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BACKGROUND: Increasing evidence suggests that post-TB lung disease (PTLD) causes significant morbidity and mortality. The aim of these clinical standards is to provide guidance on the assessment and management of PTLD and the implementation of pulmonary rehabilitation (PR).METHODS: A panel of global experts in the field of TB care and PR was identified; 62 participated in a Delphi process. A 5-point Likert scale was used to score the initial ideas for standards and after several rounds of revision the document was approved (with 100% agreement).RESULTS: Five clinical standards were defined: Standard 1, to assess patients at the end of TB treatment for PTLD (with adaptation for children and specific settings/situations); Standard 2, to identify patients with PTLD for PR; Standard 3, tailoring the PR programme to patient needs and the local setting; Standard 4, to evaluate the effectiveness of PR; and Standard 5, to conduct education and counselling. Standard 6 addresses public health aspects of PTLD and outcomes due to PR.CONCLUSION: This is the first consensus-based set of Clinical Standards for PTLD. Our aim is to improve patient care and quality of life by guiding clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage PTLD.

Intracellular organelle organisation is conserved in eukaryotic cells and is primarily achieved through active transport by motor proteins along the microtubule cytoskeleton. Microtubule posttranslational modifications (PTMs) contribute to microtubule diversity and differentially regulate motor-mediated transport. Here we show that centrosome amplification induces a global change in organelle positioning towards the cell periphery and facilitates nuclear migration through confined spaces. This reorganisation requires kinesin-1 and is analogous to loss of dynein. Cells with amplified centrosomes display increased levels of acetylated tubulin, a PTM known to enhance kinesin-1 mediated transport. Depletion of α-tubulin acetyltransferase 1 (αTAT1) to block tubulin acetylation, which has no impact on control cells, rescues the displacement of centrosomes, mitochondria and vimentin, but not Golgi or endosomes. Analyses of the distribution of acetylated microtubules indicates that the polarisation of modified microtubules, rather than levels alone, plays an important role in organelle positioning. We propose that tubulin acetylation differentially impacts kinesin-1-mediated organelle displacement, suggesting that each organelle must have its own sensing and response mechanisms to ensure fine-tuning of its distribution in cells.

Sustained TB infection overproduces reactive oxygen species (ROS) as a host defense mechanism. Research shows ROS is destructive to lung tissue. Glutathione (GSH) neutralizes ROS, although it is consumed. NAC is a precursor of GSH synthesis, and administering an appropriate dose of NAC to patients with respiratory conditions may enhance lung recovery and replenish GSH. The present review searched for articles reporting on the effects of NAC in TB treatment from 1960 to 31 May 2022. The PICO search strategy was used in Google Scholar, PubMed, SciFinder, and Wiley online library databases. The COVIDENCE tool was used to delete inappropriate content. We eventually discovered five clinical trials, one case report, seven reviews, in vitro research, and four experimental animal studies from the twenty-four accepted articles. The use of NAC resulted in increased GSH levels, decreased treatment time, and was safe with minimal adverse events. However, the evidence is currently insufficient to estimate the overall effects of NAC, thus the study warrants more NAC clinical trials to demonstrate its effects in TB treatment.

Climate change issues are heavily moralised, however, subtle differences in the moral reasoning patterns existing in the public discourse have not been fully illuminated. To address this, we have employed a variant of Zaltman Metaphor Elicitation Technique, which combines photo elicitation with environmental dilemmas that pit sacred-sacred and sacred-secular values against each other. The results from Extinction Rebellion activists and the general public reveal how groups internalise the value of nature and challenge the ecocentric-anthropocentric moral reasoning paradigm, disclosing how more subtle environmental value orientations are organised around the themes of destruction, short-sightedness, moral outrage, environmental movement, community, etc.

Rupioid skin lesions usually develop on a background of immunosuppression and are grossly hyperkeratotic cone-shaped plaques with thick, dark, adherent, and lamellate crusts resembling limpet shells.1 Relatively few etiologies, mainly infectious, are relevant to the differential diagnosis of rupioid presentations, including syphilis, HIV, scabies, histoplasmosis, rupioid psoriasis (RupP), or reactive arthritis.1 RupP is an uncommon condition resulting from a pronounced inflammatory response, leading to abnormal keratinized scale mixing with copious sero-exudate.2 The lesions exhibit classic histopathologic findings of psoriasis.1 Drug-provoked psoriasis (either drug-aggravated or drug-induced) is similarly infrequent, with lithium, beta-blockers, and antimalarials being the most common causative agents.3 Drug-induced RupP is extremely rare, with only a few reports in the literature (Table I). Table I Summary of drug-provoked rupioid psoriasis (RupP) cases identified in PubMed

This case report describes hyperpigmented, indurated, and sclerotic plaques on the anterior trunk and upper abdomen with overlying scale that were studded with firm, erythematous papules.

Pigeonpea [Cajanus cajan (L.) Millsp.] is a short-day legume species and the late maturing genotypes are more photosensitive than early types. To generate information about the inheritance of photo-sensitivity, this study was conducted under natural and artificially extended (16 h) photo-periods using F1, F2 and BC1F1 generations. Under natural photo-period, F1 hybrids showed partial dominance of earliness; while in F2 , a normal distribution that was skewed towards earliness was observed. In contrast under extended photo-period, the spread of F2 data was wide with discontinuities recorded at day 70, 82 and 103. Chisquare tests, when applied to F2 and BC1F1 data, suggested that three dominant genes (PS3 , PS2 and PS1 ) controlled the expression of photo-sensitivity. These genes were found operating in a hierarchical order with PS2 and PS1 genes failing to express in the presence of PS3 gene. Similarly in the absence of PS3 gene, PS2 expressed but it masked the expression of PS1 . Further, PS1 gene expressed only when both PS3 and PS2 were in recessive homozygous state. Hence, the proposed genetic model for photosensitivity in pigeonpea is PS3 > PS2 > PS1 and photoinsensitive genotype being a triple recessive (ps3ps3ps2 ps2ps1ps1 ). .

Background While tuberculosis is considered a risk factor for chronic obstructive pulmonary disease, a restrictive pattern of pulmonary impairment may actually be more common among tuberculosis survivors. We aimed to determine the nature of pulmonary impairment before and after treatment among people with HIV and tuberculosis and identify risk factors for long-term impairment. Methods In this prospective cohort study conducted in South Africa, we enrolled adults newly diagnosed with HIV and tuberculosis who were initiating antiretroviral therapy and tuberculosis treatment. We measured lung function and symptoms at baseline, 6, and 12 months. We compared participants with and without pulmonary impairment and constructed logistic regression models to identify characteristics associated with pulmonary impairment. Results Among 134 participants with a median CD4 count of 110 cells/μl, 112 (83%) completed baseline spirometry at which time 32 (29%) had restriction, 13 (12%) had obstruction, and 9 (7%) had a mixed pattern. Lung function was dynamic over time and 30 (33%) participants had impaired lung function at 12 months. Baseline restriction was associated with greater symptoms and with long-term pulmonary impairment (adjusted odds ratio 5.44, 95% confidence interval 1.16–25.45), while baseline obstruction was not (adjusted odds ratio 1.95, 95% confidence interval 0.28–13.78). Conclusions In this cohort of people with HIV and tuberculosis, restriction was the most common, symptomatic, and persistent pattern of pulmonary impairment. These data can help to raise awareness among clinicians about the heterogeneity of post-tuberculosis pulmonary impairment, and highlight the need for further research into mediators of lung injury in this vulnerable population.

Heavy exposure to Mycobacterium tuberculosis, the etiologic agent of tuberculosis (TB) and among the top infectious killers worldwide, results in infection that is cleared, contained, or progresses to disease. Some heavily exposed tuberculosis contacts show no evidence of infection using the tuberculin skin test (TST) and interferon gamma release assay (IGRA); yet the mechanisms underlying this "resister" (RSTR) phenotype are unclear. To identify transcriptional responses that distinguish RSTR monocytes, we performed transcriptome sequencing (RNA-seq) on monocytes isolated from heavily exposed household contacts in Uganda and gold miners in South Africa after ex vivo M. tuberculosis infection. Gene set enrichment analysis (GSEA) revealed several gene pathways that were consistently enriched in response to M. tuberculosis among RSTR subjects compared to controls with positive TST/IGRA testing (latent TB infection [LTBI]) across Uganda and South Africa. The most significantly enriched gene set in which expression was increased in RSTR relative to LTBI M. tuberculosis-infected monocytes was the tumor necrosis factor alpha (TNF-α) signaling pathway whose core enrichment (leading edge) substantially overlapped across RSTR populations. These leading-edge genes included candidate resistance genes (ABCA1 and DUSP2) with significantly increased expression among Uganda RSTRs (false-discovery rate [FDR]

The advent of COVID-19 and the persistent threat of infectious diseases such as tuberculosis, malaria, influenza and HIV/AIDS remind us of the marked impact that infections continue to have on public health. Some of the most effective protective measures are vaccines but these have been difficult to develop for some of these infectious diseases even after decades of research. The development of drugs and immunotherapies acting directly against the pathogen can be equally challenging, and such pathogen-directed therapeutics have the potential disadvantage of selecting for resistance. An alternative approach is provided by host-directed therapies, which interfere with host cellular processes required for pathogen survival or replication, or target the host immune response to infection (immunotherapies) to either augment immunity or ameliorate immunopathology. Here, we provide a historical perspective of host-directed immunotherapeutic interventions for viral and bacterial infections and then focus on SARS-CoV-2 and Mycobacterium tuberculosis, two major human pathogens of the current era, to indicate the key lessons learned and discuss candidate immunotherapeutic approaches, with a focus on drugs currently in clinical trials.

Tuberculosis, although curable, frequently leaves the individual with chronic physical and psycho-social impairment, yet these consequences have to-date been largely neglected.\ud The 1st International Post-Tuberculosis Symposium was devoted entirely to impairment after tuberculosis, and covered a number of multi-disciplinary topics. Using the Delphi process, consensus was achieved for the terms “post- tuberculosis”, “post-tuberculosis lung disease/s (PTLD)”, and “post-tuberculosis economic, social and psychological well-being” (Post-TB ESP)”, to overcome the historical challenge of varied terminology in the literature. A minimum case-definition was proposed by consensus for PTLD in adults and children. Lack of sufficient evidence hampered definitive recommendations in most domains, including prevention and treatment of PTLD, but highlighted the dire need for research and priorities were identified. The heterogeneity of respiratory outcomes and previously employed research methodologies complicates the accurate estimation of disease burden. However, consensus was reached proposing a toolkit for future PTLD measurement, and on PTLD patterns to be considered. The importance of extra-pulmonary consequences and progressive impairment throughout the life-course was identified, including tuberculosis recurrence and increased mortality. Patient advocates emphasised the need for addressing the psychological and social impacts post tuberculosis, and called for clinical guidance. Increased awareness and more research addressing post-tuberculosis complications is urgently needed.

Background and Objectives\ud Children and pregnant women use 75% of the blood supply in sub-Saharan Africa (SSA) but face widespread blood shortages. To increase safe blood supply, Africa-specific evidence and strengthened capacity for transfusion research are needed. Our study analysed seven years of SSA transfusion publications, compared researched topics against priorities, and enumerated SSA transfusion research collaborations. \ud Materials and Methods\ud Data on research topic, journal type, authors’ institutions and country were extracted from transfusion-related SSA articles published between 2008-14 and used to construct a quantitative, graphic visualisation of collaborations. Research topics were compared to those identified as priorities for SSA blood services in 2008 and 2015. \ud Results\ud 267/2176 articles (average 38/year) met criteria for analysis. They involved 1245 authors, 673 institutions, 59 countries (35 SSA) and 1375 collaborations. 41% were on transfusion-transmitted infections. 34% were published in specialist transfusion journals. Only 7% involved exclusively collaborations within SSA. Two of the top fifteen institutions by publication quantity, were from outside SSA. \ud Conclusion\ud Despite a general paucity of SSA-relevant transfusion research, Francophone SSA was well-represented. Published research topics are not well-matched to SSA research priorities; research on supply, distribution, financing and systems is particularly neglected. The study provides a baseline against which to track any re-focusing of research activity to better meet SSA’s needs. Transfusion research hubs within and beyond SSA have been identified as a springboard network for expanding SSA transfusion research capacity. \ud \ud KEYWORDS\ud Sub-Saharan Africa, blood transfusion, research, collaborations

Sustained TB infection overproduces reactive oxygen species (ROS) as a host defense mechanism. Research shows ROS is destructive to lung tissue. Glutathione (GSH) neutralizes ROS, although it is consumed. NAC is a precursor of GSH synthesis, and administering an appropriate dose of NAC to patients with respiratory conditions may enhance lung recovery and replenish GSH. The present review searched for articles reporting on the effects of NAC in TB treatment from 1960 to 31 May 2022. The PICO search strategy was used in Google Scholar, PubMed, SciFinder, and Wiley online library databases. The COVIDENCE tool was used to delete inappropriate content. We eventually discovered five clinical trials, one case report, seven reviews, in vitro research, and four experimental animal studies from the twenty-four accepted articles. The use of NAC resulted in increased GSH levels, decreased treatment time, and was safe with minimal adverse events. However, the evidence is currently insufficient to estimate the overall effects of NAC, thus the study warrants more NAC clinical trials to demonstrate its effects in TB treatment.

Summary Background Current tuberculosis treatments leave patients with clinically significant lung injury and increased all-cause mortality post-cure. Adjunctive host-directed therapies could protect the lungs, improve long-term survival, and shorten treatment duration; however, few have been tested clinically. Therefore, we aimed to assess the safety and preliminary efficacy of four host-directed therapies for tuberculosis. Methods In this prospective, open-label, phase 2, randomised controlled trial, patients with pulmonary tuberculosis were recruited at three clinical sites in South Africa. Eligible patients were aged 18–65 years, HIV-1-negative, and had rifampicin-susceptible Mycobacterium tuberculosis, a sputum Xpert cycle threshold of less than 20, and moderately advanced or far advanced disease on chest radiography. By use of numbers generated in blocks of ten and stratification by site, eligible patients were randomly assigned (1:1:1:1:1) to receive one of the four oral host-directed treatments plus standard tuberculosis treatment or standard treatment alone (the control group). Host-directed treatments were: CC-11050 (200 mg twice daily, taken with food; day 1–112); everolimus (0·5 mg/day; day 1–112); auranofin (3 mg/day for seven doses, then 6 mg/day; day 1–112); and ergocalciferol (5 mg on day 1, then 2·5 mg on day 28 and day 56). All study participants received oral rifabutin-substituted standard tuberculosis treatment for 180 days. Patients and clinicians were not masked to treatment assignment. Spirometry and sputum culture with solid and liquid media were done at baseline and up to 180 days at specified intervals throughout treatment. The primary endpoint was safety and tolerability up to day 210. Secondary preliminary efficacy endpoints were treatment effects on sputum microbiology (culture status at day 56 and the hazard ratio for stable culture conversion up to day 180) and lung function (FEV1 and forced vital capacity [FVC]) measured by spirometry at day 56, day 180, and day 540. Safety was analysed in the intention-to-treat population and preliminary efficacy primarily in the per-protocol population. The trial is registered at ClinicalTrials.gov , NCT02968927 . Post-treatment follow-up was completed in 2020. Findings Between Nov 18, 2016, and Sept 27, 2018, 200 patients were screened and randomly assigned to different treatment groups (n=40 per group, apart from n=39 in the everolimus group after one patient withdrew consent). 11 treatment-emergent serious adverse events occurred either during treatment or within 30 days after treatment discontinuation, of which three were attributable to a host-directed treatment. Life-threatening thrombocytopenia occurred in an auranofin recipient; apparent intra-abdominal sepsis leading to death occurred in another auranofin recipient and was classified as a suspected unexpected serious adverse reaction. Tuberculous spondylitis occurred as an apparent paradoxical reaction in a patient receiving ergocalciferol. Two patients in the control group had life-threatening, treatment-attributable liver injury. No treatment-emergent, treatment-attributable serious adverse events occurred in patients receiving CC-11050 or everolimus. Mean FEV1 in the control group was 61·7% of predicted (95% CI 56·3–67·1) at baseline and 69·1% (62·3–75·8) at day 180. Patients treated with CC-11050 and everolimus had increased recovery of FEV1 at day 180 relative to the control group (mean difference from control group 6·30%, 95% CI 0·06–12·54; p=0·048; and 6·56%, 0·18–12·95; p=0·044, respectively), whereas auranofin and ergocalciferol recipients did not. None of the treatments had an effect on FVC during 180 days of follow-up or on measures of sputum culture status over the course of the study. Interpretation CC-11050 and everolimus were safe and reasonably well tolerated as adjunctive therapies for tuberculosis, and analysis of preliminary efficacy suggests they might also enhance the recovery of FEV1, a key measure of lung function and predictor of all-cause mortality. Further studies of these candidates are warranted. Funding The Bill & Melinda Gates Foundation and the South African Medical Research Council.

After extensive exposure to Mycobacterium tuberculosis (Mtb), most individuals acquire latent Mtb infection (LTBI) defined by a positive tuberculin skin test (TST) or interferon-γ release assay (IGRA). To identify mechanisms of resistance to Mtb infection, we compared transcriptional profiles from highly exposed contacts who resist TST/IGRA conversion (resisters, RSTRs) and controls with LTBI using RNAseq. Gene sets related to carbon metabolism and free fatty acid (FFA) transcriptional responses enriched across 2 independent cohorts suggesting RSTR and LTBI monocytes have distinct activation states. We compared intracellular Mtb replication in macrophages treated with FFAs and found that palmitic acid (PA), but not oleic acid (OA), enhanced Mtb intracellular growth. This PA activity correlated with its inhibition of proinflammatory cytokines in Mtb-infected cells. Mtb growth restriction in PA-treated macrophages was restored by activation of AMP kinase (AMPK), a central host metabolic regulator known to be inhibited by PA. Finally, we genotyped AMPK variants and found 7 SNPs in PRKAG2, which encodes the AMPK-γ subunit, that strongly associated with RSTR status. Taken together, RSTR and LTBI phenotypes are distinguished by FFA transcriptional programs and by genetic variation in a central metabolic regulator, which suggests immunometabolic pathways regulate TST/IGRA conversion.

Background The aim of our work was to develop and validate a hydrophilic interaction liquid chromatography-electrospray ionization-tandem mass spectrometry (HILIC-ESI-MS/MS) methods for the quantification of tobramycin (TMC) and lincomycin (LMC)in plasma, microdialysis fluid and urine. Methods Protein precipitation was used to extract TMC and LMC from plasma, while microdialysis fluid and urine sample were diluted prior to instrumental analysis. Mobile phase A consisted of 2 mM ammonium acetate in 10% acetonitrile with 0.2% formic acid (v/v) and mobile phase B consisted of 2 mM ammonium acetate in 90% acetonitrile with 0.2% formic acid (v/v). Gradient separation (80%–10% of mobile phase B) for TMC was done using a SeQuant zic-HILIC analytical guard column. While separation of LMC was performed using gradient elution (100%–40% of mobile phase B) on a SeQuant zic-HILIC analytical column equipped with a SeQuant zic-HILIC guard column. Vancomycin (VCM) was used as an internal standard. A quadratic calibration was obtained over the concentration range for plasma of 0.1–20 mg/L for TMC and 0.05–20 mg/L for LMC, for microdialysis fluid of 0.1–20 mg/L for both TMC and LMC, and 1–100 mg/L for urine for both TMC and LMC. Results For TMS and LMC, validation testing for matrix effects, precision and accuracy, specificity and stability were all within acceptance criteria of ±15%. Conclusions The methods described here meet validation acceptance criteria and were suitable for application in a pilot pharmacokinetic research study performed in a sheep model.

Background Immune restoration on antiretroviral therapy (ART) can drive inflammation in people living with human immunodeficiency virus (HIV) who have pulmonary tuberculosis (TB), but its effects on the lungs have not been assessed. We evaluated associations between pulmonary inflammation, recovery of pathogen-specific CD4 T-cell function, and lung injury prior to and after ART initiation in adults with HIV and pulmonary TB. Methods This was a prospective cohort study in South Africa, following adults with HIV and pulmonary TB prior to and up to 48 weeks after ART initiation. Pulmonary-specific inflammation was defined as total glycolytic activity (TGA) on [18]F-fluorodeoxyglucose (FDG) positron emission tomography–computed tomography (PET-CT) at baseline and 4 weeks after ART initiation. Spirometry, respiratory symptom tests, and flow cytometry were performed at the same times to assess lung involvement and the frequency of mycobacteria-specific CD4 T-cells. In addition, we evaluated lung function longitudinally up to 48 weeks after ART initiation. Results Greater lung TGA on FDG PET-CT was associated with worse lung function and respiratory symptoms prior to ART initiation, and nearly half of subjects experienced worsening lung inflammation and lung function at Week 4 of ART. Worsening Week 4 lung inflammation and pulmonary function were both associated with greater increases in pathogen-specific functional CD4 T-cell responses on ART, and early decreases in lung function were independently associated with persistently lower lung function months after TB treatment completion. Conclusions Increases in pulmonary inflammation and decreases in lung function are common on ART, relate to greater ART-mediated CD4 T-cell restoration, and are associated with the persistent impairment of lung function in individuals with HIV/TB.

Atypical Aeromonas salmonicida (aAs) is currently one of the most routinely recovered bacterial pathogens isolated during disease outbreaks in farmed cleaner fish, ballan wrasse (Labrus bergylta, Ascanius). Vibrionaceae family bacteria have also been isolated from ballan wrasse in Scotland. This study determined the infectivity, pathogenicity and virulence of aAs and Vibrionaceae isolates in juvenile farmed ballan wrasse (n= 50; approx. 2 gr) using a bath challenge and fish monitored for a period of 16 days. Atypical As caused significant mortalities in contrast to Vibrionaceae isolates. Notably, differential virulence was observed between two aAs vapA type V strains at similar challenge doses. Diseased fish exhibited a systemic infection where aAs was detected in all analysed tissues (liver, spleen and kidney) by PCR and qPCR. Macroscopically, moribund and survivor fish exhibited hepatomegaly and splenomegaly. In moribund and surviving fish histopathology showed granulomatous hepatitis with eosinophilic granular cells surrounding bacterial colonies and endocarditis along with splenic histiocytosis. This is the first report of a successful aAs bath challenge model for juvenile ballan wrasse which provides an important tool for future studies on vaccine efficacy and immunocompetence.

The lack of efficient and cost-effective diagnostic tools contributes to poor control of tuberculosis in endemic countries. Moreover, host biological processes influence susceptibility, and infection resolution. It is well known that comorbidities such as type 2 diabetes mellitus (DM2) affect the host immune response, making individuals more susceptible to Mycobacterium tuberculosis infection. Currently, there are no laboratory tools that can identify those subjects who have a higher risk of developing the disease. In this study, we used a whole blood mycobacterial growth inhibition assay to assess the immune response capacity to inhibit mycobacterial growth between healthy subjects and those living with DM2 with optimal and poor glycemic control. We also measured cytokine levels in the culture supernatant by cytokine bead arrays. We included 89 patients with DM2: 54 patients with optimal control (mean age 56.2 ± 11.75 years) and 35 patients with poor control (mean age 52.05 ± 9.94 years). We also included 44 healthy subjects as controls (mean age 42.12 ± 11.75 years). We compared the Δlog UFC (a value that represents the difference between mycobacterial growth in the control tube versus the subject’s blood) between each group. Our results demonstrate that patients with DM2 had a lower capacity to inhibit M. tuberculosis growth (Δlog UFC DM2 subjects 0.9581 (-0.3897 to 2.495) vs Δlog UFC healthy subjects 0.7190 (-0.2678 to 2.098); p=0.013). Comparing subjects living with DM2 (optimal and poor glycemic control) vs healthy subjects, we found only significant differences between healthy subjects and patients poorly controlled (Δlog UFC optimal control group 0.876 (-0.3897 to 2.495); Δlog UFC poor control group 1.078 (0.068 to 2.33); Δlog UFC healthy subjects 0.7190 (-0.2678 to 2.098); p= 0.022). Therefore, glycemic control assessed by glycosylated hemoglobin values influences the capacity of the host to control the infection. Our results confirm that the whole blood mycobacterial growth inhibition assay has potential utility as an in vitro marker of M. tuberculosis immunological control in vivo in subjects living with DM2. This assay can be used to evaluate the immune response of each individual against M. tuberculosis, allowing clinicians to choose a more specific host-directed therapy.

Summary Transient nuclear envelope ruptures during interphase (NERDI) occur due to cytoskeletal compressive forces at sites of weakened lamina, and delayed NERDI repair results in genomic instability. Nuclear envelope (NE) sealing is completed by endosomal sorting complex required for transport (ESCRT) machinery. A key unanswered question is how local compressive forces are counteracted to allow efficient membrane resealing. Here, we identify the ESCRT-associated protein BROX as a crucial factor required to accelerate repair of the NE. Critically, BROX binds Nesprin-2G, a component of the linker of nucleoskeleton and cytoskeleton complex (LINC). This interaction promotes Nesprin-2G ubiquitination and facilitates the relaxation of mechanical stress imposed by compressive actin fibers at the rupture site. Thus, BROX rebalances excessive cytoskeletal forces in cells experiencing NE instability to promote effective NERDI repair. Our results demonstrate that BROX coordinates mechanoregulation with membrane remodeling to ensure the maintenance of nuclear-cytoplasmic compartmentalization and genomic stability., Graphical abstract, Highlights • Cytoskeletal forces exerted on the nucleus can rupture its membrane • BROX is recruited to sites of rupture by the ESCRT membrane remodeling machinery • BROX ubiquitinates the LINC complex protein Nesprin-2G, targeting it for degradation • BROX coordinates local relaxation of mechanical stress with membrane remodeling, Nuclear envelope (NE) integrity is essential to protect the genome from damage. Wallis et al. investigate how the NE is repaired in case of rupture. The study demonstrates that BROX is locally recruited by ESCRTs and reduces cytoskeletal stress through its action on Nesprin-2G to help reseal the ruptured membrane

Summary Background Many individuals who survive tuberculosis disease face ongoing disability and elevated mortality risks. However, the impact of post-tuberculosis sequelae is generally omitted from policy analyses and disease burden estimates. We therefore estimated the global burden of tuberculosis, inclusive of post-tuberculosis morbidity and mortality. Methods We constructed a hypothetical cohort of individuals developing tuberculosis in 2019, including pulmonary and extrapulmonary disease. We simulated lifetime health outcomes for this cohort, stratified by country, age, sex, HIV status, and treatment status. We used disability-adjusted life-years (DALYs) to summarise fatal and non-fatal health losses attributable to tuberculosis, during the disease episode and afterwards. We estimated post-tuberculosis mortality and morbidity based on the decreased lung function caused by pulmonary tuberculosis disease. Findings Globally, we estimated 122 (95% uncertainty interval [UI] 98–151) million DALYs due to incident tuberculosis disease in 2019, with 58 (38–83) million DALYs attributed to post-tuberculosis sequelae, representing 47% (95% UI 37–57) of the total burden estimate. The increase in burden from post-tuberculosis varied substantially across countries and regions, driven largely by differences in estimated case fatality for the disease episode. We estimated 12·1 DALYs (95% UI 10·0–14·9) per incident tuberculosis case, of which 6·3 DALYs (5·6–7·0) were from the disease episode and 5·8 DALYs (3·8–8·3) were from post-tuberculosis. Per-case post-tuberculosis burden estimates were greater for younger individuals, and in countries with high incidence rates. The burden of post-tuberculosis was spread over the remaining lifetime of tuberculosis survivors, with almost a third of total DALYs (28%, 95% UI 23–34) accruing 15 or more years after incident tuberculosis. Interpretation Post-tuberculosis sequelae add substantially to the overall disease burden caused by tuberculosis. This hitherto unquantified burden has been omitted from most previous policy analyses. Future policy analyses and burden estimates should take better account of post-tuberculosis, to avoid the potential misallocation of funding, political attention, and research effort resulting from continued neglect of this issue. Funding National Institutes of Health.

Background : Many individuals who survive TB disease face ongoing disability and elevated mortality risks. However, the impact of post-TB sequelae is generally omitted from policy analyses and disease burden estimates. We therefore estimated the global burden of TB, inclusive of post-TB morbidity and mortality. Methods : Lifetime health outcomes were simulated for the cohort developing TB disease globally in 2019, stratified by country, age, sex, HIV status, and treatment status. We used disability-adjusted life-years (DALYs) to summarize fatal and nonfatal health losses attributable to TB, during the disease episode and afterwards. We estimated post-TB mortality and morbidity based on the decreased lung function caused by pulmonary TB disease. Findings : Globally, we estimated 122 (95% uncertainty interval: 98, 151) million DALYs due to incident TB disease in 2019, with 58 (38, 83) million DALYs attributed to post-TB sequelae, representing 47% (37, 57) of the total burden estimate. The increase in burden from post-TB varied substantially across countries and regions, driven largely by differences in estimated case fatality for the disease episode. We estimated 12.1 (10.0, 14.9) DALYs per incident TB case, of which 6.3 (5.6, 7.0) DALYs were from the disease episode and 5.8 (3.8, 8.3) from post-TB. Per-case post-TB burden estimates were greater for younger individuals, and in countries with high incidence rates. The burden of post-TB was spread over the remaining lifetime of TB survivors, with almost one-third (28% (23, 34)) of total DALYs accruing 15 or more years after incident TB. Interpretation : Post-TB sequelae produce a substantial fraction of the disease burden caused by TB. This hitherto unquantified burden has been omitted from most prior policy analyses. Future policy analyses and burden estimates should take better account of post-TB, to avoid the potential misallocation of funding, political attention, and research effort resulting from continued neglect of this issue. Funding: NAM and TC acknowledge funding from the NIH (R01AI146555). MQ acknowledges funding from the Bill and Melinda Gates Foundation (INV-001754). AKC acknowledges funding from WEHI philanthropy. JM acknowledges funding from the Medical Research Council MR/S02042X/1). RSW acknowledges funding from Horizon 2020 and EDCTP. RMGJH acknowledges funding from the European Research Council (757699). Declaration of Interest: The authors declare no conflicts of interest.

Tuberculosis (TB) drug development proceeds from pre-clinical studies through phase 1, 2, and 3 clinical trials that progressively increase in size and duration. This progression minimizes medical risk to participants and financial risk to sponsors. Trial endpoints typically differ according to study phase (Table 20.1). There is a similar progression of endpoints in HDT trials, but in many trials these have been supplemented by measures of lung function and inflammation, exercise capacity, and symptom scores. In some cases, these novel endpoints have replaced microbiological endpoints as primary study outcomes. The use of these alternative outcome measures is discussed in the sections that follow for each trial.

Atypical Aeromonas salmonicida (aAs) and Vibrionaceae related species are bacteria routinely recovered from diseased ballan wrasse used as cleaner fish in the Atlantic salmon farming industry. Autogenous (i.e. farm specific inactivated) multivalent vaccines formulated from these microorganisms are widely used to protect farmed wrasse despite limited experimental proof that they are primary pathogens. In this study, the components of a commercial multivalent injection vaccine containing four strains of Aeromonas salmonicida and one strain of Vibrio splendidus previously isolated from ballan wrasse in Scotland, were tested for infectivity, pathogenicity and virulence via intra peritoneal injection at pre-deployment size (25–50 g) and the efficacy of the vaccine for protection against aAs assessed. Injection with 3.5 × 109, 8 × 109 1.8 × 109 and 5 × 109 cfu/fish of Vibrio splendidus, V. ichthyoenteri, Aliivibrio logeii and A. salmonicida, respectively, did not cause significant mortalities, lesions or clinical signs after a period of 14 days. IP injection with both aAs and Photobacterium indicum successfully reproduced the clinical signs and internal lesions observed during natural outbreaks of the disease. Differences in virulence (LD50 at day 8-post infection of 3.6 × 106 cfu/fish and 1.6 × 107 cfu/fish) were observed for two aAs vapA type V isolates. In addition, the LD50 for Photobacterium indicum was 2.2 × 107 cfu/fish. The autogenous vaccine was highly protective against the two aAs vapA type V isolates after 700-degree days of immunisation. The RPSFINAL values for the first isolate were 95 and 91% at 1 × 106 cfu/fish and 1 × 107 cfu/fish, respectively, and 79% at 1 × 107 cfu/fish for the second isolate tested. In addition, significantly higher anti aAs seral antibodies (IgM), were detected by ELISA in vaccinated fish in contrast with control (mock vaccinated) fish. These results suggest wrasse can be effectively immunised and protected against aAs infection by injection with oil adjuvanted vaccines prepared with inactivated homologous isolates.

Atypical Aeromonas salmonicida (aAs) and Vibrionaceae related species are bacteria routinely recovered from diseased ballan wrasse used as cleaner fish in Atlantic salmon farming. Autogenous multivalent vaccines formulated from these microorganisms are widely used by the industry to protect farmed wrasse despite limited experimental proof that they are primary pathogens. In this study, the components of a commercial multivalent injection wrasse vaccine were tested for infectivity, pathogenicity and virulence via intra peritoneal injection at pre-deployment size (25-50g) and the efficacy of the vaccine for protection against aAs assessed. Injection with 3.5×109, 8×109 1.8×109 and 5×109 cfu/fish of Vibrio splendidus, V. ichthyoenteri, Aliivibrio logeii and A. salmonicida, respectively, did not cause significant mortalities, lesions or clinical signs after a period of 14 days. IP injection with both aAs and Photobacterium indicum successfully reproduced the clinical signs and internal lesions observed during natural outbreaks of the disease. Differences in virulence (LD50 at day 8-post infection of 3.6×106 cfu/fish and 1.6×107 cfu/fish) were observed for two aAs vapA type V isolates. In addition, the LD50 for Photobacterium indicum was 2.2×107 cfu/fish. The autogenous vaccine was highly protective against the two aAs vapA type V isolates after 700-degree days of immunisation. The RPSFINAL values for the first isolate were 95 and 91% at 1×106 cfu/fish and 1×107 cfu/fish, respectively, and 79% at 1×107 cfu/fish for the second isolate tested. In addition, significantly higher anti aAs seral antibodies (IgM), were detected by ELISA in vaccinated fish in contrast with control (mock vaccinated) fish. These results suggest wrasse can be effectively immunised and protected against aAs infection by injection with oil adjuvanted vaccines prepared with inactivated homologous isolates. Further work should assess the efficacy of vaccination against other isolates that have proven to be pathogenic such as aAs type VI and Photobacterium indicum and explore the feasibility of immersion vaccination. In addition, a full characterisation of aAs isolates within the same vapA types should be performed as differences in virulence between vapA type V isolates were observed and partial genome analysis indicated small but potentially important genomic differences in these isolates.

Background The number of tuberculosis (TB) cases in Norway is increasing due to immigration from countries with high TB prevalence and few studies have been conducted on general practitioners’ (GPs) knowledge of TB in low incidence countries. The main purpose of this study was to explore knowledge, attitudes and practices of TB among Norwegian GPs using a modified Knowledge Attitude Practice (KAP) survey template. Methods A cross-sectional survey of 30 questions was distributed by email using SurveyMonkey to GPs working in municipalities either with or without an asylum reception centre in Eastern Norway (GPwAS or GPw/oAS). The questionnaire assessed demographic data and had 14 questions on TB knowledge and 7 questions on attitudes and practices. Descriptive and inferential analysis of the data was carried out using SPSS 18. Results One hundred ninety five GPs responded and 42% worked in a municipality with an asylum reception centre. There was no significant difference between the two GP groups in relation to demographic variables (all p-values > 0.2). GPwAS were more experienced in diagnosing TB patients compared to GPw/oAS (63.4% vs 44.2%, p = 0.008). There was no significant differences in participation in TB training between the two groups (8.5% vs 7.6%, p = 0.71). The majority of GPs (69%) did not consider TB as a major public health threat and misconceptions of TB epidemiology were identified. Overall, 97 (49.7%) GPs had good TB knowledge level and good TB knowledge level was associated with experience in diagnosing TB patients (p = 0.001) and recent TB training (p = 0.015). Conclusion Gaps in TB knowledge and awareness among GPs in Norway need to be addressed if GPs are to be more involved in TB management and prevention in the future. TB training had an effect on the GPs knowledge level and GPwAS had more experience with TB patients but our survey revealed no major differences in KAP between GPwAS and GPw/oAS. © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/)

Tuberculosis kills more people than any other infectious disease. Three pivotal trials testing 4-month regimens failed to meet non-inferiority margins; however, approximately four-fifths of participants were cured. Through a pooled analysis of patient-level data with external validation, we identify populations eligible for 4-month treatment, define phenotypes that are hard to treat and evaluate the impact of adherence and dosing strategy on outcomes. In 3,405 participants included in analyses, baseline smear grade of 3+ relative to 6 months to cure all. Regimen duration can be selected in order to improve outcomes, providing a stratified medicine approach as an alternative to the 'one-size-fits-all' treatment currently used worldwide.

Management accounting researchers have been slow to explore the empirical implications of the “manager effect” on management control choices. We critique the “manager effect” literature and identify research opportunities for management accounting researchers. Since the publication of Bertrand and Schoar's (2003) seminal paper, which shows that individual managers have an effect on firm behavior, a large and growing body of accounting and finance research has used publicly available data to identify individual manager effects on a variety of firm outcomes. Management accounting researchers can add significant value to this research; for example, by exploring the control choices that a firm makes to mitigate the adverse consequences associated with some managerial characteristics. In this critique we first identify some of the theoretical and methodological challenges associated with the “manager effects” research and second identify opportunities for management accounting researchers to explore these effects while overcoming some of the limitations.

Summary:. Postoperative candida infection is a rarely reported complication in cutaneous surgery, although it may develop more often in particular clinical settings. We present a 59-year-old woman with a well-controlled human immunodeficiency virus infection. She developed a bright red eruption with satellite pustules 2 weeks after excision of recurrent lentigo maligna melanoma of the left lower eyelid and periocular region. Due to defect size and complexity of the reconstruction (glabellar transposition flap, Hughes flap, composite graft from upper contralateral eyelid, and full-thickness skin graft from ipsilateral retroauricular region), she was placed on prophylactic oral amoxicillin-clavulanic acid and topical bacitracin and polymyxin. Immediate postoperative course was unremarkable, and sutures were removed after 7 days. Three days later, she developed bright red erythema and pustules within the surgical site and complained of burning. Empirically she was switched to topical gentamicin and oral ciprofloxacin, and later to linezolid, due to inadequate response. Wound culture grew Candida albicans sensitive to fluconazole and voriconazole. After oral fluconazole and topical clotrimazole initiation, the patient rapidly improved. The graft remained viable and apart from small partial dehiscence on the cheek, the healing was unremarkable. Apart from the case presentation, we also discuss different factors associated with postoperative candida infection, including immunocompromised status, surgical procedure location, and postoperative antibiotic use. Early recognition and treatment of postoperative candida infections are crucial to prevent delayed healing and associated morbidity.

Burnout has a high prevalence among healthcare workers and is increasingly recognised as an environmental problem rather than reflecting a personal inability to cope with work stress. We distributed an electronic survey, which included the Maslach Burnout Inventory Health Services Survey and a previously validated learning environment instrument, to 281 Victorian anaesthetic trainees. The response rate was 50%. We found significantly raised rates of burnout in two of three subscales. Ninety-one respondents (67%) displayed evidence of burnout in at least one domain, with 67 (49%) reporting high emotional exhaustion and 57 (42%) reporting high depersonalisation. The clinical learning environment tool demonstrated a significant negative correlation with burnout (r=-0.56, P

This was a prospective, multi-centre pharmacokinetic (PK) study conducted in three Malaysian ICUs to describe the PK of piperacillin (co-administered with tazobactam) and meropenem, and the pharmacokinetic/pharmacodynamic (PK/PD) target attainment of critically ill patients. Serial blood samples were collected to determine concentrations across seven pre-determined time-points. PK/PD target attainment was defined as a composite of: (1) the achievement of concentration 4 x the epidemiologic cut-off (ECOFF) of Pseudomonas aeruginosa and; (2) concentration below the toxicity thresholds. For piperacillin, the target concentration range was 64 – 361 mg/L and for meropenem, 8 – 64 mg/L. PK parameters were estimated using non-compartmental method. Univariate and multivariate analyses were applied. Eighty-four patients were included, 51 received piperacillin and 33 received meropenem. The most common administration method was continuous infusion (48.8%), followed by extended infusion (36.9%) and intermittent infusion (14.3%). The median (IQR) of the cohort was 58 years (42 – 69), body mass index was 23 kg/m2 (21 – 26) and the estimated Cockroft-Gault creatinine clearance (CLcr) was 62 mL/min (40 – 100). The median APACHE II and SOFA scores on admission were 13 (11 – 17) and 6 (4 – 9), respectively. Twenty-four percent of patients underwent surgery 24 hours prior to study inclusion. The volume of distribution (Vd) and CL of piperacillin were 0.42 L/kg and 0.18 L/hr/kg. The Vd and CL of meropenem were 0.37 L/kg and 0.14 L/hr/kg, respectively. Patients age, estimated CLcr and recent surgery significantly predicted the Vd and CL of both beta-lactams. Piperacillin and meropenem concentrations were highly-variable with coefficient of variation (COV) of ≥67.7%. Forty-nine patients (58.3%) achieved the PK/PD target and they tend to be older, with slower CLcr and receiving continuous infusion. Based on the most parsimonious logistic regression model, higher CLcr and intermittent infusion were significant predictors of sub-optimal PK/PD target attainment.

SummaryIn late 2018, unusual patterns of very high mortality (>50% production) were reported in intensive tilapia cage culture systems across Lake Volta in Ghana. Samples of fish and fry were collected and analysed from two affected farms between October 2018 and February 2019. Affected fish showed darkening, erratic swimming and abdominal distension with associated ascites. Histopathological observations of tissues taken from moribund fish at different farms revealed lesions indicative of viral infection. These included haematopoietic cell nuclear and cytoplasmic pleomorphism with marginalisation of chromatin and fine granulation. Transmission electron microscopy showed cells contained conspicuous virions with typical Iridovirus morphology i.e. enveloped, with icosahedral and or polyhedral geometries and with a diameter c.160 nm. PCR confirmation and DNA sequencing identified the virions as Infectious Spleen and Kidney Necrosis Virus (ISKNV). Samples of fry and older animals were all strongly positive for the presence of the virus by qPCR. All samples tested negative for TiLV and Nodavirus by qPCR. All samples collected from farms prior to the mortality event were negative for ISKNV. Follow up testing of fish and fry sampled from 5 additional sites in July 2019 showed all farms had fish that were PCR positive for ISKNV, whether there was active disease on the farm or not, demonstrating the disease was endemic to farms all over Lake Volta by that point. The results suggest that ISKNV was the cause of disease on the investigated farms and likely had a primary role in the mortality events. A common observation of coinfections with Streptococcus agalactiae and other tilapia bacterial pathogens further suggests that these may interact to cause severe pathology, particularly in larger fish. Results demonstrate that there are a range of potential threats to the sustainability of tilapia aquaculture that need to be guarded against.