External validation of a minimal-resource model to predict reduced estimated glomerular filtration rate in people with type 2 diabetes without diagnosis of chronic kidney disease in Mexico: a comparison between country-level and regional performance.

Background: Patients with type 2 diabetes are at an increased risk of chronic kidney disease (CKD) hence it is recommended that they receive annual CKD screening. The huge burden of diabetes in Mexico and limited screening resource mean that CKD screening is underperformed. Consequently, patients often have a late diagnosis of CKD. A regional minimal-resource model to support risk-tailored CKD screening in patients with type 2 diabetes has been developed and globally validated. However, population heath and care services between countries within a region are expected to differ. The aim of this study was to evaluate the performance of the model within Mexico and compare this with the performance demonstrated within the Americas in the global validation. Methods: We performed a retrospective observational study with data from primary care (Clinic Specialized in Diabetes Management in Mexico City), tertiary care (Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán) and the Mexican national survey of health and nutrition (ENSANUT-MC 2016). We applied the minimal-resource model across the datasets and evaluated model performance metrics, with the primary interest in the sensitivity and increase in the positive predictive value (PPV) compared to a screen-everyone approach. Results: The model was evaluated on 2510 patients from Mexico (primary care: 1358, tertiary care: 735, ENSANUT-MC: 417). Across the Mexico data, the sensitivity was 0.730 (95% CI: 0.689 - 0.779) and the relative increase in PPV was 61.0% (95% CI: 52.1% - 70.8%). These were not statistically different to the regional performance metrics for the Americas (sensitivity: p=0.964; relative improvement: p=0.132), however considerable variability was observed across the data sources. Conclusion: The minimal-resource model performs consistently in a representative Mexican population sample compared with the Americas regional performance. In primary care settings where screening is underperformed and access to laboratory testing is limited, the model can act as a risk-tailored CKD screening solution, directing screening resources to patients who are at highest risk.

Diagnosis codes underestimate chronic kidney disease incidence compared with eGFR-based evidence: a retrospective observational study of patients with type 2 diabetes in UK primary care.

BACKGROUND: Type two diabetes (T2D) is a leading cause of both chronic kidney disease (CKD) and onward progression to end-stage renal disease. Timely diagnosis coding of CKD in patients with T2D could lead to improvements in quality of care and patient outcomes. AIM: To assess the consistency between estimated glomerular filtration rate (eGFR)-based evidence of CKD and CKD diagnosis coding in UK primary care. DESIGN & SETTING: A retrospective analysis of electronic health record data in a cohort of people with T2D from 60 primary care centres within England between 2012 and 2022. METHOD: We estimated the incidence rate of CKD per 100 person-years using eGFR-based CKD and diagnosis codes. Logistic regression was applied to establish which attributes were associated with diagnosis coding. Time from eGFR-based CKD to entry of a diagnosis code was summarised using the median and interquartile range. RESULTS: The overall incidence of CKD was 2.32 (95% confidence interval [CI] = 2.24 to 2.41) and significantly higher for eGFR-based criteria than diagnosis codes: 1.98 (95% CI = 1.90 to 2.05) versus 1.06 (95% CI = 1.00 to 1.11), respectively; P<0.001. Only 45.4% of CKD incidences identified using eGFR-based criteria had a corresponding diagnosis code. Patients who were younger, had a higher CKD stage (G4), had an observed urine albumin-to-creatinine ratio (A1), or no observed HbA1c in the past year were more likely to have a diagnosis code. CONCLUSION: Diagnosis coding of patients with eGFR-based evidence of CKD in UK primary care is poor within patients with T2D, despite CKD being a well-known complication of diabetes.

Economic evaluation of interventions for treatment-resistant depression: A systematic review.

Background: The extraordinarily high prevalence of treatment-resistant depression (TRD), coupled with its high economic burden to both healthcare systems and society, underscore how critical it is that resources are managed optimally to address the significant challenge it presents. Objective: To review the literature on economic evaluation in TRD systematically, with the aim of informing future studies by identifying key challenges specific to the area, and highlighting good practices. Methods: A systematic literature search across seven electronic databases was conducted to identify both within-trial and model-based economic evaluations in TRD. Quality of reporting and study design was assessed using the Consensus Health Economic Criteria (CHEC). A narrative synthesis was conducted. Results: We identified 31 evaluations, including 11 conducted alongside a clinical trial and 20 model-based evaluations. There was considerable heterogeneity in the definition of treatment-resistant depression, although with a trend for more recent studies to use a definition of inadequate response to two or more antidepressive treatments. A broad range of interventions were considered, including non-pharmacological neuromodulation, pharmacological, psychological, and service-level interventions. Study quality as assessed by CHEC was generally high. Frequently poorly reported items related to discussion of ethical and distributional issues, and model validation. Most evaluations considered comparable core clinical outcomes - encompassing remission, response, and relapse. There was good agreement on the definitions and thresholds for these outcomes, and a relatively small pool of outcome measures were used. Resource criteria used to inform the estimation of direct costs, were reasonably uniform. Predominantly, however, there was a high level of heterogeneity in terms of evaluation design and sophistication, quality of evidence used (particularly health state utility data), time horizon, population considered, and cost perspective. Conclusion: Economic evidence for interventions in TRD is underdeveloped, particularly so for service-level interventions. Where evidence does exist, it is hampered by inconsistency in study design, methodological quality, and availability of high quality long-term outcomes evidence. This review identifies a number of key considerations and challenges for the design of future economic evaluations. Recommendations for research and suggestions for good practice are made. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=259848&VersionID=1542096, identifier CRD42021259848.

Development of minimal resource pre-screening tools for chronic kidney disease in people with type 2 diabetes.

Regular chronic kidney disease (CKD) screening can facilitate earlier diagnosis of CKD and preventative action to reduce the risk of CKD progression. People with type 2 diabetes are at a higher risk of developing CKD; hence, it is recommended that they undergo annual screening. However, resources may be limited, particularly in lower-to-middle income countries, and those at the highest risk of having an abnormal CKD screening result should be prioritised for screening. We have developed models to determine which patients are at a high risk of renal impairment. We have shown that, for people with type 2 diabetes and no previous diagnosis of CKD stage 3-5, it is possible to use age, gender, body mass index, duration of type 2 diabetes and blood pressure information to detect those at a higher risk of a reduced glomerular filtration rate. When blood measurements are available, triglyceride and cholesterol measurements can be used to improve the estimate of the risk. Even though risk factors were associated with an increased urine albumin:creatinine ratio, we found no clinical benefit of using the model over a screen-all approach.

Implementation of a novel mHealth application for the management of people with diabetes and recently healed foot ulceration: A feasibility study.

Background: Diabetic foot ulcers (DFUs) cause significant morbidity and mortality. Faster referral to specialist clinics is associated with a reduced risk of severe DFUs. The INTELLIN® diabetes management platform is a novel mHealth application for the management of recently healed DFUs and other complications, promoting engagement and expediting self-referral. Methods: To determine the acceptability, suitability, and usability of the INTELLIN® platform, time until reulceration, site, ischemia, neuropathy, bacterial infection, and depth (SINBAD) score and incidence of self-referral for recurrence were assessed in patients from the Salford Royal NHS Foundation Trust. Patients and clinic staff also assessed platform usability. A Markov cost-utility model was used for the health economics and outcomes research analysis. Results: 197 patients were assessed for eligibility and 15 entered the full analysis set (FAS). Through Week 52, 8/15 patients experienced recurrence, with a mean SINBAD score of 2.1 and mean duration of 2.6 days. Mean time to recurrence was 273.0 days (95% confidence interval 74.0, 484.0). No patients self-referred. Initial qualitative data showed high platform usability. The INTELLIN® platform only required a relative reduction in recurrence of 5% versus standard of care (SoC) for an incremental cost effectiveness ratio of £20,000 per quality-adjusted life-year, suggesting potential for significant cost savings upon wider adoption. The barriers to enrollment encountered demonstrate the impact of socioeconomics on mHealth. Conclusions: These results suggest that the INTELLIN® platform is required to provide only a small reduction in recurrence compared to SoC to be a cost-effective strategy for prevention of recurrent DFUs.

Treatment Preference Among People With Cystic Fibrosis: The Importance of Reducing Treatment Burden.

BACKGROUND: There is a growing consensus that the perspective of the patient should be considered in the evaluation of novel interventions. RESEARCH QUESTION: What treatment outcomes matter to people with cystic fibrosis (CF), and what trade-offs would they make to realize these outcomes? STUDY DESIGN AND METHODS: Adults attending a specialist CF center were invited to complete an online discrete choice experiment (DCE). The DCE required participants to evaluate hypothetical CF treatment profiles, defined by impact on lung function, pulmonary exacerbations, abdominal symptoms, life expectancy, quality of life, inhaled medicine usage, and physiotherapy requirement. Choice data were analyzed, using multinomial logit and latent class models. RESULTS: One hundred and three people with CF completed the survey (median age, 35 years; range, 18-76 years); 52% were female; mean FEV1 % predicted, 69% [SD, 22%]). On average, an improvement in life expectancy by 10 years or more had the greatest impact on treatment preference, followed by a 15% increase in lung function. However, it was shown that people would trade substantial reductions in these key outcomes to reduce treatment time or burden. Preference profiles were not uniform across the sample: three distinct subgroups were identified, each placing markedly different importance on the relative importance of both life expectancy and lung function compared with other attributes. INTERPRETATION: The relative importance of treatment burden to people with CF, compared with life expectancy and lung function, suggests it should be routinely captured in clinical trials as an important secondary outcome measure. When considering the patient perspective, it is important that decision-makers recognize that the values of people with CF are not homogeneous.

The Peterborough Exemplar: a protocol to evaluate the impact and implementation of a new patient-centred, system-wide community mental healthcare model in England.

BACKGROUND: Community mental healthcare has significantly grown since de-institutionalization. Despite progress, service fragmentation and gaps in service provision remain key barriers to effective community care in England. Recent mental healthcare policies highlighted the need to transform service provision by developing patient-centred, joined-up community mental healthcare. In response to policy guidance, a system-wide community mental healthcare model was developed in Peterborough (England). The "Peterborough Exemplar" is based on two main pillars: (1) the creation of knowledge exchange pathways to strengthen interorganizational relationships, and (2) the development of new, accessible community services addressing existing service gaps. This paper presents the protocol developed to evaluate the Peterborough Exemplar. METHODS: A quasi-experimental design with an intervention group and a nonequivalent comparator group has been developed to compare service provision provided in Peterborough pre- and post-intervention with services provided in Fenland, a neighbouring area where service users access usual care. Two evaluation methods will be employed to compare service provision between the two groups: (1) outcome measures completed by service users and carers will be analysed to assess quality of life and service satisfaction, and (2) service activity data will be analysed to assess service usage. In addition, qualitative interviews will be conducted with staff members of participating organizations to explore the implementation of the Exemplar in Peterborough and evaluate knowledge exchange processes among local service providers. A matched control approach will be used to compare outcome measures between the two areas. Descriptive and inferential statistics, including chi-square tests, will be used to analyse service activity data and examine differences between the two areas. A thematic analysis will be adopted to analyse qualitative data. DISCUSSION: Outcomes of the evaluation will contribute to understanding the contribution of the Peterborough Exemplar on mental health service provision locally. Evaluation findings and intermediate reporting will be shared with organizations involved in the implementation of the Peterborough Exemplar and with local decision-makers to inform the Exemplar delivery. As the Peterborough Exemplar is an Early Implementer (EI) site funded by NHS England, findings will be shared with policy-makers to inform national policy on community mental healthcare and integrated care.

Exploring the nature of perceived treatment burden: a study to compare treatment burden measures in adults with cystic fibrosis [version 1; peer review: 2 approved].

Background: Despite the importance of reducing treatment burden for people with cystic fibrosis (CF), it has not been fully understood as a concept. This study aims to quantify the treatment burden perceived by CF adults and explore the association between different validated treatment burden measures. Methods: This is a cross-sectional observational study of CF adults attending a single large UK adult center. Participants completed an online survey that contained three different treatment burden scales; CF Questionnaire-Revised (CFQ-R) subscale, CF Quality of Life (CFQoL) subscale, and the generic multimorbidity treatment burden questionnaire (MTBQ). Results: Among 101 participants, the median reported treatment burden by the CFQ-R subscale was 55.5 (IQR 33.3 - 66.6), the CFQoL subscale was 66.6 (IQR 46.6 - 86.6), and the MTBQ reversed global score was 84.6 (IQR 73.1 - 92.3). No correlation was found between respondents' demographic or clinical variables and treatment burden measured via any of the three measures. All treatment burden measures showed correlations against each other. More treatments were associated with high treatment burden as measured by the CFQ-R, CFQoL subscales, and the MTBQ. However, longer treatment time and more complex treatment plans were correlated with high treatment burden as measured by the CFQ-R and CFQoL subscales, but not with the MTBQ. Conclusions: Treatment burden is a substantial issue in CF. Currently, the only available way to evaluate it is with the CF-specific quality of life measure treatment burden subscales (CFQ-R and CFQoL); both indicated that treatment burden increases with more treatments, longer treatment time, and more complex treatments.

Understanding Uptake of Digital Health Products: Methodology Tutorial for a Discrete Choice Experiment Using the Bayesian Efficient Design.

Understanding the preferences of potential users of digital health products is beneficial for digital health policy and planning. Stated preference methods could help elicit individuals' preferences in the absence of observational data. A discrete choice experiment (DCE) is a commonly used stated preference method-a quantitative methodology that argues that individuals make trade-offs when engaging in a decision by choosing an alternative of a product or a service that offers the greatest utility, or benefit. This methodology is widely used in health economics in situations in which revealed preferences are difficult to collect but is much less used in the field of digital health. This paper outlines the stages involved in developing a DCE. As a case study, it uses the application of a DCE to reveal preferences in targeting the uptake of smoking cessation apps. It describes the establishment of attributes, the construction of choice tasks of 2 or more alternatives, and the development of the experimental design. This tutorial offers a guide for researchers with no prior knowledge of this research technique.

Structural and biochemical characterization of a nitrilase from the thermophilic bacterium, Geobacillus pallidus RAPc8.

Geobacillus pallidus RAPc8 (NRRL: B-59396) is a moderately thermophilic gram-positive bacterium, originally isolated from Australian lake sediment. The G. pallidus RAPc8 gene encoding an inducible nitrilase was located and cloned using degenerate primers coding for well-conserved nitrilase sequences, coupled with inverse PCR. The nitrilase open reading frame was cloned into an expression plasmid and the expressed recombinant enzyme purified and characterized. The protein had a monomer molecular weight of 35,790 Da, and the purified functional enzyme had an apparent molecular weight of approximately 600 kDa by size exclusion chromatography. Similar to several plant nitrilases and some bacterial nitrilases, the recombinant G. pallidus RAPc8 enzyme produced both acid and amide products from nitrile substrates. The ratios of acid to amide produced from the substrates we tested are significantly different to those reported for other enzymes, and this has implications for our understanding of the mechanism of the nitrilases which may assist with rational design of these enzymes. Electron microscopy and image classification showed complexes having crescent-like, "c-shaped", circular and "figure-8" shapes. Protein models suggested that the various complexes were composed of 6, 8, 10 and 20 subunits, respectively.

Metagenomic gene discovery: past, present and future.

It is now widely accepted that the application of standard microbiological methods for the recovery of microorganisms from the environment has had limited success in providing access to the true extent of microbial biodiversity. It follows that much of the extant microbial genetic diversity (collectively termed the metagenome) remains unexploited, an issue of considerable relevance to a wider understanding of microbial communities and of considerable importance to the biotechnology industry. The recent development of technologies designed to access this wealth of genetic information through environmental nucleic acid extraction has provided a means of avoiding the limitations of culture-dependent genetic exploitation.

Molecular analysis of the nitrile catabolism operon of the thermophile Bacillus pallidus RAPc8.

The gene cluster containing the nitrile hydratase (NHase) and amidase genes of a moderate thermophile, B. pallidus RAPc8 has been cloned and sequenced. The (5.9 kb) section of cloned DNA contained eight complete open reading frames, encoding (in order), amidase (belonging to the nitrilase related aliphatic amidase family), nitrile hydratase beta and alpha subunits (of the cobalt containing class), a 122-amino acid accessory protein, designated P14K, a homologue of the 2Fe-2S class of ferredoxins and three putative proteins with distinct homology to the cobalt uptake proteins cbiM, cbiN and cbiQ of the S. typhimurium LT2 cobalamin biosynthesis pathway. The amidase and nitrile hydratase genes were subcloned and inducibly expressed in Escherichia coli, to levels of approximately 37 U/mg and 49 U/mg, respectively, without the co-expression of additional flanking genes. However, co-expression of P14K with the NHase structural genes significantly enhanced the specific activity of the recombinant NHase. This is the first description of an accessory protein involved in thermostable NHase expression. Modelling of the P14K protein structure has suggested that this protein functions as a subunit-specific chaperone, aiding in the folding of the NHase alpha subunit prior to alpha-beta subunit association and the formation of alpha(2)beta(2) NHase holoenzyme.