From amorphous to nanocrystalline: the effect of nanograins in an amorphous matrix on the thermal conductivity of hot-wire chemical-vapor deposited silicon films.

We have measured the thermal conductivity of amorphous and nanocrystalline silicon films with varying crystalline content from 85 K to room temperature. The films were prepared by the hot-wire chemical-vapor deposition, where the crystalline volume fraction is determined by the hydrogen (H2) dilution ratio to the processing silane gas (SiH4), R = H2/SiH4. We varied R from 1 to 10, where the films transform from amorphous for R < 3 to mostly nanocrystalline for larger R. Structural analyses show that the nanograins, averaging from 2 to 9 nm in sizes with increasing R, are dispersed in the amorphous matrix. The crystalline volume fraction increases from 0 to 65% as R increases from 1 to 10. The thermal conductivities of the two amorphous silicon films are similar and consistent with the most previous reports with thicknesses no larger than a few µm deposited by a variety of techniques. The thermal conductivities of the three nanocrystalline silicon films are also similar, but are about 50-70% higher than those of their amorphous counterparts. The heat conduction in nanocrystalline silicon films can be understood as the combined contribution in both amorphous and nanocrystalline phases, where increased conduction through improved nanocrystalline percolation path outweighs increased interface scattering between silicon nanocrystals and the amorphous matrix.

Draft Genome Sequences of Eight Crimean-Congo Hemorrhagic Fever Virus Strains.

Crimean-Congo hemorrhagic fever virus (CCHFV) is a geographically widespread RNA virus with a high degree of genomic diversity that complicates sequence-based diagnostics. Here, we sequenced eight CCHFV strains for improved assay design and deposition into FDA-ARGOS, the FDA's pathogen database for development and verification of next generation sequencing assays.

Detection of Lyme disease and anaplasmosis pathogens via PCR in Pennsylvania deer ked.

Borrelia burgdorferi and Anaplasma phagocytophilum are obligate intracellular parasites that maintain their life cycles in enzoonotic vector-host cycles with Ixodes scapularis as a vector. In addition to ticks, the hosts are commonly infested with insects from the Hippoboscidae family. This study confirms the presence of B. burgdorferi and A. phagocytophilum in deer keds (Lipoptena cervi) removed from white-tailed deer using PCR. Detection of these pathogens in deer ked represents a potential novel susceptibility of wildlife and also suggests the risk of transmission of these pathogens to humans and animals alike through the bite of an infected ectoparasite. This study represents the first instance in the U.S. of detection of tick-borne pathogens in a member of the Hippoboscid family.

Anaemia in elective orthopaedic surgery - Royal Adelaide Hospital, Australia.

BACKGROUND: An anaemia clinic was established to improve the preoperative management of elective orthopaedic patients scheduled for arthroplasty. This paper is a report on the first 100 patients assessed. AIM: To assess the incidence and causes of anaemia in patients on a waiting list for elective arthroplasty in a public hospital and to assess the impact of anaemia detection in this patient population. METHODS: Patients attending an Anaemia Clinic for elective orthopaedic surgical patients, during March 2010 to June 2013 were studied. Outcome measures included change in haemoglobin preoperative results and perioperative transfusion rates by preoperative haemoglobin. RESULTS: Seventeen per cent of patients scheduled for elective surgery were found to be anaemic. Of the 100 patients who attended, approximately half were found to be iron deficient and the remainder had anaemia of chronic disease. Serum ferritin <30 µg/L alone did not identify iron deficiency in 80% of patients with iron deficiency. Patients with iron deficient anaemia were able to be treated, in all cases, to achieve a significant increase in preoperative haemoglobin. The general unavailability of erythropoietin limited effective intervention for the non-iron-deficient anaemic patients. Seven patients had their surgery cancelled because of the screening programme. CONCLUSIONS: Half of the anaemic patients in a joint replacement screening clinic were iron deficient, and treatment was effective in improving the pre-operative haemoglobin and reducing perioperative transfusion rates. This screening process should improve patient outcome. Another important finding in this group of patients is that ferritin levels cannot be reliably used as the sole indicator in the diagnosis of iron deficiency anaemia in this group of patients undergoing elective arthroplasty.

Investigation of the interactions between methadone and elvitegravir-cobicistat in subjects receiving chronic methadone maintenance.

Interactions between HIV and opioid dependence therapies are known to occur. We sought to determine if such interactions occurred between methadone and elvitegravir boosted with cobicistat (EVG/COBI). We performed a within-subject open-label pharmacokinetic and pharmacodynamic study of 11 HIV-seronegative subjects stabilized on at least 2 weeks of methadone. Subjects underwent baseline and steady-state evaluation of the effect of elvitegravir 150 mg once a day (QD) boosted with 150 mg QD of cobicistat (EVG/COBI) on methadone pharmacokinetic parameters. Safety and pharmacodynamics were monitored throughout the study. Compared to baseline values, the R-methadone mean area under the concentration-time curve to the end of the dosing period (AUCtau) (5,550 versus 6,210 h · ng/ml) and mean maximum concentration of drug in serum (Cmax) (316 versus 337 ng/ml) did not significantly increase in the presence of EVG/COBI. Compared to baseline values, the S-methadone mean AUCtau (7,040 versus 7,540 h · ng/ml) and mean Cmax (446 versus 452 ng/ml) did not significantly increase in the presence of EVG/COBI. The AUCtau, Cmax, and Ctau of elvitegravir and cobicistat did not significantly differ from those of historical controls. Opioid withdrawal or overdose was not observed among subjects in this study. The addition of EVG/COBI to stabilized patients receiving methadone did not affect methadone pharmacokinetics and pharmacodynamics. These two agents can be safely coadministered.

Pharmacokinetics and pharmacodynamics of GS-9350: a novel pharmacokinetic enhancer without anti-HIV activity.

GS-9350 is a new chemical entity under development as a potent, mechanism-based inhibitor of human cytochrome P450 3A (CYP3A) isoforms. Its intended use is to increase the systemic exposure of coadministered agents that are metabolized by CYP3A enzymes. Unlike ritonavir, which is in current clinical use for this purpose, GS-9350 is devoid of anti-HIV activity. The pharmacokinetics of GS-9350 and its efficacy in increasing systemic exposure of the probe CYP3A substrate midazolam were examined in a study involving single- and multiple-dose escalations of GS-9350 from 50 to 400 mg. Single-dose escalation from 50 to 400 mg resulted in a 164-fold increase in GS-9350 exposure, whereas multiple-dose escalation in the dosage range of 50-300 mg resulted in a 47-fold increase in exposure. GS-9350 potently inhibited midazolam apparent clearance (95% reduction), similar in effect to ritonavir 100 mg. GS-9350 was generally well tolerated at all doses, and there was no evidence of dose-limiting toxicity. Establishing proof-of-concept, GS-9350 is currently under phase II development as a potential alternative to ritonavir for use with antiretroviral agents (including the HIV integrase inhibitor elvitegravir) that are often prescribed along with a "booster" drug.

Dose-response of ritonavir on hepatic CYP3A activity and elvitegravir oral exposure.

Ritonavir, a potent inhibitor of cytochrome P450 isoform 3A (CYP3A) activity, is frequently used to boost the effects of protease inhibitors at doses of 100-400 mg per day; however, human data regarding the optimal dose required for boosting are limited. This study systematically evaluated the ritonavir dose-response relationship on presystemic and systemic CYP3A metabolism using the human immunodeficiency virus integrase inhibitor elvitegravir and midazolam as probe substrates. Ritonavir administered once daily with elvitegravir exhibited nonlinear pharmacokinetics, with a 119-fold increase in the area under the plasma concentration-time curve over the dosing interval over a 20- to 200-mg dose range. The 20-mg dose of ritonavir substantially reduced CYP3A-mediated clearance (CL), as evidenced by a 66% reduction in midazolam CL that plateaued to 17% of baseline activity at a 100-mg dose. Maximum inhibition of elvitegravir apparent oral CL was achieved with ritonavir doses of 50-100 mg. Elvitegravir and ritonavir were generally well tolerated in this study. These data provide a critical understanding of ritonavir's dose-response relationship for inhibition of CYP3A activity in humans.

Pharmacokinetic study of tenofovir disoproxil fumarate combined with rifampin in healthy volunteers.

Tenofovir disoproxil fumarate (tenofovir DF) was studied in combination with rifampin in 24 healthy subjects in a multiple-dose, open-label, single-group, two-period study. All subjects were given tenofovir DF at 300 mg once a day (QD) from days 1 to 10 (period 1). From days 11 to 20 the subjects received tenofovir DF at 300 mg combined with rifampin at 600 mg QD (period 2). The multiple-dose pharmacokinetics of tenofovir (day 10 and 20) and rifampin (day 20) were assessed. The drug-related adverse events (AEs) experienced during this study were mostly mild. Only one grade 3 AE possibly or probably related to the treatment (raised liver enzyme levels) occurred during period 2; the subject was withdrawn from the study. Pharmacokinetic data for 23 subjects were thus evaluable. Point estimates for the mean ratios of tenofovir with rifampin versus tenofovir alone for the area under the concentration-time curve from time zero to 24 h (AUC(0-24)), the maximum concentration of drug in plasma (C(max)), and the minimum concentration of drug in plasma (C(min)) were 0.88, 0.84, and 0.85, respectively. The 90% classical confidence intervals for AUC(0-24), C(max), and C(min) were 0.84 to 0.92, 0.78 to 0.90, and 0.80 to 0.91, respectively, thus suggesting pharmacokinetic equivalence. Similarly, coadministration of rifampin and tenofovir DF did not result in changes in the values of the tenofovir pharmacokinetic parameters. For rifampin, the values of the pharmacokinetic parameters found in this study were comparable to those found in the literature, indicating that tenofovir DF has no effect on the pharmacokinetics of rifampin. In conclusion, adaptation of either the rifampin or the tenofovir DF dose for the simultaneous treatment of tuberculosis and human immunodeficiency virus (HIV) infection in HIV-infected patients is probably not required.

Combined heart-kidney transplantation with single-donor allografts.

OBJECTIVES: Combined heart-kidney transplantation with allografts from the same donor has been long proved to be a feasible approach for selected patients with coexisting end-stage cardiomyopathy and renal disease. The purpose of this retrospective study is to analyze our long-term results and compare these results with heart-only transplantation over a 7-year period. METHODS: Between June 1992 and April 1999, 10 patients underwent combined heart-kidney transplantation at Cedars-Sinai Medical Center. They were all men from 44 to 70 years old (mean age, 59 +/- 8.3 years) who had a mean left ventricular ejection fraction of 19.4% +/- 5.0% (range, 9%-25%) and a mean creatinine clearance of 25.4 mL/min (range, 10-39 mL/min). Four patients underwent pretransplantation dialysis. RESULTS: There was no operative mortality. The actuarial survival at 1, 2, and 5 years was 100%, 88% +/- 11.7%, and 55% +/- 20.1%, respectively. By comparison, the operative mortality of 169 patients who underwent heart-only transplantation during the same time interval was 2.4%, with an actuarial survival at 1, 2, and 5 years of 92% +/- 2.1%, 84% +/- 2.8%, and 71% +/- 3.9%, respectively (P =.37). Eight patients showed no evidence of significant (> or =1B) cardiac allograft rejection postoperatively, and the actuarial freedom from rejection at 30 days, 1 year, and 2 years was 90% +/- 9%, 80% +/- 13%, and 80% +/- 13%, respectively. Renal allograft survival was 90% at 1 and 2 years. CONCLUSIONS: Combined heart-kidney transplantation yields satisfactory long-term results similar to those for heart-only transplantation, with a low incidence of cardiac allograft rejection and renal allograft survival when both allografts are from the same donor. This approach effectively expands the selection criteria for heart-only and kidney-only transplantation in potential candidates with coexisting end-stage cardiac and renal disease.

Phase i/ii trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults.

Tenofovir DF is an antiviral nucleotide with activity against human immunodeficiency virus type 1 (HIV-1). The pharmacokinetics, safety, and activity of oral tenofovir DF in HIV-1-infected adults were evaluated in a randomized, double-blind, placebo-controlled, escalating-dose study of four doses (75, 150, 300, and 600 mg given once daily). Subjects received a single dose of tenofovir DF or a placebo, followed by a 7-day washout period. Thereafter, subjects received their assigned study drug once daily for 28 days. Pharmacokinetic parameters were dose proportional and demonstrated no change with repeated dosing. Reductions in plasma HIV-1 RNA were dose related at tenofovir DF doses of 75 to 300 mg, but there was no increase in virus suppression between the 300- and 600-mg dose cohorts, despite dose-proportional increases in drug exposure. Grade III or IV adverse events were limited to laboratory abnormalities, including elevated creatine phosphokinase and liver function tests, which resolved with or without drug discontinuation and without sequelae. No patients developed detectable sequence changes in the reverse transcriptase gene.

Pharmacokinetics study of a novel chimeric single-chain variable fragment antibody against western equine encephalitis virus.

A novel recombinant single-chain fragment variable (scFv) antibody against western equine encephalitis (WEE) virus has been previously constructed and partially characterized. The RS10B5huFc antibody was made by fusing an anti-WEE scFv to a human heavy-chain IgG1 constant region. The RS10B5huFc antibody was functional in binding to WEE virus in enzyme-linked immunosorbent assays (ELISAs), and the Fc domain of the antibody was capable of effector functions, such as binding to protein G and human complement. In this study, the RS10B5huFc antibody was further characterized by BIAcore analyses and was found to possess a binding affinity to a WEE virus epitope (K[D] = 9.14 x 10(-6) M), 4.5-fold lower than its parental mouse monoclonal antibody (MAb) 10B5 E7E2 (K[D] = 2 x 10(-6) M). No cross-reactivity was found between the RS10B5huFc antibody and three other alphaviruses (Sindbis virus [SIN], Venezuelan equine encephalitis [VEE] virus, and eastern equine encephalitis [EEE] virus). Pharmacokinetics studies showed that the RS10B5huFc antibody (free and encapsulated) was found to be retained in the lungs of mice for greater than 48 h when administered intranasally. In contrast, when administered intramuscularly to mice, the RS10B5huFc antibody was not detected in the lungs and only found in the liver and kidneys.

An LC-MS-MS method for the determination of indinavir, an HIV-1 protease inhibitor, in human plasma.

A method for the determination of indinavir (IDV) (L-735 524) in human plasma by LC-MS-MS is discussed, and the validation data is presented. The analyte and internal standard are isolated from plasma by a simple acetonitrile precipitation of plasma proteins followed by centrifugation. LC-tandem mass spectrometry in positive ion, multiple reaction monitoring mode used pairs of ions at m/z of 614/421 for indinavir and 628/421 for internal standard, respectively. The calibration curve had a linear range from 3.0 to 12320 ng/ml when linear least square regression weighing 1/x was applied to the concentration versus peak area plot. The advantages of this method are the fast sample preparation, wide dynamic assay range and quick analysis taking only 5 min for each sample run. The robust nature of this assay has been further verified during routine use over several months involving multiple analysts.

Heart transplantation in patients seventy years of age and older: A comparative analysis of outcome.

OBJECTIVE: Advanced age has traditionally been considered a contraindication for heart transplantation because of the reported adverse effect of increased age on long-term survival. However, as the field of transplantation continues to evolve, the criteria regarding the recipient's upper age limit have been expanded and older patients are being considered as potential candidates. We analyzed the outcome of heart transplantation in patients 70 years of age and older and compared these results with those in younger patients (<70 years) over a 4-year period. METHOD: We retrospectively analyzed the results of 15 patients 70 years of age and older who underwent heart transplantation between November 1994 and May 1999 and compared them with results in 98 younger patients undergoing transplantation during the same period RESULTS: The older age group had a higher preoperative left ventricular ejection fraction (P =.02), higher incidence of female donors (P =.02), and longer cardiac allograft ischemic time (P =.01). No differences were found regarding incidence of diabetes mellitus, donor age, donor/recipient weight ratio, and mismatch (<0.80). The 30-day or to-discharge operative mortality was similar in both groups (0% in the older vs 5.1% in younger patients). Actuarial survival at 1 year and 4 years was not statistically different between the older and younger patients (93.3% +/- 6.4% vs 88.3% +/- 3.3% and 73.5% +/- 13.6% vs 69.1% +/- 5.8%, respectively). The length of intensive care unit stay and total post-transplantation hospital stay, incidence of rejection, and incidence of cytomegalovirus infection were similar between the groups. CONCLUSIONS: Heart transplantation in selected patients 70 years of age and older can be performed as successfully as in younger patients (<70 years of age) with similar morbidity, mortality, and intermediate-term survival. Advanced age as defined (> or =70 years) should not be an exclusion criterion for heart transplantation. The risks and benefits of transplant surgery should be applied individually in a selective fashion.

Evaluation of a commercial enzyme-linked immunosorbent assay for detection of Borrelia burgdorferi exposure in dogs.

OBJECTIVE: To evaluate the effectiveness of a commercially available ELISA kit for detecting antibodies against Borrelia burgdorferi in dogs. SAMPLE POPULATION: Banked sera from 440 military working dogs were used for serologic analyses. PROCEDURE: Serum samples were analyzed for antibodies against B burgdorferi by use of a commercially available ELISA and subsequently by western blot analysis as a confirmatory test. RESULTS: Results from the ELISA indicated that 89 (20%) samples were positive for exposure to B burgdorferi or canine Lyme disease vaccine, and 351 (80%) were negative. Follow-up testing by western blot analysis indicated that results for 109 (25%) samples were positive and 331 (75%) were negative for exposure. All samples that had positive results on the ELISA also had positive results on western blot analysis (true positives). Of the 351 samples that had negative results on the ELISA, only 331 had negative results on western blot analysis (true negatives). The remaining 20 samples had positive results on western blot analysis. By use of a standard 2 x 2 table, it was determined that the ELISA had a sensitivity of 82%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 94%. CONCLUSIONS AND CLINICAL RELEVANCE: The commercial ELISA kit evaluated in this study appeared to lack adequate sensitivity for detecting all potential cases of borreliosis in dogs. The ELISA was also unable to discriminate natural exposure from exposure attributable to vaccination, which could complicate interpretation of positive results and treatment of dogs with clinical signs.

Unbalanced translocation t(15;22) in "severe" Prader-Willi syndrome.

A 13-year-old girl with an unbalanced karyotype 45,XX,-15,der(22)t(15;22)(q13;q13.3) de novo had Prader-Willi syndrome (PWS), (score 13.5), but with features of mental and physical retardation more severe than usually seen in PWS. The clinical diagnosis of PWS was confirmed by methylation analysis that showed absence of the paternal band. With GTG banding, the cytogenetic breakpoint on chromosome 15q13, with 15q14 intact, encompassed the PWS region, while the breakpoint on 22q was terminal. Investigations with FISH utilised ten different probes/combinations, namely SNRPN/PML, TUPLE1/22q13.3, TUPLE/ARSA, GABRB3, three YAC clones and one cosmid for specific regions within chromosome 15q, painting probes for the long arm of chromosomes 15 and 22 and a pantelomere probe. Deletion of SNRPN,TYAC 9 (at 15q11-12), TYAC19 (at 15q13) and GABRB3 (within the PWS locus), was evident on the derivative (22) chromosome, while TYAC10 (at 15q22), cos15-5 (at 15q22) and PML (15q22) were not deleted. On the der(22), 22q13.3 and ARSA were not deleted, but the most distal non specific pantelomeric probe was deleted. Thus, the severe phenotype could be attributable to deletion on chromosome 15q extending beyond q13 to q14, (further than the usual chromosome 15q deletion (q11-13) in PWS), or be related to loss of the very terminal 22q region (from ARSA to the pantelomere) or be due to genetic factors elsewhere in the genome.

The penetration of anti-infectives into the central nervous system.

The blood-brain barrier, blood-cerebrospinal fluid (CSF) barrier, and meninges are a complex and difficult-to-study system charged with protecting the central nervous system (CNS) from toxins, including drugs. Current estimates of CNS drug exposure are limited to CSF to blood ratios, of which area-under-the curve (AUC) estimates provide the most robust measure of drug exposure. Different classes of drugs and individual drugs within classes have different CNS penetration potential that is dependent upon a variety of biologic and pharmacologic factors. Clinical data (AUC and point ratios) regarding the penetration of several anti-infective agents used for the treatment of CNS infections are provided in this article.

Failure to detect nelfinavir in the cerebrospinal fluid of HIV-1--infected patients with and without AIDS dementia complex.

OBJECTIVE: To assess the penetration of the HIV-1 protease inhibitor, nelfinavir, into cerebrospinal fluid (CSF). DESIGN: Nelfinavir, a commonly used HIV-1 protease inhibitor (PI), is highly effective for reducing plasma viral load. It is deployed clinically in combination with other antiretroviral agents, including nucleoside and nonnucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs). Despite its potency based on plasma HIV-1 RNA results, its effectiveness in reducing HIV-1 RNA levels (i.e., viral load) in the central nervous system (CNS) is less certain. We sampled the CSF as a surrogate for brain because this fluid also is separated from the blood by a barrier to free diffusion, the blood-CSF barrier (BCB), which shares properties with the blood-brain barrier (BBB). These studies of nelfinavir CSF pharmacokinetics exploited the multiple CSF samples derived from individual study subjects who were enrolled in studies the primary objective of which was to compare viral kinetics in CSF and blood in response to antiviral therapy. METHODS: Six study subjects, four with and two without AIDS dementia complex, underwent multiple lumbar punctures (LP). Intervals of CSF sampling after drug dosing were varied (from 0.48 hours to 10.3 hours after nelfinavir administration) to quantitate nelfinavir concentrations throughout the steady-state dosing interval. In four study subjects, CSF sampling was accompanied by assessment of nelfinavir levels in plasma before and after LP, whereas in the other two subjects, a single plasma sample was obtained before or after the LP. In total, 25 CSF samples were analyzed. Nelfinavir concentrations in CSF and plasma were determined using an high-performance liquid chromatography (HPLC) method with a limit of quantitation of 25 and 50 ng/ml, respectively. RESULTS: Plasma concentrations before and after LP averaged 2420+/-1365 ng/ml and 2528+/-1132 ng/ml, respectively. Nelfinavir was not detected in any of the CSF samples and levels >25 ng/ml were not present in the CSF. Thus, standard therapy with nelfinavir does not result in CSF drug concentrations at or exceeding the IC95 level for most HIV-1 isolates. However, study subjects with high CSF viral loads experienced a marked reduction in the context of the combination-drug regimen including nelfinavir with two subjects showing a comparable CSF response with that in plasma. CONCLUSIONS: Nelfinavir does not appreciably penetrate into the CSF. The clinical importance of this observation is not certain, in that in four study subjects who initiated nelfinavir in combination with other antiretroviral therapy, a comparable degree of viral suppression was obtained in both the CSF and the blood when sampled 4 weeks or later after initiating therapy.

Performance evaluations of physician executives. Interview by Barbara J. Linney.

Six senior physician executives were interviewed to see how they were doing or not doing performance reviews in their organizations. There seems to be a trend toward doing them, but it is in the beginning stages. Of the physician executives surveyed, the experience ranges from formal lengthy evaluations with rating scales to reviewing a short list of goals. Several are in the process of developing new systems or revising old ones. Probably the most useful part of a performance evaluation is the conversation between the physician executive and the person he or she reports to. If you can stop approaching performance evaluations as passing negative judgments on people, but as having a conversation to hear their concerns, learn what their goals are, and offer ways to help them achieve their potential, they can be useful, enjoyable experiences for both people.