HIV Testing in the Nation's Opioid Treatment Programs, 2005–2011: The Role of State Regulations

ObjectiveTo identify the extent to which clients in a national sample of opioid treatment programs (OTPs) received HIV testing in 2005 and 2011; to examine relationships between state laws for informed consent and pretest counseling and rates of HIV testing among OTP clients.Data SourceData were collected from a nationally representative sample of OTPs in 2005 (n = 171) and 2011 (n = 200).Study DesignRandom-effects logit and interval regression analyses were used to examine changes in HIV testing rates and the relationship of state laws to HIV testing among OTPs.Data CollectionData on OTP provision of HIV testing were collected in phone surveys from OTP managers; data also were collected on state laws for HIV testing.Principal FindingsThe percentage of OTPs offering HIV testing decreased significantly from 93 percent in 2005 to 64 percent in 2011. Similarly, the percentage of clients tested decreased from an average of 41 percent in 2005 to 17 percent in 2011. OTPs located in states whose laws do not require pretest counseling and that use opt-out consent were more likely to provide HIV testing and to test higher percentages of clients.ConclusionsThe results show the need to increase HIV testing among OTP clients; the results also underscore the beneficial possibilities of dropping pretest counseling as a requirement for HIV testing and of using the opt-out approach to informed consent for testing.     

Evaluation of 5-(Trifluoromethyl)-1,2,4-oxadiazole-Based Class IIa HDAC Inhibitors for Huntington’s Disease

Using an iterative structure–activity relationship driven approach, we identified a CNS-penetrant 5-(trifluoromethyl)-1,2,4-oxadiazole (TFMO, 12) with a pharmacokinetic profile suitable for probing class IIa histone deacetylase (HDAC) inhibition in vivo. Given the lack of understanding of endogenous class IIa HDAC substrates, we developed a surrogate readout to measure compound effects in vivo, by exploiting the >100-fold selectivity compound 12 exhibits over class I/IIb HDACs. We achieved adequate brain exposure with compound 12 in mice to estimate a class I/IIb deacetylation EC₅₀, using class I substrate H4K12 acetylation and global acetylation levels as a pharmacodynamic readout. We observed excellent correlation between the compound 12 in vivo pharmacodynamic response and in vitro class I/IIb cellular activity. Applying the same relationship to class IIa HDAC inhibition, we estimated the compound 12 dose required to inhibit class IIa HDAC activity, for use in preclinical models of Huntington’s disease.     

Prognostic value of troponins in patients with non-ST-segment elevation acute coronary syndromes and chronic kidney disease

BACKGROUND: The prognostic value of cardiac troponins (cTn) in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) and chronic kidney disease (CKD) is debated. HYPOTHESIS: We tested the performance of cTnI and cTnT for risk stratification in patients with CKD and evaluated the prognostic significance of cTnI and cTnT elevations by their magnitude across the range of CKD severity. METHODS: We examined correlations among cTn elevation, CKD, and in-hospital mortality in 31,586 high-risk patients with NSTE ACS included in the Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association Guidelines initiative (CRUSADE). Cardiac tropinins I and T levels were categorized as ratios of each site's upper limit of normal (ULN) for myocardial necrosis: normal (cTn ratio < or =1 x ULN), mild (cTn ratio > 1-3 x ULN), and major (cTn ratio > 3 x ULN) elevation. Estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease equation. Stages of CKD were categorized as normal to mild (eGFR > 60 mL/min), moderate (eGFR 30-60 mL/min), or severe (eGFR < 30 mL/min). RESULTS: Mortality increased more steeply across CKD stages (2.0%-12.9%) than across cTn ratio categories (2.7%-5.4%). In normal or mild CKD, mortality was low regardless of cTn elevations. In moderate CKD, mortality increased incrementally with cTnI (3.3% versus 5.4% versus 7.4%) and cTnT (3.7% versus 5.3% versus 7.3%) elevation. Among severe CKD patients, only major cTn elevations further distinguished risk (cTnI: 10.1% versus 9.7% versus 14.6%; cTnT: 7.0% versus 5.7% versus 14.0%). CONCLUSIONS: In patients with CKD, cTnI and cTnT perform equally in differentiating short-term prognosis following NSTE ACS; however, the prognostic impact of cTn is dependent upon the degree of CKD severity.     

Salmonellosis Pacifarin Activity of Enterobactin

Salmonellosis pacifarin activity is detected by an increased survivorship of mice, doubly infected with avirulent and virulent Salmonella typhimurium, when heretofore unknown agents, found in certain natural foodstuffs and in the supernatants of certain bacterial cultures, are fed to the infected animals as dietary supplements. We now announce the identity of one of these agents: it is enterobactin, a cyclic trimer of 2,3-dihydroxy-N-benzoyl-L-serine. Basal diets enriched with as little as 2 mg of crystalline trimer per kg of diet show pacifarin activity to a statistically significant degree. Diets supplemented with as much as 100 mg of the monomer per kg of diet show no such activity.     

Lidoflazine and propranolol combination treatment in chronic stable angina

The short-term (1 month) and long-term (6 months) safety of combination lidoflazine-propranolol therapy was investigated in an open trial of 15 patients with stable angina of effort. The possible advantages of adding lidoflazine (titrated to 360 mg daily) to patients having a therapeutic response to propranolol (80-400 mg daily) was also evaluated. Effects on non-invasive indexes of left ventricular function (echocardiography, systolic time intervals, radionuclide ventriculography) and exercise tolerance (treadmill exercise testing) were determined. There was no change in mean resting heart rate with the combination therapy, although one patient developed sinus bradycardia at a rate of 44 and had to have his propranolol dose reduced. Electrocardiographic analysis showed significant prolongation of the QTc intervals on lidoflazine-propranolol therapy compared to propranolol alone, with 3 patients having QTc interval prolongation to above .53 seconds, but there was no evidence of increased arrhythmogenesis with the combination therapy compared to propranolol alone. Left ventricular end-diastolic volume index tended to rise with combination therapy. However, lidoflazine-propranolol therapy did not produce any significant effects on resting ejection fraction determined by M-mode echocardiography or by radionuclide ventriculography. Radionuclide ventriculography determined peak exercise ejection fractions were also not significantly changed with combination therapy compared to propranolol alone. There were only small, insignificant improvements in exercise tolerance with the lidoflazine-propranolol combination treatment compared to propranolol alone. It is concluded that lidoflazine-propranolol combination therapy is generally safe but has the potential of causing serious adverse effects in certain patients, i.e. those with sick sinus disease, prolonged QTc intervals, and severe baseline left ventricular dysfunction, and that caution must be exercised in its use. Furthermore, it would appear that combination therapy provides only slight, if any, improvements in exercise tolerance in patients with chronic stable angina having a therapeutic response to oral propranolol.     

Outcome and prognostic factors for children with supratentorial primitive neuroectodermal tumors treated with carboplatin during radiotherapy: A report from the Children's Oncology Group

Background

Supratentorial PNETs (sPNET) are uncommon embryonal malignancies of the central nervous system whose prognosis has historically been poor. We evaluated the outcome and prognostic factors of children with sPNET treated prospectively on a Children's Oncology Group trial.

Procedure

Following surgery, patients received craniospinal radiotherapy with concurrent carboplatin followed by six months of maintenance chemotherapy with cyclophosphamide and vincristine.

Results

Five‐year overall survival (OS) and progression‐free survival (PFS) for all patients was 58 ± 7% and 48 ± 7%. For patients with pineoblastoma (n = 23), five‐year OS and PFS was 81 ± 9% and 62 ± 11%. Extent of resection but not M‐stage was prognostic. Five‐year OS and PFS for 37 patients with non‐pineal tumors (NPsPNET) was 44 ± 8% and 39 ± 8%, significantly worse than for PB (P = 0.055 and 0.009 respectively). Extent of resection and major radiotherapy deviations were prognostic. Five year OS was 59 +/? 11.4% for those undergoing complete resection versus 10.4 +/? 7% for those who did not (P = 0.017). Central pathologic review called 14 (38%) “classic” sPNET, 8 (22%) “undifferentiated” and 13 (35%) “malignant gliomas.” There was no significant difference between the subgroups, although survival distributions approached significance when the combined “classic” and “undifferentiated” group was compared to the “malignant gliomas.”

Conclusions

Carboplatin during RT followed by 6 months of non‐intensive chemotherapy is a feasible treatment strategy for patients with sPNET. Aggressive surgical resection should be attempted if feasible. The classification of supratentorial small cell malignancies can be difficult. Pediatr Blood Cancer 2015;62:776–783. © 2015 Wiley Periodicals, Inc.