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.

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.

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.

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.