Methodological approaches to measuring mental health in a cost-of-living crisis: A rapid review.

BACKGROUND: Cost-of-living crises are damaging to population mental health and require a public health response. It is important to assess whether public health interventions are effective. We aimed to identify population-level methods and measures and the appropriateness of the measures for vulnerable populations. METHODS: A rapid evidence review was undertaken. Nineteen databases, including grey literature, were searched for evidence published between 1970 and April 2023. RESULTS: Seven reviews, nine primary studies and two reports from grey literature were identified. Methods consisted of analyses of existing data from national or regional cohort studies, household panel surveys, repeated cross-sectional surveys, routine medical data, or data on suicide death rates. Twelve brief validated mental health measurement tools, embedded in population-level surveys, were identified. Two quasi-experimental studies used data from a UK household panel survey to examine the impact of the introduction of specific welfare policies on mental health. Studies identified socio-economic vulnerabilities, but it was not possible to determine whether data were effectively captured from people from minority ethnic groups. CONCLUSION: Population-level surveys can be used in quasi-experimental studies to measure the effects of a public health initiative with specific roll out dates to tackle cost-of-living impacts. It is unclear as to whether the identified methods and tools are suitable for use with people from minority ethnic groups.

Low energy contact X-ray brachytherapy for treatment of rectal cancer: a health technology appraisal by Health Technology Wales.

AIM: Health Technology Wales sought to evaluate the clinical and cost-effectiveness of contact X-ray brachytherapy (CXB) for early-stage rectal cancer. METHODS: Relevant studies were identified through systematic searches of MEDLINE, Embase, Cochrane Library and Scopus. A cost-utility model was developed to estimate the cost-effectiveness of CXB in National Health Service Wales, using results of the Organ Preservation in Early Rectal Adenocarcinoma (OPERA) trial. Patient perspectives were obtained through the Papillon Patient Support group and All-Wales Cancer Network. RESULTS: The OPERA randomized controlled trial showed that CXB improved complete response and organ preservation rates compared with external-beam boost for people with T2-3b, N0-1, M0 rectal cancer who are fit for surgery. Managing more of this population non-operatively after CXB was estimated to provide 0.2 quality-adjusted life years at an additional cost of £887 per person. CXB was cost effective compared with external-beam boost at a cost of £4463 per quality-adjusted life year gained. This conclusion did not change in scenario analysis and CXB was cost effective in 91% of probabilistic sensitivity analyses. Patients valued receiving clear information on all available options to support their individual treatment choices. The detrimental impact of a stoma on quality of life led some patients to reject the idea that surgery was their only option. CONCLUSION: This evidence review and cost-utility analysis indicates that CXB is likely to be clinically and cost effective, as part of a watch and wait strategy for adults fit for surgery. Wider access to CXB is supported by patient testimonies.

Oxygen-insensitive nitroreductase E. coli NfsA, but not NfsB, is inhibited by fumarate.

Escherichia coli NfsA and NfsB are founding members of two flavoprotein families that catalyze the oxygen-insensitive reduction of nitroaromatics and quinones by NAD(P)H. This reduction is required for the activity of nitrofuran antibiotics and the enzymes have also been proposed for use with nitroaromatic prodrugs in cancer gene therapy and biocatalysis, but the roles of the proteins in vivo in bacteria are not known. NfsA is NADPH-specific whereas NfsB can also use NADH. The crystal structures of E. coli NfsA and NfsB and several analogs have been determined previously. In our crystal trials, we unexpectedly observed NfsA bound to fumarate. We here present the X-ray structure of the E. coli NfsA-fumarate complex and show that fumarate acts as a weak inhibitor of NfsA but not of NfsB. The structural basis of this differential inhibition is conserved in the two protein families and occurs at fumarate concentrations found in vivo, so impacting the efficacy of these proteins.

The 3D-structure, kinetics and dynamics of the E. coli nitroreductase NfsA with NADP+ provide glimpses of its catalytic mechanism.

Nitroreductases activate nitroaromatic antibiotics and cancer prodrugs to cytotoxic hydroxylamines and reduce quinones to quinols. Using steady-state and stopped-flow kinetics, we show that the Escherichia coli nitroreductase NfsA is 20-50 fold more active with NADPH than with NADH and that product release may be rate-limiting. The crystal structure of NfsA with NADP+ shows that a mobile loop forms a phosphate-binding pocket. The nicotinamide ring and nicotinamide ribose are mobile, as confirmed in molecular dynamics (MD) simulations. We present a model of NADPH bound to NfsA. Only one NADP+ is seen bound to the NfsA dimers, and MD simulations show that binding of a second NADP(H) cofactor is unfavourable, suggesting that NfsA and other members of this protein superfamily may have a half-of-sites mechanism.

Effectiveness of tests to detect the presence of SARS-CoV-2 virus, and antibodies to SARS-CoV-2, to inform COVID-19 diagnosis: a rapid systematic review.

OBJECTIVES: We undertook a rapid systematic review with the aim of identifying evidence that could be used to answer the following research questions: (1) What is the clinical effectiveness of tests that detect the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to inform COVID-19 diagnosis? (2) What is the clinical effectiveness of tests that detect the presence of antibodies to the SARS-CoV-2 virus to inform COVID-19 diagnosis? DESIGN AND SETTING: Systematic review and meta-analysis of studies of diagnostic test accuracy. We systematically searched for all published evidence on the effectiveness of tests for the presence of SARS-CoV-2 virus, or antibodies to SARS-CoV-2, up to 4 May 2020, and assessed relevant studies for risks of bias using the QUADAS-2 framework. MAIN OUTCOME MEASURES: Measures of diagnostic accuracy (sensitivity, specificity, positive/negative predictive value) were the main outcomes of interest. We also included studies that reported influence of testing on subsequent patient management, and that reported virus/antibody detection rates where these facilitated comparisons of testing in different settings, different populations or using different sampling methods. RESULTS: 38 studies on SARS-CoV-2 virus testing and 25 studies on SARS-CoV-2 antibody testing were identified. We identified high or unclear risks of bias in the majority of studies, most commonly as a result of unclear methods of patient selection and test conduct, or because of the use of a reference standard that may not definitively diagnose COVID-19. The majority were in hospital settings, in patients with confirmed or suspected COVID-19 infection. Pooled analysis of 16 studies (3818 patients) estimated a sensitivity of 87.8% (95% CI 81.5% to 92.2%) for an initial reverse-transcriptase PCR test. For antibody tests, 10 studies reported diagnostic accuracy outcomes: sensitivity ranged from 18.4% to 96.1% and specificity 88.9% to 100%. However, the lack of a true reference standard for SARS-CoV-2 diagnosis makes it challenging to assess the true diagnostic accuracy of these tests. Eighteen studies reporting different sampling methods suggest that for virus tests, the type of sample obtained/type of tissue sampled could influence test accuracy. Finally, we searched for, but did not identify, any evidence on how any test influences subsequent patient management. CONCLUSIONS: Evidence is rapidly emerging on the effectiveness of tests for COVID-19 diagnosis and management, but important uncertainties about their effectiveness and most appropriate application remain. Estimates of diagnostic accuracy should be interpreted bearing in mind the absence of a definitive reference standard to diagnose or rule out COVID-19 infection. More evidence is needed about the effectiveness of testing outside of hospital settings and in mild or asymptomatic cases. Implementation of public health strategies centred on COVID-19 testing provides opportunities to explore these important areas of research.

The structures of E. coli NfsA bound to the antibiotic nitrofurantoin; to 1,4-benzoquinone and to FMN.

NfsA is a dimeric flavoprotein that catalyses the reduction in nitroaromatics and quinones by NADPH. This reduction is required for the activity of nitrofuran antibiotics. The crystal structure of free Escherichia coli NfsA and several homologues have been determined previously, but there is no structure of the enzyme with ligands. We present here crystal structures of oxidised E. coli NfsA in the presence of several ligands, including the antibiotic nitrofurantoin. Nitrofurantoin binds with the furan ring, rather than the nitro group that is reduced, near the N5 of the FMN. Molecular dynamics simulations show that this orientation is only favourable in the oxidised enzyme, while potentiometry suggests that little semiquinone is formed in the free protein. This suggests that the reduction occurs by direct hydride transfer from FMNH- to nitrofurantoin bound in the reverse orientation to that in the crystal structure. We present a model of nitrofurantoin bound to reduced NfsA in a viable hydride transfer orientation. The substrate 1,4-benzoquinone and the product hydroquinone are positioned close to the FMN N5 in the respective crystal structures with NfsA, suitable for reaction, but are mobile within the active site. The structure with a second FMN, bound as a ligand, shows that a mobile loop in the free protein forms a phosphate-binding pocket. NfsA is specific for NADPH and a similar conformational change, forming a phosphate-binding pocket, is likely to also occur with the natural cofactor.

Mucosal melanoma of the upper airways tract mucosal melanoma: A systematic review with meta-analyses of treatment.

BACKGROUND: Mucosal melanoma of the upper aerodigestive tract (MM-UADT) occurs in a complex anatomic region. It represents a small number of tumors of the head and neck and a small number of melanoma cases. METHODS: Search strategies initially identified 600, 11 of which were included in this study. RESULTS: All studies involved surgery and radiotherapy. None were randomized, and all were assessed as having a high risk of selection and performance bias. No studies reported quality of life, treatment-related mortality, or morbidity. The results indicate that the addition of radiotherapy to surgery reduces the rate of locoregional recurrence (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.42-0.87). There was no statistically significant difference in overall survival (HR, 1.16; 95% CI, 0.98-1.37). CONCLUSION: Surgical resection with postoperative radiotherapy remains the optimal treatment strategy for locoregional control. More robust studies and the use of molecular targeted therapies need to be undertaken to improve overall survival. © 2016 Wiley Periodicals, Inc. Head Neck 39: 819-825, 2017.

Steady-state and stopped-flow kinetic studies of three Escherichia coli NfsB mutants with enhanced activity for the prodrug CB1954.

The enzyme nitroreductase, NfsB, from Escherichia coli has entered clinical trials for cancer gene therapy with the prodrug CB1954 [5-(aziridin-1-yl)-2,4-dinitrobenzamide]. However, CB1954 is a poor substrate for the enzyme. Previously we made several NfsB mutants that show better activity with CB1954 in a cell-killing assay in E. coli. Here we compare the kinetic parameters of wild-type NfsB with CB1954 to those of the most active single, double, and triple mutants isolated to date. For wild-type NfsB the global kinetic parameters for both k(cat) and K(m) for CB1954 are about 20-fold higher than previously estimated; however, the measured specificity constant, k(cat)/K(m) is the same. All of the mutants are more active with CB1954 than the wild-type enzyme, the most active mutant showing about 100-fold improved specificity constant with CB1954 over the wild-type protein with little effect on k(cat). This enhancement in specificity constants for the mutants is not seen with the antibiotic nitrofurazone as substrate, leading to reversed nitroaromatic substrate selectivity for the double and triple mutants. However, similar enhancements in specificity constants are found with the quinone menadione. Stopped-flow kinetic studies suggest that the rate-determining step of the reaction is likely to be the release of products. The most active mutant is also selective for the 4-nitro group of CB1954, rather than the 2-nitro group, giving the more cytotoxic reduction product. The double and triple mutants should be much more effective enzymes for use with CB1954 in prodrug-activation gene therapy.