Caring for the whole person: transgender-competent HIV pre-exposure prophylaxis as part of integrated primary healthcare services in Vietnam.

INTRODUCTION: Although HIV prevalence among transgender women who have sex with men in Vietnam is high (16-18%), uptake of pre-exposure prophylaxis (PrEP) is low compared to other populations. When PrEP was initiated in 2017, gender-affirming healthcare was largely unavailable. Lack of access to competent, stigma-free healthcare is a well-documented barrier to transgender women's uptake of PrEP and primary healthcare (PHC). We aimed to demonstrate the utility of a PrEP quality improvement intervention in pinpointing and addressing barriers to PrEP use among transgender women in Vietnam. METHODS: We applied a real-world participatory continuous quality improvement (CQI) and Plan-Do-Study-Act (PDSA) methodology to ascertain barriers to PrEP uptake among transgender women and determine priority actions for quality improvement. A CQI team representing transgender women leaders, key population (KP)-clinic staff, public-sector HIV managers and project staff applied PDSA to test solutions to identified barriers that addressed the primary quality improvement outcome of the monthly change in PrEP uptake among transgender women and secondary outcomes, including month-3 PrEP continuation, the impact of offering PHC on PrEP uptake and unmet PrEP need. We utilized routine programmatic data and a descriptive cross-sectional study enrolling 124 transgender women to measure these outcomes from October 2018 to September 2021. RESULTS: Five key barriers to PrEP uptake among transgender women were identified and corresponding solutions were put in place: (1) offering gender-affirming care training to KP-clinics and community-based organizations; (2) integrating gender-affirming services into 10 KP-clinics; (3) offering PHC through five one-stop shop (OSS) clinics; (4) implementing a campaign addressing concerns related to hormone use and PrEP interactions; and (5) developing national HIV and transgender healthcare guidelines. New PrEP enrolment and month-3 PrEP continuation increased significantly among transgender women. Of 235 transgender women who initially sought healthcare other than PrEP at OSS clinics, 26.4% subsequently enrolled in PrEP. About one-third of transgender women reported unmet PrEP need, while two-thirds indicated an interest in long-acting cabotegravir. CONCLUSIONS: Offering gender-competent, integrated PHC can increase PrEP enrolment and continuation, and can be an entry-point for PrEP among those seeking care within PHC clinics. More work is needed to expand access to transgender women-led and -competent healthcare in Vietnam.

Effects of Capsaicin on Biomimetic Membranes.

Capsaicin is a natural compound that produces a warm sensation and is known for its remarkable medicinal properties. Understanding the interaction between capsaicin with lipid membranes is essential to clarify the molecular mechanisms behind its pharmacological and biological effects. In this study, we investigated the effect of capsaicin on thermoresponsiveness, fluidity, and phase separation of liposomal membranes. Liposomal membranes are a bioinspired technology that can be exploited to understand biological mechanisms. We have shown that by increasing thermo-induced membrane excess area, capsaicin promoted membrane fluctuation. The effect of capsaicin on membrane fluidity was dependent on lipid composition. Capsaicin increased fluidity of (1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) membranes, while it rigidified DOPC and cholesterol-based liposomes. In addition, capsaicin tended to decrease phase separation of heterogeneous liposomes, inducing homogeneity. We imagine this lipid re-organization to be associated with the physiological warming sensation upon consumption of capsaicin. Since capsaicin has been reported to have biological properties such as antimicrobial and as antiplatelet, the results will help unravel these biological properties.

Polyphenols Modulate Alzheimer's Amyloid Beta Aggregation in a Structure-Dependent Manner.

Some polyphenols, which are common natural compounds in fruits, vegetables, seeds, and oils, have been considered as potent inhibitors of amyloid beta (Aß) aggregation, one critical pathogenic event in Alzheimer's disease (AD). However, the mechanisms by which polyphenols affect aggregation are not fully understood. In this study, we aimed to investigate the effect of two classes of polyphenols (flavonoids and stilbenes) on the self-assembly of Aß_42, in particular, how this relates to structure. We found that the flavonoids gallocatechin gallate (GCG) and theaflavin (TF) could completely inhibit Aß aggregation, while two stilbenes, resveratrol and its glucoside derivative piceid, could also suppress Aß aggregation, but to a much lesser extent. Intriguingly, resveratrol accelerated the formation of Aß fibrils before its decreasing effect on fibrillation was detected. Atomic force microscopy (AFM) images showed a huge mass of long and thin Aß fibrils formed in the presence of resveratrol. Although the morphology was the same in the presence of piceid, the fibrils were sparse in the presence of picead. In the presence of flavonoids, Aß morphology was unchanged from prior to incubation (0 h), in agreement with amyloid beta kinetics analysis using thioflavin-T fluorescence assay. The electrochemical data showed a higher ability of GCG and TF to interact with Aß than resveratrol and piceid, which could be attributed to the presence of more aromatic rings and hydroxyl groups. In addition, the two flavonoids exhibited a similar propensity for Aß aggregation, despite having some differences in their structure. However, in the case of stilbenes, the addition of a glucoside at C-7 slightly decreased anti-Aß aggregation property compared to resveratrol. These findings contribute to a better understanding of the essential structural features of polyphenols required for inhibiting Aß aggregation, and the possible mechanisms for modulating aggregation.

Strikingly different effects of cholesterol and 7-ketocholesterol on lipid bilayer-mediated aggregation of amyloid beta (1-42).

Oxidized cholesterol has been widely reported to contribute to the pathogenesis of Alzheimer's disease (AD). However, the mechanism by which they affect the disease is not fully understood. Herein, we aimed to investigate the effect of 7-ketocholesterol (7keto) on membrane-mediated aggregation of amyloid beta (Aß-42), one of the critical pathogenic events in AD. We have shown that when cholesterol is present in lipid vesicles, kinetics of Aß nuclei formation is moderately hindered while that of fibril growth was considerably accelerated. The partial substitution of cholesterol with 7keto slightly enhanced the formation of Aß-42 nuclei and remarkably decreased fibril elongation, thus maintaining the peptide in protofibrillar aggregates, which are reportedly the most toxic species. These findings add in understanding of how cholesterol and its oxidation can affect Aß-induced cytotoxicity.

Glycosyl chains and 25-hydroxycholesterol contribute to the intracellular transport of amyloid beta (Aß-42) in Jurkat T cells.

Amyloid beta (Aß) is a peptide responsible for the development of Alzheimer's disease (AD). Misfolding and accumulation of endogenous Aß can lead to neural cell apoptosis through endoplasmic reticulum (ER) stress. Added exogenous Aß can also result in ER stress, leading to neurotoxicity and apoptosis, which is identical to that caused by the endogenous peptide. We have speculated that the endocytic transport of Aß causes ER stress and have previously shown that the oxysterol, in particular, 7-ketocholesterol (7-keto) induces more surface interaction between Aß-42 and Jurkat cells than cholesterol. However, the interaction was not enough to induce intracellular transfer of the peptide. In this study, we investigated the effect of another oxysterol, 25-hydroxycholesterol (25-OH) on the membrane raft-dependent transport of Aß-42 in Jurkat cells. Interestingly, intracellular transfer of Aß-42 was observed in the presence of 25-OH only after the inclusion of cholera toxin B subunit (CT-B), a marker used to detect the raft domain. We speculated that 25-OH can induce intracellular movement of Aß peptides. Furthermore, CT-B together with GM1 provided negative curvature, which resulted in the intracellular transport of Aß-42. Notably, we used a protofibrillar species of Aß-42 in this study. We have shown that the transport was microtubule-dependent since it could not be observed in depolymerized microtubules. These results demonstrate that oxysterols and glycosyl chains are important factors affecting intracellular transport. These compounds are also associated with aging and advanced glycation are risk factors for AD. Thus, this study should further understanding of the pathology of AD.

Effects of cigarette smoking and nicotine dependence on adherence to antiretroviral therapy among HIV-positive patients in Vietnam.

Cigarette smoking is increasingly recognized as an indicator for inferior adherence to antiretroviral therapy (ART) among HIV-positive patients. Given the limited body of work on this issue, we aimed to explore the relations between cigarette smoking, nicotine dependence, and ART adherence in Vietnam. A cross-sectional study of 1050 HIV-positive people was conducted from January to September 2013 in Hanoi (the capital) and Nam Dinh (a rural city). Adherence to ART during the last 30 days was measured by the 100-point visual analog scale (VAS). Smoking history and nicotine dependence (Fagerstrom Test of Nicotine Dependence) were self-reported by participants. Multiple logistic regression was performed to examine the association of current smoking and nicotine dependence with ART nonadherence. Using the established VAS cut point of 95 to indicate adequate adherence, the prevalence of ART nonadherence was 30.9%. Approximately 35.5% of the sample reported current smoking. No association between smoking status and ART nonadherence was found. However, participants with greater nicotine dependence (OR = 1.1, 95%CI = 1.0-1.2 per unit increase) were more likely to be nonadherent. Also, individuals who were female (OR = 1.70, 95%CI = 1.19-2.42), receiving ART in Nam Dinh (OR = 1.6, 95%CI = 1.1-2.4), and currently feeling anxiety (OR = 1.6, 95% CI = 1.2-2.1) had a higher likelihood of ART nonadherence. Additionally, current smokers reporting current pain (OR = 1.9, 95%CI = 1.2-3.1) were more likely to be nonadherent. Conversely, protective factors included living with a spouse/partner (OR = 0.5, 95%CI = 0.3-0.7) and having more than a high school education (OR = 0.4, 95%CI = 0.1-1.0). Given the high prevalence of suboptimal adherence and current smoking among HIV-positive patients, screening for smoking status and nicotine dependence during ART treatment may help to improve patients' adherence to medication. More efforts should be targeted to women, patients with mental health problems, and ART clinics in rural areas.

Localization of amyloid beta (Aß1-42) protofibrils in membrane lateral compartments: effect of cholesterol and 7-Ketocholesterol.

Cholesterol plays an important role in the interaction of Alzheimer's amyloid beta (Aß) with cell membranes, an important event in Aß-induced cytotoxicity. However, it is not fully understood how cholesterol influences the association of Aß with membrane lateral compartments. We have shown that by modulating membrane fluidity, cholesterol decreased peptide localization in solid-ordered domains and increased that in liquid-ordered domains. It changed the amount of Aß associating with liquid-disordered (Ld) phase with different tendencies depending on the composition of heterogeneous membrane systems. 7-Ketocholesterol, an oxidized derivative of cholesterol, majorly enhanced the fluidity of and Aß interaction with Ld phase. These findings are useful for clarifying the impact of cholesterol and its oxidation in Aß-induced toxicity.

Structure-dependent interactions of polyphenols with a biomimetic membrane system.

Polyphenols are naturally-occurring compounds, reported to be biologically active, and through their interactions with cell membranes. Although association of the polyphenols with the bilayer has been reported, the detailed mechanism of interaction is not yet well elucidated. We report on spatio-temporal real-time membrane dynamics observed in the presence of polyphenols. Two distinct membrane dynamics, corresponding to the two classes of polyphenols used, were observed. Flavonoids (epi-gallocatechin-3-gallate, gallocatechin, theaflavin and theaflavin-3-gallate) caused lipid membrane aggregation and rigidification. As simple structural modification through opening of the aromatic C-ring into an olefin bond, present in trans-stilbenes (resveratrol and picead), completely changed the membrane properties, increasing fluidity and inducing fluctuation. There were differences in the membrane transformations within the same class of polyphenols. Structure-dependent classification of membrane dynamics may contribute to a better understanding of the physicochemical mechanism involved in the bioactivity of polyphenols. In general, an increase in the number of hydrophilic side chains (galloyl, hydroxyl, glucoside, gallate) increased the reactivity of the polyphenols. Most notable was the difference observed through a simple addition of the gallate group. Unraveling the importance of these polyphenols, at a functional group level further opens the key to tailored design of bioactive compounds as potential drug candidates.

The effect of oxysterols on the interaction of Alzheimer's amyloid beta with model membranes.

The interaction of amyloid beta (Aß) peptide with cell membranes has been shown to be influenced by Aß conformation, membrane physicochemical properties and lipid composition. However, the effect of cholesterol and its oxidized derivatives, oxysterols, on Aß-induced neurotoxicity to membranes is not fully understood. We employed here model membranes to investigate the localization of Aß in membranes and the peptide-induced membrane dynamics in the presence of cholesterol and 7-ketocholesterol (7keto) or 25-hydroxycholesterol (25OH). Our results have indicated that oxysterols rendered membranes more sensitive to Aß, in contrast to role of cholesterol in inhibiting Aß/membrane interaction. We have demonstrated that two oxysterols had different impacts owing to distinct positions of the additional oxygen group in their structures. 7keto-containing cell-sized liposomes exhibited a high propensity toward association with Aß, while 25OH systems were more capable of morphological changes in response to the peptide. Furthermore, we have shown that 42-amino acid Aß (Aß-42) pre-fibril species had higher association with membranes, and caused membrane fluctuation faster than 40-residue isoform (Aß-40). These findings suggest the enhancing effect of oxysterols on interaction of Aß with membranes and contribute to clarify the harmful impact of cholesterol on Aß-induced neurotoxicity by means of its oxidation.