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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 -
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 Diabetes Research & Care May 2024We compared the kidney outcomes between patients with diabetic kidney disease (DKD) aged ≥75 years initiating sodium-glucose cotransporter 2 (SGLT2) inhibitors versus...
INTRODUCTION
We compared the kidney outcomes between patients with diabetic kidney disease (DKD) aged ≥75 years initiating sodium-glucose cotransporter 2 (SGLT2) inhibitors versus other glucose-lowering drugs, additionally presenting with or without proteinuria.
RESEARCH DESIGN AND METHODS
Using the Japan Chronic Kidney Disease Database, we developed propensity scores, implementing a 1:1 matching protocol. The primary outcome included the decline rate in estimated glomerular filtration rate (eGFR), and secondary outcomes incorporated a composite of a 40% reduction in eGFR or progression to end-stage kidney disease.
RESULTS
At baseline, the mean age at initiation of SGLT2 inhibitors (n=348) or other glucose-lowering medications (n=348) was 77.7 years. The mean eGFR was 59.3 mL/min/1.73m and proteinuria was 230 (33.0%) patients. Throughout the follow-up period, the mean annual rate of eGFR change was -0.80 mL/min/1.73 m/year (95% CI -1.05 to -0.54) among SGLT2 inhibitors group and -1.78 mL/min/1.73 m/year (95% CI -2.08 to -1.49) in other glucose-lowering drugs group (difference in the rate of eGFR decline between the groups was 0.99 mL/min/1.73 m/year (95% CI 0.5 to 1.38)), favoring SGLT2 inhibitors (p<0.001). Composite renal outcomes were observed 38 in the SGLT2 inhibitors group and 57 in the other glucose-lowering medications group (HR 0.64, 95% CI 0.42 to 0.97). There was no evidence of an interaction between SGLT2 inhibitors initiation and proteinuria.
CONCLUSIONS
The benefits of SGLT2 inhibitors on renal outcomes are also applicable to older patients with DKD aged≥75 years.
Topics: Humans; Sodium-Glucose Transporter 2 Inhibitors; Female; Male; Aged; Japan; Glomerular Filtration Rate; Diabetic Nephropathies; Databases, Factual; Renal Insufficiency, Chronic; Aged, 80 and over; Diabetes Mellitus, Type 2; Follow-Up Studies; Disease Progression; Hypoglycemic Agents; Prognosis; Treatment Outcome
PubMed: 38816204
DOI: 10.1136/bmjdrc-2024-004115 -
BMJ Open Diabetes Research & Care May 2024The Look AHEAD randomized clinical trial reported that an 8-year intensive lifestyle intervention (ILI) compared with diabetes support and education (DSE) in adults aged... (Randomized Controlled Trial)
Randomized Controlled Trial
Within and post-trial effects of an intensive lifestyle intervention on kidney disease in adults with overweight or obesity and type 2 diabetes mellitus: a secondary analysis of the Look AHEAD clinical trial.
INTRODUCTION
The Look AHEAD randomized clinical trial reported that an 8-year intensive lifestyle intervention (ILI) compared with diabetes support and education (DSE) in adults aged 45-76 years with type 2 diabetes and overweight/obesity delayed kidney disease progression. Here, we report long-term post-intervention follow-up for the trial's secondary outcome of kidney disease.
RESEARCH DESIGN AND METHODS
We examined effects of ILI (n=2570) versus DSE (n=2575) on decline in estimated glomerular filtration rate (eGFR) to <45 mL/min/1.73 m or need for kidney replacement therapy (KRT: dialysis or kidney transplant) during intervention and post-intervention follow-up (median 15.6 years overall).
RESULTS
Incidence of eGFR <45 mL/min/1.73 m was lower in ILI during the intervention (HR=0.80, 95% CI=0.66 to 0.98) but not post-intervention (HR=1.03, 0.86 to 1.23) or overall (HR=0.92, 0.80 to 1.04). There were no significant treatment group differences in KRT. In prespecified subgroup analyses, age×treatment interactions were significant over total follow-up: p=0.001 for eGFR <45 mL/min/1.73 m and p=0.01 for KRT. The 2205 participants aged >60 years at baseline had benefit in both kidney outcomes during intervention and overall (HR=0.75, 0.62 to 0.90 for eGFR <45 mL/min/1.73 m; HR=0.62, 0.43 to 0.91 for KRT). The absolute treatment effects were greater post-intervention: ILI reduced the rate of eGFR <45 mL/min/1.73 m by 0.46 and 0.76 cases/100 person-years during and post-intervention, respectively; and reduced KRT by 0.15 and 0.21 cases/100 person-years. The younger participants experienced no such post-intervention benefits.
CONCLUSIONS
ILI reduced kidney disease progression during and following the active intervention in persons aged ≥60 years. ILI should be considered for reducing kidney disease incidence in older persons with type 2 diabetes.
Topics: Humans; Diabetes Mellitus, Type 2; Middle Aged; Male; Female; Aged; Obesity; Glomerular Filtration Rate; Overweight; Life Style; Follow-Up Studies; Disease Progression; Diabetic Nephropathies; Risk Reduction Behavior; Prognosis
PubMed: 38816203
DOI: 10.1136/bmjdrc-2024-004079 -
BMJ Open May 2024Patients in Nova Scotia do not have access to public prenatal education programming. This study aimed to explore whether care providers find patients are uninformed or...
OBJECTIVE
Patients in Nova Scotia do not have access to public prenatal education programming. This study aimed to explore whether care providers find patients are uninformed or misinformed, and the impact of that on patients and their care providers with a focus on clinical outcomes, time, resources and informed decision-making.
METHODS
Semistructured interviews were conducted with 13 care providers around Halifax and Cape Breton. An interview guide (supplemental) of open-ended questions was used for consistency. A descriptive qualitative approach was employed to describe the contents of the interviews. Each interview was audio-taped and transcribed verbatim by an interdependent transcriber. Transcripts were analysed using established techniques in qualitative descriptive research including coding, grouping, detailing and comparing the data using NVivo V.12 software. A co-coder (SS) independently coded two interviews for inter-rater reliability.
RESULTS
The study revealed six themes: (1) concern for a significant population of Nova Scotians experiencing pregnancy, birth and postpartum uninformed and misinformed, (2) consequences for patients who are uninformed and misinformed, (3) more time and resources spent on care for patients who are uninformed or misinformed, (4) patients and their care providers need a publicly available education programme, particularly vulnerable populations, (5) emphasis on programme quality and disappointment with the programme previously been in place and (6) recommendations for an effective prenatal education programme for Nova Scotians.
CONCLUSIONS
This study shows care providers believe a public prenatal education programme could improve health literacy in Nova Scotia. Patients are seeking health education, but it is not accessible to all and being uninformed or misinformed negatively impacts patients' experiences and outcomes. This study revealed excess time and resources are being spent on individualised prenatal education by care providers with high individual and system-wide cost and explored the complicated process of providing patient-centred care for people who are uninformed or misinformed.
Topics: Humans; Nova Scotia; Qualitative Research; Female; Pregnancy; Prenatal Education; Health Personnel; Adult; Interviews as Topic; Health Services Accessibility; Prenatal Care; Communication; Male; Decision Making
PubMed: 38816061
DOI: 10.1136/bmjopen-2024-085140 -
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 2024Multiple sclerosis (MS) is an immune-mediated demyelinating disease with a significant burden of neuropsychiatric sequelae. These symptoms, including depression and...
INTRODUCTION
Multiple sclerosis (MS) is an immune-mediated demyelinating disease with a significant burden of neuropsychiatric sequelae. These symptoms, including depression and anxiety, are predictors of morbidity and mortality in people with MS. Despite a high prevalence of obsessive-compulsive disorder in MS, potentially shared pathophysiological mechanisms and overlap in possible treatments, no review has specifically examined the clinical dimensions of people with obsessive-compulsive and related disorders (OCRD) and MS. In this scoping review, we aim to map the available knowledge on the clinical dimensions of people with co-occurring OCRD and MS. Understanding the characteristics of this population in greater detail will inform more patient-centred care and create a framework for future studies.
METHODS AND ANALYSIS
We developed a search strategy to identify all articles that include people with co-occurring OCRD and MS. The search strategy (extending to the grey literature) was applied to MEDLINE, Embase, PsycINFO, Cochrane Central Register of Controlled Trials, CINAHL, Web of Science and ProQuest Dissertations & Theses. Records will undergo title and abstract screening by two independent reviewers. Articles meeting inclusion criteria based on title and abstract screening will go on to full-text review by the two independent reviewers. After reaching a consensus about articles for inclusion in the final review, data will be extracted using a standardised extraction form. The extracted data will include clinical characteristics of patients such as age, gender, medication use and severity of MS, among others.
ETHICS AND DISSEMINATION
This scoping review does not require research ethics approval. Results will be shared at national and/or international conferences, in a peer-reviewed journal publication, in a plain language summary and in a webinar for the general public.
Topics: Humans; Multiple Sclerosis; Obsessive-Compulsive Disorder; Research Design; Review Literature as Topic; Comorbidity
PubMed: 38816059
DOI: 10.1136/bmjopen-2023-074929