Considerations for partnering with Ryan White Case Managers to create equitable opportunities for people with HIV to participate in research

Many research studies focus on recruitment from one or few HIV clinics or internet-engaged populations, but this may result in inequitable representation of people with HIV (PWH), across the rural/urban/suburban continuum. Ryan White Case Managers (RWCM) meet regularly with PWH, potentially positioning them as partners in gathering research-related data from diverse groups of low-income, marginalized, PWH. Yet, data collection in partnership with RWCM, particularly over large geographic areas, has been under-explored. We partnered with RWCM and their organizations throughout Florida to administer a 10-item technology use and willingness survey to clients living with HIV; RWCMs provided process-oriented feedback. Among 382 approached RWCM, 71% completed human subjects and survey administration training; 48% gathered data on 10 predetermined survey administration days; and 68% administered at least one survey during the entire period for survey administration. Altogether, 1,268 client surveys were completed, 2.7% by rural participants. Stigma, privacy concerns, and disinterest reportedly inhibited client participation; competing obligations, policies, and narrow recruitment windows prevented some RWCM from offering the survey to clients. Research should further explore strategies and best practices to ensure equitable access to participate in research among PWH

Molecular mechanism for depolarization-induced modulation of Kv channel closure

Voltage-dependent potassium (Kv) channels provide the repolarizing power that shapes the action potential duration and helps control the firing frequency of neurons. The K(+) permeation through the channel pore is controlled by an intracellularly located bundle-crossing (BC) gate that communicates with the voltage-sensing domains (VSDs). During prolonged membrane depolarizations, most Kv channels display C-type inactivation that halts K(+) conduction through constriction of the K(+) selectivity filter. Besides triggering C-type inactivation, we show that in Shaker and Kv1.2 channels (expressed in Xenopus laevis oocytes), prolonged membrane depolarizations also slow down the kinetics of VSD deactivation and BC gate closure during the subsequent membrane repolarization. Measurements of deactivating gating currents (reporting VSD movement) and ionic currents (BC gate status) showed that the kinetics of both slowed down in two distinct phases with increasing duration of the depolarizing prepulse. The biphasic slowing in VSD deactivation and BC gate closure was strongly correlated in time and magnitude. Simultaneous recordings of ionic currents and fluorescence from a probe tracking VSD movement in Shaker directly demonstrated that both processes were synchronized. Whereas the first slowing originates from a stabilization imposed by BC gate opening, the subsequent slowing reflects the rearrangement of the VSD toward its relaxed state (relaxation). The VSD relaxation was observed in the Ciona intestinalis voltage-sensitive phosphatase and in its isolated VSD. Collectively, our results show that the VSD relaxation is not kinetically related to C-type inactivation and is an intrinsic property of the VSD. We propose VSD relaxation as a general mechanism for depolarization-induced slowing of BC gate closure that may enable Kv1.2 channels to modulate the firing frequency of neurons based on the depolarization history

Molecular mechanism for depolarization-induced modulation of Kv channel closure

Voltage-dependent potassium (Kv) channels provide the repolarizing power that shapes the action potential duration and helps control the firing frequency of neurons. The K+ permeation through the channel pore is controlled by an intracellularly located bundle-crossing (BC) gate that communicates with the voltage-sensing domains (VSDs). During prolonged membrane depolarizations, most Kv channels display C-type inactivation that halts K+ conduction through constriction of the K+ selectivity filter. Besides triggering C-type inactivation, we show that in Shaker and Kv1.2 channels (expressed in Xenopus laevis oocytes), prolonged membrane depolarizations also slow down the kinetics of VSD deactivation and BC gate closure during the subsequent membrane repolarization. Measurements of deactivating gating currents (reporting VSD movement) and ionic currents (BC gate status) showed that the kinetics of both slowed down in two distinct phases with increasing duration of the depolarizing prepulse. The biphasic slowing in VSD deactivation and BC gate closure was strongly correlated in time and magnitude. Simultaneous recordings of ionic currents and fluorescence from a probe tracking VSD movement in Shaker directly demonstrated that both processes were synchronized. Whereas the first slowing originates from a stabilization imposed by BC gate opening, the subsequent slowing reflects the rearrangement of the VSD toward its relaxed state (relaxation). The VSD relaxation was observed in the Ciona intestinalis voltage-sensitive phosphatase and in its isolated VSD. Collectively, our results show that the VSD relaxation is not kinetically related to C-type inactivation and is an intrinsic property of the VSD. We propose VSD relaxation as a general mechanism for depolarization-induced slowing of BC gate closure that may enable Kv1.2 channels to modulate the firing frequency of neurons based on the depolarization history

The COVID-19 pandemic as a catalyst for integrated global mental healthcare and tuberculosis care

Mental disorders are common among persons with tuberculosis (TB), and the COVID-19 pandemic has only amplified the mental and physical health consequences of this deadly synergy. Here, we call to attention the immense vulnerability of people with TB to mental disorders during the pandemic and highlight the unique challenges and opportunities that the pandemic brings to the future integration of global TB and mental healthcare. We argue that the pandemic era is an ideal period to accelerate this integration and we provide research and policy recommendations to actualise this urgent need

L-theanine in the adjunctive treatment of generalized anxiety disorder: a double-blind, randomised, placebo-controlled trial

Partial or non-response to antidepressants in Generalized Anxiety Disorder (GAD) is common in clinical settings, and adjunctive biological interventions may be required. Adjunctive herbal and nutraceutical treatments are a novel and promising treatment option. L-theanine is a non-protein amino acid derived most-commonly from tea (Camellia sinensis) leaves, which may be beneficial in the treatment of anxiety and sleep disturbance as suggested by preliminary evidence. We conducted a 10-week study (consisting of an 8-week double-blind placebo-controlled period, and 1-week pre-study and 2-week post-study single-blinded observational periods) involving 46 participants with a DSM-5 diagnosis of GAD. Participants received adjunctive L-theanine (450–900 mg) or matching placebo with their current stable antidepressant treatment, and were assessed on anxiety, sleep quality, and cognition outcomes. Results revealed that adjunctive L-theanine did not outperform placebo for anxiety reduction on the HAMA (p = 0.73) nor insomnia severity on the Insomnia Severity Index (ISI; p = 0.35). However, LT treated participants reported greater self-reported sleep satisfaction than placebo (ISI item 4; p = 0.015). Further, a separation in favour of L-theanine was noted on the ISI in those with non-clinical levels of insomnia symptoms (ISI ≤ 14; p = 0.007). No significant cognitive effects (trail making time and the modified emotional Stroop) were revealed. While this preliminary study did not support the efficacy of L-theanine in the treatment of anxiety symptoms in GAD, further studies to explore the application of L-theanine in sleep disturbance are warranted

Characterizing the syphilis epidemic among men who have sex with men in Lima, Peru to identify new treatment and control strategies

Abstract Background: Syphilis is an important sexually transmitted infection (STI) with serious public health consequences. Among men who have sex with men (MSM) in Lima, the prevalence and incidence are extraordinarily high. Current syndromic approaches, however, fail to identify asymptomatic cases, and in settings where large proportions of individuals test positive again after treatment, it is frequently difficult to distinguish treatment failure from reinfection. Thus, new approaches are needed to improve treatment strategies and public health control efforts. Methods/Design: Study participants will undergo baseline testing for syphilis infection along with a behavioral survey covering demographics, sexual behavior, drug and alcohol abuse and health-care seeking behavior. The cohort will be followed for 18 months at three-month intervals. Blood and earlobe scrapings will also be collected for T. pallidum DNA testing, to create molecular markers for subtyping. We will also perform cytokine testing on collected samples in order to create host immunologic profiles associated with recurrence, re-infection, treatment failure and success. Discussion: Advances in social epidemiology, molecular typing and characterization of host immune responses will offer promise in developing new understandings of syphilis management. We will share our findings with the Peruvian Ministry of Health and other public health organizations, to identify new approaches of case detection and successful treatment

Exposure to the tsunami disaster, PTSD symptoms and increased substance use – an Internet based survey of male and female residents of Switzerland

BACKGROUND: After the tsunami disaster in the Indian Ocean basin an Internet based self-screening test was made available in order to facilitate contact with mental health services. Although primarily designed for surviving Swiss tourists as well as relatives and acquaintances of the victims, the screening instrument was open to anyone who felt psychologically affected by this disaster. The aim of this study was to evaluate the influences between self-declared increased substance use in the aftermath of the tsunami disaster, trauma exposure and current PTSD symptoms. METHODS: One section of the screening covered addiction related behavior. We analyzed the relationship between increased substance use, the level of PTSD symptoms and trauma exposure using multivariable logistic regression with substance use as the dependent variable. Included in the study were only subjects who reported being residents of Switzerland and the analyses were stratified by gender in order to control for possible socio-cultural or gender differences in the use of psychotropic substances. RESULTS: In women PTSD symptoms and degree of exposure enlarged the odds of increased alcohol, pharmaceuticals and cannabis use significantly. In men the relationship was more specific: PTSD symptoms and degree of exposure only enlarged the odds of increased pharmaceutical consumption significantly. Increases in alcohol, cannabis and tobacco use were only significantly associated with the degree of PTSD symptoms. CONCLUSION: The tsunami was associated with increased substance use. This study not only replicates earlier findings but also suggests for a gender specificity of post-traumatic substance use increase

Early progression to active tuberculosis is a highly heritable trait driven by 3q23 in Peruvians

Abstract: Of the 1.8 billion people worldwide infected with Mycobacterium tuberculosis, 5–15% will develop active tuberculosis (TB). Approximately half will progress to active TB within the first 18 months after infection, presumably because they fail to mount an effective initial immune response. Here, in a genome-wide genetic study of early TB progression, we genotype 4002 active TB cases and their household contacts in Peru. We quantify genetic heritability (hg2) of early TB progression to be 21.2% (standard error 0.08). This suggests TB progression has a strong genetic basis, and is comparable to traits with well-established genetic bases. We identify a novel association between early TB progression and variants located in a putative enhancer region on chromosome 3q23 (rs73226617, OR = 1.18; P = 3.93 × 10−8). With in silico and in vitro analyses we identify rs73226617 or rs148722713 as the likely functional variant and ATP1B3 as a potential causal target gene with monocyte specific function