Modelling of an intersubband quantum confined Stark effect in Ge quantum wells for mid-infrared photonics.

In this work we theoretically investigate quantum confined Stark effect of intersubband transitions in asymmetric Ge/SiGe quantum wells for intensity modulation in the mid-infrared. Our calculations show that extinction ratios up to 1 dB and modulation speeds of several tens of GHz could be obtained in 100 µm long waveguides.

Methadone Matters: What the United States Can Learn from the Global Effort to Treat Opioid Addiction.

In the midst of an opioid epidemic, mortality related to opioid overdose continues to rise in the US. Medications to treat opioid use disorder, including methadone and buprenorphine, are highly effective in reducing the morbidity and mortality related to illicit opioid use. Despite the efficacy of these life-saving medications, the majority of people with an opioid use disorder lack access to treatment. This paper briefly reviews the evidence to support the use of medications to treat opioid use disorder with a specific focus on methadone. We discuss the current state of methadone therapy for the treatment of opioid use disorder in the US and present logistical barriers that limit its use. Next, we examine three international pharmacy-based models in which methadone dispensing to treat opioid use disorder occurs outside of an opioid treatment facility. We discuss current challenges and opportunities to incorporate similar methods of methadone dispensing for the treatment of opioid use disorder in the US. Finally, we present our vision to integrate pharmacy-based methadone dispensing into routine opioid use disorder treatment through collaboration between clinicians and pharmacies to improve local access to this life-saving medication.

Prediction of Future Chronic Opioid Use Among Hospitalized Patients.

BACKGROUND: Opioids are commonly prescribed in the hospital; yet, little is known about which patients will progress to chronic opioid therapy (COT) following discharge. We defined COT as receipt of ≥ 90-day supply of opioids with < 30-day gap in supply over a 180-day period or receipt of ≥ 10 opioid prescriptions over 1 year. Predictive tools to identify hospitalized patients at risk for future chronic opioid use could have clinical utility to improve pain management strategies and patient education during hospitalization and discharge. OBJECTIVE: The objective of this study was to identify a parsimonious statistical model for predicting future COT among hospitalized patients not on COT before hospitalization. DESIGN: Retrospective analysis electronic health record (EHR) data from 2008 to 2014 using logistic regression. PATIENTS: Hospitalized patients at an urban, safety net hospital. MAIN MEASUREMENTS: Independent variables included medical and mental health diagnoses, substance and tobacco use disorder, chronic or acute pain, surgical intervention during hospitalization, past year receipt of opioid or non-opioid analgesics or benzodiazepines, opioid receipt at hospital discharge, milligrams of morphine equivalents prescribed per hospital day, and others. KEY RESULTS: Model prediction performance was estimated using area under the receiver operator curve, accuracy, sensitivity, and specificity. A model with 13 covariates was chosen using stepwise logistic regression on a randomly down-sampled subset of the data. Sensitivity and specificity were optimized using the Youden's index. This model predicted correctly COT in 79% of the patients and no COT correctly in 78% of the patients. CONCLUSIONS: Our model accessed EHR data to predict 79% of the future COT among hospitalized patients. Application of such a predictive model within the EHR could identify patients at high risk for future chronic opioid use to allow clinicians to provide early patient education about pain management strategies and, when able, to wean opioids prior to discharge while incorporating alternative therapies for pain into discharge planning.

Ability of peripheral blood mononuclear cells to activate interferon response in vitro is predictive of virological response in HCV patients.

The most reliable predictor of treatment efficacy in hepatitis C is HCV viremia decay at week 12 [early virological response (EVR)]. We investigated whether the ability of peripheral blood mononuclear cells (PBMC) to mount an interferon (IFN) response in vitro could be predictive of EVR. Fifteen patients treated with PEG IFNalpha + RBV, with pre-therapy frozen PBMC, were retrospectively selected. After a 3 hr PBMC exposure to IFNalpha in vitro, up-regulation of mRNA for IFN-stimulated genes (ISG) was measured by membrane super-array. ISG mRNA levels in unstimulated PBMC were low, but beta2M and CASP1 were significantly higher in EVR vs non-EVR. ISG mRNA up-regulation by IFN was more pronounced in EVR vs non-EVR. For 7 genes (IP-10, IFIT1, IFIT2, IFIT3, TRAIL, KIAA1628 and OAS2) cut-off levels were established, by ROC analysis, able to correctly classify all EVR and non-EVR. Early virological response to PEG IFNalpha +RBV is correlated with the pre-therapy ability of PBMC to activate an IFN response in vitro. If validated in a wider cohort of patients, the ability of this set of ISG to discriminate between EVR and non-EVR may be useful for pre-therapy evaluation, particularly in patients with unfavourable combinations of conventional response predictors.

Trends in intentional abuse or misuse of benzodiazepines and opioid analgesics and the associated mortality reported to poison centers across the United States from 2000 to 2014.

CONTEXT: Prior works demonstrates an increased risk of death when opioid analgesics and benzodiazepines are used concomitantly to gain a high. Using poison center data, we described trends in abuse or misuse of benzodiazepines and opioid analgesics. We quantified mortality risk associated with abuse or misuse of benzodiazepines, opioid analgesics and the combination of opioid analgesics and benzodiazepines. METHODS: This was a retrospective chart review of data from the National Poison Data System which collects information from 55 poison centers located across the United States. We identified reported cases of "intentional abuse or misuse" of benzodiazepine and/or opioid analgesic exposures. Poisson regression was used to compare the number of cases from each year between 2001 and 2014 to the year 2000. Logistic regression was used to determine whether cases exposed to both benzodiazepines and opioids had greater odds of death relative to cases exposed to opioid analgesics alone. RESULTS: From 2000 to 2014, there were 125,485 benzodiazepine exposures and 84,627 opioid exposures among "intentional abuse or misuse" cases. Of the benzodiazepine exposures, 17.3% (n = 21,660) also involved an opioid. In 2010, exposures involving both opioids and benzodiazepines were 4.26-fold (95% CI: 3.87-4.70; p < .001) higher than in 2000. The risk of death was 1.55 (95% CI: 1.01-2.37; p = .04) times greater among those who used both an opioid and a benzodiazepine compared to opioids alone. This association held after adjusting for gender and age. CONCLUSION: Intentional abuse or misuse of benzodiazepines and opioids in combination increased significantly from 2000 to 2014. Benzodiazepine abuse or misuse far exceeded cases of opioid abuse or misuse. Death was greater with co-abuse or misuse of benzodiazepines and opioids. Population-level campaigns to inform the public about the risk of death with co-abuse or misuse of benzodiazepines and opioids are urgently needed to address this overdose epidemic.

Comparative analysis of total and integrated HIV-1 DNA in peripheral CD4 lymphocytes and monocytes after long treatment with HAART.

OBJECTIVE: To determine the level of total and integrated HIV-1 DNA load in CD4 lymphocytes and monocytes of patients undergoing HAART treatment for at least 2 years. METHODS: CD4 lymphocytes were isolated by subjecting monocyte-depleted blood samples to immune-purging carried out with M-450 Dynabeads. Monocytes were separated by blood through a combined procedure of cell adherence to dishes and complement induced immune lysis with anti-CD3 Mab. HIV DNA in CD4 lymphocytes and monocytes was quantified by polymerase chain reaction (PCR) based limit dilution assay with two PCR protocols, specific for total (LTR PCR) and integrated (Alu PCR) forms of HIV DNA. The replication competence of the provirus harboured in monocyte-depleted peripheral blood mononuclear cells (PBMC) and adherent monocytes was assayed by measuring HIV-1 p24 antigen produced by in-vitro cultures established with these cells. RESULTS: The CD4 lymphocytes of all patients contained a consistent number of HIV DNA copies. Most patients were also positive for HIV DNA in monocytes. The Alu PCR analysis detected, integrated provirus in CD4 lymphocytes of 9 patients and in the monocytes of only three. Four patients had replication-competence virus in their PBL. The monocytes of all patients did not produce virus in vitro. CONCLUSION: The HIV infection of CD4 lymphocytes and monocytes is maintained even after HAART related, apparent, and durable suppression of viral replication. We suggest that the viral persistent infection of monocytes may play a role in maintaining the residual HIV activity found in patients undergoing HAART.

Dynamics of viral load in plasma and HIV DNA in lymphocytes during highly active antiretroviral therapy (HAART): high viral burden in macrophages after 1 year of treatment.

In this study we evaluated the level of HIV RNA in plasma and HIV DNA in peripheral blood cells. Sixteen antiretroviral-experienced HIV patients with severe immune suppression were included in the study. After the first month, 56.2% of the patients showed undetectable levels of HIV RNA, this percentage remaining stable after 1 year (53.3%). At enrollment, 7 patients (43.7%) with a low CD4+ T cell count (mean 22 per mm3 versus 73) showed HIV DNA levels below the limit of detection (5 copies/10(5)) in lymphocytes. They all subsequently had increased HIV DNA that became detectable between the first and the third month of therapy, associated with an increase of the CD4+ T cell count (mean 22 to 95/mm3); in 4 of these patients this increase was transitory, becoming undetectable again after one year. In 7 out of the 8 patients with detectable HIV DNA at enrollment, the HIV DNA level decreased over time. Seven out of 15 patients at 1 year (46.7%) showed both undetectable levels of HIV RNA in plasma and HIV DNA in lymphocytes (p<0.05); these patients had a higher CD4+ T cell count at baseline (mean 75 versus 25/mm3) and a higher increase (306 versus 177/mm3) after 1 year. PCR-based dilution assay carried out at 1 year showed that all patients had a consistent amount of HIV DNA positive- CD4+ T lymphocytes and macrophages, with higher values in these last cells. The data indicate that a durable reservoir of virus is still present in both lymphocytes and monocytes, even after long-lasting HAART treatment.

Clinicopathological findings in five cats with paw calcification.

This retrospective study describes the clinicopathological findings in five cats with soft tissue mineralisation of interdigital spaces and footpads. Paw disease was the reason for veterinary consultation in three out of five cats. All cats had laboratory findings suggestive of renal failure and high solubility product [calciumxphosphorus]. In all cases, cytological examination of paw lesions was suggestive of calcinosis. The results of our study agree with two previous case reports of paw calcification in the cat, suggesting a metastatic pathogenesis and a correlation between paw mineralisation and renal failure.

Virological characterization of patients treated early is able to control HIV-1 replication after multiple cycles of structured therapy interruption.

This study aimed to define clinical and virological parameters associated with spontaneous control of HIV replication in patients having initiated HAART during primary HIV infection, who underwent structured therapy interruption by two protocols with either fixed or HIV viremia-guided scheme. At the end of the protocol all patients were changed to viremia-guided scheme and observed for 12 months (follow-up). Patients maintaining HIV viremia below the indications for resumption of HAART during the follow-up, were defined controllers, those who had to resume HAART were defined non-controllers. The following parameters were examined: pre-interruption therapy duration, CD4(+), HIV RNA, proviral DNA, evolution of viral quasispecies. No specific advantage was conferred by either interruption of structured therapy in the proportion of controllers and non-controllers. Pre-HAART and zenith CD4(+), pre-therapy interruption, HAART duration, but not pre-HAART HIV RNA, were significantly higher in controllers as compared to non-controllers. HIV RNA levels after the first interruption cycle of therapy were significantly lower in controllers than in non-controllers. Proviral DNA levels were also lower in controllers at this time point. HIV RNA and proviral DNA levels associated with the last interruption of therapy cycle were not different from those associated with the first cycle, and, in spite of multiple waves of virus rebound, very few gag quasispecies variants emerged in each patient. The data suggest that pre-treatment clinical parameters and virological events associated with the first viral rebound are crucial factors in determining the ability to control viral replication after multiple cycles of interruption of treatment.

Bcl-2 inhibits the caspase-dependent apoptosis induced by SARS-CoV without affecting virus replication kinetics.

Vero cells transfected with either neo- or bcl-2-plasmid were infected with SARS-CoV at a high multiplicity of infection. Apoptosis appeared after the onset of CPE and completion of virus replication, and could be prevented by Bcl-2 expression. Apoptosis is likely mediated by the mitochondrial pathway, as demonstrated by its inhibition using Bcl-2, and by the activation of the caspase cascade, resulting in PARP cleavage. Prevention of apoptosis did not affect susceptibility to infection, kinetics and extent of viral replication and release, thus implying that apoptosis is not involved in facilitating release and/or dissemination of SARS-CoV in Vero cells.

Cervicovaginal shedding of TT virus in HIV-infected women.

OBJECTIVE: TT virus (TTV) is frequently detected in the serum and in other body fluids of humans. Recently TTV-specific deoxyribonucleic acid has been detected in cervical specimens from apparently healthy women and in seminal fluid, suggesting that sexual transmission may be common. STUDY DESIGN/METHODS: TT virus-deoxyribonucleic acid prevalence was assessed in paired samples of blood and cervical smears from 110 human immunodeficiency virus-positive women. Detection and typing of human papillomavirus (HPV) present in cervical smears was also performed. RESULTS: The prevalence of TTV-deoxyribonucleic acid in cervical smears was 16.4%, without significant difference (p = 0.81) between HPV-positive (18.6%) and -negative (14.9%) samples. The distribution of high/middle and low-risk HPV types was similar in TTV-positive and -negative samples. On the contrary, women with multiple HPV infections had a significantly higher TTV-deoxyribonucleic acid prevalence (60.0%) than HPV-negative women (p = 0.04). CONCLUSIONS: TT virus excretion in the female genital tract of human immunodeficiency virus-infected women is common, further supporting sexual transmission of this virus.

Weight bearing as a measure of disease progression and efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis.

OBJECTIVE: To describe an in vivo model in the rat in which change in weight distribution is used as a measure of disease progression and efficacy of acetaminophen and two nonsteroidal anti-inflammatory drugs (NSAIDs) in a model of monosodium iodoacetate (MIA)-induced osteoarthritis (OA). METHODS: Intra-articular injections of MIA and saline were administered to male Wistar rats (175-200 g) into the right and left knee joints, respectively. Changes in hind paw weight distribution between the right (osteoarthritic) and left (contralateral control) limbs were utilized as an index of joint discomfort. Acetaminophen and two archetypal, orally administered NSAIDs, naproxen and rofecoxib, were examined for their ability to decrease MIA-induced change in weight distribution. RESULTS: A concentration-dependent increase in change in hind paw weight distribution was noted after intra-articular injection of MIA. Both naproxen and rofecoxib demonstrated the capacity to significantly (P<0.05) decrease hind paw weight distribution in a dose-dependent fashion, indicating that the change in weight distribution associated with MIA injection is susceptible to pharmacological intervention. CONCLUSION: The determination of differences in hind paw weight distribution in the rat MIA model of OA is a technically straightforward, reproducible method that is predictive of the effects of anti-inflammatory and analgesic agents. This system may be useful for the discovery of novel pharmacologic agents in human OA.