Descriptive analysis of World Health Organization-recommended second-line antiretroviral treatment: A retrospective cohort data analysis

Background. World Health Organization guidelines recommend that HIV patients who do not achieve viral suppression on efavirenz-based first-line antiretroviral therapy (ART) should be changed to a protease inhibitor (PI)-based regimen. In South Africa (SA), ~200 000 people are on second-line treatment, but little is known about these patients.Objectives. To describe second-line black African patients in a large urban area.Methods. A quantitative retrospective study of 825 second-line patients in central Johannesburg, SA (subdistrict F), was performed with data extracted from government databases. Demographic characteristics, treatment status and laboratory information were gathered, then analysed with CD4+ cell count, viral load (VL) and retention-in-care data as outcome variables.Results. The average recorded time to VL measurement after the switch to a PI-based ART regimen was 20 months, and 83.1% (570/686) of patients with a recent VL achieved viral suppression while on second-line treatment. The most recent median CD4+ cell count for the cohort was 286 cells/µL (interquartile range 160 - 478), which represented a 177 cells/µL increase from the baseline count at the start of first-line ART. Slightly less than three-quarters (72.4%) of the population remained active in care in the study clinics from initiation on first-line ART. Demographic characteristics such as being <25 years of age, male sex and geographical transfer (started initial treatment in a different region) independently predicted low CD4+ cell counts and virological failure on second-line treatment. Patients with virological failure were most likely (odds ratio (OR) 3.13, 95% confidence interval (CI) 1.50 - 6.56) to be lost to follow-up after the switch, while patients from Hillbrow Community Health Centre (OR 0.27, 95% CI 0.16 - 0.44), South Rand Hospital (OR 0.24, 95% CI 0.12 - 0.47) and Jeppe Clinic (OR 0.38, 95% CI 0.16 - 0.88), three larger sites, were most likely to remain active in care.Conclusions. VL suppression was high in patients on second-line treatment, but one-fifth of patients were lost to follow-up. Younger age, male sex and transfer from other treatment sites predicted poor treatment outcomes, highlighting opportunities for prioritisation of adherence interventions.

Generating Demand for Alternative Protein in Low- and Middle- Income Countries: Opportunities and Experiences from Nutritious and Sustainable Market Solutions

Protein consumption and the demand for high-value nutritional products is growing rapidly in emerging markets. The projected growth of the alternative protein industry may position it well to meet this demand while addressing environmental sustainability and ethical standards. However, adoption of alternative protein products over traditional animal-sourced proteins is not always a clear choice, with factors such as consumer preferences and habitual behaviors influencing consumer decisions. Insights and considerations associated with generating demand for alternative protein products in low- and middle-income countries (LMIC) were identified through 3 case studies: the OBAASIMA Project in Ghana, the Egg Initiative in Ethiopia, and the World Food Programme Farming Coalition project in Armenia. Key findings emphasize the importance of local sourcing, positive messaging, and integration within existing diets and behaviors. Therefore, these factors will be essential for the adoption of novel alternative protein products in LMIC

Scope for Credit Risk Diversification

This paper considers a simple model of credit risk and derives the limit distribution of losses under different assumptions regarding the structure of systematic risk and the nature of exposure or firm heterogeneity. We derive fat-tailed correlated loss distributions arising from Gaussian risk factors and explore the potential for risk diversification. Where possible the results are generalised to non-Gaussian distributions. The theoretical results indicate that if the firm parameters are heterogeneous but come from a common distribution, for sufficiently large portfolios there is no scope for further risk reduction through active portfolio management. However, if the firm parameters come from different distributions, then further risk reduction is possible by changing the portfolio weights. In either case, neglecting parameter heterogeneity can lead to underestimation of expected losses. But, once expected losses are controlled for, neglecting parameter heterogeneity can lead to overestimation of risk, whether measured by unexpected loss or value-at-risk

Double-Stranded RNA Attenuates the Barrier Function of Human Pulmonary Artery Endothelial Cells

Circulating RNA may result from excessive cell damage or acute viral infection and can interact with vascular endothelial cells. Despite the obvious clinical implications associated with the presence of circulating RNA, its pathological effects on endothelial cells and the governing molecular mechanisms are still not fully elucidated. We analyzed the effects of double stranded RNA on primary human pulmonary artery endothelial cells (hPAECs). The effect of natural and synthetic double-stranded RNA (dsRNA) on hPAECs was investigated using trans-endothelial electric resistance, molecule trafficking, calcium (Ca2+) homeostasis, gene expression and proliferation studies. Furthermore, the morphology and mechanical changes of the cells caused by synthetic dsRNA was followed by in-situ atomic force microscopy, by vascular-endothelial cadherin and F-actin staining. Our results indicated that exposure of hPAECs to synthetic dsRNA led to functional deficits. This was reflected by morphological and mechanical changes and an increase in the permeability of the endothelial monolayer. hPAECs treated with synthetic dsRNA accumulated in the G1 phase of the cell cycle. Additionally, the proliferation rate of the cells in the presence of synthetic dsRNA was significantly decreased. Furthermore, we found that natural and synthetic dsRNA modulated Ca2+ signaling in hPAECs by inhibiting the sarco-endoplasmic Ca2+-ATPase (SERCA) which is involved in the regulation of the intracellular Ca2+ homeostasis and thus cell growth. Even upon synthetic dsRNA stimulation silencing of SERCA3 preserved the endothelial monolayer integrity. Our data identify novel mechanisms by which dsRNA can disrupt endothelial barrier function and these may be relevant in inflammatory processes

A Transiting Hot Jupiter Orbiting a Metal-Rich Star

We announce the discovery of Kepler-6b, a transiting hot Jupiter orbiting a star with unusually high metallicity, [Fe/H] = +0.34 +/- 0.04. The planet's mass is about 2/3 that of Jupiter, Mp = 0.67 Mj, and the radius is thirty percent larger than that of Jupiter, Rp = 1.32 Rj, resulting in a density of 0.35 g/cc, a fairly typical value for such a planet. The orbital period is P = 3.235 days. The host star is both more massive than the Sun, Mstar = 1.21 Msun, and larger than the Sun, Rstar = 1.39 Rsun.Comment: 12 pages, 2 figures, submitted to the Astrophysical Journal Letter

A randomized, seven-day study to assess the efficacy and safety of a glycopyrrolate/formoterol fumarate fixed-dose combination metered dose inhaler using novel Co-Suspension™ Delivery Technology in patients with moderate-to-very severe chronic obstructive pulmonary disease

Abstract Background Long-acting muscarinic antagonist/long-acting β 2 -agonist combinations are recommended for patients whose chronic obstructive pulmonary disease (COPD) is not managed with monotherapy. We assessed the efficacy and safety of glycopyrrolate (GP)/formoterol fumarate (FF) fixed-dose combination delivered via a Co-Suspension™ Delivery Technology-based metered dose inhaler (MDI) (GFF MDI). Methods This was a Phase IIb randomized, multicenter, placebo-controlled, double-blind, chronic-dosing (7 days), crossover study in patients with moderate-to-very severe COPD (NCT01085045). Treatments included GFF MDI twice daily (BID) (GP/FF 72/9.6 μg or 36/9.6 μg), GP MDI 36 μg BID, FF MDI 7.2 and 9.6 μg BID, placebo MDI, and open-label formoterol dry powder inhaler (FF DPI) 12 μg BID or tiotropium DPI 18 μg once daily. The primary endpoint was forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV 1 AUC 0–12 ) on Day 7 relative to baseline FEV 1 . Secondary endpoints included pharmacokinetics and safety. Results GFF MDI 72/9.6 μg or 36/9.6 μg led to statistically significant improvements in FEV 1 AUC 0–12 after 7 days’ treatment versus monocomponent MDIs, placebo MDI, tiotropium, or FF DPI (p ≤ 0.0002). GFF MDI 36/9.6 μg was non-inferior to GFF MDI 72/9.6 μg and monocomponent MDIs were non-inferior to open-label comparators. Pharmacokinetic results showed glycopyrrolate and formoterol exposure were decreased following administration via fixed-dose combination versus monocomponent MDIs; however, this was not clinically meaningful. GFF MDI was well tolerated. Conclusions GFF MDI 72/9.6 μg and 36/9.6 μg BID improve lung function and are well tolerated in patients with moderate-to-very severe COPD. Trial registration ClinicalTrials.gov NCT01085045. Registered 9 March 2010

Default Risk and Equity Returns: A Comparison of the Bank-Based German and the U.S. Financial System

In this paper, we address the question whether the impact of default risk on equity returns depends on the financial system firms operate in. Using an implementation of Merton's option-pricing model for the value of equity to estimate firms' default risk, we construct a factor that measures the excess return of firms with low default risk over firms with high default risk. We then compare results from asset pricing tests for the German and the U.S. stock markets. Since Germany is the prime example of a bank-based financial system, where debt is supposedly a major instrument of corporate governance, we expect that a systematic default risk effect on equity returns should be more pronounced for German rather than U.S. firms. Our evidence suggests that a higher firm default risk systematically leads to lower returns in both capital markets. This contradicts some previous results for the U.S. by Vassalou/Xing (2004), but we show that their default risk factor looses its explanatory power if one includes a default risk factor measured as a factor mimicking portfolio. It further turns out that the composition of corporate debt affects equity returns in Germany. Firms' default risk sensitivities are attenuated the more a firm depends on bank debt financing

International Veterinary Epilepsy Task Force recommendations for systematic sampling and processing of brains from epileptic dogs and cats

Traditionally, histological investigations of the epileptic brain are required to identify epileptogenic brain lesions, to evaluate the impact of seizure activity, to search for mechanisms of drug-resistance and to look for comorbidities. For many instances, however, neuropathological studies fail to add substantial data on patients with complete clinical work-up. This may be due to sparse training in epilepsy pathology and or due to lack of neuropathological guidelines for companion animals. The protocols introduced herein shall facilitate systematic sampling and processing of epileptic brains and therefore increase the efficacy, reliability and reproducibility of morphological studies in animals suffering from seizures. Brain dissection protocols of two neuropathological centres with research focus in epilepsy have been optimised with regards to their diagnostic yield and accuracy, their practicability and their feasibility concerning clinical research requirements. The recommended guidelines allow for easy, standardised and ubiquitous collection of brain regions, relevant for seizure generation. Tissues harvested the prescribed way will increase the diagnostic efficacy and provide reliable material for scientific investigations