Accuracy of Baseline Magnetic Resonance Imaging for Staging Rectal Cancer Patients Proceeding Directly to Surgery.

BACKGROUND AND OBJECTIVES: High-resolution magnetic resonance imaging (MRI) accuracy for staging preoperative rectal cancer varies across studies. We examined MRI accuracy for T- and N-staging of rectal cancer compared with final histopathology of the resected specimen in a large Australian cohort who did not receive neoadjuvant therapy or radiation. METHODS: Retrospective analysis of prospectively-collected clinical data from 153 rectal adenocarcinomas locally staged by high-resolution MRI between January 2012 and December 2019 that did not undergo chemoradiotherapy or radiation before surgery. T- and N-stage agreement between MRI and final histopathology was assessed using Kappa statistic. Agreement at each T-stage was evaluated using log-linear modeling. N-staging accuracy was examined using positive and negative predictive values. RESULTS: Overall agreement between MRI and final histopathology for T-stage and N-stage was 55% and 65%, respectively. Kappa statistic found higher agreement between MRI and final histopathology for T-staging (κ = 0.33) versus N-staging (κ = 0.18). MRI correctly assessed 91% of T1 tumors, 43% of T2 tumors, 65% of T3 tumors, and 80% of T4 tumors. MRI accuracy was higher for N-negative tumors (74.1%) than for N-positive tumors (44.4%). CONCLUSION: MRI is moderately accurate at staging T1, T3, and T4 rectal tumors but caution when staging tumors as T2 is advised. Greater accuracy for staging N-negative versus N-positive tumors is indicated.

Metformin for preventing the progression of chronic kidney disease.

BACKGROUND: Metformin has been used in the management of diabetes for decades. It is an effective, low-cost intervention with a well-established safety profile. Emerging evidence suggests that metformin targets a number of pathways that lead to chronic kidney damage, and long-term use may, therefore, slow the rate of kidney function decline and chronic kidney disease (CKD) progression. OBJECTIVES: To evaluate the effect of metformin therapy on kidney function decline in patients with CKD with or without diabetes mellitus and assess the safety and dose tolerability in this population. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 19 July 2023 with assistance from an Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that reported kidney-related outcomes with a minimum duration of 12 months delivery of the metformin intervention and whose eligibility criteria included adult participants with either i) a diagnosis of CKD of any aetiology and/or ii) those with a diagnosis of diabetes mellitus. Comparisons included placebo, no intervention, non-pharmacological interventions, other antidiabetic medications or any other active control. Studies that included patients on any modality of kidney replacement therapy were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently carried out data extraction using a standard data extraction form. The methodological quality of the included studies was assessed using the Cochrane risk of bias tool. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: This review included 11 studies reporting on 8449 randomised participants. Studies were conducted in patient populations with Autosomal Dominant Polycystic Kidney Disease (ADPKD) (four studies) or diabetes mellitus (seven studies). Six studies compared metformin with no active control, four studies compared metformin with active controls (rosiglitazone, glyburide, pioglitazone, or glipizide), and one study included treatment arms that randomised to either metformin, diet and lifestyle modifications, or other antidiabetic therapies. The risk of bias in included studies varied; two studies were abstract-only publications and were judged to have a high risk of bias in most domains. Other included publications were judged to have a low risk of bias in most domains. Across comparisons, GRADE evaluations for most outcomes were judged as low or very low certainty, except for those relating to side effects, tolerance, and withdrawals, which were judged as moderate certainty. The evidence suggests that compared to placebo, metformin may result in i) a slightly smaller decline in kidney function (3 studies, 505 participants: MD 1.92 mL/min, 95% CI 0.33 to 3.51; I2 = 0%; low certainty), ii) very uncertain effects on the incidence of kidney failure (1 study, 753 participants: RR 1.20, 95% CI 0.17 to 8.49), iii) little or no effect on death (3 studies, 865 participants: RR 1.00, 95% CI 0.76 to 1.32; I2 = 0%; moderate certainty), iv) little or no effect on the incidence of serious adverse events (3 studies, 576 participants: RR 1.15, 95% CI 0.76 to 1.72; I2 = 0%; moderate certainty), and v) likely higher incidence of intolerance leading to study withdrawal than placebo (4 studies, 646 participants: RR 2.19, 95% CI 1.46 to 3.27; I2 = 0%; moderate certainty). The certainty of the evidence for proteinuria was very uncertain. Compared to other active controls (rosiglitazone, glyburide, pioglitazone, or glipizide), metformin i) demonstrated very uncertain effects on kidney function decline, ii) may result in little or no difference in death (3 studies, 5608 participants: RR 0.95 95% CI 0.63 to 1.43; I2 = 0%; low certainty), iii) probably results in little or no difference in intolerance leading to study withdrawal (3 studies, 5593 participants: RR 0.92, 95% CI, 0.79 to 1.08; I2 = 0%; moderate certainty), iv) probably results in little or no difference in the incidence of serious adverse events (2 studies, 5545 participants: RR 1.16, 95% CI 0.79 to 1.71; I2 = 0%; moderate certainty), and v) may increase the urinary albumin-creatinine ratio (2 studies, 3836 participants: MD 14.61, 95% CI 8.17 to 21.05; I2 = 0%; low certainty). No studies reported the incidence of kidney failure. AUTHORS' CONCLUSIONS: This review highlights the lack of RCTs reporting on the effects of metformin on kidney function, particularly in patients with CKD. Future research in this field requires adequately powered RCTs comparing metformin to placebo or standard care in those with CKD. Seven ongoing studies were identified in this review, and future updates, including their findings, may further inform the results of this review.

Lifestyle changes and patient-reported outcomes over five years in a sample of people with multiple sclerosis after a single multimodal intensive lifestyle education workshop.

INTRODUCTION: Modifiable lifestyle risk factors for progression of multiple sclerosis (MS) have been increasingly studied. This study employed a single-group design involving a one-off intensive live-in educational workshop on lifestyle modification for people with MS. We aimed to examine changes in a range of clinical and lifestyle variables and quality of life, self-efficacy, physical impact of MS and disability from baseline to 3- and 5-years post-intervention. METHODS: 95 participants completed the baseline survey. Data included lifestyle risk factors of diet quality, meat and dairy consumption, omega 3 and vitamin D supplementation, physical activity, stress reducing activities, and smoking status, and use of disease-modifying therapies (DMTs). Patient-reported outcomes included health-related quality of life, self-efficacy, physical impact of MS and disability. Generalised estimating equation models were used to account for within-participant correlation over time. RESULTS: Sixty participants (63.2%) provided data at 3- and 5-years. Significant improvements in diet quality, omega 3 supplementation, and non-smoking were seen at both timepoints. Use of DMTs and disability remained unchanged. Mental (8.8- and 6.9-point) and physical (10.5- and 7.3-point) quality of life, and self-efficacy (2.4- and 1.9-point) improved significantly at 3- and 5-years, respectively. Physical impact of MS reduced from baseline to 3-years (-3.7 points) with a trend towards reduction at 5-years (-2.9 points; p = 0.079). CONCLUSIONS: Education on lifestyle modification can lead to lifestyle modification and short and long-term improvements in mental and physical wellbeing outcomes. Results suggest potential value in lifestyle modification as an adjunctive component to standard therapy for MS.

T-stage downstaging of locally advanced rectal cancer after neoadjuvant chemoradiotherapy is not associated with reduced recurrence after adjusting for tumour characteristics.

BACKGROUND AND OBJECTIVES: Prior studies examining prognostic outcomes of locally advanced rectal adenocarcinomas achieving a complete pathological response following neoadjuvant chemoradiotherapy (nCRT) did not adjust for adverse prognostic factors in multivariate analyses and account for magnetic resonance imaging tumour staging inaccuracy pre-nCRT. We aimed to clarify prognostic outcomes in mT3 rectal adenocarcinomas with ypT-downstaging post-nCRT in robust adjusted analyses. METHODS: Retrospective analysis of prospectively-collected clinical data from 528 mT3 rectal adenocarcinomas ≤12 cm from the anal verge, any N-stage, no metastases, post-nCRT following total mesorectal excision (TME). Recurrence outcomes (local and distant combined) of tumours with complete ypT-downstaging (ypT0) post-nCRT before TME compared with no ypT-downstaging (≥ypT3) were examined using multivariate Cox regression, adjusting for confounders and accounting for pre-nCRT mT3-staging inaccuracy using bootstrapping. RESULTS: Complete ypT-downstaging was achieved in of 17.6% tumours and correlated strongly with complete pathological response. Complete ypT-downstaging was not associated with reduced recurrence hazards compared with no ypT-downstaging (hazard ratio = 0.60; 95% confidence interval [CI]: 0.23-1.56; p = 0.30). Lymphovascular invasion (LVI) and ypN+ve increased recurrence hazards by 1.8-fold (95% CI: 1.10-2.79; p = 0.02) and 2.3-fold (95% CI: 1.48-3.54; p = 0.0002), respectively. CONCLUSION: Complete ypT-downstaging was not associated with reduced recurrence after adjusting for confounders and accounting for mT3-staging inaccuracy, even in the absence of adverse prognostic factors (ypN+, LVI).

Is increasing nodal count associated with improved recurrence-free and overall survival following standard right hemicolectomy for colon cancer?

BACKGROUND AND OBJECTIVES: Increasing lymph node harvest for right-sided colon cancer is associated with improved overall survival (OS), but most relevant studies failed to report the extent of resection. We examined the association between increasing lymph node count with standard right hemicolectomy according to nodal status and prognostic outcomes in right-sided tumors. METHODS: Retrospective analysis of prospectively collected clinical data from patients with proximal colonic adenocarcinomas (n = 1390) following right hemicolectomy. Associations between lymph node counts (0-12 vs. 13-15, 16-20, and >20) and recurrence-free survival (RFS) and OS were examined using multivariate Cox modeling adjusted for confounders. RESULTS: We found no association between increasing nodal count and RFS, regardless of nodal status. In the absence of nodal metastases, increasing nodal count (16-20 and >20 vs. 0-12 nodes) was associated with 57% (95% confidence interval [CI]: 0.21-0.89) and 52% (95% CI: 0.24-0.95) improved OS, respectively. In the presence of nodal metastases, increasing nodal count was not associated with OS. Adjuvant chemotherapy did not modify this effect. CONCLUSION: Increasing nodal count (>15 nodes) with right hemicolectomy was not associated with improved RFS. Improved OS was only found for node-negative tumors, casting some doubt on the benefits of resecting more lymph nodes in the presence of nodal metastases.

Body Mass Index, sex, non-steroidal anti-inflammatory drug medications, smoking and alcohol are differentially associated with World Health Organisation criteria and colorectal cancer risk in people with Serrated Polyposis Syndrome: an Australian case-control study.

OBJECTIVE: The unknown aetiology of Serrated Polyposis Syndrome (SPS) impedes risk prediction and prevention. We investigated risk factors for SPS, overall and stratified by World Health Organization (WHO)2010 clinical criteria and by colorectal cancer (CRC). METHOD: A retrospective case-control study involving a cross-sectional analysis from 350 unrelated individuals with SPS from the Genetics of Colonic Polyposis Study and 714 controls from the Australasian Colorectal Cancer Family Registry. Univariate and multivariate logistic regression modelling was used to determine the association between risk factors and SPS and risk factors associated with CRC in SPS. RESULTS: Female biological sex (odds ratio (OR) = 4.54; 95%Confidence interval (CI) = 2.77-7.45), increasing body mass index (BMI) at age 20 years (OR = 1.09; 95%CI = 1.04-1.13), hormone replacement therapy (OR = 0.44; 95%CI = 0.20.98), and increasing weekly folate intake (OR = 0.82; 95%CI = 0.75-0.90) were associated with SPS by multivariate analysis. Increasing weekly calcium intake (OR = 0.79; 95%CI = 0.64-0.97) and smoking > 10 cigarettes daily (OR = 0.45; 95%CI = 0.23-0.86) were associated with WHO criterion I only. The consumption of 1-100 g of alcohol per week (OR = 0.39; 95%CI = 0.18-0.83) was associated with WHO criterion III only. Smoking 1-5 cigarettes daily (OR = 2.35; 95%CI = 1.09-5.05), weekly non-steroidal anti-inflammatory drug (NSAIDs) intake (OR = 0.88; 95%CI = 0.78-0.99), and increased height (OR = 1.09; 95% = 1.05-1.13), were associated with SPS fulfilling both WHO criteria I and III. Moreover, weekly NSAIDs intake (OR = 0.81; 95%CI = 0.67-0.98) was associated with a reduced likelihood of CRC in SPS. CONCLUSION: We identified novel risk and potential protective factors associated with SPS, some specific for certain WHO2010 criteria. Weekly use of NSAIDs may reduce the risk of CRC in people with SPS.

Relationship Between Dietary Phosphate Intake and Biomarkers of Bone and Mineral Metabolism in Australian Adults With Chronic Kidney Disease.

OBJECTIVE: Higher serum phosphate is associated with increased adverse outcomes including cardiovascular disease. Abnormalities of bone and mineral metabolism in chronic kidney disease (CKD), including higher serum phosphate, are important risk factors for increased cardiovascular disease. Associations between dietary phosphate intake and biochemical and cardiovascular parameters in non-dialysis CKD patients, however, have not been adequately studied. This study aimed to explore associations between phosphate intake and biomarkers of bone and mineral metabolism and intermediate cardiovascular markers in adults with stage 3-4 CKD. DESIGN AND METHODS: One hundred thirty-two participants enrolled in the IMpact of Phosphate Reduction On Vascular End-points in Chronic Kidney Disease trial were invited to participate in this sub-study. At baseline, dietary phosphate intake and its source (animal, plant, or a mixture of animal and plant) were determined using a 7-day self-administered diet food record, and measurements were made of serum and urinary phosphate, serum calcium, parathyroid hormone, fibroblast growth factor-23, and the intermediate cardiovascular markers pulse wave velocity (PWV) and abdominal aortic calcification. The relationships between dietary phosphate intake and these bone metabolism and cardiovascular markers were explored using Pearson's correlation and linear regression. The effect of source of phosphate intake was analyzed using compositional data analysis. RESULTS: Ninety participants (age 64 ± 12 years, 68% male, estimated glomerular filtration rate 26.6 ± 7.6 mL/min/1.73 m2, daily phosphate intake 1,544 ± 347 mg) completed the study. Correlations among dietary phosphate intake and biochemical measures, PWV, and abdominal aortic calcification ranged from r = -0.13 to r = +0.13. Linear regression showed no association between dietary phosphate measurements and biochemical or cardiovascular parameters. Source of phosphate intake was associated with PWV (P = .01), but not with other biomarkers of bone and mineral metabolism. Higher PWV values were associated with higher intake of plant-based relative to animal-based phosphate (1.058 [1.020-1.098], P = .003). CONCLUSION: Levels of total dietary phosphate intake measured by dietary food record show no statistically significant relationship with biochemical markers of bone and mineral metabolism or intermediate cardiovascular markers. Higher PWV levels associated with higher intake of plant-based relative to animal-based phosphate intake were an unexpected finding and further research is needed in this area.

Human milk oligosaccharide profiles and allergic disease up to 18 years.

BACKGROUND: Human milk oligosaccharides (HMO) are a diverse range of sugars secreted in breast milk that have direct and indirect effects on immunity. The profiles of HMOs produced differ between mothers. OBJECTIVE: We sought to determine the relationship between maternal HMO profiles and offspring allergic diseases up to age 18 years. METHODS: Colostrum and early lactation milk samples were collected from 285 mothers enrolled in a high-allergy-risk birth cohort, the Melbourne Atopy Cohort Study. Nineteen HMOs were measured. Profiles/patterns of maternal HMOs were determined using LCA. Details of allergic disease outcomes including sensitization, wheeze, asthma, and eczema were collected at multiple follow-ups up to age 18 years. Adjusted logistic regression analyses and generalized estimating equations were used to determine the relationship between HMO profiles and allergy. RESULTS: The levels of several HMOs were highly correlated with each other. LCA determined 7 distinct maternal milk profiles with memberships of 10% and 20%. Compared with offspring exposed to the neutral Lewis HMO profile, exposure to acidic Lewis HMOs was associated with a higher risk of allergic disease and asthma over childhood (odds ratio asthma at 18 years, 5.82; 95% CI, 1.59-21.23), whereas exposure to the acidic-predominant profile was associated with a reduced risk of food sensitization (OR at 12 years, 0.08; 95% CI, 0.01-0.67). CONCLUSIONS: In this high-allergy-risk birth cohort, some profiles of HMOs were associated with increased and some with decreased allergic disease risks over childhood. Further studies are needed to confirm these findings and realize the potential for intervention.

Are young children with asthma more likely to be less physically active?

BACKGROUND: Previous research suggests that children who experience asthma may be less physically active; however, results have been inconclusive. This study aimed to investigate whether the presence of asthma or wheeze is associated with lower physical activity levels in children, and whether sex, body mass index or earlier asthma or wheeze status modifies the association. METHODS: This study was conducted in 391 HealthNuts participants in Melbourne, Australia. Asthma and wheeze data were collected via questionnaire at age 4 and 6, and physical activity was measured through accelerometry. Using adjusted linear regression models, the cross-sectional and longitudinal associations were investigated. RESULTS: There was no evidence of a difference in time spent in moderate-to-vigorous physical activity (MVPA) at age 6 years between children with and without asthma at age 4; children with asthma spent 8.3 minutes more time physically active per day (95% CI: -5.6, 22.1, P = .24) than children without asthma. Similar results were seen for children with current wheeze (5.8 minutes per day more, 95% CI: -5.9, 17.5, P = .33) or ever wheeze or asthma (7.7 minutes per day more, 95% CI: -4.8, 20.2, P = .23) at age 4 years. Comparable null results were observed in the cross-sectional analyses. Interaction with BMI could not be assessed; however, previous asthma or wheeze status and sex were not found to modify these associations. CONCLUSION: This analysis found no evidence of asthma hindering physical activity in these young children. These results are encouraging, as they indicate that the Australian asthma and physical activity public health campaigns are being effectively communicated and adopted by the public.

Neoadjuvant Chemoradiotherapy and Tumor Recurrence in Patients with Early T-Stage Cancer of the Lower Rectum.

BACKGROUND: The role neoadjuvant chemoradiotherapy (nCRT) plays in oncological outcomes in early T-stage rectal cancer is uncertain. The present work aims to clarify prognostic outcomes by estimating the effect of nCRT on tumor recurrence prior to major surgery compared with major surgery alone. PATIENTS AND METHODS: Prospectively collected data were retrospectively analyzed for patients diagnosed with localized rectal adenocarcinoma ≤ 8 cm from the anal verge, with final histopathology ≤ T2 (≤ ypT2/≤ pT2), regardless of magnetic resonance imaging staging, between 1990 and 2017. As the effect of nCRT on recurrence varied over time, thereby violating the Cox proportional hazards assumption, the effect of nCRT on recurrence hazards was estimated using a time-varying multivariate Cox model over two separate time intervals (≤ 1 year and > 1 year postsurgery) by nCRT. RESULTS: Long-course nCRT was associated with a 5.6-fold increase in the hazard of recurrence ≤ 1 year postsurgery [hazard ratio (HR) 5.6; 95% confidence interval (CI) 1.2-24.9; P = 0.02], but there was no increase in recurrence hazards > 1 year (HR 0.84; 95% CI 0.4-2.0; P = 0.70). In subgroup analysis restricted to ≤ mrT2/≤ ypT2 and ≤ pT2 tumors (omitting > mrT2 tumors), the effect of nCRT on recurrence no longer varied over time, indicating that tumor heterogeneity was responsible for the observed increased recurrence hazards ≤ 1 year postsurgery; That is, > mrT2 tumors that were downstaged to ≤ ypT2 after nCRT were responsible for the time-varying effects of nCRT and increased recurrence hazards ≤ 1 year postsurgery. Subsequently, no difference was found in prognostic outcomes either with or without nCRT before surgery in the homogeneous population of ≤ mrT2/≤ ypT2 and ≤ pT2 tumors. CONCLUSIONS: No evidence was found to indicate that nCRT prior to surgery reduces tumor recurrence in early T-stage lower rectal cancer compared with surgery alone.

Receipt of infant HIV DNA PCR test results is associated with a reduction in retention of HIV-exposed infants in integrated HIV care and healthcare services: a quantitative sub-study nested within a cluster randomised trial in rural Malawi.

BACKGROUND: Retention of HIV-infected mothers in integrated HIV and healthcare facilities is effective at reducing mother-to-child-transmission (MTCT) of HIV. In the context of Option B+, we examined maternal and HIV-exposed infant retention across three study arms to 18 months postpartum: mother-and-infant clinics (MIP), MIP with short-messaging service (MIP + SMS) and standard of care (SOC). In particular, we focused on the impact of mothers receiving an infant's HIV PCR test result on maternal and infant study retention. METHODS: A quantitative sub-study nested within a cluster randomised trial undertaken between May 2013 and August 2016 across 30 healthcare facilities in rural Malawi enrolling HIV-infected pregnant mothers and HIV-exposed infants on delivery, was performed. Survival probabilities of maternal and HIV-exposed infant study retention was estimated using Kaplan-Meier curves. Associations between mother's receiving an infant's HIV test result and in particular, an infant's HIV-positive result on maternal and infant study retention were modelled using time-varying multivariate Cox regression. RESULTS: Four hundred sixty-one, 493, and 396 HIV-infected women and 386, 399, and 300 HIV-exposed infants were enrolled across study arms; MIP, MIP + SMS and SOC, respectively. A total of 47.5% of mothers received their infant's HIV test results < 5 months postpartum. Receiving an infant's HIV result by mothers was associated with a 70% increase in infant non-retention in the study compared with not receiving an infant's result (HR = 1.70; P-value< 0.001). Receiving a HIV-positive result was associated with 3.12 times reduced infant retention compared with a HIV-negative result (P-value< 0.001). Of the infants with a HIV-negative test result, 87% were breastfed at their final study follow-up. CONCLUSIONS: Receiving an infant's HIV test result was a driving factor for reduced infant study retention, especially an infant's HIV-positive test result. As most HIV-negative infants were still breastfed at their last follow-up, this indicates a large proportion of HIV-exposed infants were potentially at future risk of MTCT of HIV via breastfeeding but were unlikely to undergo follow-up HIV testing after breastfeeding cessation. Future studies to identify and address underlying factors associated with infant HIV testing and reduced infant retention could potentially improve infant retention in HIV/healthcare facilities. TRIAL REGISTRATION: Pan African Clinical Trial Registry: PACTR201312000678196 .

Does physical activity strengthen lungs and protect against asthma in childhood? A systematic review.

BACKGROUND: Physical activity may be a potentially modifiable risk factor for asthma and driver of lung function development. This systematic review aimed to summarize the available evidence concerning the longitudinal effect of physical activity on the development of asthma, the persistence of asthma symptoms and lung function outcomes in children and adolescents. METHODS: PubMed and Embase electronic databases were searched for all original articles that investigated the longitudinal association between physical activity and asthma outcomes or lung function outcomes in children and adolescents. The search and data extraction were conducted by two independent researchers. The methodological quality of the included studies was assessed using two critical assessment tools. RESULTS: The literature search retrieved 2298 publications from the electronic databases. All articles were screened, and 2289 were subsequently excluded, resulting in nine longitudinal studies eligible for inclusion in this review. Two studies found no association with incident wheeze, and two of four found no association with various asthma outcomes. Three studies investigated the effect on lung function: one observed an association in boys only, one observed an association in girls only, and one found no associations. CONCLUSION: The evidence was highly inconsistent for the relationship between physical activity and asthma and lung function outcomes. Hence, we conclude that there is insufficient evidence to suggest that physical activity has a long-term effect on the risk of asthma development in youth. Furthermore, there is insufficient evidence to determine the longitudinal effects of physical activity on lung function in children.

A new modeling approach for quantifying expert opinion in the drug discovery process.

Expert opinion plays an important role when choosing clusters of chemical compounds for further investigation. Often, the process by which the clusters are assigned to the experts for evaluation, the so-called selection process, and the qualitative ratings given by the experts to the clusters (chosen/not chosen) need to be jointly modeled to avoid bias. This approach is referred to as the joint modeling approach. However, misspecifying the selection model may impact the estimation and inferences on parameters in the rating model, which are of most scientific interest. We propose to incorporate the selection process into the analysis by adding a new set of random effects to the rating model and, in this way, avoid the need to model it parametrically. This approach is referred to as the combined model approach. Through simulations, the performance of the combined and joint models was compared in terms of bias and confidence interval coverage. The estimates from the combined model were nearly unbiased, and the derived confidence intervals had coverage probability around 95% in all scenarios considered. In contrast, the estimates from the joint model were severely biased under some form of misspecification of the selection model, and fitting the model was often numerically challenging. The results show that the combined model may offer a safer alternative on which to base inferences when there are doubts about the validity of the selection model. Importantly, thanks to its greater numerical stability, the combined model may outperform the joint model even when the latter is correctly specified.

Impact of selection bias on the evaluation of clusters of chemical compounds in the drug discovery process.

Expert opinion plays an important role when selecting promising clusters of chemical compounds in the drug discovery process. Indeed, experts can qualitatively assess the potential of each cluster, and with appropriate statistical methods, these qualitative assessments can be quantified into a success probability for each of them. However, one crucial element often overlooked is the procedure by which the clusters are assigned to/selected by the experts for evaluation. In the present work, the impact such a procedure may have on the statistical analysis and the entire evaluation process is studied. It has been shown that some implementations of the selection procedure may seriously compromise the validity of the evaluation even when the rating and selection processes are independent. Consequently, the fully random allocation of the clusters to the experts is strongly advocated.

Stressful life events and depression and fatigue in people with multiple sclerosis: a cross-sectional analysis of an international cohort.

BACKGROUND: Relationships between stressful life events (SLEs) and health outcomes in people living with multiple sclerosis (plwMS), beyond relapse, are not well-established. We examined associations between SLEs and fatigue and symptoms of depression in plwMS. METHODS: 948 participants were queried whether they had experienced any of the 16 SLEs (Holmes-Rahe Social Readjustment Rating Scale) in the preceding 12 months. SLEs were summated to estimate SLE number and SLE load (weighted for the degree of associated stress). Cross-sectional associations between SLE (number, load and individual) and fatigue, and depressive symptoms were examined using log-binomial or log-multinomial regression adjusted for age, sex, relapse symptoms, education, MS type at baseline, disability, fatigue, comorbidity, depression, and antidepressant/antifatigue medications, as appropriate. Sub-analyses restricted to SLEs with a negative emotional impact were performed. RESULTS: Median SLE number and load were 2 (IQR 1-2) and 57 (IQR 28-97), respectively. SLE number and load were not associated with a higher prevalence of fatigue, or depressive symptoms, even when restricting analyses to SLEs with a perceived negative emotional impact. A new relationship or family member with a negative impact was associated with a threefold and 2.5-fold higher prevalence of depressive symptoms, respectively. Serious illness was associated with a 28% higher prevalence of depressive symptoms. CONCLUSION: Psychological support for SLEs, and/or intervention targeted to SLE appraisal, may be beneficial in mitigating the adverse effects of SLEs with a perceived negative emotional impact on depressive symptoms in plwMS. Potential associations between serious illness and increased prevalence of depressive symptoms may warrant further investigation.

The outcomes of patients with kidney failure due to focal segmental glomerulosclerosis (FSGS) in Australia and New Zealand: A cohort study using the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA).

BACKGROUND: The outcomes of patients with focal segmental glomerulosclerosis (FSGS) on kidney replacement therapy (KRT) have not been well described. This study evaluated the outcomes of patients with kidney failure due to FSGS on KRT including dialysis and kidney transplantation. METHOD AND MATERIALS: All adult patients with kidney failure who commenced KRT in Australia and New Zealand from 15th of May 1963 to 31st of December 2018 were retrospectively extracted from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry. Outcomes of patients with FSGS were compared to those with other causes of kidney failure (non-FSGS). RESULTS: 85,052 patients commenced KRT during the study period, of whom 2991 (3.5%) were patients with FSGS. Compared to patients with non-FSGS, patients with FSGS experienced similar mortality on dialysis (adjusted hazard ratio [aHR] 0.98, 95% CI 0.90-1.06, p = 0.55) and following kidney transplantation (aHR 0.92, 95% CI 0.73-1.15, p = 0.47). The risk of first kidney allograft loss was higher in patients with FSGS (aHR 1.20, 95% CI 1.04-1.37, p = 0.01). However, when death was analysed as a competing risk, the survival in both groups was similar (sub-hazard ratio [SHR] 1.09, 95% CI 0.94-1.28, p = 0.26). Patients with FSGS had a longer waiting time for kidney transplantation (aHR 0.92, 95% CI 0.86-0.98, p = 0.02) and experienced an increased risk of disease recurrence in the allograft (aHR 1.73, 95% CI 1.35-2.21, p<0.001). Compared to patients with other forms of glomerular disease, patients with FSGS experienced similar dialysis and transplant patient survival and death-censored rate of kidney transplantation and allograft loss but higher rates of primary kidney disease recurrence. CONCLUSION: FSGS was associated with similar dialysis and transplant patient survival and death-censored first allograft loss compared to non-FSGS and other forms of glomerular disease.

Epidemiology and Outcomes of Children with Kidney Failure Receiving Kidney Replacement Therapy in Australia and New Zealand.

Introduction: The incidence and outcomes of kidney replacement therapy (KRT) have been well-studied in adults, but much less so in children. This study aimed to investigate the epidemiology and outcomes of KRT in children in Australia and New Zealand from 2000 to 2020. Methods: Children aged <18 years initiating KRT in Australia and New Zealand between January 1, 2000 and December 31, 2020 and reported to the Australia and New Zealand Dialysis and Transplant Registry were included. Patient survival, technique-survival, and graft survival were analyzed by Cox regression analyses. Results: Overall, 1058 children (median [interquartile range (IQR)] age 11 [5-15] years, 41% female, 66% White) were followed-up with for a median period of 12.3 years. First KRT modalities were peritoneal dialysis (PD; 48%), hemodialysis (HD; 34%), and kidney transplantation (KT; 18%). Pre-emptive KT incidence was highest in Caucasian children (80.4%) and lowest in the Indigenous population (3.2%). There was no difference in 5-year patient survival rates between 2011 and 2020 (96.9%, 95% confidence interval [CI] 93.8-98.4) and the preceding decade, 2000-2010 (94.5%, 95% CI 90.4-96.8) (P = 0.79). There was no difference in 5-year death-censored technique survival between 2011 and 2020 (51.2%, 95% CI 39.1-62) and 2000-2010 (48.8%, 95% CI 40.5-56.6) (P = 0.27). However, 5-year derath-censored graft survival was significantly higher in 2011-2020 (88.4%, 95% CI 84.6-91.4) than in 2000-2010 (84.3%, 95% CI 80.4-87.5) (P < 0.001). Conclusions: PD is the most commonly prescribed KRT modality for children in Australia and New Zealand. Patient-survival, technique-survival, and graft survival rates are excellent and graft survival has improved over the last 2 decades.

Incidence, Risk Factors, and Outcomes of Kidney Transplant Recipients With BK Polyomavirus-Associated Nephropathy.

Introduction: BK polyomavirus-associated nephropathy (BKPyVAN) is associated with graft dysfunction and loss; however, knowledge of immunosuppression reduction strategies and long-term graft, and patient outcomes across the disease spectrum is lacking. Methods: This cohort study included 14,697 kidney transplant recipients in Australia and New Zealand (2005-2019), followed for 91,306 person years. Results: BKPyVAN occurred in 460 recipients (3%) at a median posttransplant time of 4.8 months (interquartile range, 3.1-10.8). Graft loss (35% vs. 21%, P < 0.001), rejection (42% vs. 25%, P < 0.001), and death (18% vs. 13%, P = 0.002) were more common in the BKPyVAN group. The most frequent changes in immunosuppression after BKPyVAN were reduction (≤50%) in tacrolimus (172, 51%) and mycophenolate doses (134, 40%), followed by the conversion of mycophenolate to leflunomide (62, 19%) and tacrolimus to ciclosporin (20, 6%). Factors associated with the development of BKPyVAN included (adjusted hazard ratio [HR]; 95% confidence interval) male sex (1.66; 1.34-2.05), recipient age (≥70 vs. <20 [2.46; 1.30-4.65]), recipient blood group (A vs. B [2.00; 1.19-3.34]), donor age (≥70 vs. <20 [2.99; 1.71-5.22]), earlier era (1.74; 1.35-2.25), donor/recipient ethnic mismatch (1.52; 1.23-1.87), tacrolimus use (1.46; 1.11-1.91), and transplantation at a lower-volume transplant center (1.61; 1.24-2.09). The development of BKPyVAN was associated with an increased risk of all-cause (1.75; 1.46-2.09) and death-censored graft loss (2.49; 1.99-3.11), but not mortality (1.15; 0.91-1.45). Conclusions: BKPyVAN is associated with an increased risk of all-cause and death-censored graft loss, but not death. Interventional trials are urgently needed to evaluate the efficacy of immunosuppression reduction and novel strategies to minimize the adverse outcomes associated with BKPyVAN.

Multicentre registry analysis of incremental peritoneal dialysis incidence and associations with patient outcomes.

BACKGROUND: Incremental peritoneal dialysis (PD) is increasingly advocated to reduce treatment burden and costs, with potential to better preserve residual kidney function. Global prevalence of incremental PD use is unknown and use in Australia and New Zealand has not been reported. METHODS: Binational registry analysis including incident adult PD patients in Australia and New Zealand (2007-2017), examining incidence of and outcomes associated with incremental PD (first recorded PD exchange volume <42 L/week (incremental) vs. ≥42 L/week (standard)). RESULTS: Incremental PD use significantly increased from 2.7% of all incident PD in 2007 to 11.1% in 2017 (mean increase 0.84%/year). Duration of incremental PD use was 1 year or less in 67% of cases. Male sex, Aboriginal and Torres Strait Islander (ATSI) or Maori ethnicities, age 45-59 years, medical comorbidities or treatment at a centre with low use of automated PD or icodextrin was associated with lower incidence of incremental PD use. Low body mass index and higher estimated glomerular filtration rate was associated with higher incidence. After accounting for patient and centre variables, commencing PD with an incremental prescription was associated with reduced peritonitis risk (adjusted hazard ratio 0.73, 95% confidence interval (CI) 0.61-0.86).When kidney transplantation and death were considered as competing risks, the association between incremental PD and peritonitis was not significant (sub-hazard ratio [SHR] 0.91, 95%CI 0.71-1.17, p = 0.5), however cumulative incidence of 30-day transfer to haemodialysis was lower in those receiving incremental PD (SHR 0.73, 95%CI 0.56-0.94, p = 0.01). There was no association between incremental PD and death. CONCLUSIONS: Incremental PD use is increasing in Australia and New Zealand and is not associated with patient harm.