Helen Fulbright

Objective: To understand and compare the impact of 11 filters to remove records on animals or nonhumans in Ovid Embase, which are routinely used despite there being no performance data for them. To understand the indexing of relevant subject headings in Embase. Methods: To assess filter performance, we screened and categorized 3,000 records as ‘should be removed’ or ‘should be retained’ and calculated the sensitivity, specificity, and overall accuracy for each filter. We also reported on the number of records with human participants or data that were incorrectly removed by each filter. Results: Method 11 was the most sensitive, correctly retaining 90.6% records, whereas method 3 had the highest specificity, correctly removing 71.5% records. Of the records incorrectly removed by each filter, method 11 removed the fewest records with human participants or data at 10.9%, whereas method 3 removed the most at 14.3%. Filters that did not remove records indexed with ‘nonhuman/’ had higher sensitivity. Filter performance could vary by subject, publication type and language due to differences in indexing. Conclusion: In choosing a search filter, information specialists and review teams should discuss whether animals or nonhumans could feature in relevant studies.

Objectives: To evaluate the impact of continuing versus stopping biologic disease-modifying anti-rheumatic drugs (bDMARDs) during the perioperative period on surgical site infections (SSIs), delayed wound healing, and disease flares in patients with inflammatory arthritis (IA) undergoing elective non-orthopaedic surgery. Methods: We conducted a systematic review of observational studies assessing the perioperative management of bDMARDs in IA patients undergoing elective non-orthopaedic surgery. Searches were conducted across seven databases and trial registries from the year 2000 onwards. Eligible studies compared outcomes in patients who continued versus stopped biologic therapy. Risk of bias was assessed using the ROBINS-I tool and due to heterogeneity data were synthesised narratively. Results: Eight observational studies met the inclusion criteria. All studies were at moderate or serious risk of bias. Four studies compared infections with two suggesting higher infection rates in the stop biologic group. Two studies assessed delayed wound healing, both suggesting higher rates in the stop group. Disease flares were more common in patients who stopped biologics in all three of the studies reporting this outcome. No studies assessed health-related quality of life. Conclusions: The available observational evidence does not demonstrate a consistent increase in postoperative infection or wound complications related to biologic continuation, however, confidence in these findings is limited by serious risk of bias and outcome heterogeneity. High-quality randomised controlled trials are needed to inform the perioperative management guidelines for IA patients undergoing elective non-orthopaedic procedures.

Objectives: To inform users about the impact of two updated study filters for limiting database search results to randomized controlled trials on Ovid MEDLINE: a sensitivity-maximizing version (SM) and a sensitivity-and-precision-maximizing version (SaPM). To provide an updated understanding of how they compare to each other. Methods: Using the final ‘included’ records of 14 Cochrane reviews that had used the SM filter, we determined how many available records on Ovid MEDLINE would have been retrieved with each filter; investigated why records were missed; the unique yield; precision; and number-needed-to-read (NNR) for each filter. We also performed forwards and backwards citation searching on missed records (to determine if this could mitigate the risk of missing ‘includes’) and calculated the percentage change in the overall number-needed-to-screen (ONNS) when applying each filter to reproduction strategies. Results: On average, the SaPM filter reduced ONNS by 83% and retrieved 95.9% of ‘includes’ compared with 98.2% retrieved by the SM filter. The SaPM filter offered a further 28.2% mean reduction in ONNS over the SM filter. The SM filter had a unique yield of 12 and a precision of 1.5%, versus a unique yield of three and precision of 4.4% for the SaPM filter. NNR was 68 for the SaPM filter versus 189 for the SM filter. Conclusion: The SaPM filter reduced the screening burden with minimal risk of missing eligible records (which could be mitigated by citation searching). Decisions about which filter to use should consider both the needs and resources of the review.

Background: For evidence syntheses using English language limits, several different methods and approaches are available. Objective: To understand the English language (EL) limits available on Ovid MEDLINE and Embase and the application of language metadata on these databases. To compare the impact of five EL limits versus removing non-English language (NEL) records during screening. Methods: Using the records included at full text screening or excluded on NEL status during screening in seven evidence syntheses, we tested five EL limits on 1,509 MEDLINE and 1,584 Embase records. ‘Includes’ removed or ‘NEL excludes’ retrieved were investigated. Results: All EL limits performed identically, 99.8% of MEDLINE ‘includes’ were retrieved versus 99.7% on Embase. All five ‘includes’ incorrectly removed with EL limits had language metadata errors. Although 98.2% MEDLINE and 94.6% Embase ‘NEL excludes’ were removed with EL limits, eight MEDLINE and nine Embase records were available in English. Discussion: The risk of excluding potentially eligible records due to language restrictions (whether applied during the strategies or screening) could be mitigated with forward and backward citation searching. Conclusion: EL limits risk removing records with incorrect language metadata. However, EL records might also be excluded on language during screening.

Introduction: Several filters are routinely used to remove animal or nonhuman records in Ovid Embase, despite there being no performance data for them. The filters take different approaches in design. Objective: To understand and compare the impact of 11 filters to remove animal or nonhuman records in Ovid Embase. To understand the indexing of relevant subject headings in Embase. Methods: To assess filter performance, we screened and categorised 3,000 records as ‘should be removed’ or ‘should be retained’ and calculated the sensitivity, specificity and overall accuracy for each filter. We reported on the focus or content of records that were incorrectly removed, using seven categories. Results: Method 11 was the most sensitive, correctly retaining 90.6% records, whereas method 3 had the highest specificity, correctly removing 71.5% records. Out of seven categories, those in category 1 ‘uses human participants or data’ were the most excluded. Discussion: Filters that did not remove nonhuman records had higher sensitivity. Filter performance could vary by subject, publication type and language due to differences in indexing. Conclusion: In choosing a search filter, information specialists and review teams should discuss whether animals or nonhumans could feature in relevant studies.

Background: Late-onset Pompe disease is a rare inherited genetic condition that causes progressive muscle dysfunction and damage. As the disease advances, the progressive weakening of respiratory muscles significantly increases the risk of respiratory failure, which is a major contributor to premature mortality. Enzyme replacement therapy is the primary treatment for Pompe disease. Objective: To investigate the clinical impact of enzyme replacement therapies for the treatment and management of late-onset Pompe disease and establish the relative effectiveness of enzyme replacement therapy compared to best supportive care (in the absence of enzyme replacement therapy). Methods: A systematic review and network meta-analysis of published evidence on the clinical effectiveness of enzyme replacement therapy and best supportive care was undertaken. Comprehensive bibliographic database searches were conducted up to May 2024 to identify randomised controlled trials or any other prospective enzyme replacement therapy studies in patients with Pompe disease. Network meta-analyses of randomised controlled trials were undertaken to estimate indirect treatment effects for forced vital capacity % predicted and the 6-minute walk test. Other studies were summarised using narrative synthesis. Results: The review included 60 studies: 38 on enzyme replacement therapy and 22 on best supportive care. Enzyme replacement therapy studies comprised 3 randomised controlled trials, 3 randomised controlled trial extensions, 7 registry studies and 25 single-group prospective studies. Two randomised controlled trials had a high risk of bias. Best supportive care studies included 14 longitudinal and 8 cross-sectional studies. In the network meta-analyses, after approximately 1 year, enzyme replacement therapy-naive patients showed significant 6-minute walk test improvements versus placebo: ~25 m with alglucosidase alfa and ~54 m with avalglucosidase alfa. No significant differences were found for forced vital capacity % predicted or comparisons with cipaglucosidase alfa, although very few enzyme replacement therapy-naive patients taking cipaglucosidase alfa were available for inclusion in the analyses. Intra-enzyme replacement therapy comparisons showed a significant 6-minute walk test advantage for avalglucosidase alfa. However, a sensitivity analysis adjusting for skewed data revealed no significant differences. Long-term enzyme replacement therapy effectiveness was assessed in single-group studies, showing initial gains maintained for 1–3 years, followed by gradual 10- to 15-year declines in 6-minute walk test and forced vital capacity % predicted. However, small sample sizes and missing data introduce uncertainty. Long-term evidence on best supportive care is limited, with most of the evidence focused on characterising basic demographic information and support needs. A small number of studies reported declines in forced vital capacity % predicted. Formal comparisons with long-term enzyme replacement therapy studies were not possible, but declines appear to be similarly gradual. Conclusions: The network meta-analyses shows enzyme replacement therapy modestly improves 6-minute walk test and forced vital capacity % predicted after 1 year versus placebo in enzyme replacement therapy-naive patients. However, there is limited evidence to suggest meaningful differences in outcomes between alglucosidase alfa, avalglucosidase alfa and cipaglucosidase alfa with miglustat. Observational data suggest declines beyond 2–3 years, lasting up to 15 years. Long-term comparative effectiveness remains uncertain, as does enzyme replacement therapy’s impact on disease progression and supportive care needs. Funding: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme as award number NIHR161219.

Pneumocystis jirovecii Pneumonia (PJP) is a potentially life-threatening fungal infection occurring in immunocompromised individuals, particularly those receiving anti-cancer treatment. However, the incidence of PJP among children and young people (CYP) with cancer, cancer-like conditions or haematopoietic stem cell transplant (HSCT) recipients is unclear. This systematic review aimed to determine the incidence and impact of PJP in this population. Twelve databases were searched in November 2024. Any study reporting the incidence of PJP in CYP<18 years old with cancer, a cancer-like condition or having received a HSCT were included. Screening, data extraction and quality assessment (using a modified JBI critical appraisal tool for prevalence studies) were conducted in duplicate. Meta-analyses using GLMM methods were used. Of 7,194 records screened, 106 studies were included. Interpretation of the results of many studies was hindered by limited reporting. For the acute lymphoblastic leukaemia meta-analyses using confirmed events, higher pooled cumulative incidence rates were seen in the no prophylaxis group than in the prophylaxis group (2.86% vs 0.04%). Rates increased to 5.41% in the no prophylaxis group when studies reporting unconfirmed cases were included. Subgroup analyses suggested lower incidence rates in cohorts taking first-line PJP prophylaxis, compared to second-line. The cumulative incidence rate using confirmed events was 0.16% for HSCT patients receiving prophylaxis; data were not available for a no prophylaxis analysis. Only three studies were available for the HSCT total events analysis, producing a rate of 4.27%. Several analyses were subject to some uncertainty due to their high heterogeneity estimates. PROSPERO registration: CRD42025628682

National Institute for Health and Care Excellence (NICE) technology appraisal processes assume that the standard of care (SoC) is itself cost effective. However, many treatments in use in the UK National Health Service (NHS), particularly in rare diseases, were historically commissioned without formal value assessment and are priced without reference to cost-effectiveness thresholds. Cost-ineffective comparators distort how value is ascribed to new technologies, undermining the coherence of NICE’s decision-making framework, and imposing substantial opportunity costs on the NHS. Using late-onset Pompe disease (LOPD) as an exemplar, we demonstrate the implications of a cost-ineffective comparator in assessments of innovative therapies. A clinically superior enzyme replacement therapy (ERT) may command a lower value-based price than current ERTs, whilst a hypothetical curative gene therapy is valued at over £4 million against current ERT, but just £629,392 when re-anchored against best supportive care. Here, value is driven by displacement of costs rather than health gain, raising affordability concerns that may limit access to genuine innovation. The 2025 NHS 10-Year Plan grants new NICE statutory powers to withdraw access to cost-ineffective therapies, presenting an opportunity to reform technology appraisal. We propose several policy responses, including comprehensive reassessment of active guidance with decisions made with respect to a standard cost-effectiveness frontier, reviews triggered by new comparators, and use of flexible decision rules within existing frameworks. These changes could allow the evolving value of medicines to be reflected in NHS practice, redefining NICE as a body that takes a dynamic, whole-lifecycle view of value. Deliberative public and stakeholder engagement is essential for success, given the potential consequences for manufacturers and patients.

Background and Objectives Task shifting between different cadres of health worker has been proposed as an approach to address workforce shortages. Whether such reallocation is a useful strategy for a health system depends on the potential costs and consequences. Too narrow a focus has implications for population health as resources could be incorrectly directed towards inefficient activities owing to important costs and/or benefits being omitted from the evaluation. We aim to identify the key issues when evaluating the value for money of task shifting and review the applied literature to determine whether it is fit for purpose. Methods We developed an a priori logic model of task shifting and searched five databases (MEDLINE, Embase, EconLit, Social Sciences Citation Index and CEA Registry) for economic evaluations of task shifting published between 2014 and 2024. We performed forwards and backwards citation searching. We considered the scope of the evaluations with respect to the ability to capture key costs and outcomes of task shifting from the logic model. Reporting quality was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. Results The rapid review identified 26 studies for inclusion covering 16 countries. Studies evaluated task shifting to community health workers and lay health workers as well as from doctors to radiographers, non-physician clinicians and nurse-midwives. The studies included health costs and outcomes but few included changes in the capacity of the workforce to undertake tasks, access, waiting times, productivity, burden on other staff, patient satisfaction, patient productivity and health equity concerns. There was a predominance for cost-effectiveness analysis to be used to assess the value for money of task shifting but the literature did include a cost-benefit analysis, a cost-consequence analysis and an extended cost-effectiveness analysis. Conclusions The majority of studies identified a range of costs and consequences that may only be appropriate for resource allocation under the strong assumption that all longer term costs and consequences would be unaffected by the task shift.

Background: Diabetic retinopathy is a major cause of sight loss in people with diabetes, with a high risk of macular oedema, vitreous haemorrhage or other complications. Panretinal photocoagulation is the primary treatment for proliferative retinopathy. Anti-vascular endothelial growth factor drugs are used to treat various eye conditions and may be beneficial for people with proliferative or non-proliferative retinopathy. Methods: The Anti-VEGF In Diabetes project sought to investigate the clinical and cost-effectiveness of using anti-vascular endothelial growth factor to prevent retinopathy progression when compared to panretinal photocoagulation or no treatment. A systematic review with network meta-analysis of randomised controlled trials of anti-vascular endothelial growth factor (alone or in combination with panretinal photocoagulation) to treat retinopathy was conducted. The database searches were updated in May 2023. Individual participant data from larger trials were sought. A systematic review of non-randomised studies was performed. Existing cost-effectiveness analyses were reviewed, and a new economic model was developed, informed by the individual participant data meta-analysis. The model also estimated the value of undertaking further research to resolve decision uncertainty. Results: The review found that anti-vascular endothelial growth factors produced a slight, and not clinically meaningful, benefit over panretinal photocoagulation in best corrected visual acuity, after 1 year of follow-up in people with proliferative retinopathy (mean difference of 4.5 ETDRS letters; 95% credible interval −0.7 to 8.2). There was no evidence of a difference in effectiveness among the different anti-vascular endothelial growth factors. The benefit of anti-vascular endothelial growth factor appears to decline over time. Anti-vascular endothelial growth factor therapy may be more effective in people with poorer initial visual acuity. Anti-vascular endothelial growth factor had no impact on vision in people with non-proliferative retinopathy. Anti-vascular endothelial growth factor reduces rates of macular oedema and vitreous haemorrhage and may slow down the progression of retinopathy. Anti-vascular endothelial growth factors were predicted to be more costly but similarly effective to panretinal photocoagulation, with a net health benefit of −0.214 quality-adjusted life-years at a £20,000 willingness-to-pay threshold. Only under very select conditions might anti-vascular endothelial growth factors have the potential for cost-effectiveness to treat proliferative retinopathy. There is potentially significant value in reducing uncertainty through further primary research. Conclusions: Anti-vascular endothelial growth factor has no clinically meaningful benefit over panretinal photocoagulation for preserving visual acuity, but it may delay or prevent progression to macular oedema and vitreous haemorrhage. The long-term effectiveness and safety of anti-vascular endothelial growth factor treatment are unclear, particularly as additional panretinal photocoagulation and anti-vascular endothelial growth factor treatment will be required over time. Anti-vascular endothelial growth factors are therefore unlikely to be a cost-effective treatment for early proliferative retinopathy compared to panretinal photocoagulation. They are generally associated with higher costs and similar health outcomes across various scenarios. The long-term cost-effectiveness of anti-vascular endothelial growth factor is uncertain due to the lack of long-term clinical evidence. Future work: Further, robust studies with more than 2 years follow-up are required to evaluate the long-term efficacy and safety of anti-vascular endothelial growth factor use, and the effect of additional anti-vascular endothelial growth factor and panretinal photocoagulation therapy over time. Clinical trials or observational studies focusing on the use of anti-vascular endothelial growth factor in people with poorer vision at time of treatment may also be useful. Funding: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR132948.