Comparative Efficacy and Safety of Moxifloxacin and Levofloxacin in a Short Standardised Rifampicin Resistant TB Regimen: A STREAM 2 Secondary Analysis.

(1) Background: The World Health Organisation (WHO) categorises moxifloxacin and levofloxacin as Group A drugs, which should be prioritised in the treatment of rifampicin-resistant tuberculosis. We compare their relative efficacy and safety using data from the STREAM trial; (2) Methods: Marginal structural models were used to balance differences in the baseline characteristics of participants receiving the STREAM control regimen containing either moxifloxacin or levofloxacin as this was not a randomised comparison. The difference in proportions between regimens was estimated for favourable outcome, any grade 3/4 adverse event, QTcF increase to ≥500 ms, QTcF increase from baseline by at least 60 ms, and any grade 3/4 adverse event excluding QT events, using weighted analyses; (3) Results: In efficacy analyses ( = 123), the weighted risk difference (moxifloxacin-levofloxacin, wRD) for a favourable outcome was -0.

Bedaquiline-pretomanid-moxifloxacin-pyrazinamide for drug-sensitive and drug-resistant pulmonary tuberculosis treatment: a phase 2c, open-label, multicentre, partially randomised controlled trial.

Background: The current tuberculosis (TB) drug development pipeline is being re-populated with candidates, including nitroimidazoles such as pretomanid, that exhibit a potential to shorten TB therapy by exerting a bactericidal effect on non-replicating bacilli. Based on results from preclinical and early clinical studies, a four-drug combination of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide (BPaMZ) regimen was identified with treatment-shortening potential for both drug-susceptible (DS) and drug-resistant (DR) TB. This trial aimed to determine the safety and efficacy of BPaMZ.

Baseline and acquired resistance to bedaquiline, linezolid and pretomanid, and impact on treatment outcomes in four tuberculosis clinical trials containing pretomanid.

Bedaquiline (B), pretomanid (Pa) and linezolid (L) are key components of new regimens for treating rifampicin-resistant tuberculosis (TB). However, there is limited information on the global prevalence of resistance to these drugs and the impact of resistance on treatment outcomes. Mycobacterium tuberculosis (MTB) phenotypic drug susceptibility and whole-genome sequence (WGS) data, as well as patient profiles from 4 pretomanid-containing trials-STAND, Nix-TB, ZeNix and SimpliciTB-were used to investigate the rates of baseline resistance (BR) and acquired resistance (AR) to BPaL drugs, as well as their genetic basis, risk factors and impact on treatment outcomes.

Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis.

Background: The bedaquiline-pretomanid-linezolid regimen has been reported to have 90% efficacy against highly drug-resistant tuberculosis, but the incidence of adverse events with 1200 mg of linezolid daily has been high. The appropriate dose of linezolid and duration of treatment with this agent to minimize toxic effects while maintaining efficacy against highly drug-resistant tuberculosis are unclear.

Methods: We enrolled participants with extensively drug-resistant (XDR) tuberculosis (i.

A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB.

Treatment for TB is lengthy and toxic, and new regimens are needed. Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6PaMZ) or 4 months (4PaMZ); 100 mg pretomanid daily for 4 months in the same combination (4PaMZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation.

Pathways to, and use of, sexual healthcare among Black Caribbean sexual health clinic attendees in England: evidence from cross-sectional bio-behavioural surveys.

Background: In England, people of Black Caribbean (BC) ethnicity are disproportionately affected by sexually transmitted infections (STI). We examined whether differences in sexual healthcare behaviours contribute to these inequalities.

Methods: We purposively selected 16 sexual health clinics across England with high proportions of attendees of BC ethnicity.

Ethnic variations in sexual partnerships and mixing, and their association with STI diagnosis: findings from a cross-sectional biobehavioural survey of attendees of sexual health clinics across England.

Objectives: Ethnic differences in partnership types and sexual mixing patterns may contribute to elevated STI diagnosis rates among England's Black Caribbean (BC) population. We examined the differences between BC and White British/Irish (WBI) sexual health clinic (SHC) attendees' reported partnerships and sexual mixing, and whether these differences could explain ethnic inequalities in STI, focusing on attendees reporting only opposite-sex partners (past year).

Methods: We surveyed attendees at 16 SHCs across England (May to September 2016), and linked their survey responses to routinely collected data on diagnoses of bacterial STI or trichomoniasis ±6 weeks of clinic attendance ('acute STI').

Association between knowledge, risk behaviours, and testing for sexually transmitted infections among men who have sex with men: findings from a large online survey in the United Kingdom.

Objectives: In the UK, men who have sex with men (MSM) bear a disproportionate sexually transmitted infection (STI) burden. We investigated MSM's STI knowledge; whether their STI testing behaviour met national guidelines (annually if sexually active; 3-monthly if engaging in STI risk behaviours); and the relationship between STI testing in the last 3 months, STI knowledge and STI risk behaviours by HIV status.

Methods: Sexually active (in the last year) men aged > 15 years who were UK residents and were recruited from gay-orientated online dating platforms completed an anonymous online survey about STI knowledge, STI risk behaviours, and STI testing (March-May 2017).

Reduced telomere length is associated with fibrotic joint disease suggesting that impaired telomere repair contributes to joint fibrosis.

Objective: Joint fibrosis affects many synovial joints (including hip, knee and shoulder) causing stiffness and pain. The mechanism of joint fibrosis remains unknown, although genetic factors may contribute. Defects in maintenance of telomere length resulting from impaired telomere repair have been shown to cause lung and liver fibrotic disease.

Does type 2 diabetes mellitus promote intervertebral disc degeneration?

Purpose: LDD is an important cause of low back pain. Many people believe there is an adverse influence of type 2 diabetes (T2D) on lumbar intervertebral disc degeneration (LDD). We examined a population sample for epidemiological evidence of association.

The Association Between Low Back Pain and Composition of IgG Glycome.

Low back pain (LBP) is a common debilitating condition which aetiology and pathogenesis are poorly understood. We carried out a first so far analysis of associations between LBP and plasma IgG N-glycome in a sample of 4511 twins from TwinsUK database assessed for LBP, lumbar disc degeneration (LDD) as its possible cause, and IgG-glycan levels. Using weighted correlation network analysis, we established a correlation between LBP and glycan modules featured by glycans that either promote or block antibody-dependent cell-mediated cytotoxicity (ADCC).

Joint Stiffness Is Heritable and Associated with Fibrotic Conditions and Joint Replacement.

Objective: Joint stiffness is a common, debilitating, age-related symptom, which may be seen after total joint replacement (TJR). Stiffness also occurs in fibrotic conditions such as shoulder capsulitis and Dupuytren's contracture. We speculated that the two traits (TJR and fibrotic disease) are linked pathogenically.

Neuropathic pain as part of chronic widespread pain: environmental and genetic influences.

Chronic widespread pain (CWP) has complex aetiology and forms part of the fibromyalgia syndrome. Recent evidence suggests a higher frequency of neuropathic pain features in those with CWP than previously thought. The aim of this study was to determine the prevalence of neuropathic pain features in individuals with CWP and to estimate the influence of genetic and environmental factors on neuropathic pain in CWP.

Genetic and Environmental Factors in Age-Related Hearing Impairment.

Age-related hearing impairment (ARHI) is a common condition with complex etiology but a recognized genetic component. Heritability estimates for pure tone audiogram-determined hearing ability lie in the range 26-75%. The speech-in-noise (SIN) auditory test, however, may be better at encapsulating ARHI symptoms, particularly the diminished ability to segregate environmental sounds into comprehendible auditory streams.

Conformational plasticity at the IgE-binding site of the B-cell receptor CD23.

IgE antibodies play a central role in allergic disease. They recognize allergens via their Fab regions, whilst their effector functions are controlled through interactions of the Fc region with two principal cell surface receptors, FcɛRI and CD23. Crosslinking of FcɛRI-bound IgE on mast cells and basophils by allergen initiates an immediate inflammatory response, while the interaction of IgE with CD23 on B-cells regulates IgE production.

Ca2+-dependent structural changes in the B-cell receptor CD23 increase its affinity for human immunoglobulin E.

Immunoglobulin E (IgE) antibodies play a fundamental role in allergic disease and are a target for therapeutic intervention. IgE functions principally through two receptors, FcεRI and CD23 (FcεRII). Minute amounts of allergen trigger mast cell or basophil degranulation by cross-linking IgE-bound FcεRI, leading to an inflammatory response.

Crystal structure of IgE bound to its B-cell receptor CD23 reveals a mechanism of reciprocal allosteric inhibition with high affinity receptor FcεRI.

The role of IgE in allergic disease mechanisms is performed principally through its interactions with two receptors, FcεRI on mast cells and basophils, and CD23 (FcεRII) on B cells. The former mediates allergic hypersensitivity, the latter regulates IgE levels, and both receptors, also expressed on antigen-presenting cells, contribute to allergen uptake and presentation to the immune system. We have solved the crystal structure of the soluble lectin-like "head" domain of CD23 (derCD23) bound to a subfragment of IgE-Fc consisting of the dimer of Cε3 and Cε4 domains (Fcε3-4).

The crystal structure of an avian IgY-Fc fragment reveals conservation with both mammalian IgG and IgE.

Avian IgY is closely related to an ancestor of both mammalian IgG and IgE and thus provides insights into the evolution of antibody structure and function. A recombinant fragment of IgY-Fc consisting of a dimer of the Cupsilon3 and Cupsilon4 domains, Fcupsilon3-4, was expressed and crystallized and its X-ray structure determined to 1.75 A resolution.

Adaptive protein evolution grants organismal fitness by improving catalysis and flexibility.

Protein evolution is crucial for organismal adaptation and fitness. This process takes place by shaping a given 3-dimensional fold for its particular biochemical function within the metabolic requirements and constraints of the environment. The complex interplay between sequence, structure, functionality, and stability that gives rise to a particular phenotype has limited the identification of traits acquired through evolution.

Soluble CD23 monomers inhibit and oligomers stimulate IGE synthesis in human B cells.

The low affinity IgE receptor, CD23, is implicated in IgE regulation and the pathogenesis of allergic disease. CD23 is a type II integral membrane protein, comprising a lectin "head," N-terminal "stalk," and C-terminal "tail" in the extracellular sequence. Endogenous proteases cleave CD23 in the stalk and the tail to release soluble fragments that either stimulate or inhibit IgE synthesis in human B cells.

Asp-120 locates Zn2 for optimal metallo-beta-lactamase activity.

Metallo-beta-lactamases are zinc-dependent hydrolases that inactivate beta-lactam antibiotics, rendering bacteria resistant to them. Asp-120 is fully conserved in all metallo-beta-lactamases and is central to catalysis. Several roles have been proposed for Asp-120, but so far there is no agreed consensus.

Crystal structure of a human autoimmune complex between IgM rheumatoid factor RF61 and IgG1 Fc reveals a novel epitope and evidence for affinity maturation.

Rheumatoid factors (RF) are autoantibodies that recognize epitopes in the Fc region of immunoglobulin (Ig) G and that correlate with the clinical severity of rheumatoid arthritis (RA). Here we report the X-ray crystallographic structure, at 3 A resolution, of a complex between the Fc region of human IgG1 and the Fab fragment of a monoclonal IgM RF (RF61), derived from an RA patient and with a relatively high affinity for IgG Fc. In the complex, two Fab fragments bind to each Fc at epitopes close to the C terminus, and each epitope comprises residues from both Cgamma3 domains.

Effect of pH on the active site of an Arg121Cys mutant of the metallo-beta-lactamase from Bacillus cereus: implications for the enzyme mechanism.

The zinc-dependent metallo-beta-lactamases are a group of bacterial enzymes that pose a threat to the future efficacy of present-day antibiotics. Their mechanism is poorly understood, and there are no clinically useful inhibitors. While most members of the group contain two tightly bound zinc ions in their active sites, the Bacillus cereus enzyme has a much lower affinity for its second zinc (Zn2), thought to be due to the presence of Arg121 immediately beneath the floor of the active site (cf.

The crystal structure of IgE Fc reveals an asymmetrically bent conformation.

The distinguishing structural feature of immunoglobulin E (IgE), the antibody responsible for allergic hypersensitivity, is the C epsilon 2 domain pair that replaces the hinge region of IgG. The crystal structure of the IgE Fc (constant fragment) at a 2.6-A resolution has revealed these domains.