The interaction of transmission intensity, mortality, and the economy: a retrospective analysis of the COVID-19 pandemic

The COVID-19 pandemic has caused over 6.4 million registered deaths to date, and has had a profound impact on economic activity. Here, we study the interaction of transmission, mortality, and the economy during the SARS-CoV-2 pandemic from January 2020 to December 2022 across 25 European countries. We adopt a Bayesian vector autoregressive model with both fixed and random effects. We find that increases in disease transmission intensity decreases Gross domestic product (GDP) and increases daily excess deaths, with a longer lasting impact on excess deaths in comparison to GDP, which recovers more rapidly. Broadly, our results reinforce the intuitive phenomenon that significant economic activity arises from diverse person-to-person interactions. We report on the effectiveness of non-pharmaceutical interventions (NPIs) on transmission intensity, excess deaths and changes in GDP, and resulting implications for policy makers. Our results highlight a complex cost-benefit trade off from individual NPIs. For example, banning international travel increases GDP however reduces excess deaths. We consider country random effects and their associations with excess changes in GDP and excess deaths. For example, more developed countries in Europe typically had more cautious approaches to the COVID-19 pandemic, prioritising healthcare and excess deaths over economic performance. Long term economic impairments are not fully captured by our model, as well as long term disease effects (Long Covid). Our results highlight that the impact of disease on a country is complex and multifaceted, and simple heuristic conclusions to extract the best outcome from the economy and disease burden are challenging

Cardiovascular disease morbidity is associated with social deprivation in subjects with familial hypercholesterolaemia (FH): A retrospective cohort study of individuals with FH in UK primary care and the UK Simon Broome register, linked with national hospital records

Background: Social deprivation is associated with higher cardiovascular disease (CVD) morbidity and mortality. We examined whether this is also observed in people with Familial Hypercholesterolaemia (FH). // Methods: Subjects with FH and linked secondary care records in Hospital Episode Statistics (HES) were identified from UK Clinical Practice Research Datalink (CPRD) and the Simon Broome (SB) adult FH register. Cox proportional hazards regression estimated hazard ratios (HR) for composite CVD outcomes (first HES outcome of coronary heart disease, myocardial infarction, angina, stroke, transient ischaemic attack, peripheral vascular disease, heart failure, coronary revascularisation interventions (PCI and CABG)) in Index of Multiple Deprivation (IMD) quintiles. // Results: We identified 4309 patients with FH in CPRD (1988–2020) and 2956 in the SB register. Both cohorts had considerably fewer subjects in the most deprived compared to the least deprived quintile (60 % lower in CPRD and 52 % lower in SB). In CPRD, the most deprived individuals had higher unadjusted HRs for composite CVD (HR 1.71 [CI 1.22–2.40]), coronary heart disease (HR 1.63 [1.11–2.40]) and mortality (HR 1.58 [1.02–2.47]) compared to the least deprived but these became insignificant after adjusting for age, sex, smoking and alcohol consumption. In the SB register, hazard ratios for composite CVD increased with increasing deprivation quintiles and remained significant after adjustment for age, sex, smoking and alcohol consumption (adjusted HR in quintile 5 vs quintile 1 = 1.83 [1.54–2.17]). // Conclusions: Strikingly fewer individuals with FH are identified from lower socioeconomic groups, though the most deprived FH patients have the highest risk of CVD and mortality. In CPRD, this risk was largely explained by smoking and alcohol consumption, but not in the SB register. More effective strategies to detect FH and optimise risk factor management, are needed in lower socioeconomic groups

Optimizing social and economic activity while containing SARS-CoV-2 transmission using DAEDALUS

To study the trade-off between economic, social and health outcomes in the management of a pandemic, DAEDALUS integrates a dynamic epidemiological model of SARS-CoV-2 transmission with a multi-sector economic model, reflecting sectoral heterogeneity in transmission and complex supply chains. The model identifies mitigation strategies that optimize economic production while constraining infections so that hospital capacity is not exceeded but allowing essential services, including much of the education sector, to remain active. The model differentiates closures by economic sector, keeping those sectors open that contribute little to transmission but much to economic output and those that produce essential services as intermediate or final consumption products. In an illustrative application to 63 sectors in the United Kingdom, the model achieves an economic gain of between £161 billion (24%) and £193 billion (29%) compared to a blanket lockdown of non-essential activities over six months. Although it has been designed for SARS-CoV-2, DAEDALUS is sufficiently flexible to be applicable to pandemics with different epidemiological characteristics

Coronary heart disease mortality in treated familial hypercholesterolaemia: Update of the UK Simon Broome FH register

BACKGROUND AND AIMS: Patients with familial hypercholesterolaemia (FH) have an elevated risk of coronary heart disease (CHD). Here we compare changes in CHD mortality in patients with heterozygous (FH) pre 1992, before lipid-lowering therapy with statins was used routinely, and in the periods 1992–2008 and 2008–2016. METHODS: 1903 Definite (DFH) and 1650 Possible (PFH) patients (51% women) aged 20–79 years, recruited from 21 lipid clinics in the United Kingdom and followed prospectively between 1980 and 2016 for 67,060 person-years. The CHD standardised mortality ratio (SMR) compared to the population in England and Wales was calculated (with 95% Confidence intervals). RESULTS: There were 585 deaths, including 252 from CHD. Overall, the observed 2.4-fold excess coronary mortality for treated DFH post-1991 was significantly higher than the 1.78 excess for PFH (35% 95% CI 3%–76%). In patients with DFH and established coronary disease, there was a significant excess coronary mortality in all time periods, but in men it was reduced from a 4.83-fold excess (2.32–8.89) pre-1992 to 4.66 (3.46–6.14) in 1992–2008 and 2.51 (1.01–5.17) post-2008, while in women the corresponding values were 7.23 (2.65–15.73), 4.42 (2.70–6.82) and 6.34 (2.06–14.81). Primary prevention in men with DFH resulted in a progressive reduction in coronary mortality over the three time-periods, with no excess mortality evident post-2008 (0.89 (0.29–2.08)), although in women the excess persisted (post-2008 3.65 (1.75–6.72)). CONCLUSIONS: The results confirm the benefit of statin treatment in reducing CHD mortality, but suggest that FH patients with pre-existing CHD and women with FH may not be treated adequately

Urinary albumin/creatinine ratio tertiles predict risk of diabetic retinopathy progression: a natural history study from the Adolescent Cardio-Renal Intervention Trial (AdDIT) observational cohort

Aims/hypothesis: We hypothesised that adolescents with type 1 diabetes with a urinary albumin/creatinine ratio (ACR) in the upper tertile of the normal range (high ACR) are at greater risk of three-step diabetic retinopathy progression (3DR) independent of glycaemic control. Methods: This was a prospective observational study in 710 normoalbuminuric adolescents with type 1 diabetes from the non-intervention cohorts of the Adolescent Cardio-Renal Intervention Trial (AdDIT). Participants were classified as ‘high ACR’ or ‘low ACR’ (lowest and middle ACR tertiles) using baseline standardised log10 ACR. The primary outcome, 3DR, was determined from centrally graded, standardised two-field retinal photographs. 3DR risk was determined using multivariable Cox regression for the effect of high ACR, with HbA1c, BP, LDL-cholesterol and BMI as covariates; diabetes duration was the time-dependent variable. Results: At baseline mean ± SD age was 14.3 ± 1.6 years and mean ± SD diabetes duration was 7.2 ± 3.3 years. After a median of 3.2 years, 83/710 (12%) had developed 3DR. In multivariable analysis, high ACR (HR 2.1 [1.3, 3.3], p=0.001), higher mean IFCC HbA1c (HR 1.03 [1.01, 1.04], p=0.001) and higher baseline diastolic BP SD score (HR 1.43 [1.08, 1.89], p=0.01) were independently associated with 3DR risk. Conclusions/interpretation: High ACR is associated with greater risk of 3DR in adolescents, providing a target for future intervention studies

Vascular Effects of ACE (Angiotensin-Converting Enzyme) Inhibitors and Statins in Adolescents With Type 1 Diabetes

An increased albumin-creatinine ratio within the normal range can identify adolescents at higher risk of developing adverse cardio-renal outcomes as they progress into adulthood. Utilizing a parallel randomized controlled trial and observational cohort study, we characterized the progression of vascular phenotypes throughout this important period and investigated the effect of ACE (angiotensin-converting enzyme) inhibitors and statins in high-risk adolescents. Endothelial function (flow-mediated dilation and reactive hyperemia index) and arterial stiffness (carotid-femoral pulse wave velocity) were assessed in 158 high-risk participants recruited to a randomized, double-blind placebo-controlled 2×2 factorial trial (randomized, placebo-controlled trial) of ACE inhibitors and/or statins in adolescents with type 1 diabetes (AdDIT [Adolescent Type 1 Diabetes cardio-renal Intervention Trial]). Identical measures were also assessed in 215 lower-risk individuals recruited to a parallel observational study. In the randomized, placebo-controlled trial, high-risk patients randomized to ACE inhibitors had improved flow-mediated dilation after 2 to 4 years of follow-up (mean [95% CI]: 6.6% [6.0-7.2] versus 5.3% [4.7-5.9]; P=0.005), whereas no effect was observed following statin use (6.2% [5.5-6.8] versus 5.8% [5.1-6.4]; P=0.358). In the observational study, patients classed as high-risk based on albumin-creatinine ratio showed evidence of endothelial dysfunction at the end of follow-up (flow-mediated dilation=4.8% [3.8-5.9] versus 6.3% [5.8-6.7] for high-risk versus low-risk groups; P=0.015). Neither reactive hyperemia index nor pulse wave velocity were affected by either treatment (P>0.05 for both), but both were found to increase over the duration of follow-up (0.07 [0.03-0.12]; P=0.001 and 0.5 m/s [0.4-0.6]; P<0.001 for reactive hyperemia index and pulse wave velocity, respectively). ACE inhibitors improve endothelial function in high-risk adolescents as they transition through puberty. The longer-term protective effects of this intervention at this early age remain to be determined. Registration- URL: https://www.clinicaltrials.gov; Unique identifier NCT01581476

The role of guidelines and the patient's life-style in GPs' management of hypercholesterolaemia

BACKGROUND: Recent Swedish and joint European guidelines on hyperlipidaemia stress the high coronary risk for patients with already established arterio-sclerotic disease (secondary prevention) or diabetes. For the remaining group, calculation of the ten-year risk for coronary events using the Framingham equation is suggested. There is evidence that use of and adherence to guidelines is incomplete and that tools for risk estimations are seldom used. Intuitive risk estimates are difficult and systematically biased. The purpose of the study was to examine how GPs use knowledge of guidelines in their decisions to recommend or not recommend a cholesterol-lowering drug and the reasons for their decisions. METHODS: Twenty GPs were exposed to six case vignettes presented on a computer. In the course of six screens, successively more information was added to the case. The doctors were instructed to think aloud while processing the cases (Think-Aloud Protocols) and finally to decide for or against drug treatment. After the six cases they were asked to describe how they usually reason when they meet patients with high cholesterol values (Free-Report Protocols). The two sets of protocols were coded for cause-effect relations that were supposed to reflect the doctors' knowledge of guidelines. The Think-Aloud Protocols were also searched for reasons for the decisions to prescribe or not to prescribe. RESULTS: According to the protocols, the GPs were well aware of the importance of previous coronary heart disease and diabetes in their decisions. On the other hand, only a few doctors mentioned other arterio-sclerotic diseases like stroke and peripheral artery disease as variables affecting their decisions. There were several instances when the doctors' decisions apparently deviated from their knowledge of the guidelines. The arguments for the decisions in these cases often concerned aspects of the patient's life-style like smoking or overweight- either as risk-increasing factors or as alternative strategies for intervention. CONCLUSIONS: Coding verbal protocols for knowledge and for decision arguments seems to be a valuable tool for increasing our understanding of how guidelines are used in the on treatment of hypercholesterolaemia. By analysing arguments for treatment decisions it was often possible to understand why departures from the guidelines were made. While the need for decision support is obvious, the current guidelines may be too simple in some respects

ACE Inhibitors and Statins in Adolescents with Type 1 Diabetes

BACKGROUND: Among adolescents with type 1 diabetes, rapid increases in albumin excretion during puberty precede the development of microalbuminuria and macroalbuminuria, long-term risk factors for renal and cardiovascular disease. We hypothesized that adolescents with high levels of albumin excretion might benefit from angiotensin-converting-enzyme (ACE) inhibitors and statins, drugs that have not been fully evaluated in adolescents. METHODS: We screened 4407 adolescents with type 1 diabetes between the ages of 10 and 16 years of age and identified 1287 with values in the upper third of the albumin-to-creatinine ratios; 443 were randomly assigned in a placebo-controlled trial of an ACE inhibitor and a statin with the use of a 2-by-2 factorial design minimizing differences in baseline characteristics such as age, sex, and duration of diabetes. The primary outcome for both interventions was the change in albumin excretion, assessed according to the albumin-to-creatinine ratio calculated from three early-morning urine samples obtained every 6 months over 2 to 4 years, and expressed as the area under the curve. Key secondary outcomes included the development of microalbuminuria, progression of retinopathy, changes in the glomerular filtration rate, lipid levels, and measures of cardiovascular risk (carotid intima-media thickness and levels of high-sensitivity C-reactive protein and asymmetric dimethylarginine). RESULTS: The primary outcome was not affected by ACE inhibitor therapy, statin therapy, or the combination of the two. The use of an ACE inhibitor was associated with a lower incidence of microalbuminuria than the use of placebo; in the context of negative findings for the primary outcome and statistical analysis plan, this lower incidence was not considered significant (hazard ratio, 0.57; 95% confidence interval, 0.35 to 0.94). Statin use resulted in significant reductions in total, low-density lipoprotein, and non-high-density lipoprotein cholesterol levels, in triglyceride levels, and in the ratio of apolipoprotein B to apolipoprotein A1, whereas neither drug had significant effects on carotid intima-media thickness, other cardiovascular markers, the glomerular filtration rate, or progression of retinopathy. Overall adherence to the drug regimen was 75%, and serious adverse events were similar across the groups. CONCLUSIONS: The use of an ACE inhibitor and a statin did not change the albumin-to-creatinine ratio over time. (Funded by the Juvenile Diabetes Research Foundation and others; AdDIT ClinicalTrials.gov number, NCT01581476 .)

Subjects with Molecularly Defined Familial Hypercholesterolemia or Familial Defective apoB-100 Are Not Being Adequately Treated

To study whether subjects with a molecular genetic diagnosis of familial hypercholesterolemia (FH) or familial defective apoB-100 (FDB) are being adequately treated.A questionnaire regarding medical history was sent to 2611 subjects who had been provided with a molecular genetic diagnosis of FH or FDB, and a blood sample was obtained for lipid measurements.956 (36.6%) of the 2611 subjects participated. The mean age for starting lipid-lowering therapy was 33.4 (±12.1) years. Among those below 18 years of age, only 20.4% were on lipid-lowering drugs, whereas 89.1% of those aged 18 and above were on lipid-lowering drugs. The mean levels of total serum cholesterol and LDL-cholesterol were 5.7 (±1.5) mmol/l and 3.9 (±1.3) mmol/l, respectively. Among those who were on lipid-lowering drugs, 29.0% and 12.2% had levels of LDL cholesterol below 3.0 mmol/l and 2.6 mmol/l, respectively. Only 47.3% of the 956 subjects were considered as being adequately treated largely due to a failure to titrate their drug regimens. From the use of cholesterol-years score, lipid-lowering therapy must start before the age of 20 in order to prevent the subjects from contracting premature coronary heart disease.The majority of FH/FDB subjects are being diagnosed late in life and are not being adequately treated. In order to prevent them from contracting premature coronary heart disease, it is key that levels of LDL cholesterol are normalized from a young age and that sufficient doses of lipid-lowering drugs are being used

Telomeres are shorter in myocardial infarction patients compared to healthy subjects: correlation with environmental risk factors

Shorter telomeres have been reported in premature myocardial infarction (MI) patients. Our work aimed at confirming the association of shorter telomere with MI in two case-control studies and in familial hypercholesterolemia (FH) patients with coronary heart disease (CHD). The HIFMECH study compared 598 white male patients (<60 years) who survived a first MI and 653 age-matched controls from North and South Europe. Additionally, from the UK, 413 coronary artery bypass graft (CABG) patients and two groups of 367 and 94 FH patients, of whom 145 and 17 respectively had premature CHD, were recruited. Leukocyte telomere length (LTL) was measured using a real-time polymerase chain reaction-based method. In HIFMECH, LTL was significantly shorter in subjects from the North (7.99 kb, SD 4.51) compared to the South (8.27 kb, SD 4.14; p = 0.02) and in cases (7.85 kb, SD 4.01) compared to controls (8.04 kb, SD 4.46; p = 0.04). In the CABG study, LTL was significantly shorter (6.89 kb, SD 4.14) compared to the HIFMECH UK controls (7.53, SD 5.29; p = 0.007). In both samples of FH patients, LTL was shorter in those with CHD (overall 8.68 kb, SD 4.65) compared to the non-CHD subjects (9.23 kb, SD 4.83; p = 0.012). Apart from a consistent negative correlation with age, LTL was not associated across studies with any measured CHD risk factors. The present data confirms that subjects with CHD have shorter telomeres than controls and extends this to those with monogenic and polygenic forms of CHD