Novel kinetoplastid-specific cAMP binding proteins identified by RNAi screening for cAMP resistance in Trypanosoma brucei.

Cyclic AMP signalling in trypanosomes differs from most eukaryotes due to absence of known cAMP effectors and cAMP independence of PKA. We have previously identified four genes from a genome-wide RNAi screen for resistance to the cAMP phosphodiesterase (PDE) inhibitor NPD-001. The genes were named cAMP Response Protein (CARP) 1 through 4. Here, we report an additional six CARP candidate genes from the original sample, after deep sequencing of the RNA interference target pool retrieved after NPD-001 selection (RIT-seq). The resistance phenotypes were confirmed by individual RNAi knockdown. Highest level of resistance to NPD-001, approximately 17-fold, was seen for knockdown of CARP7 (Tb927.7.4510). CARP1 and CARP11 contain predicted cyclic AMP binding domains and bind cAMP as evidenced by capture and competition on immobilised cAMP. CARP orthologues are strongly enriched in kinetoplastid species, and CARP3 and CARP11 are unique to Trypanosoma. Localization data and/or domain architecture of all CARPs predict association with the T. brucei flagellum. This suggests a crucial role of cAMP in flagellar function, in line with the cell division phenotype caused by high cAMP and the known role of the flagellum for cytokinesis. The CARP collection is a resource for discovery of unusual cAMP pathways and flagellar biology.

Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections.

Millions who live in Latin America and sub-Saharan Africa are at risk of trypanosomatid infections, which cause Chagas disease and human African trypanosomiasis (HAT). Improved HAT treatments are available, but Chagas disease therapies rely on two nitroheterocycles, which suffer from lengthy drug regimens and safety concerns that cause frequent treatment discontinuation. We performed phenotypic screening against trypanosomes and identified a class of cyanotriazoles (CTs) with potent trypanocidal activity both in vitro and in mouse models of Chagas disease and HAT. Cryo-electron microscopy approaches confirmed that CT compounds acted through selective, irreversible inhibition of trypanosomal topoisomerase II by stabilizing double-stranded DNA:enzyme cleavage complexes. These findings suggest a potential approach toward successful therapeutics for the treatment of Chagas disease.

Two-eyed Seeing for youth wellness: Promoting positive outcomes with interwoven resilience resources.

Despite the challenges facing Indigenous youth and their communities due to historical and contemporary institutionalised racism in Canada, communities are drawing on the richness of their own histories to reassert their cultural heritage. Doing so supports mental health outcomes of young people in particular, as highlighted in a compelling body of research. The question facing many communities, however, is how they can facilitate such child and youth engagement in order to support related positive mental health outcomes. This article reports on findings from a Participatory Action Research (PAR) study conducted in a First Nations community in Unama'ki (Cape Breton), Atlantic Canada. The study, Spaces & Places, was a partnership between the community-based mental health service provider (Eskasoni Mental Health Services, EMHS), eight community youth (14-18 years old), and a team of academics. Situated within a resilience framework, the team explored the ways in which the community facilitated, or restricted, youth civic and cultural engagement. Foregrounded against a strong legacy of cultural reassertion within the community, findings highlight the core resilience-promoting resources that support positive youth development. Additionally, findings demonstrate how these resources provide meaningful support for youth because of the way in which they are intertwined with one another. Furthermore, cultural engagement is underpinned by the Two-eyed Seeing model, supporting youth to integrate their own culture with settler culture in ways that work best for them. Findings support community-based service structures, and underscore the importance of community resilience in the effective support of Indigenous children and youth.

Pleistocene-Holocene vicariance, not Anthropocene landscape change, explains the genetic structure of American black bear (Ursus americanus) populations in the American Southwest and northern Mexico.

The phylogeography of the American black bear (Ursus americanus) is characterized by isolation into glacial refugia, followed by population expansion and genetic admixture. Anthropogenic activities, including overharvest, habitat loss, and transportation infrastructure, have also influenced their landscape genetic structure. We describe the genetic structure of the American black bear in the American Southwest and northern Mexico and investigate how prehistoric and contemporary forces shaped genetic structure and influenced gene flow. Using a suite of microsatellites and a sample of 550 bears, we identified 14 subpopulations organized hierarchically following the distribution of ecoregions and mountain ranges containing black bear habitat. The pattern of subdivision we observed is more likely a product of postglacial habitat fragmentation during the Pleistocene and Holocene, rather than a consequence of contemporary anthropogenic barriers to movement during the Anthropocene. We used linear mixed-effects models to quantify the relationship between landscape resistance and genetic distance among individuals, which indicated that both isolation by resistance and geographic distance govern gene flow. Gene flow was highest among subpopulations occupying large tracts of contiguous habitat, was reduced among subpopulations in the Madrean Sky Island Archipelago, where montane habitat exists within a lowland matrix of arid lands, and was essentially nonexistent between two isolated subpopulations. We found significant asymmetric gene flow supporting the hypothesis that bears expanded northward from a Pleistocene refugium located in the American Southwest and northern Mexico and that major highways were not yet affecting gene flow. The potential vulnerability of the species to climate change, transportation infrastructure, and the US-Mexico border wall highlights conservation challenges and opportunities for binational collaboration.

Analyzing Phylogenetic Trees with a Tree Lattice Coordinate System and a Graph Polynomial.

Phylogenetic trees are a central tool in many areas of life science and medicine. They demonstrate evolutionary patterns among species, genes, and patterns of ancestry among sets of individuals. The tree shapes and branch lengths of phylogenetic trees encode evolutionary and epidemiological information. To extract information from tree shapes and branch lengths, representation and comparison methods for phylogenetic trees are needed. Representing and comparing tree shapes and branch lengths of phylogenetic trees are challenging, for a tree shape is unlabeled and can be displayed in numerous different forms, and branch lengths of a tree shape are specific to edges whose positions vary with respect to the displayed forms of the tree shape. In this article, we introduce representation and comparison methods for rooted unlabeled phylogenetic trees based on a tree lattice that serves as a coordinate system for rooted binary trees with branch lengths and a graph polynomial that fully characterizes tree shapes. We show that the introduced tree representations and metrics provide distance-based likelihood-free methods for tree clustering, parameter estimation, and model selection and apply the methods to analyze phylogenies reconstructed from virus sequences. [Graph polynomial; likelihood-free inference; phylogenetics; tree lattice; tree metrics.].

Fever in a patient with osteomyelitis: the diagnosis could be serotonin syndrome.

Awareness of rare differential diagnoses of common clinical presentations helps promote early detection and prompt management of serious conditions. A 54-year-old man, with an infected non-union following a high tibial osteotomy, presented with an acutely discharging abscess to his proximal tibia. He was generally unwell with a Staphylococcus aureus bacteraemia. The tibia was debrided, CERAMENT G used as dead space management and a spanning external fixator applied. Postoperatively, pregabalin and tapentadol were commenced in addition to amitriptyline and sertraline, which the patient was taking regularly. Overnight, the patient developed hyperthermia, inducible clonus, hyperreflexia, agitation, confusion and rigors. Prompt recognition of the possibility of serotonin syndrome resulted in early cessation of serotonergic medications and a positive outcome. From this case an important message is that fever in a patient taking serotonergic medications should prompt a screening neurological examination. Clinicians should also be wary when patients are commenced on multimodal analgesia, including tapentadol.

New Drugs for Human African Trypanosomiasis: A Twenty First Century Success Story.

The twentieth century ended with human African trypanosomiasis (HAT) epidemics raging across many parts of Africa. Resistance to existing drugs was emerging, and many programs aiming to contain the disease had ground to a halt, given previous success against HAT and the competing priorities associated with other medical crises ravaging the continent. A series of dedicated interventions and the introduction of innovative routes to develop drugs, involving Product Development Partnerships, has led to a dramatic turnaround in the fight against HAT caused by Trypanosoma brucei gambiense. The World Health Organization have been able to optimize the use of existing tools to monitor and intervene in the disease. A promising new oral medication for stage 1 HAT, pafuramidine maleate, ultimately failed due to unforeseen toxicity issues. However, the clinical trials for this compound demonstrated the possibility of conducting such trials in the resource-poor settings of rural Africa. The Drugs for Neglected Disease initiative (DNDi), founded in 2003, has developed the first all oral therapy for both stage 1 and stage 2 HAT in fexinidazole. DNDi has also brought forward another oral therapy, acoziborole, potentially capable of curing both stage 1 and stage 2 disease in a single dosing. In this review article, we describe the remarkable successes in combating HAT through the twenty first century, bringing the prospect of the elimination of this disease into sight.

Eskasoni First Nation's transformation of youth mental healthcare: Partnership between a Mi'kmaq community and the ACCESS Open Minds research project in implementing innovative practice and service evaluation.

AIM: ACCESS Open Minds (ACCESS OM) is a pan-Canadian project aimed at improving youth mental healthcare. This paper describes implementation of the ACCESS OM objectives for youth mental health service transformation within a pre-existing Fish Net Model of transformative youth mental healthcare service in the First Nation community of Eskasoni, on Canada's east coast. METHODS: We describe an adaptation of the ACCESS OM service transformation objectives through the complementary blending of Indigenous and Western methodologies. This concept of "Two-Eyed Seeing" is illustrated as central to engaging youth in the community and attending to their mental health needs and wellness. RESULTS: The ACCESS OM Eskasoni First Nation Youth Space acts as a central location for the site team and its activities, which expand into the rest of the community to facilitate early identification of youth in need. Rapid access to care is promoted via barrier-free availability through a central intake crisis and referral centre, and ease of contact through social media and other modalities. Youth are given the choice between standard Western mental health services, or Indigenous methods of improving well-being, or a combination of the two. CONCLUSIONS: The ACCESS OM framework has shown early results of being a positive addition to the Eskasoni community. Local leadership and community buy-in are identified as key factors to success. Further exploration, research, and evaluation of this transformation is ongoing. Successful implementation of this model in Eskasoni could act as a model for youth mental health programmes in other First Nations across Canada.

Mitochondrial DNA is critical for longevity and metabolism of transmission stage Trypanosoma brucei.

The sleeping sickness parasite Trypanosoma brucei has a complex life cycle, alternating between a mammalian host and the tsetse fly vector. A tightly controlled developmental programme ensures parasite transmission between hosts as well as survival within them and involves strict regulation of mitochondrial activities. In the glucose-rich bloodstream, the replicative 'slender' stage is thought to produce ATP exclusively via glycolysis and uses the mitochondrial F1FO-ATP synthase as an ATP hydrolysis-driven proton pump to generate the mitochondrial membrane potential (ΔΨm). The 'procyclic' stage in the glucose-poor tsetse midgut depends on mitochondrial catabolism of amino acids for energy production, which involves oxidative phosphorylation with ATP production via the F1FO-ATP synthase. Both modes of the F1FO enzyme critically depend on FO subunit a, which is encoded in the parasite's mitochondrial DNA (kinetoplast or kDNA). Comparatively little is known about mitochondrial function and the role of kDNA in non-replicative 'stumpy' bloodstream forms, a developmental stage essential for disease transmission. Here we show that the L262P mutation in the nuclear-encoded F1 subunit γ that permits survival of 'slender' bloodstream forms lacking kDNA ('akinetoplastic' forms), via FO-independent generation of ΔΨm, also permits their differentiation into stumpy forms. However, these akinetoplastic stumpy cells lack a ΔΨm and have a reduced lifespan in vitro and in mice, which significantly alters the within-host dynamics of the parasite. We further show that generation of ΔΨm in stumpy parasites and their ability to use α-ketoglutarate to sustain viability depend on F1-ATPase activity. Surprisingly, however, loss of ΔΨm does not reduce stumpy life span. We conclude that the L262P γ subunit mutation does not enable FO-independent generation of ΔΨm in stumpy cells, most likely as a consequence of mitochondrial ATP production in these cells. In addition, kDNA-encoded genes other than FO subunit a are important for stumpy form viability.

Response of pumas (Puma concolor) to migration of their primary prey in Patagonia.

Large-scale ungulate migrations result in changes in prey availability for top predators and, as a consequence, can alter predator behavior. Migration may include entire populations of prey species, but often prey populations exhibit partial migration with some individuals remaining resident and others migrating. Interactions of migratory prey and predators have been documented in North America and some other parts of the world, but are poorly studied in South America. We examined the response of pumas (Puma concolor) to seasonal migration of guanacos (Lama guanicoe) in La Payunia Reserve in northern Patagonia Argentina, which is the site of the longest known ungulate migration in South America. More than 15,000 guanacos migrate seasonally in this landscape, and some guanacos also are resident year-round. We hypothesized that pumas would respond to the guanaco migration by consuming more alternative prey rather than migrating with guanacos because of the territoriality of pumas and availability of alternative prey throughout the year at this site. To determine whether pumas moved seasonally with the guanacos, we conducted camera trapping in the summer and winter range of guanacos across both seasons and estimated density of pumas with spatial mark-resight (SMR) models. Also, we analyzed puma scats to assess changes in prey consumption in response to guanaco migration. Density estimates of pumas did not change significantly in the winter and summer range of guanacos when guanacos migrated to and from these areas, indicating that pumas do not follow the migration of guanacos. Pumas also did not consume more alternative native prey or livestock when guanaco availability was lower, but rather fed primarily on guanacos and some alternative prey during all seasons. Alternative prey were most common in the diet during summer when guanacos also were abundant on the summer range. The response of pumas to the migration of guanacos differs from sites in the western North America where entire prey populations migrate and pumas migrate with their prey or switch to more abundant prey when their primary prey migrates.

Reduced Mitochondrial Membrane Potential Is a Late Adaptation of Trypanosoma brucei brucei to Isometamidium Preceded by Mutations in the γ Subunit of the F1Fo-ATPase.

BACKGROUND: Isometamidium is the main prophylactic drug used to prevent the infection of livestock with trypanosomes that cause Animal African Trypanosomiasis. As well as the animal infective trypanosome species, livestock can also harbor the closely related human infective subspecies T. b. gambiense and T. b. rhodesiense. Resistance to isometamidium is a growing concern, as is cross-resistance to the diamidine drugs diminazene and pentamidine. METHODOLOGY/PRINCIPAL FINDINGS: Two isometamidium resistant Trypanosoma brucei clones were generated (ISMR1 and ISMR15), being 7270- and 16,000-fold resistant to isometamidium, respectively, which retained their ability to grow in vitro and establish an infection in mice. Considerable cross-resistance was shown to ethidium bromide and diminazene, with minor cross-resistance to pentamidine. The mitochondrial membrane potentials of both resistant cell lines were significantly reduced compared to the wild type. The net uptake rate of isometamidium was reduced 2-3-fold but isometamidium efflux was similar in wild-type and resistant lines. Fluorescence microscopy and PCR analysis revealed that ISMR1 and ISMR15 had completely lost their kinetoplast DNA (kDNA) and both lines carried a mutation in the nuclearly encoded γ subunit gene of F1 ATPase, truncating the protein by 22 amino acids. The mutation compensated for the loss of the kinetoplast in bloodstream forms, allowing near-normal growth, and conferred considerable resistance to isometamidium and ethidium as well as significant resistance to diminazene and pentamidine, when expressed in wild type trypanosomes. Subsequent exposure to either isometamidium or ethidium led to rapid loss of kDNA and a further increase in isometamidium resistance. CONCLUSIONS/SIGNIFICANCE: Sub-lethal exposure to isometamidium gives rise to viable but highly resistant trypanosomes that, depending on sub-species, are infective to humans and cross-resistant to at least some diamidine drugs. The crucial mutation is in the F1 ATPase γ subunit, which allows loss of kDNA and results in a reduction of the mitochondrial membrane potential.

PNT1 Is a C11 Cysteine Peptidase Essential for Replication of the Trypanosome Kinetoplast.

The structure of a C11 peptidase PmC11 from the gut bacterium, Parabacteroides merdae, has recently been determined, enabling the identification and characterization of a C11 orthologue, PNT1, in the parasitic protozoon Trypanosoma brucei. A phylogenetic analysis identified PmC11 orthologues in bacteria, archaea, Chromerids, Coccidia, and Kinetoplastida, the latter being the most divergent. A primary sequence alignment of PNT1 with clostripain and PmC11 revealed the position of the characteristic His-Cys catalytic dyad (His(99) and Cys(136)), and an Asp (Asp(134)) in the potential S1 binding site. Immunofluorescence and cryoelectron microscopy revealed that PNT1 localizes to the kinetoplast, an organelle containing the mitochondrial genome of the parasite (kDNA), with an accumulation of the protein at or near the antipodal sites. Depletion of PNT1 by RNAi in the T. brucei bloodstream form was lethal both in in vitro culture and in vivo in mice and the induced population accumulated cells lacking a kinetoplast. In contrast, overexpression of PNT1 led to cells having mislocated kinetoplasts. RNAi depletion of PNT1 in a kDNA independent cell line resulted in kinetoplast loss but was viable, indicating that PNT1 is required exclusively for kinetoplast maintenance. Expression of a recoded wild-type PNT1 allele, but not of an active site mutant restored parasite viability after induction in vitro and in vivo confirming that the peptidase activity of PNT1 is essential for parasite survival. These data provide evidence that PNT1 is a cysteine peptidase that is required exclusively for maintenance of the trypanosome kinetoplast.

Independence from Kinetoplast DNA maintenance and expression is associated with multidrug resistance in Trypanosoma brucei in vitro.

It is well known that several antitrypanosomatid drugs accumulate in the parasite's mitochondrion, where they often bind to the organellar DNA, the kinetoplast. To what extent this property relates to the mode of action of these compounds has remained largely unquantified. Here we show that single point mutations that remove the dependence of laboratory strains of the sleeping sickness parasite Trypanosoma brucei on a functional kinetoplast result in significant resistance to the diamidine and phenanthridine drug classes.

An initial evaluation of the clinical and fitness for work outcomes of a military group behavioural activation programme.

BACKGROUND: Behavioural Activation (BA) is an evidence-based psychological treatment for depression based on behavioural theory. However, in common with other talking therapies, there is limited evidence about occupational factors related to treatment. This is an important gap in the research given the emphasis placed on employment considerations in recent service initiatives. AIM: A service evaluation to investigate the clinical and fitness to work outcomes of a group BA programme for serving military personnel. METHOD: 46 patients experiencing moderate to severe depression attended a 12-session Military Behavioural Activation and Rehabilitation Course (MBARC). The primary outcomes were the Patient Health Questionnaire-9 (PHQ-9), a self-report measure of depression and the patient's medical employability category. RESULTS: Clinical and statistically significant changes were found on the PHQ-9 between pre-course and 3-month follow-up. Pretreatment 3 patients (6.5%) were psychologically fit to deploy on full operational duties in their primary role; this increased to 25 (56.8%) and 29 (65.9%) at 3 and 6-months respectively. CONCLUSION: Preliminary findings suggest that MBARC is a clinically and occupationally effective treatment for depression in military personnel. Further research is required to identify if BA delivered in a group setting would be effective in non-military settings and whether treatment benefits are maintained in the longer term.

Single point mutations in ATP synthase compensate for mitochondrial genome loss in trypanosomes.

Viability of the tsetse fly-transmitted African trypanosome Trypanosoma brucei depends on maintenance and expression of its kinetoplast (kDNA), the mitochondrial genome of this parasite and a putative target for veterinary and human antitrypanosomatid drugs. However, the closely related animal pathogens T. evansi and T. equiperdum are transmitted independently of tsetse flies and survive without a functional kinetoplast for reasons that have remained unclear. Here, we provide definitive evidence that single amino acid changes in the nuclearly encoded F1FO-ATPase subunit γ can compensate for complete physical loss of kDNA in these parasites. Our results provide insight into the molecular mechanism of compensation for kDNA loss by showing FO-independent generation of the mitochondrial membrane potential with increased dependence on the ADP/ATP carrier. Our findings also suggest that, in the pathogenic bloodstream stage of T. brucei, the huge and energetically demanding apparatus required for kDNA maintenance and expression serves the production of a single F1FO-ATPase subunit. These results have important implications for drug discovery and our understanding of the evolution of these parasites.

Cyclic AMP effectors in African trypanosomes revealed by genome-scale RNA interference library screening for resistance to the phosphodiesterase inhibitor CpdA.

One of the most promising new targets for trypanocidal drugs to emerge in recent years is the cyclic AMP (cAMP) phosphodiesterase (PDE) activity encoded by TbrPDEB1 and TbrPDEB2. These genes were genetically confirmed as essential, and a high-affinity inhibitor, CpdA, displays potent antitrypanosomal activity. To identify effectors of the elevated cAMP levels resulting from CpdA action and, consequently, potential sites for adaptations giving resistance to PDE inhibitors, resistance to the drug was induced. Selection of mutagenized trypanosomes resulted in resistance to CpdA as well as cross-resistance to membrane-permeable cAMP analogues but not to currently used trypanocidal drugs. Resistance was not due to changes in cAMP levels or in PDEB genes. A second approach, a genome-wide RNA interference (RNAi) library screen, returned four genes giving resistance to CpdA upon knockdown. Validation by independent RNAi strategies confirmed resistance to CpdA and suggested a role for the identified cAMP Response Proteins (CARPs) in cAMP action. CARP1 is unique to kinetoplastid parasites and has predicted cyclic nucleotide binding-like domains, and RNAi repression resulted in >100-fold resistance. CARP2 and CARP4 are hypothetical conserved proteins associated with the eukaryotic flagellar proteome or with flagellar function, with an orthologue of CARP4 implicated in human disease. CARP3 is a hypothetical protein, unique to Trypanosoma. CARP1 to CARP4 likely represent components of a novel cAMP signaling pathway in the parasite. As cAMP metabolism is validated as a drug target in Trypanosoma brucei, cAMP effectors highly divergent from the mammalian host, such as CARP1, lend themselves to further pharmacological development.

Pharmacological validation of Trypanosoma brucei phosphodiesterases as novel drug targets.

The development of drugs for neglected infectious diseases often uses parasite-specific enzymes as targets. We here demonstrate that parasite enzymes with highly conserved human homologs may represent a promising reservoir of new potential drug targets. The cyclic nucleotide-specific phosphodiesterases (PDEs) of Trypanosoma brucei, causative agent of the fatal human sleeping sickness, are essential for the parasite. The highly conserved human homologs are well-established drug targets. We here describe what is to our knowledge the first pharmacological validation of trypanosomal PDEs as drug targets. High-throughput screening of a proprietary compound library identified a number of potent hits. One compound, the tetrahydrophthalazinone compound A (Cpd A), was further characterized. It causes a dramatic increase of intracellular cyclic adenosine monophosphate (cAMP). Short-term cell viability is not affected, but cell proliferation is inhibited immediately, and cell death occurs within 3 days. Cpd A prevents cytokinesis, resulting in multinucleated, multiflagellated cells that eventually lyse. These observations pharmacologically validate the highly conserved trypanosomal PDEs as potential drug targets.

Patient preferences for the delivery of military mental health services.

OBJECTIVE: Knowledge of patients' preferences of military mental health care is required to inform service planning. The objective was to inform service planning by quantifying, and identifying predictors of, patient preferences for mental health care providers and location of facilities. METHOD: Sociodemographic and service characteristics and concerns about stigma were investigated for patients presenting to 4 U.K. Armed Forces Departments of Community Mental Health over a 2-months period (n = 163). RESULTS: 5% preferred to be seen by a uniformed mental health clinician, 30% by a nonuniformed clinician, and 65% reported no preference. Gender and service were associated with care provider preference and service was associated with location preference. CONCLUSION: The Armed Forces need to explore and identify ways of accommodating their patients' preference, especially regarding the uniformed status of their care provider, to achieve good engagement and acceptability.

Cyclic-nucleotide signalling in protozoa.

Compared with the impressive progress in understanding signal transduction pathways and mechanisms in mammalian systems, advances in protozoan signalling processes, including cyclic nucleotide metabolism, have been very slow. This is in large part connected to the fact that the components of these pathways are very different in the protozoan parasites, as confirmed by the recently completed genome. For instance, kinetoplastids have no equivalents to the mammalian Class I adenylyl cyclases (ACs) in their genomes nor any of the subunits of the associated G-proteins. The cyclases in kinetoplastid parasites contain a single transmembrane domain, a conserved intracellular catalytic domain and a highly variable extracellular domain - consistent with the expression of multiple receptor-activated cyclases - but no receptor ligands, agonists or antagonists have been identified. Apicomplexan AC and guanylyl cyclase (GC) are even more unusual, potentially being bifunctional, harbouring either a putative ion channel (AC) or a P-type ATPase-like domain (GC) alongside the catalytic region. Phosphodiesterases (PDEs) and cyclic-nucleotide-activated protein kinases are essentially conserved in protozoa, although mostly insensitive to inhibitors of the mammalian proteins. Some of the PDEs have now been validated as promising drug targets. In the following manuscript, we will summarize the existing literature on cAMP and cGMP in protozoa: cyclases, PDEs and cyclic-nucleotide-dependent kinases.

Do stigma and other perceived barriers to mental health care differ across Armed Forces?

OBJECTIVES: Military organizations are keen to address barriers to mental health care yet stigma and barriers to care remain little understood, especially potential cultural differences between Armed Forces. The aim of this study was to compare data collected by the US, UK, Australian, New Zealand and Canadian militaries using Hoge et al.'s perceived stigma and barriers to care measure (Combat duty in Iraq and Afghanistan, mental health problems and barriers to care. New Engl J Med 2004;351:13-22). DESIGN: Each member country identified data sources that had enquired about Hoge et al.'s perceived stigma and perceived barriers to care items in the re-deployment or immediate post-deployment period. Five relevant statements were included in the study. SETTING: US, UK Australian, New Zealand and Canadian Armed Forces. RESULTS: Concerns about stigma and barriers to care tended to be more prominent among personnel who met criteria for a mental health problem. The pattern of reported stigma and barriers to care was similar across the Armed Forces of all five nations. CONCLUSIONS: Barriers to care continue to be a major issue for service personnel within Western military forces. Although there are policy, procedural and cultural differences between Armed Forces, the nations studied appear to share some similarities in terms of perceived stigma and barriers to psychological care. Further research to understand patterns of reporting and subgroup differences is required.