between surgeries with impaired health, functional status and quality of life of the patients. A one-stage exchange procedure holds many obvious advantages compared to the two-stage approach, but outcomes of a one-stage versus two-stage procedures have never been investigated in a randomized clinical trial. The purpose of this study is primarily to investigate time-adjusted differences in functional status of patients after one-stage versus two-stage revision. Secondary, to report time-adjusted differences in quality of life, complications (including re-revisions due to infection) and mortality. Methods This study is a pragmatic, multi-center, randomized, non-inferiority trial comparing one-stage versus two-stage revision of the infected knee arthroplasty. Seven Danish hospitals are currently participating in the study, but additional hospitals can enter the study if adhering to protocol. Ninety-six patients will be included prospectively. Follow-up will be with PROM-questionnaires and clinical controls up to 10 years. The patients who are not able to participate in the randomized trial are followed in a parallel cohort study. PROM’s Oxford Knee Score and EQ5D + EQ5D VAS questionnaires are completed preoperatively and sent out to the study participants at 6 weeks, 3, 6, 9, 12, 18 and 24 months as well as 5 and 10 years postoperatively. In addition a tailor made cost questionnaire on the non-treating hospital resource use, community health and social service use, travel costs, time off work and informal care are sent out. Discussion If one of the two treatment alternatives is found superior in both domains of quality of life (both knee-specific and generic) and health economics, that treatment should be promoted. Other outcomes will open informed discussions about treatment strategies for periprosthetic knee infections. Trial registration The randomized trial is registered on ClinicalTrials.gov with ID NCT03435679 , initial release date January 31, 2018 and the cohort study is registered with ID NCT04427943 , submitted January 8, 2020 and posted June 11, 2020.

Abstract Background Current nutritional management of infants born very preterm results in significant deficiency of the essential fatty acids (FAs) arachidonic acid (ARA) and docosahexaenoic acid (DHA). The impact of this deficit on brain maturation and inflammation mediated neonatal morbidities are unknown. The aim of this study is to determine whether early supply of ARA and DHA improves brain maturation and neonatal outcomes in infants born before 29 weeks of gestation. Methods Infants born at Oslo University Hospital are eligible to participate in this double-blind randomized controlled trial. Study participants are randomized to receive an enteral FA supplement of either 0.4 ml/kg MCT-oil™ (medium chain triglycerides) or 0.4 ml/kg Formulaid™ (100 mg/kg of ARA and 50 mg/kg of DHA). The FA supplement is given from the second day of life to 36 weeks’ postmenstrual age (PMA). The primary outcome is brain maturation assessed by Magnetic Resonance Imaging (MRI) at term equivalent age. Secondary outcomes include quality of growth, incidence of neonatal morbidities, cardiovascular health and neuro-development. Target sample size is 120 infants (60 per group), this will provide 80% power to detect a 0.04 difference in mean diffusivity (MD, mm2/sec) in major white matter tracts on MRI. Discussion Supplementation of ARA and DHA has the potential to improve brain maturation and reduce inflammation related diseases. This study is expected to provide valuable information for future nutritional guidelines for preterm infants. Trial registration Clinicaltrials.gov ID: NCT03555019 . Registered 4 October 2018- Retrospectively registered.

Abstract Background The Coronavirus Disease 2019 (COVID-19) is a novel disease which has been having a worldwide affect since December 2019. Evidence regarding the effects of SARS-CoV-2 during pregnancy is conflicting. The presence of SARS-CoV-2 has been demonstrated in biological samples during pregnancy (placenta, umbilical cord or amniotic fluid); however, maternal and fetal effects of the virus are not well known. Methods Descriptive, multicentre, longitudinal, observational study in eight tertiary care hospitals throughout Spain, that are referral centres for pregnant women with COVID-19. All pregnant women with positive SARS-CoV-2 real-time reverse transcriptase polymerase chain reaction during their pregnancy or 14 days preconception and newborns born to mothers infected with SARS-CoV-2 will be included. They will continue to be followed up until 4 weeks after delivery. The aim of the study is to investigate both the effect of COVID-19 on the pregnancy, and the effect of the pregnancy status with the evolution of the SARS-CoV-2 disease. Other samples (faeces, urine, serum, amniotic fluid, cord and peripheral blood, placenta and breastmilk) will be collected in order to analyse whether or not there is a risk of vertical transmission and to describe the behaviour of the virus in other fluids. Neonates will be followed until 6 months after delivery to establish the rate of neonatal transmission. We aim to include 150 pregnant women and their babies. Ethics approval will be obtained from all the participating centres. Discussion There is little information known about COVID-19 and its unknown effects on pregnancy. This study will collect a large number of samples in pregnant women which will allow us to demonstrate the behaviour of the virus in pregnancy and postpartum in a representative cohort of the Spanish population.

Abstract The ongoing coronavirus disease 2019 (COVID-19) pandemic has caused disruption in all aspects of daily life, including the management and treatment of rare inherited metabolic disorders (IMDs). To perform a preliminary assessment of the incidence of COVID-19 in IMD patients and the impact of the coronavirus emergency on the rare metabolic community between March and April 2020, the European Reference Network for Hereditary Metabolic Diseases (MetabERN) has performed two surveys: one directed to patients’ organizations (PO) and one directed to healthcare providers (HCPs). The COVID-19 incidence in the population of rare metabolic patients was lower than that of the general European population (72.9 × 100,000 vs. 117 × 100,000). However, patients experienced extensive disruption of care, with the majority of appointments and treatments cancelled, reduced, or postponed. Almost all HCPs (90%) were able to substitute face-to-face visits with telemedicine, about half of patients facing treatment changes switched from hospital to home therapy, and a quarter reported difficulties in getting their medicines. During the first weeks of emergency, when patients and families lacked relevant information, most HCPs contacted their patients to provide them with support and information. Since IMD patients require constant follow-up and treatment adjustments to control their disease and avoid degradation of their condition, the results of our surveys are relevant for national health systems in order to ensure appropriate care for IMD patients. They highlight strong links in an interconnected community of HCPs and PO, who are able to work quickly and effectively together to support and protect fragile persons during crisis. However, additional studies are needed to better appreciate the actual impact of COVID-19 on IMD patients’ health and the mid- and long-term effects of the pandemic on their wellbeing.

Abstract Background The SARS-CoV-2 pandemic is a major challenge for health care services worldwide. It’s impact on oncologic therapies and elective surgery has been described recently, and the literature provides guidelines regarding appropriate elective patient treatment during the pandemic. However, the impact of SARS-CoV-2 pandemic on emergency surgery services has been poorly investigated up to now. Methods A 17-item web survey had been distributed to emergency surgeons in June 2020 around the world, investigating the impact of SARS-CoV-2 pandemic on patients and septic diseases both requiring emergency surgery and the time-to-intervention in emergency surgery routine, as well as experiences with surgery in COVID-19 patients. Results Ninety-eight collaborators from 31 countries responded to the survey. The majority (65.3%) estimated the impact of the SARS-CoV-2 pandemic on emergency surgical patient care as being strong or very strong. Due to the pandemic, 87.8% reported a decrease in the total number of patients undergoing emergency surgery and approximately 25% estimated a delay of more than 2 h in the time-to-diagnosis and another 2 h in the time-to-intervention. Fifty percent make structural problems with in-hospital logistics (e.g. transport of patients, closed normal wards etc.) mainly responsible for delayed emergency surgery and the frequent need (56.1%) for a triage of emergency surgical patients. 56.1% of the collaborators observed more severe septic abdominal diseases during the pandemic, especially for perforated appendicitis and severe septic cholecystitis (41.8% and 40.2%, respectively). 62.2% had experiences with surgery in COVID-19-infected patients. Conclusions The results of The WSES COVID-19 emergency surgery survey are alarming. The combination of an estimated decrease in numbers of emergency surgical patients and an observed increase in more severe septic diseases may be a result of the fear of patients from infection with COVID-19 and a consecutive delayed hospital admission and diagnosis. A critical delay in time-to-diagnosis and time-to-intervention may be a result of changes in in-hospital logistics and operating room as well as intensive care capacities. Both reflect the potentially harmful impact of SARS-CoV-2 pandemic on emergency surgery services.

Abstract Background Nigeria contributes significantly to the global burden of HIV, Hepatitis B and C infections, either singly or in combinations, despite progress in HIV care regionally and globally. Although some limited data on mono infection of HIV, Hepatitis B and C virus infections do exists, that of dual and triplex infections, including seroconversion and mother-to-child transmission (MTCT) rates necessary for planning to address the scourge of infections in pregnancy are not available. Objectives To determine the seroprevalence, rate of new infections, MTCT of dual and triple infections of HIV, Hepatitis B and C viruses and associated factors, among pregnant women in Nigeria. Method A multicenter prospective cohort study will be conducted in six tertiary health facilities randomly selected from the six geopolitical zones of Nigeria. All eligible pregnant women are to be tested at enrollment after informed consent for HIV, Hepatitis B and C virus infections. While those positive for at least two of the infections in any combination will be enrolled into the study and followed up to 6 weeks post-delivery, those negative for the three infections or positive for only one of the infections at enrolment will be retested at delivery using a rapid diagnostic test. On enrolment into the study relevant information, will be obtained, and laboratory test of CD4 count, liver function test and full blood counts, and prenatal ultrasonography will also be obtained/performed. Management of mother-newborns pairs will be according to appropriate national guidelines. All exposed newborns will be tested for HIV, HBV or HCV infection at birth and 6 weeks using PCR technique. The study data will be documented on the study case record forms. Data will be managed with SPSS for windows version 23. Ethical approval was obtained from National Health Research Ethics Committee (NHREC) (NHREC/01/01/2007–23/01/2020). Conclusion Pregnant women with multiple of HIV, HBV and HCV infections are at increased risk of hepatotoxicity, maternal and perinatal morbidity and mortality. Additionally, infected pregnant women transmit the virus to their unborn baby even when asymptomatic. Children born with any of the infection have significantly poorer quality of life and lower five-year survival rate. Unfortunately, the seroconversion and MTCT rates of dual or triplex infections among pregnant women in Nigeria have not been studied making planning for prevention and subsequent elimination of the viruses difficult. The study is expected to fill this knowledge gaps. Nigeria joining the rest of the world to eliminate the triple infection among children rest on the availability of adequate and reliable data generated from appropriately designed, and powered study using representative population sample. The establishment of the three-in-one study of prevalence, rate of new infection, rate and risk factor for MTCT of dual and triple infection of HIV, Hepatitis B and C viruses among pregnant women in Nigeria is urgently needed for policy development and planning for the improvement of the quality of life of mothers and the elimination of childhood triplex infection.

Abstract Background Recent trauma guidelines recommend non-operative management for grade III splenic injury without contrast extravasation on computed tomography. Nevertheless, such recommendations rely on low-quality evidence, and practice variation characterizes clinical management for this type of injury. We aimed to identify the role of eleven selected clinical factors influencing the management of grade III splenic injury without contrast extravasation by expert consensus and a modified Delphi approach. Methods A questionnaire was developed with the endorsement of the World Society of Emergency Surgery (WSES). This was delivered and answered live by acute care surgeons attending the 6th WSES congress in Nijmegen in 2019. A dedicated mobile phone application was utilized to collect the answers. All answers were evaluated for areas of discrepancy with an 80% threshold for consensus between respondents. Results Three factors generated discrepancy in opinion for managing this pattern of injury: the patients’ injury severity, the presence of a bleeding diathesis, and an associated intra-abdominal injury. Agreement was obtained for the other eight factors. Conclusion Researchers should focus their efforts on the identified area of discrepancy. Clinicians should use additional care in the presence of the three factors for which discordant opinions were found.

Abstract Background Ischemic stroke is a leading cause of morbidity and mortality. Thrombolytic therapy improves disability and survival rates; however, to be effective, it must be given within 4.5 h of onset. Moreover, thrombolytic therapy is frequently contraindicated. Therefore, alternative therapeutic options are required. In China, cinepazide maleate injection has been shown to improve the cerebral collateral circulation and further reduce disability in stroke patients; however, very few studies investigating this therapy have been conducted to date. Therefore, this study aimed to further confirm the efficacy and safety of cinepazide maleate injection in patients with acute ischemic stroke. Methods Patients with acute ischemic stroke were administered an intravenous infusion of 320 mg cinepazide maleate or placebo once daily for 14 days. All patients were also administered basic therapy (citicoline sodium). The primary efficacy endpoint was the proportion of patients with a modified Rankin scale (mRS) ≤2 on day 90. Secondary efficacy endpoints included Barthel Index ≥95. Safety was evaluated by recording all adverse events (AEs), monitoring laboratory parameters and vital signs, and electrocardiogram. Results In total, 937 patients with an acute ischemic stroke were included, with a mean (standard deviation, SD) National Institutes of Health Stroke Scale score of 8.8 (2.4) and a mean (SD) stroke onset of 30.9 (11.4) hours prior. Following treatment for 90 days, the proportion of patients with an mRS score ≤ 2 was significantly higher in the cinepazide maleate group than in the control group (60.9% vs. 50.1%; p = 0.0004). Moreover, the proportion of patients with a Barthel Index of ≥95 on day 90 was also significantly higher in the cinepazide maleate group than in the control group (53.4% vs. 46.7%; p = 0.0230). There were no statistically significant differences in safety parameters between the cinepazide maleate and control groups. Conclusions The results of this study show that cinepazide maleate injection is superior to placebo in improving neurological function and activities of daily living, reducing disability, and promoting functional recovery in patients with acute ischemic stroke. Cinepazide maleate injection was safe and well tolerated with no unexpected AEs reported. Trial registration Chinese Clinical Trial Registry CTR20160292 and ChiCTR1900023827 . Retrospectively registered June 13, 2019.

Abstract Background Due to the SARS-CoV-2 pandemic, public health interventions have been introduced globally in order to prevent the spread of the virus and avoid the overload of health care systems, especially for the most severely affected patients. Scientific studies to date have focused primarily on describing the clinical course of patients, identifying treatment options and developing vaccines. In Germany, as in many other regions, current tests for SARS-CoV2 are not conducted on a representative basis and in a longitudinal design. Furthermore, knowledge about the immune status of the population is lacking. Nonetheless, these data are needed to understand the dynamics of the pandemic and hence to appropriately design and evaluate interventions. For this purpose, we recently started a prospective population-based cohort in Munich, Germany, with the aim to develop a better understanding of the state and dynamics of the pandemic. Methods In 100 out of 755 randomly selected constituencies, 3000 Munich households are identified via random route and offered enrollment into the study. All household members are asked to complete a baseline questionnaire and subjects ≥14 years of age are asked to provide a venous blood sample of ≤3 ml for the determination of SARS-CoV-2 IgG/IgA status. The residual plasma and the blood pellet are preserved for later genetic and molecular biological investigations. For twelve months, each household member is asked to keep a diary of daily symptoms, whereabouts and contacts via WebApp. If symptoms suggestive for COVID-19 are reported, family members, including children

Abstract Background The European Medicine Agency granted marketing approval to 164 orphan medicinal products for rare diseases, among which 28 products intended for the treatment of hereditary metabolic diseases. Taking advantage of its privileged connection with 69 healthcare centres of excellence in this field, MetabERN, the European Reference Network for hereditary metabolic diseases, performed a survey asking health care providers from 18 European countries whether these products are available on the market, reimbursed and therefore accessible for prescription, and actually delivered in their centre. Results Responses received from 52 centres (75%) concerned the design of treatment plans, the access to marketed products, and the barriers to delivery. Treatment options are always discussed with patients, who are often involved in their treatment plan. Most products (26/28) are available in most countries (15/18). Among the 15 broadly accessible products (88.5% of the centres), 9 are delivered to most patients (mean 70.1%), and the others to only few (16.5%). Among the 10 less accessible products (40.2% of the centres), 6 are delivered to many patients (66.7%), and 4 are rarely used (6.3%). Information was missing for 3 products. Delay between prescription and delivery is on average one month. Beside the lack of availability or accessibility, the most frequent reasons for not prescribing a treatment are patients’ clinical status, characteristic, and personal choice. Conclusions Data collected from health care providers in the MetabERN network indicate that two-third of the orphan medicines approved by EMA for the treatment of hereditary metabolic diseases are accessible to treating patients, although often less than one-half of the patients with the relevant conditions actually received the approved product to treat their disease. Thus, in spite of the remarkable achievement of many products, patients concerned by EMA-approved orphan medicinal products have persistent unmet needs, which deserve consideration. The enormous investments made by the companies to develop products, and the high financial burden for the Member States to purchase these products emphasize the importance of a scrupulous appreciation of treatment value involving all stakeholders at early stage of development, before marketing authorization, and during follow up.

Abstract Background Preterm birth is a worldwide challenge with the highest burden in low- and middle-income countries. Despite availability of low-cost interventions to decrease mortality of preterm, low birth weight, and sick newborns, these interventions are not well integrated in the health systems of low- and middle-income countries. The aim of this study was to assess, from the perspective of key stakeholders comprising leaders in the public health system, the health system readiness to support health care facilities in the care provided to preterm, low birth weight, and sick newborns in different regions of Ethiopia. Methods A qualitative assessment using in-depth interviews with health facility leaders was conducted in health facilities in 3 regions of Ethiopia from December 2017 to February 2018. The interview guide was developed using a modified version of the World Health Organization health system building blocks. Results Across the public health system, adequate and reliable space, power, and water were problematic. Human resource issues (training, staffing, and retention) were critical to being able to properly care for preterm, low birth weight, and sick newborns. Problems with functional equipment and equipment distribution systems were widespread. Funds were lacking to support preterm, low birth weight, and sick newborn needs in facilities. Data collection practices, data quality, and data utilization were all problematic. There were gaps in the availability of guidelines and protocols, specifically targeting preterm, low birth weight, and sick newborn care. Key facilitators, information disseminators, and influencers identified in the study were the Health Development Army, community and religious leaders, and mothers and families who had had positive experiences or outcomes of care. Conclusions The Ethiopian health system has opportunities across all 7 World Health Organization health system building blocks to strengthen readiness to support health facilities to provide quality care and improve outcomes for preterm, low birth weight, and sick newborns.

Abstract Background MetabERN is one of the 24 European Reference Networks created according to the European Union directive 2011/24/EU on patient’s rights in cross border healthcare. MetabERN associates 69 centres in 18 countries, which provide care for patients with Hereditary Metabolic Diseases, and have the mission to reinforce research and provide training for health professionals in this field. MetabERN performed a survey in December 2017 with the aim to produce an overview documenting research activities and potentials within the network. As the centres are multidisciplinary, separated questionnaires were sent to the clinical, university and laboratory teams. Answers were received from 52 out of the 69 centres of the network, covering 16 countries. A descriptive analysis of the information collected is presented. Results The answers indicate a marked interest of the respondents for research, who expressed high motivation and commitment, and estimated that the conditions to do research in their institution were mostly satisfactory. They are active in research, which according to several indicators, is competitive and satisfies standards of excellence, as well as the education programs offered in the respondent’s universities. Research in the centres is primarily performed in genetics, pathophysiology, and epidemiology, and focuses on issues related to diagnosis. Few respondents declared having activity in human and social sciences, including research on patient’s quality of life, patient’s awareness, or methods for social support. Infrastructures offering services for medical research were rarely known and used by respondents, including national and international biobanking platforms. In contrast, respondents often participate to patient registries, even beyond their specific field of interest. Conclusions Taken as a whole, these results provide an encouraging picture of the research capacities and activities in the MetabERN network, which, with respect to the number and representativeness of the investigated centres, gives a comprehensive picture of research on Hereditary Metabolic Diseases in Europe, as well as the priorities for future actions. Marginal activity in human and social sciences points out the limited multidisciplinary constitution of the responding teams with possible consequences on their current capability to participate to patient’s empowerment programs and efficiently collaborate with patient’s advocacy groups.

Abstract Background Pregnancy and pregnancy loss may be linked to cardiovascular disease (CVD). However, the evidence is still inconsistent, especially in East Asians, whose reproductive patterns differ importantly from those in the West. We examined the associations of pregnancy, miscarriage, induced abortion, and stillbirth with CVD incidence among Chinese women. Methods In 2004–2008, the nationwide China Kadoorie Biobank recruited 302,669 women aged 30–79 years from ten diverse localities. During 7 years of follow-up, 43,968 incident cases of circulatory disease, 14,440 of coronary heart disease, and 19,925 of stroke (including 11,430 ischaemic and 2170 haemorrhagic strokes), were recorded among 289,573 women without prior CVD at baseline. Cox regression yielded multiple adjusted hazard ratios (HRs) for CVD risks associated with pregnancy outcomes. Results Overall, 99% of women had been pregnant, and among them 10%, 53%, and 7% reported having a history of miscarriage, induced abortion, and stillbirth, respectively. Each additional pregnancy was associated with an adjusted HR of 1.03 (95% confidence interval, CI: 1.02; 1.04) for circulatory disease. A history of miscarriage, induced abortion, and stillbirth, respectively, were associated with adjusted HRs of 1.04 (1.01; 1.07), 1.04 (1.02; 1.07), and 1.07 (1.03; 1.11) for circulatory disease. The relationship was stronger with recurrent pregnancy loss; adjusted HRs for each additional loss being 1.04 (1.00; 1.09) for miscarriage, 1.02 (1.01; 1.04) for induced abortion, and 1.04 (1.00; 1.08) for stillbirth. Conclusions Among Chinese women, increases in pregnancy, and a history and recurrence of miscarriage, induced abortion, and stillbirth are each associated with a higher risk of CVD.