Eric McArthur

Background: An underappreciated complication of laparoscopic nephrectomy in male living kidney donors is testicular pain, swelling, and hydrocele development. A recent cohort study in Ontario, Canada, found that male donors had a higher rate of hydrocelectomy (7.7 vs. 0.1 events/1000 person-years) and scrotal ultrasounds (25.6 vs. 6.9 events/1000 person-years) than nondonors, when followed for a median of 9 years. Objective: To conduct a replication study in Alberta, Canada, examining the long-term risk of hydrocelectomy after laparoscopic living donor nephrectomy, comparing male donors to nondonors from the general population matched on baseline health indicators. Design: Population-based matched cohort study using linked healthcare databases. Setting: Alberta, Canada (April 1, 2002, to March 31, 2021). Patients: We matched 115 male kidney donors who underwent a laparoscopic nephrectomy with 1150 nondonors. The matching characteristics were age at cohort entry, date of cohort entry, rural residence, income, prior vasectomy, and prior inguinal hernia repair. Measure: ments: The primary outcome was a hydrocelectomy, and the secondary outcome was receipt of a scrotal ultrasound. Methods: Males were followed for a median of eight years, with a maximum follow-up of 19 years. Results: The rate of hydrocelectomy was higher in donors than in nondonors (3 of 115 [2.6%] vs. 1 of 1150 [0.1%]; 3.3 vs. 0.1 events/1000 person-years; P < 0.001). The rate of scrotal ultrasounds was also higher among donors than among nondonors (23.4 vs. 7.5 events/1000 person-years; P < 0.001). Limitations: A low event rate impeded a precise estimation of the risk of hydrocelectomy attributable to donation. Conclusions: In this population-based cohort study from Alberta, Canada, rates of hydrocelectomy and receipt of a scrotal ultrasound were significantly higher in males who underwent laparoscopic living donor nephrectomy than in male nondonors matched for age and other factors. Males considering living kidney donation should be informed of the risk of developing a symptomatic ipsilateral scrotal hydrocele in the years following laparoscopic nephrectomy.

Background: A prior study of living kidney donors demonstrated a substantially higher long-term risk of hydrocelectomy among male living kidney donors who underwent laparoscopic nephrectomy compared with nondonors. Given the potential shared anatomical pathways between hydrocele and indirect inguinal hernia formation, we aimed to evaluate the donation-attributable risk of inguinal hernia repair. Objective: To evaluate long-term rates of inguinal hernia repair in male living kidney donors compared to nondonors. Design and Setting: Population-based, retrospective matched cohort study using linked health administrative databases from Ontario, Canada. Patients: 848 male living kidney donors aged ≥18 years who underwent laparoscopic donor nephrectomy between April 1, 2002, and March 31, 2023, were matched (1:10) to 8480 healthy male nondonors based on age, cohort entry date, rurality, neighbourhood income, and prior vasectomy. Individuals with prior scrotal conditions or previous inguinal hernia repair were excluded. Measurements: The primary outcome was inguinal hernia repair. Methods: Risk was assessed using Cox proportional hazards models with robust variance. Cumulative incidence was estimated at key time points using Aalen–Johansen methods, treating death as a competing event. To contextualize the findings, incidence rates were also examined after other renal (e.g., nondonor nephrectomy, pyeloplasty) and abdominal surgeries. Results: Over a median follow-up of 8.8 years, 4.7% of donors (40 of 848) and 3.4% of nondonors (287 of 8480) underwent inguinal hernia repair. Donors had a modestly higher risk of undergoing inguinal hernia repair than nondonors (4.9 vs. 3.5 events per 1000 person-years; hazard ratio (HR) 1.40; 95% CI, 1.01–1.93; P = 0.043). The cumulative incidence of inguinal hernia repair after laparoscopic donor nephrectomy was comparable to that observed after other renal and abdominal surgeries. Limitations: This study relied on administrative data, which lacked information on hernia type (direct or indirect), laterality, pre-existing asymptomatic hernias, and key confounders such as body mass index and occupation. Donors may differ from nondonors in care-seeking behaviours and lifestyle factors, which could influence the observed risk. Conclusions: In contrast to the markedly higher risk of hydrocele repair, the donation-attributable risk of inguinal hernia repair in the years following laparoscopic donor nephrectomy appears modest, and in some comparisons was not evident. These findings support current counselling and selection practices for prospective donors, for which this outcome does not warrant specific consideration.

Background: A significant barrier to kidney transplantation is limited knowledge about its potential benefits. To help patients who are receiving maintenance dialysis make more informed treatment decisions, a risk calculator (iChoose Kidney) was developed in the United States to provide individualized survival estimates for dialysis versus kidney transplantation. This tool was externally validated in Ontario, Canada, and was found to accurately predict mortality (Ontario version of the tool “Dialysis vs. Kidney Transplant-Estimated Survival in Ontario Risk Calculator”). The United States risk calculator has been updated to include additional variables (e.g., dialysis modality). Objective: To externally validate the updated iChoose Kidney risk calculator in patients from Ontario, Canada, with kidney failure using more recent data, removing race (race in clinical algorithms may perpetuate racial bias in medicine) and using a refined cohort definition (i.e., restricting to patients with no recorded contraindications to transplant). Design: External validation study. Setting: Linked administrative health care databases from Ontario, Canada. Patients: 24 793 patients receiving maintenance dialysis and 5398 kidney transplant recipients from January 1, 2011, to August 31, 2021. Measurements: Three-year mortality. Methods: Model discrimination was evaluated using the C-statistic. Calibration was assessed by comparing the observed versus predicted mortality risks, and further assessed by using loess-smoothed calibration plots. To address over- or under-prediction (calibration-in-the-large), intercepts were adjusted using a correction factor. In our updated model, we used logistic regression to calculate mortality risk, incorporating the following variables: sex assigned at birth (male vs female), age (continuous), cardiovascular disease, hypertension, diabetes, time on dialysis (i.e., 1 to 2 years, >2 to 3 years, >3 to 5 years, >5 to 7 years, >7 to 10 years, >10 to 14 years, >14 years), and dialysis modality (peritoneal dialysis, home hemodialysis, in-center dialysis). In a post-hoc analysis, we used the simplified equations from our original Canadian external validation study of the iChoose Kidney tool (i.e., age, sex, hypertension, diabetes, cardiovascular disease, time on dialysis [12 months]), with removal of the race variable as the only modification. Results: In the dialysis cohort, over a median follow-up of 2.5 years, 30.3% of patients died. In the kidney transplant recipient cohort, over a median follow-up of 2.9 years, 7.3% died. Our updated model had moderate discrimination (C-statistic for dialysis cohort: 0.67 [95% CI: 0.67, 0.68] and C-statistic for kidney transplant cohort: 0.76 [95% CI: 0.74, 0.79]). After recalibrating the intercepts, the observed and predicted mortality were similar between the dialysis cohort and the kidney transplant cohort. Similar results were found in a post-hoc analysis using the original model with the race variable removed. Limitations: Mortality risk estimates assume that all treatment options are readily accessible to patients. However, the average waiting time for a deceased donor kidney transplant in Ontario can be several years. Conclusions: After minor modifications, the iChoose Kidney risk calculator provides reliable survival estimates in patients with kidney failure from Ontario, Canada. Given the similarity in model performance between the updated model and the original model, with race removed, we will continue to use our original simplified model, but we will remove race. Our updated Dialysis vs. Kidney Transplant-Estimated Survival in Ontario Risk Calculator can continue to be a valuable tool for healthcare professionals to use with patients who are receiving maintenance dialysis to provide individualized survival estimates for dialysis versus transplantation, supporting informed decision-making about kidney transplantation.

A potential long-term complication of living kidney donation in male donors is scrotal swelling on the same side as the nephrectomy, and some undergo surgery to relieve discomfort from the fluid collection. The long-term risk for this outcome attributable to donation is unknown. To evaluate long-term scrotal surgery rates after laparoscopic nephrectomy in male living kidney donors compared with nondonors. Population-based cohort study (2002 to 2024). (ClinicalTrials.gov: NCT06716723). Linked administrative health care databases in Ontario, Canada. 898 male living kidney donors who had a laparoscopic nephrectomy were matched in a 1:10 ratio with 8980 male nondonors from the general population. The matching characteristics were age, date of cohort entry, rural residence, income, prior vasectomy, and prior inguinal hernia repair. Participants were followed for a median of 9 years, up to 22 years. The primary outcome was hospitalization for surgery to address a unilateral scrotal fluid collection. Donors and matched nondonors had a median age of 45 years. The rate of scrotal surgery was higher in donors than nondonors (70 of 898 donors [7.8%] vs. 19 of 8980 nondonors [0.2%]; 8.3 vs. 0.2 events per 1000 person-years; hazard ratio, 38.8 [95% CI, 22.1 to 67.9]; P < 0.001). The median time from donation to scrotal surgery was 5.2 years (IQR, 3.3 to 8.4 years); more than 90% of the surgeries were hydrocelectomies and were performed under general anesthesia. Over 20 years, the cumulative incidence was 13.8% in donors versus 0.7% in nondonors. The precise causal mechanism remains unknown. Laparoscopic nephrectomy is associated with a higher risk for subsequent scrotal surgery in male living kidney donors. Canadian Institutes of Health Research.

Background: Musculoskeletal disorders (MSKDs) are a leading cause of pain and disability, placing a substantial burden on health care systems. Optimizing resource use through innovative interventions is essential. Evidence from randomized controlled trials suggests that not all individuals with MSKDs require ongoing follow-up with a health care provider; for many, education alone is sufficient for symptom resolution. A stepped care model, which prioritizes patient education as a first-line intervention and reserves usual care for those with persistent symptoms, may enhance health care efficiency and reduce costs. Objective: The primary objective of this randomized controlled trial is to evaluate the effectiveness of a stepped care model compared to the 2 most common approaches for managing MSKDs: usual medical care and usual rehabilitation care. A secondary objective is to assess cost-effectiveness. Methods: This pragmatic, noninferiority, multiarm, parallel-group randomized controlled trial will enroll 369 adults with MSKDs, randomly assigned to one of three 12-week intervention groups: stepped care, usual medical care (physician-led), or usual rehabilitation care (physiotherapist-led). Participants in the stepped care group will first complete a 6-week education program. Those with persistent symptoms after 6 weeks will receive rehabilitation interventions, while participants whose symptoms have resolved will receive no further intervention. The primary outcome is functional limitations at 24 weeks. Secondary outcomes include pain severity, health-related quality of life, pain-related fear, and pain self-efficacy, assessed at baseline and at 6, 12, and 24 weeks. Linear mixed models will be used for group comparisons, and incremental cost-effectiveness analyses will evaluate cost-effectiveness. The ethics committee of the CIUSSS-CN approved the project (#2024-2982). Findings will be shared through clinical and community platforms, peer-reviewed publications, and conference presentations. Results: The Edu-First trial is funded by a project grant from the Canadian Institutes of Health Research (grant #495615). Recruitment began on January 31, 2025. As of September 2025, a total of 65 participants have been enrolled. Recruitment is expected to continue for up to 3 years, targeting approximately 10 new participants per month, and is anticipated to be completed by Winter 2028. Conclusions: We anticipate that the stepped care model will be noninferior to usual medical care and usual rehabilitation care in terms of treatment effectiveness. Furthermore, it is expected to be cost-effective by reducing reliance on expensive resources, such as provider consultations and medical investigations. By emphasizing education and self-management as the initial approach, the stepped care model may enhance access to care without compromising quality, while empowering patients to actively manage their condition. Findings from this study could inform systemic changes in MSKD care delivery, improving treatment accessibility and reducing the average cost per care episode. Trial Registration: ClinicalTrial.gov NCT06832852; https://clinicaltrials.gov/ct2/show/NCT06832852 International Registered Report Identifier (IRRID): DERR1-10.2196/77574

Background: Drug-drug interactions (DDIs) are a major concern, especially for older adults taking multiple medications. Although Health Canada and the US Food and Drug Administration (FDA) use population-based studies to identify adverse drug events, detecting harmful DDIs is challenging due to the millions of potential drug combinations. Traditional pharmacoepidemiologic studies are slow and inefficient, often missing important harmful DDIs. Objective: This protocol outlines a novel approach to efficiently identify harmful DDIs using administrative health care data. Methods: Using high-throughput computing, we will conduct multiple population-based, new-user cohort studies using Ontario’s linked administrative health care data. The cohorts will be selected from the population of Ontario residents aged 66 years and older who filled at least one oral outpatient drug prescription from 2002 to 2023. In each cohort, the exposed group will comprise individuals who are regular users of one drug (drug A) who start a new prescription for a second drug (drug B); the referent group will comprise regular users of drug A not taking drug B. We will evaluate 74 acute outcomes within 30 days of cohort entry, including hospitalizations, emergency department visits, and mortality. Propensity score methods will balance exposed and referent groups on more than 400 baseline health characteristics. Modified Poisson and binomial regression models will estimate risk ratios (RRs) and risk differences (RDs). To ensure findings are both statistically and clinically meaningful, we will apply prespecified thresholds for effect sizes (eg, lower bounds of 95% CIs≥1.33 for RRs and ≥0.1% for RDs) and control the false discovery rate at 5% using the Benjamini-Hochberg procedure to address multiplicity. Subgroup and sensitivity analyses, including negative control outcomes and E-values, will assess robustness. Results: In a preliminary analysis, we identified approximately 3.8 million older adults who filled prescriptions for over 500 unique medications during the study period (2002-2023), and therefore, approximately 200,000 potential drug combinations will be available for study. The initial drug pair cohorts had a median of 583 new users per cohort (IQR 237-2130); the median overlap in drug pair prescriptions was 57 days (IQR 30-90). The protocol was finalized on August 30, 2025, and outlines the analysis of data from 2002 to 2023. The analysis is scheduled to be completed by fall 2026, with results interpreted in 2027. The final manuscript submission is planned for December 2028. Conclusions: This study aims to identify credible signals of harmful DDIs in older adults in routine care. This study will use an innovative approach that leverages data from provincial administrative health care databases and integrates high-throughput computing and rigorous pharmacoepidemiologic methods to generate robust real-world evidence that can inform safer prescribing practices and regulatory decision-making. International Registered Report Identifier (IRRID): DERR1-10.2196/77224

BACKGROUND Musculoskeletal disorders (MSKDs) are a leading cause of pain and disability, placing a substantial burden on health care systems. Optimizing resource use through innovative interventions is essential. Evidence from randomized controlled trials suggests that not all individuals with MSKDs require ongoing follow-up with a health care provider; for many, education alone is sufficient for symptom resolution. A stepped care model, which prioritizes patient education as a first-line intervention and reserves usual care for those with persistent symptoms, may enhance health care efficiency and reduce costs. OBJECTIVE The primary objective of this randomized controlled trial is to evaluate the effectiveness of a stepped care model compared to the 2 most common approaches for managing MSKDs: usual medical care and usual rehabilitation care. A secondary objective is to assess cost-effectiveness. METHODS This pragmatic, noninferiority, multiarm, parallel-group randomized controlled trial will enroll 369 adults with MSKDs, randomly assigned to one of three 12-week intervention groups: stepped care, usual medical care (physician-led), or usual rehabilitation care (physiotherapist-led). Participants in the stepped care group will first complete a 6-week education program. Those with persistent symptoms after 6 weeks will receive rehabilitation interventions, while participants whose symptoms have resolved will receive no further intervention. The primary outcome is functional limitations at 24 weeks. Secondary outcomes include pain severity, health-related quality of life, pain-related fear, and pain self-efficacy, assessed at baseline and at 6, 12, and 24 weeks. Linear mixed models will be used for group comparisons, and incremental cost-effectiveness analyses will evaluate cost-effectiveness. The ethics committee of the CIUSSS-CN approved the project (#2024-2982). Findings will be shared through clinical and community platforms, peer-reviewed publications, and conference presentations. RESULTS The Edu-First trial is funded by a project grant from the Canadian Institutes of Health Research (grant #495615). Recruitment began on January 31, 2025. As of September 2025, a total of 65 participants have been enrolled. Recruitment is expected to continue for up to 3 years, targeting approximately 10 new participants per month, and is anticipated to be completed by Winter 2028. CONCLUSIONS We anticipate that the stepped care model will be noninferior to usual medical care and usual rehabilitation care in terms of treatment effectiveness. Furthermore, it is expected to be cost-effective by reducing reliance on expensive resources, such as provider consultations and medical investigations. By emphasizing education and self-management as the initial approach, the stepped care model may enhance access to care without compromising quality, while empowering patients to actively manage their condition. Findings from this study could inform systemic changes in MSKD care delivery, improving treatment accessibility and reducing the average cost per care episode. CLINICALTRIAL ClinicalTrial.gov NCT06832852; https://clinicaltrials.gov/ct2/show/NCT06832852 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/77574

BACKGROUND Drug-drug interactions (DDIs) are a major concern, especially for older adults taking multiple medications. Although Health Canada and the US Food and Drug Administration (FDA) use population-based studies to identify adverse drug events, detecting harmful DDIs is challenging due to the millions of potential drug combinations. Traditional pharmacoepidemiologic studies are slow and inefficient, often missing important harmful DDIs. OBJECTIVE This protocol outlines a novel approach to efficiently identify harmful DDIs using administrative health care data. METHODS Using high-throughput computing, we will conduct multiple population-based, new-user cohort studies using Ontario’s linked administrative health care data. The cohorts will be selected from the population of Ontario residents aged 66 years and older who filled at least one oral outpatient drug prescription from 2002 to 2023. In each cohort, the exposed group will comprise individuals who are regular users of one drug (drug A) who start a new prescription for a second drug (drug B); the referent group will comprise regular users of drug A not taking drug B. We will evaluate 74 acute outcomes within 30 days of cohort entry, including hospitalizations, emergency department visits, and mortality. Propensity score methods will balance exposed and referent groups on more than 400 baseline health characteristics. Modified Poisson and binomial regression models will estimate risk ratios (RRs) and risk differences (RDs). To ensure findings are both statistically and clinically meaningful, we will apply prespecified thresholds for effect sizes (eg, lower bounds of 95% CIs≥1.33 for RRs and ≥0.1% for RDs) and control the false discovery rate at 5% using the Benjamini-Hochberg procedure to address multiplicity. Subgroup and sensitivity analyses, including negative control outcomes and E-values, will assess robustness. RESULTS In a preliminary analysis, we identified approximately 3.8 million older adults who filled prescriptions for over 500 unique medications during the study period (2002-2023), and therefore, approximately 200,000 potential drug combinations will be available for study. The initial drug pair cohorts had a median of 583 new users per cohort (IQR 237-2130); the median overlap in drug pair prescriptions was 57 days (IQR 30-90). The protocol was finalized on August 30, 2025, and outlines the analysis of data from 2002 to 2023. The analysis is scheduled to be completed by fall 2026, with results interpreted in 2027. The final manuscript submission is planned for December 2028. CONCLUSIONS This study aims to identify credible signals of harmful DDIs in older adults in routine care. This study will use an innovative approach that leverages data from provincial administrative health care databases and integrates high-throughput computing and rigorous pharmacoepidemiologic methods to generate robust real-world evidence that can inform safer prescribing practices and regulatory decision-making. INTERNATIONAL REGISTERED REPORT DERR1-10.2196/77224

Background: Some men who donate a kidney have reported testicular pain after donation; however, attribution to donation is not clear as no prior studies included a comparison group of nondonors. Objective: To examine the proportion of male donors who reported testicular pain in the years after nephrectomy compared to male nondonors with similar baseline health characteristics. Design, Participants, and Setting: We enrolled 1042 living kidney donors (351 male) before nephrectomy from 17 transplant centers (12 in Canada and 5 in Australia) from 2004 to 2014. A concurrent sample of 396 nondonors (126 male) was enrolled. Follow-up occurred until November 2021. Measurements: Donors and nondonors completed the same schedule of measurements at baseline (before nephrectomy) and follow-up. During follow-up, participants completed a questionnaire asking whether they had experienced new pain in their eyes, hands, or testicles; those who experienced pain were asked to indicate on which side of the body the pain occurred (left or right). The pain questionnaire was completed by 290 of 351 male donors (83%) and 97 of 126 male nondonors (77%) a median of 3 years after baseline (interquartile range = 2-6). Methods: Inverse probability of treatment weighting on a propensity score was used to balance donors and nondonors on baseline characteristics. After weighting, the nondonor sample increased to a pseudo sample of 295, and most baseline characteristics were similar between donors and nondonors. Results: At baseline, donors (n = 290) were a mean age of 49 years; 83% were employed, and 80% were married; 246 (84.8%) underwent laparoscopic surgery and 44 (15.2%) open surgery; 253 (87.2%) had a left-sided nephrectomy and 37 (12.8%) a right-sided nephrectomy. In the weighted analysis, the risk of testicular pain was significantly greater among donors than nondonors: 51/290 (17.6%) vs 7/295 (2.3%); weighted risk ratio, 7.8 (95% confidence interval [CI] = 2.7 to 22.8). Donors and nondonors did not differ statistically in terms of self-reported eye pain or hand pain. Among donors, the occurrence of testicular pain was most often unilateral (92.2%) and on the same side as the nephrectomy (90.2%). Testicular pain occurred more often in donors who had laparoscopic vs open surgery: 48/246 (19.5%) vs 3/44 (6.8%) but was similar in those who had a left-sided vs right-sided nephrectomy: 44/253 (17.4%) vs 7/37 (18.9%). Limitations: Participants recalled their symptoms several years after baseline, and we did not assess the timing, severity, or duration of pain or any treatments received for the pain. Conclusion: Unilateral testicular pain on the same side of a nephrectomy is a potential complication of living kidney donation that warrants further investigation.

Background: Better data are necessary to determine whether baseline level of kidney function affects the rate of progressive kidney disease following pregnancy. Objective: The objective was to determine whether the baseline (pre-pregnancy) estimated glomerular filtration rate (eGFR) modifies the association between becoming pregnant and the subsequent rate of progressive kidney disease. Design: Population-based cohort study using provincial administrative health care databases in Ontario and Alberta, Canada. Setting: The sample will be accrued from April 1, 2007, to March 31, 2023, in Ontario and from April 1, 2012, to March 31, 2023, in Alberta. Follow-up for study outcomes will occur until March 31, 2024. Participants: The pregnant group will include adult female residents of Ontario or Alberta with a record of a pregnancy of 20 to 46 weeks’ gestation during the accrual period, and the non-pregnant group will include adult female residents with no prior record of pregnancy. The cohort entry dates in those in the pregnant group will be the estimated date of conception; the entry dates for those in the non-pregnant group will be randomly assigned following the distribution of dates in the pregnant group. To be eligible, individuals must be between 18 and 45 years old at cohort entry. They require at least 1 serum creatinine measurement within 2 years before entry and should not have received maintenance dialysis or a prior kidney transplant. Both groups will be categorized into one of 3 levels of baseline eGFR (≥60, 45–59, and 2 ). Inverse probability of treatment weighting on a propensity score will be used to balance the pregnant and non-pregnant groups on baseline characteristics (including age, proteinuria, hypertension, and diabetes) within the 3 categories of baseline eGFR. Measurements: The primary outcome, progressive kidney disease, will be defined as a composite of a persistent ≥40% drop in eGFR from the baseline value, a new persistent eGFR 2 , receipt of maintenance dialysis, or receipt of a kidney transplant. The secondary outcomes will be the components of the primary composite outcome examined separately and the annualized change in eGFR in mL/min per 1.73 m ² from baseline. Methods: We will test for statistical interaction to determine whether the baseline category of eGFR modifies the rate of long-term progressive kidney disease after pregnancy. We hypothesize that a statistical interaction will be present. We will present weighted cause-specific hazard ratios (HRs) and cumulative incidence function (CIF) curves for up to 10 years of follow-up for the pregnant and non-pregnant groups stratified by each eGFR category. We will perform additional pre-specified analyses to confirm whether the findings are robust and examine associations that account for baseline proteinuria. Results: Based on a feasibility analysis using ICES data in Ontario, we expect the cohort to include over 400 000 pregnant females and 1.2 million non-pregnant females. This includes at least 395 000 pregnant females with baseline eGFR ≥60 mL/min/1.73 m ² , 300 with eGFR 45 to 59 mL/min/1.73 m ² , and 110 with eGFR 2 . The median follow-up is anticipated to be 5 years (range = 1-17 years) with minimal loss to follow-up. Limitations: Measures of kidney function will be obtained as part of routine care (not according to a research schedule). Measures of baseline proteinuria are frequently missing from routine care data, even in up to 15% of those with an eGFR 2 . Conclusion: This study will investigate whether the level of baseline eGFR modifies the rate of progressive kidney disease after pregnancy and will estimate the cumulative incidence of progressive kidney disease in pregnant and non-pregnant females across 3 categories of baseline eGFR.