Not heading in the right direction: Five hundred psychiatrists' views on resourcing, demand, and workforce across New Zealand mental health services.

OBJECTIVE: To explore the views of psychiatrists (including trainees) regarding the current state and future direction of specialist mental health and addictions services in Aotearoa New Zealand. METHODS: Psychiatrists and trainee psychiatrists (registrars) in Aotearoa New Zealand were surveyed in August 2021. Of 879 eligible doctors, 540 participated (83% qualified and 17% trainee psychiatrists), a response rate of over 60%. Data were analysed quantitatively and with content analysis. RESULTS: Psychiatrists thought specialist mental health and addictions services had been neglected during recent reforms, with 94% believing current resourcing was insufficient, and only 3% considering future planning was heading in the right direction. The demand and complexity of on-call work had markedly increased in the preceding 2 years. Ninety-eight percent reported that people needing specialist treatment were often (85%) or sometimes (13%) unable to access the right care due to resourcing constraints. The pressures were similar across sub-specialties. A key theme was the distress (sometimes termed 'moral injury') experienced by psychiatrists unable to provide adequate care due to resource limitations, 'knowing what would be a good thing to do and being unable to do it . . . is soul destroying'. Recommendations were made for addressing workforce, service design and wider issues. CONCLUSION: Most psychiatrists in Aotearoa New Zealand believe the mental health system is not currently fit for purpose and that it is not heading in the right direction. Remedies include urgently addressing identified staffing challenges and boosting designated funding to adequately care for the 5% of New Zealanders with severe mental health and addiction needs.

Lived Experience of Health and Wellbeing Among Young People with Early Psychosis in Aotearoa New Zealand.

First episode psychosis (FEP) can disrupt a young person's life and future health. Those with lived experience of FEP can inform effective support. This study investigated how young people with FEP experience good health and wellbeing living in Aotearoa New Zealand. Recent clients of early intervention services (n = 12) shared their stories across varying traditional and creative platforms. Thematic analysis revealed seven themes important for living well with FEP: whanaungatanga (relationships), addressing stigma, finding out who I am with psychosis, getting the basics right, collaborative healthcare, understanding psychosis, and access to resources. The themes informed five supporting processes: whakawhanuangatanga (relationship-building), using holistic approaches, creating space for young people, reframing, and improving access to appropriate resources. These findings deepen our understanding of how we can support young people to live well with FEP. This study highlights the value of creative methods and partnering with lived experience experts to conduct meaningful health research.This trial was registered at Australian New Zealand Clinical Trials Registry (ANZCTR) CTRN12622001323718 on 12/10/2022 "retrospectively registered"; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=384775&isReview=true .

Mother nature: Applicability to contemporary attachment styles.

OBJECTIVES: Explore humanity's shifting attachment to the natural world using established attachment theories as a framework. METHODS: Investigate the analogy between human-nature connection and caregiver-child attachment styles. Draw on indigenous case studies, sociology and anthropology to highlight contemporary repercussions of this 'detachment'. RESULTS: Factors such as rapid population growth and urbanisation have disrupted the secure attachment with nature, which is evidenced in ancient egalitarian societies. These factors can be mapped onto contemporary attachment domains. CONCLUSIONS: There is an urgent need to re-establish a secure attachment to nature. This may be a pivotal strategy in addressing both mental health and environmental challenges, particularly in the context of the escalating climate crisis.

Modular Catalysis: Aptamer Enhancement of Enzyme Kinetics in a Nanoparticle Reactor.

Enzyme activity requires sequential binding and chemical transformation of substrates. While directed evolution and random mutagenesis are common methods for improving catalytic activity, these methods do not allow for independent control of KM and kcat. To achieve such control, we envisioned that the colocalization of aptamers and enzymes that act on the same molecule could increase catalytic efficiency through preconcentration of substrate. We explored this concept with cocaine esterase and anticocaine aptamers having varying KD values, both encapsulated in MS2 virus-like particles. Rate enhancements were observed with magnitudes dependent on both aptamer:enzyme stoichiometry and aptamer KD, peaking when aptamer KD and enzyme KM were roughly equivalent. This beneficial effect was lost when either aptamer binding was too tight or the aptamers were not constrained to be close to the catalyst. This work demonstrates a modular way to enhance catalysis by independently controlling substrate capture and release to the processing enzyme.

Development and profiling of mGlu7 NAMs with a range of saturable inhibition of agonist responses in vitro.

We describe here a series of metabotropic glutamate receptor 7 (mGlu7) negative allosteric modulators (NAMs) with a saturable range of activity in inhibiting responses to an orthosteric agonist in two distinct in vitro pharmacological assays. The range of inhibition among compounds in this scaffold provides highly structurally related ligands with differential degrees of receptor blockade that can be used to understand inhibitory efficacy profiles in native tissue or in vivo.

Psychological distress, loneliness, alcohol use and suicidality in New Zealanders with mental illness during a strict COVID-19 lockdown.

INTRODUCTION: People with pre-existing mental health conditions may have been disproportionally impacted by the COVID-19 pandemic and associated public health restrictions. In this study, we compared psychological outcomes, experiences and sources of stress over the pandemic lockdown in New Zealanders with and without a previous diagnosis of mental illness. METHODS: Two online surveys were conducted in New Zealand over the level 4 lockdown in April 2020 measuring psychological distress, anxiety, well-being, suicidality, alcohol use and subjective experiences. They included 3389 participants, of whom 18.4% reported having been previously diagnosed with a mental illness. RESULTS: During the lockdown, people previously diagnosed with a mental illness had about twice the risk of reporting moderate-high levels of psychological distress (K10 ⩾ 12), at least moderate levels of anxiety (GAD-7 ⩾ 10) and poor well-being (WHO-5 ⩽ 12). They reported increased alcohol use and were about four times as likely to have experienced suicidal thoughts with 3% reporting having made a suicide attempt over the lockdown period. They reported less satisfaction with, and poorer relationships with people in their 'bubble', reduced social contacts and greater loneliness. They also reported higher levels of health and financial concerns. CONCLUSION: During the COVID-19 lockdown in New Zealand, people with a previous diagnosis of a mental illness were at increased risk of detrimental psychological outcomes. This highlights the importance of recognising this and the challenges people face in pandemics.

Mother Nature: An initial exploration of new potential for attachment theory.

OBJECTIVE: This study aims to postulate new theory regarding attachment theory and its relationship to the natural world via an analysis of the existing literature regarding environmental and ecological psychology alongside what is known about attachment theory. Additionally, it draws on wider literature (including folklore) pertaining to anthropology and nomadic societies as well as indigenous societies with reference to New Zealand. CONCLUSIONS: Although merely an introductory overview, there is convincing evidence to support a case that our relationship with nature is of paramount importance for human well-being and wider societal well-being and that this relationship has been corrupted via the developed world and progressive disconnect from nature. This disconnect could be categorised through the lens of attachment theory whereby an insecure attachment has subsequently developed.This insecure attachment predisposes us, as a species, to neglect, denigrate and commodify the natural world which, in turn, is giving rise to climate change and its own psychological sequelae. However, discrepancies such as trauma arising from natural disasters suggest a more nuanced approach is needed as our relationship with nature is not entirely without danger, and, as such, there remain significant gaps when unifying this under the umbrella of attachment theory without further research/extrapolation of its importance.

Compulsory treatment order and rehospitalisation: A New Zealand study.

OBJECTIVE: The effectiveness of compulsory treatment orders (CTO) in psychiatric practice is an area in need of evidence. There are no recent New Zealand publications on outcomes for patients under CTOs. This study examined the association between CTOs and subsequent rehospitalisation for patients with schizophrenia or related disorders. METHOD: Two year outcome data for 326 consecutive patients discharged in 2013 and 2014 was obtained from the Programme for the Integration of Mental Health Data database. Regression analyses were performed with rehospitalisation as the main outcome. RESULTS: For the 54% of patients discharged under CTOs, rehospitalisation was 2-4 times more likely for the CTO group than for voluntary patients. Patients under CTOs also spent longer in hospital post index admission (IA). However, patients placed under CTOs during IA stayed longer than those under CTOs prior to IA. Ethnicity did not contribute significantly to any of the findings. CONCLUSION: This study did not show that patients under CTOs were associated with subsequent reduced resource use. The subgroup analysis suggested that studies with a longer follow-up period may provide better insight into the utility of CTOs.

Natural and anthropogenic sources of habitat variation influence exploration behaviour, stress response, and brain morphology in a coastal fish.

Evolutionary ecology aims to better understand how ecologically important traits respond to environmental heterogeneity. Environments vary both naturally and as a result of human activities, and investigations that simultaneously consider how natural and human-induced environmental variation affect diverse trait types grow increasingly important as human activities drive species endangerment. Here, we examined how habitat fragmentation and structural habitat complexity affect disparate trait types in Bahamas mosquitofish Gambusia hubbsi inhabiting tidal creeks. We tested a priori predictions for how these factors might influence exploratory behaviour, stress reactivity and brain anatomy. We examined approximately 350 adult Bahamas mosquitofish from seven tidal-creek populations across Andros Island, The Bahamas that varied in both human-caused fragmentation (three fragmented and four unfragmented) and natural habitat complexity (e.g. fivefold variation in rock habitat). Populations that had experienced severe human-induced fragmentation, and thus restriction of tidal exchange from the ocean, exhibited greater exploration of a novel environment, stronger physiological stress responses to a mildly stressful event and smaller telencephala (relative to body size). These changes matched adaptive predictions based mostly on (a) reduced chronic predation risk and (b) decreased demands for navigating tidally dynamic habitats. Populations from sites with greater structural habitat complexity showed a higher propensity for exploration and a relatively larger optic tectum and cerebellum. These patterns matched adaptive predictions related to increased demands for navigating complex environments. Our findings demonstrate environmental variation, including recent anthropogenic impacts (<50 years), can significantly affect complex, ecologically important traits. Yet trait-specific patterns may not be easily predicted, as we found strong support for only six of 12 predictions. Our results further highlight the utility of simultaneously quantifying multiple environmental factors-for example had we failed to account for habitat complexity, we would not have detected the effects of fragmentation on exploratory behaviours. These responses, and their ecological consequences, may be complex: rapid and adaptive phenotypic responses to anthropogenic impacts can facilitate persistence in human-altered environments, but may come at a cost of population vulnerability if ecological restoration was to occur without consideration of the altered traits.

Sociodemographic and clinical variables associated with discharge under compulsory treatment orders.

OBJECTIVE: To document the sociodemographic and clinical variables associated with discharge under compulsory treatment orders in patients with schizophrenia or related disorders. METHOD: Information on various sociodemographic and clinical variables were extracted from the clinical files of 349 patients discharged from an adult (age 18-65) inpatient psychiatric unit with diagnoses of schizophrenia or related disorders. Univariate and multiple logistic regression analyses with legal compulsion (compulsory versus voluntary) as outcomes were applied. RESULTS: Two hundred of the 349 discharged patients were placed under compulsory treatment orders. In the univariate logistic regression analysis, unemployment, diagnosis of schizophrenia, forensic history, dosage of antipsychotics, prescription and frequency of injectable antipsychotics, polypharmacy and a hospital stay of more than 28 days were associated with compulsory status. Being married or in partnership and living with partner was associated with voluntary status. Multiple regression models respectively confirmed most of these relationships observed in the univariate analyses. CONCLUSION: Clarification of the apparent drivers for compulsory treatment may help thoughtful reductions in the use of compulsion.

Synthesis and SAR of a series of mGlu7 NAMs based on an ethyl-8-methoxy-4-(4-phenylpiperazin-1-yl)quinoline carboxylate core.

A High-Throughput Screening (HTS) campaign identified a fundamentally new mGlu7 NAM chemotype, based on an ethyl-8-methoxy-4-(4-phenylpiperazin-1-yl)quinolone carboxylate core. The initial hit, VU0226390, was a potent mGlu7 NAM (IC50 = 647 nM, 6% L-AP4 min) with selectivity versus the other group III mGlu receptors (>30 µM vs. mGlu4 and mGlu8). A multi-dimensional optimization effort surveyed all regions of this new chemotype, and found very steep SAR, reminiscent of allosteric modulators, and unexpected piperazine mimetics (whereas classical bioisosteres failed). While mGlu7 NAM potency could be improved (IC50s ~ 350 nM), the necessity of the ethyl ester moiety and poor physiochemical and DMPK properties precluded optimization towards in vivo tool compounds or clinical candidates. Still, this hit-to-lead campaign afforded key medicinal chemistry insights and new opportunities.

Discovery of a novel 2,3-dimethylimidazo[1,2-a]pyrazine-6-carboxamide M4 positive allosteric modulator (PAM) chemotype.

This Letter details our efforts to discover structurally unique M4 PAMs containing 5,6-heteroaryl ring systems. In an attempt to improve the DMPK profiles of the 2,3-dimethyl-2H-indazole-5-carboxamide and 1-methyl-1H-benzo[d][1,2,3]triazole-6-carboxamide cores, we investigated a plethora of core replacements. This exercise identified a novel 2,3-dimethylimidazo[1,2-a]pyrazine-6-carboxamide core that provided improved M4 PAM activity and CNS penetration.

Examining the Relationships Among Cognitive Acceptance, Behavioral Commitment, Autonomous Extrinsic Motivation, and Physical Activity.

This study examined the relationships among cognitive acceptance, behavioral commitment, psychological need satisfaction, autonomous extrinsic motivation (EM) for physical activity (PA), and PA behavior. Participants (N = 456, M age = 40.7 years) completed online measures of these variables, and data were analyzed using structural equation modeling. Results indicated a direct pathway from behavioral commitment to autonomous EM, plus indirect effects via autonomy, competence, and relatedness. There was no direct pathway from cognitive acceptance to autonomous EM, but there were indirect effects via competence and autonomy satisfaction. There was a direct pathway from cognitive acceptance to self-reported PA plus indirect effects via autonomous EM. There was no direct pathway from behavioral commitment to self-reported PA, but there were indirect effects via autonomous EM. Cognitive acceptance and behavioral commitment potentially support the development of autonomous EM for PA. Future research using longitudinal and intervention-based research designs is required to determine the causal relationships among these variables.

Surveying heterocycles as amide bioisosteres within a series of mGlu7 NAMs: Discovery of VU6019278.

This letter describes a diversity-oriented library approach to rapidly assess diverse heterocycles as bioisosteric replacements for a metabolically labile amide moiety within a series of mGlu7 negative allosteric modulators (NAMs). SAR rapidly honed in on either a 1,2,4- or 1,3,4-oxadizaole ring system as an effective bioisostere for the amide. Further optimization of the southern region of the mGlu7 NAM chemotype led to the discovery of VU6019278, a potent mGlu7 NAM (IC50 = 501 nM, 6.3% L-AP4 Min) with favorable plasma protein binding (rat fu = 0.10), low predicted hepatic clearance (rat CLhep = 27.7 mL/min/kg) and high CNS penetration (rat Kp = 4.9, Kp,uu = 0.65).

Discovery of a novel 3,4-dimethylcinnoline carboxamide M4 positive allosteric modulator (PAM) chemotype via scaffold hopping.

This Letter details our efforts to replace the 2,4-dimethylquinoline carboxamide core of our previous M4 PAM series, which suffered from high predicted hepatic clearance and protein binding. A scaffold hopping exercise identified a novel 3,4-dimethylcinnoline carboxamide core that provided good M4 PAM activity and improved clearance and protein binding profiles.

The Role of Psychological Flexibility in Physical Activity Maintenance.

The purpose of this study was to investigate the role of the constituent processes of psychological flexibility (contact with the present moment, acceptance, cognitive defusion, self-as-context, value clarification, and committed action) in supporting physical activity (PA) maintenance. A total of 9 physically active participants were interviewed using the Scanlan collaborative interview method. Participants were asked to discuss their strategies for maintaining PA, before being asked whether the 6 psychological flexibility processes played a role in their PA behavior. Data were analyzed using a combination of deductive and inductive thematic analyses. Acceptance, cognitive defusion, value clarification, and committed action played a role in participants' experiences of maintaining PA. Contact with the present moment and self-as-context were reported to be relatively unimportant to participants' PA maintenance. Cultivating acceptance of PA-related discomfort, defusion from unhelpful thoughts, clarifying the value of PA, and encouraging commitment to PA would likely benefit individuals' efforts to maintain PA.

Exploring the future adult vaccine landscape-crowded schedules and new dynamics.

Amidst the backdrop of the COVID-19 pandemic, vaccine innovation has garnered significant attention, but this field was already on the cusp of a groundbreaking renaissance. Propelling these advancements are scientific and technological breakthroughs, alongside a growing understanding of the societal and economic boons vaccines offer, particularly for non-pediatric populations like adults and the immunocompromised. In a departure from previous decades where vaccine launches could be seamlessly integrated into existing processes, we anticipate potentially than 100 novel, risk-adjusted product launches over the next 10 years in the adult vaccine market, primarily addressing new indications. However, this segment is infamous for its challenges: low uptake, funding shortfalls, and operational hurdles linked to delivery and administration. To unlock the societal benefits of this burgeoning expansion, we need to adopt a fresh perspective to steer through the dynamics sparked by the rapid growth of the global adult vaccine market. This article aims to provide that fresh perspective, offering a detailed analysis of the anticipated number of adult vaccine approvals by category and exploring how our understanding of barriers to adult vaccine uptake might evolve. We incorporated pertinent insights from external stakeholder interviews, spotlighting shifting preferences, perceptions, priorities, and decision-making criteria. Consequently, this article aspires to serve as a pivotal starting point for industry participants, equipping them with the knowledge to skillfully navigate the anticipated surge in both volume and complexity.

Breaking the mold with RNA-a "RNAissance" of life science.

In the past decade, RNA therapeutics have gone from being a promising concept to one of the most exciting frontiers in healthcare and pharmaceuticals. The field is now entering what many call a renaissance or "RNAissance" which is being fueled by advances in genetic engineering and delivery systems to take on more ambitious development efforts. However, this renaissance is occurring at an unprecedented pace, which will require a different way of thinking if the field is to live up to its full potential. Recognizing this need, this article will provide a forward-looking perspective on the field of RNA medical products and the potential long-term innovations and policy shifts enabled by this revolutionary and game-changing technological platform.

Biophysics-Guided Lead Discovery of HBV Capsid Assembly Modifiers.

Hepatitis B virus (HBV) is the leading cause of chronic liver pathologies worldwide. HBV nucleocapsid, a key structural component, is formed through the self-assembly of the capsid protein units. Therefore, interfering with the self-assembly process is a promising approach for the development of novel antiviral agents. Applied to HBV, this approach has led to several classes of capsid assembly modulators (CAMs). Here, we report structurally novel CAMs with moderate activity and low toxicity, discovered through a biophysics-guided approach combining docking, molecular dynamics simulations, and a series of assays with a particular emphasis on biophysical experiments. Several of the identified compounds induce the formation of aberrant capsids and inhibit HBV DNA replication in vitro, suggesting that they possess modest capsid assembly modulation effects. The synergistic computational and experimental approaches provided key insights that facilitated the identification of compounds with promising activities. The discovery of preclinical CAMs presents opportunities for subsequent optimization efforts, thereby opening new avenues for HBV inhibition.

Heterologous Prime-Boost with Immunologically Orthogonal Protein Nanoparticles for Peptide Immunofocusing.

Protein nanoparticles are effective platforms for antigen presentation and targeting effector immune cells in vaccine development. Encapsulins are a class of protein-based microbial nanocompartments that self-assemble into icosahedral structures with external diameters ranging from 24 to 42 nm. Encapsulins from Mxyococcus xanthus were designed to package bacterial RNA when produced in E. coli and were shown to have immunogenic and self-adjuvanting properties enhanced by this RNA. We genetically incorporated a 20-mer peptide derived from a mutant strain of the SARS-CoV-2 receptor binding domain (RBD) into the encapsulin protomeric coat protein for presentation on the exterior surface of the particle. This immunogen elicited conformationally-relevant humoral responses to the SARS-CoV-2 RBD. Immunological recognition was enhanced when the same peptide was presented in a heterologous prime/boost vaccination strategy using the engineered encapsulin and a previously reported variant of the PP7 virus-like particle, leading to the development of a selective antibody response against a SARS-CoV-2 RBD point mutant. While generating epitope-focused antibody responses is an interplay between inherent vaccine properties and B/T cells, here we demonstrate the use of orthogonal nanoparticles to fine-tune the control of epitope focusing.