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Medicine, Health Care and Philosophy -     

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.

     

Insights into Mechanisms of Cisplatin Resistance and Potential for Its Clinical Reversal

Cisplatin in combination with other cytotoxic agents is the backbone for a potential cure of testicular germ cell neoplasms and is a critical factor in the substantial activity observed in the treatment of small cell lung cancer, bladder cancer, and ovarian germ cell tumors. Resistance to cisplatin at the onset of treatment or at relapse limits its curative potential, however. Laboratory studies using both cells selected for cisplatin resistance by exposure to sublethal concentrations and biopsy specimens from patients' tumors provide insights for the potential mechanisms of resistance. The mechanisms identified in vitro include a complex and wide array of related and unrelated pathways such as alterations in cellular drug transport, enhanced DNA repair dependent and independent of signal transduction pathways, and enhanced intracellular detoxification such as glutathione and metallothionein systems. Studies of these mechanisms have identified a number of agents with known potential for administration to humans and that reverse cisplatin resistance in vitro; for example, reversal of cellular accumulation defects by dipyridamole; inhibition of DNA repair by hydroxyurea, pentoxifylline, and novobiocin; inhibition of the glutathione system by ethacrynic acid and buthionine sulfoximine; and inhibition of signal transduction pathways by cyclosporine, tamoxifen, and calcium channel-blocking agents. Current phase I clinical trials are focusing on the most effective doses and schedules to administer these agents in combination with cisplatin. Initial uncontrolled trials in limited numbers of patients suggest that the addition of modulators of cisplatin has the potential to reverse resistance in patients previously failing therapy. Another promising avenue for circumventing cisplatin resistance is the development of noncross-resistant platinum analogs.     

New aspects of surgical treatment of cholelithiasis

The interventional endoscopy and new knowledge about the spontaneous course of the cholelithiasis have obtained a far-reaching influence on the indication for operation and the surgical approach. Now as ever the adequate therapy of the symptomatic cholecystolithiasis consists in the early cholecystectomy. Since in the natural course the risk of lethality is small the operation for indication depending on the age and the risk factors given must be made cautiously. This in a still higher degree concerns the asymptomatic cholelithiasis in which at present no general indication for operation is regarded necessary. Due to the low lethality of circa 1% the endoscopic papillotomy has become the therapeutic method of choice in residual and recurrent calculi after cholecystectomy, but also in risk patients with cholecystocholedocholithiasis. The endoscopic papillotomy with stone extraction before the operation suggests a decrease of the operation lethality of 3 to 5% after cholecystectomy with revision of the choledochus.     

Quantifying the magnitude of risk for balance impairment on falls in community-dwelling older adults: a systematic review and meta-analysis

ObjectivesTo evaluate and summarize the evidence linking balance impairment as a risk factor for falls in community-dwelling older adults.Study Design and SettingSystematic review and meta-analysis. English language articles in MEDLINE, EMBASE, CINAHL (1988–2009), under keywords of accidental falls, aged, risk factors, and hip, radius, ulna, and humerus fractures; and bibliographies of retrieved articles. Community-dwelling older adults in a prospective study, at least 1-year duration, age more than 60 years, and samples not specific to a single disease-defined population were included. Sample size, inclusion/exclusion criteria, demographics, clinical balance measurement scale, type of fall outcome, method of fall ascertainment, length of follow-up, and odds ratio (OR) or risk ratio (RR) were extracted. Studies must have reported adjustment for confounders. Random effects meta-analysis to generate summary risk estimate was used. A priori evaluation of sources of heterogeneity was performed.ResultsTwenty-three studies met the selection criteria. A single summary measure could not be calculated because of the nonequivalence of the OR and RR, producing an overall fall risk of RR of 1.42 (1.08, 1.85) and OR of 1.98 (1.60, 2.46).ConclusionsBalance impairment imparts a moderate increase on fall risk in community-dwelling older adults. The type of fall outcome, the length of follow-up, and the balance measurement tool impact the magnitude of the association. Specific balance measurement scales were identified with associations for an increased fall risk, but further research is required to refine recommendations for their use in clinical practice.     

Understanding capture detection.

Automatic capture detection systems are currently available in several cardiac pacing devices. All current systems use low-polarization electrodes and no beat to beat detection system is available for all types of electrodes. In addition the success ratio for currently available systems is not always 100%. Failure to detect capture reliably is often related to the behaviour of the electrode-tissue interface under different circumstances. Pacemaker electrodes can be considered electrochemical cells with complicated characteristics depending on time, temperature and electrical charge. This electrochemical cell is disturbed when a charge is transferred across the electrode-tissue interface during pacing. Several measures can be taken in order to minimise this disturbance or pace polarization artefact (PPA) including the use of high active surface area electrodes and application of tri-phasic pacing pulses. Another factor influencing detection of evoked potentials is the input circuit of the pacemaker affecting the PPA and the evoked response. Positive PPAs can be falsely interpreted as evoked potentials due to the undershoot of the second order filters applied in modern cardiac pacemakers. This paper explains the behaviour of the interface between the electrode and the cardiac tissue in combination with the pacemaker output circuits and input amplifiers under different circumstances.