Association between Serum Estradiol and Cardiovascular Health among Transgender Adults Using Gender-Affirming Estrogen Therapy.

INTRODUCTION: Gender-affirming estrogen therapy (GAET) is commonly used for feminization in transgender and non-binary (TNB) individuals, yet the optimal rate of change (ROC) in estradiol levels for cardiovascular health is unclear. We examined the association between serum estradiol levels and cardiovascular-related mortality, adverse events, and risk factors in TNB adults using GAET. METHODS: Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE and Web of Science were systematically searched (inception-April 2023) for original articles reporting serum estradiol levels and cardiovascular-related mortality, adverse events, and risk factors in TNB adults using GAET. Data extraction was completed in duplicate following PRISMA guidelines. Stratified random effects meta-analyses using serum estradiol ROC (serum estradiolbaseline-serum estradiolfollow-up/study duration) was used to assess longitudinal studies (Low:0

Prescribing patterns and medications costs in patients on maintenance hemodialysis and peritoneal dialysis.

BACKGROUND AND HYPOTHESIS: Polypharmacy is a significant clinical issue for patients on dialysis but has been incompletely studied. We investigated the prevalence and costs of polypharmacy in a population-based cohort of participants treated with hemodialysis (HD) or peritoneal dialysis (PD). METHODS: We studied adults aged ≥ 20 years in Alberta, Canada receiving maintenance HD or PD as of March 31, 2019. We characterized participants as users of 0-29 drug categories of interest and those aged ≥ 65 as users/non-users of potentially inappropriate medications (PIM). We calculated the number of drug categories, daily pill burden, total annual cost, and annual cost per participant, and compared this to an age- and sex-matched cohort from the general Alberta population. RESULTS: Among 2 248 participants (mean age 63 years; 39% female) on HD (n = 1 781) or PD (n = 467), the median number of prescribed drug categories was 6 [interquartile range (IQR) 4, 8]; median daily pill burden was 8.0 (IQR 4.6, 12.6) pills/day, with 5% prescribed ≥ 21.7 pills/day, and 16.5% prescribed ≥ 15 pills/day. Twelve % were prescribed at least one drug that is contraindicated in kidney failure. The median annual per participant cost was ${\$}$3,831, totaling approximately ${\$}$11.6 million annually for all participants. When restricting to the 1 063 participants aged ≥ 65, the median number of PIM categories was 2 (IQR 1, 2), with a median PIM pill burden of 1.2 pills/day (IQR 0.5, 2.4). Compared to PD participants, HD participants had similar daily pill burden, higher use of PIM, and higher annual per participant cost. Pill burden and associated costs for participants on dialysis were more than 3-fold and 10-fold higher, respectively, compared to the matched participants from the general population. CONCLUSION: Participants on dialysis have markedly higher use of prescription medications and associated costs than the general population. Effective methods to de-prescribe in the dialysis population are needed.

Recovery of kidney function after acute kidney disease-a multi-cohort analysis.

BACKGROUND: There are no consensus definitions for evaluating kidney function recovery after acute kidney injury (AKI) and acute kidney disease (AKD), nor is it clear how recovery varies across populations and clinical subsets. We present a federated analysis of four population-based cohorts from Canada, Denmark and Scotland, 2011-18. METHODS: We identified incident AKD defined by serum creatinine changes within 48 h, 7 days and 90 days based on KDIGO AKI and AKD criteria. Separately, we applied changes up to 365 days to address widely used e-alert implementations that extend beyond the KDIGO AKI and AKD timeframes. Kidney recovery was based on resolution of AKD and a subsequent creatinine measurement below 1.2× baseline. We evaluated transitions between non-recovery, recovery and death up to 1 year; within age, sex and comorbidity subgroups; between subset AKD definitions; and across cohorts. RESULTS: There were 464 868 incident cases, median age 67-75 years. At 1 year, results were consistent across cohorts, with pooled mortalities for creatinine changes within 48 h, 7 days, 90 days and 365 days (and 95% confidence interval) of 40% (34%-45%), 40% (34%-46%), 37% (31%-42%) and 22% (16%-29%) respectively, and non-recovery of kidney function of 19% (15%-23%), 30% (24%-35%), 25% (21%-29%) and 37% (30%-43%), respectively. Recovery by 14 and 90 days was frequently not sustained at 1 year. Older males and those with heart failure or cancer were more likely to die than to experience sustained non-recovery, whereas the converse was true for younger females and those with diabetes. CONCLUSION: Consistently across multiple cohorts, based on 1-year mortality and non-recovery, KDIGO AKD (up to 90 days) is at least prognostically similar to KDIGO AKI (7 days), and covers more people. Outcomes associated with AKD vary by age, sex and comorbidities such that older males are more likely to die, and younger females are less likely to recover.

Patterns of metformin use and glycated haemoglobin trends among patients with newly diagnosed type 2 diabetes in Alberta, Canada.

AIM: Canadian guidelines recommend metformin as first-line therapy for incident uncomplicated type 2 diabetes and the vast majority of patients are treated accordingly. However, only 54% 65% remain on treatment after 1 year, with the highest discontinuation rates within the first 3 months. The purpose of this study was: (a) to identify individual and clinical factors associated with metformin discontinuation among patients with newly diagnosed uncomplicated type 2 diabetes in Alberta, Canada, and (b) describe glycated haemoglobin (HbA1c) trajectories in the first 12 months after initiation of pharmacotherapy, stratified by metformin usage pattern. MATERIALS AND METHODS: We conducted a retrospective cohort study using linked administrative datasets from 2012 to 2017 to define a cohort of individuals with uncomplicated incident type 2 diabetes. Using logistic regression, we determined individual and clinical characteristics associated with metformin discontinuation. We categorized individuals based on patterns of metformin use and then used mean HbA1c measurements over a 12-month follow-up period to determine glycaemic trajectories for each pattern. RESULTS: Characteristics associated with metformin discontinuation were younger age, lower baseline HbA1c and having fewer comorbidities. Sex, income and location (urban/rural) were not significantly associated with metformin discontinuation. Individuals who continued metformin with higher adherence and individuals who discontinued metformin entirely had lowest HbA1c values at 12 months from treatment initiation. Those who changed therapy or had additional therapies added had higher HbA1c values at 12 months. CONCLUSION: Identifying characteristics associated with discontinuation of metformin and individuals' medication usage patterns provide an opportunity for targeted interventions to support patients' glycaemic management.

Sodium-glucose co-transporter-2 inhibitors are associated with kidney benefits at all degrees of albuminuria: A retrospective cohort study of adults with diabetes.

AIM: To estimate the real-world effectiveness of sodium-glucose co-transporter-2 inhibitors (SGLT2is) versus dipeptidyl peptidase-4 inhibitors (DPP4is) at reducing loss of kidney function and adverse kidney events in adults with varying levels of albuminuria. MATERIALS AND METHODS: In this retrospective cohort study using administrative data, we matched new SGLT2i users 1:2 to DPP4i users on diabetes therapy, chronic kidney disease (CKD) stage, albuminuria and time-conditional propensity score. Albuminuria was defined by spot urine albumin or equivalent as mild, moderate or severe. Linear regression was used to model the estimated glomerular filtration rate (eGFR), and Poisson regression for a composite kidney outcome (> 40% loss of eGFR, kidney replacement therapy or death from kidney causes) and all-cause mortality. RESULTS: SGLT2i users (n = 19 238, median age 57.9 years, female 40.9%) had mostly nil/mild albuminuria (70.7%). SGLT2is were associated with a 1.36 (95% CI 0.98-1.74) mL/min/1.73m2 (P < .001) acute (≤ 60 days) decline in eGFR, relative to DPP4is. Thereafter, SGLT2is were associated with 1.04 (95% CI 0.93-1.15) mL/min/1.73m2 (P < .001) less annual eGFR loss. SGLT2i users had fewer adverse kidney outcomes (incidence rate ratio [IRR] 0.58 [0.47-0.71]; P < .001), but not all-cause mortality (IRR 0.82 [0.66-1.01]; P = .06). Outcomes were similar considering only those with nil/mild albuminuria. CONCLUSIONS: SGLT2is may prevent eGFR decline and reduce the risk of adverse kidney events in adults with diabetes and nil or non-severe albuminuria.

The Impact of Primary Care Clinic and Family Physician Continuity on Patient Health Outcomes: A Retrospective Analysis From Alberta, Canada.

PURPOSE: Continuity of care is broadly associated with better patient health outcomes. The relative contributions of continuity with an individual physician and with a practice, however, have not generally been distinguished. This retrospective observational study examined the impact of continuity of care for patients seen at their main clinic but by different family physicians. METHODS: We analyzed linked health administrative data from 2015-2018 from Alberta, Canada to explore the association of physician and clinic continuity with rates of emergency department (ED) visits and hospitalizations across varying levels of patient complexity. Physician continuity was calculated using the known provider of care index and clinic continuity with an analogous measure. We developed zero-inflated negative binomial models to assess the association of each with all-cause ED visits and hospitalizations. RESULTS: High physician continuity was associated with lower ED use across all levels of patient complexity and with fewer hospitalizations for highly complex patients. Broadly, no (0%) clinic continuity was associated with increased use and complete (100%) clinic continuity with decreased use, with the largest effect seen for the most complex patients. Levels of clinic continuity between 1% and 50% were generally associated with slightly higher use, and levels of 51% to 99% with slightly lower use. CONCLUSIONS: The best health care outcomes (measured by ED visits and hospitalizations) are associated with consistently seeing one's own primary family physician or seeing a clinic partner when that physician is unavailable. The effect of partial clinic continuity appears complex and requires additional research. These results provide some reassurance for part-time and shared practices, and guidance for primary care workforce policy makers.

Association between sodium-glucose cotransporter-2 inhibitors and arrhythmic outcomes in patients with diabetes and pre-existing atrial fibrillation.

AIMS: Prior studies suggest that sodium-glucose cotransporter-2 inhibitors (SGLT2is) may decrease the incidence of atrial fibrillation (AF). However, it is unknown whether SGLT2i can attenuate the disease course of AF among patients with pre-existing AF and Type II diabetes mellitus (DM). In this study, our objective was to examine the association between SGLT2i prescription and arrhythmic outcomes among patients with DM and pre-existing AF. METHODS AND RESULTS: We conducted a population-based cohort study of adults with DM and AF between 2014 and 2019. Using a prevalent new-user design, individuals prescribed SGLT2i were matched 1:1 to those prescribed dipeptidyl peptidase-4 inhibitors (DPP4is) based on time-conditional propensity scores. The primary endpoint was a composite of AF-related healthcare utilization (i.e. hospitalization, emergency department visits, electrical cardioversion, or catheter ablation). Secondary outcome measures included all-cause mortality, heart failure (HF) hospitalization, and ischaemic stroke or transient ischaemic attack (TIA). Cox proportional hazard models were used to examine the association of SGLT2i with the study endpoint. Among 2242 patients with DM and AF followed for an average of 3.0 years, the primary endpoint occurred in 8.7% (n = 97) of patients in the SGLT2i group vs. 10.0% (n = 112) of patients in the DPP4i group [adjusted hazard ratio 0.73 (95% confidence interval 0.55-0.96; P = 0.03)]. Sodium-glucose cotransporter-2 inhibitors were associated with significant reductions in all-cause mortality and HF hospitalization, but there was no difference in the risk of ischaemic stroke/TIA. CONCLUSION: Among patients with DM and pre-existing AF, SGLT2is are associated with decreased AF-related health resource utilization and improved arrhythmic outcomes compared with DPP4is.

Anxiety and depressive symptoms and migraine-related outcomes in children and adolescents.

OBJECTIVE: The objective of this study was to explore the longitudinal relationship between anxiety and depressive symptoms and migraine outcomes in children and adolescents. BACKGROUND: Children and adolescents with migraine experience more anxiety and depressive symptoms than their peers without migraine, but it is unknown if these symptoms are associated with differential migraine outcomes. METHODS: In this prospective clinical cohort study, children and adolescents aged 8.0-18.0 years with migraine completed headache questionnaires and validated measures of anxiety and depressive symptoms (Patient-Reported Outcomes Measurement Information System) at an initial consultation and at their first follow-up visit with a neurologist. Changes in monthly headache frequency and changes in migraine-related disability (Pediatric Migraine Disability Assessment) were tracked at each time point. The relationships between these migraine outcomes and anxiety and depressive symptoms were estimated using models controlling for sex, age, headache frequency, and treatment type. RESULTS: There were 123 consenting participants. In models adjusted for age, sex, baseline disability score, and treatment type, baseline anxiety and depressive symptom levels were not significantly associated with change in headache frequency (for anxiety symptoms: ß = -0.05, 95% confidence interval [CI] = -0.268 to 0.166, p = 0.639; for depressive symptoms: ß = 0.14, 95% CI = -0.079 to 0.359, p = 0.209). Similarly, in models adjusted for age, sex, baseline headache frequency, and treatment type, the change in disability was not associated with baseline anxiety (ß = -0.45, 95% CI = -1.69 to 0.78, p = 0.470), nor with baseline depressive symptom scores (ß = 0.16, 95% CI = -1.07 to 1.40, p = 0.796). In post hoc exploratory analyses (N = 84 with anxiety and N = 82 with depressive symptom data at both visits), there were also no significant associations between change in mental health symptoms and change in headache frequency (for anxiety symptoms: ß = -0.084, 95% CI = -0.246 to 0.078, p = 0.306; for depressive symptoms: ß = -0.013, 95% CI = -0.164 to 0.138, p = 0.865). Similarly, the change in disability scores between visits was not related to the change in anxiety (ß = 0.85, 95% CI = -0.095 to 1.78, p = 0.077) nor depressive symptom scores (ß = 0.32, 95% CI = -0.51 to 1.15, p = 0.446). CONCLUSION: Baseline anxiety and depressive symptom levels were not associated with longitudinal migraine outcomes and neither were longitudinal changes in anxiety and depressive symptom levels; this contradicts popular clinical belief that mental health symptoms predict or consistently change in tandem with migraine outcomes.

Ten-Year Trends in Lithium Prescribing in Alberta, Canada.

AIMS: Despite lithium's clinical efficacy, it is commonly thought that its use is declining. The objective of this study is to describe the new and prevalent lithium users as well as rates of discontinuation of lithium use over a 10-year period. METHODS: This study used provincial administrative health data from Alberta, Canada between January 1, 2009 and December 31, 2018. Lithium prescriptions were identified within the Pharmaceutical Information Network database. Total and subgroup specific frequencies of new and prevalent lithium use were determined over the 10-year study period. Lithium discontinuation was also estimated through survival analysis. RESULTS: Between the calendar years of 2009 and 2018, 580,873 lithium prescriptions were dispensed in Alberta to 14,008 patients. The total number of new and prevalent lithium users appears to be decreasing over the 10-year timeframe, although the decline may have stopped or reversed in the latter years of the study period. Prevalent use of lithium was lowest among individuals between the ages of 18-24 years while the highest number of prevalent users were in the 50-64 age group, particularly among females. New lithium use was lowest amongst those 65 years and older. More than 60% (8,636) of patients prescribed lithium, discontinued use during the study timeframe. Lithium users between ages of 18-24 years were at the highest risk of discontinuations. CONCLUSIONS: Rather than a general decline in prescribing, trends in lithium use are dependent on age and sex. Further, the period soon after lithium initiation appears to be a key time period in which many lithium trials are abandoned. Detailed studies using primary data collection are needed to confirm and further explore these findings. These population-based results not only confirm a decline in lithium use, but also suggest that this may have stopped or even reversed. Population-based data on discontinuation pinpoint the period soon after initiation as the time when trials are most often discontinued.

Association of Kidney Function With Major Postoperative Events After Noncardiac Ambulatory Surgeries: A Population-Based Cohort Study.

OBJECTIVE: The aim of this study was to estimate the association between estimated glomerular filtration rate (eGFR) and acute myocardial infarction (AMI) or death after ambulatory noncardiac surgery. SUMMARY BACKGROUND DATA: People with chronic kidney disease (CKD) commonly undergo surgical procedures. Although most are performed in an ambulatory setting, the risk of major perioperative outcomes after ambulatory surgery for people with CKD is unknown. METHODS: In this retrospective population-based cohort study using administrative health data from Alberta, Canada, we included adults with measured preoperative kidney function undergoing ambulatory noncardiac surgery between April 1, 2005 and February 28, 2017. Participants were categorized into 6 eGFR categories (in mL/min/1.73m 2 )of ≥60 (G1-2), 45 to 59 (G3a), 30 to 44 (G3b), 15 to 29 (G4), <15 not receiving dialysis (G5ND), and those receiving chronic dialysis (G5D). The odds of AMI or death within 30 days of surgery were estimated using multivariable generalized estimating equation models. RESULTS: We identified 543,160 procedures in 323,521 people with a median age of 66 years (IQR 56-76); 52% were female. Overall, 2338 people (0.7%) died or had an AMI within 30 days of surgery. Compared with the G1-2 category, the adjusted odds ratio of death or AMI increased from 1.1 (95% confidence interval: 1.0-1.3) for G3a to 3.1 (2.6-3.6) for G5D. Emergency Department and Urgent Care Center visits within 30 days were frequent (17%), though similar across eGFR categories. CONCLUSIONS: Ambulatory surgery was associated with a low risk of major postoperative events. This risk was higher for people with CKD, which may inform their perioperative shared decision-making and management.

Variations in Incidence and Prognosis of Stage 4 CKD Among Adults Identified Using Different Algorithms: A Population-Based Cohort Study.

RATIONALE & OBJECTIVE: Clinical guidelines define chronic kidney disease (CKD) as abnormalities of kidney structure or function for>3 months. Assessment of the duration criterion may be implemented in different ways, potentially impacting estimates of disease incidence or prevalence in the population, individual diagnosis, and treatment decisions, especially for more severe cases. We investigated differences in incidence and prognosis of CKD stage G4 identified by 1 of 4 algorithms. STUDY DESIGN: Population-based cohort study in Alberta, Canada. SETTING & PARTICIPANTS: Residents>18 years old with incident CKD stage G4 (eGFR 15-29mL/min/1.73m2) diagnosed between April 1, 2015, and March 31, 2018, based on administrative and laboratory data. EXPOSURE: Four outpatient eGFR-based algorithms, increasing in stringency, for defining cohorts with CKD G4 were evaluated: (1) a single test, (2) first eGFR<30mL/min/1.73m2 and a second eGFR 15-29mL/min/1.73m2 measured>90 days apart (2 tests), (3) ≥2 eGFR measurements of<30mL/min/1.73m2 sustained for>90 days (qualifying period) and the last eGFR in the qualifying period of 15-29mL/min/1.73m2 (relaxed sustained), and (4) ≥2 consecutive measurements of 15-29mL/min/1.73m2 for>90 days (rigorous sustained). OUTCOME: Time to the earliest of death, eGFR improvement (a sustained increase in eGFR to≥30mL/min/1.73m2 for>90 days and>25% increase from the index eGFR), or kidney failure. ANALYTICAL APPROACH: For each of the 4 cohorts, incidence rates and event-specific cumulative incidence functions at 1 year from cohort entry were estimated. RESULTS: The incidence rates of CKD G4 decreased as algorithms became more stringent, from 190.7 (single test) to 79.9 (rigorous sustained) per 100,000 person-years. The 2 cohorts based on sustained reductions in eGFR were of comparable size and 1-year event-specific probabilities. The 2 cohorts based on a single test and a 2-test sequence were larger and experienced higher probabilities of eGFR improvement. LIMITATIONS: A short follow-up period of 1 year and a predominantly White population. CONCLUSIONS: The use of more stringent algorithms for defining CKD G4 results in substantially lower estimates of disease incidence, the identification of a group with a lower probability of eGFR improvement, and a higher risk of kidney failure. These findings can inform implementation decisions of disease definitions in clinical reporting systems and research studies. PLAIN-LANGUAGE SUMMARY: Although guidelines recommend>3 months to define chronic kidney disease (CKD), the methods for defining specific stages, particularly G4 (eGFR 15-29mL/min/1.73m2) when referral to nephrology services is recommended, have been implemented differently across studies and surveillance programs. We studied differences in incidence and prognosis of CKD G4 cohorts identified by 4 algorithms using administrative and outpatient laboratory databases in Alberta, Canada. We found that, compared with a single-test definition, more stringent definitions resulted in a lower disease incidence and identified a group with worse short-term kidney outcomes. These findings highlight the impact of the choice of algorithm used to define CKD G4 on disease burden estimates at the population level, on individual prognosis, and on treatment/referral decisions.

20-year trends in multimorbidity by race/ethnicity among hospitalized patient populations in the United States.

BACKGROUND: The challenges presented by multimorbidity continue to rise in the United States. Little is known about how the relative contribution of individual chronic conditions to multimorbidity has changed over time, and how this varies by race/ethnicity. The objective of this study was to describe trends in multimorbidity by race/ethnicity, as well as to determine the differential contribution of individual chronic conditions to multimorbidity in hospitalized populations over a 20-year period within the United States. METHODS: This is a serial cross-sectional study using the Nationwide Inpatient Sample (NIS) from 1993 to 2012. We identified all hospitalized patients aged ≥ 18 years old with available data on race/ethnicity. Multimorbidity was defined as the presence of 3 or more conditions based on the Elixhauser comorbidity index. The relative change in the proportion of hospitalized patients with multimorbidity, overall and by race/ethnicity (Black, White, Hispanic, Asian/Pacific Islander, Native American) were tabulated and presented graphically. Population attributable fractions were estimated from modified Poisson regression models adjusted for sex, age, and insurance type. These fractions were used to describe the relative contribution of individual chronic conditions to multimorbidity over time and across racial/ethnic groups. RESULTS: There were 123,613,970 hospitalizations captured within the NIS between 1993 and 2012. The prevalence of multimorbidity increased in all race/ethnic groups over the 20-year period, most notably among White, Black, and Native American populations (+ 29.4%, + 29.7%, and + 32.0%, respectively). In both 1993 and 2012, Black hospitalized patients had a higher prevalence of multimorbidity (25.1% and 54.8%, respectively) compared to all other race/ethnic groups. Native American populations exhibited the largest overall increase in multimorbidity (+ 32.0%). Furthermore, the contribution of metabolic diseases to multimorbidity increased, particularly among Hispanic patients who had the highest population attributable fraction values for diabetes without complications (15.0%), diabetes with complications (5.1%), and obesity (5.8%). CONCLUSIONS: From 1993 to 2012, the secular increases in the prevalence of multimorbidity as well as changes in the differential contribution of individual chronic conditions has varied substantially by race/ethnicity. These findings further elucidate the racial/ethnic gaps prevalent in multimorbidity within the United States. PRIOR PRESENTATIONS: Preliminary finding of this study were presented at the Society of General Internal Medicine (SGIM) Annual Conference, Washington, DC, April 21, 2017.

Perioperative management for people with kidney failure receiving dialysis: A scoping review.

BACKGROUND: People with kidney failure receiving dialysis (CKD-G5D) are more likely to undergo surgery and experience poorer postoperative outcomes than those without kidney failure. In this scoping review, we aimed to systematically identify and summarize perioperative strategies, protocols, pathways, and interventions that have been studied or implemented for people with CKD-G5D. METHODS: We searched MEDLINE, EMBASE, CINAHL Plus, Cochrane Database of Systematic Reviews, and Cochrane Controlled Trials registry (inception to February 2020), in addition to an extensive grey literature search, for sources that reported on a perioperative strategy to guide management for people with CKD-G5D. We summarized the overall study characteristics and perioperative management strategies and identified evidence gaps based on surgery type and perioperative domain. Publication trends over time were assessed, stratified by surgery type and study design. RESULTS: We included 183 studies; the most common study design was a randomized controlled trial (27%), with 67% of publications focused on either kidney transplantation or dialysis vascular access. Transplant-related studies often focused on fluid and volume management strategies and risk stratification, whereas dialysis vascular access studies focused most often on imaging. The number of publications increased over time, across all surgery types, though driven by non-randomized study designs. CONCLUSIONS: Despite many current gaps in perioperative research for patients with CKD-G5D, evidence generation supporting perioperative management is increasing, with recent growth driven primarily by non-randomized studies. Our review may inform organization of evidence-based strategies into perioperative care pathways where evidence is available while also highlighting gaps that future perioperative research can address.

Prediction of major postoperative events after non-cardiac surgery for people with kidney failure: derivation and internal validation of risk models.

BACKGROUND: People with kidney failure often require surgery and experience worse postoperative outcomes compared to the general population, but existing risk prediction tools have excluded those with kidney failure during development or exhibit poor performance. Our objective was to derive, internally validate, and estimate the clinical utility of risk prediction models for people with kidney failure undergoing non-cardiac surgery. DESIGN, SETTING, PARTICIPANTS, AND MEASURES: This study involved derivation and internal validation of prognostic risk prediction models using a retrospective, population-based cohort. We identified adults from Alberta, Canada with pre-existing kidney failure (estimated glomerular filtration rate [eGFR] < 15 mL/min/1.73m2 or receipt of maintenance dialysis) undergoing non-cardiac surgery between 2005-2019. Three nested prognostic risk prediction models were assembled using clinical and logistical rationale. Model 1 included age, sex, dialysis modality, surgery type and setting. Model 2 added comorbidities, and Model 3 added preoperative hemoglobin and albumin. Death or major cardiac events (acute myocardial infarction or nonfatal ventricular arrhythmia) within 30 days after surgery were modelled using logistic regression models. RESULTS: The development cohort included 38,541 surgeries, with 1,204 outcomes (after 3.1% of surgeries); 61% were performed in males, the median age was 64 years (interquartile range [IQR]: 53, 73), and 61% were receiving hemodialysis at the time of surgery. All three internally validated models performed well, with c-statistics ranging from 0.783 (95% Confidence Interval [CI]: 0.770, 0.797) for Model 1 to 0.818 (95%CI: 0.803, 0.826) for Model 3. Calibration slopes and intercepts were excellent for all models, though Models 2 and 3 demonstrated improvement in net reclassification. Decision curve analysis estimated that use of any model to guide perioperative interventions such as cardiac monitoring would result in potential net benefit over default strategies. CONCLUSIONS: We developed and internally validated three novel models to predict major clinical events for people with kidney failure having surgery. Models including comorbidities and laboratory variables showed improved accuracy of risk stratification and provided the greatest potential net benefit for guiding perioperative decisions. Once externally validated, these models may inform perioperative shared decision making and risk-guided strategies for this population.

Underlying genetic architecture of resistance to mastitis in dairy cattle: A systematic review and gene prioritization analysis of genome-wide association studies.

Mastitis, the most frequent disease in dairy cattle. Resistance to mastitis is a complex, polygenic trait controlled by several genes, each with small effects. Genome-wide association studies have been widely used to identify genomic variants associated with complex traits, including resistance to mastitis, to elucidate the underlying genetic architecture of the trait. However, no systematic review and gene prioritization analysis have been conducted to date on GWAS results for resistance to mastitis in dairy cattle. Hence, the objective was to perform a systematic review and gene prioritization analysis of GWAS studies to identify potential functional candidate genes associated with resistance to mastitis-related traits in dairy cattle. Four electronic databases were searched from inception to December 2020, supplemented with multiple sources of gray literature, to identify eligible articles. Annotation for genes and quantitative trait loci (QTL), and QTL enrichment analysis were conducted using GALLO. Gene prioritization analysis was performed by a guilty-by-association approach using GUILDify and ToppGene. From 52 articles included within this systematic review, 30 articles were used for further functional analyses. Gene and QTL annotation resulted in 9,125 and 43,646 unique genes and QTL, respectively, from 39 studies. In general, overlapping of genes across studies was very low (mean ± SD = 0.02% ± 0.07%). Most annotated genes were associated with somatic cell count-related traits and the Holstein breed. Within all annotated genes, 74 genes were shared among Holstein, Jersey, and Ayrshire breeds. Approximately 7.5% of annotated QTL were related to QTL class "health." Within the health QTL class, 2.6 and 2.2% of QTL were associated with clinical mastitis and somatic cell count-related traits. Enrichment analysis of QTL demonstrated that many enriched QTL were associated with somatic cell score located in Bos taurus autosomes 5, 6, 16, and 20. The prioritization analysis resulted in 427 significant genes after multiple test correction (false discovery rate of 5%) from 26 studies. Most prioritized genes were located in Bos taurus autosomes 19 and 7, and most top-ranked genes were from the cytokine superfamily (e.g., chemokines, interleukins, transforming growth factors, and tumor necrosis factor genes). Although most prioritized genes (397) were associated with somatic cell count-related traits, only 54 genes were associated with clinical mastitis-related traits. Twenty-four genes (ABCC9, ACHE, ADCYAP1, ARC, BCL2L1, CDKN1A, EPO, GABBR2, GDNF, GNRHR, IKBKE, JAG1, KCNJ8, KCNQ1, LIFR, MC3R, MYOZ3, NFKB1, OSMR, PPP3CA, PRLR, SHARPIN, SLC1A3, and TNFRSF25) were reported for both somatic cell count and clinical mastitis-related traits. Prioritized genes were mainly associated with immune response, regulation of secretion, locomotion, cell proliferation, and development. In conclusion, this study provided a fine-mapping of previously identified genomic regions associated with resistance to mastitis and identified key functional candidate genes for resistance to mastitis, which can be used to develop enhanced genomic strategies to combat mastitis by increasing mastitis resistance through genetic selection.

Clinical recovery from concussion-return to school and sport: a systematic review and meta-analysis.

OBJECTIVE: To define the time frames, measures used and modifying factors influencing recovery, return to school/learn (RTL) and return to sport (RTS) after sport-related concussion (SRC). DESIGN: Systematic review and meta-analysis. DATA SOURCES: 8 databases searched through 22 March 2022. ELIGIBILITY CRITERIA: Studies with diagnosed/suspected SRC and interventions facilitating RTL/RTS or investigating the time and modifying factors for clinical recovery. Outcomes included days until symptom free, days until RTL and days until RTS. We documented study design, population, methodology and results. Risk of bias was evaluated using a modified Scottish Intercollegiate Guidelines Network tool. RESULTS: 278 studies were included (80.6% cohort studies and 92.8% from North America). 7.9% were considered high-quality studies, while 23.0% were considered high risk of bias and inadmissible. The mean days until symptom free was 14.0 days (95% CI: 12.7, 15.4; I2=98.0%). The mean days until RTL was 8.3 (95% CI: 5.6, 11.1; I2=99.3%), with 93% of athletes having a full RTL by 10 days without new academic support. The mean days until RTS was 19.8 days (95% CI: 18.8, 20.7; I2=99.3%), with high heterogeneity between studies. Several measures define and track recovery, with initial symptom burden remaining the strongest predictor of longer days until RTS. Continuing to play and delayed access to healthcare providers were associated with longer recovery. Premorbid and postmorbid factors (eg, depression/anxiety, migraine history) may modify recovery time frames. Though point estimates suggest that female sex or younger age cohorts take longer to recover, the heterogeneity of study designs, outcomes and overlap in CIs with male sex or older age cohorts suggests that all have similar recovery patterns. CONCLUSION: Most athletes have full RTL by 10 days but take twice as long for an RTS. PROSPERO REGISTRATION NUMBER: CRD42020159928.

Rest and exercise early after sport-related concussion: a systematic review and meta-analysis.

OBJECTIVE: To synthesise the evidence regarding the risks and benefits of physical activity (PA), prescribed aerobic exercise treatment, rest, cognitive activity and sleep during the first 14 days after sport-related concussion (SRC). DESIGN: Meta-analysis was performed for PA/prescribed exercise interventions and a narrative synthesis for rest, cognitive activity and sleep. Risk of bias (ROB) was determined using the Scottish Intercollegiate Guidelines Network and quality assessed using Grading of Recommendations, Assessment, Development and Evaluations. DATA SOURCES: MEDLINE, Embase, APA PsycInfo, Cochrane Central Register of Controlled Trials, CINAHL Plus and SPORTDiscus. Searches were conducted in October 2019 and updated in March 2022. ELIGIBILITY CRITERIA: Original research articles with sport-related mechanism of injury in >50% of study sample and that evaluated how PA, prescribed exercise, rest, cognitive activity and/or sleep impact recovery following SRC. Reviews, conference proceedings, commentaries, editorials, case series, animal studies and articles published before 1 January 2001 were excluded. RESULTS: 46 studies were included and 34 had acceptable/low ROB. Prescribed exercise was assessed in 21 studies, PA in 15 studies (6 PA/exercise studies also assessed cognitive activity), 2 assessed cognitive activity only and 9 assessed sleep. In a meta-analysis of seven studies, PA and prescribed exercise improved recovery by a mean of -4.64 days (95% CI -6.69, -2.59). After SRC, early return to light PA (initial 2 days), prescribed aerobic exercise treatment (days 2-14) and reduced screen use (initial 2 days) safely facilitate recovery. Early prescribed aerobic exercise also reduces delayed recovery, and sleep disturbance is associated with slower recovery. CONCLUSION: Early PA, prescribed aerobic exercise and reduced screen time are beneficial following SRC. Strict physical rest until symptom resolution is not effective, and sleep disturbance impairs recovery after SRC. PROSPERO REGISTRATION NUMBER: CRD42020158928.

Targeted interventions and their effect on recovery in children, adolescents and adults who have sustained a sport-related concussion: a systematic review.

OBJECTIVES: We evaluated interventions to facilitate recovery in children, adolescents and adults with a sport-related concussion (SRC). DESIGN: Systematic review including risk of bias (modified Scottish Intercollegiate Guidelines Network tool). DATA SOURCES: MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Embase, APA PsycINFO, Cochrane Central Register of Controlled Trials, CINAHL Plus with Full Text, SPORTDiscus and Scopus searched until March 2022. STUDY ELIGIBILITY CRITERIA: (1) Original research including randomised controlled trials (RCTs), quasi-experimental designs, cohort, comparative effectiveness studies; (2) focus on SRC; (3) English; (4) peer-reviewed and (5) evaluated treatment. RESULTS: 6533 studies were screened, 154 full texts reviewed and 13 met inclusion (10 RCTs, 1 quasi-experimental and 2 cohort studies; 1 high-quality study, 7 acceptable and 5 at high risk of bias). Interventions, comparisons, timing and outcomes varied, precluding meta-analysis. For adolescents and adults with dizziness, neck pain and/or headaches >10 days following concussion, individualised cervicovestibular rehabilitation may decrease time to return to sport compared with rest followed by gradual exertion (HR 3.91 (95% CI 1.34 to 11.34)) and when compared with a subtherapeutic intervention (HR 2.91 (95% CI 1.01 to 8.43)). For adolescents with vestibular symptoms/impairments, vestibular rehabilitation may decrease time to medical clearance (vestibular rehab group 50.2 days (95% CI 39.9 to 60.4) compared with control 58.4 (95% CI 41.7 to 75.3) days). For adolescents with persisting symptoms >30 days, active rehabilitation and collaborative care may decrease symptoms. CONCLUSIONS: Cervicovestibular rehabilitation is recommended for adolescents and adults with dizziness, neck pain and/or headaches for >10 days. Vestibular rehabilitation (for adolescents with dizziness/vestibular impairments >5 days) and active rehabilitation and/or collaborative care (for adolescents with persisting symptoms >30 days) may be of benefit.

Amsterdam 2022 process: A summary of the methodology for the Amsterdam International Consensus on Concussion in Sport.

The purpose of this paper is to summarise the consensus methodology that was used to inform the International Consensus Statement on Concussion in Sport (Amsterdam 2022). Building on a Delphi process to inform the questions and outcomes from the 5th International Conference on Concussion in Sport, the Scientific Committee identified key questions, the answers to which would help encapsulate the current science in sport-related concussion and help guide clinical practice. Over 3½ years, delayed by 2 years due to the pandemic, author groups conducted systematic reviews on each selected topic. The 6th International Conference on Concussion in Sport was held in Amsterdam (27-30 October 2022) and consisted of 2 days of systematic review presentations, panel discussions, question and answer engagement with the 600 attendees, and abstract presentations. This was followed by a closed third day of consensus deliberations by an expert panel of 29 with observers in attendance. The fourth day, also closed, was dedicated to a workshop to discuss and refine the sports concussion tools (Concussion Recognition Tool 6 (CRT6), Sport Concussion Assessment Tool 6 (SCAT6), Child SCAT6, Sport Concussion Office Assessment Tool 6 (SCOAT6) and Child SCOAT6). We include a summary of recommendations for methodological improvements for future research that grew out of the systematic reviews.

Calculated versus measured albumin-creatinine ratio to predict kidney failure and death in people with chronic kidney disease.

Albumin-to-creatinine ratio (ACR), the preferred method to quantify proteinuria, can be calculated from urine dipstick protein or protein-to-creatinine ratio (PCR). The performance of calculated vs. measured ACR in predicting kidney failure and death without kidney failure in people with chronic kidney disease (CKD) is unknown. Here, we used population-based data from Alberta, Canada, to identify adults with incident moderate-severe CKD (sustained for more than 90 days) from 2008-04-01 to 2017-03-31, who had same-day measures of ACR and urine dipstick (ACR-dipstick cohort) or PCR (ACR-PCR cohort) in the two years before cohort entry. We followed participants until 2019-03-31 and trained competing risk models of kidney failure and death without kidney failure including age, sex, estimated glomerular filtration rate, diabetes, cardiovascular disease, and either measured or calculated ACR. Model performance was tested in cohorts created using the same algorithm in Manitoba, Canada. The ACR-dipstick and ACR-PCR cohorts included 18,731 and 4,542 people (training cohorts) and 821 and 1,831 people (testing cohorts), respectively. In internal and external testing, there was closer agreement between predictions based on measured vs. PCR-calculated ACR than between those based on measured vs. dipstick-calculated ACR. The dipstick-calculated ACR had higher Brier scores than measured ACR from year three for both outcomes, indicating worsening calibration. Models including measured or calculated ACR had similar discrimination: year one-to-five area under the receiver operating characteristic curve of 83-89% for kidney failure and 69-75% for mortality. Thus, if confirmed in different ethnic groups, calculated ACR can be used for risk predictions when the measured ACR is not available. PCR-calculated ACR may have superior performance to dipstick-calculated ACR.