Variation in the gene coding for the M5 Muscarinic receptor (CHRM5) influences cigarette dose but is not associated with dependence to drugs of addiction: evidence from a prospective population based cohort study of young adults

Background: The mesolimbic structures of the brain are important in the anticipation and perception of reward. Moreover, many drugs of addiction elicit their response in these structures. The M5 muscarinic receptor (M5R) is expressed in dopamine-containing neurones of the substantia nigra pars compacta and ventral tegmental area, and regulates the release of mesolimbic dopamine. Mice lacking M5R show a substantial reduction in both reward and withdrawal responses to morphine and cocaine. The CHRM5, the gene that codes for the M5R, is a strong biological candidate for a role in human addiction. We screened the coding and core promoter sequences of CHRM5 using denaturing high performance liquid chromatography to identify common polymorphisms. Additional polymorphisms within the coding and core promoter regions that were identified through dbSNP were validated in the test population. We investigated whether these polymorphisms influence substance dependence and dose in a cohort of 1947 young Australians.Results: Analysis was performed on 815 participants of European ancestry who were interviewed at wave 8 of the cohort study and provided DNA. We observed a 26.8% increase in cigarette consumption in carriers of the rs7162140 T-allele, equating to 20.1 cigarettes per week (p=0.01). Carriers of the rs7162140 T-allele were also found to have nearly a 3-fold increased risk of developing cannabis dependence (OR=2.9 (95%CI 1.1-7.4); p=0.03).Conclusion: Our data suggest that variation within the CHRM5 locus may play an important role in tobacco and cannabis but not alcohol addiction in European ancestry populations. This is the first study to show an association between CHRM5 and substance use in humans. These data support the further investigation of this gene as a risk factor in substance use and dependence.<br /

Systematic review of context-aware digital behavior change interventions to improve health

Health risk behaviors are leading contributors to morbidity, premature mortality associated with chronic diseases, and escalating health costs. However, traditional interventions to change health behaviors often have modest effects, and limited applicability and scale. To better support health improvement goals across the care continuum, new approaches incorporating various smart technologies are being utilized to create more individualized digital behavior change interventions (DBCIs). The purpose of this study is to identify context-aware DBCIs that provide individualized interventions to improve health. A systematic review of published literature (2013-2020) was conducted from multiple databases and manual searches. All included DBCIs were context-aware, automated digital health technologies, whereby user input, activity, or location influenced the intervention. Included studies addressed explicit health behaviors and reported data of behavior change outcomes. Data extracted from studies included study design, type of intervention, including its functions and technologies used, behavior change techniques, and target health behavior and outcomes data. Thirty-three articles were included, comprising mobile health (mHealth) applications, Internet of Things wearables/sensors, and internet-based web applications. The most frequently adopted behavior change techniques were in the groupings of feedback and monitoring, shaping knowledge, associations, and goals and planning. Technologies used to apply these in a context-aware, automated fashion included analytic and artificial intelligence (e.g., machine learning and symbolic reasoning) methods requiring various degrees of access to data. Studies demonstrated improvements in physical activity, dietary behaviors, medication adherence, and sun protection practices. Context-aware DBCIs effectively supported behavior change to improve users' health behaviors

General Gauge Mediation at the Weak Scale

We completely characterize General Gauge Mediation (GGM) at the weak scale by solving all IR constraints over the full parameter space. This is made possible through a combination of numerical and analytical methods, based on a set of algebraic relations among the IR soft masses derived from the GGM boundary conditions in the UV. We show how tensions between just a few constraints determine the boundaries of the parameter space: electroweak symmetry breaking (EWSB), the Higgs mass, slepton tachyons, and left-handed stop/sbottom tachyons. While these constraints allow the left-handed squarks to be arbitrarily light, they place strong lower bounds on all of the right-handed squarks. Meanwhile, light EW superpartners are generic throughout much of the parameter space. This is especially the case at lower messenger scales, where a positive threshold correction to $m_h$ coming from light Higgsinos and winos is essential in order to satisfy the Higgs mass constraint.Comment: 43 pages, 20 figures, mathematica package included in the sourc

Goldstini

Supersymmetric phenomenology has been largely bound to the hypothesis that supersymmetry breaking originates from a single source. In this paper, we relax this underlying assumption and consider a multiplicity of sectors which independently break supersymmetry, thus yielding a corresponding multiplicity of goldstini. While one linear combination of goldstini is eaten via the super-Higgs mechanism, the orthogonal combinations remain in the spectrum as physical degrees of freedom. Interestingly, supergravity effects induce a universal tree-level mass for the goldstini which is exactly twice the gravitino mass. Since visible sector fields can couple dominantly to the goldstini rather than the gravitino, this framework allows for substantial departures from conventional supersymmetric phenomenology. In fact, this even occurs when a conventional mediation scheme is augmented by additional supersymmetry breaking sectors which are fully sequestered. We discuss a number of striking collider signatures, including various novel decay modes for the lightest observable-sector supersymmetric particle, gravitinoless gauge-mediated spectra, and events with multiple displaced vertices. We also describe goldstini cosmology and the possibility of goldstini dark matter.Comment: 14 pages, 7 figures; references adde

MTN-001: Randomized Pharmacokinetic Cross-Over Study Comparing Tenofovir Vaginal Gel and Oral Tablets in Vaginal Tissue and Other Compartments

Background: Oral and vaginal preparations of tenofovir as pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection have demonstrated variable efficacy in men and women prompting assessment of variation in drug concentration as an explanation. Knowledge of tenofovir concentration and its active form, tenofovir diphosphate, at the putative vaginal and rectal site of action and its relationship to concentrations at multiple other anatomic locations may provide key information for both interpreting PrEP study outcomes and planning future PrEP drug development. Objective: MTN-001 was designed to directly compare oral to vaginal steady-state tenofovir pharmacokinetics in blood, vaginal tissue, and vaginal and rectal fluid in a paired cross-over design. Methods and Findings: We enrolled 144 HIV-uninfected women at 4 US and 3 African clinical research sites in an open label, 3-period crossover study of three different daily tenofovir regimens, each for 6 weeks (oral 300 mg tenofovir disoproxil fumarate, vaginal 1% tenofovir gel [40 mg], or both). Serum concentrations after vaginal dosing were 56-fold lower than after oral dosing (p<0.001). Vaginal tissue tenofovir diphosphate was quantifiable in ≥90% of women with vaginal dosing and only 19% of women with oral dosing. Vaginal tissue tenofovir diphosphate was ≥130-fold higher with vaginal compared to oral dosing (p<0.001). Rectal fluid tenofovir concentrations in vaginal dosing periods were higher than concentrations measured in the oral only dosing period (p<0.03). Conclusions: Compared to oral dosing, vaginal dosing achieved much lower serum concentrations and much higher vaginal tissue concentrations. Even allowing for 100-fold concentration differences due to poor adherence or less frequent prescribed dosing, vaginal dosing of tenofovir should provide higher active site concentrations and theoretically greater PrEP efficacy than oral dosing; randomized topical dosing PrEP trials to the contrary indicates that factors beyond tenofovir's antiviral effect substantially influence PrEP efficacy. Trial Registration: ClinicalTrials.gov NCT00592124

What works to support carers of older people and older carers? an international evidence map of interventions and outcomes

\ua9 The Author(s) 2024.Background: Unpaid carers of older people, and older unpaid carers, experience a range of adverse outcomes. Supporting carers should therefore be a public health priority. Our understanding of what works to support carers could be enhanced if future evaluations prioritise under-researched interventions and outcomes. To support this, we aimed to: map evidence about interventions to support carers, and the outcomes evaluated; and identify key gaps in current evidence. Methods: Evidence gap map review methods were used. Searches were carried out in three bibliographic databases for quantitative evaluations of carer interventions published in OECD high-income countries between 2013 and 2023. Interventions were eligible if they supported older carers (50 + years) of any aged recipient, or any aged carers of older people (50 + years). Findings: 205 studies reported across 208 publications were included in the evidence map. The majority evaluated the impact of therapeutic and educational interventions on carer burden and carers’ mental health. Some studies reported evidence about physical exercise interventions and befriending and peer support for carers, but these considered a limited range of outcomes. Few studies evaluated interventions that focused on delivering financial information and advice, pain management, and physical skills training for carers. Evaluations rarely considered the impact of interventions on carers’ physical health, quality of life, and social and financial wellbeing. Very few studies considered whether interventions delivered equitable outcomes. Conclusion: Evidence on what works best to support carers is extensive but limited in scope. A disproportionate focus on mental health and burden outcomes neglects other important areas where carers may need support. Given the impact of caring on carers’ physical health, financial and social wellbeing, future research could evaluate interventions that aim to support these outcomes. Appraisal of whether interventions deliver equitable outcomes across diverse carer populations is critical

A microscopic theory of gauge mediation

We construct models of indirect gauge mediation where the dynamics responsible for breaking supersymmetry simultaneously generates a weakly coupled subsector of messengers. This provides a microscopic realization of messenger gauge mediation where the messenger and hidden sector fields are unified into a single sector. The UV theory is SQCD with massless and massive quarks plus singlets, and at low energies it flows to a weakly coupled quiver gauge theory. One node provides the primary source of supersymmetry breaking, which is then transmitted to the node giving rise to the messenger fields. These models break R-symmetry spontaneously, produce realistic gaugino and sfermion masses, and give a heavy gravitino.Comment: 24 pages, 2 figures, accepted to JHEP for publicatio

Flavor of quiver-like realizations of effective supersymmetry

We present a class of supersymmetric models which address the flavor puzzle and have an inverted hierarchy of sfermions. Their construction involves quiver-like models with link fields in generic representations. The magnitude of Standard-Model parameters is obtained naturally and a relatively heavy Higgs boson is allowed without fine tuning. Collider signatures of such models are possibly within the reach of LHC in the near future.Comment: LaTeX, 17 pages, 3 figures. V2: reference adde