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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.

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.

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.

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.

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.

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.

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.

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.

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.

Epidemiological studies have shown that restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) are common in children and adolescents with an estimated prevalence of 2–4% [1,2]. Th...

STUDY OBJECTIVES: Previous studies have shown that non-rapid eye movement (NREM) sleep parasomnias commonly coexist with restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) in children, leading to speculation that RLS/PLMD may precipitate or worsen parasomnias. However, there are limited data about the effect of the treatment of RLS/PLMD on parasomnias in children. Hence, we performed this study to determine whether the treatment of RLS/PLMD with oral iron therapy is associated with improvement of parasomnias in children. METHODS: A retrospective database was created for children with RLS/PLMD who were treated with iron therapy. These participants were followed for at least 1 year at Cincinnati Children's Hospital Medical Center. All participants had ferritin level testing and were treated with iron therapy. In addition, all participants underwent polysomnography before starting iron therapy for RLS/PLMD except for one participant who was already on iron but required a higher dose. Most participants underwent polysomnography after iron therapy. RESULTS: A total of 226 participants were identified with the diagnosis of RLS/PLMD. Of these, 50 had parasomnias and 30 of them were treated with iron therapy. Of the 30 participants, RLS symptoms improved in 15 participants (50%) and resolution of parasomnias was noted in 12 participants (40%) participants after iron therapy. Repeat polysomnography after iron therapy was performed in 21 participants (70%). After iron therapy, there was a significant decrease in periodic limb movement index (17.2 ± 8.8 [before] versus 6.7 ± 7.3 [after] events/h, P < .001). In addition, there were significant decreases in PLMS (24.52 ± 9.42 [before] versus 7.50 ± 7.18 [after] events/h, P < .0001), PLMS-related arousals (4.71 ± 1.81 [before] versus 1.35 ± 1.43 [after] events/h, P < .0001), and total arousals (11.65 ± 5.49 [before] versus 8.94 ± 3.65 [after] events/h, P < .01) after iron therapy. CONCLUSIONS: Parasomnias are common in our cohort of children with RLS/PLMD. Iron therapy was associated with a significant improvement in periodic limb movement index, RLS symptoms, and resolution of a significant proportion of NREM sleep parasomnias, suggesting that RLS/PLMD may precipitate NREM sleep parasomnia. CITATION: Gurbani N, Dye TJ, Dougherty K, Jain S, Horn PS, Simakajornboon N. Improvement of parasomnias after treatment of restless leg syndrome/ periodic limb movement disorder in children. J Clin Sleep Med. 2019;15(5):743–748.

In services, which require significant customer participation to create value, customers who lack the knowledge, skills and motivation necessary to participate effectively can negatively impact service quality and cost outcomes. This paper develops a conceptual model to investigate the effectiveness of utilizing customer training and education (CTE) to improve customer readiness to provide effective behaviors in a professional service. The model was tested using survey data from patients diagnosed with diabetes who received CTE as part of their healthcare service. We found that customers who are taught why they have to perform the tasks, have higher levels of motivation to perform these tasks effectively. Further, as proposed by the customer readiness model, when their task performance is higher, they have improved health and lower healthcare costs.

ObjectiveProvide an overview of current research findings in pediatric central disorders of hypersomnolence (CDH) and propose a biopsychosocial model for clinical management, with a focus on interdisciplinary care and future directions for research and clinical practice.MethodsLiterature review drawing from pediatric and adult narcolepsy, as well as pediatric sleep and chronic pain research to develop an integrative biopsychosocial model for pediatric CDH.ResultsYouth with CDH are vulnerable to impairments in academics, emotional, and behavioral functioning, activity engagement and quality of life (QOL). There is a complex interrelationship between neurobiological features of disease, treatment-related factors, and psychological, sleep-related, and contextual factors across development. Research is limited largely to adults and pediatric narcolepsy type 1 and the mechanisms and evolution of morbidity remain poorly understood.ConclusionsIn addition to first-line treatment (pharmacotherapy), routine screening of bio-behavioral and psychosocial functioning and QOL is needed to identify risk for compromised functioning warranting adjunctive interventions with behavioral health specialists.

The purpose of the study was to pilot test a model to reduce hospital readmissions and emergency department use of rural, older adults with chronic diseases discharged from home health services (HHS) through the use of volunteers. The study’s priority population consistently experiences poorer health outcomes than their urban counterparts due in part to lower socioeconomic status, reduced access to health services, and incidence of chronic diseases. When they are hospitalized for complications due to poorly managed chronic diseases, they are frequently readmitted for the same conditions. This pilot study examines the use of volunteer community members who were trained as Health Coaches to mentor discharged HHS patients in following the self-care plan developed by their HHS RN; improving chronic disease self-management behaviors; reducing risk of falls, pneumonia, and flu; and accessing community resources. Program participants increased their ability to monitor and track their chronic health conditions, make positive lifestyle changes, and reduce incidents of falls, pneumonia and flu. Although differences in the ED and hospital admission rates after discharge from HHS between the treatment and comparison group (matched for gender, age, and chronic condition) were not statistically significant, the treatment group’s rate was less than the comparison group thus suggesting a promising impact of the HC program (90 day: 263 comparison vs. 129 treatment; p = 0.65; 180 day 666.67 vs. 290.32; p = 0.19). The community health coach model offers a potential approach for improving the ability of discharged older home health patients to manage chronic conditions and ultimately reduce emergent care.

BACKGROUND Injection opioid use plays a significant role in the transmission of HIV infection in many communities and several regions of the world. Access to evidence-based treatments for opioid use disorders is extremely limited. METHODS HIV Prevention Trials Network 058 (HPTN 058) was a randomized controlled trial designed to compare the impact of 2 medication-assisted treatment (MAT) strategies on HIV incidence or death among opioid-dependent people who inject drugs (PWID). HIV-negative opioid-dependent PWID were recruited from 4 communities in Thailand and China with historically high prevalence of HIV among PWID. A total of 1251 participants were randomly assigned to either (1) a 1-year intervention consisting of 2 opportunities for a 15-day detoxification with buprenorphine/naloxone (BUP/NX) combined with up to 21 sessions of behavioral drug and risk counseling [short-term medication-assisted treatment (ST-MAT)] or (2) thrice-weekly dosing for 48 weeks with BUP/NX and up to 21 counseling sessions [long-term medication-assisted treatment (LT-MAT)] followed by dose tapering. All participants were followed for 52 weeks after treatment completion to assess durability of impact. RESULTS Although the study was stopped early due to lower than expected occurrence of the primary end points, sufficient data were available to assess the impact of the interventions on drug use and injection-related risk behavior. At week 26, 22% of ST-MAT participants had negative urinalyses for opioids compared with 57% in the LT-MAT (P < 0.001). Differences disappeared in the year after treatment: at week 78, 35% in ST-MAT and 32% in the LT-MAT had negative urinalyses. Injection-related risk behaviors were significantly reduced in both groups after randomization. CONCLUSIONS Participants receiving BUP/NX 3 times weekly were more likely to reduce opioid injection while on active treatment. Both treatment strategies were considered safe and associated with reductions in injection-related risk behavior. These data support the use of thrice-weekly BUP/NX as a way to reduce exposure to HIV risk. Continued access to BUP/NX may be required to sustain reductions in opioid use.

BACKGROUND: Nondaily dosing of oral preexposure prophylaxis (PrEP) may provide equivalent coverage of sex events compared with daily dosing. METHODS: At-risk men and transgender women who have sex with men were randomly assigned to 1 of 3 dosing regimens: 1 tablet daily, 1 tablet twice weekly with a postsex dose (time-driven), or 1 tablet before and after sex (event-driven), and were followed for coverage of sex events with pre- and postsex dosing measured by weekly self-report, drug concentrations, and electronic drug monitoring. RESULTS: From July 2012 to May 2014, 357 participants were randomized. In Bangkok, the coverage of sex events was 85% for the daily arm compared with 84% for the time-driven arm (P = .79) and 74% for the event-driven arm (P = .02). In Harlem, coverage was 66%, 47% (P = .01), and 52% (P = .01) for these groups. In Bangkok, PrEP medication concentrations in blood were consistent with use of ≥2 tablets per week in >95% of visits when sex was reported in the prior week, while in Harlem, such medication concentrations occurred in 48.5% in the daily arm, 30.9% in the time-driven arm, and 16.7% in the event-driven arm (P < .0001). Creatinine elevations were more common in the daily arm (P = .050), although they were not dose limiting. CONCLUSIONS: Daily dosing recommendations increased coverage and protective drug concentrations in the Harlem cohort, while daily and nondaily regimens led to comparably favorable outcomes in Bangkok, where participants had higher levels of education and employment. CLINICAL TRIALS REGISTRATION: NCT01327651.

Caregivers of Alzheimer's patients find respite in online communities for solutions and emotional support. This study aims to understand the characteristics of information caregivers of Alzheimer's patients are searching for and the kind of support they receive through Internet-based peer support communities. Using a Web crawler written in Python Web programming language, we retrieved publicly available 2,500 random posts and their respective solutions from April 2012 to October 2016 on the solutions category of the Caregiver's Forum on ALZConnected.org . A content analysis was conducted on these randomly selected posts and 4,219 responses to those posts based on a classification system were derived from initial analyses of 750 posts and related responses. The results showed most posts (26%) related to queries about Alzheimer's symptoms, and the highest percentage of responses (45.56%) pertained to caregiver well-being. The LIWC analyses generated an average tone rating of 27.27 for the posts, implying a negative tone and 65.17 for their responses, implying a slightly positive tone. The ALZConnected.org Web site has the potential of being an emotionally supportive tool for caregivers; however, a more user-friendly interface is required to accommodate the needs of most caregivers and their technological skills. Solutions offered on the peer support groups are often subjective opinions of other caregivers and should not be considered professional or comprehensive; further research on educating caregivers using online forums is necessary.

Falls have negative consequences for older adults, but falls can be reduced through interventions that target the reduction of fall risk factors. Cognitive behavioral education programs and therapeutic yoga are two interventions that have independently been used as a means to reduce the risk of falls. The purpose of this study was to determine if adding therapeutic yoga following an education intervention improved well known fall risk factors. Potential participants were recruited through a senior center for a 12-week fall prevention program that consisted of four weeks of an evidence-informed educational program and eight weeks of therapeutic yoga. Physical performance measures and psychosocial constructs were tested at baseline (T1), between the education intervention and yoga (T2), and after yoga (T3). Physical performance measures included the chair stand test to assess lower-body strength, the Timed Up-and-Go to assess agility and dynamic balance, and the Fullerton Advanced Balance Scale to assess static and dynamic balance. Psychosocial surveys included the University of Illinois at Chicago Fear of Falling to assess fear of falling, the Leisure Constraints Scale to assess constraints to physical activity, and the Activities Balance Confidence Scale, to assess perceived balance ability. A repeated measures test was used to determine if any significant changes in fall risk factors occurred. There were significant improvements in balance confidence after education, in agility and dynamic balance after yoga, and in fear of falling across the full 12-week intervention. Adding therapeutic yoga following education improved more outcomes than education alone and this combined intervention warrants further exploration as a fall risk reduction strategy.

The relative feasibility and acceptability of daily versus non-daily dosing of oral HIV pre-exposure prophylaxis (PrEP) among women are unknown. We aimed to investigate the feasibility of non-daily PrEP regimens in adult women.We did a randomised, open-label, phase 2 clinical trial (HPTN 067/ADAPT) of oral PrEP with emtricitabine plus tenofovir disoproxil fumarate at a research centre in Cape Town, South Africa. Participants were adult women (age ≥18 years) who received directly observed dosing once a week for 5 weeks followed by random assignment (1:1:1) at week 6 to one of three unblinded PrEP regimens for self-administered dosing over 24 weeks: daily; time-driven (twice a week plus a post-sex dose); or event-driven (one tablet both before and after sex). Primary outcomes were PrEP coverage (at least one dose within the 4 days before sex and one dose within 24 h after sex), pills needed or used to achieve regimen-specific adherence and coverage, and symptoms and side-effects. All analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01327651; the trial is completed and this report presents the final analysis.Between Sept 12, 2011, and Oct 3, 2012, 191 women were enrolled to the trial. 178 (93%) completed directly observed dosing and were randomly assigned one of the three PrEP regimens for the self-administered phase: 59 were allocated the daily regimen, 59 the time-driven regimen, and 60 the event-driven regimen. Median age of women was 26 years (IQR 21-37; range 18-52). In women allocated the daily regimen, 1459 (75%) of 1952 sex events were covered by PrEP, compared with 599 (56%) of 1074 sex events among those assigned the time-driven regimen (odds ratio [OR] 2·35, 95% CI 1·43-3·83; p=0·0007) and 798 (52%) of 1542 sex events among those allotted the event-driven regimen (2·76, 1·68-4·53; p0·0001). Fewer pills were needed for complete adherence in women allocated non-daily regimens (vs daily regimen, relative mean 2·53 [95% CI 2·39-2·69] for the time-driven regimen and 4·16 [3·59-4·82] for the event-driven regimen; p0·0001). Side-effects were uncommon. Eight HIV seroconversions occurred overall, with four documented during the self-administered phase (two with the time-driven regimen and two with the event-driven regimen). Adherence to the assigned regimen was 75% (7283 of 9652 doses taken) for women allocated the daily regimen compared with 65% for those assigned the time-driven regimen (2367 of 3616 doses taken; p=0·0028) and 53% for those allotted the event-driven regimen (1161 of 2203 doses taken; p0·0001). When sex was reported in the previous week, PrEP drugs were detected (above the lower limits of quantification) more frequently in women assigned the daily regimen (73 [68%] of 107 samples) than in those allocated the time-driven regimen (42 [58%] of 72 samples) and the event-driven regimen (41 [41%] of 99 samples).Daily PrEP dosing resulted in higher coverage of sex events, increased adherence to the regimen, and augmented drug concentrations than did either time-driven or event-driven dosing. These findings support recommendations for daily use of PrEP with oral emtricitabine plus tenofovir disoproxil fumarate in women.HIV Prevention Trials Network.

RNA Polymerase II (Pol II) termination is dependent on RNA processing signals as well as specific terminator elements located downstream of the poly(A) site. One of the two major terminator classes described so far is the Co-Transcriptional Cleavage (CoTC) element. We show that homopolymer A/T tracts within the human β-globin CoTC-mediated terminator element play a critical role in Pol II termination. These short A/T tracts, dispersed within seemingly random sequences, are strong terminator elements, and bioinformatics analysis confirms the presence of such sequences in 70% of the putative terminator regions (PTRs) genome-wide.

Placebo-controlled trials of pre-exposure prophylaxis (PrEP) have reported challenges with study-product uptake and use, with the greatest challenges reported in studies with young women in sub-Saharan Africa. We conducted a qualitative sub-study to explore experiences with open-label PrEP among young women in Cape Town, South Africa participating in HTPN 067/Alternative Dosing to Augment Pre-Exposure Prophylaxis Pill Taking (ADAPT). HPTN 067/ADAPT provided open label oral FTC/TDF PrEP to young women in Cape Town, South Africa who were randomized to daily and non-daily PrEP regimens. Following completion of study participation, women were invited into a qualitative sub-study including focus groups and in-depth interviews. Interviews and groups followed a semi-structured guide, were recorded, transcribed, and translated to English from isiXhosa, and coded using framework analysis. Sixty of the 179 women enrolled in HPTN 067/ADAPT participated in either a focus group (six groups for a total of 42 participants) or an in-depth interview (n=18). This sample of mostly young, unmarried women identified facilitators of and barriers to PrEP use, as well as factors influencing study participation. Cross-cutting themes characterizing discourse suggested that women placed high value on contributing to the well-being of one's community (Ubuntu), experienced a degree of skepticism towards PrEP and the study more generally, and reported a wide range of approaches towards PrEP (ranging from active avoidance to high levels of persistence and adherence). A Mutuality Framework is proposed that identifies four dynamics (distrust, uncertainty, alignment, and mutuality) that represent distinct interactions between self, community and study and serve to contextualize women's experiences. Implications for better understanding PrEP use, and non-use, and intervention opportunities are discussed. In this sample of women, PrEP use in the context of an open-label research trial was heavily influenced by underlying beliefs about safety, reciprocity of contributions to community, and trust in transparency and integrity of the research. Greater attention to factors positioning women in the different dynamics of the proposed Mutuality Framework could direct intervention approaches in clinical trials, as well as open-label PrEP scale-up.

This article describes the impact of an 8-week community program implemented by trained volunteers on the hypertension self-management of 185 patients who were batch randomized to intervention or wait-list control groups. Compared with control group participants, a higher proportion of treatment group participants moved from the cognitive to behavioral stages of motivational readiness for being physically active ( P < .001), practicing healthy eating habits ( P = .001), handling stress well ( P = .001), and living an overall healthy lifestyle ( P = .003). They also demonstrated a greater average increase in perceived competence for self-management, F (1.134) = 4.957, P = .028, η 2 = .036, and a greater increase in mean hypertension-related knowledge, F (1.160) = 16.571, P < .0005, η 2 = .094. Enduring lifestyle changes necessary for chronic disease self-management require that psychosocial determinants of health behavior are instilled, which is typically beyond standard medical practice. We recommend peer-led, community-based programs as a complement to clinical care and support the increasing health system interest in promoting population health beyond clinical walls.

Biodiesels (fatty acid methyl esters) derived from oleaginous microbes (microalgae, yeast, and bacteria) are being actively pursued as potential renewable substitutes for petroleum diesel. Here, we report the engine performance characteristics of biodiesel produced from a microalgae (Chaetoceros gracilis), a yeast (Cryptococcus curvatus), and a bacteria (Rhodococcus opacus) in a two-cylinder diesel engine outfitted with an eddy current brake dynamometer, comparing the fuel performance to petroleum diesel (#2) and commercial biodiesel from soybeans. Key physical and chemical properties, including heating value, viscosity, density, and cetane index, for each of the microbial-derived biofuels were found to compare favorably to those of soybean biodiesel. Likewise, the horsepower, torque, and brake specific fuel consumption across a range of engine speeds also compared favorably to values determined for soybean biodiesel. Analysis of exhaust emissions (hydrocarbon, CO, CO2, O2, and NOx) revealed that all biof...

Irregular vestibular afferents exhibit significant phase leads with respect to angular velocity of the head in space. This characteristic and their connectivity with vestibulospinal neurons suggest a functionally important role for these afferents in producing the vestibulo-collic reflex (VCR). A goal of these experiments was to test this hypothesis with the use of weak galvanic stimulation of the vestibular periphery (GVS) to selectively activate or suppress irregular afferents during passive whole body rotation of guinea pigs that could freely move their heads. Both inhibitory and excitatory GVS had significant effects on compensatory head movements during sinusoidal and transient whole body rotations. Unexpectedly, GVS also strongly affected the vestibulo-ocular reflex (VOR) during passive whole body rotation. The effect of GVS on the VOR was comparable in light and darkness and whether the head was restrained or unrestrained. Significantly, there was no effect of GVS on compensatory eye and head movements during volitional head motion, a confirmation of our previous study that demonstrated the extravestibular nature of anticipatory eye movements that compensate for voluntary head movements.