Song Zhang

Osteoporotic fracture risk associated with cumulative exposure to tenofovir and other antiretroviral agents.

Background:Whereas tenofovir (TDF) exposure has been associated with decreased bone density, it remains unclear whether it is associated with increased risk of osteoporotic fractures. Methods:Patients with any osteoporotic fracture (defined as wrist, vertebral or hip fracture) occurring after HIV diagnosis were identified by International Classification of Diseases – 9th Revision (ICD-9) code in the Veterans Affairs’ Clinical Case Registry from 1988 to 2009. Osteoporotic fracture risk associated with cumulative exposure to TDF and other antiretrovirals was examined in univariate analysis and multivariate model 1 (MV1 – controlling for race, age, tobacco use, diabetes, body mass index, and hepatitis C status) and model 2 (MV2 – controlling for MV1 variables + concomitant antiretroviral exposures). Results:Among 56u200a660 patients evaluated, TDF exposure (total 46u200a062 person-years) was associated with an osteoporotic fracture hazard ratio of 1.080 [95% confidence interval (CI) 1.02–1.15, Pu200a<u200a0.001] in univariate analysis, 1.06 (0.99–1.12) in MV1 and 1.06 (0.99–1.14) in MV2. Among patients entering the cohort in the highly active antiretroviral therapy (HAART) era (nu200a=u200a32u200a439), TDF exposure was associated with a yearly hazard ratio for osteoporotic fracture of 1.16 (95% CI 1.08–1.24, P < 0.001) in univariate model, 1.13 (1.05–1.21, Pu200a=u200a0.001) in MV1 and 1.12 (1.03–1.21, Pu200a=u200a0.011) in MV2. Boosted protease inhibitor exposure was associated with hazard ratio of 1.11 (1.05–1.18, Pu200a=u200a0.001) in univariate model, 1.08 (1.01–1.15, Pu200a=u200a0.026) in MV1 and 1.05 (0.97–1.13, Pu200a=u200a0.237) in MV2. Among protease inhibitors, lopinavir/ritonavir (LPV/RTV) had an osteoporotic fracture hazard ratio of 1.09 (CI 1.00–1.20, Pu200a=u200a0.051) in MV2. Conclusion:Cumulative exposure to TDF and, among protease inhibitors, LPV/RTV was independently predictive of increased risk of osteoporotic fracture in the HAART era.

Allocating scarce resources in real-time to reduce heart failure readmissions: a prospective, controlled study

Objective To test a multidisciplinary approach to reduce heart failure (HF) readmissions that tailors the intensity of care transition intervention to the risk of the patient using a suite of electronic medical record (EMR)-enabled programmes. Methods A prospective controlled before and after study of adult inpatients admitted with HF and two concurrent control conditions (acute myocardial infarction (AMI) and pneumonia (PNA)) was performed between 1 December 2008 and 1 December 2010 at a large urban public teaching hospital. An EMR-based software platform stratified all patients admitted with HF on a daily basis by their 30-day readmission risk using a published electronic predictive model. Patients at highest risk received an intensive set of evidence-based interventions designed to reduce readmission using existing resources. The main outcome measure was readmission for any cause and to any hospital within 30u2005days of discharge. Results There were 834 HF admissions in the pre-intervention period and 913 in the post-intervention period. The unadjusted readmission rate declined from 26.2% in the pre-intervention period to 21.2% in the post-intervention period (p=0.01), a decline that persisted in adjusted analyses (adjusted OR (AOR)=0.73; 95% CI 0.58 to 0.93, p=0.01). In contrast, there was no significant change in the unadjusted and adjusted readmission rates for PNA and AMI over the same period. There were 45 fewer readmissions with 913 patients enrolled and 228 patients receiving intervention, resulting in a number needed to treat (NNT) ratio of 20. Conclusions An EMR-enabled strategy that targeted scarce care transition resources to high-risk HF patients significantly reduced the risk-adjusted odds of readmission.

The RADAR study: week 48 safety and efficacy of RAltegravir combined with boosted DARunavir compared to tenofovir/emtricitabine combined with boosted darunavir in antiretroviral-naive patients. Impact on bone health.

Background NRTI-sparing regimens may avoid long-term mitochondrial, bone and renal toxicities and maintain viral suppression. Methods In the RADAR study, 85 antiretroviral-naïve HIV-infected patients were randomized to receive either raltegravir (RAL) (nu200a=u200a42) or tenofovir/emtricitabine (TDF/FTC) (nu200a=u200a43), each with ritonavir-boosted darunavir (DRV/r). Virologic efficacy was assessed at weeks 24 and 48. Bone mineral density (BMD) was assessed by dual energy X-ray absorptiometry (DXA) scan at baseline and week 48, and bone turnover markers (BTM) assessed at weeks 0, 16 and 48. Results Using an intention-to-treat analysis, 62.5% of RAL subjects and 83.7% of TDF/FTC subjects were responders (VL<48 copies/mL) at week 48 (pu200a=u200a0.045; chi-square test). The proportions of patients achieving VL<200 copies/mL were similar: 72.5% and 86.0% (pu200a=u200a0.175). Premature treatment discontinuation was the main cause for failure. No treatment-emergent resistance was observed. Changes from baseline in RAL vs. TDF/FTC for CD4+ (+199 vs. +216 cells/µL, pu200a=u200a0.63), total cholesterol/HDL (−0.25 vs. −0.71 mg/dL (pu200a=u200a0.270), and eGFR (−4.4 vs. −7.9 ml/min, pu200a=u200a0.44) were comparable between groups. Changes in subtotal BMD to week 48 were: +9.2 with RAL vs. −7 g/cm2 with TDF/FTC (pu200a=u200a0.002). Mean CTX changes were +0.04 vs. +0.24 ng/mL (pu200a=u200a0.001), and mean P1NP changes were +3.59 vs. +30.09 ng/mL (pu200a=u200a0.023). BTM changes at week 16 predicted change in BMD by week 48 (Ru200a=u200a−0.394, pu200a=u200a0.003 for CTX; and Ru200a=u200a−0.477, p<0.001 for P1NP). Conclusion The NRTI-sparing regimen RAL+DRV/r did not achieve similar week 48 virologic efficacy compared with TDF/FTC+DRV/r, but was better with regard to markers of bone health. Trial Registration ClinicalTrials.gov NCT 00677300

Prospective Longitudinal Analysis of 2-Hydroxyglutarate Magnetic Resonance Spectroscopy Identifies Broad Clinical Utility for the Management of Patients With IDH-Mutant Glioma

Purpose Proton magnetic resonance spectroscopy (MRS) of the brain can detect 2-hydroxyglutarate (2HG), the oncometabolite produced in neoplasms harboring a mutation in the gene coding for isocitrate dehydrogenase ( IDH). We conducted a prospective longitudinal imaging study to determine whether quantitative assessment of 2HG by MRS could serve as a noninvasive clinical imaging biomarker for IDH-mutated gliomas. Patients and Methods 2HG MRS was performed in 136 patients using point-resolved spectroscopy at 3 T in parallel with standard clinical magnetic resonance imaging and assessment. Data were analyzed in patient cohorts representing the major phases of the glioma clinical course and were further subgrouped by histology and treatment type to evaluate 2HG. Histologic correlations were performed. Results Quantitative 2HG MRS was technically and biologically reproducible. 2HG concentration > 1 mM could be reliably detected with high confidence. During the period of indolent disease, 2HG concentration varied by less than ± 1 mM, and it increased sharply with tumor progression. 2HG concentration was positively correlated with tumor cellularity and significantly differed between high- and lower-grade gliomas. In response to cytotoxic therapy, 2HG concentration decreased rapidly in 1p/19q codeleted oligodendrogliomas and with a slower time course in astrocytomas and mixed gliomas. The magnitude and time course of the decrease in 2HG concentration and magnitude of the decrease in tumor volume did not differ between oligodendrogliomas treated with temozolomide or carmustine. Criteria for 2HG MRS were established to make a presumptive molecular diagnosis of an IDH mutation in gliomas technically unable to undergo a surgical procedure. Conclusion 2HG concentration as measured by MRS was reproducible and reliably reflected the disease state. These data provide a basis for incorporating 2HG MRS into clinical management of IDH-mutated gliomas.

Prompt administration of antibiotics is associated with improved outcomes in febrile neutropenia in children with cancer

Time‐to‐antibiotic (TTA) administration is a widely used quality‐of‐care measure for children with cancer and febrile neutropenia (FN). We sought to determine whether TTA is associated with outcomes of FN.

A comparative study of short‐ and long‐TE 1H MRS at 3 T for in vivo detection of 2‐hydroxyglutarate in brain tumors

2‐Hydroxyglutarate (2HG) is produced in gliomas with mutations of isocitrate dehydrogenase (IDH) 1 and 2. The 1H resonances of the J‐coupled spins of 2HG are extensively overlapped with signals from other metabolites. Here, we report a comparative study at 3 T of the utility of the point‐resolved spectroscopy sequence with a standard short TE (35 ms) and a long TE (97 ms), which had been theoretically designed for the detection of the 2HG 2.25‐ppm resonance. The performance of the methods is evaluated using data from phantoms, seven healthy volunteers and 22 subjects with IDH‐mutated gliomas. The results indicate that TEu2009=u200997 ms provides higher detectability of 2HG than TEu2009=u200935 ms, and that this improved capability is gained when data are analyzed with basis spectra that include the effects of the volume localizing radiofrequency and gradient pulses. Copyright

Age does not impact risk for urethroplasty complications after tubularized incised plate repair of hypospadias in prepubertal boys

OBJECTIVEnPatients often present before or after the recommended age of 6-18 months for hypospadias repair. Reports indicate complications may increase when repair is delayed past 6-12 months of age. We questioned if age was an independent risk for urethroplasty complications (UC).nnnMETHODSnA prospectively maintained database of consecutive patients undergoing tubularized incised plate (TIP) repair was queried for age at surgery, primary or reoperative TIP, meatal location, glansplasty suture, and learning curve. The presence of UC (fistula, dehiscence, stricture, meatal stenosis) was analyzed with logistic regression.nnnRESULTSnTIP repairs were performed for 669 consecutive prepubertal patients aged 3-144 months (mean 17.1, SD 22.5). Original meatal location was distal in 540 (80.7%), midshaft in 50 (7.5%), and proximal in 79 (11.8%). Reoperative TIP occurred in 73 (10.9%). UC occurred in 77 (11.5%). Reoperative TIP (OR 3.07, 95% CI 1.54-6.13) and meatal location (OR 1.79, 95% CI 1.34-2.40) were the only independent risk factors for UC. Neither younger nor older age increased risk for UC.nnnCONCLUSIONSnOur data from consecutive TIP repairs in prepubertal children indicate age at surgery does not increase odds of UC. Surgery can be performed any time after 3 months (in full-term, healthy boys) without raising the rate of UC.

Hepatitis C Co-infection and Severity of Liver Disease as Risk Factors for Osteoporotic Fractures Among HIV-Infected Patients

Osteoporosis is increasingly reported in the aging HIV‐positive population, and co‐infection with hepatitis C virus (HCV) may further increase the risk of osteoporosis. However, it remains unclear whether HCV‐related increased fracture risk is a function of the severity of liver disease. We calculated the time‐updated alanine aminotransferase to platelet ratio index (APRI) score (an indirect marker of hepatic fibrosis) in all HIV‐infected patients enrolled in the Veterans Affairs Clinical Case Registry between 1984 and 2009. The association between HCV co‐infection and incident osteoporotic fracture (defined as closed wrist, vertebral, or hip fracture) was assessed in univariate and multivariate Cox survival models adjusting for traditional risk factors for osteoporosis and APRI score or the presence of cirrhosis. A total of 772 osteoporotic fractures were identified among 56,660 HIV‐infected patients (98.1% male; 31.3% HCV co‐infected; median age 44.0 years) contributing 305,237 patient‐years of follow‐up. Fracture rates were significantly higher among HIV/HCV patients than HIV‐only patients (2.57 versus 2.07/1000 patient‐years, relative risku2009=u20091.24, pu2009<u20090.0001). In a Cox multivariable model including age, race, smoking, drug use, body mass index, and antiretroviral therapy, HCV co‐infection remained an independent predictor of osteoporotic fractures after controlling for presence of cirrhosis (hazard ratio [HR]u2009=u20091.32; pu2009<u20090.001) or APRI score (HRu2009=u20091.30; pu2009=u20090.003). Among HIV/HCV co‐infected patients, cirrhosis strongly predicted osteoporotic fractures (HRu2009=u20091.65; 95% confidence interval [CI] 1.11–2.44; pu2009=u20090.012), but APRI score was a weaker predictor (HRu2009=u20091.008; 95% CI 1.002–1.014; pu2009=u20090.015). In conclusion, among HIV‐infected patients, severity of liver disease partly explains the HCV‐associated increased risk of osteoporotic fractures. Other determinants of this increased risk remain to be defined.

Multiple comparison procedures

Problems can arise when researchers try to assess the statistical significance ofmore than 1 test in a study. In a single test, statistical significance isoftendeterminedbasedonanobservedeffector finding that is unlikely (<5%) to occur due to chance alone.Whenmore than 1 comparison is made, the chance of falsely detecting a nonexistent effect increases. This is known as the problem of multiple comparisons (MCs), andadjustments canbemade in statistical testing to account for this.1 In this issue of JAMA, Saitz et al2 report results of a randomized trial evaluating the efficacy of 2brief counseling interventions (ie, a brief negotiated interview and an adaptation of a motivational interview, referred to asMOTIV) in reducing drug use in primary care patients when compared with not having an intervention. Because MCs were made, the authors adjusted how they determined statistical significance. In this article,weexplainwhyadjustmentforMCs isappropriate inthisstudy and point out the limitations, interpretations, and cautions when using these adjustments.

Handheld shape discrimination hyperacuity test on a mobile device for remote monitoring of visual function in maculopathy.

PURPOSEnFrequency monitoring of age-related macular degeneration (AMD) and diabetic retinopathy (DR) is crucial for timely intervention. This study evaluated a handheld shape discrimination hyperacuity (hSDH) test iPhone app designed for visual function self-monitoring in patients with AMD and DR.nnnMETHODSnOne hundred subjects (27 visually normal, 37 with AMD, and 36 with DR) were included based on clinical documentation and visual acuity of 20/100 or better. The hSDH test was implemented on the iOS platform. A cross-sectional study was conducted to compare the hSDH test with a previously established desktop SDH (dSDH) test and to assess the effect of disease severity on the hSDH test. A user survey was also conducted to assess the usability of the hSDH test on the mobile device.nnnRESULTSnThe hSDH test and dSDH test were highly correlated (r = 0.88, P < 0.0001). Bland-Altman analysis indicated no significant difference in hSDH and dSDH measurements. One-way ANOVA indicated that the mean hSDH measurement of the eyes with advanced AMD (n = 16) or with severe to very severe nonproliferative DR (NPDR) (n = 12) was significantly worse than that of the eyes with intermediate AMD (n = 11) or with mild to moderate NPDR (n = 11) (P < 0.0001). Ninety-eight percent of 46 patients (10 with AMD and 36 with DR) who completed the usability survey reported that the hSDH test was easy to use.nnnCONCLUSIONSnThis study demonstrated that the hSDH test on a mobile device is comparable to PC-based testing methods. As a mobile app, it is intuitive to use, readily accessible, and sensitive to the severity of maculopathy. It has the potential to provide patients having maculopathy with a new tool to monitor their vision at home.