Validation of diacyl glycerolacyltransferase I as a novel target for the treatment of obesity and dyslipidemia using a potent and selective small molecule inhibitor

A highly potent and selective DGAT-1 inhibitor was identified and used in rodent models of obesity and postprandial chylomicron excursion to validate DGAT-1 inhibition as a novel approach for the treatment of metabolic diseases. Specifically, compound 4a conferred weight loss and a reduction in liver triglycerides when dosed chronically in DIO mice and depleted serum triglycerides following a lipid challenge in a dose-dependent manner, thus, reproducing major phenotypical characteristics of DGAT-1(-/-) mice.     

Menstrual cycle phase and single tablet antiretroviral medication adherence in women with HIV

Suboptimal adherence to antiretroviral (ARV) therapy among HIV-infected individuals is associated with increased risk of progression to AIDS and the development of HIV resistance to ARV medications. To examine whether the luteal phase of the menstrual cycle is independently associated with suboptimal adherence to single tablet regimen (STR) ARV medication, data were analyzed from a multicenter cohort study of HIV-infected women who reported regular menstrual cycles and were taking an STR. In a cross-sectional analysis, suboptimal adherence to an STR among women in their follicular phase was compared with suboptimal adherence among women in their luteal phase. In two-way crossover analyses, whereby the same woman was assessed for STR medication adherence in both her follicular and luteal phases, the estimated exact conditional odds of non-adherence to an STR was measured. In adjusted logistic regression analysis of the cross-sectional data (N=327), women with ≤12 years of education were more than three times more likely to have suboptimal adherence (OR=3.6, p=.04) compared to those with >12 years of education. Additionally, women with Center for Epidemiological Studies Depression Scale (CES-D) scores ≥23 were 2.5-times more likely to have suboptimal adherence (OR=2.6, p=.02) compared to those with CES-D scores <23. In conditional logistic regression analyses of the crossover data (N=184), having childcare responsibilities was associated with greater odds of ≤95% adherence. Menstrual cycle phase was not associated with STR adherence in either the cross-sectional or crossover analyses. The lack of association between phase of the menstrual cycle and adherence to an STR in HIV-infected women means attention can be given to other more important risk factors for suboptimal adherence, such as depression, level of education, and childcare responsibilities.     

SARS-CoV-2 infection and vaccination trigger long-lived B and CD4+ T lymphocytes with implications for booster strategies

BACKGROUNDImmunization against SARS-CoV-2, the causative agent of COVID-19, occurs via natural infection or vaccination. However, it is currently unknown how long infection- or vaccination-induced immunological memory will last.METHODSWe performed a longitudinal evaluation of immunological memory to SARS-CoV-2 up to 1 year after infection and following mRNA vaccination in naive individuals and individuals recovered from COVID-19 infection.RESULTSWe found that memory cells are still detectable 8 months after vaccination, while antibody levels decline significantly, especially in naive individuals. We also found that a booster injection is efficacious in reactivating immunological memory to spike protein in naive individuals, whereas it was ineffective in previously SARS-CoV-2–infected individuals. Finally, we observed a similar kinetics of decay of humoral and cellular immunity to SARS-CoV-2 up to 1 year following natural infection in a cohort of unvaccinated individuals.CONCLUSIONShort-term persistence of humoral immunity, together with the reduced neutralization capacity versus the currently prevailing SARS-CoV-2 variants, may account for reinfections and breakthrough infections. Long-lived memory B and CD4⁺ T cells may protect from severe disease development. In naive individuals, a booster dose restored optimal anti-spike immunity, whereas the needs for vaccinated individuals who have recovered from COVID-19 have yet to be defined.FUNDINGThis study was supported by funds to the Department of Experimental and Clinical Medicine, University of Florence (Project Excellence Departments 2018–2022), the University of Florence (project RICTD2122), the Italian Ministry of Health (COVID-2020-12371849), and the region of Tuscany (TagSARS CoV 2).     

Trend and causes of adult mortality in Kersa health and demographic surveillance system (Kersa HDSS), eastern Ethiopia: verbal autopsy method

Background

The health problems of adults have been neglected in many developing countries, yet many studies in these countries show high rates of premature mortality in adults. Measuring adult mortality and its cause through verbal autopsy (VA) methods is becoming an important process for mortality estimates and is a good indicator of the overall mortality rates in resource-limited settings. The objective of this analysis is to describe the levels, distribution, and trends of adult mortality over time (2008-2013) and causes of adult deaths using VA in Kersa Health and Demographic Surveillance System (Kersa HDSS).

Methods

Kersa HDSS is a demographic and health surveillance and research center established in 2007 in the eastern part of Ethiopia. This is a community-based longitudinal study where VA methods were used to assign probable cause of death. Two or three physicians independently assigned cause of death based on the completed VA forms in accordance with the World Health Organization’s International Classification of Diseases. In this analysis, the VA data considered were of all deaths of adults age 15 years and above, over a period of six years (2008–2013). The mortality fractions were determined and the causes of death analyzed. Analysis was done using STATA and graphs were designed using Microsoft Excel.

Results

A total of 1535 adult deaths occurred in the surveillance site during the study period and VA was completed for all these deaths. In general, the adult mortality rate over the six-year period was 8.5 per 1000 adult population, higher for males (9.6) and rural residents (8.6) than females (7.5) and urban residents (8.2). There is a general decrease in the mortality rates over the study period from 9.4 in 2008–2009 to 8.1 in 2012–2013. Out of the total deaths, about one-third (32.4%) occurred due to infectious and parasitic causes, and the second leading cause of death was diseases of circulatory system (11.4%), followed by gastrointestinal disorders (9.2%). Tuberculosis (TB) showed an increasing trend over the years and has been the leading cause of death in 2012 and 2013 for all adult age categories (15–49, 50–64, and 65 years and over). Chronic liver disease (CLD) was indicated as leading cause of death among adults in the age group 15–49 years.

Conclusion

The increasing TB-related mortality in the study years as well as the relative high mortality due to CLD among adults of age 15–49 years should be further investigated and triangulated with health service data to understand the root cause of death.

     

Non-physician clinicians in 47 sub-Saharan African countries

Many countries have health-care providers who are not trained as physicians but who take on many of the diagnostic and clinical functions of medical doctors. We identified non-physician clinicians (NPCs) in 25 of 47 countries in sub-Saharan Africa, although their roles varied widely between countries. In nine countries, numbers of NPCs equalled or exceeded numbers of physicians. In general NPCs were trained with less cost than were physicians, and for only 3–4 years after secondary school. All NPCs did basic diagnosis and medical treatment, but some were trained in specialty activities such as caesarean section, ophthalmology, and anaesthesia. Many NPCs were recruited from rural and poor areas, and worked in these same regions. Low training costs, reduced training duration, and success in rural placements suggest that NPCs could have substantial roles in the scale-up of health workforces in sub-Saharan African countries, including for the planned expansion of HIV/AIDS prevention and treatment programmes.     

Malonyl-coenzyme-A is a potential mediator of cytotoxicity induced by fatty-acid synthase inhibition in human breast cancer cells and xenografts

A biologically aggressive subset of human breast cancers and other malignancies is characterized by elevated fatty-acid synthase (FAS) enzyme expression, elevated fatty acid (FA) synthesis, and selective sensitivity to pharmacological inhibition of FAS activity by cerulenin or the novel compound C75. In this study, inhibition of FA synthesis at the physiologically regulated step of carboxylation of acetyl-CoA to malonyl-CoA by 5-(tetradecyloxy)-2-furoic acid (TOFA) was not cytotoxic to breast cancer cells in clonogenic assays. FAS inhibitors induced a rapid increase in intracellular malonyl-CoA to several fold above control levels, whereas TOFA reduced intracellular malonyl-CoA by 60%. Simultaneous exposure of breast cancer cells to TOFA and an FAS inhibitor resulted in significantly reduced cytotoxicity and apoptosis. Subcutaneous xenografts of MCF7 breast cancer cells in nude mice treated with C75 showed FA synthesis inhibition, apoptosis, and inhibition of tumor growth to less than 1/8 of control volumes, without comparable toxicity in normal tissues. The data suggest that differences in intermediary metabolism render tumor cells susceptible to toxic fluxes in malonyl-CoA, both in vitro and in vivo.     

The Medical Education Partnership Initiative: PEPFAR's effort to boost health worker education to strengthen health systems

The early success of the President's Emergency Plan for AIDS Relief (PEPFAR) in delivering antiretroviral medications in poor countries unmasked the reality that many lacked sufficient health workers to dispense the drugs effectively. The 2008 reauthorization of PEPFAR embraced this challenge and committed to supporting the education and training of thousands of new health workers. In 2010 the program, with financial support from the US National Institutes of Health and administrative support from the Health Resources and Services Administration, launched the Medical Education Partnership Initiative to fund thirteen African medical schools and a US university. The US university would serve as a coordinating center to improve the quantity, quality, and retention of the schools' graduates. The program was not limited to training in the delivery of services for patients with HIV/AIDS. Rather, it was based on the principle that investment in medical education and retention would lead to health system strengthening overall. Although results are limited at this stage, this article reviews the opportunities and challenges of the first year of this major transnational medical education initiative and considers directions for future efforts and reforms, national governmental roles, and the sustainability of the program over time.