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BMC Nephrology May 2024Protein carbamylation, a post-translational protein modification primarily driven by urea, independently associates with adverse clinical outcomes in patients with CKD.... (Comparative Study)
Comparative Study
BACKGROUND
Protein carbamylation, a post-translational protein modification primarily driven by urea, independently associates with adverse clinical outcomes in patients with CKD. Biomarkers used to quantify carbamylation burden have mainly included carbamylated albumin (C-Alb) and homocitrulline (HCit, carbamylated lysine). In this study, we aimed to compare the prognostic utility of these two markers in order to facilitate comparisons of existing studies employing either marker alone, and to inform future carbamylation studies.
METHODS
Both serum C-Alb and free HCit levels were assayed from the same timepoint in 1632 individuals with CKD stages 2-4 enrolled in the prospective Chronic Renal Insufficiency Cohort (CRIC) study. Adjusted Cox proportional hazard models were used to assess risks for the outcomes of death (primary) and end stage kidney disease (ESKD) using each marker. C-statistics, net reclassification improvement, and integrated discrimination improvement were used to compare the prognostic value of each marker.
RESULTS
Participant demographics included mean (SD) age 59 (11) years; 702 (43%) females; 700 (43%) white. C-Alb and HCit levels were positively correlated with one another (Pearson correlation coefficient 0.64). Higher C-Alb and HCit levels showed similar increased risk of death (e.g., the adjusted hazard ratio [HR] for death in the 4th carbamylation quartile compared to the 1st was 1.90 (95% confidence interval [CI] 1.35-2.66) for C-Alb, and 1.89 [1.27-2.81] for HCit; and on a continuous scale, the adjusted HR for death using C-Alb was 1.24 [1.11 to 1.39] per standard deviation increase, and 1.27 [1.10-1.46] using HCit). Both biomarkers also had similar HRs for ESKD. The C-statistics were similar when adding each carbamylation biomarker to base models (e.g., for mortality models, the C-statistic was 0.725 [0.707-0.743] with C-Alb and 0.725 [0.707-0.743] with HCit, both compared to a base model 0.723). Similarities were also observed for the net reclassification improvement and integrated discrimination improvement metrics.
CONCLUSIONS
C-Alb and HCit had similar performance across multiple prognostic assessments. The markers appear readily comparable in CKD epidemiological studies.
Topics: Humans; Female; Citrulline; Male; Protein Carbamylation; Biomarkers; Middle Aged; Renal Insufficiency, Chronic; Aged; Prospective Studies; Risk Assessment; Kidney Failure, Chronic; Prognosis; Proportional Hazards Models; Serum Albumin
PubMed: 38816682
DOI: 10.1186/s12882-024-03619-6 -
Journal For Immunotherapy of Cancer May 2024Artificial intelligence (AI) chatbots have become a major source of general and medical information, though their accuracy and completeness are still being assessed....
BACKGROUND
Artificial intelligence (AI) chatbots have become a major source of general and medical information, though their accuracy and completeness are still being assessed. Their utility to answer questions surrounding immune-related adverse events (irAEs), common and potentially dangerous toxicities from cancer immunotherapy, are not well defined.
METHODS
We developed 50 distinct questions with answers in available guidelines surrounding 10 irAE categories and queried two AI chatbots (ChatGPT and Bard), along with an additional 20 patient-specific scenarios. Experts in irAE management scored answers for accuracy and completion using a Likert scale ranging from 1 (least accurate/complete) to 4 (most accurate/complete). Answers across categories and across engines were compared.
RESULTS
Overall, both engines scored highly for accuracy (mean scores for ChatGPT and Bard were 3.87 vs 3.5, p<0.01) and completeness (3.83 vs 3.46, p<0.01). Scores of 1-2 (completely or mostly inaccurate or incomplete) were particularly rare for ChatGPT (6/800 answer-ratings, 0.75%). Of the 50 questions, all eight physician raters gave ChatGPT a rating of 4 (fully accurate or complete) for 22 questions (for accuracy) and 16 questions (for completeness). In the 20 patient scenarios, the average accuracy score was 3.725 (median 4) and the average completeness was 3.61 (median 4).
CONCLUSIONS
AI chatbots provided largely accurate and complete information regarding irAEs, and wildly inaccurate information ("hallucinations") was uncommon. However, until accuracy and completeness increases further, appropriate guidelines remain the gold standard to follow.
Topics: Humans; Artificial Intelligence; Immunotherapy; Neoplasms; Drug-Related Side Effects and Adverse Reactions
PubMed: 38816231
DOI: 10.1136/jitc-2023-008599 -
The Journal of Pharmacology and... May 2024Ulcerative colitis (UC) is an immune-mediated inflammatory disease that can lead to persistent damage and even cancer without any intervention. Conventional treatments...
Ulcerative colitis (UC) is an immune-mediated inflammatory disease that can lead to persistent damage and even cancer without any intervention. Conventional treatments can alleviate UC symptoms but are costly and even cause various side effects. Tauroursodeoxycholic acid (TUDCA), a secondary bile acid derivative, possesses anti-inflammatory and cytoprotective properties for various diseases, but its potential therapeutic benefits in UC have not been fully explored. Mice were subjected to colitis induction using 3% dextran sulfate sodium (DSS). The therapeutic effect of TUDCA was evaluated by body weight loss, disease activity index (DAI), colon length, and spleen weight ratio. Tissue pathology was assessed using H&E staining, while the levels of pro-inflammatory and anti-inflammatory cytokines in colonic tissue were quantified via enzyme-linked immunosorbent assay (ELISA). Tight junction proteins were detected by immunoblotting and intestinal permeability was assessed using fluorescein isothiocyanate (FITC)-dextran. Moreover, the gut microbiota was profiled using high-throughput sequencing of the 16S rDNA gene. TUDCA alleviated the colitis in mice, involving reduced DAI, attenuated colon and spleen enlargement, ameliorated histopathological lesions, and normalized the levels of pro-inflammatory and anti-inflammatory cytokines. Furthermore, TUDCA treatment inhibited the downregulation of intestinal barrier proteins including ZO-1 and occludin, thus reducing intestinal permeability. The analysis of gut microbiota suggested that TUDCA modulated the dysbiosis in mice with colitis, especially for the remarkable rise in TUDCA exerted a therapeutic efficacy in DSS-induced colitis by reducing intestinal inflammation, protecting intestinal barrier integrity, and restoring gut microbiota balance. This study demonstrates the potential therapeutic benefits of Tauroursodeoxycholic acid (TUDCA) in ulcerative colitis (UC). TUDCA effectively alleviated colitis symptoms in mice, including reducing inflammation, restoring intestinal barrier integrity and the dysbiosis of gut microbiota. This work highlights the promising role of TUDCA as a potentially alternative treatment, offering new insights into managing this debilitating condition.
PubMed: 38816229
DOI: 10.1124/jpet.123.002020 -
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 -
ESC Heart Failure May 2024This study aimed to investigate the prevalence, risk factors and prognostic implications of cognitive impairment in young and middle-aged patients with acute heart...
AIMS
This study aimed to investigate the prevalence, risk factors and prognostic implications of cognitive impairment in young and middle-aged patients with acute heart failure (HF).
METHODS
In a prospective cohort of patients with acute HF, we assessed cognitive function by the Mini-Cog, predictors of the cognitive impairment and its associations with 30 day and 1 year cardiovascular death or HF rehospitalization among young and middle-aged patients (<65 years old).
RESULTS
Among 1958 young and middle-aged patients, the prevalence of cognitive impairment was 19.6%. Predictors of cognitive impairment included older age, females, lower education levels and prior strokes. Compared with patients having normal cognitive function, cognitive impairment was associated with a higher risk of 30 day cardiovascular death or HF rehospitalization [hazard ratio (HR), 1.52, 95% confidence interval (CI), 1.07-2.17, P = 0.02], but not for 1 year cardiovascular death or HF rehospitalization (HR, 1.06, 95% CI, 0.87-1.30, P = 0.55).
CONCLUSIONS
Cognitive impairment is present in a notable proportion of young and middle-aged patients with acute HF and is associated with an increased risk of short-term adverse outcomes. Strategies for screening and intervention for cognitive impairment at a younger age are necessary, particularly for those at high risk.
PubMed: 38816208
DOI: 10.1002/ehf2.14885 -
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 2024An organisation's ability to learn and adapt is key to its long-term performance and success. Although calls to improve learning within and across health organisations... (Review)
Review
INTRODUCTION
An organisation's ability to learn and adapt is key to its long-term performance and success. Although calls to improve learning within and across health organisations and systems have increased in recent years, global health is lagging behind other sectors in attention to learning, and applications of conceptual models for organisational learning to this field are needed. LEVERAGING THE 4I FRAMEWORK: This article proposes modifications to the 4I framework for organisational learning (which outlines the processes of intuition, interpretation, integration and institutionalisation) to guide the creation, retention and exchange of knowledge within and across global health organisations.
PROPOSED EXPANSIONS
Two expansions are added to the framework to account for interorganisational learning in the highly interconnected field: (1) learning pathways across organisations via formal or informal partnerships and communities of practice and (2) learning pathways to and from macro-level 'coordinating bodies' (eg, WHO). Two additional processes are proposed by which interorganisational learning occurs: across partnerships and communities of practice, and linking global health organisations to coordinating bodies. Organisational politics across partnerships, communities of practice and coordinating bodies play an important role in determining why some insights are institutionalised while others are not; as such, the roles of the episodic influence and systemic domination forms of power are considered in the proposed additional organisational learning processes.
DISCUSSION
When lessons are not shared across partnerships, communities of practice or the research community more broadly, funding may continue to support global health studies and programmes that have already been proven ineffective, squandering research and healthcare resources that could have been invested elsewhere. The '6I' framework provides a basis for assessing and implementing organisational learning approaches in global health programming, and in health systems more broadly.
Topics: Humans; Global Health; Learning; Delivery of Health Care; Models, Organizational
PubMed: 38816060
DOI: 10.1136/bmjopen-2023-083830 -
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 2024To map the evidence and scope of physical rehabilitation services delivered by community health workers (CHWs) in sub-Saharan Africa (SSA). (Review)
Review
OBJECTIVES
To map the evidence and scope of physical rehabilitation services delivered by community health workers (CHWs) in sub-Saharan Africa (SSA).
DESIGN
Scoping review DATA SOURCES: PubMed, Scopus, Cochrane Central and databases within the EBSCOhost platform. We also searched other literature sources including reference lists, conference presentations and organisational websites such as WHO, Ministries of Health and non-governmental organisations in SSA.
ELIGIBILITY CRITERIA FOR SELECTION OF STUDIES
Articles presenting evidence on CHWs' delivery of physical rehabilitation services in SSA from September 1978 to June 2023.
DATA EXTRACTION AND SYNTHESIS
Screening was conducted by two reviewers and was guided by the inclusion criteria. Thematic content analysis of data was employed. The results are presented according to the Preferred Reporting Items for Systematic Review and Meta-Analysis extension for scoping reviews.
RESULTS
A total of 6996 articles were identified through various databases, with only 20 studies qualifying for data extraction. Evidence was presented by Eritrea, Ethiopia, Malawi, Mauritius, Namibia, South Africa and Uganda. Assessments, case management, health education, community liaison with support, health systems linkage and administration were the CHWs' scope of practice identified. The review identified home-based, community-based, community and facility-based, home and community-based and facility-based as modes of delivery. The barriers experienced are resources, societal and community attitudes, governance, geographical barriers and delivery capacity, while proximity to the community, positive job attitude and support with collaboration facilitated service delivery.
CONCLUSION
Training and integrating CHWs in national health care systems, with careful selection of existing CHWs, would minimise the barriers faced.
Topics: Humans; Community Health Workers; Africa South of the Sahara; Delivery of Health Care; Rehabilitation
PubMed: 38816054
DOI: 10.1136/bmjopen-2023-079738 -
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