Identification of non-actionable mutations with prognostic and predictive value in patients with advanced or metastatic non-small cell lung cancer.

INTRODUCTION: Lung cancer is one of the most prevalent cancers and the leading cause of cancer death. Advanced non-small cell lung cancer (aNSCLC) patients frequently harbor mutations that impact their survival outcomes. There are limited data regarding the prognostic and predictive significance of these mutations on survival outcomes in the real-world setting. METHODS: This observational retrospective study analyzed de-identified electronic medical records from the Flatiron Health Clinico-Genomic and FoundationCore® databases to identify patients with aNSCLC who initiated first-line immune checkpoint inhibitors (ICI; alone or in combination) or chemotherapy under routine care between 2016 and 2021. The primary objectives were to assess the prevalence of non-actionable mutations and to determine their association with overall survival (OS). Real-world progression-free survival (rwPFS) and real-world response (rwR) were investigated as secondary exploratory outcomes. RESULTS: Based on an assessment of 185 non-actionable mutations in 2999 patients, the most prevalent mutations were TP53 (70%), KRAS (42%), CDKN2A/B (31%), and STK11 (21%). STK11, KEAP1, and CDKN2A/B mutations were significantly associated with lower rwR, shorter rwPFS and OS. KRAS mutations were clinically associated with shorter rwPFS in CIT-treated patients. Subgroup analysis revealed that fast progressors were significantly more likely to harbor STK11, KEAP1, and CDKN2A/B mutations. Accordingly, long-term survivors (LTS) showed a significantly lower prevalence of these mutations. CONCLUSION: Our results provide evidence on the prognostic value of STK11, KEAP1, and CDKN2A/B mutations in patients with aNSCLC. Further research is required to better understand the implications of these findings on patient management and future trial design and treatment selection.

Generative processing and emotional false memories: a generation "cost" for negative false memory formation but only after delay.

Previous research shows that manipulations (e.g. levels-of-processing) that facilitate true memory often increase susceptibility to false memory. An exception is the generation effect. Using the Deese/Roediger-McDermott (DRM) paradigm, Soraci et al. found that generating rather than reading list items led to an increase in true but not false memories. They argued that generation led to enhanced item-distinctiveness that drove down false memory production. In the current study, we investigated the effects of generative processing on valenced stimuli and after a delayed retention interval to examine factors that may lead to a generation effect that increases false memories. At the immediate test, false recognition rates for both negative and neutral valanced critical lures were similar across read and generate conditions. However, after a one-week delay, we saw a valence differentiation, with a generation effect for false recognition but only for negative stimuli. The roles of item-specific and relational processing during encoding and their interaction with long-term retention are discussed.

Impact on emergency and elective hospital-based care in Scotland over the first 12 months of the pandemic: interrupted time-series analysis of national lockdowns.

OBJECTIVES: COVID-19 has resulted in the greatest disruption to National Health Service (NHS) care in its over 70-year history. Building on our previous work, we assessed the ongoing impact of pandemic-related disruption on provision of emergency and elective hospital-based care across Scotland over the first year of the pandemic. DESIGN: We undertook interrupted time-series analyses to evaluate the impact of ongoing pandemic-related disruption on hospital NHS care provision at national level and across demographics and clinical specialties spanning the period 29 March 2020-28 March 2021. SETTING: Scotland, UK. PARTICIPANTS: Patients receiving hospital care from NHS Scotland. MAIN OUTCOME MEASURES: We used the percentage change of accident and emergency attendances, and emergency and planned hospital admissions during the pandemic compared to the average admission rate for equivalent weeks in 2018-2019. RESULTS: As restrictions were gradually lifted in Scotland after the first lockdown, hospital-based admissions increased approaching pre-pandemic levels. Subsequent tightening of restrictions in September 2020 were associated with a change in slope of relative weekly admissions rate: -1.98% (-2.38, -1.58) in accident and emergency attendance, -1.36% (-1.68, -1.04) in emergency admissions and -2.31% (-2.95, -1.66) in planned admissions. A similar pattern was seen across sex, socioeconomic status and most age groups, except children (0-14 years) where accident and emergency attendance, and emergency admissions were persistently low over the study period. CONCLUSIONS: We found substantial disruption to urgent and planned inpatient healthcare provision in hospitals across NHS Scotland. There is the need for urgent policy responses to address continuing unmet health needs and to ensure resilience in the context of future pandemics.

Assessment of Alectinib vs Ceritinib in ALK-Positive Non-Small Cell Lung Cancer in Phase 2 Trials and in Real-world Data.

Importance: Quantitative assessment of bias from unmeasured confounding and missing data can help evaluate uncertainty in findings from indirect comparisons using real-world data (RWD). Objective: To compare the effectiveness of alectinib vs ceritinib in terms of overall survival (OS) in patients with ALK-positive, crizotinib-refractory, non-small cell lung cancer (NSCLC) and to assess the sensitivity of these findings to unmeasured confounding and missing data assumptions. Design, Setting, and Participants: This comparative effectiveness research study compared patients from 2 phase 2 alectinib trials and real-world patients. Patients were monitored from June 2013 to March 2020. Comparisons of interest were between alectinib trial data vs ceritinib RWD and alectinib RWD vs ceritinib RWD. RWD treatment groups were selected from nationally representative cancer data from US cancer clinics, the majority from community centers. Participants were ALK-positive patients aged 18 years or older with advanced NSCLC, prior exposure to crizotinib, and Eastern Cooperative Oncology Group Performance Status (PS) of 0 to 2. Data analysis was performed from October 2020 to March 2021. Exposures: Initiation of alectinib or ceritinib therapy. Main Outcomes and Measures: The main outcome was OS. Results: In total, there were 355 patients: 183 (85 men [46.4%]) in the alectinib trial, 91 (43 men [47.3%]) in the ceritinib RWD group, and 81 (38 men [46.9%]) in the alectinib RWD group. Patients in the alectinib trial were younger (mean [SD] age, 52.53 [11.18] vs 57.97 [11.71] years), more heavily pretreated (mean [SD] number of prior therapy lines, 1.95 [0.72] vs 1.47 [0.81]), and had more favorable baseline ECOG PS (ECOG PS of 0 or 1, 165 patients [90.2%] vs 37 patients [77.1%]) than those in the ceritinib RWD group. The alectinib RWD group (mean [SD] age, 58.69 [11.26] years) had more patients with favorable ECOG PS (ECOG PS of 0 or 1, 49 patients [92.4%] vs 37 patients [77.1%]) and more White patients (56 patients [72.7%] vs 53 patients [62.4%]) compared with the ceritinib group. Compared with ceritinib RWD, alectinib-exposed patients had significantly longer OS in alectinib trials (adjusted hazard ratio [HR], 0.59; 95% CI, 0.44-0.75; P < .001) and alectinib RWD (HR, 0.46; 95% CI, 0.29-0.63; P < .001) after adjustment for baseline confounders. For the worst-case HR estimate of 0.59, residual confounding by a hypothetical confounder associated with mortality and treatment by a risk ratio greater than 2.24 was required to reverse the findings. Conclusions were robust to plausible deviations from random missingness for missing ECOG PS and underrecorded comorbidities and central nervous system metastases in RWD. Conclusions and Relevance: Alectinib exposure was associated with longer OS compared with ceritinib in patients with ALK-positive NSCLC, and only substantial levels of bias examined reversed the findings. These findings suggest that quantitative bias analysis can be a useful tool to address uncertainty of findings for decision-makers considering RWD.

Protocol for an observational cohort study investigating personalised medicine for intensification of treatment in people with type 2 diabetes mellitus: the PERMIT study.

INTRODUCTION: For people with type 2 diabetes mellitus (T2DM) who require an antidiabetic drug as an add-on to metformin, there is controversy about whether newer drug classes such as dipeptidyl peptidase-4 inhibitors (DPP4i) or sodium-glucose co-transporter-2 inhibitors (SGLT2i) reduce the risk of long-term complications compared with sulfonylureas (SU). There is widespread variation across National Health Service Clinical Commissioning Groups (CCGs) in drug choice for second-line treatment in part because National Institute for Health and Care Excellence guidelines do not specify a single preferred drug class, either overall or within specific patient subgroups. This study will evaluate the relative effectiveness of the three most common second-line treatments in the UK (SU, DPP4i and SGLT2i as add-ons to metformin) and help target treatments according to individual risk profiles. METHODS AND ANALYSIS: The study includes people with T2DM prescribed one of the second-line treatments-of-interest between 2014 and 2020 within the UK Clinical Practice Research Datalink linked with Hospital Episode Statistics and Office of National Statistics. We will use an instrumental variable (IV) method to estimate short-term and long-term relative effectiveness of second-line treatments according to individuals' risk profiles. This method minimises bias from unmeasured confounders by exploiting the natural variation in second-line prescribing across CCGs as an IV for the choice of prescribed treatment. The primary outcome to assess short-term effectiveness will be change in haemoglobin A1c (%) 12 months after treatment initiation. Outcome measures to assess longer-term effectiveness (maximum ~6 years) will include microvascular and macrovascular complications, all-cause mortality and hospital admissions during follow-up. ETHICS AND DISSEMINATION: This study was approved by the Independent Scientific Advisory Committee (20-064) and the London School of Hygiene & Tropical Medicine Research Ethics Committee (21395). Results, codelists and other analysis code will be made available to patients, clinicians, policy-makers and researchers.

The value of innovation: association between improvements in survival of advanced and metastatic non-small cell lung cancer and targeted and immunotherapy.

BACKGROUND: Significant improvements in mortality among patients with non-small cell lung cancer (NSCLC) in the USA over the past two decades have been reported based on Surveillance, Epidemiology, and End Results (SEER) data. The timing of these improvements led to suggestions that they result from the introduction of new treatments; however, few studies have directly investigated this. The aim of this study was to investigate the extent to which population level improvements in survival of advanced and/or metastatic NSCLC (admNSCLC) patients were associated with changes in treatment patterns. METHODS: We utilized a de-identified database to select three cohorts of patients with admNSCLC: (1) patients with non-oncogene (EGFR/ALK/ROS1/BRAF) positive tumors, (2) patients with ALK-positive (ALK+) tumors, and (3) patients with EGFR-positive (EGFR+) tumors. All patients were diagnosed with admNSCLC between 2012 and 2019. Multivariable Cox models adjusting for baseline characteristics and receipt of targeted and immunotherapy were utilized to explore the relationship between these variables and changes in the hazard of death by calendar year in each cohort. RESULTS: We included 28,154 admNSCLC patients with non-oncogene positive tumors, 598 with ALK+ tumors, and 2464 with EGFR+ tumors eligible for analysis. After adjustment for differences in baseline characteristics, the hazard of death in patients who had non-oncogene positive tumors diagnosed in 2015, 2016, 2017, 2018 ,and 2019 was observed to be 12%, 11%, 17%, 20%, and 21% lower respectively than that for those diagnosed in 2012. Upon additionally adjusting for receipt of first line or second line immunotherapy, the decrease in the hazard of death by calendar year was no longer observed, suggesting improvements in survival observed over time may be explained by the introduction of these treatments. Similarly, decreases in the hazard of death were only observed in patients with ALK+ tumors diagnosed between 2017 and 2019 relative to 2012 but were no longer observed following adjustment for the use of 1st and later generation ALK inhibitors. Among patients with EGFR+ tumors, the hazard of death did not improve significantly over time. CONCLUSION: Our findings expand on the SEER data and provide additional evidence suggesting improvements in survival of patients with advanced and metastatic NSCLC over the past decade could be explained by the change in treatment patterns over this period.

Ixodes ricinus and Borrelia burgdorferi sensu lato in the Royal Parks of London, UK.

Assessing the risk of tick-borne disease in areas with high visitor numbers is important from a public health perspective. Evidence suggests that tick presence, density, infection prevalence and the density of infected ticks can vary between habitats within urban green space, suggesting that the risk of Lyme borreliosis transmission can also vary. This study assessed nymph density, Borrelia prevalence and the density of infected nymphs across a range of habitat types in nine parks in London which receive millions of visitors each year. Ixodes ricinus were found in only two of the nine locations sampled, and here they were found in all types of habitat surveyed. Established I. ricinus populations were identified in the two largest parks, both of which had resident free-roaming deer populations. Highest densities of nymphs (15.68 per 100 m2) and infected nymphs (1.22 per 100 m2) were associated with woodland and under canopy habitats in Richmond Park, but ticks infected with Borrelia were found across all habitat types surveyed. Nymphs infected with Borrelia (7.9%) were only reported from Richmond Park, where Borrelia burgdorferi sensu stricto and Borrelia afzelii were identified as the dominant genospecies. Areas with short grass appeared to be less suitable for ticks and maintaining short grass in high footfall areas could be a good strategy for reducing the risk of Lyme borreliosis transmission to humans in such settings. In areas where this would create conflict with existing practices which aim to improve and/or meet historic landscape, biodiversity and public access goals, promoting public health awareness of tick-borne disease risks could also be utilised.

Performing care: emotion work and 'dignity work' - a joint autoethnography of caring for our mum at the end of life.

In this paper we, twin sisters, present a joint autoethnographic account of providing end of life care for our mum who had terminal cancer. Using the theoretical framing of performance from Goffman's theory of Dramaturgy, we present the findings from a joint autoethnography, focusing on two key themes: performing emotion work and performing what we conceptualise as 'dignity work'. This paper's contributions are twofold. First, conceptually, this paper offers an important contribution to literature concerned with the sociology of illness, by critically engaging with Goffman's notion of frontstage and backstage performance, applied to the context of home care provided by family carers. The second contribution of this paper is methodological; we promote the under-utilised approach of a joint autoethnography and argue for its usefulness in the context of end of life care. We contend that the process of writing this paper was emotionally challenging, yet arriving at the final paper, which serves as a legacy of our mum, was cathartic. We argue for the usefulness of written diaries as a backstage arena through which other informal carers can think through, and come to terms with, experiences of death and dying.

Comparative effects of sulphonylureas, dipeptidyl peptidase-4 inhibitors and sodium-glucose co-transporter-2 inhibitors added to metformin monotherapy: a propensity-score matched cohort study in UK primary care.

AIM: To assess the comparative effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors, sulphonylureas (SUs) and dipeptidyl peptidase-4 (DPP-4) inhibitors on cardiometabolic risk factors in routine care. MATERIALS AND METHODS: Using primary care data on 10 631 new users of SUs, SGLT2 inhibitors or DPP-4 inhibitors added to metformin, obtained from the UK Clinical Practice Research Datalink, we created propensity-score matched cohorts and used linear mixed models to describe changes in glycated haemoglobin (HbA1c), estimated glomerular filtration rate (eGFR), systolic blood pressure (BP) and body mass index (BMI) over 96 weeks. RESULTS: HbA1c levels fell substantially after treatment intensification for all drugs: mean change at week 12: SGLT2 inhibitors: -15.2 mmol/mol (95% confidence interval [CI] -16.9, -13.5); SUs: -14.3 mmol/mol (95% CI -15.5, -13.2); and DPP-4 inhibitors: -11.9 mmol/mol (95% CI -13.1, -10.6). Systolic BP fell for SGLT2 inhibitor users throughout follow-up, but not for DPP-4 inhibitor or SU users: mean change at week 12: SGLT2 inhibitors: -2.3 mmHg (95% CI -3.8, -0.8); SUs: -0.8 mmHg (95% CI -1.9, +0.4); and DPP-4 inhibitors: -0.9 mmHg (95% CI -2.1,+0.2). BMI decreased for SGLT2 inhibitor and DPP-4 inhibitor users, but not SU users: mean change at week 12: SGLT2 inhibitors: -0.7 kg/m2 (95% CI -0.9, -0.5); SUs: 0.0 kg/m2 (95% CI -0.3, +0.2); and DPP-4 inhibitors: -0.3 kg/m2 (95% CI -0.5, -0.1). eGFR fell at 12 weeks for SGLT2 inhibitor and DPP-4 inhibitor users. At 60 weeks, the fall in eGFR from baseline was similar for each drug class. CONCLUSIONS: In routine care, SGLT2 inhibitors had greater effects on cardiometabolic risk factors than SUs. Routine care data closely replicated the effects of diabetes drugs on physiological variables measured in clinical trials.

Young men's alcohol consumption experiences and performances of masculinity.

BACKGROUND: By creating a dichotomy between those who are 'out-of-control' 'binge drinkers' and those for whom alcohol contributes to friendship fun, academic and alcohol policy literature often fail to acknowledge the nuances in the diverse drinking practices of men. METHODS: This paper engages with findings from a multiple qualitative method research project (comprising of individual and friendship group interviews; diaries; and participant observation), conducted with 16 young men, aged 15-24: eight living in the middle-class area of Chorlton, and eight living in the working-class area of Wythenshawe, Manchester, United Kingdom. RESULTS: This paper provides fine-grained insights into the doings, complexities and contradictions of masculinity in the context of drinking. Young men are shown to tap into different co-existing versions of masculinity, one of which is based on the exclusion of femininity (i.e. they act as tough guys), while another version is more inclusive (i.e. it allows for displays of care). CONCLUSION: This paper shows a much more complex image of young men's drinking practices than has hitherto been conceptualised in the existing literature, and brings to the fore doings of alternative masculinities. This has important implications for alcohol policy interventions targeting men, in that the complexities and contradictions of masculinity in relation to drinking must be taken seriously.

'Going the extra mile' for older people with dementia: Exploring the voluntary labour of homecare workers.

Homecare workers provide essential physical, social and emotional support to growing numbers of older people with dementia in the UK. Although it is acknowledged that the work can sometimes be demanding, some homecare workers regularly 'go the extra mile' for service users, working above and beyond the usual remit of the job. This form of voluntarism has been interpreted as an expression of an essentially caring nature, but also as the product of a work environment structured to tacitly endorse the provision of unpaid labour. This paper draws on a qualitative study of what constitutes 'good' homecare for older people with dementia. Using homecare workers' reflexive diaries (n = 11) and interviews with homecare workers (n = 14) and managers (n = 6), we explore manifestations of, and motivations for, homecare workers going the extra mile in their everyday work. We describe three modes of voluntary labour based on these accounts which we characterise as affective, performative and pragmatic. Our study highlights the complex relationships between job satisfaction, social benefit and commercial gain in the homecare work sector. Further research is needed to define the full range of affective and technical skills necessary to deliver good homecare, and to ensure that homecare work is appropriately credited.

The subjective world of home care workers in dementia: an "order of worth" analysis.

The perspective of domiciliary workers is needed to recruit a high-quality workforce and meet growing demand. An English ethnographic study yielded extensive insights. To structure analysis of the study data, we apply a method developed by political theorists Boltanski and Thévenot that identifies key variables in different values systems. This "orders of worth" framework is used to map out the distinctive features of the subjective world of home carers. The results can be drawn on to formulate recruitment and retention policies, to design reward strategies or to ensure that training and education opportunities engage effectively with the workforce.

Factors associated with choice of intensification treatment for type 2 diabetes after metformin monotherapy: a cohort study in UK primary care.

PURPOSE: To understand the patient characteristics associated with treatment choice at the first treatment intensification for type 2 diabetes. PATIENTS AND METHODS: This is a noninterventional study, using UK electronic primary care records from the Clinical Practice Research Datalink. We included adults treated with metformin monotherapy between January 2000 and July 2017. The outcome of interest was the drug prescribed at first intensification between 2014 and 2017. We used multinomial logistic regression to calculate the ORs for associations between the drugs and patient characteristics. RESULTS: In total, 14,146 people started treatment with an intensification drug. Younger people were substantially more likely to be prescribed sodium-glucose co-transporter-2 inhibitors (SGLT2is), than sulfonylureas (SUs): OR for SGLT2i prescription for those aged <30 years was 2.47 (95% CI 1.39-4.39) compared with those aged 60-70 years. Both overweight and obesity were associated with greater odds of being prescribed dipeptidyl peptidase-4 inhibitor (DPP4i) or SGLT2i. People of non-white ethnicity were less likely to be prescribed SGLT2i or DPP4i: compared with white patients, the OR of being prescribed SGLT2i among South Asians is 0.60 (95% CI 0.42-0.85), and for black people, the OR is 0.54 (95% CI 0.30-0.97). Lower socioeconomic status was also independently associated with reduced odds of being prescribed SGLT2is. CONCLUSION: Both clinical and demographic factors are associated with prescribing at the first stage of treatment intensification, with older and non-white people less likely to receive new antidiabetic treatments. Our results suggest that the selection of treatment options used at the first stage of treatment intensification for type 2 diabetes is not driven by clinical need alone.

National hospital mortality surveillance system: a descriptive analysis.

OBJECTIVE: To provide a description of the Imperial College Mortality Surveillance System and subsequent investigations by the Care Quality Commission (CQC) in National Health Service (NHS) hospitals receiving mortality alerts. BACKGROUND: The mortality surveillance system has generated monthly mortality alerts since 2007, on 122 individual diagnosis and surgical procedure groups, using routinely collected hospital administrative data for all English acute NHS hospital trusts. The CQC, the English national regulator, is notified of each alert. This study describes the findings of CQC investigations of alerting trusts. METHODS: We carried out (1) a descriptive analysis of alerts (2007-2016) and (2) an audit of CQC investigations in a subset of alerts (2011-2013). RESULTS: Between April 2007 and October 2016, 860 alerts were generated and 76% (654 alerts) were sent to trusts. Alert volumes varied over time (range: 40-101). Septicaemia (except in labour) was the most commonly alerting group (11.5% alerts sent). We reviewed CQC communications in a subset of 204 alerts from 96 trusts. The CQC investigated 75% (154/204) of alerts. In 90% of these pursued alerts, trusts returned evidence of local case note reviews (140/154). These reviews found areas of care that could be improved in 69% (106/154) of alerts. In 25% (38/154) trusts considered that identified failings in care could have impacted on patient outcomes. The CQC investigations resulted in full trust action plans in 77% (118/154) of all pursued alerts. CONCLUSION: The mortality surveillance system has generated a large number of alerts since 2007. Quality of care problems were found in 69% of alerts with CQC investigations, and one in four trusts reported that failings in care may have an impact on patient outcomes. Identifying whether mortality alerts are the most efficient means to highlight areas of substandard care will require further investigation.

A systematic review comparing the evidence for kidney function outcomes between oral antidiabetic drugs for type 2 diabetes.

Background: The development of kidney disease is a serious complication among people with type 2 diabetes mellitus, associated with substantially increased morbidity and mortality.  We aimed to summarise the current evidence for the relationship between treatments for type 2 diabetes and long-term kidney outcomes, by conducting a systematic search and review of relevant studies. Methods: We searched Medline, Embase and Web of Science, between 1st January 1980 and 15th May 2018 for published clinical trials and observational studies comparing two or more classes of oral therapy for type 2 diabetes. We included people receiving oral antidiabetic drugs. Studies were eligible that; (i) compared two or more classes of oral therapy for type 2 diabetes; (ii) reported kidney outcomes as primary or secondary outcomes; (iii) included more than 100 participants; and (iv) followed up participants for 48 weeks or more. Kidney-related outcome measures included were Incidence of chronic kidney disease, reduced eGFR, increased creatinine, 'micro' and 'macro' albuminuria. Results: We identified 15 eligible studies, seven of which were randomised controlled trials and eight were observational studies. Reporting of specific renal outcomes varied widely. Due to variability of comparisons and outcomes meta-analysis was not possible. The majority of comparisons between treatment with metformin or sulfonylurea indicated that metformin was associated with better renal outcomes. Little evidence was available for recently introduced treatments or commonly prescribed combination therapies. Conclusions: Comparative evidence for the effect of treatments for type 2 diabetes on renal outcomes, either as monotherapy or in combination is sparse.

Changing use of antidiabetic drugs in the UK: trends in prescribing 2000-2017.

OBJECTIVES: Guidelines for the use of drugs for type 2 diabetes mellitus (T2DM) have changed since 2000, and new classes of drug have been introduced. Our aim was to describe how drug choice at initiation and first stage of intensification have changed over this period, and to what extent prescribing was in accord with clinical guidelines, including adherence to recommendations regarding kidney function. DESIGN: Repeated cross-sectional study. SETTING: UK electronic primary care health records from the Clinical Practice Research Datalink. PARTICIPANTS: Adults initiating treatment with a drug for T2DM between January 2000 and July 2017. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcomes were the proportion of each class of T2DM drug prescribed for initiation and first-stage intensification in each year. We also examined drug prescribing by kidney function and country within the UK. RESULTS: Of 280 241 people initiating treatment with T2DM drugs from 2000 to 2017, 73% (204 238/280 241) initiated metformin, 15% (42 288/280 241) a sulfonylurea, 5% (12 956/280 241) with metformin and sulfonylurea dual therapy and 7% (20 759/280 241) started other options. Clinicians have increasingly prescribed metformin at initiation: by 2017 this was 89% (2475/2778) of drug initiations. Among people with an estimated glomerular filtration rate of ≤30 mL/min/1.73 m2, the most common drug at initiation was a sulfonylurea, 58% (659/1135). In 2000, sulfonylureas were the predominant drug at the first stage of drug intensification (87%, 534/615) but by 2017 this fell to 30% (355/1183) as the use of newer drug classes increased. In 2017, new prescriptions for dipeptidyl peptidase-4 inhibitors (DPP4i) and sodium/glucose cotransporter-2 inhibitors (SGLT2i) accounted for 42% (502/1183) and 22% (256/1183) of intensification drugs, respectively. Uptake of new classes differs by country with DPP4is and SGLT2is prescribed more in Northern Ireland and Wales than England or Scotland. CONCLUSIONS: Our findings show markedly changing prescribing patterns for T2DM between 2000 and 2017, largely consistent with clinical guidelines.

Investigating the association of alerts from a national mortality surveillance system with subsequent hospital mortality in England: an interrupted time series analysis.

OBJECTIVE: To investigate the association between alerts from a national hospital mortality surveillance system and subsequent trends in relative risk of mortality. BACKGROUND: There is increasing interest in performance monitoring in the NHS. Since 2007, Imperial College London has generated monthly mortality alerts, based on statistical process control charts and using routinely collected hospital administrative data, for all English acute NHS hospital trusts. The impact of this system has not yet been studied. METHODS: We investigated alerts sent to Acute National Health Service hospital trusts in England in 2011-2013. We examined risk-adjusted mortality (relative risk) for all monitored diagnosis and procedure groups at a hospital trust level for 12 months prior to an alert and 23 months post alert. We used an interrupted time series design with a 9-month lag to estimate a trend prior to a mortality alert and the change in trend after, using generalised estimating equations. RESULTS: On average there was a 5% monthly increase in relative risk of mortality during the 12 months prior to an alert (95% CI 4% to 5%). Mortality risk fell, on average by 61% (95% CI 56% to 65%), during the 9-month period immediately following an alert, then levelled to a slow decline, reaching on average the level of expected mortality within 18 months of the alert. CONCLUSIONS: Our results suggest an association between an alert notification and a reduction in the risk of mortality, although with less lag time than expected. It is difficult to determine any causal association. A proportion of alerts may be triggered by random variation alone and subsequent falls could simply reflect regression to the mean. Findings could also indicate that some hospitals are monitoring their own mortality statistics or other performance information, taking action prior to alert notification.

Validation of asthma recording in electronic health records: a systematic review.

OBJECTIVE: To describe the methods used to validate asthma diagnoses in electronic health records and summarize the results of the validation studies. BACKGROUND: Electronic health records are increasingly being used for research on asthma to inform health services and health policy. Validation of the recording of asthma diagnoses in electronic health records is essential to use these databases for credible epidemiological asthma research. METHODS: We searched EMBASE and MEDLINE databases for studies that validated asthma diagnoses detected in electronic health records up to October 2016. Two reviewers independently assessed the full text against the predetermined inclusion criteria. Key data including author, year, data source, case definitions, reference standard, and validation statistics (including sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV]) were summarized in two tables. RESULTS: Thirteen studies met the inclusion criteria. Most studies demonstrated a high validity using at least one case definition (PPV >80%). Ten studies used a manual validation as the reference standard; each had at least one case definition with a PPV of at least 63%, up to 100%. We also found two studies using a second independent database to validate asthma diagnoses. The PPVs of the best performing case definitions ranged from 46% to 58%. We found one study which used a questionnaire as the reference standard to validate a database case definition; the PPV of the case definition algorithm in this study was 89%. CONCLUSION: Attaining high PPVs (>80%) is possible using each of the discussed validation methods. Identifying asthma cases in electronic health records is possible with high sensitivity, specificity or PPV, by combining multiple data sources, or by focusing on specific test measures. Studies testing a range of case definitions show wide variation in the validity of each definition, suggesting this may be important for obtaining asthma definitions with optimal validity.

Validation of asthma recording in electronic health records: protocol for a systematic review.

BACKGROUND: Asthma is a common, heterogeneous disease with significant morbidity and mortality worldwide. It can be difficult to define in epidemiological studies using electronic health records as the diagnosis is based on non-specific respiratory symptoms and spirometry, neither of which are routinely registered. Electronic health records can nonetheless be valuable to study the epidemiology, management, healthcare use and control of asthma. For health databases to be useful sources of information, asthma diagnoses should ideally be validated. The primary objectives are to provide an overview of the methods used to validate asthma diagnoses in electronic health records and summarise the results of the validation studies. METHODS: EMBASE and MEDLINE will be systematically searched for appropriate search terms. The searches will cover all studies in these databases up to October 2016 with no start date and will yield studies that have validated algorithms or codes for the diagnosis of asthma in electronic health records. At least one test validation measure (sensitivity, specificity, positive predictive value, negative predictive value or other) is necessary for inclusion. In addition, we require the validated algorithms to be compared with an external golden standard, such as a manual review, a questionnaire or an independent second database. We will summarise key data including author, year of publication, country, time period, date, data source, population, case characteristics, clinical events, algorithms, gold standard and validation statistics in a uniform table. ETHICS AND DISSEMINATION: This study is a synthesis of previously published studies and, therefore, no ethical approval is required. The results will be submitted to a peer-reviewed journal for publication. Results from this systematic review can be used to study outcome research on asthma and can be used to identify case definitions for asthma. PROSPERO REGISTRATION NUMBER: CRD42016041798.

On the adaptive function of children's and adults' false memories.

Recent research has shown that memory illusions can successfully prime both children's and adults' performance on complex, insight-based problems (compound remote associates tasks or CRATs). The current research aimed to clarify the locus of these priming effects. Like before, Deese-Roediger-McDermott (DRM) lists were selected to prime subsequent CRATs such that the critical lures were also the solution words to a subset of the CRATs participants attempted to solve. Unique to the present research, recognition memory tests were used and participants were either primed during the list study phase, during the memory test phase, or both. Across two experiments, primed problems were solved more frequently and significantly faster than unprimed problems. Moreover, when participants were primed during the list study phase, subsequent solution times and rates were considerably superior to those produced by those participants who were simply primed at test. Together, these are the first results to show that false-memory priming during encoding facilitates problem-solving in both children and adults.