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.

     

Inducible Nitric Oxide Synthase Does Not Affect Resolution of Murine Chlamydial Genital Tract Infections or Eradication of Chlamydiae in Primary Murine Cell Culture

Mice lacking inducible nitric oxide synthase (iNOS) or treated with iNOS inhibitors resolved chlamydial genital tract infections. Additionally, treatment of primary murine cell cultures with gamma interferon restricted chlamydial growth in the absence of nitric oxide. From these results, iNOS activity is unnecessary for the resolution of chlamydial genital tract infections in mice and inhibition of chlamydial growth in culture.     

c-Fos-dependent induction of the small ras-related GTPase Rab11a in skin carcinogenesis

Malignant transformation of mouse skin by tumor promoters and chemical carcinogens, such as the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), is a multistage process leading to the formation of squamous cell carcinomas. It has been shown that mice lacking the AP-1 family member c-Fos exhibit an impaired transition from benign to malignant skin tumors. Here, we demonstrate enhanced expression of the small Ras-related GTPase Rab11a after short-term TPA treatment of mouse back skin. Expression of Rab11a in vivo and in vitro critically depended on c-Fos, because TPA application to the back skin of c-Fos-deficient mice and to mouse embryonic fibroblasts did not induce Rab11a mRNA or protein expression. Moreover, dexamethasone, which is a potent inhibitor of AP-1-mediated transactivation that exhibits anti-inflammatory and anti-tumor promoting activities, inhibited TPA-induced expression of Rab11a. Within the Rab11a gene promoter, we identified a functional AP-1 binding element that exhibited elevated c-Fos binding activity after TPA treatment of keratinocytes. Enhanced expression was not restricted to chemically induced mouse skin tumors but was also found in tumor specimens derived from patients with epithelial skin tumors. These data identify Rab11a as a novel, tumor-associated c-Fos/AP-1 target and may point to an as yet unrecognized function of Rab11a in the development of skin cancer.     

Cancer risk following appendectomy for acute appendicitis (Denmark)

Objective: Epidemiologic studies have not been able definitely to exclude that appendectomy carries a cancer risk. This study was conducted to clarify whether appendectomy is associated with a subsequent increase in cancer risk, since appendectomy is frequently an elective procedure. Methods: The present study included more than 82,000 persons who underwent appendectomy for acute appendicitis during 1977-89 according to the nation-wide Danish Hospital Discharge Register. During a follow-up interval of up to 17 years, cancer incidence was assessed by linkage to the Danish Cancer Registry and compared with the incidence in the general population of Denmark. Results: The total number of malignancies among appendectomized persons was 1.05 times higher than expected with 95 percent confidence intervals of 0.99-1.11. There was no clear significant excess of any specific cancer type. Conclusion: During a postsurgery period of nearly two decades, results of our study did not support the hypothesis that either appendectomy or acute appendicitis are likely to be associated with malignant neoplasms.     

Societal cost of cancer in Norway –Results of taking a broader cost perspective

BackgroundThe broader cost consequences of diseases may be of interest for a wide range of stakeholders. We aimed to estimate all relevant societal costs of cancer and to provide insight into the relative magnitude of the different cost categories.MethodWe used data from eight different health and work-related registries in Norway. Direct, indirect, and intangible costs (value of lost life years) were estimated over a period of one year with a combination of a top-down and a bottom-up costing approach.ResultsThe indirect costs (EUR 1,997 million per year) are almost as high as direct costs (EUR 2,154 million), and the value of lost life years and quality of life represents the greatest cost related to cancer (EUR 18,200 million). In addition, cancer is associated with other costs which are commonly omitted from cost-of-illness analyses, including informal nursing (EUR 306 million), patient time costs (EUR 85 million), and excess costs of using public funds (EUR 439 million). Breast and cervical cancer had relatively high work absenteeism costs, while pancreatic and lung cancer had relatively high production costs due to premature deaths.DiscussionDirect health care costs represent small proportions of the total societal costs of cancer. Costs commonly omitted in cost-of-illness analyses represent a significant cost and should be measured and valued in these analyses.     

Recovery concept in a Norwegian setting to be examined by the assertive community treatment model and mixed methods

Recovery is a crucial concept in the mental health field. The research of recovery is split into the categories of personal, social and clinical recovery. The purpose of this study was to explore the fragmented concept of recovery in light of assertive community treatment (ACT) in Norway. The study has a mixed methods design with a pragmatic approach. The Questionnaire about the Process of Recovery and open‐ended questions posed to 70 participants from 12 ACT teams in Norway, gathered by the “Users interview users” method, are combined with interviews or focus groups with eight of these participants. Surprisingly those under a community treatment order (CTO) report the highest degree of personal recovery. The qualitative material shows that the service users interpreted the concept of recovery differently than researchers and professionals. The ACT service users highlighted three important elements: flexible treatment, medication and access to a car. They emphasized the necessity for basic needs to be met in order to experience a meaningful recovery process, and these basic needs may be of even greater importance to those under CTOs. Their experiences should imply a greater emphasis on securing basic needs such as secure housing, sounder finances and access to the normal benefits offered by society.     

Trusting and misleading. Parents’ and children’s communication and negotiation about alcohol as described by teenagers

Background: Typically, research on parents’ and children’s interactions around alcohol issues focuses on how parenting styles and parents’ examples affect teenager’s drinking habits. In this paper, we approach the theme from the youngsters’ perspective. We ask how teenagers describe the interaction on alcohol-related issues with their parents and how they would like their parents to act during these interactions.

Data and methods: The article applies the concept of trust, which is seen as a feature connecting all kinds of communities, and especially families. We pay attention to whether alcohol issues challenge trustful relations and give rise to contradictions and complications in the interactions between parents and children.

Results: The analysis shows the ways how trust is maintained and challenged in teenagers? accounts of communication regarding alcohol with their parents. It also shows that although trust is tested in several ways, it is essential for teenagers. Even though teenagers tell how they can mislead their parents by using strategies that challenge trust, they nevertheless highlight the importance of trusting ties with parents. Teenagers do not exclude their parents from alcohol-related discussion but expect rules, communication and authority from them. Our data suggest that teenagers also want to protect their parents from disappointments caused by their own actions.

Conclusions: A trusting parent–child relationship, based on dialog rather than opposition, seems to play a significant role in guiding teenagers’ alcohol-related attitudes and practices.     

Layer-specific and whole wall global longitudinal strain predict major adverse cardiovascular events in patients with stable angina pectoris

The International Journal of Cardiovascular Imaging - Global longitudinal strain (GLS) has proven to be a powerful prognostic marker in various patient populations, but the prognostic value of...     

Surgical anatomy and pathology of the middle ear

Middle ear surgery is strongly influenced by anatomical and functional characteristics of the middle ear. The complex anatomy means a challenge for the otosurgeon who moves between preservation or improvement of highly important functions (hearing, balance, facial motion) and eradication of diseases. Of these, perforations of the tympanic membrane, chronic otitis media, tympanosclerosis and cholesteatoma are encountered most often in clinical practice. Modern techniques for reconstruction of the ossicular chain aim for best possible hearing improvement using delicate alloplastic titanium prostheses, but a number of prosthesis‐unrelated factors work against this intent. Surgery is always individualized to the case and there is no one‐fits‐all strategy. Above all, both middle ear diseases and surgery can be associated with a number of complications; the most important ones being hearing deterioration or deafness, dizziness, facial palsy and life‐threatening intracranial complications. To minimize risks, a solid knowledge of and respect for neurootologic structures is essential for an otosurgeon who must train him‐ or herself intensively on temporal bones before performing surgery on a patient.