McGill University Health Centre

Purpose An international working group (IWG) consisting of experts in X-linked hypophosphatemia (XLH) developed global guidelines providing a comprehensive, evidence-based approach to XLH diagnosis, management, and monitoring. Methods The IWG, consisting of 43 members as well as methodologists and a patient partner, conducted 2 systematic reviews (SRs) and narrative reviews to address key areas. The SRs addressed the impact of burosumab compared to conventional therapy (phosphate and active vitamin D) or no therapy on patient-important outcomes in adults. They also evaluated conventional therapy compared to no therapy. GRADE methodology was applied to evaluate the certainty of evidence. Non-GRADED recommendations were made in the presence of insufficient evidence to conduct SRs. These guidelines have been reviewed and endorsed by several medical and patient societies and organizations. Results The diagnosis of XLH is based on integrating clinical evaluation, laboratory findings confirming renal phosphate wasting (following exclusion of conditions mimicking XLH), and skeletal imaging. Fibroblast growth factor 23 measurement and DNA analysis are of value in the diagnosis, if available. Pathogenic or likely pathogenic variants in the PHEX gene are confirmatory but not necessary for the diagnosis. Management requires a multidisciplinary team knowledgeable and experienced in XLH. Effective medical therapy with burosumab can improve fracture and pseudofracture healing. Main Conclusion In adults with XLH and fractures or pseudofractures, burosumab is recommended over no therapy (strong recommendation, GRADEd). Additionally, burosumab is suggested as the preferred treatment compared to conventional therapy (conditional recommendation, GRADEd) in the absence of fractures or pseudofractures. If burosumab is not available, symptomatic adults should be treated with conventional therapy (Non-GRADEd recommendation).

Background and Aims Pregnancy in women with a prosthetic heart valve is considered high risk, primarily due to the need for effective anticoagulation. However, data on the relationship between anticoagulation practices and pregnancy outcomes are very limited. Methods The Registry of Pregnancy and Cardiac disease is a global registry that prospectively enrolled pregnancies in women with a prosthetic heart valve between January 2018 and April 2023. Detailed data on anticoagulation, including dosage and monitoring, and cardiovascular, pregnancy, and perinatal outcomes were collected. Results In total, 613 pregnancies were included of which 411 pregnancies were in women with a mechanical valve and 202 were in women with a biological valve. The chance of an uncomplicated pregnancy with a live birth in women with a mechanical valve was 54%, compared with 79% in women with a biological valve (P < .001). Thromboembolic and haemorrhagic complications most frequently occurred when low-molecular weight heparin (LMWH)–based regimens were used. Valve thrombosis occurred in 24 (6%) women, and a prosthetic valve in mitral position was associated with valve thrombosis (odds ratio 3.3; 95% confidence interval 1.9–8.0). A thromboembolic event occurred in 12 (10%) women with anti-Xa monitoring and in 9 (21%) women without (P = .060). Foetal death occurred in 20% of all pregnancies. Conclusions More favourable outcomes were found in women with a biological valve compared with a mechanical valve. In women with a mechanical valve, the use of LMWH was associated with an increased risk of thromboembolic complications. A mitral prosthetic valve was identified as a predictor for valve thrombosis. The benefit could not be confirmed nor refuted, in terms of reduced thromboembolic events, from using anti-Xa level monitoring in women on LMWH.

Preoperative risk mitigation is vital for improving surgical outcomes and patient safety, particularly in colorectal cancer (CRC) surgeries. While traditional approaches have primarily focused on postoperative care, the preoperative period is a unique opportunity for intervention to enhance patients' physiological readiness for surgery and minimize complications. This narrative review examines the general principles of preoperative risk mitigation, identifies common complications in colorectal surgery, and explores the impact of patient comorbidities on surgical outcomes. Additionally, the review discusses the strategic management of modifiable risk factors. The integration and impact of prehabilitation protocols in colorectal surgery are also evaluated. Evidence indicates that addressing modifiable preoperative risk factors can significantly improve surgical outcomes. Obesity management, nutritional optimization, and enhancing functional capacity through prehabilitation have been shown to reduce postoperative complications. Multimodal prehabilitation benefits high-risk and frail patients, improving their postoperative recovery and reducing complication rates. The preoperative period is crucial for implementing risk mitigation strategies to enhance surgical outcomes in CRC patients. Interventions targeting modifiable risk factors and integrating prehabilitation protocols can complement traditional postoperative care, improving recovery and reducing complications. Despite promising findings, further research is necessary to fully understand the long-term benefits and optimize preoperative interventions to mitigate postoperative morbidities effectively.

Introduction Pulsed Field Cryoablation (PFCA) is a dual‐energy cardiac ablation modality consisting of short‐duration ultra‐low temperature cryoablation (ULTC) followed immediately by pulsed field ablation (PFA) delivered from the same catheter. It is hypothesized that PFCA may improve contact stability during PFA, while maintaining lesion depth and effectiveness of ULTC. Methods PARALELL is a first‐in‐human multicenter study evaluating safety and effectiveness of a novel PFCA catheter and system in patients with persistent atrial fibrillation (PsAF) using the combination of pulmonary vein (PVI) and posterior wall (PWI) isolation. Results Sixty‐six patients were ablated at six sites. One groin hematoma and one intubation‐related hospitalization were the only serious procedure‐ or device‐related adverse events recorded in the study. Per protocol, acute effectiveness was evaluated in 46 patients, including 31 patients with post‐hoc analysis of cryogenic energy per lesion. After an average of 21.1 ± 9.3 lesions per patient the rates of PVI and PWI were 95.7% (176/184) and 97.7% (42/43), respectively. The average cryogenic energy per patient was highly predictive of acute isolation success with ROC AUC = 0.944% and 100% rates of both PVI and PWI in 24 patients in the optimal energy cohort. Grade I microbubbles and faint muscle contractions were detected in 1.1% and 0.5% of ablations, respectively. Conclusion This initial multi‐center experience suggests that PFCA can be efficiently performed for PVI and PWI using a single versatile catheter system, with high acute success and good early safety profile. The evaluation of the chronic 12‐month effectiveness of PFCA is ongoing.

Fungi increasingly threaten health globally. Mycoses range from life-threatening, often iatrogenic conditions, to enigmatic syndromes occurring without apparent immunosuppression. Despite some recent advances in antifungal drug development, complementary therapeutic strategies are essential for addressing these opportunistic pathogens. One promising avenue is leveraging host immunity to combat fungal infections; this necessitates deeper understanding of the molecular immunology of human fungal susceptibility to differentiate beneficial versus harmful immunopathological responses. Investigating human models of fungal diseases in natural settings, particularly through genetic immunodeficiencies and ethnographic-specific genetic vulnerabilities, reveals crucial immune pathways essential for fighting various yeasts and molds. This review highlights the diversity in intrinsic fungal susceptibility across individuals and populations, through genetic- and autoantibody-mediated processes, complementing previous principles learned from animal studies and iatrogenic contexts. Improved understanding of human immunity to fungal diseases will facilitate the development of host-directed immunotherapies and targeted public health interventions, paving the way for precision medicine in fungal disease management.

Background Humanitarian organizations are rapidly expanding their use of data in the pursuit of operational gains in effectiveness and efficiency. Ethical risks, particularly from artificial intelligence (AI) data processing, are increasingly recognized yet inadequately addressed by current humanitarian data protection guidelines. This study reports on a scoping review that maps the range of ethical issues that have been raised in the academic literature regarding data processing of people affected by humanitarian crises. Methods We systematically searched databases to identify peer-reviewed studies published since 2010. Data and findings were standardized, grouping ethical issues into the value categories of autonomy, beneficence, non-maleficence, and justice. The study protocol followed Arksey and O’Malley’s approach and PRISMA reporting guidelines. Results We identified 16,200 unique records and retained 218 relevant studies. Nearly one in three (n = 66) discussed technologies related to AI. Seventeen studies included an author from a lower-middle income country while four included an author from a low-income country. We identified 22 ethical issues which were then grouped along the four ethical value categories of autonomy, beneficence, non-maleficence, and justice. Slightly over half of included studies (n = 113) identified ethical issues based on real-world examples. The most-cited ethical issue (n = 134) was a concern for privacy in cases where personal or sensitive data might be inadvertently shared with third parties. Aside from AI, the technologies most frequently discussed in these studies included social media, crowdsourcing, and mapping tools. Conclusions Studies highlight significant concerns that data processing in humanitarian contexts can cause additional harm, may not provide direct benefits, may limit affected populations’ autonomy, and can lead to the unfair distribution of scarce resources. The increase in AI tool deployment for humanitarian assistance amplifies these concerns. Urgent development of specific, comprehensive guidelines, training, and auditing methods is required to address these ethical challenges. Moreover, empirical research from low and middle-income countries, disproportionally affected by humanitarian crises, is vital to ensure inclusive and diverse perspectives. This research should focus on the ethical implications of both emerging AI systems, as well as established humanitarian data management practices. Trial registration Not applicable.

Identifying patients for clinical studies evaluating strategies to reduce unnecessary antibiotic usage in hospitals is challenging. This study aimed to develop a predictive score to identify newly hospitalized patients with high likelihood of receiving antibiotics, thus improving patient inclusion in future studies focusing on antimicrobial stewardship (AMS) programs. This retrospective analysis used data from the PILGRIM study (NCT03765528), which included 1,600 patients across ten international sites. Predictive variables for antibiotic treatment during hospitalization were computed, and an additive score model was developed using logistic regression and 10-fold cross-validation. The PILGRIM score was validated in an independent cohort (validation cohort), with performance metrics assessed. Data from 1,258 patients was included. In the development cohort 52.8% (n = 445) and in the validation cohort 42.4% (n = 134) of patients received antibiotics. Key predictors included hematologic malignancies, immunosuppressive medication, and past hospitalization. The logistic regression model demonstrated an area under the curve of 0.74 in the validation. The final additive score incorporated these predictors plus “planned elective surgery” achieving a specificity of 92%, a positive predictive value of 78%, a sensitivity of 41%, and a negative predictive value (NPV) of 69%in validation set. The PILGRIM score effectively identifies newly hospitalized patients likely to receive antibiotics, demonstrating high specificity and PPV. Its application can improve future AMS programs and trial recruitment by facilitating targeted inclusion of patients, especially in the hematological and oncological setting. Further -external and prospective- validation is needed to broaden the model’s applicability.

Objective To review methods for developing and endorsing Quality Measures (QMs) to inform a national quality measurement framework for rheumatology care in Canada. Methods We conducted a rapid environmental scan of measure development organizations from Canada, the United Kingdom, the United States and Australia. Major phases in the development of QMs were abstracted. The results were reviewed and synthesized with members of the Canadian Rheumatology Association's Digital Measurement Subcommittee through iterative review across 3 virtual meetings. The guidance was approved at the committee and the CRA board level. Results Five key steps in the measure development cycle are proposed including: conceptualization and prioritization, measure specification development, testing and validation, implementation and reporting, continuous evaluation and maintenance. Foundational to all phases is the engagement of individuals from diverse backgrounds with lived experience of disease, healthcare providers, quality measurement scientists, and partner organizations. Measures should be aligned with domains of quality (effectiveness, efficiency, equity, patient-centeredness, safety and timeliness of care delivery) and be developed transparently. Endorsement of future QMs should, at minimum, prioritize validity, feasibility and acceptability or use/usability. Conclusion This paper establishes a comprehensive and relevant framework for the development and/or endorsement of QMs in Canadian rheumatology care. This framework will permit streamlining of future quality improvement efforts at the national level.

Background Social determinants of health (SDoH) can significantly impact overall well‐being. While existing research has explored SDoH as predictors of well‐being among women living with HIV, longitudinal studies examining these relationships over time remain limited. We examined SDoH typologies among women living with HIV in Canada and longitudinal associations with well‐being. Methods Using longitudinal survey data collected at three time points from women living with HIV in Canada (2013–2018), we conducted latent class analysis (LCA) to identify subgroups of SDoH indicators, including income, experiences of violence, food security, substance use, housing stability, HIV‐related stigma and social support at baseline (Time‐1). Multivariable linear and logistic regression examined associations between SDoH classes and well‐being (depression, discrimination [gender, racial] and HIV clinical outcomes [viral load, adherence, HIV care barriers]) at Time‐3. Results We identified three distinct SDoH classes among participants (n = 1422, mean age = 42.8): high (n = 435; 30.6%), medium (n = 377; 26.5%) and low SDoH adversity (n = 610; 42.9%). In multivariate regression analyses, the high SDoH adversity class had lower odds of achieving an undetectable viral load (adjusted Odds Ratio [aOR] = 0.46; 95% CI: 0.21, 1.01; p = 0.050) and higher probability of facing barriers to accessing care (aβ = 0.32; 95% CI: 0.19, 0.45; p < 0.001), depression (aOR = 2.52; 95% CI: 1.71, 3.71; p < 0.001), racial discrimination (aβ = 3.42; 95% CI: 1.72, 5.12; p < 0.001) and gender discrimination (aβ = 3.14; 95% CI: 1.42, 4.87; p < 0.001), compared with the low SDoH adversity class at 5‐year follow‐up. Conclusions SDoH adversities were associated with poor wellbeing among women living with HIV in Canada. Integrated, comprehensive person‐centred care approaches that address SDoH are needed to improve health and wellbeing.

Trials in cardiac surgery are often hampered at the design level by small sample sizes and ethical considerations. The conventional analytical approach, combining frequentist statistics with null hypothesis significance testing, has known limitations and its associated p-values are often misinterpreted, leading to dichotomous conclusions of trial results. The Bayesian statistical framework may overcome these limitations through probabilistic reasoning, and is subsequently introduced in this Primer. The Bayesian framework combines prior beliefs and currently obtained data (the likelihood), resulting in updated beliefs, also known as posterior distributions. These distributions subsequently facilitate probabilistic interpretations. Several previous cardiac surgery trials have been performed under a Bayesian framework and this Primer enhances the understanding of their basic concepts by linking results to graphical presentations. Furthermore, contemporary trials that were initially analysed under a frequentist framework, are re-analysed within a Bayesian framework to demonstrate several interpretative advantages.

Background Climate change is intensifying extreme heat events, posing significant risks to cardiovascular health. While sex differences in heat vulnerability have been observed, the evidence remains inconsistent. This systematic review and meta-analysis examined sex-specific associations between extreme heat exposure and cardiovascular disease (CVD) outcomes over the past decade. Methods We searched PubMed, Embase, and Scopus for studies published between 2004 and 2024 that reported sex-stratified cardiovascular outcomes associated with heat exposure following the PRISMA guidelines. The quality of the evidence was evaluated following the Navigation Guide Criteria. Random-effects meta-analysis was conducted to calculate pooled relative risk ratios (RRR) comparing males to females for studies addressing incremental temperature increase. Heat wave studies were synthesized narratively due to methodological heterogeneity. Results Of 6126 articles, 79 met inclusion criteria (62 in meta-analysis, 17 in narrative synthesis), primarily from East Asia, Europe, and North America. A 1 °C temperature increase was associated with elevated cardiovascular risks for both sexes. The pooled relative risk ratio (RRR) comparing males to females was 1.008 [1.002–1.014] for mortality, suggesting slightly higher female vulnerability, but not for morbidity (RRR 0.996 [0.987–1.004]). Significant heterogeneity was noted (Mortality I² = 50.3%, Morbidity I² = 70.3%). Heat wave studies showed inconsistent sex-specific impacts across populations. Conclusions Females showed marginally higher vulnerability to heat-related cardiovascular mortality compared to males, while no significant sex differences were observed for morbidity outcomes. Future research should focus on understanding these mechanisms and developing sex-specific interventions.

Objective To describe barriers and strategies amongst healthcare professionals (HCP) for optimal non-invasive respiratory support (NRS) provision in extremely preterm infants. Study design A cross-sectional web-based anonymized 19-question survey was sent to HCPs across Canadian tertiary care NICUs. The survey inquired about perspectives on NRS devices and management strategies, respiratory event monitoring, NRS failure, and possible solutions. Result 391 responses from 61 physicians, 173 nurses, and 147 respiratory therapists were analyzed. HCP perspectives varied regarding appropriateness of different NRS settings and interfaces, documentation of cardiorespiratory events, and prevention of NRS failure. Obtaining effective NRS was deemed challenging by 48% of HCPs. NRS training was deemed adequate by 89% of respiratory therapists and 78% of physicians, but only 56% of nurses. Conclusion Substantial interprofessional variations exist in perceived benefits of various aspects of NRS. Better evidence on NRS modalities/settings, together with development of interdisciplinary guidelines and enhanced training, might reduce variability.

Background Lomitapide reduces plasma low-density lipoprotein cholesterol (LDL-C) and is approved for the treatment of homozygous familial hypercholesterolemia (HoFH). This study aims to determine the effect of lomitapide on HDL and cholesterol efflux in a cohort of patients with HoFH. Patients and methods Analysis included plasma samples from 17 HoFH patients enrolled in the lomitapide phase 3 Aegerion clinical study (NCT00730236). Samples taken at baseline (pre-lomitapide) and weeks 56 and 66 (assumed steady-state on lomitapide) were analyzed for HDL-C levels and cholesterol efflux capacity (CEC) pathways via ABCA1, ABCG1, and SR–BI cholesterol uptake. Results Treatment with lomitapide is associated with a statistically significant decrease of both LDL-C and apo B when compared to baseline levels, p < 0.01. However, the reduction of Lp(a) appears only at a higher dose when compared to baseline (− 27% against values around − 55% for LDL-C and apo B). HDL-C shows a small 4.2% increase between the baseline and the treatment with a high dosage of lomitapide, while apo A–I displays an opposite small 3% decrease. Total efflux and ABCA1 mediated CEC decreased especially at higher dosage of lomitapide, with marked dose-dependent increase of SR–BI cholesterol uptake (+ 21.4% and + 64.3%, respectively, at a low and high dosages of lomitapide). However, ABCG1 did not change consistently. Conclusions Our report raises the hypothesis that lomitapide promotes lipidation of HDL particles independently of ABCA1 and ABCG1 through a process involving SR–BI pathway. This effect impairs the total efflux process suggesting that lomitapide drives the reverse cholesterol transport through SR–BI receptors in HoFH patients.

Introduction Performing total joint replacements (TJR) in patients with solid organ transplantations (SOT) is associated with an increased risk of complications and reoperation. The aim of this study is to report on implant survivorship, patient survivorship, and complication rates for total knee arthroplasty (TKA) and total hip arthroplasty (THA) performed in heart, lung, liver and kidney transplant recipients. Materials and methods Forty patients with heart, lung, liver, or kidney transplants who underwent primary THA or TKA between January 1, 2013, and July 31, 2023, were included. Implant survivorship, reoperation-free survivorship, patient survivorship, and complication rates were compared between the subgroups. Results At a mean follow-up of 5.18 years, Implant survivorship and reoperation-free survival for the entire cohort at the last follow-up were 97.5% and 85%, respectively. Kaplan–Meier survival estimates demonstrated 5- and 10-year reoperation-free survival rates of 86.5% (95% CI: 76%–98.4%) and 57.6% (95% CI: 25.6%–100%), respectively. The lung transplant group had the shortest reoperation-free survival, although not statistically significant (p = 0.07), a significantly higher risk of reoperation, with a hazard ratio (HR) of 6.9 (95% CI: 1.1–41.2, p = 0.04) and both the lowest 5-year patient survivorship at 68.6% (p = 0.04) and the highest risk of death after TJR with a HR of 7 (95% CI: 1.2–45.5, p = 0.03). Conclusion Patients with SOT exhibit excellent mid-term implant survivorship, with a rate of 97.5%. Lung transplant recipients show the lowest rates of both reoperation-free survival and overall patient survivorship compared to heart, kidney, and liver transplant recipients. Despite this, the 90-day complication rates are similar across all organ groups.

Oncogenic translocations involving the MET gene have been reported in several cancer types, but detailed clinicogenomic characterization of these cancers is not well defined. In addition, prospective clinical trials evaluating the antitumor activity of MET inhibitors in MET rearrangement-positive cancers are limited. Here, in a pan-cancer analysis of >46,000 solid tumors with comprehensive genomic profiling, we identified oncogenic MET rearrangements in ~0.04% of cancers. Preliminary analysis from a phase 2 clinical trial of the type I MET tyrosine kinase inhibitor (TKI) vebreltinib in MET fusion-positive solid tumors demonstrated an objective response rate of 50% and disease control rate of 79%, with antitumor activity seen in diverse cancer types including lung adenocarcinoma, intrahepatic cholangiocarcinoma, among others. Similar to MET exon 14-altered lung cancer, secondary mutations in the kinase domain can confer resistance to MET TKIs in MET fusion-positive cancers. Overall, these data categorize MET rearrangements as actionable targets in solid tumors.

Tuberculosis (TB) is an infectious disease closely intertwined with stigma, discrimination, and the social determinants of health. Communities of people affected by TB are experts in their care pathways, but the TB field continues to fall short of meaningfully engaging communities in TB research. This is a missed opportunity to improve the quality, relevance, person-centeredness, positive impact, and sustainability of TB research outputs. We acknowledge the important progress that has been made to date regarding community engagement in TB, but emphasize persisting barriers to meaningful engagement, and the urgent need for updated and comprehensive TB-specific standards for such engagement in research. We highlight that core components of these standards should include the mobilisation of communities affected by TB, bilateral training in community engagement (for researchers and communities), as well as ensuring appropriate remuneration, representation of priority groups, and the use of non-stigmatising language in the engagement process. In addition, to meaningfully incorporate the experiences and expertise of communities affected by TB, their engagement in the research process should occur as early as possible, ideally before research priorities and directions are set, and the scope of the research should encompass questions and outputs relevant to the community. Further, knowledge-sharing between researchers and the community should be ensured, not only of the research outputs but also regarding the engagement process itself, so that lessons learned can be carried forward. Lastly, the sustainability of community engagement processes (whether within institutions or projects) should be ensured, including through adequate funding for such engagement and the training, community mobilisation and relationship-building that this requires.

Background To reach UNAIDS 95-95-95 targets, digital HIV self-testing (HIVST) strategy aided by applications, platforms, and readers can engage young people and adults living with undetected HIV infection. Evidence on its acceptability, feasibility, impact exists, yet accuracy data are limited. Methods A secondary data analysis of a quasi-RCT of digital HIVST in South Africa was performed. We hypothesized app-guided digital interpretation of oral self-test enhanced test accuracy. We compared accuracy between digital HIVST supervised vs. unsupervised (with/without healthcare worker). Self-test results were interpreted and uploaded by participants, compared using computer vision technology, against lab reference standard by trained healthcare professionals. Results 1513 digital HIVST participants reported pooled Sensitivity (Sn) = 95.52% (95% CI, 94.48%-96.56%); Specificity (Sp): 99.93% (95% CI, 99.79%-100.06%); Positive predictive value (PPV): 99.22% (95% CI, 98.78%-99.67%); Negative Predictive Value (NPV): 99.57% (95% CI, 99.24%-99.90%). 565 participants on supervised digital HIVST, reported a pooled Sn: 93.65% (95% CI, 91.64-95.66); Sp: 100.00% (95% CI, 100.00-100.00); PPV: 100.00% (95% CI, 100.00-100.00); NPV: 99.21% (95% CI, 98.48-99.94). 968 unsupervised digital HIVST participants, reported a pooled Sn: 97.18% (95% CI, 96.13-98.24); Sp: 99.89% (95% CI, 99.67-100.10); PPV: 98.57% (95% CI, 97.82-99.33); NPV: 99.77% (95% CI, 99.47-100.08). Non-digital HIVST vs. study digital HIVST data at 5% significance level - Sn: chi = 0.6495, p-value = 0.4203, Sp: chi = 0.3831, p-value = 0.5259. Supervised vs. unsupervised HIVST at 5% significance level - Sn: chi = 0.973, p-value = 0.3237, Sp: chi = 0.527, p-value = 0.4449. Conclusions Digital HIVST improved interpretation of test results, increased accuracy and predictive value estimations (upper limit 98%-100%), removing subjectivity. Unsupervised digital HIVST users performed better than supervised. Digital HIVST results can potentially signal a rapid triage to therapy or prevention pathways, while awaiting lab confirmation. Findings have implications for scale up of digital HIVST initiatives in global settings.