Device-measured physical activity and cardiometabolic health: the Prospective Physical Activity, Sitting, and Sleep (ProPASS) consortium.

BACKGROUND AND AIMS: Physical inactivity, sedentary behaviour (SB), and inadequate sleep are key behavioural risk factors of cardiometabolic diseases. Each behaviour is mainly considered in isolation, despite clear behavioural and biological interdependencies. The aim of this study was to investigate associations of five-part movement compositions with adiposity and cardiometabolic biomarkers. METHODS: Cross-sectional data from six studies (n = 15 253 participants; five countries) from the Prospective Physical Activity, Sitting and Sleep consortium were analysed. Device-measured time spent in sleep, SB, standing, light-intensity physical activity (LIPA), and moderate-vigorous physical activity (MVPA) made up the composition. Outcomes included body mass index (BMI), waist circumference, HDL cholesterol, total:HDL cholesterol ratio, triglycerides, and glycated haemoglobin (HbA1c). Compositional linear regression examined associations between compositions and outcomes, including modelling time reallocation between behaviours. RESULTS: The average daily composition of the sample (age: 53.7 ± 9.7 years; 54.7% female) was 7.7 h sleeping, 10.4 h sedentary, 3.1 h standing, 1.5 h LIPA, and 1.3 h MVPA. A greater MVPA proportion and smaller SB proportion were associated with better outcomes. Reallocating time from SB, standing, LIPA, or sleep into MVPA resulted in better scores across all outcomes. For example, replacing 30 min of SB, sleep, standing, or LIPA with MVPA was associated with -0.63 (95% confidence interval -0.48, -0.79), -0.43 (-0.25, -0.59), -0.40 (-0.25, -0.56), and -0.15 (0.05, -0.34) kg/m2 lower BMI, respectively. Greater relative standing time was beneficial, whereas sleep had a detrimental association when replacing LIPA/MVPA and positive association when replacing SB. The minimal displacement of any behaviour into MVPA for improved cardiometabolic health ranged from 3.8 (HbA1c) to 12.7 (triglycerides) min/day. CONCLUSIONS: Compositional data analyses revealed a distinct hierarchy of behaviours. Moderate-vigorous physical activity demonstrated the strongest, most time-efficient protective associations with cardiometabolic outcomes. Theoretical benefits from reallocating SB into sleep, standing, or LIPA required substantial changes in daily activity.

The randomized controlled trial (NAVKIDS2) of a patient navigator program created for children with chronic kidney disease.

Patient navigators enable adult patients to circumnavigate complex health systems, improving access to health care and outcomes. Here, we aimed to evaluate the effects of a patient navigation program in children with chronic kidney disease (CKD). In this multi-center, randomized controlled trial, we randomly assigned children (aged 0-16 years) with CKD stages 1-5 (including children on dialysis or with kidney transplants), from low socioeconomic status backgrounds, and/or residing in remote areas, to receive patient navigation at randomization (immediate) or at six months (waitlist). The primary outcome was self-rated health (SRH) of participating children at six months, using intention to treat analysis. Secondary outcomes included caregivers' SRH and satisfaction with health care, children's quality of life, hospitalizations, and missed school days. Repeated measures of the primary outcome from baseline to six months were analyzed using cumulative logit mixed effects models. Semi-structured interviews were thematically evaluated. Of 398 screened children, 162 were randomized (80 immediate and 82 waitlist); mean age (standard deviation) of 8.8 (4.8) years with 64.8% male. SRH was not significantly different between the immediate and wait-listed groups at six months. There were also no differences across all secondary outcomes between the two groups. Caregivers' perspectives were reflected in seven themes: easing mental strain, facilitating care coordination, strengthening capacity to provide care, reinforcing care collaborations, alleviating family tensions, inability to build rapport and unnecessary support. Thus, in children with CKD, self-rated health may not improve in response to a navigator program, but caregivers gained skills related to providing and accessing care.

An Economic Evaluation of a Web-Based Management Support System for Children With Urinary Incontinence: The eADVICE Trial.

PURPOSE: Children who require specialist outpatient care typically wait substantial periods during which their condition may progress, making treatment more difficult and costly. Timely and effective therapy during this period may reduce the need for lengthy specialist care. This study evaluated the cost-effectiveness of an individualized, evidence-informed, web-based program for children with urinary incontinence awaiting a specialist appointment (Electronic Advice and Diagnosis Via the Internet following Computerized Evaluation [eADVICE]) compared to usual care. eADVICE was supervised by a primary physician and delivered by an embodied conversational agent. MATERIALS AND METHODS: A trial-based cost-effectiveness analysis was performed from the perspective of the health care funder as a substudy of eADVICE, a multicenter, waitlist-controlled, randomized trial. Outcomes measures were incremental cost per incremental change in continence status and quality of life on an intention-to-treat basis. Uncertainty was examined using cost-effectiveness planes, scenarios, and 1-way sensitivity analyses. Costs were valued in 2021 Australian dollars. RESULTS: The use of eADVICE was found to be cost saving and beneficial (dominant) over usual care, with a higher proportion of children dry over 14 days at 6 months (risk difference 0.13; 95%CI 0.02-0.23, P = .03) and mean health care costs reduced by $188 (95%CI $61-$315) per participant. CONCLUSIONS: An individualized, evidence-informed, web-based program delivered by an embodied conversational agent is likely cost saving for children with urinary incontinence awaiting a specialist appointment. The potential economic impact of such a program is favorable and substantial, and may be transferable to outpatient clinic settings for other chronic health conditions.

A Randomized Controlled Trial of a Web-Based Management Support System for Children With Urinary Incontinence: The eADVICE Trial.

PURPOSE: Children referred to specialist outpatient clinics by primary care providers often have long waiting times before being seen. We assessed whether an individualized, web-based, evidence-informed management support for children with urinary incontinence while waiting reduced requests for specialist appointments. MATERIALS AND METHODS: A multicenter, waitlisted randomized controlled trial was conducted for children (5-18 years) with urinary incontinence referred to tertiary pediatric continence clinics. Participants were randomized to the web-based eHealth program electronic Advice and Diagnosis Via the Internet following Computerized Evaluation (eADVICE), which used an embodied conversational agent to engage with the child at the time of referral (intervention) or 6 months later (control). The primary outcome was the proportion of participants requesting a clinic appointment at 6 months. Secondary outcomes included persistent incontinence, and the Paediatric incontinence Questionnaire (PinQ) score. RESULTS: From 2018 to 2020, 239 children enrolled, with 120 randomized to eADVICE and 119 to the control arm. At baseline, participants' mean age was 8.8 years (SD 2.2), 62% were males, mean PinQ score was 5.3 (SD 2.2), 36% had daytime incontinence, and 97% had nocturnal enuresis. At 6 months, 78% of eADVICE participants vs 84% of controls requested a clinic visit (relative risk 0.92, 95% CI 0.79, 1.06, P = .3), and 23% eADVICE participants vs 10% controls were completely dry (relative risk 2.23, 95% CI 1.10, 4.50, P = .03). The adjusted mean PinQ score was 3.5 for eADVICE and 3.9 for controls (MD -0.37, 95% CI -0.71, -0.03, P = .03). CONCLUSIONS: The eADVICE eHealth program for children awaiting specialist appointments doubled the proportion who were dry at 6 months and improved quality of life but did not reduce clinic appointment requests.

Causal Relationship Between Kidney Function and Cancer Risk: A Mendelian Randomization Study.

RATIONALE & OBJECTIVE: Patients treated with kidney replacement therapy experience a 1.5 to 2-fold increased risk of cancer and cancer mortality compared to the general population. Whether this excess risk extends to people with earlier stages of chronic kidney disease is unclear. This study explored the potentially causal relationship between reduced kidney function and cancer. STUDY DESIGN: Two-sample Mendelian randomization (MR). SETTING & PARTICIPANTS: Genome Wide Association Study (GWAS) summary statistics for estimated glomerular filtration rate (eGFR) (n=567,460) and urinary albuminuria (UACR) (n=127,865) from the CKDGen consortium and cancer outcomes from the UK Biobank (n=407,329). EXPOSURES: eGFR and UACR. OUTCOMES: Overall cancer incidence, cancer-related mortality, and site-specific colorectal, lung, and urinary tract cancer incidence. ANALYTICAL APPROACH: Univariable and multivariable MR were conducted for all outcomes using inverse-variance weighted methods. RESULTS: The mean eGFR and median UACR were 91.4 mL/min/1.73m2 and 9.32 mg/g in the CKDGen and 90.4 mL/min/1.73m2 and 9.29 mg/g in the UK Biobank. There were 98,093 cases of cancer, 6,664 colorectal, 3584 lung, and 3,271 urinary tract. There were 15,850 cases of cancer-related death, The genetic instruments for eGFR and UACR comprised 34 and 38 variants, respectively. Genetically predicted kidney function (eGFR and UACR) was not associated with overall cancer risk or cancer death. No associations of genetically predicted eGFR and UACR with overall cancer incidence were observed; odds ratio (95%CI; p-value) of 0.88 (0.40-1.97; p=0.76) and 0.90 (0.78-1.04; p=0.16), respectively. An adjusted generalized additive model for eGFR and cancer demonstrated evidence of non-linearity. There was no evidence of a causal association between eGFR and cancer in a stratified MR. LIMITATIONS: To avoid overlapping samples a smaller GWAS for UACR was used, reducing the strength of the instrument and potentially introducing population stratification. CONCLUSIONS: These findings did not demonstrate a causal association of kidney function with overall cancer incidence or cancer-related death.

Improving Diverse and Equitable Involvement of Patients and Caregivers in Research in CKD: Report of a Better Evidence and Translation-Chronic Kidney Disease (BEAT-CKD) Workshop.

Patient and caregiver involvement can enhance the uptake and impact of research, but the involvement of patients and caregivers who are underserved and marginalized is often limited. A better understanding of how to make involvement in research more broadly accessible, supportive, and inclusive for patients with chronic kidney disease (CKD) and caregivers is needed. We conducted a national workshop involving patients, caregivers, clinicians, and researchers from across Australia to identify strategies to increase the diversity of patients and caregivers involved in CKD research. Six themes were identified. Building trust and a sense of safety was considered pivotal to establishing meaningful relationships to support knowledge exchange. Establishing community and connectedness was expected to generate a sense of belonging to motivate involvement. Balancing stakeholder goals, expectations, and responsibilities involved demonstrating commitment and transparency by researchers. Providing adequate resources and support included strategies to minimize the burden of involvement for patients and caregivers. Making research accessible and relatable was about nurturing patient and caregiver interest by appealing to intrinsic motivators. Adapting to patient and caregiver needs and preferences required tailoring the approach for individuals and the target community. Strategies and actions to support these themes may support more diverse and equitable involvement of patients and caregivers in research in CKD.

µ-Opioid Receptor Activation at the Dorsal Reticular Nucleus Shifts Diffuse Noxious Inhibitory Controls to Hyperalgesia in Chronic Joint Pain in Male Rats.

BACKGROUND: The dorsal reticular nucleus is a pain facilitatory area involved in diffuse noxious inhibitory control (DNIC) through opioidergic mechanisms that are poorly understood. The hypothesis was that signaling of µ-opioid receptors is altered in this area with prolonged chronic inflammatory pain and that this accounts for the loss of DNICs occurring in this condition. METHODS: Monoarthritis was induced in male Wistar rats (n = 5 to 9/group) by tibiotarsal injection of complete Freund's adjuvant. The immunolabeling of µ-opioid receptors and the phosphorylated forms of µ-opioid receptors and cAMP response element binding protein was quantified. Pharmacologic manipulation of µ-opioid receptors at the dorsal reticular nucleus was assessed in DNIC using the Randall-Selitto test. RESULTS: At 42 days of monoarthritis, µ-opioid receptor labeling decreased at the dorsal reticular nucleus, while its phosphorylated form and the phosphorylated cAMP response element binding protein increased. [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin acetate (DAMGO) enhanced DNIC analgesia in normal animals (means ± SD: pre-DNIC: 126.9 ± 7.0 g; DNIC - DAMGO: 147.5 ± 8.0 g vs. DNIC + DAMGO: 198.1 ± 19.3 g; P < 0.001), whereas it produced hyperalgesia in monoarthritis (pre-DNIC: 67.8 ± 7.5 g; DNIC - DAMGO: 70.6 ± 7.7 g vs. DNIC + DAMGO: 32.2 ± 2.6 g; P < 0.001). An ultra-low dose of naloxone, which prevents the excitatory signaling of the µ-opioid receptor, restored DNIC analgesia in monoarthritis (DNIC - naloxone: 60.0 ± 6.1 g vs. DNIC + naloxone: 98.0 ± 13.5 g; P < 0.001), compared to saline (DNIC - saline: 62.5 ± 5.2 g vs. DNIC + saline: 64.2 ± 3.8 g). When injected before DAMGO, it restored DNIC analgesia and decreased the phosphorylated cAMP response element binding protein in monoarthritis. CONCLUSIONS: The dorsal reticular nucleus is likely involved in a facilitatory pathway responsible for DNIC hyperalgesia. The shift of µ-opioid receptor signaling to excitatory in this pathway likely accounts for the loss of DNIC analgesia in monoarthritis.

Outcomes for clinical trials involving adults with chronic kidney disease: a multinational Delphi survey involving patients, caregivers and health professionals.

BACKGROUND: Many outcomes of high priority to patients and clinicians are infrequently and inconsistently reported across trials in chronic kidney disease (CKD), which generates research waste and limits evidence-informed decision making. We aimed to generate consensus among patients/caregivers and health professionals on critically important outcomes for trials in CKD prior to kidney failure and the need for kidney replacement therapy, and to describe the reasons for their choices. METHODS: This was an online two-round international Delphi survey. Adult patients with CKD (all stages and diagnoses), caregivers and health professionals who could read English, Spanish or French were eligible. Participants rated the importance of outcomes using a Likert scale (7-9 indicating critical importance) and a Best-Worst Scale. The scores for the two groups were assessed to determine absolute and relative importance. Comments were analysed thematically. RESULTS: In total, 1399 participants from 73 countries completed Round 1 of the Delphi survey, including 628 (45%) patients/caregivers and 771 (55%) health professionals. In Round 2, 790 participants (56% response rate) from 63 countries completed the survey including 383 (48%) patients/caregivers and 407 (52%) health professionals. The overall top five outcomes were: kidney function, need for dialysis/transplant, life participation, cardiovascular disease and death. In the final round, patients/caregivers indicated higher scores for most outcomes (17/22 outcomes), and health professionals gave higher priority to mortality, hospitalization and cardiovascular disease (mean difference >0.3). Consensus was based upon the two groups yielding median scores of ≥7 and mean scores >7, and the proportions of both groups rating the outcome as 'critically important' being >50%. Four themes reflected the reasons for their priorities: imminent threat of a health catastrophe, signifying diminishing capacities, ability to self-manage and cope, and tangible and direct consequences. CONCLUSION: Across trials in CKD, the outcomes of highest priority to patients, caregivers and health professionals were kidney function, need for dialysis/transplant, life participation, cardiovascular disease and death.

Sensitivity and specificity of Aboriginal-developed items to supplement the adapted PHQ-9 screening measure for depression: results from the Getting it Right study.

OBJECTIVE: To determine the psychometric properties of an Aboriginal and Torres Strait Islander-developed depressive symptom screening scale. DESIGN: Prospective diagnostic accuracy study. SETTING: Ten primary health care services or residential alcohol and other drug rehabilitation services in Australia that predominantly serve Aboriginal and Torres Strait Islander peoples. PARTICIPANTS: 500 adults (18 years or older) who identified as Aboriginal and/or Torres Strait Islander and were able to communicate sufficiently to respond to questionnaire and interview questions. Recruitment occurred between 25 March 2015 and 2 November 2016. MAIN OUTCOME MEASURE: Criterion validity of seven Aboriginal and Torres Strait Islander-developed items, using the adapted Patient Health Questionnaire 9 (aPHQ-9) and depression module of the Mini International Neuropsychiatric Interview (MINI) 6.0.0 as the criterion standards. RESULTS: The seven-item scale had good internal consistency (α = 0.83) and correlated highly with the aPHQ-9 (ρ = 0.76). All items were significantly associated with diagnosis of a current major depressive episode. Discriminant function and decision tree analysis identified three items forming a summed scale that classified 85% of participants correctly. These three items showed equivalent sensitivity and specificity to the aPHQ-9 when compared with the MINI-identified diagnosis of a current major depressive episode. CONCLUSION: Three items developed by and for Aboriginal and Torres Strait Islander people may provide effective, efficient and culturally appropriate screening for depression in Aboriginal and Torres Strait Islander health care contexts.

Longitudinal associations between socioeconomic position and overall health of children with chronic kidney disease and their carers.

BACKGROUND: Disadvantaged socioeconomic position (SEP) is an important predictor of poor health in children with chronic kidney disease (CKD). The time course over which SEP influences the health of children with CKD and their carers is unknown. METHODS: This prospective longitudinal study included 377 children, aged 6-18 years with CKD (stages I-V, dialysis, and transplant), and their primary carers. Mixed effects ordinal regression was performed to assess the association between SEP and carer-rated child health and carer self-rated health over a 4-year follow-up. RESULTS: Adjusted for CKD stage, higher family household income (adjusted odds ratio (OR) (95% CI) 3.3, 1.8-6.0), employed status of primary carers (1.7, 0.9-3.0), higher carer-perceived financial status (2.6, 1.4-4.8), and carer home ownership (2.2, 1.2-4.0) were associated with better carer-rated child health. Household income also had a differential effect on the carer's self-rated health over time (p = 0.005). The predicted probabilities for carers' overall health being 'very good' among lower income groups at 0, 2, and 4 years were 0.43 (0.28-0.60), 0.34 (0.20-0.51), and 0.25 (0.12-0.44), respectively, and 0.81 (0.69-0.88), 0.84 (0.74-0.91), and 0.88 (0.76-0.94) for carers within the higher income group. CONCLUSIONS: Carers and their children with CKD in higher SEP report better overall child and carer health compared with those in lower SEP. Carers of children with CKD in low-income households had poorer self-rated health compared with carers in higher-income households at baseline, and this worsened over time. These cumulative effects may contribute to health inequities between higher and lower SEP groups over time. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information.

School attendance and sport participation amongst children with chronic kidney disease: a cross-sectional analysis from the Kids with CKD (KCAD) study.

BACKGROUND: School attendance and life participation, particularly sport, is a high priority for children with chronic kidney disease (CKD). This study is aimed at assessing the association between CKD stage, sports participation, and school absences in children with CKD. METHODS: Using data from the binational Kids with CKD study (ages 6-18 years, n = 377), we performed multivariable regression to evaluate the association between CKD stage, school absences, and sports participation. RESULTS: Overall, 62% of participants played sport with the most frequent sport activities engaged in being swimming (17%) and soccer (17%). Compared to children with CKD 1-2, the incidence rate ratios (IRR) (95% CI) for sports participation amongst children with CKD 3-5, dialysis, or transplant were 0.84 (0.64-1.09), 0.59 (0.39-0.90), and 0.75 (0.58-0.96), respectively. The median (IQR) days of school absences within a four-week period were 1 day (0-1), with children on dialysis reporting the highest number of school absences (9 days (5-15)), followed by transplant recipients (2 days (1-7)), children with CKD 3-5 (1 day (0-3)), and with CKD 1-2 (1 day (0-3)). Duration of CKD modified the association between CKD stage and school absences, with children with a transplant experiencing a higher number of missed school days with increasing duration of CKD, but not in children with CKD 1-5 or on dialysis (p-interaction < 0.01). CONCLUSIONS: Children receiving dialysis and with a kidney transplant had greater school absences and played fewer sports compared to children with CKD stages 1-2. Innovative strategies to improve school attendance and sport participation are needed to improve life participation of children with CKD.

Mendelian randomization for nephrologists.

Confounding is a major limitation of observational studies. Mendelian randomization (MR) is a powerful study design that uses genetic variants as instrumental variables to enable examination of the causal effect of an exposure on an outcome in observational data. With the emergence of large-scale genome-wide association studies in nephrology over the past decade, MR has become a popular method to establish causal inferences. However, MR is a complex and challenging methodology that requires careful consideration to ensure robust results. This review article aims to summarize the basic concepts of MR, its application and relevance in nephrology, and the methodological challenges and limitations as well as discuss the current guidelines for design and reporting. With reference to a clinically relevant example of examining the causal relationship between the estimated glomerular filtration rate and cancer, this review outlines the key steps to conducting an MR study, including the key considerations and potential pitfalls at each step. These include defining the clinical question, selecting the data sources, identifying and refining appropriate genetic variants by considering linkage disequilibrium and associations with potential confounders, harmonization of variants across data sets, validation of the genetic instrument by assessing its strength, estimation of the causal effects, confirming the validity of the findings, and interpreting and reporting results.

Longitudinal assessment of the health-related quality of life of children and adolescents with chronic kidney disease.

In this multi-center longitudinal cohort study conducted in Australia and New Zealand, we assessed the trajectories of health-related quality of life (HRQoL) in children with chronic kidney disease (CKD) over time. A total of 377 children (aged 6-18 years) with CKD stages 1-5 (pre-dialysis), dialysis, or transplant, were followed biennially for four years. Multi Attribute Utility (MAU) scores of HRQoL were measured at baseline and at two and four years using the McMaster Health Utilities Index Mark 3 tool, a generic multi-attribute, preference-based system. A multivariable linear mixed model was used to assess the trajectories of HRQoL over time in 199 children with CKD stage 1-5, 43 children receiving dialysis and 135 kidney transplant recipients. An interaction between CKD stage at baseline and follow-up time indicated that the slopes of the HRQoL scores differed between children by CKD stage at inception. Over half of the cohort on dialysis at baseline had received a kidney transplant by the end of year four and the MAU scores of these children increased by a meaningful amount averaging 0.05 (95% confidence interval 0.01 to 0.09) per year in comparison to those who were transplant recipients at baseline. The mean difference between baseline and year two MAU scores was 0.09 (95% confidence interval -0.05, 0.23), (Cohen's d effect size 0.31). Thus, improvement in HRQoL over time of children on dialysis at baseline was likely to have been driven by their transition from dialysis to transplantation. Additionally, children with CKD stage 1-5 and transplant recipients at baseline had no changes in their disease stage or treatment modality and experienced stable HRQoL over time.

Influence of poor sleep on cardiovascular disease-free life expectancy: a multi-resource-based population cohort study.

BACKGROUND: The complexity of sleep hinders the formulation of sleep guidelines. Recent studies suggest that different unhealthy sleep characteristics jointly increase the risks for cardiovascular disease (CVD). This study aimed to estimate the differences in CVD-free life expectancy between people with different sleep profiles. METHODS: We included 308,683 middle-aged adults from the UK Biobank among whom 140,181 had primary care data linkage. We used an established composite sleep score comprising self-reported chronotype, duration, insomnia complaints, snoring, and daytime sleepiness to derive three sleep categories: poor, intermediate, and healthy. We also identified three clinical sleep disorders captured by primary care and inpatient records within 2 years before enrollment in the cohort: insomnia, sleep-related breathing disorders, and other sleep disorders. We estimated sex-specific CVD-free life expectancy with three-state Markov models conditioning on survival at age 40 across different sleep profiles and clinical disorders. RESULTS: We observed a gradual loss in CVD-free life expectancy toward poor sleep such as, compared with healthy sleepers, poor sleepers lost 1.80 [95% CI 0.96-2.75] and 2.31 [1.46-3.29] CVD-free years in females and males, respectively, while intermediate sleepers lost 0.48 [0.41-0.55] and 0.55 [0.49-0.61] years. Among men, those with clinical insomnia or sleep-related breathing disorders lost CVD-free life by 3.84 [0.61-8.59] or 6.73 [5.31-8.48] years, respectively. Among women, sleep-related breathing disorders or other sleep disorders were associated with 7.32 [5.33-10.34] or 1.43 [0.20-3.29] years lost, respectively. CONCLUSIONS: Both self-reported and doctor-diagnosed poor sleep are negatively associated with CVD-free life, especially pronounced in participants with sleep-related breathing disorders.

Long-term Trends in Infection-Related Mortality in Adults Treated With Maintenance Dialysis.

RATIONALE & OBJECTIVE: Infection is 1 of the top 3 causes of death in patients receiving maintenance dialysis. We evaluated the trends over time and risk factors for infection-related deaths among people receiving dialysis. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: We included all adults who began dialysis between 1980 and 2018 in Australia and New Zealand. EXPOSURE: Age, sex, dialysis modality, and dialysis era. OUTCOME: Infection-related death. ANALYTICAL APPROACH: Incidence was described and standardized mortality ratios (SMR) calculated for infection-related death. Fine-Gray subdistribution hazards models were fitted, with non-infection-related death and kidney transplantation treated as competing events. RESULTS: The study comprised 46,074 patients who received hemodialysis and 20,653 who were treated with peritoneal dialysis who were followed for 164,536 and 69,846 person-years, respectively. There were 38,463 deaths during the follow-up period, 12% of which were ascribed to infection. The overall rate of mortality from infection (per 10,000 person-years) was 185 and 232 for patients treated with hemodialysis and peritoneal dialysis, respectively. The rates were 184 and 219 for males and females, respectively; and 99, 181, 255, and 292 for patients aged 18-44, 45-64, 65-74, 75 years and over, respectively. The rates were 224 and 163 for those commencing dialysis in years 1980-2005 and 2006-2018, respectively. The overall SMR declined over time, from 37.1 (95% CI, 35.5-38.8) in years 1980-2005 to 19.3 (95% CI, 18.4-20.3) in years 2006-2018, consistent with the declining 5-year SMR trend (P<0.001). Infection-related mortality was associated with being female, older age, and Aboriginal and/or a Torres Strait Islander or Maori. LIMITATIONS: Mediation analyses defining the causal relationships between infection type and infection-related death could not be undertaken as disaggregating the data was not feasible. CONCLUSIONS: The excess risk of infection-related death in patients on dialysis has improved substantially over time but remains more than 20 times higher than in the general population.

Sex Disparity in Cause-Specific and All-Cause Mortality Among Incident Dialysis Patients.

RATIONALE & OBJECTIVE: Early mortality rates of female patients receiving dialysis have been, at times, observed to be higher than rates among male patients. The differences in cause-specific mortality between male and female incident dialysis patients with kidney failure are not well understood and were the focus of this study. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Incident patients who had initiated dialysis in Australia and New Zealand in 1998-2018. EXPOSURE: Sex. OUTCOMES: Cause-specific and all-cause mortality while receiving dialysis, censored for kidney transplant. ANALYTICAL APPROACH: Adjusted cause-specific proportional hazards models, focusing on the first 5 years following initiation of dialysis. RESULTS: Among 53,414 patients (20,876 [39%] female) followed for a median period of 2.8 (IQR, 1.3-5.2) years, 27,137 (51%) died, with the predominant cause of death attributed to cardiovascular disease (18%), followed by dialysis withdrawal (16%). Compared with male patients, female patients were more likely to die in the first 5 years after dialysis initiation (adjusted hazard ratio [AHR], 1.08 [95% CI, 1.05-1.11]). Even though female patients experienced a lower risk of cardiovascular disease-related mortality (AHR, 0.93 [95% CI, 0.89-0.98]) than male patients, they experienced a greater risk of infection-related (AHR, 1.20 [95% CI, 1.10-1.32]) and dialysis withdrawal-related (AHR, 1.19 [95% CI, 1.13-1.26]) mortality. LIMITATIONS: Possibility of residual and unmeasured confounders. CONCLUSIONS: Compared with male patients, female patients had a higher risk of all-cause mortality in the first 5 years after dialysis initiation, a difference driven by higher rates of mortality from infections and dialysis withdrawals. These findings may inform the study of sex differences in mortality in other geographic settings.

Can white-light endoscopy or narrow-band imaging avoid biopsy of colorectal endoscopic mucosal resection scars? A multicenter randomized single-blind crossover trial.

BACKGROUND : Current guidelines suggest that routine biopsy of post-endoscopic mucosal resection (EMR) scars can be abandoned, provided that a standardized imaging protocol with virtual chromoendoscopy is used. However, few studies have examined the accuracy of advanced endoscopic imaging, such as narrow-band imaging (NBI) vs. white-light endoscopy (WLE) for prediction of histological recurrence. We aimed to assess whether NBI accuracy is superior to that of WLE and whether one or both techniques can replace biopsies. METHODS : The study was a multicenter, randomized, pathologist-blind, crossover trial, with consecutive patients undergoing first colonoscopy after EMR of lesions ≥ 20 mm. Computer-generated randomization and opaque envelope concealed allocation. Patients were randomly assigned to scar examination with NBI followed by WLE (NBI + WLE), or WLE followed by NBI (WLE + NBI). Histology was the reference method, with biopsies being performed for all tissues. RESULTS : The study included 203 scars (103 in the NBI + WLE group, 100 in the WLE + NBI group). Recurrence was confirmed histologically in 29.6 % of the scars. The diagnostic accuracy of NBI was not statistically different from that of WLE (95 % [95 %CI 92 %-98 %] vs. 94 % [95 %CI 90 %-97 %]; P = 0.48). The negative predictive values (NPVs) were 96 % (95 %CI 93 %-99 %) for NBI and 93 % (95 %CI 89 %-97 %) for WLE (P = 0.06). CONCLUSIONS : The accuracy of NBI for the diagnosis of recurrence was not superior to that of WLE. Endoscopic assessment of EMR scars with WLE and NBI achieved an NPV that would allow routine biopsy to be avoided in cases of negative optical diagnosis.

Donors With a Prior History of Cancer: Factors of Non-Utilization of Kidneys for Transplantation.

Cancer transmission from deceased donors is an exceedingly rare but potentially fatal complication in transplant recipients. We aimed to quantify the likelihood of non-utilization of kidneys for transplantation from donors with a prior cancer history. We included all intended and actual deceased donors in Australia and New Zealand between 1989 and 2017. Association between prior cancer history and non-utilization of donor kidneys was examined using adjusted logistic regression. Of 9,485 deceased donors, 345 (4%) had a prior cancer history. Of 345 donors with a prior cancer history, 197 (57%) were utilized for transplantation. Donor characteristics of age, sex and comorbidities were similar between utilized and non-utilized donors with prior cancer. The time from cancer to organ donation was similar between utilized and non-utilized donors, irrespective of cancer subtypes. Donors with a prior cancer history were less likely to be utilized [adjusted OR (95% CI) 2.29 (1.68-3.13)] than donors without prior cancer. Of all actual donors, the adjusted OR for non-utilization among those with prior cancer was 2.36 (1.58-3.53). Non-melanoma skin cancer was the most frequent prior cancer type for utilized and non-utilized potential donors. Donors with prior cancers were less likely to be utilized for transplantation, with no discernible differences in cancer characteristics between utilized and non-utilized donors.

Apathy and Depression in Huntington's Disease: Distinct Longitudinal Trajectories and Clinical Correlates.

OBJECTIVE: Huntington's disease (HD) is an autosomal-dominant neurodegenerative disease resulting in motor disturbances, dementia, and psychiatric symptoms. Apathy is a common manifestation and rated as one of the most impactful by patients and caregivers. It can often be difficult to distinguish from depression because of shared features and frequent overlap. This study examined the longitudinal trajectories and clinical correlates of apathy and depression. METHODS: Data were drawn from the Cooperative Huntington Observational Research Trial, a prospective, multicenter observational study that recruited 1,082 patients with HD. Measures of cognition, function, neuropsychiatric symptoms, motor function, and medication use were completed annually over 5 years. RESULTS: Overall, 423 patients (39%) showed evidence of apathy at study baseline, and both the prevalence and overall severity of apathy increased over time. Depression, by contrast, affected a similar proportion at baseline, although levels remained relatively stable over the study. Apathy was associated with worse cognition, function, neuropsychiatric symptoms, and motor symptoms. Depression was associated with worse neuropsychiatric symptoms, suicidal ideation, and independence but not other outcomes after control for other variables. CONCLUSIONS: Apathy in HD increased over time and was associated with worse clinical outcomes. These associations were independent of depression and other clinical variables. The findings highlight the need to distinguish between apathy and depression given their distinct implications for prognosis and management.

Resolution of elevated interleukin-6 after surgery is associated with return of normal cognitive function.

BACKGROUND: Unresolved surgical inflammation might induce chronic cognitive decline in older adults. Although inflammatory biomarkers have been correlated with perioperative cognitive impairment and delirium, the effects of prolonged inflammation on cognition are not well studied. This prospective cohort study investigated 1-yr dynamics in plasma interleukin-6 levels and executive function. METHODS: Patients undergoing major surgery (n=170) aged ≥65 yr completed Trail Making Test B and other neuropsychological assessments with plasma interleukin-6 levels collected on postoperative days 1-9 and 90, and at 1-yr. Mixed-effects analyses were conducted for Trail Making Test B (and other assessments), including interleukin-6 levels, time, and additional confounders (fixed effects), and a random effect for participant. RESULTS: Changes in interleukin-6 levels were associated with changes in Trail Making Test B over 1 yr in a generalised additive model (ß=0.074, P<0.001) supporting that unresolved inflammation impaired executive function. This result was robust to confounders, outlier rejection, and fitting to non-linear models. Changes in interleukin-6 levels also correlated with changes in Trail Making Test A and Controlled Oral Word Association Test. Sensitivity analyses conducted on binary definitions of cognitive decline (>1, >1.5, or >2 standard deviations from baseline) were also associated with interleukin-6 changes. CONCLUSIONS: Delayed resolution of inflammation is associated with cognitive impairment after surgery. Monitoring interleukin-6 might provide an opportunity to intervene with anti-inflammatory therapies in vulnerable patients. CLINICAL TRIAL REGISTRATION: NCT01980511, NCT03124303.