MicroRNA-17 Modulates Regulatory T Cell Function by Targeting Co-regulators of the Foxp3 Transcription Factor.

Regulatory T (Treg) cells are important in maintaining self-tolerance and immune homeostasis. The Treg cell transcription factor Foxp3 works in concert with other co-regulatory molecules, including Eos, to determine the transcriptional signature and characteristic suppressive phenotype of Treg cells. Here, we report that the inflammatory cytokine interleukin-6 (IL-6) actively repressed Eos expression through microRNA-17 (miR-17). miR-17 expression increased in Treg cells in the presence of IL-6, and its expression negatively correlated with that of Eos. Treg cell suppressive activity was diminished upon overexpression of miR-17 in vitro and in vivo, which was mitigated upon co-expression of an Eos mutant lacking miR-17 target sites. Also, RNAi of miR-17 resulted in enhanced suppressive activity. Ectopic expression of miR-17 imparted effector-T-cell-like characteristics to Treg cells via the de-repression of genes encoding effector cytokines. Thus, miR-17 provides a potent layer of Treg cell control through targeting Eos and additional Foxp3 co-regulators.

Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease: known knowns and known unknowns.

The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease (CKD) updates the KDIGO 2012 guideline and has been developed with patient partners, clinicians, and researchers around the world, using robust methodology. This update, based on a substantially broader base of evidence than has previously been available, reflects an exciting time in nephrology. New therapies and strategies have been tested in large and diverse populations that help to inform care; however, this guideline is not intended for people receiving dialysis nor those who have a kidney transplant. The document is sensitive to international considerations, CKD across the lifespan, and discusses special considerations in implementation. The scope includes chapters dedicated to the evaluation and risk assessment of people with CKD, management to delay CKD progression and its complications, medication management and drug stewardship in CKD, and optimal models of CKD care. Treatment approaches and actionable guideline recommendations are based on systematic reviews of relevant studies and appraisal of the quality of the evidence and the strength of recommendations which followed the "Grading of Recommendations Assessment, Development, and Evaluation" (GRADE) approach. The limitations of the evidence are discussed. The guideline also provides practice points, which serve to direct clinical care or activities for which a systematic review was not conducted, and it includes useful infographics and describes an important research agenda for the future. It targets a broad audience of people with CKD and their healthcare, while being mindful of implications for policy and payment.

Metformin induces lactate accumulation and accelerates renal cyst progression in Pkd1-deficient mice.

Metabolic reprogramming is a potential treatment strategy for autosomal dominant polycystic kidney disease (ADPKD). Metformin has been shown to inhibit the early stages of cyst formation in animal models. However, metformin can lead to lactic acidosis in diabetic patients with advanced chronic kidney disease, and its efficacy in ADPKD is still not fully understood. Here, we investigated the effect of metformin in an established hypomorphic mouse model of PKD that presents stable and heritable knockdown of Pkd1. The Pkd1 miRNA transgenic mice of both genders were randomized to receive metformin or saline injections. Metformin was administrated through daily intraperitoneal injection from postnatal day 35 for 4 weeks. Unexpectedly, metformin treatment at a concentration of 150 mg/kg increased disease severity, including kidney-to-body weight ratio, cystic index and plasma BUN levels, and was associated with increased renal tubular cell proliferation and plasma lactate levels. Functional enrichment analysis for cDNA microarrays from kidney samples revealed significant enrichment of several pro-proliferative pathways including ß-catenin, hypoxia-inducible factor-1α, protein kinase Cα and Notch signaling pathways in the metformin-treated mutant mice. The plasma metformin concentrations were still within the recommended therapeutic range for type 2 diabetic patients. Short-term metformin treatment in a second Pkd1 hypomorphic model (Pkd1RC/RC) was however neutral. These results demonstrate that metformin may exacerbate late-stage cyst growth associated with the activation of lactate-related signaling pathways in Pkd1 deficiency. Our findings indicate that using metformin in the later stage of ADPKD might accelerate disease progression and call for the cautious use of metformin in these patients.

Gut flora metagenomic analysis coupled with metabolic and deep immune profiling in chronic kidney disease.

BACKGROUND: Perturbation of gut microbiota has been linked to chronic kidney disease (CKD), which was correlated with a sophisticated milieu of metabolic and immune dysregulation. METHODS: To clarify the underlying host-microbe interaction in CKD, we performed multi-omics measurements, including systems-level gut microbiome, targeted serum metabolome and deep immunotyping, in a cohort of patients and non-CKD controls. RESULTS: Our analyses on functional profiles of the gut microbiome showed a decrease in the diversity and abundance of carbohydrate-active enzyme (CAZyme) genes but an increase in the abundance of antibiotic resistance, nitrogen cycling enzyme and virulence factor genes in CKD. Moreover, models generated using measurements of serum metabolites (amino acids, bile acids and short-chain fatty acids) or immunotypes were predictive of renal impairment but less so than many of the functional profiles derived from gut microbiota, with the CAZyme genes being the top-performing model to accurately predict the early stage of diseases. In addition, co-occurrence analyses revealed coordinated host-microbe relationships in CKD. Specifically, the highest fractions of significant correlations were identified with circulating metabolites by several taxonomic and functional profiles of gut microbiome, while immunotype features were moderately associated with the abundance of microbiome-encoded metabolic pathways and serum levels of amino acids (e.g. B cell cluster tryptophan and B cell cluster tryptophan metabolism). CONCLUSION: Overall, our multi-omics integration revealed several signatures of systems-level gut microbiome in robust associations with host-microbe co-metabolites and renal function, which may have aetiological and diagnostic implications in CKD.

Global data monitoring systems and early identification for kidney diseases.

BACKGROUND: Data monitoring and surveillance systems are the cornerstone for governance and regulation, planning, and policy development for chronic disease care. Our study aims to evaluate health systems capacity for data monitoring and surveillance for kidney care. METHODS: We leveraged data from the third iteration of the International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA), an international survey of stakeholders (clinicians, policymakers and patient advocates) from 167 countries conducted between July and September 2022. ISN-GKHA contains data on availability and types of kidney registries, the spectrum of their coverage, as well as data on national policies for kidney disease identification. RESULTS: Overall, 167 countries responded to the survey, representing 97.4% of the global population. Information systems in forms of registries for dialysis care were available in 63% (n = 102/162) of countries, followed by kidney transplant registries (58%; n = 94/162), and registries for non-dialysis chronic kidney disease (19%; n = 31/162) and acute kidney injury (9%; n = 14/162). Participation in dialysis registries was mandatory in 57% (n = 58) of countries; however, in more than half of countries in Africa (58%; n = 7), Eastern and Central Europe (67%; n = 10), and South Asia (100%; n = 2), participation was voluntary. The least-reported performance measures in dialysis registries were hospitalization (36%; n = 37) and quality of life (24%; n = 24). CONCLUSIONS: The variability of health information systems and early identification systems for kidney disease across countries and world regions warrants a global framework for prioritizing the development of these systems.

The Influencing Factors of Implementation in Emergency Medical Service Systems - A Scoping Review.

OBJECTIVES: Emergency medical services (EMS) provide health care in situations with limited time and resources. Challenges arise when introducing novel medications, treatments, or technologies or modifying existing practices in these settings. Effective implementation strategies are pivotal for their success. This study aims to identify and categorize potential facilitators and barriers in the implementation of prehospital EMS through a review of relevant research articles. METHODS: We searched PubMed and EMbase to identify studies published before December 2023, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for our search strategy and scoping review. We included original articles written in English that report on the factors that influence the implementation in prehospital settings. We extracted and categorized the factors into different themes. RESULTS: Out of the 371 retrieved papers, we selected 19 (5%) for inclusion in this review. We extracted 46 influencing factors from the selected articles and categorized them into ten themes: (1) Outer system, (2) Inner system, (3) Practitioner characteristics, (4) Resources, (5) Communication and collaboration, (6) Patient factors, (7) Intervention characteristics, (8) De-implementation of prior practices, (9) Logistical issues, and (10) Quality improvement. CONCLUSIONS: This study examined the literature on EMS implementation factors and proposed a 10-theme EMS model framework. Key factors include training/education, equipment/tools, communication with hospitals, and practitioners' attitudes.

Transcriptome landscape reveals the chronic inflammatory response in kidneys affected by the combinatory effect of leptospirosis and nephrotoxic injury.

Leptospirosis can cause chronic kidney damage, putting patients at risk of additional kidney injury due to other factors that can lead to renal failure. To understand the combined effect, the transcriptome profiles of kidneys of mice with adenine-induced and chronically Leptospira-infected kidneys were analysed. Chronic inflammation and T-helper 17 immune responses were activated and a high-level expression of Indoleamine 2,3-dioxygenase 1 protein was found. The results indicate that the combination may predispose patients to chronic inflammation, kidney function disruption, and symptoms seen in progressive chronic kidney disease (CKD). Furthermore, immunometabolic regulation may contribute to renal injury caused by chronic leptospirosis with secondary nephrotoxic injury. This study identified several significantly disrupted genes that could serve as potential targets for the diagnosis or treatment of CKD. Our work provides insight into the combined effect of leptospirosis and secondary kidney damage and the molecular basis for rapid progression of CKD.

Development, implementation, and evaluation of entrustable professional activities (EPAs) for medical radiation technologists in Taiwan: a nationwide experience.

BACKGROUND: Competency-based medical education (CBME) is an outcomes-oriented approach focused on developing competencies that translate into clinical practice. Entrustable professional activities (EPAs) bridge competency assessment and clinical performance by delineating essential day-to-day activities that can be entrusted to trainees. EPAs have been widely adopted internationally, but not yet implemented for medical radiation professionals in Taiwan. MATERIALS AND METHODS: A nationwide consensus process engaged 97 experts in radiation technology education representing diagnostic radiography, radiation therapy, and nuclear medicine. Preliminary EPAs were developed through the focus group discussion and the modified Delphi method. The validity of these EPAs was evaluated using the QUEPA and EQual tools. RESULTS: Through iterative consensus building, six core EPAs with 18 component observable practice activities (OPAs) in total were developed, encompassing routines specific to each radiation technology specialty. QUEPA and EQual questionnaire data verified these EPAs were valid, and of high quality for clinical teaching and evaluation. CONCLUSION: The consensus development of tailored EPAs enables rigorous competency assessment during medical radiation technology education in Taiwan. Further expansion of EPAs and training of clinical staff could potentially enhance care quality by producing competent professionals.

A Cluster-Randomized Control Study Comparing a New Cue "Two Compressions per Second" with "100-120 Compressions per Minute" in Training of Bystander Cardiopulmonary Resuscitation.

BACKGROUND: Chest compression at a rate of 100-120 compressions per minute (cpm) during cardiopulmonary resuscitation (CPR) is associated with the highest survival rates. Performing compressions at a faster rate may exhaust the rescuers. OBJECTIVES: To compare a new cue of 'two compressions per second' to the traditional cue of '100-120 compressions per minute' on compression rate in CPR training. METHODS: In this cluster-randomized study, students from two senior high schools were assigned into two groups. For the experimental group, the cue for the compression rate was 'two compressions per second'. For the control group, the cue was '100-120 cpm'. Except the different cues, all participants underwent the same standardized CPR training program. Verbal compression rate-related feedback was not obtained during practice. Quality indicators of chest compressions were recorded by a sensorized manikin. The primary outcome measure was mean compression rate at course conclusion. The secondary outcome measures were individual compression quality indicators at course conclusion and 3 months after training. RESULTS: We included 164 participants (85 participants, experimental group; 79 participants, control group). Both groups had similar characteristics. The experimental group had a significantly lower mean compression rate at course conclusion (144.3 ± 16.17 vs. 152.7 ± 18.38 cpm, p = 0.003) and at 3 months after training (p = 0.09). The two groups had similar mean percentage of adequate compression rate (≥ 100 cpm), mean compression depth, and mean percentage of complete recoil at course conclusion and 3 months after training. CONCLUSION: The new cue of 'two compressions per second' resulted in participants having a lower compression rate, although it still exceeded 120 cpm.

Identification of Endothelial Cell Protein C Receptor by Urinary Proteomics as Novel Prognostic Marker in Non-Recovery Kidney Injury.

Acute kidney injury is a common and complex complication that has high morality and the risk for chronic kidney disease among survivors. The accuracy of current AKI biomarkers can be affected by water retention and diuretics. Therefore, we aimed to identify a urinary non-recovery marker of acute kidney injury in patients with acute decompensated heart failure. We used the isobaric tag for relative and absolute quantification technology to find a relevant marker protein that could divide patients into control, acute kidney injury with recovery, and acute kidney injury without recovery groups. An enzyme-linked immunosorbent assay of the endothelial cell protein C receptor (EPCR) was used to verify the results. We found that the EPCR was a usable marker for non-recovery renal failure in our setting with the area under the receiver operating characteristics 0.776 ± 0.065; 95%CI: 0.648-0.905, (p < 0.001). Further validation is needed to explore this possibility in different situations.