High-dose vitamin D versus placebo to prevent complications in COVID-19 patients: Multicentre randomized controlled clinical trial.

BACKGROUND: The role of oral vitamin D3 supplementation for hospitalized patients with COVID-19 remains to be determined. The study was aimed to evaluate whether vitamin D3 supplementation could prevent respiratory worsening among hospitalized patients with COVID-19. METHODS AND FINDINGS: We designed a multicentre, randomized, double-blind, sequential, placebo-controlled clinical trial. The study was conducted in 17 second and third level hospitals, located in four provinces of Argentina, from 14 August 2020 to 22 June 2021. We enrolled 218 adult patients, hospitalized in general wards with SARS-CoV-2 confirmed infection, mild-to-moderate COVID-19 and risk factors for disease progression. Participants were randomized to a single oral dose of 500 000 IU of vitamin D3 or matching placebo. Randomization ratio was 1:1, with permuted blocks and stratified for study site, diabetes and age (≤60 vs >60 years). The primary outcome was the change in the respiratory Sepsis related Organ Failure Assessment score between baseline and the highest value recorded up to day 7. Secondary outcomes included the length of hospital stay; intensive care unit admission; and in-hospital mortality. Overall, 115 participants were assigned to vitamin D3 and 105 to placebo (mean [SD] age, 59.1 [10.7] years; 103 [47.2%] women). There were no significant differences in the primary outcome between groups (median [IQR] 0.0 [0.0-1.0] vs 0.0 [0.0-1.0], for vitamin D3 and placebo, respectively; p = 0.925). Median [IQR] length of hospital stay was not significantly different between vitamin D3 group (6.0 [4.0-9.0] days) and placebo group (6.0 [4.0-10.0] days; p = 0.632). There were no significant differences for intensive care unit admissions (7.8% vs 10.7%; RR 0.73; 95% CI 0.32 to 1.70; p = 0.622), or in-hospital mortality (4.3% vs 1.9%; RR 2.24; 95% CI 0.44 to 11.29; p = 0.451). There were no significant differences in serious adverse events (vitamin D3 = 14.8%, placebo = 11.7%). CONCLUSIONS: Among hospitalized patients with mild-to-moderate COVID-19 and risk factors, a single high oral dose of vitamin D3 as compared with placebo, did not prevent the respiratory worsening. TRIAL REGISTRATION: ClincicalTrials.gov Identifier: NCT04411446.

Applying systems thinking to identify enablers and challenges to scale-up interventions for hypertension and diabetes in low-income and middle-income countries: protocol for a longitudinal mixed-methods study.

INTRODUCTION: There is an urgent need to reduce the burden of non-communicable diseases (NCDs), particularly in low-and middle-income countries, where the greatest burden lies. Yet, there is little research concerning the specific issues involved in scaling up NCD interventions targeting low-resource settings. We propose to examine this gap in up to 27 collaborative projects, which were funded by the Global Alliance for Chronic Diseases (GACD) 2019 Scale Up Call, reflecting a total funding investment of approximately US$50 million. These projects represent diverse countries, contexts and adopt varied approaches and study designs to scale-up complex, evidence-based interventions to improve hypertension and diabetes outcomes. A systematic inquiry of these projects will provide necessary scientific insights into the enablers and challenges in the scale up of complex NCD interventions. METHODS AND ANALYSIS: We will apply systems thinking (a holistic approach to analyse the inter-relationship between constituent parts of scaleup interventions and the context in which the interventions are implemented) and adopt a longitudinal mixed-methods study design to explore the planning and early implementation phases of scale up projects. Data will be gathered at three time periods, namely, at planning (TP), initiation of implementation (T0) and 1-year postinitiation (T1). We will extract project-related data from secondary documents at TP and conduct multistakeholder qualitative interviews to gather data at T0 and T1. We will undertake descriptive statistical analysis of TP data and analyse T0 and T1 data using inductive thematic coding. The data extraction tool and interview guides were developed based on a literature review of scale-up frameworks. ETHICS AND DISSEMINATION: The current protocol was approved by the Monash University Human Research Ethics Committee (HREC number 23482). Informed consent will be obtained from all participants. The study findings will be disseminated through peer-reviewed publications and more broadly through the GACD network.

High-dose vitamin D versus placebo to prevent complications in COVID-19 patients: A structured summary of a study protocol for a randomised controlled trial (CARED-TRIAL).

OBJECTIVES: To evaluate whether a single high dose of oral cholecalciferol improves the respiratory outcomes as compared with placebo among adults COVID-19 patients at moderate risk of clinical complications. TRIAL DESIGN: The CARED trial is an investigator-initiated, multicentre, randomized, parallel, two-arm, sequential, double-blind and placebo-controlled clinical trial. It was planned as a pragmatic trial since the inclusion criteria are broad and the study procedures are as simple as possible, in order to be implemented in the routine clinical practice in general wards in the pandemic setting and a middle-income country context. The sequential design involves two stages. The first stage will assess the effects of vitamin D supplementation on blood oxygenation (physiological effects). The second stage will assess the effects on clinical outcomes. PARTICIPANTS: Participants of either gender admitted to general adult wards in 21 hospital sites located in four provinces of Argentina are invited to participate in the study if they meet the following inclusion criteria and none of the exclusion criteria: Inclusion criteria SARS-CoV-2 confirmed infection by RT-PCR; Hospital admission at least 24 hours before; Expected hospitalization in the same site ≥24 hours; Oxygen saturation ≥90% (measured by pulse oximetry) breathing ambient air; Age ≥45 years or at least one of the following conditions: ○ Hypertension; ○ Diabetes; ○ At least moderate COPD or asthma; ○ Cardiovascular disease (history of myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting or valve replacement surgery); ○ Body mass index ≥30; Willingness to sign informed consent (online supplementary material 1 and 2). EXCLUSION CRITERIA: Age <18 years; Women in childbearing age; >= 72 hs since current admission; Requirement for a high dose of oxygen (>5 litres/minute) or mechanical ventilation (non-invasive or invasive); History of chronic kidney disease requiring haemodialysis or chronic liver failure; Inability for oral intake. Chronic supplementation with pharmacological vitamin D; Current treatment with anticonvulsants; History of: ○ Sarcoidosis; ○ Malabsorption syndrome; ○ Known hypercalcemia or serum calcium >10.5 mg/dL; Life expectancy <6 months; Known allergy to study medication; Any condition at discretion of investigator impeding to understand the study and give informed consent. INTERVENTION AND COMPARATOR: The intervention consists in a single oral dose of 500.000 IU of commercially available cholecalciferol soft gel capsules (5 capsules of 100.000 IU) or matching placebo MAIN OUTCOMES: The primary outcome for the first stage is the change in the respiratory Sepsis-related Organ Failure Assessment (SOFAr) score between pre-treatment value and the worst value recorded during the first 7 seven days of hospitalization, the death or discharge, whichever occurs first. The SOFAr score measured as the ratio between the pulse oximetry saturation (SpO2) and FiO2 (27, 28) is used instead of the arterial partial pressure of oxygen (PaO2). SOFAr score is a 4-points scale, with higher values indicating deeper respiratory derangement as follows: 1 PaO2 <400; 2 PaO2 <300; 3 PaO2 <200; 4 PaO2 <100. The primary outcome for the second stage is the combined occurrence of requirement ≥40% of FiO2, invasive or non-invasive ventilation, up to 30 days or hospital discharge. RANDOMISATION: A computer-generated random sequence and the treatment assignment is performed through the web-based randomization module available in the electronic data capture system (Castor®). A randomization ratio 1:1, stratified and with permuted blocks was used. Stratification variables were diabetes (yes/no), age (≤60/>60 years) and the site. BLINDING (MASKING): Double-blind was achieved by using placebo soft gel capsules with the same organoleptic properties as the active medication. Central management of the medication is carried out by a pharmacist in charge of packaging the study drug in unblinded fashion, who have no contact with on-site investigators. Medication is packaged in opaque white bottles, each containing five soft gel capsules of the active drug or matching placebo, corresponding to complete individual treatment. Treatment codes are kept under the pharmacist responsibility, and all researchers are unaware of them. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The first stage is planned to include 200 patients (100 per group), the second stage is planned to include 1064 additional patients. The total sample size is 1264 patients. TRIAL STATUS: Currently the protocol version is the number 1.4 (from October 13th, 2020). The recruitment is ongoing since August 11th, 2020, and the first subject was enrolled on August 14th. Since then, 21 sites located in four provinces of Argentina were initiated, and 167 patients were recruited by January 11th, 2021. We anticipate to finish the recruitment for the first stage in mid-February, 2021, and in August, 2021 for the second stage. TRIAL REGISTRATION: The study protocol is registered in ClinicalTrials.gov (identifier number NCT04411446 ) on June 2, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Preocupaciones y demandas frente a COVID-19: Encuesta al personal de salud

La pandemia por COVID-19 afectó la organización de los servicios de salud y tuvo consecuencias en los equipos de salud, según las condiciones laborales y de bioseguridad pre-existentes en cada institución. Durante la primera semana de abril de 2020 se realizó un estudio de corte transversal. El objetivo fue indagar acerca de las condiciones que determinan el clima organizacional: liderazgo, comunicación, recursos institucionales, cohesión/gestión de conflictos y capacitación;y cómo éstas eran percibidas por el personal de salud para hacer frente a la pandemia. Se realizaron 5670 encuestas a trabajadores/as y 50 entrevistas a informantes clave de los tres subsectores del sistema de salud (público, privado y de seguridad social). En las encuestas, el 72.9% fueron mujeres, el 51.4% médicos/as y el grupo etario predominante fue el de menores de 40 años. El 47.8% de los/as participantes refirió pluriempleo. En las entrevistas, el 52% fueron varones, el 60% médicos/ as, la edad media 44.8 años. Se estratificaron las dimensiones y se identificaron predictores independientes de percepción: edad, género, tipo de tareas, subsector y jurisdicción. La dimensión percibida con mayor frecuencia como inadecuada fue la de recursos institucionales y la disponibilidad de equipos de protección personal fue identificada como una de las principales preocupaciones. Surgieron demandas de estrategias de contención para el personal de salud y de comunicación institucional clara y uniforme. En conclusión, al momento del estudio el personal de salud percibía serios déficits en sus organizaciones respecto de las condiciones necesarias para enfrentar la pandemia, con diferencias entre subsectores del sistema. The COVID-19 pandemic affected the organization of health services and had consequences for health teams, according to the pre-existing safety and working conditions. During the first week of April 2020, a cross sectional study was carried out with a qualitative-quantitative approach. The aim was to explore the conditions determining the organizational climate: leadership, communication, institutional resources, cohesion/conflict management, and training;and how these were perceived by health personnel to deal with the pandemic. A total of 5670 healthcare workers participated in an online survey and 50 were interviewed, from all subsectors of the Argentinean health system (public, private and union-health insurance);72.9% were women, 51.4% were physicians, and the predominant age group was under 40 years. In the qualitative sample (interviews), 52% were men, 62% were physicians, and the average age was 44.8 years. The dimensions of the organizational climate were stratified and five independent predictors of perception of conditions were identified: age, gender, tasks performed, health system subsector, and jurisdiction. The condition most frequently perceived as inadequate were the inaccessibility of institutional resources and the access to personal protective equipment was a major concern. Claims included the need of institutional strategies to support healthcare workers and of a clear and uniform communication. In conclusion, at the time of the study, the health personnel perceived serious deficits in their organizations regarding the conditions necessary to confront COVID-19, with differences among subsectors of the health system.

Association Between Vitamin D Deficiency and COVID-19 Incidence, Complications, and Mortality in 46 Countries: An Ecological Study.

Each patient's immune defenses play a major role in mitigating the impact (ie, morbidity and mortality) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). Vitamin D is an important modulator of the immune system. Although serum 25-hydroxyvitamin D levels can be raised through diet or supplements, most vitamin D in the body is the result of dermal synthesis from ultraviolet radiation. The production of vitamin D in the skin, however, can be limited by latitude, skin-covering clothes, the use of sunblock, and skin pigmentation. Vitamin D deficiency affects a high percentage of the world population. Serum 25-hydroxyvitamin D levels are suboptimal, not only in specific risk groups but also in adults from many countries. Low vitamin D levels, therefore, represent a risk factor for several different pathologies, including SAR-CoV-2. This study used an ecological design to assess the association between vitamin D deficiency and COVID-19 incidence, complications, and mortality across 46 countries. All data were obtained from published sources. The results of the study suggest an association at the population level between the prevalence of vitamin D deficiency and the risk of being infected with COVID-19, severity of the disease, and risk of dying from it.

Vitamin D supplementation as a rational pharmacological approach in the COVID-19 pandemic.

The COVID-19 pandemic has reached most of the countries worldwide causing death, which often results from an inflammatory storm associated with severe acute respiratory syndrome (SARS). This has prompted researchers to seek specific novel and definitive treatments urgently. In this context, it is interesting to evaluate the preventive and therapeutic effects of existing pharmacological agents that could be useful. In this regard, vitamin D supplementation, particularly in individuals likely to be deficient, may be a promising option. Vitamin D is a hormone that modulates many of the same inflammatory and oxidative signaling pathways triggered during COVID-19. For example, vitamin D suppresses the actions of the renin-angiotensin system, which has a determining role in the pathophysiology of the inflammatory response related to COVID-19. This paper analyzes the evidence that vitamin D supplementation might be a valuable preventive/therapeutic measure in groups at risk for or infected with COVID-19. It also discusses how clinical studies could be best designed to evaluate the possible advantages of vitamin D supplementation for the benefit of public health during the pandemic.

[Concerns and demands regarding COVID-19. Survey of health personnel]

The COVID-19 pandemic affected the organization of health services and had consequences for health teams, according to the pre-existing safety and working conditions. During the first week of April 2020, a cross sectional study was carried out with a qualitative-quantitative approach. The aim was to explore the conditions determining the organizational climate: leadership, communication, institutional resources, cohesion/conflict management, and training;and how these were perceived by health personnel to deal with the pandemic. A total of 5670 healthcare workers participated in an online survey and 50 were interviewed, from all subsectors of the Argentinean health system (public, private and union-health insurance);72.9% were women, 51.4% were physicians, and the predominant age group was under 40 years. In the qualitative sample (interviews), 52% were men, 62% were physicians, and the average age was 44.8 years. The dimensions of the organizational climate were stratified and five independent predictors of perception of conditions were identified: age, gender, tasks performed, health system subsector, and jurisdiction. The condition most frequently perceived as inadequate were the inaccessibility of institutional resources and the access to personal protective equipment was a major concern. Claims included the need of institutional strategies to support healthcare workers and of a clear and uniform communication. In conclusion, at the time of the study, the health personnel perceived serious deficits in their organizations regarding the conditions necessary to confront COVID-19, with differences among subsectors of the health system.