Health-Related Quality of Life Burden Among Adults with Vitiligo: Relationship to Disease Severity and Disease Location.

INTRODUCTION: Vitiligo was historically regarded as a cosmetic disorder; however, it is an autoimmune disease. As a visible condition, it affects patient well-being. We assessed the impact of disease severity, lesion location, and body surface area (BSA) affected on patient health-related quality of life (HRQoL). METHODS: Retrospective data were from the Adelphi Real World Vitiligo Disease Specific Programme: a cross-sectional survey of physicians and their patients with vitiligo (10/2021-07/2022). Patient-reported outcomes were assessed by the Vitiligo-Specific Quality of Life Instrument (VitiQoL), Hospital Anxiety and Depression Scale (HADS), and EQ-5D-5L. The Work Productivity and Impairment Questionnaire (WPAI) questionnaire was used to assess disease-related impairment of daily activities. Data were stratified by physician-reported disease severity, presence/absence of vitiligo on the face, and BSA percentage affected. RESULTS: In total, 1388 patients were included. Mean (SD) VitiQoL, HADS depression, and anxiety scores were higher for those with severe disease [40.5 (26.1), 5.2 (4.4), and 6.8 (4.7)] than those with mild [24.8 (18.8), 3.6 (3.8), 4.2 (3.8)] or moderate [27.1 (22.6), 3.8 (4.5), 4.3 (4.4)] disease. Patients with face affected reported higher VitiQoL [30.0 (22.3) versus 23.2 (19.3)], and HADS scores [depression, 4.3 (4.3) versus 3.2 (3.9); anxiety, 5.0 (4.3) versus 3.8 (3.9)] than those without. Patients with ≥ 5% BSA affected had higher VitiQoL, depression and anxiety scores [27.9 (21.8), 4.0 (4.4), and 4.5 (4.2)] than those with 0-5% [24.6 (19.7), 3.4 (3.7), and 4.3 (4.1)]. Patients with severe vitiligo, facial lesions, or ≥ 5% BSA reported higher activity impairment. Mean EQ-5D-5L-utility score was approximately 0.9 regardless of disease severity or total BSA affected. CONCLUSIONS: These data demonstrate the impact disease severity can have on HRQoL and daily activities for patients with vitiligo. Lesions that are more severe, on the face, or covering a greater BSA are more often associated with poorer outcomes and activity impairment. These data also highlight the potential insensitivity of commonly used HRQoL measures and a need for more sensitive disease-specific measures.

Vitiligo is a disorder that causes patches of skin to lose pigment. In this study, we examined medical records of patients who have non-segmental vitiligo (the most common type of vitiligo) to better understand how the following factors affect the quality of life of patients with non-segmental vitiligo: (a) disease severity, (b) whether the face was affected, and (c) how much of the body was affected. Using a variety of measures, we found that patients with non-segmental vitiligo had lower quality of life, more symptoms of anxiety and depression, and higher activity impairment than those who did not. Our research highlights the differences in the measures used to assess the quality of life of patients, as well as the need for new therapies for non-segmental vitiligo.

Establishing adherence-concentration-efficacy thresholds of TDF-FTC pre-exposure prophylaxis for HIV prevention in African women: a protocol for the Women TDF-FTC Benchmark Study.

Background: Oral pre-exposure prophylaxis (PrEP) using co-formulated emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) is a potent HIV prevention method for men and women, with its efficacy highly dependent on adherence. A pivotal HIV efficacy study combined with a directly observed pharmacological study defined the thresholds for HIV protection in men who have sex with men (MSM), which are the keys to PrEP promotion and development of new PrEP agents. For African women at risk for HIV and belonging to a priority group considered due to disproportionately high incident HIV infections, the variable adherence in PrEP clinical trials and the limited pharmacologic data have resulted in a lack of clarity about the PrEP adherence required for HIV protection. We propose a study to quantify the adherence-concentration-efficacy thresholds of TDF/FTC PrEP among African cisgender women to inform decisions about optimal PrEP dosing and adherence for HIV protection. Methods: We randomized 45 low-risk HIV-uninfected African women, aged 18-30 years old, to directly observe the TDF/FTC PrEP of two, four, or seven doses per week for 8 weeks. A complementary age-matched pregnant women cohort at high risk of HIV, who will receive seven doses per week, was recruited (N = 15) with the primary aim of establishing benchmark concentrations in dried blood spots and peripheral blood mononuclear cells. Plasma, whole blood (WB), urine, hair, vaginal fluid, and vaginal tissue (non-pregnant women only) were archived for future testing. Drug concentrations were measured using methods validated for each biological matrix. Pharmacokinetic models were fitted to drug concentrations to quantify concentration-adherence thresholds. To define the drug concentrations associated with HIV protection, we applied the newly defined thresholds from the primary pharmacologic trial to the subset of women randomized to TDF/FTC or TDF in the Partners PrEP Study with the drug concentration assessed in plasma and WB samples. Multiple imputation was used to construct a data set with drug concentrations at each visit when an HIV test was performed for the entire cohort, replicating the work for MSM. Discussion: The proposed study generated the first African women-specific TDF-PrEP adherence-concentration-efficacy thresholds essential for guiding the accurate interpretation of TDF/FTC PrEP programs and clinical trials of novel HIV prevention products using TDF/FTC as an active control. Clinical Trial Registration: ClinicalTrials.gov, identifier (NCT05057858).

Acceptability, usability, and credibility of a mindfulness-based digital therapeutic for pediatric concussion: A mixed-method study.

Background: The ability to cope with concussion symptoms and manage stress is an important determinant of risk for prolonged symptoms. Objective: This open-label mixed-methods pilot study assessed the acceptability and credibility of a mindfulness-based intervention delivered through a digital therapeutic (DTx; therapeutic smartphone app) for pediatric concussion. Methods: Participants aged 12 to 18 years were recruited from an emergency department within 48 hours of a concussion (acute cohort) or from a tertiary care clinic at least 1-month post-concussion (persisting symptoms cohort). Participants completed a novel 4-week mindfulness-based intervention, for 10 to 15 minutes/day, at a minimum of 4 days/week. At 2 weeks, participants completed a credibility and expectancy questionnaire. At 4 weeks, participants completed questionnaires assessing satisfaction, usability and working alliance, as well as a semi-structured phone interview. Results: Ten participants completed the study outcomes (7 acute; 3 persisting symptoms). The intervention was perceived as credible (median/max possible = 6.50/9.00 [6.83,8.75]) and DTx was usable (median/max possible = 70.00/100.00 [55.00,82.50]). Participants rated their satisfaction with the DTx (median/max possible = 27.00/32.00 [24.50,29.50]) and the working alliance with the digital mindfulness guides (median/max possible = 3.92/5.00 [3.38-4.33]) as high. Four themes were identified from the qualitative data: (a) positive attributes; (b) negative attributes; (c) ideas for modifications; and (d) technical issues. Conclusion: Results show modifications to the DTx, instructions and mindfulness intervention, and potential ways to increase adherence by leveraging positive attributes. A randomized control trial will assess the effectiveness of the DTx MBI to decrease the risk of persisting symptoms and reduce the symptom burden following pediatric concussion.

Zinc finger knuckle genes are associated with tolerance to drought and dehydration in chickpea (Cicer arietinum L.).

Chickpea (Cicer arietinum L.) is a very important food legume and needs improved drought tolerance for higher seed production in dry environments. The aim of this study was to determine diversity and genetic polymorphism in zinc finger knuckle genes with CCHC domains and their functional analysis for practical improvement of chickpea breeding. Two CaZF-CCHC genes, Ca04468 and Ca07571, were identified as potentially important candidates associated with plant responses to drought and dehydration. To study these genes, various methods were used including Sanger sequencing, DArT (Diversity array technology) and molecular markers for plant genotyping, gene expression analysis using RT-qPCR, and associations with seed-related traits in chickpea plants grown in field trials. These genes were studied for genetic polymorphism among a set of chickpea accessions, and one SNP was selected for further study from four identified SNPs between the promoter regions of each of the two genes. Molecular markers were developed for the SNP and verified using the ASQ and CAPS methods. Genotyping of parents and selected breeding lines from two hybrid populations, and SNP positions on chromosomes with haplotype identification, were confirmed using DArT microarray analysis. Differential expression profiles were identified in the parents and the hybrid populations under gradual drought and rapid dehydration. The SNP-based genotypes were differentially associated with seed weight per plant but not with 100 seed weight. The two developed and verified SNP molecular markers for both genes, Ca04468 and Ca07571, respectively, could be used for marker-assisted selection in novel chickpea cultivars with improved tolerance to drought and dehydration.

Predicting externalizing behaviors in typically developing toddlers at 24 months: Insights from parenting at 12 months.

Early observational assessment of parent and child behaviors may identify risk factors associated with the development of early child externalizing behaviors. This study aimed to examine factors associated with child externalizing behaviors at 24-months of age, including early maternal depression, family social risk and the parent-child relationship. Using a longitudinal design in 89 mother-child dyads (n = 43 female), maternal depressive symptoms and social risk were measured post-birth, and 12-months later parent-child interaction was assessed using the Emotional Availability Scales. To assess child externalizing behaviors, a parent-report questionnaire was administered when children were 24-months old. Increased early maternal depressive symptoms (p = .03), but not higher social risk (p = 0.17), were associated with higher child externalizing behaviors in children at age 24-months. After adjusting for early maternal depressive symptoms and familial social risk, lower levels of observed maternal structuring (ß = -2.60, 95 %CI = -4.56, -0.64, p = .01) and lower levels of non-hostility (ß = -3.39, 95 %CI -6.64, -0.14, p = .04) when the child was 12-months old were associated with higher parent-report of externalizing behaviors. However, the child's observed interaction behavior was not associated with the mother's report of child externalizing behavior. Interventions targeting specific post-natal maternal mental health and early parenting behaviors may reduce the risk for the development of later child externalizing problems.

Patient and family burden in pediatric atopic dermatitis and its treatment pattern in Japan.

BACKGROUND: This study evaluated the level of burden in pediatric and adolescent atopic dermatitis (AD) patients in Japan, the associated burden on caregivers/families, and whether this burden varied with age. METHODS: Data were drawn from the Adelphi Pediatric AD Disease Specific Programme (DSP)™, a cross-sectional survey of physicians and their patients conducted in Japan between July and December 2022. Physicians reported patient demographics, clinical characteristics, disease burden, and current/previous therapies. Patients and/or caregivers reported perceived disease severity and impact of AD, including the Children's Dermatology Life Quality Index (CDLQI) and Dermatitis Family Impact questionnaire (DFI). RESULTS: Overall, 55 physicians provided data for 537 AD patients aged ≤17. Mean (SD) overall scores for CDLQI, POEM, and DFI were 9.3 (6.3), 8.3 (6.8), and 11.7 (7.2), respectively. Age was associated with higher patient and/or caregiver-reported CDLQI scores, which increased by 0.543 points per year of age (P = 0.01). Patients with severe disease reported a more significant impact on quality of life factors compared with mild patients (P < 0.001). Age was associated with higher caregiver-reported burden, with DFI scores increasing by 0.325 per year (P = 0.01). Physician-reported impact on caregivers showed that age was significantly associated with increased burden on sleep, daily activities, work, and mood (P < 0.05), with disease severity associated with impact across all factors (P < 0.01). CONCLUSIONS: Both increasing age and disease severity were associated with the increased impact of AD on patients and their caregivers. Disease control/modification through appropriate therapeutic intervention at a younger age may relieve the burden of pediatric AD on patients and their families.

Sexual behaviour and incidence of sexually transmitted infections among men who have sex with men (MSM) using daily and event-driven pre-exposure prophylaxis (PrEP): Four-year follow-up of the Amsterdam PrEP (AMPrEP) demonstration project cohort.

BACKGROUND: An increasing number of countries are currently implementing or scaling-up HIV pre-exposure prophylaxis (PrEP) care. With the introduction of PrEP, there was apprehension that condom use would decline and sexually transmitted infections (STIs) would increase. To inform sexual health counselling and STI screening programmes, we aimed to study sexual behaviour and STI incidence among men who have sex with men (MSM) and transgender women who use long-term daily or event-driven PrEP. METHODS AND FINDINGS: The Amsterdam PrEP demonstration project (AMPrEP) was a prospective, closed cohort study, providing oral daily PrEP and event-driven PrEP to MSM and transgender women from 2015 to 2020. Participants could choose their PrEP regimen and could switch at each three-monthly visit. STI testing occurred at and, upon request, in-between 3-monthly study visits. We assessed changes in numbers of sex partners and condomless anal sex (CAS) acts with casual partners over time using negative binomial regression, adjusted for age. We assessed HIV incidence and changes in incidence rates (IRs) of any STI (i.e., chlamydia, gonorrhoea, or infectious syphilis) and individual STIs over time using Poisson regression, adjusted for age and testing frequency. A total of 367 participants (365 MSM) commenced PrEP and were followed for a median 3.9 years (interquartile range [IQR] = 3.4-4.0). Median age was 40 years (IQR = 32-48), 315 participants (85.8%) self-declared ethnicity as white and 280 (76.3%) had a university or university of applied sciences degree. Overall median number of sex partners (past 3 months) was 13 (IQR = 6-26) and decreased per additional year on PrEP (adjusted rate ratio [aRR] = 0.86/year, 95% confidence interval [CI] = 0.83-0.88). Overall median number of CAS acts with casual partners (past 3 months) was 10 (IQR = 3-20.5) and also decreased (aRR = 0.92/year, 95% CI = 0.88-0.97). We diagnosed any STI in 1,092 consultations during 1,258 person years, resulting in an IR of 87/100 person years (95% CI = 82-92). IRs of any STI did not increase over time for daily PrEP or event-driven PrEP users. Two daily PrEP users, and no event-driven PrEP users, were diagnosed with HIV during their first year on PrEP. Study limitations include censoring follow-up due to COVID-19 measures and an underrepresentation of younger, non-white, practically educated, and transgender individuals. CONCLUSIONS: In this prospective cohort with a comparatively long follow-up period of 4 years, we observed very low HIV incidence and decreases in the numbers of casual sex partners and CAS acts over time. Although the STI incidence was high, it did not increase over time. TRIAL REGISTRATION: The study was registered at the Netherlands Trial Register (NL5413) https://www.onderzoekmetmensen.nl/en/trial/22706.

A Pilot Randomized Controlled Trial of an mHealth Intervention to Improve PrEP Adherence Among Young Sexual Minority Men.

This randomized controlled study assessed the feasibility, acceptability, and preliminary impact of the PrEP iT! mHealth intervention designed to improve PrEP adherence among young men who have sex with men (YMSM). A national sample of 80 YMSM in the U.S. (Mage = 25 years; 54% racial/ethnic minority), recruited through social media ads, were randomized to either the PrEP iT! or usual PrEP care conditions. Participants completed online surveys and submitted self-collected dried blood sample (DBS) data as measures of PrEP adherence. Differences in PrEP adherence across treatment arms and between participants with high versus low engagement in PrEP iT! were assessed. Retention was high at the three (94%) and six (93%) month assessment, and participants in PrEP iT! reported satisfactory acceptability of the intervention. There were no significant differences in self-reported or DBS-derived PrEP adherence between randomized groups. However, YMSM in the PrEP iT! group with high PrEP adherence (the equivalent of four or more doses/week through self-report and DBS-derived measures) demonstrated significantly higher engagement in the intervention than those with low PrEP adherence (the equivalent of 3 or fewer doses/week). Overall, the PrEP iT! intervention demonstrated strong feasibility and acceptability. The finding that high PrEP iT! intervention engagement was associated with protective levels of PrEP adherence suggests it is a viable adherence support tool that should be further evaluated in definitive trial among YMSM who need basic support, or as part of a more comprehensive adherence support package for those who need greater assistance.Trial registration Clinical Trials # NCT04509076 (registered August 10, 2020).

Patient Burden of Nonsegmental Vitiligo: A US Real-World Survey of Dermatologists and Their Patients.

INTRODUCTION: Vitiligo is a chronic autoimmune disease characterized by destruction of melanocytes, leading to skin depigmentation. Vitiligo can have a high quality-of-life burden and profound impact on psychosocial well-being. The objectives of this study were to describe the self-reported patient burden among patients with nonsegmental vitiligo with ≤ 10% affected body surface area, summarize the physician-reported psychosocial and psychological impact of vitiligo on patient lives, and describe disease characteristics and treatment history, goals, and satisfaction. METHODS: Data were drawn from the Adelphi Vitiligo Disease Specific Programme™, a real-world, cross-sectional survey with retrospective data collection of physicians and patients with vitiligo, collected in the United States between October 2021 and April 2022. Separate surveys for dermatologists and patients contained questions on clinical and demographic characteristics of patients with vitiligo and burden of vitiligo. Treatment history, goals, and satisfaction were assessed together with the impact of vitiligo on quality of life. RESULTS: Sixty-one dermatologists provided data for 326 patients with ≤ 10% affected body surface area (adults, n = 221; adolescents, n = 105); 90 of those patients also responded to the survey. The most common treatments were topical corticosteroids, topical calcineurin inhibitors, and narrow-band ultraviolet-B phototherapy, with the main treatment goal being repigmentation. Physician-reported treatment satisfaction was 56%; 25% of patients reported frustration with treatment options. Physicians reported impact of vitiligo on everyday life in 46% of patients. Patients reported 12.7% overall work impairment; mean scores for Hospital Anxiety and Depression Scale anxiety and depression domains were 3.5 and 2.2, respectively, and mean Vitiligo-specific Quality of Life index score was 26.9. Patients with facial involvement experienced higher burden than those without. CONCLUSION: A high patient burden was reported by dermatologists and their patients with vitiligo who had ≤ 10% affected body surface area, including psychosocial and psychological consequences. These findings highlight an unmet need in the treatment of vitiligo.

Vitiligo is a chronic disease in which cells that produce the skin pigment melanin are attacked, causing patches of skin to lose color and become pale. Vitiligo can have emotional impacts such as social or psychological distress that can affect the day-to-day well-being of individuals. However, there is a lack of studies that assess the ways that vitiligo affects the everyday lives of people with the condition in the United States. Dermatologists and people with vitiligo answered survey questions on treatment goals, any vitiligo treatments currently and previously used, and how satisfied they were with the results of treatment. The surveys also contained questions that assessed the impact of vitiligo on everyday life. Sixty-one dermatologists answered questions about 326 patients and 90 of those patients also provided their own answers to the survey questions. Both dermatologists and patients reported that restoring color to patches of pale skin was their goal in treating vitiligo. However, dermatologists and patients both reported that they were dissatisfied with the results of available treatments. Dermatologists and patients both reported that vitiligo impacted aspects of everyday life. Emotional and psychological impacts such as anxiety and depression were reported, as well as negative effects on patients' work and social lives due to vitiligo. These results confirm that vitiligo impacts the day-to-day well-being of patients. Furthermore, this study highlights that there is a need for improvements in the treatment of vitiligo.

Drug concentrations in hair and dried blood spots as PrEP adherence metrics during pregnancy and postpartum.

We evaluated hair tenofovir (TFV) concentrations as an adherence metric for HIV pre-exposure prophylaxis (PrEP) during pregnancy and postpartum and compared hair levels with tenofovir-diphosphate (TFV-DP) levels in dried blood spots (DBS). Overall, 152 hair samples from 102 women and 36 hair-DBS paired samples from 29 women were collected from a subset of women in a cluster randomized trial. Having a partner known to be living with HIV was associated with higher hair TFV levels (p<0.001). Hair TFV concentrations were strongly correlated with DBS TFV-DP levels (r=0.76, p<0.001), indicating hair as promising cumulative adherence metric for perinatal PrEP assessment.

Cumulative tenofovir exposure among patients with human immunodeficiency virus/hepatitis B co-infection with differential viral suppression.

This case-control study explored cumulative tenofovir exposure among patients with HIV/HBV co-infection with HIV viral suppression. Among patients taking tenofovir disoproxil fumarate, median TFV-DP levels in dried blood spots were ∼3-fold lower among patients with incomplete HBV viral suppression (n=4) compared to those with complete suppression (n=5) (516 vs.1456 fmol/punch).

No observed bidirectional effect between tenofovir diphosphate concentrations and gender-affirming hormone concentrations among transgender persons switching from tenofovir disoproxil fumarate/emtricitabine to tenofovir alafenamide/emtricitabine for HIV pre-exposure prophylaxis.

AIMS: Many transgender and gender diverse (TGD) individuals have expressed concerns about the potential for oral pre-exposure prophylaxis to affect hormonal concentrations achieved from taking gender-affirming hormone therapy (GAHT). The purpose of this study was to understand the bidirectional effects between hormone and intraerythrocytic tenofovir diphosphate concentrations when switching from tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) to tenofovir alafenamide/emtricitabine (TAF/FTC) in TGD users/nonusers of GAHT. METHODS: The study evaluated stored blood samples and dried blood spot cards from TGD adults without HIV who took ≥12 weeks of TDF/FTC and then switched to ≥12 weeks of TAF/FTC for pre-exposure prophylaxis. RESULTS: Thirty-nine individuals met the study inclusion criteria. Regardless of sex assigned at birth and the use of GAHT, there were no significant differences in hormone concentrations when individuals taking GAHT were taking TDF/FTC and then switched to TAF/FTC. Further, there was no significant difference in intraerythrocytic tenofovir diphosphate concentrations between users and nonusers of GAHT. CONCLUSION: There are no bidirectional effects between hormone and intraerythocytic tenofovir diphosphate concentrations when switching from TDF/FTC to TAF/FTC in TGD users/nonusers of GAHT.

Fetal alcohol spectrum disorder and attention deficit hyperactivity disorder stimulant trial in children: an N-of-1 pilot trial to compare stimulant to placebo (FASST): protocol.

INTRODUCTION: Fetal alcohol spectrum disorder (FASD) is a neurodevelopmental disorder caused by alcohol exposure during pregnancy. FASD is associated with neurodevelopmental deviations, and 50%-94% of children with FASD meet the Diagnostic and Statistical Manual of Mental Disorders-fifth edition diagnostic criteria for attention deficit hyperactivity disorder (ADHD). There is a paucity of evidence around medication efficacy for ADHD symptoms in children with FASD. This series of N-of-1 trials aims to provide pilot data on the feasibility of conducting N-of-1 trials in children with FASD and ADHD. METHODS AND ANALYSIS: A pilot N-of-1 randomised trial design with 20 cycles of stimulant and placebo (four cycles of 2-week duration) for each child will be conducted (n=20) in Melbourne, Australia.Feasibility and tolerability will be assessed using recruitment and retention rates, protocol adherence, adverse events and parent ratings of side effects. Each child's treatment effect will be determined by analysing teacher ADHD ratings across stimulant and placebo conditions (Wilcoxon rank). N-of-1 data will be aggregated to provide an estimate of the cohort treatment effect as well as individual-level treatment effects. We will assess the sample size and number of cycles required for a future trial. Potential mediating factors will be explored to identify variables that might be associated with treatment response variability. ETHICS AND DISSEMINATION: The study was approved by the Hospital and Health Service Human Research Ethics Committee (HREC/74678/MonH-2021-269029), Monash (protocol V6, 25 June 2023).Individual outcome data will be summarised and provided to participating carers and practitioners to enhance care. Group-level findings will be presented at a local workshop to engage stakeholders. Findings will be presented at national and international conferences and published in peer-reviewed journals. All results will be reported so that they can be used to inform prior information for future trials. TRIAL REGISTRATION NUMBER: NCT04968522.

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.

Cefadroxil and cephalexin pharmacokinetics and pharmacodynamics in children with musculoskeletal infections.

Cephalexin, a first-generation cephalosporin, is the first-line oral therapy for children with musculoskeletal infections due to methicillin-susceptible Staphylococcus aureus (MSSA). Cefadroxil, a similar first-generation cephalosporin, is an attractive alternative to cephalexin given its longer half-life. In this study, we describe the comparative pharmacokinetics (PK) and pharmacodynamics (PD) of cephalexin and cefadroxil in children with musculoskeletal infections. Children aged 6 months to 18 years with a musculoskeletal infection were enrolled in a prospective, open-label, crossover PK study and given single oral doses of cefadroxil (50-75 mg/kg up to 2,000 mg) and cephalexin (50 mg/kg up to 1,375 mg). Population PK models were developed and used for dosing simulations. Our primary PD target was the achievement of free antibiotic concentrations above the minimum inhibitory concentration (fT >MIC) for 40% of the day for MICs ≤ 4 mg/L. PK of cephalexin (n = 15) and cefadroxil (n = 14) were best described using a one-compartment, first-order absorption model, with a lag time component for cefadroxil. PK parameters were notable for cefadroxil's longer half-life (1.61 h) than cephalexin's (1.10 h). For pediatric weight bands, our primary PD target was achieved by cephalexin 25 mg/kg/dose, maximum 750 mg/dose, administered three times daily and cefadroxil 40 mg/kg/dose, maximum 1,500 mg/dose, administered twice daily. More aggressive dosing was required to achieve higher PD targets. Among children with musculoskeletal infections, oral cephalexin and cefadroxil achieved PD targets for efficacy against MSSA. Given less frequent dosing, twice-daily cefadroxil should be further considered as an alternative to cephalexin for oral step-down therapy for serious infections due to MSSA.

Tenofovir-Diphosphate and Emtricitabine-Triphosphate Adherence Benchmarks in Dried Blood Spots for Persons with HIV Receiving Tenofovir Alafenamide and Emtricitabine-based Antiretroviral Therapy (QUANTI-TAF).

BACKGROUND: QUANTI-TAF aimed to establish tenofovir-diphosphate/emtricitabine-triphosphate (TFV-DP/FTC-TP) adherence benchmarks in dried blood spots (DBS) for persons with HIV (PWH) receiving tenofovir alafenamide/emtricitabine (TAF/FTC)-based antiretroviral therapy (ART). METHODS: During a 16-week pharmacokinetic study, PWH received TAF/FTC-based ART co-encapsulated with an ingestible sensor to directly measure cumulative (enrollment to final visit) and 10-day adherence. At monthly visits, intraerythrocytic concentrations of TAF/FTC anabolites (TFV-DP/FTC-TP) in DBS were quantified by LC-MS/MS and summarized at steady-state (week 12 or 16) as median (IQR). Linear mixed-effects models evaluated factors associated with TFV-DP/FTC-TP. RESULTS: 84 participants (86% male, 11% female, and 4% transgender), predominantly receiving bictegravir/TAF/FTC (73%) enrolled. 92% completed week 12 or 16 (94% receiving unboosted ART). TFV-DP for <85% (7/72), ≥85%-<95% (9/72), and ≥95% (56/72) cumulative adherence was 2696 (2039-4108), 3117 (2332-3339), and 3344 (2605-4293) fmol/punches. All participants with ≥85% cumulative adherence had TFV-DP ≥1800 fmol/punches. Adjusting for cumulative adherence, TFV-DP was higher with boosted ART, lower BMI, and in non-Blacks. FTC-TP for <85% (14/77), ≥85%-<95% (6/77), and ≥95% (57/77) 10-day adherence was 3.52 (2.64-4.48), 4.58 (4.39-5.06), and 4.96 (4.21-6.26) pmol/punches. All participants with ≥85% 10-day adherence had FTC-TP ≥2.5 pmol/punches. Low-level viremia (HIV-1 RNA ≥20-<200 copies/mL) occurred at 60/335 (18%) visits in 33/84 (39%) participants (range: 20-149 copies/mL), with similar TFV-DP (3177 [2494-4149] fmol/punches) compared with HIV-1 RNA <20 copies/mL visits (3279 [2580-4407] fmol/punches). CONCLUSIONS: We propose PK-based TFV-DP (≥1800 fmol/punches)/FTC-TP (≥2.5 pmol/punches) benchmarks in DBS for PWH receiving unboosted TAF/FTC-based ART with ≥85% adherence. In the setting of high adherence, low-level viremia was common.

Parent screening questionnaires to detect cognitive and language delay at 2 years in high-risk infants: an analysis from the Victorian Infant Collaborative Study 2016-2017 cohort.

OBJECTIVE: To determine the accuracy of two developmental screening questionnaires to detect cognitive or language delay, defined using the Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III), in children born extremely preterm (EP: <28 weeks' gestation) or extremely low birth weight (ELBW: <1000 g). DESIGN: Prospective cohort study. SETTING: State of Victoria, Australia. PATIENTS: 211 infants born EP/ELBW assessed at 2 years' corrected age (mean 2.2, SD 0.2). MAIN OUTCOME MEASURES: Cognitive and language delay (<-1 SD) on the Bayley-III. The screening questionnaires were the Parent Report of Children's Abilities-Revised (PARCA-R) and the Ages & Stages Questionnaires Third Edition (ASQ-3). RESULTS: The PARCA-R performed better than the ASQ-3, but neither questionnaire had substantial agreement with the Bayley-III to detect cognitive delay; kappa (95% CI): PARCA-R 0.43 (0.23, 0.63); ASQ-3 0.15 (-0.05, 0.35); sensitivity (95% CI): PARCA-R 70% (53%, 84%) ASQ-3 62% (47%, 76%); specificity (95% CI): PARCA-R 73% (60%, 84%) ASQ-3 53% (38%, 68%). When both tools were used in combination (below cut-off on at least one assessment), sensitivity increased to 78% (60%, 91%) but specificity fell to 45% (29%, 62%). Similar trends were noted for language delay on the Bayley-III, although kappa values were better than for cognitive delay. CONCLUSIONS: Neither screening questionnaire identified cognitive delay well, but both were better at identifying language delay. The PARCA-R detects delay on the Bayley-III more accurately than the ASQ-3. Sensitivity for detecting delay is greatest when the PARCA-R and ASQ-3 were used in combination, but resulted in lower specificity.

Updates to the Melbourne Children's Regional Infant Brain Software Package (M-CRIB-S).

The delineation of cortical areas on magnetic resonance images (MRI) is important for understanding the complexities of the developing human brain. The previous version of the Melbourne Children's Regional Infant Brain (M-CRIB-S) (Adamson et al. Scientific Reports, 10(1), 10, 2020) is a software package that performs whole-brain segmentation, cortical surface extraction and parcellation of the neonatal brain. Available cortical parcellation schemes in the M-CRIB-S are the adult-compatible 34- and 31-region per hemisphere Desikan-Killiany (DK) and Desikan-Killiany-Tourville (DKT), respectively. We present a major update to the software package which achieves two aims: 1) to make the voxel-based segmentation outputs derived from the Freesurfer-compatible M-CRIB scheme, and 2) to improve the accuracy of whole-brain segmentation and cortical surface extraction. Cortical surface extraction has been improved with additional steps to improve penetration of the inner surface into thin gyri. The improved cortical surface extraction is shown to increase the robustness of measures such as surface area, cortical thickness, and cortical volume.

Satisfaction with Control of Mild to Moderate Atopic Dermatitis with Ruxolitinib Cream: US Physician and Patient Perspectives.

INTRODUCTION: The 2021 US approval of ruxolitinib cream for treatment of atopic dermatitis (AD) in patients aged ≥ 12 years was based on the results of two pivotal phase 3 studies. Currently, real-world data to describe effectiveness of ruxolitinib cream and physician satisfaction with treatment remain limited. Our objective is to describe disease control among adults with mild to moderate AD prescribed ruxolitinib cream and physician satisfaction with treatment. METHODS: Data were from the Adelphi AD Disease Specific Programme™, a US real-world, cross-sectional survey of physician-reported data, undertaken between August 2022 and March 2023. For patients aged ≥ 18 years, physicians reported patient demographics, clinical characteristics, treatment patterns, and physician satisfaction with disease control. Descriptive analysis of data for patients with mild to moderate AD prior to the initiation of ruxolitinib cream and treated with ruxolitinib cream for ≥ 1 month was undertaken. RESULTS: Among physician-reported data from 1360 patients with AD, 149 patients had received ruxolitinib cream (in combination or as monotherapy) for ≥ 1 month, including 59 patients receiving monotherapy. Prior to treatment with ruxolitinib cream, 84.6% of patients had moderate AD (Investigator's Global Assessment, IGA of 3), whereas after treatment (median duration, 26 weeks), only 21.5% had an IGA of 3, with 48.3% of patients having clear or almost clear skin (IGA of 0/1). For these patients, 81.2% were not currently experiencing a flare, and physicians were satisfied with disease control for 87.3%. Results were similar in patients receiving monotherapy. The most frequent physician-reported reasons for prescribing ruxolitinib cream included relieving itch, improving lesion redness/thickness, achieving disease control, and reducing/controlling flares. CONCLUSIONS: These real-world findings demonstrate effective disease control and physician satisfaction with ruxolitinib cream for the treatment of AD in adults in a clinical practice setting. Outcomes were similar whether ruxolitinib cream was prescribed as monotherapy or in combination regimens, suggesting a role for ruxolitinib cream across the spectrum of disease.

Atopic dermatitis (AD) is a disease in which skin can be itchy, inflamed, and cracked. Traditional therapies for mild to moderate AD can be limited by side effects and long-term safety issues. After US approval of ruxolitinib cream for the treatment of mild to moderate AD in 2021, the goal of this study was to describe disease control and doctor satisfaction with ruxolitinib cream in a real-world setting. The Adelphi AD Disease Specific Programme™ surveyed 159 doctors who treated people with AD between August 2022 and March 2023. Doctors reported records from 1360 patients with mild to moderate AD. In these patients, ruxolitinib cream was used for at least 1 month in 149 patients and was used alone in 59 patients. Before the use of ruxolitinib cream, nearly 85% of the 149 patients had moderate AD. After the use of ruxolitinib cream, about 20% had moderate AD, with half having clear or almost clear skin. About 80% were not currently experiencing flares. Doctors were satisfied with disease control in more than 85% of patients. Patients applying ruxolitinib cream alone had similar results. Doctors most often prescribed ruxolitinib cream for itch relief, disease control, and to reduce or control flares. In summary, when ruxolitinib cream was used by patients, it provided good disease control, and doctors were satisfied with results. Outcomes were similar in patients who applied ruxolitinib cream alone or with another treatment. This suggests that ruxolitinib cream may be useful for patients with AD of differing levels of severity.