Vaccine Efficacy of ALVAC-HIV and Bivalent Subtype C gp120-MF59 in Adults.

BACKGROUND: A safe, effective vaccine is essential to eradicating human immunodeficiency virus (HIV) infection. A canarypox-protein HIV vaccine regimen (ALVAC-HIV plus AIDSVAX B/E) showed modest efficacy in reducing infection in Thailand. An analogous regimen using HIV-1 subtype C virus showed potent humoral and cellular responses in a phase 1-2a trial in South Africa. Efficacy data and additional safety data were needed for this regimen in a larger population in South Africa. METHODS: In this phase 2b-3 trial, we randomly assigned 5404 adults without HIV-1 infection to receive the vaccine (2704 participants) or placebo (2700 participants). The vaccine regimen consisted of injections of ALVAC-HIV at months 0 and 1, followed by four booster injections of ALVAC-HIV plus bivalent subtype C gp120-MF59 adjuvant at months 3, 6, 12, and 18. The primary efficacy outcome was the occurrence of HIV-1 infection from randomization to 24 months. RESULTS: In January 2020, prespecified criteria for nonefficacy were met at an interim analysis; further vaccinations were subsequently halted. The median age of the trial participants was 24 years; 70% of the participants were women. The incidence of adverse events was similar in the vaccine and placebo groups. During the 24-month follow-up, HIV-1 infection was diagnosed in 138 participants in the vaccine group and in 133 in the placebo group (hazard ratio, 1.02; 95% confidence interval, 0.81 to 1.30; P = 0.84). CONCLUSIONS: The ALVAC-gp120 regimen did not prevent HIV-1 infection among participants in South Africa despite previous evidence of immunogenicity. (HVTN 702 ClinicalTrials.gov number, NCT02968849.).

Analysis of the HIV Vaccine Trials Network 702 Phase 2b-3 HIV-1 Vaccine Trial in South Africa Assessing RV144 Antibody and T-Cell Correlates of HIV-1 Acquisition Risk.

BACKGROUND: The ALVAC/gp120 + MF59 vaccines in the HIV Vaccine Trials Network (HVTN) 702 efficacy trial did not prevent human immunodeficiency virus-1 (HIV-1) acquisition. Vaccine-matched immunological endpoints that were correlates of HIV-1 acquisition risk in RV144 were measured in HVTN 702 and evaluated as correlates of HIV-1 acquisition. METHODS: Among 1893 HVTN 702 female vaccinees, 60 HIV-1-seropositive cases and 60 matched seronegative noncases were sampled. HIV-specific CD4+ T-cell and binding antibody responses were measured 2 weeks after fourth and fifth immunizations. Cox proportional hazards models assessed prespecified responses as predictors of HIV-1 acquisition. RESULTS: The HVTN 702 Env-specific CD4+ T-cell response rate was significantly higher than in RV144 (63% vs 40%, P = .03) with significantly lower IgG binding antibody response rate and magnitude to 1086.C V1V2 (67% vs 100%, P < .001; Pmag < .001). Although no significant univariate associations were observed between any T-cell or binding antibody response and HIV-1 acquisition, significant interactions were observed (multiplicity-adjusted P ≤.03). Among vaccinees with high IgG A244 V1V2 binding antibody responses, vaccine-matched CD4+ T-cell endpoints associated with decreased HIV-1 acquisition (estimated hazard ratios = 0.40-0.49 per 1-SD increase in CD4+ T-cell endpoint). CONCLUSIONS: HVTN 702 and RV144 had distinct immunogenicity profiles. However, both identified significant correlations (univariate or interaction) for IgG V1V2 and polyfunctional CD4+ T cells with HIV-1 acquisition. Clinical Trials Registration . NCT02968849.

Emerging roles for IL-6 family cytokines as positive and negative regulators of ectopic lymphoid structures.

IL-6 family cytokines display broad effects in haematopoietic and non-haematopoietic cells that regulate immune homeostasis, host defence, haematopoiesis, development, reproduction and wound healing. Dysregulation of these activities places this cytokine family as important mediators of autoimmunity, chronic inflammation and cancer. In this regard, ectopic lymphoid structures (ELS) are a pathological hallmark of many tissues affected by chronic disease. These inducible lymphoid aggregates form compartmentalised T cell and B cell zones, germinal centres, follicular dendritic cell networks and high endothelial venules, which are defining qualities of peripheral lymphoid organs. Accordingly, ELS can support local antigen-specific responses to self-antigens, alloantigens, pathogens and tumours. ELS often correlate with severe disease progression in autoimmune conditions, while tumour-associated ELS are associated with enhanced anti-tumour immunity and a favourable prognosis in cancer. Here, we discuss emerging roles for IL-6 family cytokines as regulators of ELS development, maintenance and activity and consider how modulation of these activities has the potential to aid the successful treatment of autoimmune conditions and cancers where ELS feature.

"SILVAMP TB LAM" Rapid Urine Tuberculosis Test Predicts Mortality in Patients Hospitalized With Human Immunodeficiency Virus in South Africa.

Reducing diagnostic delay is key toward decreasing tuberculosis-associated deaths in people living with human immunodeficiency virus. In tuberculosis patients with retrospective urine testing, the point-of-care Fujifilm SILVAMP TB LAM (FujiLAM) could have rapidly diagnosed tuberculosis in up to 89% who died. In FujiLAM negative patients, the probability of 12-week survival was 86-97%.

Early antituberculosis drug exposure in hospitalized patients with human immunodeficiency virus-associated tuberculosis.

AIMS: Patients hospitalized at the time of human immunodeficiency virus-associated tuberculosis (HIV-TB) diagnosis have high early mortality. We hypothesized that compared to outpatients, there would be lower anti-TB drug exposure in hospitalized HIV-TB patients, and amongst hospitalized patients exposure would be lower in patients who die or have high lactate (a sepsis marker). METHODS: We performed pharmacokinetic sampling in hospitalized HIV-TB patients and outpatients. Plasma rifampicin, isoniazid and pyrazinamide concentrations were measured in samples collected predose and at 1, 2.5, 4, 6 and 8 hours on the third day of standard anti-TB therapy. Twelve-week mortality was ascertained for inpatients. Noncompartmental pharmacokinetic analysis was performed. RESULTS: Pharmacokinetic data were collected in 59 hospitalized HIV-TB patients and 48 outpatients. Inpatient 12-week mortality was 11/59 (19%). Rifampicin, isoniazid and pyrazinamide exposure was similar between hospitalized and outpatients (maximum concentration [Cmax ]: 7.4 vs 8.3 µg mL-1 , P = .223; 3.6 vs 3.5 µg mL-1 , P = .569; 50.1 vs 46.8 µg mL-1 , P = .081; area under the concentration-time curve from 0 to 8 hours: 41.0 vs 43.8 mg h L-1 , P = 0.290; 13.5 vs 12.4 mg h L-1 , P = .630; 316.5 vs 292.2 mg h L-1 , P = .164, respectively) and not lower in inpatients who died. Rifampicin and isoniazid Cmax were below recommended ranges in 61% and 39% of inpatients and 44% and 35% of outpatients. Rifampicin exposure was higher in patients with lactate >2.2 mmol L-1 . CONCLUSION: Mortality in hospitalized HIV-TB patients was high. Early anti-TB drug exposure was similar to outpatients and not lower in inpatients who died. Rifampicin and isoniazid Cmax were suboptimal in 61% and 39% of inpatients and rifampicin exposure was higher in patients with high lactate. Treatment strategies need to be optimized to improve survival.

12 tips for effective questioning in medical education.

Questioning is one of the most frequently used and powerful teaching strategies across levels and settings in medical education. Although the concept of asking questions may seem like a simple practice, many medical educators lack pedagogical training. When effectively executed, questioning can elicit positive outcomes in learner participation, concentration, and understanding of content. When used incorrectly, questioning can leave learners feeling singled out and not in a position to learn, or worse - threatened or humiliated. There is a lot of literature in medical education about what ineffective questioning looks like, but little about how to enact effective questioning, such as what kind of questions should be asked and how to design those questions to improve learning. The following twelve tips will help medical educators be purposeful and effective as they plan, ask, and analyze questions in classroom or clinical settings.

When did "teaching" become a taboo word for clinician educators?

In our recent work with clinician educators leading UME small groups, we noticed a phenomenon - many clinician educators are saying they don't teach, they just facilitate. Medical schools have moved to a new model of curriculum that integrates basic, clinical, and social science concepts. As curriculum shifts, so too must the definition and role of a teacher in medical education. The purpose of this article is to explore the work of current clinician educators and to encourage clinician educators to embrace their teaching role and seek educator development opportunities. In this article, we explore the history of how and why the word "teaching" became taboo for clinician educators. Then we explain the current state of the complex work of teaching for today's clinician educators and its implications for educator development.

Clinical, microbiologic, and immunologic determinants of mortality in hospitalized patients with HIV-associated tuberculosis: A prospective cohort study.

BACKGROUND: In high-burden settings, case fatality rates are reported to be between 11% and 32% in hospitalized patients with HIV-associated tuberculosis, yet the underlying causes of mortality remain poorly characterized. Understanding causes of mortality could inform the development of novel management strategies to improve survival. We aimed to assess clinical and microbiologic determinants of mortality and to characterize the pathophysiological processes underlying death by evaluating host soluble inflammatory mediators and determined the relationship between these mediators and death as well as biomarkers of disseminated tuberculosis. METHODS AND FINDINGS: Adult patients with HIV hospitalized with a new diagnosis of HIV-associated tuberculosis were enrolled in Cape Town between 2014 and 2016. Detailed tuberculosis diagnostic testing was performed. Biomarkers of tuberculosis dissemination and host soluble inflammatory mediators at baseline were assessed. Of 682 enrolled participants, 576 with tuberculosis (487/576, 84.5% microbiologically confirmed) were included in analyses. The median age was 37 years (IQR = 31-43), 51.2% were female, and the patients had advanced HIV with a median cluster of differentiation 4 (CD4) count of 58 cells/L (IQR = 21-120) and a median HIV viral load of 5.1 log10 copies/mL (IQR = 3.3-5.7). Antituberculosis therapy was initiated in 566/576 (98.3%) and 487/576 (84.5%) started therapy within 48 hours of enrolment. Twelve-week mortality was 124/576 (21.5%), with 46/124 (37.1%) deaths occurring within 7 days of enrolment. Clinical and microbiologic determinants of mortality included disseminated tuberculosis (positive urine lipoarabinomannan [LAM], urine Xpert MTB/RIF, or tuberculosis blood culture in 79.6% of deaths versus 60.7% of survivors, p = 0.001), sepsis syndrome (high lactate in 50.8% of deaths versus 28.9% of survivors, p < 0.001), and rifampicin-resistant tuberculosis (16.9% of deaths versus 7.2% of survivors, p = 0.002). Using non-supervised two-way hierarchical cluster and principal components analyses, we describe an immune profile dominated by mediators of the innate immune system and chemotactic signaling (interleukin-1 receptor antagonist [IL-1Ra], IL-6, IL-8, macrophage inflammatory protein-1 beta [MIP-1ß]/C-C motif chemokine ligand 4 [CCL4], interferon gamma-induced protein-10 [IP-10]/C-X-C motif chemokine ligand 10 [CXCL10], MIP-1 alpha [MIP-1α]/CCL3), which segregated participants who died from those who survived. This immune profile was associated with mortality in a Cox proportional hazards model (adjusted hazard ratio [aHR] = 2.2, 95%CI = 1.9-2.7, p < 0.001) and with detection of biomarkers of disseminated tuberculosis. Clinicians attributing causes of death identified tuberculosis as a cause or one of the major causes of death in 89.5% of cases. We did not perform longitudinal sampling and did not have autopsy-confirmed causes of death. CONCLUSIONS: In this study, we did not identify a major contribution from coinfections to these deaths. Disseminated tuberculosis, sepsis syndrome, and rifampicin resistance were associated with mortality. An immune profile dominated by mediators of the innate immune system and chemotactic signaling was associated with both tuberculosis dissemination and mortality. These findings provide pathophysiologic insights into underlying causes of mortality and could be used to inform the development of novel treatment strategies and to develop methods to risk stratify patients to appropriately target novel interventions. Causal relationships cannot be established from this study.

HIV-Associated Mycobacterium tuberculosis Bloodstream Infection Is Underdiagnosed by Single Blood Culture.

We assessed the additional diagnostic yield for Mycobacterium tuberculosis bloodstream infection (BSI) by doing more than one tuberculosis (TB) blood culture from HIV-infected inpatients. In a retrospective analysis of two cohorts based in Cape Town, South Africa, 72/99 (73%) patients with M. tuberculosis BSI were identified by the first of two blood cultures during the same admission, with 27/99 (27%; 95% confidence interval [CI], 18 to 36%) testing negative on the first culture but positive on the second. In a prospective evaluation of up to 6 blood cultures over 24 h, 9 of 14 (65%) patients with M. tuberculosis BSI had M. tuberculosis grow on their first blood culture; 3 more patients (21%) were identified by a second independent blood culture at the same time point, and the remaining 2 were diagnosed only on the 4th and 6th blood cultures. Additional blood cultures increase the yield for M. tuberculosis BSI, similar to what is reported for nonmycobacterial BSI.

Hemostatic Changes Associated With Increased Mortality Rates in Hospitalized Patients With HIV-Associated Tuberculosis: A Prospective Cohort Study.

BACKGROUND: Mortality rates remain high for human immunodeficiency virus (HIV)-associated tuberculosis, and our knowledge of contributing mechanisms is limited. We aimed to determine whether hemostatic changes in HIV-tuberculosis were associated with mortality or decreased survival time and the contribution of mycobacteremia to these effects. METHODS: We conducted a prospective study in Khayelitsha, South Africa, in hospitalized HIV-infected patients with CD4 cell counts <350/µL and microbiologically proved tuberculosis. HIV-infected outpatients without tuberculosis served as controls. Plasma biomarkers reflecting activation of procoagulation and anticoagulation, fibrinolysis, endothelial cell activation, matricellular protein release, and tissue damage were measured at admission. Cox proportional hazard models were used to assess variables associated with 12-week mortality rates. RESULTS: Of 59 patients with HIV-tuberculosis, 16 (27%) died after a median of 12 days (interquartile range, 0-24 days); 29 (64%) of the 45 not receiving anticoagulants fulfilled criteria for disseminated intravascular coagulation. Decreased survival time was associated with higher concentrations of markers of fibrinolysis, endothelial activation, matricellular protein release, and tissue damage and with decreased concentrations for markers of anticoagulation. In patients who died, coagulation factors involved in the common pathway were depleted (factor II, V, X), which corresponded to increased plasma clotting times. Mycobacteremia modestly influenced hemostatic changes without affecting mortality. CONCLUSIONS: Patients with severe HIV-tuberculosis display a hypercoagulable state and activation of the endothelium, which is associated with mortality.

Mortality in Severe Human Immunodeficiency Virus-Tuberculosis Associates With Innate Immune Activation and Dysfunction of Monocytes.

Background: Case fatality rates among hospitalized patients diagnosed with human immunodeficiency virus (HIV)-associated tuberculosis remain high, and tuberculosis mycobacteremia is common. Our aim was to define the nature of innate immune responses associated with 12-week mortality in this population. Methods: This prospective cohort study was conducted at Khayelitsha Hospital, Cape Town, South Africa. Hospitalized HIV-infected tuberculosis patients with CD4 counts <350 cells/µL were included; tuberculosis blood cultures were performed in all. Ambulatory HIV-infected patients without active tuberculosis were recruited as controls. Whole blood was stimulated with Escherichia coli derived lipopolysaccharide, heat-killed Streptococcus pneumoniae, and Mycobacterium tuberculosis. Biomarkers of inflammation and sepsis, intracellular (flow cytometry) and secreted cytokines (Luminex), were assessed for associations with 12-week mortality using Cox proportional hazard models. Second, we investigated associations of these immune markers with tuberculosis mycobacteremia. Results: Sixty patients were included (median CD4 count 53 cells/µL (interquartile range [IQR], 22-132); 16 (27%) died after a median of 12 (IQR, 0-24) days. Thirty-one (52%) grew M. tuberculosis on blood culture. Mortality was associated with higher concentrations of procalcitonin, activation of the innate immune system (% CD16+CD14+ monocytes, interleukin-6, tumour necrosis factor-ɑ and colony-stimulating factor 3), and antiinflammatory markers (increased interleukin-1 receptor antagonist and lower monocyte and neutrophil responses to bacterial stimuli). Tuberculosis mycobacteremia was not associated with mortality, nor with biomarkers of sepsis. Conclusions: Twelve-week mortality was associated with greater pro- and antiinflammatory alterations of the innate immune system, similar to those reported in severe bacterial sepsis.

Stepping into the future of behavioral health: Opportunities, challenges, and possibilities.

To improve our practices of today and to overcome the problems that confront us at present, the behavioral health field must anticipate what the future is likely to bring. Such foresight is particularly important right now because of the changes and disruptions that have occurred due to the COVID-19 pandemic over the past 3 years. We begin by recounting major developments in the mental health field since the founding of the National Institute of Mental Health (NIMH) more than 70 years ago, including some firsthand experiences of the senior author. Subsequently, we review the present situation of the behavioral health field with particular attention to the effects of COVID-19 and our current workforce crisis. Likely future scenarios are then described in two principal domains: clinical developments and community developments. Clinical developments over the next decade are likely to include much more self-directed, integrated, virtual, and personalized care. Community developments are likely to include self-empowering community interventions, better population health management, new collaborations with public health, and continued efforts to address stigma. To increase the probability of the future described, several facilitators are also outlined to create the conditions under which expected future developments can be expected to flourish. These include addressing the behavioral health workforce crisis, modernizing behavioral health clinical training, fostering opportunities for cross-sector work, fostering opportunities to engage in policy issues, creating centers of excellence for innovation in behavioral health, and fostering an integrated framework that undergirds behavioral health. The future we have described holds considerable promise for the behavioral health field and for all who suffer from mental or substance use conditions. We must begin working today to turn this potential future into tomorrow's reality. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Looking Toward the Future of Integrated Care: History, Developments, and Opportunities.

For almost five decades, the development and implementation of integrated care-the simultaneous combination of primary care with mental health and substance use care-has been a major challenge for the behavioral health care field. Integrated care is exceptionally important because many people with behavioral health conditions also have chronic physical health conditions. Early research findings in the mid-1980s showed that persons with mental illness are likely to develop chronic physical conditions earlier and more severely than other people. These findings precipitated efforts to understand this problem and to develop further appropriate integrated care solutions. Subsequently, the US Surgeon General made care integration a major focus of his landmark 1999 Report on Mental Health, as did the 2008 Mental Health Parity and Addiction Equity Act and the 2010 Patient Protection and Affordable Care Act. However, it was not until 2014, and later, that integrated care actually began to be implemented more broadly. This article reviews these major developmental milestones, examines current activities, and explores likely developments over the next several years. Major current issues include the response to the COVID-19 pandemic, adjusting to its effects on the behavioral health care workforce, and the growing realization that behavioral health care must address the social determinants of life. Likely developments over the next several years will include devising ways to address our workforce crisis, developing effective community interventions, and implementing population health management strategies; implementing the CMS Innovation in Behavioral Health Model; improving reimbursement practices; and exploring the potential of AI for integrated care. Implications for future service organization and training of behavioral health care providers also are discussed. Granted the severity of the current workforce crisis in behavioral health care, urgent efforts are needed to advance the deployment of integrated care in the short-term future.

CompARE: study protocol for a phase III randomised controlled platform trial comparing alternative regimens for escalating treatment of intermediate and high-risk oropharyngeal cancer.

BACKGROUND: Patients with intermediate and high-risk oropharyngeal cancer (OPC) have poorer response to standard treatment and poorer overall survival compared to low-risk OPC. CompARE is designed to test alternative approaches to intensified treatment for these patients to improve survival. METHODS: CompARE is a pragmatic phase III, open-label, multicenter randomised controlled trial with an adaptive multi-arm, multi-stage design and an integrated QuinteT Recruitment Intervention. Eligible OPC patients include those with human papillomavirus (HPV) negative, T1-T4, N1-N3 or T3-4, N0, or HPV positive N3, T4, or current smokers (or ≥ 10 pack years previous smoking history) with T1-T4, N2b-N3. CompARE was originally designed with four arms (one control [arm 1] and three experimental: arm 2-induction chemotherapy followed by arm 1; arm 3-dose-escalated radiotherapy plus concomitant cisplatin; and arm 4-resection of primary followed by arm 1). The three original experimental arms have been closed to recruitment and a further experimental arm opened (arm 5-induction durvalumab followed by arm 1 and then adjuvant durvalumab). Currently recruiting are arm 1 (control): standard treatment of 3-weekly cisplatin 100 mg/m2 or weekly 40 mg/m2 with intensity-modulated radiotherapy using 70 Gy in 35 fractions ± neck dissection determined by clinical and radiological assessment 3 months post-treatment, and arm 5 (intervention): one cycle of induction durvalumab 1500 mg followed by standard treatment then durvalumab 1500 mg every 4 weeks for a total of 6 months. The definitive and interim primary outcome measures are overall survival time and event-free survival (EFS) time, respectively. Secondary outcome measures include quality of life, toxicity, swallowing outcomes, feeding tube incidence, surgical complication rates, and cost-effectiveness. The design anticipates that after approximately 7 years, 84 required events will have occurred to enable analysis of the definitive primary outcome measure for this comparison. Planned interim futility analyses using EFS will also be performed. DISCUSSION: CompARE is designed to be efficient and cost-effective in response to new data, emerging new treatments or difficulties, with the aim of bringing new treatment options for these patients. TRIAL REGISTRATION: ISRCTN ISRCTN41478539 . Registered on 29 April 2015.

Restoration of a paraventricular thalamo-accumbal behavioral suppression circuit prevents reinstatement of heroin seeking.

Lack of behavioral suppression typifies substance use disorders, yet the neural circuit underpinnings of drug-induced behavioral disinhibition remain unclear. Here, we employ deep-brain two-photon calcium imaging in heroin self-administering mice, longitudinally tracking adaptations within a paraventricular thalamus to nucleus accumbens behavioral inhibition circuit from the onset of heroin use to reinstatement. We find that select thalamo-accumbal neuronal ensembles become profoundly hypoactive across the development of heroin seeking and use. Electrophysiological experiments further reveal persistent adaptations at thalamo-accumbal parvalbumin interneuronal synapses, whereas functional rescue of these synapses prevents multiple triggers from initiating reinstatement of heroin seeking. Finally, we find an enrichment of µ-opioid receptors in output- and cell-type-specific paraventricular thalamic neurons, which provide a mechanism for heroin-induced synaptic plasticity and behavioral disinhibition. These findings reveal key circuit adaptations that underlie behavioral disinhibition in opioid dependence and further suggest that recovery of this system would reduce relapse susceptibility.

Corticostriatal ensemble dynamics across heroin self-administration to reinstatement.

Corticostriatal projection neurons from prelimbic medial prefrontal cortex to the nucleus accumbens core critically regulate drug-seeking behaviors, yet the underlying encoding dynamics whereby these neurons contribute to drug seeking remain elusive. Here we use two-photon calcium imaging to visualize the activity of corticostriatal neurons in mice from the onset of heroin use to relapse. We find that the activity of these neurons is highly heterogeneous during heroin self-administration and seeking, with at least 8 distinct neuronal ensembles that display both excitatory and inhibitory encoding dynamics. These neuronal ensembles are particularly apparent during relapse, where excitatory responses are amplified compared to heroin self-administration. Moreover, we find that optogenetic inhibition of corticostriatal projection neurons attenuates heroin seeking regardless of the relapse trigger. Our results reveal the precise corticostriatal activity dynamics underlying drug-seeking behaviors and support a key role for this circuit in mediating relapse to drug seeking.

Scoping review on Physical Health Conditions in Irish Travellers (Mincéiri).

OBJECTIVE: The objective of this scoping review was to collate physical health conditions in Mincéiri-Irish Travellers. DESIGN: Scoping review. SEARCH STRATEGY AND CHARTING METHOD: MEDLINE/PubMed, EMBASE, PEDro, AMED, CINAHL, PsycINFO, SCOPUS as well as reports and grey literature were searched for primary data reporting physical health conditions of Irish Travellers up to 4 April 2023. Data was extracted, described and organised meaningfully into tables according to reported physical health conditions. ELIGIBILITY CRITERIA: The population was Travellers. The concept referred to physical health conditions. The context was Irish Travellers based in any location or setting. Exclusion criteria was data/research other than primary data relating to physical health conditions of Irish Travellers. RESULTS: From 198 citations generated from the database search, 11 unique studies (20 reports) were included in this scoping review, including n=7397 participants. Driven by the data, physical health conditions were categorised into cardiovascular diseases, respiratory diseases, injuries/musculoskeletal/arthritic disorders, genetic disorders and gut/bowel conditions. This review showed that the metabolic syndrome, asthma, bronchitis, tuberculosis and intentional injuries were 2-3 times more prevalent in Irish Travellers compared with the background population. Genetic conditions were also described in a proportion of Travellers. CONCLUSIONS: Overall, Irish Travellers experience a disproportionate burden of physical health conditions compared with background populations. Healthcare providers need to be aware of the unique physical health burden experienced by many Irish Travellers. Multifaceted strategies are needed to improve the health profile of this vulnerable and marginalised group.

A machine learning framework for the quantification of experimental uveitis in murine OCT.

This paper presents methods for the detection and assessment of non-infectious uveitis, a leading cause of vision loss in working age adults. In the first part, we propose a classification model that can accurately predict the presence of uveitis and differentiate between different stages of the disease using optical coherence tomography (OCT) images. We utilize the Grad-CAM visualization technique to elucidate the decision-making process of the classifier and gain deeper insights into the results obtained. In the second part, we apply and compare three methods for the detection of detached particles in the retina that are indicative of uveitis. The first is a fully supervised detection method, the second is a marked point process (MPP) technique, and the third is a weakly supervised segmentation that produces per-pixel masks as output. The segmentation model is used as a backbone for a fully automated pipeline that can segment small particles of uveitis in two-dimensional (2-D) slices of the retina, reconstruct the volume, and produce centroids as points distribution in space. The number of particles in retinas is used to grade the disease, and point process analysis on centroids in three-dimensional (3-D) shows clustering patterns in the distribution of the particles on the retina.

Interplay between systemic inflammation, anemia, and mycobacterial dissemination and its impact on mortality in TB-associated HIV: a prospective cohort study.

Introduction: Anemia frequently affects people living with HIV (PLHIV). Nevertheless, the impact of anemia on treatment outcomes of patients with HIV-associated tuberculosis (TB) and the underlying molecular profiles are not fully characterized. The aim of this study was to investigate the interplay between anemia, the systemic inflammatory profile, dissemination of TB and death in HIV-TB patients in an ad hoc analysis of results from a prospective cohort study. Methods: 496 hospitalized PLHIV ≥18 years old, with CD4 count <350 cells/µL and high clinical suspicion of new TB infection were enrolled in Cape Town between 2014-2016. Patients were classified according to anemia severity in non-anemic, mild, moderate, or severe anemia. Clinical, microbiologic, and immunologic data were collected at baseline. Hierarchical cluster analysis, degree of inflammatory perturbation, survival curves and C-statistics analyses were performed. Results: Through the analysis of several clinical and laboratory parameters, we observed that those with severe anemia exhibited greater systemic inflammation, characterized by high concentrations of IL-8, IL-1RA and IL-6. Furthermore, severe anemia was associated with a higher Mtb dissemination score and a higher risk of death, particularly within 7 days of admission. Most of the patients who died had severe anemia and had a more pronounced systemic inflammatory profile. Discussion: Therefore, the results presented here reveal that severe anemia is associated with greater TB dissemination and increased risk of death in PLHIV. Early identification of such patients through measurement of Hb levels may drive closer monitoring to reduce mortality. Future investigations are warranted to test whether early interventions impact survival of this vulnerable population.