Identifying genes associated with disease outcomes using joint sparse canonical correlation analysis-An application in renal clear cell carcinoma.

Somatic changes like copy number aberrations (CNAs) and epigenetic alterations like methylation have pivotal effects on disease outcomes and prognosis in cancer, by regulating gene expressions, that drive critical biological processes. To identify potential biomarkers and molecular targets and understand how they impact disease outcomes, it is important to identify key groups of CNAs, the associated methylation, and the gene expressions they impact, through a joint integrative analysis. Here, we propose a novel analysis pipeline, the joint sparse canonical correlation analysis (jsCCA), an extension of sCCA, to effectively identify an ensemble of CNAs, methylation sites and gene (expression) components in the context of disease endpoints, especially tumor characteristics. Our approach detects potentially orthogonal gene components that are highly correlated with sets of methylation sites which in turn are correlated with sets of CNA sites. It then identifies the genes within these components that are associated with the outcome. Further, we aggregate the effect of each gene expression set on tumor stage by constructing "gene component scores" and test its interaction with traditional risk factors. Analyzing clinical and genomic data on 515 renal clear cell carcinoma (ccRCC) patients from the TCGA-KIRC, we found eight gene components to be associated with methylation sites, regulated by groups of proximally located CNA sites. Association analysis with tumor stage at diagnosis identified a novel association of expression of ASAH1 gene trans-regulated by methylation of several genes including SIX5 and by CNAs in the 10q25 region including TCF7L2. Further analysis to quantify the overall effect of gene sets on tumor stage, revealed that two of the eight gene components have significant interaction with smoking in relation to tumor stage. These gene components represent distinct biological functions including immune function, inflammatory responses, and hypoxia-regulated pathways. Our findings suggest that jsCCA analysis can identify interpretable and important genes, regulatory structures, and clinically consequential pathways. Such methods are warranted for comprehensive analysis of multimodal data especially in cancer genomics.

Systematic Reviews and Meta-analyses in Regional Anesthesia and Pain Medicine (Part II): Guidelines for Performing the Systematic Review.

In Part I of this series, we provide guidance for preparing a systematic review protocol. In this article, we highlight important steps and supplement with exemplars on conducting and reporting the results of a systematic review. We suggest how authors can manage protocol violations, multiplicity of outcomes and analyses, and heterogeneity. The quality (certainty) of the evidence and strength of recommendations should follow the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. It is our goal that Part II of this series provides valid guidance to authors and peer reviewers who conduct systematic reviews to adhere to important constructs of transparency, structure, reproducibility, and accountability. This will likely result in more rigorous systematic reviews being submitted for publication to the journals like Regional Anesthesia & Pain Medicine and Anesthesia & Analgesia .

"Three Good Things" Digital Intervention Among Health Care Workers: A Randomized Controlled Trial.

PURPOSE: Positive psychology shows promise in improving positive affect and happiness. We tested a digital version of a positive psychology intervention called Three Good Things (3GT) among health care workers to assess whether gratitude practice improved well-being. METHODS: All members of a large academic medicine department were invited. Participants were randomized to an immediate intervention group or control group (delayed intervention). Participants completed outcome measures surveys (demographics, depression, positive affect, gratitude, and life satisfaction) at baseline, and at 1 month and 3 months post-intervention. Controls completed additional surveys at 4 and 6 months (completion of the delayed intervention). During the intervention, we sent 3 text messages per week asking for 3GT that occurred that day. We used linear mixed models to compare the groups and to look at the effects of department role, sex, age, and time on outcomes. RESULTS: Of 468 eligible individuals, 223 (48%) enrolled and were randomized with high retention through the end of the study. Most (87%) identified as female. For the intervention group, positive affect improved slightly at 1 month, then declined slightly but remained significantly improved at 3 months. Depression, gratitude, and life satisfaction scores showed a similar trend but were not statistically different between groups. CONCLUSIONS: Our research showed adherence to a positive psychology intervention for health care workers created small positive improvements immediately post-intervention but were not sustained. Further work should evaluate whether utilizing different duration or intensity of the intervention improves benefits.

Comparing Very Low-Carbohydrate vs DASH Diets for Overweight or Obese Adults With Hypertension and Prediabetes or Type 2 Diabetes: A Randomized Trial.

PURPOSE: Adults with a triple multimorbidity (hypertension, prediabetes or type 2 diabetes, and overweight or obesity), are at increased risk of serious health complications, but experts disagree on which dietary patterns and support strategies should be recommended. METHODS: We randomized 94 adults from southeast Michigan with this triple multimorbidity using a 2 × 2 diet-by-support factorial design, comparing a very low-carbohydrate (VLC) diet vs a Dietary Approaches to Stop Hypertension (DASH) diet, as well as comparing results with and without multicomponent extra support (mindful eating, positive emotion regulation, social support, and cooking). RESULTS: Using intention-to-treat analyses, compared with the DASH diet, the VLC diet led to greater improvement in estimated mean systolic blood pressure (-9.77 mm Hg vs -5.18 mm Hg; P = .046), greater improvement in glycated hemoglobin (-0.35% vs -0.14%; P = .034), and greater improvement in weight (-19.14 lb vs -10.34 lb; P = .0003). The addition of extra support did not have a statistically significant effect on outcomes. CONCLUSIONS: For adults with hypertension, prediabetes or type 2 diabetes, and overweight or obesity, the VLC diet resulted in greater improvements in systolic blood pressure, glycemic control, and weight over a 4-month period compared with the DASH diet. These findings suggest that larger trials with longer follow-up are warranted to determine whether the VLC diet might be more beneficial for disease management than the DASH diet for these high-risk adults.

Changes in Serum, Red Blood Cell, and Colonic Fatty Acids in a Personalized Omega-3 Fatty Acid Supplementation Trial.

This study evaluated changes in fatty acids from sera, red blood cells, and colonic biopsies from a phase Ib clinical trial of personalized ω-3 fatty acid dosing in 47 healthy volunteers. The trial aimed to reduce colonic prostaglandin E2 (PGE2), a pro-inflammatory product of arachidonic acid (AA) oxidation. The personalized doses ranged 2-10 grams/day (54% eicosapentaenoic acid, EPA, 24% other ω-3 fatty acids). In colon, increases in ω-3 highly unsaturated fatty acids (HUFA) and EPA:AA ratios each were correlated with decreases in PGE2. Changes in either colonic EPA:AA ratios or ω-3 HUFA were significantly correlated with changes in the same fatty acid measures in red blood cells or serum. The only blood-based measure significantly correlated with changes in colonic PGE2 was change in red blood cell ω-3 HUFA (ρ = -0.39), and the increase in red blood cell ω-3 HUFA was significantly greater in participants who had at least a median reduction in colonic PGE2 vs. those who did not. In summary, fatty acid changes in blood did reflect fatty acid changes in the colon, but additional factors will be needed for optimizing dosing models that seek to predict the anti-inflammatory effects of ω-3 fatty acids on the colon.

Continuous Glucose Monitoring With Low-Carbohydrate Nutritional Coaching to Improve Type 2 Diabetes Control: Randomized Quality Improvement Program.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a leading cause of morbidity and mortality globally, with adverse health consequences largely related to hyperglycemia. Despite clinical practice guideline recommendations, effective pharmacotherapy, and interventions to support patients and providers, up to 60% of patients diagnosed with T2DM are estimated to have hemoglobin A1c (HbA1c) levels above the recommended targets owing to multilevel barriers hindering optimal glycemic control. OBJECTIVE: The aim of this study is to compare changes in HbA1c levels among patients with suboptimally controlled T2DM who were offered the opportunity to use an intermittently viewed continuous glucose monitor and receive personalized low-carbohydrate nutrition counseling (<100 g/day) versus those who received usual care (UC). METHODS: This was a 12-month, pragmatic, randomized quality improvement program. All adult patients with T2DM who received primary care at a university-affiliated primary care clinic (N=1584) were randomized to either the UC or the enhanced care (EC) group. Within each program arm, we identified individuals with HbA1c >7.5% (58 mmol/mol) who were medically eligible for tighter glycemic control, and we defined these subgroups as UC-high risk (UC-HR) or EC-HR. UC-HR participants (n=197) received routine primary care. EC-HR participants (n=185) were invited to use an intermittently viewed continuous glucose monitor and receive low-carbohydrate nutrition counseling. The primary outcome was mean change in HbA1c levels from baseline to 12 months using an intention-to-treat difference-in-differences analysis comparing EC-HR with UC-HR groups. We conducted follow-up semistructured interviews to understand EC-HR participant experiences with the intervention. RESULTS: HbA1c decreased by 0.41% (4.5 mmol/mol; P=.04) more from baseline to 12 months among participants in the EC-HR group than among those in UC-HR; however, only 61 (32.9%) of 185 EC-HR participants engaged in the program. Among the EC-HR participants who wore continuous glucose monitors (61/185, 32.9%), HbA1c was 1.1% lower at 12 months compared with baseline (P<.001). Interviews revealed themes related to EC-HR participants' program engagement and continuous glucose monitor use. CONCLUSIONS: Among patients with suboptimally controlled T2DM, a combined approach that includes continuous glucose monitoring and low-carbohydrate nutrition counseling can improve glycemic control compared with the standard of care.

Physician Suicide in the United States:Updated Estimates from the National Violent Death Reporting System.

Physician suicide and well-being are critical issues but studies use varying methodologies and suicide is frequently underreported. This study sought to update data on physician suicides in the United States. The National Violent Death Reporting System (NVDRS) at the Centers for Disease Control collects details about violent deaths. The study used 2010-2015 data from 27 NVDRS states to identify suicide deaths among physicians or non-physicians and calculate annual standardized mortality rates (SMR). Of 63,780 victims total, there were 357 physicians identified over 6 years, (307 men and 50 women). If results are extrapolated to all 50 states, there would be approximately 119 physician suicides annually. The SMR for physicians overall was not statistically different from that of non-physicians. This is the first study in 16 years to update estimated physician suicide rates in the United States. The research used strict criteria to identify physicians so results likely represent the lower boundary of physician suicides. Findings show that physician suicide is not significantly lower than that of non-physicians and emphasizes the importance of focusing on structural changes to reduce stigma around mental health in the medical community.

Technology-Facilitated Depression Self-Management Linked with Lay Supporters and Primary Care Clinics: Randomized Controlled Trial in a Low-Income Sample.

Purpose: To test whether technology-facilitated self-management support improves depression in primary care settings. Methods: We randomized 204 low-income primary care patients who had at least moderate depressive symptoms to intervention or control. Intervention participants received 12 months of weekly automated interactive voice response telephone calls that assessed their symptom severity and provided self-management strategies. Their patient-nominated supporter (CarePartner) received corresponding guidance on self-management support, and their primary care team received urgent notifications. Those randomized to enhanced usual care received printed generic self-management instructions. Results: One-year attrition rate was 14%. By month 6, symptom severity on the Patient Health Questionnaire-9 (PHQ-9) decreased 2.5 points more in the intervention arm than in the control arm (95% CI -4.2 to -0.8, p = 0.003). This benefit was similar at month 12 (p = 0.004). Intervention was also over twice as likely to lead to ≥50% reduction in symptom severity by month 6 (OR = 2.2 (1.1, 4.7)) and a decrease of ≥5 PHQ-9 points by month 12 (OR = 2.3 (1.2, 4.4)). Conclusions: Technology-facilitated self-management guidance with lay support and clinician notifications improves depression for primary care patients. Subsequent research should examine implementation and generalization to other chronic conditions. clinicaltrials.gov, identifier NCT01834534.

Bayesian inference of dependent kappa for binary ratings.

In medical and social science research, reliability of testing methods measured through inter- and intraobserver agreement is critical in disease diagnosis. Often comparison of agreement across multiple testing methods is sought in situations where testing is carried out on the same experimental units rendering the outcomes to be correlated. In this article, we first developed a Bayesian method for comparing dependent agreement measures under a grouped data setting. Simulation studies showed that the proposed methodology outperforms the competing methods in terms of power, while maintaining a decent type I error rate. We further developed a Bayesian joint model for comparing dependent agreement measures adjusting for subject and rater-level heterogeneity. Simulation studies indicate that our model outperforms a competing method that is used in this context. The developed methodology was implemented on a key measure on a dichotomous rating scale from a study with six raters evaluating three classification methods for chest radiographs for pneumoconiosis developed by the International Labor Office.

Potentially Preventable Hospitalizations Among Older Adults: 2010-2014.

PURPOSE: We undertook a study to examine national trends in potentially preventable hospitalizations-those for ambulatory care-sensitive conditions that could have been avoided if patients had timely access to primary care-across 3,200 counties and various subpopulations of older adults in the United States. METHODS: We used 2010-2014 Medicare claims data to examine trends in potentially preventable hospitalizations among beneficiaries aged 65 years and older and developed heat maps to examine county-level variation. We used a generalized estimating equation and adjusted the model for demographics, comorbidities, dual eligibility (Medicare and Medicaid), ZIP code-level income, and county-level number of primary care physicians and hospitals. RESULTS: Across the 3,200 study counties, potentially preventable hospitalizations decreased in 327 counties, increased in 123 counties, and did not change in the rest. At the population level, the adjusted rate of potentially preventable hospitalizations declined by 3.45 percentage points from 19.42% (95% CI, 18.4%-20.5%) in 2010 to 15.97% (95% CI, 15.3%-16.6%) in 2014; it declined by 2.93, 2.87, and 3.33 percentage points among White, Black, and Hispanic patients to 14.96% (95% CI, 14.67%-15.24%), 17.92% (95% CI, 17.27%-18.58%), and 17.10% (95% CI, 16.25%-18.0%), respectively. Similarly, the rate for dually eligible patients fell by 3.71 percentage points from 21.62% (95% CI, 20.5%-22.8%) in 2010 to 17.91% (95% CI, 17.2%-18.7%) in 2014. (P <.001 for all). CONCLUSIONS: During 2010-2014, rates of potentially preventable hospitalization did not change in the majority of counties. At the population level, although the rate declined among all subpopulations, dually eligible patients and Black and Hispanic patients continued to have substantially higher rates compared with non-dually eligible and White patients, respectively.

Effective Hearing Loss Screening in Primary Care: The Early Auditory Referral-Primary Care Study.

PURPOSE: Hearing loss, the second most common disability in the United States, is under-diagnosed and under-treated. Identifying it in early stages could prevent its known substantial adverse outcomes. METHODS: A multiple baseline design was implemented to assess a screening paradigm for identifying and referring patients aged ≥55 years with hearing loss at 10 family medicine clinics in 2 health systems. Patients completed a consent form and the Hearing Handicap Inventory for the Elderly (HHI). An electronic alert prompted clinicians to screen for hearing loss during visits. RESULTS: The 14,877 eligible patients during the study period had 36,701 encounters. Referral rates in the family medicine clinics increased from a baseline rate of 3.2% to 14.4% in 1 health system and from a baseline rate of 0.7% to 4.7% in the other. A general medicine comparison group showed referral rate increase from the 3.0% baseline rate to 3.3%. Of the 5,883 study patients who completed the HHI 25.2% (n=1,484) had HHI scores suggestive of hearing loss; those patients had higher referral rates, 28% vs 9.2% (P <.001). Of 1,660 patients referred for hearing testing, 717 had audiology data available for analysis: 669 (93.3%) were rated appropriately referred and 421 (58.7%) were considered hearing aid candidates. Overall, 71.5% of patients contacted felt their referral was appropriate. CONCLUSION: An electronic alert used to remind clinicians to ask patients aged ≥55 years about hearing loss significantly increased audiology referrals for at-risk patients. Audiologic and audiogram data support the effectiveness of the prompt. Clinicians should consider adopting this method to identify patients with hearing loss to reduce its known and adverse sequelae.

Free vitamin D levels in steroid-sensitive nephrotic syndrome and healthy controls.

INTRODUCTION: Body stores of vitamin D are measured as "total" serum 25-hydroxy vitamin D (25(OH)D). Its largest component is protein bound and lost in urine in nephrotic syndrome (NS). Our study investigates whether "free" 25(OH)D levels are a better guide to bone health and need for vitamin D supplementation in patients with steroid-sensitive NS (SSNS). METHODS: A cross-sectional study was performed in children with SSNS and healthy controls. Blood was tested for albumin, creatinine, calcium, phosphate, ALP, total and free (by direct ELISA) 25(OH)D, iPTH, and urine for protein-creatinine ratio. RESULTS: Seventy-nine NS patients (48 in relapse, 31 in remission) and 60 healthy controls were included. The levels of total 25(OH)D were significantly different (lowest in NS relapse and highest in controls) (p < 0.001). Corrected calcium and phosphate levels were normal, and there were no differences in free 25(OH)D, ALP, or iPTH levels between groups. Only total and not free 25(OH)D correlated significantly and negatively with urinary protein creatinine ratios (rs = - 0.42 vs. 0.04). Free 25(OH)D values of 3.75 and 2.85 pg/ml corresponded to total 25(OH)D levels of 20 and 12 ng/ml, respectively, in healthy controls. CONCLUSION: These results confirm that total 25(OH)D levels are low in NS and related to degree of proteinuria. However levels of free 25(OH)D, ALP, and iPTH did not change in relapse or remission in comparison with healthy controls. Our results suggest that in proteinuric renal diseases, free 25(OH)D rather than total 25(OH)D levels should be used to diagnose vitamin D deficiency and guide therapy.

Increases in Colonic Bacterial Diversity after ω-3 Fatty Acid Supplementation Predict Decreased Colonic Prostaglandin E2 Concentrations in Healthy Adults.

BACKGROUND: The intestinal microbiome is an important determinant of inflammatory balance in the colon that may affect response to dietary agents. OBJECTIVE: This is a secondary analysis of a clinical trial, the Fish Oil Study, to determine whether interindividual differences in colonic bacteria are associated with variability in the reduction of colonic prostaglandin E2 (PGE2) concentrations after personalized supplementation with ω-3 (n-3) fatty acids. METHODS: Forty-seven healthy adults (17 men, 30 women, ages 26-75 y) provided biopsy samples of colonic mucosa and luminal stool brushings before and after personalized ω-3 fatty acid supplementation that was based on blood fatty acid responses. Samples were analyzed using 16S ribosomal RNA sequencing. The data analyses focused on changes in bacterial community diversity. Linear regression was used to evaluate factors that predict a reduction in colonic PGE2. RESULTS: At baseline, increased bacterial diversity, as measured by the Shannon and Inverse Simpson indexes in both biopsy and luminal brushing samples, was positively correlated with dietary fiber intakes and negatively correlated with fat intakes. Dietary supplementation with ω-3 fatty acids increased the Yue and Clayton community dis-similarity index between the microbiome in luminal brushings and colon biopsy samples post-supplementation (P = 0.015). In addition, there was a small group of individuals with relatively high Prevotella abundance who were resistant to the anti-inflammatory effects of ω-3 fatty acid supplementation. In linear regression analyses, increases in diversity of the bacteria in the luminal brushing samples, but not in the biopsy samples, were significant predictors of lower colonic PGE2 concentrations post-supplementation in models that included baseline PGE2, baseline body mass index, and changes in colonic eicosapentaenoic acid-to-arachidonic acid ratios. The changes in bacterial diversity contributed to 6-8% of the interindividual variance in change in colonic PGE2 (P = 0.001). CONCLUSIONS: Dietary supplementation with ω-3 fatty acids had little effect on intestinal bacteria in healthy humans; however, an increase in diversity in the luminal brushings significantly predicted reductions in colonic PGE2. This trial was registered at www.clinicaltrials.gov as NCT01860352.

Default Priors for the Intercept Parameter in Logistic Regressions.

In logistic regression, separation occurs when a linear combination of predictors perfectly discriminates the binary outcome. Because finite-valued maximum likelihood parameter estimates do not exist under separation, Bayesian regressions with informative shrinkage of the regression coefficients offer a suitable alternative. Classical studies of separation imply that efficiency in estimating regression coefficients may also depend upon the choice of intercept prior, yet relatively little focus has been given on whether and how to shrink the intercept parameter. Alternative prior distributions for the intercept are proposed that downweight implausibly extreme regions of the parameter space, rendering regression estimates that are less sensitive to separation. Through simulation and the analysis of exemplar datasets, differences across priors stratified by established statistics measuring the degree of separation are quantified. Relative to diffuse priors, these proposed priors generally yield more efficient estimation of the regression coefficients themselves when the data are nearly separated. They are equally efficient in non-separated datasets, making them suitable for default use. Modest differences were observed with respect to out-of-sample discrimination. These numerical studies also highlight the interplay between priors for the intercept and the regression coefficients: findings are more sensitive to the choice of intercept prior when using a weakly informative prior on the regression coefficients than an informative shrinkage prior.

Review and Comparison of Computational Approaches for Joint Longitudinal and Time-to-Event Models.

Joint models for longitudinal and time-to-event data are useful in situations where an association exists between a longitudinal marker and an event time. These models are typically complicated due to the presence of shared random effects and multiple submodels. As a consequence, software implementation is warranted that is not prohibitively time consuming. While methodological research in this area continues, several statistical software procedures exist to assist in the fitting of some joint models. We review the available implementation for frequentist and Bayesian models in the statistical programming languages R, SAS, and Stata. A description of each procedure is given including estimation techniques, input and data requirements, available options for customization, and some available extensions, such as competing risks models. The software implementations are compared and contrasted through extensive simulation, highlighting their strengths and weaknesses. Data from an ongoing trial on adrenal cancer patients is used to study different nuances of software fitting on a practical example.

Comparison of digital and film chest radiography for detection and medical surveillance of silicosis in a setting with a high burden of tuberculosis.

BACKGROUND: Continuing use of analog film and digital chest radiography for screening and surveillance for pneumoconiosis and tuberculosis in lower and middle income countries raises questions of equivalence of disease detection. This study compared analog to digital images for intra-rater agreement across formats and prevalence of changes related to silicosis and tuberculosis among South African gold miners using the International Labour Organization classification system. METHODS: Miners with diverse radiological presentations of silicosis and tuberculosis were recruited. Digital and film chest images on each subject were classified by four expert readers. RESULTS: Readings of film and soft copy digital images showed no significant differences in prevalence of tuberculosis or silicosis, and intra-rater agreement across formats was fair to good. Hard copy images yielded higher prevalences. CONCLUSION: Film and digital soft copy images show consistent prevalence of findings, and generally fair to good intra-rater agreement for findings related to silicosis and tuberculosis.

Nerve Growth Factor and Selected Cytokines in Women With and Without Vulvodynia.

OBJECTIVE: The aim of the study was to assess the association between cytokines/neurokines after in vitro stimulation with Candida antigen or lipopolysaccharide (LPS) in blood samples among women with and without vulvodynia. MATERIALS AND METHODS: Women with vulvodynia and asymptomatic controls at three offices at the University of Michigan were examined clinically and completed a comprehensive survey in this cross-sectional study. Cytokine/neurokine levels were determined on blood samples using established ELISA protocols. Analysis of 48 cases and 42 ethnically matched controls included descriptive statistics (median, minimal, and maximal levels of cytokines/neurokines), overall and in cases and controls. Because of left-censored measurements, interval censored survival analysis was used to assess the association between case/control status and pain characteristics with cytokine/neurokine levels. RESULTS: Participants ranged in age from 19 to 60 years. Levels of IL1ß, IL1-RA, TNFα, IL-6, and IL-8 increased substantially after LPS stimulation, whereas no response was seen on IFNγ or nerve growth factor (NGF). Each increased after Candida antigen stimulation, although responses to Candida antigen stimulation of IL1ß, IL-6, and TNFα were less robust than after LPS. Only NGF was significantly increased in vulvodynia cases compared with controls (Exp ß (95% CI) = 2.08 [1.08-3.98]) after 24-hour Candida antigen stimulation and persisted when controlled for age, use of oral contraceptives, or history of Candida vulvovaginitis. No association between cytokine/neurokine levels and pain characteristics was found. CONCLUSIONS: Compared with that of control women, whole blood from women with vulvodynia demonstrates an enhanced production of NGF, but not of a set of inflammation-related cytokines, in response to Candida antigen stimulation.

Association between changes in quality of life and mortality in hemodialysis patients: results from the DOPPS.

Background: Cross-sectional health-related quality of life (HR-QOL) measures are associated with mortality in hemodialysis (HD) patients. The impact of changes in HR-QOL on outcomes remains unclear. We describe the association of prior changes in HR-QOL with subsequent mortality among HD patients. Methods: A total of 13 784 patients in the Dialysis Outcomes and Practice Patterns Study had more than one measurement of HR-QOL. The impact of changes between two measurements of the physical (PCS) and mental (MCS) component summary scores of the SF-12 on mortality was estimated with Cox regression. Results: Mean age was 62 years (standard deviation: 14 years); 59% were male and 32% diabetic. Median time between HR-QOL measurements was 12 months [interquartile range (IQR): 11, 14]. Median initial PCS and MCS scores were 37.5 (IQR: 29.4, 46.2) and 46.4 (IQR: 37.2, 54.9); median changes in PCS and MCS scores were -0.2 (IQR: -5.5, 4.7) and -0.1 (IQR: -6.8, 5.9), respectively. The adjusted hazard ratio (HR) for a 5-point decline in HR-QOL score was 1.09 [95% confidence interval (CI): 1.06-1.12] for PCS and 1.05 (95% CI: 1.03-1.08) for MCS. Adjusting for the second QOL score, the change was not associated with mortality: HR = 1.01 (95% CI: 0.98-1.05) for delta PCS and 1.01 (95% CI: 0.98-1.03) for delta MCS. Categorizing the first and second scores as predictors, only the second PCS or MCS score was associated with mortality. Conclusions: In our study, only the most recent HR-QOL score was associated with mortality. Hence, the predictive power of a measurement of HR-QOL is not affected by changes in HR-QOL prior to that measurement; more frequent HR-QOL measurements are needed to improve the prediction of outcomes in HD. Further studies are needed to determine the optimal frequency and appropriate instrument to be used for serial measurements.

The effect of vitamin D and calcium supplementation in pediatric steroid-sensitive nephrotic syndrome.

BACKGROUND: Low serum levels of total 25-hydroxycholecalciferol (25(OH)D) occur in nephrotic syndrome (NS). We aimed to assess the effects of vitamin D3 and calcium supplementation on 25(OH)D levels, bone mineralization, and NS relapse rate in children with steroid-sensitive NS. METHODS: A randomized controlled trial (RCT) was performed in children with steroid-sensitive NS. The treatment group received vitamin D3 (60,000 IU orally, weekly for 4 weeks) and calcium supplements (500 to 1,000 mg/day for 3 months) after achieving NS remission. Blood samples for bone biochemistry were taken during relapse (T0), after 6 weeks (T1) and 6 months (T2) of randomization, whereas a lumbar DXA scan was performed at T0 and T2. Renal ultrasound was performed after study completion in the treatment group and in all patients with hypercalciuria. RESULTS: Of the 48 initial recruits, 43 patients completed the study. Post-intervention, 25(OH)D levels showed significant improvements in the treatment group compared with controls at T1 (p < 0.001) and T2 (p < 0.001). However, this was not associated with differences in bone mineral content (BMC) (p = 0.44) or bone mineral density (BMD) (p = 0.64) between the groups. Additionally, there was no reduction in relapse number in treated patients (p = 0.54). Documented hypercalciuria occurred in 52% of patients in the treatment group, but was not associated with nephrocalcinosis. CONCLUSIONS: Although supplementation with calcium and vitamin D improved 25(OH)D levels significantly, there was no effect on BMC, BMD or relapse rate over a 6-month follow-up. Occurrence of hypercalciuria mandates caution and appropriate monitoring if using such therapy. Appropriate dosage of vitamin D3 remains uncertain and studies examining biologically active vitamin D may provide answers.