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RMD Open May 2024To compare the effectiveness of a strategy administering baricitinib versus one using TNF-inhibitors (TNFi) in patients with rheumatoid arthritis (RA) after conventional... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
PERFECTRA: a pragmatic, multicentre, real-life study comparing treat-to-target strategies with baricitinib versus TNF inhibitors in patients with active rheumatoid arthritis after failure on csDMARDs.
OBJECTIVE
To compare the effectiveness of a strategy administering baricitinib versus one using TNF-inhibitors (TNFi) in patients with rheumatoid arthritis (RA) after conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) failure in a real-life treat-to-target (T2T) setting.
METHODS
Patients with biological and targeted synthetic DMARD (b/tsDMARD) naïve RA with disease duration ≤5 years without contraindications to b/tsDMARD were randomised to either TNFi or baricitinib when csDMARD failed to achieve disease control in a T2T setting. Changes in clinical and patient-reported outcome measures (PROMs) were assessed at 12-week intervals for 48 weeks. The primary endpoint was non-inferiority, with testing for superiority if non-inferiority is demonstrated, of baricitinib strategy in the number of patients achieving American College of Rheumatology 50 (ACR50) response at 12 weeks. Secondary endpoints included 28-joint count Disease Activity Score with C reactive protein (DAS28-CRP) <2.6, changes in PROMs and radiographic progression.
RESULTS
A total of 199 patients (TNFi, n=102; baricitinib, n=97) were studied. Both study groups were similar. Baricitinib was both non-inferior and superior in achieving ACR50 response at week 12 (42% vs 20%). Moreover, 75% of baricitinib patients achieved DAS28-CRP <2.6 at week 12 compared with 46% of TNFi patients. On secondary outcomes throughout the duration of the study, the baricitinib strategy demonstrated comparable or better outcomes than TNFi strategy. Although not powered for safety, no unexpected safety signals were seen in this relatively small group of patients.
CONCLUSION
Up to present, in a T2T setting, patients with RA failing csDMARDs have two main strategies to consider, Janus Kinases inhibitor versus bDMARDs (in clinical practice, predominantly TNFi). The PERFECTRA study suggested that starting with baricitinib was superior over TNFi in achieving response at 12 weeks and resulted in improved outcomes across all studied clinical measures and PROMs throughout the study duration in these patients.
Topics: Humans; Purines; Sulfonamides; Arthritis, Rheumatoid; Pyrazoles; Azetidines; Male; Female; Middle Aged; Antirheumatic Agents; Aged; Treatment Outcome; Tumor Necrosis Factor Inhibitors; Treatment Failure; Adult; Patient Reported Outcome Measures; Severity of Illness Index
PubMed: 38816210
DOI: 10.1136/rmdopen-2024-004291 -
BMJ Open Diabetes Research & Care May 2024ACE cleaves angiotensin I (Ang I) to angiotensin II (Ang II) inducing vasoconstriction via Ang II type 1 (AT1) receptor, while ACE2 cleaves Ang II to Ang (1-7) causing...
INTRODUCTION
ACE cleaves angiotensin I (Ang I) to angiotensin II (Ang II) inducing vasoconstriction via Ang II type 1 (AT1) receptor, while ACE2 cleaves Ang II to Ang (1-7) causing vasodilatation by acting on the Mas receptor. In diabetic kidney disease (DKD), it is still unclear whether plasma or urine ACE2 levels predict renal outcomes or not.
RESEARCH DESIGN AND METHODS
Among 777 participants with diabetes enrolled in the Urinary biomarker for Continuous And Rapid progression of diabetic nEphropathy study, the 296 patients followed up for 9 years were investigated. Plasma and urinary ACE2 levels were measured by the ELISA. The primary end point was a composite of a decrease of estimated glomerular filtration rate (eGFR) by at least 30% from baseline or initiation of hemodialysis or peritoneal dialysis. The secondary end points were a 30% increase or a 30% decrease in albumin-to-creatinine ratio from baseline to 1 year.
RESULTS
The cumulative incidence of the renal composite outcome was significantly higher in group 1 with lowest tertile of plasma ACE2 (p=0.040). Group 2 with middle and highest tertile was associated with better renal outcomes in the crude Cox regression model adjusted by age and sex (HR 0.56, 95% CI 0.31 to 0.99, p=0.047). Plasma ACE2 levels demonstrated a significant association with 30% decrease in ACR (OR 1.46, 95% CI 1.044 to 2.035, p=0.027) after adjusting for age, sex, systolic blood pressure, hemoglobin A1c, and eGFR.
CONCLUSIONS
Higher baseline plasma ACE2 levels in DKD were protective for development and progression of albuminuria and associated with fewer renal end points, suggesting plasma ACE2 may be used as a prognosis marker of DKD.
TRIAL REGISTRATION NUMBER
UMIN000011525.
Topics: Humans; Male; Female; Diabetic Nephropathies; Angiotensin-Converting Enzyme 2; Biomarkers; Middle Aged; Glomerular Filtration Rate; Peptidyl-Dipeptidase A; Aged; Prognosis; Disease Progression; Follow-Up Studies
PubMed: 38816205
DOI: 10.1136/bmjdrc-2024-004237 -
BMJ Open May 2024This study aimed to analyse the current status, trends and risk factors of disease burden from 1990 to 2019 among Chinese children.
OBJECTIVES
This study aimed to analyse the current status, trends and risk factors of disease burden from 1990 to 2019 among Chinese children.
DESIGN AND PARTICIPANTS
It was a retrospective study on data from the Global Burden of Disease Study 2019 (GBD 2019). Data of disease burden and risk factors were extracted from the GBD 2019. Children were divided into two groups of <5 and 5-14 years. Data were analysed using GBD results query tool, Excel and Pareto analysis.
PRIMARY OUTCOME MEASURES
Disability-Adjusted Life Years (DALYs) and deaths.
RESULTS
The overall disease burden for both children <5 years and those aged 5-14 years significantly decreased from 1990 to 2019. For children aged <5 years, in 2019, the leading cause of deaths and DALYs were 'neonatal disorders', and the top risk factor was 'low birth weight'. Compared with data of 1990, the ranking of causes of deaths and DALYs in 2019 saw the most significant increase for 'HIV/AIDS and sexually transmitted infections' and 'skin and subcutaneous diseases' respectively. Conversely, the ranking of deaths/DALYs causes that dropped most significantly was 'nutritional deficiencies'. For children aged 5-14, in 2019, the leading deaths and DALYs causes were 'unintentional injuries' and 'mental disorders' respectively. The top risk factors were 'alcohol use' and 'short gestation', respectively. The ranking of deaths and DALYs causes rose most significantly were 'HIV/AIDS and sexually transmitted infections' and 'neonatal disorders', respectively. Conversely, the ranking of deaths causes that dropped most significantly were 'other infectious diseases', 'enteric infections' and 'nutritional deficiencies'. For DALYs, the causes that dropped most significantly in ranking were 'other infectious diseases'.
CONCLUSIONS
The disease burden of children has significantly changed from 1990 to 2019, with notable differences between children aged <5 and 5-14 years. To optimise the allocation of health resources, it is necessary to adjust management strategies based on the latest disease burden.
Topics: Humans; Child; Child, Preschool; China; Retrospective Studies; Adolescent; Global Burden of Disease; Risk Factors; Infant; Female; Male; Infant, Newborn; Disability-Adjusted Life Years; Cost of Illness; Cause of Death; Quality-Adjusted Life Years
PubMed: 38816057
DOI: 10.1136/bmjopen-2023-076013 -
BMJ Open May 2024Late-life treatment-resistant depression (LL-TRD) is common and increases risk for accelerated ageing and cognitive decline. Impaired sleep is common in LL-TRD and is a...
INTRODUCTION
Late-life treatment-resistant depression (LL-TRD) is common and increases risk for accelerated ageing and cognitive decline. Impaired sleep is common in LL-TRD and is a risk factor for cognitive decline. Slow wave sleep (SWS) has been implicated in key processes including synaptic plasticity and memory. A deficiency in SWS may be a core component of depression pathophysiology. The anaesthetic propofol can induce electroencephalographic (EEG) slow waves that resemble SWS. Propofol may enhance SWS and oral antidepressant therapy, but relationships are unclear. We hypothesise that propofol infusions will enhance SWS and improve depression in older adults with LL-TRD. This hypothesis has been supported by a recent small case series.
METHODS AND ANALYSIS
SWIPED (Slow Wave Induction by Propofol to Eliminate Depression) phase I is an ongoing open-label, single-arm trial that assesses the safety and feasibility of using propofol to enhance SWS in older adults with LL-TRD. The study is enrolling 15 English-speaking adults over age 60 with LL-TRD. Participants will receive two propofol infusions 2-6 days apart. Propofol infusions are individually titrated to maximise the expression of EEG slow waves. Preinfusion and postinfusion sleep architecture are evaluated through at-home overnight EEG recordings acquired using a wireless headband equipped with dry electrodes. Sleep EEG recordings are scored manually. Key EEG measures include sleep slow wave activity, SWS duration and delta sleep ratio. Longitudinal changes in depression, suicidality and anhedonia are assessed. Assessments are performed prior to the first infusion and up to 10 weeks after the second infusion. Cognitive ability is assessed at enrolment and approximately 3 weeks after the second infusion.
ETHICS AND DISSEMINATION
The study was approved by the Washington University Human Research Protection Office. Recruitment began in November 2022. Dissemination plans include presentations at scientific conferences, peer-reviewed publications and mass media. Positive results will lead to a larger phase II randomised placebo-controlled trial.
TRIAL REGISTRATION NUMBER
NCT04680910.
Topics: Humans; Propofol; Cognitive Dysfunction; Aged; Sleep, Slow-Wave; Electroencephalography; Male; Anesthetics, Intravenous; Depressive Disorder, Treatment-Resistant; Female; Middle Aged; Clinical Trials, Phase I as Topic
PubMed: 38816055
DOI: 10.1136/bmjopen-2024-087516 -
BMJ Open May 2024Compulsory admissions are associated with feelings of fear, humiliation and powerlessness. The number of compulsory admissions in Germany and other high-income countries... (Randomized Controlled Trial)
Randomized Controlled Trial
Effectiveness of a peer-supported crisis intervention to reduce the proportion of compulsory admissions in acute psychiatric crisis interventions in an outreach and outpatient setting: study protocol for an exploratory cluster randomised trial combined with qualitative methods.
INTRODUCTION
Compulsory admissions are associated with feelings of fear, humiliation and powerlessness. The number of compulsory admissions in Germany and other high-income countries has increased in recent years. Peer support has been shown to increase the self-efficacy of individuals with mental health conditions in acute crises and to reduce the use of coercive measures in clinical settings. The objective of this study is to reduce the number of compulsory admissions by involving peer support workers (PSWs) in acute mental health crises in outreach and outpatient settings.
METHODS AND ANALYSIS
This one-year intervention is an exploratory, cluster randomised study. Trained PSWs will join the public crisis intervention services (CIS) in two of five regions (the intervention regions) in the city of Bremen (Germany). PSWs will participate in crisis interventions and aspects of the mental health services. They will be involved in developing and conducting an antistigma training for police officers. The remaining three regions will serve as control regions. All individuals aged 18 and older who experience an acute mental health crisis during the operating hours of the regional CIS in the city of Bremen (around 2000 in previous years) will be included in the study. Semistructured interviews will be conducted with PSWs, 30 patients from control and intervention regions, as well as two focus group discussions with CIS staff. A descriptive comparison between all participants in the intervention and control regions will assess the proportion of compulsory admissions in crisis interventions during the baseline and intervention years, including an analysis of temporal changes.
ETHICS AND DISSEMINATION
This study was approved by the Ethics Committee of the University of Bremen (file 2022-09) on 20 June 2022. The results will be presented via scientific conferences, scientific journals and communicated to policy-makers and practitioners.
TRIAL REGISTRATION NUMBER
DRKS00029377.
Topics: Humans; Crisis Intervention; Peer Group; Germany; Qualitative Research; Mental Disorders; Randomized Controlled Trials as Topic; Commitment of Mentally Ill; Male; Adult; Female; Mental Health Services
PubMed: 38816053
DOI: 10.1136/bmjopen-2023-083385 -
BMJ Open May 2024Depressed mood is a psychological state characterised by sadness or loss of interest in activities. Depressed mood is a highly prevalent symptom across major mental... (Review)
Review
INTRODUCTION
Depressed mood is a psychological state characterised by sadness or loss of interest in activities. Depressed mood is a highly prevalent symptom across major mental disorders. However, there is limited understanding of the burden and management of comorbid depressed mood across major mental disorders. Therefore, this scoping review aims to summarise knowledge on depressed mood among persons with anxiety and/or psychosis. The specific aims are to describe the epidemiology and risk factors of depressed mood as a transdiagnostic target among persons with anxiety and/or psychosis, to identify commonly used outcome measures for depressed mood and to outline initial evidence of psychometric robustness and to identify and summarise the effectiveness of commonly applied depressed mood modification interventions. Our hope is that the proposed review will provide insights into the burden of depressed mood in persons with anxiety and psychosis and help to identify evidence gaps and recommendations for future research.
METHODS AND ANALYSIS
This scoping review will be conducted per Arksey and O'Malley's framework. We will first search for peer-reviewed articles and grey literature published from 2004 to 2023 in PubMed, Scopus, Web of Science, Africa-Wide Information, CINAHL, PsycINFO, Academic Search Premier, Humanities International Complete, Sabinet, SocINDEX, Open Grey and Google Scholar. We will include articles reporting depressed mood (subthreshold depression) among persons with anxiety and/or psychosis. Studies recruiting participants meeting depression diagnostic criteria and those published in non-English languages will be excluded. Two independent researchers will extract the data. We will analyse and chart data collaboratively with researchers with lived experiences of depressed mood.
ETHICS AND DISSEMINATION
This study does not require ethical approval as it is a literature review. The results will be submitted for publication in a peer-reviewed journal.
Topics: Humans; Psychotic Disorders; Depression; Research Design; Review Literature as Topic; Anxiety Disorders; Anxiety
PubMed: 38816047
DOI: 10.1136/bmjopen-2023-077695 -
BMJ Open May 2024To evaluate co-prescribing of sedatives hypnotics and opioids.
OBJECTIVE
To evaluate co-prescribing of sedatives hypnotics and opioids.
DESIGN
Retrospective study evaluating the association of patient characteristics and comorbidities with coprescribing.
SETTING AND PARTICIPANTS
Using the national Merative MarketScan Database between 2005 and 2018, we identified patients who received an incident sedative prescription with or without subsequent, incident opioid prescriptions within a year of the sedative prescription in the USA.
OUTCOME MEASURES
Coprescription of sedative-hypnotics and opioids.
RESULTS
A total of 2 632 622 patients (mean (SD) age, 43.2 (12.34) years; 1 297 356 (62.5%) female) received incident prescriptions for sedatives over the course of the study period. The largest proportion of sedative prescribing included benzodiazepines (71.1%); however, z-drugs (19.9%) and barbiturates (9%) were also common. About 557 845 (21.2%) patients with incident sedatives also received incident opioid prescriptions. About 59.2% of these coprescribed patients received opioids coprescription on the same day. Multivariate logistic regression findings showed that individuals with a comorbidity index score of 1, 2 or ≥3 (aOR 1.19 (95% CI 1.17 to 1.21), 1.17 (95% C 1.14 to 1.19) and 1.25 (95% C 1.2 to 1.31)) and substance use disorder (1.21 (95% C 1.19 to 1.23)) were more likely to be coprescribed opioids and sedatives. The likelihood of receiving both opioid and sedative prescriptions was lower for female patients (aOR 0.93; 95% CI 0.92 to 0.94), and those receiving a barbiturate (aOR 0.3; 95% CI 0.29 to 0.31) or z-drugs (aOR 0.67; 95% CI 0.66 to 0.68) prescriptions at the index date.
CONCLUSIONS
Coprescription of sedatives with opioids was associated with the presence of comorbidities and substance use disorder, gender and types of sedatives prescribed at the index date. Additionally, more than half of the coprescribing occurred on the same day which warrants further evaluation of current prescribing and dispensing best practice guidelines.
Topics: Humans; Hypnotics and Sedatives; Female; Male; Analgesics, Opioid; Retrospective Studies; Adult; Middle Aged; United States; Practice Patterns, Physicians'; Drug Prescriptions; Comorbidity; Benzodiazepines; Logistic Models
PubMed: 38816043
DOI: 10.1136/bmjopen-2023-082339 -
Journal of the International... 2024Recent studies have shown social determinants of health (SDOH) to impact HIV care engagement. This cross-sectional study (Oct 20-Apr 21) assessed the impact of a range...
Recent studies have shown social determinants of health (SDOH) to impact HIV care engagement. This cross-sectional study (Oct 20-Apr 21) assessed the impact of a range of SDOH on HIV care engagement using data from HIV Care Connect, a consortium of three HIV care facility-led programs (Alabama, Florida, Mississippi). The exposures were captured using the PRAPARE (Protocol for Responding to and Assessing Patient Assets, Risks, and Experiences) scale. The outcome was captured using the Index of Engagement in HIV Care scale. Participants (n = 132) were predominantly non-White (87%) and male (52%) with a median age of 41 years. Multivariable logistic regression adjusted for various sociodemographics showed lower HIV care engagement to be associated with being uninsured/publicly insured, having 1-3 unmet needs, socially integrating ≤five times/week, and having stable housing. Factors such as unmet needs, un-/underinsurance, and social integration may be addressed by healthcare and community organizations.
Topics: Humans; Cross-Sectional Studies; Male; HIV Infections; Adult; Social Determinants of Health; Female; Middle Aged; Southeastern United States; Young Adult; Patient Acceptance of Health Care
PubMed: 38816001
DOI: 10.1177/23259582241251728 -
The Journal of Biological Chemistry May 2024Infiltration of monocyte-derived cells to sites of infection and injury is greater in males than in females, due in part, to increased chemotaxis, the process of...
Infiltration of monocyte-derived cells to sites of infection and injury is greater in males than in females, due in part, to increased chemotaxis, the process of directed cell movement toward a chemical signal. The mechanisms governing sexual dimorphism in chemotaxis are not known. We hypothesized a role for the store-operated calcium entry (SOCE) pathway in regulating chemotaxis by modulating leading and trailing edge membrane dynamics. We measured the chemotactic response of bone marrow derived macrophages (BMDMs) migrating towards complement component 5a (C5a). Chemotactic ability was dependent on sex and inflammatory phenotype (M0, M1, M2), and correlated with SOCE. Notably, females exhibited a significantly lower magnitude of SOCE than males. When we knocked out the SOCE gene, stromal interaction molecule 1 (STIM1), it eliminated SOCE and equalized chemotaxis across both sexes. Analysis of membrane dynamics at the leading and trailing edges showed that STIM1 influences chemotaxis by facilitating retraction of the trailing edge. Using BTP2 to pharmacologically inhibit SOCE mirrored the effects of STIM1 knockout, demonstrating a central role of STIM/Orai-mediated calcium signaling. Importantly, by monitoring the recruitment of adoptively transferred monocytes in an in vivo model of peritonitis, we show that increased infiltration of male monocytes during infection is dependent on STIM1. These data support a model in which STIM1-dependent SOCE is necessary and sufficient for mediating the sex difference in monocyte recruitment and macrophage chemotactic ability by regulating trailing edge dynamics.
PubMed: 38815866
DOI: 10.1016/j.jbc.2024.107422 -
The Lancet. Microbe May 2024Serial measurement of virological and immunological biomarkers in patients admitted to hospital with COVID-19 can give valuable insight into the pathogenic roles of...
Early trajectories of virological and immunological biomarkers and clinical outcomes in patients admitted to hospital for COVID-19: an international, prospective cohort study.
BACKGROUND
Serial measurement of virological and immunological biomarkers in patients admitted to hospital with COVID-19 can give valuable insight into the pathogenic roles of viral replication and immune dysregulation. We aimed to characterise biomarker trajectories and their associations with clinical outcomes.
METHODS
In this international, prospective cohort study, patients admitted to hospital with COVID-19 and enrolled in the Therapeutics for Inpatients with COVID-19 platform trial within the Accelerating COVID-19 Therapeutic Interventions and Vaccines programme between Aug 5, 2020 and Sept 30, 2021 were included. Participants were included from 108 sites in Denmark, Greece, Poland, Singapore, Spain, Switzerland, Uganda, the UK, and the USA, and randomised to placebo or one of four neutralising monoclonal antibodies: bamlanivimab (Aug 5 to Oct 13, 2020), sotrovimab (Dec 16, 2020, to March 1, 2021), amubarvimab-romlusevimab (Dec 16, 2020, to March 1, 2021), and tixagevimab-cilgavimab (Feb 10 to Sept 30, 2021). This trial included an analysis of 2149 participants with plasma nucleocapsid antigen, anti-nucleocapsid antibody, C-reactive protein (CRP), IL-6, and D-dimer measured at baseline and day 1, day 3, and day 5 of enrolment. Day-90 follow-up status was available for 1790 participants. Biomarker trajectories were evaluated for associations with baseline characteristics, a 7-day pulmonary ordinal outcome, 90-day mortality, and 90-day rate of sustained recovery.
FINDINGS
The study included 2149 participants. Participant median age was 57 years (IQR 46-68), 1246 (58·0%) of 2149 participants were male and 903 (42·0%) were female; 1792 (83·4%) had at least one comorbidity, and 1764 (82·1%) were unvaccinated. Mortality to day 90 was 172 (8·0%) of 2149 and 189 (8·8%) participants had sustained recovery. A pattern of less favourable trajectories of low anti-nucleocapsid antibody, high plasma nucleocapsid antigen, and high inflammatory markers over the first 5 days was observed for high-risk baseline clinical characteristics or factors related to SARS-CoV-2 infection. For example, participants with chronic kidney disease demonstrated plasma nucleocapsid antigen 424% higher (95% CI 319-559), CRP 174% higher (150-202), IL-6 173% higher (144-208), D-dimer 149% higher (134-165), and anti-nucleocapsid antibody 39% lower (60-18) to day 5 than those without chronic kidney disease. Participants in the highest quartile for plasma nucleocapsid antigen, CRP, and IL-6 at baseline and day 5 had worse clinical outcomes, including 90-day all-cause mortality (plasma nucleocapsid antigen hazard ratio (HR) 4·50 (95% CI 3·29-6·15), CRP HR 3·37 (2·30-4·94), and IL-6 HR 5·67 (4·12-7·80). This risk persisted for plasma nucleocapsid antigen and CRP after adjustment for baseline biomarker values and other baseline factors.
INTERPRETATION
Patients admitted to hospital with less favourable 5-day biomarker trajectories had worse prognosis, suggesting that persistent viral burden might drive inflammation in the pathogenesis of COVID-19, identifying patients that might benefit from escalation of antiviral or anti-inflammatory treatment.
FUNDING
US National Institutes of Health.
PubMed: 38815595
DOI: 10.1016/S2666-5247(24)00015-6