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Abstract Background Sepsis is associated with a highest mortality rate in the ICU. Present study tests the efficacy of combined therapy with vitamin C, hydrocortisone and thiamine (combined therapy) in the ovine model of sepsis induced by Pseudomonas aeruginosa. In this study, sepsis was induced in sheep by instillation of Pseudomonas aeruginosa (1 × 1011 CFU) into the lungs via bronchoscope, under anesthesia. Nine hours after injury, intravenous infusion of vitamin C (0.75 g every 6 h), hydrocortisone (25 mg every 6 h), and thiamine (100 mg every 12 h) or saline was given to the treatment and control groups. Cardiopulmonary variables were recorded. Results The survival rate was 16.7% in control and 33.3% in treatment groups. In the control group, mean arterial pressure dropped from 93.6 ± 8.6 to 75.5 ± 9.7 mmHg by 9 h, which was not affected by the combined therapy. Pulmonary dysfunction was not attenuated by the combined therapy either. The combined therapy had no effect on increased extravascular lung water content and fluid effusion into thoracic cavity. The bacterial number in the bronchoalveolar lavage fluid was significantly increased in the treatment group than the control group. The blood bacterial number remained comparable between groups. Conclusions Combined vitamin C, hydrocortisone, and thiamine did not attenuate severity of ovine sepsis.

Background: In revision total knee arthroplasty, tibial cones have demonstrated improved longevity and reduced incidence of aseptic loosening. Several currently available “off-the-shelf” (OTS) cone systems may not have sizes to accommodate all patient bone morphologies. Methods: Computed tomographies from one hundred primary total knee arthroplasty patients and dimensions of 4 OTS cones were obtained. Press-fit stems were positioned in 3D tibia models to fit the diaphyseal trajectory. Cones were positioned around the stem at 1, 6, and 13 mm resections measured from the trough of the medial tibial plateau, simulating proximal tibial cuts and bone loss. Tibias were examined for cortical breaching following modeled cone preparation. Results: Increased rate of breaching was observed as size and depth of the cone increased. In 2/49 (4.1%) male and 19/46 (41.3%) female tibias, cones could not be positioned without breaching. No breaches were found in 22/49 (45.0%) male and 5/46 (10.9%) female tibias. For every 1 centimeter increase in patient height, odds of breaching decreased by 12% (odds ratio: 0.88, confidence interval: 0.84, 0.92). For every size increase in cone width, odds of breaching increased by 34% (odds ratio: 1.34, confidence interval: 1.28, 1.47). Placing cones deeper also increased breaching compared to the 1 mm cut. Conclusions: In revision total knee arthroplasty, smaller OTS or custom tibial cones may be needed to fit a patient’s proximal tibial geometry. This is especially true in patients not accommodated by the OTS cone sizes we tested, which impacted shorter patients and/or those with substantial bone loss requiring more tibial resection and deeper cone placement. Use of smaller or custom tibial cones should be considered where indicated.

Background: A common tibial construct for revision total knee arthroplasty includes a long diaphyseal engaging press-fit stem. Due to tibial canal bowing, compromises are often necessary to match patient anatomy when choosing stemmed implants. The objective of this study is to determine through 3-D modeling whether current implant press-fit options appropriately fit patient anatomy, or whether an alternative angle between the stem and baseplate could increase the cortical engagement of long press-fit tibial stems. Methods: Preoperative computerized tomography scans from 100 patients undergoing TKA were imported into an image-processing software program. Three-dimensional models were created with tibial stems placed at a fixed perpendicular angle and a custom angle to the revision tibial baseplate. Stem diameter, depth, offset, and contact surface area were measured and analyzed between the 2 groups. Results: Significantly more cortical contact, larger stem diameter, and smaller offset of the custom keel from the center of the baseplate were associated with free custom tibial stem placement vs a fixed perpendicular baseplate-stem interface (P < .001). Statistically significant differences were also found between different patient demographics. Conclusions: Custom free-angle stem placement allows for increased stem diameter and cortical contact of press-fit tibial stems compared to existing constructs that must interface with the baseplate at a 90-degree angle. Current revision tibia implants limit fixation of tibial press-fit stems and often mismatch with patient anatomy. Alternative ways to fit patient anatomy may be beneficial for patients with extreme mismatch. In the future, custom keel angles may help to resolve this problem.

On 2022 September 26, the Double Asteroid Redirection Test (DART) spacecraft impacted Dimorphos, the satellite of binary near-Earth asteroid (65803) Didymos. This demonstrated the efficacy of a kinetic impactor for planetary defense by changing the orbital period of Dimorphos by 33 minutes. Measuring the period change relied heavily on a coordinated campaign of lightcurve photometry designed to detect mutual events (occultations and eclipses) as a direct probe of the satellite’s orbital period. A total of 28 telescopes contributed 224 individual lightcurves during the impact apparition from 2022 July to 2023 February. We focus here on decomposable lightcurves, i.e., those from which mutual events could be extracted. We describe our process of lightcurve decomposition and use that to release the full data set for future analysis. We leverage these data to place constraints on the postimpact evolution of ejecta. The measured depths of mutual events relative to models showed that the ejecta became optically thin within the first ∼1 day after impact and then faded with a decay time of about 25 days. The bulk magnitude of the system showed that ejecta no longer contributed measurable brightness enhancement after about 20 days postimpact. This bulk photometric behavior was not well represented by an HG photometric model. An HG _1 G _2 model did fit the data well across a wide range of phase angles. Lastly, we note the presence of an ejecta tail through at least 2023 March. Its persistence implied ongoing escape of ejecta from the system many months after DART impact.

Island bat species are disproportionately at risk of extinction, and Hawaiʻi’s only native terrestrial land mammal, the Hawaiian hoary bat (Lasiurus semotus) locally known as ʻōpeʻapeʻa, is no exception. To effectively manage this bat species with an archipelago-wide distribution, it is important to determine the population size on each island and connectivity between islands. We used 18 nuclear microsatellite loci and one mitochondrial gene from 339 individuals collected from 1988–2020 to evaluate genetic diversity, population structure and estimate effective population size on the Islands of Hawaiʻi, Maui, Oʻahu, and Kauaʻi. Genetic differentiation occurred between Hawaiʻi and Maui, both of which were differentiated from Oʻahu and Kauaʻi. The population on Maui presents the greatest per-island genetic diversity, consistent with their hypothesized status as the original founding population. A signature of isolation by distance was detected between islands, with contemporary migration analyses indicating limited gene flow in recent generations, and male-biased sex dispersal within Maui. Historical and long-term estimates of genetic effective population sizes were generally larger than contemporary estimates, although estimates of contemporary genetic effective population size lacked upper bounds in confidence intervals for Hawaiʻi and Kauaʻi. Contemporary genetic effective population sizes were smaller on Oʻahu and Maui. We also detected evidence of past bottlenecks on all islands with the exception of Hawaiʻi. Our study provides population-level estimates for the genetic diversity and geographic structure of ‘ōpeʻapeʻa, that could be used by agencies tasked with wildlife conservation in Hawaiʻi.

Background: Few studies have described children with spinal multidrug-resistant tuberculosis (MDR-TB). Treatment involves surgery and medical care with long courses of drug therapy. Methods: Hospital and laboratory records at Brooklyn Chest and Tygerberg Children's Hospitals, Cape Town, South Africa, were analysed (January 2004 until December 2010) searching for children treated for MDR spinal TB. Results: Of the 11 children identified, 4 were excluded. Of the 7 remaining, 5 were boys; median age: 8 years, median delay to treatment initiation: 36 weeks. Among them one child died, five have completed treatment and one is near the end of therapy. Medications were well-tolerated and although two of the surviving children have spinal deformity, none have significant neurological deficit. Conclusions: The diagnosis of spinal MDR-TB is often delayed in children, frequently leading to advanced disease and severe vertebral damage. Children tolerate therapy well and, once identified, it is a condition that can be treated successfully. [ABSTRACT FROM AUTHOR]

Childhood tuberculosis is neglected in endemic areas with resource constraints, as children are considered to develop mild forms of disease and to contribute little to the maintenance of the tuberculosis epidemic. However, children contribute a significant proportion of the disease burden and suffer severe tuberculosis-related morbidity and mortality, particularly in endemic areas. This review provides an overview of well-documented concepts and principles, and demonstrates how this 'old wisdom' applies to current and future challenges in the field of childhood tuberculosis; the aim was to articulate some of the most pressing issues, to provide a rational framework for discussion, and to stimulate thought and further scientific study. The prechemotherapy literature that described the natural history of disease in children identified three central concepts: (1) the need for accurate case definitions, (2) the importance of risk stratification, and (3) the diverse spectrum of disease pathology, which necessitates accurate disease classification. The relevance of these concepts and their application to pertinent issues such as the diagnosis of childhood tuberculosis are discussed. The concepts are also linked to the basic principles of antituberculosis treatment, providing a simplified approach to the diagnosis and treatment of childhood tuberculosis that is independent of resource constraints. The main challenges for future research are highlighted and in conclusion it is emphasized that the infrastructure provided by the directly observed therapy, short-course strategy, combined with well-targeted interventions, slightly improved resources, and greatly improved political commitment, may lead to a dramatic reduction in tuberculosis-related morbidity and mortality among children. [ABSTRACT FROM AUTHOR]

RATIONALE: Comparison of the early bactericidal activity (EBA) of rifapentine and its pharmacokinetics with those of rifampin to determine the cause of poor clinical response and regrowth between doses, leading to rifamycin monoresistance at relapse. OBJECTIVES: Determination of the dose size of rifapentine that gives sufficient drug exposure to prevent regrowth. METHODS: EBA study over initial 5 days of treatment of 123 patients, half at Durban and half at Cape Town, who received single rifapentine doses of 300, 600, 900, or 1,200 mg rifapentine or five daily doses of 150, 300, or 600 mg rifampin, with a pharmacokinetic study on 58 patients measuring standard parameters for each dose size of rifamycin and their desacetyl metabolites. RESULTS: The EBAs for both rifamycins were similar, with a linear relationship to log dose at lower doses and a curvilinear response at higher doses giving a plateau at 1,136 mg rifapentine. The area under the concentration-time curve (AUC) divided by the minimal inhibitory concentration (MIC) agreed well for both rifamycins on the assumption that the only free 2% of free rifapentine and the 14% of free rifampin after plasma binding were active in the lesions. CONCLUSIONS: Only the free proportions of the rifamycins were active in lesions. From consideration of the pulse size and the duration of the postantibiotic lag, a 1,200-mg dose of rifapentine seemed necessary to improve response and to prevent regrowth between doses, and hence rifamycin monoresistance. [ABSTRACT FROM AUTHOR]

Aim: The purpose of this study was to explore sexual dimorphism in the distance between mental foramen to lower border of mandible in Chinese patients attending Faculty of Dentistry, MMMC and to derive a discriminant equation for determining sex using the data obtained. Material and method: The archived digital orthopantomograms at the institutional database were screened and 140 radiographs were selected based on inclusion and exclusion criteria for analysis of mental foramen. Measurements between the three reference points (superior and inferior border of mental foramen and lower border of mandible) were made using Romexis software (Version: 3.0.1.R) measuring and drawing tools. The data obtained were tabulated and subjected to discriminant function analysis. Results: Distance between mental foramen to lower border of mandible (both Right and Left S-L and I-L) were significantly higher in male than female at the level of P

Indigenous Peoples associate their own laws with the laws of the natural world, which are formally known as or translated as Natural or First Law. These laws come from the Creator and the Land through our ancestral stories and therefore, they are sacred. All aspects of life and existence depend on living and following these natural First Laws. Since colonization, Indigenous Peoples’ Natural Laws have been forcibly replaced by modern-day laws that do not take into account the sacred relationship between the Earth and all of her inhabitants. The force of societies who live outside of Natural Law has ensured the modern-day consequences of not living in balance with nature. Pandemics and global environmental change, including climate change, are all consequences of not following the Natural Laws that are encapsulated by the interconnected nature of the universe. Here we discuss Natural Law from an Indigenous paradigm and worldview which carries implications for planetary health and wider environmental movements around the globe.

Previous studies have demonstrated that the Pleistocene saber-toothed cat Smilodon fatalis had many forelimb adaptations for increased strength, presumably to grapple with and subdue prey. The Rancho La Brea tar pits yield large samples of juvenile limb bones forming a growth series that allow us to examine how Smilodon kittens grew up. Almost all available juvenile limb bones were measured, and reduced major axis fits were calculated to determine the allometric growth trends. Contrary to expectations based on their robust limbs, Smilodon kittens show the typical pattern of growth found in other large felids (such as the Ice Age lion, Panthera atrox, as well as living tigers, cougars, servals, and wildcats) where the limb grows longer and more slender faster than they grow thick. This adaptation is thought to give felids greater running speed. Smilodon kittens do not grow increasingly more robust with age. Instead, they start out robust and follow the ancestral felid growth pattern, while maintaining their robustness compared to other felids. Apparently, the growth of felid forelimbs is highly canalized and their ontogeny is tightly constrained.

Pulmonary edema is a hallmark of acute respiratory distress syndrome (ARDS). Smoke inhalation causes ARDS, thus significantly increasing the mortality of burn patients. Adipose-derived stem cells (ASCs) exert potent anti-inflammatory properties. The goal of the present study was to test the safety and ecfficacy of ASCs, in a well-characterized clinically relevant ovine model of ARDS.Female sheep were surgically prepared. ARDS was induced by cooled cotton smoke inhalation. Following injury, sheep were ventilated, resuscitated with lactated Ringer's solution, and cardiopulmonary hemodynamics were monitored for 48 hours in a conscious state. Pulmonary microvascular hyper-permeability was assessed by measuring lung lymph flow, extravascular lung water content, protein content in plasma and lung lymph fluid. Sheep were randomly allocated to two groups: 1) ASCs: infused with 200 million of ASCs in 200mL of PlasmaLyteA starting 1 hours post-injury, n = 5; 2) control, treated with 200mL of PlasmaLyteA in a similar pattern, n = 5.Lung lymph flow increased 9-fold in control sheep as compared to baseline. Protein in the plasma was significantly decreased, while it was increased in the lung lymph. The treatment with ASCs significantly attenuated these changes. Treatment with ASCs almost led to the reversal of increased pulmonary vascular permeability and lung water content. Pulmonary gas exchange was significantly improved by ASCs. Infusion of the ASCs did not negatively affect pulmonary artery pressure and other hemodynamic variables.ASCs infusion was well tolerated. The results suggest that intravenous ASCs modulate pulmonary microvascular hyper-permeability and prevent the onset of ARDS in our experimental model.

A bibliography of Donald Preziosi’s complete publications.

Many paleontologists have noticed the broadly similar patterns between the changes in Cenozoic mammalian diversity and taxonomic dominance and climate changes. Yet detailed studies of fossil population samples with fine-scale temporal resolution during episodes of climate change like the Eocene-Oligocene transition in the White River Group, and the late Pleistocene at Rancho La Brea tar pits, demonstrates that most fossil mammal species are static and show no significant microevolutionary response to major climate changes. This mismatch between patterns seems best explained by species sorting. As the punctuated equilibrium model demonstrated, over long time spans most fossil species are stable and do not respond to climate change. Instead, change occurs at the next hierarchical level, with species sorting adding and subtracting to the total diversity pattern revealed by coarse-scale taxon counting, apparently responding to longer-term changes in climate as revealed by proxies like the oxygen isotope record.

Background: New drugs, but also shorter, better-tolerated regimens are needed to tackle the high global burden of tuberculosis complicated by drug resistance and retroviral disease. We investigated new multiple-agent combinations over the first 14 days of treatment to assess their suitability for future development.Methods: In this prospective, randomised, early bactericidal activity (EBA) study, treatment-naive, drug-susceptible patients with uncomplicated pulmonary tuberculosis were admitted to hospitals in Cape Town, South Africa, between Oct 7, 2010, and Aug 19, 2011. Patients were randomised centrally by computer-generated randomisation sequence to receive bedaquiline, bedaquiline-pyrazinamide, PA-824-pyrazinamide, bedaquiline-PA-824, PA-824-moxifloxacin-pyrazinamide, or unmasked standard antituberculosis treatment as positive control. The primary outcome was the 14-day EBA assessed in a central laboratory from the daily fall in colony forming units (CFU) of M tuberculosis per mL of sputum in daily overnight sputum collections. Bilinear regression curves were fitted for each group separately and groups compared with ANOVA for ranks, followed by pair-wise comparisons adjusted for multiplicity. Clinical staff were partially masked but laboratory personnel were fully masked. This study is registered, NCT01215851.Findings: The mean 14-day EBA of PA-824-moxifloxacin-pyrazinamide (n=13; 0·233 [SD 0·128]) was significantly higher than that of bedaquiline (14; 0·061 [0·068]), bedaquiline-pyrazinamide (15; 0·131 [0·102]), bedaquiline-PA-824 (14; 0·114 [0·050]), but not PA-824-pyrazinamide (14; 0·154 [0·040]), and comparable with that of standard treatment (ten; 0·140 [0·094]). Treatments were well tolerated and appeared safe. One patient on PA-824-moxifloxacin-pyrazinamide was withdrawn because of corrected QT interval changes exceeding criteria prespecified in the protocol.Interpretation: PA-824-moxifloxacin-pyrazinamide is potentially suitable for treating drug-sensitive and multidrug-resistant tuberculosis. Multiagent EBA studies can contribute to reducing the time needed to develop new antituberculosis regimens.Funding: The Global Alliance for TB Drug Development (TB Alliance). [ABSTRACT FROM AUTHOR]

Carl Flügge is best known for the promotion of studies demonstrating the transmission of all manner of infections, but particularly tuberculosis, by coughed droplets. But it is seldom recognised that Flügge was also influential in a number of other fields comprising the practice of hygiene. One-hundred years following his death in 1923, we review literature related to the studies of Flügge and his colleagues and students and illustrate the particular emphasis he laid upon the environment within which disease and its transmission might be fostered or prevented, embracing and studying aspects essential to the health of any community ranging from fundamental microbiology in the laboratory to subjects as disparate as housing, clean water supply, nutrition, sanitation, socio-economic circumstances and climate. Very early in his career he promoted breast feeding for the prevention of seasonal gastro-enteritis and later the sheltering of cough as a means of preventing the transmission of infected respiratory droplets, not only as regards tuberculosis, but also concerning all manner of other respiratory infections. By the time of Flügge's death the complexification of available scientific methodologies comprising hygiene made it difficult for any individual to comprehend and study the wide range of hygiene-related subjects such as Flügge did. Carl Flügge was one of the last holistic hygienists and an originator of the study of environmental health as a pillar of hygiene., (© 2024. The Author(s).)

Background: Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level., Methods: We systematically searched MEDLINE, Embase and Web of Science (1990-2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration-time curve from 0 to 24 h post-dose (AUC 0-24 ) and peak plasma concentration ( C max ) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC 0-24 and C max were assessed with linear mixed-effects models., Results: Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC 0-24 were summarised for isoniazid (18.7 (95% CI 15.5-22.6) h·mg·L -1 ), rifampicin (34.4 (95% CI 29.4-40.3) h·mg·L -1 ), pyrazinamide (375.0 (95% CI 339.9-413.7) h·mg·L -1 ) and ethambutol (8.0 (95% CI 6.4-10.0) h·mg·L -1 ). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC 0-24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC 0-24 for isoniazid and pyrazinamide. N -acetyltransferase 2 rapid acetylators had lower isoniazid AUC 0-24 and slow acetylators had higher isoniazid AUC 0-24 than intermediate acetylators. Determinants of C max were generally similar to those for AUC 0-24 ., Conclusions: This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring., Competing Interests: Conflict of interest: H.S. Schaaf reports grants from the NIH/IMPAACT; and honoraria from Ann Lake publications (sponsored by Johnson & Johnson) for an educational publication on the management of MDR-TB in children. A. Bekker reports grants from IMPAACT, UNITAID; lecture honoraria from Sandoz; support for attending PENTA PIM meeting; and received generic LPV/r, 3TC and ABC for the PETITE study. D.J. Bell reports support for attending a meeting from ViiV pharmaceuticals; and attendance fees for an advisory board meeting from ViiV pharmaceuticals. L. Choo reports grants from the UKRI MRC DFID Wellcome NIHR Joint Global Health Trials, TB Alliance Support for trial drug purchase and UKRI COVID-19 Grant Extension Allocation Award. P. Denti reports a grant for WHO expert review for TB drugs in children. S.M. Graham reports participation on a data safety monitoring board for the TB CHAMP trial; and leadership roles as a co-chair for the Guidelines Development Committee of the WHO updated recommendations and consolidated guidelines on child and adolescent TB, and as a core member for the WHO Child and Adolescent TB Working Group. S.K. Heysell reports grants from the NIH, DANIDA and EDTCP; royalties or licences from UpToDate; and honoraria for lectures from Henry Stewart Talks. A. Kwara reports a grant from the NIH/NICHD. V. Mave reports grants from the NIH and CDC. C.A. Peloquin reports a grant from the NIH. V. Roy reports a grant from the Delhi State TB Association; and leadership roles as a member of the Delhi State TB Association and the MAMC TB Committee. E.M. Svensson reports grants from the NWO personal Veni, IMI UNITE4TB consortium, TB Alliance, UNITAID BenefitKids consortium, WHO expert review, NIH support for IMPAACT studies, Blueprint, Probex, ACTG study Clo-FAST, Janssen Pharmaceuticals, EDCTP support PanTB-HM and Legochem; and leadership or fiduciary roles in the ISOP DI&E committee and BenNeLux PMX organising committee. U. Thatte reports participation on a data safety monitoring board for an ICMR TB trial. T.A. Thomas reports grants from the NIH and the University of Virginia. D.J. Touw reports a grant from Chiesi; consulting fees from Pure IMS and Sanguin; and participation on a data safety monitoring board for the FORMAT trial. A. Turkova reports grants from the UKRI MRC DFID Wellcome NIHR Joint Global Health Trials and MRC Grants for core funding of the Medical Research Council Clinical Trials Unit at the UCL; and TB Alliance Support for SHINE trial drug purchase. All of this work was declared by the authors to be outside the submitted work. All other authors declare no competing interests., (Copyright ©The authors 2023.)

Treatment options for children with Rifampicin-resistant tuberculosis (RR-TB) remain limited, and para-aminosalicylic acid (PAS) is still a relevant component of treatment regimens. Prevention of resistance to companion drugs by PAS is dose related, and at higher concentrations, PAS may exhibit significant bactericidal activity in addition to its bacteriostatic properties. The optimal dosing of PAS in children is uncertain, specifically for delayed-release granule preparations, which are the most used. A population pharmacokinetic model was developed describing PAS pharmacokinetics in children receiving routine RR-TB treatment. Model-based simulations evaluated current World Health Organization (WHO) weight-band doses against the adult pharmacokinetic target of 50 to 100 mg/liter for peak concentrations. Of 27 children included, the median (range) age and weight were 3.87 (0.58 to 13.7) years and 13.3 (7.15 to 30.5) kg, respectively; 4 (14.8%) were HIV positive. PAS followed one-compartment kinetics with first-order elimination and transit compartment absorption. The typical clearance in a 13-kg child was 9.79 liters/h. Increased PAS clearance was observed in both pharmacokinetic profiles from the only patient receiving efavirenz. No effect of renal function, sex, ethnicity, nutritional status, HIV status, antiretrovirals (lamivudine, abacavir, and lopinavir-ritonavir), or RR-TB drugs was detected. In simulations, target concentrations were achieved only using the higher WHO dose range of 300 mg/kg once daily. A transit compartment adequately describes absorption for the slow-release PAS formulation. Children should be dosed at the higher range of current WHO-recommended PAS doses and in a once-daily dose to optimize treatment.

Tuberculous meningitis (TBM) remains a major cause of morbidity and mortality in children with tuberculosis (TB), yet there are currently no estimates of the global burden of pediatric TBM. Due to frequent non-specific clinical presentation and limited and inadequate diagnostic tests, children with TBM are often diagnosed late or die undiagnosed. Even when diagnosed and treated, 20% of children with TBM die. Of survivors, the majority have substantial neurological disability with significant negative impact on children and their families. Surveillance data on this devastating form of TB can help to quantify the contribution of TBM to the overall burden, morbidity and mortality of TB in children and the epidemiology of TB more broadly. Pediatric TBM usually occurs shortly after primary infection with Mycobacterium tuberculosis and reflects ongoing TB transmission to children. In this article we explain the public health importance of pediatric TBM, discuss the epidemiology within the context of overall TB control and health system functioning and the limitations of current surveillance strategies. We provide a clear rationale for the benefit of improved surveillance of pediatric TBM using a TB care cascade framework to support monitoring and evaluation of pediatric TB, and TB control more broadly. Considering the public health implications of a diagnosis of TBM in children, we provide recommendations to strengthen pediatric TBM surveillance and outline how improved surveillance can help us identify opportunities for prevention, earlier diagnosis and improved care to minimize the impact of TBM on children globally., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 du Preez, Jenkins, Donald, Solomons, Graham, Schaaf, Starke, Hesseling and Seddon.)

Mycobacterium bovis bacille Calmette-Guérin (BCG), an experimental vaccine designed to protect cattle from bovine tuberculosis, was administered for the first time to a newborn baby in Paris in 1921. Over the past century, BCG has saved tens of millions of lives and has been given to more humans than any other vaccine. It remains the sole tuberculosis vaccine licensed for use in humans. BCG provides long-lasting strong protection against miliary and meningeal tuberculosis in children, but it is less effective for the prevention of pulmonary tuberculosis, especially in adults. Evidence mainly from the past two decades suggests that BCG has non-specific benefits against non-tuberculous infections in newborn babies and in older adults, and offers immunotherapeutic benefit in certain malignancies such as non-muscle invasive bladder cancer. However, as a live attenuated vaccine, BCG can cause localised or disseminated infections in immunocompromised hosts, which can also occur following intravesical installation of BCG for the treatment of bladder cancer. The legacy of BCG includes fundamental discoveries about tuberculosis-specific and non-specific immunity and the demonstration that tuberculosis is a vaccine-preventable disease, providing a foundation for new vaccines to hasten tuberculosis elimination., Competing Interests: Declaration of interests SHEK is coinventor of the tuberculosis vaccine VPM1002 and coholder of a patent licensed to Serum Institute of India, Pune, India. MGN is coholder of patents on trained immunity licensed to Trained Therapeutix Discovery. CL reports personal fees from Chiesi, Gilead, Janssen, Novartis, Oxford Immunotec, and Insmed, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

BACKGROUND: High-dose isoniazid (INH H ) (15-20 mg/kg/day) could be administered to overcome low-level INH resistance, but pharmacokinetic data are sparse. METHODS: This observational study included South African children (<15 years) receiving INH H as preventive therapy, or treatment for multidrug-resistant TB (MDR-TB) exposure or disease. Pharmacokinetic sampling was performed after an INH dose of 20 mg/kg. Non-compartmental analysis and multivariable regression models were used to evaluate associations of key covariates with area under the curve (AUC 0-24 ) and maximum concentration (C max ). AUC and C max values were compared against proposed adult targets. RESULTS: Seventy-seven children were included, with median age of 3.7 years; 51 (66%) had MDR-TB disease and 26 (34%) had MDR-TB exposure. Five were HIV-positive, of whom four were ≥5 years old. The median AUC 0-24 was 19.46 µgh/mL (IQR 10.76-50.06) and C max was 5.14 µg/mL (IQR 2.69-13.2). In multivariable analysis of children aged <5 years, MDR-TB disease (vs. exposure) was associated with considerably lower AUC 0-24 (geometric mean ratio GMR 0.19, 95% CI 0.15-0.26; P < 0.001) and C max (GMR 0.20, 95% CI 0.15-0.26; P < 0.001). CONCLUSIONS: INH concentrations in children with MDR-TB disease were much lower than expected, but comparable to previous reports in children with MDR-TB exposure. Further studies should confirm these findings and explore possible causes.

Mycobacterium tuberculosis culture from gastric lavage from apparently healthy children following tuberculin skin test conversion, despite normal chest radiography (CR), is well known but is a contentious subject. A consensus statement regarding classification of childhood tuberculosis excluded this condition, stating that more data were needed. To assist in this discussion, we reviewed early publications that reported the occurrence of this phenomenon and early anatomical pathology studies that described changes that occur in children following tuberculosis infection. Pathology studies describe frequent cavitation in primary foci in children from whom positive M. tuberculosis cultures might easily arise. These foci were very small in some children who might have normal CR. Positive cultures might also arise from ulcerated mediastinal lymph nodes that are invisible on CR. Young children with recent infection very likely have active primary pulmonary tuberculosis., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Anton Ghon is well known in the field of childhood tuberculosis, and the tuberculosis primary focus and complex are frequently called the Ghon focus and complex; this is largely the result of the wide publication of the English translation of his monograph "Der primäre Lungenherd bei der Tuberkulose der Kinder." Ghon's studies are frequently quoted, but precise details of his monograph are neglected, his results often misquoted, and his later publications virtually unknown. This review highlights aspects of Ghon's anatomical pathology studies in children and adults not necessarily dying of tuberculosis but with signs of tuberculosis infection. Ghon found a single primary tuberculosis focus in approximately 80% of tuberculosis-infected children situated close to the pleura in two-thirds of cases. Cavitation of the focus was common, and lymphatic spread involved lymph nodes in the abdomen and neck in many children. Studies amongst adults and children frequently found the healed primary tuberculosis focus to be completely calcified without histological signs of tuberculosis activity; however, particularly in the presence of pulmonary tuberculosis, histological signs of tuberculosis activity were often found in the lymph nodes of the angulus venosus, despite apparent healing with extensive calcification. Both earlier studies and more recent investigations, with molecular biological tools, unavailable to Ghon and earlier researchers, have confirmed the presence of viable mycobacteria in apparently normal or healed thoracic nodes and also found molecular biological indications of viable mycobacteria in these nodes. As suggested by Ghon, lympho-haematogenous spread of tuberculosis may be more common than is usually appreciated., (© 2020 S. Karger AG, Basel.)

Following its introduction as an antituberculosis agent close to 75 years ago, the use of para-aminosalicylic acid (PAS) has been limited by gastrointestinal intolerance and multiple formulations were produced in attempts to reduce its occurrence. More recently, an enteric-coated, granular, slow-release PAS formulation (PASER) was introduced and is now in wide-spread use for the treatment of drug-resistant tuberculosis. The current PASER dosing regimen is based on recommendations derived from older studies using a variety of different PAS formulations and relegate PAS to a role as an exclusively bacteriostatic agent. However, there is ample evidence that if sufficiently high serum concentrations are reached, PAS can be bactericidal and that intolerance following once daily dosing, that aids the achievement of such concentrations, is no worse than that following intermittent daily dosing. In particular, prevention of resistance to companion drugs appears to be dependent on the size of the single dose, and hence the peak concentrations, and not on maintaining serum levels consistently above minimum inhibitory concentration. We present a narrative review of the development of PAS formulations, dosing practices, and published data regarding pharmacokinetics and pharmacodynamics and the relationship of PAS dosage to intolerance and efficacy. Our conclusions suggests that we are at present not using PAS to its maximum ability to contribute to regimen efficacy and protect companion drugs., (© 2020 The British Pharmacological Society.)

Purpose: Para-aminosalicylic acid (PAS) is currently one of the add-on group C medicines recommended by the World Health Organization for multidrug-resistant tuberculosis treatment. At the recommended doses (8-12 g per day in two to three divided doses) of the widely available slow-release PAS formulation, studies suggest PAS exposures are lower than those reached with older PAS salt formulations and do not generate bactericidal activity. Understanding the PASER dose-exposure-response relationship is crucial for dose optimization. The objective of our study was to establish a representative population pharmacokinetics model for PASER and evaluate the probability of bactericidal and bacteriostatic target attainment with different dosing regimens., Methods: To this end, we validated and optimized a previously published population pharmacokinetic model on an extended dataset. The probability of target attainment was evaluated for once-daily doses of 12 g, 14 g, 16 g and 20 g PASER., Results: The final optimized model included the addition of variability in bioavailability and allometric scaling with body weight on disposition parameters. Peak PAS concentrations over minimum inhibitory concentration of 100, which is required for bactericidal activity are achieved in 53%, 65%, 72% and 84% of patients administered 12, 14, 16 and 20 g once-daily PASER, respectively, when MIC is 1 mg/L. For the typical individual, the exposure remained above 1 mg/L for ≥ 98% of the dosing interval in all the evaluated PASER regimens., Conclusion: The pharmacokinetic/pharmacodynamic parameters linked to bactericidal activity should be determined for 14 g, 16 g and 20 g once-daily doses of PASER.

Para-aminosalicylic acid (PAS), often the last drug remaining for treatment of drug-resistant tuberculosis, is notorious for causing gastrointestinal intolerance; however, the cause of PAS intolerance is uncertain. The objective of this study was to assess relationships between peak concentrations of PAS administered as a granular slow-release enteric coated formulation, and its metabolites acetyl-PAS and glycine-PAS, and intolerance. PAS and its metabolites were measured in 29 adult patients with drug-resistant tuberculosis at Brooklyn Hospital, Cape Town, randomized to receive granular slow-release enteric-coated PAS 4 g twice daily or 8 g once daily for 1 week, followed by the alternative regimen. Concentrations of PAS and its metabolites were determined by liquid chromatography and tandem mass spectrometry, and a visual analogue scale evaluated intolerance. Spearman's correlation test assessed the relationship between maximum plasma concentrations (C max ) and intolerance scores. A large interindividual variability was observed for the PAS C max (40.42-68.55 mg/L) following 4 g twice daily; (62.69-102.41 mg/L) for 8 g once daily and a similar wide C max range found for the metabolites acetyl-PAS and glycine-PAS. Twenty-six patients reported at least 1 intolerance episode, but most visual analogue scale scores clustered around 0. Significant inverse associations were found between acetyl-PAS C max and bloating (rho = -0.448; P = .025) and diarrhea (rho = -0.407; P = .044) for the twice-daily regimen and a similar inverse association found for glycine-PAS and diarrhea (rho = -0.412; P = .041). Plasma concentrations of the metabolites did not correlate with the occurrence of gastrointestinal symptoms, but higher metabolite concentrations correlated with lower intolerance scores; slow metabolism of PAS and its continued presence in the intestinal tract may be the main cause of intolerance., (© 2019, The American College of Clinical Pharmacology.)

Rifampicin was discovered in 1965 and remains one of the most important drugs in tuberculosis treatment that is valued for its sterilizing activity and ability to shorten treatment. Antimicrobial activity of rifampicin was initially proved in vitro; subsequently numerous in vivo studies showed the bactericidal properties and dose-dependent effect of rifampicin. Rifampicin was first during the late 1960s to treat patients suffering from chronic drug-resistant pulmonary TB. Decades later, rifampicin continues to be studied with particular emphasis on whether higher doses could shorten the duration of treatment without increasing relapse or having adverse effects. Lesion-specific drug penetration and pharmacokinetics of rifampicin are improving our understanding of effective concentration while potentially refining drug regimen designs. Another prospective aspect of high-dose rifampicin is its potential use in treating discrepant mutation thereby eliminating the need for MDR treatment. To date, several clinical trials have shown the safety, efficacy, and tolerability of high-dose rifampicin. Currently, high-dose rifampicin has been used successfully in a routine clinical setting for the treatment of high-risk patients. However, the WHO and other relevant policy makers have not committed to implementing a controlled rollout thereof. This review describes the course that rifampicin has travelled to the present-day exploration of high-dose rifampicin treatment., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The transmission of tuberculosis (TB) occurs mainly via inhalation of airborne droplet nuclei; however, the precise details of this process remain uncertain. We reviewed the literature from 1870 to 1940, when Mycobacterium tuberculosis was discovered and the concept of transmission emerged as a hallmark of the infectious disease. By 1940, laboratory experiments, animal studies and clinical observation had demonstrated that cough was central to TB transmission, and that guinea pigs close to patients with cough could be infected, mainly by patients coughing small droplets likely containing only 1-2 bacilli. A minority of pulmonary TB patients, usually during the early stages of the disease, with thin watery sputum, more successfully coughed small infectious droplets than patients with heavily smear-positive tenacious sputum who were often too ill and too weak to cough vigorously. There was ongoing debate regarding the possible importance of desiccated sputum particles found in surface dust. Investigation of TB transmission has a history of more than 130 years.

The mutant prevention concentration (MPC) is a well-known concept in the chemotherapy of many bacterial infections, but is seldom considered in relation to tuberculosis (TB) treatment, as the required concentrations are generally viewed as unachievable without undue toxicity. Early studies revealed single mutations conferring high MICs of first- and second-line anti-TB agents; however, the growing application of genomics and quantitative drug susceptibility testing in TB suggests a wide range of MICs often determined by specific mutations and strain type. In paediatric TB, pharmacokinetic studies indicate that despite increasing dose recommendations, a proportion of children still do not achieve adult-derived targets. When considering the next stage in anti-TB drug dosing and the introduction of novel therapies for children, we suggest consideration of MPC and its incorporation into pharmacokinetic studies to more accurately determine appropriate concentration targets in children, to restrict the growth of resistant mutants and better manage drug-resistant TB., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Recent early bactericidal activity (EBA) studies of isoniazid-based antituberculosis therapies have shown a lower EBA over the first two treatment days than in earlier years. To quantify this trend and evaluate factors contributing to it, we extracted individual data from 18 studies with a total of 182 participants using isoniazid-containing therapies between 1992 and 2015 at a single site and laboratory in Cape Town, South Africa. We recalculated EBA as the daily fall in CFU per milliliter sputum up to day 2 of therapy (EBA 0-2 ) for individual patients and treatment groups and used mixed-effects linear models to investigate the correlation between pretreatment CFU, EBA 0-2 , and year of study. We found that mean pretreatment CFU and year of study accounted for 46% and 47%, respectively, of the variation in mean EBA 0-2 Mean pretreatment CFU differed between the periods 1992 to 2001 and 2007 to 2015 by 0.92 log 10 CFU (95% confidence interval [CI], 0.57 to 1.28; P < 0.0001). On average, pretreatment CFU dropped by 0.053 log 10 CFU (95% CI, 0.029 to 0.076; P = 0.0004) and EBA 0-2 by 0.012 log 10 CFU (95% CI, 0.006 to 0.018; P = 0.001) per year. The EBA 0-2 of isoniazid-based antituberculosis therapy is strongly correlated with baseline mycobacterial load and shows a declining trend over the past 2 decades., (Copyright © 2017 American Society for Microbiology.)