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Objective: This study described the structural and mechanical changes in the left atrium (LA) and left ventricle (LV) in a canine model of chronic mitral regurgitation (MR), in an attempt to identify markers linked to the onset of atrial tachyarrhythmias (ATA) or LV dysfunction., Methods: Animals underwent baseline and terminal echocardiography and cardiac magnetic resonance imaging. Under echocardiographic guidance, chordae tendinae were avulsed until there was severe MR, defined by regurgitant jet area to LA area (RJA/LAA) of >70%. At terminal surgery, rapid atrial pacing was performed to test inducibility of ATA., Result: Twelve canines underwent mitral valve chordae avulsion and were survived for an average of 8.8 ± 1.3 months. LA volume increased over 111% (p < 0.01), LV end systolic volumes increased over 57% (p < 0.01), and LV end diastolic volumes increased over 48% (p < 0.01). Increased LV mass was negatively correlated to ejection fraction (EF) (p = 0.01). During rapid atrial pacing, six canines developed inducible atrial arrhythmias. There were no differences in LA volume, function or LV strain between canines with ATAs and those without. Independently, six developed LV dysfunction with an average decrease of EF of 16 ± 4%. Canines with reduced EF experienced markedly increased LAV min (p = 0.02) and impaired LV global radial strain (GRS) (p = 0.05)., Conclusion: Our experimental canine model replicated electrophysiological and hemodynamic consequences of clinical MR. Although LA function and LV strain did not associate with ATA inducibility, LAV min , LV mass, and LV GRS emerged as potential indicators of LV dysfunction. These markers may have clinical value in guiding timely surgical intervention., (Copyright © 2025. Published by Elsevier Inc.)

Background: The role of IL-6 responses in human tuberculosis risk is unknown. IL-6 signalling inhibitors, such as tocilizumab, are thought to increase the risk of progression to tuberculosis, and screening for latent Mycobacterium tuberculosis infection before using these drugs is widely recommended. We used single nucleotide polymorphisms (SNPs) in and near the IL-6 receptor gene (IL6R), including the non-synonymous variant, rs2228145, for which the C allele contributes to reduced classic (cis) IL-6 signalling activity, to test the hypothesis that altered IL-6 signalling is causally associated with the risk of developing tuberculosis., Methods: We performed a meta-analysis of genome-wide association studies (GWAS) published in English from database inception to Jan 1, 2024. GWAS were identified from the European Bioinformatics Institute, MRC Integrative Epidemiology Unit catalogues, and MEDLINE, selecting publicly available studies for which tuberculosis was an outcome and that included the IL6R rs2228145 SNP. Using each study's population-level summary statistics, effect estimates were extracted for each additional copy of the C allele of rs2228145. We used these estimates to perform multi-ancestry, two-sample mendelian randomisation analyses to estimate the causal effect of reduced IL-6 signalling on tuberculosis. Our primary analyses used rs2228145-C as a genetic instrument, weighted on C-reactive protein (CRP) reduction as a measure of the effect on IL-6 signalling. We also took an alternative, ancestry-specific, multiple SNP approach using IL-6 receptor plasma protein as an exposure. Additionally, we compared the effects of rs2228145 in tuberculosis with those in critical COVID-19, rheumatoid arthritis, Crohn's disease, and coronary artery disease using the summary statistics extracted from GWAS., Findings: 17 GWAS were included, collating data for 19 302 individuals with tuberculosis (cases) and 1 019 821 population controls across multiple ancestries. For each additional rs2228145-C allele, the odds of tuberculosis reduced (odds ratio [OR] 0·94 [95% CI 0·92-0·97]; p=6·8 × 10 -6 ). Multi-ancestry mendelian randomisation analyses supported these findings, with decreased odds of tuberculosis associated with readouts of reduced IL-6 signalling (0·52 [0·39-0·69] for each natural log CRP decrease; p=6·8 × 10 -6 ), with weak evidence of heterogeneity (I 2 =0·315; p=0·11). Ancestry-specific, multiple SNP mendelian randomisation using increase in IL-6 receptor plasma protein as an exposure revealed a similar reduced risk of tuberculosis (OR 0·94 [95% CI 0·93-0·96]; p=2·4 × 10 -10 ). The protective effects on tuberculosis seen with rs2228145-C were similar in size and direction to those observed in critical COVID-19 (0·66 [0·50-0·86]), Crohn's disease (0·57 [0·44-0·74]), and rheumatoid arthritis (0·45 [0·36-0·58]), all of which benefit from the therapeutic effects of IL-6 antagonism., Interpretation: Our findings propose a causal relationship between reduced IL-6 signalling and lower risk of tuberculosis, akin to the effect seen in other IL-6 mediated diseases. This study suggests that IL-6 antagonists do not increase the risk of tuberculosis but rather should be investigated as therapeutic adjuncts in its treatment., Funding: UK National Institute for Health and Care Research, Wellcome Trust, EU European Regional Development Fund, the Welsh Government, and UK Research and Innovation., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction : At our tertiary orthopaedic centre, mycobacterial cultures are routinely performed on bone and joint samples sent for bacterial culture. Methods : From laboratory records, we ascertained the number of mycobacterial cultures performed, the number positive for Mycobacterium tuberculosis complex (MTBC) and/or non-tuberculous mycobacteria (NTM), and the characteristics of individuals from whom mycobacteria were isolated. We collected the same data from 100 individuals with negative mycobacterial cultures. Results : Excluding sample types that were not bone or joint samples, 6162 mycobacterial cultures were performed between 4 July 2017 and 30 September 2022. A total of 22 patients had MTBC and 6 patients had NTM newly isolated from bone or joint samples placed in mycobacterial culture, while a further 1 patient had both Mycobacterium tuberculosis and Mycobacterium avium isolated. To identify one new mycobacterial infection of bone or joint (MTBC or NTM) that would not have been detected with routine bacterial cultures alone, 229 (95 % CI of 158-347) mycobacterial cultures were needed. Mycobacterial cultures were much less likely to be positive in samples taken from prosthetic joints. They were more likely to be positive in spinal samples and in samples taken from patients with suspected sarcoma. In patients from whom MTBC had been isolated, granulomatous inflammation was reported in 86 % (18 of 21) of contemporaneous histological specimens. Conclusions : Targeted, rather than routine, mycobacterial culture of bone and joint specimens should be considered in settings with a low burden of tuberculosis., Competing Interests: The contact author has declared that none of the authors has any competing interests., (Copyright: © 2024 Tom A. Yates et al.)

Most phase III trials in drug-resistant tuberculosis have either been underpowered to quantify differences in microbiological endpoints or have taken up to a decade to complete. Composite primary endpoints, dominated by differences in treatment discontinuation and regimen changes, may mask important differences in treatment failure and relapse. Although new regimens for drug-resistant tuberculosis appear very effective, resistance to new drugs is emerging rapidly. There is a need for shorter, safer and more tolerable regimens, including those active against bedaquiline-resistant tuberculosis. Transitioning from multiple regimen A versus regimen B trials to a single large phase III platform trial would accelerate the acquisition of robust estimates of relative efficacy and safety. Further efficiencies could be achieved by adopting modern adaptive platform designs. Collaboration among trialists, affected community representatives, funders and regulators is essential for developing such a phase III platform trial for drug-resistant tuberculosis treatment regimens., ((c) 2024 The authors; licensee World Health Organization.)

Tuberculin skin test surveys in primary school children can be used to quantify Mycobacterium tuberculosis transmission at community level. KwaZulu-Natal province, South Africa, is home to 11.5 million people and suffers a burden of tuberculosis disease that is among the highest in the world. The last tuberculin survey in the province was undertaken in 1979. We performed a tuberculin skin test survey nested within a demographic and health household surveillance programme in Northern KwaZulu-Natal. We enrolled children aged between six and eight years of age attending primary schools in this community. Mixture analysis was used to determine tuberculin skin test thresholds and the Annual Risk of Tuberculous Infection derived from age at testing and infection prevalence. The Community Infection Ratio, a measure of the relative importance of within-household and community transmission, was calculated from data on tuberculin positivity disaggregated by household tuberculosis contact. Between June and December 2013, we obtained tuberculin skin test results on 1240 children. Mixture analysis proved unstable, suggesting two potential thresholds for test positivity. Using a threshold of ≥10mm or treating all non zero reactions as positive yielded estimates of the Annual Risk of Tuberculous Infection of 1.7% (1.4-2.1%) or 2.4% (2.0-3.0%). Using the same thresholds and including children reported to be receiving TB treatment as cases, resulted in estimates of 2.0% (1.6-2.5%) or 2.7% (2.2-3.3%). The Community Infection Ratio was 0.58 (0.33-1.01). The force of infection in this community is lower than that observed in Western Cape province, South Africa, but higher than that observed in community settings in most other parts of the world. Children in this community are commonly infected with Mycobacterium tuberculosis outside the home. Interventions to interrupt transmission are urgently needed., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Yates et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The heritability of susceptibility to tuberculosis (TB) disease has been well recognized. Over 100 genes have been studied as candidates for TB susceptibility, and several variants were identified by genome-wide association studies (GWAS), but few replicate. We established the International Tuberculosis Host Genetics Consortium to perform a multi-ancestry meta-analysis of GWAS, including 14,153 cases and 19,536 controls of African, Asian, and European ancestry. Our analyses demonstrate a substantial degree of heritability (pooled polygenic h 2 = 26.3%, 95% CI 23.7-29.0%) for susceptibility to TB that is shared across ancestries, highlighting an important host genetic influence on disease. We identified one global host genetic correlate for TB at genome-wide significance (p<5 × 10 -8 ) in the human leukocyte antigen (HLA)-II region (rs28383206, p-value=5.2 × 10 -9 ) but failed to replicate variants previously associated with TB susceptibility. These data demonstrate the complex shared genetic architecture of susceptibility to TB and the importance of large-scale GWAS analysis across multiple ancestries experiencing different levels of infection pressure., Competing Interests: HS, VN, TY, JG, TP, PD, MM, EH, AM, AH No competing interests declared, (© 2024, Schurz et al.)

Objective: A right minithoracotomy (RMT) is a minimally invasive surgical approach that has been increasingly performed for the concomitant Cox maze IV procedure (CMP) and mitral valve surgery (MVS). Little is known regarding whether long-term rhythm and survival outcomes are affected by the RMT as compared with the traditional median sternotomy (MS) approach., Methods: Between April 2004 and April 2021, 377 patients underwent the concomitant CMP and MVS, of whom 38% had RMT. Propensity score matching yielded 116 pairs. Freedom from atrial tachyarrhythmias (ATA) was assessed with prolonged monitoring annually for 8 years. Survival, rhythm, and perioperative outcomes were compared., Results: The unmatched RMT cohort had a greater freedom from ATA recurrence at 1 year (99% vs 90%, P = 0.001) and 3 years (94% vs 86%, P = 0.045). The matched RMT cohort had longer cardiopulmonary bypass (median: 215 [199 to 253] vs 170 [136 to 198] min, P < 0.001) and aortic cross-clamp (110 [98 to 124] vs 86 [71 to 102] min, P < 0.001) times but shorter intensive care time (48 [24 to 95] vs 71 [26 to 144] h, P = 0.001) and length of stay (8 [6 to 11] vs 10 [7 to 14] h, P < 0.001). More pacemakers (18% vs 4%, P < 0.001) and postoperative transfusions (57% vs 41%, P = 0.014) occurred in the MS cohort. The 30-day mortality ( P = 0.651) and 8-year survival ( P = 0.072) was not significantly different between the cohorts., Conclusions: Early 1-year and 3-year freedom from ATA recurrence was better in the RMT cohort compared with the MS cohort. Despite longer operative times, the RMT cohort had shorter lengths of stay, fewer postoperative transfusions, and fewer pacemakers placed., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Ralph J. Damiano, Jr, MD, is a consultant for Medtronic and Edwards Lifesciences and a speaker for AtriCure Inc.

Objectives: The mechanism by which mitral valve (MV) disease leads to atrial fibrillation (AF) remains poorly understood. Delayed-enhancement cardiac magnetic resonance imaging (DE-MRI) has been used to assess left atrial (LA) fibrosis in patients with lone AF before catheter ablation; however, few studies have used DE-MRI to assess MV-induced LA fibrosis in patients with or without AF undergoing MV surgery., Methods: Between March 2018 and September 2022, 38 subjects were enrolled; 15 age-matched controls, 14 patients with lone mitral regurgitation (MR), and 9 patients with MR and AF (MR + AF). Indexed LA volume, total LA wall, and regional LA posterior wall (LAPW) enhancement were defined by the DE-MRI. One-way analysis of variance was performed., Results: LA volume and LA enhancement were associated (r = 0.451, P  = .004). LA volume differed significantly between controls (37.1 ± 10.6 mL) and patients with lone MR (71.0 ± 35.9, P  = .020 and controls and patients with MR + AF (99.3 ± 47.4, P  < .001). The difference in LA enhancement was significant between MR + AF (16.7 ± 9.6%) versus controls (8.3 ± 3.9%, P  = .006) and MR + AF versus lone MR (8.0 ± 4.8%, P  = .004). Similarly, the was significantly more LAPW enhancement in the MR + AF (17.5 ± 8.7%) versus control (9.2 ± 5.1%, P  = .011) and MR + AF versus lone MR (9.8 ± 6.0%, P  = .020)., Conclusions: Patients with MR + AF had significantly more total and LAPW fibrosis compared with both controls and lone MR. Volume and delayed enhancement were associated, but there was no difference between MR and MR + AF., Competing Interests: Ralph J. Damiano, MD, discloses a financial relationship with Medtronic, Inc, AtriCure, Inc, and Edwards Lifesciences. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (© 2023 The Author(s).)

Background: Bipolar radiofrequency (RF) clamps are commonly used during surgical ablation for atrial fibrillation (AF). This study examined the efficacy of an irrigated bipolar RF clamp to create transmural lesions in an ex vivo human heart model., Methods: Ten donor hearts, turned down for transplantation, were explanted and arrested with cold cardioplegia. The ablations of the Cox Maze IV procedure were performed using the Cardioblate LP (Medtronic, Inc) irrigated bipolar RF clamp. In the first 5 hearts, each lesion was created with a single application of RF, whereas in the remaining 5 hearts, each lesion was created with a double application of RF without unclamping. Each lesion was cross-sectioned and stained with 2,3,5-triphenyl-tetrazolium chloride to assess ablation depth and transmurality., Results: A total of 100 lesions were analyzed. In the single-ablation group, 222 of 260 sections (85%) and 37 of 50 lesions (74%) were transmural. The efficacy improved significantly in the double-ablation group, in which 348 of 359 sections (97%, P < .001) and 46 of 50 lesions (92%, P = .017) were transmural. Overall, in nontransmural lesions, the epicardial fat thickness was significantly greater (1.69 ± 0.70 mm vs 0.45 ±0.10 mm, P < .001) than the transmural lesions., Conclusions: A single ablation on human atrial tissue with an irrigated bipolar RF clamp was insufficient to reliably create transmural lesions, but a double ablation significantly increased the lesion and section transmurality. Nontransmural lesions were associated with significantly thicker layers of epicardial fat, which likely decreased tissue energy delivery due to the higher resistance of fat to current flow., (Copyright © 2023 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Gastro-oesophageal reflux disease (GORD) is associated with idiopathic pulmonary fibrosis (IPF) in observational studies. It is not known if this association arises because GORD causes IPF or because IPF causes GORD, or because of confounding by factors, such as smoking, associated with both GORD and IPF. We used bidirectional Mendelian randomisation (MR), where genetic variants are used as instrumental variables to address issues of confounding and reverse causation, to examine how, if at all, GORD and IPF are causally related., Methods: A bidirectional two-sample MR was performed to estimate the causal effect of GORD on IPF risk and of IPF on GORD risk, using genetic data from the largest GORD (78 707 cases and 288 734 controls) and IPF (4125 cases and 20 464 controls) genome-wide association meta-analyses currently available., Results: GORD increased the risk of IPF, with an OR of 1.6 (95% CI 1.04-2.49; p=0.032). There was no evidence of a causal effect of IPF on the risk of GORD, with an OR of 0.999 (95% CI 0.997-1.000; p=0.245)., Conclusions: We found that GORD increases the risk of IPF, but found no evidence that IPF increases the risk of GORD. GORD should be considered in future studies of IPF risk and interest in it as a potential therapeutic target should be renewed. The mechanisms underlying the effect of GORD on IPF should also be investigated., Competing Interests: Conflict of interest: R.G. Jenkins reports grants from AstraZeneca, Biogen, Galecto, GlaxoSmithKline, RedX, Pliant and Genetech, consulting fees from Bristol-Myers Squibb, Daewoong, Veracyte, Resolution Therapeutics, RedX, Pliant and Chiesi, and advisory board participation with Boehringer Ingelheim, Galapagos, Vicore and Roche, outside the submitted work, and has a leadership role with NuMedii, and a leadership role and is a trustee for Action for Pulmonary Fibrosis. T.M. Maher reports consulting fees from Boehringer Ingelheim, Roche/Genentech, AstraZeneca, Bayer, Blade Therapeutics, Bristol-Myers Squibb, Galapagos, Galecto, GlaxoSmithKline, IQVIA, Pliant, Respivant, Theravance and Veracyte, and lecture honoraria from Boehringer Ingelheim and Roche/Genentech, outside the submitted work. P.L. Molyneaux reports grants from AstraZeneca, consulting fees from Hoffman-La Roche, Boehringer Ingelheim, Trevi, Redex and AstraZeneca, and lecture honoraria from Boehringer Ingelheim and Hoffman-La Roche, outside the submitted work. L.V. Wain reports grants from Orion Pharma, GlaxoSmithKline, Genentech and AstraZeneca, consulting fees from Galapagos and Boehringer Ingelheim, travel support from Genentech, and advisory board participation with Galapagos, outside the submitted work; and is an Associate Editor for the European Respiratory Journal. All other authors have nothing to disclose., (Copyright ©The authors 2023.)

Background: Malakoplakia is a rare condition characterized by inflammatory masses with specific histological characteristics. These soft tissue masses can mimic tumors and tend to develop in association with chronic or recurrent infections, typically of the urinary tract. A specific defect in innate immunity has been described. In the absence of randomized controlled trials, management is based on an understanding of the biology and on case reports., Case Presentation: Here we describe a case of presacral malakoplakia in a British Indian woman in her late 30s, presenting with complex unilateral foot drop. Four years earlier, she had suffered a protracted episode of intrapelvic sepsis following a caesarean delivery. Resection of her presacral soft tissue mass was not possible. She received empiric antibiotics, a cholinergic agonist, and ascorbic acid. She responded well to medical management both when first treated and following a recurrence of symptoms after completing an initial 8 months of therapy. Whole exome sequencing of the patient and her parents was undertaken but no clear causal variant was identified., Conclusions: Malakoplakia is uncommon but the diagnosis should be considered where soft tissue masses develop at the site of chronic or recurrent infections. Obtaining tissue for histological examination is key to making the diagnosis. This case suggests that surgical resection is not always needed to achieve a good clinical and radiological outcome., (© 2023. The Author(s).)

IL-6 responses are ubiquitous in Mycobacterium tuberculosis ( Mtb ) infections, but their role in determining human tuberculosis (TB) disease risk is unknown. We used single nucleotide polymorphisms (SNPs) in and near the IL-6 receptor ( IL6R ) gene, focusing on the non-synonymous variant, rs2228145, associated with reduced classical IL-6 signalling, to assess the effect of altered IL-6 activity on TB disease risk. We identified 16 genome wide association studies (GWAS) of TB disease collating 17,982 cases of TB disease and 972,389 controls across 4 continents. Meta-analyses and Mendelian randomisation analyses revealed that reduced classical IL-6 signalling was associated with lower odds of TB disease, a finding replicated using multiple, independent SNP instruments and 2 separate exposure variables. Our findings establish a causal relationship between IL-6 signalling and the outcome of Mtb infection, suggesting IL-6 antagonists do not increase the risk of TB disease and should be investigated as adjuncts in treatment.

Healthcare facilities are important sites for the transmission of pathogens spread via bioaerosols, such as Mycobacterium tuberculosis. Natural ventilation can play an important role in reducing this transmission. We aimed to measure rates of natural ventilation in clinics in KwaZulu-Natal and Western Cape provinces, South Africa, then use these measurements to estimate Mycobacterium tuberculosis transmission risk. We measured ventilation in clinic spaces using a tracer-gas release method. In spaces where this was not possible, we estimated ventilation using data on indoor and outdoor carbon dioxide levels. Ventilation was measured i) under usual conditions and ii) with all windows and doors fully open. Under various assumptions about infectiousness and duration of exposure, measured absolute ventilation rates were related to risk of Mycobacterium tuberculosis transmission using the Wells-Riley Equation. In 2019, we obtained ventilation measurements in 33 clinical spaces in 10 clinics: 13 consultation rooms, 16 waiting areas and 4 other clinical spaces. Under usual conditions, the absolute ventilation rate was much higher in waiting rooms (median 1769 m3/hr, range 338-4815 m3/hr) than in consultation rooms (median 197 m3/hr, range 0-1451 m3/hr). When compared with usual conditions, fully opening existing doors and windows resulted in a median two-fold increase in ventilation. Using standard assumptions about infectiousness, we estimated that a health worker would have a 24.8% annual risk of becoming infected with Mycobacterium tuberculosis, and that a patient would have an 0.1% risk of becoming infected per visit. Opening existing doors and windows and rearranging patient pathways to preferentially use better ventilated clinic spaces result in important reductions in Mycobacterium tuberculosis transmission risk. However, unless combined with other tuberculosis infection prevention and control interventions, these changes are insufficient to reduce risk to health workers, and other highly exposed individuals, to acceptable levels., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Beckwith et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Expert consensus guidelines recommend surgical ablation (SA) for patients with symptomatic atrial fibrillation (AF), but less than half of patients with AF undergoing cardiac procedures receive concomitant SA. Complete isolation of the left atrial posterior wall (LAPW) has been shown to be the most critical part of the Cox maze procedure. The purpose of this study was to investigate the performance of a novel radiofrequency (RF) bipolar device, EnCompass™ (AtriCure, Inc., Mason, OH, USA), designed to isolate the LAPW in a single application., Methods: Five adult pigs underwent SA in a beating heart model. After a single ablation, the heart was arrested, explanted, and stained with triphenyl-tetrazolium-chloride for histological assessment. Each lesion was sectioned, and the ablation depth, muscle, and fat thickness were determined. The lesion width, energy delivery, and ablation times were compared with those from a reference RF clamp (Synergy™, AtriCure)., Results: Transmurality was documented in 100% of lesions (5 of 5) and cross sections (160 of 160). Electrical isolation was documented in every instance. There was no evidence of clot, charring, or pulmonary vein stenosis. Compared with the reference clamp, the lesions created by the EnCompass™ clamp were 1.5 times wider on average. The average energy delivered was 5 times higher over a duration that was 4.5 times longer due to the increased volume of tissue ablated., Conclusions: The EnCompass™ clamp reproducibly created transmural isolation of the LAPW with a single application. This may allow for simplification of the SA strategy and increased adoption of AF treatment during concomitant surgery.

Transmission of respiratory pathogens, such as Mycobacterium tuberculosis and severe acute respiratory syndrome coronavirus 2, is more likely during close, prolonged contact and when sharing a poorly ventilated space. Reducing overcrowding of health facilities is a recognised infection prevention and control (IPC) strategy; reliable estimates of waiting times and 'patient flow' would help guide implementation. As part of the Umoya omuhle study, we aimed to estimate clinic visit duration, time spent indoors versus outdoors, and occupancy density of waiting rooms in clinics in KwaZulu-Natal (KZN) and Western Cape (WC), South Africa. We used unique barcodes to track attendees' movements in 11 clinics, multiple imputation to estimate missing arrival and departure times, and mixed-effects linear regression to examine associations with visit duration. 2,903 attendees were included. Median visit duration was 2 hours 36 minutes (interquartile range [IQR] 01:36-3:43). Longer mean visit times were associated with being female (13.5 minutes longer than males; p<0.001) and attending with a baby (18.8 minutes longer than those without; p<0.01), and shorter mean times with later arrival (14.9 minutes shorter per hour after 0700; p<0.001). Overall, attendees spent more of their time indoors (median 95.6% [IQR 46-100]) than outdoors (2.5% [IQR 0-35]). Attendees at clinics with outdoor waiting areas spent a greater proportion (median 13.7% [IQR 1-75]) of their time outdoors. In two clinics in KZN (no appointment system), occupancy densities of ~2.0 persons/m2 were observed in smaller waiting rooms during busy periods. In one clinic in WC (appointment system, larger waiting areas), occupancy density did not exceed 1.0 persons/m2 despite higher overall attendance. In this study, longer waiting times were associated with early arrival, being female, and attending with a young child. Occupancy of waiting rooms varied substantially between rooms and over the clinic day. Light-touch estimation of occupancy density may help guide interventions to improve patient flow., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Karat et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Stakeholder engagement helps ensure that research is relevant, clinical innovations are responsive, and healthcare services are patient-centered., Objective: Establish and sustain a Veteran engagement board involving older Veterans and caregivers to provide input on aging-related research and clinical demonstration projects., Design and Participants: The Older Veteran Engagement Team (OVET)-a group of eight Veterans and one caregiver who range in age from 62 to 92-was formed in November 2017 and has met monthly since January 2018. The OVET provides feedback on topics that reflect the foci of the VA Eastern Colorado Geriatric Research Education and Clinical Center (GRECC) (e.g., physical functioning, hearing health, and emotional wellness/mental health). Ongoing evaluation documents the return on investment of Veteran engagement., Main Measures: The OVET member and provider/investigator meeting evaluations with longitudinal follow-up at 6 and 12 months., Results: Return on investment of Veteran engagement is multi-faceted. For OVET, ROI ranges from grant support to improved healthcare quality/efficiency to social-emotional benefits. To date, funding awards total over $2.3 M for NIH and VA-funded projects to which OVET provided substantive feedback. Documented impacts on healthcare services include reductions in patient wait times, more appropriate utilization of services and increased patient satisfaction. Social-emotional benefits include generativity, as OVET members contribute to improving clinical and community-based supports for other Veterans. The OVET provides an opportunity for older Veterans to share their lived experience with trainees and early career investigators who are preparing for careers serving Veterans., Conclusion: The OVET is similar to other established stakeholder engagement groups; team members offer their individual viewpoints at any stage of research, clinical demonstration, or quality improvement projects. The OVET provides a mechanism for the voice of older Veterans and caregivers to shape aspects of individual projects. Importantly, these projects support patient-centered care and promote the characteristics of an age-friendly healthcare system., (© 2021. The Author(s).)

Background: There is a high risk of Mycobacterium tuberculosis ( Mtb ) transmission in healthcare facilities in high burden settings. WHO guidelines on tuberculosis (TB) infection prevention and control (IPC) recommend a range of measures to reduce transmission in healthcare settings. These were evaluated primarily based on evidence for their effects on transmission to healthcare workers in hospitals. To estimate the overall impact of IPC interventions, it is necessary to also consider their impact on community-wide TB incidence and mortality., Methods: We developed an individual-based model of Mtb transmission in households, primary healthcare (PHC) clinics, and all other congregate settings. The model was parameterised using data from a high HIV prevalence community in South Africa, including data on social contact by setting, by sex, age, and HIV/antiretroviral therapy status; and data on TB prevalence in clinic attendees and the general population. We estimated the proportion of disease in adults that resulted from transmission in PHC clinics, and the impact of a range of IPC interventions in clinics on community-wide TB., Results: We estimate that 7.6% (plausible range 3.9%-13.9%) of non-multidrug resistant and multidrug resistant TB in adults resulted directly from transmission in PHC clinics in the community in 2019. The proportion is higher in HIV-positive people, at 9.3% (4.8%-16.8%), compared with 5.3% (2.7%-10.1%) in HIV-negative people. We estimate that IPC interventions could reduce incident TB cases in the community in 2021-2030 by 3.4%-8.0%, and deaths by 3.0%-7.2%., Conclusions: A non-trivial proportion of TB results from transmission in clinics in the study community, particularly in HIV-positive people. Implementing IPC interventions could lead to moderate reductions in disease burden. We recommend that IPC measures in clinics should be implemented for their benefits to staff and patients, but also for their likely effects on TB incidence and mortality in the surrounding community., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Elevated rates of tuberculosis in healthcare workers demonstrate the high rate of Mycobacterium tuberculosis (Mtb ) transmission in health facilities in high-burden settings. In the context of a project taking a whole systems approach to tuberculosis infection prevention and control (IPC), we aimed to evaluate the potential impact of conventional and novel IPC measures on Mtb transmission to patients and other clinic attendees., Methods: An individual-based model of patient movements through clinics, ventilation in waiting areas, and Mtb transmission was developed, and parameterised using empirical data from eight clinics in two provinces in South Africa. Seven interventions-codeveloped with health professionals and policy-makers-were simulated: (1) queue management systems with outdoor waiting areas, (2) ultraviolet germicidal irradiation (UVGI) systems, (3) appointment systems, (4) opening windows and doors, (5) surgical mask wearing by clinic attendees, (6) simple clinic retrofits and (7) increased coverage of long antiretroviral therapy prescriptions and community medicine collection points through the Central Chronic Medicine Dispensing and Distribution (CCMDD) service., Results: In the model, (1) outdoor waiting areas reduced the transmission to clinic attendees by 83% (IQR 76%-88%), (2) UVGI by 77% (IQR 64%-85%), (3) appointment systems by 62% (IQR 45%-75%), (4) opening windows and doors by 55% (IQR 25%-72%), (5) masks by 47% (IQR 42%-50%), (6) clinic retrofits by 45% (IQR 16%-64%) and (7) increasing the coverage of CCMDD by 22% (IQR 12%-32%)., Conclusions: The majority of the interventions achieved median reductions in the rate of transmission to clinic attendees of at least 45%, meaning that a range of highly effective intervention options are available, that can be tailored to the local context. Measures that are not traditionally considered to be IPC interventions, such as appointment systems, may be as effective as more traditional IPC measures, such as mask wearing., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: In light of the role that airborne transmission plays in the spread of SARS-CoV-2, as well as the ongoing high global mortality from well-known airborne diseases such as tuberculosis and measles, there is an urgent need for practical ways of identifying congregate spaces where low ventilation levels contribute to high transmission risk. Poorly ventilated clinic spaces in particular may be high risk, due to the presence of both infectious and susceptible people. While relatively simple approaches to estimating ventilation rates exist, the approaches most frequently used in epidemiology cannot be used where occupancy varies, and so cannot be reliably applied in many of the types of spaces where they are most needed., Methods: The aim of this study was to demonstrate the use of a non-steady state method to estimate the absolute ventilation rate, which can be applied in rooms where occupancy levels vary. We used data from a room in a primary healthcare clinic in a high TB and HIV prevalence setting, comprising indoor and outdoor carbon dioxide measurements and head counts (by age), taken over time. Two approaches were compared: approach 1 using a simple linear regression model and approach 2 using an ordinary differential equation model., Results: The absolute ventilation rate, Q, using approach 1 was 2407 l/s [95% CI: 1632-3181] and Q from approach 2 was 2743 l/s [95% CI: 2139-4429]., Conclusions: We demonstrate two methods that can be used to estimate ventilation rate in busy congregate settings, such as clinic waiting rooms. Both approaches produced comparable results, however the simple linear regression method has the advantage of not requiring room volume measurements. These methods can be used to identify poorly-ventilated spaces, allowing measures to be taken to reduce the airborne transmission of pathogens such as Mycobacterium tuberculosis, measles, and SARS-CoV-2., Competing Interests: The authors have declared that no competing interests exist.

Background: Ending the global tuberculosis (TB) epidemic requires a focus on treating individuals with latent TB infection (LTBI) to prevent future cases. Promising trials of shorter regimens have shown them to be effective as preventative TB treatment, however there is a paucity of data on self-administered treatment completion rates. This pilot trial assessed treatment completion, adherence, safety and the feasibility of treating LTBI in the UK using a weekly rifapentine and isoniazid regimen versus daily rifampicin and isoniazid, both self-administered for 12 weeks., Methods: An open label, randomised, multi-site pilot trial was conducted in London, UK, between March 2015 and January 2017. Adults between 16 and 65 years with LTBI at two TB clinics who were eligible for and agreed to preventative therapy were consented and randomised 1:1 to receive either a weekly combination of rifapentine/isoniazid ('intervention') or a daily combination of rifampicin/isoniazid ('standard'), with both regimens taken for twelve weeks; treatment was self-administered in both arms. The primary outcome, completion of treatment, was self-reported, defined as taking more than 90% of prescribed doses and corroborated by pill counts and urine testing. Adverse events were recorded., Results: Fifty-two patients were successfully enrolled. In the intervention arm 21 of 27 patients completed treatment (77.8, 95% confidence interval [CI] 57.7-91.4), compared with 19 of 25 (76.0%, CI 54.9-90.6) in the standard of care arm. There was a similar adverse effect profile between the two arms., Conclusion: In this pilot trial, treatment completion was comparable between the weekly rifapentine/isoniazid and the daily rifampicin/isoniazid regimens. Additionally, the adverse event profile was similar between the two arms. We conclude that it is safe and feasible to undertake a fully powered trial to determine whether self-administered weekly treatment is superior/non-inferior compared to current treatment., Trial Registration: The trial was funded by the NIHR, UK and registered with ISRCTN ( 26/02/2013-No.04379941 ).

Institutions such as hospitals and nursing or long-stay residential homes accommodate individuals at considerable risk of mortality should they acquire SARS-CoV-2 infection. In these settings, polymerase chain reaction tests play a central role in infection prevention and control. Here, we argue that both false negative and false positive tests are possible and that careful consideration of the prior probability of infection and of test characteristics are needed to prevent harm. We outline evidence suggesting that regular systematic testing of asymptomatic and pre-symptomatic individuals could play an important role in reducing transmission of SARS-CoV-2 within institutions. We discuss how such a programme might be organised, arguing that frequent testing and rapid reporting of results are particularly important. We highlight studies demonstrating that polymerase chain reaction testing of pooled samples can be undertaken with acceptable loss of sensitivity, and advocate such an approach where test capacity is limited. We provide an approach to calculating the most efficient pool size. Given the current limitations of tests for SARS-CoV-2 infection, physical distancing and meticulous infection prevention and control will remain essential in institutions caring for vulnerable people., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Yates TA et al.)

Infection prevention and control (IPC) measures to reduce transmission of drug-resistant and drug-sensitive tuberculosis (TB) in health facilities are well described but poorly implemented. The implementation of TB IPC has been assessed primarily through quantitative and structured approaches that treat administrative, environmental, and personal protective measures as discrete entities. We present an on-going project entitled Umoya omuhle ("good air"), conducted in two provinces of South Africa, that adopts an interdisciplinary, 'whole systems' approach to problem analysis and intervention development for reducing nosocomial transmission of Mycobacterium tuberculosis (Mtb) through improved IPC. We suggest that TB IPC represents a complex intervention that is delivered within a dynamic context shaped by policy guidelines, health facility space, infrastructure, organisation of care, and management culture. Methods drawn from epidemiology, anthropology, and health policy and systems research enable rich contextual analysis of how nosocomial Mtb transmission occurs, as well as opportunities to address the problem holistically. A 'whole systems' approach can identify leverage points within the health facility infrastructure and organisation of care that can inform the design of interventions to reduce the risk of nosocomial Mtb transmission.

BACKGROUND: In South Africa, it is generally estimated that only 0.5-0.6% of people's contacts occur in clinics. Both people with infectious tuberculosis and people with increased susceptibility to disease progression may spend more time in clinics, however, increasing the importance of clinic-based transmission to overall disease incidence. METHODS: We developed an illustrative mathematical model of Mycobacterium tuberculosis transmission in clinics and other settings. We assumed that 1% of contact time occurs in clinics. We varied the ratio of clinic contact time of human immunodeficiency virus (HIV) positive people compared to HIV-negative people, and of people with infectious TB compared to people without TB, while keeping the overall proportion of contact time occurring in clinics, and each person's total contact time, constant. RESULTS: With clinic contact rates respectively 10 and 5 times higher in HIV-positive people and people with TB, 10.7% (plausible range 8.5-13.4%) of TB resulted from transmission in clinics. With contact rates in HIV-positive people and people with TB respectively 5 and 2 times higher, 5.3% (plausible range 4.3-6.3%) of all TB was due to transmission in clinics. CONCLUSION: The small amount of contact time that generally occurs in clinics may greatly underestimate their contribution to TB disease in high TB-HIV burden settings.