Bio-SIEVE: Exploring Instruction Tuning Large Language Models for Systematic Review Automation

Medical systematic reviews can be very costly and resource intensive. We explore how Large Language Models (LLMs) can support and be trained to perform literature screening when provided with a detailed set of selection criteria. Specifically, we instruction tune LLaMA and Guanaco models to perform abstract screening for medical systematic reviews. Our best model, Bio-SIEVE, outperforms both ChatGPT and trained traditional approaches, and generalises better across medical domains. However, there remains the challenge of adapting the model to safety-first scenarios. We also explore the impact of multi-task training with Bio-SIEVE-Multi, including tasks such as PICO extraction and exclusion reasoning, but find that it is unable to match single-task Bio-SIEVE's performance. We see Bio-SIEVE as an important step towards specialising LLMs for the biomedical systematic review process and explore its future developmental opportunities. We release our models, code and a list of DOIs to reconstruct our dataset for reproducibility

Gene expression profiling and expanded immunohistochemistry tests to guide selection of chemotherapy regimens in breast cancer management: a systematic review

OBJECTIVES: The aim of this report was to assess the clinical effectiveness of two Gene expression profiling (GEP) and two expanded immunohistochemistry (IHC) tests compared with current prognostic tools in guiding the use of adjuvant chemotherapy in patients with early breast cancer. METHODS: A systematic review of the evidence on clinical effectiveness of OncotypeDX, IHC4, MammaPrint and Mammostrat, compared with current clinical practice using clinicopathological parameters, in women with early breast cancer was conducted. Ten databases were searched to include citations to May 2016. RESULTS: Searches identified 7064 citations, of which 41 citations satisfied the criteria for the review. A narrative synthesis was performed. Evidence for OncotypeDX demonstrated the impact of the test on decision-making and there was some support for OncotypeDX predicting chemotherapy benefit. There were relatively lower levels of evidence for the other three tests included in the analysis. MammaPrint, Mammostrat and IHC4 tests were limited to a small number of studies. Limitations in relation to study design were identified for all tests. CONCLUSIONS: The evidence base for OncotypeDX is considered to be the most robust. Methodological weaknesses relating to heterogeneity of patient cohorts and issues arising from the retrospective nature of the evidence were identified. Further evidence is required for all of the tests using prospective randomised controlled trial data

Prognostic factors for liver, blood and kidney adverse events from glucocorticoid sparing immune-suppressing drugs in immune-mediated inflammatory diseases: a prognostic systematic review

Background: Immune-suppressing drugs can cause liver, kidney or blood toxicity. Prognostic factors for these adverse-events are poorly understood. Purpose: To ascertain prognostic factors associated with liver, blood or kidney adverse-events in people receiving immune-suppressing drugs. Data sources: MEDLINE, Web of Science, EMBASE and the Cochrane library (01 January 1995 to 05 January 2023), and supplementary sources. Data extraction and synthesis: Data were extracted by one reviewer using a modified CHARMS-PF checklist and validated by another. Two independent reviewers assessed risk of bias using Quality in Prognostic factor Studies tool and assessed the quality of evidence using a Grading of Recommendations Assessment, Development and Evaluation-informed framework. Results: Fifty-six studies from 58 papers were included. High-quality evidence of the following associations was identified: elevated liver enzymes (6 studies) and folate non-supplementation (3 studies) are prognostic factors for hepatotoxicity in those treated with methotrexate; that mercaptopurine (vs azathioprine) (3 studies) was a prognostic factor for hepatotoxicity in those treated with thiopurines; that mercaptopurine (vs azathioprine) (3 studies) and poor-metaboliser status (4 studies) were prognostic factors for cytopenia in those treated with thiopurines; and that baseline elevated liver enzymes (3 studies) are a prognostic factor for hepatotoxicity in those treated with anti-tumour necrosis factors. Moderate and low quality evidence for several other demographic, lifestyle, comorbidities, baseline bloods/serologic or treatment-related prognostic factors were also identified. Limitations: Studies published before 1995, those with less than 200 participants and not published in English were excluded. Heterogeneity between studies included different cut-offs for prognostic factors, use of different outcome definitions and different adjustment factors. Conclusions: Prognostic factors for target-organ damage were identified which may be further investigated for their potential role in targeted (risk-stratified) monitoring. PROSPERO registration number: CRD42020208049

Fractional exhaled nitric oxide for the management of asthma in adults: Systematic review

The aim of this review was to evaluate the clinical effectiveness of fractional exhaled nitric oxide (FeNO) measured in a clinical setting for the management of asthma in adults. 13 electronic databases were searched and studies were selected against predefined inclusion criteria. Quality assessment was conducted using QUADAS-2. Class effect meta-analyses were performed. Six studies were included. Despite high levels of heterogeneity in multiple study characteristics, exploratory class effect meta-analyses were conducted. Four studies reported a wider definition of exacerbation rates (major or severe exacerbation) with a pooled rate ratio of 0.80 (95% CI 0.63–1.02). Two studies reported rates of severe exacerbations (requiring oral corticosteroid use) with a pooled rate ratio of 0.89 (95% CI 0.43–1.72). Inhaled corticosteroid use was reported by four studies, with a pooled standardised mean difference of −0.24 (95% CI −0.56–0.07). No statistically significant differences for health-related quality of life or asthma control were found. FeNO guided management showed no statistically significant benefit in terms of severe exacerbations or ICS use, but showed a statistically significant reduction in exacerbations of any severity. However, further research is warranted to clearly define which management protocols (including cut-off points) offer best efficacy and which patient groups would benefit the most

Pirfenidone for Treating Idiopathic Pulmonary Fibrosis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

The National Institute for Health and Care Excellence (NICE) published guidance on the use of pirfenidone (Esbriet®, Roche) for the treatment of mild to moderate idiopathic pulmonary fibrosis (IPF) in 2013. NICE decided to review existing guidance following publication of an additional clinical trial, and invited the manufacturer of pirfenidone to submit evidence of its clinical and cost effectiveness for the treatment of mild to moderate IPF when compared with best supportive care (BSC) or nintedanib; nintedanib was a comparator only for moderate IPF. An independent Evidence Review Group (ERG) critiqued the company submission and this paper summarises their report and subsequent NICE guidance. The key clinical effectiveness evidence was based on three randomised controlled trials (RCTs) and an open-label extension study. Supportive data were provided from two additional RCTs conducted in Japan, while one additional open-label study was included for safety outcomes. Meta-analysis of the three key RCTs found pirfenidone to be effective at reducing disease progression compared with placebo, but statistically significant differences were not identified in all of the RCTs. A statistically significant reduction in all-cause mortality was only demonstrated when pooling data across studies. The treatment effects of pirfenidone and nintedanib were broadly similar, based on an indirect comparison using network meta-analysis, although they have slightly different adverse event profiles. There remains considerable uncertainty in the cost-effectiveness estimates for pirfenidone versus BSC, particularly due to uncertainty regarding the duration of treatment effect and the method used to implement the stopping rule within the economic model

Vedolizumab for the Treatment of Adults with Moderate-to-Severe Active Ulcerative Colitis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer of vedolizumab (Takeda UK) to submit evidence of the clinical effectiveness and cost effectiveness of vedolizumab for the treatment of patients with moderate-to-severe active ulcerative colitis (UC). The Evidence Review Group (ERG) produced a critical review of the evidence for the clinical effectiveness and cost effectiveness of the technology, based upon the company's submission to NICE. The evidence was derived mainly from GEMINI 1, a Phase 3, multicentre, randomised, double-blinded, placebo-controlled study of the induction and maintenance of clinical response and remission by vedolizumab (MLN0002) in patients with moderate-to-severe active UC with an inadequate response to, loss of response to or intolerance of conventional therapy or anti-tumour necrosis factor (TNF)-α. The clinical evidence showed that vedolizumab performed significantly better than placebo in both the induction and maintenance phases. In the post hoc subgroup analyses in patients with or without prior anti-TNF-α therapy, vedolizumab performed better then placebo (p value not reported). In addition, a greater improvement in health-related quality of life was observed in patients treated with vedolizumab, and the frequency and types of adverse events were similar in the vedolizumab and placebo groups, but the evidence was limited to short-term follow-up. There were a number of limitations and uncertainties in the clinical evidence base, which warrants caution in its interpretation-in particular, the post hoc subgroup analyses and high dropout rates in the maintenance phase of GEMINI 1. The company also presented a network meta-analysis of vedolizumab versus other biologic therapies indicated for moderate-to-severe UC. However, the ERG considered that the results presented may have underestimated the uncertainty in treatment effects, since fixed-effects models were used, despite clear evidence of heterogeneity among the trials included in the network. Results from the company's economic evaluation (which included price reductions to reflect the proposed patient access scheme for vedolizumab) suggested that vedolizumab is the most effective option compared with surgery and conventional therapy in the following three populations: (1) a mixed intention-to-treat population, including patients who have previously received anti-TNF-α therapy and those who are anti-TNF-α naïve; (2) patients who are anti-TNF-α naïve only; and (3) patients who have previously failed anti-TNF-α therapy only. The ERG concluded that the results of the company's economic evaluation could not be considered robust, because of errors in model implementation, omission of relevant comparators, deviations from the NICE reference case and questionable model assumptions. The ERG amended the company's model and demonstrated that vedolizumab is expected to be dominated by surgery in all three populations

Patient-reported outcome measures in carotid artery revascularization: systematic review and psychometric analysis

Objective: Patient-reported outcome measures (PROMs) provide a way to measure the impact of a disease and its associated treatments on the quality of life from the patients’ perspective. The aim of this review was to identify PROMs that have been developed and/or validated in patients with carotid artery stenosis (CAS) undergoing revascularisation and to assess their psychometric properties and examine suitability for research and clinical use. Methods: Eight electronic databases including MEDLINE and CINAHL were searched using a two-stage search approach to identify studies reporting the development and/or validation of relevant PROMs in patients with CAS undergoing revascularisation. Supplementary citation searching and hand-searching reference lists of included studies were also undertaken. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) and Oxford criteria were used to assess the methodological quality of the included studies and the psychometric properties of the PROMs were evaluated using established assessment criteria. Results: Five studies reporting on six PROMs were included: 36-Item Short Form Health Survey (SF-36), Euro-QoL-5-Dimension Scale (EQ-5D), Hospital Anxiety and Depression Scale (HADS), Dizziness Handicap Inventory (DHI), Quality of life for carotid artery disease scale and a disease-specific PROM for CAS. The rigour of the psychometric assessment of the PROMs was variable with most only attempting to assess a single psychometric criterion. No study reported evidence on construct validity and test-retest reliability. Evidence for acceptability for the use of SF-36, EQ-5D and the disease-specific PROM were rated good in most studies. Only one study reported a Cronbach alpha score >0.70 as evidence of internal consistency. Overall, the psychometric evaluation of all included PROMs was rated as poor within the CAS population undergoing revascularisation. Conclusions: This review highlighted a lack of evidence in validated PROMs used for patients undergoing carotid artery revascularisation. As a result, the development and validation of a new PROM for this patient population is warranted in order to provide data which can supplement traditional clinical outcomes (stroke<30 days post-procedural, myocardial infarction and death) and capture changes in health status and quality of life to help inform treatment decisions

Development of the asymmetric amino-cope arrangement

The research described in this thesis is aimed at demonstrating the synthetic utility of the asymmetric amino-Cope rearrangement and highlight its potential for future application in natural product synthesis. Using the recently developed asymmetric anionic amino-Cope methodology, rearrangement of diasteromerically pure 3-amino-l,5-hexadiene substrates provided the target aldehyde in good yield and with high levels of asymmetric induction (up to 94% e.e.). The aldehyde obtained was used for the successful formation of2,4-disubstituted lactones with no apparent loss of stereochemical integrity. This could lead to a plausible route to biologically significant compounds...