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Seizures are known to occur with diurnal and other rhythms. To gain insight into the neurophysiology of periodicity of seizures, we tested the hypothesis that intracranial high-frequency oscillations (HFOs) show diurnal rhythms and sleep-wake cycle variation. We further hypothesized that HFOs have different rhythms within and outside the seizure-onset zone (SOZ).In drug-resistant epilepsy patients undergoing stereotactic-EEG (SEEG) monitoring to localize SOZ, we analyzed the number of 50-200 Hz HFOs/channel/minute (HFO density) through a 24-hour period. The distribution of HFO density during the 24-hour period as a function of the clock time was analyzed with cosinor model, and for non-uniformity with the sleep-wake cycle.HFO density showed a significant diurnal rhythm overall and both within and outside SOZ. This diurnal rhythm of HFO density showed significantly lower amplitude and longer acrophase within SOZ compared to outside SOZ. The peaks of difference in HFO density within and outside SOZ preceded the seizures by approximately 4 hours. The difference in HFO density within and outside SOZ also showed a non-uniform distribution as a function of sleep-wake cycle, with peaks at first hour after arousal and ±2 hours around sleep onset.Our study shows that the diurnal rhythm of intracranial HFOs is more robust outside the SOZ. This suggests cortical tissue within SOZ generates HFOs relatively more uniformly throughout the day with attenuation of expected diurnal rhythm. The difference in HFO density within and outside SOZ also showed non-uniform distribution according to clock times and the sleep-wake cycle, which can be a potential biomarker for preferential times of pathological cortical excitability. A temporal correlation with seizure occurrence further substantiates this hypothesis.

This paper presents reflections on mentorship from scientists and mentors of the National Institute on Aging (NIA)-funded Carolina Center on Alzheimer’s Disease and Minority Research (CCADMR). Using a network approach to mentoring, this program aims to increase the pipeline of underrepresented minority (URM) scientists studying Alzheimer’s disease (AD) disparities. Six mentors and five scientists participated in interviews. Thematic analysis identified recurring themes; transcripts of mentors and scientists were compared. Most common thematic categories identified by mentors included experience interacting with scientists, goals as a mentor, recruitment of underrepresented minorities, scientists’ challenges, and programmatic qualities. The most mentioned categories by scientists were challenges, seminars, working with mentors, career development, and project experience. The CCADMR will use findings to enhance the experience and training methods for future grant years. Results can benefit other training programs focused on aging and AD.

Background Trust is an important cornerstone of patient-provider communication. Accurate reporting of pre-exposure prophylaxis (PrEP) adherence is vital for providers to determine who needs adherence support, especially adolescent girls and young women (AGYW) disproportionately affected by newly diagnosed HIV. Methods This is a secondary analysis of the HPTN 082 open-label PrEP demonstration trial. From 2016–2018, 451 AGYW aged 16–25 years were enrolled in South Africa (Cape Town and Johannesburg) and Zimbabwe (Harare). PrEP was initiated by 427, and 354 (83%) had month three patient-reported adherence responses and intracellular tenofovir diphosphate (TFV-DP) measurements. The patient-reported adherence response to ‘In the past month, how often did you take the tablet?’ was dichotomized as ‘high’ if the response was every day or most days, and ‘low’ if some days or not many days or never. The biomarker marker evidence of adherence in dried blood spots was defined as ‘high’ if TFV-DP ≥ 700, and ‘low’ if Results AGYW who reported trust in their providers were almost four-fold (aOR 3.72, 95% CI 1.20–11.51) more likely to have concordant adherence (high self-reported adherence and high TFV-DP concentrations) compared to discordant non-adherence (high self-reported adherence and low TFV-DP concentrations). Conclusion Education and training of providers to build trusting relationships with AGYW may lead to more accurate reporting of PrEP adherence. With accurate reporting, adequate support can be provided to bolster adherence. Trial registration ClinicalTrials.gov Identifier: NCT02732730.

Background Trust is an important cornerstone of patient-provider communication. Accurate reporting of pre-exposure prophylaxis (PrEP) adherence is vital for providers to determine who needs adherence support, especially adolescent girls, and young women (AGYW) who are disproportionately affected by newly diagnosed HIV infections. Methods We examined if trust in the PrEP provider was associated with concordance between patient-reported adherence and intracellular tenofovir-diphosphate (TFV-DP) in dried blood spots. The patient-reported adherence response ‘In the past month, how often did you take the tablet?’ was dichotomized as ‘high’ if the response was every day or most days, and ‘low’ if some days or not many days or never. The biomarker marker evidence of adherence was defined as ‘high’ if TFV-DP ≥ 700, and ‘low’ if Trial Registration: ClinicalTrials.gov Identifier: NCT02732730 (11/04/2016)

Parenteral and enteral nutrition support are key components of care for various medical and physiological conditions in infants, children, and adults. Nutrition support practices have advanced over time, driven by the goals of safe and sufficient delivery of needed nutrients and improved patient outcomes. These advances have been, and continue to be, dependent on research and development studies. Such studies address aspects of enteral and parenteral nutrition support: formulations, delivery devices, health outcomes, cost-effectiveness, and related metabolism. The studies are supported by public funding from the government and by private funding from foundations and from the nutrition support industry. To build public trust in nutrition support research findings, it is important to underscore ethical research conduct and reporting of results for all studies, including those with industry sponsors. In 2019, American Society for Parenteral and Enteral Nutrition's (ASPEN's) Board of Directors established a task force to ensure integrity in nutrition support research that is done as collaborative partnerships between the public (government and individuals) and private groups (foundations, academia, and industry). In this ASPEN Position Paper, the Task Force presents principles of ethical research to guide administrators, researchers, and funders. The Task Force identifies ways to curtail bias and to minimize actual or perceived conflict of interests, as related to funding sources and research conduct. Notably, this paper includes a Position Statement to describe the Task Force's guidance on Public-Private Partnerships for research and funding. This paper has been approved by the ASPEN Board of Directors.

In this study, we used data from the Health and Retirement Study (HRS) to investigate factors associated with older adults’ engagement with advance care planning (ACP) across varying levels of cognitive functioning status. Our analysis used a sample of 17,698 participants in the HRS 2014 survey. Survey descriptive procedures (Proc SurveyMeans, Proc SurveyFreq) and logistic regression procedures (Proc SurveyLogistic) were used. Race, ethnicity, level of cognition, education, age, and number of chronic diseases consistently predicted ACP. Participants with lower levels of cognition were less likely to have a living will and durable power of attorney for healthcare (DPOAH). African American and Hispanic participants, younger participants, and those with lower cognition and education levels were less likely to engage in ACP. Marital status and loneliness predicted ACP engagement. Some results varied across the cognition cohorts. Our results indicated that sociodemographic status, together with health and cognitive status, has a significant role in predicting ACP. The results can provide valuable insights on ACP for older adults with or at risk of Alzheimer’s disease and related dementia and other cognitive impairments, caregivers, families, and healthcare providers.

Many bacterial pathogens use their type IV pilus (T4P) to facilitate and maintain an infection in a human host. Small-molecule inhibitors of the production or assembly of the T4P are promising for the treatment and prevention of infections by these bacteria, especially in our fight against antibiotic-resistant pathogens. With the pressing antibiotic resistance pandemic, antivirulence has been increasingly explored as an alternative strategy against bacterial infections. The bacterial type IV pilus (T4P) is a well-documented virulence factor and an attractive target for small molecules for antivirulence purposes. The PilB ATPase is essential for T4P biogenesis because it catalyzes the assembly of monomeric pilins into the polymeric pilus filament. Here, we describe the identification of two PilB inhibitors by a high-throughput screen (HTS) in vitro and their validation as effective inhibitors of T4P assembly in vivo. We used Chloracidobacterium thermophilum PilB as a model enzyme to optimize an ATPase assay for the HTS. From a library of 2,320 compounds, benserazide and levodopa, two approved drugs for Parkinson's disease, were identified and confirmed biochemically to be PilB inhibitors. We demonstrate that both compounds inhibited the T4P-dependent motility of the bacteria Myxoccocus xanthus and Acinetobacter nosocomialis. Additionally, benserazide and levodopa were shown to inhibit A. nosocomialis biofilm formation, a T4P-dependent process. Using M. xanthus as a model, we showed that both compounds inhibited T4P assembly in a dose-dependent manner. These results suggest that these two compounds are effective against the PilB protein in vivo. The potency of benserazide and levodopa as PilB inhibitors both in vitro and in vivo demonstrate potentials of the HTS and its two hits here for the development of anti-T4P chemotherapeutics.IMPORTANCE Many bacterial pathogens use their type IV pilus (T4P) to facilitate and maintain an infection in a human host. Small-molecule inhibitors of the production or assembly of the T4P are promising for the treatment and prevention of infections by these bacteria, especially in our fight against antibiotic-resistant pathogens. Here, we report the development and implementation of a method to identify anti-T4P chemicals from compound libraries by high-throughput screen. This led to the identification and validation of two T4P inhibitors both in the test tubes and in bacteria. The discovery and validation pipeline reported here as well as the confirmation of two anti-T4P inhibitors provide new venues and leads for the development of chemotherapeutics against antibiotic-resistant infections. National Science Foundation [MCB-1417726, MCB-1919455]; Lay Nam Chang Dean's Discovery Fund; GSDA; Lewis Edward Goyette Fellowship; Liberati Scholarship from Virginia Tech Published version This work was partially supported by the National Science Foundation grants MCB-1417726 and MCB-1919455 and a Lay Nam Chang Dean's Discovery Fund to Z.Y. K.J.D. was the recipient of a GSDA and the Lewis Edward Goyette Fellowship, as well as the Liberati Scholarship from Virginia Tech. We thank Kurt Piepenbrink for providing bacterial strains. We acknowledge Andreas Sukmana for his early contribution to the implementation of the HTS. K.J.D., N.J.V., P.S., and Z.Y. designed research and analyzed data. K.J.D. and N.J.V. performed experiments. M.O. aided in figure preparations. W.S. and P.R.C. provided analysis of HTS results. K.J.D. and Z.Y. wrote the manuscript. There are no conflicts of interest to declare.

Background and Objectives Older adults undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA) experience significant challenges while navigating their homes after surgery and are at higher risk for falls and injuries. This study explored the specific home and community physical environment challenges faced by community-dwelling older adults while performing daily activities and actions taken to modify their homes before surgery. Research Design and Methods Using a qualitative descriptive methodology, semistructured interviews were conducted with 22 older adult–care partner dyads pre- and postsurgery to identify key built environment barriers and facilitators in addition to home modifications made pre- and postsurgery. Results Challenges anticipated by participants to perform daily activities presurgery varied from those experienced postsurgery. Lack of support along stairs or in bathrooms, flooring material, and transitions were significant concerns raised by the participants before surgery. Size and layout of home and ergonomics of resting furniture were recognized as issues postsurgery. Modifications ranged from easy fixes such as rearranging furniture, removing clutter, and installing grab bars to high-cost structural changes such as remodeling critical spaces such as bathrooms. Although participants agreed on the importance of conducting proactive home assessments and modifications before surgery, perceived costs and lack of knowledge or services limit older adults from implementing some changes. Discussion and Implications Home modifications must be considered proactively before an event such as a THA or TKA. These should be done within the context of the specific needs, abilities, financial capabilities, and social and physical home environments of the individual and the residential caregivers.

Objectives: This was a study conducted in Atlanta, GA, in the United States with Chinese elderly immigrants, examining the relationship between visual preference and motivation to walk in a particular outdoor space. Backgrounds: Outdoor walking promotes the well-being of older adults. However, their declined body functions impact their motivation to walk outside. For elderly immigrants living in a country with different cultural backgrounds from their homelands, it is important to find the ways to enhance their motivation of outdoor walking. Method: Visual preference survey was conducted to assess preferences of first-generation Chinese elderly immigrants attending a care facility setting. Preferences included Chinese classical walking spaces or American modern walking spaces. The data were interpreted using descriptive statistics and factorial experiment analysis. Results: A total of 95 Chinese elderly immigrants gave valid responses to the visual preference survey. Survey results revealed that respondents had a high preference for Chinese classical walking spaces even though they had an average time of 26 years as a U.S. resident. Although the functions and purposes of the walking spaces caused safety and comfort concerns, the interaction effects of design style, design function, and design purpose illustrated that Chinese classical style had high effectiveness to promote outdoor walking of Chinese elderly immigrants. Conclusions: These results support the significance of culturally sensitive care environments in promoting outdoor walking for elderly Chinese immigrants. It also indicates that spaces designed with an assigned cultural style had higher attractiveness to older adults from the same assigned cultural background.

The built environment of an older person’s home can reduce or promote the possibility of a fall or other injury. A user-friendly tool can help the residents to evaluate their home environment withi...

The bacterium Myxococcus xanthus forms both developmental and vegetative types of biofilms. While the former has been studied on both agar plates and submerged surfaces, the latter has been investigated predominantly on agar surfaces as swarming colonies. Here we describe the development of a microplate-based assay for the submerged biofilms of M. xanthus under vegetative conditions. We examined the impacts of inoculation, aeration, and temperature to optimize the conditions for the assay. Aeration was observed to be critical for the effective development of submerged biofilms by M. xanthus, an obligate aerobic bacterium. In addition, temperature plays an important role in the development of M. xanthus submerged biofilms. It is well established that the formation of submerged biofilms by many bacteria requires both exopolysaccharide (EPS) and the type IV pilus (T4P). EPS constitutes part of the biofilm matrix that maintains and organizes bacterial biofilms while the T4P facilitates surface attachment as adhesins. For validation, we used our biofilm assay to examine a multitude of M. xanthus strains with various EPS and T4P phenotypes. The results indicate that the levels of EPS, but not of piliation, positively correlate with submerged biofilm formation in M. xanthus.

The bacterium

Heterozygous de novo or inherited gain-of-function mutations in the MTOR gene cause Smith-Kingsmore Syndrome (SKS). SKS is a rare autosomal dominant condition, and individuals with SKS display macrocephaly/megalencephaly, developmental delay, intellectual disability, and seizures. A few dozen individuals are reported in the literature. Here, we report a cohort of 28 individuals with SKS that represent 9 new MTOR pathogenic variants, including p.R1480_C1483del or Δ(R1480-C1483). We conducted a detailed natural history study on these patients and found prevalent pathophysiological deficits among SKS individuals, in addition to the common neurodevelopmental symptoms. The new symptoms include sleep-wake disturbance, hyperphagia, and hyperactivity, which are indicative of homeostatic imbalance. To better characterize SKS variants, we developed MTOR mutant cellular models and performed biochemical and cellular circadian rhythm assays to study the variants. We showed that these SKS alleles display a range of MTOR activities under nutrient-deficient basal conditions and respond to MTOR inhibitors differently. For example, Δ(R1480-C1483) is more active than the classic SKS variant C1483F and less responsive to MTOR inhibition by rapamycin. Further, we showed that optimal MTOR activity, important for metabolic and protein homeostasis, is required for normal circadian function. These data can help guide treatment strategies. As SKS is caused by gain of function mutations in MTOR, we used rapamycin to treat several patients. While higher doses caused delayed sleep-wake phase disorder, lower doses improved not only sleep but also aggression and repetitive behaviors. Thus, our study expands both the clinical and molecular spectrum of SKS and offers treatment options guided by molecular and sleep/wake data to improve both cognitive and non-cognitive homeostatic functions.

Restless sleep disorder (RSD) is a newly defined sleep-related movement disorder characterized by large muscle movements (LMM) in sleep. We examined the sleep study, clinical characteristics, and daytime functioning in children with RSD and compared them to children with periodic limb movement disorder (PLMD) or restless legs syndrome (RLS). Video polysomnography from 47 children with restless sleep was retrospectively reviewed for LMM and age- and sex-matched to 34 children with PLMD and 12 children with RLS. Data examined included PSG characteristics, ferritin, Pediatric Quality of Life (PedsQL), and Epworth Sleepiness Scale (ESS). Fourteen children met the clinical criteria for RSD with an LMM index of 5 or more per hour of sleep. Mean ESS was elevated in patients with RSD compared to either the PLMD or RLS groups though the result did not reach statistical significance (RSD = 10.20 ± 6.81, PLMD = 6.19 ± 4.14, RLS = 6.25 ± 4.90). The PedsQL score was significantly decreased in the RLS group compared to RSD and was reduced overall in all three groups (PedsQL Total RSD = 70.76 ± 18.05, PLMD = 57.05 ± 20.33, RLS = 53.24 ± 16.97). Serum ferritin values were similar in all three groups (RSD = 26.89 ± 10.29, PLMD = 33.91 ± 20.31, RLS = 23.69 ± 12.94 ng/mL, p = ns). Children with RSD demonstrate increased daytime sleepiness compared to PLMD or RLS and all three disease groups showed decreased quality of life. Further studies are needed to examine long-term consequences of RSD.

Objectives To assess clinically asymptomatic infants with single-ventricle physiology (SVP) for sleep-disordered breathing (SDB) in the supine and car seat positions using polysomnography. Polysomnography results also were compared with results of a standard Car Seat Challenge to measure the dependability of the standard Car Seat Challenge. Study design This was an observational study of 15 infants with SVP. Polysomnography data included Obstructive Index, Central Index, Arousal Index, Apnea Hypopnea Index, and sleep efficiency. Polysomnography heart rate and oxygen saturation data were used to compare polysomnography with the standard Car Seat Challenge. Results Polysomnography demonstrated that all 15 infants had SDB and 14 had obstructive sleep apnea (Obstructive Index ≥1/hour) in both the supine and car seat positions. Infants with SVP had a statistically significant greater median Obstructive Index in the car seat compared with supine position (6.3 vs 4.2; P = .03), and median spontaneous Arousal Index was greater in the supine position compared with the car seat (20.4 vs 15.2; P = .01). Comparison of polysomnography to standard Car Seat Challenge results demonstrated 5 of 15 (33%) of infants with SVP with abnormal Obstructive Index by polysomnography would have passed a standard Car Seat Challenge. Conclusions Infants with SVP without clinical symptoms of SDB may be at high risk for SDB that appears worse in the car seat position. The standard Car Seat Challenge is not dependable in the identification of infants with SVP and SDB. Further studies are warranted to further delineate its potential impact of SDB on the clinical outcomes of infants with SVP.

Vagus nerve stimulator (VNS)-associated sleep disordered breathing (SDB) is a poorly understood side effect of VNS treatment. We present a patient with VNS-associated SDB who underwent sleep laboratory VNS titration, evaluation by drug-induced sleep endoscopy, and treatment including adenotonsillectomy and positive airway pressure therapy. This case is unique as it is the first to document, in real time, the inverse correlation of VNS current with airflow. This case offers unique insights into mechanisms and treatment of VNS-associated SDB, and a novel approach in its management. Most importantly, this case highlights the need for collaboration between physicians managing epilepsy with VNS and those managing sleep.

PilB is the assembly ATPase for the bacterial type IV pilus (T4P), and as a consequence, it is essential for T4P-mediated bacterial motility. In some cases, PilB has been demonstrated to regulate the production of exopolysaccharide (EPS) during bacterial biofilm development independently of or in addition to its function in pilus assembly. While the ATPase activity of PilB resides at its C-terminal region, the N terminus of a subset of PilBs forms a novel cyclic-di-GMP (cdG)-binding domain. This multi-domain structure suggests that PilB binds cdG and adenine nucleotides through separate domains which may influence the functionality of PilB in both motility and biofilm development. Here, Chloracidobacterium thermophilum PilB is used to investigate ligand binding by its separate domains and by the full-length protein. Our results confirm the specificity of these individual domains for their respective ligands and demonstrate communications between these domains in the full-length protein. It is clear that when the N- and the C-terminal domains of PilB bind to cdG and ADP, respectively, they mutually influence each other in conformation and in their binding to ligands. We propose that the interactions between these domains in response to their ligands play critical roles in modulating or controlling the functions of PilB as a regulator of EPS production and as the T4P assembly ATPase. National Science FoundationNational Science Foundation (NSF) [MCB-1417726, MCB-1919455] This work was supported by National Science Foundation grants MCB-1417726 and MCB-1919455 to Z.Y.

An association between migraine and sleep disturbances in children was reported, yet limited clinical data exist. The current study addresses the clinical presentation, polysomnographic (PSG) characteristics, and comorbid sleep diagnoses of children with migraine referred to the sleep clinic.A retrospective review was performed of headache center patients evaluated by the sleep center between 2007 and 2017. Children ≤18 years old, diagnosed with migraine headache, and who had PSG within one year of evaluation in the headache clinic, were included. PSG findings, as well as demographics, were compared to a group of controls aged 5-14 years-old.In sum, 185 children with a diagnosis of migraine were included: 39% males, 75% Caucasian, mean age 13.5 ± 3.4, and 57% obese. Additionally, 180 children were included in the control group. The common presenting sleep symptoms were snoring (66%), sleep onset and sleep maintenance problems (25%), and excessive daytime sleepiness (20%). For the sleep diagnosis, 40% had obstructive sleep apnea (OSA), 27% had insomnia, 15% had periodic limb movement disorder (PLMD), and 6% had a central disorder of hypersomnolence. In terms of sleep architecture, children with migraine had significantly higher NREM 2 (p 0.001) and a lower percentage of NREM3 (p 0.001) compared to controls after adjustment for demographics and the presence of sleep-disordered breathing.Children referred to the sleep clinic who also had migraine, experience various types of sleep complaints. OSA, insomnia, and PLMD were relatively common in this population. Changes in sleep architecture, specifically increased NREM2 and decreased slow wave sleep compared to the control group, were also observed.

STUDY OBJECTIVES: Although respiratory abnormalities occurring during wakefulness are well recognized in patients with Rett syndrome (RS), less has been reported regarding sleep-disordered breathing (SDB) in this population. This study aims to characterize the presenting complaints, types and severity of SDB, and treatment modalities of patients with RS and sleep concerns. METHODS: Retrospective chart review of pediatric patients with RS referred to our academic tertiary care institution from January 2007 to July 2017. RESULTS: Thirteen patients were identified, 11 female (84.6%); mean age at polysomnography (PSG) was 10.3 years (standard deviation 4.94). Eleven were white (84.6%), 2 were black (15.4%). The most common presenting symptoms were snoring (10/13, 77%) and witnessed apnea (7/13, 53.8%). On baseline PSG, all patients (100%) exhibited hyperapneas followed by a central apnea during wake. Nine (69.2%) had obstructive sleep apnea (OSA) (obstructive apnea-hypopnea index (oAHI) > 1); four had severe OSA (oAHI ≥ 10). One had central sleep apnea (central apnea index > 5) and severe OSA. No patients exhibited hypoventilation on baseline PSG. Mean AHI of all patients was 8.77 ± 8.82 (oAHI 6.51 ± 6.91) events/h. Mean oxyhemoglobin nadir was 88.52 ± 5.6%. Treatment modalities included observation: 5 (38%), acetazolamide: 2 (15%), nasal mometasone: 1 (7.7%), adenotonsillectomy: 3 (23.1%), and positive airway pressure: 2 (15%). CONCLUSIONS: Regarding patients with RS referred to the sleep medicine clinic, snoring and witnessed apneas were the most common presenting complaints. In addition to breathing abnormalities during wake, OSA was very common in our cohort. Further studies are needed to examine the pathogenesis of OSA in RS and relationships between disease genotype and respiratory abnormality phenotype. CITATION: Sarber KM, Howard JJM, Dye TJ, Pascoe JE, Simakajornboon N. Sleep-disordered breathing in pediatric patients with rett syndrome. J Clin Sleep Med. 2019;15(10):1451–1457.

We evaluated the relationship between 2 types of social relationships, ie, (1) external support for use of HIV pre-exposure prophylaxis (PrEP) and related study supplies and (2) participants' disclosure of PrEP use and condom use and HIV PrEP adherence among daily-dosing regimen participants in HIV Prevention Trials Network (HPTN) 067, an open-label trial of oral tenofovir (TFV) disoproxil fumarate (TDF) 300 mg/emtricitabine (FTC) 200 mg.Using HPTN 067 survey data, we developed scales examining (1) Low Perceived External Support for PrEP: low perceived support by others for PrEP use or perceived negative reactions to the pill case (scoring ranges from 0 to 2) and (2) Participant-Staff Disclosure Challenges Scale, which identifies challenges to sharing nonuse of PrEP or condoms to study staff (scoring ranges from 0 to 4); these scales are the primary independent variables. Adherence, the dependent variable, was determined using log-transformed plasma TFV concentrations. generalized estimating equation (GEE) linear regression was used to assess the association between both scales and adherence.Participants (n = 161) included HIV-uninfected women in South Africa, and men who have sex with men and transgender women, in Thailand and the United States. In multivariable analyses, higher scores in the Participant-Staff Disclosure Challenges Scale were significantly associated with lower PrEP adherence [exp(β) = 0.62, 95% CI: (0.46 to 0.84); P = 0.002] as were increased days since the last PrEP dose [exp(β) = 0.73, 95% CI: (0.65 to 0.83); P ≤ 0.001].Given the association with adherence, study staff-participant interactions and participants' disclosure of PrEP challenges may be worthwhile intervention targets for improving PrEP adherence in confirmatory studies.

The HPTN 067/ADAPT Study evaluated the feasibility, acceptability and patterns of adherence and coverage for three randomly assigned oral FTC/TDF pre-exposure prophylaxis (PrEP) dosing regimens to prevent HIV infection: daily, time-driven (twice a week with a post-sex dose), and event-driven (pre/post-sex dosing). Using qualitative methods, we explored facilitators and barriers for each regimen among a subset of men who have sex with men (MSM) participants in Bangkok, Thailand. Between August 2013 and March 2014, 32 (of 179) HPTN 067/ADAPT participants joined in six focus group discussions, and six attended key-informant interviews – two per each study regimen. Facilitators of PrEP adherence included use of strategies to have PrEP available when needed and constructing convenient dosing regimens, simplicity in regimen requirements with recognition that more complex regimens may take some time to master, ability to plan for sex (non-daily regimens), receipt of social and technology support, ability to use a PrEP regimen that best matches to one’s own patterns of sex, and experiences with PrEP as a part of health and well-being. Challenges to PrEP adherence included perceptions of no or low HIV risk, difficulties following regimens when drinking (intoxicated), concerns about short or long-term side-effects of PrEP, experience of HIV stigma (fears of being misidentified as HIV positive), inability to forecast sex events for non-daily regimens, and affordability of PrEP outside of study context influencing uptake and use in the community. Preferences for regimens varied, suggesting that multiple PrEP effective regimen options (daily and non-daily) should be available to fit those with different needs.

Author(s): Velloza, Jennifer; Bacchetti, Peter; Hendrix, Craig W; Murnane, Pamela; Hughes, James P; Li, Maoji; Curlin, Marcel E; Holtz, Timothy H; Mannheimer, Sharon; Marzinke, Mark A; Amico, K Rivet; Liu, Albert; Piwowar-Manning, Estelle; Eshleman, Susan H; Dye, Bonnie J; Gandhi, Monica; Grant, Robert M; HPTN 067/ADAPT Study Team | Abstract: BackgroundThe effectiveness of oral emtricitabine (FTC)/tenofovir (TFV) disoproxil fumarate-based HIV pre-exposure prophylaxis (PrEP) depends on adherence. Pharmacologic measures help interpret patterns and predictors of PrEP adherence.SettingWe analyzed data from the subsample of men who have sex with men enrolled in HPTN 067/ADAPT in Bangkok, Thailand, and Harlem, NY, U.S.MethodsAfter a 5-week directly observed therapy period, participants were randomized to daily, time-driven, or event-driven PrEP. Follow-up occurred at weeks 4, 12, and 24 after randomization. Plasma and hair FTC/TFV levels indicated short- and long-term PrEP use, respectively. Electronic pill bottle data (Wisepill) were collected weekly. Pearson correlation coefficients between PrEP use measures were calculated; linear mixed models assessed predictors of plasma and hair drug concentrations.ResultsAmong 350 participants (median age: 31 years, interquartile range: 25-38), 49.7% were from Harlem, half had less than college education, and 21% reported heavy alcohol use. In multivariable models, being enrolled in Harlem, being in non-daily arms, and having less than college education were associated with lower hair FTC/TFV concentrations; heavy alcohol use was associated with higher concentrations. Similar results were found for plasma concentrations by site and arm, but older age and greater number of sex partners were associated with higher concentrations. Hair and plasma FTC/TFV concentrations were moderately correlated with Wisepill data (r ≥ 0.29) across visits.ConclusionsIn HPTN067, plasma, hair, and Wisepill data correlated with one another and served as complementary adherence measures. Site, arm, education, age, alcohol, and sexual behavior influenced patterns of adherence.

Ralstonia solanacearum causes bacterial wilt disease, leading to severe crop losses. Xylem sap from R. solanacearum-infected tomato is enriched in the disaccharide trehalose. Water-stressed plants also accumulate trehalose, which increases drought tolerance via abscisic acid (ABA) signaling. Because R. solanacearum-infected plants suffer reduced water flow, we hypothesized that bacterial wilt physiologically mimics drought stress, which trehalose could mitigate. We found that R. solanacearum-infected plants differentially expressed drought-associated genes, including those involved in ABA and trehalose metabolism, and had more ABA in xylem sap. Consistent with this, treating tomato roots with ABA reduced both stomatal conductance and stem colonization by R. solanacearum. Treating roots with trehalose increased xylem sap ABA and reduced plant water use by lowering stomatal conductance and temporarily improving water use efficiency. Trehalose treatment also upregulated expression of salicylic acid (SA)-dependent tomato defense genes; increased xylem sap levels of SA and other antimicrobial compounds; and increased bacterial wilt resistance of SA-insensitive NahG tomato plants. Additionally, trehalose treatment increased xylem concentrations of jasmonic acid and related oxylipins. Finally, trehalose-treated plants were substantially more resistant to bacterial wilt disease. Together, these data show that exogenous trehalose reduced both water stress and bacterial wilt disease and triggered systemic disease resistance, possibly through a Damage Associated Molecular Pattern (DAMP) response pathway. This suite of responses revealed unexpected linkages between plant responses to biotic and abiotic stress and suggested that R. solanacearum-infected plants increase trehalose to improve water use efficiency and increase wilt disease resistance. The pathogen may degrade trehalose to counter these efforts. Together, these results suggest that treating tomatoes with exogenous trehalose could be a practical strategy for bacterial wilt management.

Background Pre-exposure prophylaxis (PrEP) is highly effective and an important prevention tool for African adolescent girls and young women (AGYW), but adherence and persistence are challenging. PrEP adherence support strategies for African AGYW were studied in an implementation study. Methods and findings HIV Prevention Trials Network (HPTN) 082 was conducted in Cape Town, Johannesburg (South Africa) and Harare (Zimbabwe) from October 2016 to October 2018 to evaluate PrEP uptake, persistence, and the effect of drug level feedback on adherence. Sexually active HIV–negative women ages 16–25 were offered PrEP and followed for 12 months; women who accepted PrEP were randomized to standard adherence support (counseling, 2-way SMS, and adherence clubs) or enhanced adherence support with adherence feedback from intracellular tenofovir-diphosphate (TFV-DP) levels in dried blood spots (DBS). PrEP uptake, persistence through 12 months (no PrEP hold or missed visits), and adherence were assessed. The primary outcome was high adherence (TFV-DP ≥700 fmol/punch) at 6 months, compared by study arm. Of 451 women enrolled, median age was 21 years, and 39% had curable sexually transmitted infections (STIs). Most (95%) started PrEP, of whom 55% had uninterrupted PrEP refills through 12 months. Of those with DBS, 84% had detectable TFV-DP levels at month 3, 57% at month 6, and 31% at month 12. At 6 months, 36/179 (21%) of AGYW in the enhanced arm had high adherence and 40/184 (22%) in the standard adherence support arm (adjusted odds ratio [OR] of 0.92; 95% confidence interval [CI] 0.55, 1.34; p = 0.76). Four women acquired HIV (incidence 1.0/100 person-years), with low or undetectable TFV-DP levels at or prior to seroconversion, and none of whom had tenofovir or emtricitabine resistance mutations. The study had limited power to detect a modest effect of drug level feedback on adherence, and there was limited awareness of PrEP at the time the study was conducted. Conclusions In this study, PrEP initiation was high, over half of study participants persisted with PrEP through month 12, and the majority of young African women had detectable TFV-DP levels through month 6 with one-fifth having high adherence. Drug level feedback in the first 3 months of PrEP use did not increase the proportion with high adherence at month 6. HIV incidence was 1% in this cohort with 39% prevalence of curable STIs and moderate PrEP adherence. Strategies to support PrEP use and less adherence-dependent formulations are needed for this population. Trial registration ClinicalTrials.gov NCT02732730., Connie Celum and co-workers report on use of pre-exposure prophylaxis by young women in Southern Africa., Author summary Why was this study done? HIV incidence remains high (4%) in young African women. Pre-exposure prophylaxis (PrEP) has over 90% efficacy in preventing HIV infection when used consistently and could reduce HIV incidence in young African women. Adherence was low in placebo-controlled efficacy trials of oral PrEP among young African women. Qualitative research among a subset of women at unblinding of the efficacy trials indicated that women thought drug level feedback would support their adherence and foster open discussions with counselors about adherence. Drug level feedback should be evaluated as a strategy to increase PrEP adherence among young African women. What did the researchers do and find? A cohort of 451 young women in South Africa and Zimbabwe who were at risk for HIV were recruited and offered PrEP, among whom 95% initiated PrEP. Half were randomized to receive drug level feedback at months 2 and 3 plus the standard adherence support package (2-way SMS, brief counseling, and optional PrEP adherence clubs), and half received the standard adherence support package without drug level feedback. The majority had detectable intracellular drug levels through the first 6 months, and 21% had high adherence at month 6, defined as intracellular tenofovir-diphosphate (TFV-DP) ≥700 fmol/punch. PrEP adherence did not differ based on whether they were randomized to receive drug level feedback at months 2 and 3 or to standard of care (SOC) PrEP adherence support without drug level feedback. What do these findings mean? Drug level feedback was not associated with improved PrEP adherence among young African women. Additional strategies need to be evaluated for their effectiveness in increasing adherence with oral PrEP for young African women. Longer-acting and less user-dependent PrEP formulations may also overcome adherence challenges with daily oral PrEP.

Narcolepsy is a life-long sleep disorder with two distinct subtypes, narcolepsy type I and narcolepsy type II. It is now well recognized that the loss of hypocretin neurons underlies the pathogenesis of narcolepsy type I, however, the pathogenesis of narcolepsy type II is currently unknown. Both genetic and environmental factors play an important role in the pathogenesis of narcolepsy. There is increasing evidence that autoimmune processes may play a critical role in the loss of hypocretin neurons. Infections especially streptococcus and influenza have been proposed as a potential trigger for the autoimmune-mediated mechanism. Several recent studies have shown increased cases of pediatric narcolepsy following the 2009 H1N1 pandemic. The increased cases in Europe seem to be related to a specific type of H1N1 influenza vaccination (Pandemrix), while the increased cases in China are related to influenza infection. Children with narcolepsy can have an unusual presentation at disease onset including complex motor movements which may lead to delayed diagnosis. All classic narcolepsy tetrads are present in only a small proportion of children. The diagnosis of narcolepsy is confirmed by either obtaining cerebrospinal fluid hypocretin or overnight sleep study with the multiple sleep latency test (MSLT). There are limitations of using MSLT in young children such that a negative MSLT test cannot exclude narcolepsy. HLA markers have limited utility in narcolepsy, but it may be useful in young children with clinical suspicion of narcolepsy. For management, both pharmacologic and non-pharmacologic treatments are important in the management of narcolepsy. Pharmacotherapy is primarily aimed to address excessive daytime sleepiness and REM-related symptoms such as cataplexy. In addition to pharmacotherapy, routine screening of behavioral and psychosocial issues is warranted to identify patients who would benefit from bio-behavior intervention.

The bacterial type IV pilus (T4P) is a prominent virulence factor in many significant human pathogens, some of which have become increasingly antibiotic resistant. Antivirulence chemotherapeutics are considered a promising alternative to antibiotics because they target the disease process instead of bacterial viability. However, a roadblock to the discovery of anti-T4P compounds is the lack of a high-throughput screen (HTS) that can be implemented relatively easily and economically. Here, we describe the first HTS for the identification of inhibitors specifically against the T4P assembly ATPase PilB in vitro. Chloracidobacterium thermophilum PilB (CtPilB) had been demonstrated to have robust ATPase activity and the ability to bind its expected ligands in vitro. We utilized CtPilB and MANT-ATP, a fluorescent ATP analog, to develop a binding assay and adapted it for an HTS. As a proof of principle, we performed a pilot screen with a small compound library of kinase inhibitors and identified quercetin as a PilB inhibitor in vitro. Using Myxococcus xanthus as a model bacterium, we found quercetin to reduce its T4P-dependent motility and T4P assembly in vivo. These results validated our HTS as effective in identifying PilB inhibitors. This assay may prove valuable in seeking leads for the development of antivirulence chemotherapeutics against PilB, an essential and universal component of all bacterial T4P systems. IMPORTANCE Many bacterial pathogens use their type IV pili (T4P) to facilitate and maintain infection of a human host. Small chemical compounds that inhibit the production or assembly of T4P hold promise in the treatment and prevention of infections, especially in the era of increasing threats from antibiotic-resistant bacteria. However, few chemicals are known to have inhibitory or anti-T4P activity. Their identification has not been easy due to the lack of a method for the screening of compound collections or libraries on a large scale. Here, we report the development of an assay that can be scaled up to screen compound libraries for inhibitors of a critical T4P assembly protein. We further demonstrate that it is feasible to use whole cells to examine potential inhibitors for their activity against T4P assembly in a bacterium. Fralin Life Science Institute; National Science FoundationNational Science Foundation (NSF) [MCB-1417726, MCB-1919455]; GSDA fellowship; Liberati Scholarship; Open Access Subvention Fund (OASF) of Virginia Tech This work was partially supported by the Fralin Life Science Institute and National Science Foundation grants MCB-1417726 and MCB-1919455 to Z.Y. K.J.D. is the recipient of a GSDA fellowship and the Liberati Scholarship. We would like to acknowledge the Open Access Subvention Fund (OASF) of Virginia Tech for its support in the publication of this article. K.J.D., N.J.V., and Z.Y. designed research and analyzed data. K.J.D. and N.J.V. performed experiments. P.S. provided guidelines for HTS. K.J.D. and Z.Y. wrote the manuscript.?; We thank Andreas Sukamana for conducting some of the early experiments for the work reported here. There is no conflict of interest to declare.

Contains fulltext : 245031.pdf (Publisher’s version ) (Closed access) PURPOSE: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants. METHODS: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing. RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies. CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.

Objective The effects of vagus nerve stimulation (VNS) on sleep disordered breathing (SDB) have been reported in limited case series. Detailed studies, particularly in the pediatric population, have not been performed. The primary purpose of this study is to describe clinical characteristics, polysomnographic findings, and management of children treated with VNS. Methods A retrospective review of medical records and polysomnography data was performed in patients ages 0–20 years old receiving VNS therapy for refractory epilepsy at Cincinnati Children's Hospital Medical Center. Results 22 subjects met the inclusion criteria. 50% were male. The mean age at the time of VNS insertion was 8.4 ± 4.0 years. The mean age at the first PSG was 10.6 ± 4.3 years. Common presentations to sleep clinics included snoring (77.3%), frequent nighttime awakening (68.1%), and parasomnias (63.6%). The median apnea-hypopnea index (AHI) was 4.5/hr (IQR 3.0–13.1) and the median obstructive index (OI) was 4.1/hr (1.5–12.8). Obstructive sleep apnea (OSA) was diagnosed after VNS insertion in 19 patients (86.4%), 8 of which (36.3%) had severe OSA. Six patients (27.3%) had significant hypoventilation. For management, 6 patients (27.2%) were treated with bilevel PAP, 3 patients (13.6%) with CPAP, 2 patients (9.1%) with ventilator, 4 patients (18.2%) with upper airway surgeries, and 9 patients (40.9%) received medications only. Conclusions SDB is common in pediatric patients with medically refractory epilepsy managed with VNS who were referred to sleep medicine clinics. Both OSA and nocturnal alveolar hypoventilation are relatively common in this population. Management of SDB often involves the use of positive airway pressure therapy or upper airway surgeries. Further studies are needed to assess the prevalence, risk factors, and the effect of treatments on epilepsy control. This study highlights the need for screening of SDB prior to and following VNS implantation.

Purpose Sleep disorders are common in epilepsy. Additionally, events of staring, jerking, or nocturnal behaviors are common presentations in neurology or sleep practice. Moreover, sleepiness and nocturnal awakenings are common symptoms in children with epilepsy and differentiation form ongoing seizures and sleep disorders is needed. However, limited data exist for the best evaluation methods. This study evaluated the usefulness of combined video electroencephalography (EEG) and polysomnography (PSG) studies (vEEG/PSG). Methods Polysomnography custom database was searched for combined vEEG/PSG studies, performed from July 2010 to April 2014, which identified 240 studies. From chart review, data were collected for presenting symptoms, sleep disorder and epilepsy/neurology diagnoses, and EEG and PSG results. Results Most common indications for performing combined vEEG/PSG were correlating sleep events with seizure occurrence, evaluating sleepiness, nocturnal awakenings and nocturnal events. Sleep physician evaluation and/or PSG were abnormal in 94% of the studies. The EEG was abnormal in 53% and events or seizures were recorded in 40% of the studies. Hence, vEEG/PSG addressed the diagnostic questions. Additionally, as compared to children with epilepsy, a significantly larger number of children with spells/parasomnia had a normal sleep evaluation including a normal PSG (9 Vs 37%, p = 0.00003). Conclusions This study demonstrates that combined video EEG and polysomnography is useful in addressing the common management questions in children with epilepsy and suspicious nocturnal events. Additionally, sleep disorders are more common in children with epilepsy than parasomnia. Hence sleep evaluation is important in children with epilepsy. Further prospective studies are needed.

People suffering from Urinary Incontinence (UI) seek support and advice through online communities. The research team conducted a content analysis of nafc.org to investigate characteristics of information searched by users to analyze the effectiveness of this forum. Forty posts and the corresponding 249 responses were randomly selected and analyzed using a classification system derived by a research team from a nursing department in one of the universities in the southeastern region of the United States. The Linguistic Inquiry and Word Count (LIWC) generated an average tone rating of 35.21 for question posts and 53.20 for response posts. The findings highlighted the user’s need to seek advice concerning symptoms of UI resulting in 72.5% of question posts in this category and the responders need to empathize with the initial poster by sharing their own experiences resulting in 41.76% of responses in this category. We plan to continue the study with the analysis of 200 questions and their corresponding responses to better explore the emotions and needs shared in the forum.

Background: Enteral feeding via feeding tube (FT) provides essential nutrition support to critically ill patients or those who cannot intake adequate nutrition via the oral route. Unfortunately, 1%–2% of FTs placed blindly at bedside enter the airway undetected (as confirmed by x‐ray), where they could result in adverse events. Misplaced FTs can cause complications including pneumothorax, vocal cord injury, bronchopleural fistula, pneumonia, and death. X‐ray is typically performed to confirm FT placement before feeding, but may delay nutrition intake, may not universally identify misplacement, and adds cost and radiation exposure. Methods: A prospective case series was conducted to evaluate a novel FT with a camera to provide real‐time visualization, guiding placement. The primary end point was the clinician's ability to identify anatomical markers in the gastrointestinal tract and/or airway using the camera. Results: The Kangaroo Feeding Tube with IRIS Technology tube was placed in 45 subjects with 1 misplaced tube; 3 placements were postpyloric, with the remainder gastric. Clinicians correctly identified the stomach in 44 of 45 placements at a median depth of 60.0 cm (range 45.0–85.0 cm). A stomach image was obtained in 42 subjects (93.3%). Agreement between camera image and radiographic confirmation of placement was 93% (P = .014) with small deviations in recognizing stomach vs small bowel. No device‐related adverse events occurred. Conclusions: Direct visualization of the stomach using a camera‐equipped FT can assist with FT placement, help avoid misplacements, and with further studies to evaluate the safety of eliminating confirmatory x‐ray before feeding, could potentially preclude the need for radiographic confirmation.

It is now recognized that there are two types of narcolepsy. Narcolepsy type I or Narcolepsy with cataplexy is caused by the loss of hypocretin or orexin neurons. Narcolepsy type II or narcolepsy without cataplexy has normal hypocretin and the etiology is unknown. Hypocretin is a neuropeptide produced by neurons in the lateral hypothalamus. Both genetic and environmental factors play a crucial role in the pathogenesis of narcolepsy. Most patients with narcolepsy type I and half of patients with narcolepsy type II carry HLA-DQB1*0602. HLA-DQB1*0602 forms a heterodimer with HLA-DQA1*0102 and may act as an antigen presenter to the T cell receptors, resulting in narcolepsy susceptibility. In addition, narcolepsy has been shown to be linked to polymorphisms in other non-HLA genes that may affect immune regulatory function, leading to speculation that autoimmune processes may play a crucial role in the loss of hypocretin neurons. Infections have been proposed as a potential trigger for the autoimmune-mediated mechanism. Several recent studies have shown increased cases of narcolepsy, especially in children and adolescents in relation with H1N1 influenza. The increased cases in Europe seems to be related to a specific type of H1N1 influenza vaccination (Pandemrix), while the increased cases in China are related to influenza infection. The data from the Pediatric Working Group of the Sleep Research Network have shown similar increases of early onset narcolepsy in the United States.

The HPTN 067/Alternative Dosing to Augment Pre-Exposure Prophylaxis Pill Taking (ADAPT) study evaluated daily and non-daily dosing schedules for oral pre-exposure prophylaxis (PrEP) to prevent HIV. A qualitative sub-study including focus groups and in-depth interviews was conducted among men who have sex with men participating in New York City to understand their experience with PrEP and study dosing schedules. The 37 sub-study participants were 68% black, 11% white, and 8% Asian; 27% were of Hispanic/Latino ethnicity. Mean age was 34 years. Themes resulting from qualitative analysis include: PrEP is a significant advance for HIV prevention; non-daily dosing of PrEP is congruent with HIV risk; and pervasive stigma connected to HIV and risk behavior is a barrier to PrEP adherence, especially for non-daily dosing schedules. The findings underscore how PrEP intersects with other HIV prevention practices and highlight the need to understand and address multidimensional stigma related to PrEP use.

Alzheimer’s caregivers seek social support through online communities to deal with their issues. The research team conducted a content analysis of ALZConnected.org to investigate the characteristics of information searched by caregivers and responses received. Two-hundred fifty posts and related responses were randomly selected and analyzed using a classification tool derived from the analysis of 500 posts and related responses spanning a yearlong period. The Linguistic Inquiry and Word Count (LIW C) generated an average tone rating of 25.94 for the posts and 52.69 for the responses. The findings highlighted the caregiver’s need for emotional support (59.6%), and confusion about Alzheimer’s symptoms (12%). Most responses suggested informational resources (40.16%) and advised to seek professional assistance (21.31%). One of the key needs identified to inform future design of an Alzheimer’s Caregiver Forum was a design sensitive to the capabilities of its elder user audience.

BACKGROUND: Oral pre-exposure prophylaxis (PrEP) is highly efficacious but low adherence undermines effectiveness. Depression, common in African women, may be a barrier to consistent PrEP use. We aimed to assess the relationship between depression, psychosocial mediators, and PrEP adherence among South African women. METHODS: We analyzed data from 174 South African women in HPTN 067, an open-label oral PrEP trial conducted from 2011–2013. Participants were followed for 24 weeks. PrEP adherence was measured via Wisepill™ and weekly self-report interview data. We considered participants “adherent” at week 24 if Wisepill™ and interviews indicated that ≥80% of expected doses were taken in the prior month. Elevated depressive symptoms were assessed using the 20-item Center for Epidemiological Studies-Depression (CES-D) scale. We used marginal structural models to estimate the effect of elevated symptoms at baseline on PrEP adherence at week 24 and to assess whether the direct effect changed meaningfully after accounting for mediating effects of stigma, social support, and PrEP optimism. RESULTS: High PrEP adherence occurred less often among women with elevated depressive symptoms (N=35; 44.3%) compared with those without (N=52; 54.7%; adjusted relative risk [aRR]: 0.79; 95% confidence interval [CI]: 0.63–0.99). The effect of elevated depressive symptoms on PrEP adherence persisted in models accounting for the mediating influence of stigma (aRR: 0.74; 95% CI: 0.51–0.97) and PrEP optimism (aRR: 0.75; 95% CI: 0.55–0.99). We also found a direct effect of similar magnitude and direction when accounting for social support as the mediating variable, although this adjusted relative risk estimate was not statistically significant (aRR: 0.77; 95% CI: 0.57–1.03). CONCLUSIONS: Depressive symptoms were common and associated with lower PrEP adherence among South African women. Future work is needed to determine whether depression services integrated with PrEP delivery could improve PrEP effectiveness among African women.