Host and pathogen factors that influence variability of Mycobacterium tuberculosis lipid body content in sputum from patients with tuberculosis: an observational study.

BACKGROUND: High proportions of Mycobacterium tuberculosis cells in sputum containing triacylglycerol-rich lipid bodies have been shown to be associated with treatment failure or relapse following antituberculous chemotherapy. Although lipid body determination is a potential biomarker for supporting clinical trial and treatment decisions, factors influencing variability in sputum frequencies of lipid body-positive (%LB+) M tuberculosis in patients are unknown. We aimed to test our hypothesis that exposure to host-generated NO and M tuberculosis strains are factors associated with differences in sputum %LB+. METHODS: In this observational study, we determined %LB+ frequencies before treatment by microscopy in patients with smear-positive tuberculosis from two separate prospective observational study settings (Gondar, Ethiopia, recruited between May 1, 2010, and April 30, 2011, and Fajara, The Gambia, who provided sputum samples before treatment between May 5, 2010, and Dec 22, 2011). In Ethiopia, fractional exhaled nitric oxide (FeNO) was measured as a biomarker of host NO, and M tuberculosis strain differences were determined by spoligotyping. Treatment response was assessed by percentage weight change after 7 months. In The Gambia, treatment responses were assessed as change in BMI and radiographic burden of disease after 6 months. Sputum M tuberculosis isolates were studied in vitro for their %LB+ and triacylglycerol synthase 1 (tgs1) mRNA responses to NO exposure. Propidium iodide staining was used as a measure of NO strain toxicity. Correlation between in vitro %LB+ frequencies following NO exposure and those of the same strain in sputum was examined with linear regression and Dunnett's multiple comparison test. FINDINGS: In Ethiopia, 73 patients who were smear positive for pulmonary tuberculosis were recruited (43 [59%] were male and 30 [41%] were female). Of these, the %LB+ in the sputum of 59 patients showed linear correlation with log10 FeNO (r2=0·28; p<0·0001) and an association with strain spoligotype was suggested. Seven M tuberculosis strains from The Gambia showed different dose-responses to NO in vitro, demonstrated by changing lipid body content, tgs1 transcription, and bacterial toxicity. In sputum %LB+ frequencies correlated with in vitro %LB+ responses to NO of the corresponding isolate. In a subset of 34 patients across both cohorts, higher sputum %LB+ frequencies before treatment were associated with weaker responses to treatment than lower sputum %LB+ frequencies. INTERPRETATION: M tuberculosis strain and exposure to host-generated NO are associated with sputum %LB+. Our results support the use of M tuberculosis strain-dependent sputum %LB+ as a predictive biomarker of treatment response. FUNDING: The Medical Research Council, the University of Leicester, and the University of Gondar.

Transmission of monkeypox/mpox virus: A narrative review of environmental, viral, host, and population factors in relation to the 2022 international outbreak.

Monkeypox virus (MPXV) has spread globally. Emerging studies have now provided evidence regarding MPXV transmission, that can inform rational evidence-based policies and reduce misinformation on this topic. We aimed to review the evidence on transmission of the virus. Real-world studies have isolated viable viruses from high-touch surfaces for as long as 15 days. Strong evidence suggests that the current circulating monkeypox (mpox) has evolved from previous outbreaks outside of Africa, but it is yet unknown whether these mutations may lead to an inherently increased infectivity of the virus. Strong evidence also suggests that the main route of current MPXV transmission is sexual; through either close contact or directly, with detection of culturable virus in saliva, nasopharynx, and sperm for prolonged periods and the presence of rashes mainly in genital areas. The milder clinical presentations and the potential presence of presymptomatic transmission in the current circulating variant compared to previous clades, as well as the dominance of spread amongst men who have sex with men (MSMs) suggests that mpox has a developed distinct clinical phenotype that has increased its transmissibility. Increased public awareness of MPXV transmission modalities may lead to earlier detection of the spillover of new cases into other groups.

Exhaled SARS-CoV-2 RNA viral load kinetics measured by facemask sampling associates with household transmission.

OBJECTIVES: No studies have examined longitudinal patterns of naturally exhaled SARS-CoV-2 RNA viral load (VL) during acute infection. We report this using facemask sampling (FMS) and assessed the relationship between emitted RNA VL and household transmission. METHODS: Between December 2020 and February 2021, we recruited participants within 24 hours of a positive RT-qPCR on upper respiratory tract sampling (URTS) (day 0). Participants gave FMS (for 1 hour) and URTS (self-taken) on seven occasions up to day 21. Samples were analysed by RT-qPCR (from sampling matrix strips within the mask) and symptom diaries were recorded. Household transmission was assessed through reporting of positive URTS RT-qPCR in household contacts. RESULTS: Analysis of 203 FMS and 190 URTS from 34 participants showed that RNA VL peaked within the first 5 days following sampling. Concomitant URTS, FMS RNA VL, and symptom scores, however, were poorly correlated, but a higher severity of reported symptoms was associated with FMS positivity up to day 5. Of 28 participants who had household contacts, 12 (43%) reported transmission. Frequency of household transmission was associated with the highest (peak) FMS RNA VL obtained (negative genome copies/strip: 0% household transmission; 1 to 1000 copies/strip: 20%; 1001 to 10 000 copies/strip: 57%; >10 000 copies/strip: 75%; p = 0.048; age adjusted OR of household transmission per log increase in copies/strip: 4.97; 95% CI, 1.20-20.55; p = 0.02) but not observed with peak URTS RNA VL. DISCUSSION: Exhaled RNA VL measured by FMS is highest in early infection, can be positive in symptomatic patients with concomitantly negative URTS, and is strongly associated with household transmission.

Four-Month High-Dose Rifampicin Regimens for Pulmonary Tuberculosis.

BACKGROUND: Shorter but effective tuberculosis treatment regimens would be of value to the tuberculosis treatment community. High-dose rifampicin has been associated with more rapid and secure lung sterilization and may enable shorter tuberculosis treatment regimens. METHODS: We randomly assigned adults who were given a diagnosis of rifampicin-susceptible pulmonary tuberculosis to a 6-month control regimen, a similar 4-month regimen of rifampicin at 1200 mg/d (study regimen 1 [SR1]), or a 4-month regimen of rifampicin at 1800 mg/d (study regimen 2 [SR2]). Sputum specimens were collected at regular intervals. The primary end point was a composite of treatment failure and relapse in participants who were sputum smear positive at baseline. The noninferiority margin was 8 percentage points. Using a sequence of ordered hypotheses, noninferiority of SR2 was tested first. RESULTS: Between January 2017 and December 2020, 672 patients were enrolled in six countries, including 191 in the control group, 192 in the SR1 group, and 195 in the SR2 group. Noninferiority was not shown. Favorable responses rates were 93, 90, and 87% in the control, SR1, and SR2 groups, respectively, for a country-adjusted absolute risk difference of 6.3 percentage points (90% confidence interval, 1.1 to 11.5) comparing SR2 with the control group. The proportions of participants experiencing a grade 3 or 4 adverse event were 4.0, 4.5, and 4.4% in the control, SR1, and SR2 groups, respectively. CONCLUSIONS: Four-month high-dose rifampicin regimens did not have dose-limiting toxicities or side effects but failed to meet noninferiority criteria compared with the standard 6-month control regimen for treatment of pulmonary tuberculosis. (Funded by the MRC/Wellcome Trust/DFID Joint Global Health Trials Scheme; ClinicalTrials.gov number, NCT02581527.)

A Persistent Tuberculosis Outbreak in the UK Is Characterized by Hydrophobic fadB4-Deficient Mycobacterium tuberculosis That Replicates Rapidly in Macrophages.

The genetic diversity of Mycobacterium tuberculosis can influence disease severity and transmissibility. To better understand how this diversity influences individuals and communities, we phenotyped M. tuberculosis that was causing a persistent outbreak in the East Midlands, United Kingdom. Compared to nonoutbreak isolates, bacilli had higher lipid contents and more hydrophobic cell surfaces. In macrophage infection models, the bacteria increased more rapidly, provoked the enhanced accumulation of macrophage lipid droplets and enhanced the secretion of IL-1ß. Natural deletions in fadB4, nrdB, and plcC distinguished the outbreak isolates from other lineage 3 isolates in the region. fadB4 is annotated with a putative role in cell envelope biosynthesis, so the loss of this gene has the potential to alter the interactions of bacteria with immune cells. Reintroduction of fadB4 to the outbreak strain led to a phenotype that more closely resembled those of nonoutbreak strains. The improved understanding of the microbiological characteristics and the corresponding genetic polymorphisms that associate with outbreaks have the potential to inform tuberculosis control. IMPORTANCE Tuberculosis (TB) killed 1.5 million people in 2020 and affects every country. The extent to which the natural genetic diversity of Mycobacterium tuberculosis influences disease manifestation at both the individual and epidemiological levels remains poorly understood. Insights into how pathogen polymorphisms affect patterns of TB have the potential to translate into clinical and public health practice. Two distinct lineage 3 strains isolated from local TB outbreaks, one of which (CH) was rapidly terminated and the other of which (Lro) persistently transmitted for over a decade, provided us with an opportunity to study these issues. We compared genome sequences, microbiological characteristics, and early immune responses that were evoked upon infection. Our results indicate that the natural lack of fadB4 in the Lro strain contributes to its unique features.

Long-term Outcomes After Lung Cancer Resection in Smokers: Analysis of the National Lung Screening Trial.

BACKGROUND: Smoking is a known risk factor for perioperative complications after lung resection; however, little data exists looking at the impact of smoking status (current versus former) on long-term oncologic outcomes after lung cancer surgery. We sought to compare overall survival (OS), progression-free survival (PFS), and cancer-specific mortality (CSM) in current and former smokers using data from the National Lung Screening Trial (NLST). Additionally, we performed subset analysis in current smokers in order to evaluate the effect of modern surgical techniques on long-term outcomes. METHODS: Patients with clinical stage IA or IB NSCLC who underwent upfront resection within 180 days of diagnosis were identified in the NLST database. Cox proportional hazard regression models were used to assess differences in patient and treatment characteristics with respect to OS and PFS, with a cause-specific hazard model used for CSM. RESULTS: A total of 593 patients were included in the study (269 former smokers, 324 current smokers). Lobar resection (LR) was performed more often than sublobar resection (SLR) (481 vs. 112), and thoracotomy was performed more often than thoracoscopy (482 vs. 86). Comparison of current versus former smokers showed no difference in OS or PFS after resection. Higher CSM was seen in current smokers (p = 0.049). Subset analysis of current smokers revealed no difference in OS or PFS between sub-lobar and lobar resection or thoracotomy and thoracoscopy. Although higher CSM was associated with thoracoscopy versus thoracotomy in this group, this finding was limited by a relatively small thoracoscopy sample size of 44 patients (p = 0.026). CONCLUSION: Our analysis of the NLST database shows no significant difference in OS and PFS when comparing current and former smokers undergoing resection for stage I NSCLC. Active smoking status was associated with higher CSM. Subset analysis of current smokers showed no difference in OS or PFS between sub-lobar and lobar resection or thoracotomy and thoracoscopy. Higher CSM was seen in current smokers who underwent thoracoscopy compared to thoracotomy; however, this finding was limited by a small sample size.

Exhaled SARS-CoV-2 quantified by face-mask sampling in hospitalised patients with COVID-19.

BACKGROUND: Human to human transmission of SARS-CoV-2 is driven by the respiratory route but little is known about the pattern and quantity of virus output from exhaled breath. We have previously shown that face-mask sampling (FMS) can detect exhaled tubercle bacilli and have adapted its use to quantify exhaled SARS-CoV-2 RNA in patients admitted to hospital with Coronavirus Disease-2019 (COVID-19). METHODS: Between May and December 2020, we took two concomitant FMS and nasopharyngeal samples (NPS) over two days, starting within 24 h of a routine virus positive NPS in patients hospitalised with COVID-19, at University Hospitals of Leicester NHS Trust, UK. Participants were asked to wear a modified duckbilled facemask for 30 min, followed by a nasopharyngeal swab. Demographic, clinical, and radiological data, as well as International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) mortality and deterioration scores were obtained. Exposed masks were processed by removal, dissolution and analysis of sampling matrix strips fixed within the mask by RT-qPCR. Viral genome copy numbers were determined and results classified as Negative; Low: ≤999 copies; Medium: 1000-99,999 copies and High ≥ 100,000 copies per strip for FMS or per 100 µl for NPS. RESULTS: 102 FMS and NPS were collected from 66 routinely positive patients; median age: 61 (IQR 49 - 77), of which FMS was positive in 38% of individuals and concomitant NPS was positive in 50%. Positive FMS viral loads varied over five orders of magnitude (<10-3.3 x 106 genome copies/strip); 21 (32%) patients were asymptomatic at the time of sampling. High FMS viral load was associated with respiratory symptoms at time of sampling and shorter interval between sampling and symptom onset (FMS High: median (IQR) 2 days (2-3) vs FMS Negative: 7 days (7-10), p = 0.002). On multivariable linear regression analysis, higher FMS viral loads were associated with higher ISARIC mortality (Medium FMS vs Negative FMS gave an adjusted coefficient of 15.7, 95% CI 3.7-27.7, p = 0.01) and deterioration scores (High FMS vs Negative FMS gave an adjusted coefficient of 37.6, 95% CI 14.0 to 61.3, p = 0.002), while NPS viral loads showed no significant association. CONCLUSION: We demonstrate a simple and effective method for detecting and quantifying exhaled SARS-CoV-2 in hospitalised patients with COVID-19. Higher FMS viral loads were more likely to be associated with developing severe disease compared to NPS viral loads. Similar to NPS, FMS viral load was highest in early disease and in those with active respiratory symptoms, highlighting the potential role of FMS in understanding infectivity.

The Destiny of Postoperative Residual Ventricular Septal Defects After Surgical Repair in Infants and Children.

PURPOSE: Residual ventricular septal defects (rVSDs) of small size are commonly seen on transesophageal echocardiography after surgical repair. This study aimed to determine the destiny of rVSD found on intraoperative echocardiogram. METHODS: Patients undergoing surgical repair of VSD as the primary procedure with available intraoperative and discharge echocardiograms between 2007 and 2017 were reviewed. Presence of an rVSD on intraoperative echo triggered review of discharge echo and of subsequent follow-up echocardiograms. RESULTS: One hundred four patients were analyzed. The mean age and weight for the entire cohort were 1.4 ± 2.9 years (median, 5.4 months; range, 29 days to 14 years) and 8.8 ± 9.9 kg (median, 5.1 kg; range, 2.7-58 kg), respectively. Sixty (57%) patients had rVSD at discharge, with mean size of residual VSD of 1.38 ± 0.92 mm (mode, 0.6; median, 2.2 mm; range, 0.5-3.9 mm). The mean follow-up time was 3.7 ± 3.1 years (range, 1 month to 9.3 years). Among those with rVSD at discharge, a residual shunt persisted in 73% at one-month follow-up. On follow-up at three years postdischarge, of the 60 patients with early rVSD, 6 had a persistent rVSD (10%) with a mean diameter of 3.0 ± 0.8 mm (range, 2.4-3.9 mm). CONCLUSIONS: Residual VSD after surgical repair is detected frequently on postoperative echocardiogram. The presence of rVSD was not associated with any preoperative, intraoperative, or postoperative factors. By three years of follow-up, only six patients continued to demonstrate rVSD with a mean diameter of 3 mm, suggesting that defects 3 mm or greater may be less likely to close spontaneously after three years.

Modified Blood Patch Used to Treat a High Output Chyle Leak After McKeown Esophagectomy.

Chyle leaks after esophagectomy are associated with significant morbidity and mortality. High-output fistulas are particularly difficult to manage, as the likelihood of spontaneous closure with conservative management is low. Leaks that fail to resolve with conservative management are referred for thoracic duct ligation or embolization. Some patients, however, are not candidates for these procedures or have persistent output despite intervention. We report a case of a post-McKeown esophagectomy patient with a high-output chyle leak despite intraoperative thoracic duct ligation. Treatment was successful with a modified blood patch through a neck drain.

Left Ventricular Function Recovery After Transapical TAVR in Patients With Previous Coronary Artery Bypass Graft Surgery.

OBJECTIVE: The transapical (TA) approach is an alternative access technique for transcatheter aortic valve replacement (TAVR) in patients with symptomatic aortic valve stenosis. The impact of prior coronary artery bypass graft (CABG) surgery and how it affects left ventricular function recovery is not well defined. METHODS: Patients who had TAVR at a single center between June 2012 and December 2016 were reviewed. High-risk patients who underwent the procedure via a TA approach were divided into 2 groups based on their history of CABG surgery. Postoperative outcomes were compared between groups. CABG/TA-TAVR patients were subdivided into 2 per baseline left ventricular ejection fraction (LVEF) <50%. The changes in LVEF and valve function at follow-up (1 to 12 months) were analyzed using paired t-tests. RESULTS: Of 923 cases in total, 183 (19.8%) were performed via a TA approach. The mean ± SD Society of Thoracic Surgeons risk score of TA patients was 10.2 ± 4.6. Forty-nine (27%) had a surgical history of CABG. Overall all-cause mortality rates at 30 days, 1 year, and 2 years were similar for both groups (P = 0.59, P = 0.64, P = 0.78). Subgrouping of CABG-TAVR patients (n = 49) identified 24 patients (49%) with LVEF ≥50% vs. 25 (51%) with LVEF <50%. At 1-year follow-up, significant improvements in LVEF (low LVEF group) and valve function for both groups were observed. LVEF ≥50% group (LVEF: ∆: -3%, P = 0.878; aortic valve area [AVA]: ∆: 1.3 cm2, P < 0.001; mean gradient: ∆: -38 mmHg, P < 0.001); LVEF <50% group (LVEF: ∆: 10%, P = 0.01; AVA: ∆: 1.3 cm2, P < 0.001; MG: ∆: -31 mmHg, P < 0.001). CONCLUSIONS: TA-TAVR can be safely performed with acceptable postoperative outcomes in patients with a history of CABG surgery. In those with reduced EF, significant improvements in LV and valve functions are seen at 1-year follow-up.

Emergent Repair of Paraesophageal Hernias and the Argument for Elective Repair.

BACKGROUND AND OBJECTIVES: A feared complication of large paraesophageal hernias is incarceration necessitating emergent repair. According to previous studies, patients who require an emergent operation are subject to increased morbidity compared with patients undergoing elective operations. In this study, we detail patients who underwent hernia repair emergently and compare their outcomes with elective patients. METHODS: A retrospective analysis was performed of the paraesophageal hernia repair operations between 2010 and 2016. Patients were divided into 2 groups: patients with hernias that were repaired electively and patients with hernias that were repaired emergently. Perioperative complications and follow-up data regarding morbidity, mortality, and recurrence were also recorded. A propensity analysis was used to compare emergent and elective groups. RESULTS: Thirty patients had hernias repaired emergently, and 199 patients underwent elective procedures. Patients undergoing emergent repair were more likely to have a type IV hernia, have a partial gastrectomy or gastrostomy tube insertion as part of their procedure, have a postoperative complication, and have a longer hospital stay. However, propensity analysis was used to demonstrate that when characteristics of the emergent and elective groups were matched, differences in these factors were no longer significant. Having an emergent operation did not increase a patient's risk for recurrence. CONCLUSION: Patients who had their hernias repaired emergently experienced complications at similar rates as those of elective patients with advanced age or comorbid conditions as demonstrated by the propensity analysis. The authors therefore recommend evaluation of all paraesophageal hernias for elective repair, especially in younger patients who are otherwise good operative candidates.

The Eating Habits Confidence Survey: reliability and validity in overweight and obese postmenopausal women.

BACKGROUND AND PURPOSE: Psychometric properties of the Eating Habits Confidence Survey (EC) were evaluated in a sample of 86 overweight and obese postmenopausal women. METHODS: Inter-item correlations and coefficient alphas of the total and subscale scores were conducted. Correlations of the EC to the Eating Self-Efficacy Scale (ESES), Eating Behavior Inventory (EBI), and Binge Eating Scale (BES) were examined as approaches to concurrent and contrast validity. RESULTS: Cronbach's alphas were adequate for total (.83) and subscale (.64-.80) scores. Only the EC subscale "sticking to it" correlated with the other eating scales. This correlation demonstrates concurrent validity with the other scales that reflected persistence in healthy eating, and contrast validity with them in that the other scales measured different issues under the rubric of eating self-efficacy and behaviors. CONCLUSIONS: Thus, the EC performed well among a different demographic than those used during its development. This inexpensive and easily administered survey manifests credible validity and reliability. Nevertheless, evidence for its validity and reliability needs to be accrued when it is used in diverse populations.

Initial development and testing of a questionnaire of parental self-efficacy for enacting healthy lifestyles in their children.

PURPOSE: The purpose of this study was to develop and test a questionnaire to assess parental self-efficacy for enacting healthy diet and physical activity behaviors in their 6- to 11-year-old children. DESIGN AND METHODS: A 35-item questionnaire was developed and tested with 146 U.S. parents. RESULTS: Participant responses resulted in a 34-item questionnaire with two subscales (dietary behaviors and physical activity behaviors), which were valid and reliable in the study sample. PRACTICE IMPLICATIONS: This new measure will serve as a tool for the assessment of parental self-efficacy for enacting healthy lifestyles in their children 6-11 years old.

Evaluation of trend localization with multi-variate visualizations.

Multi-valued data sets are increasingly common, with the number of dimensions growing. A number of multi-variate visualization techniques have been presented to display such data. However, evaluating the utility of such techniques for general data sets remains difficult. Thus most techniques are studied on only one data set. Another criticism that could be levied against previous evaluations of multi-variate visualizations is that the task doesn't require the presence of multiple variables. At the same time, the taxonomy of tasks that users may perform visually is extensive. We designed a task, trend localization, that required comparison of multiple data values in a multi-variate visualization. We then conducted a user study with this task, evaluating five multivariate visualization techniques from the literature (Brush Strokes, Data-Driven Spots, Oriented Slivers, Color Blending, Dimensional Stacking) and juxtaposed grayscale maps. We report the results and discuss the implications for both the techniques and the task.

Seroreactivities against Saccharomyces cerevisiae and Mycobacterium avium subsp. paratuberculosis p35 and p36 antigens in Crohn's disease patients.

Crohn's disease (CD) is an idiopathic chronic inflammatory bowel disease (IBD). Accurate diagnosis of the disease is of great clinical importance to assess its prognosis and success of therapy. Recent studies have validated and confirmed the potential utility of anti-Saccharomyces cerevisiae (baker's yeast; ASCA) IgG/IgA antibodies and anti-M. avium ss. paratuberculosis p35/p36 antibodies, separately, as serological markers to identify patients with CD. The efficacy of these markers was evaluated in the same patients with Crohn's disease. The anti-ASCA IgA/IgG and the anti-M. avium ss. paratuberculosis p35/p36 antibodies were positive in 60% (36/60) and 86.7% (52/60) of CD patients, respectively. When all the serologic markers were considered, the sensitivity in detecting CD was increased to 95.0% (57/60); 21 of 24 ASCA-negative patients were p35/p36-positive and five of eight of p35/p36-negative patients were ASCA-positive. This investigation further establishes the utility of p35 and p36 recombinant clones for the diagnosis of CD, and reveals the complimentary role of ASCA and p35 and p36 for effective detection of CD. Larger studies are needed to investigate the combined use of these serologic markers for the diagnosis of CD.