New Metrics Needed in the Evaluation of Hearing Hazard Associated With Industrial Noise Exposure.

OBJECTIVES: To evaluate (1) the accuracy of the International Organization for Standardization (ISO) standard ISO 1999 [(2013), International Organization for Standardization, Geneva, Switzerland] predictions of noise-induced permanent threshold shift (NIPTS) in workers exposed to various types of high-intensity noise levels, and (2) the role of the kurtosis metric in assessing noise-induced hearing loss (NIHL). DESIGN: Audiometric and shift-long noise exposure data were acquired from a population (N = 2,333) of screened workers from 34 industries in China. The entire cohort was exclusively divided into subgroups based on four noise exposure levels (85 ≤ LAeq.8h < 88, 88 ≤ LAeq.8h < 91, 91 ≤ LAeq.8h < 94, and 94 ≤ LAeq.8h ≤ 100 dBA), two exposure durations (D ≤ 10 years and D > 10 years), and four kurtosis categories (Gaussian, low-, medium-, and high-kurtosis). Predicted NIPTS was calculated using the ISO 1999 model for each participant and the actual measured NIPTS was corrected for age and sex also using ISO 1999. The prediction accuracy of the ISO 1999 model was evaluated by comparing the NIPTS predicted by ISO 1999 with the actual NIPTS. The relation between kurtosis and NIPTS was also investigated. RESULTS: Overall, using the average NIPTS value across the four audiometric test frequencies (2, 3, 4, and 6 kHz), the ISO 1999 predictions significantly (p < 0.001) underestimated the NIPTS by 7.5 dB on average in participants exposed to Gaussian noise and by 13.6 dB on average in participants exposed to non-Gaussian noise with high kurtosis. The extent of the underestimation of NIPTS by ISO 1999 increased with an increase in noise kurtosis value. For a fixed range of noise exposure level and duration, the actual measured NIPTS increased as the kurtosis of the noise increased. The noise with kurtosis greater than 75 produced the highest NIPTS. CONCLUSIONS: The applicability of the ISO 1999 prediction model to different types of noise exposures needs to be carefully reexamined. A better understanding of the role of the kurtosis metric in NIHL may lead to its incorporation into a new and more accurate model of hearing loss due to noise exposure.

Intensity of renal support in critically ill patients with acute kidney injury.

BACKGROUND: The optimal intensity of renal-replacement therapy in critically ill patients with acute kidney injury is controversial. METHODS: We randomly assigned critically ill patients with acute kidney injury and failure of at least one nonrenal organ or sepsis to receive intensive or less intensive renal-replacement therapy. The primary end point was death from any cause by day 60. In both study groups, hemodynamically stable patients underwent intermittent hemodialysis, and hemodynamically unstable patients underwent continuous venovenous hemodiafiltration or sustained low-efficiency dialysis. Patients receiving the intensive treatment strategy underwent intermittent hemodialysis and sustained low-efficiency dialysis six times per week and continuous venovenous hemodiafiltration at 35 ml per kilogram of body weight per hour; for patients receiving the less-intensive treatment strategy, the corresponding treatments were provided thrice weekly and at 20 ml per kilogram per hour. RESULTS: Baseline characteristics of the 1124 patients in the two groups were similar. The rate of death from any cause by day 60 was 53.6% with intensive therapy and 51.5% with less-intensive therapy (odds ratio, 1.09; 95% confidence interval, 0.86 to 1.40; P=0.47). There was no significant difference between the two groups in the duration of renal-replacement therapy or the rate of recovery of kidney function or nonrenal organ failure. Hypotension during intermittent dialysis occurred in more patients randomly assigned to receive intensive therapy, although the frequency of hemodialysis sessions complicated by hypotension was similar in the two groups. CONCLUSIONS: Intensive renal support in critically ill patients with acute kidney injury did not decrease mortality, improve recovery of kidney function, or reduce the rate of nonrenal organ failure as compared with less-intensive therapy involving a defined dose of intermittent hemodialysis three times per week and continuous renal-replacement therapy at 20 ml per kilogram per hour. (ClinicalTrials.gov number, NCT00076219.)

Intensity of renal replacement therapy in acute kidney injury: perspective from within the Acute Renal Failure Trial Network Study.

Determination of the optimal dose of renal replacement therapy in critically ill patients with acute kidney injury has been controversial. Questions have recently been raised regarding the design and execution of the US Department of Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network (ATN) Study, which demonstrated no improvement in 60-day all-cause mortality with more intensive management of renal replacement therapy. In the present article we present our rationale for these aspects of the design and conduct of the study, including our use of both intermittent and continuous modalities of renal support, our approach to initiation of study therapy and the volume management during study therapy. In addition, the article presents data on hypotension during therapy and recovery of kidney function in the perspective of other studies of renal support in acute kidney injury. Finally, we address the implications of the ATN Study results for clinical practice from the perspective of the study investigators.

A randomized controlled study of effects of dietary magnesium oxide supplementation on bone mineral content in healthy girls.

CONTEXT: The role of magnesium (Mg) as a determinant of bone mass has not been extensively explored. Limited studies suggest that dietary Mg intake and bone mineral density are correlated in adults, but no data from interventional studies in children and adolescents are available. OBJECTIVE: We sought to determine whether Mg supplementation in periadolescent girls enhances accrual of bone mass. DESIGN: We carried out a prospective, placebo-controlled, randomized, one-year double-blind trial of Mg supplementation. SETTING: The study was conducted in the Clinical Research Centers at Yale University School of Medicine. PATIENTS OR OTHER PARTICIPANTS: Healthy 8- to 14-yr-old Caucasian girls were recruited from community pediatricians' offices. Dietary diaries from over 120 volunteers were analyzed, and those with dietary Mg intake of less than 220 mg/d were invited to participate in the intervention. INTERVENTION: Magnesium (300 mg elemental Mg per day in two divided doses) or placebo was given orally for 12 months. MAIN OUTCOME MEASURE: The primary outcome measure was interval change in bone mineral content (BMC) of the total hip, femoral neck, Ward's area, and lumbar spine (L1-L4) after 12 months of Mg supplementation. RESULTS: Significantly increased accrual (P = 0.05) in integrated hip BMC occurred in the Mg-supplemented vs. placebo group. Trends for a positive Mg effect were evident in the pre- and early puberty and in mid-late puberty. Lumbar spinal BMC accrual was slightly (but not significantly) greater in the Mg-treated group. Compliance was excellent; 73% of capsules were ingested as inferred by pill counts. Serum mineral levels, calciotropic hormones, and bone markers were similar between groups. CONCLUSIONS: Oral Mg oxide capsules are safe and well tolerated. A positive effect of Mg supplementation on integrated hip BMC was evident in this small cohort.

Amygdala and hippocampal volumes in adolescents and adults with bipolar disorder.

BACKGROUND: The purported functions of medial temporal lobe structures suggest their involvement in the pathophysiology of bipolar disorder (BD). Previous reports of abnormalities in the volume of the amygdala and hippocampus in patients with BD have been inconsistent in their findings and limited to adult samples. Appreciation of whether volumetric abnormalities are early features of BD or whether the abnormalities represent neurodegenerative changes associated with illness duration is limited by the paucity of data in juvenile samples. OBJECTIVE: To investigate amygdala and hippocampal volume in adults and adolescents with BD. SETTING AND PARTICIPANTS: Subjects included 36 individuals (14 adolescents and 22 adults) in outpatient treatment for BD type I at a university hospital or Veterans Affairs medical center or in the surrounding community, and 56 healthy comparison subjects (23 adolescents and 33 adults). DESIGN AND MAIN OUTCOME MEASURES: Amygdala and hippocampal volumes were defined and measured on high-resolution anatomic magnetic resonance imaging scans. We used a mixed-model, repeated-measures statistical analysis to compare amygdala and hippocampal volumes across groups while covarying for total brain volume, age, and sex. Potential effects of illness features were explored, including rapid cycling, medication, alcohol or other substance dependence, duration, and mood state. RESULTS: For both the amygdala and hippocampal regions, we found an overall significant volume reduction in the BD compared with the control group (P<.0001). Amygdala volume reductions (15.6%) were highly significant (P<.0001). We observed a nonsignificant trend (P =.054) toward reductions in hippocampal volumes of lesser magnitude (5.3%). Effects of illness features were not detected. CONCLUSIONS: These results suggest that BD is associated with decreased volumes of medial temporal lobe structures, with greater effect sizes in the amygdala than in the hippocampus. These abnormalities are likely manifested early in the course of illness, as they affected adolescent and adult subjects similarly in this sample.

Model to predict mortality in critically ill adults with acute kidney injury.

BACKGROUND AND OBJECTIVES: Acute kidney injury (AKI) requiring dialysis is associated with high mortality. Most prognostic tools used to describe case complexity and to project patient outcome lack predictive accuracy when applied in patients with AKI. In this study, we developed an AKI-specific predictive model for 60-day mortality and compared the model to the performance of two generic (Sequential Organ Failure Assessment [SOFA] and Acute Physiology and Chronic Health Evaluation II [APACHE II]) scores, and a disease specific (Cleveland Clinic [CCF]) score. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data from 1122 subjects enrolled in the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network study; a multicenter randomized trial of intensive versus less intensive renal support in critically ill patients with AKI conducted between November 2003 and July 2007 at 27 VA- and university-affiliated centers. RESULTS: The 60-day mortality was 53%. Twenty-one independent predictors of 60-day mortality were identified. The logistic regression model exhibited good discrimination, with an area under the receiver operating characteristic (ROC) curve of 0.85 (0.83 to 0.88), and a derived integer risk score yielded a value of 0.80 (0.77 to 0.83). Existing scoring systems, including APACHE II, SOFA, and CCF, when applied to our cohort, showed relatively poor discrimination, reflected by areas under the ROC curve of 0.68 (0.64 to 0.71), 0.69 (0.66 to 0.73), and 0.65 (0.62 to 0.69), respectively. CONCLUSIONS: Our new risk model outperformed existing generic and disease-specific scoring systems in predicting 60-day mortality in critically ill patients with AKI. The current model requires external validation before it can be applied to other patient populations.

Design of combination angiotensin receptor blocker and angiotensin-converting enzyme inhibitor for treatment of diabetic nephropathy (VA NEPHRON-D).

Both angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) can slow the progression of diabetic nephropathy. Even with ACEI or ARB treatment, the proportion of patients who progress to end-stage renal disease (ESRD) remains high. Interventions that achieve more complete blockade of the renin-angiotensin system, such as combination ACEI and ARB, might be beneficial. This approach may decrease progression of nondiabetic kidney disease. In diabetic nephropathy, combination therapy decreases proteinuria, but its effect in slowing progression is unknown. In addition, the potential for hyperkalemia may limit the utility of combined therapy in this population. VA NEPHRON-D is a randomized, double-blind, multicenter clinical trial to assess the effect of combination losartan and lisinopril, compared with losartan alone, on the progression of kidney disease in 1850 patients with diabetes and overt proteinuria. The primary endpoints are time to (1) reduction in estimated GFR (eGFR) of > 50% (if baseline < 60 ml/min/1.73 m(2)); (2) reduction in eGFR of 30 ml/min/1.73 m(2) (if baseline > or = 60 ml/min/1.73 m(2)); (3) progression to ESRD (need for dialysis, renal transplant, or eGFR < 15 ml/min/1.73 m(2)); or (4) death. The secondary endpoint is time to change in eGFR or ESRD. Tertiary endpoints are cardiovascular events, slope of change in eGFR, and change in albuminuria at 1 yr. Specific safety endpoints are serious hyperkalemia (potassium > 6 mEq/L, requiring admission, emergency room visit, or dialysis), all-cause mortality, and other serious adverse events. This paper discusses the design and key methodological issues that arose during the planning of the study.

Design of the VA/NIH Acute Renal Failure Trial Network (ATN) Study: intensive versus conventional renal support in acute renal failure.

The optimal management of renal replacement therapy (RRT) in acute renal failure (ARF) is uncertain. The VA/NIH Acute Renal Failure Trail Network Study (ATN Study) tests the hypothesis that a strategy of intensive RRT will decrease 60-day all-cause mortality in critically ill patients with ARF. Dose separation between the two treatment arms is achieved by increasing the frequency of intermittent hemodialysis (IHD) and sustained low efficiency dialysis (SLED) treatments from three times per week to six times per week, and by increasing continuous venovenous hemodiafiltration (CVVHDF) effluent volume from 20 mL/kg/hr to 35 mL/kg/hr. In both treatment arms, subjects convert between IHD and CVVHDF or SLED as hemodynamic status changes over time. This strategy attempts to replicate the conversion between modalities of RRT that occurs in clinical practice. However, in order to implement this strategy, flexible criteria needed to be developed to provide a balance between the need for uniformity of treatment between groups and practitioner discretion regarding modality of RRT to maintain patient safety. In order to address safety and ethical issues similar to those raised by the Office of Human Research Protections in its review of the ARDS Network studies, a survey of practitioner practices was performed and observational data on the management of RRT in comparable critically ill patients with ARF managed outside of the research context is being collected prospectively. These data will help inform the study's DSMB and site IRB's of the relationship between the study's treatment arms and concurrent clinical practice.

Randomized controlled trial of clopidogrel plus aspirin to prevent hemodialysis access graft thrombosis.

Thrombosis of hemodialysis vascular access grafts represents a major medical and economic burden. Experimental and clinical models suggest a role for antiplatelet agents in the prevention of thrombosis. The study was designed to determine the efficacy of the combination of aspirin and clopidogrel in the prevention of graft thrombosis. The study was a randomized, double-blind trial conducted at 30 hemodialysis units at Veterans Affairs medical centers. Participants undergoing hemodialysis with a polytetrafluoroethylene graft in the arm were randomized to receive either double placebos or aspirin (325 mg) and clopidogrel (75 mg) daily. Participants were to be monitored while receiving study medications for a minimum of 2 yr. The study was stopped after randomization of 200 participants, as recommended by the Data Safety and Monitoring Board because of a significantly increased risk of bleeding among the participants receiving aspirin and clopidogrel therapy. The cumulative incidence of bleeding events was significantly greater for those participants, compared with participants receiving placebos [hazard ratio, 1.98; 95% confidence interval (CI), 1.19 to 3.28; P = 0.007]. Twenty-three participants in the placebo group and 44 participants in the active treatment group experienced a bleeding event (P = 0.006). There was no significant benefit of active treatment in the prevention of thrombosis (hazard ratio, 0.81; 95% CI, 0.47 to 1.40; P = 0.45), although there was a trend toward a benefit among participants who had not experienced previous graft thrombosis (hazard ratio, 0.52; 95% CI, 0.22 to 1.26; P = 0.14). In the hemodialysis population, therapy with aspirin and clopidogrel was associated with a significantly increased risk of bleeding and probably would not result in a reduced frequency of graft thrombosis.