Durlobactam in combination with β-lactams to combat .

() presents significant clinical challenges. This study evaluated the synergistic effects of a β-lactam and β-lactamase inhibitor combination against and explored the underlying mechanisms. Synergy was assessed through MIC tests and time-kill studies, and binding affinities of nine β-lactams and BLIs to eight target receptors (L,D-transpeptidases [LDT] 1-5, D,D-carboxypeptidase, penicillin-binding protein [PBP] B, and PBP-lipo) were assessed using mass spectrometry and kinetic studies.

When and why do people change their minds in favor of vaccination? Longitudinal analyses of switching COVID-19 vaccination preferences.

Background: Vaccinations are a cornerstone of public health. However, reluctance to accepting vaccines is common. Using longitudinal data, we investigated which individual and contextual factors were associated with switching preferences from initial hesitancy or unwillingness toward acceptance of a first COVID-19 vaccination.

Postpartum Screening for Type 2 Diabetes in Women With a History of Gestational Diabetes Mellitus: A Cost-Effectiveness Analysis in Singapore.

Objectives: In Singapore, diabetes imposes a huge population health and economic burden. Despite that, there is paucity of evidence on the health economics of screening programs for type 2 diabetes, especially in the context of screening after gestational diabetes (GDM). The objective of this study is to assess cost-effectiveness of universal lifelong screening for type 2 diabetes after GDM, which is supported by current guidelines, compared with elective screening where 54% of mothers with GDM undertake one-off screening.

Epigenetic programming of host lipid metabolism associated with resistance to TST/IGRA conversion after exposure to .

(Mtb) exposure leads to a range of outcomes including clearance, latent TB infection (LTBI), and pulmonary tuberculosis (TB). Some heavily exposed individuals resist tuberculin skin test (TST) and interferon-gamma (IFNγ) release assay (IGRA) conversion (RSTR), which suggests that they employ IFNγ-independent mechanisms of Mtb control. Here, we compare monocyte epigenetic profiles of RSTR and LTBI from a Ugandan household contact cohort.

The multivariate Bernoulli detector: change point estimation in discrete survival analysis.

Time-to-event data are often recorded on a discrete scale with multiple, competing risks as potential causes for the event. In this context, application of continuous survival analysis methods with a single risk suffers from biased estimation. Therefore, we propose the multivariate Bernoulli detector for competing risks with discrete times involving a multivariate change point model on the cause-specific baseline hazards.

Baseline and end-of-treatment host serum biomarkers predict relapse in adults with pulmonary tuberculosis.

Background: There is a need for new tools for monitoring of the response to TB treatment. Such tools may allow for tailored treatment regimens, and stratify patients initiating TB treatment into different risk groups. We evaluated combinations between previously published host biomarkers and new candidates, as tools for monitoring TB treatment response, and prediction of relapse.

MR1-restricted T cell clonotypes are associated with "resistance" to Mycobacterium tuberculosis infection.

T cells are required for protective immunity against Mycobacterium tuberculosis. We recently described a cohort of Ugandan household contacts of tuberculosis cases who appear to "resist" M. tuberculosis infection (resisters; RSTRs) and showed that these individuals harbor IFN-γ-independent T cell responses to M.

HIV co-infection is associated with reduced Mycobacterium tuberculosis transmissibility in sub-Saharan Africa.

Persons living with HIV are known to be at increased risk of developing tuberculosis (TB) disease upon infection with Mycobacterium tuberculosis (Mtb). However, it has remained unclear how HIV co-infection affects subsequent Mtb transmission from these patients. Here, we customized a Bayesian phylodynamic framework to estimate the effects of HIV co-infection on the Mtb transmission dynamics from sequence data.

Capturing Recent Infection by Tuberculin Skin Test vs. Interferon-Gamma Release Assay.

Reductions in tuberculosis (TB) incidence require identification of individuals at high risk of developing active disease, such as those with recent () infection. Using a prospective household contact (HHC) study in Kampala, Uganda, we diagnosed new infection using both the tuberculin skin test (TST) and interferon-gamma release assay (IGRA). Our study aimed to determine if the TST adds additional value to the characterization of IGRA converters.

Age and sex influence antibody profiles associated with tuberculosis progression.

Antibody features vary with tuberculosis (TB) disease state. Whether clinical variables, such as age or sex, influence associations between Mycobacterium tuberculosis-specific antibody responses and disease state is not well explored. Here we profiled Mycobacterium tuberculosis-specific antibody responses in 140 TB-exposed South African individuals from the Adolescent Cohort Study.

Durlobactam, a Diazabicyclooctane β-Lactamase Inhibitor, Inhibits BlaC and Peptidoglycan Transpeptidases of .

Peptidoglycan synthesis is an underutilized drug target in (). Diazabicyclooctanes (DBOs) are a class of broad-spectrum β-lactamase inhibitors that also inhibit certain peptidoglycan transpeptidases that are important in mycobacterial cell wall synthesis. We evaluated the DBO durlobactam as an inhibitor of BlaC, the β-lactamase, and multiple peptidoglycan transpeptidases (PonA1, Ldt, Ldt, Ldt, and Ldt).

-dependent monocyte expression quantitative trait loci, cytokine production, and TB pathogenesis.

Introduction: The heterogeneity of outcomes after (Mtb) exposure is a conundrum associated with millennia of host-pathogen co-evolution. We hypothesized that human myeloid cells contain genetically encoded, Mtb-specific responses that regulate critical steps in tuberculosis (TB) pathogenesis.

Methods: We mapped genome-wide expression quantitative trait loci (eQTLs) in Mtb-infected monocytes with RNAseq from 80 Ugandan household contacts of pulmonary TB cases to identify monocyte-specific, Mtb-dependent eQTLs and their association with cytokine expression and clinical resistance to tuberculin skin test (TST) and interferon-γ release assay (IGRA) conversion.

Epigenetic programming of host lipid metabolism associates with resistance to TST/IGRA conversion after exposure to tuberculosis.

(Mtb) exposure leads to a range of outcomes including clearance, latent TB infection (LTBI), and pulmonary tuberculosis (TB). Some heavily exposed individuals resist tuberculin skin test (TST) and interferon gamma release assay (IGRA) conversion (RSTR), which suggests that they employ IFNγ-independent mechanisms of Mtb control. Here, we compare monocyte epigenetic profiles of RSTR and LTBI from a Ugandan household contact cohort.

TLR2 on CD4+ and CD8+ T cells promotes control of Mycobacterium tuberculosis infection.

Although a role for TLR2 on T cells has been indicated in prior studies, in vivo stimulation of TLR2 on T cells by Mtb and its impact on Mtb infection has not been tested. Furthermore, it is not known if the enhanced susceptibility to Mtb of Tlr2 gene knockout mice is due to its role in macrophages, T cells, or both. To address TLR2 on T cells, we generated Tlr2xCd4 mice, which lack expression of TLR2 on both CD4 and CD8 T cells, to study the in vivo role of TLR2 on T cells after aerosol infection with virulent Mtb.

Production of Proinflammatory Cytokines by CD4+ and CD8+ T Cells in Response to Mycobacterial Antigens among Children and Adults with Tuberculosis.

Tuberculosis (TB), caused by (Mtb), remains a leading cause of pediatric morbidity and mortality. Young children are at high risk of TB following Mtb exposure, and this vulnerability is secondary to insufficient host immunity during early life. Our primary objective was to compare CD4+ and CD8+ T-cell production of proinflammatory cytokines IFN-gamma, IL-2, and TNF-alpha in response to six mycobacterial antigens and superantigen staphylococcal enterotoxin B (SEB) between Ugandan adults with confirmed TB (n = 41) and young Ugandan children with confirmed (n = 12) and unconfirmed TB (n = 41), as well as non-TB lower respiratory tract infection (n = 39).

More Tailored Approaches to Tuberculosis Treatment and Prevention.

Recent advances in the treatment of tuberculosis (TB) have led to improvements unprecedented in our lifetime. Decades of research in developing new drugs, especially for multidrug-resistant TB, have created not only multiple new antituberculous agents but also a new approach to development and treatment, with a focus on maximizing the benefit to the individual patient. Prevention of TB disease has also been improved and recognized as a critical component of global TB control.

Connecting patients notified with hepatitis C to treatment (CONNECT Study): A randomized controlled trial of active case management by a health department to support primary care practitioners.

Background: Despite subsidised access to direct-acting antivirals (DAAs), hepatitis C (HCV) treatment uptake in Australia is declining. Interventions are needed to link people living with HCV to care and treatment. We implemented and measured effectiveness of a state-wide, health department-led, enhanced case management through the primary care practitioner for all HCV notifications, aiming to encourage and support treatment commencement.

Mycobacterium tuberculosis -induced monocyte transcriptional responses associated with resistance to tuberculin skin test/interferon-γ release assay conversion in people with HIV.

Objective: To determine whether Mycobacterium tuberculosis (Mtb)-induced monocyte transcriptional responses differ in people with HIV (PWH) who do (RSTR) or do not (LTBI) resist tuberculin skin test/interferon-γ (IFN-γ) release assay (TST/IGRA) conversion after exposure.

Design: We compared ex-vivo Mtb-induced monocyte transcriptional responses in a Ugandan tuberculosis (TB) household contact study of RSTR and LTBI individuals among PWH.

Methods: Monocytes were isolated from peripheral blood mononuclear cells from 19 household contacts of pulmonary TB patients, and their transcriptional profiles were measured with RNA-Seq after a 6 h infection with Mtb (H37Rv) or media.