Historical Review of the Use of Relative Risk Statistics in the Portrayal of the Purported Hazards of High LDL Cholesterol and the Benefits of Lipid-Lowering Therapy.

The manner in which clinical trial investigators present their findings to healthcare providers and the public can have a substantial influence on their impact. For example, if a heart attack occurs in 2% of those in the placebo group and in 1% of those in the drug-treated group, the benefit to the treated population is only one percentage point better than no treatment. This finding is unlikely to generate much enthusiasm from the study sponsors and in the reporting of the findings to the public. Instead, trial directors can amplify the magnitude of the appearance of the treatment benefit by using the relative risk (RR) value of a 50% reduction of the risk of a heart attack, since one is 50% of two. By using the RR type of data analysis, clinical trial directors can promote the outcome of their trial in their publication and to the media as highly successful while minimizing or disregarding entirely the absolute risk (AR) reduction of only one percentage point. The practice of expressing the RR without the AR has become routinely deployed in the reporting of findings in many different areas of clinical research. We have provided a historical perspective on how this form of data presentation has become commonplace in the reporting of findings from randomized controlled trials (RCTs) on coronary heart disease (CHD) event monitoring and prevention over the past four decades. We assert that the emphasis on RR coupled with insufficient disclosure of AR in the reporting of RCT outcomes has led healthcare providers and the public to overestimate concerns about high cholesterol and to be misled as to the magnitude of the benefits of cholesterol-lowering therapy. The goal of this review is to prompt the scientific community to address this misleading approach to data presentation.

Correction: Historical Review of the Use of Relative Risk Statistics in the Portrayal of the Purported Hazards of High LDL Cholesterol and the Benefits of Lipid-Lowering Therapy.

[This corrects the article DOI: 10.7759/cureus.38391.].

Relation of glycemic status with unrecognized MI and the subsequent risk of mortality: The Jackson Heart Study.

Background: Almost 1/3 to 1/2 of initial myocardial infarctions (MI) may be silent or unrecognized (UMI), which forecasts future clinical events. Further, limited data exist to describe the potential risk for UMI in African-Americans. The relationship of glucose status with UMI was examined in the Jackson Heart Study: a cohort of African-American individuals. Methods and results: At baseline, there were 5,073 participants with an initial 12-lead electrocardiogram (ECG) and fasting glucose measured. Of these participants, 106(2.1%) had a UMI, and 268(4.2%) had a recognized MI. This population consisted of 3,233 (63.7%) participants with normal fasting glucose (NFG), 533 (10.5%) with IFG, and 1,039 (20.4%) with DM. Logistic regression investigated the relationship between glucose status and UMI. Cox proportional hazard models determined the significance of all-cause mortality during follow-up by MI status. The sample was 65% female with a mean age of 55.3 ± 12.9 years. Over a mean follow-up of 10.4 years, there were 795 deaths. Relative to NFG, the crude odds ratio (OR) estimates for UMI at baseline with IFG and DM were 1.00(95% CI:0.48-2.14) and 3.22(2.15-4.81), respectively. With adjustment, DM continued to be significantly associated with UMI [2.30 (1.42-3.71)]. Overall, participants with a baseline UMI had an adjusted Hazard ratio (HR) of 2.00(1.39-2.78) of death compared to no prior MI. Compared to those with no MI, those with a recognizedMI had an adjusted HR of 1.70(1.31-2.17) for mortality. Conclusions: DM is associated with UMI in African-Americans. Further, a UMI carried similar risk of death compared to those with a recognized MI.

Risk of Silent Myocardial Infarction in Prediabetic Patients: A Case-Control Study in a Veteran Population.

OBJECTIVES: In the management of cardiovascular disease, it is important to identify patients at risk early on, to provide interventions to prevent the disease and its complications. The goal of our study was to investigate the association between glucose levels and silent myocardial infarction (SMI) among patients, who consisted of veterans within the Veterans Affairs clinical system. METHODS: Among the group of patients with an initially normal electrocardiogram, a cohort of patients with a subsequent diagnosis of SMI was selected as the case cohort, whereas 4 patients for each study subject, without evidence of coronary artery disease and normal electrocardiogram within the previous 6 months, were identified and constituted the control cohort. We conducted an adjusted logistic regression model using the stepwise function to assess the association between glucose level and SMI. RESULTS: Of the 540 patients included in the study, 108 (20.0%) with an SMI diagnosis made up the case cohort. We observed that as compared with those who had normal levels of glucose, those who were prediabetic were 3.99 times as likely (95% confidence interval 1.48-12.85) to have SMI, whereas the diabetic patients were 3.80 times as likely (95% confidence interval 1.39-12.38) to experience SMI. CONCLUSIONS: SMIs have been shown to be predictive of subsequent cardiovascular events, including another MI and death, and that indicates the importance of identifying a group at high risk for a SMI. As such, our findings could be extremely beneficial for targeted intervention toward prediabetics and to improve health outcomes in the entire population.

Abnormal Fasting Glucose Increases Risk of Unrecognized Myocardial Infarctions in an Elderly Cohort.

OBJECTIVES: To investigate glucose levels as a risk factor for unrecognized myocardial infarctions (UMIs). DESIGN: Cohort SETTING: Cardiovascular Health Study. PARTICIPANTS: Individuals aged 65 and older with fasting glucose measurements (N=4,355; normal fasting glucose (NFG), n = 2,041; impaired fasting glucose (IFG), n = 1,706; DM: n = 608; 40% male, 84% white, mean age 72.4 ± 5.6). MEASUREMENTS: The relationship between glucose levels and UMI was examined. Participants with prior coronary heart disease (CHD) or UMI on initial electrocardiography were excluded. Using Minnesota codes, UMI was identified according to the presence of pathological Q-waves or minor Q-waves with ST-T abnormalities. Crude and adjusted hazard ratios (HRs) were calculated. Analyses were adjusted for age, sex, body mass index (BMI), hypertension, antihypertensive and lipid-lowering medication use, total cholesterol, high-density lipoprotein cholesterol, and smoking status. RESULTS: Over a mean follow-up of 6 years, there were 459 incident UMIs (NFG, n=202; IFG, n=183; DM, n=74). Participants with IFG were slightly more likely than those with NFG to experience a UMI (hazard ratio (HR)=1.11, 95% confidence interval (CI)=0.91-1.36, p = .30), and those with DM were more likely than those with NFG to experience a UMI (HR=1.65, 95% CI=1.25-2.13, p < .001). After adjustment HR for UMI in IFG those with IFG were no more likely than those with NFG to experience a UMI (HR=1.01, 95% CI=0.82-1.24, p = .93), whereas those with DM were more likely than those with NFG to experience a UMI (HR=1.37, 95% CI=1.02-1.81, p = .03). The 2-hour oral glucose tolerance test was not statistically significantly associated with UMI. CONCLUSION: Fasting glucose status, particularly in the diabetic range, forecasted UMI during 6 years of follow-up in elderly adults. Further studies are needed to clarify the level of glucose at which risk is greater. J Am Geriatr Soc 67:43-49, 2019.

Prediabetes and the association with unrecognized myocardial infarction in the multi-ethnic study of atherosclerosis.

BACKGROUND: With one-quarter of initial myocardial infarctions (MI) being unrecognized MI (UMI), recognition is critical to minimize further cardiovascular risk. Diabetes mellitus is an established risk factor for UMI. If impaired fasting glucose (IFG) also increased the risk for UMI, it would represent a significant public health challenge due to the rapid worldwide increase in IFG prevalence. We compared participants with IFG to those with normal fasting glucose (NFG) to determine if IFG was associated with UMIs. METHODS: We performed cross-sectional analyses from the MESA, a population-based cohort study. There were 6,814 participants recruited during July 2000 to September 2002 from the general community at 6 field sites. After excluding those with diabetes mellitus or missing variables, 5,885 participants were included. At baseline, there were 4,955 participants with NFG and 930 participants with IFG. The main outcome was an UMI defined by the presence of pathological Q waves or minor Q waves with ST-T abnormalities on initial 12-lead electrocardiogram. Logistic regression was used to generate crude ORs and adjust for covariates. RESULTS: There was a higher prevalence of UMI in those with IFG compared with those with NFG [3.5% (n = 72) vs 1.4% (n = 30)]. After adjustment for multiple risk factors, there was a higher odds of an UMI among those with IFG compared with those with NFG [OR: 1.60 (95% CI: 1.0-2.5); P = .048]. CONCLUSIONS: Impaired fasting glucose is associated with unrecognized myocardial infarctions in a multi-ethnic population free of baseline cardiovascular disease.

A role for PACE4 in osteoarthritis pain: evidence from human genetic association and null mutant phenotype.

OBJECTIVES: The aim of this study was to assess if genetic variation in the PACE4 (paired amino acid converting enzyme 4) gene Pcsk6 influences the risk for symptomatic knee osteoarthritis (OA). METHODS: Ten PCSK6 single nucleotide polymorphisms were tested for association in a discovery cohort of radiographic knee OA (n=156 asymptomatic and 600 symptomatic cases). Meta-analysis of the minor allele at rs900414 was performed in three additional independent cohorts (total n=674 asymptomatic and 2068 symptomatic). Pcsk6 knockout mice and wild-type C57BL/6 mice were compared in a battery of algesiometric assays, including hypersensitivity in response to intraplantar substance P, pain behaviours in response to intrathecal substance P and pain behaviour in the abdominal constriction test. RESULTS: In the discovery cohort of radiographic knee OA, an intronic single nucleotide polymorphism at rs900414 was significantly associated with symptomatic OA. Replication in three additional cohorts confirmed that the minor allele at rs900414 was consistently increased among asymptomatic compared to symptomatic radiographic knee OA cases in all four cohorts. A fixed-effects meta-analysis yielded an OR=1.35 (95% CI 1.17 to 1.56; p=4.3×10(-5) and no significant between-study heterogeneity). Studies in mice revealed that Pcsk6 knockout mice were significantly protected against pain in a battery of algesiometric assays. CONCLUSIONS: These results suggest that a variant in PCSK6 is strongly associated with protection against pain in knee OA, offering some insight as to why, in the presence of the same structural damage, some individuals develop chronic pain and others are protected. Studies in Pcsk6 null mutant mice further implicate PACE4 in pain.

Does diabetes hide osteoarthritis pain?

Clinical practice and research efforts related to the highly prevalent and disabling disease, osteoarthritis (OA), have long been hampered by an inadequate case definition. Much of the difficulty is due to a lack of agreement between X-rays evidence of OA and a patient's report of pain at that site. Such discordance between reported pain and radiographic evidence of OA has been attributed to several factors. This paper proposes another possible explanation, for at least a portion of such patients. It is hypothesized that an insidiously increasing diabetic neuropathy, particularly in the lower extremity, while first causing some pain, may gradually inhibit the ability to feel pain which might have otherwise been reported by those patients without neuropathy. Many of these patients with early stage glucose dysmetabolism will proceed to develop overt type 2 diabetes; however, the pain-inhibiting neuropathy caused by glucose metabolism dysfunction may manifest long before such a diagnosis. The high prevalence of diabetes and pre-diabetic conditions, especially among the aged population, could mean that a substantial number of individuals with osteoarthritis will have both diseases to varying degrees over time. Validating and quantifying this hypothesized association would be useful to millions of persons and would significantly impact both research and clinical practice dealing with these major diseases of older persons.

The Ile585Val TRPV1 variant is involved in risk of painful knee osteoarthritis.

OBJECTIVE: To assess if a coding variant in the gene encoding transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is associated with genetic risk of painful knee osteoarthritis (OA). METHODS: The Ile585Val TRPV1 variant encoded by rs8065080 was genotyped in 3270 cases of symptomatic knee OA, 1098 cases of asymptomatic knee OA and 3852 controls from seven cohorts from the UK, the USA and Australia. The genetic association between the low-pain genotype Ile-Ile and risk of symptomatic and asymptomatic knee OA was assessed. RESULTS: The TRPV1 585 Ile-Ile genotype, reported to be associated with lower thermal pain sensitivity, was associated with a lower risk of symptomatic knee OA in a comparison of symptomatic cases with healthy controls, with an odds ratio (OR) of 0.75 (95% CI 0.64 to 0.88; p=0.00039 by meta-analysis) after adjustment for age, sex and body mass index. No difference was seen between asymptomatic OA cases and controls (OR=1.02, 95% CI 0.82 to 1.27 p=0.86) but the Ile-Ile genotype was associated with lower risk of symptomatic versus asymptomatic knee OA adjusting for covariates and radiographic severity (OR=0.73, 95% CI 0.57 to 0.94 p=0.0136). TRPV1 expression in articular cartilage was increased by inflammatory cytokines (tumour necrosis factor α and interleukin 1). However, there were no differences in TRPV1 expression in healthy and arthritic synovial tissue. CONCLUSIONS: A genotype involved in lower peripheral pain sensitivity is significantly associated with a decreased risk of painful knee OA. This indicates a role for the pro-nociceptive gene TRPV1 in genetic susceptibility to symptomatic knee OA, which may also be influenced by a role for this molecule in cartilage function.

Role of the Nav1.7 R1150W amino acid change in susceptibility to symptomatic knee osteoarthritis and multiple regional pain.

OBJECTIVE: To assess the genetic association of pain in patients with knee osteoarthritis (OA) and those with multiple regional pain with the R1150W variant in the α-subunit of the voltage-gated sodium channel Na(V)1.7. METHODS: Knee OA patients from 2 UK cohorts (1,411 from the Genetics of Osteoarthritis and Lifestyle study and 267 from the Hertfordshire Cohort Study; 74% with symptomatic OA) with Western Ontario and McMaster Universities OA Index (WOMAC) pain scores were genotyped for rs6746030 (encoding the R1150W change). One hundred seventy-six knee OA patients (53% symptomatic) from the Clearwater Osteoarthritis Study were also tested. A total of 4,295 samples (both affected and unaffected OA) from all 3 studies with data on multiple regional pain were tested. Fixed-effects meta-analyses were carried out with the WOMAC, symptomatic OA (adjusting for radiographic severity), and multiple regional pain as outcomes. RESULTS: No association with the WOMAC was seen in the UK cohorts. Overall, the meta-analysis of WOMAC yielded a summary statistic of ß = 0.47 (95% confidence interval [95% CI] 0.04, 0.89; P = 0.030) for the variant allele. The meta-analysis of symptomatic versus asymptomatic OA did not demonstrate an association with rs6746030 (odds ratio [OR] 0.90 [95% CI 0.71, 1.15], P = 0.38). The meta-analysis of multiple regional pain resulted in a significant OR of 1.40 (95% CI 1.08, 1.80; P = 0.0085). No interstudy heterogeneity was seen for any of the analyses. CONCLUSION: We find evidence that the R1150W amino acid change in the Na(V)1.7 α-chain is associated with multiple regional pain. This variant is confirmed to be involved in genetic susceptibility to pain, but it does not appear to have a major role in OA-specific pain.

Job-related osteoarthritis of the knee, foot, hand, and cervical spine.

OBJECTIVES: To assess the influence of occupational exposures on risk of site-specific radiographic osteoarthritis (OA) of the knee, hand, foot, and cervical spine. METHODS: Using a cross-sectional design, data collected from men and women aged 40 years and older participating in the Clearwater Osteoarthritis Study were analyzed (n = 3436). Subjects' occupational exposures were queried using the study intake form, including stair climbing, standing on a rigid surface, squatting, and jolting. Physical examinations including radiographs of the knee, hand, foot, and cervical spine were conducted. The Kellgren and Lawrence ordinal scale was used to determine evidence of radiographic OA. RESULTS: Both the unadjusted and adjusted odds ratios (ORs) for men and women indicated that age and body mass index were associated with OA. There were no other significant odds ratios for the cervical spine. Among men, there were significant associations with knee OA for stair climbing and jolting of the legs and with foot OA with stair climbing. Among women, there was a significant association between standing on a rigid surface and knee OA. For hand OA in women, there was a significant association for jolting of the hands. CONCLUSIONS: Although the association with stair climbing was found in other investigations for knee OA, it was also associated with foot OA in this study. In addition, the jolting feature was seen in only one other study for men (knees) and novel for women (hands).

The epidemiology of aplastic anemia in Thailand.

Aplastic anemia has been linked to environmental exposures, from chemicals and medical drugs to infectious agents. The disease occurs more frequently in Asia than in the West, with incidence rates 2- to 3-fold higher. We report updated results of an epidemiologic study conducted in Thailand from 1989 to 2002, in which 541 patients and 2261 controls were enrolled. Exposures were determined by in-person interview. We observed significantly elevated relative risk estimates for benzene (3.5) and other solvents (2.0) and for sulfonamides (5.6), thiazides (3.8), and mebendazole (3.0). Chloramphenicol use was infrequent, and no significant association was observed. Agricultural pesticides were implicated in Khonkaen (northeastern Thailand). There were significant associations with organophosphates (2.1), DDT (6.7), and carbamates (7.4). We found significant risks for farmers exposed to ducks and geese (3.7) and a borderline association with animal fertilizer (2.1). There was a significant association in Khonkaen with drinking other than bottled or distilled water (2.8). Nonmedical needle exposure was associated in Bangkok and Khonkaen combined (3.8). Most striking was the large etiologic fraction in a rural region accounted for by animal exposures and drinking of water from sources such as wells, rural taps, and rainwater, consistent with an infectious etiology for many cases of aplastic anemia in Thailand.

Invasive group A streptococcal infections in Florida.

BACKGROUND: Several previous studies of invasive Group A streptococcal (GAS) disease have been hindered by small sample sizes (< or = 100 patients) and limited generalizability. METHODS: We conducted a population-based study of invasive GAS disease. The objectives of the study were to describe the clinical features of individuals who were hospitalized for invasive GAS disease and to identify risk factors for hospital mortality. The cases were 257 patients who were hospitalized throughout Florida during a 4-year period and reported to the Florida Department of Health. Logistic regression was used to calculate adjusted odds ratios (OR) for mortality and 95% confidence intervals (CI). RESULTS: The overall mortality was 18% (41 of 228). Admission into an intensive care unit was a strong predictor of mortality (OR, 20.41; 95% CI, 6.41-64.96). Treatment with clindamycin reduced mortality in patients who had necrotizing fasciitis (OR, 0.11; 95% CI, 0.01-0.89) but not in patients who did not have necrotizing fasciitis (OR, 1.01; 95% CI, 0.31-3.33). CONCLUSION: Clindamycin reduces mortality in patients with invasive GAS disease who have necrotizing fasciitis.