Digital pathology for reporting histopathology samples, including cancer screening samples - definitive evidence from a multisite study.

AIMS: To conduct a definitive multicentre comparison of digital pathology (DP) with light microscopy (LM) for reporting histopathology slides including breast and bowel cancer screening samples. METHODS: A total of 2024 cases (608 breast, 607 GI, 609 skin, 200 renal) were studied, including 207 breast and 250 bowel cancer screening samples. Cases were examined by four pathologists (16 study pathologists across the four speciality groups), using both LM and DP, with the order randomly assigned and 6 weeks between viewings. Reports were compared for clinical management concordance (CMC), meaning identical diagnoses plus differences which do not affect patient management. Percentage CMCs were computed using logistic regression models with crossed random-effects terms for case and pathologist. The obtained percentage CMCs were referenced to 98.3% calculated from previous studies. RESULTS: For all cases LM versus DP comparisons showed the CMC rates were 99.95% [95% confidence interval (CI) = 99.90-99.97] and 98.96 (95% CI = 98.42-99.32) for cancer screening samples. In speciality groups CMC for LM versus DP showed: breast 99.40% (99.06-99.62) overall and 96.27% (94.63-97.43) for cancer screening samples; [gastrointestinal (GI) = 99.96% (99.89-99.99)] overall and 99.93% (99.68-99.98) for bowel cancer screening samples; skin 99.99% (99.92-100.0); renal 99.99% (99.57-100.0). Analysis of clinically significant differences revealed discrepancies in areas where interobserver variability is known to be high, in reads performed with both modalities and without apparent trends to either. CONCLUSIONS: Comparing LM and DP CMC, overall rates exceed the reference 98.3%, providing compelling evidence that pathologists provide equivalent results for both routine and cancer screening samples irrespective of the modality used.

Self-directed versus peer-supported digital self-management programmes for mental and sexual wellbeing after acquired brain injury (HOPE4ABI): protocol for a feasibility randomised controlled trial.

BACKGROUND: Acquired brain injury (ABI) can lead to biopsychosocial changes such as depression, low self-esteem and fatigue. These changes can cause, and be caused by, sexual issues affecting relationships and wellbeing. Given the relationship between sexual wellbeing and mental health, it is feasible that supporting sexual wellbeing will benefit psychological wellbeing. However, neurorehabilitation is inconsistent and often fragmented across the UK, and psychological, sexual and social support are lacking. Research shows that self-management and peer-support programmes can improve quality of life, self-efficacy and psychological wellbeing after brain injury. This protocol describes a feasibility randomised controlled trial (RCT) of a digital self-management programme to support mental and sexual wellbeing (known as HOPE4ABI), co-designed with and for people with ABI. METHODS: This mixed-methods feasibility RCT has two parallel trial arms of the 8-week digital HOPE4ABI self-management programme. Eligibility criteria include age > 18 years, diagnosed or suspected ABI > 3 months prior to trial entry, access to an Internet-enabled device and ability to engage with the intervention. Referrals to the study website will be made via the National Health Service (NHS), social media and partnering organisations. Sixty eligible participants will be randomised at a ratio of 1:1 to peer-supported (n = 30) or self-directed (n = 30) HOPE4ABI programmes. Primary feasibility outcomes include recruitment and retention rates, engagement, adherence and usage. Secondary outcomes related to standardised measures of quality of life, sexual wellbeing and mental wellbeing. Participants and peer facilitators will be interviewed after the course to assess acceptability across both trial arms. DISCUSSION: This feasibility trial data is not sufficiently powered for inferential statistical analyses but will provide evidence of the feasibility of a full RCT. Quantitative trial data will be analysed descriptively, and participant screening data representing age, ethnicity and gender will be presented as proportions at the group level. These data may indicate trends in reach to particular demographic groups that can inform future recruitment strategies to widen participation. Progression to a definitive trial will be justified if predetermined criteria are met, relating to recruitment, retention, engagement and acceptability. TRIAL REGISTRATION: ISRCTN46988394 registered on March 1, 2023.

Rising arterial stiffness with accumulating comorbidities associates with heart failure with preserved ejection fraction.

AIMS: Comorbidities play a significant role towards the pathophysiology of heart failure with preserved ejection fraction (HFpEF), characterized by abnormal macrovascular function and altered ventricular-vascular coupling. However, our understanding of the role of comorbidities and arterial stiffness in HFpEF remains incomplete. We hypothesized that HFpEF is preceded by a cumulative rise in arterial stiffness as cardiovascular comorbidities accumulate, beyond that associated with ageing. METHODS AND RESULTS: Arterial stiffness was assessed using pulse wave velocity (PWV) in five groups: Group A, healthy volunteers (n = 21); Group B, patients with hypertension (n = 21); Group C, hypertension and diabetes mellitus (n = 20); Group D, HFpEF (n = 21); and Group E, HF with reduced ejection fraction (HFrEF) (n = 11). All patients were aged 70 and above. Mean PWV increased from Groups A to D (PWV 10.2, 12.2, 13.0, and 13.7 m/s, respectively) as vascular comorbidities accumulated independent of age, renal function, haemoglobin, obesity (body mass index), smoking status, and hypercholesterolaemia. HFpEF exhibited the highest PWV and HFrEF displayed near-normal levels (13.7 vs. 10 m/s, P = 0.003). PWV was inversely related to peak oxygen consumption (r = -0.304, P = 0.03) and positively correlated with left ventricular filling pressures (E/e') on echocardiography (r = -0.307, P = 0.014). CONCLUSIONS: This study adds further support to the concept of HFpEF as a disease of the vasculature, underlined by an increasing arterial stiffness that is driven by vascular ageing and accumulating vascular comorbidities, for example, hypertension and diabetes. Reflecting a pulsatile arterial afterload associated with diastolic dysfunction and exercise capacity, PWV may provide a clinically relevant tool to identify at-risk intermediate phenotypes (e.g. pre-HFpEF) before overt HFpEF occurs.

The Fatty Liver, Cirrhosis, and Liver Cancer Study (TENDENCY): Protocol for a Multicenter Case-Control Study.

BACKGROUND: Hepatocellular cancer (HCC) is associated with high mortality, and early diagnosis leads to better survival. Patients with cirrhosis, especially due to nonalcoholic fatty liver disease and viral hepatitis, are at higher risk of developing HCC and form the main screening group. The current screening methods for HCC (6-monthly screening with serum alpha fetoprotein and ultrasound liver) have low sensitivity; hence, there is a need for better screening markers for HCC. OBJECTIVE: Our study, TENDENCY, aims to validate the novel screening markers (methylated septin 9, urinary volatile organic compounds, and urinary peptides) for HCC diagnosis and study these noninvasive biomarkers in liver disease. METHODS: This is a multicenter, nested case-control study, which involves comparing the plasma levels of methylated septin 9 between confirmed HCC cases and patients with cirrhosis (control group). It also includes the comparison of urine samples for the detection of HCC-specific volatile organic compounds and peptides. Based on the findings of a pilot study carried out at University Hospital Coventry & Warwickshire, we estimated our sample size to be 308 (n=88, 29% patients with HCC; n=220, 71% patients with cirrhosis). Urine and plasma samples will be collected from all participants and will be frozen at -80 °C until the end of recruitment. Gas chromatography-mass spectrometry will be used for urinary volatile organic compounds detection, and capillary electrophoresis-mass spectrometry will be used for urinary peptide identification. Real-time polymerase chain reaction will be used for the qualitative detection of plasma methylated septin 9. The study will be monitored by the Research and Development department at University Hospital Coventry & Warwickshire. RESULTS: The recruitment stage was completed in March 2023. The TENDENCY study is currently in the analysis stage, which is expected to finish by November 2023. CONCLUSIONS: There is lack of effective screening tests for hepatocellular cancer despite higher mortality rates. The application of more sensitive plasma and urinary biomarkers for hepatocellular cancer screening in clinical practice will allow us to detect the disease at earlier stages and hence, overall, improve HCC outcomes. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/44264.

Obstructive Sleep Apnoea and Cardiac Arrhythmias (OSCA) trial: a nested cohort study using injectable loop recorders and Holter monitoring in patients with obstructive sleep apnoea.

INTRODUCTION: Obstructive sleep apnoea (OSA) is associated with increased cardiovascular mortality despite continuous positive airways pressure (CPAP) therapy. This excess risk may be related to increased arrhythmia risk, especially atrial fibrillation (AF). The true incidence of arrhythmia in patients with OSA is unknown. Implantable loop recorders (ILR) are powerful tools for detecting arrhythmias long-term. Cardiac autonomic function may be important in arrhythmogenesis in these patients but needs further study. We aim to identify the true incidence of arrhythmias (especially AF) using ILRs, assess cardiac autonomic function using Holter monitors in patients with OSA and explore cardiovascular outcomes. METHODS AND ANALYSIS: A two-centre (University Hospital Coventry and St. Cross Hospital, Rugby) nested cohort study using Reveal LINQ (Medtronic, UK) ILR to identify precise arrhythmia (atrial/ventricular) incidence in patients with moderate-severe OSA. 200 patients will be randomised 1:1 to standard care alone or standard care+ILR (+Holter monitor at baseline and 12 months). The primary objective is to compare arrhythmia detection over 3 years between the two groups. Cardiac autonomic function will be assessed in the ILR-arm at baseline and 12 months post CPAP. Secondary objectives will explore the mechanisms linking OSA and arrhythmia using cardiac autonomic function parameters based on Holter recordings and circulating biomarkers (high sensitivity Troponin-T, N-terminal pro B-type natriuretic peptide, matrix metalloproteinase-9, fibroblast growth factor 23, high sensitivity C-reactive protein, interleukin-6 and tumour necrosis factor-α) before and after CPAP initiation in the ILR-arm. ETHICS AND DISSEMINATION: This study has been approved by the Health Research Authority after examination by the Solihull Research and Ethics Committee. The main ethical considerations was the minimally invasive nature of ILR insertion outside of usual care. Patient advisory groups were consulted with a positive outcome for this type of research. We plan on publishing papers in peer-reviewed journals based on the primary objective and any interesting findings from secondary objectives. We will endeavour to publish all relevant data. TRIAL REGISTRATION NUMBER: NCT03866148.

Adjusting for treatment selection in phase II/III clinical trials with time to event data.

Phase II/III clinical trials are efficient two-stage designs that test multiple experimental treatments. In stage 1, patients are allocated to the control and all experimental treatments, with the data collected from them used to select experimental treatments to continue to stage 2. Patients recruited in stage 2 are allocated to the selected treatments and the control. Combined data of stage 1 and stage 2 are used for a confirmatory phase III analysis. Appropriate analysis needs to adjust for selection bias of the stage 1 data. Point estimators exist for normally distributed outcome data. Extending these estimators to time to event data is not straightforward because treatment selection is based on correlated treatment effects and stage 1 patients who do not get events in stage 1 are followed-up in stage 2. We have derived an approximately uniformly minimum variance conditional unbiased estimator (UMVCUE) and compared its biases and mean squared errors to existing bias adjusted estimators. In simulations, one existing bias adjusted estimator has similar properties as the practically unbiased UMVCUE while the others can have noticeable biases but they are less variable than the UMVCUE. For confirmatory phase II/III clinical trials where unbiased estimators are desired, we recommend the UMVCUE or the existing estimator with which it has similar properties.

Transcriptional Profiles Analysis of COVID-19 and Malaria Patients Reveals Potential Biomarkers in Children.

The clinical presentation overlap between malaria and COVID-19 poses special challenges for rapid diagnosis in febrile children. In this study, we collected RNA-seq data of children with malaria and COVID-19 infection from the public databases as raw data in fastq format paired end files. A group of six, five and two biological replicates of malaria, COVID-19 and healthy donors respectively were used for the study. We conducted differential gene expression analysis to visualize differences in the expression profiles. Using edgeR, we explored particularly gene expression levels in different phenotype groups and found that 1084 genes and 2495 genes were differentially expressed in the malaria samples and COVID-19 samples respectively when compared to healthy controls. The highly expressed gene in the COVID-19 group we found CD151 gene which is facilitates in T cell proliferation, while in the malaria group, among the highly expressed gene we identified GBP5 gene which involved in inflammatory response and response to bacterium. By comparing both malaria and COVID-19 infections, the overlap of 62 differentially expressed genes patterns were identified. Among them, three genes (ENSG00000234998, H2AC19 and TXNDC5) were highly upregulated in both infections. Strikingly, we observed 13 genes such as HBQ1, HBM, SLC7A5, SERINC2, ATP6V0C, ST6GALNAC4, RAD23A, PNPLA2, GAS2L1, TMEM86B, SLC6A8, UBALD1, RNF187 were downregulated in children with malaria and uniquely upregulated in children with COVID-19, thus may be further validated as potential biomarkers to delineate COVID-19 from malaria-related febrile infection. The hemoglobin complexes and lipid metabolism biological pathways are highly expressed in both infections. Our study provided new insights for further investigation of the biological pattern in hosts with malaria and COVID-19 coinfection.

Transcriptional Profiles Analysis of COVID-19 and Malaria Patients Reveals Potential Biomarkers in Children

The clinical presentation overlap between malaria and COVID-19 poses special challenges for rapid diagnosis in febrile children. In this study, we collected RNA-seq data of children with malaria and COVID-19 infection from the public databases as raw data in fastq format paired end files. A group of six, five and two biological replicates of malaria, COVID-19 and healthy donors respectively were used for the study. We conducted differential gene expression analysis to visualize differences in the expression profiles. Using edgeR, we explored particularly gene expression levels in different phenotype groups and found that 1084 genes and 2495 genes were differentially expressed in the malaria samples and COVID-19 samples respectively when compared to healthy controls. The highly expressed gene in the COVID-19 group we found CD151 gene which is facilitates in T cell proliferation, while in the malaria group, among the highly expressed gene we identified GBP5 gene which involved in inflammatory response and response to bacterium. By comparing both malaria and COVID-19 infections, the overlap of 62 differentially expressed genes patterns were identified. Among them, three genes (ENSG00000234998, H2AC19 and TXNDC5) were highly upregulated in both infections. Strikingly, we observed 13 genes such as HBQ1, HBM, SLC7A5, SERINC2, ATP6V0C, ST6GALNAC4, RAD23A, PNPLA2, GAS2L1, TMEM86B, SLC6A8, UBALD1, RNF187 were downregulated in children with malaria and uniquely upregulated in children with COVID-19, thus may be further validated as potential biomarkers to delineate COVID-19 from malaria-related febrile infection. The hemoglobin complexes and lipid metabolism biological pathways are highly expressed in both infections. Our study provided new insights for further investigation of the biological pattern in hosts with malaria and COVID-19 coinfection.

Implementation of respondent driven sampling in Nairobi, Kenya, for tracking key family planning indicators among adolescents and youth: lessons learnt.

OBJECTIVE: Adolescents and youth constitute a significant proportion of the population in developing nations. Conventional survey methods risk missing adolescents/youth because their family planning/contraception (FP/C) behavior is hidden. Respondent-driven sampling (RDS), a modified chain-referral recruitment sampling approach, was used to reach unmarried adolescents/youth aged 15-24 in Nairobi, Kenya to measure key FP/C indicators. Seeds were selected and issued with three coupons which they used to invite their peers, male or female, to participate in the study. Referred participants were also given coupons to invite others till sample size was achieved. We report on key implementation parameters following standard RDS reporting recommendations. RESULTS: A total of 1674 coupons were issued to generate a sample size of 1354. Coupon return rate was 82.7%. Study participants self-administered most survey questions and missing data was low. Differential enrolment by gender was seen with 56.0% of females recruiting females while 44.0% of males recruited males. In about two months, it was possible to reach the desired sample size using RDS methodology. Implementation challenges included presentation of expired coupons, recruitment of ineligible participants and difficulty recruiting seeds and recruits from affluent neighborhoods. Challenges were consistent with RDS implementation in other settings and populations. RDS can complement standard surveillance/survey approaches, particularly for mobile populations like adolescents/youth.

Effectiveness and Safety of Early Initiation of Poststernotomy Cardiac Rehabilitation Exercise Training: The SCAR Randomized Clinical Trial.

Importance: Guidelines recommend that cardiac rehabilitation (CR) exercise training should not start until 6 weeks after sternotomy, although this is not evidence based. Limited data suggest that starting earlier is not detrimental, but clinical trials are needed. Objective: To compare the effectiveness and safety of CR exercise training started either 2 weeks (early CR) or 6 weeks (usual-care CR) after sternotomy. Design, Setting, and Participants: This was an assessor-blind, noninferiority, parallel-group, randomized clinical trial that conducted participant recruitment from June 12, 2017, to March 17, 2020. Participants were consecutive cardiac surgery sternotomy patients recruited from 2 outpatient National Health Service rehabilitation centers: University Hospital, Coventry, UK, and Hospital of St Cross, Rugby, UK. Interventions: Participants were randomly assigned to 8 weeks of twice-weekly supervised CR exercise training starting either 2 weeks (early CR) or 6 weeks (usual-care CR) after sternotomy. Exercise training adhered to existing guidelines, including functional strength and cardiovascular components. Main Outcomes and Measures: Outcomes were assessed at baseline (inpatient after surgery), after CR (10 or 14 weeks after sternotomy), and 12 months after randomization. The primary outcome was the change in 6-minute walk test distance from baseline to after CR. Secondary outcomes included safety, functional fitness, and quality of life. Results: A total of 158 participants (mean [SD] age, 63 [11.5] years, 133 male patients [84.2%]) were randomly assigned to study groups; 118 patients (usual-care CR, 61 [51.7%]; early CR, 57 [48.3%]) were included in the primary analysis. Early CR was not inferior to usual-care CR (noninferiority margin, 35 m); the mean change in 6-minute walk distance from baseline to after CR was 28 m greater in the early CR group (95% CI, -11 to 66; P = .16). Mean differences for secondary outcomes were not statistically significant, indicating noninferiority of early CR. There were 46 vs 58 adverse events and 14 vs 18 serious adverse events in usual-care CR and early CR, respectively. There was no difference between the groups in the likelihood of participants having an adverse or serious adverse event. Conclusions and Relevance: Starting exercise training from 2 weeks after sternotomy was as effective as starting 6 weeks after sternotomy for improving 6-minute walk distance. With appropriate precautions, clinicians and CR professionals can consider starting exercise training as early as 2 weeks after sternotomy. Trial Registration: ClinicalTrials.gov Identifier: NCT03223558.

Kolkata-Coventry comparative registry study of acute heart failure: an insight into the impact of public, private and universal health systems on patient outcomes in low-middle income cities (KOLCOV HF Study).

INTRODUCTION: Survival gaps in acute heart failure (AHF) continue to expand globally. Multinational heart failure (HF) registries have highlighted variations between countries. Whether discrepancies in HF practice and outcomes occur across different health systems (ie, private, public or universal healthcare) within a city or between countries remain unclear. Insight into organisational care is also scarce. With increasing public scrutiny of health inequalities, a study to address these limitations is timely. METHOD: KOLCOV-HF study prospectively compared patients with AHF in public (Nil Ratan Sircar Hospital (NRS)) versus private (Apollo Gleneagles Hospital (AGH)) hospitals of Kolkata, India, and one with universal health coverage in a socioeconomically comparable city of Coventry, England (University Hospitals Coventry & Warwickshire (UHCW)). Data variables were adapted from UK's National HF Audit programme, collected over 24 months. Predictors of in-hospital mortality and length of hospitalisation were assessed for each centre. RESULTS: Among 1652 patients, in-hospital mortality was highest in government-funded NRS (11.9%) while 3 miles north, AGH had significantly lower mortality (7.5%, p=0.034), similar to UHCW (8%). This could be attributed to distinct HF phenotypes and differences in clinical and organisational care. As expected, low blood pressure was associated with a significantly greater risk of death in patients served by public hospitals UHCW and NRS. CONCLUSION: Marked differences in HF characteristics, management and outcomes exist intra-regionally, and between low-middle versus high-income countries across private, public and universal healthcare systems. Physicians and policymakers should take caution when applying country-level data locally when developing strategies to address local evidence-practice gaps in HF.

CORRECTED ARTICLE: Effect of Dietary Potassium Restriction on Serum Potassium, Disease Progression, and Mortality in Chronic Kidney Disease: A Systematic Review and Meta-Analysis.

OBJECTIVE: Low-potassium diets are recommended to reduce serum potassium (Sk) and prevent complications of chronic kidney disease (CKD), but evidence underpinning this recommendation has not been systematically reviewed and synthesized. We conducted a systematic review comparing change in Sk, CKD progression, and mortality between those on a low-potassium versus unrestricted potassium diet. METHODS: We searched Medline, AMED, PsycINFO, CINAHL, Cochrane Central Register of Controlled Trials, and Clinicaltrials.org from inception to 3 April 2018. We included randomized and observational studies that compared these outcomes in adults with CKD who ate a restricted versus unrestricted amount of dietary potassium. We pooled mean change in Sk and adjusted hazard ratios of disease progression and mortality using random-effects meta-analyses. RESULTS: We identified 5,563 articles, of which seven studies (3,489 participants) met our inclusion criteria. We found very low-quality evidence that restricted (1,295 mg/d) versus unrestricted (1,570 mg/d) dietary potassium lowered Sk by -0.22 mEq/L (95% confidence interval [CI]: -0.33, -0.10; I2 = 0%). Higher (4,558 mg/d) versus lower (1,725 mg/d) dietary potassium was not significantly associated with disease progression (hazard ratio [HR]: 1.14, 95% CI: [0.77, 1.70] I² = 57%). Higher (4,414 mg/d) compared with lower (1,670 mg/d) dietary potassium intake was not significantly associated with reduced mortality risk (HR: 0.80, 95% CI: [0.46, 1.41] I² = 78%). CONCLUSIONS: Very-low-quality evidence supports consensus that dietary potassium restriction reduces Sk in normokalemia but whether this is associated with risk of death in those with CKD is uncertain. High-quality randomized controlled trials are needed.

Biased Survival Predictions When Appraising Health Technologies in Heterogeneous Populations.

INTRODUCTION: Time-to-event data from clinical trials are routinely extrapolated using parametric models to estimate the cost effectiveness of novel therapies, but how this approach performs in the presence of heterogeneous populations remains unknown. METHODS: We performed a simulation study of seven scenarios with varying exponential distributions modelling treatment and prognostic effects across subgroup and complement populations, with follow-up typical of clinical trials used to appraise the cost effectiveness of therapies by agencies such as the UK National Institute for Health and Care Excellence (NICE). We compared established and emerging methods of estimating population life-years (LYs) using parametric models. We also proved analytically that an exponential model fitted to censored heterogeneous survival times sampled from two distinct exponential distributions will produce a biased estimate of the hazard rate and LYs. RESULTS: LYs are underestimated by the methods in the presence of heterogeneity, resulting in either under- or overestimation of the incremental benefit. In scenarios where the overestimation of benefit is likely, which is of interest to the healthcare provider, the method of taking the average LYs from all plausible models has the least bias. LY estimates from complete Kaplan-Meier curves have high variation, suggesting mature data may not be a reliable solution. We explore the effect of increasing trial sample size and accounting for detected treatment-subgroup interactions. CONCLUSIONS: The bias associated with heterogeneous populations suggests that NICE may need to be more cautious when appraising therapies and to consider model averaging or the separate modelling of subgroups when heterogeneity is suspected or detected.

Development of a model to demonstrate the impact of National Institute of Health and Care Excellence cost-effectiveness assessment on health utility for targeted medicines.

Advances in medical technology have led to a better understanding of heterogeneity of diseases and patients, and to the development of targeted medicines. This development is beneficial to society but can come at an increased cost to pharmaceutical manufacturers due to the costs associated with developing and manufacturing a diagnostic test. For such medicines, the conventional pricing structure, where a therapy is approved if it is deemed cost-effective, may not appropriately incentivize targeted drug development. We model the decision-making processes for both the healthcare provider and the pharmaceutical manufacturer, capturing their main priorities, and populate it with information from a recent appraisal by the National Institute of Health and Care Excellence. Healthcare providers prefer a stratified drug to be developed for a subgroup of the population when the drug is on average effective in the subgroup but with a detrimental effect in the complement. Whilst pharmaceutical manufacturers' preferences are similar, regions of disagreement exist. We show how preferences can be aligned by either penalizing the development of a non-stratified drug or rewarding the development of a stratified drug. The cost and position of alignment depends on the true value of health to the healthcare provider, among other parameters.

Systematic review with meta-analysis: volatile organic compound analysis to improve faecal immunochemical testing in the detection of colorectal cancer.

BACKGROUND: Faecal immunochemical test (FIT) is emerging as a valid test to rule-out the presence of colorectal cancer (CRC). However, the accuracy of FIT is dependent on the cut-off applied. An additional low-cost test could improve further detection of CRC. AIMS: To evaluate the efficacy of combined FIT and volatile organic compounds (VOC) in the detection of CRC within symptomatic populations. METHODS: Systematic reviews on the diagnostic accuracy of FIT and VOC, for the detection of CRC, were updated. Meta-analyses were performed adopting a bivariate model for sensitivity and specificity. Clinical utility of combined FIT and VOC was estimated using Fagan's nomogram. Post-test probability of FIT negatives was used as a pre-test probability for VOC. RESULTS: The pooled sensitivity and specificity of FIT at 10 µg/g faeces, for the detection of CRC, were 0.914 (95% confidence interval [CI] = 0.894-0.936) and 0.783 (CI = 0.850-0.696), respectively. For VOC, the sensitivity was 0.837 (CI = 0.781-0.881) and the specificity was 0.803 (CI = 0.870-0.712). The area under the curve for FIT and VOC were 0.926 and 0.885, respectively. In a population with 5% CRC prevalence, the estimated probability of having CRC following a negative FIT was 0.5% and following both negative FIT and VOC was 0.1%. CONCLUSIONS: In a FIT-negative symptomatic population, VOC can be a good test to rule-out the presence of CRC. The estimated probability reduction by 0.4% when both tests being negative offers adequate safety netting in primary care for the exclusion of CRC. The number needed to colonoscope to identify one CRC is eight if either FIT or VOC positive. Cost-effectiveness and clinical accuracy of this approach will need further evaluation.

Extrapolating Parametric Survival Models in Health Technology Assessment Using Model Averaging: A Simulation Study.

Previous work examined the suitability of relying on routine methods of model selection when extrapolating survival data in a health technology appraisal setting. Here we explore solutions to improve reliability of restricted mean survival time (RMST) estimates from trial data by assessing model plausibility and implementing model averaging. We compare our previous methods of selecting a model for extrapolation using the Akaike information criterion (AIC) and Bayesian information criterion (BIC). Our methods of model averaging include using equal weighting across models falling within established threshold ranges for AIC and BIC and using BIC-based weighted averages. We apply our plausibility assessment and implement model averaging to the output of our previous simulations, where 10,000 runs of 12 trial-based scenarios were examined. We demonstrate that removing implausible models from consideration reduces the mean squared error associated with the restricted mean survival time (RMST) estimate from each selection method and increases the percentage of RMST estimates that were within 10% of the RMST from the parameters of the sampling distribution. The methods of averaging were superior to selecting a single optimal extrapolation, aside from some of the exponential scenarios where BIC already selected the exponential model. The averaging methods with wide criterion-based thresholds outperformed BIC-weighted averaging in the majority of scenarios. We conclude that model averaging approaches should feature more widely in the appraisal of health technologies where extrapolation is influential and considerable uncertainty is present. Where data demonstrate complicated underlying hazard rates, funders should account for the additional uncertainty associated with these extrapolations in their decision making. Extended follow-up from trials should be encouraged and used to review prices of therapies to ensure a fair price is paid.

Utilisation of pharmacy-based sexual and reproductive health services: a quantitative retrospective study.

OBJECTIVES: To explore the utilisation of pharmacy-based sexual and reproductive health services (SRHS) in order to optimise delivery and identify barriers to access. METHODS: The health provider Umbrella offers six SRHS from over 120 pharmacies in Birmingham (England). In this retrospective study, data collected between August 2015 and August 2018 were used to analyse uptake, user characteristics and attendance patterns according to day of the week. RESULTS: A total of 60 498 requests for a pharmacy service were included in the analysis. Emergency contraception (50.4%), condoms (33.1%) and STI self-sampling kits (9.6%) accounted for more than 90% of all requests. A lower uptake of services was observed for the contraceptive injection (0.6%), oral contraception (5.4%) and chlamydia treatment (1.0%). Services were most likely to be requested by those self-identifying as female (85.6%), and those aged 16-24 years (53.8%). Based on available ethnicity data (n=54 668), most requests for a service were made by White/White British individuals (43.4%) and Asian/Asian British people (23.1%). The largest number of services were delivered on Mondays (20.9%) and the lowest on Sundays (5.0%). A high proportion of requests for services on Saturdays (57.0%), Sundays (67.6%) and Mondays (54.4%) were made by females presenting for emergency contraception. CONCLUSION: The evaluation of healthcare utilisation is important to help refine and optimise the delivery of services. However, information relating to pharmacy-based SRHS is scarce and often limited to a single type of service provision. Overall, a wide range of pharmacy-based services were accessed by a diverse range of people, suggesting that pharmacies are a suitable provider of many SRHS. However, the routinely collected data analysed in the study had several limitations restricting the analysis. Sexual health providers should ensure they collect data which are as comprehensive as is possible in order to help understand the utilisation of services.

Diagnostic concordance and discordance in digital pathology: a systematic review and meta-analysis.

BACKGROUND: Digital pathology (DP) has the potential to fundamentally change the way that histopathology is practised, by streamlining the workflow, increasing efficiency, improving diagnostic accuracy and facilitating the platform for implementation of artificial intelligence-based computer-assisted diagnostics. Although the barriers to wider adoption of DP have been multifactorial, limited evidence of reliability has been a significant contributor. A meta-analysis to demonstrate the combined accuracy and reliability of DP is still lacking in the literature. OBJECTIVES: We aimed to review the published literature on the diagnostic use of DP and to synthesise a statistically pooled evidence on safety and reliability of DP for routine diagnosis (primary and secondary) in the context of validation process. METHODS: A comprehensive literature search was conducted through PubMed, Medline, EMBASE, Cochrane Library and Google Scholar for studies published between 2013 and August 2019. The search protocol identified all studies comparing DP with light microscopy (LM) reporting for diagnostic purposes, predominantly including H&E-stained slides. Random-effects meta-analysis was used to pool evidence from the studies. RESULTS: Twenty-five studies were deemed eligible to be included in the review which examined a total of 10 410 histology samples (average sample size 176). For overall concordance (clinical concordance), the agreement percentage was 98.3% (95% CI 97.4 to 98.9) across 24 studies. A total of 546 major discordances were reported across 25 studies. Over half (57%) of these were related to assessment of nuclear atypia, grading of dysplasia and malignancy. These were followed by challenging diagnoses (26%) and identification of small objects (16%). CONCLUSION: The results of this meta-analysis indicate equivalent performance of DP in comparison with LM for routine diagnosis. Furthermore, the results provide valuable information concerning the areas of diagnostic discrepancy which may warrant particular attention in the transition to DP.