The inherent drug susceptibility of microorganisms is determined by multiple factors, including growth state, the rate of drug diffusion into and out of the cell, and the intrinsic vulnerability of ...drug targets with regard to the corresponding antimicrobial agent. Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), remains a significant source of global morbidity and mortality, further exacerbated by its ability to readily evolve drug resistance. It is well accepted that drug resistance in M. tuberculosis is driven by the acquisition of chromosomal mutations in genes encoding drug targets/promoter regions; however, a comprehensive description of the molecular mechanisms that fuel drug resistance in the clinical setting is currently lacking. In this context, there is a growing body of evidence suggesting that active extrusion of drugs from the cell is critical for drug tolerance. M. tuberculosis encodes representatives of a diverse range of multidrug transporters, many of which are dependent on the proton motive force (PMF) or the availability of ATP. This suggests that energy metabolism and ATP production through the PMF, which is established by the electron transport chain (ETC), are critical in determining the drug susceptibility of M. tuberculosis. In this review, we detail advances in the study of the mycobacterial ETC and highlight drugs that target various components of the ETC. We provide an overview of some of the efflux pumps present in M. tuberculosis and their association, if any, with drug transport and concomitant effects on drug resistance. The implications of inhibiting drug extrusion, through the use of efflux pump inhibitors, are also discussed.
The emergence of drug resistance continues to plague TB control, with a global increase in the prevalence of MDR-TB. This acts as a gateway to XDR-TB and thus emphasizes the urgency for drug ...development and optimal treatment options. Bedaquiline is the first new anti-TB drug approved by the FDA in 40 years and has been shown to be an effective treatment option for MDR Mycobacterium tuberculosis infection. Bedaquiline has also recently been included in clinical trials for new regimens with the aim of improving and shortening treatment periods. Alarmingly, efflux-mediated bedaquiline resistance, as well as efflux-mediated cross-resistance to clofazimine, has been identified in treatment failures. This mechanism of resistance results in efflux of a variety of anti-TB drugs from the bacterial cell, thereby decreasing the intracellular drug concentration. In doing so, the bacillus is able to render the antibiotic treatment ineffective. Recent studies have explored strategies to reverse the resistance phenotype conferred by efflux pump activation. It was observed that the addition of efflux pump inhibitors partially restored drug susceptibility in vitro and in vivo. This has significant clinical implications, especially in MDR-TB management where treatment options are extremely limited. This review aims to highlight the current efflux pump inhibitors effective against M. tuberculosis, the effect of efflux pump inhibitors on mycobacterial growth and the clinical promise of treatment with efflux pump inhibitors and standard anti-TB therapy.
Following primary SARS-CoV-2 vaccination, whether boosters or breakthrough infections provide greater protection against SARS-CoV-2 infection is incompletely understood. Here we investigated ...SARS-CoV-2 antibody correlates of protection against new Omicron BA.4/5 (re-)infections and anti-spike IgG antibody trajectories after a third/booster vaccination or breakthrough infection following second vaccination in 154,149 adults ≥18 y from the United Kingdom general population. Higher antibody levels were associated with increased protection against Omicron BA.4/5 infection and breakthrough infections were associated with higher levels of protection at any given antibody level than boosters. Breakthrough infections generated similar antibody levels to boosters, and the subsequent antibody declines were slightly slower than after boosters. Together our findings show breakthrough infection provides longer-lasting protection against further infections than booster vaccinations. Our findings, considered alongside the risks of severe infection and long-term consequences of infection, have important implications for vaccine policy.
Understanding the trajectory, duration, and determinants of antibody responses after SARS-CoV-2 infection can inform subsequent protection and risk of reinfection, however large-scale representative ...studies are limited. Here we estimated antibody response after SARS-CoV-2 infection in the general population using representative data from 7,256 United Kingdom COVID-19 infection survey participants who had positive swab SARS-CoV-2 PCR tests from 26-April-2020 to 14-June-2021. A latent class model classified 24% of participants as 'non-responders' not developing anti-spike antibodies, who were older, had higher SARS-CoV-2 cycle threshold values during infection (i.e. lower viral burden), and less frequently reported any symptoms. Among those who seroconverted, using Bayesian linear mixed models, the estimated anti-spike IgG peak level was 7.3-fold higher than the level previously associated with 50% protection against reinfection, with higher peak levels in older participants and those of non-white ethnicity. The estimated anti-spike IgG half-life was 184 days, being longer in females and those of white ethnicity. We estimated antibody levels associated with protection against reinfection likely last 1.5-2 years on average, with levels associated with protection from severe infection present for several years. These estimates could inform planning for vaccination booster strategies.
In 1954 the Supreme Court decidedBrown v. Board of Education; ten years later, Congress enacted the Civil Rights Act. These monumental changes in American law dramatically expanded educational ...opportunities for racial and ethnic minority children across the country. They also changed the experiences of white children, who have learned in increasingly diverse classrooms. The authors of this commemorative volume include leading scholars in law, education, and public policy, as well as important historical figures. Taken together, the chapters trace the narrative arc of school desegregation in the United States, beginning in California in the 1940s, continuing throughBrown v. Board, the Civil Rights Act, and three important Supreme Court decisions about school desegregation and voluntary integration in 1974, 1995, and 2007. The authors also assess the status of racial and ethnic equality in education today and consider the viability of future legal and policy reform in pursuit of the goals ofBrown. This remarkable collection of voices in conversation with one another lays the groundwork for future discussions about the relationship between law and educational equality, and ultimately for the creation of new public policy. A valuable reference for scholars and students alike, this dynamic text is an important contribution to the literature by an outstanding group of authors.
Micro- and small-sized sustainable fashion businesses benefit greatly from their formal and informal networks which provide a wide variety of support and services. This exploratory study reports on ...the findings of a UK-based research project that investigated 27 firms in this category. We focus on four case studies comprising two designers running their own labels and two product developers who support other designers. Our analysis maps the networks of these micro- and small-sized sustainable fashion businesses. Taking an approach informed by actor-network theory (ANT), we describe human, organizational, and social media actors in formal and informal networks. We show how networks are formed and extended through supply-chain relationships, professional networks, and the serendipity of personal and online contacts. Focusing on informal networks, the article also discusses the models of working and the role that geographical (or physical) and cognitive proximity plays. The networks of sustainable businesses particularly depend on trust and shared values and help designers to understand and increase their sustainable practices.
The physiological effects of vaccination against SARS-CoV-2 (COVID-19) are well documented, yet the behavioural effects not well known. Risk compensation suggests that gains in personal safety, as a ...result of vaccination, are offset by increases in risky behaviour, such as socialising, commuting and working outside the home. This is potentially important because transmission of SARS-CoV-2 is driven by contacts, which could be amplified by vaccine-related risk compensation. Here, we show that behaviours were overall unrelated to personal vaccination, but-adjusting for variation in mitigation policies-were responsive to the level of vaccination in the wider population: individuals in the UK were risk compensating when rates of vaccination were rising. This effect was observed across four nations of the UK, each of which varied policies autonomously.
Abstract
Background
“Classic” symptoms (cough, fever, loss of taste/smell) prompt severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) testing in the United ...Kingdom. Studies have assessed the ability of different symptoms to identify infection, but few have compared symptoms over time (reflecting variants) and by vaccination status.
Methods
Using the COVID-19 Infection Survey, sampling households across the United Kingdom, we compared symptoms in PCR-positives vs PCR-negatives, evaluating sensitivity of combinations of 12 symptoms (percentage symptomatic PCR-positives reporting specific symptoms) and tests per case (TPC) (PCR-positives or PCR-negatives reporting specific symptoms/ PCR-positives reporting specific symptoms).
Results
Between April 2020 and August 2021, 27 869 SARS-CoV-2 PCR-positive episodes occurred in 27 692 participants (median 42 years), of whom 13 427 (48%) self-reported symptoms (“symptomatic PCR-positives”). The comparator comprised 3 806 692 test-negative visits (457 215 participants); 130 612 (3%) self-reported symptoms (“symptomatic PCR-negatives”). Symptom reporting in PCR-positives varied by age, sex, and ethnicity, and over time, reflecting changes in prevalence of viral variants, incidental changes (eg, seasonal pathogens (with sore throat increasing in PCR-positives and PCR-negatives from April 2021), schools reopening) and vaccination rollout. After May 2021 when Delta emerged, headache and fever substantially increased in PCR-positives, but not PCR-negatives. Sensitivity of symptom-based detection increased from 74% using “classic” symptoms, to 81% adding fatigue/weakness, and 90% including all 8 additional symptoms. However, this increased TPC from 4.6 to 5.3 to 8.7.
Conclusions
Expanded symptom combinations may provide modest benefits for sensitivity of PCR-based case detection, but this will vary between settings and over time, and increases tests/case. Large-scale changes to targeted PCR-testing approaches require careful evaluation given substantial resource and infrastructure implications.
Within the COVID-19 Infection Survey, recruiting representative households across the UK general population, SARS-CoV-2-associated symptoms varied by viral variant, vaccination status and demographics. However, differences are modest and do not currently warrant large-scale changes to targeted testing approaches.
Abstract
Background
Despite targeted interventions to improve contraceptive implant acceptability and uptake in rural Papua New Guinea (PNG), ongoing use of this method remains limited. Previous ...literature has suggested community attitudes and intrinsic factors within the decision-making process may be negatively impacting on implant uptake, however these elements have not previously been studied in detail in this context. We set out to explore community attitudes towards the contraceptive implant and the pathways to decision making around implant use in a rural community on Karkar Island, PNG.
Methods
We conducted 10 focus-group (FGD) and 23 in-depth interviews (IDI) using semi-structured topic guides. Key sampling characteristics included age, exposure or non-exposure to implants, marital status, education and willingness to participate in discussion. Four FGDs were held with women, four with men and two with mixed gender. IDIs were carried out with five women (current implant users, former implant users, implant never users), five men, five religious leaders (Catholic and non-Catholic), four village leaders and four health workers. Two in-depth interviews (four participants) were analysed as dyads and the remaining participant responses were analysed individually.
Results
Men were supportive of their wives using family planning but there was a community-wide lack of familiarity about the contraceptive implant which influenced its low uptake. Men perceived family planning to be ‘women’s business’ but remained strongly influential in the decision making processes around method use. Young men were more receptive to biomedical information than older men and had a greater tendency towards wanting to use implants. Older men preferred to be guided by prominent community members for decisions concerning implants whilst young men were more likely to engage with health services directly.
Conclusions
In communities where a couple’s decision to use the contraceptive implant is strongly coloured by gendered roles and social perceptions, having a detailed understanding of the relational dynamics affecting the decision-making unit is useful in targeting future healthcare interventions. Engaging groups who are reluctant to connect with health information, as well as those who are most influential in the decision making process, will have the greatest impact on increasing implant acceptability and uptake.
SARS-CoV-2 reinfections increased substantially after Omicron variants emerged. Large-scale community-based comparisons across multiple Omicron waves of reinfection characteristics, risk factors, and ...protection afforded by previous infection and vaccination, are limited. Here we studied ~45,000 reinfections from the UK's national COVID-19 Infection Survey and quantified the risk of reinfection in multiple waves, including those driven by BA.1, BA.2, BA.4/5, and BQ.1/CH.1.1/XBB.1.5 variants. Reinfections were associated with lower viral load and lower percentages of self-reporting symptoms compared with first infections. Across multiple Omicron waves, estimated protection against reinfection was significantly higher in those previously infected with more recent than earlier variants, even at the same time from previous infection. Estimated protection against Omicron reinfections decreased over time from the most recent infection if this was the previous or penultimate variant (generally within the preceding year). Those 14-180 days after receiving their most recent vaccination had a lower risk of reinfection than those >180 days from their most recent vaccination. Reinfection risk was independently higher in those aged 30-45 years, and with either low or high viral load in their most recent previous infection. Overall, the risk of Omicron reinfection is high, but with lower severity than first infections; both viral evolution and waning immunity are independently associated with reinfection.
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