Toxin release by conditional remodelling of ParDE1 from Mycobacterium tuberculosis leads to gyrase inhibition.

Mycobacterium tuberculosis, the causative agent of tuberculosis, is a growing threat to global health, with recent efforts towards its eradication being reversed in the wake of the COVID-19 pandemic. Increasing resistance to gyrase-targeting second-line fluoroquinolone antibiotics indicates the necessity to develop both novel therapeutics and our understanding of M. tuberculosis growth during infection. ParDE toxin-antitoxin systems also target gyrase and are regulated in response to both host-associated and drug-induced stress during infection. Here, we present microbiological, biochemical, structural, and biophysical analyses exploring the ParDE1 and ParDE2 systems of M. tuberculosis H37Rv. The structures reveal conserved modes of toxin-antitoxin recognition, with complex-specific interactions. ParDE1 forms a novel heterohexameric ParDE complex, supported by antitoxin chains taking on two distinct folds. Curiously, ParDE1 exists in solution as a dynamic equilibrium between heterotetrameric and heterohexameric complexes. Conditional remodelling into higher order complexes can be thermally driven in vitro. Remodelling induces toxin release, tracked through concomitant inhibition and poisoning of gyrase activity. Our work aids our understanding of gyrase inhibition, allowing wider exploration of toxin-antitoxin systems as inspiration for potential therapeutic agents.

"They Just Helped Save My Life:" Client Perspectives on the Los Angeles County Full Service Partnership (FSP) Program for Serious Mental Illness.

The purpose of this qualitative study was to elicit client perspectives on the Los Angeles County Full Service Partnership (FSP) program - an adaptation of Assertive Community Treatment (ACT). Semi-structured interviews were conducted with 20 FSP clients. Qualitative data were analyzed using thematic analysis. Two major themes were identified from the interview data: (1) Clients' acknowledgement of the material benefits of the FSP program; and (2) FSP's impact on restoring and stabilizing clients' social and treatment relationships. Interviewees greatly valued the material (i.e., basic needs, housing assistance) and relational (i.e., relationships with providers, restored personal relationships) aspects of the program, but did not ascribe the same degree of value to mental health treatment. Interviewees' emphases on material and relational aspects reflect the status of assertive mental health treatment as an intervention on intermediary determinants of health in the lives of persons diagnosed with serious mental illness.

Perspectives Regarding Medications for Opioid Use Disorder Among Individuals with Mental Illness.

Most people with co-occurring opioid use disorder (OUD) and mental illness do not receive effective medications for treating OUD. To investigate perspectives of adults in a publicly-funded mental health system regarding medications for OUD (MOUD), we conducted semi-structured telephone interviews with 13 adults with OUD (current or previous diagnosis) receiving mental health treatment. Themes that emerged included: perceiving or using MOUDs as a substitute for opioids or a temporary solution to prevent withdrawal symptoms; negative perceptions about methadone/methadone clinics; and viewing MOUD use as "cheating". Readiness to quit was important for patients to consider MOUDs. All participants were receptive to discussing MOUDs with their mental health providers and welcomed the convenience of receiving care for their mental health and OUD at the same location. In conclusion, clients at publicly-funded mental health clinics support MOUD treatment, signaling a need to expand access and build awareness of MOUDs in these settings.

CBT for difficult-to-treat depression: self-regulation model.

BACKGROUND: Cognitive behavioural therapy (CBT) is an effective treatment for depression but a significant minority of clients do not complete therapy, do not respond to it, or subsequently relapse. Non-responders, and those at risk of relapse, are more likely to have adverse childhood experiences, early-onset depression, co-morbidities, interpersonal problems and heightened risk. This is a heterogeneous group of clients who are currently difficult to treat. AIM: The aim was to develop a CBT model of depression that will be effective for difficult-to-treat clients who have not responded to standard CBT. METHOD: The method was to unify theory, evidence and clinical strategies within the field of CBT to develop an integrated CBT model. Single case methods were used to develop the treatment components. RESULTS: A self-regulation model of depression has been developed. It proposes that depression is maintained by repeated interactions of self-identity disruption, impaired motivation, disengagement, rumination, intrusive memories and passive life goals. Depression is more difficult to treat when these processes become interlocked. Treatment based on the model builds self-regulation skills and restructures self-identity, rather than target negative beliefs. A bespoke therapy plan is formed out of ten treatment components, based on an individual case formulation. CONCLUSIONS: A self-regulation model of depression is proposed that integrates theory, evidence and practice within the field of CBT. It has been developed with difficult-to-treat cases as its primary purpose. A case example is described in a concurrent article (Barton et al., 2022) and further empirical tests are on-going.

Before and During the First COVID-19 Surge: Work Conditions, Burnout, and Mental Health Among Resident Physicians in a Department of Psychiatry in the USA.

OBJECTIVE: Resident physicians are critical frontline workers during pandemics, and little is known about their health. The study examined occupational and mental health risks among US psychiatry residents before and during the first COVID-19 surge. METHODS: Longitudinal data were collected from a cohort of US psychiatry residents at one academic medical center in October 2019, before the pandemic, and April 2020 after the initiation of a state-level stay-at-home order. Primary outcome measures were psychological work empowerment, defined as one's self-efficacy towards their work role, and occupational burnout. A secondary outcome was mental health. In May and June 2020, resident engagement sessions were conducted to disseminate study findings and consider their implications. RESULTS: Fifty-seven out of 59 eligible residents participated in the study (97%). Half the study sample reported high burnout. From before to during the first COVID-19 surge, psychological work empowerment increased in the total sample (p = 0.03); and mental health worsened among junior residents (p = 0.004), not senior residents (p = 0.12). High emotional exhaustion and depersonalization were associated with worse mental health (p < 0.001). In engagement sessions, themes related to residents' work conditions, COVID-19, and racism emerged as potential explanations for survey findings. CONCLUSIONS: The study is exploratory and novel. During early COVID, psychiatry residents' well-being was impacted by occupational and societal factors. Postpandemic, there is a growing psychiatrist shortage and high demand for mental health services. The findings highlight the potential importance of physician wellness interventions focused on early career psychiatrists who were first responders during COVID.

Engaging Same-Day Peer Ambassadors to Increase Coronavirus Disease 2019 Vaccination Among People Experiencing Unsheltered Homelessness in Los Angeles County: A Hybrid Feasibility-Evaluation Study.

BACKGROUND: This study aimed to evaluate the feasibility and acceptability of engaging unhoused peer ambassadors (PAs) in coronavirus disease 2019 (COVID-19) vaccination efforts to reach people experiencing unsheltered homelessness in Los Angeles County. METHODS: From August to December 2021, vaccinated PAs aged ≥18 years who could provide informed consent were recruited during vaccination events for same-day participation. Events were held at encampments, service providers (eg, housing agencies, food lines, and mobile showers), and roving locations around Los Angeles. PAs were asked to join outreach alongside community health workers and shared their experience getting vaccinated, receiving a $25 gift card for each hour they participated. Postevent surveys evaluated how many PAs enrolled and how long they participated. In October 2021, we added a preliminary effectiveness evaluation of how many additional vaccinations were attributable to PAs. Staff who enrolled the PAs estimated the number of additional people vaccinated because of talking with the PA. RESULTS: A total of 117 PAs were enrolled at 103 events, participating for an average of 2 hours. At events with the effectiveness evaluation, 197 additional people were vaccinated over 167 PA hours ($21.19 gift card cost per additional person vaccinated), accounting for >25% of all vaccines given at these events. DISCUSSION: Recruiting same-day unhoused PAs is a feasible, acceptable, and preliminarily effective technique to increase COVID-19 vaccination in unsheltered settings. The findings can inform delivery of other health services for people experiencing homelessness.

Life Events, Barriers to Care, and Outcomes Among Minority Women Experiencing Depression: A Longitudinal, Mixed-Method Examination.

ABSTRACT: The long-term course of depression is not well-understood among minority women. We assessed depression trajectory, barriers to depression care, and life difficulties among minority women accessing health and social service programs as part of the Community Partners in Care study. Data include surveys ( N = 339) and interviews ( n = 58) administered at 3-year follow-up with African American and Latina women with improved versus persistent depression. The majority of the sample reported persistent depression (224/339, 66.1%), ≥1 barrier to mental health care (226/339, 72.4%), and multiple life difficulties (mean, 2.7; SD, 2.3). Many barriers to care ( i.e. , related to stigma and care experience, finances, and logistics) and life difficulties ( i.e. , related to finances, trauma, and relationships) were more common among individuals reporting persistent depression. Results suggest the importance of past experiences with depression treatment, ongoing barriers to care, and negative life events as contributors to inequities in depression outcomes experienced by minority women.

Threaded Rings that Swim in Excitable Media.

Cardiac tissue and the Belousov-Zhabotinsky reaction provide two notable examples of excitable media that support scroll waves, in which a filament core is the source of spiral waves of excitation. Here we consider a novel topological configuration in which a closed filament loop, known as a scroll ring, is threaded by a pair of counterrotating filaments that are perpendicular to the plane of the ring and end on the boundary of a thin medium. We simulate the dynamics of this threaded ring (thring) in the photosensitive Belousov-Zhabotinsky excitable medium, using the modified Oregonator reaction-diffusion equations. These computations reveal that the threading topology induces an exotic motion in which the thring swims in the plane of the ring. We propose a light templating protocol to create a thring in the photosensitive Belousov-Zhabotinsky medium and provide experimental confirmation that this protocol indeed yields a thring.

Community Interventions to Promote Mental Health and Social Equity.

PURPOSE OF REVIEW: We review recent community interventions to promote mental health and social equity. We define community interventions as those that involve multi-sector partnerships, emphasize community members as integral to the intervention, and/or deliver services in community settings. We examine literature in seven topic areas: collaborative care, early psychosis, school-based interventions, homelessness, criminal justice, global mental health, and mental health promotion/prevention. We adapt the social-ecological model for health promotion and provide a framework for understanding the actions of community interventions. RECENT FINDINGS: There are recent examples of effective interventions in each topic area. The majority of interventions focus on individual, family/interpersonal, and program/institutional social-ecological levels, with few intervening on whole communities or involving multiple non-healthcare sectors. Findings from many studies reinforce the interplay among mental health, interpersonal relationships, and social determinants of health. There is evidence for the effectiveness of community interventions for improving mental health and some social outcomes across social-ecological levels. Studies indicate the importance of ongoing resources and training to maintain long-term outcomes, explicit attention to ethics and processes to foster equitable partnerships, and policy reform to support sustainable healthcare-community collaborations.

Changing Rates of Mental Health Disorders Among Veterans Treated in the VHA During Troop Drawdown, 2007-2013.

Nationally representative data on mental health disorder prevalence are critical to set informed mental health priorities and policies. Data indicating mental health diagnoses within our nation's veteran population treated at the Veterans Health Administration (VHA) are available, but have yet to be examined for changing trends to inform both VHA and community care. We use VHA national program evaluation data from a time of increasing military enrollment (2007) to troop draw down (2013) to examine changes over time in the number of diagnoses in veterans receiving VHA services. The number of veterans in all diagnostic categories increased during our study period with the smallest increase in psychotic disorders (8%) and the largest in posttraumatic stress disorder (71%). Trends in behavioral health diagnoses among veterans have important implications for policy and clinician competencies within VHA and community providers as veteran mental health care needs change.

Growing a Community-Academic Partnership: Lessons Learned in Forming a Qualitative Interview Team for the Community Partners in Care Study.

By engaging, partnering, and building trust with community members, research on vulnerable populations may offer opportunities to improve population health in communities that suffer from health disparities. While the literature on participatory and partnered approaches offers techniques and strategies for forming community-academic partnerships, less information is available about how partnerships can grow and evolve over time. In this article, we describe the expansion of a long-standing partnership that uses principles of community partnered participatory research (CPPR), a variant of community-based participatory research (CBPR). We outline the preparation and executive phases of conducting qualitative interviewing with highly vulnerable study participants who have already been participants in a longitudinal survey. We describe the challenges and concerns at each phase of the research and summarize some lessons learned. To grow and evolve, the partnership must constantly be reaffirmed in the experiences of new members.

Whole Person Care in Under-resourced Communities: Stakeholder Priorities at Long-Term Follow-Up in Community Partners in Care.

Objective: Depressed individuals may require help from different agencies to address health and social needs, but how such coordination occurs in under-resourced communities is poorly understood. This study sought to identify priorities of Latino and African American depressed clients, explore whether service providers understand client priorities, and describe how providers address them. Methods: Between October 2014 and February 2015, we interviewed 104 clients stratified by depression history and 50 representatives of different programs in health and social community agencies who participated in Community Partners in Care, a cluster-randomized trial of coalition-building approaches to delivering depression quality improvement programs. Clients were queried about their most pressing needs; program representatives identified their clients' needs and explained how they addressed them. Results: Physical and mental health were clients' top priorities, followed by housing, caring for and building relationships with others, and employment. While persistently depressed clients prioritized mental health, those with improved depression prioritized relationships with others. Program representatives identified housing, employment, mental health, and improving relationships with others as clients' top priorities. Needs assessment, client-centered services, and linkages to other agencies were main strategies used to address client needs. Conclusion: Depressed clients have multiple health and social needs, and program representatives in under-resourced communities understand the complexity of clients' needs. Agencies rely on needs assessment and referrals to meet their clients' needs, which enhances the importance of agency partnership in "whole person" initiatives. Our results illustrate agency capacity to adopt integrated care models that will address clients' multiple needs through multi-sector collaboration and describe potential strategies to help reach the goal of whole person care.

Stakeholder Perspectives on the Social Determinants of Mental Health in Community Coalitions.

Objective: Although evidence supports the potential for community coalitions to positively address social determinants of mental health, little is known about the views of stakeholders involved in such efforts. This study sought to understand county leaders' perspectives about social determinants related to the Health Neighborhood Initiative (HNI), a new county effort to support community coalitions. Design: Descriptive, qualitative study, 2014. Setting: Community coalitions, located in a large urban city, across eight service planning areas, that serve under-resourced, ethnic minority populations. Procedures: We conducted key informant interviews with 49 health care and community leaders to understand their perspectives about the HNI. As part of a larger project, this study focused on leaders' views about social determinants of health related to the HNI. All interviews were audio-recorded and transcribed. An inductive approach to coding was used, with text segments grouped by social determinant categories. Results: County leaders described multiple social determinants of mental health that were relevant to the HNI community coalitions: housing and safety, community violence, and employment and education. Leaders discussed how social determinants were interconnected with each other and the need for efforts to address multiple social determinants simultaneously to effectively improve mental health. Conclusions: Community coalitions have an opportunity to address multiple social determinants of health to meet social and mental health needs of low-resourced communities. Future research should examine how community coalitions, like those in the HNI, can actively engage with community members to identify needs and then deliver evidence-based care.

A Window of Opportunity: Visions and Strategies for Behavioral Health Policy Innovation.

Objective: The New York City's Thrive (ThriveNYC) and the Los Angeles County Health Neighborhood Initiative (HNI) are two local policies focused on addressing the social determinants of behavioral health as a preventive strategy for improving health service delivery. On January 29, 2016, leaders from both initiatives came together with a range of federal agencies in health care, public health, and policy research at the RAND Corporation in Arlington, Virginia. The goal of this advisory meeting was to share lessons learned, consider research and evaluation strategies, and create a dialogue between stakeholders and federal funders - all with the purpose to build momentum for policy innovation in behavioral health equity. Methods: This article analyzes ethnographic notes taken during the meeting and in-depth interviews of 14 meeting participants through Kingdon's multiple streams theory of policy change. Results: Results demonstrated that stakeholders shared a vision for behavioral health policy innovation focused on community engagement and social determinants of health. In addition, Kingdon's model highlighted that the problem, policy and politics streams needed to form a window of opportunity for policy change were coupled, enabling the possibility for behavioral health policy innovation. Conclusions: The advisory meeting suggested that local policy makers, academics, and community members, together with federal agents, are working to implement behavioral health policy innovation.

Community Partnering for Behavioral Health Equity: Public Agency and Community Leaders' Views of its Promise and Challenge.

Objective: To understand potential for multi-sector partnerships among community-based organizations and publicly funded health systems to implement health improvement strategies that advance health equity. Design: Key stakeholder interviewing during HNI planning and early implementation to elicit perceptions of multi-sector partnerships and innovations required for partnerships to achieve system transformation and health equity. Setting: In 2014, the Los Angeles County (LAC) Board of Supervisors approved the Health Neighborhood Initiative (HNI) that aims to: 1) improve coordination of health services for behavioral health clients across safety-net providers within neighborhoods; and 2) address social determinants of health through community-driven, public agency sponsored partnerships with community-based organizations. Participants: Twenty-five semi-structured interviews with 49 leaders from LAC health systems, community-based organizations; and payers. Results: Leaders perceived partnerships within and beyond health systems as transformative in their potential to: improve access, value, and efficiency; align priorities of safety-net systems and communities; and harness the power of communities to impact health. Leaders identified trust as critical to success in partnerships but named lack of time for relationship-building, limitations in service capacity, and questions about sustainability as barriers to trust-building. Leaders described the need for procedural innovations within health systems that would support equitable partnerships including innovations that would increase transparency and normalize information exchange, share agenda-setting and decision-making power with partners, and institutionalize partnering through training and accountability. Conclusions: Leaders described improving procedural justice in public agencies' relationships with communities as key to effective partnering for health equity.

Stabilising Peptoid Helices Using Non-Chiral Fluoroalkyl Monomers.

Stability towards protease degradation combined with modular synthesis has made peptoids of considerable interest in the fields of chemical biology, medicine, and biomaterials. Given their tertiary amide backbone, peptoids lack the capacity to hydrogen-bond, and as such, controlling secondary structure can be challenging. The incorporation of bulky, charged, or chiral aromatic monomers can be used to control conformation but such building blocks limit applications in many areas. Through NMR and X-ray analysis we demonstrate that non-chiral neutral fluoroalkyl monomers can be used to influence the Kcis/trans equilibria of peptoid amide bonds in model systems. The cis-isomer preference displayed is highly unprecedented given that neither chirality nor charge is used to control the peptoid amide conformation. The application of our fluoroalkyl monomers in the design of a series of linear peptoid oligomers that exhibit stable helical structures is also reported.

Excited-State Aromatic Interactions in the Aggregation-Induced Emission of Molecular Rotors.

Small, apolar aromatic groups, such as phenyl rings, are commonly included in the structures of fluorophores to impart hindered intramolecular rotations, leading to desirable solid-state luminescence properties. However, they are not normally considered to take part in through-space interactions that influence the fluorescent output. Here, we report on the photoluminescence properties of a series of phenyl-ring molecular rotors bearing three, five, six, and seven phenyl groups. The fluorescent emissions from two of the rotors are found to originate, not from the localized excited state as one might expect, but from unanticipated through-space aromatic-dimer states. We demonstrate that these relaxed dimer states can form as a result of intra- or intermolecular interactions across a range of environments in solution and solid samples, including conditions that promote aggregation-induced emission. Computational modeling also suggests that the formation of aromatic-dimer excited states may account for the photophysical properties of a previously reported luminogen. These results imply, therefore, that this is a general phenomenon that should be taken into account when designing and interpreting the fluorescent outputs of luminescent probes and optoelectronic devices based on fluorescent molecular rotors.

Surviving Depression: Clinical Qualitative Analysis of Long-Term Survival for Ethnically Diverse, Depressed Patients.

Depression is persistent and recurrent across ethnic groups. Few narrative analyses of long-term outcomes for ethnically diverse adults with depression exist. We combined 9 years of quantitative data, qualitative interviews at 10 years, clinician ratings of outcomes, and a community discussion group with the objective of describing long-term recovery and survival of diverse primary care patients after an episode of depression. Nearly half of participants were found to be depressed at some time over a 10-year period, and most cases across ethnic groups were judged to need further treatment. The ethnically diverse community members that analyzed the transcripts emphasized assets that participants showed in surviving multiple life stresses. Different sex and ethnic/racial groups had different characteristics of engaging in care, with Latino women in particular raising concerns about care engagement, coping with stress, and long-term outcomes.

Structural characterization suggests models for monomeric and dimeric forms of full-length ezrin.

Ezrin is a member of the ERM (ezrin-radixin-moesin) family of proteins that have been conserved through metazoan evolution. These proteins have dormant and active forms, where the latter links the actin cytoskeleton to membranes. ERM proteins have three domains: an N-terminal FERM [band Four-point-one (4.1) ERM] domain comprising three subdomains (F1, F2, and F3); a helical domain; and a C-terminal actin-binding domain. In the dormant form, FERM and C-terminal domains form a stable complex. We have determined crystal structures of the active FERM domain and the dormant FERM:C-terminal domain complex of human ezrin. We observe a bistable array of phenylalanine residues in the core of subdomain F3 that is mobile in the active form and locked in the dormant form. As subdomain F3 is pivotal in binding membrane proteins and phospholipids, these transitions may facilitate activation and signaling. Full-length ezrin forms stable monomers and dimers. We used small-angle X-ray scattering to determine the solution structures of these species. As expected, the monomer shows a globular domain with a protruding helical coiled coil. The dimer shows an elongated dumbbell structure that is twice as long as the monomer. By aligning ERM sequences spanning metazoan evolution, we show that the central helical region is conserved, preserving the heptad repeat. Using this, we have built a dimer model where each monomer forms half of an elongated antiparallel coiled coil with domain-swapped FERM:C-terminal domain complexes at each end. The model suggests that ERM dimers may bind to actin in a parallel fashion.

Clinical Factors Associated with Successful Discharge from Assertive Community Treatment.

We sought to explore clinical factors associated with successful transition from Assertive Community Treatment to less intensive clinical services. Mixed-method observational follow up study of veterans discharged from three VA-affiliated ACT teams to less intensive clinical services. Of the 240 veterans in ACT, 9% (n = 21) were discharged during the study period. Among the 11 of 21 discharged veterans who enrolled in the follow up study, reason for discharge, designated by the veteran's primary clinician at the time of discharge, predicted outcomes (p = 0.02) at 9 months, with "disengagement" as a reason for discharge predicting poorer outcomes. Six of 11 veterans experienced poor outcomes at 9 months, including incarceration and substance use relapse. ACT clinicians rarely discharge clients. Many clients may experience negative clinical events following ACT discharge, and clients may be difficult to follow post-discharge. Client disengagement from ACT may indicate higher likelihood of poor outcomes following discharge to less intensive clinical services.