Anakinra or tocilizumab in patients admitted to hospital with severe covid-19 at high risk of deterioration (IMMCoVA): A randomized, controlled, open-label trial.

BACKGROUND: Anakinra and tocilizumab are used for severe Covid-19, but only one previous randomized controlled trial (RCT) has studied both. We performed a multi-center RCT comparing anakinra or tocilizumab versus usual care (UC) for adults at high risk of deterioration. METHODS: The study was conducted June 2020 to March 2021. Eligibility required ≥ 5 liters/minute of Oxygen to maintain peripheral oxygen saturation at ≥ 93%, CRP > 70 mg/L, ferritin > 500 µg/L and at least two points where one point was awarded for lymphocytes < 1x 109/L; D-dimer ≥ 0.5 mg/L and; lactate dehydrogenase ≥ 8 microkatal/L. Patients were randomly assigned 1:1:1 to receive either a single dose of tocilizumab (8 mg/kg) or anakinra 100 mg IV QID for seven days or UC alone. The primary outcome was time to recovery. RESULTS: Recruitment was ended prematurely when tocilizumab became part of usual care. Out of a planned 195 patients, 77 had been randomized, 27 to UC, 28 to anakinra and 22 to tocilizumab. Median time to recovery was 15, 15 and 11 days. Rate ratio for recovery for UC vs anakinra was 0.91, 0.47 to 1.78, 95% [CI], p = 0.8 and for UC vs tocilizumab 1.13, 0.55 to 2.30; p = 0.7. There were non-significant trends favoring tocilizumab (and to limited degree anakinra) vs UC for some secondary outcomes. Safety profiles did not differ significantly. CONCLUSION: Premature closure of trial precludes firm conclusions. Anakinra or tocilizumab did not significantly shorten time to clinical recovery compared to usual care. (IMMCoVA, NCT04412291, EudraCT: 2020-00174824).

In-person vs video hookup instructions: a comparison of home sleep apnea testing quality.

STUDY OBJECTIVES: The high prevalence of obstructive sleep apnea (OSA) in the general population makes diagnosing OSA a high priority. Typically, patients receive in-person instructions to hook up the home sleep apnea test devices. Using recorded video instructions would save health care personnel time and improve access to OSA diagnostics for patients in remote areas. The aim of this study was to compare the quality of home sleep apnea test recordings when using in-person and video hookup instructions in a randomized study. METHODS: A total of 100 patients aged 18 to 70 years with suspected OSA were randomized to receive either in-person or video hookup instructions for the Nox T3 device (Nox Medical, Reykjavik, Iceland). The overall quality of the resulting sleep studies was analyzed by determining the number of technically invalid studies. The recording quality of 4 sensors (pulse oximeter, nasal cannula, thorax and abdominal respiratory inductance plethysmography belts) was assessed by checking for signal artifacts. RESULTS: No significant difference was found between the 2 groups in any quality index. Only 1 (2%) and 2 (3.9%) sleep studies were technically invalid in the in-person and video instructions group, respectively. The average ± standard deviation recording quality of the 4 sensors combined was 94.8% ± 13.6% for the in-person and 96.0% ± 11.0% for the video instructions group. CONCLUSIONS: This study found no difference in home sleep apnea test recording quality between the 2 groups. Video hookup instructions are therefore viable and an important step toward a telemedicine-based way of diagnosing OSA. CITATION: Horne AF, Olafsdottir KA, Arnardottir ES. In-person vs video hookup instructions: a comparison of home sleep apnea testing quality. J Clin Sleep Med. 2022;18(8):2069-2074.

Immunoprofiling of active and inactive systemic juvenile idiopathic arthritis reveals distinct biomarkers: a single-center study.

BACKGROUND: This study aimed to perform an immunoprofiling of systemic juvenile idiopathic arthritis (sJIA) in order to define biomarkers of clinical use as well as reveal new immune mechanisms. METHODS: Immunoprofiling of plasma samples from a clinically well-described cohort consisting of 21 sJIA patients as well as 60 age and sex matched healthy controls, was performed by a highly sensitive proteomic immunoassay. Based on the biomarkers being significantly up- or down-regulated in cross-sectional and paired analysis, related canonical pathways and cellular functions were explored by Ingenuity Pathway Analysis (IPA). RESULTS: The well-studied sJIA biomarkers, IL6, IL18 and S100A12, were confirmed to be increased during active sJIA as compared to healthy controls. IL18 was the only factor found to be increased during inactive sJIA as compared to healthy controls. Novel factors, including CASP8, CCL23, CD6, CXCL1, CXCL11, CXCL5, EIF4EBP1, KITLG, MMP1, OSM, SIRT2, SULT1A1 and TNFSF11, were found to be differentially expressed in active and/or inactive sJIA and healthy controls. No significant pathway activation could be predicted based on the limited factor input to the IPA. High Mobility Group Box 1 (HMGB1), a damage associated molecular pattern being involved in a series of inflammatory diseases, was determined to be higher in active sJIA than inactive sJIA. CONCLUSIONS: We could identify a novel set of biomarkers distinguishing active sJIA from inactive sJIA or healthy controls. Our findings enable a better understanding of the immune mechanisms active in sJIA and aid the development of future diagnostic and therapeutic strategies.

Conceptual Framework for Personal Recovery in Patients With Acute Myocardial Infarction.

Background Although there has been movement in cardiology to advance patient-centered approaches to postacute myocardial infarction (AMI) care, work remains to be done in aligning patient preferences with clinical care. Our objective was to characterize patients' experience of AMI and treatment to develop a new conceptual framework of patient-centered recovery in cardiology. Methods and Results We conducted in-depth interviews with people who previously experienced an AMI (2016-2019). The interview focused on participants' experiences of their recovery, which were audio-recorded, transcribed verbatim, and analyzed using a phenomenological framework. The overarching theme described by the 42 participants was feeling like a "different person" after the AMI. This shift manifested itself in both losses and gains, each of which posed new challenges to everyday life. The experience appeared to be an active process requiring people to take responsibility for their health. In terms of loss, participants describe how the AMI threatened their sense of safety and security and led to social isolation, fragility, uncertainty about the future, and difficulty expressing emotions accompanied this new fear. A conceptual framework describing the relationship between AMI, identity change, and functioning was developed. Conclusions Participants experienced the AMI as an unexpected disruption in their lives that had far-reaching effects on their daily functioning, and were resolved in numerous ways. The conceptual framework may assist in providing a theoretical basis for future interventions in cardiology that not only engage and retain patients in care but also improve long-term adherence to secondary prevention and other aspects of self-care.

Therapeutic administration of etoposide coincides with reduced systemic HMGB1 levels in macrophage activation syndrome.

BACKGROUND: Macrophage activation syndrome (MAS) is a potentially fatal complication of systemic inflammation. HMGB1 is a nuclear protein released extracellularly during proinflammatory lytic cell death or secreted by activated macrophages, NK cells, and additional cell types during infection or sterile injury. Extracellular HMGB1 orchestrates central events in inflammation as a prototype alarmin. TLR4 and the receptor for advanced glycation end products operate as key HMGB1 receptors to mediate inflammation. METHODS: Standard ELISA and cytometric bead array-based methods were used to examine the kinetic pattern for systemic release of HMGB1, ferritin, IL-18, IFN-γ, and MCP-1 before and during treatment of four children with critical MAS. Three of the patients with severe underlying systemic rheumatic diseases were treated with biologics including tocilizumab or anakinra when MAS developed. All patients required intensive care therapy due to life-threatening illness. Add-on etoposide therapy was administered due to insufficient clinical response with standard treatment. Etoposide promotes apoptotic rather than proinflammatory lytic cell death, conceivably ameliorating subsequent systemic inflammation. RESULTS: This therapeutic intervention brought disease control coinciding with a decline of the increased systemic HMGB1, IFN-γ, IL-18, and ferritin levels whereas MCP-1 levels evolved independently. CONCLUSION: Systemic HMGB1 levels in MAS have not been reported before. Our results suggest that the molecule is not merely a biomarker of inflammation, but most likely also contributes to the pathogenesis of MAS. These observations encourage further studies of HMGB1 antagonists. They also advocate therapeutic etoposide administration in severe MAS and provide a possible biological explanation for its mode of action.

"Is My Heart Healing?" A Meta-synthesis of Patients' Experiences After Acute Myocardial Infarction.

BACKGROUND: Recovery from acute myocardial infarction (AMI) has been primarily understood in a narrow medical sense. For patients who survive, secondary prevention focuses largely on enhancing clinical outcomes. As a result, there is a lack of descriptive accounts of patients' experiences after AMI and little is known about how people go about the challenge of recovering from such an event. OBJECTIVE: We conducted a meta-synthesis of the available literature on qualitative accounts of patients' experiences after AMI. METHODS: We searched for relevant papers that were descriptive, qualitative accounts of participants' experiences after AMI across 4 electronic databases (April 2016). Using an adapted meta-ethnography approach, we analyzed the findings by translating studies into one another and synthesizing the findings from the studies. RESULTS: After a review of titles/abstracts, reading each article twice in full, and cross-referencing articles, this process resulted in 17 studies with 224 participants (48% women) aged 23 to 90 years. All participants provided a first-person account of an AMI within the 3-day to 25-year time frame. Two major themes emerged that characterized patients' experiences: navigating lifestyle changes and navigating the emotional reaction to the event-consisting of various subthemes. CONCLUSION: Although AMI tends to be seen as a discrete event, participants are left with little professional guidance as to how to negotiate significant, and often discordant, psychosocial changes that have long-lasting effects on their lives, similar to persons with chronic illnesses but without research in place to figure out how to best support them.

Pharmacovigilance in juvenile idiopathic arthritis patients treated with biologic or synthetic drugs: combined data of more than 15,000 patients from Pharmachild and national registries.

BACKGROUND: The availability of methotrexate and the introduction of multiple biological agents have revolutionized the treatment of juvenile idiopathic arthritis (JIA). Several international and national drug registries have been implemented to accurately monitor the long-term safety/efficacy of these agents. This report aims to present the combined data coming from Pharmachild/PRINTO registry and the national registries from Germany (BiKeR) and Sweden. METHODS: Descriptive statistics was used for demographic, clinical data, drug exposure, adverse events (AEs) and events of special interest (ESIs). For the Swedish register, AE data were not available. RESULTS: Data from a total of 15,284 patients were reported: 8274 (54%) from the Pharmachild registry and 3990 (26%) and 3020 (20%) from the German and the Swedish registries, respectively. Pharmachild children showed a younger age (median of 5.4 versus 7.6 years) at JIA onset and shorter disease duration at last available visit (5.3 versus 6.1-6.8) when compared with the other registries. The most frequent JIA category was the rheumatoid factor-negative polyarthritis (range of 24.6-29.9%). Methotrexate (61-84%) and etanercept (24%-61.8%) were the most frequently used synthetic and biologic disease-modifying anti-rheumatic drugs (DMARDs), respectively. There was a wide variability in glucocorticoid use (16.7-42.1%). Serious AEs were present in 572 (6.9%) patients in Pharmachild versus 297 (7.4%) in BiKeR. Infection and infestations were the most frequent AEs (29.4-30.1%) followed by gastrointestinal disorders (11.5-19.6%). The most frequent ESIs were infections (75.3-89%). CONCLUSIONS: This article is the first attempt to present a very large sample of data on JIA patients from different national and international registries and represents the first proposal for data merging as the most powerful tool for future analysis of safety and effectiveness of immunosuppressive therapies in JIA. REGISTRY REGISTRATION: The Pharmachild registry is registered at ClinicalTrials.gov ( NCT01399281 ) and at the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) ( http://www.encepp.eu/encepp/viewResource.htm?id=19362 ). The BiKeR registry is registered at ENCePP ( http://www.encepp.eu/encepp/viewResource.htm?id=20591 ).

High systemic levels of the cytokine-inducing HMGB1 isoform secreted in severe macrophage activation syndrome.

Macrophage activation syndrome (MAS) is a potentially fatal complication of systemic inflammation. High mobility group box 1 (HMGB1) is a nuclear protein extensively leaked extracellularly during necrotic cell death or actively secreted by natural killer (NK) cells, macrophages and additional cells during infection or sterile injury. Extracellular HMGB1 orchestrates key events in inflammation as a prototypic alarmin. The redox states of its three cysteines render the molecule mutually exclusive functions: fully reduced "all-thiol HMGB1" exerts chemotactic activity; "disulfide HMGB1" has cytokine-inducing, toll-like receptor 4 (TLR4)-mediated effects­while terminally oxidized "sulfonyl HMGB1" lacks inflammatory activity. This study examines the kinetic pattern of systemic HMGB1 isoform expression during therapy in four children with severe MAS. Three of the four patients with underlying systemic rheumatic diseases were treated with biologics and two suffered from triggering herpes virus infections at the onset of MAS. All patients required intensive care unit therapy due to life-threatening illness. Tandem mass-spectrometric analysis revealed dramatically increased systemic levels of the cytokine-inducing HMGB1 isoform during early MAS. Disease control coincided with supplementary etoposide therapy initiated to boost apoptotic cell death, when systemic HMGB1 levels drastically declined and the molecule emerged mainly in its oxidized, noninflammatory isoform. Systemic interferon (IFN)-γ and ferritin peaked concomitantly with HMGB1, whereas interleukin (IL)-18 and monocyte chemotactic protein (MCP)-1 levels developed differently. In conclusion, this work provides new insights in HMGB1 biology, suggesting that the molecule is not merely a biomarker of inflammation, but most likely also contributes to the pathogenesis of MAS. These observations encourage further studies of disulfide HMGB1 antagonists to improve outcome of MAS.