BCG-mediated protection against M. tuberculosis is sustained post-malaria infection independent of parasite virulence.

Tuberculosis (TB) and malaria remain serious threats to global health. Bacillus Calmette-Guerin (BCG), the only licensed vaccine against TB protects against severe disseminated forms of TB in infants but shows poor efficacy against pulmonary TB in adults. Co-infections have been reported as one of the factors implicated in vaccine inefficacy. Given the geographical overlap of malaria and TB in areas where BCG vaccination is routinely administered, we hypothesized that virulence-dependent co-infection with Plasmodium species could alter the BCG-specific immune responses thus resulting in failure to protect against Mycobacterium tuberculosis. We compared virulent Plasmodium berghei and non-virulent Plasmodium chabaudi, their effects on B cells, effector and memory T cells, and the outcome on BCG-induced efficacy against M. tuberculosis infection. We demonstrate that malaria co-infection modulates both B- and T-cell immune responses but does not significantly alter the ability of the BCG vaccine to inhibit the growth of M. tuberculosis irrespective of parasite virulence. This malaria-driven immune regulation may have serious consequences in the early clinical trials of novel vaccines, which rely on vaccine-specific T-cell responses to screen novel vaccines for progression to the more costly vaccine efficacy trials.

Peripheral Blood Mucosal-Associated Invariant T Cells in Tuberculosis Patients and Healthy Mycobacterium tuberculosis-Exposed Controls.

BACKGROUND: In human blood, mucosal-associated invariant T (MAIT) cells are abundant T cells that recognize antigens presented on non-polymorphic major histocompatibility complex-related 1 (MR1) molecules. The MAIT cells are activated by mycobacteria, and prior human studies indicate that blood frequencies of MAIT cells, defined by cell surface markers, decline during tuberculosis (TB) disease, consistent with redistribution to the lungs. METHODS: We tested whether frequencies of blood MAIT cells were altered in patients with TB disease relative to healthy Mycobacterium tuberculosis-exposed controls from Peru and South Africa. We quantified their frequencies using MR1 tetramers loaded with 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil. RESULTS: Unlike findings from prior studies, frequencies of blood MAIT cells were similar among patients with TB disease and latent and uninfected controls. In both cohorts, frequencies of MAIT cells defined by MR1-tetramer staining and coexpression of CD161 and the T-cell receptor alpha variable gene TRAV1-2 were strongly correlated. Disease severity captured by body mass index or TB disease transcriptional signatures did not correlate with MAIT cell frequencies in patients with TB. CONCLUSIONS: Major histocompatibility complex (MHC)-related 1-restrictied MAIT cells are detected at similar levels with tetramers or surface markers. Unlike MHC-restricted T cells, blood frequencies of MAIT cells are poor correlates of TB disease but may play a role in pathophysiology.

A Review of Murine Cytomegalovirus as a Model for Human Cytomegalovirus Disease-Do Mice Lie?

Since murine cytomegalovirus (MCMV) was first described in 1954, it has been used to model human cytomegalovirus (HCMV) diseases. MCMV is a natural pathogen of mice that is present in wild mice populations and has been associated with diseases such as myocarditis. The species-specific nature of HCMV restricts most research to cell culture-based studies or to the investigation of non-invasive clinical samples, which may not be ideal for the study of disseminated disease. Initial MCMV research used a salivary gland-propagated virus administered via different routes of inoculation into a variety of mouse strains. This revealed that the genetic background of the laboratory mice affected the severity of disease and altered the extent of subsequent pathology. The advent of genetically modified mice and viruses has allowed new aspects of disease to be modeled and the opportunistic nature of HCMV infection to be confirmed. This review describes the different ways that MCMV has been used to model HCMV diseases and explores the continuing difficulty faced by researchers attempting to model HCMV congenital cytomegalovirus disease using the mouse model.

Correction: Discovery and validation of a prognostic proteomic signature for tuberculosis progression: A prospective cohort study.

[This corrects the article DOI: 10.1371/journal.pmed.1002781.].

Discovery and validation of a prognostic proteomic signature for tuberculosis progression: A prospective cohort study.

BACKGROUND: A nonsputum blood test capable of predicting progression of healthy individuals to active tuberculosis (TB) before clinical symptoms manifest would allow targeted treatment to curb transmission. We aimed to develop a proteomic biomarker of risk of TB progression for ultimate translation into a point-of-care diagnostic. METHODS AND FINDINGS: Proteomic TB risk signatures were discovered in a longitudinal cohort of 6,363 Mycobacterium tuberculosis-infected, HIV-negative South African adolescents aged 12-18 years (68% female) who participated in the Adolescent Cohort Study (ACS) between July 6, 2005 and April 23, 2007, through either active (every 6 months) or passive follow-up over 2 years. Forty-six individuals developed microbiologically confirmed TB disease within 2 years of follow-up and were selected as progressors; 106 nonprogressors, who remained healthy, were matched to progressors. Over 3,000 human proteins were quantified in plasma with a highly multiplexed proteomic assay (SOMAscan). Three hundred sixty-one proteins of differential abundance between progressors and nonprogressors were identified. A 5-protein signature, TB Risk Model 5 (TRM5), was discovered in the ACS training set and verified by blind prediction in the ACS test set. Poor performance on samples 13-24 months before TB diagnosis motivated discovery of a second 3-protein signature, 3-protein pair-ratio (3PR) developed using an orthogonal strategy on the full ACS subcohort. Prognostic performance of both signatures was validated in an independent cohort of 1,948 HIV-negative household TB contacts from The Gambia (aged 15-60 years, 66% female), longitudinally followed up for 2 years between March 5, 2007 and October 21, 2010, sampled at baseline, month 6, and month 18. Amongst these contacts, 34 individuals progressed to microbiologically confirmed TB disease and were included as progressors, and 115 nonprogressors were included as controls. Prognostic performance of the TRM5 signature in the ACS training set was excellent within 6 months of TB diagnosis (area under the receiver operating characteristic curve [AUC] 0.96 [95% confidence interval, 0.93-0.99]) and 6-12 months (AUC 0.76 [0.65-0.87]) before TB diagnosis. TRM5 validated with an AUC of 0.66 (0.56-0.75) within 1 year of TB diagnosis in the Gambian validation cohort. The 3PR signature yielded an AUC of 0.89 (0.84-0.95) within 6 months of TB diagnosis and 0.72 (0.64-0.81) 7-12 months before TB diagnosis in the entire South African discovery cohort and validated with an AUC of 0.65 (0.55-0.75) within 1 year of TB diagnosis in the Gambian validation cohort. Signature validation may have been limited by a systematic shift in signal magnitudes generated by differences between the validation assay when compared to the discovery assay. Further validation, especially in cohorts from non-African countries, is necessary to determine how generalizable signature performance is. CONCLUSIONS: Both proteomic TB risk signatures predicted progression to incident TB within a year of diagnosis. To our knowledge, these are the first validated prognostic proteomic signatures. Neither meet the minimum criteria as defined in the WHO Target Product Profile for a progression test. More work is required to develop such a test for practical identification of individuals for investigation of incipient, subclinical, or active TB disease for appropriate treatment and care.

Four-Gene Pan-African Blood Signature Predicts Progression to Tuberculosis.

Rationale: Contacts of patients with tuberculosis (TB) constitute an important target population for preventive measures because they are at high risk of infection with Mycobacterium tuberculosis and progression to disease.Objectives: We investigated biosignatures with predictive ability for incident TB.Methods: In a case-control study nested within the Grand Challenges 6-74 longitudinal HIV-negative African cohort of exposed household contacts, we employed RNA sequencing, PCR, and the pair ratio algorithm in a training/test set approach. Overall, 79 progressors who developed TB between 3 and 24 months after diagnosis of index case and 328 matched nonprogressors who remained healthy during 24 months of follow-up were investigated.Measurements and Main Results: A four-transcript signature derived from samples in a South African and Gambian training set predicted progression up to two years before onset of disease in blinded test set samples from South Africa, the Gambia, and Ethiopia with little population-associated variability, and it was also validated in an external cohort of South African adolescents with latent M. tuberculosis infection. By contrast, published diagnostic or prognostic TB signatures were predicted in samples from some but not all three countries, indicating site-specific variability. Post hoc meta-analysis identified a single gene pair, C1QC/TRAV27 (complement C1q C-chain / T-cell receptor-α variable gene 27) that would consistently predict TB progression in household contacts from multiple African sites but not in infected adolescents without known recent exposure events.Conclusions: Collectively, we developed a simple whole blood-based PCR test to predict TB in recently exposed household contacts from diverse African populations. This test has potential for implementation in national TB contact investigation programs.

Congenital Central Hypoventilation Syndrome: A Case-Based Learning Opportunity for Neonatal Clinicians.

Congenital central hypoventilation syndrome (CCHS) is a rare and sporadic neurocristopathy characterized by alveolar hypoventilation and autonomic nervous system dysfunction. CCHS manifests quickly after birth, initially as respiratory distress. Mortality risk is estimated at 38 percent, with a median age of death of three months of age. A timely and accurate diagnosis is critical. Genetic testing for PHOX2B gene mutations is necessary to confirm the diagnosis; however, laboratory turnaround time often imposes an additional 7-14-day waiting period on an often anxious family. Neonatal clinicians should recognize that families require disease-specific education, emotional support, and time to rehearse daily caregiving in preparation for discharge. Therefore, this article presents the key clinical, pathophysiologic, and diagnostic factors, as well as a discussion of discharge needs. A case report of an infant, born to parents with no known history of CCHS, is included as a case-based learning opportunity for readers.

Experiences and impact of psychiatric inpatient admissions far away from home: a qualitative study with young people, parents/carers and healthcare professionals.

BACKGROUND: There are significant clinical, policy and societal concerns about the impact on young people (YP), from admission to psychiatric wards far from home. However, research evidence is scarce. AIMS: To investigate the impact of at-distance admissions to general adolescent units, from the perspectives of YP, parents/carers and healthcare professionals (HCPs) including service commissioners, to inform clinical practice, service development and policy. METHOD: Semistructured interviews with purposive samples of YP aged 13-17 years (n=28) and parents/carers (n=19) across five large regions in England, and a national sample of HCPs (n=51), were analysed using a framework approach. RESULTS: There was considerable agreement between YP, parents/carers and HCPs on the challenges of at-distance admissions. YP and parents/carers had limited or no involvement in decision-making processes around admission and highlighted a lack of available information about individual units. Being far from home posed challenges with maintaining home contact and practical/financial challenges for families visiting. HCPs struggled with ensuring continuity of care, particularly around maintaining access to local clinical teams and educational support. However, some YP perceived separation from their local environment as beneficial because it removed them from unhelpful environments. At-distance admissions provided respite for some families struggling to support their child. CONCLUSIONS: At-distance admissions lead to additional distress, uncertainty, compromised continuity of care and educational, financial and other practical difficulties, some of which could be better mitigated. For a minority, there are some benefits from such admissions. CLINICAL IMPLICATIONS: Standardised online information, accessible prior to admission, is needed for all Child and Adolescent Mental Health Services units. Additional practical and financial burden placed on families needs greater recognition and consideration of potential sources of support. Policy changes should incorporate findings that at-distance or adult ward admissions may be preferable in certain circumstances.

Age and sex influence antibody profiles associated with tuberculosis progression.

Antibody features vary with tuberculosis (TB) disease state. Whether clinical variables, such as age or sex, influence associations between Mycobacterium tuberculosis-specific antibody responses and disease state is not well explored. Here we profiled Mycobacterium tuberculosis-specific antibody responses in 140 TB-exposed South African individuals from the Adolescent Cohort Study. We identified distinct response features in individuals progressing to active TB from non-progressing, matched controls. A multivariate antibody score differentially associated with progression (SeroScore) identified progressors up to 2 years before TB diagnosis, earlier than that achieved with the RISK6 transcriptional signature of progression. We validated these antibody response features in the Grand Challenges 6-74 cohort. Both the SeroScore and RISK6 correlated better with risk of TB progression in adolescents compared with adults, and in males compared with females. This suggests that age and sex are important, underappreciated modifiers of antibody responses associated with TB progression.

T cell receptor repertoires associated with control and disease progression following Mycobacterium tuberculosis infection.

Antigen-specific, MHC-restricted αß T cells are necessary for protective immunity against Mycobacterium tuberculosis, but the ability to broadly study these responses has been limited. In the present study, we used single-cell and bulk T cell receptor (TCR) sequencing and the GLIPH2 algorithm to analyze M. tuberculosis-specific sequences in two longitudinal cohorts, comprising 166 individuals with M. tuberculosis infection who progressed to either tuberculosis (n = 48) or controlled infection (n = 118). We found 24 T cell groups with similar TCR-ß sequences, predicted by GLIPH2 to have common TCR specificities, which were associated with control of infection (n = 17), and others that were associated with progression to disease (n = 7). Using a genome-wide M. tuberculosis antigen screen, we identified peptides targeted by T cell similarity groups enriched either in controllers or in progressors. We propose that antigens recognized by T cell similarity groups associated with control of infection can be considered as high-priority targets for future vaccine development.

The Effectiveness of Interventions for the Prevention or Treatment of Paternal Perinatal Anxiety: A Systematic Review.

Background: The worldwide prevalence of paternal perinatal anxiety (PPA) ranges between 3.4% and 25.0% antenatally, and 2.4% and 51.0% postnatally. Experiencing PPA can adversely impact the individual, partners, and infants. Research concerning PPA is lagging and fragmented compared to research for new mothers. Objectives: To establish the effectiveness of prevention or treatment interventions for PPA in adults identifying as male. Data sources: We completed searches of Medline, EMBASE, PsycINFO and Web of Science from inception to 2 December 2021, as well as hand searches of references from relevant papers. Search selection and data extraction: Randomised controlled trials delivering prevention or treatment interventions and reporting anxiety outcomes for new/expectant fathers in the perinatal mental health period were included. Our review follows the PRISMA reporting guidelines. One reviewer independently screened 5170 titles/abstracts; second reviewers screened 50%. Two reviewers independently screened full text, extracted data, and conducted risk of bias assessments. Synthesis: Cochrane's collaboration tool 2 was used to assess quality. Primarily results are synthesised narratively, a post-hoc sub-group analysis was completed on four studies using the same outcome measure. Main results: Twelve of the 5170 studies fulfilled the inclusion criteria. Studies used psychoeducational or practical skills interventions. Interventions mostly involved couple-dyads and three studies assessed PPA as a primary outcome. Included interventions were prevention-based; no treatment interventions were found. Father-only interventions consistently reported a significant reduction of PPA. Conclusions: Systematic searching yielded no treatment interventions, highlighting a substantial gap in the evidence base. Within a limited and heterogenous sample, no studies targeted diagnosed PPA. Evidence suggested father-focused interventions may be effective in preventing PPA, regardless of the intervention delivery mode or intervention content. However, consistency between study design and options within the field are lacking compared to interventions available for mothers.

Prospective multicentre head-to-head validation of host blood transcriptomic biomarkers for pulmonary tuberculosis by real-time PCR.

Background: Sensitive point-of-care screening tests are urgently needed to identify individuals at highest risk of tuberculosis. We prospectively tested performance of host-blood transcriptomic tuberculosis signatures. Methods: Adults without suspicion of tuberculosis were recruited from five endemic South African communities. Eight parsimonious host-blood transcriptomic tuberculosis signatures were measured by microfluidic RT-qPCR at enrolment. Upper respiratory swab specimens were tested with a multiplex bacterial-viral RT-qPCR panel in a subset of participants. Diagnostic and prognostic performance for microbiologically confirmed prevalent and incident pulmonary tuberculosis was tested in all participants at baseline and during active surveillance through 15 months follow-up, respectively. Results: Among 20,207 HIV-uninfected and 963 HIV-infected adults screened; 2923 and 861 were enroled. There were 61 HIV-uninfected (weighted prevalence 1.1%) and 10 HIV-infected (prevalence 1.2%) tuberculosis cases at baseline. Parsimonious signature diagnostic performance was superior among symptomatic (AUCs 0.85-0.98) as compared to asymptomatic (AUCs 0.61-0.78) HIV-uninfected participants. Thereafter, 24 HIV-uninfected and 9 HIV-infected participants progressed to incident tuberculosis (1.1 and 1.0 per 100 person-years, respectively). Among HIV-uninfected individuals, prognostic performance for incident tuberculosis occurring within 6-12 months was higher relative to 15 months. 1000 HIV-uninfected participants were tested for respiratory microorganisms and 413 HIV-infected for HIV plasma viral load; 7/8 signature scores were higher (p < 0.05) in participants with viral respiratory infections or detectable HIV viraemia than those without. Conclusions: Several parsimonious tuberculosis transcriptomic signatures met triage test targets among symptomatic participants, and incipient test targets within 6 months. However, the signatures were upregulated with viral infection and offered poor specificity for diagnosing sub-clinical tuberculosis.

Single-cell profiling reveals distinct subsets of CD14+ monocytes drive blood immune signatures of active tuberculosis.

Introduction: Previous studies suggest that monocytes are an important contributor to tuberculosis (TB)-specific immune signatures in blood. Methods: Here, we carried out comprehensive single-cell profiling of monocytes in paired blood samples of active TB (ATB) patients at diagnosis and mid-treatment, and healthy controls. Results: At diagnosis, ATB patients displayed increased monocyte-to-lymphocyte ratio, increased frequency of CD14+CD16- and intermediate CD14+CD16+ monocytes, and upregulation of interferon signaling genes that significantly overlapped with previously reported blood TB signatures in both CD14+ subsets. In this cohort, we identified additional transcriptomic and functional changes in intermediate CD14+CD16+ monocytes, such as the upregulation of inflammatory and MHC-II genes, and increased capacity to activate T cells, reflecting overall increased activation in this population. Single-cell transcriptomics revealed that distinct subsets of intermediate CD14+CD16+ monocytes were responsible for each gene signature, indicating significant functional heterogeneity within this population. Finally, we observed that changes in CD14+ monocytes were transient, as they were no longer observed in the same ATB patients mid-treatment, suggesting they are associated with disease resolution. Discussion: Together, our study demonstrates for the first time that both intermediate and classical monocytes individually contribute to blood immune signatures of ATB and identifies novel subsets and associated gene signatures that may hold disease relevance.

Assessment of a Multifaceted Approach, Including Frequent PCR Testing, to Mitigation of COVID-19 Transmission at a Residential Historically Black University.

Importance: COVID-19 posed an unprecedented threat to residential colleges in the fall of 2020. While there were mathematical models of COVID-19 transmission, there were no established or tested protocols of COVID-19 testing or mitigation for school administrators to follow. Objective: To investigate the association of a multifaceted COVID-19 mitigation strategy using social, behavioral, and educational interventions and a program of frequent testing with prevalence of disease spread. Design, Setting, and Participants: This cohort study was conducted as a retrospective review of COVID-19 positivity from August 16, 2020, to April 30, 2021, at Delaware State University, a publicly funded historically Black university. Participants included all students, faculty, and staff members with a campus presence. Positivity rates after use of mitigation strategies and testing on campus were compared with those of the surrounding community. Data were analyzed from July through September 2021. Exposures: Mitigation strategies included education and outreach about social distancing, masking, and handwashing, and a COVID-19 testing plan consisted of twice-weekly polymerase chain reaction (PCR) screening using anterior nasal samples (fall and early spring semester) and then saliva-based samples (middle to late spring semester). Main Outcomes and Measures: Cumulative tests, infections, daily quarantine, and isolation residence hall occupancy were measured, and comparisons were made with statewide COVID-19 positivity rates. Results: The campus cohort included 2320 individuals (1575 resident students, 415 nonresident students, and 330 faculty or staff members). There were 1488 (64.1%) women and 832 (35.9%) men; mean (SD) age was 27.5 (12.9) years. During the fall semester, 36 500 COVID-19 PCR tests were performed. Weekly positivity rates ranged from 0 of 372 tests to 16 of 869 tests (1.8%) (mean [SD] positivity rate, 0.5% [0.5%]; 168 positive results and 36 312 negative results). During the same period, statewide positivity ranged from 589 of 25 120 tests (2.3%) to 5405 of 54 596 tests (9.9%) (mean [SD] positivity rate, 4.8% [2.6%]). In the spring semester, 39 045 PCR tests were performed. Weekly positivity rates ranged from 4 of 2028 tests (0.2%) to 36 of 900 tests (4.0%) (mean [SD] positivity rate, 0.8% [0.9%]; 267 positive results and 38 767 negative results). During the same period, statewide positivity ranged from 1336 of 37 254 tests (3.6%) to 3630 of 42 458 tests (8.5%) (mean [SD] positivity rate, 5.1% [1.3%]). Compared with statewide rates, campus positivity rates were mean (SD) 4.4 (2.6) percentage points lower during the fall semester (P < .001) and mean (SD) 5.6 (1.6) percentage points lower during the spring semester (P < .001). Total daily quarantine and isolation residence hall occupancy ranged from 0 to 43 students in the fall and 1 to 47 students during the spring. Conclusions and Relevance: This study found that the combination of campuswide mitigation policies and twice-weekly COVID-19 PCR screening was associated with a significant decrease in COVID-19 positivity at a residential historically Black university campus compared with the surrounding community. Given the socioeconomic demographics of many students at historically Black colleges and universities, keeping these resident campuses open is critical not only to ensure access to educational resources, but also to provide housing and food security.

Randomized Trial of Therapy Dogs Versus Deliberative Coloring (Art Therapy) to Reduce Stress in Emergency Medicine Providers.

OBJECTIVE: Cognitive stress during shift work contributes to burnout in emergency department (ED) workers. We hypothesize that if physicians and nurses interact with a therapy dog for 5 minutes while on ED shift, both their perceived and their manifested stress levels will decrease. METHODS: In this single-center, prospective, randomized controlled clinical trial (NCT03628820), we tested the effectiveness of therapy dogs versus coloring a mandala and versus no intervention (control) on provider stress. Consenting emergency medicine physicians and nurses provided three self-reported assessments of stress and saliva samples at the start (T1), at the middle (T2), and near the end (T3) of shift. Thirty minutes prior to T2, participants were randomized to either interacting with a therapy dog or coloring for 5 minutes; controls had neither. Stress was assessed on visual analog scale (VAS, 0-100 mm) and with salivary cortisol (Salimetrics) and the modified Perceived Stress Scale (mPSS-10). To assess potential change in participant behavior, patients of providers in either group were asked to complete an internally derived survey of empathic behaviors displayed by providers at T1 and T3. RESULTS: We enrolled 122 providers (n = 39 control, n = 40 coloring, n = 43 dog); 48% were residents, and 60% enrolled on an evening shift. At T1, mean (±SD) VAS score was not different between groups (18.2 [±17.8] mm). At T3, VAS tended to increase with coloring (24.5 mm), remain unchanged in controls (20 mm), and decreased slightly with dogs (13.6 mm, p = 0.018 vs. coloring, Tukey's post hoc). Salivary cortisol levels were consistently highest at the beginning of each providers' shift and were significantly decreased versus control in both the dog and the coloring groups (p < 0.05, Tukey's). We observed no difference between groups for the mPSS-10 nor in patient reported survey of empathic behaviors. CONCLUSION: This randomized controlled clinical trial demonstrates preliminary evidence that a 5-minute therapy dog interaction while on shift can reduce provider stress in ED physicians and nurses.

Diagnostic accuracy of plasma kynurenine/tryptophan ratio, measured by enzyme-linked immunosorbent assay, for pulmonary tuberculosis.

INTRODUCTION: The World Health Organization has identified the need for a non-sputum-based test capable of detecting active tuberculosis (TB) as a priority. The plasma kynurenine-to-tryptophan (K/T) ratio, largely mediated by activity of the enzyme indoleamine 2,3-dioxygenase, may have potential as a suitable biomarker for active TB. METHOD: We evaluated a commercial enzyme-linked immunosorbent assay (ELISA) in comparison to mass spectrometry for measuring the K/T ratio. We also used ELISA to determine the K/T ratio in plasma from patients with active TB compared to latently infected controls, with and without HIV. RESULTS: The two methods showed good agreement, with a mean bias of 0.01 (limit of agreement from -0.06 to 0.10). Using ELISA, it was found that HIV-infected patients with active TB disease had higher K/T ratios than those without TB (median, 0.101 [interquartile range (IQR), 0.091-0.140] versus 0.061 [IQR, 0.034-0.077], P<0.0001). At a cutoff of 0.080, the K/T ratio produced a sensitivity of 90%, a specificity of 80%, a positive predictive value (PPV) of 82%, and a negative predictive value (NPV) of 90%. In a receiver operating characteristics analysis, the K/T ratio had an area under the curve of 0.93. HIV-uninfected patients with active TB also had higher K/T ratios than those with latent TB infections (median, 0.064 [IQR, 0.040-0.088] versus 0.022 [IQR, 0.016-0.027], P<0.0001). A cutoff of 0.040 gave a sensitivity of 85%, a specificity of 92%, a PPV of 91%, and an NPV of 84%. CONCLUSION: The plasma K/T ratio is a sensitive biomarker for active TB. The K/T ratio can be measured from blood using ELISA. The K/T ratio should be evaluated as an initial test for TB.

RISK6, a 6-gene transcriptomic signature of TB disease risk, diagnosis and treatment response.

Improved tuberculosis diagnostics and tools for monitoring treatment response are urgently needed. We developed a robust and simple, PCR-based host-blood transcriptomic signature, RISK6, for multiple applications: identifying individuals at risk of incident disease, as a screening test for subclinical or clinical tuberculosis, and for monitoring tuberculosis treatment. RISK6 utility was validated by blind prediction using quantitative real-time (qRT) PCR in seven independent cohorts. Prognostic performance significantly exceeded that of previous signatures discovered in the same cohort. Performance for diagnosing subclinical and clinical disease in HIV-uninfected and HIV-infected persons, assessed by area under the receiver-operating characteristic curve, exceeded 85%. As a screening test for tuberculosis, the sensitivity at 90% specificity met or approached the benchmarks set out in World Health Organization target product profiles for non-sputum-based tests. RISK6 scores correlated with lung immunopathology activity, measured by positron emission tomography, and tracked treatment response, demonstrating utility as treatment response biomarker, while predicting treatment failure prior to treatment initiation. Performance of the test in capillary blood samples collected by finger-prick was noninferior to venous blood collected in PAXgene tubes. These results support incorporation of RISK6 into rapid, capillary blood-based point-of-care PCR devices for prospective assessment in field studies.

Controlled clinical trial of canine therapy versus usual care to reduce patient anxiety in the emergency department.

OBJECTIVE: Test if therapy dogs reduce anxiety in emergency department (ED) patients. METHODS: In this controlled clinical trial (NCT03471429), medically stable, adult patients were approached if the physician believed that the patient had "moderate or greater anxiety." Patients were allocated on a 1:1 ratio to either 15 min exposure to a certified therapy dog and handler (dog), or usual care (control). Patient reported anxiety, pain and depression were assessed using a 0-10 scale (10 = worst). Primary outcome was change in anxiety from baseline (T0) to 30 min and 90 min after exposure to dog or control (T1 and T2 respectively); secondary outcomes were pain, depression and frequency of pain medication. RESULTS: Among 93 patients willing to participate in research, 7 had aversions to dogs, leaving 86 (92%) were willing to see a dog six others met exclusion criteria, leaving 40 patients allocated to each group (dog or control). Median and mean baseline anxiety, pain and depression scores were similar between groups. With dog exposure, median anxiety decreased significantly from T0 to T1: 6 (IQR 4-9.75) to T1: 2 (0-6) compared with 6 (4-8) to 6 (2.5-8) in controls (P<0.001, for T1, Mann-Whitney U and unpaired t-test). Dog exposure was associated with significantly lower anxiety at T2 and a significant overall treatment effect on two-way repeated measures ANOVA for anxiety, pain and depression. After exposure, 1/40 in the dog group needed pain medication, versus 7/40 in controls (P = 0.056, Fisher's exact test). CONCLUSIONS: Exposure to therapy dogs plus handlers significantly reduced anxiety in ED patients.

Detection of Tuberculosis Recurrence, Diagnosis and Treatment Response by a Blood Transcriptomic Risk Signature in HIV-Infected Persons on Antiretroviral Therapy.

HIV-infected individuals are at high risk of tuberculosis disease and those with prior tuberculosis episodes are at even higher risk of disease recurrence. A non-sputum biomarker that identifies individuals at highest tuberculosis risk would allow targeted microbiological testing and appropriate treatment and also guide need for prolonged therapy. We determined the utility of a previously developed whole blood transcriptomic correlate of risk (COR) signature for (1) predicting incident recurrent tuberculosis, (2) tuberculosis diagnosis and (3) its potential utility for tuberculosis treatment monitoring in HIV-infected individuals. We retrieved cryopreserved blood specimens from three previously completed clinical studies and measured the COR signature by quantitative microfluidic real-time-PCR. The signature differentiated recurrent tuberculosis progressors from non-progressors within 3 months of diagnosis with an area under the Receiver-operating characteristic (ROC) curve (AUC) of 0.72 (95% confidence interval (CI), 0.58-0.85) amongst HIV-infected individuals on antiretroviral therapy (ART). Twenty-five of 43 progressors (58%) were asymptomatic at microbiological diagnosis and thus had subclinical disease. The signature showed excellent diagnostic discrimination between HIV-uninfected tuberculosis cases and controls (AUC 0.97; 95%CI 0.94-1). Performance was lower in HIV-infected individuals (AUC 0.83; 95%CI 0.81-0.96) and signature scores were directly associated with HIV viral loads. Tuberculosis treatment response in HIV-infected individuals on ART with a new recurrent tuberculosis diagnosis was also assessed. Signature scores decreased significantly during treatment. However, pre-treatment scores could not differentiate between those who became sputum negative before and after 2 months. Direct application of the unmodified blood transcriptomic COR signature detected subclinical and active tuberculosis by blind validation in HIV-infected individuals. However, prognostic performance for recurrent tuberculosis, and performance as diagnostic and as treatment monitoring tool in HIV-infected persons was inferior to published results from HIV-negative cohorts. Our results suggest that performance of transcriptomic signatures comprising interferon stimulated genes are negatively affected in HIV-infected individuals, especially in those with incompletely suppressed viral loads.

A Conceptual Framework: The Musical Self as a Unique Pathway to Outcomes in the Acute Pediatric Health Setting.

This article reports on a project at the Royal Children's Hospital Melbourne in which the music therapy team synthesized their practice and related theories to propose a new conceptual framework for music therapy in their acute pediatric setting. The impetus for the project was the realization that in the process of producing key statements about the non-musical benefits of music therapy, the cost was often the suppression of information about the patient's unique musical potential as the major (mediating) pathway from referral reason, to music therapy, and to effective outcomes. The purpose of the project was to articulate how this team of clinicians conceive of the patient's musical self as the major theoretical pathway for music therapy in an evidence-based acute medical setting. The clinicians' shared reflexive process across six months involved robust directed discussion, annotation of shared reading, and documentation of all engagement in words and diagrams. The outcome was a consensus framework including three constructs: the place of music in the life of the infant, child, and young people, Culture and Context, and Musical Manifestations. The constructs were tested in a clinical audit, and found to be robustly inclusive. In addition to the conceptual framework, this project serves to demonstrate a process by which clinical teams may reflect on their individual practice and theory together to create a consensus stance for the overall service they provide in the one setting.