A Phase 1 Clinical Trial to Assess the Safety and Pharmacokinetics of a Tenofovir Alafenamide/Elvitegravir Insert Administered Rectally for HIV Prevention.

BACKGROUND: On-demand topical products could be an important tool for HIV prevention. We evaluated the safety, pharmacokinetics, and ex vivo pharmacodynamics of a tenofovir alafenamide/elvitegravir (TAF/EVG; 16 mg/20 mg) insert administered rectally. METHODS: MTN-039 was a Phase 1, open-label, single-arm, 2-dose study. Blood, rectal fluid (RF), and rectal tissue (RT) were collected over 72 hours (hr) following rectal administration of one and two TAF/EVG inserts for each participant. ClinicalTrials.gov Identifier: NCT04047420. RESULTS: TAF/EVG inserts were safe and well tolerated. EVG and tenofovir (TFV) were detected in blood plasma at low concentrations: median peak concentrations after 2 inserts were EVG 2.4 ng/mL and TFV 4.4 ng/mL. RT EVG peaked at 2-hr (median 2 inserts= 9 ng/mg) but declined to BLQ in the majority of samples at 24-hr, whereas TFV-DP remained high >2,000 fmol/million cells for 72-hr with 2 inserts. Compared to baseline, median cumulative log10 HIV p24 antigen of ex vivo rectal tissue HIV infection was reduced at each timepoint for both 1 and 2 inserts (p<0.065 and p<0.039, respectively). DISCUSSION: Rectal administration of TAF/EVG inserts achieved high rectal tissue concentrations of EVG and TFV-DP with low systemic drug exposure and demonstrable ex vivo inhibition of HIV infection for 72 hours.

Tenofovir Douche as HIV Preexposure Prophylaxis for Receptive Anal Intercourse: Safety, Acceptability, Pharmacokinetics, and Pharmacodynamics (DREAM 01).

BACKGROUND: Despite highly effective HIV preexposure prophylaxis (PrEP) options, no options provide on-demand, nonsystemic, behaviorally congruent PrEP that many desire. A tenofovir-medicated rectal douche before receptive anal intercourse may provide this option. METHODS: Three tenofovir rectal douches-220 mg iso-osmolar product A, 660 mg iso-osmolar product B, and 660 mg hypo-osmolar product C-were studied in 21 HIV-negative men who have sex with men. We sampled blood and colorectal tissue to assess safety, acceptability, pharmacokinetics, and pharmacodynamics. RESULTS: The douches had high acceptability without toxicity. Median plasma tenofovir peak concentrations for all products were several-fold below trough concentrations associated with oral tenofovir disoproxil fumarate (TDF). Median colon tissue mucosal mononuclear cell (MMC) tenofovir-diphosphate concentrations exceeded target concentrations from 1 hour through 3 to 7 days after dosing. For 6-7 days after a single product C dose, MMC tenofovir-diphosphate exceeded concentrations expected with steady-state oral TDF 300 mg on-demand 2-1-1 dosing. Compared to predrug baseline, HIV replication after ex vivo colon tissue HIV challenge demonstrated a concentration-response relationship with 1.9 log10 maximal effect. CONCLUSIONS: All 3 tenofovir douches achieved tissue tenofovir-diphosphate concentrations and colorectal antiviral effect exceeding oral TDF and with lower systemic tenofovir. Tenofovir douches may provide a single-dose, on-demand, behaviorally congruent PrEP option, and warrant continued development. Clinical Trials Registration . NCT02750540.

Prevalence of SARS-CoV-2 Infection among Children and Adults in 15 US Communities, 2021

During January-August 2021, the Community Prevalence of SARS-CoV-2 Study used time/location sampling to recruit a cross-sectional, population-based cohort to estimate SARS-CoV-2 seroprevalence and nasal swab sample PCR positivity across 15 US communities. Survey-weighted estimates of SARS-CoV-2 infection and vaccine willingness among participants at each site were compared within demographic groups by using linear regression models with inverse variance weighting. Among 22,284 persons >2 months of age and older, median prevalence of infection (prior, active, or both) was 12.9% across sites and similar across age groups. Within each site, average prevalence of infection was 3 percentage points higher for Black than White persons and average vaccine willingness was 10 percentage points lower for Black than White persons and 7 percentage points lower for Black persons than for persons in other racial groups. The higher prevalence of SARS-CoV-2 infection among groups with lower vaccine willingness highlights the disparate effect of COVID-19 and its complications.

Tenofovir, emtricitabine, lamivudine and dolutegravir concentrations in plasma and urine following drug intake cessation in a randomized controlled directly observed pharmacokinetic trial to aid point-of-care testing.

BACKGROUND: Poor adherence to ART and pre-exposure prophylaxis (PrEP) can impact patient and public health. Point-of-care testing (POCT) may aid monitoring and adherence interventions. OBJECTIVES: We report the pharmacokinetics of tenofovir [dosed as tenofovir disoproxil (TDF) and tenofovir alafenamide (TAF)], emtricitabine (FTC), lamivudine (3TC) and dolutegravir (DTG) in plasma and urine following drug cessation to evaluate adherence targets in urine for POCT. METHODS: Subjects were randomized (1:1) to receive DTG/FTC/TAF or DTG/3TC/TDF for 15 days. Plasma and spot urine were collected on Day 15 (0-336 h post final dose). Drug concentrations were quantified using LC-MS, and non-linear mixed-effects models applied to determine drug disposition between matrices and relationship with relevant plasma [dolutegravir protein-adjusted 90% inhibitory concentration (PA-IC90 = 64 ng/mL) and minimum effective concentration (MEC = 324 ng/mL)] and urinary thresholds [tenofovir disoproxil fumarate 1500 ng/mL]. RESULTS: Of 30 individuals enrolled, 29 were included (72% female at birth, 90% Caucasian). Median (range) predicted time to plasma dolutegravir PA-IC90 and MEC were 83.5 (41.0-152) and 49.0 h (23.7-78.9), corresponding to geometric mean (90%) urine concentrations of 5.42 (4.37-6.46) and 27.4 ng/mL (22.1-32.7). Tenofovir in urine reached 1500 ng/mL by 101 h (58.6-205) with an equivalent plasma concentration of 6.20 ng/mL (4.21-8.18). CONCLUSIONS: These data support use of a urinary tenofovir threshold of <1500 ng/mL (tenofovir disoproxil fumarate-based regimens) as a marker of three or more missed doses for a POCT platform. However, due to low dolutegravir concentrations in urine, POCT would be limited to a readout of recent dolutegravir intake (one missed dose).

History of Rectal Product Use and Country of Residence Influence Preference for Rectal Microbicide Dosage Forms Among Young Sexual and Gender Minorities: A Multi-country Trial Comparing Placebo Douche, Suppository, and Insert Products.

The DESIRE Study (MTN-035) explored product preference among three placebo rectal microbicide (RM) formulations, a rectal douche (RD), a suppository, and an insert, among 210 sexually active transgender people and men who have sex with men in five counties: the United States, Peru, Thailand, South Africa, and Malawi. Participants used each product prior to receptive anal sex (RAS) for 1 month, following a randomly assigned sequence, then selected their preferred product via computer assisted self-interview. In-depth interviews examined reasons for preference. We compared product preference and prior product use by country to explore whether geographic location and experience with the similar products impacted preference. A majority in the United States (56%) and Peru (58%) and nearly half in South Africa (48%) preferred the douche. Most in Malawi (59%) preferred the suppository, while half in Thailand (50%) and nearly half in South Africa (47%) preferred the insert. Participants who preferred the douche described it as quick and easy, already routinized, and serving a dual purpose of cleansing and protecting. Those who preferred the insert found it small, portable, discreet, with quick dissolution. Those who preferred the suppository found the size and shape acceptable and liked the added lubrication it provided. Experience with product use varied by country. Participants with RD experience were significantly more likely to prefer the douche (p = 0.03). Diversifying availability of multiple RM dosage forms can increase uptake and improve HIV prevention efforts globally.

RESUMEN: El estudio DESIRE (MTN-035) exploró la preferencia de producto entre tres formulaciones de microbicida rectal (MR) de placebo, una ducha rectal, un supositorio y un inserto, entre 210 personas transgénero y hombres que tienen sexo con hombres en cinco países: los Estados Unidos, Perú., Tailandia, Sudáfrica y Malawi. Los participantes utilizaron cada producto antes del sexo anal receptive (SAR) durante un mes, siguiendo una secuencia asignada al azar, luego seleccionaron su producto preferido mediante una autoentrevista asistida por computadora. Las entrevistas en profundidad examinaron los motivos de preferencia. Comparamos la preferencia de producto y el uso previo del producto por país para explorar si la ubicación geográfica y la experiencia con la forma farmacéutica impactaron la preferencia. Una mayoría en los Estados Unidos (56%) y Perú (58%) y casi la mitad en Sudáfrica (48%) prefirieron la ducha rectal. La mayoría en Malawi (59%) prefirió el supositorio, mientras que la mitad en Tailandia (50%) y casi la mitad en Sudáfrica (47%) prefirió el inserto. Los participantes que prefirieron la ducha rectal la describieron como rápida y fácil, ya parte de su rutina y que tenía el doble propósito de limpiar y proteger. Los que prefirieron el inserto lo consideraron pequeño, portátil, discreto y de rápida disolución. Los que prefirieron el supositorio encontraron que tenía un tamaño y forma aceptables y proveía lubricación adicional. La experiencia con el uso del producto varió según el país. Los participantes con experiencia con duchas rectales tenían significativamente más probabilidades de preferir la ducha rectal (p = 0,03). Diversificar la disponibilidad de múltiples formas farmacéuticas de MR puede aumentar la aceptación y mejorar los esfuerzos de prevención del VIH a nivel mundial.

"Sorry for Holding You Up": Surgeons' Apologies for Lateness in Clinic Settings.

Doctors running late may convey a lack of respect which can impair the therapeutic relationship. This study examines how surgeons address lateness in consultations with patients. We analyzed 52 consultation recordings from a range of surgical specialties in an Australian metropolitan setting. Conversation analysis was used to analyze interactional sequences where lateness was addressed. Six sequences were identified within four recordings. The two consultations with two apologies include a surgeon and registrar apologizing in a neurosurgical consultation and a surgeon apologizing twice within a colorectal consultation. Apologies were either accepted or responded to with an account for not accepting the apology. When these accounts were made, consultations could only progress when patients accepted an explanation for lateness or the degree of complainability about lateness was reduced. The infrequent occurrence of apologies for lateness, and the way in which these sequences unfolded when they did occur, suggest that there is greater acceptability of lateness for surgeons than in ordinary social situations.

Patient and Clinician Sociodemographics and Sexual History Screening at a Multisite Federally Qualified Health Center: A Mixed Methods Study.

PURPOSE: In 2018, there were 68 million sexually transmitted infections in the United States. Sexual history screening is an evidence-based practice endorsed by guidelines to identify risk of these infections and adverse sexual health outcomes. In this mixed methods study, we investigated patient- and clinician-level characteristics associated with receipt of sexual history screening, and contextualized these differences in more depth. METHODS: We collected sociodemographics of patients from the electronic health record and sociodemographics of their primary care clinicians via a census survey. Semistructured interviews were conducted with key practice staff. We conducted multilevel crossed random effects logistic regression analysis and thematic analysis on quantitative and qualitative data, respectively. RESULTS: A total of 53,246 patients and 56 clinicians from 13 clinical sites participated. Less than one-half (42.4%) of the patients had any sexual history screening documented in their health record. Patients had significantly higher odds of documented screening if they were gay or lesbian (OR = 1.23), were cisgender women (OR = 1.10), or had clinicians who were cisgender women (OR = 1.80). Conversely, patients' odds of documented screening fell significantly with age (OR per year = 0.99) and with the number of patients their clinicians had on their panels (OR per patient = 0.99), and their odds were significantly lower if their primary language was not English (OR = 0.91). In interviews, key staff expressed discomfort discussing sexual health and noted assumptions about patients who are older, in long-term relationships, or from other cultures. Discordance of patient-clinician gender and patients' sexual orientation were also noted as barriers. CONCLUSIONS: Interventions are needed to address the interplay between the social and contextual factors identified in this study, especially those that elicited discomfort, and the implementation of sexual history screening.

Weekly somapacitan had no adverse effects on glucose metabolism in adults with growth hormone deficiency.

PURPOSE: The long-term effects of long-acting growth hormone (LAGH) analogues on glucose metabolism in adult growth hormone deficiency (AGHD) are not known. We investigated the impact of LAGH somapacitan, administered once-weekly, on glucose metabolism in patients with AGHD. METHODS: In post hoc-defined analyses, we compared the effects of somapacitan with daily growth hormone (GH) and placebo on fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-ß) in patients with AGHD across a unique data set from three phase 3 randomized controlled trials (REAL 1, REAL 2 and REAL Japan). RESULTS: No new cases of diabetes mellitus were reported with somapacitan. Among GH-naïve patients (n = 120 somapacitan, n = 119 daily GH), higher changes from baseline in FPG, HOMA-IR and fasting insulin levels were observed with daily GH versus somapacitan at 34 weeks, but not at 86 weeks. HbA1c and HOMA-ß did not differ between groups at either timepoint. Among treatment-naïve patients, sex, age, fasting insulin, glucose tolerance status and body mass index did not influence changes in glucose metabolism. In previously treated patients (REAL 1 extension: n = 51 somapacitan, n = 52 daily GH; REAL 2: n = 61 and n = 31, respectively; REAL Japan: n = 46 and n = 16, respectively), the difference in changes from baseline were not statistically significant between somapacitan and daily GH for any glucose metabolism parameters. CONCLUSIONS: Somapacitan, compared with daily GH, did not adversely affect glucose metabolism up to 86 weeks in a large cohort of treatment-naïve or previously treated patients with AGHD. Trial registrations (date of registration): NCT02229851 (2 September 2014), NCT02382939 (3 March 2015), NCT03075644 (7 March 2017).

A dyadic advance care planning intervention for people with early-stage dementia and their family caregivers in a community care setting: a feasibility trial.

BACKGROUND: Advance care planning (ACP) is highly relevant for people with early-stage dementia to communicate their care preferences for serious illness conditions with their family caregivers before they become mentally incapacitated. METHODS: A multi-centre, quasi-experimental study was conducted to test the feasibility and acceptability of a theory-guided, dyadic ACP intervention ('Have a Say' programme) among participants with early-stage dementia-family caregiver dyads. The feasibility of the trial design, intervention procedures, subject recruitment and retention, and study instruments were assessed. Study outcomes were measured at baseline (T0), immediately after the intervention (T1), and at 1 month (T2) and 3 months post-intervention (T3). Acceptability of the intervention was determined by the satisfaction score, completion rate and qualitative interviews as process evaluation with a purposive sample of participants and ACP facilitators. Generalised estimating equations were performed to examine differential changes between groups over time, with covariates adjusted. RESULTS: Subject recruitment from five elderly community centres yielded a recruitment rate of 60% and resulted in 36 client-caregiver dyads. The intervention was acceptable to the dyads, with a mean satisfaction score of 4.4 out of 5 and completion rate of 94.4%. The attrition rates at T1, T2, and T3 were 8.3%, 13.9%, and 19.4%, respectively. The intervention group reported a significantly greater improvement in the readiness for ACP at T1, self-efficacy for ACP at T3, and dyadic concordance on end-of-life care preferences at all time points than the control group, but not on depressive symptoms. Family caregivers in the intervention group reported a significantly higher caregiving burden at T2 than the control group. The qualitative findings revealed that triadic involvement of and trusting relationships among the dyads and ACP facilitators, and documentation of clients' views are the programme strengths, while the structured format and discussion about medical issues posed implementation challenges. CONCLUSIONS: This ACP intervention and trial design were feasible and acceptable to the dyads. Several refinements were identified, including adding a nurse-led group-based session for information giving, allowing flexibility in arrangement, and adding measure of ACP engagement of family caregivers. A rigorous trial to test the effects of the ACP intervention is warranted. TRIAL REGISTRATION: Retrospectively registered on 14/08/2020 at clinicaltrials.gov (Identifier: NCT04513106).

A latent trajectory analysis of young sexual and gender minorities' adherence to three rectal microbicide placebo formulations (MTN-035; a randomized crossover trial).

BACKGROUND: Rectal microbicides (RM) are biomedical HIV prevention products that aim to prevent or reduce the transmission of HIV and other sexually transmitted infections (STIs). RM modalities may be beneficial for populations who have complex lifestyles, difficulties adhering to pre-exposure prophylaxis (PrEP) regimens, and/or have limited access to care. MTN-035 (DESIRE; Developing and Evaluating Short-Acting Innovations for Rectal Use), a randomized crossover trial, aimed to evaluate the safety and acceptability of, and adherence to, three placebo RM modalities (douche, insert, and suppository) prior to receptive anal intercourse. METHODS: We conducted latent trajectory analysis to identify clusters of individuals who shared similar trajectories in acceptability and adherence for each product (douche, insert, and suppository) over time. We analyzed weekly short messaging service (SMS) use reports for each modality as reported by enrolled sexual and gender minority (SGM) participants. RESULTS: Two trajectories for each product were identified: a "protocol compliant" trajectory (i.e., at least one product use occasion per week) and "high use" trajectory (i.e., more than three product use occasions per week). Participants with high use were more likely to lack access to PrEP and have higher intentions to utilize RM modalities compared to those who were protocol compliant. CONCLUSIONS: This study highlighted high adherence to RM modalities among SGM. As research into viable HIV prevention modalities continues to evolve, tailored intervention strategies are needed to support the uptake of and adherence to alternative prevention modalities that are behaviorally congruent with targeted users. TRIAL REGISTRATION: NCT03671239 (14/09/2018).

Sensory-based interventions for the immediate de-escalation of agitation in people with dementia: A systematic review.

Objectives: Sensory-based interventions are commonly used to reduce the occurrence of agitation in people with dementia over extended periods. However, the evidence regarding their immediate de-escalation effects is unclear. The objectives of this systematic review are to (a) identify which sensory-based interventions have been used for de-escalating agitation and (b) examine the immediate effects of these interventions on de-escalating agitation in people with dementia.Methods: A systematic review was performed in accordance with PRISMA guidelines. Data sources were identified by searching Embase, Medline, PsycINFO, and CINAHL for publications up to 2 March 2022. The de-escalating agitation effect had to be measured during the intervention or within 15 min after commencing the treatment. Only randomized controlled trials or quasi-experimental studies published in English were included.Results: Nine studies met the inclusion criteria: two randomized controlled trials, one cross-over study, and six quasi-experimental studies. All were conducted in Western countries, involving a total of 246 participants. Music-related interventions were investigated in seven studies, and a positive effect on de-escalating agitation was found, with no side-effects. All of the studies had methodological limitations, including a single group design, blinding, an insufficient sample size, and imprecisely reported results.Conclusion: There is a profound dearth of rigorous studies examining the immediate agitation de-escalating effects of sensory-based interventions on people with dementia. However, the limited evidence on music-related interventions is encouraging. More rigorous research is recommended to confirm the effects.

Longitudinal associations of relationship support and strain and internalized homophobia with mental health among middle-aged and older gay and bisexual men.

Objectives: Mental health concerns (e.g. depression, anxiety) that negatively impact gay, bisexual, and other men who have sex with men (GBMSM) persist over the life course and into old age, but less is known about potential contributors to GBMSM's mental health. Close relationships can be a source of risk or resilience from stress, exerting direct relationships on mental health, and may mediate well-established associations between minority stress and mental health. This study examined whether primary partner relationship support and strain were uniquely associated with, and mediated the association between internalized homophobia, and mental health among older GBMSM.Methods: GBMSM (N = 517, M age = 60) from the Multicenter AIDS Cohort Study, who were in primary relationships with men, provided self-report data at four timepoints. We used multilevel modeling to examine longitudinal associations among relationship support and strain and internalized homophobia with depression and anxiety.Results: Relationship strain, but not support, was positively associated with mental health concerns longitudinally. There was a significant, positive indirect effect of internalized homophobia on depression and anxiety through strain, but no support. Internalized homophobia was positively associated with relationship strain, which was positively associated with mental health symptoms longitudinally.Conclusions: Relationship strain was associated with depression and anxiety longitudinally among middle-aged and older GBMSM and mediated associations of internalized homophobia with mental health. The role of partner support warrants further investigation. Mental health interventions are critically needed for older GBMSM and, for partnered GBMSM, should include strategies for reducing relationship strain to foster well-being.

Dementia literacy in an ageing world.

AIMS: This discursive article aims to capture and explore the most pertinent nursing aspects of dementia literacy (DL). BACKGROUND: Older people constitute a rapidly increasing proportion of the global population, experiencing higher risk of developing chronic disease, including dementia. It is important that older adults receive and understand reliable health-related information, as age-related changes may affect the level of health literacy in an older person. It has been suggested that older adults may have poorer health literacy than younger adults, associated with poorer health outcomes. Health literacy, how people receive, interpret and act on health information, play a significant role in dementia-related disorders, both as a possible predicter of onset of dementia and as a potential modifier of cognitive decline. Dementia literacy constitutes one aspect of health literacy in relation to nursing care, related to knowledge of dementia-related disorders and approaches towards older people with dementia. DESIGN: This discursive article explores the importance of DL for the nursing profession, including dementia-related assessment, education and interventions. METHOD: This article is informed by analysis of relevant descriptive and empirical literature and policy documents related to DL, an increasingly important aspect of dementia-related nursing care. Valid assessment tools that can accurately assess aspects an individuals' DL are examined; these have the potential to help nurses detect dementia-related symptoms. With early detection and prevention of dementia, older people may have better chance of benefiting from evolving treatment options. CONCLUSION: Greater attention needs to be given to the issue of DL in older people, especially in terms of nursing assessment and care. Globally, increased DL-related education is urgently required to improve knowledge of this concept; this includes public awareness initiatives to better understanding this chronic condition. IMPLICATION NURSING PRACTICE: Enhancing DL has the potential to empower older people to have greater access to healthcare services and to make more informed decisions about their health care. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution, as this is a discursive article.

Loneliness at end-of-life: A scoping review.

AIMS AND OBJECTIVES: To map and synthesise the literature on loneliness at end-of-life and identify key knowledge gaps in loneliness research. BACKGROUND: Declined health conditions, reduced social engagement, loss of social roles, and fear of death may lead to loneliness at end-of-life. However, systematic information about loneliness at end-of-life is scant. METHODS: This scoping review followed the methodology proposed by Arksey and O'Malley. Nine electronic databases were searched from January 2001 to July 2022. Studies about loneliness at end-of-life were included. Two review authors independently screened and selected relevant studies and performed the data charting. The PAGER framework was employed to collate, summarise and report the results. The PRISMA-ScR checklist was included. RESULTS: A total of 23 studies were included in this review (12 qualitative, 10 quantitative, and one mixed-methods design). There was not reliable data about the prevalence of loneliness among adults at end-of-life internationally. Three or 20-item UCLA loneliness scale was frequently used to measure loneliness. Factors predisposed adults at end-of-life to loneliness included passive and active withdrawal from social networks, inability to share emotions and to be understood, and inadequate support on spirituality. Four strategies were identified to alleviate loneliness, yet none have been substantiated in clinical trials. Interventions facilitating spirituality, social interactions and connectedness seem effective in alleviating loneliness. CONCLUSIONS: This is the first scoping review on loneliness at end-of-life, synthesising evidence from qualitative, quantitative, and mixed-methods studies. Loneliness among adults at end-of-life is under-investigated and there is a prominent need to address existential loneliness at end-of-life. RELEVANCE TO CLINICAL PRACTICE: All nurses should proactively assess loneliness or perceived social isolation for clients with life-limiting conditions, regardless of social networks. Collaborative efforts (e.g., medical-social collaborations) to promote self-worthiness, social engagement and connectedness with significant others and social networks are needed. PATIENT OR PUBLIC CONTRIBUTION: No patient or public involvement.

MTN-033: a Phase 1 Study Comparing Applicator versus "as Lubricant" Delivery of Rectal Dapivirine Gel.

Data to inform behaviorally congruent delivery of rectal microbicides as lubricants are scant. Dapivirine (DPV) is a nonnucleoside reverse transcriptase inhibitor which has been demonstrated to be well-tolerated and efficacious in multiple clinical trials when used in a vaginal ring formulation. DPV gel administered rectally with an applicator was found to be well-tolerated in a phase 1 clinical trial. MTN-033, a single site, open label, sequence randomized, crossover study, enrolled HIV-negative men to receive 0.05% DPV gel intrarectally using an applicator (2.5 g) and self-administered on an artificial phallus as lubricant (up to 10 g). The study evaluated the pharmacokinetics (in plasma, rectal fluid, and mucosal rectal tissue), safety, acceptability, and pharmacodynamics of DPV gel when applied rectally. Statistical comparisons between methods of application were performed using mixed effects models or Wilcoxon's signed rank tests. Sixteen participants used DPV gel by applicator and 15/16 participants used gel as lubricant (mean, 1.8 g; SD, 0.8). DPV plasma AUC0-24h after use as lubricant was estimated to be 0.41 times the AUC0-24h (95% CI 0.24, 0.88) after use with applicator. While DPV was quantifiable in plasma and luminal fluid, it was not quantifiable in tissue for both applicator and as lubricant administration. No related adverse events (AE) were reported, and 15/15 participants felt the gel was easy to use. Evidence of local delivery and systemic absorption of DPV when dosed as an anal lubricant supports the feasibility and potential for development of lubricant-delivered rectal microbicides. There were no safety concerns associated with use of DPV gel and participants reported finding it easy to use. However, lower DPV exposure in plasma and lack of quantifiable DPV in rectal tissue indicate that higher potency, concentration, and longer half-life antiretrovirals with optimized formulations will be needed to achieve protective tissue concentrations.

Growth Hormone Stops Excessive Inflammation After Partial Hepatectomy, Allowing Liver Regeneration and Survival Through Induction of H2-Bl/HLA-G.

BACKGROUND AND AIMS: Growth hormone (GH) is important for liver regeneration after partial hepatectomy (PHx). We investigated this process in C57BL/6 mice that express different forms of the GH receptor (GHR) with deletions in key signaling domains. APPROACH AND RESULTS: PHx was performed on C57BL/6 mice lacking GHR (Ghr-/- ), disabled for all GH-dependent Janus kinase 2 signaling (Box1-/- ), or lacking only GH-dependent signal transducer and activator of transcription 5 (STAT5) signaling (Ghr391-/- ), and wild-type littermates. C57BL/6 Ghr-/- mice showed striking mortality within 48 hours after PHx, whereas Box1-/- or Ghr391-/- mice survived with normal liver regeneration. Ghr-/- mortality was associated with increased apoptosis and elevated natural killer/natural killer T cell and macrophage cell markers. We identified H2-Bl, a key immunotolerance protein, which is up-regulated by PHx through a GH-mediated, Janus kinase 2-independent, SRC family kinase-dependent pathway. GH treatment was confirmed to up-regulate expression of the human homolog of H2-Bl (human leukocyte antigen G [HLA-G]) in primary human hepatocytes and in the serum of GH-deficient patients. We find that injury-associated innate immune attack by natural killer/natural killer T cell and macrophage cells are instrumental in the failure of liver regeneration, and this can be overcome in Ghr-/- mice by adenoviral delivery of H2-Bl or by infusion of HLA-G protein. Further, H2-Bl knockdown in wild-type C57BL/6 mice showed elevated markers of inflammation after PHx, whereas Ghr-/- backcrossed on a strain with high endogenous H2-Bl expression showed a high rate of survival following PHx. CONCLUSIONS: GH induction of H2-Bl expression is crucial for reducing innate immune-mediated apoptosis and promoting survival after PHx in C57BL/6 mice. Treatment with HLA-G may lead to improved clinical outcomes following liver surgery or transplantation.

Sexual behavior and medication adherence in men who have sex with men participating in a pre-exposure prophylaxis study of combinations of Maraviroc, Tenofovir Disoproxil Fumarate and/or Emtricitabine (HPTN 069/ACTG 5305).

HPTN 069/ACTG 5305 was designed to evaluate potential new PrEP regimens that included maraviroc, tenofovir disoproxil fumarate, and/or emtricitabine. The current analyses assessed antiretroviral (ARV) plasma concentrations in relation to sexual behavior in 224 cisgender men who have sex with men and 2 transgender women at risk for HIV. Poisson generalized estimating equations (GEE) regression were used to test for associations between self-reported sexual behavior, sociodemographic, behavioral variables, and study drug levels The median (IQR) age was 30 [25, 37] years old; 48.2% had completed college; 27.4% were Black and 21.7% Latino. At weeks 24 and 48, one third of participants reported condomless anal sex (CAS) in the prior month with more than one partner. CAS was associated with daily ARV drug use (χ2 = 12.64, p = 0.002). Older individuals and those with greater education were more likely to ingest ARV drugs daily (χ2 = 9.36, p = 0.009 and χ2 = 8.63, p = 0.013, respectively), while neither race nor ethnicity was associated with daily ARV drug use. Participants who reported recent condomless anal sex and/or advanced education had higher rates of daily ARV drug use. These data support the need for ongoing adherence counseling in clinical trials of new PrEP modalities.

Acceptability of a Dapivirine/Placebo Gel Administered Rectally to HIV-1 Seronegative Adults (MTN-026).

This study describes the acceptability of a rectal microbicide gel formulation using dapivirine (DPV) among men and women from two countries (United States and Thailand) participating in the Microbicide Trials Network-026 trial. We evaluated participants' acceptability of a rectal DPV/placebo gel as part of a Phase I trial (N = 26; 18 male, 8 female). Participants reported favorable acceptability of the study gel, with most participants reporting that they liked the gel the same (n = 14; 53.8%) or more (n = 11; 42.4%) than when they started the trial. Over half of participants noted that they would prefer the gel over condoms (n = 13; 50%) or that they liked condoms and the gel equally (n = 8; 30.8%). Side effects across products included leakage (n = 8; 30.8%), diarrhea (n = 4; 15.4%), or soiling (n = 1; 3.8%). The high acceptability of a rectal gel underscores its promise as a short-acting biomedical prevention, warranting future research for HIV prevention.Trial Registration: NCT03239483.

RESUMEN: Este estudio describe la aceptabilidad de un microbicida rectal (RM) con dapivirina (DPV) formulado como un gel por hombres y mujeres de dos países (Estados Unidos y Tailandia) que participaron como parte del Microbicide Trials Network (MTN)-026. Evaluamos la aceptabilidad de un gel rectal de DPV y un placebo como parte de un estudio de Fase I (N = 26; 18 hombres, 8 mujeres). Los participants informaron una aceptabilidad favorable sobre el gel del estudio; la mayoría de los participantes informaron que les gustó el gel igual (n = 14; 53.8%) o más (n = 11; 42.4%) que cuando comenzaron el estudio. Más de la mitad de los participantes señalaron que preferirían el gel sobre los condones (n = 13; 50%) o que les gustaban los condones y el gel por igual (n = 8; 30,8%). Los efectos de los productos incluyeron fugas (n = 8; 30,8%), diarrea (n = 4; 15,4%) o ensuciamiento (n = 1; 3,8%). La alta aceptabilidad de un gel rectal enfatiza su promesa para la prevención biomédica de acción corta y justifica futuras investigaciones para la prevención del VIH.

A 'good dyadic relationship' between older couples with one having mild cognitive impairment: a Q-methodology.

BACKGROUND: Cognitive impairment gradually brings changes to the relationship between older married couples. Therefore, this study aimed to understand the individual viewpoints of couple dyads on the important attributes of a 'good dyadic relationship' in the context of mild cognitive impairment (MCI), and to explore if the congruencies and discrepancies in their perceptions related to the quality and closeness of their relationship and well-being. METHODS: Q-methodology was used to reveal the perceptions of a 'good dyadic relationship' among couples with one having MCI. The participating couples were separated in two rooms and independently ranked 18 relationship attributes from least to most important on a 7-point Q-sort response grid. All participants also completed a post-sort interview and surveys to assess their psychological well-being and closeness. Q-sorts were analyzed using by-person factor analysis. RESULTS: Forty people with MCI and forty spousal partners completed the Q-sort. Three viewpoints, accounting for 48% of the total variance, were identified and were labeled 'Provider,' 'Problem-solver,' and 'Partner.' Different viewpoints of a 'good dyadic relationship' primarily varied by perceived importance of commitment, dedication, tolerance, and personal space. Despite these differences, there was wide consensus that respecting each other and cherishing the current moment are two universally salient attributes of a good relationship across all viewpoints. Couples with discrepant views scored significantly higher on perceptions of the quality of the relationship and closeness with the partner. CONCLUSIONS: This study advances the theoretical understanding of the dyadic relationship between couples with one having MCI, from both perspectives. MCI is a state in which couples can openly discuss their expectations. The findings provide practitioners with insights to work with couples experiencing MCI.

PCO-Based BLE Mesh Accelerator.

Bluetooth Low Energy (BLE) mesh networks enable diverse communication for the Internet of Things (IoT). However, existing BLE mesh implementations cannot simultaneously achieve low-power operation, symmetrical communication, and scalability. A major limitation of mesh networks is the inability of the BLE stack to handle network-scalable time synchronization. Pulse-coupled oscillators (PCOs) have been studied extensively and are able to achieve fast and reliable synchronization across a range of applications and network topologies. This paper presents a lightweight physical (PHY) layer accelerator to the BLE stack that enables scalable synchronization command with a PCO. The accelerator is a fully digital solution that can be synthesized with only the standard cells available in any silicon technology. This paper provides a detailed analysis of PCO-based BLE mesh networks and explores per-node system-level requirements. Finally, the analytical results are validated with measurements of a custom radio node based on the ubiquitous AD9364 transceiver.