MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway.

The Hippo pathway plays a central role in tissue homoeostasis, and its dysregulation contributes to tumorigenesis. Core components of the Hippo pathway include a kinase cascade of MST1/2 and LATS1/2 and the transcription co-activators YAP/TAZ. In response to stimulation, LATS1/2 phosphorylate and inhibit YAP/TAZ, the main effectors of the Hippo pathway. Accumulating evidence suggests that MST1/2 are not required for the regulation of YAP/TAZ. Here we show that deletion of LATS1/2 but not MST1/2 abolishes YAP/TAZ phosphorylation. We have identified MAP4K family members--Drosophila Happyhour homologues MAP4K1/2/3 and Misshapen homologues MAP4K4/6/7-as direct LATS1/2-activating kinases. Combined deletion of MAP4Ks and MST1/2, but neither alone, suppresses phosphorylation of LATS1/2 and YAP/TAZ in response to a wide range of signals. Our results demonstrate that MAP4Ks act in parallel to and are partially redundant with MST1/2 in the regulation of LATS1/2 and YAP/TAZ, and establish MAP4Ks as components of the expanded Hippo pathway

Cluster Perturbation Theory for Hubbard models

Cluster perturbation theory is a technique for calculating the spectral weight of Hubbard models of strongly correlated electrons, which combines exact diagonalizations on small clusters with strong-coupling perturbation theory at leading order. It is exact in both the strong- and weak-coupling limits and provides a good approximation to the spectral function at any wavevector. Following the paper by S\'en\'echal et al. (Phys. Rev. Lett. {\bf 84}, 522 (2000)), we provide a more complete description and derivation of the method. We illustrate some of its capabilities, in particular regarding the effect of doping, the calculation of ground state energy and double occupancy, the disappearance of the Fermi surface in the $t-t'$ Hubbard model, and so on. The method is applicable to any model with on-site repulsion only.Comment: 11 pages, 10 figures (RevTeX 4

KAI407, a potent non-8-aminoquinoline compound that kills Plasmodium cynomolgi early dormant liver stage parasites in vitro.

Preventing relapses of Plasmodium vivax malaria through a radical cure depends on use of the 8-aminoquinoline primaquine, which is associated with safety and compliance issues. For future malaria eradication strategies, new, safer radical curative compounds that efficiently kill dormant liver stages (hypnozoites) will be essential. A new compound with potential radical cure activity was identified using a low-throughput assay of in vitro-cultured hypnozoite forms of Plasmodium cynomolgi (an excellent and accessible model for Plasmodium vivax). In this assay, primary rhesus hepatocytes are infected with P. cynomolgi sporozoites, and exoerythrocytic development is monitored in the presence of compounds. Liver stage cultures are fixed after 6 days and stained with anti-Hsp70 antibodies, and the relative proportions of small (hypnozoite) and large (schizont) forms relative to the untreated controls are determined. This assay was used to screen a series of 18 known antimalarials and 14 new non-8-aminoquinolines (preselected for blood and/or liver stage activity) in three-point 10-fold dilutions (0.1, 1, and 10 μM final concentrations). A novel compound, designated KAI407 showed an activity profile similar to that of primaquine (PQ), efficiently killing the earliest stages of the parasites that become either primary hepatic schizonts or hypnozoites (50% inhibitory concentration [IC50] for hypnozoites, KAI407, 0.69 μM, and PQ, 0.84 μM; for developing liver stages, KAI407, 0.64 μM, and PQ, 0.37 μM). When given as causal prophylaxis, a single oral dose of 100 mg/kg of body weight prevented blood stage parasitemia in mice. From these results, we conclude that KAI407 may represent a new compound class for P. vivax malaria prophylaxis and potentially a radical cure

Telehealth experiences in Canadian veterans: associations, strengths and barriers to care during the COVID-19 pandemic.

INTRODUCTION: Identifying barriers to care in veteran populations is critical, as veterans face increased social isolation, relationship strains and financial insecurities. For Canadian veterans experiencing barriers to accessing healthcare, telehealth may be a promising alternative with comparable effectiveness to in-person services; however, the potential benefits and limitations of telehealth require further examination to determine its long-term utility, and to inform health policy and planning. The goal of the present research was to identify predictors and barriers to telehealth usage in Canadian veterans in the context of the COVID-19 pandemic. METHODS: Data were drawn from baseline data of a longitudinal survey examining the psychological functioning of Canadian veterans during the COVID-19 pandemic. Participants were 1144 Canadian veterans aged 18-93 years (M RESULTS: Findings suggest that sociodemographic factors and previous telehealth use were significantly associated with telehealth use during the COVID-19 pandemic. Qualitative evidence highlighted both the benefits (eg, reducing barriers of access) and drawbacks (eg, not all services can be delivered) of telehealth services. CONCLUSIONS: This paper provided a deeper understanding of Canadian veterans\u27 experiences with accessing telehealth care during the COVID-19 pandemic. While for some, the use of telehealth mitigated perceived barriers (eg, safety concerns of leaving home), others felt that not all health services could be appropriately carried out through telehealth. Altogether, findings support the use of telehealth services in increasing care accessibility for Canadian veterans. Continued use of quality telehealth services may be a valuable form of care that extends the reach of healthcare professionals

The roles of personality and resilience in associations between combat experiences and posttraumatic stress disorder among Canadian Armed Forces Veterans

Canadian Armed Forces (CAF) Veterans encounter unique challenges associated with their service. Exposure to service-related traumatic events places them at risk for developing adverse mental health outcomes, including posttraumatic stress disorder (PTSD). Our research aimed to assess whether the HEXACO personality model and resilience impacted associations between combat experiences and PTSD symptomatology in CAF Veterans in the past month. We recruited a sample of 245 CAF Veterans (81 % men; Mage = 48.47, SDage = 10.34) to complete a battery of questionnaires. PTSD symptoms were significantly associated with more combat experience, lower resilience, lower extraversion, higher emotionality, and lower agreeableness. However, personality traits did not moderate the relationship between combat experiences and PTSD symptoms. Overall, this research can be used to enhance researchers\u27 and clinicians\u27 understanding of personality traits as risk and protective factors for PTSD symptoms

Physical and psychological challenges faced by military, medical and public safety personnel relief workers supporting natural disaster operations: a systematic review

Natural disasters, including floods, earthquakes, and hurricanes, result in devastating consequences at the individual and community levels. To date, much of the research reflecting the consequences of natural disasters focuses heavily on victims, with little attention paid to the personnel responding to such disasters. We conducted a systematic review of the challenges faced by military, medical and public safety personnel supporting natural disaster relief operations. Specifically, we report on the current evidence reflecting challenges faced, as well as positive outcomes experienced by military, medical and public safety personnel following deployment to natural disasters. The review included 382 studies. A large proportion of the studies documented experiences of medical workers, followed by volunteers from humanitarian organizations and military personnel. The most frequently reported challenges across the studies were structural (i.e., interactions with the infrastructure or structural institutions), followed by resource limitations, psychological, physical, and social challenges. Over 60% of the articles reviewed documented positive or transformative outcomes following engagement in relief work (e.g., the provision of additional resources, support, and training), as well as self-growth and fulfillment. The current results emphasize the importance of pre-deployment training to better prepare relief workers to manage expected challenges, as well as post-deployment supportive services to mitigate adverse outcomes and support relief workers’ well-being

Risk Factors for Moral Injury Among Canadian Armed Forces Personnel

Objectives: The traumatic nature of high-risk military deployment events, such as combat, is well-recognized. However, whether other service-related events and demographic factors increase the risk of moral injury (MI), which is defined by consequences of highly stressful and morally-laden experiences, is poorly understood. Therefore, the objective of this study was to examine determinants of MI in Canadian Armed Forces (CAF) personnel. Methods: Data were obtained from the 2018 Canadian Armed Forces Members and Veterans Mental Health Follow-up Survey (CAFVMHS; unweighted n = 2,941). To identify military characteristics, sociodemographic variables, and deployment-related factors associated with increased levels of MI, a series of multiple linear regressions were conducted across deployed and non-deployed groups. Results: When all variables were considered among the deployed personnel, rank, experiencing military related sexual trauma, child maltreatment (i.e., physical abuse, emotional abuse and neglect), and stressful deployment experiences were significant predictors of increased MI total scores (β = 0.001 to β = 0.51, p &lt; 0.05). Feeling responsible for the death of an ally and inability to respond in a threatening situation were the strongest predictors of MI among stressful deployment experiences. Within the non-deployed sample, experiencing military-related or civilian sexual trauma and rank were significant predictors of increased MI total scores (β = 0.02 to β = 0.81, p &lt; 0.05). Conclusion: Exposure to stressful deployment experiences, particularly those involving moral-ethical challenges, sexual trauma, and childhood maltreatment were found to increase levels of MI in CAF personnel. These findings suggest several avenues of intervention, including education and policies aimed at mitigating sexual misconduct, as well as pre-deployment training to better prepare military personnel to deal effectively with morally injurious experiences.</p

Risk Factors for Moral Injury Among Canadian Armed Forces Personnel

Objectives: The traumatic nature of high-risk military deployment events, such as combat, is well-recognized. However, whether other service-related events and demographic factors increase the risk of moral injury (MI), which is defined by consequences of highly stressful and morally-laden experiences, is poorly understood. Therefore, the objective of this study was to examine determinants of MI in Canadian Armed Forces (CAF) personnel. Methods: Data were obtained from the 2018 Canadian Armed Forces Members and Veterans Mental Health Follow-up Survey (CAFVMHS; unweighted n = 2,941). To identify military characteristics, sociodemographic variables, and deployment-related factors associated with increased levels of MI, a series of multiple linear regressions were conducted across deployed and non-deployed groups. Results: When all variables were considered among the deployed personnel, rank, experiencing military related sexual trauma, child maltreatment (i.e., physical abuse, emotional abuse and neglect), and stressful deployment experiences were significant predictors of increased MI total scores (β = 0.001 to β = 0.51, p &lt; 0.05). Feeling responsible for the death of an ally and inability to respond in a threatening situation were the strongest predictors of MI among stressful deployment experiences. Within the non-deployed sample, experiencing military-related or civilian sexual trauma and rank were significant predictors of increased MI total scores (β = 0.02 to β = 0.81, p &lt; 0.05). Conclusion: Exposure to stressful deployment experiences, particularly those involving moral-ethical challenges, sexual trauma, and childhood maltreatment were found to increase levels of MI in CAF personnel. These findings suggest several avenues of intervention, including education and policies aimed at mitigating sexual misconduct, as well as pre-deployment training to better prepare military personnel to deal effectively with morally injurious experiences.</p

Moral injury associated with increased odds of past-year mental health disorders: a Canadian Armed Forces examination

Background: Potentially morally injurious experiences (PMIEs) are common during military service. However, it is unclear to what extent PMIEs are related to well-established adverse mental health outcomes. Objective: The objective of this study was to use a population-based survey to determine the associations between moral injury endorsement and the presence of past-year mental health disorders in Canadian Armed Forces (CAF) personnel and Veterans. Methods: Data were obtained from the 2018 Canadian Armed Forces Members and Veterans Mental Health Follow-up Survey (CAFVMHS). With a sample of 2,941 respondents, the weighted survey sample represented 18,120 active duty and 34,380 released CAF personnel. Multiple logistic regressions were used to assess the associations between sociodemographic characteristics (e.g. sex), military factors (e.g. rank), moral injury (using the Moral Injury Events Scale [MIES]) and the presence of specific mental health disorders (major depressive episode, generalized anxiety disorder, panic disorder, social anxiety disorder, PTSD, and suicidality). Results: While adjusting for selected sociodemographic and military factors, the odds of experiencing any past-year mental health disorder were 1.97 times greater (95% CI = 1.94–2.01) for each one-unit increase in total MIES score. Specifically, PTSD had 1.91 times greater odds (95% CI = 1.87–1.96) of being endorsed for every unit increase in MIES total score, while odds of past-year panic disorder or social anxiety were each 1.86 times greater (95% CI = 1.82–1.90) for every unit increase in total MIES score. All findings reported were statistically significant (p \u3c .001). Conclusion: These findings emphasize that PMIEs are robustly associated with the presence of adverse mental health outcomes among Canadian military personnel. The results of this project further underscore the necessity of addressing moral injury alongside other mental health concerns within the CAF

Exposure to moral stressors and associated outcomes in healthcare workers:Prevalence, correlates, and impact on job attrition

Introduction: Healthcare workers (HCWs) often experience morally challenging situations in their workplaces that may contribute to job turnover and compromised well-being. This study aimed to characterize the nature and frequency of moral stressors experienced by HCWs during the COVID-19 pandemic, examine their influence on psychosocial-spiritual factors, and capture the impact of such factors and related moral stressors on HCWs’ self-reported job attrition intentions.Methods: A sample of 1204 Canadian HCWs were included in the analysis through a web-based survey platform whereby work-related factors (e.g. years spent working as HCW, providing care to COVID-19 patients), moral distress (captured by MMD-HP), moral injury (captured by MIOS), mental health symptomatology, and job turnover due to moral distress were assessed.Results: Moral stressors with the highest reported frequency and distress ratings included patient care requirements that exceeded the capacity HCWs felt safe/comfortable managing, reported lack of resource availability, and belief that administration was not addressing issues that compromised patient care. Participants who considered leaving their jobs (44%; N = 517) demonstrated greater moral distress and injury scores. Logistic regression highlighted burnout (AOR = 1.59; p &lt; .001), moral distress (AOR = 1.83; p &lt; .001), and moral injury due to trust violation (AOR = 1.30; p = .022) as significant predictors of the intention to leave one’s job.Conclusion: While it is impossible to fully eliminate moral stressors from healthcare, especially during exceptional and critical scenarios like a global pandemic, it is crucial to recognize the detrimental impacts on HCWs. This underscores the urgent need for additional research to identify protective factors that can mitigate the impact of these stressors.Introducción: Los trabajadores de la salud (TS) a menudo experimentan situaciones moralmente desafiantes en sus lugares de trabajo que pueden contribuir a la rotación laboral y comprometer su bienestar. Este estudio tuvo como objetivo caracterizar la naturaleza y frecuencia de los estresores morales experimentados por los TS durante la pandemia por COVID-19, examinar su influencia en los factores psicosociales-espirituales y capturar el impacto de dichos factores y los estresores morales relacionados a las intenciones de abandono laboral de los TS.Métodos: Se incluyó en el análisis una muestra de 1.204 TS canadienses a través de una encuesta en plataforma web en la que se analizaron factores relacionados con el trabajo (p. ej., años trabajados como TS, brindando atención a pacientes con COVID-19), angustia moral (evaluado con MMD-HP), daño moral (evaluado con MIOS), sintomatología de salud mental y rotación laboral debido a angustia moral.Resultados: Los estresores morales con mayor frecuencia reportados y tasas de angustia incluyeron requerimientos de atención al paciente que excedieron la capacidad en la que los TS se sentían seguros/cómodos de manejarlos, falta de disponibilidad de recursos y la creencia de que la administración no estaba abordando los problemas que comprometían la atención al paciente. Los participantes que consideraron dejar sus trabajos (44%; N = 517) demostraron mayores puntuaciones de angustia y daño moral. La regresión logística destacó el burnout (AOR = 1,59; p &lt; 0,001), la angustia moral (AOR = 1,83; p &lt; 0,001) y el daño moral debido a la violación de la confianza (AOR = 1,30; p = 0,022) como predictores significativos asociados a la intención de dejar el trabajo.Conclusión: Si bien, es imposible eliminar por completo los estresores morales de la atención sanitaria, especialmente durante escenarios críticos y excepcionales como una pandemia global, es crucial reconocer los impactos perjudiciales para los TS. Esto subraya la necesidad urgente de realizar investigaciones adicionales para identificar factores protectores que puedan mitigar el impacto de estos factores estresantes.</div