Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance.

INTRODUCTION: 2018 World Health Organization (WHO) guidelines for the treatment of isoniazid (H)-resistant (Hr) tuberculosis recommend a four-drug regimen: rifampicin (R), ethambutol (E), pyrazinamide (Z) and levofloxacin (Lfx), with or without H ([H]RZE-Lfx). This is used once Hr is known, such that patients complete 6 months of Lfx (≥6[H]RZE-6Lfx). This cohort study assessed the impact of fluoroquinolones (Fq) on treatment effectiveness, accounting for Hr mutations and degree of phenotypic resistance. METHODS: This was a retrospective cohort study of 626 Hr tuberculosis patients notified in London, 2009-2013. Regimens were described and logistic regression undertaken of the association between regimen and negative regimen-specific outcomes (broadly, death due to tuberculosis, treatment failure or disease recurrence). RESULTS: Of 594 individuals with regimen information, 330 (55.6%) were treated with (H)RfZE (Rf=rifamycins) and 211 (35.5%) with (H)RfZE-Fq. The median overall treatment period was 11.9 months and median Z duration 2.1 months. In a univariable logistic regression model comparing (H)RfZE with and without Fqs, there was no difference in the odds of a negative regimen-specific outcome (baseline (H)RfZE, cluster-specific odds ratio 1.05 (95% CI 0.60-1.82), p=0.87; cluster NHS trust). Results varied minimally in a multivariable model. This odds ratio dropped (0.57, 95% CI 0.14-2.28) when Hr genotype was included, but this analysis lacked power (p=0.42). CONCLUSIONS: In a high-income setting, we found a 12-month (H)RfZE regimen with a short Z duration to be similarly effective for Hr tuberculosis with or without a Fq. This regimen may result in fewer adverse events than the WHO recommendations

A Small Molecule that Induces Intrinsic Pathway Apoptosis with Unparalleled Speed

Apoptosis is generally believed to be a process thatrequires several hours, in contrast to non-programmed forms of cell death that can occur in minutes. Our findings challenge the time-consuming nature of apoptosis as we describe the discovery and characterization of a small molecule, named Raptinal, which initiates intrinsic pathway caspase-dependent apoptosis within minutes in multiple cell lines. Comparison to a mechanistically diverse panel of apoptotic stimuli reveals that Raptinal-induced apoptosis proceeds with unparalleled speed. The rapid phenotype enabled identification of the criticalroles of mitochondrial voltage-dependent anion channel function, mitochondrial membrane potential/coupled respiration, and mitochondrial complex I, III, and IV function for apoptosis induction. Use of Raptinal in whole organisms demonstrates its utility for studying apoptosis invivo for a variety of applications. Overall, rapid inducers of apoptosis are powerful tools that will be used in a variety of settings to generate further insight into the apoptotic machinery. Palchaudhuri etal. describe the discovery of a small molecule called "Raptinal" that induces unusually rapid apoptotic cell death via the intrinsic pathway. Their work describes the utility of Raptinal as a tool for apoptosis induction relative to other available small molecules

Genetic and Proteomic Approaches to Identify Cancer Drug Targets

While target-based small-molecule discovery has taken centre-stage in the pharmaceutical industry, there are many cancer-promoting proteins not easily addressed with a traditional target-based screening approach. In order to address this problem, as well as to identify modulators of biological states in the absence of knowing the protein target of the state switch, alternative phenotypic screening approaches, such as gene expression-based and high-content imaging, have been developed. With this renewed interest in phenotypic screening, however, comes the challenge of identifying the binding protein target(s) of small-molecule hits. Emerging technologies have the potential to improve the process of target identification. In this review, we discuss the application of genomic (gene expression-based), genetic (short hairpin RNA and open reading frame screening), and proteomic approaches to protein target identification

Conformational Changes in DNA upon Ligand Binding Monitored by Circular Dichroism

Circular dichroism (CD) spectroscopy is an optical technique that measures the difference in the absorption of left and right circularly polarized light. This technique has been widely employed in the studies of nucleic acids structures and the use of it to monitor conformational polymorphism of DNA has grown tremendously in the past few decades. DNA may undergo conformational changes to B-form, A-form, Z-form, quadruplexes, triplexes and other structures as a result of the binding process to different compounds. Here we review the recent CD spectroscopic studies of the induction of DNA conformational changes by different ligands, which includes metal derivative complex of aureolic family drugs, actinomycin D, neomycin, cisplatin, and polyamine. It is clear that CD spectroscopy is extremely sensitive and relatively inexpensive, as compared with other techniques. These studies show that CD spectroscopy is a powerful technique to monitor DNA conformational changes resulting from drug binding and also shows its potential to be a drug-screening platform in the future

Track E Implementation Science, Health Systems and Economics

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138412/1/jia218443.pd

Exploiting immune cell metabolic machinery for functional HIV cure and the prevention of inflammaging.

An emerging paradigm in immunology suggests that metabolic reprogramming and immune cell activation and functions are intricately linked. Viral infections, such as HIV infection, as well as cancer force immune cells to undergo major metabolic challenges. Cells must divert energy resources in order to mount an effective immune response. However, the fact that immune cells adopt specific metabolic programs to provide host defense against intracellular pathogens and how this metabolic shift impacts immune cell functions and the natural course of diseases have only recently been appreciated. A clearer insight into how these processes are inter-related will affect our understanding of several fundamental aspects of HIV persistence. Even in patients with long-term use of anti-retroviral therapies, HIV infection persists and continues to cause chronic immune activation and inflammation, ongoing and cumulative damage to multiple organs systems, and a reduction in life expectancy. HIV-associated fundamental changes to the metabolic machinery of the immune system can promote a state of "inflammaging", a chronic, low-grade inflammation with specific immune changes that characterize aging, and can also contribute to the persistence of HIV in its reservoirs. In this commentary, we will bring into focus evolving concepts on how HIV modulates the metabolic machinery of immune cells in order to persist in reservoirs and how metabolic reprogramming facilitates a chronic state of inflammation that underlies the development of age-related comorbidities. We will discuss how immunometabolism is facilitating the changing paradigms in HIV cure research and outline the novel therapeutic opportunities for preventing inflammaging and premature development of age-related conditions in HIV + individuals

Candidaemia in the elderly: epidemiology, management and adherence to the European Confederation of Medical Mycology quality indicators

Background: Candidaemia in the elderly has not been extensively investigated. Objectives: We compared the management of candidaemia in the elderly patients (age ≥65 years) and the very elderly subgroup of patients (age ≥75 years) with those belonging to the younger group (age <65 years) using the European Confederation of Medical Mycology (ECMM) Quality (EQUAL) standard. Patients & Methods: Over a 10-year period (April 2011-March 2020), patients with candida bloodstream infection were identified. Data pertaining to demographics, clinical risk factors, antifungal treatment, central venous catheter and investigations such as echocardiogram and fundoscopy were obtained from electronic sources and medical case notes. Results: A total of 174 episodes of candidaemia were recorded, comprising of 74 episodes in younger patients and 100 in the elderly, of whom 56 were in the very elderly patients. Of the 177 Candida species recovered, 79 were Candida albicans. EQUAL scores were analysed for 148 patients. The mean score was significantly lower in the elderly (10.4) and the very elderly (9.7) patients compared to the patients in the younger age group (12.19) (P < .01). In particular, this was due to lower blood culture volume drawn (P < .01) and, in the very elderly group, significantly lower scores for the quality indicators pertaining to echocardiogram and fundoscopy (P = .03). The overall mean EQUAL score was 11.16 (median 11; interquartile range 8-14). The 30-day survival was 68% and was similar between all groups. Conclusions: Areas of improvement were identified in the management of candidaemia in the elderly patients

Candidaemia in the elderly: Epidemiology, management and adherence to the European Confederation of Medical Mycology quality indicators

Background: Candidaemia in the elderly has not been extensively investigated. Objectives: We compared the management of candidaemia in the elderly patients (age ≥65 years) and the very elderly subgroup of patients (age ≥75 years) with those belonging to the younger group (age <65 years) using the European Confederation of Medical Mycology (ECMM) Quality (EQUAL) standard. Patients & Methods: Over a 10-year period (April 2011-March 2020), patients with candida bloodstream infection were identified. Data pertaining to demographics, clinical risk factors, antifungal treatment, central venous catheter and investigations such as echocardiogram and fundoscopy were obtained from electronic sources and medical case notes. Results: A total of 174 episodes of candidaemia were recorded, comprising of 74 episodes in younger patients and 100 in the elderly, of whom 56 were in the very elderly patients. Of the 177 Candida species recovered, 79 were Candida albicans. EQUAL scores were analysed for 148 patients. The mean score was significantly lower in the elderly (10.4) and the very elderly (9.7) patients compared to the patients in the younger age group (12.19) (P < .01). In particular, this was due to lower blood culture volume drawn (P < .01) and, in the very elderly group, significantly lower scores for the quality indicators pertaining to echocardiogram and fundoscopy (P = .03). The overall mean EQUAL score was 11.16 (median 11; interquartile range 8-14). The 30-day survival was 68% and was similar between all groups. Conclusions: Areas of improvement were identified in the management of candidaemia in the elderly patients