An Industry Perspective on the use of Forced Degradation Studies to Assess Comparability of Biopharmaceuticals.

Forced degradation, also known as stress testing, is used throughout pharmaceutical development for many purposes including assessing the comparability of biopharmaceutical products according to ICH Guideline Q5E. These formal comparability studies, the results of which are submitted to health authorities, investigate potential impacts of manufacturing process changes on the quality, safety, and efficacy of the drug. Despite the wide use of forced degradation in comparability assessments, detailed guidance on the design and interpretation of such studies is scarce. The BioPhorum Development Group is an industry-wide consortium enabling networking and sharing of common practices for the development of biopharmaceuticals. The BioPhorum Development Group Forced Degradation Workstream recently conducted several group discussions and a benchmarking survey to understand current industry approaches for the use of forced degradation studies to assess comparability of protein-based biopharmaceuticals. The results provide insight into the design of forced degradation studies, analytical characterization and testing strategies, data evaluation criteria, as well as some considerations and differences for non-platform modalities (e.g., non-traditional mAbs). This article presents survey responses from several global companies of various sizes and provides an industry perspective and experience regarding the practicalities of using forced degradation to assess comparability.

Understanding the uptake of virtual care for first and return outpatient appointments in child and adolescent mental health services: a mixed-methods study.

OBJECTIVE: To describe patterns of virtual and in-person outpatient mental health service use and factors that may influence the choice of modality in a child and adolescent service. DESIGN: A pragmatic mixed-methods approach using routinely collected administrative data between 1 April 2020 and 31 March 2022 and semi-structured interviews with clients, caregivers, clinicians and staff. Interview data were coded according to the Consolidated Framework for Implementation Research (CFIR) and examined for patterns of similarity or divergence across data sources, respondents or other relevant characteristics. SETTING: Child and adolescent outpatient mental health service, Nova Scotia, Canada. PARTICIPANTS: IWK Health clinicians and staff who had participated in virtual mental healthcare following its implementation in March 2020 and clients (aged 12-18 years) and caregivers of clients (aged 3-18 years) who had received treatment from an IWK outpatient clinic between 1 April 2020 and 31 March 2022 (n=1300). Participants (n=48) in semi-structured interviews included nine clients aged 13-18 years (mean 15.7 years), 10 caregivers of clients aged 5-17 years (mean 12.7 years), eight Community Mental Health and Addictions booking and registration or administrative staff and 21 clinicians. RESULTS: During peak pandemic activity, upwards of 90% of visits (first or return) were conducted virtually. Between waves, return appointments were more likely to be virtual than first appointments. Interview participants (n=48) reported facilitators and barriers to virtual care within the CFIR domains of 'outer setting' (eg, external policies, client needs and resources), 'inner setting' (eg, communications within the service), 'individual characteristics' (eg, personal attributes, knowledge and beliefs about virtual care) and 'intervention characteristics' (eg, relative advantage of virtual or in-person care). CONCLUSIONS: Shared decision-making regarding treatment modality (virtual vs in-person) requires consideration of client, caregiver, clinician, appointment, health system and public health factors across episodes of care to ensure accessible, safe and high-quality mental healthcare.

Preliminary clinical and cost effectiveness of augmented depression therapy versus cognitive behavioural therapy for the treatment of anhedonic depression (ADepT): a single-centre, open-label, parallel-group, pilot, randomised, controlled trial.

Background: Anhedonia (reduced interest/pleasure) symptoms and wellbeing deficits are core to depression and predict a poor prognosis. Current depression psychotherapies fail to target these features adequately, contributing to sub-optimal outcomes. Augmented Depression Therapy (ADepT) has been developed to target anhedonia and wellbeing. We aimed to establish clinical and economic proof of concept for ADepT and to examine feasibility of a future definitive trial comparing ADepT to Cognitive Behavioural Therapy (CBT). Methods: In this single-centre, open-label, parallel-group, pilot randomised controlled trial, adults meeting diagnostic criteria for a current major depressive episode, scoring ≥10 on the Patient Health Questionnaire (PHQ-9) and exhibiting anhedonic features (PHQ-9 item 1 ≥ 2) were recruited primarily from high intensity Improving Access to Psychological Therapy (IAPT) service waiting lists in Devon, UK. Participants were randomised to receive 20 sessions of CBT or ADepT, using a mimimisation algorithm to balance depression severity and antidepressant use between groups. Treatment was delivered in an out-patient university-based specialist mood disorder clinic. Researcher-blinded assessments were completed at intake and six, 12, and 18 months. Co-primary outcomes were depression (PHQ-9) and wellbeing (Warwick Edinburgh Mental Wellbeing Scale) at 6 months. Primary clinical proof-of-concept analyses were intention to treat. Feasibility (including safety) and health economic analyses used complete case data. This trial is registered at the ISRCTN registry, ISRCTN85278228. Findings: Between 3/29/2017 and 7/31/2018, 82 individuals were recruited (102% of target sample) and 41 individuals were allocated to each arm. A minimum adequate treatment dose was completed by 36/41 (88%) of CBT and 35/41 (85%) of ADepT participants. There were two serious adverse events in each arm (primarily suicide attempts; none of which were judged to be trial- or treatment-related), with no other evidence of harms. Intake and six-month primary outcome data was available for 37/41 (90%) CBT participants and 32/41 (78%) ADepT participants. Between-group effects favoured ADepT over CBT for depression (meanΔ = -1.35, 95% CI = -3.70, 1.00, d = 0.23) and wellbeing (meanΔ = 2.64, 95% CI = -1.71, 6.99, d = 0.27). At 18 months, the advantage of ADepT over CBT was preserved and ADepT had a >80% probability of cost-effectiveness. Interpretation: These findings provide proof of concept for ADepT and warrant continuation to definitive trial. Funding: NIHR Career Development Fellowship.

Protocol for a pragmatic cluster randomised controlled trial assessing the clinical effectiveness and cost-effectiveness of Electronic RIsk-assessment for CAncer for patients in general practice (ERICA).

INTRODUCTION: The UK has worse cancer outcomes than most comparable countries, with a large contribution attributed to diagnostic delay. Electronic risk assessment tools (eRATs) have been developed to identify primary care patients with a ≥2% risk of cancer using features recorded in the electronic record. METHODS AND ANALYSIS: This is a pragmatic cluster randomised controlled trial in English primary care. Individual general practices will be randomised in a 1:1 ratio to intervention (provision of eRATs for six common cancer sites) or to usual care. The primary outcome is cancer stage at diagnosis, dichotomised to stage 1 or 2 (early) or stage 3 or 4 (advanced) for these six cancers, assessed from National Cancer Registry data. Secondary outcomes include stage at diagnosis for a further six cancers without eRATs, use of urgent referral cancer pathways, total practice cancer diagnoses, routes to cancer diagnosis and 30-day and 1-year cancer survival. Economic and process evaluations will be performed along with service delivery modelling. The primary analysis explores the proportion of patients with early-stage cancer at diagnosis. The sample size calculation used an OR of 0.8 for a cancer being diagnosed at an advanced stage in the intervention arm compared with the control arm, equating to an absolute reduction of 4.8% as an incidence-weighted figure across the six cancers. This requires 530 practices overall, with the intervention active from April 2022 for 2 years. ETHICS AND DISSEMINATION: The trial has approval from London City and East Research Ethics Committee, reference number 19/LO/0615; protocol version 5.0, 9 May 2022. It is sponsored by the University of Exeter. Dissemination will be by journal publication, conferences, use of appropriate social media and direct sharing with cancer policymakers. TRIAL REGISTRATION NUMBER: ISRCTN22560297.

Improving the repeatability of deep learning models with Monte Carlo dropout.

The integration of artificial intelligence into clinical workflows requires reliable and robust models. Repeatability is a key attribute of model robustness. Ideal repeatable models output predictions without variation during independent tests carried out under similar conditions. However, slight variations, though not ideal, may be unavoidable and acceptable in practice. During model development and evaluation, much attention is given to classification performance while model repeatability is rarely assessed, leading to the development of models that are unusable in clinical practice. In this work, we evaluate the repeatability of four model types (binary classification, multi-class classification, ordinal classification, and regression) on images that were acquired from the same patient during the same visit. We study the each model's performance on four medical image classification tasks from public and private datasets: knee osteoarthritis, cervical cancer screening, breast density estimation, and retinopathy of prematurity. Repeatability is measured and compared on ResNet and DenseNet architectures. Moreover, we assess the impact of sampling Monte Carlo dropout predictions at test time on classification performance and repeatability. Leveraging Monte Carlo predictions significantly increases repeatability, in particular at the class boundaries, for all tasks on the binary, multi-class, and ordinal models leading to an average reduction of the 95% limits of agreement by 16% points and of the class disagreement rate by 7% points. The classification accuracy improves in most settings along with the repeatability. Our results suggest that beyond about 20 Monte Carlo iterations, there is no further gain in repeatability. In addition to the higher test-retest agreement, Monte Carlo predictions are better calibrated which leads to output probabilities reflecting more accurately the true likelihood of being correctly classified.

Digital Facilitation to Support Patient Access to Web-Based Primary Care Services: Scoping Literature Review.

BACKGROUND: The use of web-based services within primary care (PC) in the National Health Service in England is increasing, with medically underserved populations being less likely to engage with web-based services than other patient groups. Digital facilitation-referring to a range of processes, procedures, and personnel that seek to support patients in the uptake and use of web-based services-may be a way of addressing these challenges. However, the models and impact of digital facilitation currently in use are unclear. OBJECTIVE: This study aimed to identify, characterize, and differentiate between different approaches to digital facilitation in PC; establish what is known about the effectiveness of different approaches; and understand the enablers of digital facilitation. METHODS: Adopting scoping review methodology, we searched academic databases (PubMed, EMBASE, CINAHL, Web of Science, and Cochrane Library) and gray literature published between 2015 and 2020. We conducted snowball searches of reference lists of included articles and articles identified during screening as relevant to digital facilitation, but which did not meet the inclusion criteria because of article type restrictions. Titles and abstracts were independently screened by 2 reviewers. Data from eligible studies were analyzed using a narrative synthesis approach. RESULTS: A total of 85 publications were included. Most (71/85, 84%) were concerned with digital facilitation approaches targeted at patients (promotion of services, training patients to improve their technical skills, or other guidance and support). Further identified approaches targeted PC staff to help patients (eg, improving staff knowledge of web-based services and enhancing their technical or communication skills). Qualitative evidence suggests that some digital facilitation may be effective in promoting the uptake and use of web-based services by patients (eg, recommendation of web-based services by practice staff and coaching). We found little evidence that providing patients with initial assistance in registering for or accessing web-based services leads to increased long-term use. Few studies have addressed the effects of digital facilitation on health care inequalities. Those that addressed this suggested that providing technical training for patients could be effective, at least in part, in reducing inequalities, although not entirely. Factors affecting the success of digital facilitation include perceptions of the usefulness of the web-based service, trust in the service, patients' trust in providers, the capacity of PC staff, guidelines or regulations supporting facilitation efforts, and staff buy-in and motivation. CONCLUSIONS: Digital facilitation has the potential to increase the uptake and use of web-based services by PC patients. Understanding the approaches that are most effective and cost-effective, for whom, and under what circumstances requires further research, including rigorous evaluations of longer-term impacts. As efforts continue to increase the use of web-based services in PC in England and elsewhere, we offer an early typology to inform conceptual development and evaluations. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42020189019; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=189019.

Health Equity and Disparities in ROP Care: A Need for Systematic Evaluation.

Retinopathy of prematurity (ROP) is a vasoproliferative retinal disorder that can have devastating visual sequelae if not managed appropriately. From an ophthalmology standpoint, ROP care is complex, since it spans multiple care settings and providers, including those in the neonatal intensive care unit (NICU), step down nurseries, and the outpatient clinic setting. This requires coordination and communication between providers, ancillary staff, and most importantly, effective communication with the patient's family members and caregivers. Often, factors related to the social determinants of health play a significant role in effective communication and care coordination with the family, and it is important for ophthalmologists to recognize these risk factors. The aim of this article is to (1) review the literature related to disparities in preterm birth outcomes and infants at risk for ROP; (2) identify barriers to ROP care and appropriate follow up, and (3) describe patient-oriented solutions and future directions for improving ROP care through a health equity lens.

The epidemiology and economics of pooled testing for disease investigations of lead exposure involving beef cattle in Saskatchewan (2007-2019).

From 2007 to 2019, the Western College of Veterinary Medicine Disease Investigation Unit conducted lead investigations in 12 beef cow-calf herds and tested 1104 presumed exposed but clinically unaffected cattle, 49 of which were unsafe for slaughter (blood lead ≥ 0.1 ppm). In all investigations, the lead source should be evaluated, and all potentially exposed animals intended for food should be tested. Clinically affected animals should be tested individually. Individual testing of clinically unaffected animals may be expensive for large groups. However, pooling a conservative number of blood samples (n = 2 to 5) from clinically unaffected cattle may efficiently identify groups that are safe for slaughter. If a pooled test produces a blood lead concentration over the minimum threshold (0.1 ppm/n), these samples should be individually re-tested. Herd size, lead toxicity prevalence, pool size, and number of pools that require individual re-testing all affect the potential cost savings of pooled testing.

L'épidémiologie et l'économie des tests d'échantillons groupés pour les enquêtes sur les maladies d'exposition au plomb chez les bovins de boucherie en Saskatchewan (2007­2019). De 2007 à 2019, l'Unité d'investigation des maladies du Western College of Veterinary Medicine a mené des enquêtes sur le plomb dans 12 troupeaux de vaches-veaux de boucherie et a testé 1104 bovins présumés exposés mais cliniquement non affectés, dont 49 étaient dangereux pour l'abattage (plomb sanguin ≥ 0,1 ppm). Dans toutes les enquêtes, la source de plomb doit être évaluée et tous les animaux potentiellement exposés destinés à l'alimentation doivent être testés. Les animaux cliniquement atteints doivent être testés individuellement. Les tests individuels d'animaux cliniquement indemnes peuvent être coûteux pour les grands groupes. Cependant, le regroupement d'un nombre prudent d'échantillons de sang (n = 2 à 5) provenant de bovins cliniquement indemnes peut identifier efficacement les groupes qui sont sans danger pour l'abattage. Si un test groupé produit une concentration sanguine de plomb supérieure au seuil minimum (0,1 ppm/n), ces échantillons doivent être retestés individuellement. La taille du troupeau, la prévalence de la toxicité du plomb, la taille du pool et le nombre de pools qui nécessitent un nouveau test individuel affectent tous les économies de coûts potentielles des tests groupés.(Traduit par Dr Serge Messier).

Adding web-based behavioural support to exercise referral schemes for inactive adults with chronic health conditions: the e-coachER RCT.

BACKGROUND: There is modest evidence that exercise referral schemes increase physical activity in inactive individuals with chronic health conditions. There is a need to identify additional ways to improve the effects of exercise referral schemes on long-term physical activity. OBJECTIVES: To determine if adding the e-coachER intervention to exercise referral schemes is more clinically effective and cost-effective in increasing physical activity after 1 year than usual exercise referral schemes. DESIGN: A pragmatic, multicentre, two-arm randomised controlled trial, with a mixed-methods process evaluation and health economic analysis. Participants were allocated in a 1 : 1 ratio to either exercise referral schemes plus e-coachER (intervention) or exercise referral schemes alone (control). SETTING: Patients were referred to exercise referral schemes in Plymouth, Birmingham and Glasgow. PARTICIPANTS: There were 450 participants aged 16-74 years, with a body mass index of 30-40 kg/m2, with hypertension, prediabetes, type 2 diabetes, lower limb osteoarthritis or a current/recent history of treatment for depression, who were also inactive, contactable via e-mail and internet users. INTERVENTION: e-coachER was designed to augment exercise referral schemes. Participants received a pedometer and fridge magnet with physical activity recording sheets, and a user guide to access the web-based support in the form of seven 'steps to health'. e-coachER aimed to build the use of behavioural skills (e.g. self-monitoring) while strengthening favourable beliefs in the importance of physical activity, competence, autonomy in physical activity choices and relatedness. All participants were referred to a standard exercise referral scheme. PRIMARY OUTCOME MEASURE: Minutes of moderate and vigorous physical activity in ≥ 10-minute bouts measured by an accelerometer over 1 week at 12 months, worn ≥ 16 hours per day for ≥ 4 days including ≥ 1 weekend day. SECONDARY OUTCOMES: Other accelerometer-derived physical activity measures, self-reported physical activity, exercise referral scheme attendance and EuroQol-5 Dimensions, five-level version, and Hospital Anxiety and Depression Scale scores were collected at 4 and 12 months post randomisation. RESULTS: Participants had a mean body mass index of 32.6 (standard deviation) 4.4 kg/m2, were referred primarily for weight loss and were mostly confident self-rated information technology users. Primary outcome analysis involving those with usable data showed a weak indicative effect in favour of the intervention group (n = 108) compared with the control group (n = 124); 11.8 weekly minutes of moderate and vigorous physical activity (95% confidence interval -2.1 to 26.0 minutes; p = 0.10). Sixty-four per cent of intervention participants logged on at least once; they gave generally positive feedback on the web-based support. The intervention had no effect on other physical activity outcomes, exercise referral scheme attendance (78% in the control group vs. 75% in the intervention group) or EuroQol-5 Dimensions, five-level version, or Hospital Anxiety and Depression Scale scores, but did enhance a number of process outcomes (i.e. confidence, importance and competence) compared with the control group at 4 months, but not at 12 months. At 12 months, the intervention group incurred an additional mean cost of £439 (95% confidence interval -£182 to £1060) compared with the control group, but generated more quality-adjusted life-years (mean 0.026, 95% confidence interval 0.013 to 0.040), with an incremental cost-effectiveness ratio of an additional £16,885 per quality-adjusted life-year. LIMITATIONS: A significant proportion (46%) of participants were not included in the primary analysis because of study withdrawal and insufficient device wear-time, so the results must be interpreted with caution. The regression model fit for the primary outcome was poor because of the considerable proportion of participants [142/243 (58%)] who recorded no instances of ≥ 10-minute bouts of moderate and vigorous physical activity at 12 months post randomisation. FUTURE WORK: The design and rigorous evaluation of cost-effective and scalable ways to increase exercise referral scheme uptake and maintenance of moderate and vigorous physical activity are needed among patients with chronic conditions. CONCLUSIONS: Adding e-coachER to usual exercise referral schemes had only a weak indicative effect on long-term rigorously defined, objectively assessed moderate and vigorous physical activity. The provision of the e-coachER support package led to an additional cost and has a 63% probability of being cost-effective based on the UK threshold of £30,000 per quality-adjusted life-year. The intervention did improve some process outcomes as specified in our logic model. TRIAL REGISTRATION: Current Controlled Trials ISRCTN15644451. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 63. See the NIHR Journals Library website for further project information.

When health-care professionals refer patients with chronic conditions to an exercise referral scheme, the effects on long-term increases in physical activity are limited. We therefore developed the e-coachER support package to add to usual exercise referral schemes and to prompt the use of skills such as self-monitoring and goal-setting. This package was also intended to empower patients to increase their levels of physical activity long term. The seven-step programme was delivered online (via an interactive website). As part of the package, we mailed participants a guide for accessing the online programme, a pedometer and a fridge magnet with a notepad to record physical activity. We aimed to determine whether or not adding the e-coachER support to usual exercise referral schemes resulted in lasting changes in moderate and vigorous physical activity and whether or not it offers good value for money compared with exercise referral schemes alone. A total of 450 inactive individuals were recruited across Plymouth, Birmingham and Glasgow and were referred to an exercise referral scheme for the following participant-reported main reasons: weight loss (50%), low mood (19%), osteoarthritis (12%), type 2 diabetes (10%) and high blood pressure (8%). Half of the individuals were given access to the e-coachER support and the other half were not. All individuals were mailed a wrist-worn movement sensor (accelerometer) to wear for 1 week and a survey to assess other outcomes at the start of the study as well as at 4 and 12 months post randomisation. At the start of the study, the participants were inactive and most had multiple health conditions. The participants had an average body mass index of 33 kg/m² and an average age of 50 years. Most (83%) were white. Participants with access to e-coachER support were only slightly more active at 12 months than those who did not have access, but we cannot be confident in the findings because we had data from fewer participants than planned. The lack of a clear effect may have been as a result of around one-third of participants not accessing the website, but otherwise there was reasonable engagement. The provision of the e-coachER support package led to an additional cost of £439 per participant over a 12-month period.

Randomised feasibility trial and embedded qualitative process evaluation of a new intervention to facilitate the involvement of older patients with multimorbidity in decision-making about their healthcare during general practice consultations: the VOLITION study protocol.

BACKGROUND: The number of older people with multiple health problems is increasing worldwide. This creates a strain on clinicians and the health service when delivering clinical care to this patient group, who themselves carry a large treatment burden. Despite shared decision-making being acknowledged by healthcare organisations as a priority feature of clinical care, older patients with multimorbidity are less often involved in decision-making when compared with younger patients, with some evidence suggesting associated health inequalities. Interventions aimed at facilitating shared decision-making between doctors and patients are outdated in their assessments of today's older patient population who need support in prioritising complex care needs in order to maximise quality of life and day-to-day function. AIMS: To undertake feasibility testing of an intervention ('VOLITION') aimed at facilitating the involvement of older patients with more than one long-term health problem in shared decision-making about their healthcare during GP consultations.To inform the design of a fully powered trial to assess intervention effectiveness. METHODS: This study is a cluster randomised controlled feasibility trial with qualitative process evaluation interviews. Participants are patients, aged 65 years and above with more than one long-term health problem (multimorbidity), and the GPs that they consult with. This study aims to recruit 6 GP practices, 18 GPs and 180 patients. The intervention comprises two components: (i) a half-day training workshop for GPs in shared decision-making; and (ii) a leaflet for patients that facilitate their engagement with shared decision-making. Intervention implementation will take 2 weeks (to complete delivery of both patient and GP components), and follow-up duration will be 12 weeks (from index consultation and commencement of data collection to final case note review and process evaluation interview). The trial will run from 01/01/20 to 31/01/21; 1 year 31 days. DISCUSSION: Shared decision-making for older people with multimorbidity in general practice is under-researched. Emerging clinical guidelines advise a patient-centred approach, to reduce treatment burden and focus on quality of life alongside disease control. The systematic development, testing and evaluation of an intervention is warranted and timely. This study will test the feasibility of implementing a new intervention in UK general practice for future evaluation as a part of routine care. TRIAL REGISTRATION: CLINICAL TRIALS.GOV registration number NCT03786315, registered 24/12/18.

Awareness and use of online appointment booking in general practice: analysis of GP Patient Survey data.

BACKGROUND: General practices are required to provide online booking to patients in line with policy to digitise access. However, uptake of online booking by patients is currently low and there is little evidence about awareness and use by different patient groups. AIM: To examine variability in awareness and use of online appointment booking in general practice. METHOD: Secondary analysis of two questions from the GP Practice Survey data (2018) asking about awareness and use of online booking of appointments. Multivariable logistic regression was used to examine associations with age, gender, ethnicity, deprivation, the presence of a long-term condition, long-term sickness and being deaf. RESULTS: In total, 43.3% (277 278/647 064) of responders reported being aware of being able to book appointments online, while only 15% (93 671/641 073) reported doing so. There was evidence of variation by all factors considered, with strong deprivation gradients in both awareness and use (for example, most versus least deprived quintile OR for use: 0.63 (95% CI = 0.61 to 0.65). There was a reduction in awareness and use in patients >75 years of age. Patients with long-term conditions were more aware and more likely to use online booking. CONCLUSION: While over 40% of patients know that they can book appointment online, the number that actually do so is far lower. With the constant push for online services within the NHS and the roll out of the NHS app, practices should be aware that not all patient groups will book appointments online and that other routes of access need to be maintained to avoid widening health inequalities.

Primary Care 2030: Creating an Enabling Ecosystem for Disruptive Primary Care Models to Achieve Universal Health Coverage in Low- and Middle-Income Countries.

Background: Forty years after Alma Ata, there is renewed commitment to strengthen primary health care as a foundation for achieving universal health coverage, but there is limited consensus on how to build strong primary health care systems to achieve these goals. Methods: We convened a diverse group of global stakeholders for a high-level dialogue on how to create an enabling ecosystem for disruptive primary care innovation. We focused our discussion on four themes: workforce innovation and strengthening; impactful use of data and technology; private sector engagement; and innovative financing mechanisms. Findings: Here, we present a summary of our convening's proceedings, with specific recommendations for strengthening primary health care systems within each of these four domains. Conclusions: In the wake of the Astana Declaration, there is global consensus that high-quality primary health care must be the foundation for universal health coverage. Significant disruptive innovation will be required to realize this goal. We offer our recommendations to the global community to catalyze further discourse and inform policy-making and program development on the path to Health for All by 2030.

Workforce predictive risk modelling: development of a model to identify general practices at risk of a supply-demand imbalance.

OBJECTIVE: This study aimed to develop a risk prediction model identifying general practices at risk of workforce supply-demand imbalance. DESIGN: This is a secondary analysis of routine data on general practice workforce, patient experience and registered populations (2012 to 2016), combined with a census of general practitioners' (GPs') career intentions (2016). SETTING/PARTICIPANTS: A hybrid approach was used to develop a model to predict workforce supply-demand imbalance based on practice factors using historical data (2012-2016) on all general practices in England (with over 1000 registered patients n=6398). The model was applied to current data (2016) to explore future risk for practices in South West England (n=368). PRIMARY OUTCOME MEASURE: The primary outcome was a practice being in a state of workforce supply-demand imbalance operationally defined as being in the lowest third nationally of access scores according to the General Practice Patient Survey and the highest third nationally according to list size per full-time equivalent GP (weighted to the demographic distribution of registered patients and adjusted for deprivation). RESULTS: Based on historical data, the predictive model had fair to good discriminatory ability to predict which practices faced supply-demand imbalance (area under receiver operating characteristic curve=0.755). Predictions using current data suggested that, on average, practices at highest risk of future supply-demand imbalance are currently characterised by having larger patient lists, employing more nurses, serving more deprived and younger populations, and having considerably worse patient experience ratings when compared with other practices. Incorporating findings from a survey of GP's career intentions made little difference to predictions of future supply-demand risk status when compared with expected future workforce projections based only on routinely available data on GPs' gender and age. CONCLUSIONS: It is possible to make reasonable predictions of an individual general practice's future risk of undersupply of GP workforce with respect to its patient population. However, the predictions are inherently limited by the data available.

The real costs of teaching medical students in general practice: a cost-collection survey of teaching practices across England.

BACKGROUND: Current funding arrangements for undergraduate medical student placements in general practice are widely regarded as outdated, inequitable, and in need of urgent review. AIM: To undertake a detailed costing exercise to inform the setting of a national English tariff for undergraduate medical student placements in general practice. DESIGN AND SETTING: A cost-collection survey in teaching practices across all regions of England between January 2017 and February 2017. METHOD: A cost-collection template was sent to 50 selected teaching practices across all 25 medical schools in England following the development of a cost-collection tool and an initial pilot study. Detailed guidance on completion was provided for practices. Data were analysed by the Department of Health and Social Care. RESULTS: A total of 49 practices submitted data. The mean cost per half-day student placement in general practice was 111 GBP, 95% confidence interval = 100 to 121 (146 USD), with small differences between students in different years of study. Based on 10 sessions per student per week this equated to around 1100 GBP (1460 USD) per student placement week. CONCLUSION: The costs of undergraduate placements in general practice are considerably greater than funding available at time of writing, and broadly comparable with secondary care funding in the same period. The actual cost of placing a medical student full time in general practice for a 37-week academic year is 40 700 GBP (53 640 USD) compared with the average payment rate of only 22 000 GBP (28 990 USD) per year at the time this study was undertaken.

Interventions for involving older patients with multi-morbidity in decision-making during primary care consultations.

BACKGROUND: Older patients with multiple health problems (multi-morbidity) value being involved in decision-making about their health care. However, they are less frequently involved than younger patients. To maximise quality of life, day-to-day function, and patient safety, older patients require support to identify unmet healthcare needs and to prioritise treatment options. OBJECTIVES: To assess the effects of interventions for older patients with multi-morbidity aiming to involve them in decision-making about their health care during primary care consultations. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; all years to August 2018), in the Cochrane Library; MEDLINE (OvidSP) (1966 to August 2018); Embase (OvidSP) (1988 to August 2018); PsycINFO (OvidSP) (1806 to August 2018); the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (Ovid) (1982 to September 2008), then in Ebsco (2009 to August 2018); Centre for Reviews and Dissemination Databases (Database of Abstracts and Reviews of Effects (DARE)) (all years to August 2018); the Health Technology Assessment (HTA) Database (all years to August 2018); the Ongoing Reviews Database (all years to August 2018); and Dissertation Abstracts International (1861 to August 2018). SELECTION CRITERIA: We sought randomised controlled trials (RCTs), cluster-RCTs, and quasi-RCTs of interventions to involve patients in decision-making about their health care versus usual care/control/another intervention, for patients aged 65 years and older with multi-morbidity in primary care. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. Meta-analysis was not possible; therefore we prepared a narrative synthesis. MAIN RESULTS: We included three studies involving 1879 participants: two RCTs and one cluster-RCT. Interventions consisted of: · patient workshop and individual coaching using behaviour change techniques; · individual patient coaching utilising cognitive-behavioural therapy and motivational interviewing; and · holistic patient review, multi-disciplinary practitioner training, and organisational change. No studies reported the primary outcome 'patient involvement in decision-making' or the primary adverse outcome 'less patient involvement as a result of the intervention'. Comparing interventions (patient workshop and individual coaching, holistic patient review plus practitioner training, and organisational change) to usual care: we are uncertain whether interventions had any effect on patient reports of high self-rated health (risk ratio (RR) 1.40, 95% confidence interval (CI) 0.36 to 5.49; very low-certainty evidence) or on patient enablement (mean difference (MD) 0.60, 95% CI -9.23 to 10.43; very low-certainty evidence) compared with usual care. Interventions probably had no effect on health-related quality of life (adjusted difference in means 0.00, 95% CI -0.02 to 0.02; moderate-certainty evidence) or on medication adherence (MD 0.06, 95% CI -0.05 to 0.17; moderate-certainty evidence) but probably improved the number of patients discussing their priorities (adjusted odds ratio 1.85, 95% CI 1.44 to 2.38; moderate-certainty evidence) and probably increased the number of nurse consultations (incident rate ratio from adjusted multi-level Poisson model 1.37, 95% CI 1.17 to 1.61; moderate-certainty evidence) compared with usual care. Practitioner outcomes were not measured. Interventions were not reported to adversely affect rates of participant death or anxiety, emergency department attendance, or hospital admission compared with usual care. Comparing interventions (patient workshop and coaching, individual patient coaching) to attention-control conditions: we are uncertain whether interventions affect patient-reported high self-rated health (RR 0.38, 95% CI 0.15 to 1.00, favouring attention control, with very low-certainty evidence; RR 2.17, 95% CI 0.85 to 5.52, favouring the intervention, with very low-certainty evidence). We are uncertain whether interventions affect patient enablement and engagement by increasing either patient activation (MD 1.20, 95% CI -8.21 to 10.61; very low-certainty evidence) or self-efficacy (MD 0.29, 95% CI -0.21 to 0.79; very low-certainty evidence); or whether interventions affect the number of general practice visits (MD 0.51, 95% CI -0.34 to 1.36; very low-certainty evidence), compared to attention-control conditions. The intervention may however lead to more patient-reported changes in management of their health conditions (RR 1.82, 95% CI 1.35 to 2.44; low-certainty evidence). Practitioner outcomes were not measured. Interventions were not reported to adversely affect emergency department attendance nor hospital admission when compared with attention control. Comparing one form of intervention with another: not measured. There was 'unclear' risk across studies for performance bias, detection bias, and reporting bias; however, no aspects were 'high' risk. Evidence was downgraded via GRADE, most often because of 'small sample size' and 'evidence from a single study'. AUTHORS' CONCLUSIONS: Limited available evidence does not allow a robust conclusion regarding the objectives of this review. Whilst patient involvement in decision-making is seen as a key mechanism for improving care, it is rarely examined as an intervention and was not measured by included studies. Consistency in design, analysis, and evaluation of interventions would enable a greater likelihood of robust conclusions in future reviews.

Evaluating Augmented Depression Therapy (ADepT): study protocol for a pilot randomised controlled trial.

BACKGROUND: While existing psychological treatments for depression are effective for many, a significant proportion of depressed individuals do not respond to current approaches and few remain well over the long-term. Anhedonia (a loss of interest or pleasure) is a core symptom of depression which predicts a poor prognosis but has been neglected by existing treatments. Augmented Depression Therapy (ADepT) has been co-designed with service users to better target anhedonia alongside other features of depression. This mixed methods pilot trial aims to establish proof of concept for ADepT and to examine the feasibility and acceptability of a future definitive trial evaluating the clinical and cost-effectiveness of ADepT, compared to an evidence-based mainstream therapy (Cognitive Behavioural Therapy; CBT) in the acute treatment of depression, the prevention of subsequent depressive relapse, and the enhancement of wellbeing. METHODS: We aim to recruit 80 depressed participants and randomise them 1:1 to receive ADepT (15 weekly acute and 5 booster sessions in following year) or CBT (20 weekly acute sessions). Clinical and health economic assessments will take place at intake and at 6-, 12-, and 18-month follow-up. Reductions in PHQ-9 depression severity and increases in WEMWBS wellbeing at 6-month assessment (when acute treatment should be completed) are the co-primary outcomes. Quantitative and qualitative process evaluation will assess mechanism of action, implementation issues, and contextual moderating factors. To evaluate proof of concept, intake-post effect sizes and the proportion of individuals showing reliable and clinically significant change on outcome measures in each arm at each follow-up will be reported. To evaluate feasibility and acceptability, we will examine recruitment, retention, treatment completion, and data completeness rates and feedback from patients and therapists about their experience of study participation and therapy. Additionally, we will establish the cost of delivery of ADepT. DISCUSSION: We will proceed to definitive trial if any concerns about the safety, acceptability, feasibility, and proof of concept of ADepT and trial procedures can be rectified, and we recruit, retain, and collect follow-up data on at least 60% of the target sample. TRIAL REGISTRATION: ISCRTN85278228, registered 27/03/2017.

Examining spatiotemporal variability of urban particulate matter and application of high-time resolution data from a network of low-cost air pollution sensors.

Traditional air monitoring approaches using regulatory monitors have historically been used to assess regional-scale trends in air pollutants across large geographical areas. Recent advances in air pollution sensor technologies could provide additional information about nearby sources, support the siting of regulatory monitoring stations, and improve our knowledge of finer-scale spatiotemporal variation of ambient air pollutants and their associated health effects. Sensors are now being developed that are much smaller and lower cost than traditional ambient air monitoring systems and are capable of being deployed as a network to provide greater coverage of a given area. The CitySpace project conducted by the US EPA and the Shelby County Health Department included the deployment of a network of 17 sensor pods using Alphasense OPC-N2 particulate matter (PM) sensors integrated with meteorological sensors in Memphis, TN for six months. Sensor pods were collocated with a federal equivalent method (FEM) tapered element oscillating microbalance (TEOM) monitor both before and after the primary study period. Six of the sensor pods were found to meet the data quality objective (DQO) of coefficient of determination (R2) greater than 0.5 when collocated with the TEOM. Seven pods were decommissioned before the end of the study due to mechanical failure. The six pods meeting the DQO were used to examine the spatiotemporal variability of fine PM (PM2.5) across the Memphis area. One site was found to have higher relative PM2.5 concentrations when compared to the other sites in the network. The 1-min data from this sensor pod were evaluated to quantify the regional urban background and local-scale contributions to PM2.5 at that monitoring location. This method found that approximately 20% of the PM2.5 was attributed to local sources at this location, compared to 9% at a local regulatory monitoring site. Additionally, the 1-min data were combined with 1-min wind speed and wind direction data to examine potential sources in the area using the nonparametric trajectory analysis (NTA) technique. This method geographically identified local source areas that contributed to the measured concentrations at the high reading sensor location throughout the course of the study.

Assessment of Bony Subfibular Impingement in Flatfoot Patients Using Weight-Bearing CT Scans.

BACKGROUND:: Lateral hindfoot pain in patients with flatfoot deformity is frequently attributed to subfibular impingement. It remains unclear whether this is primarily due to bony or soft-tissue impingement. No studies have used weight-bearing CT scans to evaluate subfibular impingement. METHODS:: Patients with posterior tibial tendonitis were retrospectively searched and reviewed. Subjects had documented flatfoot deformity, posterior tibial tenderness, weight-bearing plain radiographs, and a weight-bearing CT scan. CT scans were evaluated for calcaneofibular impingement on the coronal view and talocalcaneal impingement on the sagittal view. The distance between these structures was measured, along with the sinus tarsi volume. In the second part of this study, 6 normal volunteers underwent weight-bearing CT scans on a platform that held both feet in 20 degrees of varus, followed by 20 degrees of valgus. The same measurements were performed. RESULTS:: Thirty-five percent of flatfoot patients with posterior tibial tendonitis had bony impingement between the fibula and calcaneus on the coronal view. Thirty-eight percent had bony impingement between the talus and calcaneus on the sagittal view. Subjects with bony impingement based on CT scan had significantly higher talonavicular abduction angles on plain radiographs than those without impingement. Sinus tarsi volume decreased by more than half when the subtalar joint moved from varus to valgus in normal controls. CONCLUSION:: Bony subfibular impingement in patients with flatfeet was less common than previously reported. Accurate diagnosis of bony impingement may be useful for surgical decision-making. LEVEL OF EVIDENCE:: Level III, retrospective comparative study.