IL-1α and TNF-α Down-Regulate CRH Receptor-2 mRNA Expression in the Mouse Heart

Two receptors (CRH receptor type 1 and CRH receptor type 2) have been identified for the stress-induced neuropeptide, CRH and related peptides, urocortin, and urocortin II. We previously found marked down-regulation of cardiac CRH receptor type 2 expression following administration of bacterial endotoxin, lipopolysaccharide, a model of systemic immune activation, and inflammation. We postulated that inflammatory cytokines may regulate CRH receptor type 2. We show that systemic IL-1α administration significantly down-regulates CRH receptor type 2 mRNA in mouse heart. In addition, TNFα treatment also reduces CRH receptor type 2 mRNA expression, although the effect was not as marked as with IL-1α. However, CRH receptor type 2 mRNA expression is not altered in adult mouse ventricular cardiomyocytes stimulated in vitro with TNFα or IL-1α. Thus, cytokine regulation may be indirect. Exogenous administration of corticosterone in vivo or acute restraint stress also reduces cardiac CRH receptor type 2 mRNA expression, but like cytokines, in vitro corticosterone treatment does not modulate expression in cardiomyocytes. Interestingly, treatment with urocortin significantly decreases CRH receptor type 2 mRNA in cultured cardiomyocytes. We speculate that in vivo, inflammatory mediators such as lipopolysaccharide and/or cytokines may increase urocortin, which in turn down-regulates CRH receptor type 2 expression in the heart. Because CRH and urocortin increase cardiac contractility and coronary blood flow, impaired CRH receptor type 2 function during systemic inflammation may ultimately diminish the adaptive cardiac response to adverse conditions

Remdesivir for the Treatment of COVID-19: A Systematic Review of the Literature

In March 2020, the World Health Organization declared the spread of SARS-CoV-2 a global pandemic. To date, coronavirus disease-2019 (COVID-19) has spread to over 200 countries, leading to over 1.6 million cases and over 99,000 deaths. Given that there is neither a vaccine nor proven treatment for COVID-19, there is currently an urgent need for effective pharmacotherapy. To address the need for an effective treatment of SARS-CoV-2 during the worldwide pandemic, this systematic review of intravenous (IV) remdesivir was performed. Remdesivir, an anti-viral prodrug originally developed to treat Ebola virus disease, has shown broad spectrum activity against the Coronavirus family. A recent case report reported improvement of clinical symptoms with remdesivir in a patient with COVID-19. After conducting a systematic search of 18 clinical trial registries and three large scientific databases, we identified 86 potentially eligible items. Following removal of duplicates (n = 21), eligible studies were reviewed independently by two authors. After the first round of screening, inter-rater agreement was 98.5% (κ = 0.925). After the second round of full-text screening, inter-rater agreement was 100%. A total of seven ongoing and recruiting clinical trials of remdesivir (100-200 milligrams, intravenous [IV]) were included. We identified the following primary outcomes: patients discharged (n = 2); time to clinical status improvement (n = 2); improved O2 saturation (n = 2); body temperature normalization (n = 2); and clinical status (n = 1). Secondary outcomes in all identified studies included documentation of adverse events. Phase 3 trials are expected to be completed between April 2020–2023. Therefore, despite supportive data from in vitro and in vivo studies, the clinical effectiveness of IV remdesivir for treatment of COVID-19 and potential side effects remain incompletely defined in the human population

Results from a Phase 1 Study of Sodium Selenite in Combination with Palliative Radiation Therapy in Patients with Metastatic Cancer.

In preclinical studies, selenite had single agent activity and radiosensitized tumors in vivo. Here we report results from a Phase 1 trial in 15 patients with metastatic cancer treated with selenite (5.5 to 49.5 mg) orally as a single dose 2 hours before each radiation therapy (RT) treatment. Patients received RT regimens that were standard of care. The primary objective of the study was to assess the safety of this combination therapy. Secondary objectives included measurement of pharmacokinetics (PK) and evaluation of efficacy. Endpoints included assessment of PK, toxicity, tumor response, and pain before and after treatment. The half-life of selenite was 18.5 hours. There were no adverse events attributable to selenite until the 33 mg dose level, at which the primary toxicities were grade 1 GI side effects. One patient treated with 49.5 mg had grade 2 GI toxicity. Although this was not a DLT, it was felt that the highest acceptable dose in this patient population was 33 mg. Most patients had stabilization of disease within the RT fields, with some demonstrating objective evidence of tumor regression. Most patients had a marked improvement in pain and seven out of nine patients with prostate cancer had a decrease in PSA ranging from 11-78%. Doses up to 33 mg selenite were well tolerated in combination with RT. A randomized, well controlled study is needed at the 33 mg dose level to determine if selenite results in clinically meaningful improvements in the response to palliative RT

Estimating the effect of moving meat-free products to the meat aisle on sales of meat and meat-free products: A non-randomised controlled intervention study in a large UK supermarket chain

Background Reducing meat consumption could bring health and environmental benefits, but there is little research to date on effective interventions to achieve this. A non-randomised controlled intervention study was used to evaluate whether prominent positioning of meat-free products in the meat aisle was associated with a change in weekly mean sales of meat and meat-free products. Methods and findings Weekly sales data were obtained from 108 stores: 20 intervention stores that moved a selection of 26 meat-free products into a newly created meat-free bay within the meat aisle and 88 matched control stores. The primary outcome analysis used a hierarchical negative binomial model to compare changes in weekly sales (units) of meat products sold in intervention versus control stores during the main intervention period (Phase I: February 2019 to April 2019). Interrupted time series analysis was also used to evaluate the effects of the Phase I intervention. Moreover, 8 of the 20 stores enhanced the intervention from August 2019 onwards (Phase II intervention) by adding a second bay of meat-free products into the meat aisle, which was evaluated following the same analytical methods. During the Phase I intervention, sales of meat products (units/store/week) decreased in intervention (approximately −6%) and control stores (−5%) without significant differences (incidence rate ratio [IRR] 1.01 [95% CI 0.95–1.07]. Sales of meat-free products increased significantly more in the intervention (+31%) compared to the control stores (+6%; IRR 1.43 [95% CI 1.30–1.57]), mostly due to increased sales of meat-free burgers, mince, and sausages. Consistent results were observed in interrupted time series analyses where the effect of the Phase II intervention was significant in intervention versus control stores. Conclusions Prominent positioning of meat-free products into the meat aisle in a supermarket was not effective in reducing sales of meat products, but successfully increased sales of meat-free alternatives in the longer term. A preregistered protocol (https://osf.io/qmz3a/) was completed and fully available before data analysis.</p

Effects of a Tailored Follow-Up Intervention on Health Behaviors, Beliefs, and Attitudes

Background: The high rates of relapse that tend to occur after short-term behavioral interventions indicate the need for maintenance programs that promote long-term adherence to new behavior patterns. Computer-tailored health messages that are mailed to participants or given in brief telephone calls offer an innovative and time-efficient alternative to ongoing face-to-face contact with healthcare providers. Methods: Following a 1-year behavior change program, 22 North Carolina health departments were randomly assigned to a follow-up intervention or control condition. Data were collected from 1999 to 2001 by telephone-administered surveys at preintervention and postintervention for 511 low-income, midlife adult women enrolled in the Well-Integrated Screening and Evaluation for Women Across the Nation (WISEWOMAN) program at local North Carolina health departments. During the year after the behavior change program, intervention participants were mailed six sets of computer-tailored health messages and received two computer-tailored telephone counseling sessions. Main outcomes of dietary and physical activity behaviors, beliefs, and attitudes were measured. Results: Intervention participants were more likely to move forward into more advanced stages of physical activity change (p = 0.02); control participants were more likely to increase their level of dietary social support at follow-up (p = 0.05). Both groups maintained low levels of reported saturated fat and cholesterol intake at follow-up. No changes were seen in physical activity in either group. Conclusions: Mailed computer-tailored health messages and telephone counseling calls favorably modified forward physical activity stage movement but did not appreciably affect any other psychosocial or behavioral outcomes

Characterization of electrospun nanocomposite scaffolds and biocompatibility with adipose-derived human mesenchymal stem cells

Electrospun nanocomposite scaffolds were fabricated by encapsulating multi-walled carbon nanotubes (MWNT) in poly (lactic acid) (PLA) nanofibers. Scanning electron microscopy (SEM) confirmed the fabrication of nanofibers, and transmission electron microscopy identified the alignment and dispersion of MWNT along the axis of the fibers. Tensile testing showed an increase in the tensile modulus for a MWNT loading of 0.25 wt% compared with electrospun nanofibrous mats without MWNT reinforcement. Conductivity measurements indicated that the confined geometry of the fibrous system requires only minute doping to obtain significant enhancements at 0.32 wt%. Adipose-derived human mesenchymal stem cells (hMSCs) were seeded on electrospun scaffolds containing 1 wt% MWNT and 0 wt% MWNT, to determine the efficacy of the scaffolds for cell growth, and the effect of MWNT on hMSC viability and proliferation over two weeks in culture. Staining for live and dead cells and DNA quantification indicated that the hMSCs were alive and proliferating through day 14. SEM images of hMSCs at 14 days showed morphological differences, with hMSCs on PLA well spread and hMSCs on PLA with 1% MWNT closely packed and longitudinally aligned

Human error mitigation initiative (HEMI) : summary report.

Despite continuing efforts to apply existing hazard analysis methods and comply with requirements, human errors persist across the nuclear weapons complex. Due to a number of factors, current retroactive and proactive methods to understand and minimize human error are highly subjective, inconsistent in numerous dimensions, and are cumbersome to characterize as thorough. An alternative and proposed method begins with leveraging historical data to understand what the systemic issues are and where resources need to be brought to bear proactively to minimize the risk of future occurrences. An illustrative analysis was performed using existing incident databases specific to Pantex weapons operations indicating systemic issues associated with operating procedures that undergo notably less development rigor relative to other task elements such as tooling and process flow. Future recommended steps to improve the objectivity, consistency, and thoroughness of hazard analysis and mitigation were delineated

Statistical methodologies to pool across multiple intervention studies

Combining and analyzing data from heterogeneous randomized controlled trials of complex multiple-component intervention studies, or discussing them in a systematic review, is not straightforward. The present article describes certain issues to be considered when combining data across studies, based on discussions in an NIH-sponsored workshop on pooling issues across studies in consortia (see Belle et al. in Psychol Aging, 18(3):396-405, 2003). Several statistical methodologies are described and their advantages and limitations are explored. Whether weighting the different studies data differently, or via employing random effects, one must recognize that different pooling methodologies may yield different results. Pooling can be used for comprehensive exploratory analyses of data from RCTs and should not be viewed as replacing the standard analysis plan for each study. Pooling may help to identify intervention components that may be more effective especially for subsets of participants with certain behavioral characteristics. Pooling, when supported by statistical tests, can allow exploratory investigation of potential hypotheses and for the design of future interventions

Systematic review of the performance of HIV viral load technologies on plasma samples.

BACKGROUND: Viral load (VL) monitoring is the standard of care in developing country settings for detecting HIV treatment failure. Since 2010 the World Health Organization has recommended a phase-in approach to VL monitoring in resource-limited settings. We conducted a systematic review of the accuracy and precision of HIV VL technologies for treatment monitoring. METHODS AND FINDINGS: A search of Medline and Embase was conducted for studies evaluating the accuracy or reproducibility of commercially available HIV VL assays. 37 studies were included for review including evaluations of the Amplicor Monitor HIV-1 v1.5 (n = 25), Cobas TaqMan v2.0 (n = 11), Abbott RealTime HIV-1 (n = 23), Versant HIV-1 RNA bDNA 3.0 (n = 15), Versant HIV-1 RNA kPCR 1.0 (n = 2), ExaVir Load v3 (n = 2), and NucliSens EasyQ v2.0 (n = 1). All currently available HIV VL assays are of sufficient sensitivity to detect plasma virus levels at a lower detection limit of 1,000 copies/mL. Bias data comparing the Abbott RealTime HIV-1, TaqMan v2.0 to the Amplicor Monitor v1.5 showed a tendency of the Abbott RealTime HIV-1 to under-estimate results while the TaqMan v2.0 overestimated VL counts. Compared to the Amplicor Monitor v1.5, 2-26% and 9-70% of results from the Versant bDNA 3.0 and Abbott RealTime HIV-1 differed by greater than 0.5log10. The average intra and inter-assay variation of the Abbott RealTime HIV-1 were 2.95% (range 2.0-5.1%) and 5.44% (range 1.17-30.00%) across the range of VL counts (2log10-7log10). CONCLUSIONS: This review found that all currently available HIV VL assays are of sufficient sensitivity to detect plasma VL of 1,000 copies/mL as a threshold to initiate investigations of treatment adherence or possible treatment failure. Sources of variability between VL assays include differences in technology platform, plasma input volume, and ability to detect HIV-1 subtypes. Monitoring of individual patients should be performed on the same technology platform to ensure appropriate interpretation of changes in VL. Prospero registration # CD42013003603

Systematic review of the use of dried blood spots for monitoring HIV viral load and for early infant diagnosis.

BACKGROUND: Dried blood spots (DBS) have been used as alternative specimens to plasma to increase access to HIV viral load (VL) monitoring and early infant diagnosis (EID) in remote settings. We systematically reviewed evidence on the performance of DBS compared to plasma for VL monitoring and EID. METHODS AND FINDINGS: Thirteen peer reviewed HIV VL publications and five HIV EID papers were included. Depending on the technology and the viral load distribution in the study population, the percentage of DBS samples that are within 0.5 log of VL in plasma ranged from 52-100%. Because the input sample volume is much smaller in a blood spot, there is a risk of false negatives with DBS. Sensitivity of DBS VL was found to be 78-100% compared to plasma at VL below 1000 copies/ml, but this increased to 100% at a threshold of 5000 copies/ml. Unlike a plasma VL test which measures only cell free HIV RNA, a DBS VL also measures proviral DNA as well as cell-associated RNA, potentially leading to false positive results when using DBS. The systematic review showed that specificity was close to 100% at DBS VL above 5000 copies/ml, and this threshold would be the most reliable for predicting true virologic failure using DBS. For early infant diagnosis, DBS has a sensitivity of 100% compared to fresh whole blood or plasma in all studies. CONCLUSIONS: Although limited data are available for EID, DBS offer a highly sensitive and specific sampling strategy to make viral load monitoring and early infant diagnosis more accessible in remote settings. A standardized approach for sampling, storing, and processing DBS samples would be essential to allow successful implementation. TRIAL REGISTRATION: PROSPERO Registration #: CRD42013003621