Correction: Retention on ART and viral suppression among patients in alternative models of differentiated HIV service delivery in KwaZulu-Natal, South Africa.

[This corrects the article DOI: 10.1371/journal.pgph.0000336.].

Asymmetrical nucleosomal DNA signatures regulate transcriptional directionality.

Despite the symmetrical structure of nucleosomes, in vitro studies have shown that transcription proceeds with different efficiency depending on the orientation of the DNA sequence around them. However, it is unclear whether this functional asymmetry is present in vivo and whether it could regulate transcriptional directionality. Here, we report that the proximal and distal halves of nucleosomal DNA contribute differentially to nucleosome stability in the genome. In +1 nucleosomes, this asymmetry facilitates or hinders transcription depending on the orientation of its underlying DNA, and this difference is associated with an asymmetrical interaction between DNA and histones. These properties are encoded in the DNA signature of +1 nucleosomes, since its incorporation in the two orientations into downstream nucleosomes renders them asymmetrically accessible to MNase and inverts the balance between sense and antisense transcription. Altogether, our results show that nucleosomal DNA endows nucleosomes with asymmetrical properties that modulate the directionality of transcription.

Postnatal clubs: Implementation of a differentiated and integrated model of care for mothers living with HIV and their HIV-exposed uninfected babies in Cape Town, South Africa.

BACKGROUND: Despite the overall reduction in the HIV mother-to-child transmission (MTCT) rate in South Africa, poor adherence and retention in care during breastfeeding contribute to this period being a major driver of MTCT in South Africa. To improve this retention, postnatal clubs were created as an integrated, differentiated model of care providing psychosocial support and comprehensive care for the mother-infant pairs (MIP), including HIV and under-5-child services. We describe the implementation of these facility-based clubs and examine its health outcomes in a peri-urban primary health care setting in Cape Town, South Africa. METHODS: In this prospective cohort study, conducted between June 2016 and December 2019, MIPs were recruited into postnatal clubs between 6 weeks and 6 months of age and followed-up until 18 months of age. Outcomes including maternal Viral Load (VL), and children's HIV testing were compared to a historical control group. Children's immunizations and maternal sexual and reproductive health outcomes are also described. RESULTS: During the implementation of the postnatal club study period, 484 MIP were recruited with 84% overall attendance, 95% overall viral load suppression, and 98% overall uptake of HIV infant testing. Compared to historical controls, the club infant rapid test uptake was 1.6 times higher (95% CI: 1.4-1.9) at 9 months and 2.0 times higher at 18 months (95% CI: 1.6-2.6). Through 12 months and between 12-18 months, maternal VL monitoring was higher in the club group compared to the historical control by 1.5 times (95% CI: 1.3-1.6) and 2.6 times (95% CI: 2.1-3.2), respectively, with similar maternal VL suppression. Of 105 infants attending the 12 months visit, 99% were fully vaccinated by one year. CONCLUSION: MIP in the postnatal clubs showed better PMTCT outcomes than historical controls with high levels of retention in care. Other outcomes such as immunisation results suggest that integration of services, such as in the postnatal club, is feasible and beneficial for MIPs.

Teaching the physiology of the human body in non-formal spaces: pilot experience of a Service-Learning methodology and the interaction between students of different educational levels.

Research institutes and universities have strengthened the development of biomedicine outreach activities, constituing a non-formal education system of science literacy, although with little commitment from undergraduate students. However, as a Service-Learning methodology, these outreach activities could work as a tool for the acquisition of skills by students of Health Science Degrees. Described here is the development of the workshop entitled "Exploring the human body" at the Biodonostia Health Research Institute and the pilot experience of its implementation as a Service-Learning activity at the University of Málaga. Firstly, 359 secondary education students were mentored by Ph.D. students through a 5-station workshop with experiments and activities related to the physiology of the human body. Then, 301 undergraduate students of Medicine and Nursing Degrees advised 965 secondary education students. Both groups of students assessed the workshop via questionnaires and a debriefing. The data showed an overall score of 4.6 out of 5 for the workshop. Undergraduate students reported a positive impact on their academic background (4.8 out of 5), mainly due to the improvement of oral communication skills (34%). Therefore, this methodology could be a valid and applicable tool to develop the cross-disciplinary competences of undergraduate students.

Accuracy of a Smartwatch to Assess Heart Rate Monitoring and Atrial Fibrillation in Stroke Patients.

(1) Background: Consumer smartwatches may be a helpful tool to screen for atrial fibrillation (AF). However, validation studies on older stroke patients remain scarce. The aim of this pilot study from RCT NCT05565781 was to validate the resting heart rate (HR) measurement and the irregular rhythm notification (IRN) feature in stroke patients in sinus rhythm (SR) and AF. (2) Methods: Resting clinical HR measurements (every 5 min) were assessed using continuous bedside ECG monitoring (CEM) and the Fitbit Charge 5 (FC5). IRNs were gathered after at least 4 h of CEM. Lin's concordance correlation coefficient (CCC), Bland-Altman analysis, and mean absolute percentage error (MAPE) were used for agreement and accuracy assessment. (3) Results: In all, 526 individual pairs of measurements were obtained from 70 stroke patients-age 79.4 years (SD ± 10.2), 63% females, BMI 26.3 (IQ 22.2-30.5), and NIHSS score 8 (IQR 1.5-20). The agreement between the FC5 and CEM was good (CCC 0.791) when evaluating paired HR measurements in SR. Meanwhile, the FC5 provided weak agreement (CCC 0.211) and low accuracy (MAPE 16.48%) when compared to CEM recordings in AF. Regarding the accuracy of the IRN feature, analysis found a low sensitivity (34%) and high specificity (100%) for detecting AF. (4) Conclusion: The FC5 was accurate at assessing the HR during SR, but the accuracy during AF was poor. In contrast, the IRN feature was acceptable for guiding decisions regarding AF screening in stroke patients.

Blocking FGF23 signaling improves the growth plate of mice with X-linked hypophosphatemia.

Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone. X-linked hypophosphatemia (XLH) is the most prevalent inherited phosphate wasting disorder due to mutations in the PHEX gene, which cause elevated circulating FGF23 levels. Clinically, it is characterized by growth impairment and defective mineralization of bones and teeth. Treatment of XLH is challenging. Since 2018, neutralizing antibodies against FGF23 have dramatically improved the therapy of XLH patients, although not all patients fully respond to the treatment, and it is very costly. C-terminal fragments of FGF23 have recently emerged as blockers of intact FGF23 signaling. Here, we analyzed the effect on growth and bone of a short 26 residues long C-terminal FGF23 (cFGF23) fragment and two N-acetylated and C-amidated cFGF23 peptides using young XLH mice (Phex C733RMhda mice). Although no major changes in blood parameters were observed after 7 days of treatment with these peptides, bone length and growth plate structure improved. The modified peptides accelerated the growth rate probably by improving growth plate structure and dynamics. The processes of chondrocyte proliferation, death, hypertrophy, and the cartilaginous composition in the growth plate were partially improved in young treated XLH mice. In conclusion, these findings contribute to understand the role of FGF23 signaling in growth plate metabolism and show that this may occur despite continuous hypophosphatemia.

Silene uniflora Extracts for Strawberry Postharvest Protection.

Halophytes are gaining considerable attention due to their applications in saline agriculture, phytoremediation, medicine, and secondary metabolite production. This study investigated the bioactive components present in Silene uniflora (sea campion) hydromethanolic extract, and their antimicrobial activity was evaluated both in vitro and ex situ against two strawberry phytopathogens, namely Botrytis cinerea (grey mold) and Colletotrichum nymphaeae (anthracnose fruit rot). The main identified phytochemicals were mome inositol, saturated fatty acid esters, and cyclotetracosane. In vitro tests demonstrated complete inhibition of the growth of B. cinerea and C. nymphaeae at extract concentrations of 1000 and 1500 µg·mL-1, respectively, with an activity comparable to that of fosetyl-Al and substantially higher than that of azoxystrobin. This activity was improved upon conjugation with chitosan oligomers (COS), yielding inhibition values of 750 and 1000 µg·mL-1. The COS-S. uniflora conjugate complexes were then tested as protective treatments for postharvest storage of strawberry fruit, resulting in high protection against artificially inoculated B. cinerea and C. nymphaeae at doses of 3750 and 5000 µg·mL-1, respectively. The reported results open the door to the valorization of this halophyte as a source of biorationals for strawberry protection.

A Coating Based on Bioactive Compounds from Streptomyces spp. and Chitosan Oligomers to Control Botrytis cinerea Preserves the Quality and Improves the Shelf Life of Table Grapes.

Botrytis cinerea is the most harmful postharvest disease of table grapes. Among the strategies that can be envisaged for its control, the use of coatings based on natural products is particularly promising. The study presented herein focuses on the assessment of the antagonistic capacity of two Streptomyces species and their culture filtrates against B. cinerea. Firstly, the secondary metabolites were characterized by gas chromatography-mass spectrometry, with N1-(4-hydroxybutyl)-N3-methylguanidine acetate and 2R,3S-9-[1,3,4-trihydroxy-2-butoxymethyl]guanine acetate as the main compounds produced by S. lavendofoliae DSM 40217; and cyclo(leucyloprolyl) and cyclo(phenylalanylprolyl) as the most abundant chemical species for S. rochei DSM 41729. Subsequently, the capacity of S. lavendofoliae DSM 40217 and S. rochei DSM 41729 to inhibit the growth of the pathogen was tested in dual culture plate assays, finding 85-90% inhibition. In agar dilution tests, their culture filtrates resulted in effective concentration values (EC90) in the 246-3013 µg·mL-1 range. Upon the formation of conjugate complexes with chitosan oligomers (COS) to improve solubility and bioavailability, a synergistic behavior was observed, resulting in lower EC90 values, ranging from 201 to 953 µg·mL-1. Ex situ tests carried out on 'Timpson' and 'Red Globe' table grapes using the conjugate complexes as coatings were found to maintain the turgor of the grapes and delay the appearance of the pathogen by 10-15 days at concentrations in the 750-1000 µg·mL-1 range. Hence, the conjugate complexes of COS and the selected Streptomyces spp. culture filtrates may be put forward as promising protection treatments for the sustainable control of gray mold.

Attrition from Care Among Men Initiating ART in Male-Only Clinics Compared with Men in General Primary Healthcare Clinics in Khayelitsha, South Africa: A Matched Propensity Score Analysis.

Men have higher rates of attrition from antiretroviral therapy (ART) programs than women. In Khayelitsha, a high HIV prevalence area in South Africa, two public sector primary healthcare clinics offer services, including HIV testing and treatment, exclusively to men. We compared attrition from ART care among men initiating ART at these clinics with male attrition in six general primary healthcare clinics in Khayelitsha. We described baseline characteristics of patients initiating ART at the male and general clinics from 1 January 2014 to 31 March 2018. We used exposure propensity scores (generated based on baseline health and age) to match male clinic patients 1:1 to males at other clinics. The association between attrition (death or loss to follow-up, defined as no visits for nine months) and clinic type was estimated using Cox proportional hazards regression. Follow-up time began at ART initiation and ended at attrition, clinic transfer, or dataset closure. Before matching, patients from male clinics (n = 784) were younger than males from general clinics (n = 2726), median age: 31.2 vs 35.5 years. Those initiating at male clinics had higher median CD4 counts at ART initiation [Male Clinic 1: 329 (IQR 210-431), Male Clinic 2: 364 (IQR 260-536), general clinics 258 (IQR 145-398), cells/mm3]. In the matched analysis (1451 person-years, 1568 patients) patients initiating ART at male clinics had lower attrition (HR 0.71; 95% CI 0.60-0.85). In separate analyses for each of the two male clinics, only the more established male clinic showed a protective effect. Male-only clinics reached younger, healthier men, and had lower ART attrition than general services. These findings support clinic-specific adaptations to create more male-friendly environments.

Outcomes of flucytosine-containing combination treatment for cryptococcal meningitis in a South African national access programme: a cross-sectional observational study.

BACKGROUND: Although flucytosine is a key component of WHO-recommended induction treatment for HIV-associated cryptococcal meningitis, this antifungal agent is not widely available in low-income and middle-income countries due to limited production and cost. In 2018, a national flucytosine access programme was initiated in South Africa. We aimed to determine the effectiveness of flucytosine-containing induction regimens in routine care to motivate for the urgent registration of flucytosine and its inclusion in treatment guidelines. METHODS: In this cross-sectional study, we compared outcomes of adults aged 18 years and older with incident laboratory-confirmed cryptococcal meningitis treated with or without flucytosine-containing regimens at 19 sentinel hospitals in South Africa. A case of cryptococcosis was defined as illness in an adult with: (1) positive cerebrospinal fluid (CSF) India ink microscopy; (2) a positive CSF cryptococcal antigen test; or (3) culture of Cryptococcus neoformans or Cryptococcus gattii from CSF or any other specimen. We excluded patients without a case report form, those with an unknown or negative HIV serology result, those with a recurrent episode, and those who did not receive antifungal treatment in hospital. We assessed cumulative in-hospital mortality at 14 days and 30 days and calculated the overall crude in-hospital case-fatality ratio. We used random-effects logistic regression to examine the association between treatment group and in-hospital mortality. FINDINGS: From July 1, 2018, to March 31, 2020, 10 668 individuals were diagnosed with laboratory-confirmed cryptococcal meningitis, 7787 cases diagnosed at non-enhanced surveillance sites and 567 cases from eight enhanced surveillance sites with no access to flucytosine were excluded. Of 2314 adults with a first episode of cryptococcosis diagnosed at 19 facilities with access to flucytosine, 1996 had a case report form and of these, 1539 received induction antifungal treatment and were confirmed HIV-seropositive first-episode cases. Of 1539 patients who received antifungal therapy, 596 (38·7%) individuals received a flucytosine-containing regimen and 943 (61·3%) received another regimen. The median age was 36 years (IQR 32-43) and 906 (58·9%) participants were male and 633 (41·1%) were female. The crude in-hospital case-fatality ratio was 23·9% (95% CI 20·0-27·0; 143 of 596) in those treated with flucytosine-containing regimens and 37·2% (95% CI 34·0-40·0; 351 of 943) in those treated with other regimens. Patients admitted to non-academic hospitals (adjusted odds ratio [aOR] 1·95 [95% CI 1·53-2·48]; p<0·0001) and those who were antiretroviral treatment-experienced (aOR 1·30 [1·02-1·67]; p=0·033) were more likely to receive flucytosine. After adjusting for relevant confounders, flucytosine treatment was associated with a 53% reduction in mortality (aOR 0·47 [95% CI 0·35-0·64]; p<0·0001). Among survivors, the median length of hospital admission in the flucytosine group was 11 days (IQR 8-15) versus 17 days (13-21) in the comparison group (p=0·0010). INTERPRETATION: In-hospital mortality among patients treated with a flucytosine-containing regimen was comparable to reduced mortality reported in patients receiving a flucytosine-containing regimen in a recent multicentre African clinical trial. Flucytosine-based treatment can be delivered in routine care in a middle-income country with a substantial survival benefit. FUNDING: National Institute for Communicable Diseases, a Division of the National Health Laboratory Service. TRANSLATION: For the Zulu translation of the abstract see Supplementary Materials section.

HIV Self-testing Among Previously Diagnosed HIV-Positive People in Khayelitsha, South Africa: No Evidence of Harm but may Facilitate Re-engagement in ART Care.

In South Africa, where an estimated 34% of nearly 7-million HIV-positive people were not on antiretroviral therapy (ART) in 2019, innovative strategies to diagnose and link people to care are needed. HIV self-testing (HIVST) is one such strategy. However, there is concern that access to HIVST might result in re-testing among people on ART, with a risk of false negative results and disengagement from care. Between November 2017 and December 2018, HIVST kits were distributed at a private pharmacy and at HIV testing outreach events. Each participant was instructed to report their result via SMS and those who did not were followed-up telephonically 10 days later. Electronic medical records of participants were searched for evidence of HIV services 6 months before and after enrollment. Of 1482 participants, 163 (11%) were previously diagnosed HIV-positive prior to taking the test. Of these, 123 reported a result, however 87% reported a negative result. Of the 163 previously diagnosed, 84 were not in ART care prior to the test, with 15 (18%) linking to care post-test. Of 79 who were in ART care prior to the test, 76 (96%) remained in care, even though 51 (67%) had reported a negative result. Overall, 29% of participants reported their result via SMS, and 48% when telephoned. Despite efforts to dissuade them, some previously diagnosed HIV-positive utilised HIVST. For those disengaged from care this may facilitate re-engagement. Self-testing among those already in care, regardless of the reported result, did not disrupt their treatment, and their reasons for doing the test remain unclear.

Dwarf Pomegranate (Punica granatum L. var. nana): Source of 5-HMF and Bioactive Compounds with Applications in the Protection of Woody Crops.

While the properties of edible pomegranate varieties have been widely explored, there is little information on ornamental types. In this study, possible alternatives for the valorization of dwarf pomegranate fruits have been explored. The characterization of their hydromethanolic extract by gas chromatography-mass spectrometry evidenced the presence of high contents of 5-hydroxymethylfurfural (a carbon-neutral feedstock for the production of fuels and other chemicals) and ß- and γ-sitosterol stereoisomers. The microbicidal activity of the crude extract, both alone and in a conjugate complex with chitosan oligomers (COS), was investigated against three plant pathogenic microorganisms that cause significant losses in woody crops: Erwinia amylovora, E. vitivora, and Diplodia seriata. In in vitro assays, a strong synergistic behavior was found after conjugation of the bioactive constituents of the fruit extract with COS, resulting in minimum inhibitory concentration (MIC) values of 750 and 375 µg·mL-1 against E. amylovora and E. vitivora, respectively, and an EC90 value of 993 µg·mL-1 against D. seriata. Hence, extracts from the non-edible fruits of this Punicaceae may hold promise as a source of high value-added phytochemicals or as environmentally friendly agrochemicals.

The Combination of Galanin (1-15) and Escitalopram in Rats Suggests a New Strategy for Alcohol Use Disorder Comorbidity with Depression.

Alcohol use disorder (AUD) is highly prevalent, and over 50% of AUD patients also suffer major depressive disorders. Selective 5-HT reuptake inhibitors (SSRIs) can reduce rodent ethanol drinking but exert modest clinical efficacy in alcoholic individuals. Finding new pharmacological strategies that could modulate alcohol consumption and depression is necessary. We have analyzed the effect of Galanin (1-15) [GAL(1-15)] on escitalopram (ESC)-mediated effect in alcohol consumption using the alcohol self-administration test, the nuclei involved in the effect, and whether GAL(1-15) + ESC modulated the response in despair or anxiety tests in animals under chronic alcohol intake. GAL(1-15) + ESC combination substantially reduced alcohol intake in the alcohol self-administration test and, moreover, enhanced the reduction of reward capacity of ESC on different reinforcers such as sucrose or saccharine. GAL(1-15) + ESC coadministration significantly decreases the number of C-Fos-IR TH cell bodies in the VTA, and PCA analysis suggests that one functional network, including VTA, RMTg and DR, is involved in these effects. Significantly in rats with chronic alcohol consumption, GAL(1-15) reversed adverse ESC-mediated effects in the depression-related behavioural test and forced swimming test. The results open up the possibility of using GAL(1-15) in combination with the SSRI Escitalopram as a novel strategy in AUD comorbidity with depression.

An analysis of the HIV testing cascade of a group of HIV-exposed infants from birth to 18 months in peri-urban Khayelitsha, South Africa.

BACKGROUND: Despite the reduction of HIV mother-to-child transmission, there are concerns regarding transmission rate in the breastfeeding period. We describe the routine uptake of 6 or 10 (6/10) weeks, 9 months and 18 months testing, with and without tracing, in a cohort of infants who received HIV PCR testing at birth (birth PCR) (with and without point of care (POC) testing) in a peri-urban primary health care setting in Khayelitsha, South Africa. METHODS: In this cohort study conducted between November 2014 and February 2018, HIV-positive mothers and their HIV-exposed babies were recruited at birth and all babies were tested with birth PCR. Results of routine 6/10 weeks PCR, 9 months and 18 months testing were followed up by a patient tracer. We compared testing at 6/10 weeks with a subgroup from historical cohort who was not tested with birth PCR. RESULTS: We found that the uptake of 6/10 weeks testing was 77%, compared to 82% with tracing. When including all infants in the cascade and comparing to a historical cohort without birth testing, we found that infants who tested a birth were 22% more likely to have a 6/10 weeks test compared to those not tested at birth. There was no significant difference between the uptake of 6/10 weeks testing after birth PCR POC versus birth PCR testing without POC. Uptake of 9 months and 18 months testing was 39% and 24% respectively. With intense tracing efforts, uptake increased to 45% and 34% respectively. CONCLUSION: Uptake of HIV testing for HIV-exposed uninfected infants in the first 18 months of life shows good completion of the 6/10 weeks PCR but suboptimal uptake of HIV testing at 9 months and 18 months, despite tracing efforts. Birth PCR testing did not negatively affect uptake of the 6/10 weeks HIV test compared to no birth PCR testing.

Attrition from HIV care among youth initiating ART in youth-only clinics compared with general primary healthcare clinics in Khayelitsha, South Africa: a matched propensity score analysis.

INTRODUCTION: Youth living with HIV (YLWH) are less likely to initiate antiretroviral therapy (ART) and remain in care than older adults. It is important to identify effective strategies to address the needs of this growing population and prevent attrition from HIV care. Since 2008, two clinics have offered youth-targeted services exclusively to youth aged 12-25 in Khayelitsha, a high HIV-prevalence, low-income area in South Africa. We compared ART attrition among youth in these two clinics to youth in regular clinics in the same area. METHODS: We conducted a propensity score matched cohort study of individuals aged 12-25 years initiating ART at eight primary care clinics in Khayelitsha between 1 January 2008 and 1 April 2018. We compared attrition, defined as death or loss to follow-up, between those attending two youth clinics and those attending general primary healthcare clinics, using Cox proportional hazards regression. Follow-up time began at ART initiation and ended at attrition, clinic transfer or dataset closure. We conducted sub-analyses of patients attending adherence clubs. RESULTS: The distribution of age, sex and CD4 count at ART initiation was similar across Youth Clinic A (N = 1383), Youth Clinic B (N = 1299) and general clinics (N = 3056). Youth at youth clinics were more likely than those at general clinics to have initiated ART before August 2011 (Youth Clinic A: 16%, Youth Clinic B: 23% and general clinics: 11%). Youth clinics were protective against attrition: HR 0.81 (95% CI: 0.71-0.92) for Youth Clinic A and 0.85 (0.74-0.98) for Youth Clinic B, compared to general clinics. Youth Clinic A club patients had lower attrition after joining an adherence club than general clinic patients in adherence clubs (crude HR: 0.56, 95% CI: 0.32-0.96; adjusted HR: 0.48, 95% CI: 0.28-0.85), while Youth Clinic B showed no effect (crude HR: 0.83, 95% CI: 0.48-1.45; adjusted HR: 1.07, 95% CI: 0.60-1.90). CONCLUSIONS: YLWH were more likely to be retained in ART care in two different youth-targeted clinics compared to general clinics in the same area. Our findings suggest that multiple approaches to making clinics more youth-friendly can contribute to improving retention in this important group.

Genome-wide sequencing analysis of Sgs1, Exo1, Rad51, and Srs2 in DNA repair by homologous recombination.

Homologous recombination is essential to maintain genome stability in response to DNA damage. Here, we have used genome-wide sequencing to quantitatively analyze at nucleotide resolution the dynamics of DNA end resection, re-synthesis, and gene conversion at a double-strand break. Resection initiates asymmetrically in an MRX-independent manner before proceeding steadily in both directions. Sgs1, Exo1, Rad51, and Srs2 differently regulate the rate and symmetry of early and late resection. Exo1 also ensures the coexistence of resection and re-synthesis, while Srs2 guarantees a constant and symmetrical DNA re-polymerization. Gene conversion is MMR independent, spans only a minor fraction of the resected region, and its unidirectionality depends on Srs2. Finally, these repair factors prevent the development of alterations remote from the DNA lesion, such as subtelomeric instability, duplication of genomic regions, and over-replication of Ty elements. Altogether, this approach allows a quantitative analysis and a direct genome-wide visualization of DNA repair by homologous recombination.

Delivering PrEP to Young Women in a Low-Income Setting in South Africa: Lessons for Providing Both Convenience and Support.

Daily oral pre-exposure prophylaxis (PrEP) is a key tool in addressing high HIV incidence among young women, and breaking the cycle of transmission. From 2017 to 2020, Médecins Sans Frontières (MSF) offered PrEP, in conjunction with contraception and risk-reduction counselling, to women aged 18-25, in a government-run clinic in Khayelitsha, a low income high HIV prevalence area in South Africa. Drawing on clinical, quantitative, and qualitative interview data, we describe participants' experiences and engagement with the PrEP program, participant adherence (measured by TFV-DP levels in dried blood spots) over time, and the indirect benefits of the PrEP program. Of 224 screened and eligible participants, 164 (73.2%) initiated PrEP, with no large differences between those who initiated and those who did not. Overall, 47 (29%) completed 18 months follow-up, with 15 (9.1%) attending all visits. 76 (46.9%) participants were lost to follow-up, 15 (9.1%) exited when leaving the area, and 28.7% of exits happened in the first month of the study. We identified two different trajectories of PrEP adherence: 67% of participants had, on average, consistently low TFV-DP levels, with the remaining 33% having sustained high adherence. Few baseline characteristics predicted good adherence. The main reported barrier to taking PrEP was forgetting to take or travel with the pills. Encouragement from others declined as a reported facilitator from month 6 to 18 (family: 93.1% vs 77.6%, p = 0.016, friends: 77.6% vs 41.4%, p ≤ 0.001, partners: 62.1% vs 46.6%, p = 0.096, other PrEP users: 89.7% vs 74.1%, p = 0.020). Disclosure to friends and family in some cases opened dialogue around sex, and helped to educate others about PrEP. Self-reported sex with more than one partner, and sex without a condom, decreased significantly after enrolment (p < 0.001, p = 0.063). In the individual interviews, participants credited their PrEP experience with changing their behaviour. Recognising the challenges with, but overall benefits from a package of care that includes the option of PrEP, lessons drawn from this study can help maximise persistence on PrEP within resource constraints. PrEP providers need to address participants' need for both convenience and social support.

Galanin (1-15) Enhances the Behavioral Effects of Fluoxetine in the Olfactory Bulbectomy Rat, Suggesting a New Augmentation Strategy in Depression.

BACKGROUND: Selective serotonergic reuptake inhibitors, including fluoxetine (FLX), are the most commonly used for the treatment of major depression. However, they are effective for remission in only 30% of patients. Recently, we observed that Galanin (1-15) [GAL(1-15)] enhanced the antidepressant effects of FLX in naïve animals, suggesting a new augmentation strategy in depression. METHODS: We have analyzed in an animal model of depression, the olfactory bulbectomy (OBX) rats, the effect of GAL(1-15) on FLX-mediated responses in the forced swimming test and the sucrose preference test and the involvement of GAL receptor 2 with its antagonist, M871. We have also studied the corticosterone levels in OBX after the coadministration of GAL(1-15) with FLX. Moreover, we studied whether the effects of GAL(1-15) on FLX actions were mediated via auto- and heteroreceptor 5-HT1A (5-HT1AR), analyzing the binding characteristics, mRNA levels, and functionality of 5-HT1AR in the dorsal hippocampus. RESULTS: GAL(1-15) enhances the antidepressant-like effects induced by FLX in OBX animals in the forced swimming test and the sucrose preference test. The involvement of the GALR2 was demonstrated with M871. Importantly, the mechanism underlying the GAL(1-15)/FLX interactions in the OBX animals involves the 5-HT1AR in the hippocampus at the plasma membrane (increase of affinity and density of 5HT1AR in the DG) and transcriptional (increase of 5HT1AR mRNA levels in DG and CA1) levels. Besides, the coadministration of GAL(1-15) and FLX also reduced OBX-increased corticosterone levels. CONCLUSIONS: The results open the possibility to use GAL(1-15) in combination with FLX as a novel strategy for the treatment of depression.