Suicide after leaving the UK Armed Forces 1996-2018: A cohort study.

BACKGROUND: There are comparatively few international studies investigating suicide in military veterans and no recent UK-wide studies. This is important because the wider context of being a UK Armed Forces (UKAF) veteran has changed in recent years following a period of intensive operations. We aimed to investigate the rate, timing, and risk factors for suicide in personnel who left the UKAF over a 23-year period. METHODS AND FINDINGS: We carried out a retrospective cohort study of suicide in personnel who left the regular UKAF between 1996 and 2018 linking national databases of discharged personnel and suicide deaths, using survival analysis to examine the risk of suicide in veterans compared to the general population and conditional logistic regression to investigate factors most strongly associated with suicide after discharge. The 458,058 individuals who left the UKAF accumulated over 5,852,100 person years at risk, with a median length of follow-up of 13 years, were mostly male (91%), and had a median age of 26 years at discharge. 1,086 (0.2%) died by suicide. The overall rate of suicide in veterans was slightly lower than the general population (standardised mortality ratio, SMR [95% confidence interval, CI] 94 [88 to 99]). However, suicide risk was 2 to 3 times higher in male and female veterans aged under 25 years than in the same age groups in the general population (age-specific mortality ratios ranging from 160 to 409). Male veterans aged 35 years and older were at reduced risk of suicide (age-specific mortality ratios 47 to 80). Male sex, Army service, discharge between the ages of 16 and 34 years, being untrained on discharge, and length of service under 10 years were associated with higher suicide risk. Factors associated with reduced risk included being married, a higher rank, and deployment on combat operations. The rate of contact with specialist NHS mental health services (273/1,086, 25%) was lowest in the youngest age groups (10% for 16- to 19-year-olds; 23% for 20- to 24-year-olds). Study limitations include the fact that information on veterans was obtained from administrative databases and the role of pre-service vulnerabilities and other factors that may have influenced later suicide risk could not be explored. In addition, information on contact with support services was only available for veterans in contact with specialist NHS mental health services and not for those in contact with other health and social care services. CONCLUSIONS: In this study, we found suicide risk in personnel leaving the UKAF was not high but there are important differences according to age, with higher risk in young men and women. We found a number of factors which elevated the risk of suicide but deployment was associated with lower risk. The focus should be on improving and maintaining access to mental health care and social support for young service leavers, as well as implementing general suicide prevention measures for all veterans regardless of age.

International perspective on military exposure data sources, applications, and opportunities for collaboration.

Military personnel may be exposed to a range of hazards. The assessment, documentation and reporting of military exposure information are important steps to guide health protection, services, and research to support actively serving members and veterans. In 2021, a Working Group of researchers from veteran and defense administrations across the Five Eyes countries (Australia, Canada, New Zealand, the United Kingdom, and the United States) was established to examine large military exposure data sources available in each country, their applications, and opportunities to leverage information across administrations and internationally. We provide a brief summary of this work here to highlight some successful examples of data applications and to elicit interest in this evolving area of exposure science.

A universal vaccine candidate against Plasmodium vivax malaria confers protective immunity against the three PvCSP alleles.

Malaria is a highly prevalent parasitic disease in regions with tropical and subtropical climates worldwide. Among the species of Plasmodium causing human malaria, P. vivax is the second most prevalent and the most geographically widespread species. A major target of a pre-erythrocytic vaccine is the P. vivax circumsporozoite protein (PvCSP). In previous studies, we fused two recombinant proteins representing three allelic variants of PvCSP (VK210, VK247 and P. vivax-like) to the mumps virus nucleocapsid protein to enhance immune responses against PvCSP. The objective of the present study was to evaluate the protective efficacy of these recombinants in mice challenged with transgenic P. berghei parasites expressing PvCSP allelic variants. Formulations containing Poly (I:C) or Montanide ISA720 as adjuvants elicited high and long-lasting IgG antibody titers specific to each PvCSP allelic variant. Immunized mice were challenged with two existing chimeric P. berghei parasite lines expressing PvCSP-VK210 and PvCSP-VK247. We also developed a novel chimeric line expressing the third allelic variant, PvCSP-P. vivax-like, as a new murine immunization-challenge model. Our formulations conferred partial protection (significant delay in the time to reach 1% parasitemia) against challenge with the three chimeric parasites. Our results provide insights into the development of a vaccine targeting multiple strains of P. vivax.

A single dose of ChAdOx1 Chik vaccine induces neutralizing antibodies against four chikungunya virus lineages in a phase 1 clinical trial.

Chikungunya virus (CHIKV) is a reemerging mosquito-borne virus that causes swift outbreaks. Major concerns are the persistent and disabling polyarthralgia in infected individuals. Here we present the results from a first-in-human trial of the candidate simian adenovirus vectored vaccine ChAdOx1 Chik, expressing the CHIKV full-length structural polyprotein (Capsid, E3, E2, 6k and E1). 24 adult healthy volunteers aged 18-50 years, were recruited in a dose escalation, open-label, nonrandomized and uncontrolled phase 1 trial (registry NCT03590392). Participants received a single intramuscular injection of ChAdOx1 Chik at one of the three preestablished dosages and were followed-up for 6 months. The primary objective was to assess safety and tolerability of ChAdOx1 Chik. The secondary objective was to assess the humoral and cellular immunogenicity. ChAdOx1 Chik was safe at all doses tested with no serious adverse reactions reported. The vast majority of solicited adverse events were mild or moderate, and self-limiting in nature. A single dose induced IgG and T-cell responses against the CHIKV structural antigens. Broadly neutralizing antibodies against the four CHIKV lineages were found in all participants and as early as 2 weeks after vaccination. In summary, ChAdOx1 Chik showed excellent safety, tolerability and 100% PRNT50 seroconversion after a single dose.

Recombinant Plasmodium vivax circumsporozoite surface protein allelic variants: antibody recognition by individuals from three communities in the Brazilian Amazon.

Circumsporozoite protein (CSP) variants of P. vivax, besides having variations in the protein repetitive portion, can differ from each other in aspects such as geographical distribution, intensity of transmission, vectorial competence and immune response. Such aspects must be considered to P. vivax vaccine development. Therefore, we evaluated the immunogenicity of novel recombinant proteins corresponding to each of the three P. vivax allelic variants (VK210, VK247 and P. vivax-like) and of the C-terminal region (shared by all PvCSP variants) in naturally malaria-exposed populations of Brazilian Amazon. Our results demonstrated that PvCSP-VK210 was the major target of humoral immune response in studied population, presenting higher frequency and magnitude of IgG response. The IgG subclass profile showed a prevalence of cytophilic antibodies (IgG1 and IgG3), that seem to have an essential role in protective immune response. Differently of PvCSP allelic variants, antibodies elicited against C-terminal region of protein did not correlate with epidemiological parameters, bringing additional evidence that humoral response against this protein region is not essential to protective immunity. Taken together, these findings increase the knowledge on serological response to distinct PvCSP allelic variants and may contribute to the development of a global and effective P. vivax vaccine.

The Spinal Cord Injury Pressure Ulcer Scale (SCIPUS): an assessment of validity using Rasch analysis.

STUDY DESIGN: Secondary analysis of retrospective data. OBJECTIVE: The aim of this study was to further validate the Spinal Cord Injury Pressure Ulcer Scale (SCIPUS) using Rasch analysis. SETTING: Two rehabilitation centers in Canada. METHOD: Data were collected as part of the Spinal Cord Injury Knowledge Mobilization Network (SCI KMN) initiative. The SCIPUS was completed within 72 h of inpatient admission. Persons admitted for initial rehabilitation in two inpatient spinal cord rehabilitation programs were included in the project. RESULTS: Data from 886 participants were analyzed, approximately 60% of whom were males. Rasch analyses demonstrated that the SCIPUS, in its current format did not meet criteria required for true measurement. A transformed version of the SCIPUS obtained by deletion of misfitting items and modification of the response scales improved fit to the model and showed preliminary evidence of unidimensionality. The person separation index, however indicated that the scale requires further adjustments of its scoring options. CONCLUSIONS: In its original form, the SCIPUS does not meet the requirements of the Rasch model and its total score should be used cautiously. However, following some adjustments to the items such as addressing DIF between sites to insure a standardized assessment across sites and adding response options to some of the items, interval-scale measurement should be possible.

CRISPR/Cas9-mediated mutagenesis of phytoene desaturase in diploid and octoploid strawberry.

BACKGROUND: Gene editing using CRISPR/Cas9 is a simple and powerful tool for elucidating genetic controls and for crop improvement and its use has been reported in a growing number of important food crops, including recently Fragaria. In order to inform application of the technology in Fragaria, we targeted the visible endogenous marker gene PDS (phytoene desaturase) in diploid Fragaria vesca ssp. vesca 'Hawaii 4' and octoploid F. × ananassa 'Calypso'. RESULTS: Agrobacterium-mediated transformation of leaf and petiole explants was used for efficient stable integration of constructs expressing plant codon-optimised Cas9 and single guide sequences under control of the Arabidopsis U6-26 consensus promoter and terminator or Fragaria vesca U6III regulatory sequences. More than 80% ('Hawaii 4') and 50% ('Calypso') putative transgenic shoot lines (multiple shoots derived from a single callus) exhibited mutant phenotypes. Of mutant shoot lines selected for molecular analysis, approximately 75% ('Hawaii 4') and 55% ('Calypso') included albino regenerants with bi-allelic target sequence variants. Our results indicate the PDS gene is functionally diploid in 'Calypso'. CONCLUSION: We demonstrate that CRISPR/Cas9 may be used to generate biallelic mutants at high frequency within the genomes of diploid and octoploid strawberry. The methodology, observations and comprehensive data set presented will facilitate routine application of this technology in Fragaria to single and multiple gene copy targets where mutant phenotypes cannot be identified visually.

ACTing in Partnership to Accelerate Impact.

Partnership between funders plays a vital role in tackling the AIDS epidemic and can help partners deliver "more than the sum of their parts." But how do partnerships form? How is value leveraged and maximized? How can partnerships achieve policy change? This article addresses these questions through the example of the Accelerating Children's HIV/AIDS Treatment Initiative, an ambitious $200 million public private partnership with a goal of doubling the number of children living with HIV on treatment in 9 priority African countries over a 2-year period. It describes how the partnership formed between the US President's Emergency Plan for AIDS Relief (PEPFAR) and the Children's Investment Fund Foundation (CIFF), and the differing styles, vision, and resources each organization contributed. It also gives examples of policy influence at global level and policy change at national level. Finally, the article considers whether working in partnership was more or less effective than independent funding, with reflections on the value and challenges of collaboration.

Inhibitors of retrograde trafficking active against ricin and Shiga toxins also protect cells from several viruses, Leishmania and Chlamydiales.

Medical countermeasures to treat biothreat agent infections require broad-spectrum therapeutics that do not induce agent resistance. A cell-based high-throughput screen (HTS) against ricin toxin combined with hit optimization allowed selection of a family of compounds that meet these requirements. The hit compound Retro-2 and its derivatives have been demonstrated to be safe in vivo in mice even at high doses. Moreover, Retro-2 is an inhibitor of retrograde transport that affects syntaxin-5-dependent toxins and pathogens. As a consequence, it has a broad-spectrum activity that has been demonstrated both in vitro and in vivo against ricin, Shiga toxin-producing O104:H4 entero-hemorrhagic E. coli and Leishmania sp. and in vitro against Ebola, Marburg and poxviruses and Chlamydiales. An effect is anticipated on other toxins or pathogens that use retrograde trafficking and syntaxin-5. Since Retro-2 targets cell components of the host and not directly the pathogen, no selection of resistant pathogens is expected. These lead compounds need now to be developed as drugs for human use.

Vaccinia Virus Uses Retromer-Independent Cellular Retrograde Transport Pathways To Facilitate the Wrapping of Intracellular Mature Virions during Virus Morphogenesis.

Poxviruses, such as vaccinia virus (VACV), undertake a complex cytoplasmic replication cycle which involves morphogenesis through four distinct virion forms and includes a crucial wrapping step whereby intracellular mature virions (IMVs) are wrapped in two additional membranes to form intracellular enveloped virions (IEVs). To determine if cellular retrograde transport pathways are required for this wrapping step, we examined VACV morphogenesis in cells with reduced expression of the tetrameric tethering factor known as the GARP (Golgi-associated retrograde pathway), a central component of retrograde transport. VACV multistep replication was significantly impaired in cells transfected with small interfering RNA targeting the GARP complex and in cells with a mutated GARP complex. Detailed analysis revealed that depletion of the GARP complex resulted in a reduction in the number of IEVs, thereby linking retrograde transport with the wrapping of IMVs. In addition, foci of viral wrapping membrane proteins without an associated internal core accumulated in cells with a mutated GARP complex, suggesting that impaired retrograde transport uncouples nascent IMVs from the IEV membranes at the site of wrapping. Finally, small-molecule inhibitors of retrograde transport strongly suppressed VACV multistep growth in vitro and reduced weight loss and clinical signs in an in vivo murine model of systemic poxviral disease. This work links cellular retrograde transport pathways with the morphogenesis of poxviruses and identifies a panel of novel inhibitors of poxvirus replication. IMPORTANCE Cellular retrograde transport pathways traffic cargo from endosomes to the trans-Golgi network and are a key part of the intracellular membrane network. This work reveals that the prototypic poxvirus vaccinia virus (VACV) exploits cellular retrograde transport pathways to facilitate the wrapping of intracellular mature virions and therefore promote the production of extracellular virus. Inhibition of retrograde transport by small-molecule inhibitors reduced the replication of VACV in cell culture and alleviated disease in mice experimentally infected with VACV. This research provides fundamental new knowledge about the wrapping step of poxvirus morphogenesis, furthers our knowledge of the complex cellular retrograde pathways, and identifies a new group of antipoxvirus drugs.

Risky driving among UK regular armed forces personnel: changes over time.

OBJECTIVES: To compare the prevalence of self-reported risky driving in a sample of UK military personnel at 2 different time points (2004 and 2009), and to identify the incidence of new onset risky driving and possible determinants of becoming a new risky driver. METHODS: Data were used from 2 phases of a military cohort study investigating the health and well-being of UK military personnel between 2004 and 2009. Participants were included if they were undertaking regular (rather than reserve) engagements, had completed both surveys and reported being a driver at both surveys. Univariable and multivariable logistic regression analyses were performed to examine the relationship between risky driving status and sociodemographic and military characteristics. Data analysis was conducted in 2011. RESULTS: The prevalence of risky driving reduced from 18% to 14%, over an average of 3.3 years. The incidence of new onset risky driving was 7%. Predictors for becoming a new risky driver were: younger age, not being in a relationship at phase 2 and harmful alcohol use. Those deployed after 2007 were less likely to become risky drivers following deployment, compared with those deployed before 2007 (adjusted OR 0.62 (95% CI 0.40 to 0.95)). CONCLUSIONS: The prevalence of becoming a risky driver appears to have reduced over time. This paper suggests a number of explanations for this reduction, including changes in the way that the UK military have dealt with road safety with the introduction of the road safety campaign (in 2007).

Orally delivered water soluble Coenzyme Q10 (Ubisol-Q10) blocks on-going neurodegeneration in rats exposed to paraquat: potential for therapeutic application in Parkinson's disease.

BACKGROUND: Paraquat, still used as an herbicide in some parts of the world, is now regarded as a dangerous environmental neurotoxin and is linked to the development Parkinson's disease (PD). Paraquat interacts with cellular redox systems and causes mitochondrial dysfunction and the formation of reactive oxygen species, which in turn, plays a crucial role in the pathophysiology of PD. Various antioxidant therapies have been explored with the expectations that they deliver health benefits to the PD patients, however, no such therapies were effective. Here we have tested the neuroprotective efficacy of a novel water-soluble CoQ10 (Ubisol-Q10), in a rat model of paraquat-induced neurodegeneration in order to evaluate its potential application in the management of PD. RESULTS: We have developed a rat model of progressive nigrostriatal degeneration by giving rats five intraperitoneal injections of paraquat (10 mg/kg/injection), once every five days. Neuronal death occurred over a period of 8 weeks with close to 50% reduction in the number of tyrosine hydroxylase-positive cells. Ubisol-Q10, at 6 mg CoQ10/kg body weight/day, was delivered as a supplement in drinking water. The intervention begun after the completion of paraquat injections when the neurodegenerative process had already began and about 20% of TH-positive neurons were lost. Ubisol-Q10 treatment halted the progression of neurodegeneration and remaining neurons were protected. The outcomes were evaluated based on the number of surviving tyrosine hydroxylase-positive neurons in the substantia nigra region and improved motor skills in response to the Ubisol-Q10 intervention. To maintain this neuroprotection, however, continuous Ubisol- Q10 supplementation was required, if withdrawn, the neuronal death pathway resumed, suggesting that the presence of CoQ10 was essential for blocking the pathway. CONCLUSION: The CoQ10, given orally as Ubisol-Q10 in drinking solution, was effective in blocking the progression of neurodegeneration when administered therapeutically (post-toxin injection), at a much lower concentration than other previously tested oil soluble formulations and well within the acceptable daily intake of 12 mg/kg/day. Such unprecedented neuroprotection has never been reported before. These results are very encouraging and suggest that Ubisol-Q10 should be further tested and developed as a therapy for halting the progression of PD.

Targeting the "cytokine storm" for therapeutic benefit.

Inflammation is the body's first line of defense against infection or injury, responding to challenges by activating innate and adaptive responses. Microbes have evolved a diverse range of strategies to avoid triggering inflammatory responses. However, some pathogens, such as the influenza virus and the Gram-negative bacterium Francisella tularensis, do trigger life-threatening "cytokine storms" in the host which can result in significant pathology and ultimately death. For these diseases, it has been proposed that downregulating inflammatory immune responses may improve outcome. We review some of the current candidates for treatment of cytokine storms which may prove useful in the clinic in the future and compare them to more traditional therapeutic candidates that target the pathogen rather than the host response.

Impacts of wheelchair acquisition on children from a person-occupation-environment interactional perspective.

PURPOSE: Mobility aids not only compensate for a locomotor disability, they also increase users' opportunities for social participation. The objective was to explore the impacts of wheelchair (WC) acquisition on children's social participation, personal factors and social environment. METHODS: A literature review was done in MEDLINE for the years 1996 to 2011 (June) with an age range from birth to 12 years. The studies selected had to be in French or English and concern the impacts of a WC on children, their social participation or social environment. RESULTS: The studies retained (n = 9) indicate generally positive impacts. A trend towards improved participation in personal care, mobility, interpersonal relationships and play was observed. Data regarding the effect on the development of cognitive functions are contradictory. For the social environment, a positive change was observed in parents' attitudes and their own social participation after their child tried Assistive Technology. CONCLUSION: The results illustrate the complex interaction between person, environment and social participation. Although they are a compensatory aid, WCs do not have a negative impact on motor development. Finally, methodologically speaking, the subject seems to have been explored sufficiently to now be studied in greater depth by means of empirical studies generating evidence-based data.

What are the effects of having an illness or injury whilst deployed on post deployment mental health? A population based record linkage study of UK army personnel who have served in Iraq or Afghanistan.

BACKGROUND: The negative impact of sustaining an injury on a military deployment on subsequent mental health is well-documented, however, the relationship between having an illness on a military operation and subsequent mental health is unknown. METHODS: Population based study, linking routinely collected data of attendances at emergency departments in military hospitals in Iraq and Afghanistan [Operational Emergency Department Attendance Register (OpEDAR)], with data on 3896 UK Army personnel who participated in a military health study between 2007 and 2009 and deployed to Iraq or Afghanistan between 2003 to 2009. RESULTS: In total, 13.8% (531/3896) of participants had an event recorded on OpEDAR during deployment; 2.3% (89/3884) were medically evacuated. As expected, those medically evacuated for an injury were at increased risk of post deployment probable PTSD (odds ratio 4.27, 95% confidence interval 1.80-10.12). Less expected was that being medically evacuated for an illness was also associated with a similarly increased risk of probable PTSD (4.39, 1.60-12.07) and common mental disorders (2.79, 1.41-5.51). There was no association between having an OpEDAR event and alcohol misuse. Having an injury caused by hostile action was associated with increased risk of probable PTSD compared to those with a non-hostile injury (3.88, 1.15 to 13.06). CONCLUSIONS: Personnel sustaining illnesses on deployment are just as, if not more, at risk of having subsequent mental health problems as personnel who have sustained an injury. Monitoring of mental health problems should consider those with illnesses as well as physical injuries.

Perceived impacts of a first wheelchair on social participation.

PURPOSE: To document perceived impacts in users' daily activities and social roles (social participation) following the acquisition of a first manual or powered wheelchair. METHODS: A qualitative design with a phenomenological approach was used. Semi-structured interviews were conducted. An interview guide was developed based on the 12 social participation categories in the Disability Creation Process (DCP) conceptual model as themes underlying the questions: 'What has changed in your daily life since you got your new wheelchair?' and 'What has not changed in your daily life that you thought you would do differently with your new wheelchair?' RESULTS AND DISCUSSION: The average age of the ten participants was 64.3 years (±16.3) and 90% had received a manual wheelchair. Four main themes emerged from the detailed analysis: changes in daily activities, expectations not met, impacts on social roles and emotional changes. The participants considered the changes in daily activities to be generally positive. Expectations not met mainly related to outdoor mobility. The participants had not anticipated the impacts on social roles and emotional changes, which demonstrate the complexity of human occupation. CONCLUSION: Getting a wheelchair is a major and complex event in a person's life.

Regions of the Cf-9B disease resistance protein able to cause spontaneous necrosis in Nicotiana benthamiana lie within the region controlling pathogen recognition in tomato.

The tomato Cf-9 and Cf-9B genes both confer resistance to the leaf mold fungus Cladosporium fulvum but only Cf-9 confers seedling resistance and recognizes the avirulence (Avr) protein Avr9 produced by C. fulvum. Using domain swaps, leucine-rich repeats (LRR) 5 to 15 of Cf-9 were shown to be required for Cf-9-specific resistance to C. fulvum in tomato, and the entire N-terminus up to LRR15 of Cf-9B was shown to be required for Cf-9B-specific resistance. Finer domain swaps showed that nine amino-acid differences in LRR 13 to 15 provided sufficient Cf-9-specific residues in a Cf-9B context for recognition of Avr9 in Nicotiana tabacum or sufficient Cf-9B residues in a Cf-9 context for a novel necrotic response caused by the expression of Cf-9B in N. benthamiana. The responses conferred by LRR 13 to 15 were enhanced by addition of LRR 10 to 12, and either region of Cf-9B was found to cause necrosis in N. benthamiana when the other was replaced by Cf-9 sequence in a Cf-9B context. As a consequence, the domain swap with LRR 13 to 15 of Cf-9 in a Cf-9B context gained the dual ability to recognize Avr9 and cause necrosis in N. benthamiana. Intriguingly, two Cf-9B-specific domain swaps gave differing results for necrosis assays in N. benthamiana compared with disease resistance assays in transgenic tomato. The different domain requirements in these two cases suggest that the two assays detect unrelated ligands or detect related ligands in slightly different ways. A heat-sensitive necrosis-inducing factor present in N. benthamiana intercellular washing fluids was found to cause a necrotic response in N. tabacum plants carrying Hcr9-9A, Cf-9B, and Cf-9 but not in plants carrying only Cf-9. We postulate that this necrosis-inducing factor is recognized by Cf-9B either directly as a ligand or indirectly as a regulator of Cf-9B autoactivity.

Impact of wheelchair acquisition on social participation.

PURPOSE: Efficient mobility could be a prerequisite to carrying out many daily activities and social roles (social participation). The aim of this study was to assess the impact of wheelchair acquisition on social participation. METHODS: Single group pre/post design where the intervention was the acquisition of a wheelchair paid for by the provincial government. Data were collected retrospectively from the participants' medical files. Individuals were excluded if they received an assistive device other than a wheelchair or contacted the centre only for wheelchair repairs. Social participation was measured using the Reintegration to Normal Living Index (RNLI) questionnaire. RESULTS: The sample (n = 42) had a mean age of 64.2 +/- 18.5 years, and 50% of them (n = 21) did not have a wheelchair before the intervention. The total RNLI scores pre- (46.9/100 +/- 24.7) and post-acquisition (29.7/100 +/- 18.5) showed a significant improvement in participation (p < 0.001). No difference was found between those who had their first wheelchair (n = 21) compared with replacement. Single-item analysis of the RNLI showed a significant difference for 5 of the 11 items. Age and diagnosis were significantly correlated (p < 0.05) with some of the items. CONCLUSION: Social participation improved significantly following wheelchair acquisition although confounding variables may have contributed to this improvement.