New limits proposed for the management of non-mutagenic impurities.

Multiple international guidelines exist that describe both quality and safety considerations for the control of the broad spectrum of impurities inherent to drug substance and product manufacturing processes. However, regarding non-mutagenic impurities (NMI) the most relevant ICH Q3A/B guidelines are not applicable during early phases of drug development leading to confusion about acceptable limits at this stage. Thus, there is need for more flexible approaches that ensure that patient safety remains paramount, while taking into consideration the limited duration of exposure. An EFPIA survey, which collected quantitative data from different types of studies applied to qualify impurities in accordance with ICH Q3A, shows that no toxicities could be attributed to any of the 467 impurities at any tested level in vivo. This data combined with earlier published toxicological datasets encompassing drug substances and intermediates, food related substances and chemicals provide convincing evidence that for NMIs, the application of a generic 5 mg/day limit for an exposure duration <6 months, and a 1 mg/day generic limit for life-long exposure, provides sufficient margins to ensure patient safety. Hence, application of these absolute limits to trigger qualification studies (instead of the relative limits described in Q3A/B), is considered warranted. This approach will prevent conduct of unnecessary dedicated impurity qualification studies and the resulting use of animals.

Semiquantitative sensitization safety assessment of extractable and leachables associated with parenteral pharmaceutical products.

Extractable and leachables (E&Ls) associated with parenteral pharmaceutical products should be assessed for patient safety. One essential safety endpoint is local or systemic sensitization. However, there are no regulatory guidelines for quantitative sensitization safety assessment of E&Ls. A semiquantitative sensitization safety assessment workflow is developed to refine the sensitization safety assessment of E&Ls associated with parenteral pharmaceutical products. The workflow is composed of two sequential steps: local skin sensitization and systemic sensitization safety assessment. The local skin sensitization step has four tiers. The output from this step is the acceptable exposure level for local sensitization (AELls) and this safety threshold can be used for local sensitization safety assessment. From the derived AELls, the systemic sensitization safety assessment at step 2 proceeds in 2 tiers. The output from this workflow is the derivation of acceptable exposure level for systemic sensitization (AELss). When the estimated human daily exposure (HDE) is compared with the AELss, the margin of exposure is calculated to determine the sensitization safety of E&Ls following parenteral administration. The current work represents an initial effort to develop a scientifically robust process for sensitization safety assessment of E&Ls associated with parenteral pharmaceutical products.

Acceptable intakes (AIs) for 11 small molecule N-nitrosamines (NAs).

Low levels of N-nitrosamines (NAs) were detected in pharmaceuticals and, as a result, health authorities (HAs) have published acceptable intakes (AIs) in pharmaceuticals to limit potential carcinogenic risk. The rationales behind the AIs have not been provided to understand the process for selecting a TD50 or read-across analog. In this manuscript we evaluated the toxicity data for eleven common NAs in a comprehensive and transparent process consistent with ICH M7. This evaluation included substances which had datasets that were robust, limited but sufficient, and substances with insufficient experimental animal carcinogenicity data. In the case of robust or limited but sufficient carcinogenicity information, AIs were calculated based on published or derived TD50s from the most sensitive organ site. In the case of insufficient carcinogenicity information, available carcinogenicity data and structure activity relationships (SARs) were applied to categorical-based AIs of 1500 ng/day, 150 ng/day or 18 ng/day; however additional data (such as biological or additional computational modelling) could inform an alternative AI. This approach advances the methodology used to derive AIs for NAs.

Bifidobacterium breve BBG-001 and intestinal barrier function in preterm babies: Exploratory Studies from the PiPS Trial.

BACKGROUND: Uncertainty remains about the role of probiotics to prevent necrotising enterocolitis (NEC) some of which arises from the variety of probiotic interventions used in different trials, many with no prior evidence of potential efficacy. Mechanistic studies of intestinal barrier function embedded in a large probiotic trial could provide evidence about which properties of probiotics might be important for NEC prevention thus facilitating identification of strains with therapeutic potential. METHODS: Intestinal permeability, stool microbiota, SCFAs and mucosal inflammation were assessed from the second postnatal week in babies enrolled to a randomised controlled trial of B. breve BBG-001 (the PiPS trial). Results were compared by allocation and by stool colonisation with the probiotic. RESULTS: Ninety-four preterm babies were recruited across six nested studies. B. breve BBG-001 content was higher by allocation and colonisation; Enterobacteriaceae and acetic acid levels were higher by colonisation. No measure of intestinal barrier function showed differences. The PiPS trial found no evidence of efficacy to reduce NEC. CONCLUSIONS: That the negative results of the PiPS trial were associated with failure of this probiotic to modify intestinal barrier function supports the possibility that the tests described here have the potential to identify strains to progress to large clinical trials. IMPACT: Uncertainty about the therapeutic role of probiotics to prevent necrotising enterocolitis is in part due to the wide range of bacterial strains with no previous evidence of efficacy used in clinical trials. We hypothesised that mechanistic studies embedded in a probiotic trial would provide evidence about which properties of probiotics might be important for NEC prevention. The finding that the probiotic strain tested, Bifidobacterium breve BBG-001, showed neither effects on intestinal barrier function nor clinical efficacy supports the possibility that these tests have the potential to identify strains to progress to large clinical trials.

Harmonized 3Rs-based non-mutagenic impurity qualification study designs developed using the results of an IQ consortium survey.

As per the ICH Q3A(R2) and Q3B(R2) regulatory guidelines, safety studies may be needed when an impurity in new drug substances or products is above the qualification threshold, and such qualification studies should be conducted in one nonclinical species for a duration of 14-90 days. However, the guidelines do not specify details about species selection, recommended study design, and the exact study duration that would support clinical use of a specific duration. This lack of guidance leads to ambiguity and sponsors have used various study designs to qualify impurities. In 2018, the European Medicines Agency provided a draft reflection paper encouraging the incorporation of 3Rs (Replacement, Reduction, and Refinement) principles for animal use into impurity qualification. As a response, the IQ DruSafe Impurity Working Group (WG) surveyed the IQ member companies to capture the current practices for impurity qualification, and evaluate study designs for a potential reduction in animal testing. This article summarizes the results and learnings from the survey. Additionally, the WG leveraged the survey learnings and provided harmonized study design considerations aimed towards achieving the study objectives, while supporting the 3Rs initiative in reducing the total number of animals used (up to 90%) for impurity qualification.

An In Vivo Comparison of Hemostatic Gelatin Matrix Products in a Porcine Spleen Biopsy-punch Model.

Flowable gelatin matrix products have established themselves as effective, easy-to-use hemostatic agents useful in a variety of surgical situations. A recently reformulated gelatin matrix, Surgiflo® (Ethicon Inc., Somerville, NJ), can be prepared quickly and provides consistent flow over an 8-hr. period. No in vivo studies have yet been reported comparing hemostasis with the new Surgiflo to other currently marketed flowable gelatin matrix products. This study was conducted to determine whether Surgiflo in actual use has hemostatic qualities different from another commercial gelatin matrix. An in vivo model based on porcine spleen biopsy punch-induced bleeding was used to compare Surgiflo and Floseal™ (Baxter Healthcare Corporation, Hayward, CA), both with thrombin. Time required to achieve hemostasis and proportion of sites achieving hemostasis within 30 s were determined for both hemostatic agents and a control of saline-soaked gauze. Results were stratified by the degree of initial bleeding (mild, moderate, severe). Hemostasis was achieved within 3 minutes at all sites for both test products regardless of level of initial bleeding, and control sites continued bleeding past 10 minutes. There were no statistically significant differences between Surgiflo and Floseal for either mean time to hemostasis or proportion of sites hemostatic within 30 s. In this realistic in vivo model both gelatin matrix products were effective, and there were no significant differences observed in hemostatic efficacy between Surgiflo and Floseal. Other factors, such as ease of preparation and application, in-use stability, and economic considerations may affect a surgeon's decision in selection of a desirable hemostatic product.

Hemostatic effectiveness of Fibrin pad after partial nephrectomy in swine.

BACKGROUND: Current management of severe surgical or traumatic bleeding is often achieved by manual tamponade or occlusion using devices such as tourniquets or ligatures. There are some clinical scenarios where these options are either marginally effective or impractical. The present study evaluates a new combination device (Fibrin pad) consisting of biologically active components (human thrombin and fibrinogen) delivered to the targeted site by an absorbable synthetic matrix (oxidized regenerated cellulose and polyglactin 910) in a swine severe bleeding model. In this model, severe bleeding can be managed by concurrent use of several currently available treatments, or a more convenient option that offers performance and safety advantages. MATERIALS AND METHODS: Partial nephrectomies were performed on swine and treated with either Fibrin pad (FP) or conventional therapy (CTR)-temporary occlusion of renal artery, electrocautery, SURGIFLO, EVITHROM, SURGICEL NU-KNIT, and PDS II suture). After intraoperative hemostasis was confirmed, the animals were closed and recovered, then survived for 2, 14, or 56 d. RESULTS: Hemostasis was achieved at surgery and maintained in all FP and CTR treated animals. FP was as effective as CTR at establishing durable hemostasis. Treatment with FP did not require temporary occlusion of the renal artery and decreased the total treatment time by half. No animals in either group had complications related to postoperative bleeding at any time during the study. There was no evidence of pulmonary thrombi or evidence of thrombotic complications. No biologically significant adverse local tissue response was present in association with the Fibrin pad at any study interval, and no biologically relevant or consistent changes in blood parameters were identified. CONCLUSIONS: Fibrin pad was as effective as CTR for the primary management of severe bleeding without occlusion of the renal artery and a shorter surgical time. No evidence of a systemic or local adverse response was identified due to exposure to the Fibrin pad.

Does antibiotic choice for the treatment of suspected late-onset sepsis in premature infants determine the risk of developing necrotising enterocolitis? A systematic review.

BACKGROUND: Necrotising enterocolitis (NEC) is a significant cause of infant morbidity and mortality, disproportionately affecting those of extreme prematurity and/or very low birth weight. A number of risk factors have been identified, including an association between the use of antibiotics, and the subsequent development of NEC. AIM: This review sought to address whether the choice of antibiotic(s) used to treat infants with suspected late-onset sepsis (LOS) influences the risk of developing NEC. METHODS: A systematic review was performed across Web of Knowledge, Cochrane Library, Ovid Medline, EMBASE and CINAHL databases, up to February 2018, assessing the primary outcome of NEC occurrence, as extracted directly from the published articles. Studies were included if they were randomised control trials (or featured adequate adjustment for confounders); included clear criteria for defining LOS/NEC; and assessed occurrence of NEC in premature infants treated for LOS with intravenous antibiotics. Studies were excluded if non-original, not exclusively featuring premature infants, or where treatment was given for early-onset sepsis only. FINDINGS: 2291 titles and abstracts were identified, of which one study (81 subjects) was suitable for analysis, following screening against eligibility criteria. This suggested a decreased risk of developing definite NEC following treatment with a vancomycin/aztreonam combination, versus a vancomycin/gentamicin regimen (OR = 0·08, 95%CI = 0·00-1·45). CONCLUSION: This systematic review identified one study where the occurrence of NEC was reported in the context of comparing different antibiotic regimens for late onset sepsis and highlights that the type of antibiotic used to treat LOS in preterm infants might be a determinant of the risk of developing NEC. Although it is known that different antibiotic combinations impact the enteric microbiome and that antibiotic exposure is a risk factor for NEC, there is a paucity of well-designed studies that look at the relationship between NEC risk and specific antibiotic exposures.

An in vivo comparison of the efficacy of hemostatic powders, using two porcine bleeding models.

BACKGROUND: Usage of topical hemostatic agents in surgery is increasing, including use during minimally invasive procedures, and even for surgeries that have a low risk of bleeding complications. A novel product, Surgicel® Powder - Absorbable Hemostatic Powder (SP), made from oxidized regenerated cellulose (ORC) fabric, has been developed for adjunctive use in surgical procedures to assist in control of oozing bleeding over broad areas and where access could be difficult with a fabric ORC product. This study compares the new SP to other commercially available hemostatic powder products in two in vivo models. METHODS: Hemostatic efficacy of SP was compared to two polysaccharide-based hemostats in a porcine liver punch biopsy model and to three polysaccharide-based hemostats and one non-regenerated oxidized cellulose hemostat in a porcine liver abrasion model. Primary outcomes measured were hemostatic efficacy, defined as hemostasis within 10 minutes of application, and time-to-hemostasis (TTH). RESULTS: In the punch biopsy model, SP displayed significantly higher effective hemostasis rates than one of the polysaccharide hemostats (p=0.047) and faster TTH than both (p<0.001). In the liver abrasion model, SP had significantly higher effective hemostasis rates (p≤0.002) and faster TTH (p<0.001) than the other four hemostatic agents. The amount of powder applied within the ranges used did not appear to affect hemostatic efficacy. CONCLUSION: In both the liver punch biopsy model of mild to moderate bleeding and the liver abrasion model of mild but diffuse oozing, SP provided more effective hemostasis and faster TTH than other marketed hemostatic powders. The results from this in vivo study suggest that Surgicel Powder may be useful in clinical applications where control of oozing capillary, mild venous, and small arterial hemorrhage is required including bleeding in difficult-to-access locations.

From in vivo to in vitro: The medical device testing paradigm shift.

Amid growing efforts to advance the replacement, reduction, and refinement of the use of animals in research, there is a growing recognition that in vitro testing of medical devices can be more effective, both in terms of cost and time, and also more reliable than in vivo testing. Although the technological landscape has evolved rapidly in support of these concepts, regulatory acceptance of alternative testing methods has not kept pace. Despite the acceptance by regulators of some in vitro tests (cytotoxicity, gene toxicity, and some hemocompatibility assays), many toxicity tests still rely on animals (irritation, sensitization, acute toxicity, reproductive/developmental toxicity), even where other industrial sectors have already abandoned them. Bringing about change will require a paradigm shift in current approaches to testing - and a concerted effort to generate better data on risks to human health from exposure to leachable chemicals from medical devices, and to boost confidence in the use of alternative methods to test devices. To help advance these ideas, stir debate about best practices, and coalesce around a roadmap forward, the JHU-Center for Alternatives to Animal Testing (CAAT) hosted a symposium believed to be the first gathering dedicated to the topic of in vitro testing of medical devices. Industry representatives, academics, and regulators in attendance presented evidence to support the unique strengths and challenges associated with the approaches currently in use as well as new methods under development, and drew next steps to push the field forward from their presentations and discussion.

Changing drinking pattern does not influence health perception: a longitudinal study of the atherosclerosis risk in communities study.

OBJECTIVE: To investigate if dynamic changes in the pattern of alcoholic beverages consumption are associated with modifications in health perception. DESIGN, SETTING, AND PARTICIPANTS: This study investigated 12 332 middle aged men and women from the atherosclerosis risk in communities study who reported drinking status and perceived health triennially from 1987 to 1995. Crude and adjusted risks for change in health perception between visits two and three by change in drinking status between visits one and two were computed. In the multivariate analysis the sample was restricted to participants with stable drinking status between visit two and three and stable health perception between visits one and two, to assure that exposure and outcome were not temporary. Covariates included age, sex, race, income, smoking status, educational level, and obesity. RESULTS: Health for persons who stopped or started drinking, or continued to abstain was more likely to decline than was health for persons who continued to drink even after adjustment and restrictions (drinking cessation: OR = 1.6, 95% CI = 1.1, 2.3; started drinking; OR = 1.4, 95% CI = 0.9, 2.2; continued abstaining from alcohol: OR = 1.5, 95% CI = 1.3, 1.9). Among participants with poor perceived health, starting, stopping, or continuing to abstain from alcohol did not improve health in relation to participants that continued to drink. CONCLUSION: Increasing and decreasing drinking patterns and continuous abstinence were associated with declining health perception in comparison with continuous drinking, while starting or stopping drinking did not improve health perception of persons with poor perceived health. These findings suggest that change in health perception was not biologically related to alcohol consumption.

Lower extremity arterial disease assessed by ankle-brachial index in a middle-aged population of African Americans and whites: the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Lower extremity arterial disease (LEAD) is one of the most common manifestations of atherosclerosis. Its epidemiologic characteristics have not been well described, particularly in African Americans. Our purpose was to estimate the prevalence of LEAD and its associations with cardiovascular risk factors in a biracial population of men and women aged 45 to 64 years. METHODS: We examined 15,173 African-American and white men and women who participated in the baseline examination (1987-1989) of the Atherosclerosis Risk in Communities (ARIC) Study. LEAD was defined by a resting ankle-brachial index (ABI), the ratio of ankle systolic blood pressure to brachial systolic pressure, of < or = 0.90. Cross-sectional analyses were used to determine the association of LEAD with cardiovascular risk factors. RESULTS: The age-adjusted prevalence of ABI < or = 0.90 was 3.1% in African-American men, 4.4% in African-American women, 2.3% in white men, and 3.2% in white women. Cigarette smoking was the single most important risk factor for prevalent LEAD. The odds ratio estimate for LEAD in ever smokers versus never smokers was 6.6 (95% confidence interval [CI]=2.0-21.5) in African-American men, 2.3 (95% CI=1.5-3.5) in African-American women, 10.4 (95% CI=3.8-28.3) in white men, and 1.9 (95% CI=1.4-2.6) in white women, after adjustment for age, LDL cholesterol, hypertension, and diabetes. Prevalent LEAD was also associated with hypertension, diabetes, and higher concentrations of total cholesterol, triglycerides, LDL-cholesterol, and fibrinogen, and lower concentrations of HDL cholesterol, but the associations were not always significant across race/ethnic and gender groups. The associations of LEAD with plasma lipids were generally stronger in African Americans than whites. CONCLUSIONS: The prevalence of LEAD appears to be higher in African Americans than whites. Elevations in traditional cardiovascular risk factors are associated with a higher prevalence of LEAD across race/ethnic and gender groups.

Risk factors for coronary heart disease in African Americans: the atherosclerosis risk in communities study, 1987-1997.

BACKGROUND: As part of the Atherosclerosis Risk in Communities Study, the race-specific incidence rates and risk factor prediction for coronary heart disease (CHD) were determined for black and white persons over 7 to 10 years of follow-up, from 1987 to 1997. METHODS: The sample included 14 062 men and women (2298 black women, 5686 white women, 1396 black men, and 4682 white men) aged 45 to 64 years who were free of clinical CHD at baseline. RESULTS: Average age-adjusted incidence rates (95% confidence intervals) for CHD per 1000 person-years were as follows: black women, 5.1 (4.2-6.2); white women, 4.0 (3.5-4.6); black men, 10.6 (8.9-12.7); and white men, 12.5 (11.5-13.7). Incidence rates (95% confidence intervals) using a definition for CHD that excluded revascularization procedures were as follows: black women, 4.9 (4.6-6.0); white women, 2.9 (2.5-3.4); black men, 9.2 (7.6-11.1); and white men, 7.9 (7.0-8.8). In a multivariable analysis, hypertension was a particularly strong risk factor in black women, with hazard rate ratios (95% confidence intervals) as follows: black women, 4.8 (2.5-9.0); white women, 2.1 (1.6-2.9); black men, 2.0 (1.3-3.0); and white men, 1.6 (1.3-1.9). Diabetes mellitus was somewhat more predictive in white women than in other groups. Hazard rate ratios (95% confidence intervals) were as follows: black women, 1.8 (1.2-2.8); white women, 3.3 (2.4-4.6); black men, 1.6 (1.1-2.5); and white men, 2.0 (1.6-2.6). Low-density lipoprotein cholesterol level was similarly predictive in all race-sex groups (hazard rate ratio, 1.2-1.4 per SD increment of low-density lipoprotein cholesterol level). High-density lipoprotein cholesterol level seemed somewhat more protective in white than in black persons. CONCLUSIONS: Findings from this study, along with clinical trial evidence showing efficacy, support aggressive management of traditional risk factors in black persons, as in white persons. Understanding the intriguing racial differences in risk factor prediction may be an important part of further elucidating the causes of CHD and may lead to better methods of preventing and treating CHD.

An innovative method of fracture reduction in an arthroscopically assisted cannulated screw fixation of an Ideberg type III glenoid fracture.

Significantly displaced intra-articular glenoid fractures treated nonoperatively have been found to have poor functional outcomes. For this reason, most are treated with open reduction and internal fixation. Conventional open techniques involve extensive exposure and soft tissue dissection. Moreover, visualization of the fracture and its reduction can also be difficult even with standard open techniques. We present a case of an Ideberg type III glenoid fracture treated with an arthroscopically assisted percutaneous screw fixation, using the coracoid as a reduction aide. This reduction technique is not previously reported in the literature. Arthroscopically assisted percutaneous glenoid fixation has showed promising early results in the literature. In our case, the fracture united and the patient returned to all his normal daily activities by 7 weeks postoperatively. This suggests arthroscopically assisted glenoid fixation provides good functional and radiological outcomes, without the need for extensive soft tissue dissection.

Alcohol intake and cerebral abnormalities on magnetic resonance imaging in a community-based population of middle-aged adults: the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND AND PURPOSE: Although the risks associated with heavy drinking for increased stroke and neurodegenerative changes are well established, the effects on the brain of low to moderate alcohol intake are unclear. Subclinical cerebral abnormalities identified on MRI have been associated with neurocognitive decline and incident stroke. We examined the associations of alcohol intake with MRI-defined cerebral abnormalities in a middle-aged, population-based cohort. METHODS: During 1993-1994, a total of 1909 middle-aged adults (40% men and 49% blacks) from 2 communities in the Atherosclerosis Risk in Communities (ARIC) Study (Forsyth County, North Carolina, and Jackson, Miss) underwent a cerebral MRI examination. Trained neuroradiologists coded the images for the presence of infarction and the extent (10-point scale) of white matter lesions, ventricular size, and sulcal size. RESULTS: In logistic regression analyses, there was no association between alcohol intake and the presence of MRI infarction. In linear regression analyses, alcohol intake was not associated with white matter grade. However, intake of each additional alcoholic drink per week was associated with a 0.01 grade greater ventricular size (P=0.03) and a 0.009 grade greater sulcal size (P=0.02) after adjustment for age, sex, race, body mass index, smoking, income, sports index, and diabetes. The positive associations of alcohol intake with ventricular and sulcal size were consistent across sex and race subgroups. CONCLUSIONS: A protective effect of low to moderate alcohol intake on cerebral infarction was not found; moreover, increased alcohol intake was associated with brain atrophy.

Mitochondrial reactive oxygen production is dependent on the aromatic hydrocarbon receptor.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (dioxin; TCDD) is a pervasive environmental contaminant that induces hepatic and extrahepatic oxidative stress. We have previously shown that dioxin increases mitochondrial respiration-dependent reactive oxygen production. In the present study we examined the dependence of mitochondrial reactive oxygen production on the aromatic hydrocarbon receptor (AHR), cytochrome P450 1A1 (CYP1A1), and cytochrome P450 1A2 (CYP1A2), proteins believed to be important in dioxin-induced liver toxicity. Congenic Ahr(-/-), Cyp1a1(-/-) and Cyp1a2(-/-) knockout mice, and C57BL/6J inbred mice as their Ahr/Cyp1a1/Cyp1a2(+/+) wild-type (wt) counterparts, were injected intraperitoneally with dioxin (15 microg/kg body weight) or corn-oil vehicle on 3 consecutive days. Liver mitochondria were examined 1 week following the first treatment. The level of mitochondrial H(2)O(2) production in vehicle-treated Ahr(-/-) mice was one fifth that found in vehicle-treated wt mice. Whereas dioxin caused a rise in succinate-stimulated mitochondrial H(2)O(2) production in the wt, Cyp1a1(-/-), and Cyp1a2(-/-) mice, this increase did not occur with the Ahr(-/-) knockout. The lack of H(2)O(2) production in Ahr(-/-) mice was not due to low levels of Mn(2+)-superoxide dismutase (SOD2) as shown by Western immunoblot analysis, nor was it due to high levels of mitochondrial glutathione peroxidase (GPX1) activity. Dioxin decreased mitochondrial aconitase (an enzyme inactivated by superoxide) by 44% in wt mice, by 26% in Cyp1a2(-/-) mice, and by 24% in Cyp1a1(-/-) mice; no change was observed in Ahr(-/-) mice. Dioxin treatment increased mitochondrial glutathione levels in the wt, Cyp1a1(-/-), and Cyp1a2(-/-) mice, but not in Ahr(-/-) mice. These results suggest that both constitutive and dioxin-induced mitochondrial reactive oxygen production is associated with a function of the AHR, and these effects are independent of either CYP1A1 or CYP1A2.

Familial aggregation of hypertension treatment and control in the Genetic Epidemiology Network of Arteriopathy (GENOA) study.

PURPOSE: To assess if the treatment and control of hypertension aggregates in families. METHODS: The Genetic Epidemiology Network of Arteriopathy (GENOA) study enrolled sibships between 1997 and 1999, including 1329 hypertensive non-Hispanic blacks (1057 sibling pairs) from Jackson, Mississippi, 1133 hypertensive non-Hispanic whites (859 sibling pairs) from Rochester, Minnesota, and 752 hypertensive Hispanic whites (627 sibling pairs) from Starr County, Texas. Hypertension awareness and drug treatment were ascertained at examination; control was defined by blood pressure levels <140/90 mm Hg. As a measure of familial aggregation, odds ratios were calculated to assess concordance between sibling pairs in the treatment and control of hypertension. RESULTS: Overall, 90.5% of subjects were aware of their hypertension; 90.6% of those who were aware were treated with antihypertensive drugs and 56.0% of those treated had their hypertension controlled. There was statistically significant sib-sib concordance in the treatment of hypertension (odds ratio [OR] = 1.61; 95% confidence interval [CI]: 1.25 to 2.47; P = 0.003) and in the control of drug-treated hypertension (OR = 1.51; 95% CI: 1.25 to 1.81; P <0.0001). CONCLUSION: These findings suggest that the treatment and control of hypertension aggregates in families.

Genome-wide linkage analyses for hypertension genes in two ethnically and geographically diverse populations.

We report the results of a genome-wide linkage scan for hypertension genes in 450 African American hypertensive sibpairs from Jackson, MS, and 539 non-Hispanic white hypertensive sibpairs from Rochester, MN. In the Jackson samples we identified one LOD score peak >1.0 on chromosome 1. In the Rochester sample, no genomic region had a LOD score >1.0. These analyses provide no appreciable evidence of hypertension genes with strong effects independent of other genetic and environmental contexts and suggest that stratified linkage analyses may be required to identify hypertension susceptibility genes in these populations.

Comparison of m-mode echocardiographic left ventricular mass measured using digital and strip chart readings: the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: Epidemiological and clinical studies frequently use echocardiography to measure LV wall thicknesses and chamber dimension for estimating quantitative measures of LV mass. While echocardiographic M-mode LV images have traditionally been measured using hand-held calipers and strip-chart paper tracings, digitized M-mode LV image measurements made directly on the computer screen using electronic calipers have become standard practice. We sought to determine if systematic differences in LV mass occur between the two methods by comparing LV mass measured from simultaneous M-mode strip chart recordings and digitized recordings. METHODS: The Atherosclerosis Risk in Communities study applied the latter method. To determine if systematic differences in LV mass occur between the two methods, LV mass was measured from simultaneous M-mode strip chart recordings and digitized recordings. RESULTS: We found no difference in LV mass (p > .25) and a strong correlation in LV mass between the two methods (r = 0.97). Neither age, sex, nor hypertension status affected the correlation of LV mass between the two methods. CONCLUSIONS: We conclude that digital estimates of LV mass provide unbiased estimates comparable to the strip-chart method.

Left ventricular structure and systolic function in African Americans: the Atherosclerosis Risk in Communities (ARIC) study.

OBJECTIVES: To estimate prevalence of left ventricular (LV) hypertrophy and its relation to systolic function in a population-based sample of African Americans. DESIGN: A baseline 2D guided M-mode echocardiogram was conducted as part of a longitudinal cohort study to assess prevalence and cross-sectional relationships between echocardiographic and clinical parameters. SETTING: Data were collected as part of the Atherosclerosis Risk in Communities study. PARTICIPANTS: Analysis is limited to 1543 African Americans, aged 51-70 years, without clinically apparent cardiovascular or echocardiographically determined valvular disease. MAIN OUTCOME MEASURES: LV hypertrophy prevalence was defined as LV mass/ height2.7 > or = 51 g/m2.7. LV systolic chamber function was assessed at the midwall using the ratio of observed midwall fractional shortening (MWS%) to the value predicted from circumferential end-systolic stress. RESULTS: The prevalence of LV hypertrophy was 33% in men, 38% in women. The prevalence of concentric hypertrophy (LV hypertrophy with relative wall thickness > or = 0.45) was greater than that of eccentric hypertrophy (men: 24% vs 9%; women: 27% vs 11% women). Observed/predicted (O/P) MWS% was strongly and inversely related to LV mass/ height2.7 (P<.001) and LV hypertrophy (P<.001). The O/P MWS% was inversely related to LV mass/height2.7 quartile: O/P MWS% was 106% and 99% in the first and 97% and 89% in the fourth quartile of LV mass/height2.7 for men and women, respectively. Adjusting for age, adiposity, diabetes, blood pressure, antihypertensive medication use, and smoking did not remove association between O/P MWS% and LV mass/height2.7. CONCLUSIONS: LV hypertrophy was highly prevalent in this population-based middle-aged sample of African Americans and was associated with poorer LV systolic chamber function.