Delivering treatment to morally injured UK military personnel and Veterans: The clinician experience.

This study explored the experiences of clinicians in providing treatment in cases of military-related moral injury (MI). Qualitative interviews were carried out with 15 clinicians. Clinicians found patients experienced particular maladaptive appraisals following MI, which were considered different from the responses experienced after threat-based trauma. To address MI-related distress, clinicians utilized a range of treatment approaches. Several difficulties in providing care to patients following MI were described, including the impact of providing treatment on the clinicians own mental health. This study provides detailed insight into the approaches currently used to identify and treat UK Veterans with MI-related psychological problems. These findings highlight the need to evaluate the effectiveness of the treatments currently provided for MI-related psychological problems and suggest developing best practice guidance may improve clinician confidence in delivering care to those adversely impacted by MI.

Increases in Endogenous or Exogenous Progestins Promote Virus-Target Cell Interactions within the Non-human Primate Female Reproductive Tract.

Currently, there are mounting data suggesting that HIV-1 acquisition in women can be affected by the use of certain hormonal contraceptives. However, in non-human primate models, endogenous or exogenous progestin-dominant states are shown to increase acquisition. To gain mechanistic insights into this increased acquisition, we studied how mucosal barrier function and CD4+ T-cell and CD68+ macrophage density and localization changed in the presence of natural progestins or after injection with high-dose DMPA. The presence of natural or injected progestins increased virus penetration of the columnar epithelium and the infiltration of susceptible cells into a thinned squamous epithelium of the vaginal vault, increasing the likelihood of potential virus interactions with target cells. These data suggest that increasing either endogenous or exogenous progestin can alter female reproductive tract barrier properties and provide plausible mechanisms for increased HIV-1 acquisition risk in the presence of increased progestin levels.

Characterization of the Influence of Semen-Derived Enhancer of Virus Infection on the Interaction of HIV-1 with Female Reproductive Tract Tissues.

UNLABELLED: The majority of human immunodeficiency virus type 1 (HIV-1) transmission events occur in women when semen harboring infectious virus is deposited onto the mucosal barriers of the vaginal, ectocervical, and endocervical epithelia. Seminal factors such as semen-derived enhancer of virus infection (SEVI) fibrils were previously shown to greatly enhance the infectivity of HIV-1 in cell culture systems. However, when SEVI is intravaginally applied to living animals, there is no effect on vaginal transmission. To define how SEVI might function in the context of sexual transmission, we applied HIV-1 and SEVI to intact human and rhesus macaque reproductive tract tissues to determine how it influences virus interactions with these barriers. We show that SEVI binds HIV-1 and sequesters most virions to the luminal surface of the stratified squamous epithelium, significantly reducing the number of virions that penetrated the tissue. In the simple columnar epithelium, SEVI was no longer fibrillar in structure and was detached from virions but allowed significantly deeper epithelial virus penetration. These observations reveal that the action of SEVI in intact tissues is very different in the anatomical context of sexual transmission and begin to explain the lack of stimulation of infection observed in the highly relevant mucosal transmission model. IMPORTANCE: The most common mode of HIV-1 transmission in women occurs via genital exposure to the semen of HIV-infected men. A productive infection requires the virus to penetrate female reproductive tract epithelial barriers to infect underlying target cells. Certain factors identified within semen, termed semen-derived enhancers of virus infection (SEVI), have been shown to significantly enhance HIV-1 infectivity in cell culture. However, when applied to the genital tracts of living female macaques, SEVI did not enhance virus transmission. Here we show that SEVI functions very differently in the context of intact mucosal tissues. SEVI decreases HIV-1 penetration of squamous epithelial barriers in humans and macaques. At the mucus-coated columnar epithelial barrier, the HIV-1/SEVI interaction is disrupted. These observations suggest that SEVI may not play a significant stimulatory role in the efficiency of male-to-female sexual transmission of HIV.

Auricular reconstruction after human bite amputation using the Baudet technique.

OBJECTIVE: This study aimed to present a case of a successful re-implantation of an amputated auricle following a human bite using the Baudet technique. METHODS: Case report and review of the literature. RESULTS: The patient had a very satisfactory postoperative result in terms of appearance and function of the reattached auricle. Cartilage loss was minimal. CONCLUSION: Reattachment of an amputated auricle as a composite graft following a traumatic human bite is feasible. The Baudet technique is a simple alternative that avoids the complexity of microsurgical anastomosis while improving upon the high failure rate associated with simple reattachment.

A Blog-Based Study of Autistic Adults' Experiences of Aloneness and Connection and the Interplay with Well-Being: Corpus-Based and Thematic Analyses.

Background: Autistic adults appear to be more vulnerable to mental ill health, with loneliness being a variable associated with multiple outcomes of poorer well-being. However, a description of meaningful social connection that is suitable for autistic adults is missing from this research, along with a missing understanding of the conditions that contribute to well-being. Methods: In this study, autistic adults' experiences of connectedness and aloneness were systematically searched for within data collected from blogs. This contributed a creative method to hear the viewpoint of autistic adults. Corpus-based and thematic analyses explored the descriptions and contexts of relationships. A total of 16 autistic authors contributed views. Results: Social connection was desired and was achieved through self-acceptance and rejecting deficit-based views of being autistic, and selectively choosing important relationships. Meaningful social connection changed over time, being more difficult to attain in childhood, and benefiting from self-learning and effortfully applying neuro-normative skills in social communication. Loneliness was only described alongside other causes of unhappiness and was not associated with being autistic. Conclusions: The findings offer some explanation for the high estimates of both loneliness and mental ill health for autistic adults. We consider the implications for autistic individuals, clinicians, educators, and researchers. We are also cautious not to imply that these views reflect all autistic people. The findings suggest that improvements are needed in society to share communication differences and relationship expectations for autistic individuals to be accepted and valued.

Why is this an important issue?: Autistic adults appear to be vulnerable to mental ill health, though this is often misunderstood. Being lonely, or dissatisfied with social relationships, has been linked to poorer well-being. However, most research uses questionnaires to assess loneliness, which make assumptions that need updating for autistic adults. For example, having fewer friends does not necessarily mean feeling lonely. We are also missing an understanding of what contexts make autistic people feel alone or connected. What was the purpose of this study?: The purpose of this study was to hear the experiences of aloneness and social connectedness as described personally by autistic adults. We chose to use data from online blogs, because the topics and descriptions were chosen through personal motivation of the authors and minimize assumptions made by researchers. What did the researchers do?: We created a dataset of descriptions of social connectedness from the top trending blogs written by autistic authors. We used systematic search methods to do this. We chose 33 search terms that describe social connection and aloneness, as not to presume that autistic people are lonely, such as "friendships" and "belonging." We analyzed the descriptions first using a computer program to find patterns in language, including the most frequent descriptions. This is called corpus-based analysis. It was chosen to reduce the bias that researchers can introduce when they look for themes in what people talk about. Second, we used a method called thematic analysis to explore the shared meanings in the descriptions, which helped us to understand the contexts of relationships. We collected views from 16 autistic authors. What were the results of the study?: The results showed that the blog authors desired social connection and had meaningful relationships. This was achieved through self-acceptance and self-compassion. Authors said that they learned about themselves over time. They learnt social skills that they thought were expected by non-autistic peers. They also rejected the view that being autistic was a negative thing. Loneliness was described only when people had other things making them unhappy, such as anxiety or depression, and was not associated with being autistic more generally. What do these findings add to what was already known?: Unhappiness with social relationships seems to occur in certain circumstances, which change over time. Importantly, these autistic authors said they felt connected when they had a positive identity, were understood by the people important to them, and were able to make choices about how to invest in relationships. What are potential weaknesses in the study?: We only heard from a small sample of autistic people, likely those with good internet skills who were interested in social media. This might be a group of people who are motivated to connect with other people. Also, we could not follow up on the meanings of what was written because we had no interaction with participants. How will these findings help autistic adults now or in the future?: Within health care, there seems to be a risk of misunderstanding autistic clients when practitioners use questionnaires to assess well-being or loneliness, when the questionnaires are not created for autistic people. We recommend not assuming loneliness, but instead, asking whether feeling lonely occurs under certain circumstances. There is more for clinicians and researchers and society to do to share the responsibility for social communication differences.

Preclinical evaluation of triiodothyronine nanoparticles as a novel therapeutic intervention for resuscitation from cardiac arrest.

BACKGROUND: Given emerging evidence of rapid non-genomic cytoprotective effects of triiodothyronine (T3), we evaluated the resuscitative efficacy of two nanoparticle formulations of T3 (T3np) designed to prolong cell membrane receptor-mediated signaling. METHODS: Swine (n = 40) were randomized to intravenous vehicle (empty np), EPI (0.015 mg/kg), T3np (0.125 mg/kg), or T3np loaded with phosphocreatine (T3np + PCr; 0.125 mg/kg) during CPR following 7-min cardiac arrest (n = 10/group). Hemodynamics and biomarkers of heart (cardiac troponin I; cTnI) and brain (neuron-specific enolase; NSE) injury were assessed for up to 4-hours post-ROSC, at which time the heart and brain were collected for post-mortem analysis. RESULTS: Compared with vehicle (4/10), the rate of ROSC was higher in swine receiving T3np (10/10; p < 0.01), T3np + PCr (8/10; p = 0.08) or EPI (10/10; p < 0.01) during CPR. Although time to ROSC and survival duration were comparable between groups, EPI was associated with a ∼2-fold higher post-ROSC concentration of cTnI vs T3np and T3np + PCr and the early post-ROSC rise in NSE and neuronal injury were attenuated in T3np-treated vs EPI-treated animals. Analysis of hippocampal ultrastructure revealed deterioration of mitochondrial integrity, reduced active zone length, and increased axonal vacuolization in EPI-treated animals vs controls. However, the frequency of these abnormalities was diminished in animals resuscitated with T3np. CONCLUSIONS: T3np achieved a ROSC rate and post-ROSC survival that was superior to vehicle and comparable to EPI. The attenuation of selected biomarkers of cardiac and neurologic injury at individual early post-ROSC timepoints in T3np-treated vs EPI-treated animals suggests that T3np administration during CPR may lead to more favorable outcomes in cardiac arrest.

Randomized controlled phase IIa clinical trial of safety, pharmacokinetics and pharmacodynamics of tenofovir and tenofovir plus levonorgestrel releasing intravaginal rings used by women in Kenya.

Introduction: Globally, many young women face the overlapping burden of HIV infection and unintended pregnancy. Protection against both may benefit from safe and effective multipurpose prevention technologies. Methods: Healthy women ages 18-34 years, not pregnant, seronegative for HIV and hepatitis B surface antigen, not using hormonal contraception, and at low risk for HIV were randomized 2:2:1 to continuous use of a tenofovir/levonorgestrel (TFV/LNG), TFV, or placebo intravaginal ring (IVR). In addition to assessing genital and systemic safety, we determined TFV concentrations in plasma and cervicovaginal fluid (CVF) and LNG levels in serum using tandem liquid chromatography-mass spectrometry. We further evaluated TFV pharmacodynamics (PD) through ex vivo CVF activity against both human immunodeficiency virus (HIV)-1 and herpes simplex virus (HSV)-2, and LNG PD using cervical mucus quality markers and serum progesterone for ovulation inhibition. Results: Among 312 women screened, 27 were randomized to use one of the following IVRs: TFV/LNG (n = 11); TFV-only (n = 11); or placebo (n = 5). Most screening failures were due to vaginal infections. The median days of IVR use was 68 [interquartile range (IQR), 36-90]. Adverse events (AEs) were distributed similarly among the three arms. There were two non-product related AEs graded >2. No visible genital lesions were observed. Steady state geometric mean amount (ssGMA) of vaginal TFV was comparable in the TFV/LNG and TFV IVR groups, 43,988 ng/swab (95% CI, 31,232, 61,954) and 30337 ng/swab (95% CI, 18,152, 50,702), respectively. Plasma TFV steady state geometric mean concentration (ssGMC) was <10 ng/ml for both TFV IVRs. In vitro, CVF anti-HIV-1 activity showed increased HIV inhibition over baseline following TFV-eluting IVR use, from a median of 7.1% to 84.4% in TFV/LNG, 15.0% to 89.5% in TFV-only, and -27.1% to -20.1% in placebo participants. Similarly, anti-HSV-2 activity in CVF increased >50 fold after use of TFV-containing IVRs. LNG serum ssGMC was 241 pg/ml (95% CI 185, 314) with rapid rise after TFV/LNG IVR insertion and decline 24-hours post-removal (586 pg/ml [95% CI 473, 726] and 87 pg/ml [95% CI 64, 119], respectively). Conclusion: TFV/LNG and TFV-only IVRs were safe and well tolerated among Kenyan women. Pharmacokinetics and markers of protection against HIV-1, HSV-2, and unintended pregnancy suggest the potential for clinical efficacy of the multipurpose TFV/LNG IVR. Clinical Trial Registration: NCT03762382 [https://clinicaltrials.gov/ct2/show/NCT03762382].

Helicobacter pylori induction of eosinophil migration is mediated by the cag pathogenicity island via microbial-epithelial interactions.

The host immune response directed against Helicobacter pylori is ineffective in eliminating the organism and strains harboring the cag pathogenicity island augment disease risk. Because eosinophils are a prominent component of H. pylori-induced gastritis, we investigated microbial and host mechanisms through which H. pylori regulates eosinophil migration. Our results indicate that H. pylori increases production of the chemokines CCL2, CCL5, and granulocyte-macrophage colony-stimulating factor by gastric epithelial cells and that these molecules induce eosinophil migration. These events are mediated by the cag pathogenicity island and by mitogen-activated protein kinases, suggesting that eosinophil migration orchestrated by H. pylori is regulated by a virulence-related locus.

Acceptability of an intravaginal ring for simultaneously preventing HIV infection and pregnancy: Qualitative findings of the Kisumu Combined Ring Study, 2019.

Multipurpose prevention technology intravaginal rings (MPT IVRs) may offer a promising solution for addressing women's multiple sexual and reproductive health needs. We describe MPT IVR acceptability perspectives and examine user experiences of 25 cisgender women aged 18-34 years enrolled in a phase IIa randomized, partially blinded, placebo-controlled evaluation of tenofovir-based IVRs with and without contraceptive co-formulation. All took part in an individual, audio-recorded, semi-structured qualitative interview. A thematic analysis of transcribed interviews was completed in MaxQDA. Participants shared little to no knowledge of or experience with IVRs prior to joining the study. Four MPT IVR themes were identified: physical well-being, method reliability, personal management, and societal endorsement. Commonly cited of concern, but less described as being experienced, were physical discomforts (e.g., painful insertion/removal; inability to carry out daily activities/chores; foreign body sensation; expulsion; sexual interference, or debilitating side effects). Uncertainty regarding efficacy influenced perspectives about intended prevention benefits. Personal choices in managing reproduction and sexual behaviors had to be congruent with sociocultural values and norms for acceptance beyond the individual user level. Participants viewed broader community acceptance as likely to be mixed given community opposition to the use of modern family planning methods. They also shared concerns that IVR use could lead to infertility, especially among nulliparous women, or that it would encourage premarital sex or high-risk sexual behaviors among adolescent and young women. While a MPT IVR may not be suitable for all women, first-hand testimonials could help influence collective receptivity. Additional community acceptability research is needed. Clinical Trial Registration The study is registered at http://ClinicalTrials.gov under the identifier NCT03762382.

Genital microbiota of women using a 90 day tenofovir or tenofovir and levonorgestrel intravaginal ring in a placebo controlled randomized safety trial in Kenya.

In a phase-IIa trial, we investigated the influence of 90 days continuous-delivery tenofovir (TFV) intravaginal rings (IVRs) with/without levonorgestrel (LNG) on the genital microbiota of Kenyan women. Eligible women (n = 27; 18-34 years; negative for HIV, sexually transmitted infections, and Amsel-bacterial vaginosis) were randomized 2:2:1 to use of IVRs containing TFV, TFV/LNG, or placebo. Using vaginal wall and IVR swabs at IVR insertion and removal, the genital microbial composition was determined using 16S rRNA gene sequencing. The presence of Candida spp. was determined using qPCR. The vaginal total bacterial burden appeared to decrease with TFV and TFV/LNG IVR use (log100.57 and log100.27 decrease respectively; p > 0.05). The TFV/LNG IVR was more 'stabilizing': 50% of the participants' microbiota community state types remained unchanged and 50% shifted towards higher Lactobacillus abundance. Specifically, TFV/LNG IVR use was accompanied by increased abundances of Lactobacillus gasseri/hominis/johnsonii/taiwanensis (16.3-fold) and L. fermentum/reuteri/vaginalis (7.0-fold; all p < 0.01). A significant shift in the overall microbial α-diversity or ß-diversity was not observed for either IVR, and IVR use did not influence Candida spp. prevalence. TFV/LNG and TFV IVRs did not adversely affect the genital microbiota and are safe to use. Our findings support further studies assessing their efficacy in preventing HIV/HSV-2 and unintended pregnancies.

Combination strategies for repair, plasticity, and regeneration using regulation of gene expression during the chronic phase after spinal cord injury.

Although recovery after spinal cord injury (SCI) is rare in humans, recent literature indicates that some patients do recover sensorimotor function years after the trauma. This study seeks to elucidate the genetic underpinnings of SCI repair through the investigation of neurodegenerative and regenerative associated genes involved in the response to SCI during the chronic phase in adult rats. Intervention on the level of gene regulation focused on enhancing naturally attempting SCI regenerative genes has the potential to promote SCI repair. Our aim was to analyze gene expression characteristics of candidate genes involved in the neuro-degenerative and -regenerative processes following various animal models of SCI. We compiled data showing gene expression changes after SCI in adult rats and created a chronological time-line of candidate genes differentially expressed during the chronic phase of SCI. Compiled data showed that SCI induced a transient upregulation of endogenous neuro-regenerative genes not only within a few hours but also within a few days, weeks, and months after SCI. For example, gene controlling growth-associated protein-43 (GAP-43), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and others, showed significant changes in mRNA accumulation in SCI animals, from 48 hours to 12 weeks after SCI. Similarly, inhibitory genes, such as RhoA, LINGO-1, and others, were upregulated as late as 4 to 14 days after injury. This indicates that gene specific regulation changes, corresponding to repair and regenerative attempts, are naturally orchestrated over time after injury. These delayed changes after SCI give ample time for therapeutic gene modulation through upregulation or silencing of specific genes responsible for the synthesis of the corresponding biogenic proteins. By following the examination of differential gene regulation during the chronic phase, we have determined times, successions, co-activations, interferences, and dosages for potential therapeutic synchronized interventions. Finally, local cellular specificities and their neuropathophysiologies have been taken into account in the elaboration of the combination treatment strategy we propose. The interventions we propose suggest the delivery of exogenous therapeutic agents to upregulate or downregulate chosen genes or the expression of the downstream proteins to revert the post-traumatic stage of SCI during the chronic phase. The proposed combination and schedule of local cell-specific treatment should enhance intrinsic regenerative machinery and provide a promising strategy for treating patients sustaining chronic SCI.

Regulation of gastric B cell recruitment is dependent on IL-17 receptor A signaling in a model of chronic bacterial infection.

Th17-driven immune responses contribute to the pathogenesis of many chronic inflammatory diseases. In this study, we investigated the role of IL-17 signaling in chronic gastric inflammation induced by Helicobacter pylori, a Gram-negative bacterium that persistently colonizes the human stomach. Wild-type C57BL/6 mice and mice lacking IL-17RA (IL-17RA(-/-)) were orogastrically infected with H. pylori. Differences in bacterial colonization density and gastric inflammation were not apparent at 1 mo postinfection, but by 3 mo postinfection, H. pylori colonization density was higher and mononuclear gastric inflammation more severe in infected IL-17RA(-/-) mice than in infected wild-type mice. A striking feature was a marked increase in gastric B cells, plasma cells, and lymphoid follicles, along with enhanced H. pylori-specific serum Ab responses, in infected IL-17RA(-/-) mice. Fewer gastric neutrophils and lower levels of neutrophil-recruiting chemokines were detected in infected IL-17RA(-/-) mice than in infected wild-type mice. Gastric IL-17a and IL-21 transcript levels were significantly higher in infected IL-17RA(-/-) mice than in infected wild-type mice or uninfected mice, which suggested that a negative feedback loop was impaired in the IL-17RA(-/-) mice. These results underscore an important role of IL-17RA signaling in regulating B cell recruitment. In contrast to many chronic inflammatory diseases in which IL-17RA signaling promotes an inflammatory response, IL-17RA signaling down-regulates the chronic mononuclear inflammation elicited by H. pylori infection.

Corrections for measurements of tritium in subterranean vapor using silica gel.

Hazardous contaminants buried within vadose zones can accumulate in soil gas. The concentrations and spatial extent of these contaminants are measured to evaluate potential transport to groundwater for public risk evaluation. Tritium is an important contaminant found and monitored for in vadose zones across numerous sites within the US nuclear weapons complex, including Los Alamos National Laboratory. The extraction, collection, and laboratory analysis of tritium from subterranean soil gas presents numerous technical challenges that have not been fully studied. Particularly, the lack of moisture in the soil gas in the vadose zone makes it difficult to obtain enough sample (e.g., > 5 g) to provide for the required measurement sensitivity, and often, only small amounts of moisture can be collected. Further, although silica gel has high affinity for water vapor and is prebaked prior to sampling, there is still sufficient residual moisture in the prebaked gel to dilute the relatively small amount of sampled moisture; thereby, significantly lowering the "true" tritium concentration in the soil gas. This paper provides an evaluation of the magnitude of the bias from dilution, provides methods to correct past measurements by applying a correction factor (CF), and evaluates the uncertainty of the CF values. For this, 10,000 Monte Carlo calculations were performed, and distribution parameters of CF values were determined and evaluated. The mean and standard deviation of the distribution of CF values were 1.53 ± 0.36, and the minimum, median, and maximum values were 1.14, 1.43, and 5.27, respectively.

The impact of moral injury on the wellbeing of UK military veterans.

BACKGROUND: Experiences of potentially morally injurious events (PMIEs) have been found to negatively impact the mental health of US personnel/veterans, yet little is known about the effect of PMIEs on the mental health of the UK Armed Forces (AF). This cross-sectional study aimed to examine the association between PMIEs and the mental health outcomes of UK AF veterans. METHOD: Assessments of PMIE exposure and self-report measures of common mental disorders were administered using an online questionnaire to 204 UK veterans. Subjects were classified as having experienced a morally injurious event (n = 66), a non-morally injurious traumatic event (n = 57), a 'mixed' event (n = 31), or no event (n = 50). RESULTS: Potentially morally injurious experiences were associated with adverse mental health outcomes, including likely anxiety disorders and suicidal ideation, compared to those who reported no event exposure. The likelihood of meeting criteria for probable PTSD was greatest in those who had experienced a non-morally injurious trauma. No statistically significant association between alcohol misuse and experiencing a PMIE or traumatic event was observed. CONCLUSIONS: The results provide preliminary evidence that potentially morally injurious experiences are associated with adverse mental health outcomes in UK AF veterans. Further work is needed to better understand the interplay between morally injurious events and threat-based trauma in order to design effective pathways for prevention and intervention for people exposed to highly challenging events.

The only way is up: priorities for implementing long-acting antiretrovirals for HIV prevention and treatment.

PURPOSE OF REVIEW: Long-acting HIV treatment and prevention (LAHTP) can address some of the achievement gaps of daily oral therapy to bring us closer to achieving Joint United Nations Programme on HIV/AIDS Fast-track goals. Implementing these new technologies presents individual-level, population-level, and health systems-level opportunities and challenges. RECENT FINDINGS: To optimize LAHTP implementation and impact, decision-makers should define and gather relevant data to inform their investment case within the existing health systems context. Programmatic observations from scale-up of antiretroviral therapy, oral preexposure prophylaxis, voluntary medical male circumcision, and family planning offer lessons as planning begins for implementation of LAHTP. Additional data intelligence should be derived from formative studies, pragmatic clinical trials, epidemiologic and economic modeling of LAHTP. Key implementation issues that need to be addressed include optimal communication strategies for demand creation; target setting; logistics and supply chain of commodities needed for LAHTP delivery; human resource planning; defining and operationalizing monitoring and evaluating metrics; integration into health systems. SUMMARY: Successful LAHTP implementation can bolster treatment and prevention coverage levels if implementation issues outlined above are proactively addressed in parallel with research and development so that health systems can more rapidly integrate new technologies as they gain regulatory approval.

The impact of trauma exposure and moral injury on UK military veterans: a qualitative study.

Background: Exposure to a potentially morally injurious event (PMIE) has been found to be associated with a range of adverse mental health outcomes. However, how the psychological consequences following PMIEs compare to those encountered after a traumatic, but not a PMIE, remain poorly understood. Objective: The aim was to qualitatively explore UK military veterans' responses to experiences of trauma and moral injury and the impact of such events on psychological wellbeing. Method: Thirty male veterans who reported exposure to traumatic and/or morally injurious events were recruited. Semi-structured qualitative interviews were conducted, and data were analysed using thematic analysis. Results: Six veterans described exposure to a non-morally injurious traumatic event, 15 reported experiencing a PMIE, and 9 described exposure to a 'mixed' event which was simultaneously morally injurious and traumatic. Veterans who encountered a PMIE described experiencing moral dissonance, or a clash between concurrently held sets of values (e.g. military values versus civilian values), which provoked considerable psychological distress. Veterans' cognitions and responses were found to differ following a PMIE compared to a traumatic, but not PMIE, which could have negative implications for daily functioning. Several risk and protective factors for experiencing distress following a PMIE were described. Conclusions: This study provides some of the first evidence that events experienced by UK veterans can simultaneously be morally injurious and traumatic or life-threatening as well as highlighting the process by which moral injury may occur in UK veterans. These findings illustrate the need to examine effective pathways for prevention and intervention for veterans who have experienced a morally injurious event.

Antecedentes: La exposición a un potencial evento moralmente perjudicial (PMIE por sus siglas en inglés) se ha asociado con un rango de resultados adversos en salud mental. Sin embargo, como las consecuencias psicológicas seguidas de PMIEs comparadas a aquellas encontradas después de un evento traumático, pero no un PMIE, permanece pobremente comprendido.Objetivo: El objetivo fue explorar cualitativamenbte las respuestas a experiencias de trauma y daño moral de veteranos militares del Reino Unido y el impacto de tales eventos en el bienestar psicológico.Método: Se reclutaron treinta veteranos varones que reportaron exposición a eventos traumáticos y/o moralmente perjudiciales. Se condujeron entrevistas cualitativas semiestructuradas, y los datos fueron analizados usando análisis temáticos.Resultados: Seis veteranos describieron exposición a eventos traumáticos no moralmente perjudiciales, quince reportaron haber experimentado un PMIE, y nueve describieron exposición a un evento 'mixto' el cual fue simultáneamente moralmente perjudicial y traumático. Los veteranos que encontraron una PMIE describieron experimentar disonancia moral, o un choque entre conjuntos de valores mantenidos simultáneamente (ej. Valores militares versus valores civiles), los cuales provocaron sufrimiento psicológico considerable. Se encontraron que las respuestas y cogniciones de los veteranos diferían después de un PMIE comparada con un evento traumático, pero no el PMIE, el cual podría tener implicancias negativas para el funcionamiento diario. Se describieron varios factores de riesgo y protectores por la experimentación de sufrimiento seguido a un PMIE.Conclusiones: este estudio provee algunas de las primeras evidencias que los eventos experimentados por los veteranos del Reino Unido pueden ser simultáneamente moralmente perjudiciales y traumáticos o de amenaza vital así como tambien enfatizar el proceso por el cual el daño moral puede ocurrir en los veteranos del Reino Unido. Estos hallazgos enfatizan la necesidad de examinar las vías efectivas para la prevención e intervención a veteranos que han experimentado un evento moral perjudicial.

Role of the dosR-dosS two-component regulatory system in Mycobacterium tuberculosis virulence in three animal models.

The Mycobacterium tuberculosis dosR gene (Rv3133c) is part of an operon, Rv3134c-Rv3132c, and encodes a response regulator that has been shown to be upregulated by hypoxia and other in vitro stress conditions and may be important for bacterial survival within granulomatous lesions found in tuberculosis. DosR is activated in response to hypoxia and nitric oxide by DosS (Rv3132c) or DosT (Rv2027c). We compared the virulence levels of an M. tuberculosis dosR-dosS deletion mutant (DeltadosR-dosS [DeltadosR-S]), a dosR-complemented strain, and wild-type H37Rv in rabbits, guinea pigs, and mice infected by the aerosol route and in a mouse hollow-fiber model that may mimic in vivo granulomatous conditions. In the mouse and the guinea pig models, the DeltadosR-S mutant exhibited a growth defect. In the rabbit, the DeltadosR-S mutant did not replicate more than the wild type. In the hollow-fiber model, the mutant phenotype was not different from that of the wild-type strain. Our analyses reveal that the dosR and dosS genes are required for full virulence and that there may be differences in the patterns of attenuation of this mutant between the animal models studied.

Dynamic respiratory muscle function in late-onset Pompe disease.

Maximal inspiratory pressure (PIMAX) reflects inspiratory weakness in late-onset Pompe disease (LOPD). However, static pressure tests may not reveal specific respiratory muscle adaptations to disruptions in breathing. We hypothesized that dynamic respiratory muscle functional tests reflect distinct ventilatory compensations in LOPD. We evaluated LOPD (n = 7) and healthy controls (CON, n = 7) during pulmonary function tests, inspiratory endurance testing, dynamic kinematic MRI of the thorax, and ventilatory adjustments to single-breath inspiratory loads (inspiratory load compensation, ILC). We observed significantly lower static and dynamic respiratory function in LOPD. PIMAX, spirometry, endurance time, and maximal diaphragm descent were significantly correlated. During single-breath inspiratory loads, inspiratory time and airflow acceleration increased to preserve volume, and in LOPD, the response magnitudes correlated to maximal chest wall kinematics. The results indicate that changes in diaphragmatic motor function and strength among LOPD subjects could be detected through dynamic respiratory testing. We concluded that neuromuscular function significantly influenced breathing endurance, timing and loading compensations.

Tuberculous granulomas are hypoxic in guinea pigs, rabbits, and nonhuman primates.

Understanding the physical characteristics of the local microenvironment in which Mycobacterium tuberculosis resides is an important goal that may allow the targeting of metabolic processes to shorten drug regimens. Pimonidazole hydrochloride (Hypoxyprobe) is an imaging agent that is bioreductively activated only under hypoxic conditions in mammalian tissue. We employed this probe to evaluate the oxygen tension in tuberculous granulomas in four animal models of disease: mouse, guinea pig, rabbit, and nonhuman primate. Following infusion of pimonidazole into animals with established infections, lung tissues from the guinea pig, rabbit, and nonhuman primate showed discrete areas of pimonidazole adduct formation surrounding necrotic and caseous regions of pulmonary granulomas by immunohistochemical staining. This labeling could be substantially reduced by housing the animal under an atmosphere of 95% O(2). Direct measurement of tissue oxygen partial pressure by surgical insertion of a fiber optic oxygen probe into granulomas in the lungs of living infected rabbits demonstrated that even small (3-mm) pulmonary lesions were severely hypoxic (1.6 +/- 0.7 mm Hg). Finally, metronidazole, which has potent bactericidal activity in vitro only under low-oxygen culture conditions, was highly effective at reducing total-lung bacterial burdens in infected rabbits. Thus, three independent lines of evidence support the hypothesis that hypoxic microenvironments are an important feature of some lesions in these animal models of tuberculosis.

Superoxide dismutase A antigens derived from molecular analysis of sarcoidosis granulomas elicit systemic Th-1 immune responses.

BACKGROUND: Sarcoidosis is an idiopathic granulomatous disease with pathologic and immunologic features similar to tuberculosis. Routine histologic staining and culture fail to identify infectious agents. An alternative means for investigating a role of infectious agents in human pathogenesis involves molecular analysis of pathologic tissues for microbial nucleic acids, as well as recognition of microbial antigens by the host immune system. Molecular analysis for superoxide dismutase A (sodA) allows speciation of mycobacteria. SodA is an abundantly secreted virulence factor that generates cellular immune responses in infected hosts. The purpose of this study is to investigate if target antigens of the sarcoidosis immune response can be identified by molecular analysis of sarcoidosis granulomas. METHODS: We detected sodA amplicons in 12 of 17 sarcoidosis specimens, compared to 2 of 16 controls (p = 0.001, two-tailed Fisher's exact test), and 3 of 3 tuberculosis specimens (p = 0.54). Analysis of the amplicons revealed sequences identical to M. tuberculosis (MTB) complex, as well as sequences which were genetically divergent. Using peripheral blood mononuclear cells (PBMC) from 12 of the 17 sarcoidosis subjects, we performed enzyme-linked immunospot assay (ELISPOT) to assess for immune recognition of MTB sodA peptides, along with PBMC from 26 PPD- healthy volunteers, and 11 latent tuberculosis subjects. RESULTS: Six of 12 sarcoidosis subjects recognized the sodA peptides, compared to one of 26 PPD- controls (p = 0.002), and 6/11 PPD+ subjects (p = .68). Overall, 10 of the 12 sarcoidosis subjects from whom we obtained PBMC and archival tissue possessed molecular or immunologic evidence for sodA. CONCLUSION: Dual molecular and immunologic analysis increases the ability to find infectious antigens. The detection of Th-1 immune responses to sodA peptides derived from molecular analysis of sarcoidosis granulomas reveals that these are among the target antigens contributing to sarcoidosis granulomatous inflammation.