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Abstract Background Huntington’s disease (HD) is a genetic neurological disorder predominantly characterised by the progressive loss of GABAergic medium spiny neurons in the striatum resulting in motor dysfunction. One potential strategy for the treatment of HD is the development of cell replacement therapies to restore neuronal circuitry and function by the replacement of lost neurons. We propose the generation of lineage-specific human lateral ganglionic eminence precursors (hiLGEP) using direct reprogramming technology provides a novel and clinically viable cell source for cell replacement therapy for HD. Methods hiLGEPs were derived by direct reprogramming of adult human dermal fibroblasts (aHDFs) using chemically modified mRNA (cmRNA) and a defined reprogramming medium. hiLGEPs were differentiated in vitro using an optimised striatal differentiation medium. Acquisition of a striatal precursor and neural cell fate was assessed through gene expression and immunocytochemical analysis of key markers. hiLGEP-derived striatal neuron functionality in vitro was demonstrated by calcium imaging using Cal-520. To investigate the ability for hiLGEP to survive, differentiate and functionally integrate in vivo, we transplanted hiLGEPs into the striatum of quinolinic acid (QA)-lesioned rats and performed behavioural assessment using the cylinder test over the course of 14 weeks. Survival and differentiation of hiLGEPs was assessed at 8 and 14-weeks post-transplant by immunohistochemical analysis. Results We demonstrate the capability to generate hiLGEPs from aHDFs using cmRNA encoding the pro-neural genes SOX2 and PAX6, combined with a reprogramming medium containing Gö6983, Y-27,632, N-2 and Activin A. hiLGEPs generated functional DARPP32 + neurons following 14 days of culture in BrainPhys™ media supplemented with dorsomorphin and Activin A. We investigated the ability for hiLGEPs to survive transplantation, differentiate to medium spiny-like striatal neurons and improve motor function in the QA lesion rat model of HD. Fourteen weeks after transplantation, we observed STEM121 + neurons co-expressing MAP2, DARPP32, GAD65/67, or GABA. Rats transplanted with hiLGEPs also demonstrated reduction in motor function impairment as determined by spontaneous exploratory forelimb use when compared to saline transplanted animals. Conclusion This study provides proof-of-concept and demonstrates for the first time that aHDFs can be directly reprogrammed to hiLGEPs which survive transplantation, undergo neuronal differentiation to generate medium spiny-like striatal neurons, and reduce functional impairment in the QA lesion rat model of HD.

Abstract Objective To evaluate implementation of a patient decision aid for symptomatic uterine fibroid management to improve shared decision-making at five clinical settings across the United States. Methods We used a type 3 hybrid effectiveness-implementation stepped-wedge design and the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) planning and evaluation framework. We conducted clinician training, monthly reach tracking with feedback to site clinical leads, patient and clinician surveys, and visit audio-recordings. Implementation strategies included assessment of organizational readiness for shared decision-making, synchronous clinician training, audit and feedback of decision aid reach, and access to multiple decision aid formats. Outcomes and analyses included patient-level reach, clinician-level adoption, and associations of patient-reported decision aid exposure (as treated) and setting-level implementation (intention-to-treat) with patient-reported (collaboRATE measure) and observed (OPTION-5 measure) shared decision-making. We also designed and assessed setting-level plans for sustainability and other factors impacting sustained decision aid use. Results The decision aid was adopted by 72 of the 74 eligible gynecologists (97%) and reached 2553 patients across five settings. CollaboRATE scores improved among patients who reported receiving the decision aid (as-treated analysis, 69% vs. 59%; OR 1.6, 95% CI 1.16–2.27). CollaboRATE scores remained consistent before and after setting-level decision aid implementation (intention-to-treat analysis, 64% vs. 63%; OR 0.86, 95% CI 0.61–1.22). Participants would prefer to receive a decision aid at multiple time points (91.9% before the visit, 90.7% during the visit, 86.5% after the visit). Shared decision-making experiences did not improve when comparing pre vs. post-implementation collaboRATE scores across included settings (intention-to-treat, 64% vs. 63%; OR 0.86, 95% CI 0.61–1.22). Conclusion When patients with symptomatic uterine fibroids are given decision aids, they report higher shared decision-making scores. However, the differences we observed between the as-treated and intention-to-treat results suggest that unaddressed implementation challenges continue to limit the extent to which patients receive decision aids and likely hinder their overall impact. Future efforts to implement decision aids should explore enhancing their integration into clinical workflows and standard operating procedures, supported by organizational incentives that prioritize shared decision-making. Trial registration ClinicalTrials.gov NCT03985449; registered 6 June 2019.

Abstract Background Mesenchymal stromal cell (MSC) therapy holds great potential yet efficacy and safety concerns with cell therapy persist. The beneficial effects of MSCs are often attributed to their secretome that includes extracellular vesicles (EVs). EVs carry biologically active molecules, protected by a lipid bilayer. However, several barriers hinder large-scale MSC EV production. A serum-free culturing approach is preferred for producing clinical-grade MSC-derived EVs but this can affect both yield and purity. Consequently, new strategies have been explored, including genetically engineering MSCs to alter EV compositions to enhance potency, increase circulation time or mediate targeting. However, efficient transfection of MSCs is challenging. Typical sources of MSC include adipose tissue and bone marrow, which both require invasive extraction procedures. Here, we investigate the use of urine-derived stem cells (USCs) as a non-invasive and inexhaustible source of MSCs for EV production. Methods We isolated, expanded, and characterized urine-derived stem cells (USCs) harvested from eight healthy donors at three different time points during the day. We evaluated the number of clones per urination, proliferation capacity and conducted flow cytometry to establish expression of surface markers. EVs were produced in chemically defined media and characterized. PEI/DNA transfection was used to genetically engineer USCs using transposon technology. Results There were no differences between time points for clone number, doubling time or viability. USCs showed immunophenotypic characteristics of MSCs, such as expression of CD73, CD90 and CD105, with no difference at the assessed time points, however, male donors had reduced CD73 + cells. Expanded USCs were incubated without growth factors or serum for 72 h without a loss in viability and EVs were isolated. USCs were transfected with high efficiency and after 10 days of selection, pure engineered cell cultures were established. Conclusions Isolation and expansion of MSCs from urine is non-invasive, robust, and without apparent sex-related differences. The sampling time point did not affect any measured markers or USC isolation potential. USCs offer an attractive production platform for EVs, both native and engineered.

Abstract Background Home-based healthcare services are facing challenges and pressures of increasing needs due to an ageing population, rising workload for an overburdened workforce, and limited financial resources. The trust model is an approach to address the challenges, by organizing the home-based healthcare services into smaller, autonomous interdisciplinary teams. The aim is to involve users and next of kin in decision-making and trusting frontline workers’ professional judgement, thus making the services more flexible and individually tailored. This study explores frontline workers’ practices and experiences of working within interdisciplinary teams according to the trust model’s goals. Methods Observations, individual-, and focus groups interviews were conducted within home-based healthcare service in a Norwegian municipality. The participants were leaders and frontline workers at different levels of the home-based healthcare services, including registered nurses, auxiliary nurses, occupational therapists, physiotherapists, and other unskilled healthcare personnel. Data was analysed thematically. Results The results are presented in terms of themes: ‘We all want the best for service users’, ‘Belonging to an interdisciplinary team’ and ‘Maintaining belonging to those with similar work tasks and responsibilities’. The results show a diversity among the participants’ experiences of working within interdisciplinary teams. It demonstrates a dilemma between creating belonging to and forming identities within the interdisciplinary team, and at the same time, the importance of maintaining belonging and identity with those in the same profession or with the same tasks and responsibilities. Conclusion This study suggests that the frontline workers need for dual belonging seems to be underestimated within the trust model, and by acknowledging this, organisations and policymakers can create environments that support both. Which in turn can enhance the possibility to deliver flexible and individually tailored services for service users.

Background Despite wide adoption in the healthcare of safety event report (SER) systems, there is a paucity of unified structures for prompt analysis and action while retaining reporter confidentiality. We used a synesis framework to change siloed reviews of safety reports to a comprehensive appraisal of quality, safety, productivity and reliability to facilitate interventions.Methods After a needs assessment survey, we launched serial plan-do-study-act cycles to (1) enhance teams’ ability to access SERs, (2) facilitate regular multidisciplinary review of SERs to identify actionable opportunities, (3) allocate action priority using failure mode and effects analysis, and (4) launch actions and summarise data. Team of Teams model allowed for empowered execution. Measures included process—completion of review, team engagement, proportion of ‘open’ (those without action plan) reports within 1 month of filing; outcome—number of actions launched and completed, dissemination of actions and postintervention survey results; and balancing—resources invested.Results 26 multidisciplinary leaders reviewed 3175 of the 3406 total reported SERs across four clinical units over 18 months. The proportion of reviewed to total SERs increased significantly from the first 6 months (75%) to the second 12 months (99%) (p

Objective Understanding patients’ wishes and preferences during hospitalisation is a crucial component of care. We identified a gap related to documentation of advance directives and patient preferences for care and focused on ensuring appropriate goals of care discussions were occurring and documented. Our aim was to improve the documentation of advance care planning notes to include 80% of targeted hospitalised patients.Patients and methods Hospitalised patients in two community hospitals were included. We performed serial Plan-Do-Measure-Act cycles. The first intervention introduced the ‘surprise question’ during an afternoon huddle. Intervention 2 emphasised documentation of the advance care planning note. The third intervention used a structured approach led by administrators at daily multidisciplinary huddles and identified patients with an Elderly Risk Assessment score of 16 or greater as targets for advance care planning documentation.Results From a baseline performance under 10%, we increased to greater than 80% of patients with Elderly Risk Assessment scores of 16 or higher having documented advance care planning. We were able to sustain this performance over subsequent years.Conclusion A structured approach that identifies a targeted population at higher risk of mortality, and implementation of a checklist at a daily multidisciplinary huddle provided sustained improvement in advance care planning documentation. This provides the opportunity for improved patient care that is aligned with their values and preferences.

Abstract Background In the high disease burden and resource-constrained contexts of sub-Saharan Africa (SSA), health workers experience a range of psychosocial stressors that leave them vulnerable to developing burnout, which can reduce service quality and negatively impact their own health and wellbeing. As universal testing and treatment (UTT) for HIV scales up across SSA, we sought to understand the implications of this human resource-intensive approach to HIV prevention to inform decision-making about health workforce staffing and support needs. Methods Using the Maslach Burnout Inventory-Human Services Survey (MBI-HSS), we assessed the prevalence of three domains of burnout—emotional exhaustion, depersonalization, and personal accomplishment—among three cadres of health workers delivering health services in areas receiving a UTT intervention in Zambia and South Africa. These cadres included health facility workers (n = 478), community health workers (n = 159), and a study-specific cadre of community HIV care providers (n = 529). We used linear regression to assess risk factors associated with emotional exhaustion, the only domain with sufficient variation in our sample. Results The MBI-HSS was completed by 1499/2153 eligible participants (69.6% response rate). Less than 1% of health workers met Maslach’s definition for burnout. All groups of health workers reported lower levels of emotional exhaustion than found in previous studies of this type (mean score scores ranged from 10.7 to 15.4 out of 54 across health cadres). Higher emotional exhaustion was associated with higher educational attainment (βadj = 2.24, 95% CI 0.76 to 3.72), greater years providing HIV services (βadj = 0.20, 95% CI 0.03 to 0.36), and testing negative for HIV at last HIV test (βadj = − 3.88 − 95% CI 5.69 to − 2.07). Working as a CHW was significantly associated with lower emotional exhaustion (βadj = − 2.52, 95% CI − 4.69 to − 0.35). Among all health workers, irrespective of HIV status, witnessing stigmatizing behaviors towards people living with HIV among their co-workers was associated with significantly increased emotional exhaustion (βadj = 3.38, 95% CI 1.99 to 4.76). Conclusions The low level of burnout detected among health workers is reassuring. However, it remains important to assess how UTT may affect levels of emotional exhaustion among health workers over time, particularly in the context of emerging global pandemics, as burnout may impact the quality of HIV services they provide and their own mental health and wellbeing. Interventions to reduce HIV stigma in health facilities may protect against emotional exhaustion among health workers, as well as interventions to increase mindfulness and resilience among health workers at risk of burnout. Trial registration ClinicalTrials.gov number: NCT01900977.

Stimulator of Interferon Genes (STING) is essential for the inflammatory response to cytosolic DNA. Despite that aberrant activation of STING is linked to an increasing number of inflammatory diseases, the development of inhibitors has been challenging, with no compounds in the pipeline beyond the preclinical stage. We previously identified endogenous nitrated fatty acids as novel reversible STING inhibitors. With the aim of improving the specificity and efficacy of these compounds, we developed and tested a library of nitroalkene-based compounds for in vitro and in vivo STING inhibition. The structure-activity relationship study revealed a robustly improved electrophilicity and reduced degrees of freedom of nitroalkenes by conjugation with an aromatic moiety. The lead compounds CP-36 and CP-45, featuring a β-nitrostyrene moiety, potently inhibited STING activity in vitro and relieved STING-dependent inflammation in vivo. This validates the potential for nitroalkene compounds as drug candidates for STING modulation to treat STING-driven inflammatory diseases, providing new robust leads for preclinical development.

Summary: Background: It is unknown if early COVID-19 monoclonal antibody (mAb) therapy can reduce risk of Long COVID. The mAbs amubarvimab/romlusevimab were previously demonstrated to reduce risk of hospitalization/death by 79%. This study assessed the impact of amubarvimab/romlusevimab on late outcomes, including Long COVID. Methods: Non-hospitalized high-risk adults within 10 days of COVID-19 symptom onset enrolled in a randomized, double-blind, placebo-controlled phase 2/3 trial of amubarvimab/romlusevimab for COVID-19 treatment. Late symptoms, assessed using a participant-completed symptom diary, were a pre-specified exploratory endpoint. The primary outcome for this analysis was the composite of Long COVID by participant self-report (presence of COVID-19 symptoms as recorded in the diary at week 36) or hospitalization or death by week 36. Inverse probability weighting (IPW) was used to address incomplete outcome ascertainment, giving weighted risk ratios (wRR) comparing amubarvimab/romlusevimab to placebo. Findings: Participants received amubarvimab/romlusevimab (n = 390) or placebo (n = 390) between January and July 2021. Median age was 49 years, 52% were female, 18% Black/African American, 49% Hispanic/Latino, and 9% COVID-19-vaccinated at entry. At week 36, 103 (13%) had incomplete outcome ascertainment, and 66 (17%) on amubarvimab/romlusevimab and 92 (24%) on placebo met the primary outcome (wRR = 0.70, 95% confidence interval (CI) 0.53–0.93). The difference was driven by fewer hospitalizations/deaths with amubarvimab/romlusevimab (4%) than placebo (13%). Among 652 participants with available diary responses, 53 (16%) on amubarvimab/romlusevimab and 44 (14%) on placebo reported presence of Long COVID. Interpretation: Amubarvimab/romlusevimab treatment, while highly effective in preventing hospitalizations/deaths, did not reduce risk of Long COVID. Additional interventions are needed to prevent Long COVID. Funding: National Institute of Allergy and Infectious Diseases of the National Institutes of Health. Amubarvimab and romlusevimab supplied by Brii Biosciences.

Objectives: The objectives of this study were (1) to systematically review the currently used definitions of incidental 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography findings (IPFs) in the literature and (2) to propose an IPF definition. Methods: A systematic search was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. The search was guided by the question “How is IPF defined?” and was performed in MEDLINE, Embase, and the Cochrane Library. The retrieved studies were reviewed and analyzed. The definitions of IPFs in the included studies were compiled into two sets of categories based on the description of FDG uptake and the specification of clinical factors in defining IPFs. Results: The systematic literature search identified 4852 publications accessible for title–abstract screening, which yielded 395 studies for full-text assessment. Sixty-five studies met the eligibility criteria and were included. Sixty-two percent mentioned “FDG uptake” in their definition. In 40% of the definitions, “Focal FDG uptake” was specified, while “FDG uptake in the surrounding tissue” was included in 15%. Fifty-seven percent stated that IPFs were “Unrelated to PET/CT indication”. Thirty-four percent specified IPFs as “Present in other organ than PET/CT indication”, whereas 20% included “No known disease related to IPF”. Seventeen percent of the definitions comprised a “New finding”, while 15% and 11% encompassed a “Clinical asymptomatic patient” and “Not a metastasis”, respectively. Finally, 5% of the definitions included “Potential clinical significance”. Conclusions: No generally accepted definition of IPFs currently exists. We propose an IPF definition based on explicit FDG uptake and clinical patient-related factors.

Summary: Background: Research in healthy young adults shows that characteristic patterns of brain activity define individual “brain-fingerprints” that are unique to each person. However, variability in these brain-fingerprints increases in individuals with neurological conditions, challenging the clinical relevance and potential impact of the approach. Our study shows that brain-fingerprints derived from neurophysiological brain activity are associated with pathophysiological and clinical traits of individual patients with Parkinson’s disease (PD). Methods: We created brain-fingerprints from task-free brain activity recorded through magnetoencephalography in 79 PD patients and compared them with those from two independent samples of age-matched healthy controls (N = 424 total). We decomposed brain activity into arrhythmic and rhythmic components, defining distinct brain-fingerprints for each type from recording durations of up to 4 min and as short as 30 s. Findings: The arrhythmic spectral components of cortical activity in patients with Parkinson’s disease are more variable over short periods, challenging the definition of a reliable brain-fingerprint. However, by isolating the rhythmic components of cortical activity, we derived brain-fingerprints that distinguished between patients and healthy controls with about 90% accuracy. The most prominent cortical features of the resulting Parkinson’s brain-fingerprint are mapped to polyrhythmic activity in unimodal sensorimotor regions. Leveraging these features, we also demonstrate that Parkinson’s symptom laterality can be decoded directly from cortical neurophysiological activity. Furthermore, our study reveals that the cortical topography of the Parkinson’s brain-fingerprint aligns with that of neurotransmitter systems affected by the disease’s pathophysiology. Interpretation: The increased moment-to-moment variability of arrhythmic brain-fingerprints challenges patient differentiation and explains previously published results. We outline patient-specific rhythmic brain signaling features that provide insights into both the neurophysiological signature and symptom laterality of Parkinson’s disease. Thus, the proposed definition of a rhythmic brain-fingerprint of Parkinson’s disease may contribute to novel, refined approaches to patient stratification. Symmetrically, we discuss how rhythmic brain-fingerprints may contribute to the improved identification and testing of therapeutic neurostimulation targets. Funding: Data collection and sharing for this project was provided by the Quebec Parkinson Network (QPN), the Pre-symptomatic Evaluation of Novel or Experimental Treatments for Alzheimer’s Disease (PREVENT-AD; release 6.0) program, the Cambridge Centre for Aging Neuroscience (Cam-CAN), and the Open MEG Archives (OMEGA). The QPN is funded by a grant from Fonds de Recherche du Québec - Santé (FRQS). PREVENT-AD was launched in 2011 as a $13.5 million, 7-year public-private partnership using funds provided by McGill University, the FRQS, an unrestricted research grant from Pfizer Canada, the Levesque Foundation, the Douglas Hospital Research Centre and Foundation, the Government of Canada, and the Canada Fund for Innovation. The Brainstorm project is supported by funding to SB from the NIH (R01-EB026299-05). Further funding to SB for this study included a Discovery grant from the Natural Sciences and Engineering Research Council of Canada of Canada (436355-13), and the CIHR Canada research Chair in Neural Dynamics of Brain Systems (CRC-2017-00311).

Introduction: Snakebites are a neglected tropical disease. In many areas, envenoming incidence and antivenom administration rates are unknown. This study compared antivenom (AV) availability to rates of envenoming and recommendations to treat (RTT) in South Africa. Methods: This retrospective study identified, extracted, and reviewed all cases of envenoming (snake bites and spits) reported to the Poisons Information Helpline of the Western Cape of South Africa (PIHWC) from June 1, 2015 to May 31, 2020 by public hospitals in the Western Cape. A standardized interview was administered to the pharmacies of the 40 hospitals in winter and summer to determine how many vials of monovalent and polyvalent AV they had on hand at the time of the call and their expiration dates. Descriptive analysis was used to compare rates of envenoming and recommendations to treat to antivenom stock in winter and summer and by hospital type and location. Results: Public hospitals reported 300 envenomings, 122 from snakes. The PIHWC recommended antivenom administration in 26% of cases (N = 32). All hospital pharmacies queried answered our questions. Our study demonstrates urban district hospitals have higher ratios of AV vials compared to mean annual rates of envenoming and RTT than rural district hospitals at both the winter and summer timepoints. Conclusion: This study evaluates antivenom supply and demand in a province of South Africa. The findings suggest South African urban hospitals have a relative excess of antivenom, and thus more capacity to meet demand, than their rural counterparts. It supports consideration of a redistribution of antivenom supply chains to match seasonal and local rates of envenoming. It indicates a need for higher quality, prospective data characterizing envenoming incidence and treatment.

Summary: Background: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19. Methods: The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care). Findings: Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61–1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64–1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09–0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality. Interpretation: Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19. Funding: Hellenic Foundation for Research and Innovation.

Summary: Background: Smoking impacts DNA methylation, but data are lacking on smoking-related differential methylation by sex or dietary intake, recent smoking cessation (

Summary: Background: Liver transplantation is traditionally performed around the clock to minimize organ ischemic time. However, the prospect of prolonging preservation times holds the potential to streamline logistics and transform liver transplantation into a semi-elective procedure, reducing the need for nighttime surgeries. Dual hypothermic oxygenated machine perfusion (DHOPE) of donor livers for 1–2 h mitigates ischemia-reperfusion injury and improves transplant outcomes. Preclinical studies have shown that DHOPE can safely extend the preservation of donor livers for up to 24 h. Methods: We conducted an IDEAL stage 2 prospective clinical trial comparing prolonged (≥4 h) DHOPE to conventional (1–2 h) DHOPE for brain-dead donor livers, enabling transplantation the following morning. Liver allocation to each group was based on donor hepatectomy end times. The primary safety endpoint was a composite of all serious adverse events (SAE) within 30 days after transplantation. The primary feasibility endpoint was defined as the number of patients assigned and successfully receiving a prolonged DHOPE-perfused liver graft. Trial registration at: WHO International Clinical Trial Registry Platform, number NL8740. Findings: Between November 1, 2020 and July 16, 2022, 24 patients were enrolled. The median preservation time was 14.5 h (interquartile range [IQR], 13.9–15.5) for the prolonged group (n = 12) and 7.9 h (IQR, 7.6–8.6) for the control group (n = 12; p = 0.01). In each group, three patients (25%; 95% CI 3.9–46%, p = 1) experienced a SAE. Markers of ischemia-reperfusion injury and oxidative stress in both perfusate and recipients were consistently low and showed no notable discrepancies between the two groups. All patients assigned to either the prolonged group or control group successfully received a liver graft perfused with either prolonged DHOPE or control DHOPE, respectively. Interpretation: This first-in-human clinical trial demonstrates the safety and feasibility of DHOPE in prolonging the preservation time of donor livers to enable daytime transplantation. The ability to extend the preservation window to up to 20 h using hypothermic oxygenated machine preservation at a 10 °C temperature has the potential to reshape the landscape of liver transplantation. Funding: University Medical Center Groningen, the Netherlands.

Through their effects on sleep duration, bedroom environments, and pollen allergies, seasonal variations may impact positive airway pressure (PAP) adherence. We analyzed daily PAP telemonitoring data from 25,846 adults (median age 64 years, 67.8% male) treated with PAP for at least 4 months [mean (standard deviation, SD) duration of PAP: 5.5 years (SD 4.1)] to examine seasonal changes in PAP adherence, leaks, and residual apnea-hypopnea index. We demonstrate a significant decrease in PAP adherence in June compared to January (mean (SD): 0.37 (1.54) h/night) that achieved the minimal clinically important difference (MCID) of 30 min in 13.9% of adults. Furthermore, we provide novel data supporting the association of rising temperatures with seasonal changes in PAP use. Indeed, the most pronounced decline in PAP adherence was observed during the hottest days, while PAP adherence was only slightly reduced during the coolest days of June. Clinicians should be aware of seasonal changes in PAP adherence that are likely to be exacerbated by climate change.

Introduction: The regenerative and immunomodulatory properties of multipotent mesenchymal stromal cells (MSCs) make them an intriguing asset for therapeutic applications. An off-the-shelf approach, using pre-expanded cryopreserved allogenic MSCs, bypasses many practical difficulties of cellular therapy. Reconstitution of a MSC product away from cytotoxic cryoprotectants towards a preferred administration solution might be favorable for several indications. Variations in MSC handling accompanied by a non-standardized use of reconstitution solutions complicate a general clinical standardization of MSC cellular therapies. In this study, we aimed to identify a simple and clinically compatible approach for thawing, reconstitution, and post-thaw storage of cryopreserved MSCs. Methods: Human adipose tissue-derived MSCs were expanded in human platelet lysate (hPL) supplemented culture medium and cryopreserved using a dimethyl sulfoxide (DMSO)-based cryoprotectant. Isotonic solutions (saline, Ringer's acetate and phosphate buffered saline (PBS)) with or without 2% human serum albumin (HSA) were used as thawing, reconstitution, and storage solutions. MSCs were reconstituted to 5 × 106 MSCs/mL for evaluating MSC stability. Total MSC numbers and viability were determined using 7-aminoactinomycin D (7-AAD) and flow cytometry. Results: For thawing cryopreserved MSCs the presence of protein was proven to be essential. Up to 50% of MSCs were lost when protein-free thawing solutions were used. Reconstitution and post-thaw storage of MSCs in culture medium and widely used PBS demonstrated poor MSC stability (>40% cell loss) and viability (90% viability with no observed cell loss for at least 4 h. Reconstitution of MSCs to low concentrations was identified as critical. Diluting MSCs to 40% cell loss) and lower viability (

Abstract Background The Communicate Study is a partnership project which aims to transform the culture of healthcare systems to achieve excellence in culturally safe care for First Nations people. It responds to the ongoing impact of colonisation which results in First Nations peoples experiencing adverse outcomes of hospitalisation in Australia’s Northern Territory. In this setting, the majority of healthcare users are First Nations peoples, but the majority of healthcare providers are not. Our hypotheses are that strategies to ensure cultural safety can be effectively taught, systems can become culturally safe and that the provision of culturally safe healthcare in first languages will improve experiences and outcomes of hospitalisation. Methods We will implement a multicomponent intervention at three hospitals over 4 years. The main intervention components are as follows: cultural safety training called ‘Ask the Specialist Plus’ which incorporates a locally developed, purpose-built podcast, developing a community of practice in cultural safety and improving access to and uptake of Aboriginal language interpreters. Intervention components are informed by the ‘behaviour change wheel’ and address a supply–demand model for interpreters. The philosophical underpinnings are critical race theory, Freirean pedagogy and cultural safety. There are co-primary qualitative and quantitative outcome measures: cultural safety, as experienced by First Nations peoples at participating hospitals, and proportion of admitted First Nations patients who self-discharge. Qualitative measures of patient and provider experience, and patient-provider interactions, will be examined through interviews and observational data. Quantitative outcomes (documentation of language, uptake of interpreters (booked and completed), proportion of admissions ending in self-discharge, unplanned readmission, hospital length of stay, costs and cost benefits of interpreter use) will be measured using time-series analysis. Continuous quality improvement will use data in a participatory way to motivate change. Programme evaluation will assess Reach, Effectiveness, Adoption, Implementation and Maintenance (‘RE-AIM’). Discussion The intervention components are innovative, sustainable and have been successfully piloted. Refinement and scale-up through this project have the potential to transform First Nations patients’ experiences of care and health outcomes. Trial registration Registered with ClinicalTrials.gov Protocol Record 2008644

Vascular calcifications in aorto-iliac arteries are emerging as crucial risk factors for cardiovascular diseases (CVDs) with profound clinical implications. This systematic review, following PRISMA guidelines, investigated methodologies for measuring these calcifications and explored their correlation with CVDs and clinical outcomes. Out of 698 publications, 11 studies met the inclusion criteria. In total, 7 studies utilized manual methods, while 4 studies utilized automated technologies, including artificial intelligence and deep learning for image analyses. Age, systolic blood pressure, serum calcium, and lipoprotein(a) levels were found to be independent risk factors for aortic calcification. Mortality from CVDs was correlated with abdominal aorta calcification. Patients requiring reintervention after endovascular recanalization exhibited a significantly higher volume of calcification in their iliac arteries. Conclusions: This review reveals a diverse landscape of measurement methods for aorto-iliac calcifications; however, they lack a standardized reproducibility assessment. Automatic methods employing artificial intelligence appear to offer broader applicability and are less time-consuming. Assessment of calcium scoring could be routinely employed during preoperative workups for risk stratification and detailed surgical planning. Additionally, its correlation with clinical outcomes could be useful in predicting the risk of reinterventions and amputations.

Objective Paternal participation and experiences in childhood weight management is an understudied studied area. Given the important role fathers play in childhood obesity prevention and treatment, the aim of this study was to explore Norwegian fathers’ experiences of helping to prevent further weight gain in their children with overweight or obesity. Methods Data were collected through semi-structured interviews with eight fathers of ten children with overweight or obesity and analysed by qualitative content analysis. Results The analysis resulted in one overall theme: Balancing between assuming and avoiding responsibility for weight management with a desire to preserve the child’s dignity, comprising two themes: 1) Alternating between concern, helplessness and responsibility, 2) Needing acknowledgement, and flexible and tailored professional support, both of which have several sub-themes. Conclusion Fathers need guidance on how to talk to their children to prevent further weight gain, while at the same time emphasizing safeguarding the child’s dignity. Healthcare professionals should address parents’ own emotional barriers and include fathers to a greater extent as a resource in family-centred counselling and tailor guidance and support to help with childhood weight management.

Summary: Background: With the emergence of SARS-CoV-2 variants resistant to monoclonal antibody therapies and limited global access to therapeutics, the evaluation of novel therapeutics to prevent progression to severe COVID-19 remains a critical need. Methods: Safety, clinical and antiviral efficacy of inhaled interferon-β1a (SNG001) were evaluated in a phase II randomized controlled trial on the ACTIV-2/A5401 platform (ClinicalTrials.gov NCT04518410). Adult outpatients with confirmed SARS-CoV-2 infection within 10 days of symptom onset were randomized and initiated either orally inhaled nebulized SNG001 given once daily for 14 days (n = 110) or blinded pooled placebo (n = 110) between February 10 and August 18, 2021. Findings: The proportion of participants reporting premature treatment discontinuation was 9% among SNG001 and 13% among placebo participants. There were no differences between participants who received SNG001 or placebo in the primary outcomes of treatment emergent Grade 3 or higher adverse events (3.6% and 8.2%, respectively), time to symptom improvement (median 13 and 9 days, respectively), or proportion with unquantifiable nasopharyngeal SARS-CoV-2 RNA at days 3 (28% [26/93] vs. 39% [37/94], respectively), 7 (65% [60/93] vs. 66% [62/94]) and 14 (91% [86/95] vs. 91% [83/81]). There were fewer hospitalizations with SNG001 (n = 1; 1%) compared with placebo (n = 7; 6%), representing an 86% relative risk reduction (p = 0.07). There were no deaths in either arm. Interpretation: In this trial, SNG001 was safe and associated with a non-statistically significant decrease in hospitalization for COVID-19 pneumonia. Funding: The ACTIV-2 platform study is funded by the NIH. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number UM1 AI068634, UM1 AI068636 and UM1 AI106701. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Introduction The SARS-CoV-2 (COVID-19) pandemic overwhelmed some primary health care (PHC) systems, while others adapted and recovered. In Nigeria, large, within-state variations existed in the ability to maintain PHC service volumes. Identifying characteristics of high-performing local government areas (LGAs) can improve understanding of subnational health systems resilience.Methods Employing a sequential explanatory mixed-methods design, we quantitatively identified ‘positive deviant’ LGAs based on their speed of recovery of outpatient and antenatal care services to prepandemic levels using service volume data from Nigeria’s health management information system and matched them to comparators with similar baseline characteristics and slower recoveries. 70 semistructured interviews were conducted with LGA officials, facility officers and community leaders in sampled LGAs to analyse comparisons based on Kruk’s resilience framework.Results A total of 57 LGAs were identified as positive deviants out of 490 eligible LGAs that experienced a temporary decrease in PHC-level outpatient and antenatal care service volumes. Positive deviants had an average of 8.6% higher outpatient service volume than expected, and comparators had 27.1% lower outpatient volume than expected after the initial disruption to services. Informants in 12 positive deviants described health systems that were more integrated, aware and self-regulating than comparator LGAs. Positive deviants were more likely to employ demand-side adaptations, whereas comparators primarily focused on supply-side adaptations. Barriers included long-standing financing and PHC workforce gaps.Conclusion Sufficient flexible financing, adequate PHC staffing and local leadership enabled health systems to recover service volumes during COVID-19. Resilient PHC requires simultaneous attention to bottom-up and top-down capabilities connected by strong leadership.

We report a case of subcutaneous mycosis in the form of a subcutaneous cyst of the index finger, successfully treated by surgery and posaconazole in an 84-year-old female kidney transplant patient. Intra-operative mycological analysis enabled the diagnosis of Phialophora chinensis phaeohyphomycosis. Phialophora chinensis is an environmental mold recently described in human pathology in cases of chromoblastomycosis. This is the first case of subcutaneous phaeohyphomycosis due to Phialophora chinensis in an immunocompromised patient.

Abstract Background Insomnia is common in the general population and is a risk factor for ill-health, which highlights the importance of treating insomnia effectively and cost-efficiently. Cognitive-behavioural therapy for insomnia (CBT-I) is recommended as first-line treatment due to its long-term effectiveness and few side-effects, but its availability is limited. The aim of this pragmatic, multicentre randomized controlled trial is to investigate the effectiveness of group-delivered CBT-I in primary care compared to a waiting-list control group. Methods A pragmatic multicentre randomized controlled trial will be conducted with about 300 participants recruited across 26 Healthy Life Centres in Norway. Participants will complete online screening and provide consent before enrolment. Those who meet the eligibility criteria will be randomized to a group-delivered CBT-I or to a waiting list according to a 2:1 ratio. The intervention consists of four two-hour sessions. Assessments will be performed at baseline, 4 weeks, 3- and 6 months post-intervention, respectively. The primary outcome is self-reported insomnia severity at 3 months post-intervention. Secondary outcomes include health-related quality of life, fatigue, mental distress, dysfunctional beliefs and attitudes about sleep, sleep reactivity, 7-day sleep diaries, and data obtained from national health registries (sick leave, use of relevant prescribed medications, healthcare utilization). Exploratory analyses will identify factors influencing treatment effectiveness, and we will conduct a mixed-method process evaluation to identify facilitators and barriers of participants’ treatment adherence. The study protocol was approved by the Regional Committee for Medical and Health Research ethics in Mid-Norway (ID 465241). Discussion This large-scale pragmatic trial will investigate the effectiveness of group-delivered cognitive behavioural therapy versus waiting list in the treatment of insomnia, generating findings that are generalizable to day-to-day treatment of insomnia in interdisciplinary primary care services. The trial will identify those who would benefit from the group-delivered therapy, and will investigate the rates of sick leave, medication use, and healthcare utilization among adults who undergo the group-delivered therapy. Trial registration The trial was retrospectively registered in the ISRCTN registry (ISRCTN16185698).

Abstract Background Recruiting participants for lifestyle programmes is known to be challenging. Insights into recruitment strategies, enrolment rates and costs are valuable but rarely reported. We provide insight into the costs and results of used recruitment strategies, baseline characteristics and feasibility of at-home cardiometabolic measurements as part of the Supreme Nudge trial investigating healthy lifestyle behaviours. This trial was conducted during the COVID-19 pandemic, requiring a largely remote data collection approach. Potential sociodemographic differences were explored between participants recruited through various strategies and for at-home measurement completion rates. Methods Participants were recruited from socially disadvantaged areas around participating study supermarkets (n = 12 supermarkets) across the Netherlands, aged 30–80 years, and regular shoppers of the participating supermarkets. Recruitment strategies, costs and yields were logged, together with completion rates of at-home measurements of cardiometabolic markers. Descriptive statistics are reported on recruitment yield per used method and baseline characteristics. We used linear and logistic multilevel models to assess the potential sociodemographic differences. Results Of 783 recruited, 602 were eligible to participate, and 421 completed informed consent. Most included participants were recruited via letters/flyers at home (75%), but this strategy was very costly per included participant (89 Euros). Of paid strategies, supermarket flyers were the cheapest (12 Euros) and the least time-invasive (

Abstract Background Expanding the health workforce to increase the availability of skilled birth attendants (SBAs) presents an opportunity to expand the power and well-being of frontline health workers. The role of the SBA holds enormous potential to transform the relationship between women, birthing caregivers, and the broader health care delivery system. This paper will present a novel approach to the community-based skilled birth attendant (SBA) role, the Skilled Health Entrepreneur (SHE) program implemented in rural Sylhet District, Bangladesh. Case presentation The SHE model developed a public–private approach to developing and supporting a cadre of SBAs. The program focused on economic empowerment, skills building, and formal linkage to the health system for self-employed SBAs among women residents. The SHEs comprise a cadre of frontline health workers in remote, underserved areas with a stable strategy to earn adequate income and are likely to remain in practice in the area. The program design included capacity-building for the SHEs covering traditional techno-managerial training and supervision in programmatic skills and for developing their entrepreneurial skills, professional confidence, and individual decision-making. The program supported women from the community who were social peers of their clients and long-term residents of the community in becoming recognized, respected health workers linked to the public system and securing their livelihood while improving quality and access to maternal health services. This paper will describe the SHE program's design elements to enhance SHE empowerment in the context of discourse on social power and FLHWs. Conclusion The SHE model successfully established a private SBA cadre that improved birth outcomes and enhanced their social power and technical skills in challenging settings through the mainstream health system. Strengthening the agency, voice, and well-being of the SHEs has transformative potential. Designing SBA interventions that increase their power in their social context could expand their economic independence and reinforce positive gender and power norms in the community, addressing long-standing issues of poor remuneration, overburdened workloads, and poor retention. Witnessing the introduction of peer or near-peer women with well-respected, well-compensated roles among their neighbors can significantly expand the effectiveness of frontline health workers and offer a model for other women in their own lives.

Summary: Background: Anti-PD-1 and PD-L1 antibodies (mAbs) are approved immunotherapy agents to treat metastatic non-small cell lung cancer (NSCLC) patients. Only a minority of patients responds to these treatments and biomarkers predicting response are currently lacking. Methods: Immunoscore-Immune-Checkpoint (Immunoscore-IC), an in vitro diagnostic test, was used on 471 routine single FFPE-slides, and the duplex-immunohistochemistry CD8 and PD-L1 staining was quantified using digital-pathology. Analytical validation was performed on two independent cohorts of 206 NSCLC patients. Quantitative parameters related to cell location, number, proximity and clustering were analysed. The Immunoscore-IC was applied on a first cohort of metastatic NSCLC patients (n = 133), treated with anti-PD1 or anti-PD-L1 mAbs. Another independent cohort (n = 132) served as validation. Findings: Anti-PDL1 clone (HDX3) has similar characteristics as anti-PD-L1 clones (22C3, SP263). Densities of PD-L1+ cells, CD8+ cells and distances between CD8+ and PD-L1+ cells were quantified and the Immunoscore-IC classification was computed. Using univariate Cox model, 5 histological dichotomised variables (CD8 free of PD-L1+ cells, CD8 clusters, CD8 cells in proximity of PD-L1 cells, CD8 density and PD-L1 cells in proximity of CD8 cells) were significantly associated with Progression-Free Survival (PFS) (all P

Bats are presumed reservoirs of diverse α- and β- coronaviruses (CoVs) and understanding the diversity of bat-CoVs and the role bats play in CoV transmission is highly relevant in the context of the current COVID pandemic. We sampled bats in Côte d'Ivoire (2016–2018) living at ecotones between anthropogenic and wild habitats in the Marahoué National Park, a recently encroached protected area, to detect and characterize the CoVs circulating in bats and humans. A total of 314 bats were captured, mostly during the rainy season (78%), and CoV RNA was detected in three of the bats (0.96%). A CoV RNA sequence similar to Chaerephon bat coronavirus/Kenya/KY22/2006 (BtKY22) was found in a Chaerephon cf. pumilus and a Mops sp. fecal swab, while a CoV RNA sequence similar to the two almost identical Kenya bat coronaviruses BtKY55 and BtKY56 (BtKY55/56) was detected in an Epomops buettikoferi oral swab. Phylogenetic analyses indicated differences in the degree of evolutionary host-virus co-speciation for BtKY22 and BtKY55/56. To assess potential for human exposure to these viruses, we conducted human syndromic and community-based surveillance in clinics and high-risk communities. We collected data on participant characteristics, livelihoods, animal contact, and high-risk behaviors that may be associated with exposure to zoonotic diseases. We then collected biological samples for viral testing from 401 people. PCR testing of these biological samples revealed no evidence of CoV infection among the enrolled individuals. We identified higher levels of exposure to bats in people working in crop production and in hunting, trapping and fishing. Finally, we used the ‘Spillover’ risk-ranking tool to assess the potential for viral spillover and concluded that, while there is no evidence to suggest imminent risk of spillover for these CoVs, their host range and other traits suggest caution and vigilance are warranted in people with high exposure risk.

Abstract Background Surviving breast cancer does not necessarily mean complete recovery to a premorbid state of health. Among the multiple psychological and somatic symptoms that reduce the quality of life of breast cancer survivors, persistent pain after breast cancer treatment (PPBCT) with a prevalence of 15–65% is probably the most invalidating. Once chronic, PPBCT is difficult to treat and requires an individualized multidisciplinary approach. In the past decades, several somatic and psychological risk factors for PPBCT have been identified. Studies aiming to prevent PPBCT by reducing perioperative pain intensity have not yet shown a significant reduction of PPBCT prevalence. Only few studies have been performed to modify psychological distress around breast cancer surgery. The AMAZONE study aims to investigate the effect of online cognitive behavioral therapy (e-CBT) on the prevalence of PPBCT. Methods The AMAZONE study is a multicenter randomized controlled trial, with an additional control arm. Patients (n=138) scheduled for unilateral breast cancer surgery scoring high for surgical or cancer-related fears, general anxiety or pain catastrophizing are randomized to receive either five sessions of e-CBT or online education consisting of information about surgery and a healthy lifestyle (EDU). The first session is scheduled before surgery. In addition to the online sessions, patients have three online appointments with a psychotherapist. Patients with low anxiety or catastrophizing scores (n=322) receive treatment as usual (TAU, additional control arm). Primary endpoint is PPBCT prevalence 6 months after surgery. Secondary endpoints are PPBCT intensity, the intensity of acute postoperative pain during the first week after surgery, cessation of postoperative opioid use, PPBCT prevalence at 12 months, pain interference, the sensitivity of the nociceptive and non-nociceptive somatosensory system as measured by quantitative sensory testing (QST), the efficiency of endogenous pain modulation assessed by conditioned pain modulation (CPM) and quality of life, anxiety, depression, catastrophizing, and fear of recurrence until 12 months post-surgery. Discussion With perioperative e-CBT targeting preoperative anxiety and pain catastrophizing, we expect to reduce the prevalence and intensity of PPBCT. By means of QST and CPM, we aim to unravel underlying pathophysiological mechanisms. The online application facilitates accessibility and feasibility in a for breast cancer patients emotionally and physically burdened time period. Trial registration NTR NL9132 , registered December 16 2020.

The field of bone tissue engineering is steadily being improved by novel experimental approaches. Nevertheless, microbial adhesion after scaffold implantation remains a limitation that could lead to the impairment of the regeneration process, or scaffold rejection. The present study introduces a methodology that employs laser-based strategies for the development of antimicrobial interfaces on tricalcium phosphate–hydroxyapatite (TCP-HA) scaffolds. The outer surfaces of the ceramic scaffolds with inner porosity were structured using a femtosecond laser (λ = 800 nm; τ = 70 fs) for developing micropatterns and altering local surface roughness. The pulsed laser deposition of ZnO was used for the subsequent functionalization of both laser-structured and unmodified surfaces. The impact of the fs irradiation was investigated by Raman spectroscopy and X-ray diffraction. The effects of the ZnO-layered ceramic surfaces on initial bacterial adherence were assessed by culturing Staphylococcus aureus on both functionalized and non-functionalized scaffolds. Bacterial metabolic activity and morphology were monitored via the Resazurin assay and microscopic approaches. The presence of ZnO evidently decreased the metabolic activity of bacteria and led to impaired cell morphology. The results from this study have led to the conclusion that the combination of fs laser-structured surface topography and ZnO could yield a potential antimicrobial interface for implants in bone tissue engineering.

Abstract Background Elevated body mass index (BMI) represents a risk factor for cancer-related fatigue (CRF). Weight loss interventions are feasible and safe in cancer survivors, leading to improved cardio-metabolic and quality of life (QOL) outcomes and modulating inflammatory biomarkers. Randomized data are lacking showing that a lifestyle intervention aimed at weight loss, combining improved diet, exercise, and motivational counseling, reduces CRF. Motivating to Exercise and Diet, and Educating to healthy behaviors After breast cancer (MEDEA) is a multi-center, randomized controlled trial evaluating the impact of weight loss on CRF in overweight or obese survivors of breast cancer. Herein, we described the MEDEA methodology. Methods Patients (N = 220) with stage I–III breast cancer and BMI ≥ 25 kg/m2, within 12 months of primary treatment, and able to walk ≥ 400 m are eligible to enroll. Participants are randomized 1:1 to health education alone vs. a personalized telephone-based weight loss intervention plus health education. Both arms receive a health education program focusing on healthy living. Patients in the intervention arm are paired with an individual lifestyle coach, who delivers the intervention through 24 semi-structured telephone calls over 1 year. Intervention goals include weight loss ≥ 10% of baseline, caloric restriction of 500–1000 Kcal/day, and increased physical activity (PA) to 150 (initial phase) and 225–300 min/week (maintenance phase). The intervention is based on the social cognitive theory and is adapted from the Breast Cancer Weight Loss trial (BWEL, A011401). The primary endpoint is the difference in self-reported CRF (EORTC QLQ-C30) between arms. Secondary endpoints include the following: QOL (EORTC QLQ-C30, -BR45, -FA12), anxiety, and depression (HADS); weight and BMI, dietary habits and quality, PA, and sleep; health care costs (hospital-admissions, all-drug consumption, sick leaves) and cost-effectiveness (cost per quality-adjusted life-year); and patient motivation and satisfaction. The primary analysis of MEDEA will compare self-reported CRF at 12 months post-randomization between arms, with 80.0% power (two-sided α = 0.05) to detect a standardized effect size of 0.40. Discussion MEDEA will test the impact of a weight loss intervention on CRF among overweight or obese BC survivors, potentially providing additional management strategies and contributing to establish weight loss support as a new standard of clinical care. Trial registration ClinicalTrials.gov NCT04304924

Abstract Background Provoked vestibulodynia (PVD) is a prevalent chronic pain condition especially among young women. Pain is localized to the vulvar vestibule and is provoked by touch or pressure, such as penetrative intercourse. PVD can have profound consequences, adversely affecting a woman’s sexual life, relation to her partner, and her psychological health. There is an urgent need for well-designed randomized clinical trials (RCTs) to identify the most effective interventions for this neglected women’s health condition. Aims The primary aim of this study is to assess the feasibility of undertaking a full-scale RCT of somatocognitive therapy (SCT), a multimodal physiotherapy intervention, for women with PVD. The secondary aim is to evaluate the implementation and acceptability of SCT and its potential treatment effectiveness in PVD. In the full-scale RCT, SCT will be compared to standard PVD treatment. Methods A multimethod feasibility study with a single-arm before-after trial and qualitative interviews. Ten women with PVD, aged 18–33 were recruited from the Vulva Clinic at Oslo University Hospital. The intervention took place at Oslo Metropolitan University. Participants were assessed at baseline, post-treatment, and the 8-month follow-up with the tampon test and self-report questionnaires. The main feasibility outcomes were evaluation of recruitment rate, adherence to assessment tools, and follow-up rate. The participants’ experiences with the primary outcome and the intervention were explored with semi-structured interviews. Results Ten out of 18 eligible patients were recruited over 11 weeks. None were lost to follow-up. Adherence to self-report questionnaires was excellent. Adherence to tampon tests and to the reporting of treatments was good, whereas adherence to the 14-day diary was poor. No adverse events were reported. The tampon test was suboptimal as a primary outcome. SCT was found to be an acceptable treatment, based on Global Perceived Effect scores and the participants’ experiences. Conclusion The findings suggest that it is feasible to deliver a full-scale RCT of the SCT intervention for women with PVD. Some changes are suggested to optimize the protocol, such as increasing recruitment sites, change of primary outcome measures, and adding a booster session. Trial registration ClinicalTrials.gov NCT04208204 . Retrospectively registered on December 23, 2019.

Abstract Background Carotid atherosclerotic plaques remain silent until their rupture, which may lead to detrimental ischemic events such as strokes. This is due, in part, to intraplaque hemorrhages (IPH) and the resulting inflammatory processes, which may promote carotid plaque vulnerability. Currently, the benefits of carotid endarterectomy remain unclear for asymptomatic patients. Interestingly, the completion of physical activity (PA) may have beneficial effects; however, the paucity of current data warrants robust longitudinal interventions. We therefore aim to study the effects of a 6-month longitudinal personalized home-based PA program on IPH, biological, and inflammatory markers in asymptomatic stroke patients. Methods Eighty patients (≥ 18 years old) will be recruited for the Physical Activity and Carotid Atherosclerotic Plaque Hemorrhage (PACAPh) clinical trial from the Hospices Civils de Lyon. Patients will be eligible if they present with carotid stenosis ≥ 50% and are asymptomatic from any ischemic events for at least 6 months. Recruited patients will be randomized into either a PA or a control group, and assessed at baseline and after 6 months. At both time points, all patients will be assessed using magnetic resonance imaging to assess IPH, blood sampling to measure inflammatory markers and monocytic phenotyping, PA and sedentary behavior questionnaires, 6-min walking test, and maximal isometric quadricep contraction test. The randomized PA intervention will consist of reaching a daily walking step goal individually tailored to each patient. Steps will be collected using a wirelessly connected wristband. The number of steps completed by individuals in the PA group will be re-evaluated bimonthly to encourage walking habits. Discussion The PACAPh study is the first of its kind representing a feasible, easily accessible therapeutic strategy for asymptomatic stroke patients. We hypothesize that the personalized home-based PA program will reduce IPH and modulate inflammatory and biological parameters in patients presenting with carotid plaques. If the results of the PACAPh study prove to be beneficial on such health parameters, the implementation of such kind of intervention in the daily treatment of these patients would be an advantageous and cost-effective practice to adopt globally. Trial registration This study has been approved by the National Ethics Committee (IDRCB:2019-A01543-54/SI:19.06.21.40640). ClinicalTrials.gov NCT04053166

BackgroundAdvanced practice nurses (APNs) are in high demand in critical care units. In Norway, APNs are educated at the master’s degree level and acquire the competence to ensure the independent, safe, and effective treatment of patients in constantly and rapidly changing health situations. APNs’ competence embraces expert knowledge and skills to perform complex decision-making in the clinical context; therefore, it is essential that educational institutions in nursing facilitate learning activities that ensure and improve students’ achievement of the required competence. In clinical practice studies of APN education, face-to-face reflection group (FFRG) meetings, held on campus with the participation of a nurse educator and advanced practice nursing students (APNSs), are a common learning activity to improve the competence of APNSs. Although FFRG meetings stimulate APNSs’ development of required competencies, they may also result in unproductive academic discussions, reduce the time that APNSs spend in clinical practice, and make it impossible for nurse preceptors (NPs) to attend the meetings, which are all challenges that need to be addressed. ObjectiveThis study aimed to address the challenges experienced in FFRG meetings by implementing virtual reflection group (VRG) meetings and to explore the experiences of APNSs, NPs, and nurse educators in VRG meetings as an active learning method supported by technology to stimulate students’ development of the required competence to become APNs in critical care. MethodsThis study adopted a qualitative explorative design with 2 focus group interviews and used inductive content analysis to explore the collected data. ResultsThe main finding is that reflection group meetings supported by technology resulted in a better-structured active learning method. The VRG meeting design allowed APNSs to spend more time in clinical practice placements. The APNSs and NPs experienced that they participated actively and effectively in the meetings, which led to a perceived increase in competence. The APNSs also perceived an improved learning experience compared with their prior expectations. ConclusionsUsers perceived that the implemented novel teaching design supported by technology, the VRG meeting, was a more effective method than FFRG meetings on campus to develop APNSs’ required competence in critical care. The VRG was also perceived as an improved method to solve the challenges encountered in FFRG meetings. Specifically, the APNSs felt that they were prepared to undertake complex decision-making with a higher level of analytic cognition in a clinical context and to lead professional discussions in the ward. This developed teaching design can easily be adapted to diverse educational programs at various levels of professional education.

Abstract Kyphoscoliotic Ehlers–Danlos syndrome (kEDS) is a rare genetic disorder combining congenital hypotonia, congenital/early onset and progressive kyphoscoliosis, and generalized joint hypermobility. Vascular fragility is another characteristic of the disease rarely described. We report a severe case of kEDS‐PLOD1 with several vascular complications leading to difficulties in disease management.

Abstract Background A new wireless and beltless monitoring device utilising fetal and maternal electrocardiography (ECG) and uterine electromyography, known as ‘non-invasive fetal ECG’ (NIFECG) was registered for clinical use in Australia in 2018. The safety and reliability of NIFECG has been demonstrated in controlled settings for short periods during labour. As far as we are aware, at the time our study commenced, this was globally the first trial of such a device in an authentic clinical setting for the entire duration of a woman’s labour. Methods This study aimed to assess the feasibility of using NIFECG fetal monitoring for women undergoing continuous electronic fetal monitoring during labour and birth. Women were eligible to participate in the study if they were at 36 weeks gestation or greater with a singleton pregnancy, planning to give birth vaginally and with obstetric indications as per local protocol (NSW Health Fetal Heart Rate Monitoring Guideline GL2018_025. 2018) for continuous intrapartum fetal monitoring. Written informed consent was received from participating women in antenatal clinic prior to the onset of labour. This single site clinical feasibility study took place between January and July 2020 at the Royal Hospital for Women in Sydney, Australia. Quantitative and qualitative data were collected to inform the analysis of results using the NASSS (Non-adoption, Abandonment, Scale up, Spread and Sustainability) framework, a validated tool for analysing the implementation of new health technologies into clinical settings. Results Women responded positively about the comfort and freedom of movement afforded by the NIFECG. Midwives reported that when no loss of contact occurred, the device enabled them to focus less on the technology and more on supporting women’s physical and emotional needs during labour. Midwives and obstetricians noticed the benefits for women but expressed a need for greater certainty about the reliability of the signal. Conclusion The NIFECG device enables freedom of movement and positioning for labouring women and was well received by women and the majority of clinicians. Whilst measurement of the uterine activity was reliable, there was uncertainty for clinicians in relation to loss of contact of the fetal heart rate. If this can be ameliorated the device shows potential to be used as routinely as cardiotocography (CTG) for fetal monitoring. This is the first time the NASSS framework has been used to synthesise the implementation needs of a health technology in the care of women during labour and birth. Our findings contribute new knowledge about the determinants for implementation of a complex technology in a maternity care setting. Trial registration The Universal Trial Number is reU1111-1228-9845 and the Australian and New Zealand Clinical Trial Registration Number is 12619000293167p. Trial registration occurred on the 20 February, 2019. The trial protocol may be viewed at http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377027

Objective: To describe protocol adaptations to the Fibromyalgia Integrative Training for Teens (FIT Teens) randomized controlled trial in response to the COVID-19 pandemic. The overarching aims of the FIT Teens multi-site 3-arm comparative effectiveness trial are to assess whether a specialized neuromuscular exercise training intervention combined with cognitive-behavioral therapy (CBT) is superior to CBT alone or graded aerobic exercise alone. Design/methods: The trial was originally designed as an in-person, group-based treatment with assessments at baseline, mid- and post-treatment, and four follow-up time points. The original study design and methodology was maintained with specific modifications to screening, consenting, assessments, and group-based treatments to be delivered in remote (telehealth) format in response to COVID-19 restrictions. Results: Study enrollment was paused in March 2020 for five months to revise operations manuals, pilot remote treatment sessions for accuracy and fidelity, complete programming of REDCap assent/consent and assessment materials, train study staff for new procedures and obtain regulatory approvals. The trial was relaunched and has been successfully implemented in remote format since July 2020. Trial metrics thus far demonstrate a consistent rate of enrollment, strong attendance at remote treatment sessions, high retention rates and high treatment fidelity after protocol adaptations were implemented. Conclusions: Preliminary findings indicate that FIT Teens protocol adaptations from in-person to remote are feasible and allowed for sustained enrollment, retention, and treatment fidelity comparable to the in-person format. Methodologic and statistical considerations resulting from the adaptations are discussed as well as implications for interpretation of results upon completion of the trial.

Brexit was presented as an opportunity to promote innovation by breaking free from the European Union regulatory framework. Since the beginning of 2021 the Medicines and Healthcare products Regulatory Agency (MHRA) has operated as the independent regulatory agency for the United Kingdom. The MHRA's regulatory activity in 2021 was analyzed and compared to that of other international regulatory bodies. The MHRA remained reliant on EU regulatory decision-making for novel medicines and there were significant regulatory delays for a small number of novel medicines in the UK, the reasons being so far unclear. In addition, the MHRA introduced innovation initiatives, which show early promise for quicker authorization of innovative medicines for cancer and other areas of unmet need. Longer-term observation and analysis is needed to show the full impact of post-Brexit pharmaceutical regulatory policy.

Purpose The family environment is crucial in the prevention and treatment of childhood obesity; however, there is a lack of knowledge concerning paternal perceptions and experiences in childhood weight management. The aim of this study was to explore (i) perceptions of contributing factors to childhood overweight and obesity among fathers of children with overweight or obesity and (ii) the fathers’ experiences of their parental role caring for a child with overweight or obesity. Method A qualitative content analysis was conducted of data from semi-structured in-depth interviews with eight Norwegian fathers of ten children and adolescents with overweight or obesity. Results The analysis identified one overall theme; Feeling uncertain and struggling to understand their own responsibility for the child’s overweight or obesity, which consists of two themes; 1)Trying hard to figure out the child’s obesity as a complex interaction of factors and 2)Family functioning—negotiating roles and responsibility in parenthood. Conclusion Fathers must be met with understanding about their uncertainty and their struggle to understand their individual responsibility for their child’s weight excess. It can be necessary to address the significance of family functioning, collaboration, responsibility within the familiy in addition to structural responsibility in clinical dialogues and counselling in order to help with weight management

Limited access to mental health and behavioral interventions is a public health issue that predated and is further worsened by coronavirus disease 2019 (COVID-19) social distancing restrictions. The Healthy Action to Benefit Independence and Thinking (HABIT) program is a cognitive rehabilitation and wellness program for patients with a diagnosis of mild cognitive impairment and their partners that involves groups of up to 32 people (16 dyads) at a time. Thus, the public health recommendation to avoid groups at the start of the COVID-19 pandemic immediately impacted our ability to offer this treatment protocol. This brief report provides patient and partner satisfaction data as well as clinical outcomes with a virtual adaptation of the HABIT program developed because of the COVID-19 pandemic. At the time of their participation, patients who attended in-person sessions had an average age of 74.4 years and those who attended virtual sessions had an average age of 75.4 years (P=.60). Both groups had an average of 16.3 years of education (P=.95). Approximately half of the patients in both groups were male (30 of 57 [53%]), most were White (54 of 57 [95%]) and were accompanied to the program by a spouse (50 of 57 [88%]). Overall, patient and partner satisfaction with the HABIT program remained high, ranging from a mean score of 5.8 to 6.6 on a rating scale of 1 to 7 for patients and partners, and clinical outcomes remained consistent with our face-to-face formatting when compared with pre–COVID pandemic sessions. The most notable changes across both formats were improvements in patient anxiety (Cohen's d=0.25 face-to-face; d=0.39 virtual), partner anxiety (d=0.37 face-to-face; d=0.34 virtual), and partner depression (d=0.37 face-to-face; d=0.35 virtual). This preliminary program evaluation suggests that transitioning the HABIT program to virtual formatting provides high-quality care similar to our in-person care models. Ongoing program evaluation is planned as we continue using virtual treatment for safety. Even after COVID-19 pandemic public health restrictions are lifted, these findings will have continued relevance to ongoing demand for telehealth.

Abstract Background As part of a research project aimed at evaluating a hospital‐based adolescent transition programme, we asked ourselves what is known about the ethical and methodological challenges of research involving adolescent patients as co‐researchers. The aim of our review was to summarize empirical evidence and identify knowledge gaps about the involvement of young patients as co‐researchers. Methods We conducted a scoping review through searches in MEDLINE, EMBASE, PsychINFO, AMED. Results We found reports of young patients being actively engaged as co‐researchers in any stage of a research project, although commonly they were not involved in every stage. Including young patients as co‐researchers is resource demanding and time‐consuming. Involving young patients as co‐researchers contributes to the fulfilment of their right to participation and may improve the relevance of research. Benefits for the young co‐researcher include empowerment, skills building and raised self‐esteem. Few authors go into detail about ethical considerations when involving young co‐researchers. None of the included articles discuss legal considerations. Discussion and conclusion No lists of recommendations are given, but recommendations can be deduced from the articles. There is need for time, funding and flexibility when including young patients as co‐researchers. Knowledge gaps concern legal and ethical dilemmas of including a vulnerable group as co‐researchers. More reflection is needed about what meaningful participation is and what it entails in this context. Patient or Public Contribution This review is part of a research project where the hospital youth council has been involved in discussions of focus area and methods.

Abstract Background Individuals who are ‘moderately’ or ‘severely’ dependent consume alcohol at levels that are likely to have a severe impact on their own health and mortality, the health and behaviours of others (family members) and to have economic and social implications. Treatment guidelines suggest that treatment needs to be planned with medically assisted withdrawal (also referred to as detoxification), and aftercare support but outcomes are poor with low proportions engaging in after care and high relapse rates. An approach of structured preparation before alcohol detoxification (SPADe) puts an emphasis on introducing lifestyle changes, development of coping strategies for cravings, stress and emotions as well as introducing changes to the immediate family and social environment in advance of alcohol cessation. Such a pre-habilitation paradigm compliments the established treatment approach. The key research question was: can we design a large scale, randomised controlled trial (RCT) that will answer whether such an approach is more effective than usual care in helping individuals to maintain longer periods of alcohol abstinence? Methods This is a pragmatic, parallel, two-arm, feasibility RCT comparing SPADe and usual care against usual care only in maintaining alcohol abstinence in adults with alcohol dependence receiving care in two community addiction services in London. Feasibility outcomes, exploration of primary and secondary clinical outcomes and health economic outcomes are analysed. The trial follows the guidelines of phase 2 of the Medical Research Council (MRC) for complex interventions. Results We were able to recruit 48/50 participants during a period of 9 months. Retention in the trial for the whole period of the 12 months was 75%. Treatment compliance was overall 44%. Data completion for the primary outcome was 65%, 50% and 63% at 3, 6 and 12 months, respectively. The intervention group had more days abstinent in the previous 90 days at the 12 months (n = 54.5) versus control (n = 41.5). Conclusions The results of this feasibility trial indicate that with the appropriate modifications, a full multicentred trial would be possible to test the effectiveness and cost-effectiveness of a pre-habilitation approach such as the SPADe group intervention in addition to usual care against usual care only. Trial registration Name of registry: ISRCTN; Trial Registration Number: 14621127 ; Date of Registration: 22/02/2017.

Abstract Background Genital erosive lichen planus (GELP) is a genital subtype of lichen planus, a chronic autoimmune inflammatory disease of unknown aetiology. In women, GELP is characterised by painful vulvo-vaginal mucosal erosions and scarring, often resulting in poor sexual health and reduced quality of life. Treatment options are limited and often with little effect. Apremilast, a phosphodiesterase 4-inhibitor, has been shown to have a positive effect on psoriasis and other inflammatory skin diseases. We aim to investigate the effect and safety of peroral apremilast in women with GELP in a randomised placebo-controlled double-blinded clinical trial. Methods We will recruit 42 adult women with characteristic clinical and/or histological features of moderate-to-severe GELP from a specialised vulva clinic in Oslo, Norway. The patients will be randomised 1:1 to either apremilast 30 mg BID (with an initial dose titration on days 1–6) or a placebo for 24 weeks. The concomitant use of topical corticosteroids will be allowed. The primary end point will be the mean GELP score, a clinical scoring system, at week 24 in the apremilast-treated patients versus the placebo-treated patients. The secondary end points will include the mean GELP score improvement from weeks 0 to 24, patient-reported use of topical steroids, the pain score on a visual analogue scale and the number of patients with GELP score improvements at weeks 16 and 24. The Physician Global Assessment , Patient Global Assessment and selected quality of life and sexual function assessments will be recorded at weeks 0, 16 and 24. The exploratory endpoints include description of immunohistochemical changes before and after apremilast therapy, assessed in vulvar or vaginal biopsies at weeks 0 and 24. Regular follow-ups for possible adverse events will be conducted. Discussion The study design is based on experience from studies on apremilast in other inflammatory skin diseases using equivalent apremilast doses for approved indications. The trial may provide evidence for the use of apremilast in women with this burdensome genital dermatosis. Trial registration ClinicalTrials.gov NCT0365666 . Registered on 4 September 2018.

Plain English summary User involvement is a topic that has received increasing attention in research aimed at ensuring relevant and needed knowledge. It can be practised in a variety of ways, and the literature claims that there is no gold standard for how it should be done. This paper presents a user involvement process conducted autumn 2019 to spring 2020, hereby referred to as needs-led research (NLR), inspired by the James Lind Alliance (JLA). The scope of the process is the ‘performance of the trust model in community home-based health care services’. The trust model is a new way of organising home-based health care services where small interdisciplinary teams work with the service users and their next of kin on tailoring the services based on the users’ answers to the question ‘What matters to you?’ Through a five-step process, in which representatives of service users, next of kin and clinicians participated in meetings and online surveys, the goal of the NLR process was to explore research priorities and, ultimately, to develop a final top 10 list of questions relevant to the field of research. This paper describes the NLR process and discusses its strengths and limitations. We found the process to be important when identifying relevant research questions concerning a topic on which little research has been conducted, and in which we as researchers have little experience. The final top 10 list is also presented.

Plain Language Summary Assistive technology is used to provide older adults with the opportunity to preserve their quality of life and their ability to cope in everyday life live independently longer and enhance participation in everyday life. This commentary describes dialogue cafés as a method for involving residents in an assisted living facility in discussions about assistive technology. It elaborates on how dialogue cafés are useful for directing research and development and for engaging older adults in assistive technology discussions. Six dialogue cafés were held between 2016 and 2019 with residents (aged between 65 to 92) as participants in an assisted living facility in Norway. Reports that were written after each café by the group leaders and rapporteurs provide the material for the analyses in this paper. The study demonstrated that the engagement process was found to be positive by the participants in the dialogue café groups. It also succeeded in directing the research and technology development in the project. The dialogue cafés seemed to demonstrate a two-way learning process for the researchers and the participants.

Introduction: Patient-reported outcome and experience measures (PROM and PREM) are used to guide individual care and quality improvement (QI). QI with patient-reported data is preferably organized around patients, which is challenging across organisations. We aimed to investigate network-broad learning for QI with outcome data. Methods: In three obstetric care networks using individual-level PROM/PREM, a learning strategy for cyclic QI based on aggregated outcome data was developed, implemented and evaluated. The strategy included clinical, patient-reported, and professional-reported data; together translated into cases for interprofessional discussion. This study’s data generation (including focus groups, surveys, observations) and analysis were guided by a theoretical model for network collaboration. Results: The learning sessions identified opportunities and actions to improve quality and continuity of perinatal care. Professionals valued the data (especially patient-reported) combined with in-dept interprofessional discussion. Main challenges were professionals’ time constraints, data infrastructure, and embedding improvement actions. Network-readiness for QI depended on trustful collaboration through connectivity and consensual leadership. Joint QI required information exchange and support including time and resources. Conclusions: Current fragmented healthcare organization poses barriers for network-broad QI with outcome data, but also offers opportunities for learning strategies. Furthermore, joint learning could improve collaboration to catalyse the journey towards integrated, value-based care.

Introduction: To provide more integrated care, several countries have implemented the Flexible Assertive Community Treatment (FACT) model. However, this model does not guarantee full integration, especially in complex and fragmented service systems like in Norway. Hence, we investigated which barriers that might reduce the potential for integrated care in the Norwegian system, as described by staff in FACT teams, and how they adjust their way of working to increase the opportunities for integration. Methods: Online focus group interviews involving 35 staff members of five Norwegian FACT teams were conducted using a semi-structured interview guide. The material was analysed using thematic text analysis. Results: Six themes described the barriers to integrated care in the service system: fragmentation, different legislation and digital systems, challenges in collaboration, bureaucracy and limited opening hours. Three themes described adjustments in the teams’ way of working to enhance integration: working as the responsible co-ordinator, being a collaborator, and the only entry channel into the service system. Conclusion: The FACT team staff described several barriers to integration within the system. However, they made some adjustments in their way of working that might provide opportunities for integrated care within complex and fragmented service systems.

Abstract Background The COVID-19 pandemic has imposed an enormous burden on health care systems around the world. In the past, the administration of convalescent plasma of patients having recovered from SARS and severe influenza to patients actively having the disease showed promising effects on mortality and appeared safe. Whether or not this also holds true for the novel SARS-CoV-2 virus is currently unknown. Methods DAWn-Plasma is a multicentre nation-wide, randomized, open-label, phase II proof-of-concept clinical trial, evaluating the clinical efficacy and safety of the addition of convalescent plasma to the standard of care in patients hospitalized with COVID-19 in Belgium. Patients hospitalized with a confirmed diagnosis of COVID-19 are eligible when they are symptomatic (i.e. clinical or radiological signs) and have been diagnosed with COVID-19 in the 72 h before study inclusion through a PCR (nasal/nasopharyngeal swab or bronchoalveolar lavage) or a chest-CT scan showing features compatible with COVID-19 in the absence of an alternative diagnosis. Patients are randomized in a 2:1 ratio to either standard of care and convalescent plasma (active treatment group) or standard of care only. The active treatment group receives 2 units of 200 to 250 mL of convalescent plasma within 12 h after randomization, with a second administration of 2 units 24 to 36 h after ending the first administration. The trial aims to include 483 patients and will recruit from 25 centres across Belgium. The primary endpoint is the proportion of patients that require mechanical ventilation or have died at day 15. The main secondary endpoints are clinical status on day 15 and day 30 after randomization, as defined by the WHO Progression 10-point ordinal scale, and safety of the administration of convalescent plasma. Discussion This trial will either provide support or discourage the use of convalescent plasma as an early intervention for the treatment of hospitalized patients with COVID-19 infection. Trial registration ClinicalTrials.gov NCT04429854 . Registered on 12 June 2020 - Retrospectively registered.

Abstract Background Novel coronavirus SARS-CoV-2 is known to be susceptible in vitro to exposure to hydroxychloroquine and its effect has been found to be potentiated by azithromycin. We hypothesise that early administration of hydroxychloroquine alone or in combination with azithromycin can prevent respiratory deterioration in patients admitted to intensive care due to rapidly progressive COVID-19 infection. Methods Design: Prospective, multi-centre, double-blind, randomised, controlled trial (RCT). Participants: Adult (> 18 years) within 24 h of admission to the intensive care unit with proven or suspected COVID-19 infection, whether or not mechanically ventilated. Exclusion criteria include duration symptoms of febrile disease for ≥ 1 week, treatment limitations in place or moribund patients, allergy or intolerance of any study treatment, and pregnancy. Interventions: Patients will be randomised in 1:1:1 ratio to receive Hydroxychloroquine 800 mg orally in two doses followed by 400 mg daily in two doses and azithromycin 500 mg orally in one dose followed by 250 mg in one dose for a total of 5 days (HC-A group) or hydroxychloroquine + placebo (HC group) or placebo + placebo (C-group) in addition to the best standard of care, which may evolve during the trial period but will not differ between groups. Primary outcome is the composite percentage of patients alive and not on end-of-life pathway who are free of mechanical ventilation at day 14. Secondary outcomes: The percentage of patients who were prevented from needing intubation until day 14, ICU length of stay, and mortality (in hospital) at day 28 and 90. Discussion Although both investigational drugs are often administered off label to patients with severe COVID-19, at present, there is no data from RCTs on their safety and efficacy. In vitro and observational trial suggests their potential to limit viral replication and the damage to lungs as the most common reason for ICU admission. Therefore, patients most likely to benefit from the treatment are those with severe but early disease. This trial is designed and powered to investigate whether the treatment in this cohort of patients leads to improved clinical patient-centred outcomes, such as mechanical ventilation-free survival. Trial registration Clinical trials.gov: NCT04339816 (Registered on 9 April 2020, amended on 22 June 2020); Eudra CT number: 2020-001456-18 (Registered on 29 March 2020).