Correction of Defective T-Regulatory Cells From Patients With Crohn's Disease by Ex Vivo Ligation of Retinoic Acid Receptor-α.

BACKGROUND & AIMS: Crohn's disease (CD) is characterized by an imbalance of effector and regulatory T cells in the intestinal mucosa. The efficacy of anti-adhesion therapies led us to investigate whether impaired trafficking of T-regulatory (Treg) cells contributes to the pathogenesis of CD. We also investigated whether proper function could be restored to Treg cells by ex vivo expansion in the presence of factors that activate their regulatory activities. METHODS: We measured levels of the integrin α4ß7 on Treg cells isolated from peripheral blood or lamina propria of patients with CD and healthy individuals (controls). Treg cells were expanded ex vivo and incubated with rapamycin with or without agonists of the retinoic acid receptor-α (RARA), and their gene expression profiles were analyzed. We also studied the cells in cytokine challenge, suppression, and flow chamber assays and in SCID mice with human intestinal xenografts. RESULTS: We found that Treg cells from patients with CD express lower levels of the integrin α4ß7 than Treg cells from control patients. The pathway that regulates the expression of integrin subunit α is induced by retinoic acid (RA). Treg cells from patients with CD incubated with rapamycin and an agonist of RARA (RAR568) expressed high levels of integrin α4ß7, as well as CD62L and FOXP3, compared with cells incubated with rapamycin or rapamycin and all-trans retinoic acid. These Treg cells had increased suppressive activities in assays and migrated under conditions of shear flow; they did not produce inflammatory cytokines, and RAR568 had no effect on cell stability or lineage commitment. Fluorescently labeled Treg cells incubated with RAR568 were significantly more likely to traffic to intestinal xenografts than Treg cells expanded in control medium. CONCLUSIONS: Treg cells from patients with CD express lower levels of the integrin α4ß7 than Treg cells from control patients. Incubation of patients' ex vivo expanded Treg cells with rapamycin and an RARA agonist induced expression of α4ß7 and had suppressive and migratory activities in culture and in intestinal xenografts in mice. These cells might be developed for treatment of CD. ClinicalTrials.gov, Number: NCT03185000.

Costs and Outcomes of Increasing Access to Bariatric Surgery: Cohort Study and Cost-Effectiveness Analysis Using Electronic Health Records.

OBJECTIVES: To estimate costs and outcomes of increasing access to bariatric surgery in obese adults and in population subgroups of age, sex, deprivation, comorbidity, and obesity category. METHODS: A cohort study was conducted using primary care electronic health records, with linked hospital utilization data, for 3,045 participants who underwent bariatric surgery and 247,537 participants who did not undergo bariatric surgery. Epidemiological analyses informed a probabilistic Markov model to compare bariatric surgery, including equal proportions with adjustable gastric banding, gastric bypass, and sleeve gastrectomy, with standard nonsurgical management of obesity. Outcomes were quality-adjusted life-years (QALYs) and net monetary benefits at a threshold of £30,000 per QALY. RESULTS: In a UK population of 250,000 adults, there may be 7,163 people with morbid obesity including 1,406 with diabetes. The immediate cost of 1,000 bariatric surgical procedures is £9.16 million, with incremental discounted lifetime health care costs of £15.26 million (95% confidence interval £15.18-£15.36 million). Patient-years with diabetes mellitus will decrease by 8,320 (range 8,123-8,502). Incremental QALYs will increase by 2,142 (range 2,032-2,256). The estimated cost per QALY gained is £7,129 (range £6,775-£7,506). Net monetary benefits will be £49.02 million (range £45.72-£52.41 million). Estimates are similar for subgroups of age, sex, and deprivation. Bariatric surgery remains cost-effective if the procedure is twice as costly, or if intervention effect declines over time. CONCLUSIONS: Diverse obese individuals may benefit from bariatric surgery at acceptable cost. Bariatric surgery is not cost-saving, but increased health care costs are exceeded by health benefits to obese individuals.

Effectiveness of behavioural weight loss interventions delivered in a primary care setting: a systematic review and meta-analysis.

BACKGROUND: Overweight and obesity have negative health effects. Primary care clinicians are best placed to intervene in weight management. Previous reviews of weight loss interventions have included studies from specialist settings. The aim of this review was to estimate the effect of behavioural interventions delivered in primary care on body weight in overweight and obese adults. METHODS: The review included randomized controlled trials (RCTs) of behavioural interventions in obese or overweight adult participants in a primary care setting, with weight loss as the primary outcome, and a minimum of 12 months of follow-up. A systematic search strategy was implemented in Medline, Embase, Web of Science and the Cochrane Central Registry of Controlled Trials. Risk of bias was assessed using the Cochrane Risk of Bias tool and behavioural science components of interventions were evaluated. Data relating to weight loss in kilograms were extracted, and the results combined using meta-analysis. RESULTS: Fifteen RCTs, with 4539 participants randomized, were selected for inclusion. The studies were heterogeneous with respect to inclusion criteria and type of intervention. Few studies reported interventions informed by behavioural science theory. Pooled results from meta-analysis indicated a mean weight loss of -1.36 kg (-2.10 to -0.63, P < 0.0001) at 12 months, and -1.23 kg (-2.28 to -0.18, P = 0.002) at 24 months. CONCLUSION: Behavioural weight loss interventions in primary care yield very small reductions in body weight, which are unlikely to be clinically significant. More effective management strategies are needed for the treatment of overweight and obesity.

Systematic review of prognostic factors associated with progression to late age-related macular degeneration: Pinnacle study report 2.

There is a need to identify accurately prognostic factors that determine the progression of intermediate to late-stage age-related macular degeneration (AMD). Currently, clinicians cannot provide individualised prognoses of disease progression. Moreover, enriching clinical trials with rapid progressors may facilitate delivery of shorter intervention trials aimed at delaying or preventing progression to late AMD. Thus, we performed a systematic review to outline and assess the accuracy of reporting prognostic factors for the progression of intermediate to late AMD. A meta-analysis was originally planned. Synonyms of AMD and disease progression were used to search Medline and EMBASE for articles investigating AMD progression published between 1991 and 2021. Initial search results included 3229 articles. Predetermined eligibility criteria were employed to systematically screen papers by two reviewers working independently and in duplicate. Quality appraisal and data extraction were performed by a team of reviewers. Only 6 studies met the eligibility criteria. Based on these articles, exploratory prognostic factors for progression of intermediate to late AMD included phenotypic features (e.g. location and size of drusen), age, smoking status, ocular and systemic co-morbidities, race, and genotype. Overall, study heterogeneity precluded reporting by forest plots and meta-analysis. The most commonly reported prognostic factors were baseline drusen volume/size, which was associated with progression to neovascular AMD, and outer retinal thinning linked to progression to geographic atrophy. In conclusion, poor methodological quality of included studies warrants cautious interpretation of our findings. Rigorous studies are warranted to provide robust evidence in the future.

Metadata-enhanced contrastive learning from retinal optical coherence tomography images.

Deep learning has potential to automate screening, monitoring and grading of disease in medical images. Pretraining with contrastive learning enables models to extract robust and generalisable features from natural image datasets, facilitating label-efficient downstream image analysis. However, the direct application of conventional contrastive methods to medical datasets introduces two domain-specific issues. Firstly, several image transformations which have been shown to be crucial for effective contrastive learning do not translate from the natural image to the medical image domain. Secondly, the assumption made by conventional methods, that any two images are dissimilar, is systematically misleading in medical datasets depicting the same anatomy and disease. This is exacerbated in longitudinal image datasets that repeatedly image the same patient cohort to monitor their disease progression over time. In this paper we tackle these issues by extending conventional contrastive frameworks with a novel metadata-enhanced strategy. Our approach employs widely available patient metadata to approximate the true set of inter-image contrastive relationships. To this end we employ records for patient identity, eye position (i.e. left or right) and time series information. In experiments using two large longitudinal datasets containing 170,427 retinal optical coherence tomography (OCT) images of 7912 patients with age-related macular degeneration (AMD), we evaluate the utility of using metadata to incorporate the temporal dynamics of disease progression into pretraining. Our metadata-enhanced approach outperforms both standard contrastive methods and a retinal image foundation model in five out of six image-level downstream tasks related to AMD. We find benefits in both a low-data and high-data regime across tasks ranging from AMD stage and type classification to prediction of visual acuity. Due to its modularity, our method can be quickly and cost-effectively tested to establish the potential benefits of including available metadata in contrastive pretraining.

A smoking cessation smartphone app that delivers real-time 'context aware' behavioural support: the Quit Sense feasibility RCT.

Background: During a quit attempt, cues from a smoker's environment are a major cause of brief smoking lapses, which increase the risk of relapse. Quit Sense is a theory-guided Just-In-Time Adaptive Intervention smartphone app, providing smokers with the means to learn about their environmental smoking cues and provides 'in the moment' support to help them manage these during a quit attempt. Objective: To undertake a feasibility randomised controlled trial to estimate key parameters to inform a definitive randomised controlled trial of Quit Sense. Design: A parallel, two-arm randomised controlled trial with a qualitative process evaluation and a 'Study Within A Trial' evaluating incentives on attrition. The research team were blind to allocation except for the study statistician, database developers and lead researcher. Participants were not blind to allocation. Setting: Online with recruitment, enrolment, randomisation and data collection (excluding manual telephone follow-up) automated through the study website. Participants: Smokers (323 screened, 297 eligible, 209 enrolled) recruited via online adverts on Google search, Facebook and Instagram. Interventions: Participants were allocated to 'usual care' arm (n = 105; text message referral to the National Health Service SmokeFree website) or 'usual care' plus Quit Sense (n = 104), via a text message invitation to install the Quit Sense app. Main outcome measures: Follow-up at 6 weeks and 6 months post enrolment was undertaken by automated text messages with an online questionnaire link and, for non-responders, by telephone. Definitive trial progression criteria were met if a priori thresholds were included in or lower than the 95% confidence interval of the estimate. Measures included health economic and outcome data completion rates (progression criterion #1 threshold: ≥ 70%), including biochemical validation rates (progression criterion #2 threshold: ≥ 70%), recruitment costs, app installation (progression criterion #3 threshold: ≥ 70%) and engagement rates (progression criterion #4 threshold: ≥ 60%), biochemically verified 6-month abstinence and hypothesised mechanisms of action and participant views of the app (qualitative). Results: Self-reported smoking outcome completion rates were 77% (95% confidence interval 71% to 82%) and health economic data (resource use and quality of life) 70% (95% CI 64% to 77%) at 6 months. Return rate of viable saliva samples for abstinence verification was 39% (95% CI 24% to 54%). The per-participant recruitment cost was £19.20, which included advert (£5.82) and running costs (£13.38). In the Quit Sense arm, 75% (95% CI 67% to 83%; 78/104) installed the app and, of these, 100% set a quit date within the app and 51% engaged with it for more than 1 week. The rate of 6-month biochemically verified sustained abstinence, which we anticipated would be used as a primary outcome in a future study, was 11.5% (12/104) in the Quit Sense arm and 2.9% (3/105) in the usual care arm (estimated effect size: adjusted odds ratio = 4.57, 95% CIs 1.23 to 16.94). There was no evidence of between-arm differences in hypothesised mechanisms of action. Three out of four progression criteria were met. The Study Within A Trial analysis found a £20 versus £10 incentive did not significantly increase follow-up rates though reduced the need for manual follow-up and increased response speed. The process evaluation identified several potential pathways to abstinence for Quit Sense, factors which led to disengagement with the app, and app improvement suggestions. Limitations: Biochemical validation rates were lower than anticipated and imbalanced between arms. COVID-19-related restrictions likely limited opportunities for Quit Sense to provide location tailored support. Conclusions: The trial design and procedures demonstrated feasibility and evidence was generated supporting the efficacy potential of Quit Sense. Future work: Progression to a definitive trial is warranted providing improved biochemical validation rates. Trial registration: This trial is registered as ISRCTN12326962. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (NIHR award ref: 17/92/31) and is published in full in Public Health Research; Vol. 12, No. 4. See the NIHR Funding and Awards website for further award information.

Smokers often fail to quit because of urges to smoke triggered by their surroundings (e.g. being around smokers). We developed a smartphone app ('Quit Sense') which learns about an individual's surroundings and locations where they smoke. During a quit attempt, Quit Sense uses in-built sensors to identify when smokers are in those locations and sends 'in the moment' advice to help prevent them from smoking. We ran a feasibility study to help plan for a future large study to see if Quit Sense helps smokers to quit. This feasibility study was designed to tell us how many participants complete study measures; recruitment costs; how many participants install and use Quit Sense; and estimate whether Quit Sense may help smokers to stop and how it might do this. We recruited 209 smokers using online adverts on Google search, Facebook and Instagram, costing £19 per participant. Participants then had an equal chance of receiving a web link to the National Health Service SmokeFree website ('usual care group') or receive that same web link plus a link to the Quit Sense app ('Quit Sense group'). Three-quarters of the Quit Sense group installed the app on their phone and half of these used the app for more than 1 week. We followed up 77% of participants at 6 months to collect study data, though only 39% of quitters returned a saliva sample for abstinence verification. At 6 months, more people in the Quit Sense group had stopped smoking (12%) than the usual care group (3%). It was not clear how the app helped smokers to quit based on study measures, though interviews found that the process of training the app helped people quit through learning about what triggered their smoking behaviour. The findings support undertaking a large study to tell us whether Quit Sense really does help smokers to quit.

Developing and validating a multivariable prediction model which predicts progression of intermediate to late age-related macular degeneration-the PINNACLE trial protocol.

AIMS: Age-related macular degeneration (AMD) is characterised by a progressive loss of central vision. Intermediate AMD is a risk factor for progression to advanced stages categorised as geographic atrophy (GA) and neovascular AMD. However, rates of progression to advanced stages vary between individuals. Recent advances in imaging and computing technologies have enabled deep phenotyping of intermediate AMD. The aim of this project is to utilise machine learning (ML) and advanced statistical modelling as an innovative approach to discover novel features and accurately quantify markers of pathological retinal ageing that can individualise progression to advanced AMD. METHODS: The PINNACLE study consists of both retrospective and prospective parts. In the retrospective part, more than 400,000 optical coherent tomography (OCT) images collected from four University Teaching Hospitals and the UK Biobank Population Study are being pooled, centrally stored and pre-processed. With this large dataset featuring eyes with AMD at various stages and healthy controls, we aim to identify imaging biomarkers for disease progression for intermediate AMD via supervised and unsupervised ML. The prospective study part will firstly characterise the progression of intermediate AMD in patients followed between one and three years; secondly, it will validate the utility of biomarkers identified in the retrospective cohort as predictors of progression towards late AMD. Patients aged 55-90 years old with intermediate AMD in at least one eye will be recruited across multiple sites in UK, Austria and Switzerland for visual function tests, multimodal retinal imaging and genotyping. Imaging will be repeated every four months to identify early focal signs of deterioration on spectral-domain optical coherence tomography (OCT) by human graders. A focal event triggers more frequent follow-up with visual function and imaging tests. The primary outcome is the sensitivity and specificity of the OCT imaging biomarkers. Secondary outcomes include sensitivity and specificity of novel multimodal imaging characteristics at predicting disease progression, ROC curves, time from development of imaging change to development of these endpoints, structure-function correlations, structure-genotype correlation and predictive risk models. CONCLUSIONS: This is one of the first studies in intermediate AMD to combine both ML, retrospective and prospective AMD patient data with the goal of identifying biomarkers of progression and to report the natural history of progression of intermediate AMD with multimodal retinal imaging.

Protocol for the OUTREACH trial: a randomised trial comparing delivery of cancer systemic therapy in three different settings: patient's home, GP surgery and hospital day unit.

BACKGROUND: The national Cancer Reform Strategy recommends delivering care closer to home whenever possible. Cancer drug treatment has traditionally been administered to patients in specialist hospital-based facilities. Technological developments mean that nowadays, most treatment can be delivered in the out-patient setting. Increasing demand, care quality improvements and patient choice have stimulated interest in delivering some treatment to patients in the community, however, formal evaluation of delivering cancer treatment in different community settings is lacking. This randomised trial compares delivery of cancer treatment in the hospital with delivery in two different community settings: the patient's home and general practice (GP) surgeries. METHODS/DESIGN: Patients due to receive a minimum 12 week course of standard intravenous cancer treatment at two hospitals in the Anglia Cancer Network are randomised on a 1:1:1 basis to receive treatment in the hospital day unit (control arm), or their own home, or their choice of one of three neighbouring GP surgeries. Overall patient care, treatment prescribing and clinical review is undertaken according to standard local practice. All treatment is dispensed by the local hospital pharmacy and treatment is delivered by the hospital chemotherapy nurses. At four time points during the 12 week study period, information is collected from patients, nursing staff, primary and secondary care teams to address the primary end point, patient-perceived benefits (using the emotional function domain of the EORTC QLQC30 patient questionnaire), as well as secondary end points: patient satisfaction, safety and health economics. DISCUSSION: The Outreach trial is the first randomised controlled trial conducted which compares delivery of out-patient based intravenous cancer treatment in two different community settings with standard hospital based treatment. Results of this study may better inform all key stakeholders regarding potential costs and benefits of transferring clinical services from hospital to the community. TRIAL REGISTRATION NUMBER: ISRCTN: ISRCTN66219681.

Hospitalisation among patients with diabetes associated with a Diabetes Integrated Care Initiative: a mixed methods case study.

Integrated care has been postulated to result in improvements to diabetes outcomes, including reduced hospitalisation. The Diabetes Integrated Care Initiative (DICI) aimed to integrate primary, secondary and community diabetes care in East Cambridgeshire and Fenland (ECF). The aims of this study were to describe changes in care and hospitalisation rates over the first 3 years of the initiative, 2009-2012. The evaluation involved a mixed-methods approach, including a before-after design with controls from adjacent geographical areas and from patients without diabetes, alongside a 30-month ethnographic study including interviews with patients and health professionals. Over the three years, admission rates among patients with diabetes in the intervention area continued to grow. In fact, the increases in admissions in ECF were 7.4% (95% CI 5.2-9.2) and 45.5% (95% CI 42.5-48.5) greater than in the neighbouring areas of Huntingdonshire and Greater Cambridge, respectively. The rates of increase in diabetic foot, non-elective or other hospital admissions were not reduced. In summary, the DICI was not associated with improved diabetes care or reduced diabetes hospitalisation over the 3 years studied, despite substantial investment. While the principle of integration remains an ideal, linking different providers in ECF, especially those that are positioned between primary and secondary care, created barriers rather than bridges to better diabetes outcomes.

Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT): urinary screening and baseline biochemical and cardiovascular assessments.

OBJECTIVE: We assessed the association between early increases in albumin excretion and cardiovascular (CV) and renal markers in a large cohort of young people with type 1 diabetes. RESEARCH DESIGN AND METHODS: As part of preliminary screening for a multicenter, randomized controlled trial of statins/ACE inhibitors, we measured albumin-creatinine ratio (ACR) in six early morning urine samples from 3,353 adolescents (10-16 years of age) and calculated tertiles based on an established algorithm. From those subjects deemed to be at higher risk (upper ACR tertile), we recruited 400 into the intervention study (trial cohort). From those subjects deemed to be at lower risk (middle-lower ACR tertiles), we recruited 329 to the observation cohort. At baseline, vascular measurements (carotid intima-media thickness, pulse wave velocity [PWV], flow-mediated dilatation, digital pulse amplitude tonometry), renal markers (symmetric dimethylarginine, cystatin C, creatinine), and CV disease markers (lipids and apolipoproteins [Apo] A-1 and B, C-reactive protein, asymmetric dimethylarginine) were assessed. RESULTS: Age- and sex-adjusted PWV was higher in the trial than in the observational cohort (5.00 ± 0.84 vs. 4.86 ± 0.70 m/s; P = 0.021). Similarly, non-HDL cholesterol (2.95 ± 0.83 vs. 2.81 ± 0.78 mmol/L; P = 0.02) and ApoB-ApoA-1 ratio (0.50 ± 0.14 vs. 0.47 ± 0.11; P = 0.04) were higher in the trial cohort. Cystatin C and creatinine were decreased (0.88 ± 0.13 vs. 0.90 ± 0.13 mg/L, P = 0.04; 51.81 ± 10.45 vs. 55.35 ± 11.05 µmol/L, P < 0.001; respectively) and estimated glomerular filtration rate (137.05 ± 23.89 vs. 129.31 ± 22.41 mL/min/1.73 m(2); P < 0.001) increased in the trial compared with the observational cohort. CONCLUSIONS: Our data demonstrate that in adolescents with type 1 diabetes, the group with the highest tertile of albumin excretion showed more evidence of early renal and CV disease than those in the lower tertiles.

Incidence of type 2 diabetes after bariatric surgery: population-based matched cohort study.

BACKGROUND: The effect of currently used bariatric surgical procedures on the development of diabetes in obese people is not well defined. We aimed to assess the effect of bariatric surgery on development of type 2 diabetes in a large population of obese individuals. METHODS: We did a matched cohort study of adults (age 20­100 years) identified from a UK-wide database of family practices, who were obese (BMI ≥30 kg/m2) and did not have diabetes. We enrolled 2167 patients who had undergone bariatric surgery between Jan 1, 2002, and April 30, 2014, and matched them--according to BMI, age, sex, index year, and HbA1c--with 2167 controls who had not had surgery. Procedures included laparoscopic gastric banding (n=1053), gastric bypass (795), and sleeve gastrectomy (317), with two procedures undefined. The primary outcome was development of clinical diabetes, which we extracted from electronic health records. Analyses were adjusted for matching variables, comorbidity, cardiovascular risk factors, and use of antihypertensive and lipid-lowering drugs. FINDINGS: During a maximum of 7 years of follow-up (median 2·8 years [IQR 1·3­4·5]), 38 new diagnoses of diabetes were made in bariatric surgery patients and 177 were made in controls. By the end of 7 years of follow-up, 4·3% (95% CI 2·9­6·5) of bariatric surgery patients and 16·2% (13·3­19·6) of matched controls had developed diabetes. The incidence of diabetes diagnosis was 28·2 (95% CI 24·4­32·7) per 1000 person-years in controls and 5·7 (4·2­7·8) per 1000 person-years in bariatric surgery patients; the adjusted hazard ratio was 0·20 (95% CI 0·13­0·30, p<0·0001). This estimate was robust after varying the comparison group in sensitivity analyses, excluding gestational diabetes, or allowing for competing mortality risk. INTERPRETATION: Bariatric surgery is associated with reduced incidence of clinical diabetes in obese participants without diabetes at baseline for up to 7 years after the procedure. FUNDING: UK National Institute for Health Research.

Developmental changes in cochlear orientation--implications for cochlear implantation.

OBJECTIVES: To investigate changes in cochlear orientation with age and discuss the implications of any change with respect to cochlear implantation. STUDY DESIGN: Cross-sectional study of computed tomographic scans of the temporal bones in patients with no congenital abnormalities. PATIENTS: One hundred fifty-nine patients were included in the study, making a total of 318 ears. The age range was 9 months to 85 years. INTERVENTION: Axial computed tomographic scans showing the basal turn of the cochlea were identified. The angle of the basal turn of the cochlea was measured by drawing a line through the long axis of the basal turn and measuring its angle with a line drawn through the midsagittal plane. The patients were grouped according to age, and a 1-way analysis of variance was used to identify any statistically significant change in basal turn angulation. Interobserver and intraobserver errors were calculated and presented as repeatability coefficients. The basal turn angles of 3 difficult cases of cochlear implantation were related to the findings. RESULTS: The mean basal turn angle was 54.6 degrees (range, 46.8-63.8 degrees; standard deviation, 3.5). There was a statistically significant reduction in the angulation of the basal turn with increasing age (F = 10.1; p = 0.002). The majority of the change occurs between the ages of 11 and 15 years. The interobserver reliability coefficient was 4.8. The intraobserver reliability coefficient was 2.0. The 3 difficult cases had basal turn angles that were at the upper limit of the reference range. CONCLUSION: There is a statistically significant reduction in basal turn angulation relative to the midsagittal plane with increasing age. However, care should be taken in interpreting these results in light of the inherent error in the measuring technique, although the intraobserver repeatability coefficient was only 2.0. The more obtuse angulation of the basal turn in children may have implications for cochlear implantation.