Improving reporting of adverse drug reactions: Systematic review

BACKGROUND: Adverse drug reactions (ADRs) are a significant cause of morbidity and mortality, with many being identified post-marketing. Improvement in current ADR reporting, including utility of underused or innovative methods, is crucial to improve patient safety and public health. OBJECTIVES: To evaluate methods to improve ADR reporting via a systematic literature review. METHODS: Data sources were Medline, Embase, Cochrane Library and National Library for health searches on ADR reporting (January 1997 to August 2007) including cross-referenced articles. Twenty-four out of 260 eligible studies were identified and critically assessed. Studies were grouped as follows: i) spontaneous reporting (11); ii) medical chart/note review (2); iii) patient interviews/questionnaires (3); and iv) combination methods including computer-assisted methods (8). RESULTS: Using computerized monitoring systems (CMS) to generate signals associated with changes in laboratory results with other methods can improve ADR reporting. Educational interventions combined with reminders and/or prescription card reports can improve hospital-based ADR reporting, and showed short to medium term improvement. CONCLUSIONS: The use of electronic health data combined with other methods for ADR reporting can improve efficiency and accuracy for detecting ADRs and can be extended to other health care settings. Although methods with educational intervention appear to be effective, few studies have reviewed long-term effects to assess if the improvements can be sustained

Bisphosphonates and evidence for association with esophageal and gastric cancer:A systematic review and metaanalysis

OBJECTIVES: Concerns have been raised about a possible link between bisphosphonate use, and in particular alendronate, and upper gastrointestinal (UGI) cancer. A number of epidemiological studies have been published with conflicting results. We conducted a systematic review and meta-analysis of observational studies, to determine the risk of esophageal and gastric cancer in users of bisphosphonates compared with non-users. DESIGN: We searched PubMed, MEDLINE, EMBASE, Web of Knowledge and Cochrane Database of Systematic Reviews for studies investigating bisphosphonates and esophageal or gastric cancer. We calculated pooled ORs and 95% CIs for the risk of esophageal or gastric cancer in bisphosphonate users compared with non-users. We performed a sensitivity analysis of alendronate as this was the most common single drug studied and is also the most widely used in clinical practice. RESULTS: 11 studies (from 10 papers) examining bisphosphonate exposure and UGI cancer (gastric and esophageal), met our inclusion criteria. All studies were retrospective, 6/11 (55%) case–control and 5/11(45%) cohort, and carried out using data from 5 longitudinal clinical databases. Combining 5 studies (1 from each database), we found no increased risk, OR 1.11 (95% CI 0.97 to 1.27) of esophageal cancer in bisphosphonate users compared with non-users and no increased risk of gastric cancer in bisphosphonate users, OR 0.96 (95% CI 0.82 to 1.12). CONCLUSION: This is the fourth and most detailed meta-analysis on this topic. We have not identified any compelling evidence for a significantly raised risk of esophageal cancer or gastric cancer in male and female patients prescribed bisphosphonates

Cross-sectional analysis of adverse outcomes in 1,029 pregnancies of Afro-Caribbean women in Trinidad with and without systemic lupus erythematosus

The objective of the study was to examine pregnancy outcomes in women with systemic lupus erythematosus (SLE) and population controls in Trinidad. We performed a cross-sectional analysis of adverse outcomes in pregnancies of Afro-Caribbean women with SLE and without SLE. One hundred and twenty-two female adult cases of SLE and 203 neighbourhood age-matched women without SLE were interviewed concerning details of their reproductive history, and the anticardiolipin antibody (ACL) status was established for women with SLE. A total of 1,029 pregnancies were reported (356 by women with SLE, 673 by women without SLE). In women with ≥ 1 pregnancy the total number of pregnancies was similar in women with a diagnosis of SLE and women without; however, a lower proportion of women with SLE had ever been pregnant compared with women without SLE (80% versus 91%, P = 0.002). In multivariate logistic regression analyses adjusted for maternal age, district of residence, pregnancy order and smoking, SLE pregnancies were more than twice as likely to end in foetal death than non-SLE pregnancies (odds ratio (OR), 2.4; 95% confidence interval (CI), 1.2–4.7). This effect was driven by a large increase in the odds of stillbirth (OR, 8.5; 95% CI, 2.5–28.8). The odds of early miscarriage (OR, 1.4; 95% CI, 0.6–3.1) and of mid-trimester miscarriage (OR, 1.9; 95% CI, 0.4–9.5) were higher, but were not statistically significantly different, in SLE pregnancies than in non-SLE pregnancies. The odds of ectopic pregnancy (OR, 7.5; 95% CI, 0.9–62.5) and of preterm birth (OR, 3.4; 95% CI, 1.2–10.0) were higher in SLE pregnancies conceived after diagnosis than in non-SLE pregnancies. There was no evidence of raised levels of IgG or IgM ACL among the majority (93/97 women, 96%) of SLE cases who reported sporadic mid-trimester miscarriage or stillbirth, although there was evidence of high levels of IgM and IgG ACL among women reporting three or more miscarriages and three consecutive miscarriages, and of raised IgG ACL among those experiencing ectopic pregnancy. In conclusion, we found evidence for a large increase in risk of stillbirth in the pregnancies of Afro-Caribbean Trinidadian women with SLE (not accounted for by high ACL status). There was some evidence of an increased risk of preterm delivery and ectopic pregnancy in pregnancies conceived after a diagnosis of maternal SLE

Burden of disease scenarios for 204 countries and territories, 2022–2050: a forecasting analysis for the Global Burden of Disease Study 2021

BackgroundFuture trends in disease burden and drivers of health are of great interest to policy makers and the public at large. This information can be used for policy and long-term health investment, planning, and prioritisation. We have expanded and improved upon previous forecasts produced as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) and provide a reference forecast (the most likely future), and alternative scenarios assessing disease burden trajectories if selected sets of risk factors were eliminated from current levels by 2050.MethodsUsing forecasts of major drivers of health such as the Socio-demographic Index (SDI; a composite measure of lag-distributed income per capita, mean years of education, and total fertility under 25 years of age) and the full set of risk factor exposures captured by GBD, we provide cause-specific forecasts of mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) by age and sex from 2022 to 2050 for 204 countries and territories, 21 GBD regions, seven super-regions, and the world. All analyses were done at the cause-specific level so that only risk factors deemed causal by the GBD comparative risk assessment influenced future trajectories of mortality for each disease. Cause-specific mortality was modelled using mixed-effects models with SDI and time as the main covariates, and the combined impact of causal risk factors as an offset in the model. At the all-cause mortality level, we captured unexplained variation by modelling residuals with an autoregressive integrated moving average model with drift attenuation. These all-cause forecasts constrained the cause-specific forecasts at successively deeper levels of the GBD cause hierarchy using cascading mortality models, thus ensuring a robust estimate of cause-specific mortality. For non-fatal measures (eg, low back pain), incidence and prevalence were forecasted from mixed-effects models with SDI as the main covariate, and YLDs were computed from the resulting prevalence forecasts and average disability weights from GBD. Alternative future scenarios were constructed by replacing appropriate reference trajectories for risk factors with hypothetical trajectories of gradual elimination of risk factor exposure from current levels to 2050. The scenarios were constructed from various sets of risk factors: environmental risks (Safer Environment scenario), risks associated with communicable, maternal, neonatal, and nutritional diseases (CMNNs; Improved Childhood Nutrition and Vaccination scenario), risks associated with major non-communicable diseases (NCDs; Improved Behavioural and Metabolic Risks scenario), and the combined effects of these three scenarios. Using the Shared Socioeconomic Pathways climate scenarios SSP2-4.5 as reference and SSP1-1.9 as an optimistic alternative in the Safer Environment scenario, we accounted for climate change impact on health by using the most recent Intergovernmental Panel on Climate Change temperature forecasts and published trajectories of ambient air pollution for the same two scenarios. Life expectancy and healthy life expectancy were computed using standard methods. The forecasting framework includes computing the age-sex-specific future population for each location and separately for each scenario. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline.FindingsIn the reference scenario forecast, global and super-regional life expectancy increased from 2022 to 2050, but improvement was at a slower pace than in the three decades preceding the COVID-19 pandemic (beginning in 2020). Gains in future life expectancy were forecasted to be greatest in super-regions with comparatively low life expectancies (such as sub-Saharan Africa) compared with super-regions with higher life expectancies (such as the high-income super-region), leading to a trend towards convergence in life expectancy across locations between now and 2050. At the super-region level, forecasted healthy life expectancy patterns were similar to those of life expectancies. Forecasts for the reference scenario found that health will improve in the coming decades, with all-cause age-standardised DALY rates decreasing in every GBD super-region. The total DALY burden measured in counts, however, will increase in every super-region, largely a function of population ageing and growth. We also forecasted that both DALY counts and age-standardised DALY rates will continue to shift from CMNNs to NCDs, with the most pronounced shifts occurring in sub-Saharan Africa (60·1% [95% UI 56·8–63·1] of DALYs were from CMNNs in 2022 compared with 35·8% [31·0–45·0] in 2050) and south Asia (31·7% [29·2–34·1] to 15·5% [13·7–17·5]). This shift is reflected in the leading global causes of DALYs, with the top four causes in 2050 being ischaemic heart disease, stroke, diabetes, and chronic obstructive pulmonary disease, compared with 2022, with ischaemic heart disease, neonatal disorders, stroke, and lower respiratory infections at the top. The global proportion of DALYs due to YLDs likewise increased from 33·8% (27·4–40·3) to 41·1% (33·9–48·1) from 2022 to 2050, demonstrating an important shift in overall disease burden towards morbidity and away from premature death. The largest shift of this kind was forecasted for sub-Saharan Africa, from 20·1% (15·6–25·3) of DALYs due to YLDs in 2022 to 35·6% (26·5–43·0) in 2050. In the assessment of alternative future scenarios, the combined effects of the scenarios (Safer Environment, Improved Childhood Nutrition and Vaccination, and Improved Behavioural and Metabolic Risks scenarios) demonstrated an important decrease in the global burden of DALYs in 2050 of 15·4% (13·5–17·5) compared with the reference scenario, with decreases across super-regions ranging from 10·4% (9·7–11·3) in the high-income super-region to 23·9% (20·7–27·3) in north Africa and the Middle East. The Safer Environment scenario had its largest decrease in sub-Saharan Africa (5·2% [3·5–6·8]), the Improved Behavioural and Metabolic Risks scenario in north Africa and the Middle East (23·2% [20·2–26·5]), and the Improved Nutrition and Vaccination scenario in sub-Saharan Africa (2·0% [–0·6 to 3·6]).InterpretationGlobally, life expectancy and age-standardised disease burden were forecasted to improve between 2022 and 2050, with the majority of the burden continuing to shift from CMNNs to NCDs. That said, continued progress on reducing the CMNN disease burden will be dependent on maintaining investment in and policy emphasis on CMNN disease prevention and treatment. Mostly due to growth and ageing of populations, the number of deaths and DALYs due to all causes combined will generally increase. By constructing alternative future scenarios wherein certain risk exposures are eliminated by 2050, we have shown that opportunities exist to substantially improve health outcomes in the future through concerted efforts to prevent exposure to well established risk factors and to expand access to key health interventions.FundingBill & Melinda Gates Foundation

30 Year Patterns of Mortality in Tobago, West Indies, 1976-2005: Impact of Glucose Intolerance and Alcohol Intake

OBJECTIVES: To determine the main predictors of all-cause and cardiovascular (CV) mortality in a rural West Indian population in Plymouth, Tobago over 30 years. METHODS: Questionnaire survey for CV risk factors and alcohol consumption patterns administered at baseline in 1976 with 92.5% response rate. 831/832 patients were followed up until 2005 or death. RESULTS: Hypertension (>140/90 mm Hg) was prevalent in 48% of men and 44% of women, and 21% of men and 17% of women had diabetes. Evidence showed most predictors for all cause and cardiovascular mortality having the main effects at ages 160/95 mm Hg (HR 1.68, 95% CI 1.09-2.60), diabetes (HR 3.28, 95% CI 1.89-5.69), and BMI (HR 1.04, 95% CI 1.00-1.07). The main predictors of cardiovascular mortality were similar in the fully adjusted model: high sessional alcohol intake (HR 2.47 95% CI 1.10-5.57), severe hypertension (HR 2.78 95% CI 1.56-4.95), diabetes (HR 3.68 95% CI 1.77-7.67) and additionally LVH, (HR 5.54 95% CI 1.38-22.26), however BMI did not show independent effects. For men, high sessional alcohol intake explains 27% of all cause mortality, and 40% of cardiovascular mortality at age <60 yrs. In adults aged <60 years, the attributable risk fraction for IGT/Diabetes and all cause mortality and cardiovascular mortality is 28% in women vs. 11% in men, and 22% in women vs. 6% in men respectively. CONCLUSIONS: In this Afro-Caribbean population we found that a major proportion of deaths are attributable to high sessional alcohol intake (in males), diabetes, and hypertension and these risk factors primarily operate in those below 60 years

Aspirin in people with dementia, long-term benefits and harms:A systematic review

Purpose: People with dementia may have indications for aspirin prescription and clinicians are asked to balance the potential risks against benefits. This review examines the evidence for risk and benefit of long-term aspirin use in people with dementia aged over 65 years, including randomised controlled trials and observational studies.Methods: We searched three databases for research published between 2007 to 2019. Each eligible article was assessed for risk of bias, and confidence in findings was rated using Grading of Recommendations Assessment, Development and Evaluation (GRADE).Results: Four papers met inclusion criteria, one randomised controlled trial, two cohort study, and one with pooled data. All looked only at dementia of the Alzheimer's type, and none addressed myocardial or cerebral infarction as outcomes. Dementia progression was reported by two studies, with conflicting results. The trial found no significant effect of aspirin on mortality (odds ratio aspirin vs no aspirin 1.07, 95% confidence interval 0.58-1.97) but found more events of severe bleeding with aspirin (OR aspirin vs no aspirin 6.9, 1.5-31.2). An excess in intracranial haemorrhage in the aspirin group was judged plausible based on two non-randomised studies.Conclusions: The review findings are limited because studies include only people with Alzheimer's type dementia and lack confirmatory studies, although an increased risk of bleeding events is recognised. Further research that addresses the benefits and risks of aspirin in more representative groups of people with dementia is needed to guide prescribing decisions

FCGR3B copy number variation is associated with systemic lupus erythematosus risk in Afro-Caribbeans.

OBJECTIVES: To evaluate FCGR3B copy number variation (CNV) in African and European populations and to determine if FCGR3B copy number is associated with SLE and SLE nephritis risk in Afro-Caribbeans, adjusting for African genetic ancestry. METHODS: We estimated FCGR3B to determine if there were ethnic variations in CNV (unrelated unadmixed Europeans and Africans). We then examined CNV at FCGR3B in relation to SLE and SLE nephritis within a case-control collection of 134 cases of SLE (37 with SLE nephritis) and 589 population controls of mainly Afro-Caribbean descent resident in Trinidad. RESULTS: We found a significant difference in copy number FCGR3B distribution between unadmixed African and European UK cohorts, with 27 (29%) vs 3 (5%) for those with low (0 or 1) copy FCGR3B, respectively, P = 0.002. In a Trinidadian SLE case-control study, low FCGR3B CNV was associated with SLE risk 1.7 (95% CI 1.1, 2.8), P = 0.02, which remained after adjustment for African genetic ancestry; odds ratios (ORs) 1.7 (95% CI 1.0, 2.8), P = 0.04. CONCLUSION: Our studies suggest that FCGR3B low copy number is associated with SLE risk in Afro-Caribbean populations independently of CNV due to African ancestry

Trends in hospital admissions for adverse drug reactions in England: analysis of national hospital episode statistics 1998–2005

BACKGROUND: Adverse drug reactions (ADRs) are a frequent cause of mortality and morbidity to patients worldwide, with great associated costs to the healthcare providers including the NHS in England. We examined trends in hospital admissions associated with adverse drug reaction in English hospitals and the accuracy of national reporting. METHODS: Data from the Hospital Episode Statistics database (collected by the Department of Health) was obtained and analysed for all English hospital episodes (1998-2005) using ICD-10 codes with a primary (codes including the words ('drug-induced' or 'due to') or secondary diagnosis of ADR (Y40-59). More detailed analysis was performed for the year 2004-2005 RESULTS: Between 1998 and 2005 there were 447 071 ADRs representing 0.50% of total hospital episodes and over this period the number of ADRs increased by 45%. All ADRs with an external code increased over this period. In 2005 the total number of episodes (all age groups) was 13,706,765 of which 76,692 (0.56%) were drug related. Systemic agents, which include anti-neoplastic drugs, were the most implicated class (15.7%), followed by analgesics (11.7%) and cardiovascular drugs (10.1%). There has been a 6 fold increase in nephropathy secondary to drugs and a 65% decline in drug induced extra-pyramidal side effects. 59% of cases involving adverse drug reactions involved patients above 60 years of age. CONCLUSION: ADRs have major public health and economic implications. Our data suggest that national Hospital Episode Statistics in England have recognised limitations and that consequently, admissions associated with adverse drug reactions continue to be under-recorded. External causes of ADR have increased at a greater rate than the increase in total hospital admissions. Improved and more detailed reporting combined with educational interventions to improve the recording of ADRs are needed to accurately monitor the morbidity caused by ADRs and to meaningfully evaluate national initiatives to reduce adverse drug reactions

Stratified genome-wide association analysis of type 2 diabetes reveals subgroups with genetic and environmental heterogeneity

Type 2 diabetes (T2D) is a heterogeneous illness caused by genetic and environmental factors. Previous genome wide association studies (GWAS) have identified many genetic variants associated with T2D and found evidence of differing genetic profiles by age-at-onset. This study seeks to explore further the genetic and environmental drivers of T2D by analysing subgroups based on age-at-onset of diabetes and body mass index (BMI). In UK Biobank, 36 494 T2D cases were stratified into 3 subgroups and GWAS performed for all T2D cases and for each subgroup relative to 421 021 controls. Altogether, 18 SNPs significantly associated genome-wide with T2D in one or more subgroups also showed evidence of heterogeneity between the subgroups, (Cochrane's Q p < 0.01) with 2 remaining significant after multiple testing (in CDKN2B and CYTIP). Combined risk scores, based on genetic profile, BMI and age, resulted in excellent diabetes prediction (AUC = 0.92). A modest improvement in prediction (AUC = 0.93) was seen when the contribution of genetic and environmental factors was evaluated separately for each subgroup. Increasing sample sizes of genetic studies enables us to stratify disease cases into subgroups which have sufficient power to highlight areas of genetic heterogeneity. Despite some evidence that optimising combined risk scores by subgroup improves prediction, larger sample sizes are likely needed for prediction when using a stratification approach