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Statistical approaches that could be used as standardized methodology for evaluating reliability and validity of data obtained using remote audiometry are proposed. Using data from the Nurses' Health Study II ( n = 31), the approaches to evaluate the reliability and validity of hearing threshold measurements obtained by a self-administered iPhone-based hearing assessment application (Decibel Therapeutics, Inc., Boston, MA) compared with measurements obtained by clinical (soundbooth) audiometry are described. These approaches use mixed-effects models to account for multilevel correlations, intraclass correlation coefficients (ICCs) of single and averaged measurements, and regression techniques with the generalized estimating equations (GEEs) to account for between-ear correlations. Threshold measurements obtained using the iPhone application were moderately reliable. The reliability was improved substantially by averaging repeated measurements; good reliability was achieved by averaging three repeated measurements. In the linear regression analyses that assessed validity, the range of intercepts (2.3–8.4) and range of slopes (0.4–0.7) indicated that the measurements from the application were likely biased from those obtained by clinical audiometry. When evaluating alternative hearing assessment tools, it is recommended to assess reliability through mixed-effects models and use ICCs to determine the number of repeated assessments needed to achieve satisfactory reliability. When evaluating validity, GEE methods are recommended to estimate regression coefficients.

Background One limitation of the use of 24-hour collection is impracticality. We analysed the performance of spot urine measurements to estimate 24-hour excretion in patients with kidney stones. Methods A total of 74 adult patients from two centres performed a 24-hour urine collection. A sample of the last micturition was sent for spot urine analysis. Twenty patients were asked to collect two additional spot urine samples, one before dinner and the other after dinner. Urinary concentrations of creatinine, calcium, oxalate, uric acid, citrate and magnesium were measured in the 24-hour and each of the spot urine samples. Four approaches were used to estimate 24-hour urinary excretion, multiplying the ratio of the spot urinary analyte to creatinine concentration by (i) measured 24-hour urinary creatinine excretion (Prediction 1), (ii) estimated 24-hour urinary creatinine excretion (Prediction 2), (iii) assumed 1-g 24-hour urinary creatinine excretion (Prediction 3) or (iv) assumed 1.5-g 24-hour urinary creatinine excretion (Prediction 4). For each parameter we computed Lin's concordance correlation coefficients (CCCs), Bland–Altman plots and 95% limits of agreement. Results The performance of estimates obtained with Prediction 1 and Prediction 2 was similar, except for citrate and uric acid, for which Prediction 2 performed worse. Both approaches performed moderately well: citrate CCC {0.82 [95% confidence interval (CI) 0.75–0.90]}, oxalate [0.66 (95% CI 0.55–0.78)], magnesium [0.66 (95% CI 0.54–0.77)], calcium [0.63 (95% CI 0.50–0.75)] and uric acid [0.52 (95% CI 0.36–0.68)]. The performance of Predictions 3 and 4 was worse. Conclusions Although spot urine samples may hold promise for clinical and population-based research, at present they have limited utility in clinical practice. Measuring or estimating 24-hour creatinine, rather than assuming a given creatinine excretion, will be necessary in future studies of spot urine samples.

To examine whether the cross-sectional gene-diet interaction for prevalent hyperuricemia among women translates prospectively to risk of incident female gout.We analyzed the interaction between genetic predisposition and adherence to a healthy dietary pattern (i.e., Dietary Approaches to Stop Hypertension [DASH] score) on risk of incident female gout in 18,244 women from Nurses' Health Study (NHS; discovery) and 136,786 women from 3 additional prospective female cohorts from US and UK (replication). Genetic risk score (GRS) was calculated from 114 urate-associated loci.In the NHS and replication cohorts, association between diet and gout risk was larger and stronger among women with higher genetic risk. In all cohorts combined, compared with women with unhealthy DASH score (mean), multivariable relative risk (mRR) for incident female gout among women with healthy DASH score (≥mean) was 0.67 (95% CI 0.60-0.76) among higher GRS (≥mean) and 0.91 (0.78-1.05) among lower GRS (P multiplicative interaction=0.001); mRR for higher vs. lower GRS was 2.03 (1.80-2.29) and 1.50 (1.31-1.71) among unhealthy and healthy DASH score groups, respectively. Additive interaction was also significant, in both the discovery and replication cohorts (P0.001), with 51% of the excess risk attributable to the additive gene-diet interaction in all cohorts combined.The deleterious effect of genetic predisposition on risk of incident female gout was more pronounced among women with unhealthy diet, with nearly half the excess risk attributable to this gene-diet interaction. These data elucidate the important synergy of genetics and diet for female gout development. This article is protected by copyright. All rights reserved.

OBJECTIVE: Single-ear hearing measurements, such as better-ear, worse-ear or left/right ear, are often used as outcomes in auditory research, yet measurements in the two ears of the same individual are often strongly but not perfectly correlated. We propose a both-ear method using the Generalized Estimating Equation approach for analysis of correlated binary ear data to evaluate determinants of ear-specific outcomes that includes information from both ears of the same individual. DESIGN: We first theoretically evaluated bias in odds ratio (OR) estimates based on worse-ear and better-ear hearing outcomes. A simulation study was conducted to compare the finite sample performances of single-ear and both-ear methods in logistic regression models. As an illustrative example, the single-ear and both-ear methods were applied to estimate the association of Dietary Approaches to Stop Hypertension (DASH) adherence scores with hearing threshold elevation among 3,135 women, aged 48–68 years, in the Nurses’ Health Study II. RESULTS: Based on statistical theories, the worse-ear and better-ear methods could bias the OR estimates. The simulation results led to the same conclusion. In addition, the simulation results showed that the both-ear method had satisfactory finite sample performance and was more efficient than the single-ear method. In the illustrative example, the confidence intervals of the estimated ORs for the association of DASH scores and hearing threshold elevation using the both-ear method were narrower, indicating greater precision, than for those obtained using the other methods. CONCLUSIONS: The worse-ear and better-ear methods may lead to biased estimates, and the left/right ear method typically results in less efficient estimates. In certain settings, the both-ear method using the Generalized Estimating Equation approach for analyses of audiometric data may be preferable to the single-ear methods.

ObjectivesTo evaluate the joint (combined) association of excess adiposity and genetic predisposition with the risk of incident female gout, and compare to their male counterparts; and determine the proportion attributable to body mass index (BMI) only, genetic risk score (GRS) only, and to their interaction.MethodsWe prospectively investigated potential gene-BMI interactions in 18 244 women from the Nurses’ Health Study and compared with 10 888 men from the Health Professionals Follow-Up Study. GRS for hyperuricaemia was derived from 114 common urate-associated single nucleotide polymorphisms.ResultsMultivariable relative risk (RR) for female gout was 1.49 (95% CI 1.42 to 1.56) per 5 kg/m2increment of BMI and 1.43 (1.35 to 1.52) per SD increment in the GRS. For their joint association of BMI and GRS, RR was 2.18 (2.03 to 2.36), more than the sum of each individual factor, indicating significant interaction on an additive scale (p for interaction ConclusionsWhile excess adiposity and genetic predisposition both are strongly associated with a higher risk of gout, the excess risk of both combined was higher than the sum of each, particularly among women.

Background Osteoporosis and low bone density (LBD) may be associated with higher risk of hearing loss, but findings are inconsistent and longitudinal data are scarce. Bisphosphonates may influence risk, but the relation has not been studied in humans. We longitudinally investigated associations of osteoporosis and LBD, bisphosphonate use, vertebral fracture (VF), hip fracture (HF), and risk of self-reported moderate or worse hearing loss. Design Longitudinal cohort study. Setting The Nurses' Health Study (NHS) (1982-2016) and Nurses' Health Study II (NHS II) (1995-2017). Participants Participants included 60,821 NHS women, aged 36-61 years at baseline, and 83,078 NHS II women, aged 31-48 years at baseline (total n = 143,899). Measurements Information on osteoporosis, LBD, bisphosphonate use, VF, HF, and hearing status was obtained from validated biennial questionnaires. In a subcohort (n = 3749), objective hearing thresholds were obtained by audiometry. Multivariable-adjusted Cox proportional hazards models were used to examine independent associations between osteoporosis (NHS), osteoporosis/LBD (NHS II), and risk of hearing loss. Results The multivariable-adjusted relative risk (MVRR, 95% confidence interval) of moderate or worse hearing loss was higher among women with osteoporosis or LBD in both cohorts. In NHS, compared with women without osteoporosis, the MVRR was 1.14 (1.09, 1.19) among women with osteoporosis; in NHS II, the MVRR was 1.30 (1.21, 1.40) among women with osteoporosis/LBD. The magnitude of the elevated risk was similar among women who did and did not use bisphosphonates. VF was associated with higher risk (NHS: 1.31 [1.16, 1.49]; NHS II: 1.39 [1.13, 1.71]), but HF was not (NHS: 1.00 [0.86, 1.16];NHS II: 1.15 [0.75,1.74]). Among participants with audiometric measurements, compared with women without osteoporosis/LBD, the mean multivariable-adjusted hearing thresholds were higher (i.e., worse) among those with osteoporosis/LBD who used bisphosphonates. Conclusion Osteoporosis and LBD may be important contributors to aging-related hearing loss. Among women with osteoporosis, the risk of hearing loss was not influenced by bisphosphonate use.

Purpose:The etiology of calcium-oxalate kidney stone formation remains elusive. Biallelic mutations in HOGA1 are responsible for primary hyperoxaluria type 3 and result in oxalate overproduction an...

ImportancePersistent tinnitus is common, disabling, and difficult to treat.ObjectiveTo evaluate the association between circulating metabolites and persistent tinnitus.Design, Setting, and ParticipantsThis was a population-based case-control study of 6477 women who were participants in the Nurses’ Health Study (NHS) and NHS II with metabolomic profiles and tinnitus data. Information on tinnitus onset and frequency was collected on biennial questionnaires (2009-2017). For cases, metabolomic profiles were measured (2015-2021) in blood samples collected after the date of the participant’s first report of persistent tinnitus (NHS, 1989-1999 and 2010-2012; NHS II, 1996-1999). Data analyses were performed from January 24, 2022, to January 14, 2023.ExposuresIn total, 466 plasma metabolites from 488 cases of persistent tinnitus and 5989 controls were profiled using 3 complementary liquid chromatography tandem mass spectrometry approaches.Main Outcomes and MeasuresLogistic regression was used to estimate odds ratios (ORs) of persistent tinnitus (per 1 SD increase in metabolite values) and 95% CIs for each individual metabolite. Metabolite set enrichment analysis was used to identify metabolite classes enriched for associations with tinnitus.ResultsOf the 6477 study participants (mean [SD] age, 52 [9] years; 6477 [100%] female; 6121 [95%] White individuals) who were registered nurses, 488 reported experiencing daily persistent (≥5 minutes) tinnitus. Compared with participants with no tinnitus (5989 controls), those with persistent tinnitus were slightly older (53.0 vs 51.8 years) and more likely to be postmenopausal, using oral postmenopausal hormone therapy, and have type 2 diabetes, hypertension, and/or hearing loss at baseline. Compared with controls, homocitrulline (OR, 1.32; (95% CI, 1.16-1.50); C38:6 phosphatidylethanolamine (PE; OR, 1.24; 95% CIs, 1.12-1.38), C52:6 triglyceride (TAG; OR, 1.22; 95% CIs, 1.10-1.36), C36:4 PE (OR, 1.22; 95% CIs, 1.10-1.35), C40:6 PE (OR, 1.22; 95% CIs, 1.09-1.35), and C56:7 TAG (OR, 1.21; 95% CIs, 1.09-1.34) were positively associated, whereas α-keto-β-methylvalerate (OR, 0.68; 95% CIs, 0.56-0.82) and levulinate (OR, 0.60; 95% CIs, 0.46-0.79) were inversely associated with persistent tinnitus. Among metabolite classes, TAGs (normalized enrichment score [NES], 2.68), PEs (NES, 2.48), and diglycerides (NES, 1.65) were positively associated, whereas phosphatidylcholine plasmalogens (NES, −1.91), lysophosphatidylcholines (NES, −2.23), and cholesteryl esters (NES,−2.31) were inversely associated with persistent tinnitus.Conclusions and RelevanceThis population-based case-control study of metabolomic profiles and tinnitus identified novel plasma metabolites and metabolite classes that were significantly associated with persistent tinnitus, suggesting that metabolomic studies may help improve understanding of tinnitus pathophysiology and identify therapeutic targets for this challenging disorder.

Tinnitus, the perception of sound without the corresponding external stimulus, currently affects 15% of the US population. There is a critical need to unravel the heterogeneous etiologies underlying tinnitus and identify tailored treatment targets. Metabolomic studies have elucidated biological pathways underlying several neurodegenerative disorders and could identify metabolic perturbations that influence tinnitus development. We conducted the first large-scale metabolomic study to identify novel tinnitus biomarkers. We cross-sectionally evaluated plasma metabolite profiles and persistent tinnitus among 6477 women (488 with daily tinnitus ≥5 minutes and 5989 controls). A broad array of 466 metabolites was measured using liquid-chromatography mass spectrometry. Logistic regression was used to estimate odds ratios (OR, per 1 SD increase in metabolite values) and 95% confidence intervals (CI) for each individual metabolite while Metabolite Set Enrichment Analysis (MSEA) was used to identify metabolite classes enriched for associations with tinnitus; all models were adjusted for multiple comparisons. Compared with controls, homocitrulline (OR(95%CI)=1.32(1.16-1.50), C38:6 phosphatidylethanolamine (PE; 1.24(1.12-1.38)), C52:6 triglyceride (TAG; 1.22(1.10-1.36)), C36:4 PE (1.22(1.1-1.35)), C40:6 PE (1.22(1.09-1.35)), and C56:7 TAG (1.21(1.09-1.34)) were positively associated, whereas alpha-keto-beta-methylvalerate (0.68(0.56-0.82)) and levulinate (0.60(0.46-0.79)) were inversely associated with tinnitus (adjusted-p

BackgroundKidney stone disease (KSD) is linked to obesity, metabolic syndrome and biochemical alterations including higher serum calcium concentration. The mechanisms by which these phenotypes associate with KSD are uncertain. We aimed to establish the effects of adiposity on KSD using conventional and genetic epidemiological techniques.MethodsWe assessed observational associations between measures of adiposity and incident KSD in 479,405 people from the UK Biobank. To facilitate Mendelian randomization (MR) analyses, we undertook genome-wide association studies (GWAS) of KSD in the UK Biobank in combined and sex-specific subsets. Univariable, multivariable and mediation MR analyses were used to calculate odds ratio (OR) or beta coefficient (ß) for risk of KSD per genetically instrumented higher marker of adiposity, metabolic syndrome parameter, biochemical phenotype, and inflammation and identify violations of MR assumptions.FindingsObservational analyses demonstrated that measures of central adiposity (waist-to-hip ratio (WHR) and waist circumference (WC)) are more strongly associated with incident KSD than measures of general adiposity (body mass index (BMI)). Three novel KSD-GWAS loci were identified (SLC2A12, TRPV5, and SLC28A1); no sex-specific loci were detected. MR analyses established that higher central adiposity is causally linked to both KSD and higher adjusted serum calcium concentrations independent of BMI (one standard deviation higher WHR: OR for KSD=1·43, p=4·1×10−6; ß for serum calcium concentration=0·11mmol/L, p=2·7×10−7). Mediation analyses indicated that 12% of the effect of WHR on KSD is due its role in elevating serum calcium concentration. Our MR studies indicated that other components of the metabolic syndrome, serum uric acid levels, and biomarkers of inflammation are unlikely to be implicated in the causation of KSD.InterpretationOur study indicates that visceral adipose depots elevate serum calcium concentration and cause an increased risk of KSD. Therapies targeting central adipose deposition may affect calcium homeostasis and have utility for the prevention of KSD.

OBJECTIVE Weight loss diets may reduce serum urate (SU) by lowering insulin resistance while providing cardiometabolic benefits, something urate-lowering drugs have not shown in trials. We aimed to examine the effects of weight loss diets on SU and cardiometabolic risk factors. RESEARCH DESIGN AND METHODS This secondary study of the Dietary Intervention Randomized Controlled Trial (DIRECT) used stored samples from 235 participants with moderate obesity randomly assigned to low-fat, restricted-calorie (n = 85); Mediterranean, restricted-calorie (n = 76); or low-carbohydrate, non–restricted-calorie (n = 74) diets. We examined SU changes at 6 and 24 months overall and among those with hyperuricemia (SU ≥416 μmol/L), a relevant subgroup at risk for gout. RESULTS Among all participants, average SU decreases were 48 μmol/L at 6 months and 18 μmol/L at 24 months, with no differences between diets (P > 0.05). Body weight, HDL cholesterol (HDL-C), total cholesterol:HDL-C ratio, triglycerides, and insulin concentrations also improved in all three groups (P < 0.05 at 6 months). Adjusting for covariates, changes in weight and fasting plasma insulin concentrations remained associated with SU changes (P < 0.05). SU reductions among those with hyperuricemia were 113, 119, and 143 μmol/L at 6 months for low-fat, Mediterranean, and low-carbohydrate diets (all P for within-group comparison < 0.001; P > 0.05 for between-group comparisons) and 65, 77, and 83 μmol/L, respectively, at 24 months (all P for within-group comparison < 0.01; P > 0.05 for between-group comparisons). CONCLUSIONS Nonpurine-focused weight loss diets may simultaneously improve SU and cardiovascular risk factors likely mediated by reducing adiposity and insulin resistance. These dietary options could provide personalized pathways to suit patient comorbidity and preferences for adherence.

The overall prevalence of kidney stones (KS) in the US rose from 3.2% in 1980 to 10.1% in 2016, but the trends in important subgroups have not been reported. We examined the prevalence trends of KS in subgroups of age, sex and race in the US and identified relevant laboratory factors associated with a history of KS using National Health and Nutrition Examination Survey (NHANES) data. We conducted a cross-sectional study among 28,209 US adults aged ≥ 20 years old in the NHANES from 2007 to 2016. We calculated the prevalence of a self-reported history of KS by using weights and standardized to the 2010 US Census population. We also compared relevant laboratory values according to the history of KS. The prevalence of KS decreased from 8.7% in 2007–2008 to 7.2% in 2011–2012 but then increased to 9.0% in 2013–2014 and 10.1% in 2015–2016. However, the overall prevalence of KS increased over 2007–2016 (p-trend = 0.02). Prevalence of KS among men was higher than women. Among men aged 20–79, there were significant quadratic trends in the prevalence of KS. Whereas, the prevalence of KS increased as a linear trend among women aged 20–59 years over 2007–2016. There were no consistent trends in the prevalence of KS by race. The prevalence trend of KS among non-Hispanic whites was 9.8% from 2007 to 2010 then dropped to 7.9% in 2011–2012 and increased to 10.6% in 2013–2014 and 12.1% in 2015–2016. A similar trend was also observed among non-Hispanic blacks. Among Hispanic, the prevalence of KS was 7.6% in 2007–2008 and 7.4% in 2009–2010 and then fluctuated over the next several time periods. For non-Hispanic Asians, the range was 4.4–4.6%. Regarding relevant laboratory factors, after adjusting for sex, race, age, BMI, smoking status, alcohol drinking, history of diabetes and gout, urine albumin-creatinine ratio and serum osmolality were independently associated with the history of KS in women and men. In conclusion, there was substantial variability in KS prevalence across individual 2-year time periods. This variation of period-specific prevalence values emphasizes the importance of looking at long-term trends and using more than a single 2-year cycle in analyses to increase the precision of the estimate. However, there was an overall increase in the prevalence of KS over 2007-2016.

Context Chronic hypoparathyroidism (HypoPT) is conventionally managed with oral calcium and active vitamin D. Recombinant human parathyroid hormone (1–84) (rhPTH[1–84]) is a therapy targeting the pathophysiology of HypoPT by replacing parathyroid hormone. Objective To compare changes in the estimated glomerular filtration rate (eGFR) in patients with chronic HypoPT receiving or not receiving rhPTH(1–84) during a 5-year period. Design/Setting A retrospective analysis of patients with chronic HypoPT treated with or without rhPTH(1–84). Patients Sixty-nine patients with chronic HypoPT from 4 open-label, long-term trials (NCT00732615, NCT01268098, NCT01297309, and NCT02910466) composed the rhPTH(1–84) cohort and 53 patients with chronic HypoPT not receiving rhPTH(1–84) from the Geisinger Healthcare Database (01/2004–06/2016) composed the historical control cohort. Interventions The rhPTH(1–84) cohort (N = 69) received rhPTH(1–84) therapy; the historical control cohort (N = 53) did not receive rhPTH(1–84). Main Outcome Measures Changes in eGFR from baseline during a 5-year follow-up were examined in multivariate regression analyses. Results At baseline, demographic characteristics and eGFR were similar between cohorts, though the proportions with diabetes and cardiac disorders were lower in the rhPTH(1–84) cohort. At the end of follow-up, mean eGFR increased by 2.8 mL/min/1.73 m2 in the rhPTH(1–84) cohort, while mean eGFR fell by 8.0 mL/min/1.73 m2 in the control cohort. In the adjusted model, the difference in the annual eGFR change between the rhPTH(1–84) cohort and the control cohort was 1.7 mL/min/1.73 m2 per year (P = 0.009). Conclusions Estimated glomerular filtration rate was preserved for over 5 years among patients with chronic HypoPT receiving rhPTH(1–84) treatment, contrasting with an eGFR decline among those not receiving rhPTH(1–84).

Rationale & Objective Cytokine release syndrome is a well-known complication of chimeric antigen receptor T-cell (CAR-T) therapy and can lead to multiorgan dysfunction. However, the nephrotoxicity of CAR-T therapy is unknown. We aimed to characterize the occurrence, cause, and outcomes of acute kidney injury (AKI), along with the occurrence of electrolyte abnormalities, among adults with diffuse large B-cell lymphoma receiving CAR-T therapy. Study Design Case series. Setting & Participants We reviewed the course of 78 adults receiving CAR-T therapy with axicabtagene ciloleucel or tisagenlecleucel at 2 major cancer centers between October 2017 and February 2019. Baseline demographics, comorbid conditions, medications, and laboratory values were obtained from electronic health records. AKI was defined using KDIGO (Kidney Disease: Improving Global Outcomes) criteria. The cause, clinical course, and outcome of AKI events and electrolyte abnormalities in the first 30 days after CAR-T infusion were characterized using data contained in electronic health records. Results Among 78 patients receiving CAR-T therapy, cytokine release syndrome occurred in 85%, of whom 62% were treated with tocilizumab. AKI occurred in 15 patients (19%): 8 had decreased kidney perfusion, 6 developed acute tubular necrosis, and 1 patient had urinary obstruction related to disease progression. Those with acute tubular necrosis and obstruction had the longest lengths of stay and highest 60-day mortality. Electrolyte abnormalities were common; hypophosphatemia, hypokalemia, and hyponatremia occurred in 75%, 56%, and 51% of patients, respectively. Limitations Small sample size; AKI adjudicated by retrospective chart review; lack of biopsy data. Conclusions In this case series of patients with diffuse large B-cell lymphoma receiving CAR-T therapy, AKI and electrolyte abnormalities occurred commonly in the context of cytokine release syndrome.

BACKGROUND: Diet plays an important role in kidney stone formation. Several individual components have been associated with the risk of kidney stone formation, but there is limited evidence regarding the role of healthful dietary patterns. OBJECTIVE: To prospectively study the association between adherence to the Mediterranean diet and the risk of incident kidney stones. METHODS: We conducted a longitudinal study using 3 different cohorts: the Health Professionals Follow-up Study (n = 42,902 men), the Nurses’ Health Study I (n = 59,994 women), and the Nurses’ Health Study II (n = 90,631 women). We assessed diet every 4 y using an FFQ and calculated adherence to a Mediterranean diet using the alternate Mediterranean diet score (aMED). A subgroup of 6077 participants provided ≥1 24-h urine sample, and urinary solute excretion was analyzed. We used Cox proportional hazards regression to examine the independent association between the aMED and incidence of kidney stones, adjusting for potential confounders. We used adjusted linear regression models to study the relation between aMED and urine composition. RESULTS: During 3,316,633 person-years of follow-up, 6576 cases of incident kidney stones were identified. For participants in the highest aMED score category, the risk of developing a kidney stone was between 13% and 41% lower compared with participants in the lowest score (pooled HR: 0.72, 95% CI: 0.59, 0.87; P value for trend

Introduction We investigated the relation between self-reported hearing loss and risk of subjective cognitive function (SCF) decline among women. Methods We conducted a longitudinal study of 20,193 women in the Nurses' Health Study aged ≥66 years who reported their hearing status and had no subjective cognitive concerns in 2012. SCF scores were assessed by a 7-item questionnaire in 2012 and 2014. SCF decline was defined as a new report of at least one cognitive concern during follow-up. Results Self-reported hearing loss was associated with higher risk of SCF decline. Compared with women with no hearing loss, the multivariable-adjusted odds ratios (95% confidence interval) for incident SCF score ≥1 were 1.35 (1.25, 1.47), 1.39 (1.24, 1.56), and 1.40 (1.21, 1.75) among women with mild, moderate, and severe hearing loss, respectively. Recent progression of hearing loss was associated with even higher risk. Discussion Self-reported hearing loss was associated with higher risk of incident subjective cognitive function decline in women.

Background: Studies have suggested that dietary nitrate could lower blood pressure levels whereas ambient particulate matter (PM) may increase risk of hypertension. However, it is unknown if these exposures may modify each other. Objectives: We collected information on dietary nitrate intake and vegetables consumption and estimated long-term exposures to ambient PM for women in the Nurses’ Health Study. Methods: Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for risk of hypertension were calculated using Cox proportional hazards models with adjustment for potential demographic, lifestyle and dietary confounders. Interactions were assessed with multiplicative interaction terms and stratified models. Results: Increases in dietary nitrate intake (per 150 mg/d) and green leafy vegetables consumption (per serving/day) were both significantly associated with decreases in hypertension risk (both multivariable-adjusted HRs were 0.97, 95% CI: 0.94, 0.99). Long-term exposure to ambient PM with an aerodynamic diameter ≤ 2.5 µm (PM2.5) was associated with an increased risk of hypertension, with a multivariable-adjusted HR of hypertension of 1.06 (95% CI: 1.02, 1.11) per 10 µg/m3 increase in PM2.5. Ambient PM2.5 significantly modified the associations of dietary nitrate intake (Pinteraction = 0.02) and green leafy vegetables consumption (Pinteraction = 0.004). The associations with dietary factors were gradually weakened with increasing PM2.5: the fully-adjusted HRs for risk of hypertension were 0.94 (95% CI: 0.89, 0.99) and 0.94 (95% CI: 0.90, 0.99) for per 150 mg/d increase in nitrate intake and per serving/d increase in green leafy vegetables consumption, respectively, in the lowest PM2.5 quartile, and 1.00 (95% CI: 0.94, 1.06) and 1.02 (95% CI: 0.97, 1.08), respectively, in the highest PM2.5 quartile. Conclusion: Our research highlights a potentially protective effect of dietary nitrate intake in the prevention of hypertension and suggests that these benefits are attenuated by increasing exposure to ambient PM2.5.

BackgroundMen are at higher risk of developing stones compared with women; however, recent data suggest a changing epidemiology, with women being relatively more affected than before.MethodsTo estimate the proportion of excess risk among men, we analysed data from large cohorts (Health Professionals Follow-up Study and Nurses’ Health Study I and II). Kidney stone incidence rates were computed and hazard ratios (HRs) and 95% confidence intervals (CIs) generated with age-adjusted Cox proportional regression models. Mediation analysis estimated the excess risk for men explained by risk factors, including waist circumference, high blood pressure, diabetes, use of thiazides and dietary intake. The 24-h urine composition was also examined.ResultsThe analysis included 268 553 participants, contributing 5 872 249 person-years of follow-up. A total of 10 302 incident stones were confirmed and the overall incidence rate was 271 and 159 per 100 000 person-years for men and women, respectively. The age-adjusted HR was 2.32 (95% CI 2.20, 2.45) and the risk of stones was consistently higher across categories of age (HRs ranging from 2.02 to 2.76) for men compared with women. The risk remained higher among men, but tended to decrease over time (48.1%), while it increased among women. Urine supersaturations for calcium oxalate and uric acid were higher among men, primarily because of higher oxalate (26.3%), uric acid (16.3%), phosphate (23.5%) and lower pH.ConclusionsThe risk of kidney stones is higher among men and this difference is only partly explained by lifestyle risk factors; differences in urine chemistries explain a substantial fraction of the excess risk.

Background The relation between sodium intake and cardiovascular disease remains controversial, owing in part to inaccurate assessment of sodium intake. Assessing 24-hour urinary excretion over a period of multiple days is considered to be an accurate method. Methods We included individual-participant data from six prospective cohorts of generally healthy adults; sodium and potassium excretion was assessed with the use of at least two 24-hour urine samples per participant. The primary outcome was a cardiovascular event (coronary revascularization or fatal or nonfatal myocardial infarction or stroke). We analyzed each cohort using consistent methods and combined the results using a random-effects meta-analysis. Results Among 10,709 participants, who had a mean (±SD) age of 51.5±12.6 years and of whom 54.2% were women, 571 cardiovascular events were ascertained during a median study follow-up of 8.8 years (incidence rate, 5.9 per 1000 person-years). The median 24-hour urinary sodium excretion was 3270 mg (10th to 90th percentile, 2099 to 4899). Higher sodium excretion, lower potassium excretion, and a higher sodium-to-potassium ratio were all associated with a higher cardiovascular risk in analyses that were controlled for confounding factors (P≤0.005 for all comparisons). In analyses that compared quartile 4 of the urinary biomarker (highest) with quartile 1 (lowest), the hazard ratios were 1.60 (95% confidence interval [CI], 1.19 to 2.14) for sodium excretion, 0.69 (95% CI, 0.51 to 0.91) for potassium excretion, and 1.62 (95% CI, 1.25 to 2.10) for the sodium-to-potassium ratio. Each daily increment of 1000 mg in sodium excretion was associated with an 18% increase in cardiovascular risk (hazard ratio, 1.18; 95% CI, 1.08 to 1.29), and each daily increment of 1000 mg in potassium excretion was associated with an 18% decrease in risk (hazard ratio, 0.82; 95% CI, 0.72 to 0.94). Conclusions Higher sodium and lower potassium intakes, as measured in multiple 24-hour urine samples, were associated in a dose-response manner with a higher cardiovascular risk. These findings may support reducing sodium intake and increasing potassium intake from current levels. (Funded by the American Heart Association and the National Institutes of Health.).

BACKGROUND AND OBJECTIVES: Diet is an important contributor to kidney stone formation, but there are limited data regarding long-term changes in dietary factors after a kidney stone. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: We analyzed data from three longitudinal cohorts, the Health Professionals Follow-Up Study and Nurses’ Health Study I and II, comparing changes in dietary factors in participants with and without kidney stones during follow-up. The daily intake of dietary calcium, supplemental calcium, animal protein, caffeine, fructose, potassium, sodium, oxalate, phytate, vitamin D, vitamin C, sugar-sweetened beverages, fluids, net endogenous acid production, and Dietary Approaches to Stop Hypertension score were assessed by repeat food frequency questionnaires and computed as absolute differences; a difference-in-differences approach was used to account for temporal changes using data from participants without kidney stones from the same calendar period. RESULTS: Included were 184,398 participants with no history of kidney stones, 7095 of whom became confirmed stone formers. Several intakes changed significantly over time in stone formers, with some showing a relative increase up to 8 years later, including caffeine (difference in differences, 8.8 mg/d; 95% confidence interval [95% CI], 3.4 to 14.1), potassium (23.4 mg/d; 95% CI, 4.6 to 42.3), phytate (12.1 mg/d; 95% CI, 2.5 to 21.7), sodium (43.1 mg/d; 95% CI, 19.8 to 66.5), and fluids (47.1 ml/d; 95% CI, 22.7 to 71.5). Other dietary factors showed a significant decrease, such as oxalate (−7.3 mg/d; 95% CI, −11.4 to −3.2), vitamin C (−34.2 mg/d; 95% CI, −48.8 to −19.6), and vitamin D (−18.0 IU/d; 95% CI, −27.9 to −8.0). A significant reduction was observed in sugar-sweetened beverages intake of −0.5 (95% CI, −0.8 to −0.3) and −1.4 (95% CI, −1.8 to −1.0) servings per week and supplemental calcium of −105.1 (95% CI, −135.4 to −74.7) and −69.4 (95% CI, −95.4 to −43.4) mg/d for women from Nurses’ Health Study I and II, respectively. Animal protein, dietary calcium, fructose intake, Dietary Approaches to Stop Hypertension score, and net endogenous acid production did not change significantly over time. CONCLUSIONS: After the first episode of a kidney stone, mild and inconsistent changes were observed concerning dietary factors associated with kidney stone formation.

Background: The relationship between sodium intake and cardiovascular disease (CVD) remains controversial, in part, due to inaccurate assessment of sodium intake. 24-hour urinary excretion over multiple days is considered the optimal method. Methods: We included individual participant data from 6 prospective cohorts among generally healthy adults with sodium and potassium excretion assessed by at least two 24-hour urine collections. Out of 10,709 participants (54% women; mean [SD] age, 51.5 [12.6] years), 571 incident CVD events (including myocardial infarction, coronary revascularization, and stroke) were ascertained during a median follow-up of 8.8 years. We analyzed each cohort using consistent methods and combined the results using random-effects meta-analysis. Results: Median 24-hour urinary sodium excretion (10 th -90 th percentile) was 3,270 (2,099-4,899) mg. Higher sodium excretion, lower potassium excretion and higher sodium-to-potassium ratio were all associated with higher risk of CVD events after controlling for confounding factors (all P values for trend≤0.02); there was no evidence of nonlinearity. The hazard ratio [HR] comparing top with bottom quartiles was 1.67 [95% confidence interval [CI]: 1.21-2.30] for sodium, 0.77 [0.57-1.02] for potassium and 1.72 [1.27-2.32] for sodium-to-potassium ratio. Each 1,000 mg/d increment in sodium excretion was associated with an 18% increase in CVD risk (95%CI: 5%-32%) and each 1,000 mg/d increment in potassium excretion was associated with 18% lower risk (95%CI: 6%-28%). Conclusions: Higher sodium and lower potassium intakes, measured in multiple 24-hour urine samples, were associated with higher risk of CVD in a dose-response manner. These findings support current recommendations to reduce sodium and increase potassium intakes.

IMPORTANCE: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. OBJECTIVE: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. DESIGN, PARTICIPANTS, AND SETTING: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (

Persistent tinnitus is common, disabling, and difficult to treat. High-dose aspirin may precipitate tinnitus, but longitudinal data on typical dose aspirin and other analgesics are scarce.To investigate independent associations of aspirin, NSAIDs, and acetaminophen and risk of incident persistent tinnitus.Longitudinal cohort study.Nurses' Health Study II (1995-2017).A total of 69,455 women, age 31-48 years, without tinnitus at baseline.Information on analgesic use and tinnitus obtained by biennial questionnaires.After 1,120,936 person-years of follow-up, 10,452 cases of incident persistent tinnitus were reported. For low-dose aspirin, the risk of developing persistent tinnitus was not elevated among frequent low-dose aspirin users. For moderate dose aspirin, frequent use was associated with higher risk of tinnitus among women aged60 years, but not among older women (p-interactionInformation on tinnitus and analgesic use was self-reported. Information on indications for analgesic use was not available. Studies in non-White women and men are needed.The risk of developing persistent tinnitus was not elevated among frequent low-dose aspirin users. Among younger women, frequent moderate-dose aspirin use was associated with higher risk. Frequent NSAID use and frequent acetaminophen use were associated with higher risk of incident persistent tinnitus among all women, and the magnitude of the risks tended to be greater with increasing frequency of use. Our results suggest analgesic users are at higher risk for developing tinnitus and may provide insight into the precipitants of this challenging disorder, but additional investigation to determine whether there is a causal association is needed.

ObjectiveUse of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) in routine clinical practice is inconsistent, and availability of clinician-recorded SLEDAI scores in real-world datasets is limited. This study aimed to validate a machine learning model to estimate SLEDAI score categories using clinical notes and to apply the model to a large, real-world dataset to generate estimated score categories for use in future research studies.MethodsA machine learning model was developed to estimate an individual patient’s SLEDAI score category (no activity, mild activity, moderate activity or high/very high activity) for a specific encounter date using clinical notes. A training cohort of 3504 encounters and a separate validation cohort of 1576 encounters were created from the OM1 SLE Registry. Model performance was assessed using the area under the receiver operating characteristic curve (AUC), calculated using a binarised version of the outcome that sets the positive class to be those records with clinician-recorded SLEDAI scores >5 and the negative class to be records with scores ≤5. Model performance was evaluated by categorising the scores into the four disease activity categories and by calculating the Spearman’s R value and Pearson’s R value.ResultsThe AUC for the two categories was 0.93 for the development cohort and 0.91 for the validation cohort. The model had a Spearman’s R value of 0.7 and a Pearson’s R value of 0.7 when calculated using the four disease activity categories.ConclusionThe model performs well when estimating SLEDAI score categories using unstructured clinical notes.

Objectives The urinary excretion of organic and inorganic substances and their concentrations have attracted extensive attention for their role in the pathogenesis of urinary stone disease. The urinary excretion of specific factors associates with sex and age and seems to have a hereditary component, but the precise genomic determinants remain ill-defined. Methods Genome-wide association studies previously conducted in 3 cohorts (Genetic Epidemiology Network of Arteriopathy study, January 1, 2006, through December 31, 2012; the combined Nurses' Health Study (NHS), NHS II, and Health Professionals Follow-up Study, January 1, 1994, through December 31, 2003; and the Prevention of Renal and Vascular End-stage Disease study, January 1, 1997, through December 31, 1998) were combined into meta-analyses to evaluate genetic associations with available urinary phenotypes relevant to stone pathogenesis (calcium, magnesium, and uric acid excretion; total urine volume). Results One region on chromosome 9q21.13 showed strong evidence of an association with urinary magnesium excretion. The strongest signal in this region was near TRPM6, whose protein product mediates magnesium transport in the colon and kidney, and C9orf40, C9orf41, NMRK1, and OSTF1 (rs1176815; P=1.70×10–14, with each copy of the A allele corresponding to a daily 5.29-mg decrease in magnesium excretion). The single nucleotide polymorphism (SNP) that achieved genome-wide significance for calcium excretion (rs17216707 on chromosome 20; P=1.12×10–8) was previously associated with fibroblast growth factor 23 levels, which regulate phosphorus and vitamin D metabolism. Urine volume and uric acid excretion did not have any genome-wide significant SNPs. Conclusion Common variants near genes important for magnesium metabolism and bone health associate with urinary magnesium and calcium excretion.

Rationale & Objective The intestinal microbiome may affect urinary stone disease by modulating the amount of oxalate absorbed from the intestine and subsequently excreted in urine. This study sought to explore the association between antibiotics, which alter the intestinal microbiota, and risk for urinary stone disease. Study Design Prospective cohort study. Setting & Participants 5,010 women in the Nurses’ Health Study (NHS) I and II who had collected 24-hour urine samples. Exposures Use of antibiotics during the age range of 40 to 49 (NHS II), 40 to 59 (NHS I), and 20 to 39 years (both cohorts). Outcomes Incident symptomatic urinary stone disease; urine composition. Analytical Approach Cause-specific hazards regression adjusted for age, body mass index, comorbid conditions, thiazide use, and dietary factors. Follow-up was censored at the time of asymptomatic kidney stones, cancer, or death. Results Cumulative use of antibiotics for a total of 2 or more months during the age range of 40 to 49 years (NHS II) and 40 to 59 years (NHS II) was associated with significantly higher risk for developing incident stones compared with no use (pooled HR, 1.48; 95% CI, 1.12-1.96). Similar results were found for the period of 20 to 39 years (pooled HR, 1.36; 95% CI, 1.00-1.84). Results were unchanged after excluding participants who reported urinary tract infection with their stone event or as the most common reason for antibiotic use. Urine composition was generally similar across antibiotic groups except for marginally lower urine pH and citrate values among those taking antibiotics for 2 or more months. Limitations Observational design; lack of information for type of antibiotic used; relatively large span of time between antibiotic use and urine collection. Conclusions Use of antibiotics for more than 2 months in early adulthood and middle age is associated with higher risk for urinary stone disease in later life.

We conducted a prospective study of dietary patterns and longitudinal change in audiometric hearing thresholds among 3,135 women (mean age = 59 years) in the Nurses’ Health Study II (2012–2018). Diet adherence scores for the Dietary Approaches to Stop Hypertension (DASH) and Alternate Mediterranean (AMED) diets and the Alternate Healthy Eating Index 2010 (AHEI-2010) were calculated using validated food-frequency questionnaires. Baseline and 3-year follow-up hearing sensitivities were assessed by pure-tone audiometry at 19 US sites. We used multivariable-adjusted logistic regression models to examine independent associations between diet adherence scores and risk of ≥5 dB elevation in the pure-tone average (PTA) of low-frequency (LPTA0.5,1,2 kHz), mid-frequency (MPTA3,4 kHz), and high-frequency (HPTA6,8 kHz) hearing thresholds. Higher adherence scores were associated with lower risk of hearing loss. Compared with the lowest quintile of DASH score, the multivariable-adjusted odds ratios for mid-frequency and high-frequency threshold elevation in the highest quintile were 0.71 (95% confidence interval (CI): 0.55, 0.92; P for trend = 0.003) and 0.75 (95% CI: 0.59, 0.96; P for trend = 0.02); for AMED and AHEI scores, for mid-frequency threshold elevation, they were 0.77 (95% CI: 0.60, 0.99; P for trend = 0.02) and 0.72 (95% CI: 0.57, 0.92; P for trend = 0.002). Nonsignificant inverse associations were observed for high-frequency threshold elevation. There were no significant associations between adherence scores and low-frequency threshold elevation. Our findings indicate that eating a healthy diet might reduce the risk of acquired hearing loss.

ObjectiveTo investigate whether women and men with Parkinson disease (PD) differ in their biochemical and clinical responses to long-term treatment with inosine.MethodsThe Safety of Urate Elevation in Parkinson’s Disease (SURE-PD) trial enrolled 75 people with early PD and baseline serum urate below 6 mg/dL and randomized them to 3 double-blinded treatment arms: oral placebo or inosine titrated to produce mild (6.1–7.0 mg/dL) or moderate (7.1–8.0 mg/dL) serum urate elevation for up to 2 years. Parkinsonism, serum urate, and plasma antioxidant capacity were measured at baseline and repeatedly on treatment; CSF urate was assessed once, at 3 months. Here in secondary analyses results are stratified by sex.ResultsInosine produced an absolute increase in average serum urate from baseline that was 50% greater in women (3.0 mg/dL) than in men (2.0 mg/dL), consistent with expected lower baseline levels in women. Similarly, only among women was CSF urate significantly greater on mild or moderate inosine (+87% [p < 0.001] and +98% [p < 0.001], respectively) than on placebo (in contrast to men: +10% [p = 0.6] and +14% [p = 0.4], respectively). Women in the higher inosine dosing group showed a 7.0 Unified Parkinson’s Disease Rating Scale (UPDRS) points/year lower rate of decline vs placebo (p = 0.01). In women, slower rates of UPDRS change were associated with greater increases in serum urate (r = −0.52; p = 0.001), and with greater increases in plasma antioxidant capacity (r = −0.44; p = 0.006). No significant associations were observed in men.ConclusionsInosine produced greater increases in serum and CSF urate in women compared to men in the SURE-PD trial, consistent with the study's design and with preliminary evidence for slower clinical decline in early PD among women treated with urate-elevating doses of inosine.Clinicaltrials.gov identifierNCT00833690.Classification of evidenceThis study provides Class II evidence that inosine produced greater urate elevation in women than men and may slow PD progression in women.

The use of proton pump inhibitors (PPIs) has increased rapidly in the past 2 decades. Concerns about the regular use of PPIs contributing to mortality have been raised.We conducted a prospective cohort study using data collected from the Nurses' Health Study (2004-2018) and the Health Professionals Follow-up Study (2004-2018). Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% CIs for mortality according to PPI use. We used a modified lag-time approach to minimize reverse causation (ie, protopathic bias).Among 50,156 women and 21,731 men followed for 831,407 person-years and a median of 13.8 years, we documented 22,125 deaths, including 4592 deaths from cancer, 5404 from cardiovascular diseases, and 12,129 deaths from other causes. Compared with nonusers of PPIs, PPI users had significantly higher risks of all-cause mortality (HR, 1.19; 95% CI, 1.13-1.24) and mortality due to cancer (HR, 1.30; 95% CI, 1.17-1.44), cardiovascular diseases (HR, 1.13; 95% CI, 1.02-1.26), respiratory diseases (HR, 1.32; 95% CI, 1.12-1.56), and digestive diseases (HR, 1.50; 95% CI, 1.10-2.05). Upon applying lag times of up to 6 years, the associations were attenuated and no longer statistically significant (all-cause: HR, 1.04; 95% CI, 0.97-1.11; cancer: HR, 1.07; 95% CI, 0.89-1.28; cardiovascular diseases: HR, 0.94; 95% CI, 0.81-1.10; respiratory diseases: HR, 1.20; 95% CI, 0.95-1.50; digestive diseases: HR, 1.38; 95% CI, 0.88-2.18). Longer duration of PPI use did not confer higher risks for all-cause and cause-specific mortality.After accounting for protopathic bias, PPI use was not associated with higher risks of all-cause mortality and mortality due to major causes.

Background and Aims Kidney stone disease is a highly prevalent condition. Men are at higher risk of developing stones compared with women, however recent data suggest a changing epidemiology with women being relatively more affected than in the past. The reasons for such differences and changes over time are not clear. Method We analyzed the association between sex and the first symptomatic incident kidney stone using data from three large, longitudinal cohorts. Incidence rates for men and women overall and across categories of age and calendar time were computed and hazard ratios (HRs) and 95% confidence intervals (CIs) generated with age-adjusted Cox proportional hazards regression models. Mediation analysis was performed in order to estimate the amount of excess risk for men explained by established risk factors, including BMI, waist circumference, history of high blood pressure, history of diabetes, use of thiazides, dietary intakes of animal protein, caffeine, fructose, potassium, sodium, oxalate, phytate, dietary and supplemental intakes of calcium, vitamin C and vitamin D, sugar-sweetened beverages and total fluid intake. Results The analysis included data from 268,616 participants, contributing 5,876,205 person-years of follow-up, during which 10,303 incident stone events were confirmed. The overall incidence rate of kidney stones was 271 and 158 per 100,000 person-years for men and women, respectively. The age-adjusted HR for men compared with women was 2.32 (95% CI 2.20, 2.45). About 18% of the difference in rates was explained by the risk factors included in the analysis. The risk of stones was consistently higher across categories of age among men compared with women. With regard to calendar time, the risk remained higher among men, but tended to decrease over time while it increased among women, resulting in a relative risk reduction of 38% for after 2009 compared with before 1990. Conclusion The risk of kidney stones is higher among men compared with women. This difference is only partly explained by modifiable risk factors.

Objectives Tinnitus and hearing loss commonly coexist, however, the temporal relation between tinnitus and hearing loss is complex and not fully understood. Our objective was to examine the longitudinal association between persistent tinnitus, bothersome tinnitus, and 3-year elevation of audiometric hearing thresholds. Design We conducted a longitudinal cohort study among 3106 women (mean age 59 years) who were participants in the Nurses' Health Study II (2012-2018). Information on tinnitus was obtained from biennial questionnaires. Longitudinal changes in air conduction thresholds (0.5 to 8 kHz) were assessed by pure-tone audiometry conducted by licensed audiologists at 19 audiology testing sites across the United States. Logistic regression was used to estimate multivariable-adjusted odds ratios (MVORs, 95% confidence interval [CI]) and evaluate the relations of persistent tinnitus (several days per week or more), bothersome tinnitus (interferes with work, sleep, or daily activities), and risk of 3-year elevation of hearing thresholds. Results Persistent tinnitus was associated with higher risk of 3-year elevation of hearing thresholds across a broad range of frequencies. Compared with women without tinnitus, the MVORs (95% CI) for ≥5-dB threshold elevation among women with persistent tinnitus were 1.01 (0.81, 1.25) at 0.5 kHz, 1.45 (1.17, 1.81) at 1 kHz, 1.25 (1.00, 1.56) at 2 kHz, 1.34 (1.07, 1.69) at 3 kHz, 1.34 (1.06, 1.70) at 4 kHz, 1.49 (1.16, 1.91) at 6 kHz, and 1.63 (1.25, 2.12) at 8 kHz. The magnitudes of the associations for ≥10-dB threshold elevation were similar. The magnitudes of the associations were substantially greater among women with bothersome tinnitus. For example, compared with women without tinnitus, the MVORs (95% CI) for a ≥5- and ≥10-dB elevation of hearing thresholds at 4 kHz were 2.97 (1.50, 5.89) and 2.79 (1.38, 5.65), respectively. The risk was elevated even among women with tinnitus who had clinically normal hearing thresholds at baseline. In analyses that examined the association of tinnitus and elevation of low-, mid- and high-frequency pure-tone average (PTA) hearing thresholds, the results were similar. Compared with women without tinnitus, the MVORs (95% CI) for ≥5-dB PTA elevation among women with persistent tinnitus were 1.29 (0.99,1.67) for LPTA(0.5,1,2 kHz); 1.44 (1.16, 1.78) for MPTA(3,4 kHz); and 1.38 (1.11, 1.71) for HPTA(6,8 kHz). For ≥10-dB elevation, the MVORs were 2.85 (1.55, 5.23), 1.52 (1.10, 2.09), and 1.41 (1.10, 1.82), respectively. Conclusion Persistent tinnitus was associated with substantially higher risk of 3-year hearing threshold elevation, even among women with clinically normal baseline hearing. The magnitudes of the associations were greater among those with bothersome tinnitus. Monitoring hearing sensitivities may be indicated in patients with tinnitus, including those without audiometric evidence of hearing impairment.

The etiology of calcium-oxalate kidney stone formation remains elusive. Biallelic mutations inAn observational analytic case control study was designed to determine the prevalence of pathogenicThe carrier prevalence of pathogenic mutations among the Ashkenazi Jews was 1.7% compared to 2.8% in the corresponding control group (p=0.9 OR=0.6 95% CI 0.01-3.51). We did not detect any mutation among the nonAshkenazi study group. No correlation was detected between hyperoxaluria andThis study shows that mutations in

Purpose: Cystinuria is a genetic disorder with both autosomal recessive and incompletely dominant inheritance. The disorder disrupts cystine and other dibasic amino acid transport in proximal tubules of the kidney, resulting in recurrent kidney stone formation. Currently, there are no consensus guidelines on evaluation and management of this disease. This article represents the consensus of the author panel and will provide clinicians with a stepwise framework for evaluation and clinical management of patients with cystinuria based on evidence in the existing literature. Materials and Methods: A search of MEDLINE(®)/PubMed(®) and Cochrane databases was performed using the following key words: “cystine nephrolithiasis,” “cystinuria,” “penicillamine, cystine,” and “tiopronin, cystine.” In total, as of May 2018, these searches yielded 2335 articles, which were then evaluated for their relevance to the topic of evaluation and management of cystinuria. Evidence was evaluated by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Results: Twenty-five articles on the topic of cystinuria or cystine nephrolithiasis were deemed suitable for inclusion in this study. The literature supports a logical evaluation process and step-wise treatment approach beginning with conservative measures: fluid intake and dietary modification. If stone formation recurs, proceed to pharmacotherapeutic options by first alkalinizing the urine and then using cystine-binding thiol drugs. Conclusions: The proposed clinical pathways provide a framework for efficient evaluation and treatment of patients with cystinuria, which should improve overall outcomes of this rare, but highly recurrent, form of nephrolithiasis.

We examined the relation between self-reported hearing loss, hearing aid use, and risk of subjective cognitive function (SCF) decline.We conducted an 8-year (2008-2016) longitudinal study of 10,107 men aged ≥62 years who reported their hearing status in 2006 and had no subjective cognitive concerns in 2008. Change in SCF scores was assessed by a 6-item questionnaire, and subjective decline was defined as new report of at least one SCF concern during follow-up.Hearing loss was associated with higher risk of SCF decline. Compared with no hearing loss, the multivariable-adjusted relative risk (95% CI) of incident SCF decline was 1.30 (1.18, 1.42), 1.42 (1.26, 1.61), and 1.54 (1.22, 1.96) among men with mild, moderate, and severe hearing loss (no hearing aids), respectively (P-trend.001). Among men with severe hearing loss who used hearing aids, the multivariable-adjusted relative risk (95% CI) was 1.37 (1.18, 1.60).Hearing loss was associated with substantially higher risk of subsequent subjective cognitive decline in men.

BACKGROUND Chronic inflammation may lead to cochlear damage, and the only longitudinal study that examined biomarkers of systemic inflammation and risk of hearing loss found an association with a single biomarker in individuals

The association between the intake of trace metals and the risk of incident stones has not been longitudinally investigated.We performed a prospective analysis of 193,551 participants in the Health Professionals Follow-up Study, and the Nurses' Health Study I and II. During a followup of 3,316,580 person-years there was a total of 6,576 incident stones. We used multivariate regression models to identify associations of the intake of zinc, iron, copper and manganese with the risk of stones. In a subset of participants with 24-hour urine collections we examined the association between the intake of trace metals and urine composition.After multivariate adjustment total and dietary intakes of zinc and iron were not significantly associated with incident stones. A higher intake of manganese was associated with a lower risk of stones. The pooled HR of the highest quintile of total manganese intake compared with the lowest intake was 0.82 (95% CI 0.68-0.98, p = 0.02). Total but not dietary copper intake was marginally associated with a higher risk of stones (pooled HR 1.14, 95% CI 1.02-1.28, p = 0.01). There were no statistically significant associations of the total intake of manganese and copper with urinary supersaturation.Zinc and iron intake was not associated with a risk of stones. Copper intake may be associated with a higher risk in some individuals. Higher total manganese intake was associated with a lower risk of stones but not with traditional 24-hour urinary composite markers of stone risk. Further research is needed to elucidate the mechanisms by which manganese may reduce kidney stone formation.

Background Statins are among the most commonly used medications in the United States, and statin use is associated with increased risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). However, previous studies are limited by lack of adjustment for important confounders. Objective Examine the relation between statins and skin cancer risk in the Nurses' Health Study and Health Professionals Follow-up Study. Methods Cox proportional hazards regression was used to evaluate associations. Results During follow-up (2000-2010), we documented 10,201 BCC, 1393 SCC, and 333 melanoma cases. History of high cholesterol level was not associated with risk of BCC (pooled multivariable-adjusted hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.00-1.09), SCC (HR, 0.95; 95% CI, 0.85-1.06), or melanoma (HR, 0.87; 95% CI, 0.64-1.19). Statin use was not associated with risk of BCC (HR, 1.04; 95% CI, 0.99-1.09]), SCC (HR, 1.08; 95% CI, 0.94-1.24), or melanoma (HR, 1.04; 95% CI, 0.78-1.38). There was a trend toward higher BCC risk with longer duration of statin use in men ( P trend = .003) but not in women ( P trend = .86). Limitations Lack of treatment data. Conclusion History of high cholesterol level was not associated with skin cancer risk. Longer duration of statin use was associated with a trend toward higher BCC risk in men.