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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 2024The incidence of papillary thyroid cancer (PTC) continues to rise all over the world, 10-15% of the patients have a poor prognosis. Although immunotherapy has been...
BACKGROUND
The incidence of papillary thyroid cancer (PTC) continues to rise all over the world, 10-15% of the patients have a poor prognosis. Although immunotherapy has been applied in clinical practice, its therapeutic efficacy remains far from satisfactory, necessitating further investigation of the mechanism of PTC immune remodeling and exploration of novel treatment targets.
METHODS
This study conducted a single-cell RNA sequencing (scRNA-seq) analysis using 18 surgical tissue specimens procured from 14 patients diagnosed with adjacent tissues, non-progressive PTC or progressive PTC. Key findings were authenticated through spatial transcriptomics RNA sequencing, immunohistochemistry, multiplex immunohistochemistry, and an independent bulk RNA-seq data set containing 502 samples.
RESULTS
A total of 151,238 individual cells derived from 18 adjacent tissues, non-progressive PTC and progressive PTC specimens underwent scRNA-seq analysis. We found that progressive PTC exhibits the following characteristics: a significant decrease in overall immune cells, enhanced immune evasion of tumor cells, and disrupted antigen presentation function. Moreover, we identified a subpopulation of lysosomal associated membrane protein 3 (LAMP3) dendritic cells (DCs) exhibiting heightened infiltration in progressive PTC and associated with advanced T stage and poor prognosis of PTC. LAMP3 DCs promote CD8 T cells exhaustion (mediated by NECTIN2-TIGIT) and increase infiltration abundance of regulatory T cells (mediated by chemokine (C-C motif) ligand 17 (CCL17)-chemokine (C-C motif) receptor 4 (CCR4)) establishing an immune-suppressive microenvironment. Ultimately, we unveiled that progressive PTC tumor cells facilitate the retention of LAMP3 DCs within the tumor microenvironment through NECTIN3-NECTIN2 interactions, thereby rendering tumor cells more susceptible to immune evasion.
CONCLUSION
Our findings expound valuable insights into the role of the interaction between LAMP3 DCs and T-cell subpopulations and offer new and effective ideas and strategies for immunotherapy in patients with progressive PTC.
Topics: Humans; Dendritic Cells; Thyroid Cancer, Papillary; Lysosomal-Associated Membrane Protein 3; Thyroid Neoplasms; Male; Female; Tumor Microenvironment; Middle Aged; Tumor Escape; T-Lymphocyte Subsets; Neoplasm Proteins
PubMed: 38816233
DOI: 10.1136/jitc-2024-008983 -
The Journal of Pharmacology and... May 2024Haloperidol decanoate (HD) was implicated in cognitive impairment. Agomelatine (AGO) was claimed to improve cognition. We aimed at investigating the effects of HD + low-...
High- Dose Agomelatine Combined to Haloperidol Decanoate Improves Cognition, Downregulating , Against Upregulating , Maintaining , Though Alters Cardiac Electrophysiology.
Haloperidol decanoate (HD) was implicated in cognitive impairment. Agomelatine (AGO) was claimed to improve cognition. We aimed at investigating the effects of HD + low- or high- dose AGO on cognition, verifying the melatonergic/dopaminergic-to-the cholinergic hypothesis of cognition and exploring relevant cardiovascular issues in adult male albino rats. HD + high- dose AGO prolonged the step through latency increased the time spent in bright light , reduced the time spent in dim light , and increased the percent of alternations despite the reductions in brain acetylcholine level by -10.67%, Neurodegeneration was minimal, while the mean power frequency of source wave was reduced by -23.39% Concurrently, the relative expression of brain melatonin type-2 receptors was reduced by , against increased expressions of dopamine type- 5 receptors ) and angiopoietin-like 4 ( ). Meanwhile, ECG demonstrated inverted P wave and reduced P wave duration by and PR interval , prolonged RR interval by , increased R wave amplitude by , a depressed ST segment and inverted T wave. In rats administered AGO, HD, or HD+ low- dose AGO, Alzheimer's disease-like neuropathologic features were more evident, accompanied by extensive ECG and neurochemical alterations. HD + high- dose AGO enhances cognition but alters cardiac electrophysiology. Given the issue of cognitive impairment associated with haloperidol decanoate (HD) and the claimed cognitive enhancing activity of agomelatine (AGO), combined high- dose AGO to HD improved cognition of adult male rats, and exhibited minimal neurodegenerative changes. HD+ high- dose AGO was relatively safe regarding triggering epileptogenesis, while altered cardiac electrophysiology. In presence of low ACh, the melatonergic/dopaminergic hypothesis, added to ANGPTL4 and KLF9, could have some clue, thus, offering novel targets for pharmacologic manipulation of cognition.
PubMed: 38816228
DOI: 10.1124/jpet.123.002087 -
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 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 2024Around the world, the disability rights movements and the social model of disability have placed emphasis on the importance of social participation for people with... (Review)
Review
INTRODUCTION
Around the world, the disability rights movements and the social model of disability have placed emphasis on the importance of social participation for people with disability. People with physical disability who have high and complex support needs often need support to access their communities, however, very little is known about the interaction between support and social participation for this population of people. Therefore, the aim of this scoping review is to explore the literature related to the interaction between support and social participation for adults with disability and understand any existing gaps in the literature where further research may be required in order to maximise quality support and social participation.
METHODS AND ANALYSIS
This scoping review will be conducted and reported according to scoping review guidelines outlined by Arksey and O'Malley and later modified by Levac , as well as the Preferred Reporting Items for Systematic Reviews and Meta-Analysis: Extension for Scoping Reviews. Thorough database searches will be conducted across MEDLINE, PsycINFO, CINAHL and Scopus. The search will be limited to papers published in English from 2013 onwards. Citations will be uploaded into Covidence and screened by two independent reviewers. Data extraction will extract data regarding participants, housing, support and study characteristics, as well as qualitative and quantitative data relevant to the research question. A narrative synthesis will be used to summarise findings. A minimum of three consultants with lived experience of disability will be engaged to review and contribute to the final scoping review paper.
ETHICS AND DISSEMINATION
It is anticipated that the findings of this scoping review will be made available in peer-reviewed publications and also in plain language formats to ensure accessibility to a wide range of audiences. Ethics will not be required for this scoping review.
Topics: Humans; Disabled Persons; Social Participation; Social Support; Research Design; Review Literature as Topic
PubMed: 38816056
DOI: 10.1136/bmjopen-2023-083102 -
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