Methotrexate for the neurologist.

The use of methotrexate in clinical practice has expanded significantly in recent years, as an effective chemotherapeutic agent as well as disease-modifying treatment for conditions such as rheumatoid arthritis, psoriasis and Crohn's disease. It is also used as a steroid-sparing agent for a range of inflammatory diseases of the central and peripheral nervous systems. Clinical neurologists must, therefore, know how to start and uptitrate methotrexate, its monitoring requirements and its potential toxicities. This review aims first to explore the evidence base for using methotrexate in various neurological diseases and second to discuss important practicalities around its use, ensuring its safe application and appropriate monitoring.

In-hospital mortality is associated with inflammatory response in NAFLD patients admitted for COVID-19.

BACKGROUND & AIMS: Although metabolic risk factors are associated with more severe COVID-19, there is little evidence on outcomes in patients with non-alcoholic fatty liver disease (NAFLD). We here describe the clinical characteristics and outcomes of NAFLD patients in a cohort hospitalised for COVID-19. METHODS: This study included all consecutive patients admitted for COVID-19 between February and April 2020 at Imperial College Healthcare NHS Trust, with either imaging of the liver available dated within one year from the admission or a known diagnosis of NAFLD. Clinical data and early weaning score (EWS) were recorded. NAFLD diagnosis was based on imaging or past medical history and patients were stratified for Fibrosis-4 (FIB-4) index. Clinical endpoints were admission to intensive care unit (ICU)and in-hospital mortality. RESULTS: 561 patients were admitted. Overall, 193 patients were included in the study. Fifty nine patients (30%) died, 9 (5%) were still in hospital, and 125 (65%) were discharged. The NAFLD cohort (n = 61) was significantly younger (60 vs 70.5 years, p = 0.046) at presentation compared to the non-NAFLD (n = 132). NAFLD diagnosis was not associated with adverse outcomes. However, the NAFLD group had higher C reactive protein (CRP) (107 vs 91.2 mg/L, p = 0.05) compared to non-NAFLD(n = 132). Among NAFLD patients, male gender (p = 0.01), ferritin (p = 0.003) and EWS (p = 0.047) were associated with in-hospital mortality, while the presence of intermediate/high risk FIB-4 or liver cirrhosis was not. CONCLUSION: The presence of NAFLD per se was not associated with worse outcomes in patients hospitalised for COVID-19. Though NAFLD patients were younger on admission, disease stage was not associated with clinical outcomes. Yet, mortality was associated with gender and a pronounced inflammatory response in the NAFLD group.

Cost-effectiveness of strategies to improve HCV screening, linkage-to-care and treatment in remand prison settings in England.

BACKGROUND: A simplified cascade-of-care may improve screening and treatment uptake among incarcerated individuals. We assessed the cost-effectiveness of traditional and simplified screening and treatment in a London remand prison. METHODS: Using empirical data from Her Majesty's Prison (HMP) Wormwood Scrubs, London, we designed a decision tree and Markov transition state model using national average data for HCV screening and treatment for the base-case scenario. This compared two alternative strategies; (a) general prison population screening and treatment and (b) prioritising screening and treatment among people who inject drugs (PWID) combined with general prison population screening and treatment. Strategies varied the rates of screening (47%-90%), linkage-to-care (60%-86%) and treatment (21%-85%). Cost, utility and disease transition rates were obtained from existing literature. Outcome measures were as follows: screening, treatment and disease-related costs per admitted individual, quality-adjusted life years (QALYs). Incremental cost-effectiveness ratios (ICERs) were calculated for each intervention. All costs and utilities were discounted at a rate of 3.5% per annum. Both univariate and probabilistic sensitivity analyses have been conducted. RESULTS: In our cohort of 5239 incarcerated individuals with an estimated chronic HCV prevalence of 2.6%, all strategy ICER values (£3565-10 300) fell below the national willingness to pay threshold (£30 000). Increased successful treatment (7%-54%) was observed by an optimising cascade-of-care. A robust sensitivity analysis identified treatment cost of, QALY for mild liver disease and probability of completing treatment as important factors that impact the ICER value. CONCLUSION: In our remand setting, optimising adherence to the cascade-of-care is cost-effective. Where universal screening is not practical, a stratified approach focused on intensive screening and treatment of PWID also results in increased treatment uptake and is highly cost-effective.

Time matters: Point of care screening and streamlined linkage to care dramatically improves hepatitis C treatment uptake in prisoners in England.

BACKGROUND: In England, opt-out dry blood spot prison screening for HIV, hepatitis B and hepatitis C (HCV) has been introduced to scale-up access to care. Recent advances in point-of-care HCV diagnostics provide an opportunity to improve diagnosis and treatment uptake. We compared the retention along and time intervals between each aspect of the HCV care continuum for an alternative rapid point-of-care-testing and simplified treatment strategy with existing national opt-out HCV dry blood spot testing and treatment at a large remand prison in West London. METHODS: Between September 2017 and December 2018 universal opt-out dry blood spot HCV testing, clinical assessment and treatment uptake were recorded at Her Majesty's Prison Wormwood Scrubs. Outcomes were compared to a point-of-care-based (salivary Oraquick® anti-HCV screening and Xpert® HCV fingerstick viral load) screening and streamlined treatment pathway offered to all new arrivals to the HMP Wormwood Scrubs substance misuse unit, which ran in parallel to dry blood spot testing between September and December 2018. RESULTS: During the study period 2442 out of 5239 inmates (46.6%) underwent dry blood spot screening, resulting in 62 (2.6%) HCV RNA positive cases. Thirteen (21.3%) individuals commenced therapy and no viral relapse cases were observed to date. In comparison, 162 out of 181 (89.5%) inmates admitted to the substance misuse unit agreed to rapid point-of-care testing; 20 (12.3%) HCV RNA positive cases. Seventeen (85.0%) of eligible inmates commenced treatment. The median length of stay (90 vs 30 days), time to screening (6 vs 2 days), assessment (14 vs 3 days) and treatment (36 vs 1 day) were shorter for the rapid point-of-care screen-and-treat group. CONCLUSION: Current scaling-up of prison dry blood spot HCV screening and treatment in England is sub-optimal. In our setting, the cascade of care is time and resource sensitive and is greatly improved by the introduction of a simplified screen-and-treat strategy.

The cost impact of outreach testing and treatment for hepatitis C in an urban Drug Treatment Unit.

BACKGROUND & AIMS: In developed countries persons who inject drugs (PWID) represents a significant risk for chronic hepatitis C virus (HCV). It is reported that up to half of persons with chronic HCV remain undiagnosed and reliance on attendance to specialist clinics remain a barrier to treatment. This study assesses the feasibility and cost-effectiveness of outreach screening and treatment within a Drug Treatment Unit (DTU). METHODS: All persons attending a London DTU were offered HCV testing, and where appropriate follow-up and treatment by a specialist nurse at the DTU. Three years of data informed a cost-effective-analysis using a validated Markov model. A hypothetical scenario in which only direct acting antiviral (DAA) treatments were used was also assessed. RESULTS: Of 321 persons eligible, 216 were screened, 89 were HCV positive and 66 had confirmatory evidence of viraemia. All were infected with either HCV genotype 1 or 3. Treatment was initiated in 29 persons, 22 with interferon based and 7 DAA only regimens. Following initial treatment 21 (72%) achieved SVR12. It is estimated that this programme represents an average per-patient cost-saving of £2498 and a quality-adjusted life year (QALY) gain of 4.10 over a lifetime. In a hypothetical scenario of all oral DAA treatment, an incremental cost per QALY of £1029 was estimated. CONCLUSION: This study demonstrates feasibility and cost effectiveness of outreach testing and treatment of hepatitis C within comparable DTU settings. Additional costs of newer DAA therapies would not be prohibitive when considering willingness-to-pay thresholds commonly used by policy makers.

A clinician's guide to the cost and health benefits of hepatitis C cure assessed from the individual patient perspective.

BACKGROUND AND AIMS: The hepatitis C virus (HCV) remains a considerable public health challenge. Novel direct-acting antiviral (DAA) regimens offer high cure rates and the promise of reduced HCV incidence and prevalence following the up-scaling of treatment. This has focused attention towards affordability. This study aimed to estimate the economic value of cure to evaluate the treatment costs justifiable from the patient perspective. PATIENTS AND METHODS: A published, validated HCV model was utilized to contrast clinical and cost outcomes for patients aged 30-70 years, stratified by METAVIR F0-F4, for (i) no treatment and (ii) successful treatment [i.e. sustained virologic response (SVR)] ignoring the cost of treatment. Regression equations were fitted and used to determine the financial expenditure justifiable to achieve a cost-neutral or a cost-effective [£20 000 per quality-adjusted life-year (QALY)] cure. Model inputs were derived from UK literature; costs and utilities were discounted at 3.5% over a lifetime horizon. RESULTS: To achieve cost-neutrality, the maximum discounted expenditure justifiable for SVR was £3774-43 607 across ages and fibrosis stages. Spending between £19 745 (70 years, F0) and £188 420 (30 years, F4) on SVR is expected to be cost-effective at £20 000/QALY willingness-to-pay threshold. CONCLUSION: Heterogeneity across HCV patients is considerable, which can obscure the relevance of conventional cohort-based economic models evaluated at the mean, particularly when considering the value of treatment at the individual patient level. By quantifying the full exposition of HCV cost-savings and health benefits realizable following HCV cure, this study provides insight into the economic value of successful treatment from the patient perspective.

A real-world intention-to-treat analysis of a decade's experience of treatment of hepatitis C with interferon-based therapies.

Objectives: To assess the uptake of pegylated interferon (PegIFN) plus ribavirin (RBV)-based regimens in patients with hepatitis C virus (HCV) in a large, single-centre, real-world setting over 10 years. Methods: This was a single centre, retrospective analysis of data from patients who attended their first appointment for treatment of HCV genotype 1-3 between 2003 and 2013. Patients were stratified by HCV genotype. The total number of patients who attended their first appointment, incidence of patients who did not proceed to treatment and associated reasons, and incidence of patients treated were analysed. Sustained virological response (SVR) rates were also reported for all patient populations. Results: Overall, 1,132 patients attended their first appointment; 47.8% were included in the genotype 1 group (genotype 1a: 22.2%, genotype 1b: 13.3%, genotype 1 other: 12.3%), 7.7% in the genotype 2 group and 44.5% in the genotype 3 group. A greater proportion of patients received treatment versus those who did not receive treatment (84.4% vs 15.6%, respectively). Reasons for declining treatment included: patient declined treatment with PegIFN plus RBV: 35.0%, medical contraindications: 20.3% and mental health-related contraindications: 13.6%. An SVR was achieved in 52.6% of patients who attended their first appointment and 62.3% of patients who received treatment. Conclusions: Approximately half of the patients included in this study achieved an SVR. A noteworthy proportion of patients did not receive treatment due to a reluctance to receive PegIFN plus RBV or contraindications to therapy. Results suggest an ongoing need for improvement in the treatment uptake and overall outcomes - particularly for genotype 2 and 3 patients for whom availability of interferon-free regimens is limited. The introduction of more tolerable direct-acting antiviral regimes may help overcome barriers to uptake demonstrated within this cohort.

Hepatocellular Carcinoma Surveillance: Are We Utilizing It?

BACKGROUND AND GOALS: International guidelines recommend 6-monthly ultrasound scan surveillance in cirrhotic patients for hepatocellular carcinoma (HCC) screening. The aim of this study was to evaluate HCC surveillance and to provide the outcomes for the largest reported cirrhosis cohort in the United Kingdom. STUDY: We retrospectively reviewed all cirrhotic patients during the 6 months before April 1, 2014 at 3 teaching hospitals within the Imperial College Healthcare NHS Trust. All patients with cirrhosis eligible for HCC screening in the cohort were reviewed for evidence of screening and were characterized as either "routine" or "overdue." Reasons for failure to meet guidelines were identified in overdue patients. Univariate analyses were conducted to determine clinical and sociodemographic predictors of surveillance with a view to performing multivariate analysis. RESULTS: Of the 898 patients eligible for inclusion, 65% patients had HCC surveillance performed in the past 6 months. During the observation period, 61 (6.8%) cases of HCC were detected. Thirty-eight were picked up on surveillance, 9 incidentally and in 14 cases it could not be determined from the notes. Within this cohort HCCs diagnosed on surveillance did not demonstrate significantly superior outcomes compared with those picked up incidentally. CONCLUSIONS: Surveillance of patients with cirrhosis within this cohort is suboptimal. Although disappointing at a local level, this is likely to be reflective of practice elsewhere.

Is antenatal screening for hepatitis C virus cost-effective? A decade's experience at a London centre.

BACKGROUND & AIMS: This study aims to assess the cost-effectiveness of a routine universal antenatal hepatitis C virus (HCV) screening programme at a London centre. METHODS: Ten years' retrospective antenatal screening and outcome data informed a cost-effectiveness analysis using the previously validated MONARCH model. The cost and quality of life outcomes associated with the screening and treatment of newly identified hepatitis C cases were used to generate cost-effectiveness estimates for the screening programme. RESULTS: A total of 35,355 women were screened between 1st November 2003 and 1st March 2013; 136 women (0.38%) were found to be HCV antibody positive. Of 78 (0.22%) viraemic cases, 44 (0.12%) were newly diagnosed. In addition, the screening programme identified three (6.8%) vertical transmissions in children of newly diagnosed mothers. Of 16 newly diagnosed mothers biopsied, all were in the F0-F2 METAVIR disease stages, and 50% had HCV genotype 1. Postnatal treatment with pegylated interferon and ribavirin was initiated in 19 women, with 14 (74%) achieving sustained virologic response. The total cost of screening and confirmation of diagnoses was estimated to be £240,641. This translates to £5469 per newly diagnosed individual. The incremental cost-effectiveness ratio of this screening and treatment strategy was £2400 per QALY gained. Treatment with newer direct-acting antiviral regimens would have a projected cost of £9139 per QALY gained, well below the £20,000-30,000/QALY gained willingness-to-pay threshold applied by policy advisory bodies. CONCLUSIONS: This study demonstrates that an antenatal screening and treatment programme is feasible and effective, at a cost considered acceptable.

A European single centre experience of management of hepatitis C virus genotype 4 infection with pegylated-interferon and ribavirin.

New direct acting antiviral agents are revolutionising hepatitis C virus (HCV) treatment. However, to date limited clinical trial data exists for outcomes in genotype 4 (GT4) HCV patients. GT4 HCV is more common in Africa, the Middle East, and Asia, and limited data exists to date for outcomes in Europe. We report the first "real-life" sustained virological response (SVR) outcomes using pegylated interferon and ribavirin for HCV GT4 in the UK, and the largest European single centre cohort. HCV GT4 patients treated at a London, UK centre between 2002 and 2014 were assessed for SVR outcomes. Patient age, sex, region of origin, co-infection with HIV, pre-treatment liver biopsy histological assessment, genotype subtyping, treatment duration, and dose reductions were compared against SVR outcomes on univariate analysis. Multivariate analysis was performed on results with P < 0.1. A total of 118 patients were treated with HCV GT4 during the study period, 57 achieved SVR (48%). On univariate analysis age ≥45 (P < 0.0001), high viral load (P < 0.0001), Ishak staging 5-6 (P < 0.0001), and non-Egyptian Africans (P = 0.0059) were all negatively associated with SVR. Eastern Europeans appeared to have higher SVR (P < 0.0001). Using multivariate correlation viral load (P = 0.0005); Ishak staging (P = 0.0031) and age (P = 0.0003) were associated with SVR but not country of origin (P = 0.0645). Outcomes with pegylated interferon and ribavirin for HCV GT4 in this "real-life" setting were sub-optimal especially in the context of newer regimens. Patients with older age, high viral loads, and advanced disease need prioritisation for alternative treatments.

Revisional laparoscopic parastomal hernia repair.

BACKGROUND: We herein report a laparoscopically performed re-do operation on a patient who had previously undergone a laparoscopic parastomal hernia repair. CASE REPORT: We describe the case of a 71-year-old patient who presented within 3 months of her primary laparoscopic parastomal hernia repair with recurrence. On relaparoscopy, dense adhesions to the mesh were found, and the mesh had migrated into the hernia sac. This had allowed loops of small bowel to herniate into the sac. The initial part of the procedure involved the lysis of adhesions. A piece of Gore-Tex DualMesh with a central keyhole and a radial slit was cut so that it could provide at least 3 cm to 5 cm of overlap of the fascial defect. The tails of the mesh were wrapped around the bowel, and the mesh was secured to the margins of the hernia with circumferential metal tacking and 4 transfascial sutures. The patient remains in satisfactory condition and no recurrence or any surgery-related problem has been observed during 8 months of follow-up. CONCLUSION: Revisional laparoscopic repair of parastomal hernias seems feasible and has been shown to be safe and effective in this case. The success of this approach depends on longer follow-up reports and standardization of the technical elements.

Multidisciplinary crisis simulations: the way forward for training surgical teams.

BACKGROUND: High-reliability organizations have stressed the importance of non-technical skills for safety and of regularly providing such training to their teams. Recently safety skills training has been applied in the practice of medicine. In this study, we developed and piloted a module using multidisciplinary crisis scenarios in a simulated operating theatre to train entire surgical teams. METHODS: Twenty teams participated (n = 80); each consisted of a trainee surgeon, anesthetist, operating department practitioner (ODP), and scrub nurse. Crisis scenarios such as difficult intubation, hemorrhage, or cardiac arrest were simulated. Technical and non-technical skills (leadership, communication, team skills, decision making, and vigilance), were assessed by clinical experts and by two psychologists using relevant technical and human factors rating scales. Participants received technical and non-technical feedback, and the whole team received feedback on teamwork. RESULTS: Trainees assessed the training favorably. For technical skills there were no differences between surgical trainees' assessment scores and the assessment scores of the trainers. However, nurses overrated their technical skill. Regarding non-technical skills, leadership and decision making were scored lower than the other three non-technical skills (communication, team skills, and vigilance). Surgeons scored lower than nurses on communication and teamwork skills. Surgeons and anesthetists scored lower than nurses on leadership. CONCLUSIONS: Multidisciplinary simulation-based team training is feasible and well received by surgical teams. Non-technical skills can be assessed alongside technical skills, and differences in performance indicate where there is a need for further training. Future work should focus on developing team performance measures for training and on the development and evaluation of systematic training for technical and non-technical skills to enhance team performance and safety in surgery.