Epigenome-wide epidemiologic studies of human immunodeficiency virus infection, treatment, and disease progression

Despite significant advances in the treatment and care of people with HIV (PWH), several challenges remain in our understanding of disease pathogenesis to improve patient care. HIV infection can modify the host epigenome and as such can impact disease progression, as well as the molecular processes driving non-AIDS comorbidities in PWH. Epigenetic epidemiologic studies including epigenome-wide association studies (EWAS) offer a unique set of tools to expand our understanding of HIV disease and to identify novel strategies applicable to treatment and diagnosis in this patient population. In this review, we summarize the current state of knowledge from epigenetic epidemiologic studies of PWH, identify the main challenges of this approach, and highlight future directions for the field. Emerging epigenetic epidemiologic studies of PWH can expand our understanding of HIV infection and health outcomes, improve scientific validity through collaboration and replication, and increase the coverage of diverse populations affected by the global HIV pandemic. Through this review, we hope to highlight the potential of EWAS as a tool for HIV research and to engage more investigators to explore its application to important research questions.

Enhancing Nutrition and Antenatal Infection Treatment (ENAT) study: protocol of a pragmatic clinical effectiveness study to improve birth outcomes in Ethiopia

IntroductionThe WHO Nutrition Target aims to reduce the global prevalence of low birth weight by 30% by the year 2025. The Enhancing Nutrition and Antenatal Infection Treatment (ENAT) study will test the impact of packages of pregnancy interventions to enhance maternal nutrition and infection management on birth outcomes in rural Ethiopia.Methods and analysisENAT is a pragmatic, open-label, 2×2 factorial, randomised clinical effectiveness study implemented in 12 rural health centres in Amhara, Ethiopia. Eligible pregnant women presenting at antenatal care (ANC) visits at <24 weeks gestation are enrolled (n=2400). ANC quality is strengthened across all centres. Health centres are randomised to receive an enhanced nutrition package (ENP) or standard nutrition care, and within each health centre, individual women are randomised to receive an enhanced infection management package (EIMP) or standard infection care. At ENP centres, women receive a regular supply of adequately iodised salt and iron–folate (IFA), enhanced nutrition counselling and those with mid-upper arm circumference of <23 cm receive a micronutrient fortified balanced energy protein supplement (corn soya blend) until delivery. In standard nutrition centres, women receive routine counselling and IFA. EIMP women have additional screening/treatment for urinary and sexual/reproductive tract infections and intensive deworming. Non-EIMP women are managed syndromically per Ministry of Health Guidelines. Participants are followed until 1-month post partum, and a subset until 6 months. The primary study outcomes are newborn weight and length measured at <72 hours of age. Secondary outcomes include preterm birth, low birth weight and stillbirth rates; newborn head circumference; infant weight and length for age z-scores at birth; maternal anaemia; and weight gain during pregnancy.Ethics and disseminationENAT is approved by the Institutional Review Boards of Addis Continental Institute of Public Health (001-A1-2019) and Mass General Brigham (2018P002479). Results will be disseminated to local and international stakeholders.Registration numberISRCTN15116516.

Convalescent Plasma Therapy: The Early Use in Moderate to Severe COVID-19 Patients in Hospitals with Limited Resources

COVID-19 cases in Indonesia in the period of June-July 2021 showed a catastrophic spike. During this period, a recently discovered variant, the delta variant, appeared to be one of the sources of COVID-19 infection. Treatment modalities are limited due to reduced stock of drugs. A case of a 63-year-old man has been reported, with a history of having been vaccinated with two doses of Sinovac, experiencing moderate-to-severe symptoms of COVID-19 infection then given convalescent plasma therapy since his initial admission to the hospital. Three days after being given convalescent plasma therapy, the improvement was noticeable. Shortness of breath, cough, fever, and weakness were less complained. On the seventh day the patient fully recovered and got discharged. Convalescent plasma therapy was e ective in early stage and was able to improve outcomes. Indonesia needs sucient stocks of convalescent plasma as a therapy to overcome the limitations of medicines.

HBV enveloped particle secretion is positively regulated by GRP78 through direct interaction with preS1

Hepatitis B virus (HBV) infection is a common cause of liver diseases worldwide. Existing drugs do not effectively eliminate HBV from infected hepatocytes; thus, novel curative therapies are needed. Enveloped-particle secretion is a key but poorly studied aspect of the viral life cycle. Here, we report that GRP78 positively regulates HBV enveloped-particle secretion. GRP78 is the specific target of preS1 binding; HBV can upregulate GRP78 in liver cell lines and sera from chronic hepatitis B patients. GRP78 promoted intact HBV-particle secretion in liver cell lines and an HBV transgenic-mouse model. Some peptides screened from preS1 via phage display could inhibit viral-particle secretion by interacting with GRP78 via hydrogen bonds and hydrophobic interactions, thereby disturbing the interaction with HBV particles. These results provide insight into enveloped-particle secretion in the HBV life cycle. GRP78 might be a potential target for HBV-infection treatment via restricting GRP78–preS1 interactions to block viral-particle secretion.

Praziquantel Treatment of Schistosoma mansoni Infected Mice Renders Them Less Susceptible to Reinfection

Beyond transient control of the infection, additional benefits of mass drug administration of praziquantel in endemic communities have been suggested in communities but not mechanistically investigated experimentally. The present study sought to evaluate the additional and hitherto unreported benefits of repeated mass drug administration of praziquantel. We used a tractable mouse model of Schistosoma mansoni infection to assess the effects of repeated infection-treatment cycles on the host susceptibility to reinfection. Parasitaemia was assessed by quantification of Schistosoma egg burden in liver tissues and morbidity was followed up by histological observation of liver lesions by microscopy and using biochemical measurement of liver transaminases. Immune responses were further determined by serum probing of schistosoma-specific antibodies, cytokines and quantification of liver cellular and soluble mediator responses by flow cytometry and ELISA, respectively. At similar ages and comparable gender distribution, groups of mice undergoing higher number of infections treatment cycles over a longer period, remained susceptible to reinfection by the parasite, as judged by the presence of eggs and the associated increasing pathology in the liver tissues. However, notably, there was a clear and significantly higher propensity to lower egg burden upon reinfection when compared to counterparts undergoing a lower number of infection-treatment cycles. This relative reduction of susceptibility to infection was paralleled by a more robust humoral response against parasite antigens, elevated serum IL-4 and liver cytokines. Of note, praziquantel treatment of infected mice left them at a higher baseline of serum IL-4, IgE and liver cytokines but lower CD4+ T cell -derived cytokines when compared to infected non-treated mice supporting an immunological treatment-induced advantage of previously infected mice over naïve mice and infected/not treated mice. Notably, repeated infection-treatment cycles did not preclude the infection-driven aggravation of collagen deposition in the livers over time and was corroborated by a more robust local production of inflammatory cytokines in the most exposed livers. Taken together, our data reveal that treatment of S. mansoni-infected hosts with praziquantel rewires the immune system to a conformation less permissive to subsequent reinfection in mice. Provided the data are translatable from mouse to human, our findings may provide mechanistic support to the potential benefits of more frequent MDAs in high transmission areas to allow rapid acquisition of protective immunity against reinfection.

Precision medicine in bronchiectasis

Bronchiectasis, due to its highly heterogenous nature, requires an individualised approach to therapy. Patients experience symptoms and exacerbations driven by a combination of impaired mucociliary clearance, airway inflammation and airway infection. Treatment of bronchiectasis aims to enhance airway clearance and to address the underlying causes of inflammation and infection susceptibility. Bronchiectasis has multiple causes and so the pathophysiology leading to individual symptoms and exacerbations are different between individuals. Standardised investigations are recommended by international guidelines to identify the underlying causes of bronchiectasis. The process of identifying the underlying biology within an individual is called “endotyping” and is an emerging concept across chronic diseases. Endotypes that have a specific treatment are referred to as “treatable traits” and a treatable traits approach to managing patients with bronchiectasis in a holistic and evidence-based manner is the key to improved outcomes. Bronchiectasis is an area of intense research. Endotyping allows identification of subsets of patients to allow medicines to be tested differently in the future where trials, rather than trying to achieve a “one size fits all” solution, can test efficacy in subsets of patients where the treatment is most likely to be efficacious.

Clinical and parasitological assessment in mice treated with highly diluted Atropa belladonna

Introduction: The infection by Trypanosoma cruzi is a public health problem and there is no effective treatment currently. Immunomodulatory effects of Atropa belladonna may offer benefits1 Objective: To evaluate the effect of A. belladonna in murine infection by T. cruzi. Methodology: The experiment was blind, controlled and randomized by draw. Eighty five Swiss male mice, at 8 weeks of age, were infected with 1400 blood trypomastigotes of T. cruzi Y strain (via IP) and divided into the following groups: without treatment (CI), treated with the mother tincture of A. belladonna (GTM-HN Cristiano), treated with A. belladonna 5cH (G5cH), treated with A. belladonna 6cH (G6cH), treated with A. belladonna 30cH (G30cH). Cereal alcohol 70 ° GL was used for dilutions as well as water in final preparations (Sigma-SP-Brazil). Oral treatment, diluted with water (1mL/100mL water), offered ad libitum 48 hours before infection, available during 16h. After infection, treatment of 56/56h for 16h, until the 9th day of infection2. Parasitological parameters: Curve of parasitemia, total parasitemia (PT), Maximum Peak of Parasites (PMP), Pre-Patent Period (PPP), Patent Period (PP), and Survival. Clinical parameters: water, food, excreta, weight and temperature. Results: G6cH and G30cH groups displayed better survival rates (1.54 and 1.42 times versus IC), and higher curve of parasitemia - G6cH (p = 0.00), G30cH (p = 0.02) – when compared to CI. PMP was lower in GTM (P = 0.01) and G5cH (p = 0.04) groups; PT was lower in GTM (p = 0.01), G5cH (p = 0.05) and G6cH (p = 0.05) groups when compared to CI. There was no difference in PPP and PP parameters in all groups, with a tendency of a higher PPP in G5cH and G6cH groups and lower PPP in G30cHgroup.The mice weight was higher in GTM (