Determinants of lipid clinic referral and attendance in a multi-ethnic adult population in south London: a cross-sectional study.

BACKGROUND: Primary dyslipidaemias, including familial hypercholesterolaemia, are underdiagnosed genetic disorders that substantially increase risk for premature coronary artery disease in adults. Early identification of primary dyslipidaemias via lipid clinic referral optimises patient management and enables cascade screening of relatives. Improving the identification of primary dyslipidaemias, and understanding disparities in ascertainment and management, is an NHS priority. We aimed to assess determinants of lipid clinic referral or attendance (LCR) in ethnically diverse adults. METHODS: We did a retrospective cross-sectional study using the Lambeth DataNet containing anonymised data from 41 general practitioner (GP) practices in south London. We looked at referral data for adult patients aged 18 years and older from Jan 1, 1995, until May 14, 2018. LCR was the main outcome. We used sequential multilevel logistic regression models adjusted for practice effects to estimate the odds of LCR assessed across six ethnic groups (reference group White) and patient-level factors (demographic, socioeconomic, lifestyle, comorbidities, total cholesterol [TC] >7·5mmol/L, statin prescription, and practice factors). The study was approved by NHS South East London Clinical Commissioning Group (CCG) and NHS Lambeth CCG. FINDINGS: 780 (0·23%) of 332 357 adult patients were coded as referred (n=538) or seen (n=252) in a lipid clinic. 164 487 (46·49%) were women (appendix). The fully adjusted model for odds of LCR showed the following significant associations for age (odds ratio [OR] 0·96, 95% CI 0·96-0·97, p<0·001); Black, African, Caribbean, or Black-British ethnicity (0·67, 0·53-0·84, p=0·001); ex-smoker status (1·29, 1·05-1·57, p=0·014); TC higher than 7·5 mmol/L (12·18, 9·60-15·45, p<0·001); statin prescription (14·01, 10·85-18·10, p<0·001); diabetes (0·72, 0·58-0·91, p=0·005); high-frequency GP attendance at seven or more GP consultations in the past year (1·49, 1·21-1·84, p<0·001); high GP-density (0·5-0·99 full-time equivalent GPs per 1000 patients; 2·70, 1·23-5·92, p=0·013). Sensitivity analyses for LCR restricted to familial hypercholesterolaemia-coded patients (n=581) found associations with TC higher than 7·5 mmol/L (4·26, 1·89-9·62, p<0·001), statin prescription (16·96, 2·19-131·36, p=0·007), and high GP-density (5·73, 1·27-25·93, p=0·023), with no significant associations with ethnicity. The relative contribution of GP practices to LCR was 6·32% of the total variance. There were no significant interactions between ethnicity and deprivation, age, or obesity. INTERPRETATION: While interpretation is limited by the accuracy and completeness of coded records, the study showed factors associated with a higher likelihood of LCR included individuals recorded as having TC higher than 7·5 mmol/L, statin prescription, ex-smoker status, high-frequency GP attendance, and registration at a GP practice with 0·5-0·99 GP density. Patients with increasing age; Black, African, Caribbean, or Black-British ethnicity patients; and patients with diabetes had lower odds of LCR. Finally, the difference in odds of LCR between Black and White patients highlights potential health inequalities. FUNDING: NHS Race & Health Observatory.

Frequency and impact of medication reviews for people aged 65 years or above in UK primary care: an observational study using electronic health records.

BACKGROUND: Medication reviews in primary care provide an opportunity to review and discuss the safety and appropriateness of a person's medicines. However, there is limited evidence about access to and the impact of routine medication reviews for older adults in the general population, particularly in the UK. We aimed to quantify the proportion of people aged 65 years and over with a medication review recorded in 2019 and describe changes in the numbers and types of medicines prescribed following a review. METHODS: We used anonymised primary care electronic health records from the UK's Clinical Practice Research Datalink (CPRD GOLD) to define a population of people aged 65 years or over in 2019. We counted people with a medication review record in 2019 and used Cox regression to estimate associations between demographic characteristics, diagnoses, and prescribed medicines and having a medication review. We used linear regression to compare the number of medicines prescribed as repeat prescriptions in the three months before and after a medication review. Specifically, we compared the 'prescription count' - the maximum number of different medicines with overlapping prescriptions people had in each period. RESULTS: Of 591,726 people prescribed one or more medicines at baseline, 305,526 (51.6%) had a recorded medication review in 2019. Living in a care home (hazard ratio 1.51, 95% confidence interval 1.40-1.62), medication review in the previous year (1.83, 1.69-1.98), and baseline prescription count (e.g. 5-9 vs 1 medicine 1.41, 1.37-1.46) were strongly associated with having a medication review in 2019. Overall, the prescription count tended to increase after a review (mean change 0.13 medicines, 95% CI 0.12-0.14). CONCLUSIONS: Although medication reviews were commonly recorded for people aged 65 years or over, there was little change overall in the numbers and types of medicines prescribed following a review. This study did not examine whether the prescriptions were appropriate or other metrics, such as dose or medicine changes within the same class. However, by examining the impact of medication reviews before the introduction of structured medication review requirements in England in 2020, it provides a useful benchmark which these new reviews can be compared with.

Sex, Age, and Socioeconomic Differences in Nonfatal Stroke Incidence and Subsequent Major Adverse Outcomes.

BACKGROUND AND PURPOSE: Data about variations in stroke incidence and subsequent major adverse outcomes are essential to inform secondary prevention and prioritizing resources to those at the greatest risk of major adverse end points. We aimed to describe the age, sex, and socioeconomic differences in the rates of first nonfatal stroke and subsequent major adverse outcomes. METHODS: The cohort study used linked Clinical Practice Research Datalink and Hospital Episode Statistics data from the United Kingdom. The incidence rate (IR) ratio of first nonfatal stroke and subsequent major adverse outcomes (composite major adverse cardiovascular events, recurrent stroke, cardiovascular disease-related, and all-cause mortality) were calculated and presented by year, sex, age group, and socioeconomic status based on an individual's location of residence, in adults with incident nonfatal stroke diagnosis between 1998 and 2017. RESULTS: A total of 82 774 first nonfatal stroke events were recorded in either primary care or hospital data-an IR of 109.20 per 100 000 person-years (95% CI, 108.46-109.95). Incidence was significantly higher in women compared with men (IR ratio, 1.13 [95% CI, 1.12-1.15]; P<0.001). Rates adjusted for age and sex were higher in the lowest compared with the highest socioeconomic status group (IR ratio, 1.10 [95% CI, 1.08-1.13]; P<0.001). For subsequent major adverse outcomes, the overall incidence for major adverse cardiovascular event was 38.05 per 100 person-years (95% CI, 37.71-38.39) with a slightly higher incidence in women compared with men (38.42 versus 37.62; IR ratio, 1.02 [95% CI, 1.00-1.04]; P=0.0229). Age and socioeconomic status largely accounted for the observed higher incidence of adverse outcomes in women. CONCLUSIONS: In the United Kingdom, incidence of initial stroke and subsequent major adverse outcomes are higher in women, older populations, and people living in socially deprived areas.

Long-term body mass index changes in overweight and obese adults and the risk of heart failure, cardiovascular disease and mortality: a cohort study of over 260,000 adults in the UK.

BACKGROUND: Although obesity is a well-recognised risk factor for cardiovascular disease (CVD), the impact of long-term body mass index (BMI) changes in overweight or obese adults, on the risk of heart failure, CVD and mortality has not been quantified. METHODS: This population-based cohort study used routine UK primary care electronic health data linked to secondary care and death-registry records. We identified adults who were overweight or obese, free from CVD and who had repeated BMI measures. Using group-based trajectory modelling, we examined the BMI trajectories of these individuals and then determined incidence rates of CVD, heart failure and mortality associated with the different trajectories. Cox-proportional hazards regression determined hazards ratios for incident outcomes. RESULTS: 264,230 individuals (mean age 49.5 years (SD 12.7) and mean BMI 33.8 kg/m2 (SD 6.1)) were followed-up for a median duration of 10.9 years. Four BMI trajectories were identified, corresponding at baseline, with World Health Organisation BMI classifications for overweight, class-1, class-2 and class-3 obesity respectively. In all four groups, there was a small, stable upwards trajectory in BMI (mean BMI increase of 1.06 kg/m2 (± 3.8)). Compared with overweight individuals, class-3 obese individuals had hazards ratios (HR) of 3.26 (95% CI 2.98-3.57) for heart failure, HR of 2.72 (2.58-2.87) for all-cause mortality and HR of 3.31 (2.84-3.86) for CVD-related mortality, after adjusting for baseline demographic and cardiovascular risk factors. CONCLUSION: The majority of adults who are overweight or obese retain their degree of overweight or obesity over the long term. Individuals with stable severe obesity experience the worst heart failure, CVD and mortality outcomes. These findings highlight the high cardiovascular toll exacted by continuing failure to tackle obesity.

The changing clinical pattern of endemic Burkitt lymphoma in Western Africa: Experience from a tertiary center in Ghana.

BACKGROUND: Burkitt lymphoma (BL) is the most common childhood cancer in Ghana, where the endemic variant is the predominant subtype and historically presents as a highly chemo-sensitive jaw tumor. This study aimed to update the current epidemiological characteristics of childhood BL in our institution. PROCEDURE: Patient data for all children diagnosed with BL and seen at Korle Bu Teaching Hospital between January 2007 and December 2012 were retrospectively analyzed. RESULTS: BL was diagnosed in 173 children (<13 years) during the study period, with the abdomen as the most common tumor site (46%) followed by the jaw (31%). Abdominal tumors were associated with advanced/disseminated disease (P = 0.002), and were more likely to occur in females irrespective of tumor stage (relative risk = 1.56 [95% CI; 1.1-12.3]). Twenty-five percent (43/173) of the study cohort died and mortality was influenced by increasing age (P = 0.02) and advanced disease (P = 0.03). Treatment delay was experienced by nine in ten patients primarily due to familial financial constraint (75%). Treatment abandonment was observed as a first event in 94% of patients and two thirds of children in the study were eventually lost to follow-up. CONCLUSION: The predominance of primary abdominal tumors in our study cohort may indicate a changing epidemiological pattern of BL in Ghana. High rates of treatment delay and abandonment were evident and are likely to be contributing factors to the poor childhood cancer survival outcomes seen in resource-limited countries in Africa.

Advancing familial hypercholesterolaemia (FH) screening in primary care: an updated systematic review of systematic screening methods for identificaton of FH.

BACKGROUND: Familial Hypercholesterolaemia (FH) is a greatly underdiagnosed and treatable genetic lipid disorder which significantly increases risk of premature cardiovascular disease. The prevalence of monogenic FH is thought to be 1 in 250-350. The NHS Long Term Plan aims to increase FH detection to at least 25% over 5 years in collaboration with primary care, supported by the NHS genomics programme. AIM: This systematic review evaluates systematic screening methods for FH in adults aged ≥18 years in primary care. METHOD: Seven databases [Cochrane, PubMed, Ovid, CINAHL, ProQuest, Web of Science, Scopus], four clinical trial registries [ISRCTN, ANZCTR, Clinicaltrials.gov, WHO-ICTRP] and relevant grey literature [OpenGrey] from March 2020 to May 2023 were searched. Only studies including adults were eligible. Risk of bias was assessed using ROBINS-I. RESULTS: 831 records were screened. No randomised, controlled studies were identified. From full-text review, five eligible non-randomised studies out of 57 (6.90%) were identified. The included studies all used automated FH case-identification from electronic medical records (EMR) and were high quality studies with a moderate risk of bias. Narrative synthesis reported outcomes which included three algorithmic studies, with a pooled detection rate, DR 14.4% (95%CI 11.67-16.62), one supervised Machine Learning [Ensemble] study, DR 15.5% (95%CI 15.47-15.53) and one study utilising a hybrid diagnostic EMR model and/or FH genotype confirmation DR 25.0% (95%CI 16.30-35.8). No adverse effects were reported in these studies. CONCLUSION: Incorporating automated case-finding from EMR with clinical follow-up in primary care can enhance FH identification. Pathways incorporating genotyping showed the best detection rate.

Obesity, metabolic health and clinical outcomes after incident cardiovascular disease: A nationwide population-based cohort study.

BACKGROUND: The association between metabolic syndrome and increased cardiovascular disease (CVD) risk is well-established. However, in patients with incident CVD, the relationship between obesity, metabolic health, and subsequent CVD and mortality outcomes are less well-established. This study investigated the association between body mass index (BMI), metabolic health and the risk of subsequent cardiovascular mortality and morbidity outcomes in patients with incident CVD events. METHODS: This cohort study identified 130 685 patients from the nationwide Clinical Practice Research Datalink (CPRD GOLD) and Hospital Episode Statistics (HES) databases in the United Kingdom. Patients were ≥18 years with incident CVD [coronary heart disease (CHD), stroke, or peripheral vascular disease (PVD)] between 1 January 1998 and 31 December 2017. BMI (in kg/m2 ) was categorized as underweight (<18.5), normal (18.5-24.9), overweight (25.0-29.9) and obese (≥30). Within each BMI category, patients were grouped by increasing count of 1, 2 or 3 metabolic risk factors [RF] (dyslipidaemia, diabetes mellitus and hypertension) and were regarded as metabolically unhealthy while absence of these factors was considered metabolically healthy (MH). Multivariable Cox regression was used to assess the risk (hazard ratio with 95% confidence interval) of subsequent outcomes (non-fatal CHD, stroke, PVD, incident heart failure, CVD-mortality and all-cause mortality) in BMI subgroups with incremental count of metabolic RFs. RESULTS: During a median follow-up of 13.0 years, a higher BMI was associated with reduced risk for stroke, PVD, CVD-mortality and all-cause mortality within each metabolic risk category, while increasing metabolic RFs within each BMI subgroup accounted for increasing risks. When compared with patients with normal BMI and no RF, CVD-mortality risk in overweight patients with no RF was 0.76 (0.70-0.84), and in obese patients with no RF was 0.85 (0.76-0.96). The respective risk for all-cause mortality in patients with overweight and no RF was 0.69 (0.65-0.72), and in obese patients with no RF was 0.75 (0.70-0.79). Subsequent outcomes of stroke and PVD showed similar trends. In contrast, the risk of subsequent non-fatal CHD events and incident HF increased with higher BMI and with incremental metabolic risk factors within each BMI category. Underweight was constantly associated with increased risk for all outcomes regardless of the presence of metabolic RFs except for non-fatal CHD events. CONCLUSIONS: In patients with incident CVD, overweight and obesity were related to a more favourable prognosis for subsequent stroke, PVD and mortality (CVD-related and all-cause) irrespective of the presence of other metabolic risk factors.

Cardiovascular outcomes and mortality after incident ischaemic stroke in patients with a recent cancer history.

BACKGROUND: Up to 10% of patients with ischaemic stroke have comorbid cancer and stroke in these patients is thought to have a poor short-term prognosis. There is little known about the long-term cardiovascular morbidity and mortality outcomes after incident ischaemic stroke in patients with recent cancer history. OBJECTIVE: To assess the risk of subsequent cardiovascular morbidity and mortality outcomes in patients with an incident ischaemic stroke and recent cancer history. METHODS: Patients aged ≥18 years with an incident ischaemic stroke between 1998 and 2017, with any diagnosis of cancer within 12 months before the stroke event, and no prior history of serious vascular event were identified from UK Clinical Practice Research Datalink (CPRD GOLD) linked to Hospital Episode Statistics (HES) data. To minimize selection bias, these patients were propensity-score matched with patients with incident ischaemic stroke and no history of cancer. Propensity-score matching was done using covariates such as demographic data, vascular risk factors, comorbid conditions, and prescribed medication. Multivariable models (Competing risks and Cox regression) were used to determine the risk of subsequent major adverse cardiovascular event (MACE) outcomes and all-cause mortality. RESULTS: Our cohort included 22,460 patients with a median age of 75 (IQR 64-83) years and a follow-up of 12.3 (IQR 7.2-16.7) years. Recent cancer was identified in 1,149 patients (5.1%) at the time of incident ischaemic stroke. The patients with recent cancer history had a lower risk of composite MACE (sub-distribution hazard ratio (SHR) 0.83 [95% CI: 0.75-0.92]) and recurrent stroke (SHR 0.85 95% CI:0.75-0.96]) and a higher risk of all-cause mortality (hazard ratio 1.67 [95% CI:1.47-1.91]). The risk of coronary heart disease, peripheral vascular disease, heart failure, and CVD-related death outcomes did not differ significantly between the groups. CONCLUSIONS: After incident ischaemic stroke, patients with recent cancer history have a lower risk of composite MACE and recurrent stroke outcomes but a higher risk of all-cause mortality when compared with patients without a prior history of cancer.

How does cholesterol burden change the case for investing in familial hypercholesterolaemia? A cost-effectiveness analysis.

BACKGROUND AND AIMS: This study aimed to ascertain how the long-term benefits and costs of diagnosis and treatment of familial hypercholesterolaemia (FH) vary by prognostic factors and 'cholesterol burden', which is the effect of long-term exposure to low-density lipoprotein cholesterol (LDL-C) on cardiovascular disease (CVD) risk. METHODS: A new cost-effectiveness model was developed from the perspective of the UK National Health Service (NHS), informed by routine data from individuals with FH. The primary outcome was net health gain (i.e., health benefits net of the losses due to costs), expressed in quality-adjusted life years (QALYs) at the £15,000/QALY threshold. Prognostic factors included pre-treatment LDL-C, age, gender, and CVD history. RESULTS: If cholesterol burden is considered, diagnosis resulted in positive net health gain (i.e., it is cost-effective) in all individuals with pre-treatment LDL-C ≥ 4 mmol/L, and in those with pre-treatment LDL-C ≥ 2 mmol/L aged ≥50 years or who have CVD history. If cholesterol burden is not considered, diagnosis resulted in lower net health gain, but still positive in children aged 10 years with pre-treatment LDL-C ≥ 6 mmol/L and adults aged 30 years with pre-treatment LDL-C ≥ 4 mmol/L. CONCLUSIONS: Diagnosis and treatment of most people with FH results in large net health gains, particularly in those with higher pre-treatment LDL-C. Economic evaluations of FH interventions should consider the sensitivity of the study conclusions to cholesterol burden, particularly where interventions target younger patients, and explicitly consider prognostic factors such as pre-treatment LDL-C, age, and CVD history.

A population-based study exploring phenotypic clusters and clinical outcomes in stroke using unsupervised machine learning approach.

Individuals developing stroke have varying clinical characteristics, demographic, and biochemical profiles. This heterogeneity in phenotypic characteristics can impact on cardiovascular disease (CVD) morbidity and mortality outcomes. This study uses a novel clustering approach to stratify individuals with incident stroke into phenotypic clusters and evaluates the differential burden of recurrent stroke and other cardiovascular outcomes. We used linked clinical data from primary care, hospitalisations, and death records in the UK. A data-driven clustering analysis (kamila algorithm) was used in 48,114 patients aged ≥ 18 years with incident stroke, from 1-Jan-1998 to 31-Dec-2017 and no prior history of serious vascular events. Cox proportional hazards regression was used to estimate hazard ratios (HRs) for subsequent adverse outcomes, for each of the generated clusters. Adverse outcomes included coronary heart disease (CHD), recurrent stroke, peripheral vascular disease (PVD), heart failure, CVD-related and all-cause mortality. Four distinct phenotypes with varying underlying clinical characteristics were identified in patients with incident stroke. Compared with cluster 1 (n = 5,201, 10.8%), the risk of composite recurrent stroke and CVD-related mortality was higher in the other 3 clusters (cluster 2 [n = 18,655, 38.8%]: hazard ratio [HR], 1.07; 95% CI, 1.02-1.12; cluster 3 [n = 10,244, 21.3%]: HR, 1.20; 95% CI, 1.14-1.26; and cluster 4 [n = 14,014, 29.1%]: HR, 1.44; 95% CI: 1.37-1.50). Similar trends in risk were observed for composite recurrent stroke and all-cause mortality outcome, and subsequent recurrent stroke outcome. However, results were not consistent for subsequent risk in CHD, PVD, heart failure, CVD-related mortality, and all-cause mortality. In this proof of principle study, we demonstrated how a heterogenous population of patients with incident stroke can be stratified into four relatively homogenous phenotypes with differential risk of recurrent and major cardiovascular outcomes. This offers an opportunity to revisit the stratification of care for patients with incident stroke to improve patient outcomes.

Association between pain intensity and depressive symptoms in community-dwelling adults: longitudinal findings from the Survey of Health, Ageing and Retirement in Europe (SHARE).

PURPOSE: To investigate the longitudinal associations between pain and depressive symptoms in adults. METHODS: Prospective cohort study on data from 28,515 community-dwelling adults ≥ 50 years, free from depression at baseline (Wave 5), with follow-up in Wave 6 of the Survey of Health, Ageing and Retirement in Europe (SHARE). Significant depressive symptoms were defined by a EURO-D score ≥ 4. The longitudinal association between baseline pain intensity and significant depressive symptoms at follow-up was analysed using logistic regression models; odds ratios (ORs) and confidence intervals (CI) were calculated, adjusting for socio-demographic and clinical factors, physical inactivity, loneliness, mobility and functional impairments. RESULTS: Mean age was 65.4 years (standard deviation 9.0, range 50-99); 14,360 (50.4%) participants were women. Mean follow-up was 23.4 (standard deviation 3.4) months. At baseline, 2803 (9.8%) participants reported mild pain, 5253 (18.4%) moderate pain and 1431 (5.0%) severe pain. At follow-up, 3868 (13.6%) participants-1451 (10.3%) men and 2417 (16.8%) women-reported significant depressive symptoms. After adjustment, mild, moderate and severe baseline pain, versus no pain, were associated with an increased likelihood of significant depressive symptoms at follow-up: ORs (95% CI) were 1.20 (1.06-1.35), 1.32 (1.20-1.46) and 1.39 (1.19-1.63), respectively. These associations were more pronounced in men compared to women, and consistent in participants aged 50-64 years, those without mobility or functional impairment, and those without loneliness at baseline. CONCLUSION: Higher baseline pain intensity was longitudinally associated with a greater risk of significant depressive symptoms at 2-year follow-up, in community-dwelling adults without baseline depression.

Alternative cascade-testing protocols for identifying and managing patients with familial hypercholesterolaemia: systematic reviews, qualitative study and cost-effectiveness analysis.

Background: Cascade testing the relatives of people with familial hypercholesterolaemia is an efficient approach to identifying familial hypercholesterolaemia. The cascade-testing protocol starts with identifying an index patient with familial hypercholesterolaemia, followed by one of three approaches to contact other relatives: indirect approach, whereby index patients contact their relatives; direct approach, whereby the specialist contacts the relatives; or a combination of both direct and indirect approaches. However, it is unclear which protocol may be most effective. Objectives: The objectives were to determine the yield of cases from different cascade-testing protocols, treatment patterns, and short- and long-term outcomes for people with familial hypercholesterolaemia; to evaluate the cost-effectiveness of alternative protocols for familial hypercholesterolaemia cascade testing; and to qualitatively assess the acceptability of different cascade-testing protocols to individuals and families with familial hypercholesterolaemia, and to health-care providers. Design and methods: This study comprised systematic reviews and analysis of three data sets: PASS (PASS Software, Rijswijk, the Netherlands) hospital familial hypercholesterolaemia databases, the Clinical Practice Research Datalink (CPRD)-Hospital Episode Statistics (HES) linked primary-secondary care data set, and a specialist familial hypercholesterolaemia register. Cost-effectiveness modelling, incorporating preceding analyses, was undertaken. Acceptability was examined in interviews with patients, relatives and health-care professionals. Result: Systematic review of protocols: based on data from 4 of the 24 studies, the combined approach led to a slightly higher yield of relatives tested [40%, 95% confidence interval (CI) 37% to 42%] than the direct (33%, 95% CI 28% to 39%) or indirect approaches alone (34%, 95% CI 30% to 37%). The PASS databases identified that those contacted directly were more likely to complete cascade testing (p < 0.01); the CPRD-HES data set indicated that 70% did not achieve target treatment levels, and demonstrated increased cardiovascular disease risk among these individuals, compared with controls (hazard ratio 9.14, 95% CI 8.55 to 9.76). The specialist familial hypercholesterolaemia register confirmed excessive cardiovascular morbidity (standardised morbidity ratio 7.17, 95% CI 6.79 to 7.56). Cost-effectiveness modelling found a net health gain from diagnosis of -0.27 to 2.51 quality-adjusted life-years at the willingness-to-pay threshold of £15,000 per quality-adjusted life-year gained. The cost-effective protocols cascaded from genetically confirmed index cases by contacting first- and second-degree relatives simultaneously and directly. Interviews found a service-led direct-contact approach was more reliable, but combining direct and indirect approaches, guided by index patients and family relationships, may be more acceptable. Limitations: Systematic reviews were not used in the economic analysis, as relevant studies were lacking or of poor quality. As only a proportion of those with primary care-coded familial hypercholesterolaemia are likely to actually have familial hypercholesterolaemia, CPRD analyses are likely to underestimate the true effect. The cost-effectiveness analysis required assumptions related to the long-term cardiovascular disease risk, the effect of treatment on cholesterol and the generalisability of estimates from the data sets. Interview recruitment was limited to white English-speaking participants. Conclusions: Based on limited evidence, most cost-effective cascade-testing protocols, diagnosing most relatives, select index cases by genetic testing, with services directly contacting relatives, and contacting second-degree relatives even if first-degree relatives have not been tested. Combined approaches to contact relatives may be more suitable for some families. Future work: Establish a long-term familial hypercholesterolaemia cohort, measuring cholesterol levels, treatment and cardiovascular outcomes. Conduct a randomised study comparing different approaches to contact relatives. Study registration: This study is registered as PROSPERO CRD42018117445 and CRD42019125775. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 16. See the NIHR Journals Library website for further project information.

Familial hypercholesterolaemia is an inherited condition that causes raised cholesterol levels from birth and increases risk of heart disease if left untreated. After someone in a family is found to have familial hypercholesterolaemia (called an index case), their close relatives need to be contacted and checked to see if they have familial hypercholesterolaemia, using genetic or cholesterol testing. This is called 'cascade testing'. We planned to find the most cost-effective and acceptable way to do this. The relatives could be contacted for testing by the index case (indirect approach), by a health-care professional (direct approach) or by a combination of both approaches. We found, based on looking at hospital records, that more relatives were tested if health-care professionals directly contacted relatives. In previous studies, slightly more relatives were tested for familial hypercholesterolaemia with a combination approach. Interviews with patients also suggested that the direct approach was the most effective, but the most acceptable and successful approach depends on family relationships: using one approach for some families and using both for other families. Furthermore, by looking at the health-care records of large numbers of patients, we confirmed that people with a recorded diagnosis of familial hypercholesterolaemia in general practice records have a much higher risk of heart disease than the general population, and this was especially so for those with previous heart disease and/or raised cholesterols levels when diagnosed. However, one-quarter of new patients with familial hypercholesterolaemia recorded in their records were not treated within 2 years, with less than one-third reaching recommended cholesterol levels. We used what we had learned to help us estimate the most cost-effective way to do cascade testing. This showed that if the health service directly contact all relatives simultaneously for further assessment, rather than the current approach whereby close (first-degree) relatives are contacted first, this was cost-effective and good value for money.

Behaviours of Patients Who Take Their Strong Opioids as Unmeasured 'Sips'.

CONTEXT: Some patients take their strong opioid painkillers as unmeasured sips. OBJECTIVES: To investigate how and why patients take their medication in this way. METHODS: Patient receiving specialist palliative care who take their strong opioid painkillers as unmeasured sips were recruited. Measurement was made of the mass of two sips per patient and qualitative interviews using a topic guide were conducted. Interview transcripts were thematically analyzed using a phenomenological approach. RESULTS: Only two of 16 patients were taking within 20% of the correct dose of their breakthrough liquid strong analgesia. Many varied the dose depending on the severity of the pain episode. Convenience, confusion about the correct dose, and issues with spoons were the other main reasons for people choosing to sip. CONCLUSION: This is the first published study exploring the behavior of patients who take their strong analgesia as unmeasured sips. Knowing that patients who sip are likely to be taking an incorrect dose, and the reasons behind sipping may help clinicians to help these patients to manage their pain better.

Does acupressure help reduce nausea and vomiting in palliative care patients? A double blind randomised controlled trial.

INTRODUCTION: Nausea and vomiting are common symptoms for patients with advanced cancer. While there is evidence for acupuncture point stimulation for treatment of these symptoms for patients having anticancer treatment, there is little for when they are not related to such treatment. OBJECTIVE: To determine whether acupressure at the pericardium 6 site can help in the treatment of nausea and vomiting suffered by palliative care patients with advanced cancer. MATERIALS AND METHODS: Double blind randomised controlled trial-active versus placebo acupressure wristbands. In-patients with advanced cancer in two specialist palliative care units who fitted either or both of the following criteria were approached: Nausea that was at least moderate; Vomiting daily on average for the prior 3 days. RESULTS: 57 patients were randomised to have either active or placebo acupressure wristbands. There was no difference in any of the outcome measures between the two groups: change from baseline number of vomits; Visual Analogue Scale for 'did acupressure wristbands help you to feel better?'; total number of as needed doses of antiemetic medication; need for escalation of antiemetics. CONCLUSIONS: In contrast to a previously published feasibility study, active acupressure wristbands were no better than placebo for specialist palliative care in-patients with advanced cancer and nausea and vomiting.

Comparison of Risk of Serious Cardiovascular Events after Hemorrhagic versus Ischemic Stroke: A Population-Based Study.

BACKGROUND: Patients with ischemic stroke are considered a very high risk population for subsequent cardiovascular events and guidelines recommend intensive preventive strategies. However, there is no clear recommendation that patients with hemorrhagic stroke should also be regarded as a very high cardiovascular risk population. OBJECTIVE: To compare the risk of subsequent cardiovascular morbidity/mortality between patients with incident hemorrhagic and ischemic stroke. METHODS: Patients aged ≥18 years with incident hemorrhagic or ischemic stroke between 1998 and 2017 and no prior history of serious vascular event were identified from UK Clinical Practice Research Datalink (CPRD GOLD) linked to Hospital Episode Statistics data. RESULTS: The cohort included 32,091 patients with an overall follow-up of 381,237 person-years (median: 11.8 years). After adjusting for potential confounders, patients with incident hemorrhagic stroke had no significantly different risk of subsequent cardiovascular morbidity compared with patients with incident ischemic stroke-coronary heart disease (CHD; hazard ratio [HR]: 0.86, 95% confidence interval [CI]: 0.56-1.32), recurrent stroke (HR: 0.92, 95% CI: 0.83-1.02), peripheral vascular disease (PVD; HR: 1.15, 95% CI:0.56-2.38), or heart failure (HR: 1.03, 95% CI: 0.61-1.74). Patients with incident hemorrhagic stroke had significantly higher risk of subsequent cardiovascular disease (CVD)-related mortality (HR: 2.35, 95% CI: 2.04-2.72) and all-cause mortality (HR: 2.16, 95% CI: 1.94-2.41). Propensity-score matched analysis of 1,039 patients with hemorrhagic stroke and 1,039 with ischemic stroke showed similar risk in subsequent cardiovascular morbidity-CHD (stratified HR [sHR]: 0.92, 95% CI: 0.55-1.54), recurrent stroke (sHR: 0.93, 95% CI: 0.82-1.02), PVD (sHR: 1.04 95% CI: 0.45-2.41), or heart failure (sHR: 0.71, 95% CI: 0.39-1.27). CONCLUSION: The risk of subsequent cardiovascular events is similar between patients with incident hemorrhagic and ischemic stroke. Patients with previous hemorrhagic stroke should be regarded as a population at very high risk for subsequent CVD.

Understanding the barriers and enablers of pharmacogenomic testing in primary care: a qualitative systematic review with meta-aggregation synthesis.

Introduction: Pharmacogenomic testing can indicate which drugs may have limited therapeutic action or lead to adverse effects, hence guiding rational and safe prescribing. However, in the UK and other countries, there are still significant barriers to implementation of testing in primary care. Objective: This systematic review presents the barriers and enablers to the implementation of pharmacogenomics in primary care setting. Materials & methods: MEDLINE, EMBASE, PsycINFO and CINAHL databases were searched through to July 2020 for studies that reported primary qualitative data of primary care professionals and patient views. Following screening, data extraction and quality assessment, data synthesis was undertaken using meta-aggregation based on the theoretical domain's framework (TDF). Confidence in the synthesized findings relating to credibility and dependability was established using CONQual. Eligible papers were categorized into six TDF domains - knowledge; social and professional roles; behavioral regulation; beliefs and consequences; environmental context and resources; and social influences. Results: From 1669 citations, eighteen eligible studies were identified across seven countries, with a sample size of 504 participants including both primary care professionals and patients. From the data, 15 synthesized statements, all with moderate CONQual rating emerged. These categories range from knowledge, awareness among Primary Care Physicians and patients, professional relationships, negative impact of PGx, belief that PGx can reduce adverse drug reactions, clinical evidence, cost-effectiveness, informatics, reporting issues and social issues. Conclusion: Through use of TDF, fifteen synthesized statements provide policymakers with valuable recommendations for the implementation of pharmacogenomics in primary care. In preparation, policymakers need to consider the introduction of effective educational strategies for both PCPs and patients to raise knowledge, awareness, and engagement. The actual introduction of PGx will require reorganization with decision support tools to aid use of PGx in primary care, with a clear delegation of roles and responsibilities between general professionals and pharmacists supplemented by a local pool of experts. Furthermore, policy makers need to address the cost effectiveness of pharmacogenomics and having appropriate infrastructure supporting testing and interpretation including informatic solutions for utilizing pharmacogenomic results.

Electronic health record-based facilitation of familial hypercholesterolaemia detection sensitivity of different algorithms in genetically confirmed patients.

Aims: Familial hypercholesterolaemia (FH) is a disorder of LDL cholesterol clearance, resulting in increased risk of cardiovascular disease. Recently, we developed a Dutch Lipid Clinic Network (DLCN) criteria-based algorithm to facilitate FH detection in electronic health records (EHRs). In this study, we investigated the sensitivity of this and other algorithms in a genetically confirmed FH population. Methods and results: All patients with a healthcare insurance-related coded diagnosis of 'primary dyslipidaemia' between 2018 and 2020 were assessed for genetically confirmed FH. Data were extracted at the time of genetic confirmation of FH (T1) and during the first visit in 2018-2020 (T2). We assessed the sensitivity of algorithms on T1 and T2 for DLCN ≥ 6 and compared with other algorithms [familial hypercholesterolaemia case ascertainment tool (FAMCAT), Make Early Diagnoses to Prevent Early Death (MEDPED), and Simon Broome (SB)] using EHR-coded data and using all available data (i.e. including non-coded free text). 208 patients with genetically confirmed FH were included. The sensitivity (95% CI) on T1 and T2 with EHR-coded data for DLCN ≥ 6 was 19% (14-25%) and 22% (17-28%), respectively. When using all available data, the sensitivity for DLCN ≥ 6 was 26% (20-32%) on T1 and 28% (22-34%) on T2. For FAMCAT, the sensitivity with EHR-coded data on T1 was 74% (67-79%) and 32% (26-39%) on T2, whilst sensitivity with all available data was 81% on T1 (75-86%) and 45% (39-52%) on T2. For Make Early Diagnoses to Prevent Early Death MEDPED and SB, using all available data, the sensitivity on T1 was 31% (25-37%) and 17% (13-23%), respectively. Conclusions: The FAMCAT algorithm had significantly better sensitivity than DLCN, MEDPED, and SB. FAMCAT has the best potential for FH case-finding using EHRs.

Cost-Effectiveness of Screening Algorithms for Familial Hypercholesterolaemia in Primary Care.

Although familial hypercholesterolemia (FH) screening within primary care is considered cost-effective, which screening approach is cost-effective has not been established. This study determines the cost-effectiveness of six case-finding strategies for screening of electronic health records to identify index patients who have genetically confirmed monogenic FH in English primary care. A decision tree was constructed to represent pathways of care for each approach (FH Case Identification Tool (FAMCAT) versions 1 and 2, cholesterol screening, Dutch Lipid Clinic Network (DLCN), Simon Broome criteria, no active screening). Clinical effectiveness was measured as the number of monogenic FH cases identified. Healthcare costs for each algorithm were evaluated from an NHS England perspective over a 12 week time horizon. The primary outcome was the incremental cost per additional monogenic FH case identified (ICER). FAMCAT2 was found to dominate (cheaper and more effective) cholesterol and FAMCAT1 algorithms, and extendedly dominate DLCN. The ICER for FAMCAT2 vs. no active screening was 8111 GBP (95% CI: 4088 to 14,865), and for Simon Broome vs. FAMCAT2 was 74,059 GBP (95% CI: -1,113,172 to 1,697,142). Simon Broome found the largest number of FH cases yet required 102 genetic tests to identify one FH patient. FAMCAT2 identified fewer, but only required 23 genetic tests.

Development and Validation of Population Clusters for Integrating Health and Social Care: Protocol for a Mixed Methods Study in Multiple Long-Term Conditions (Cluster-Artificial Intelligence for Multiple Long-Term Conditions).

BACKGROUND: Multiple long-term health conditions (multimorbidity) (MLTC-M) are increasingly prevalent and associated with high rates of morbidity, mortality, and health care expenditure. Strategies to address this have primarily focused on the biological aspects of disease, but MLTC-M also result from and are associated with additional psychosocial, economic, and environmental barriers. A shift toward more personalized, holistic, and integrated care could be effective. This could be made more efficient by identifying groups of populations based on their health and social needs. In turn, these will contribute to evidence-based solutions supporting delivery of interventions tailored to address the needs pertinent to each cluster. Evidence is needed on how to generate clusters based on health and social needs and quantify the impact of clusters on long-term health and costs. OBJECTIVE: We intend to develop and validate population clusters that consider determinants of health and social care needs for people with MLTC-M using data-driven machine learning (ML) methods compared to expert-driven approaches within primary care national databases, followed by evaluation of cluster trajectories and their association with health outcomes and costs. METHODS: The mixed methods program of work with parallel work streams include the following: (1) qualitative semistructured interview studies exploring patient, caregiver, and professional views on clinical and socioeconomic factors influencing experiences of living with or seeking care in MLTC-M; (2) modified Delphi with relevant stakeholders to generate variables on health and social (wider) determinants and to examine the feasibility of including these variables within existing primary care databases; and (3) cohort study with expert-driven segmentation, alongside data-driven algorithms. Outputs will be compared, clusters characterized, and trajectories over time examined to quantify associations with mortality, additional long-term conditions, worsening frailty, disease severity, and 10-year health and social care costs. RESULTS: The study will commence in October 2021 and is expected to be completed by October 2023. CONCLUSIONS: By studying MLTC-M clusters, we will assess how more personalized care can be developed, how accurate costs can be provided, and how to better understand the personal and medical profiles and environment of individuals within each cluster. Integrated care that considers "whole persons" and their environment is essential in addressing the complex, diverse, and individual needs of people living with MLTC-M. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/34405.

Statin treatment and LDL-cholesterol treatment goal attainment among individuals with familial hypercholesterolaemia in primary care.

OBJECTIVES: Guidance recommends statin treatment in familial hypercholesterolaemia (FH) to achieve at least a 50% reduction in low-density lipoprotein cholesterol (LDL-C). We assessed statin prescribing rates and LDL-C treatment goal attainment among individuals with FH in primary care. METHODS: Using primary care electronic health records from the UK Clinical Practice Research Datalink, we identified adults with recorded diagnosis of FH, statin treatment and measures of LDL-C prior to (baseline) and 12 months after initiating statin treatment. The percentage change in LDL-C was determined, and then baseline and treatment characteristics were assessed by LDL-C treatment goal attainment. RESULTS: Of 3064 adults (mean age 50.8 years) with recorded diagnosis of FH and repeat LDL-C measures, 50% reduction in LDL-C from baseline was attained in 895 individuals (29.2%) in 12 months. Compared with those who did not attain this goal, these people were predominantly women; they were older at time of FH diagnosis (53.4 years vs 49.7 years) and first statin treatment (53.2 years vs 49.2 years) and had higher pretreatment total cholesterol (8.20 (SD 1.38) mmol/L vs 7.57 (SD 1.39) mmol/L) and pretreatment LDL-C (5.83 (SD 1.36) mmol/L vs 5.25 (SD 1.40) mmol/L). A higher proportion of individuals who attained the treatment goal was prescribed high-potency and medium-potency statins (24.3% and 71.7% vs 20.2% and 69.3%, respectively). CONCLUSIONS: Less than a third of individuals on statin treatment for FH in the community achieve recommended reductions in LDL-C. Greater awareness and optimisation of treatment for FH using higher-potency statins are needed.