Richard Fordham

Background: GaitSmart (GS) is a sensor-based digital medical device that can be used with the integrated app vGym to provide a personalised rehabilitation programme for older people undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA). This study aimed to determine whether the GS intervention used in the rehabilitation of older people undergoing THA or TKA is potentially cost-effective compared to the current standard of care (SoC). Methods: Decision-analytic modelling was conducted to estimate the cost-effectiveness over a seventeen-week time horizon from an NHS perspective. UK clinical and cost data from the GaitSmart randomised clinical trial was used to obtain the input parameters, and a sensitivity analysis was performed to address uncertainties. Results: Over a seventeen-week time horizon, GS incurred cost savings of GBP 450.56 and a 0.02 gain in quality-adjusted life years (QALYs) compared to the SoC. These results indicate that GS is the dominant intervention because the device demonstrated greater effectiveness and lower costs. Probabilistic sensitivity analyses confirm the robustness of our results. Conclusions: GS appears to offer short-term efficiency benefits and demonstrates cost-effectiveness for the improvement in gait in people undergoing THA or TKA, compared to the SoC.

Background: GaitSmart (GS) is a sensor-based digital medical device that can be used with the integrated app vGym to provide a personalised rehabilitation programme for older people undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA). This study aimed to determine whether the GS intervention used in the rehabilitation of older people undergoing THA or TKA is potentially cost-effective compared to the current standard of care (SoC). Methods: Decision-analytic modelling was conducted to estimate cost-effectiveness over a seventeen- week time horizon, from an NHS perspective. UK clinical and cost data from the GaitSmart randomised clinical trial was used to obtain input parameters, and sensitivity analysis was performed to address uncertainty. Results: Over a seventeen-week time horizon, GS incurred cost savings of £450.56 and a 0.02 gain in quality-adjusted life years (QALYs) compared to the SoC. These results indicate that GS is the dominant intervention because the device demonstrated greater effectiveness and lower costs. Probabilistic sensitivity analyses confirm the robustness of our results. Conclusion: GS appears to offer short-term efficiency benefits and demonstrates cost-effectiveness for the improvement of gait in people undergoing THA or TKA, compared to the SoC. These findings provided new evidence to inform policymakers.

Background Interstitial lung disease frequently complicates systemic autoimmune disorders including scleroderma, idiopathic inflammatory myositis and mixed connective tissue disease, resulting in considerable morbidity and mortality. Based on the results of trials undertaken in scleroderma, cyclophosphamide is the standard of care for individuals with severe or progressive connective tissue disease-associated interstitial lung disease. Observational studies suggest that the anti-CD20 monoclonal antibody, rituximab is an effective rescue therapy in treatment of refractory connective tissue disease-associated interstitial lung disease, but it has not been studied as first-line therapy in clinical trials. Objectives To compare the safety and efficacy of rituximab against that of cyclophosphamide as treatment for individuals with severe, progressive interstitial lung disease associated with scleroderma, idiopathic inflammatory myositis or mixed connective tissue disease. Methods This was a Phase IIb, multicentre, randomised, double-blind, double-dummy study assessing the superiority of rituximab compared with cyclophosphamide, conducted in rheumatology or interstitial lung disease units at 11 UK centres. The study recruited individuals with extensive and/or progressive connective tissue disease-associated interstitial lung disease, excluding those with significant comorbidities, including airflow obstruction. Participants were randomised 1 : 1 to receive either rituximab 1 g given intravenously, twice at an interval of 2 weeks, or intravenous cyclophosphamide given monthly for 6 months at a dose of 600 mg/m2 body surface area. The primary end point for the study was the change in forced vital capacity at 24 weeks. Secondary end points included safety and tolerability, corticosteroid exposure, forced vital capacity change at 48 weeks and patient-reported quality of life. A cost-effectiveness analysis was undertaken to assess the impact of rituximab use in the United Kingdom National Health Service. Results One hundred and one subjects (70 females) with a mean age of 56.3 years were randomised; 51 to rituximab and 50 to cyclophosphamide. Ninety-seven were included in the modified intention-to-treat population for the primary and secondary efficacy analyses (49 in the rituximab group and 48 in the cyclophosphamide group). 38.6% had scleroderma, 44.6% idiopathic inflammatory myositis and 16.8% mixed connective tissue disease. Four subjects withdrew prior to the first dose of therapy (two in each arm). At 24 weeks, both rituximab and cyclophosphamide improved forced vital capacity from baseline [(mean ± standard deviation) 97 ± 234 and 99 ± 329 ml, respectively]. Using an adjusted mixed-effects model corrected for diagnosis and baseline forced vital capacity the difference in forced vital capacity at 24 weeks between rituximab and cyclophosphamide was −40 ml (95% CI −153 to 74 ml), p = 0.49. Other physiological and quality-of-life parameters improved in both arms following treatment but were not statistically significantly different between groups. Numerically fewer adverse events were reported by subjects receiving rituximab. Corticosteroid exposure over the 48 weeks of the trial was numerically less in the rituximab arm [13,291 (±14,657) mg of hydrocortisone equivalent per subject in the cyclophosphamide arm versus 11,469 (±10,041) mg per subject in the rituximab group; these differences did not reach statistical significance]. Limitations of the study include a disproportionate number of subjects being recruited from a single centre and insufficient subjects in each subgroup to determine whether there were treatment differences between individual connective tissue diseases. Based on the results of the trial, from a UK healthcare payer perspective, rituximab is more cost-effective than cyclophosphamide as a treatment for severe or progressive connective tissue disease-interstitial lung disease. Conclusions Rituximab improved forced vital capacity and patient-reported quality of life at 24 weeks but was not superior to cyclophosphamide. Rituximab should be considered as a therapeutic alternative to cyclophosphamide in individuals with connective tissue disease-associated interstitial lung disease requiring systemic therapy. Future work should explore the role of repeated dosing of rituximab and the use of rituximab earlier in the course of connective tissue disease-associated interstitial lung disease. Trial registration This trial is registered as ISRCTN16474148. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation Programme (NIHR award ref: 11/116/03) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 4. See the NIHR Funding and Awards website for further award information.

This article details a correction to: Landrigan PJ, Raps H, Cropper M, et al. The Minderoo-Monaco Commission on Plastics and Human Health. Annals of Global Health. 2023; 89(1): 23. DOI: https://doi.org/10.5334/aogh.4056.

Background: It is useful to document whether each newly dominant SARS-CoV-2 variant of concern was more or less dangerous than preceding dominant variant(s). We assessed if the emergence of the Alpha (B.1.1.7) variant in autumn 2020 could be linked to higher case fatality rates, compared to original wild-type COVID-19, subgrouping by age band, sex, deprivation or month of diagnosis as potential risk factors. Methods: Observational study and secondary analysis were conducted of SARS-CoV-2 cases diagnosed due to medical need or occupational exposure in an administrative area of Eastern England, UK (base population 1 million), who first tested positive in the period 1 March 2020 to 28 February 2021. Multivariate logistic regression was performed to examine relationships of age group, sex, deprivation group and month of diagnosis with case fatality rates within 28 days of diagnosis. Marginal probabilities for risk of dying were calculated separately for the first two main ‘wave’ periods of the English pandemic. Results: Older age and male sex consistently raised the risk of mortality in both wave periods. Higher deprivation was linked to mortality risk in the first wave period, but not in the second wave. Mortality decreased over time during the first wave period, but slightly increased over time during the second wave. Cases were younger in the second wave, and median age of the deceased varied little between waves. Interpretation: The Alpha variant of SARS-CoV-2 did not lead to higher mortality rates for any age, deprivation or sex group, compared to case fatality rates in the early part of the pandemic period.

Aim To estimate annual societal costs associated with chemotherapy for early breast cancer in the UK. Design Mixed methods: (a) an incidence-based cost-of-illness model was developed of indirect costs in patients with breast cancer and carers, and estimated from diagnosis through active treatment until death; (b) interviews with stakeholders were also undertaken to understand actual experiences and impacts of these costs. Data sources Model data were collated from relevant national data sources covering general population statistics, UK cancer registries, clinical guidelines and published literature, and patient survey data. Patient and staff views were collected through semistructured interviews. Participants Model: patients with early breast cancer receiving systemic anticancer therapy in the UK. Interviews were undertaken with women who had chemotherapy and medical practitioners involved in breast cancer care. Results Total costs of chemotherapy in the UK economy are over £248 million. Societal productivity losses amount to £141.4 million, which includes £3.2 million associated with premature mortality, short-term and long-term work absence (£28.6 million and £105 million, respectively). £3.4 million is associated with mortality losses from secondary malignancies due to adjuvant chemotherapy. A further £1.1 million in lost productivity arises from informal care provision. Out-of-pocket costs per round of chemotherapy account for £4.2 million, or an annual average of almost £1100 per patient. Interview findings support the cost burden modelled and also highlight the impact on cognitive function of patients and how this could increase the cost burden to patients, their families and wider society. In addition, estimated costs for carer emotional well-being are £82 million in lost quality of life. Conclusion Chemotherapy use carries significant indirect costs for society, as well as patients and their carers. These wider costs and societal perspective should be considered by commissioners to ensure chemotherapy is better targeted at those who most need it and to avoid placing unnecessary costs on patients, their caregivers and wider society.

We evaluated the FDA approved SARS-CoV-2 immunoassay (developed at Mount Sinai, by Krammer and colleagues) for the identification of COVID-19 seroconversion and potential cross-reactivity of the assay in a United Kingdom (UK) National Health Service (NHS) hospital setting. In our ‘set up’ cohort we found that the SARS-CoV-2 IgG was detectable in 100% of patients tested 14 days post positive COVID-19 nucleic acid test. Serum samples taken from pregnant women in 2018 were used as a negative control group with zero false positives. We also analysed samples from patients with non-COVID-19 viral infections, paraproteinaemia or autoantibodies and found false positive results in 6/179. Modification of the sensitivity threshold to five standard deviations from the mean of the control group eliminated all false positive result in the ‘set up’ cohort. We confirmed the validity of the test with a revised threshold on an independent prospective ‘validation cohort’ of patient samples. Taking data from both cohorts we report a sensitivity of the Mount Sinai assay of 96.6% (28/29) and specificity of 100% (299/299) using a revised threshold cut-off, at a time point at least 14 days since the diagnostic antigen test. Finally, we conducted a health economic probabilistic sensitivity analysis (PSA) on the costs of producing the tests, and the mean cost we estimate to be 13.63 pounds sterling (95%CI 9.63 - 18.40), allowing its cost effectiveness to be tested against other antibody tests. In summary, we report that the Mount Sinai IgG ELISA assay is highly sensitive test for SARS-Cov-2 infection, however modification of thresholding was required to minimise false positive results.

The aim of this trial is to evaluate the effect of SENATOR software on incident, adverse drug reactions (ADRs) in older, multimorbid, hospitalized patients. The SENATOR software produces a report designed to optimize older patients’ current prescriptions by applying the published STOPP and START criteria, highlighting drug-drug and drug-disease interactions and providing non-pharmacological recommendations aimed at reducing the risk of incident delirium. We will conduct a multinational, pragmatic, parallel arm Prospective Randomized Open-label, Blinded Endpoint (PROBE) controlled trial. Patients with acute illnesses are screened for recruitment within 48 h of arrival to hospital and enrolled if they meet the relevant entry criteria. Participants’ medical history, current prescriptions, select laboratory tests, electrocardiogram, cognitive status and functional status are collected and entered into a dedicated trial database. Patients are individually randomized with equal allocation ratio. Randomization is stratified by site and medical versus surgical admission, and uses random block sizes. Patients randomized to either arm receive standard routine pharmaceutical clinical care as it exists in each site. Additionally, in the intervention arm an individualized SENATOR-generated medication advice report based on the participant’s clinical and medication data is placed in their medical record and a senior medical staff member is requested to review it and adopt any of its recommendations that they judge appropriate. The trial’s primary outcome is the proportion of patients experiencing at least one adjudicated probable or certain, non-trivial ADR, during the index hospitalization, assessed at 14 days post-randomization or at index hospital discharge if it occurs earlier. Potential ADRs are identified retrospectively by the site researchers who complete a Potential Endpoint Form (one per type of event) that is adjudicated by a blinded, expert committee. All occurrences of 12 pre-specified events, which represent the majority of ADRs, are reported to the committee along with other suspected ADRs. Participants are followed up 12 (+/− 4) weeks post-index hospital discharge to assess medication quality and healthcare utilization. This is the first clinical trial to examine the effectiveness of a software intervention on incident ADRs and associated healthcare costs during hospitalization in older people with multi-morbidity and polypharmacy. Clinicaltrials.gov NCT02097654 , 27 March 2014.

Improving adherence to ocular hypertension (OH)/glaucoma therapy is highly likely to prevent or reduce progression of optic nerve damage. The present study used a behaviour change counselling intervention to determine whether education and support was beneficial and cost-effective in improving adherence with glaucoma therapy.