Human SRMAtlas: A Resource of Targeted Assays to Quantify the Complete Human Proteome.

The ability to reliably and reproducibly measure any protein of the human proteome in any tissue or cell type would be transformative for understanding systems-level properties as well as specific pathways in physiology and disease. Here, we describe the generation and verification of a compendium of highly specific assays that enable quantification of 99.7% of the 20,277 annotated human proteins by the widely accessible, sensitive, and robust targeted mass spectrometric method selected reaction monitoring, SRM. This human SRMAtlas provides definitive coordinates that conclusively identify the respective peptide in biological samples. We report data on 166,174 proteotypic peptides providing multiple, independent assays to quantify any human protein and numerous spliced variants, non-synonymous mutations, and post-translational modifications. The data are freely accessible as a resource at http://www.srmatlas.org/, and we demonstrate its utility by examining the network response to inhibition of cholesterol synthesis in liver cells and to docetaxel in prostate cancer lines.

Muscle Mass and Serum Creatinine Concentration by Race and Ethnicity among Hemodialysis Patients.

SIGNIFICANCE STATEMENT: Serum creatinine is a product of skeletal muscle metabolism. Differences in serum creatinine concentration between Black and non-Black individuals have been attributed to differences in muscle mass but have not been thoroughly examined. Furthermore, other race and ethnic groups have not been considered. If differences in body composition explain differences in serum concentration by race or ethnicity, then estimates of body composition could be used in eGFR equations rather than race. Adjustment for intracellular water (ICW) as a proxy of muscle mass among patients with kidney failure in whom creatinine clearance should minimally influence serum concentration does not explain race- and ethnicity-dependent differences. BACKGROUND: Differences in serum creatinine concentration among groups defined by race and ethnicity have been ascribed to differences in muscle mass. We examined differences in serum creatinine by race and ethnicity in a cohort of patients receiving hemodialysis in whom creatinine elimination by the kidney should have little or no effect on serum creatinine concentration and considered whether these differences persisted after adjustment for proxies of muscle mass. METHODS: We analyzed data from 501 participants in the A Cohort Study to Investigate the Value of Exercise in ESKD/Analyses Designed to Investigate the Paradox of Obesity and Survival in ESKD study who had been receiving hemodialysis for >1 year. We examined the independent associations among race and ethnicity (Black, Asian, non-Hispanic White, and Hispanic), serum creatinine, and ICW (L/m 2 ), a proxy for muscle mass, derived by whole-body multifrequency bioimpedance spectroscopy, using multivariable linear regression with adjustment for several demographic, clinical, and laboratory characteristics. We examined the association of race and ethnicity with serum creatinine concentration with and without adjustment for ICW. RESULTS: Black, Asian, and Hispanic patients had higher serum creatinine concentrations (+1.68 mg/dl [95% confidence interval (CI), 1.09 to 2.27], +1.61 mg/dl [95% CI, 0.90 to 2.32], and +0.83 [95% CI, 0.08 to 1.57], respectively) than non-Hispanic White patients. Overall, ICW was associated with serum creatinine concentration (0.26 mg/dl per L/m 2 ICW; 95% CI, 0.006 to 0.51) but was not statistically significantly different by race and ethnicity. Black, Asian, and Hispanic race and ethnicity remained significantly associated with serum creatinine concentration after adjustment for ICW. CONCLUSION: Among patients receiving dialysis, serum creatinine was higher in Black, Asian, and Hispanic patients than in non-Hispanic White patients. Differences in ICW did not explain the differences in serum creatinine concentration across race groups.

Rurality of patient residence and access to transplantation among children with kidney failure in the United States.

BACKGROUND: Residence in rural areas is often a barrier to health care access. To date, differences in access to kidney transplantation among children who reside in rural and micropolitan areas of the US have not been explored. METHODS: A retrospective cohort study of children < 18 years who developed kidney failure between 2000 and 2019 according to the United States Renal Data System (USRDS). We examined the association between rurality of patient residence and time to living and/or deceased donor kidney transplantation (primary outcomes) and waitlist registration (secondary outcome) using Fine-Gray models. RESULTS: We included 18,530 children, of whom 14,175 (76.5%) received a kidney transplant (39.8% from a living and 60.2% from a deceased donor). Residence in micropolitan (subhazard ratio (SHR) 1.16; 95% CI 1.06-1.27) and rural (SHR 1.18; 95% CI 1.06-1.3) areas was associated with better access to living donor transplantation compared with residence in metropolitan areas. There was no statistically significant association between residence in micropolitan (SHR, 0.95; 95%CI 0.88-1.03) and rural (SHR, 0.94; 95%CI 0.86-1.03) areas compared with metropolitan areas in the access of children to deceased donor transplantation. There was also no difference in the time to waitlist registration comparing micropolitan (SHR 1.04; 95%CI 0.98-1.10) and rural (SHR 1.05; 95% CI 0.98-1.13) versus metropolitan areas. CONCLUSIONS: In children with kidney failure, residence in rural and micropolitan areas was associated with better access to living donor transplantation and similar access to deceased donor transplantation compared with residence in metropolitan areas.

Intensive BP Control in Patients with CKD and Risk for Adverse Outcomes.

SIGNIFICANCE STATEMENT: Although most guidelines recommend tightly controlling BP in patients with CKD, individuals with advanced kidney disease or severe albuminuria were not well-represented in trials examining the effect of this intervention on kidney outcomes. To examine the effect of intensive BP control on the risk of kidney outcomes in patients with CKD, the authors pooled individual-level data from seven trials. They found that overall, intensive BP control was associated with a 13% lower, but not significant, risk of a kidney outcome. However, the intervention's effect on the kidney outcome differed depending on baseline eGFR. Data from this pooled analysis suggested a benefit of intensive BP control in delaying KRT onset in patients with stages 4-5 CKD, but not necessarily in those with stage 3 CKD. BACKGROUND: The effect of intensive BP lowering (to systolic BP of <120 mm Hg) on the risk of kidney failure requiring KRT remains unclear in patients with advanced CKD. Such patients were not well represented in trials evaluating intensive BP control. METHODS: To examine the effect of intensive BP lowering on KRT risk-or when not possible, trial-defined kidney outcomes-we pooled individual-level data from seven trials that included patients with eGFR<60 ml/min per 1.73 m 2 . We performed prespecified subgroup analyses to evaluate the effect of intensive BP control by baseline albuminuria and eGFR (CKD stages 4-5 versus stage 3). RESULTS: Of 5823 trial participants, 526 developed the kidney outcome and 382 died. Overall, intensive (versus usual) BP control was associated with a lower risk of kidney outcome and death in unadjusted analyses but these findings did not achieve statistical significance. However, the intervention's effect on the kidney outcome differed depending on baseline eGFR ( P interaction=0.05). By intention-to-treat analysis, intensive (versus usual) BP control was associated with a 20% lower risk of the primary kidney outcome in those with CKD GFR stages 4-5, but not in CKD GFR stage 3. There was no interaction between intensive BP control and the severity of albuminuria for kidney outcomes. CONCLUSIONS: Data from this pooled analysis of seven trials suggest a benefit of intensive BP control in delaying KRT onset in patients with stages 4-5 CKD but not necessarily with stage 3 CKD. These findings suggest no evidence of harm from intensive BP control, but also point to the need for future trials of BP targets focused on populations with advanced kidney disease. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023_02_27_JASN0000000000000060.mp3.

Melatonin for migraine prevention in children and adolescents: A randomized, double-blind, placebo-controlled trial after single-blind placebo lead-in.

BACKGROUND: Melatonin is effective for migraine prevention in adults. We hypothesized that melatonin would also be effective for migraine prevention in children and adolescents. METHODS: This was a randomized, double-blind trial of melatonin (3 mg or 6 mg) versus placebo for migraine prevention in 10-17 year-olds with 4-28/28 headache days at baseline. Participants were recruited from the UCSF Child & Adolescent Headache Program, UCSF child neurology clinic, and social media advertisements. Migraine diagnosis was confirmed by a headache specialist. Participants completed an 8-week single-blind placebo run-in. Those meeting randomization criteria (≥4 headache days and ≥23/28 electronic diary entries during weeks 5-8) were randomized 1:1:1 to placebo:melatonin 3 mg:melatonin 6 mg nightly for 8 weeks. The primary outcome measure was migraine days in weeks 5-8 of randomized treatment between melatonin (combined 6 mg + 3 mg) versus placebo. We aimed to enroll n = 210. RESULTS: The study closed early due to slow enrollment (n = 72). Two participants were in the single-blind phase when the study closed, therefore the meaningful n = 70. Sixteen percent (11/70) were lost to follow-up during the single-blind phase. An additional 21% (15/70) did not meet randomization criteria (<4 headache days: n = 5, <23/28 diary days: n = 7, both: n = 3). Sixty-three percent (44/70) were eligible to randomize, of whom 42 randomized (n = 14 per arm). Taking another preventive at enrollment (OR 8.3, 95% CI 1.01 to 68.9) was the only variable associated with meeting randomization criteria. Of those randomized, 91% (38/42) provided diary data in the final 4-weeks. However, given the amount of missing data, only those with ≥21/28 diary days were analyzed-7/14 (50%) in the placebo group, and 20/28 (71%) in the melatonin groups combined. Median (IQR) migraine/migrainous days in weeks 5-8 of double-blind treatment was 2 (1-7) in the placebo group versus 2 (1-12) in the melatonin groups combined; the difference in medians (95% CI for the difference) was 0 days (-9 to 3). There were no differences in adverse events between groups. CONCLUSIONS: When compared to recall at enrollment, headache days decreased across the single-blind placebo phase and the double-blind phase. There was no suggestion of superiority of melatonin; however, given the substantial portion of missing data, numerically higher in the placebo arm, and underpowering, this should not be interpreted as proof of inefficacy. Melatonin was generally well tolerated with no serious adverse events. Future migraine preventive trials in this age group may find this trial helpful for anticipating enrollment needs if using a single-blind placebo run-in. Enriching for those already on a migraine preventive may improve randomization rates in future trials, though would change the generalizability of results.

Increased Colorectal Cancer Screening Sustained with Mailed Fecal Immunochemical Test Outreach.

BACKGROUND & AIMS: Reports of mailed fecal immunochemical test (FIT) outreach effectiveness over time are minimal. We aimed to better evaluate a mailed FIT program with longitudinal metrics. METHODS: A total of 10,771 patients aged 50 to 75 years not up-to-date with colorectal cancer screening were randomized to intervention or usual care. The intervention arm received an advanced notification call and informational postcard prior to a mailed FIT. Usual care was at the discretion of the primary care provider. Patients were followed for up to 2.5 years. The primary outcome was the difference in cumulative proportion of completed FIT screening between arms. Screening was further examined with the proportion of time up-to-date, consistency of adherence, and frequency of abnormal FIT. RESULTS: The cumulative proportion of FIT completion was higher in the outreach intervention (73.2% vs 55.1%; P < .001). The proportion of time covered by screening was higher in the intervention group (46.8% vs 27.3%; Δ19.6%; 95% confidence interval, 18.2%-20.9%). Patients assigned to FIT outreach were more likely to consistently complete FITs (2 completed of 2 offered) (50.1% vs 21.8%; P < .001). However, for patients who did not complete the FIT during the first cycle, only 17.1% completed a FIT during the second outreach cycle. The number and overall proportion of abnormal FIT was significantly higher in the outreach intervention (6.9% Outreach vs 4.1% Usual Care; P < .01). CONCLUSIONS: Organized mailed FIT outreach significantly increased colorectal cancer screening over multiple years in this safety-net health system. Although mailing was overall effective, the effect was modest in patients who did not complete FIT in first cycle of intervention. (ClincialTrials.gov, NCT02613260).

Disentangling the impact of alcohol use and hepatitis C on insulin action in Latino individuals.

BACKGROUND: Alcohol, insulin resistance (IR), and hepatitis C (HCV) are all significant contributors to adverse outcomes of chronic liver disease. Latinos are disproportionately affected by these risk factors. We investigated the relationship between alcohol use and insulin action in a prospective cohort of Latino individuals with and without HCV. METHODS: One hundred fifty-three nondiabetic Latino individuals (60 HCV+, 93 HCV-) underwent clinical evaluation and metabolic testing; 56 had repeat testing over a median follow-up of 1.5 years. Peripheral IR and hepatic IR were measured via steady-state plasma glucose (SSPG) and endogenous glucose production during a two-step, 240-min insulin suppression test. Insulin secretion (IS) was measured using the graded glucose infusion test. Alcohol use was categorized as none, moderate (≤1 drink/day for women and ≤2 drinks/day for men), and heavy (>moderate). Multivariable models including HCV status assessed associations of alcohol use with baseline SSPG, hepatic IR and IS, and changes in these parameters over time. RESULTS: Overall, the median age was 44 years, 63.4% were male, 66.7% overweight/ obese, and 31.9% had heavy lifetime alcohol use while 60.4% had moderate lifetime alcohol use. SSPG and IS were similar by levels of alcohol use at baseline and alcohol use was not statistically significantly associated with change in these measures over time. However, lifetime daily heavy alcohol use (vs. not heavy, coef 2.4 µU-mg/kg-min-ml, p = 0.04) and HCV status (coef 4.4 µU-mg/kg-min-ml, p = 0.0003) were independently associated with higher baseline hepatic IR, and current heavy alcohol use was associated with greater change in hepatic IR in follow-up (coef 5.8 µU-mg/kg-min-ml, p = 0.03). CONCLUSIONS: In this cohort of Latino individuals, lifetime and current heavy alcohol use influenced hepatic IR and its change over time. Strategies to decrease rates of heavy alcohol use or increase abstinence along with lifestyle modification and anti-HCV therapy to reduce metabolic risk are critical to prevent adverse liver and metabolic outcomes in Latino individuals.

Longitudinal Assessment of Body Composition and Its Association With Survival Among Participants of the ACTIVE/ADIPOSE Study.

OBJECTIVES: The importance of muscle wasting as a predictor of mortality in the hemodialysis population is not clear. Lack of association of muscle mass with survival in some studies could be related to reliance on single measures or to incorporation of excess extracellular water (ECW) into estimates of muscle mass. We examined changes in body composition over a 2-year period and the association of body composition with survival. DESIGN AND METHODS: We analyzed data from 325 adults receiving hemodialysis in the Bay Area. We estimated ECW, intracellular water (ICW), and fat mass by whole-body bioimpedance spectroscopy (BIS) at 0, 12, and 24 months from enrollment. We used linear mixed modeling to examine changes in body mass index and BIS-derived estimates of body composition and Cox modeling with BIS-derived estimates as time-varying independent variables to examine associations between body composition and survival in multivariable analyses. RESULTS: Body mass index declined over time. Considering individual components of body composition, ICW declined (-0.09 kg/m2 per year, 95% confidence interval -0.14 to -0.04), but fat mass and ECW did not change significantly. There were 120 deaths over a median of 5.2 years. The relationship between ICW and mortality was not linear such that the association was steeper at low values of ICW, whereas higher ICW was associated with better survival that was relatively stable above 9 kg/m2. Higher ECW was associated with higher mortality, and fat mass was not associated with survival. These associations were independent of markers of inflammation and nutritional status. CONCLUSIONS: ICW declined over 2 years in this cohort, whereas fat mass and ECW remained relatively stable. Higher ICW was associated with better survival, but higher fat mass was not. Higher ECW was associated with worse survival. These results suggest that muscle mass may predict survival among patients on hemodialysis.

Association between Longer Travel Distance for Transplant Care and Access to Kidney Transplantation and Graft Survival in the United States.

BACKGROUND: Transplant candidates may gain an advantage by traveling to receive care at a transplant center that may have more favorable characteristics than their local center. Factors associated with longer travel distance for transplant care and whether the excess travel distance (ETD) is associated with access to transplantation or with graft failure are unknown. METHODS: This study of adults in the United States wait-listed for kidney transplantation in 1995-2015 used ETD, defined as distance a patient traveled beyond the nearest transplant center for initial waiting list registration. We used linear regression to examine patient and center characteristics associated with ETD and Fine-Gray models to examine the association between ETD (modeled as a spline) and time to deceased or living donor transplantation or graft failure. RESULTS: Of 373,365 patients, 11% had an ETD≥50 miles. Traveling excess distance was more likely among patients who were of non-Black race or those whose nearest transplant center had lower annual living donor transplant volume. At an ETD of 50 miles, we observed a lower likelihood of deceased donor transplantation (subhazard ratio [SHR], 0.85; 95% confidence interval [95% CI], 0.84 to 0.87) but higher likelihood of living donor transplantation (SHR, 1.14; 95% CI, 1.12 to 1.16) compared with those who received care at their nearest center. ETD was weakly associated with higher risk of graft failure. CONCLUSIONS: Patients who travel excess distances for transplant care have better access to living donor but not deceased donor transplantation and slightly higher risk of graft failure. Traveling excess distances is not clearly associated with better outcomes, especially if living donors are unavailable.

Association Between Dialysis Facility Ownership and Access to the Waiting List and Transplant in Pediatric Patients With End-stage Kidney Disease in the US.

Importance: Care of adults at profit vs nonprofit dialysis facilities has been associated with lower access to transplant. Whether profit status is associated with transplant access for pediatric patients with end-stage kidney disease is unknown. Objective: To determine whether profit status of dialysis facilities is associated with placement on the kidney transplant waiting list or receipt of kidney transplant among pediatric patients receiving maintenance dialysis. Design, Setting, and Participants: This retrospective cohort study reviewed the US Renal Data System records of 13 333 patients younger than 18 years who started dialysis from 2000 through 2018 in US dialysis facilities (followed up through June 30, 2019). Exposures: Time-updated profit status of dialysis facilities. Main Outcomes and Measures: Cox models, adjusted for clinical and demographic factors, were used to examine time to wait-listing and receipt of kidney transplant by profit status of dialysis facilities. Results: A total of 13 333 pediatric patients who started receiving maintenance dialysis were included in the analysis (median age, 12 years [IQR, 3-15 years]; 6054 females [45%]; 3321 non-Hispanic Black patients [25%]; 3695 Hispanic patients [28%]). During a median follow-up of 0.87 years (IQR, 0.39-1.85 years), the incidence of wait-listing was lower at profit facilities than at nonprofit facilities, 36.2 vs 49.8 per 100 person-years, respectively (absolute risk difference, -13.6 (95% CI, -15.4 to -11.8 per 100 person-years; adjusted hazard ratio [HR] for wait-listing at profit vs nonprofit facilities, 0.79; 95% CI, 0.75-0.83). During a median follow-up of 1.52 years (IQR, 0.75-2.87 years), the incidence of kidney transplant (living or deceased donor) was also lower at profit facilities than at nonprofit facilities, 21.5 vs 31.3 per 100 person-years, respectively; absolute risk difference, -9.8 (95% CI, -10.9 to -8.6 per 100 person-years) adjusted HR for kidney transplant at profit vs nonprofit facilities, 0.71 (95% CI, 0.67-0.74). Conclusions and Relevance: Among a cohort of pediatric patients receiving dialysis in the US from 2000 through 2018, profit facility status was associated with longer time to wait-listing and longer time to kidney transplant.

Recovery of kidney function after dialysis initiation in children and adults in the US: A retrospective study of United States Renal Data System data.

BACKGROUND: Little is known about factors associated with recovery of kidney function-and return to dialysis independence-or temporal trends in recovery after starting outpatient dialysis in the United States. Understanding the characteristics of individuals who may have the potential to recover kidney function may promote better recognition of such events. The goal of this study was to determine factors associated with recovery of kidney function in children compared with adults starting dialysis in the US. METHODS AND FINDINGS: We determined factors associated with recovery of kidney function-defined as survival and discontinuation of dialysis for ≥90-day period-in children versus adults who started maintenance dialysis between 1996 and 2015 according to the United States Renal Data System (USRDS) followed through 2016 in a retrospective cohort study. We also examined temporal trends in recovery rates over the last 2 decades in this cohort. Among 1,968,253 individuals included for study, the mean age was 62.6 ± 15.8 years, and 44% were female. Overall, 4% of adults (83,302/1,953,881) and 4% of children (547/14,372) starting dialysis in the outpatient setting recovered kidney function within 1 year. Among those who recovered, the median time to recovery was 73 days (interquartile range [IQR] 43-131) in adults and 100 days (IQR 56-189) in children. Accounting for the competing risk of death, children were less likely to recover kidney function compared with adults (sub-hazard ratio [sub-HR] 0.81; 95% CI 0.74-0.89, p-value <0.001; point estimates <1 indicating increased risk for a negative outcome). Non-Hispanic black (NHB) adults were less likely to recover compared with non-Hispanic white (NHW) adults, but these racial differences were not observed in children. Of note, a steady increase in the incidence of recovery of kidney function was noted initially in adults and children between 1996 and 2010, but this trend declined thereafter. The diagnoses associated with the highest recovery rates of recovery were acute tubular necrosis (ATN) and acute interstitial nephritis (AIN) in both adults and children, where 25%-40% of patients recovered kidney function depending on the calendar year of dialysis initiation. Limitations to our study include the potential for residual confounding to be present given the observational nature of our data. CONCLUSIONS: In this study, we observed that discontinuation of outpatient dialysis due to recovery occurred in 4% of patients with end-stage kidney disease (ESKD) and was more common among those with ATN or AIN as the cause of their kidney disease. While recovery rates rose initially, they declined starting in 2010. Additional studies are needed to understand how to best recognize and promote recovery in patients whose potential to discontinue dialysis is high in the outpatient setting.

Bariatric surgery prior to transplantation and risk of early hospital re-admission, graft failure, or death following kidney transplantation.

Bariatric surgery has been shown to be safe in the dialysis population. Whether bariatric surgery before kidney transplantation influences posttransplant outcomes has not been examined nationally. We included severely obese (BMI >35) dialysis patients between 18 and 70 years who received a kidney transplant according to the US Renal Data System. We determined the association between history of bariatric surgery and risk of 30-day readmission, graft failure, or death after transplantation using multivariable logistic, Fine-Gray, and Cox models. We included 12 573 patients, of whom 503 (4%) received bariatric surgery before transplantation. Median age at transplant was 53 years; 42% were women. Overall, history of bariatric surgery was not statistically significantly associated with graft failure (HR 1.02; 95% CI 0.77-1.35) or death (HR 1.10; 95% CI 0.84-1.45). However, sleeve gastrectomy (vs. no bariatric surgery) was associated with lower risk of graft failure (HR 0.39; 95% CI 0.16-0.95). In conclusion, history of bariatric surgery prior to kidney transplantation was not associated with allograft or patient survival, but findings varied by surgery type. Sleeve gastrectomy was associated with better graft survival and should be considered in severely obese transplant candidates receiving dialysis.

Benign paroxysmal torticollis: phenotype, natural history, and quality of life.

BACKGROUND: Benign paroxysmal torticollis (BPT) is characterized by attacks of head tilt associated with vomiting, irritability, and/or ataxia in early childhood. BPT is associated with migraine but risk factors are unknown. Impact on quality of life is also unknown. METHODS: Parents/caregivers of children with ongoing or resolved BPT participated in telephone interviews (n = 73). Those with ongoing BPT completed the Infant Toddler Quality of Life questionnaire (ITQoL). RESULTS: Median age of children at the time of interview was 2.9 years (range 0.25-23). BPT was ongoing in 52% (n = 38). Nineteen percent (n = 14) developed migraine (median age 9.25 years, range 2.5-23) and 63% (n = 46) developed another episodic syndrome associated with migraine. Proportion of patients who developed migraine was higher among those with certain migrainous symptoms during BPT attacks vs. those without: phonophobia (58 vs. 21%, p = 0.02), photophobia and phonophobia (55 vs. 23%, p = 0.05), and photophobia, phonophobia, and motion sensitivity (60 vs. 22%, p = 0.02). ITQoL results showed significant impact of BPT on quality of life. CONCLUSIONS: Children with BPT may develop migraine or other episodic syndromes associated with migraine. Presence of migrainous features during BPT episodes may increase likelihood of developing migraine. Though characterized as "benign," BPT can significantly impact children and families. IMPACT: Benign paroxysmal torticollis (BPT) is a rare condition of early childhood characterized by episodes of head tilt associated with vomiting, irritability, ataxia, pallor, and/or malaise. This cohort study describes the phenotypic spectrum of BPT, variable treatment, natural history and association with migraine, and impact on development and quality of life. Children with BPT may go on to develop migraine or episodic syndromes that may be associated with migraine; presence of migrainous features during attacks may increase odds of developing migraine. BPT can have significant impact on quality of life, demonstrated by findings from the Infant Toddler Quality of Life questionnaire.

Later high school start time is associated with lower migraine frequency in adolescents.

OBJECTIVE: To determine whether high school start time is associated with headache frequency in adolescents with migraine. BACKGROUND: Adolescence is marked by a physiologic delayed circadian phase, characterized by later bedtimes and wake times. The American Academy of Pediatrics (AAP) recommends that high schools start no earlier than 8:30 a.m., but most high schools in the United States start earlier. The study hypothesis was that adolescents with migraine whose high schools start at 8:30 a.m. or later (late group) would have lower headache frequency than those whose schools start earlier than 8:30 a.m. (early group). METHODS: This was a cross-sectional Internet survey study of US high schoolers with migraine recruited online through social media. Comparisons were made between the late group and the early group. The primary outcome measure was self-reported headache days/month. RESULTS: In total, 1012 respondents constituted the analytic set: n = 503 in the late group versus n = 509 in the early group. Mean (SD) self-reported headache days/month was 4.8 (4.6) versus 7.7 (6.1) in the late and early groups, respectively (p < 0.001); mean difference -2.9 (95% CI -2.2 to -3.6). Mean (SD) self-reported hours of sleep on a school night was 7.9 (0.9) versus 6.9 (1.3), p < 0.001. Adjusting for total hours of sleep, sex, taking a migraine preventive, days of acute medication use, hours of homework, grade level, and missing breakfast, mean (SD) self-reported headache days/month remained lower in the late group than in the early group: 5.8 (95% CI 5.3-6.2) versus 7.1 (95% CI 6.7-7.4), (p < 0.001); mean difference -1.3 (95% CI -1.9 to -0.7). CONCLUSION: Adolescents with migraine who attend high schools that follow AAP recommendations for start times have lower self-reported headache frequency than those whose high schools start before 8:30 a.m. If prospective studies confirm this finding, shifting to a later high school start time may be an effective strategy for migraine prevention in adolescents.

Predialysis fluid overload and gait speed: a repeated measures analysis among patients on chronic dialysis.

BACKGROUND: Slow gait speed is associated with hospitalization and death. We examined whether predialysis fluid overload contributes to gait speed impairment. METHODS: We measured predialysis gait speed at baseline and 12 and 24 months among 298 patients recruited in the A Cohort Study to Investigate the Value of Exercise in ESRD/Analyses Designed to Investigate the Paradox of Obesity and Survival in ESRD. We used multivariable linear mixed modeling to examine associations between patient data and gait speed. We then added either bioimpedance-estimated volume of predialysis fluid overload or volume of delivered ultrafiltration to ascertain whether fluid excess was associated with gait speed and its trajectory. We also tested whether fluid overload change with time was predictive of gait speeds. RESULTS: The mean baseline gait speed was 1.01 m/s and it declined by an average of 0.08 m/s/year. Older age, nonwhite race, Hispanic ethnicity, diabetes, recent fall, recent hospitalization, tobacco use and lower serum albumin were associated with slower gait speed. Each liter of predialysis fluid overload was associated with a 0.02 m/s slower gait speed [95% confidence interval (CI) 0.01-0.04, P = 0.008] and 0.05 m/s additional slowing per year (95% CI 0.03-0.06, P < 0.0001). Higher ultrafiltration volumes were associated with 0.07 m/s slower gait speed per 3% body weight removed (0.002-0.14, P = 0.045) but not with gait speed trajectory (P = 0.08). Patients who increased fluid overload walked 0.08 m/s slower compared with those who decreased fluid overload (95% CI 0.003-0.15, P = 0.04). CONCLUSIONS: Predialysis fluid overload was associated with slower gait speed and gait speed decline over time. Interventions that limit fluid overload may lead to improvements in physical performance.

Effect of Acute Stroke Care Regionalization on Intravenous Alteplase Use in Two Urban Counties.

Importance: Intravenous alteplase is an effective treatment for acute ischemic stroke and is significantly underutilized. It is known that stroke centers with accreditation are more likely to provide intravenous alteplase treatment, and therefore, policies that increase the number of certified stroke centers and the number of acute ischemic stroke patients routed to these centers may be beneficial. Objective: To determine whether increasing access to primary stroke centers (regionalization) led to an increase in intravenous alteplase use in acute ischemic stroke patients. Design: An observational, longitudinal study to examine treatment trends with log-link binomial regression modeling to compare pre-post policy implementation changes in the proportions of patients treated with intravenous alteplase in two counties. Setting: Two urban counties, Santa Clara and San Mateo, in the western region of US that regionalized acute stroke care between 2005 and 2010. Participants: Patients with primary or secondary diagnosis of stroke were identified from the statewide patient discharge database by International Classification of Diseases (ICD-9) codes. We linked ambulance and hospital data to create complete patient care records. Main outcomes and measures: Stroke treatment, defined as a documented primary procedure code for intravenous alteplase administration (ICD-9: 99.10). Results: In Santa Clara County, intravenous alteplase was administered to 35 patients (1.7%) in the pre-regionalization period and 240 patients (2.1%) in the post-regionalization period. In San Mateo County, intravenous alteplase was administered to 29 patients (1.3%) in the pre-policy period and 135 patients (3.2%) in the post-policy period. After regionalization of stroke care, intravenous alteplase increased two-fold in San Mateo County [adjusted RR 2.20, p = 0.003, 95% CI (1.31, 3.69)] but did not show any statistically significant change in Santa Clara County [adjusted RR 1.10, p = 0.55, 95% CI (0.80, 1.51)]. In the post-regionalization phase, when compared with Santa Clara County, we found that San Mateo County had greater change in paramedic stroke detection, higher number of transports to primary stroke centers and more frequent use of intravenous alteplase at stroke centers. Conclusions: Our findings suggest that greater post-regionalization improvements in San Mateo County contributed to significantly better county-level thrombolysis use than Santa Clara County.

Higher eGFR at Dialysis Initiation Is Not Associated with a Survival Benefit in Children.

BACKGROUND: Study findings suggest that initiating dialysis at a higher eGFR level in adults with ESRD does not improve survival. It is less clear whether starting dialysis at a higher eGFR is associated with a survival benefit in children with CKD. METHODS: To investigate this issue, we performed a retrospective cohort study of pediatric patients aged 1-18 years who, according to the US Renal Data System, started dialysis between 1995 and 2015. The primary predictor was eGFR at the time of dialysis initiation, categorized as higher (eGFR>10 ml/min per 1.73 m2) versus lower eGFR (eGFR≤10 ml/min per 1.73 m2). RESULTS: Of 15,170 children, 4327 (29%) had a higher eGFR (median eGFR, 12.8 ml/min per 1.73 m2) at dialysis initiation. Compared with children with a lower eGFR (median eGFR, 6.5 ml/min per 1.73 m2), those with a higher eGFR at dialysis initiation were more often white, girls, underweight or obese, and more likely to have GN as the cause of ESRD. The risk of death was 1.36 times higher (95% confidence interval, 1.24 to 1.50) among children with a higher (versus lower) eGFR at dialysis initiation. The association between timing of dialysis and survival differed by treatment modality-hemodialysis versus peritoneal dialysis (P<0.001 for interaction)-and was stronger among children initially treated with hemodialysis (hazard ratio, 1.56, 95% confidence interval, 1.39 to 1.75; versus hazard ratio, 1.07, 95% confidence interval, 0.91 to 1.25; respectively). CONCLUSIONS: In children with ESRD, a higher eGFR at dialysis initiation is associated with lower survival, particularly among children whose initial treatment modality is hemodialysis.

Urinary Incontinence and Nocturia in Older Men: Associations with Body Mass, Composition and Strength in the Health ABC Study.

PURPOSE: In younger men lower body mass is associated with fewer urinary symptoms, including incontinence and nocturia. However, lower body mass may have different implications in older men due to age associated muscle atrophy and decreased strength. MATERIALS AND METHODS: We performed a prospective analysis of community dwelling men 70 to 79 years old in the multicenter Health ABC (Aging and Body Composition) study who underwent measurement of body mass on physical examination, composition using dual x-ray absorptiometry and strength according to grip and lower leg dynamometry. We evaluated associations with prevalent incontinence and nocturia on structured questionnaires as well as concurrent changes in urinary symptoms during 3 years using multivariate logistic regression. RESULTS: Of the 1,298 men analyzed 22% reported incontinence and 52% reported nocturia at baseline. Higher body mass index, fat mass and lower appendicular lean mass, and grip and quadriceps strength corrected for body mass index were associated with an increased prevalence of incontinence (each p <0.05). Higher body mass index and greater fat mass were also associated with an increased nocturia prevalence (each p <0.05). Concurrent 5% or greater decrease in body mass or fat mass was not associated with lower odds of new or worsening incontinence or nocturia, whereas a 5% or greater decrease in maximum grip strength was associated with higher odds of new or worsening incontinence. CONCLUSIONS: Older men with a higher body mass index and greater fat mass are more likely to report prevalent incontinence and nocturia. However, late life decreases in strength but not increases in body mass or fat mass were associated with a concurrent increase in urinary incontinence.

Sex Disparities in Risk of Mortality Among Children With ESRD.

RATIONALE & OBJECTIVE: In the general population, girls have lower mortality risk compared with boys. However, few studies have focused on sex differences in survival and in access to kidney transplantation among children with end-stage kidney disease. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Children aged 2 to 19 years registered in the US Renal Data System who started renal replacement therapy (RRT) between 1995 and 2011. PREDICTOR: Study participant sex. OUTCOME: Time to death and time to kidney transplantation. ANALYTICAL APPROACH: We used adjusted Cox models to examine the association between sex and all-cause mortality. We used Fine-Gray models to examine the association between sex and kidney transplantation accounting for the competing risk for death. RESULTS: We included 14,024 children, of whom 1,880 died during a median 7.1 years of follow-up. In adjusted analyses, the HR for death was higher for girls (HR, 1.36; 95% CI, 1.25-1.50) than boys. When we further adjusted our survival models for transplantation as a time-dependent covariate, the hazard rate of death in girls was partially attenuated but remained statistically significantly higher than that for boys (HR, 1.28; 95% CI, 1.17-1.41). Girls were also less likely to receive a kidney transplant than boys (adjusted subdistribution HR, 0.91; 95% CI, 0.88-0.95) in analyses treating death as a competing risk. LIMITATIONS: Lack of data for disease course before the onset of RRT and observational study data. CONCLUSIONS: The mortality rate was substantially higher for girls than for boys treated with RRT. Access to transplantation was lower for girls than boys, but differences in transplantation access accounted for only a small proportion of the survival differences by sex.

Muscle Relaxant Use Among Hemodialysis Patients: Prevalence, Clinical Indications, and Adverse Outcomes.

RATIONALE & OBJECTIVE: Muscle relaxants are often used to treat musculoskeletal pain or cramping, which are commonly experienced by hemodialysis patients. However, the extent to which muscle relaxants are prescribed in this population and the risks associated with their use have not been characterized. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: 140,899 Medicare-covered adults receiving hemodialysis in 2011, identified in the US Renal Data System. EXPOSURE: Time-varying muscle relaxant exposure. OUTCOMES: Primary outcomes were time to first emergency department visit or hospitalization for altered mental status, fall, or fracture. Secondary outcomes were death and composites of death with each of the primary outcomes. ANALYTICAL APPROACH: Multivariable Cox regression analysis. RESULTS: 10% of patients received muscle relaxants in 2011. 11%, 6%, 3%, and 13% had an episode of altered mental status, fall, fracture, and death, respectively. Muscle relaxant use was associated with higher risk for altered mental status (HR, 1.39; 95% CI, 1.29-1.51) and fall (HR, 1.18; 95% CI, 1.05-1.33) compared to no use. Muscle relaxant use was not statistically significantly associated with higher risk for fracture (HR, 1.17; 95% CI, 0.98-1.39). Muscle relaxant use was associated with lower hazard of death (HR, 0.85; 95% CI, 0.76-0.94). However, hazards were higher for altered mental status or death (HR, 1.17; 95% CI, 1.10-1.25), fall or death (HR, 1.14; 95% CI, 1.06-1.22), and fracture or death (HR, 1.10; 95% CI, 1.01-1.20). LIMITATIONS: A causal association between muscle relaxant use and outcomes cannot be inferred, and residual confounding cannot be excluded. Exposure and outcomes were ascertained using administrative claims. CONCLUSIONS: Muscle relaxant use was common in hemodialysis patients and associated with altered mental status and falls. We could not rule out a clinically meaningful association between muscle relaxant use and fracture. The lower risk for death with muscle relaxants may have been the result of residual confounding. Future research to define the appropriate use of muscle relaxants in this population is warranted.