A Canadian Study of Cisplatin Metabolomics and Nephrotoxicity (ACCENT): A Clinical Research Protocol

Background: Cisplatin, a chemotherapy used to treat solid tumors, causes acute kidney injury (AKI), a known risk factor for chronic kidney disease and mortality. AKI diagnosis relies on biomarkers which are only measurable after kidney damage has occurred and functional impairment is apparent; this prevents timely AKI diagnosis and treatment. Metabolomics seeks to identify metabolite patterns involved in cell tissue metabolism related to disease or patient factors. The A Canadian study of Cisplatin mEtabolomics and NephroToxicity (ACCENT) team was established to harness the power of metabolomics to identify novel biomarkers that predict risk and discriminate for presence of cisplatin nephrotoxicity, so that early intervention strategies to mitigate onset and severity of AKI can be implemented. Objective: Describe the design and methods of the ACCENT study which aims to identify and validate metabolomic profiles in urine and serum associated with risk for cisplatin-mediated nephrotoxicity in children and adults. Design: Observational prospective cohort study. Setting: Six Canadian oncology centers (3 pediatric, 1 adult and 2 both). Patients: Three hundred adults and 300 children planned to receive cisplatin therapy. Measurements: During two cisplatin infusion cycles, serum and urine will be measured for creatinine and electrolytes to ascertain AKI. Many patient and disease variables will be collected prospectively at baseline and throughout therapy. Metabolomic analyses of serum and urine will be done using mass spectrometry. An untargeted metabolomics approach will be used to analyze serum and urine samples before and after cisplatin infusions to identify candidate biomarkers of cisplatin AKI. Candidate metabolites will be validated using an independent cohort. Methods: Patients will be recruited before their first cycle of cisplatin. Blood and urine will be collected at specified time points before and after cisplatin during the first infusion and an infusion later during cancer treatment. The primary outcome is AKI, defined using a traditional serum creatinine-based definition and an electrolyte abnormality-based definition. Chart review 3 months after cisplatin therapy end will be conducted to document kidney health and survival. Limitations: It may not be possible to adjust for all measured and unmeasured confounders when evaluating prediction of AKI using metabolite profiles. Collection of data across multiple sites will be a challenge. Conclusions: ACCENT is the largest study of children and adults treated with cisplatin and aims to reimagine the current model for AKI diagnoses using metabolomics. The identification of biomarkers predicting and detecting AKI in children and adults treated with cisplatin can greatly inform future clinical investigations and practices

Making the match

Over time there has been a steady increase in the number of Canadians studying medicine outside of Canada, and especially in Ireland. These Canadians now find themselves classified as international medical graduates (IMGs), and face substantial challenges in matching back to Canadian residency programmes. Preparing for this increasingly competitive match is extremely daunting, and there is limited data on how to ensure success. The Irish medical schools have a reputation for training competent physicians who successfully match back to Canada or the United States, and in some ways are now a victim of their own success, with an increasing number of Canadians choosing to study in Ireland. The challenge for the future will be for Irish medical schools to maintain these successful match rates in order to continue to attract North American students. IMGs are physicians who have graduated from a medical school outside of the country in which they intend to practise. In Canada, this means any medical school not accredited by the Committee on Accreditation of Canadian Medical Schools (CACMS) or the Liaison Committee on Medical Education (LCME). Compared to Canadian medical graduates (CMGs), IMGs face substantial barriers when attempting to match to residency programmes in Canada. In 2017 alone, 411 (22.7%) IMGs matched to a Canadian residency programme, compared to 2,714 (96.5%) CMGs, amounting to an almost seven-fold difference in matching rates. An IMG must apply through the Canadian Resident Matching Service (CaRMS) to the small amount of designated IMG positions, which is much lower than the number that CMGs are applying to, in order to be considered for the match. CaRMS uses a specialised system – the Roth-Peranson algorithm – to match all prospective residents with postgraduate medical residency programmes throughout the country. The process of matching is two sided: prospective residents assign rank orders to their preferred programmes, while programmes simultaneously rank their preferred residents, based on written application and interview scores. The algorithm then compares the rank order lists of applicants and programmes, and determines the match outcome.</p

Enhanced thermally aided memory performance using few-layer ReS 2 transistors

Thermally varying hysteretic gate operation in few-layer ReS 2 and MoS 2 back gate field effect transistors (FETs) is studied and compared for memory applications. Clockwise hysteresis at room temperature and anti-clockwise hysteresis at higher temperature (373 K for ReS 2 and 400 K for MoS 2) are accompanied by step-like jumps in transfer curves for both forward and reverse voltage sweeps. Hence, a step-like conductance (STC) crossover hysteresis between the transfer curves for the two sweeps is observed at high temperature. Furthermore, memory parameters such as the RESET-to-WRITE window and READ window are defined and compared for clockwise hysteresis at low temperature and STC-type hysteresis at high temperature, showing better memory performance for ReS 2 FETs as compared to MoS 2 FETs. Smaller operating temperature and voltage along with larger READ and RESET-to-WRITE windows make ReS 2 FETs a better choice for thermally aided memory applications. Finally, temperature dependent Kelvin probe force microscopy measurements show decreasing (constant) surface potential with increasing temperature for ReS 2 (MoS 2). This indicates less effective intrinsic trapping at high temperature in ReS 2, leading to earlier occurrence of STC-type hysteresis in ReS 2 FETs as compared to MoS 2 FETs with increasing temperature.Peer reviewe

Implementing a fluid volume management program to decrease intra-dialytic hypotensive events in a paediatric in-centre haemodialysis unit: a quality improvement project

Background Intra-dialytic hypotension (IDH) is the most common serious adverse event in paediatric haemodialysis (HD). Repeated IDH results in chronic multi-organ damage and increased mortality. At the Hospital for Sick Children, Toronto, retrospective data from all in-centre HD sessions revealed frequently occurring IDH events (16.5 ± 5.6% of HD sessions per week). Based on literature review and clinical expertise, fluid volume management was selected as a potential modifiable risk factor to decrease IDH. Root causes identified as contributing to IDH were incorporated into a Paediatric haemodialysis fluid volume management (PedHDfluid) program using the Model for Improvement methodology including rapid cycles of change. Methods Multiple measures were evaluated including (i) Outcome: IDH events per number of HD sessions per week; (ii) Process: number of changes to estimated dry weight per number of HD sessions per week; (iii) Balancing: time spent on dry weight meeting per week. Data was analysed using statistical process control charts. We aimed to decrease IDH in our dialysis unit to < 10% of HD sessions per week over a 6-month period by implementing a PedHDfluid program, including a multifaceted dry weight assessment protocol, multidisciplinary meetings and electronic health records “Dry Weight Evaluation flow sheet/synopsis”. Results The project resulted in a decline in IDH events from 16.5 ± 5.6% to 8.8 ± 3.3% of HD sessions per week. More frequent dry weight changes and increased awareness of fluid removal goals were noted. Conclusions A multidisciplinary approach including regular assessment, guidelines and systematic discussion, with an embedded electronic health record assessment and data gathering tool may sustainably reduce IDH events

Implementing a fluid volume management program to decrease intra-dialytic hypotensive events in a paediatric in-centre haemodialysis unit: a quality improvement project

Background: Intra-dialytic hypotension (IDH) is the most common serious adverse event in paediatric haemodialysis (HD). Repeated IDH results in chronic multi-organ damage and increased mortality. At the Hospital for Sick Children, Toronto, retrospective data from all in-centre HD sessions revealed frequently occurring IDH events (16.5 ± 5.6% of HD sessions per week). Based on literature review and clinical expertise, fluid volume management was selected as a potential modifiable risk factor to decrease IDH. Root causes identified as contributing to IDH were incorporated into a Paediatric haemodialysis fluid volume management (PedHDfluid) program using the Model for Improvement methodology including rapid cycles of change. Methods: Multiple measures were evaluated including (i) Outcome: IDH events per number of HD sessions per week; (ii) Process: number of changes to estimated dry weight per number of HD sessions per week; (iii) Balancing: time spent on dry weight meeting per week. Data was analysed using statistical process control charts. We aimed to decrease IDH in our dialysis unit to \u3c 10% of HD sessions per week over a 6-month period by implementing a PedHDfluid program, including a multifaceted dry weight assessment protocol, multidisciplinary meetings and electronic health records “Dry Weight Evaluation flow sheet/synopsis”. Results: The project resulted in a decline in IDH events from 16.5 ± 5.6% to 8.8 ± 3.3% of HD sessions per week. More frequent dry weight changes and increased awareness of fluid removal goals were noted. Conclusions: A multidisciplinary approach including regular assessment, guidelines and systematic discussion, with an embedded electronic health record assessment and data gathering tool may sustainably reduce IDH events. Graphical abstract: A higher resolution version of the Graphical abstract is available as Supplementary information [Figure not available: see fulltext.

Perspectives of Pediatric Nephrologists, Intensivists and Nurses Regarding AKI Management and Expected Outcomes

Background: Acute kidney injury (AKI) in critically ill children is associated with increased risk for short- and long-term adverse outcomes. Currently, there is no systematic follow-up for children who develop AKI in intensive care unit (ICU). Objective: This study aimed to assess variation regarding management, perceived importance, and follow-up of AKI in the ICU setting within and between healthcare professional (HCP) groups. Design: Anonymous, cross-sectional, web-based surveys were administered nationally to Canadian pediatric nephrologists, pediatric intensive care unit (PICU) physicians, and PICU nurses, via professional listservs. Setting: All Canadian pediatric nephrologists, PICU physicians, and nurses treating children in the ICU were eligible for the survey. Patients: N/A. Measurements: Surveys included multiple choice and Likert scale questions on current practice related to AKI management and long-term follow-up, including institutional and personal practice approaches, and perceived importance of AKI severity with different outcomes. Methods: Descriptive statistics were performed. Categorical responses were compared using Chi-square or Fisher’s exact tests; Likert scale results were compared using Mann-Whitney and Kruskal-Wallis tests. Results: Surveys were completed by 34/64 (53%) pediatric nephrologists, 46/113 (41%) PICU physicians, and 82 PICU nurses (response rate unknown). Over 65% of providers reported hemodialysis to be prescribed by nephrology; a mix of nephrology, ICU, or a shared nephrology-ICU model was reported responsible for peritoneal dialysis and continuous renal replacement therapy (CRRT). Severe hyperkalemia was the most important renal replacement therapy (RRT) indication for both nephrologists and PICU physicians (Likert scale from 0 [not important] to 10 [most important]; median = 10, 10, respectively). Nephrologists reported a lower threshold of AKI for increased mortality risk; 38% believed stage 2 AKI was the minimum compared to 17% of PICU physicians and 14% of nurses. Nephrologists were more likely than PICU physicians and nurses to recommend long-term follow-up for patients who develop any AKI during ICU stay (Likert scale from 0 [none] to 10 [all patients]; mean=6.0, 3.8, 3.7, respectively) ( P < .05). Limitations: Responses from all eligible HCPs in the country could not obtained. There may be differences in opinions between HCPs that completed the survey compared to those that did not. Additionally, the cross-sectional design of our study may not adequately reflect changes in guidelines and knowledge since survey completion, although no specific guidelines have been released in Canada since survey dissemination. Conclusions: Canadian HCP groups have variable perspectives on pediatric AKI management and follow-up. Understanding practice patterns and perspectives will help optimize pediatric AKI follow-up guideline implementation

Long-Term Outcomes of C3 Glomerulopathy and Immune-Complex Membranoproliferative Glomerulonephritis in Children

Introduction: The reclassification of membranoproliferative glomerulonephritis (MPGN) into immune-complex MPGN (IC-MPGN) and C3 glomerulopathy (C3G) has provided insights into 2 distinct diseases. Although outcomes in adults are poor in both diseases, the pediatric literature is scarce and limited to small, single-center cohorts. Methods: We conducted a retrospective analysis of 165 pediatric patients across 17 hospitals to compare outcomes between children with IC-MPGN and C3G. Results: Forty-two percent of patients initially diagnosed with MPGN were reclassified as C3G after a review of renal biopsy reports. There was a trend toward higher serum creatinine levels in patients with C3G compared with IC-MPGN both at diagnosis (mean 168.9 [range 45.4–292.4] vs. 93.7 [range 70.7–116.6] μmol/l, P = 0.25) and after a mean follow-up time of 4 years (mean 145.0 (range −8.1 to 298.1) vs 99.1 (range 46.3–151.9) μmol/l, P = 0.47), although the estimated glomerular filtration rate (eGFR) was not significantly different. Steroid treatment was associated with a significant improvement in eGFR versus no steroids in C3G (mean +43.0 (range 12.9–73.0) vs. −3.0 (range −23.1 to 17.2) ml/min per 1.73 m2, P = 0.02) but not in IC-MPGN. Overall kidney function was preserved in both groups although hypertension remained prevalent in 42.5% of the cohort at the last follow-up, and the urine protein/creatinine ratio remained elevated (mean 253.8 [range 91.9–415.7] mg/mmol). Conclusion: This large pediatric IC-MPGN/C3G cohort revealed nearly half of the patients were misclassified, and there may be a trend toward worse renal prognosis in C3G although they may have greater steroid responsiveness. The overall prognosis appears to be more favorable than in adults; however, persistent hypertension and proteinuria suggest suboptimal disease control