Evaluation of immune profiles associated with control of mycobacterial growth in systemic lupus erythematosus (SLE) patients.

Tuberculosis (TB) is an infectious disease with the burden concentrated in low- and middle-income countries. Systemic lupus erythematosus (SLE) is an autoimmune disease associated with widespread inflammation that is prevalent in some TB endemic areas including East Africa and parts of Southeast Asia. SLE patients are known to be at higher risk of becoming infected with M. tb, developing TB disease. However, the immune mechanisms underlying this susceptibility are not well understood, particularly in the absence of immunosuppressive drugs. We present a pilot study in which we have evaluated intracellular cytokine responses and ex vivo ability to control mycobacterial growth using peripheral blood mononuclear cells (PBMC) collected from SLE patients before and during SLE treatment. After six months of treatment, SLE patients had the highest frequencies of CD8+ T cells, NK cells and NKT cells producing IFN-γ and/or TNF-α. This group also showed superior control of mycobacterial growth, and proinflammatory cytokine-producing NK and NKT cells correlated with mycobacterial growth inhibition at the individual patient level. These findings contribute to a better understanding of autoimmune profiles associated with control of mycobacterial growth in SLE patients, which may inform intervention strategies to reduce risk of TB disease in this population.

Development and validation of the Moral Injury Symptom Scale - Clinician Version - Short Form (MISS-CV-SF).

BACKGROUND: Moral injury occurs when one witnesses or perpetrates an act that transgresses strongly held moral beliefs and expectations. First documented among active military and veterans, moral injury is increasingly studied in healthcare personnel impacted by the coronavirus pandemic. Measurement of moral injury among this population, particularly nurses, is still in its infancy. OBJECTIVE: To develop the Moral Injury Symptom Scale - Clinician-Short Form and validate it among United States based acute care nurses. . METHODS: The Moral Injury Symptom Scale - Military Version was modified for a healthcare audience. 174 acute care nurses responded to a survey package including the scale and related instruments. Reliability and validity, including convergent and discriminant validities, were assessed, and a cutoff score was calculated using the area under the receiver operating characteristic curve. RESULTS: Reliability (Cronbach α = .75) and validity were established and a cutoff score of 41, based on functional impairment caused by moral injury, demonstrated 86.4% sensitivity and 69.6% specificity. Nurses who screened positive for moral injury experienced higher depression, anxiety, work exhaustion, interpersonal disengagement, emotional exhaustion, and depersonalization. . CONCLUSIONS: The Moral Injury Symptom Scale - Clinician Version - Short Form is a valid and reliable instrument with strong psychometric properties that can assess moral injury in acute care nurses, a population at risk due to the challenges of providing care during the pandemic. Appropriate measurement and establishing prevalence should prompt support and intervention from healthcare organizations. .

Urinary syndecan-1 in dogs anesthetized with isoflurane or sevoflurane: A randomized, prospective study.

BACKGROUND: Syndecan-1 (SDC1) is an established marker of endothelial glycocalyx shedding. Most research on SDC1 has focused on plasma or serum concentrations, and little is known about urine concentrations. OBJECTIVES: Measure urinary SDC1 concentrations in dogs undergoing anesthesia with either sevoflurane or isoflurane and assess the effects of anesthesia duration and IV crystalloids on urinary SDC1 concentrations. ANIMALS: Thirty-one client-owned dogs undergoing anesthesia for magnetic resonance imaging (MRI) with or without surgery for suspected intervertebral disk disease (IVDD) were used. METHODS: Dogs with suspected IVDD were randomized to undergo anesthesia with either sevoflurane or isoflurane. Urine was collected before and immediately after anesthesia for the analysis of SDC1. Urinary creatinine concentrations also were measured, and the ratio of urinary SDC1 to urinary creatinine (USCR) was used to account for dilution. RESULTS: Median (range) USCR was significantly higher after anesthesia compared with baseline for all groups combined (P < .05). No significant difference was found between the groups for age, sex, weight, and type of anesthesia. Multiple regression analysis of the effect of the independent variables inhalant type, age, weight, sex, anesthesia time, surgery, and quantity of IV fluids on the dependent variable SDC1 found that only the quantity of IV fluids significantly predicted a change (P < .001). CONCLUSIONS AND CLINICAL IMPORTANCE: The total volume of lactated Ringer's solution administered to anesthetized dogs may affect USCR. Further investigations are warranted to evaluate the relationship between IV fluids and SDC1.

Safety, tolerability, viral kinetics, and immune correlates of protection in healthy, seropositive UK adults inoculated with SARS-CoV-2: a single-centre, open-label, phase 1 controlled human infection study.

BACKGROUND: A SARS-CoV-2 controlled human infection model (CHIM) has been successfully established in seronegative individuals using a dose of 1×101 50% tissue culture infectious dose (TCID50) pre-alpha SARS-CoV-2 virus. Given the increasing prevalence of seropositivity to SARS-CoV-2, a CHIM that could be used for vaccine development will need to induce infection in those with pre-existing immunity. Our aim was to find a dose of pre-alpha SARS-CoV-2 virus that induced infection in previously infected individuals. METHODS: Healthy, UK volunteers aged 18-30 years, with proven (quantitative RT-PCR or lateral flow antigen test) previous SARS-CoV-2 infection (with or without vaccination) were inoculated intranasally in a stepwise dose escalation CHIM with either 1×101, 1×102, 1×10³, 1×104, or 1×105 TCID50 SARS-CoV-2/human/GBR/484861/2020, the same virus used in the seronegative CHIM. Post-inoculation, volunteers were quarantined in functionally negative pressure rooms (Oxford, UK) for 14 days and until 12-hourly combined oropharyngeal-nasal swabs were negative for viable virus by focus-forming assay. Outpatient follow-up continued for 12 months post-enrolment, with additional visits for those who developed community-acquired SARS-CoV-2 infection. The primary objective was to identify a safe, well tolerated dose that induced infection (defined as two consecutive SARS-CoV-2 positive PCRs starting 24 h after inoculation) in 50% of seropositive volunteers. This study is registered with ClinicalTrials.gov (NCT04864548); enrolment and follow-up to 12 months post-enrolment are complete. FINDINGS: Recruitment commenced on May 6, 2021, with the last volunteer enrolled into the dose escalation cohort on Nov 24, 2022. 36 volunteers were enrolled, with four to eight volunteers inoculated in each dosing group from 1×101 to 1×105 TCID50 SARS-CoV-2. All volunteers have completed quarantine, with follow-up to 12 months complete. Despite dose escalation to 1×105 TCID50, we were unable to induce sustained infection in any volunteers. Five (14%) of 36 volunteers were considered to have transient infection, based on the kinetic of their PCR-positive swabs. Transiently infected volunteers had significantly lower baseline mucosal and systemic SARS-CoV-2-specific antibody titres and significantly lower peripheral IFNγ responses against a CD8+ T-cell SARS-CoV-2 peptide pool than uninfected volunteers. 14 (39%) of 36 volunteers subsequently developed breakthrough infection with the omicron variant after discharge from quarantine. Most adverse events reported by volunteers in quarantine were mild, with fatigue (16 [44%]) and stuffy nose (16 [44%]) being the most common. There were no serious adverse events. INTERPRETATION: Our study demonstrates potent protective immunity induced by homologous vaccination and homologous or heterologous previous SARS-CoV-2 infection. The community breakthrough infections seen with the omicron variant supports the use of newer variants to establish a model with sufficient rate of infection for use in vaccine and therapeutic development. FUNDING: Wellcome Trust and Department for Health and Social Care.

Safety of a controlled human infection model of tuberculosis with aerosolised, live-attenuated Mycobacterium bovis BCG versus intradermal BCG in BCG-naive adults in the UK: a dose-escalation, randomised, controlled, phase 1 trial.

BACKGROUND: Mycobacterium tuberculosis is the main causative agent of tuberculosis. BCG, the only licensed vaccine, provides inadequate protection against pulmonary tuberculosis. Controlled human infection models are useful tools for vaccine development. We aimed to determine a safe dose of aerosol-inhaled live-attenuated Mycobacterium bovis BCG as a surrogate for M tuberculosis infection, then compare the safety and tolerability of infection models established using aerosol-inhaled and intradermally administered BCG. METHODS: This phase 1 controlled human infection trial was conducted at two clinical research facilities in the UK. Healthy, immunocompetent adults aged 18-50 years, who were both M tuberculosis-naive and BCG-naive and had no history of asthma or other respiratory diseases, were eligible for the trial. Participants were initially enrolled into group 1 (receiving the BCG Danish strain); the trial was subsequently paused because of a worldwide shortage of BCG Danish and, after protocol amendment, was restarted using the BCG Bulgaria strain (group 2). After a dose-escalation study, during which participants were sequentially allocated to receive either 1 × 103, 1 × 104, 1 × 105, 1 × 106, or 1 × 107 colony-forming units (CFU) of aerosol BCG, the maximum tolerated dose was selected for the randomised controlled trial. Participants in this trial were randomly assigned (9:12), by variable block randomisation and using sequentially numbered sealed envelopes, to receive aerosol BCG (1 × 107 CFU) and intradermal saline or intradermal BCG (1 × 106 CFU) and aerosol saline. Participants were masked to treatment allocation until day 14. The primary outcome was to compare the safety of a controlled human infection model based on aerosol-inhaled BCG versus one based on intradermally administered BCG, and the secondary outcome was to evaluate BCG recovery in the airways of participants who received aerosol BCG or skin biopsies of participants who received intradermal BCG. BCG was detected by culture and by PCR. The trial is registered at ClinicalTrials.gov, NCT02709278, and is complete. FINDINGS: Participants were assessed for eligibility between April 7, 2016, and Sept 29, 2018. For group 1, 15 participants were screened, of whom 13 were enrolled and ten completed the study; for group 2, 60 were screened and 33 enrolled, all of whom completed the study. Doses up to 1 × 107 CFU aerosol-inhaled BCG were sufficiently well tolerated. No significant difference was observed in the frequency of adverse events between aerosol and intradermal groups (median percentage of solicited adverse events per participant, post-aerosol vs post-intradermal BCG: systemic 7% [IQR 2-11] vs 4% [1-13], p=0·62; respiratory 7% [1-19] vs 4% [1-9], p=0·56). More severe systemic adverse events occurred in the 2 weeks after aerosol BCG (15 [12%] of 122 reported systemic adverse events) than after intradermal BCG (one [1%] of 94; difference 11% [95% CI 5-17]; p=0·0013), but no difference was observed in the severity of respiratory adverse events (two [1%] of 144 vs zero [0%] of 97; 1% [-1 to 3]; p=0·52). All adverse events after aerosol BCG resolved spontaneously. One serious adverse event was reported-a participant in group 2 was admitted to hospital to receive analgesia for a pre-existing ovarian cyst, which was deemed unrelated to BCG infection. On day 14, BCG was cultured from bronchoalveolar lavage samples after aerosol infection and from skin biopsy samples after intradermal infection. INTERPRETATION: This first-in-human aerosol BCG controlled human infection model was sufficiently well tolerated. Further work will evaluate the utility of this model in assessing vaccine efficacy and identifying potential correlates of protection. FUNDING: Bill & Melinda Gates Foundation, Wellcome Trust, National Institute for Health Research Oxford Biomedical Research Centre, Thames Valley Clinical Research Network, and TBVAC2020.

Validation of the Moral Injury Outcome Scale in acute care nurses.

Introduction: Moral injury, predominantly studied in military populations, has garnered increased attention in the healthcare setting, in large part due to the psychological and emotional consequences of the COVID-19 pandemic. The measurement of moral injury with instrumentation adapted from military settings and validated by frontline healthcare personnel is essential to assess prevalence and guide intervention. This study aimed to validate the Moral Injury Outcome Scale (MIOS) in the population of acute care. Methods: A sample of 309 acute care nurses completed surveys regarding moral injury, depression, anxiety, burnout, professional fulfillment, spiritual wellbeing, and post-traumatic stress disorder symptoms. Confirmatory factor analysis was conducted as well as an assessment of reliability and validity. Results: The internal consistency of the 14-item MIOS was 0.89. The scale demonstrated significant convergent and discriminant validity, and the test of construct validity confirmed the two-factor structure of shame and trust violations in this clinical population. Regression analysis indicated age, race, and marital status-related differences in the experience of moral injury. Discussion: The MIOS is valid and reliable in acute care nursing populations and demonstrates sound psychometric properties. Scores among nurses diverge from those of military personnel in areas that may inform distinctions in interventions to address moral injury in these populations.

Work-related perceptions and coping strategies of acute care chaplains: a qualitative analysis.

Hospital-based chaplains provide crucial spiritual and emotional care to patients, families, and staff during times of intense life changes and crises. Chaplains are regularly exposed to suffering and their work may result in personal mental and emotional health challenges. To understand chaplains' perceptions of the impact of their work and methods to cope, a secondary analysis of a mixed-methods study on chaplain well-being was undertaken. Qualitative interviews were conducted with nine hospital-based chaplains and data were coded and analyzed using thematic analysis. Results revealed that participants perceive their work as offering both trials and rewards, and their efforts to cope with trials include interpersonal support, intrapersonal resources, and spiritual resilience. Personal insights into chaplains' experiences may help inform organizational interventions to support these essential members of the care team.

Reproductive decision-making and the utilization of preimplantation genetic testing among individuals with inherited aortic or vascular disease.

Preimplantation genetic testing for monogenic disorders (PGT-M) is a reproductive technology used in conjunction with in-vitro fertilization (IVF) to reduce the risk of passing on a known genetic condition from parent to child. There is limited research describing the experience and emotional impact of PGT-M among individuals with inherited aortic or vascular disease (IAVD). Our qualitative study aims to explore the factors that influence reproductive decision-making and the uptake of PGT-M within this population. Individuals diagnosed with IAVD who have considered PGT-M, and/or their reproductive partner, were recruited using internal clinical databases and advocacy organizations. Virtual semi-structured interviews were conducted using an interview guide that included questions related to participants' lived experience of their condition, risk perception, reproductive history, familiarity with PGT-M/IVF, and financial/psychosocial considerations. A total of 17 interviews were completed (13 affected individuals, 4 unaffected partners) and analyzed using thematic analysis. Emergent themes included: (1) the lived experience and perceived severity of disease; (2) need for comprehensive, balanced, and timely information; (3) and impact of personal values and circumstances. When discussing the impact of lived experience on reproductive decision-making, participants identified the physical and emotional impact of disease and variability of disease as factors influencing the uptake of PGT-M. Many described PGT-M as the only reproductive option presented to them by providers. Even so, participants expressed gaps in their understanding of PGT-M, particularly regarding cost/insurance coverage and the experience of IVF. Finally, participants recognized that the decision to pursue PGT-M primarily requires introspection and evaluation of one's values, but that cost remains a significant consideration. The findings from our study highlight the complexity of reproductive decision-making for individuals with IAVD and provide insight into their psychological and informational needs when engaging in this process. Providers can use these findings to tailor their discussions about reproductive decision-making with this patient cohort.

Case report: Recovery and sequential imaging of a patient with osmotic demyelination syndrome.

A 4-year-old neutered-male Australian Shepherd was presented to an emergency and referral hospital for an acute onset of neurologic signs and abnormal mentation. Seven days prior, the patient had been diagnosed with hypoadrenocorticism and was treated accordingly at another hospital. Based on recent clinical history, the neurologic signs were consistent with thalamic and brainstem deficits and suspected to be caused by osmotic demyelination syndrome secondary to rapid correction of hyponatremia. A brain MRI confirmed lesions consistent with osmotic demyelination syndrome. The patient's clinical signs initially worsened, and he required intensive nursing care with multimodal sedation, close monitoring of electrolytes and tailored fluid therapy. The patient recovered and was discharged on day seven of hospitalization. Four and a half months later, re-evaluation of the patient showed complete resolution of the neurological deficits with a now unremarkable neurological exam, and follow-up MRI revealed still present, yet improved bilateral thalamic lesions. This is the first known veterinary case report of sequential brain imaging of a dog that has recovered from osmotic demyelination syndrome. In humans, patients can have evidence of near to full clinical recovery, yet imaging findings may still be abnormal several months after recovery. This report details similar imaging findings in a canine with improved clinical signs, despite persistent lesions on brain MRI. Prognosis of canines with osmotic demyelination syndrome may be better than previously perceived, despite the severity of clinical signs and brain lesions apparent on MRI.

A Mixed-Methods Pilot Study of a Well-Being Intervention for Healthcare Chaplains.

This mixed-methods pilot study explored the psychological and emotional experiences of chaplains and the feasibility, acceptability, and impact of workshops designed to support chaplain well-being. After the workshops, scores on a measure of self-compassion increased, while secondary traumatic stress and burnout scores decreased. Qualitative data reflected the range of experiences of chaplaincy as well as the benefits of the workshops. This pilot study supports further exploration of organizational interventions to promote chaplain well-being.

Inflammation and immune activation are associated with risk of Mycobacterium tuberculosis infection in BCG-vaccinated infants.

Tuberculosis vaccine development is hindered by the lack of validated immune correlates of protection. Exploring immune correlates of risk of disease and/or infection in prospective samples can inform this field. We investigate whether previously identified immune correlates of risk of TB disease also associate with increased risk of M.tb infection in BCG-vaccinated South African infants, who became infected with M.tb during 2-3 years of follow-up. M.tb infection is defined by conversion to positive reactivity in the QuantiFERON test. We demonstrate that inflammation and immune activation are associated with risk of M.tb infection. Ag85A-specific IgG is elevated in infants that were subsequently infected with M.tb, and this is coupled with upregulated gene expression of immunoglobulin-associated genes and type-I interferon. Plasma levels of IFN-[Formula: see text]2, TNF-[Formula: see text], CXCL10 (IP-10) and complement C2 are also higher in infants that were subsequently infected with M.tb.

Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes.

Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P < 0.001 for each trait) and discriminate pathogenic from non-pathogenic variants (area under the curve 0.82-0.84 across endophenotypes). An effect size threshold of ≥ 0.5 times the endophenotype standard deviation nominates up to 35% of rare variants of uncertain significance or not in ClinVar in disease susceptibility genes with pathogenic potential. We propose that variant associations with quantitative endophenotypes for monogenic diseases can provide evidence supporting pathogenicity.

The uptake and utility of genetic testing and genetic counseling for hypertrophic cardiomyopathy-A systematic review and meta-analysis.

Genetic testing and genetic counseling are routinely indicated for patients with hypertrophic cardiomyopathy (HCM); however, the uptake and utility of these services is not entirely understood. This systematic review and meta-analysis summarizes the uptake and utility of genetic counseling and genetic testing for patients with HCM and their at-risk family members, as well as the impact of genetic counseling/testing on patient-reported outcomes (PROs). A systematic search was performed through March 12, 2021. Meta-analyses were performed whenever possible; other findings were qualitatively summarized. Forty-eight studies met inclusion criteria (47 observational, 1 randomized). Uptake of genetic testing in probands was 57% (95% confidence interval [CI]: 40, 73). Uptake of cascade screening for at-risk relatives were as follows: 61% for cascade genetic testing (95% CI: 45, 75), 58% for cardiac screening (e.g. echocardiography) (95% CI: 40, 73), and 69% for either/both approaches (95% CI: 43, 87). In addition, relatives of probands with a positive genetic test result were significantly more likely to undergo cascade screening compared to relatives of probands with a negative result (odds ratio = 3.17, 95% CI: 2.12, 4.76). Overall, uptake of genetic counseling in both probands and relatives ranged from 37% to 84%. Multiple studies found little difference in PROs between individuals receiving positive versus negative genetic test results; however, other studies found that individuals with positive genetic test results experienced worse psychological outcomes. Genetic testing may also inform life choices, particularly decisions related to reproduction and insurance. Genetic counseling was associated with high satisfaction, increased perceived personal control and empowerment, and decreased anxiety. Approximately half to three-quarters of patients with HCM and their relatives undergo genetic testing or cascade screening. PROs after genetic testing varied and genetic counseling was associated with high satisfaction and improved PROs.

Case Report: Successful Intravenous Lipid Emulsion Therapy for Canine Amphetamine Toxicosis.

A 4-year-old, female-spayed, mixed breed dog, weighing 24.2 kg, was presented for acute ingestion of ~12.3 mg/kg of Adderall XRⓇ, an extended-release amphetamine medication. In dogs, the oral median lethal dose for amphetamines ranges anywhere from 9-11 mg/kg to 20-27 mg/kg. On presentation, the patient was agitated, tachycardic and hypertensive. Initial treatment was instituted with intravenous lipid emulsion (IVLE) therapy, and baseline and post-treatment amphetamine concentrations were quantified in serum and plasma. In both serum and plasma, post-IVLE concentrations of amphetamine were lower 1 h after treatment and IVLE was the only treatment instituted during this time. The dog improved significantly while in hospital and was discharged <24 h after presentation. This is the first known reported use of IVLE for treatment of amphetamine toxicosis with documented decreases in both serum and plasma amphetamine levels shortly after administration of IVLE.

Cascade testing for inherited cardiac conditions: Risk perception and screening after a negative genetic test result.

First-degree relatives of a proband with an inherited cardiac condition (ICC) are offered predictive genetic testing for the pathogenic or likely pathogenic (P/LP) cardiac gene variant (CGV) to clarify their risk for the familial condition. Relatives who test negative for a familial P/LP CGV typically do not require longitudinal cardiac surveillance. To our knowledge, no previous study has investigated adjustment to risk reduction and subsequent screening practices in genotype-negative relatives from an ICC population. We thus investigated risk perception and ongoing screening practices in genotype-negative adults who received cardiac genetic counseling. Correlations between clinical and demographic variables and risk perception and screening practices were also investigated. On average, participants (n = 71) reported a perceived 19.5% lifetime risk of developing the ICC in their family, despite their negative genetic test result. The majority (54%) of participants reported having undergone cardiac screening after disclosure of their negative result. There were no significant correlations between clinical and demographic variables and risk perception or screening practices. Furthermore, risk perception was not found to impact the likelihood of cardiac screening. These findings suggest that even with comprehensive cardiac genetic counseling, a proportion of this population did not accurately comprehend or recall their cardiac disease risk. Additional interventions beyond traditional result disclosure should be explored to help genotype-negative individuals adjust to their reduction in risk for a familial ICC.

Blood mercury concentrations in four sympatric gull species from South Western France: Insights from stable isotopes and biologging.

Mercury (Hg) is a toxic trace element widely distributed in the environment, which particularly accumulates in top predators, including seabirds. Among seabirds, large gulls (Larus sp) are generalist feeders, foraging in both terrestrial and marine habitats, making them relevant bioindicators of local coastal Hg contamination. In the present study, we reported blood Hg concentrations in adults and chicks of four different gull species breeding on the French Atlantic coast: the European herring gull (Larus argentatus), the Lesser black-backed gull (L. fuscus), the Great black-backed gull (L. marinus) and the Yellow-legged gull (L. michahellis). We also investigated the potential role of foraging ecology in shaping Hg contamination across species, using the unique combination of three dietary tracers (carbon, nitrogen and sulfur stable isotopes) and biologging (GPS tracking). A high concentration of Hg was associated with high trophic position and a marine diet in gulls, which was corroborated by birds' space use strategy during foraging trips. Adults of all four species reached Hg concentrations above reported toxicity thresholds. Specifically, adults of Great black-backed gulls had a high trophic marine specialized diet and significantly higher Hg concentrations than the three other species. Blood Hg was 4-7 times higher in adults than in chicks, although chicks of all species received mainly marine and high trophic position prey, which is expected to be the cause of blood Hg concentrations of toxic concern. By using both stable isotopes and GPS tracking, the present study provides compelling insights on the main feeding habits driving Hg contamination in a seabird assemblage feeding in complex coastal environments.

Functional in-vitro evaluation of the non-specific effects of BCG vaccination in a randomised controlled clinical study.

Bacille Calmette-Guérin (BCG), the only currently licenced tuberculosis vaccine, may exert beneficial non-specific effects (NSE) in reducing infant mortality. We conducted a randomised controlled clinical study in healthy UK adults to evaluate potential NSE using functional in-vitro growth inhibition assays (GIAs) as a surrogate of protection from four bacteria implicated in infant mortality. Volunteers were randomised to receive BCG intradermally (n = 27) or to be unvaccinated (n = 8) and were followed up for 84 days; laboratory staff were blinded until completion of the final visit. Using GIAs based on peripheral blood mononuclear cells, we observed a significant reduction in the growth of the Gram-negative bacteria Escherichia coli and Klebsiella pneumonia following BCG vaccination, but no effect for the Gram-positive bacteria Staphylococcus aureus and Streptococcus agalactiae. There was a modest association between S. aureus nasal carriage and growth of S. aureus in the GIA. Our findings support a causal link between BCG vaccination and improved ability to control growth of heterologous bacteria. Unbiased assays such as GIAs are potentially useful tools for the assessment of non-specific as well as specific effects of TB vaccines. This study was funded by the Bill and Melinda Gates Foundation and registered with ClinicalTrials.gov (NCT02380508, 05/03/2015; completed).

Diagnostic validity and clinical utility of genetic testing for hypertrophic cardiomyopathy: a systematic review and meta-analysis.

OBJECTIVE: This study summarises the diagnostic validity and clinical utility of genetic testing for patients with hypertrophic cardiomyopathy (HCM) and their at-risk relatives. METHODS: A systematic search was performed in PubMed (MEDLINE), Embase, CINAHL and Cochrane Central Library databases from inception through 2 March 2020. Subgroup and sensitivity analyses were prespecified for individual sarcomere genes, presence/absence of pathogenic variants, paediatric and adult cohorts, family history, inclusion of probands, and variant classification method. Study quality was assessed using the Newcastle-Ottawa tool. RESULTS: A total of 132 articles met inclusion criteria. The detection rate based on pathogenic and likely pathogenic variants was significantly higher in paediatric cohorts compared with adults (56% vs 42%; p=0.01) and in adults with a family history compared with sporadic cases (59% vs 33%; p=0.005). When studies applied current, improved, variant interpretation standards, the adult detection rate significantly decreased from 42% to 33% (p=0.0001) because less variants met criteria to be considered pathogenic. The mean difference in age-of-onset in adults was significantly earlier for genotype-positive versus genotype-negative cohorts (8.3 years; p<0.0001), MYH7 versus MYBPC3 cohorts (8.2 years; p<0.0001) and individuals with multiple versus single variants (7.0 years; p<0.0002). Overall, disease penetrance in adult cohorts was 62%, but differed significantly depending on if probands were included or excluded (73% vs 55%; p=0.003). CONCLUSIONS: This systematic review and meta-analysis is the first, to our knowledge, to collectively quantify historical understandings of detection rate, genotype-phenotype associations and disease penetrance for HCM, while providing the answers to important routine clinical questions and highlighting key areas for future study.