Background GUIDE-IT, the largest trial to date, published in August 2017, evaluating the effectiveness of natriuretic peptide (NP)-guided treatment of heart failure (HF), was stopped early for futility on a composite outcome. However, the reported effect sizes on individual outcomes of all-cause mortality and HF admissions are potentially clinically relevant. Objective This systematic review and meta-analysis aims to combine all available trial level evidence to determine if NP-guided treatment of HF reduces all-cause mortality and HF admissions in patients with HF. Study selection Eight databases, no language restrictions, up to November 2017 were searched for all randomised controlled trials comparing NP-guided treatment versus clinical assessment alone in adult patients with HF. No language restrictions were applied. Publications were independently double screened and extracted. Fixed-effect meta-analyses were conducted. Findings 89 papers were included, reporting 19 trials (4554 participants), average ages 62-80 years. Pooled risk ratio estimates for all-cause mortality (16 trials, 4063 participants) were 0.87, 95% CI 0.77 to 0.99 and 0.80, 95% CI 0.72 to 0.89 for HF admissions (11 trials, 2822 participants). Sensitivity analyses, restricted to low risk of bias, produced similar estimates, but were no longer statistically significant. Conclusions Considering all the evidence to date, the pooled effects suggest that NP-guided treatment is beneficial in reducing HF admissions and all-cause mortality. However, there is still insufficient high-quality evidence to make definitive recommendations on the use of NP-guided treatment in clinical practice. Trial registration number Systematic Review Cochrane Database Number: CD008966.
\n \n\n \n \nIntroduction: There is a lack ofevidence about resource use and costs of childhood cancer care in Egypt. Knowledge about resource use/costs can help in better resource planning to improve care and outcomes efficiently. In this study, we estimated patterns and trends of hospital resource use and costs for children with cancer (n = 8886, aged 0-18 years) treated at Children's Cancer Hospital, Egypt (CCHE), between 2013 and 2017, by ICCC-3 groups, at one and three years post-diagnosis. Methods: We estimated costs from the healthcare provider perspective, expressed in USD 2019. We also studied resource use/cost trends, and factors associated with inpatient days and costs. Results: For all cancers combined, median costs were $14,774 (IQR: $6,559-$23,738) at one year and $19,799 (IQR: $8,921-$34,204) at three years post-diagnosis. Median inpatient days were 38 days (IQR: 17-60) at one year, and 43 days (IQR: 20-74) at three years post-diagnosis. Patients with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and neuroblastoma imposed the greatest financial burden on CCHE, representing 53.1% of total costs. AML patients had the highest costs/resource use of all childhood cancers. Cost trends decreased by 2.9% (P < 0.001) for all cancers combined, due to economic instability in Egypt between 2013 and 2017. The use of IV supportive drugs increased by 24.3% (P < 0.001) over time for children with solid tumors. Conclusion: These findings will inform hospital resource planning and budgeting to promote value in care delivery, with implications for pediatric oncology practice and policy in Egypt/CCHE. Estimated costs provide the foundation for cost-effectiveness analysis.
\n \n\n \n \nIntroduction: Survival outcomes of children with relapsed/refractory (r/r) acute leukemia remain poor. Novel expensive treatments have been developed to improve their outcomes, yet, limited evidence exists about cost-effectiveness of alternative treatment strategies. Areas covered: A systematic review was conducted to summarize health-economic evidence about costs/cost-effectiveness of treating r/r acute leukemia in children/young adults. We searched Medline, Embase, and Cochrane databases until August 13th, 2021. Eligible articles included peer-reviewed original studies addressing r/r pediatric/young-adult acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML). Quality assessment was conducted using Consolidated Health Economics Evaluation Reporting Standards (CHEERS) checklist. Expert Opinion: The majority of papers focused on CAR-T cell therapy, which is still a novel treatment for r/r ALL, and was found to be cost-effective, yet, there remain concerns over its long-term effectiveness, affordability, and equity in access. The next best treatment option is Blinatumomab, followed by Clofarabine therapy, whereas FLA-IDA salvage chemotherapy provides least value for money. The quality of evidence is moderate to high, with limited generalizability of findings due to high variability in outcomes obtained from modeling studies. Limited studies evaluated r/r AML. We provide recommendations to deliver cost-effective treatments in real-world contexts, with implications for healthcare policy and practice.
\n \n\n \n \nBackground People with reduced kidney function have increased cardiovascular disease (CVD) risk. We present a policy model that simulates individuals\u2019 long-term health outcomes and costs to inform strategies to reduce risks of kidney and CVDs in this population. Methods and findings We used a United Kingdom primary healthcare database, the Clinical Practice Research Datalink (CPRD), linked with secondary healthcare and mortality data, to derive an open 2005\u20132013 cohort of adults (\u226518 years of age) with reduced kidney function (\u22652 measures of estimated glomerular filtration rate [eGFR] <90 mL/min/1.73 m2 \u226590 days apart). Data on individuals\u2019 sociodemographic and clinical characteristics at entry and outcomes (first occurrences of stroke, myocardial infarction (MI), and hospitalisation for heart failure; annual kidney disease stages; and cardiovascular and nonvascular deaths) during follow-up were extracted. The cohort was used to estimate risk equations for outcomes and develop a chronic kidney disease\u2013cardiovascular disease (CKD\u2013CVD) health outcomes model, a Markov state transition model simulating individuals\u2019 long-term outcomes, healthcare costs, and quality of life based on their characteristics at entry. Model-simulated cumulative risks of outcomes were compared with respective observed risks using a split-sample approach. To illustrate model value, we assess the benefits of partial (i.e., at 2013 levels) and optimal (i.e., fully compliant with clinical guidelines in 2019) use of cardioprotective medications. The cohort included 1.1 million individuals with reduced kidney function (median follow-up 4.9 years, 45% men, 19% with CVD, and 74% with only mildly decreased eGFR of 60\u201389 mL/min/1.73 m2 at entry). Age, kidney function status, and CVD events were the key determinants of subsequent morbidity and mortality. The model-simulated cumulative disease risks corresponded well to observed risks in participant categories by eGFR level. Without the use of cardioprotective medications, for 60- to 69-year-old individuals with mildly decreased eGFR (60\u201389 mL/min/1.73 m2), the model projected a further 22.1 (95% confidence interval [CI] 21.8\u201322.3) years of life if without previous CVD and 18.6 (18.2\u201318.9) years if with CVD. Cardioprotective medication use at 2013 levels (29%\u201344% of indicated individuals without CVD; 64%\u201376% of those with CVD) was projected to increase their life expectancy by 0.19 (0.14\u20130.23) and 0.90 (0.50\u20131.21) years, respectively. At optimal cardioprotective medication use, the projected health gains in these individuals increased by further 0.33 (0.25\u20130.40) and 0.37 (0.20\u20130.50) years, respectively. Limitations include risk factor measurements from the UK routine primary care database and limited albuminuria measurements. Conclusions The CKD\u2013CVD policy model is a novel resource for projecting long-term health outcomes and assessing treatment strategies in people with reduced kidney function. The model indicates clear survival benefits with cardioprotective treatments in this population and scope for further benefits if use of these treatments is optimised.
\n \n\n \n \nBackground: We aimed to understand the time period of cancer diagnosis and the cancer types detected in primary care patients with unexpected weight loss (UWL) to inform cancer guidelines. Methods: This retrospective matched cohort study used cancer registry linked electronic health records from the UK\u2019s Clinical Practice Research Datalink from between 2000 and 2014. Univariable and multivariable time-to-event analyses examined the association between UWL, and all cancers combined, cancer site and stage. Results: In all, 63,973 patients had UWL recorded, of whom 1375 (2.2%) were diagnosed with cancer within 2 years (days-to-diagnosis: mean 181; median 80). Men with UWL (HR 3.28 (2.88\u20133.73)) and women (1.87 (1.68\u20132.08)) were more likely than comparators to be diagnosed with cancer within 3 months. The association was greatest in men aged \u226550 years and women \u226570 years. The commonest cancers were pancreas, cancer of unknown primary, gastro-oesophageal, lymphoma, hepatobiliary, lung, bowel and renal-tract. The majority were late-stage, but there was some evidence of association with stage II and stage III cancers. In the 3\u201324 months after presenting with UWL, cancer diagnosis was less likely than in comparators. Conclusion: UWL recorded in primary care is associated with a broad range of cancer sites of early and late-stage.
\n \n\n \n \nBackground Patients with myeloma experience substantial delays in their diagnosis, which can adversely affect their prognosis. Aim To generate a clinical prediction rule to identify primary care patients who are at highest risk of myeloma. Design and setting Retrospective open cohort study using electronic health records data from the UK\u2019s Clinical Practice Research Datalink (CPRD) between 1 January 2000 and 1 January 2014. Method Patients from the CPRD were included in the study if they were aged \u226540 years, had two full blood counts within a year, and had no previous diagnosis of myeloma. Cases of myeloma were identified in the following 2 years. Derivation and external validation datasets were created based on geographical region. Prediction equations were estimated using Cox proportional hazards models including patient characteristics, symptoms, and blood test results. Calibration, discrimination, and clinical utility were evaluated in the validation set. Results Of 1 281 926 eligible patients, 737 (0.06%) were diagnosed with myeloma within 2 years. Independent predictors of myeloma included: older age; male sex; back, chest and rib pain; nosebleeds; low haemoglobin, platelets, and white cell count; and raised mean corpuscular volume, calcium, and erythrocyte sedimentation rate. A model including symptoms and full blood count had an area under the curve of 0.84 (95% CI = 0.81 to 0.87) and sensitivity of 62% (95% CI = 55% to 68%) at the highest risk decile. The corresponding statistics for a second model, which also included calcium and inflammatory markers, were an area under the curve of 0.87 (95% CI = 0.84 to 0.90) and sensitivity of 72% (95% CI = 66% to 78%). Conclusion The implementation of these prediction rules would highlight the possibility of myeloma in patients where GPs do not suspect myeloma. Future research should focus on the prospective evaluation of further external validity and the impact on clinical practice.
\n \n\n \n \nBackground: Behavioral weight management programs (BWMPs) enhance weight loss in the short term, but longer term cardiometabolic effects are uncertain as weight is commonly regained. We assessed the impact of weight regain after BWMPs on cardiovascular risk factors, diabetes, and cardiovascular disease. Methods: Trial registries, 11 databases, and forward-citation searching (latest search, December 19) were used to identify articles published in English, from any geographical region. Randomized trials of BWMPs in adults with overweight/obesity reporting cardiometabolic outcomes at \u226512 months at and after program end were included. Differences between more intensive interventions and comparator groups were synthesized using mixed-effects, meta-regression, and time-to-event models to assess the impact of weight regain on cardiovascular disease incidence and risk. Results: One hundred twenty-four trials reporting on \u22651 cardiometabolic outcomes with a median follow-up of 28 (range, 11-360) months after program end were included. Median baseline participant body mass index was 33 kg/m2; median age was 51 years. Eight and 15 study arms (7889 and 4202 participants, respectively) examined the incidence of cardiovascular disease and type 2 diabetes, respectively, with imprecise evidence of a lower incidence for at least 5 years. Weight regain in BWMPs relative to comparators reduced these differences. One and 5 years after program end, total cholesterol/HDL (high-density lipoprotein) ratio was 1.5 points lower at both times (82 studies; 19 003 participants), systolic blood pressure was 1.5 mm mercury and 0.4 mm lower (84 studies; 30 836 participants), and HbA1c (%) 0.38 lower at both times (94 studies; 28 083 participants). Of the included studies, 22% were judged at high risk of bias; removing these did not meaningfully change results. Conclusions: Despite weight regain, BWMPs reduce cardiometabolic risk factors with effects lasting at least 5 years after program end and dwindling with weight regain. Evidence that they reduce the incidence of cardiovascular disease or diabetes is less certain. Few studies followed participants for \u22655 years. Registration: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42018105744.
\n \n\n \n \nBackground: Long-term monitoring is important in chronic condition management. Despite considerable costs of monitoring, there is no or poor evidence on how, what and when to monitor. The aim of this study was to improve understanding, methods, evidence base and practice of clinical monitoring in primary care, focusing on two areas: Chronic kidney disease and chronic heart failure. Objectives: The research questions were as follows: Does the choice of test affect better care while being affordable to the NHS? Can the number of tests used to manage individuals with early-stage kidney disease, and hence the costs, be reduced? Is it possible to monitor heart failure using a simple blood test? Can this be done using a rapid test in a general practitioner consultation? Would changes in the management of these conditions be acceptable to patients and carers? Design: Various study designs were employed, including cohort, feasibility study, Clinical Practice Research Datalink analysis, seven systematic reviews, two qualitative studies, one cost-effectiveness analysis and one cost recommendation. Setting: This study was set in UK primary care. Data sources: Data were collected from study participants and sourced from UK general practice and hospital electronic health records, and worldwide literature. Participants: The participants were NHS patients (Clinical Practice Research Datalink: 4.5 million patients), chronic kidney disease and chronic heart failure patients managed in primary care (including 750 participants in the cohort study) and primary care health professionals. Interventions: The interventions were monitoring with blood and urine tests (for chronic kidney disease) and monitoring with blood tests and weight measurement (for chronic heart failure). Main outcome measures: The main outcomes were the frequency, accuracy, utility, acceptability, costs and cost-effectiveness of monitoring. Results: Chronic kidney disease: Serum creatinine testing has increased steadily since 1997, with most results being normal (83% in 2013). Increases in tests of creatinine and proteinuria correspond to their introduction as indicators in the Quality and Outcomes Framework. The Chronic Kidney Disease Epidemiology Collaboration equation had 2.7% greater accuracy (95% confidence interval 1.6% to 3.8%) than the Modification of Diet in Renal Disease equation for estimating glomerular filtration rate. Estimated annual transition rates to the next chronic kidney disease stage are \u2248 2% for people with normal urine albumin, 3\u20135% for people with microalbuminuria (3\u201330 mg/mmol) and 3\u201312% for people with macroalbuminuria (> 30 mg/mmol). Variability in estimated glomerular filtration rate-creatinine leads to misclassification of chronic kidney disease stage in 12\u201315% of tests in primary care. Glycaemiccontrol and lipid-modifying drugs are associated with a 6% (95% confidence interval 2% to 10%) and 4% (95% confidence interval 0% to 8%) improvement in renal function, respectively. Neither estimated glomerular filtration rate-creatinine nor estimated glomerular filtration rate-Cystatin C have utility in predicting rate of kidney function change. Patients viewed phrases such as \u2018kidney damage\u2019 or \u2018kidney failure\u2019 as frightening, and the term \u2018chronic\u2019 was misinterpreted as serious. Diagnosis of asymptomatic conditions (chronic kidney disease) was difficult to understand, and primary care professionals often did not use \u2018chronic kidney disease\u2019 when managing patients at early stages. General practitioners relied on Clinical Commissioning Group or Quality and Outcomes Framework alerts rather than National Institute for Health and Care Excellence guidance for information. Cost-effectiveness modelling did not demonstrate a tangible benefit of monitoring kidney function to guide preventative treatments, except for individuals with an estimated glomerular filtration rate of 60\u201390 ml/minute/1.73 m2, aged < 70 years and without cardiovascular disease, where monitoring every 3\u20134 years to guide cardiovascular prevention may be cost-effective. Chronic heart failure: Natriuretic peptide-guided treatment could reduce all-cause mortality by 13% and heart failure admission by 20%. Implementing natriuretic peptide-guided treatment is likely to require predefined protocols, stringent natriuretic peptide targets, relative targets and being located in a specialist heart failure setting. Remote monitoring can reduce all-cause mortality and heart failure hospitalisation, and could improve quality of life. Diagnostic accuracy of point-of-care N-terminal prohormone of B-type natriuretic peptide (sensitivity, 0.99; specificity, 0.60) was better than point-of-care B-type natriuretic peptide (sensitivity, 0.95; specificity, 0.57).Within-person variation estimates for B-type natriuretic peptide and weight were as follows: Coefficient of variation, 46% and coefficient of variation, 1.2%, respectively. Point-of-care N-terminal prohormone of B-type natriuretic peptide within-person variability over 12 months was 881 pg/ml (95% confidence interval 380 to 1382 pg/ml), whereas between-person variability was 1972 pg/ml (95% confidence interval 1525 to 2791 pg/ml). For individuals, monitoring provided reassurance; future changes, such as increased testing, would be acceptable. Point-of-care testing in general practice surgeries was perceived positively, reducing waiting time and anxiety. Community heart failure nurses had greater knowledge of National Institute for Health and Care Excellence guidance than general practitioners and practice nurses. Health-care professionals believed that the cost of natriuretic peptide tests in routine monitoring would outweigh potential benefits. The review of cost-effectiveness studies suggests that natriuretic peptide-guided treatment is cost-effective in specialist settings, but with no evidence for its value in primary care settings. Limitations: No randomised controlled trial evidence was generated. The pathways to the benefit of monitoring chronic kidney disease were unclear. Conclusions: It is difficult to ascribe quantifiable benefits to monitoring chronic kidney disease, because monitoring is unlikely to change treatment, especially in chronic kidney disease stages G3 and G4. New approaches to monitoring chronic heart failure, such as point-of-care natriuretic peptide tests in general practice, show promise if high within-test variability can be overcome. Future work: The following future work is recommended: Improve general practitioner\u2013patient communication of early-stage renal function decline, and identify strategies to reduce the variability of natriuretic peptide. Study registration: This study is registered as PROSPERO CRD42015017501, CRD42019134922 and CRD42016046902.
\n \n\n \n \nAims: We used data from a recent systematic review to investigate weight regain after behavioural weight management programmes (BWMPs, sometimes referred to as lifestyle modification programmes) and its impact on quality-of-life and cost-effectiveness. Materials and Methods: Trial registries, databases and forward-citation searching (latest search December 2019) were used to identify randomized trials of BWMPs in adults with overweight/obesity reporting outcomes at \u226512 months, and after programme end. Two independent reviewers screened records. One reviewer extracted data and a second checked them. The differences between intervention and control groups were synthesized using mixed-effect, meta-regression and time-to-event models. We examined associations between weight difference and difference in quality-of-life. Cost-effectiveness was estimated from a health sector perspective. Results: In total, 155 trials (n > 150 000) contributed to analyses. The longest follow-up was 23 years post-programme. At programme end, intervention groups achieved \u20132.8 kg (95%CI \u20133.2 to \u20132.4) greater weight loss than controls. Weight regain after programme end was 0.12-0.32 kg/year greater in intervention relative to control groups, with a between-group difference evident for at least 5 years. Quality-of-life increased in intervention groups relative to control at programme end and thereafter returned to control as the difference in weight between groups diminished. BWMPs with this initial weight loss and subsequent regain would be cost-effective if delivered for under \u00a3560 (\u00a38.80-\u00a33900) per person. Conclusions: Modest rates of weight regain, with persistent benefits for several years, should encourage health care practitioners and policymakers to offer obesity treatments that cost less than our suggested thresholds as a cost-effective intervention to improve long-term weight management. Registration: The review is registered on PROSPERO, CRD42018105744.
\n \n\n \n \nBACKGROUND: Many clinical pathways for the diagnosis of disease are based on diagnostic tests that are performed in sequence. The performance of the full diagnostic sequence is dictated by the diagnostic performance of each test in the sequence as well as the conditional dependence between them, given true disease status. Resulting estimates of performance, such as the sensitivity and specificity of the test sequence, are key parameters in health-economic evaluations. We conducted a methodological review of statistical methods for assessing the performance of diagnostic tests performed in sequence, with the aim of guiding data analysts towards classes of methods that may be suitable given the design and objectives of the testing sequence. METHODS: We searched PubMed, Scopus and Web of Science for relevant papers describing methodology for analysing sequences of diagnostic tests. Papers were classified by the characteristics of the method used, and these were used to group methods into themes. We illustrate some of the methods using data from a cohort study of repeat faecal immunochemical testing for colorectal cancer in symptomatic patients, to highlight the importance of allowing for conditional dependence in test sequences and adjustment for an imperfect reference standard. RESULTS: Five overall themes were identified, detailing methods for combining multiple tests in sequence, estimating conditional dependence, analysing sequences of diagnostic tests used for risk assessment, analysing test sequences in conjunction with an imperfect or incomplete reference standard, and meta-analysis of test sequences. CONCLUSIONS: This methodological review can be used to help researchers identify suitable analytic methods for studies that use diagnostic tests performed in sequence.
\n \n\n \n \nBackground: Cancer places a high burden on society and health-care systems. Cancer research requires high-quality data, which is resource-intensive to obtain. Using administrative datasets such as cancer registries could improve the efficiency of cancer studies if data were valid and timely. We aimed to compare the validity and timeliness of diagnostic cancer data on-site during the SYMPLIFY study to that obtained from the cancer registries of England and Wales. Methods: Cancer data were collected from 5461 participants across 44 hospital sites during a prospective observational study in England and Wales, SYMPLIFY (ISRCTN10226380). Linked cancer data were obtained from Digital Health and Care Wales (DHCW), the Welsh Cancer Intelligence and Surveillance Unit (WCISU), and the English National Cancer Registration Dataset (NCRD) and Rapid Cancer Registration Dataset (RCRD), regularly between April, 2022, and September, 2023. The primary objectives of the study were to evaluate the validity (via assessment of the proportion of completed data fields and concordance with SYMPLIFY sites), and timeliness of the data in all datasets, for all cancers diagnosed within 9 months of study enrolment. Data fields investigated were cancer site via International Classification of Disease, 10th Revision (ICD-10) code; cancer morphology via International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3) morphology histology code and broad morphological grouping; overall stage; and TNM classification. Findings: For data collected between April, 2022, and September, 2023, completeness at the last data cut available for each dataset ranged from 84% to 100% for ICD-O-3 morphology, from 43% to 100% for overall stage, and from 74% to 83% for TNM stage. The concordance between SYMPLIFY data and NCRD was 96% (95% CI 92\u201398) for ICD-10, 60% (53\u201366) for ICD-O-3 morphology, 83% (78\u201388) for ICD-O-3 broad morphology groupings, 73% (67\u201378) for stage, and 51% (44\u201359) for TNM; and with WCISU was 89% (95% CI 81\u201394) for ICD-10, 63% (53\u201373) for ICD-O-3 morphology, 80% (70\u201387) for ICD-O-3 broad morphology groupings, 83% (74\u201390) for overall stage, and 49% (38\u201361) for TNM stage. Concordance between SYMPLIFY and RCRD was 95% (95% CI 92\u201398) for ICD-10, 67% (60\u201374) for ICD-O-3 morphology, 85% (79\u201390) for ICD-O-3 broad morphology groupings, and 73% (65\u201380) for overall stage; and between SYMPLIFY and DHCW was 96% (91\u201399) for ICD-10, 74% (64\u201383) for ICD-O-3 morphology, 84% (75\u201391) for ICD-O-3 broad morphology groupings, and 87% (74\u201395) for stage. The SYMPLIFY dataset reached completion at 12 months post-enrolment in November, 2022, compared with 13 months for NCRD in December, 2023. RCRD and DHCW reached completion at 13 months and 15 months post-enrolment, in December, 2022, and February, 2023, respectively. Interpretation: We report similar completeness of data fields, concordance, and timeliness between on-site and centrally collected cancer outcomes data. Our findings suggest that central registry data can help alleviate the resource burden in clinical trials and improve cancer research. Cancer registries might need additional resources to provide data for registry-based trials at scale. Funding: GRAIL Bio UK.
\n \n\n \n \nAbstractObjective To determine if the characteristics of behavioural weight loss programmes influence the rate of change in weight after the end of the programme. Design Systematic review and meta-analysis. Data sources Trial registries, 11 electronic databases, and forward citation searching (from database inception; latest search December 2019). Randomised trials of behavioural weight loss programmes in adults with overweight or obesity, reporting outcomes at \u226512 months, including at the end of the programme and after the end of the programme. Review methods Studies were screened by two independent reviewers with discrepancies resolved by discussion. 5% of the studies identified in the searches met the inclusion criteria. One reviewer extracted the data and a second reviewer checked the data. Risk of bias was assessed with Cochrane's risk of bias tool (version 1). The rate of change in weight was calculated (kg/month; converted to kg/year for interpretability) after the end of the programme in the intervention versus control groups by a mixed model with a random intercept. Associations between the rate of change in weight and prespecified variables were tested. Results Data were analysed from 249 trials (n=59 081) with a mean length of follow-up of two years (longest 30 years). 56% of studies (n=140) had an unclear risk of bias, 21% (n=52) a low risk, and 23% (n=57) a high risk of bias. Regain in weight was faster in the intervention versus the no intervention control groups (0.12-0.32 kg/year) but the difference between groups was maintained for at least five years. Each kilogram of weight lost at the end of the programme was associated with faster regain in weight at a rate of 0.13-0.19 kg/year. Financial incentives for weight loss were associated with faster regain in weight at a rate of 1-1.5 kg/year. Compared with programmes with no meal replacements, interventions involving partial meal replacements were associated with faster regain in weight but not after adjustment for weight loss during the programme. Access to the programme outside of the study was associated with slower regain in weight. Programmes where the intensity of the interaction reduced gradually were also associated with slower regain in weight in the multivariable analysis, although the point estimate suggested that the association was small. Other characteristics did not explain the heterogeneity in regain in weight. Conclusion Faster regain in weight after weight loss was associated with greater initial weight loss, but greater initial weight loss was still associated with reduced weight for at least five years after the end of the programme, after which data were limited. Continued availability of the programme to participants outside of the study predicted a slower regain in weight, and provision of financial incentives predicted faster regain in weight; no other clear associations were found.
\n \n\n \n \nBackground: Evidence for kidney function monitoring intervals in primary care is weak, and based mainly on expert opinion. In the absence of trials of monitoring strategies, an approach combining a model for the natural history of kidney function over time combined with a cost-effectiveness analysis offers the most feasible approach for comparing the effects of monitoring under a variety of policies. This study aimed to create a model for kidney disease progression using routinely collected measures of kidney function. Methods: This is an open cohort study of patients aged \u226518 years, registered at 643 UK general practices contributing to the Clinical Practice Research Datalink between 1 April 2005 and 31 March 2014. At study entry, no patients were kidney transplant donors or recipients, pregnant or on dialysis. Hidden Markov models for estimated glomerular filtration rate (eGFR) stage progression were fitted to four patient cohorts defined by baseline albuminuria stage; adjusted for sex, history of heart failure, cancer, hypertension and diabetes, annually updated for age. Results: Of 1,973,068 patients, 1,921,949 had no recorded urine albumin at baseline, 37,947 had normoalbuminuria (<3mg/mmol), 10,248 had microalbuminuria (3-30mg/mmol), and 2,924 had macroalbuminuria (>30mg/mmol). Estimated annual transition probabilities were 0.75-1.3%, 1.5-2.5%, 3.4-5.4% and 3.1-11.9% for each cohort, respectively. Misclassification of eGFR stage was estimated to occur in 12.1% (95%CI: 11.9-12.2%) to 14.7% (95%CI: 14.1-15.3%) of tests. Male gender, cancer, heart failure and age were independently associated with declining renal function, whereas the impact of raised blood pressure and glucose on renal function was entirely predicted by albuminuria. Conclusions: True kidney function deteriorates slowly over time, declining more sharply with elevated urine albumin, increasing age, heart failure, cancer and male gender. Consecutive eGFR measurements should be interpreted with caution as observed improvement or deterioration may be due to misclassification.
\n \n\n \n \nBackground Unexpected weight loss (UWL) is a presenting feature of cancer in primary care. Existing research proposes simple combinations of clinical features (risk factors, symptoms, signs, and blood test data) that, when present, warrant cancer investigation. More complex combinations may modify cancer risk to sufficiently rule-out the need for investigation. We aimed to identify which clinical features can be used together to stratify patients with UWL based on their risk of cancer. Methods and findings We used data from 63,973 adults (age: mean 59 years, standard deviation 21 years; 42% male) to predict cancer in patients with UWL recorded in a large representative United Kingdom primary care electronic health record between January 1, 2000 and December 31, 2012. We derived 3 clinical prediction models using logistic regression and backwards stepwise covariate selection: Sm, symptoms-only model; STm, symptoms and tests model; Tm, tests-only model. Fifty imputations replaced missing data. Estimates of discrimination and calibration were derived using 10-fold internal cross-validation. Simple clinical risk scores are presented for models with the greatest clinical utility in decision curve analysis. The STm and Tm showed improved discrimination (area under the curve > 0.91), calibration, and greater clinical utility than the Sm. The Tm was simplest including age-group, sex, albumin, alkaline phosphatase, liver enzymes, C-reactive protein, haemoglobin, platelets, and total white cell count. A Tm score of 5 balanced ruling-in (sensitivity 84.0%, positive likelihood ratio 5.36) and ruling-out (specificity 84.3%, negative likelihood ratio 0.19) further cancer investigation. A Tm score of 1 prioritised ruling-out (sensitivity 97.5%). At this threshold, 35 people presenting with UWL in primary care would be referred for investigation for each person with cancer referred, and 1,730 people would be spared referral for each person with cancer not referred. Study limitations include using a retrospective routinely collected dataset, a reliance on coding to identify UWL, and missing data for some predictors. Conclusions Our findings suggest that combinations of simple blood test abnormalities could be used to identify patients with UWL who warrant referral for investigation, while people with combinations of normal results could be exempted from referral.
\n \n\n \n \nObjectives: To mitigate risk of mortality from coronavirus 2019 infection (COVID-19), the UK government recommended \u2018shielding\u2019 of vulnerable people through self-isolation for 12 weeks. Methods: A retrospective cohort study using a nationally representative English primary care database comparing people aged >= 40 years who were recorded as being advised to shield using a fixed ratio of 1:1, matching to people with the same diagnoses not advised to shield (n = 77,360 per group). Time-to-death was compared using Cox regression, reporting the hazard ratio (HR) of mortality between groups. A sensitivity analysis compared exact matched cohorts (n = 24,752 shielded, n = 61,566 exact matches). Results: We found a time-varying HR of mortality between groups. In the first 21 days, the mortality risk in people shielding was half those not (HR = 0.50, 95%CI:0.41\u20130.59. p < 0.0001). Over the remaining nine weeks, mortality risk was 54% higher in the shielded group (HR=1.54, 95%CI:1.41\u20131.70, p < 0.0001). Beyond the shielding period, mortality risk was over two-and-a-half times higher in the shielded group (HR=2.61, 95%CI:2.38\u20132.87, p < 0.0001). Conclusions: Shielding halved the risk of mortality for 21 days. Mortality risk became higher across the remainder of the shielding period, rising to two-and-a-half times greater post-shielding. Shielding may be beneficial in the next wave of COVID-19.
\n \n\n \n \nPURPOSEChildhood cancer treatment is complex, resource-intensive, and expensive, and resource-limited settings would benefit from providing cost-effective treatment approaches on the basis of evidence. Effective implementation of cost-effective evidence-based treatment requires knowledge about factors influencing its use. In this study, we determined the clinicians' perceptions of the barriers and facilitators to implementing cost-effective evidence-based treatment for children with cancer in a resource-limited pediatric oncology setting in Egypt.METHODSWe conducted a qualitative study on the basis of semistructured interviews with senior clinicians who make high-level decisions on treatment protocols and tailored decisions for the atypically complicated group of patients. Purposive sampling was used to recruit the participants. Thematic analysis was conducted semantically to develop themes of barriers and facilitators.RESULTSFourteen participants agreed to participate in the study: nine pediatric oncologists; three surgeons; and two radiation oncologists. We identified four main themes of barriers and facilitators: Awareness and orientation; knowledge, skills, and attitudes; system, resources, and context; and clinical practice. The main barriers included absence of easily available costs/cost-effectiveness data, limited resources and inability to pay for expensive novel (cost-effective) drugs, and gap between evidence and practice. The main facilitators included adopting standard treatment protocols on the basis of clinical effectiveness, leadership support, availability of patients' clinical and cost data from local context, and existing knowledge and skills in clinical research and health economic evaluation. The interview participants also provided suggestions to promote the implementation of cost-effective evidence-based treatment in priority areas.CONCLUSIONOur study findings provide an understanding of the barriers and facilitators affecting the implementation of cost-effective evidence-based treatment for childhood cancers in Egypt. We provide practical recommendations to address the implementation gaps with implications on practice, policy, and research.
\n \n\n \n \nBehavioural weight management programmes (BWMPs) lead to weight loss but subsequent weight regain may harm mental health outcomes. We searched for randomised trials of BWMPs in adults with overweight/obesity with follow-up \u226512 months from baseline that measured weight change both at and after programme-end. We included only studies reporting mental health at or after programme-end. We meta-analysed changes in various mental health outcomes using a random-effects model by nature of the comparator group and by time since programme end. Subgroup analysis explored heterogeneity. We used mixed models and meta-regression to analyse the association between change in weight and change in depression and/or anxiety over time, with higher scores indicating greater depression and/or anxiety. We included 47 studies. When comparing BWMPs (diet and/or exercise) to control, most estimates included the possibility of no difference, but pooled estimates for psychological wellbeing, self-esteem and mental-health composite scores at programme-end, anxiety at 1\u20136 months, and depression at 7\u201312 months after programme-end suggested improvements in intervention arms relative to control, with 95% CIs excluding no difference. Pooled estimates found no evidence that BWMPs harmed mental health at programme end or beyond. Mental health composite scores at programme-end favoured diet and exercise interventions over diet alone, with 95% CIs excluding no difference. All other measures and timepoints included the possibility of no difference or could not be meta-analysed due to high heterogeneity or a paucity of data. Mixed models and meta-regression of the association between change in depression and/or anxiety scores over time, and change in weight, were inconclusive. Despite weight regain after BWMPs, our meta-analyses found no evidence of mental health harm and some evidence that BWMPs may improve some dimensions of mental health at and after programme-end.
\n \n\n \n \nBackground: Unexpected weight loss is a presenting feature of cancer in primary care. Data from primary care are lacking to quantify how much weight loss over what period should trigger further investigation for cancer. This research aimed to quantify cancer diagnosis rates associated with measured weight change in people attending primary care. Methods: Retrospective cohort study of primary care electronic health records data linked to the Surveillance, Epidemiology, and End Results cancer registry (Integrated healthcare delivery system in Washington State, United States). Multivariable Cox regression incorporating time varying covariates using splines to model non-linear associations (age, percentage weight change, and weight change interval). Fifty thousand randomly selected patients aged 40 years and over followed for up to 9 years (1 January 2006 to 31 December 2014). Outcome measures are hazard ratios (95% confidence intervals) to quantify the association between percentage weight change and cancer diagnosis for all cancers combined, individual cancer sites and stages; percentage risk of cancer diagnosis within 6 months of the end of each weight change episode; and the positive predictive value for cancer diagnosis. Results: There were 43 302 included in the analysis after exclusions. Over 287 858 patient-years of follow-up, including 24 272 (56.1%) females, 23 980 (55.4%) aged 40 to 59 years, 15 113 (34.9%) 60 to 79 years, and 4209 (9.7%) aged 80 years and over. Adjusted hazard ratios (95% confidence interval) for cancer diagnosis in a 60 years old ranged from 1.04 (1.02 to 1.05, P < 0.001) for 1% weight loss to 1.44 (1.23 to 1.68, P < 0.001) for 10%. An independent linear association was observed between percentage weight loss and increasing cancer risk. The absolute risk of cancer diagnosis increased with increasing age (up to 85 years) and as the weight change measurement interval decreased (<1 year). The positive predictive value for a cancer diagnosis within 1 year of \u22655% measured weight loss in a 60 to 69 years old was 3.41% (1.57% to 6.37%) in men and 3.47% (1.68% to 6.29%) in women. The risk of cancer diagnosis was significantly increased for pancreatic, myeloma, gastro-oesophageal, colorectal, breast, stage II and IV cancers. Conclusions: Weight loss is a sign of undiagnosed cancer regardless of the interval over which it occurs. Guidelines should resist giving an arbitrary cut-off for the interval of weight loss and focus on the percentage of weight loss and the patient's age. Future studies should focus on the association between diagnostic evaluation of weight change and risk of cancer mortality.
\n \n\n \n \nBackground: Analysis of circulating tumour DNA could stratify cancer risk in symptomatic patients. We aimed to evaluate the performance of a methylation-based multicancer early detection (MCED) diagnostic test in symptomatic patients referred from primary care. Methods: We did a multicentre, prospective, observational study at National Health Service (NHS) hospital sites in England and Wales. Participants aged 18 or older referred with non-specific symptoms or symptoms potentially due to gynaecological, lung, or upper or lower gastrointestinal cancers were included and gave a blood sample when they attended for urgent investigation. Participants were excluded if they had a history of or had received treatment for an invasive or haematological malignancy diagnosed within the preceding 3 years, were taking cytotoxic or demethylating agents that might interfere with the test, or had participated in another study of a GRAIL MCED test. Patients were followed until diagnostic resolution or up to 9 months. Cell-free DNA was isolated and the MCED test performed blinded to the clinical outcome. MCED predictions were compared with the diagnosis obtained by standard care to establish the primary outcomes of overall positive and negative predictive value, sensitivity, and specificity. Outcomes were assessed in participants with a valid MCED test result and diagnostic resolution. SYMPLIFY is registered with ISRCTN (ISRCTN10226380) and has completed follow-up at all sites. Findings: 6238 participants were recruited between July 7 and Nov 30, 2021, across 44 hospital sites. 387 were excluded due to staff being unable to draw blood, sample errors, participant withdrawal, or identification of ineligibility after enrolment. Of 5851 clinically evaluable participants, 376 had no MCED test result and 14 had no information as to final diagnosis, resulting in 5461 included in the final cohort for analysis with an evaluable MCED test result and diagnostic outcome (368 [6\u00b77%] with a cancer diagnosis and 5093 [93\u00b73%] without a cancer diagnosis). The median age of participants was 61\u00b79 years (IQR 53\u00b74\u201373\u00b70), 3609 (66\u00b71%) were female and 1852 (33\u00b79%) were male. The MCED test detected a cancer signal in 323 cases, in whom 244 cancer was diagnosed, yielding a positive predictive value of 75\u00b75% (95% CI 70\u00b75\u201380\u00b71), negative predictive value of 97\u00b76% (97\u00b71\u201398\u00b70), sensitivity of 66\u00b73% (61\u00b72\u201371\u00b71), and specificity of 98\u00b74% (98\u00b71\u201398\u00b78). Sensitivity increased with increasing age and cancer stage, from 24\u00b72% (95% CI 16\u00b70\u201334\u00b71) in stage I to 95\u00b73% (88\u00b75\u201398\u00b77) in stage IV. For cases in which a cancer signal was detected among patients with cancer, the MCED test's prediction of the site of origin was accurate in 85\u00b72% (95% CI 79\u00b78\u201389\u00b73) of cases. Sensitivity 80\u00b74% (95% CI 66\u00b71\u201390\u00b76) and negative predictive value 99\u00b71% (98\u00b72\u201399\u00b76) were highest for patients with symptoms mandating investigation for upper gastrointestinal cancer. Interpretation: This first large-scale prospective evaluation of an MCED diagnostic test in a symptomatic population demonstrates the feasibility of using an MCED test to assist clinicians with decisions regarding urgency and route of referral from primary care. Our data provide the basis for a prospective, interventional study in patients presenting to primary care with non-specific signs and symptoms. Funding: GRAIL Bio UK.
\n \n\n \n \nBackground: Unexpected weight loss (UWL) in patients consulting in primary care presents dilemmas for management because of the broad differential diagnoses associated with UWL. Research on the risks of serious disease among patients with UWL to date has largely taken place in secondary care, limiting generalizability to primary care patients. In this study, we use a large matched cohort study to estimate the risks of 12 serious diseases among patients presenting to primary care with UWL where this was recorded, stratified by age and sex, in order to inform a rational clinical approach to patients presenting with UWL. Methods: This was a retrospective matched cohort study using electronic health records (EHRs) from the UK Clinical Practice Research Datalink (CPRD). Each patient with UWL (ascertained from EHR coding) was matched to five patients without UWL and followed until the earliest of a diagnosis of the serious disease, date of death, exit from the CPRD database, or end of the study. Observed absolute risks of the 12 serious diseases were estimated as probabilities, and hazard ratios (HRs) were estimated with Cox proportional hazards models. Results: Between 2000 and 2012, 70 193 patients in CPRD had at least one record of UWL and were matched with 295 579 patients without UWL. Patients with UWL had significantly higher risk of nearly all serious diseases examined compared with patients without. HRs ranged from 1.43 for congestive heart failure [95% confidence interval (CI): 1.27\u20131.62] to 9.70 for malabsorption (95% CI: 6.81\u201313.82). The absolute risks of any given serious disease were relatively low (<6% after 1 year). The magnitude and rank order of absolute risks varied by age and sex. Depression was the most common diagnosis among women aged <80 with UWL (3.74% of women aged <60 and 2.46% of women aged 60\u201379), whereas diabetes was the most common in men <60 with UWL (2.96%) and cancer was the most common in men aged 60 and over with UWL (3.79% of men aged 60\u201370 and 5.28% of men aged \u226580). Conclusions: This analysis provides new evidence to patients and clinicians about the risks of serious disease among patients presenting with UWL in primary care. Depending on age and sex, the results suggest that workup for UWL should include screening for diabetes, thyroid dysfunction, depression, and dementia. If performed in a timely manner, this workup could be used to triage patients eligible for cancer pathway referral.
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