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 AND HYPOTHESIS: 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 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 functional profiles derived from gut microbiota, with the CAZyme genes being the top performing model to accurately predict 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 be of etiological and diagnostic implications in CKD.

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.

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.

Tumor necrosis factor-alpha blockade suppresses BK polyomavirus replication.

PURPOSE: BK Polyomavirus (BKPyV) infection manifests as renal inflammation and can cause kidney damage. Tumor necrosis factor-α (TNF-α) is increased in renal inflammation and injury. The aim of this study was to investigate the effect of TNF-α blockade on BKPyV infection. METHODS: Urine specimens from 22 patients with BKPyV-associated nephropathy (BKPyVN) and 35 non-BKPyVN kidney transplant recipients were analyzed. RESULTS: We demonstrated increased urinary levels of TNF-α and its receptors, TNFR1 and TNFR2, in BKPyVN patients. Treating BKPyV-infected human proximal tubular cells (HRPTECs) with TNF-α stimulated the expression of large T antigen and viral capsid protein-1 mRNA and proteins and BKPyV promoter activity. Knockdown of TNFR1 or TNFR2 expression caused a reduction in TNF-α-stimulated viral replication. NF-κB activation induced by overexpression of constitutively active IKK2 significantly increased viral replication and the activity of the BKPyV promoter containing an NF-κB binding site. The addition of a NF-κB inhibitor on BKPyV-infected cells suppressed viral replication. Blockade of TNF-α functionality by etanercept reduced BKPyV-stimulated expression of TNF-α, interleukin-1ß (IL-1ß), IL-6 and IL-8 and suppressed TNF-α-stimulated viral replication. In cultured HRPTECs and THP-1 cells, BKPyV infection led to increased expression of TNF-α, interleukin-1 ß (IL-1ß), IL-6 and TNFR1 and TNFR2 but the stimulated magnitude was far less than that induced by poly(I:C). This may suggest that BKPyV-mediated autocrine effect is not a major source of TNFα. CONCLUSION: TNF-α stimulates BKPyV replication and inhibition of its signal cascade or functionality attenuates its stimulatory effect. Our study provides a therapeutic anti-BKPyV target.

Comparing the effects of blended learning and traditional instruction on basic life support for laypersons: A randomized controlled trial.

BACKGROUND/PURPOSE: Blended learning offers the advantages of both instructor-led and self-instruction methods in basic life support (BLS). Our study aims to compare the effects of blended learning with those of traditional instructor-led methods on the performance of laypersons taking BLS courses. METHODS: A total of 108 participants were randomly assigned to three groups: traditional instruction (group A, n = 36), blended learning with two rounds of practice (group B, n = 36), and blended learning with three rounds of practice (group C, n = 36). Group A received a 90-min lecture and a 30-min hands-on practice session using a manikin and a metronome. Participants in groups B and C received 18-min standardized online video lessons and performed hands-on practice twice and thrice, respectively. The primary outcome was chest compression at a correct speed (100-120 compressions per min) after the training course. Secondary outcomes included knowledge test scores, attitudes and confidence, and individual skill performance after training. RESULTS: Patient characteristics were similar between the groups. Blended learning with practicing thrice resulted in the highest compressions at a correct speed (group A vs. B vs. C, 68.09 vs 80.03 vs 89.42, p = 0.015) and the shortest average hands-off time (group A vs. B vs. C, 1.12 vs 0.86 vs 0.17 s, p = 0.015). Both blended groups performed better in confirming environmental safety (p < 0.001). No differences in scores of the knowledge test, attitude, or confidence were noted among the three groups. CONCLUSION: Blended learning with three rounds of hands-on practice may be considered an alternative teaching method.

Effectiveness of tutor shadowing on faculty development in problem-based learning.

BACKGROUND: To enhance tutors' teaching skills, tutor shadowing for novice tutors of problem-based learning (PBL) in addition to conventional faculty development (FD) was applied. This study aimed to develop a tutoring-skill scale (TS-scale) and evaluate the effect of shadowing on PBL tutors. METHODS: This study employed a before-and-after study design with three phases. In phase 1, a TS-scale was elaborated. A validity examination was performed in phase 2. Phase 3 was a study of the effectiveness using a TS-scale survey of novice PBL tutors before and after the FD course. The FD course for novice PBL tutors included an FD workshop and PBL shadowing activities. RESULTS: A TS-scale with a 32-item questionnaire of self-rated confidence for PBL tutors was identified in phase 1. In phase 2, 7 experienced specialists in medical education were invited to evaluate the content validity of the scale. The item content validity index (I-CVI) ranged from 0.86 to 1, and the scale-CVI (S-CVI) was 0.95. A total of 85 novice PBL tutors completed the TS-scale before the FD course, yielding a Cronbach's alpha of 0.98. An exploratory factor analysis with varimax rotation was performed. The twenty-four items with significant loadings greater than 0.5 were incorporated into a new TS-scale and were grouped into three factors: student contact, medical expertise, and teaching expertise. In phase 3, 76 novice PBL tutors completed the 24-item TS-scale before (pretest) and after (posttest) the FD course. Their self-rated confidence improved significantly across the three factors after the FD course. The pretest and posttest scores did not differ according to the tutors' gender, the grades they taught, or their specialty background. CONCLUSIONS: Novice PBL tutors benefit from FD that incorporates tutor shadowing in the 3 key domains of tutoring competencies. The TS-scale developed in this study can be applied in future research on FD design.

Moving from tangibility toward digitalization: investigating team dynamics and facilitator support among medical students in conventional and digital small-group tutorials.

BACKGROUND: Small group tutorials (SGT) promotes self-directed learning and is widely used in medical education. The coronavirus pandemic (COVID-19) has accelerated the trend toward SGT digitalization, with unclear effect. We hypothesize that team dynamics and facilitator support influence SGT satisfaction in digital versus conventional SGT. METHODS: During the spring semester of year 2021, medical students (the second, third, and fourth year; n = 433) participating in conventional face-to-face and digital SGT curricula were enrolled. Participating students completed the collaborative learning attitude scale (including team dynamics, team acquaintance, and facilitator support dimensions) and teamwork satisfaction scale, previously validated for small-group collaborative learning, and chose preference between conventional or digital SGT in future curricula. Exploratory factor analysis (EFA) was performed to extract the essential structural factors of these scales. Paired t-tests were conducted to compare differences in different dimensions and satisfaction between the conventional and digital SGT settings. Two sets of multiple regression analyses were done; one with team satisfaction scale results and the other with preference for digital SGT as the dependent variable were used to evaluate determinants of these two variables. RESULTS: The EFA results revealed that the original collaborative learning attitude scale was concentrated on two dimensions: team dynamics and facilitator support. No significant differences were noted between the SGT settings for the two dimensions and teamwork satisfaction. Regression analyses showed that teamwork dynamics was independently correlated with teamwork satisfaction in both conventional and digital SGT. Facilitator support was positively correlated with teamwork satisfaction in conventional, but not digital SGT. Higher teamwork satisfaction was an important determinant of preference for digital SGT among medical students. CONCLUSIONS: Team dynamics were closely linked to teamwork satisfaction among medical students in both conventional and digital SGT, while the role of facilitator support became less obvious during digital SGT.

"Glocalization" in medical education: A framework underlying implementing CBME in a local context.

BACKGROUND/PURPOSE: The implementation of competency-based medical education is a social construction process within a local and cultural context. However, little is known about the process of adaptation to different systems, known as "glocalization". We analyzed the documents in the development of a milestone project from adapting global standards into a local context and identified a framework underlying this process. METHODS: Taiwan Society of Emergency Medicine (TSEM) had developed learning milestones based on the ACGME's version through series of consensus methods including committee work, nominal group technique (NGT), and a modified Delphi method. We applied qualitative content analysis to characterize the evolution of the three versions of TSEM and the original ACGME milestones documents and to explore the meaning behind the differences revealed by the glocalization process. RESULTS: We found 48 differences between ACGME and TSEM milestones. Among these differences, one was made by committee work, 44 came from NGT, and 3 were from the modified Delphi process. Two themes and seven sub-themes emerged from the coding process to explain the contextualization process of the milestones. CONCLUSION: We identified a framework that incorporates local expression and local needs into the process called glocalization through which global models of competency-based standards could be optimally implemented in a local context with different systems and cultures.

Fully digital problem-based learning for undergraduate medical students during the COVID-19 period: Practical considerations.

Digital problem-based learning (PBL) was originally introduced as a means to improve student engagement and increase flexibility. However, its use becomes mandatory during the coronavirus disease 2019 (COVID-19) period, accelerating changes in medical education. Few elaborated on the implementation details of digital PBL curricula. Technical guidance can be important but under-recognized prerequisite of a successful digital PBL session. In National Taiwan University College of Medicine, we established a digital PBL curriculum and previously validated a confidence questionnaire for surveying undergraduate students receiving digital PBL sessions. In this opinion piece, we gleaned multiple procedural details from our experiences based on students'/tutors' feedback, which we summarized in a 5″W″ recommendations (Who), timing/duration (When), location (Where), software/hardware/topics (What), and evaluation aspects (Why). Suggestions on how to optimally prepare for digital PBL session are also provided. We believe that these tips can further facilitate the wide adoption of digital PBL.

Developing a competency-based framework for resident-as-teacher.

BACKGROUND/PURPOSE: Residents play an important role as teachers of junior colleagues and medical students. Clinical teaching also helps residents in clinical learning. However, the skills required for residents to be competent teachers are rarely described systemically. Beyond the widely adopted six core competencies for postgraduate training by the Accreditation Council for Graduate Medical Education (ACGME), the teaching competencies should be further developed, and the milestones should be clearly defined to serve as better references for resident training programs. METHODS: Twenty members, including five experts from major teaching hospitals across Taiwan and 15 from a public medical center, were invited to a workgroup to collaboratively develop a competency-based framework. The development process was similar to that suggested by the ACGME. The teaching competencies framework were drafted by an experienced physician educator. The draft was sent to each group member, and feedback was collected. Two workgroup meetings were held for consensus formation. The contents of the teaching competencies of residents were confirmed after two rounds of revision. The outline of the framework was also reported at an international meeting in September 2019. RESULTS: Two core competencies, instruction and assessment, with three sub-competencies and 37 milestones, were adopted in the final edition of resident-as-teacher competencies. The sub-competencies were "dissemination of knowledge" and "teaching of procedural skills" for instruction, and "direct observation and feedback" for assessment. CONCLUSION: A competency-based framework for resident-as-teacher was developed. The framework can be applied in combination with other existing competencies for holistic postgraduate training programs.

Characteristics, prognostic factors, and chronological trends of out-of-hospital cardiac arrests with shockable rhythms in Taiwan - A 7-year observational study.

BACKGROUND: The study aimed to explore the characteristics, predictors, and chronological trends of outcomes for adult out-of-hospital cardiac arrests (OHCAs) with shockable rhythms. METHODS: A 7-year, community-wide observational study using an Utstein-style registry was conducted. Patients who were not transported, those who experienced trauma and those who lacked electronic electrocardiography data were excluded; those with initial shockable rhythms of ventricular fibrillation (VF) or pulseless ventricular tachycardia (pVT) were included. Outcomes were survival of discharge (SOD) and favorable neurological status (CPC 1-2). The outcome predictors, chronological trends, and their relationship with system interventions were analyzed. RESULTS: Of the 1544 shockable OHCAs (incidence 12.6%) included, 97.6% had VF and 2.4% had pVT. VF showed better outcomes than pVT. Predictors for both outcomes (SOD; CPC 1-2) were chronological change (adjusted odds ratio [aOR]: 1.133; 1.176), younger age (aOR: 0.973; 0.967), shorter response time (aOR: 0.998; 0.999), shorter scene time (aOR: 0.999; 0.999), witnessed collapse (aOR: 1.668; 1.670), and bystander cardiopulmonary resuscitation (BCPR) (aOR: 1.448; 1.576). Predictors for only SOD were public location (aOR: 1.450) and successful prehospital defibrillation (aOR: 3.374). The use of the supraglottic airway was associated with adverse outcomes. Chronologically with system interventions, BCPR rate, the proportion of shockable OHCA, and improved neurological outcomes increased over time. CONCLUSION: The incidence of shockable OHCA remained low in Asian community. VF showed better outcomes than pVT. Over time, the incidence of shockable rhythm, BCPR rate and patient outcomes did improve with health system interventions. The number of prehospital defibrillations did not predict outcomes.

Effects of Suramin on Polycystic Kidney Disease in a Mouse Model of Polycystin-1 Deficiency.

The aberrant activation of the purinergic signaling pathway has been shown to promote cyst growth and fluid secretion in autosomal dominant polycystic kidney disease (ADPKD). Suramin is an anti-parasitic drug that has strong anti-purinergic properties. Whether suramin could have a therapeutic effect on ADPKD has not been fully investigated. We examined the effect of suramin on cyst progression in a Pkd1 microRNAs transgenic mouse model that presented stable Pkd1 knockdown and moderate disease progression. The Pkd1-deficient mice were treated with suramin (60 mg/kg) by intraperitoneal injection twice a week from postnatal days 35 to 90. Kidney-to-body weight ratios, cyst indices, and blood urea nitrogen (BUN) levels were measured. Cell proliferation and macrophage infiltration were determined by immunohistochemistry. The suramin-treated group had significantly lower renal cyst densities, cell proliferation, and macrophage infiltration compared with saline-treated controls. Suramin significantly inhibited ERK phosphorylation and the expression of Il1b, Il6, Nlrp3, Tgfb, Fn1, P2rx7, and P2ry2 mRNAs in the kidneys. However, BUN levels remained high despite the reduction in cyst growth. Furthermore, plasma cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) levels were significantly higher in the suramin-treated group compared with the control group. Periodic acid-Schiff staining revealed degenerative changes and epithelial cell vacuolation in the non-cystic renal tubules, which indicated phospholipidosis following suramin treatment. These results suggest that suramin may reduce renal cyst growth and inflammation, but the associated tubular cell injuries could limit its therapeutic potential. Other purinergic receptor antagonists with less nephrotoxicity may deserve further investigation for the treatment of ADPKD.

Duodenal Ulcer with Massive Gastrointestinal Hemorrhage as an Initial Manifestation in Multiple Myeloma with Extramedullary Disease: A Case Report.

Plasma cell neoplasms are characterized by dysregulated proliferation of mature B cells, which can present with either single (solitary plasmacytoma) or systemic (multiple myeloma (MM)) involvement. MM with extramedullary plasmacytoma (EMP) is a rare disease that accounts for approximately 3-5% of all plasmacytomas. EMP with gastrointestinal (GI) system involvement is an even rarer entity, accounting for <1% of MM cases. We present a case of aggressive MM with EMP invading the duodenum, initially presented with massive upper GI hemorrhage and small bowel obstruction. A 67-year-old woman was admitted to our hospital owing to a lack of either gas or feces passage for 3 days. Abdominal distention and vomit with a high coffee ground content were observed for 24 h. The patient's condition was initially diagnosed as small bowel obstruction, upper gastrointestinal bleeding, severe anemia, acute renal failure, and hypercalcemia. Furthermore, an analysis of immunoelectrophoresis in the blood, bone marrow aspiration, and tissue biopsy supported the diagnosis of MM and EMP invading the duodenum, upper GI hemorrhage, and small bowel obstruction. Our study provided the possible involvement of MM and EMP in the differential diagnosis of patients with unexplained GI hemorrhage and small bowel obstruction. A thorough review of the literature regarding the association between MM, GI hemorrhage, and small bowel obstruction is presented in this study.

Augmenting the effect of virtual labs with "teacher demonstration" and "student critique" instructional designs to scaffold the development of scientific literacy.

Virtual labs provide space for students to iteratively test, observe, and revise their understanding so as to improve their scientific literacy. However, one of the challenges that students face is that they need to think and act like scientists so as to be sensitively alert to methodological flaws and various sources of error. This study thus compared the effect of two instructional approaches using a virtual lab to enhance students' scientific literacy. Before students were given the opportunity to conduct science inquiries with the virtual lab, they were required to critique problematic inquiry cases (the critique group) or watch teachers' demonstrations (the teacher demonstration group) before taking part in the inquiry. By analyzing data from 50 middle school students, this study found that the effect of applying virtual labs can be augmented by an instructional design that engages students in critiquing experiments prior to their inquiry with the virtual lab. This study also found a limitation of the use of virtual labs in helping students transfer what they have learned from the teacher's demonstration to new inquiry contexts. A close relation among scientific literacy post-test scores, critiquing performance, and inquiry performance in the inquiry activity was detected, suggesting that student critiquing prior to inquiry is in alignment with the goal of developing students' inquiry skills and scientific literacy with virtual labs.

Transcriptomic signatures of exacerbated progression in leptospirosis subclinical chronic kidney disease with secondary nephrotoxic injury.

High-incidence regions of leptospirosis caused by Leptospira spp. coincide with chronic kidney disease. This study investigated whether asymptomatic leptospirosis is an emerging culprit that predisposes to progressive chronic kidney disease when superimposed on secondary nephrotoxic injury. Kidney histology/function and whole transcriptomic profiles were evaluated for Leptospira-infected C57/BL6 mice with adenine-induced kidney injury. The extent of tubulointerstitial kidney lesions and expression of inflammation/fibrosis genes in infected mice with low-dose (0.1%) adenine, particularly in high-dose (0.2%) adenine-fed superimposed on Leptospira-infected mice, were significantly increased compared with mice following infection or adenine diet alone, and the findings are consistent with renal transcriptome analysis. Pathway enrichment findings showed that integrin-ß- and fibronectin-encoding genes had distinct expression within the integrin-linked kinase-signaling pathway, which were upregulated in 0.2% adenine-fed Leptospira-infected mice but not in 0.2% adenine-fed mice, indicating that background subclinical Leptospiral infection indeed enhanced subsequent secondary nephrotoxic kidney injury and potential pathogenic molecules associated with secondary nephrotoxic leptospirosis. Comparative analysis of gene expression patterns with unilateral ureteric obstruction-induced mouse renal fibrosis and patients with chronic kidney disease showed that differentially expressed orthologous genes such as hemoglobin-α2, PDZ-binding kinase, and DNA topoisomerase II-α were identified in infected mice fed with low-dose and high-dose adenine, respectively, revealing differentially expressed signatures identical to those found in the datasets and may serve as markers of aggravated kidney progression. This study indicates that background subclinical leptospirosis, when subjected to various degrees of subsequent secondary nephrotoxic injury, may predispose to exacerbated fibrosis, mimicking the pathophysiological process of progressive chronic kidney disease.NEW & NOTEWORTHYLeptospira-infected mice followed by secondary nephrotoxic injury exacerbated immune/inflammatory responses and renal fibrosis. Comparison with the murine model revealed candidates involved in the progression of renal fibrosis in chronic kidney disease (CKD). Comparative transcriptome study suggests that secondary nephrotoxic injury in Leptospira-infected mice recapitulates the gene expression signatures found in CKD patients. This study indicates that secondary nephrotoxic injury may exacerbate CKD in chronic Leptospira infection implicating in the progression of CKD of unknown etiology.

Hemodialysis Use and Practice Patterns: An International Survey Study.

RATIONALE & OBJECTIVE: Hemodialysis (HD) is the most common form of kidney replacement therapy. This study aimed to examine the use, availability, accessibility, affordability, and quality of HD care worldwide. STUDY DESIGN: A cross-sectional survey. SETTING & PARTICIPANTS: Stakeholders (clinicians, policy makers, and consumer representatives) in 182 countries were convened by the International Society of Nephrology from July to September 2018. OUTCOMES: Use, availability, accessibility, affordability, and quality of HD care. ANALYTICAL APPROACH: Descriptive statistics. RESULTS: Overall, representatives from 160 (88%) countries participated. Median country-specific use of maintenance HD was 298.4 (IQR, 80.5-599.4) per million population (pmp). Global median HD use among incident patients with kidney failure was 98.0 (IQR, 81.5-140.8) pmp and median number of HD centers was 4.5 (IQR, 1.2-9.9) pmp. Adequate HD services (3-4 hours 3 times weekly) were generally available in 27% of low-income countries. Home HD was generally available in 36% of high-income countries. 32% of countries performed monitoring of patient-reported outcomes; 61%, monitoring of small-solute clearance; 60%, monitoring of bone mineral markers; 51%, monitoring of technique survival; and 60%, monitoring of patient survival. At initiation of maintenance dialysis, only 5% of countries used an arteriovenous access in almost all patients. Vascular access education was suboptimal, funding for vascular access procedures was not uniform, and copayments were greater in countries with lower levels of income. Patients in 23% of the low-income countries had to pay >75% of HD costs compared with patients in only 4% of high-income countries. LIMITATIONS: A cross-sectional survey with possibility of response bias, social desirability bias, and limited data collection preventing in-depth analysis. CONCLUSIONS: In summary, findings reveal substantial variations in global HD use, availability, accessibility, quality, and affordability worldwide, with the lowest use evident in low- and lower-middle-income countries.