Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia (COVID STEROID) trial—Protocol and statistical analysis plan

Introduction

Severe acute respiratory syndrome coronavirus-2 has caused a pandemic of coronavirus disease (COVID-19) with many patients developing hypoxic respiratory failure. Corticosteroids reduce the time on mechanical ventilation, length of stay in the intensive care unit and potentially also mortality in similar patient populations. However, corticosteroids have undesirable effects, including longer time to viral clearance. Clinical equipoise on the use of corticosteroids for COVID-19 exists.

Methods

The COVID STEROID trial is an international, randomised, stratified, blinded clinical trial. We will allocate 1000 adult patients with COVID-19 receiving ≥10 L/min of oxygen or on mechanical ventilation to intravenous hydrocortisone 200 mg daily vs placebo (0.9% saline) for 7 days. The primary outcome is days alive without life support (ie mechanical ventilation, circulatory support, and renal replacement therapy) at day 28. Secondary outcomes are serious adverse reactions at day 14; days alive without life support at day 90; days alive and out of hospital at day 90; all-cause mortality at day 28, day 90, and 1 year; and health-related quality of life at 1 year. We will conduct the statistical analyses according to this protocol, including interim analyses for every 250 patients followed for 28 days. The primary outcome will be compared using the Kryger Jensen and Lange test in the intention to treat population and reported as differences in means and medians with 95% confidence intervals.

Discussion

The COVID STEROID trial will provide important evidence to guide the use of corticosteroids in COVID-19 and severe hypoxia.

     

Physical child abuse demands increased awareness during health and socioeconomic crises like COVID-19: A review and education material

Background and purposePhysical abuse of children, i.e., nonaccidental injury (NAI) including abusive head trauma (AHT) is experienced by up to 20% of children; however, only 0.1% are diagnosed. Healthcare professionals issue less than 20% of all reports suspecting NAI to the responsible authorities. Insufficient knowledge concerning NAI may partly explain this low percentage. The risk of NAI is heightened during health and socioeconomic crises such as COVID-19 and thus demands increased awareness. This review provides an overview and educational material on NAI and its clinical presentation.MethodsWe combined a literature review with expert opinions of the senior authors into an educational paper aiming to help clinicians to recognize NAI and act appropriately by referral to multidisciplinary child protection teams and local authorities.ResultsDespite the increased risk of NAI during the current COVID-19 crisis, the number of reports suspecting NAI decreased by 42% during the lockdown of the Danish society. Healthcare professionals filed only 17% of all reports of suspected child abuse in 2016.InterpretationThe key to recognizing and suspecting NAI upon clinical presentation is to be aware of inconsistencies in the medical history and suspicious findings on physical and paraclinical examination. During health and socioeconomic crises the incidence of NAI is likely to peak. Recognition of NAI, adequate handling by referral to child protection teams, and reporting to local authorities are of paramount importance to prevent mortality and physical and mental morbidity.

Physical abuse of children, i.e., non-accidental injury (NAI) including abusive head trauma (AHT), is experienced by up to 20% of children; however, only 0.1% are diagnosed with the ICD-10 code: T74.1 physical abuse (Christoffersen 2010, Stoltenborgh et al. 2013, Oldrup et al. 2016).During the current COVID-19 crisis some European countries have reported an alarming increase in domestic violence by one-third (Delaleu 2020). Likewise, the risk of NAI is heightened during health and socioeconomic crises (Baird 2020, Peterman et al. 2020). Therefore, a Joint Leaders’ statement by the World Health Organization, UNICEF, Save the Children International, and SOS Children’s Villages International among others, highlights the acute risk of violence against children due to COVID-19 and calls for increased awareness (World Health Organization 2020).The vast majority of NAI is reported by staff working at institutions (daycares, kindergartens, schools), which are temporarily closed during the COVID-19 pandemic. Healthcare professionals issue less than 20% of reports regarding suspected maltreatment to the responsible child protection authorities (Christoffersen 2010, Oldrup et al. 2016). Failure to recognize NAI due to insufficient knowledge among healthcare professionals may partly explain this low percentage (Villadsen et al. 2015).Healthcare professionals need to be aware of the increased risk of NAI during COVID-19 and future health and socio-economic crises in order to act appropriately based on current knowledge of the issue. Only then can they begin to recognize patterns of NAI from the medical history and objective findings, and act appropriately through immediate consultation and referral to multidisciplinary child protection teams, who can clarify the suspicion and ensure child protection.     

A Randomized Double-Blind Placebo-Controlled First-In-Human Phase 1 Trial of TransCon PTH in Healthy Adults

TransCon PTH is a sustained-release, essentially inactive prodrug transiently bound to an inert carrier, designed to release PTH(1-34), and in development for hypoparathyroidism (HP). This phase 1, randomized, placebo-controlled, single and multiple ascending dose (SAD and MAD, respectively) trial evaluated safety, tolerability, pharmacodynamics (PD), and pharmacokinetics (PK) of TransCon PTH in healthy adults. SAD and MAD cohorts consisted of 10 subjects (eight active, two placebo) who received up to seven single or six multiple ascending doses of TransCon PTH, respectively. TransCon PTH doses ranged from 3.5 to 124 μg PTH(1-34) for the SAD cohorts and 3.5 to 24 μg PTH(1-34)/day for the MAD cohorts. The primary PK endpoint was Free PTH. The PD endpoints included albumin adjusted serum calcium (sCa), fractional excretion of calcium (FECa), intact endogenous PTH(1-84), bone turnover markers, renal tubular maximum reabsorption of phosphate/glomerular filtration rate (TMP/GFR), serum phosphate (sP) and magnesium, and 1,25 dihydroxyvitamin D. TransCon PTH was generally well tolerated; there were no drug-related serious adverse events (SAEs), and all AEs were transient in nature. Free PTH demonstrated an effective half-life of approximately 60 hours and a dose-dependent, sustained exposure with an infusion-like profile within the calculated physiologic range for active PTH at steady-state. Albumin-adjusted sCa demonstrated a dose-dependent, sustained response with complete control of FECa despite modest hypercalcemia at higher doses. Renal tubular maximum reabsorption of phosphate/glomerular filtration rate (TMP/GFR) showed a dose-dependent decrease, resulting in a dose-dependent decrease in sP. TransCon PTH administered daily for 10 days showed no increase in the osteoblastic bone formation markers, serum bone-specific alkaline phosphatase (BSAP) or P1NP, or the osteoclastic bone resorption marker, urine NTx, but modestly and transiently increased the osteoclast marker, serum CTx. These phase 1 data support TransCon PTH as a daily replacement therapy for HP providing physiological levels of PTH 24 hours per day and advancement into phase 2 clinical development. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.     

Abnormal vomer development in human fetuses with isolated cleft palate.

OBJECTIVE: The aim of this study was to elucidate the prenatal human development of the vomer with emphasis on the vomeral footplate and to assess vomeral morphology in fetuses with isolated cleft palate. MATERIAL AND METHODS: Nine human fetuses of which four were normal (menstrual age [MA] 13 to 21 weeks) and five with isolated cleft palate (14 to 19 weeks MA) were studied. Midaxial cranial tissue blocks from the fetuses were cut frontally in 4microm serial sections. Sections were stained with toluidine blue in 30% ethanol. RESULTS: From 16 weeks MA, the vomeral footplate of normal fetuses was formed from bilateral ossifications located below a U-shaped vomeral body. Later in development, an osseous connection was found between the footplate and the vomeral body. Neither bilateral areas of ossification below the vomer nor a vomeral footplate was observed in isolated cleft palate fetuses. CONCLUSIONS: In normal fetuses, the base or footplate of the vomeral bone appears from 16 weeks MA in frontal sections. In fetuses with isolated cleft palates, with no connection between the nasal septum and the maxillary processes, this vomeral footplate does not develop in the period observed (14 to 19 weeks MA).     

Circulatory response to single circuit weight and walking training sessions of similar energy cost in middle‐aged overweight females

The aim of this study was to compare circulatory responses to circuit weight (CWT) and aerobic walking training sessions of similar energy cost in middle‐aged overweight females. Thirty‐three middle‐aged pre‐menopausal females participated in the experiment. They were divided into overweight (n=18, 36·2 ± 6·3 years, 166·3 ± 8·0 cm, 83·5 ± 9·7 kg, BMI 30·2 ± 3·1 kg m^–2) and non‐overweight control (n=15, 34·1 ± 6·3 years, 165·0 ± 5·6 cm, 61·6 ± 5·0 kg, BMI 22·7 ± 1·5 kg m^–2) groups. Individual physical working capacity (PWC) was measured using the cycle ergometer test (calculated at the level of predicted HR_max (205 – ½ age). A CWT session consisted of leg extension, bench press, sit‐ups and leg press exercises. The subjects performed four circuits at the maximal possible speed, using a work‐to‐rest ratio of 60 s. Blood pressure (BP) was measured during every rest period between the exercises, and the heart rate (HR) was recorded continuously during the whole CWT programme. During the walking training session, the subjects walked as fast as possible on the indoor track. The total energy cost of the walking training session was the same as during the CWT session, approximately 270 kcal, and was controlled by a CALTRAC accelerometer. HR and BP were measured every 5 min during the walking training session. The PWC index was significantly (P<0·05) higher in the overweight group in comparison with the control females (215·4 ± 76·1 and 187·9 ± 42·4 W, respectively). The resting BP was normal in both groups (<140/90 mmHg). HR was between 120 and 140 beats min^–1 during CWT and walking sessions. There were no differences in BP during both training sessions in overweight and control subjects. It was concluded that both CWT and walking training sessions were acceptable forms of physical activity to increase cardiovascular fitness in middle‐aged overweight and normal body weight females.     

Perception of sexuality and fertility in women living with HIV: a questionnaire study from two Nordic countries

Introduction

As the human immunodeficiency virus (HIV)-positive population ages, issues concerning sexuality and fertility, among others, are becoming relevant. HIV is still surrounded by stigma and taboos, and there have been few studies conducted in industrialized settings concerning these questions. We therefore wanted to investigate the perception of sexuality and fertility in women living with HIV (WLWH) in an industrialized setting, using a questionnaire.

Methods

WLWH were recruited at their regular outpatient clinic visits, at the major Departments of Infectious Diseases in Denmark and Finland, from January 2012 to October 2013. A questionnaire was developed, study participants were informed of the nature of study and, if they agreed to participate and signed a consent form, they filled in the questionnaire. Demographic information on the participants was obtained from patient files (in Finland) or from a national HIV cohort (in Denmark). Statistical analysis was performed using STATA^®, version 11.

Results

In total, 560 women were included in the study. The median age was 44 years. The majority were of white European origin, with fully suppressed HIV viral load, CD4 cell count >350 µL and mild or no symptoms of their HIV infection. A total of 62% were sexually active, stating condom use as their sole form of contraception. Of the sexually inactive women, one-third were in steady relationships. Eighty percent reported prior pregnancies, of which the majority had one or more children. Most children were born prior to the women''s HIV diagnosis and the mode of conception was predominantly natural. One-quarter of the participating women desired pregnancy, while more than half did not. The remaining quarter either stated that they already had the desired number of children or chose not to answer the question. Fourteen percent stated that their HIV diagnosis ended their wish for children; of these women, the median time of diagnosis was between 1995 and 1996. Pregnancy had been attempted unsuccessfully in one-quarter of study participants. The final question inquired what the risk of mother-to-child transmission was, with all precautions taken. Fifteen percent estimated the risk to be above two percent.

Conclusions

In conclusion, the majority of WLWH in industrialized settings in Denmark and Finland have few HIV-related symptoms, are sexually active and have a strong desire for children.