Cytotoxic screening and antibacterial activity of Withaferin A.

Cancer and bacterial infections are among the leading causes of death worldwide. Plant-derived bioactive compounds constitute promising alternatives for development of new therapeutics. This study aimed at evaluating the biological activity of Withaferin A using 6 tumor cell lines: A549 (lung cancer), U87MG (glioblastoma), SH-SY5Y (neuroblastoma), B16-F10 (mouse melanoma), HeLa (uterine colon cancer) and K562 (chronic myeloid leukemia). In addition, 17 other standard bacterial strains and several multidrug resistant bacteria (MDR) clinical isolates were examined. Cell viability was assessed using the following assays: MTT, neutral red, and dsDNA PicoGreen®. Further, oxidative stress was measured by quantification of reactive oxygen species (ROS) production. The activity against bacteria was determined by the minimum inhibitory concentration (MIC), minimum bacterial concentration (CBM) and antibiofilm activity in the production of strains. Withaferin A was effective, as evidenced by its cytotoxic activity in tumor cell lines, enhanced ROS production in tumor cells and bactericidal and antibiofilm activity. Data demonstrated that Withaferin A may be therapeutically considered as an antitumor and antibacterial agent.

Water Use and Management in the Bakken Shale Oil Play in North Dakota.

Oil and natural gas development in the Bakken shale play of North Dakota has grown substantially since 2008. This study provides a comprehensive overview and analysis of water quantity and management impacts from this development by (1) estimating water demand for hydraulic fracturing in the Bakken from 2008 to 2012; (2) compiling volume estimates for maintenance water, or brine dilution water; (3) calculating water intensities normalized by the amount of oil produced, or estimated ultimate recovery (EUR); (4) estimating domestic water demand associated with the large oil services population; (5) analyzing the change in wastewater volumes from 2005 to 2012; and (6) examining existing water sources used to meet demand. Water use for hydraulic fracturing in the North Dakota Bakken grew 5-fold from 770 million gallons in 2008 to 4.3 billion gallons in 2012. First-year wastewater volumes grew in parallel, from an annual average of 1,135,000 gallons per well in 2008 to 2,905,000 gallons in 2012, exceeding the mean volume of water used in hydraulic fracturing and surpassing typical 4-year wastewater totals for the Barnett, Denver, and Marcellus basins. Surprisingly, domestic water demand from the temporary oilfield services population in the region may be comparable to the regional water demand from hydraulic fracturing activities. Existing groundwater resources are inadequate to meet the demand for hydraulic fracturing, but there appear to be adequate surface water resources, provided that access is available.

Volume and accreditation, but not specialty, affect quality standards in colonoscopy.

BACKGROUND: The Global Rating Scale, defined by the Joint Advisory Group for Gastrointestinal Endoscopy, requires monitoring of endoscopic performance indicators. There are known variations in colonoscopic performance, and investigation of factors causing this is needed. This study aimed to analyse the impact of endoscopist specialty and procedural volume on the quality of colonoscopy. METHODS: Data collected prospectively from a UK hospital endoscopy service between June 2007 and January 2010 were analysed. The main endpoint was the adenoma detection rate (ADR). Secondary endpoints were polyp detection rate (PDR), reported caecal intubation rate (CIR) and reported complications. Multivariable binary regression models were built to adjust for confounding patient-level and endoscopist-level variation. RESULTS: A total of 10,026 colonoscopies were included, with an overall ADR of 19.2 per cent, a CIR of 90.2 per cent and a perforation rate of 0.06 per cent. In univariable analyses, surgeons had a higher ADR and higher PDR, but lower CIR, compared with physicians. Surgeons had a significantly different case mix in terms of age, sex and indication for colonoscopy. After adjusting for this case mix in multivariable analysis, specialty was no longer a significant predictor of ADR; however, surgeons retained their higher PDR and physicians their higher CIR. Endoscopists accredited for screening and those performing more than 100 colonoscopies per year had a higher ADR. CONCLUSION: Adjusting for case mix, physicians and surgeons performed equally well in terms of ADR. Accreditation and a higher annual number of colonoscopies were more important factors in achieving quality standards.

The tongue and its control by sleep state-dependent modulators.

The neural networks controlling vital functions such as breathing are embedded in the brain, the neural and chemical environment of which changes with state, i.e., wakefulness, non-rapid eye movement (non-REM) sleep and REM sleep, and with commonly administered drugs such as anaesthetics, sedatives and ethanol. One particular output from the state-dependent chemical brain is the focus of attention in this paper; the motor output to the muscles of the tongue, specifically the actions of state-dependent modulators acting at the hypoglossal motor pool. Determining the mechanisms underlying the modulation of the hypoglossal motor output during sleep is relevant to understanding the spectrum of increased upper airway resistance, airflow limitation, hypoventilation and airway obstructions that occur during natural and drug-influenced sleep in humans. Understanding the mechanisms underlying upper airway dysfunction in sleep-disordered breathing is also important given the large and growing prevalence of obstructive sleep apnea syndrome which constitutes a major public health problem with serious clinical, social and economic consequences.

A serological survey of leptospirosis in cattle of rural communities in the province of KwaZulu-Natal, South Africa.

A serological survey of leptospirosis in cattle originating from rural communities of the province of KwaZulu-Natal (KZN) in South Africa was carried out between March 2001 and December 2003. The survey was designed as a 2-stage survey, using the local diptank as the primary sampling point. In total, 2021 animals from 379 diptanks in 33 magisterial districts were sampled and tested with the microscopic agglutination test (MAT). The apparent prevalence at district level was adjusted for clustering and diagnostic test sensitivity and specificity and displayed in maps. The prevalence of leptospirosis in cattle originating from communal grazing areas of KZN was found to be 19.4% with a 95% confidence interval of 14.8-24.1%. At district level the prevalence of leptospirosis varied from 0 to 63% of cattle. Bovine leptospirosis was found to occur in communal grazing areas throughout the province with the exception of 2 districts. The southeastern regions showed a higher prevalence than other areas of the province; while in some of the northern and western districts a lower prevalence was noted. Several serovars were detected by the MAT and although Leptospira interrogans serovar pomona occurred most frequently, serovars tarrasovi, bratislava, hardjo, canicola and icterohaemorrhagica were also frequently identified. The findings of the survey are discussed.

Impact of Percoll purification on isolation of primary human hepatocytes.

Research and therapeutic applications create a high demand for primary human hepatocytes. The limiting factor for their utilization is the availability of metabolically active hepatocytes in large quantities. Centrifugation through Percoll, which is commonly performed during hepatocyte isolation, has so far not been systematically evaluated in the scientific literature. 27 hepatocyte isolations were performed using a two-step perfusion technique on tissue obtained from partial liver resections. Cells were seeded with or without having undergone the centrifugation step through 25% Percoll. Cell yield, function, purity, viability and rate of bacterial contamination were assessed over a period of 6 days. Viable yield without Percoll purification was 42.4 × 106 (SEM ± 4.6 × 106) cells/g tissue. An average of 59% of cells were recovered after Percoll treatment. There were neither significant differences in the functional performance of cells, nor regarding presence of non-parenchymal liver cells. In five cases with initial viability of <80%, viability was significantly increased by Percoll purification (71.6 to 87.7%, p = 0.03). Considering our data and the massive cell loss due to Percoll purification, we suggest that this step can be omitted if the initial viability is high, whereas low viabilities can be improved by Percoll centrifugation.

A serological prevalence survey of Brucella abortus in cattle of rural communities in the province of KwaZulu-natal, South Africa.

A serological survey of Brucella abortus in cattle originating from communal grazing areas of Kwa Zulu Natal was carried out between March 2001 and December 2003. The survey was designed as a 2-stage survey, considering the diptank as the primary sampling unit. In total 46 025 animals from 446 diptanks of 33 magisterial districts were sampled and tested using the Rose Bengal test and Complement Fixation Test. The apparent prevalence at district level was adjusted for clustering, diagnostic test sensitivity and specificity, and mapped using ArcView version 3.3. The prevalence of brucellosis in communal grazing areas of Kwa-Zulu Natal was found to be 1.45 % (0.84-2.21%) and varied from 0 to 15.6 % between magisterial districts. In 19 of the 33 magisterial districts no serological reactors were observed. A large variation in prevalence was found within diptank areas. Brucellosis was found to be most prevalent in the northeastern area of the province. The findings of the survey are discussed.

Tracing the origins of genotype VIIh Newcastle disease in southern Africa.

It is widely accepted that Newcastle disease is endemic in most African countries, but little attention has been afforded to establishing the sources and frequency of the introductions of exotic strains. Newcastle disease outbreaks have a high cost in Africa, particularly on rural livelihoods. Genotype VIIh emerged in South-East Asia and has since caused serious outbreaks in poultry in Malaysia, Indonesia, southern China, Vietnam and Cambodia. Genotype VIIh reached the African continent in 2011, with the first outbreaks reported in Mozambique. Here, we used a combination of phylogenetic evidence, molecular dating and epidemiological reports to trace the origins and spread of subgenotype VIIh Newcastle disease in southern Africa. We determined that the infection spread northwards through Mozambique, and then into the poultry of the north-eastern provinces of Zimbabwe. From Mozambique, it also reached neighbouring Malawi and Zambia. In Zimbabwe, the disease spread southward towards South Africa and Botswana, causing outbreaks in backyard chickens in early-to-mid 2013. In August 2013, the disease entered South Africa's large commercial industry, and the entire country was infected within a year, likely through fomites and the movements of cull chickens. Illegal poultry trading or infected waste from ships and not wild migratory birds was the likely source of the introduction to Mozambique in 2011.

Obstructive sleep apnea as a cause of systemic hypertension. Evidence from a canine model.

Several epidemiological studies have identified obstructive sleep apnea (OSA) as a risk factor for systemic hypertension, but a direct etiologic link between the two disorders has not been established definitively. Furthermore, the specific physiological mechanisms underlying the association between OSA and systemic hypertension have not been identified. The purpose of this study was to systematically examine the effects of OSA on daytime and nighttime blood pressure (BP). We induced OSA in four dogs by intermittent airway occlusion during nocturnal sleep. Daytime and nighttime BP were measured before, during, and after a 1-3-mo long period of OSA. OSA resulted in acute transient increases in nighttime BP to a maximum of 13.0+/-2.0 mmHg (mean+/-SEM), and eventually produced sustained daytime hypertension to a maximum of 15.7+/-4.3 mmHg. In a subsequent protocol, recurrent arousal from sleep without airway occlusion did not result in daytime hypertension. The demonstration that OSA can lead to the development of sustained hypertension has considerable importance, given the high prevalence of both disorders in the population.

Phylogenetic analysis of low-pathogenicity avian influenza H6N2 viruses from chicken outbreaks (2001-2005) suggest that they are reassortants of historic ostrich low-pathogenicity avian influenza H9N2 and H6N8 viruses.

Low-pathogenicity (LPAI) and high-pathogenicity (HPAI) avian influenza viruses are periodically isolated from South African ostriches, but during 2002 the first recorded outbreak of LPAI (H6N2) in South African chickens occurred on commercial farms in the Camperdown area of KwaZulu/Natal (KZN) Province. Sequence analysis of all eight genes were performed and phylogenetic analysis was done based on the hemagglutinin and neuraminidasc sequences. Results from phylogenetic analyses indicated that the H6N2 chicken viruses most likely arose from a reassortment between two South African LPAI ostrich isolates: an H9N2 virus isolated in 1995 and an H6N8 virus isolated in 1998. Two cocirculating sublineages of H6N2 viruses were detected, both sharing a recent common ancestor. One of these sublineages was restricted to the KZN province. The neuraminidase gene contained a 22-amino acid deletion in the NA-stalk region, which is associated with adaptation to growth in chickens, whereas the other group, although lacking the NA-stalk deletion, spread to commercial farms in other provinces. The persistence of particular H6N2 types in some regions for at least 2 yr supports reports from Asia and southern California suggesting that H6N2 viruses can form stable lineages in chickens. It is probable that the ostrich H6N8 and H9N2 progenitors of the chicken H6N2 viruses were introduced to ostriches by wild birds. Ostriches, in which AI infections are often subclinical, may serve as mixing vessels for LPAI strains that occasionally spill over into other poultry.

A questionnaire survey of perceptions and preventive measures related to animal health amongst cattle owners of rural communities in KwaZulu-Natal, South Africa.

A questionnaire survey of 315 cattle owners from the rural districts of KwaZulu-Natal was carried out. The aim of the survey was to improve our understanding of local farmers' perceptions and practices of animal disease prevention and control and to establish the extent of their relationship with veterinary services. The survey showed that many owners practice preventive measures such as deworming, tick control and vaccination. Traditional medicines were in use by over half the respondents (58.9 %). Diseases are regarded as an important management problem (56.1 %); ticks, worms and diarrhoea dominated the mentioned health problems in cattle. Veterinary services still play an important role and are a frequent source of advice to owners. The findings of the survey and their context are discussed.

Respiratory activation of the genioglossus muscle involves both non-NMDA and NMDA glutamate receptors at the hypoglossal motor nucleus in vivo.

Brainstem respiratory neurons innervate the hypoglossal motor nucleus which in turn transmits this respiratory drive signal to the genioglossus muscle of the tongue. The mechanism of this transmission is important to help maintain an open airspace for effective breathing, and is thought to rely almost exclusively on non-N-methyl-d-aspartate (non-NMDA) glutamate receptor activation during respiration. However those studies were performed in slices of medulla from neonatal animals in vitro which may have led to an underestimation of the contribution of NMDA glutamate receptors that may normally operate in intact preparations. The current study tests the hypothesis that both NMDA and non-NMDA receptors contribute to respiratory drive transmission at the hypoglossal motor nucleus in vivo. Experiments were performed in urethane-anesthetized and tracheotomized adult Wistar rats in which vagus nerves were either intact or sectioned. In the presence of augmented genioglossus activity produced by vagotomy, microdialysis perfusion of either an NMDA receptor antagonist (D-2-amino-5-phosphonovaleric acid, 0.001-10 mM) or a non-NMDA receptor antagonist (6-cyano-7-nitroquinoxaline-2, 3-dione disodium salt, 0.001-1 mM) to the hypoglossal motor nucleus reduced respiratory-related genioglossus activity in a dose-dependent manner (P < 0.001) indicating that both NMDA and non-NMDA glutamate receptors are necessary for transmission of the respiratory drive signal to genioglossus muscle in vivo. Similar effects were observed in the vagus nerve intact rats. Further experiments demonstrated that each delivered antagonist had effects that were specific to its respective receptor. Regression analysis also revealed that the activity of both NMDA and non-NMDA receptors at the hypoglossal motor nucleus is related to levels of the prevailing respiratory drive. These results show that both NMDA and non-NMDA glutamate receptors at the hypoglossal motor nucleus are involved in transmission of the respiratory drive signal to genioglossus muscle in vivo.

Diuretics and hypertension in black adults.

A randomized controlled, single-blind trial was conducted to compare the effectiveness of a high-dose diuretic with a combination of a diuretic and metoprolol in black adults with hypertension. All subjects were first treated with 50 mg/d of hydrochlorothiazide for four weeks. Only subjects with a diastolic blood pressure of 95 mm Hg or higher at the end of this four-week period entered the randomized trial. We hypothesized that black patients with uncontrolled hypertension and low plasma renin activity on usual-dose hydrochlorothiazide therapy (ie, 50 mg/d) would respond better to higher doses of hydrochlorothiazide (ie, 100 to 150 mg/d) than to a usual-dose diuretic and metoprolol. Diuretic-metoprolol combination therapy was significantly more effective than high-dose diuretic therapy regardless of plasma renin status.

What is the role of timing in the surgical and rehabilitative care of community-dwelling older persons with acute hip fracture?

OBJECTIVE: To determine the relationship of surgical repair of acute hip fracture within 2 days of hospital admission, followed by more than 5 sessions per week of physical and occupational therapy (PT/OT), to outcomes after acute hip fracture. DESIGN: Comparison of hip fracture outcomes via secondary analysis of data obtained by retrospective medical record review according to timing of surgical repair and frequency of PT/OT, adjusted for patient, medical care, and hospital characteristics. SAMPLE: The study included the medical records of 1880 elderly Medicare recipients admitted from the community to 284 acute care hospitals in 5 states during 1981 and 1982 or 1985 and 1986 with a primary diagnosis of acute hip fracture who underwent surgical repair and received PT/OT. INTERVENTIONS: None. MAIN OUTCOME MEASURES: The postoperative day when ambulation first occurred, the length of hospital stay, and return to the community. RESULTS: Earlier surgical repair was associated with a shorter length of hospital stay (5 fewer days, P < .001) without a statistically significant increase in medical complications. High frequency PT/OT was associated with earlier ambulation (odds ratio [OR], 1.76; 95% confidence limits [CL], 1.50, 2.07). Patients who ambulated earlier [corrected] had shorter lengths of stay (6.5 fewer days, P < .001), were more likely to return to the community (OR, 1.45; 95% CL, 1.16, 1.81), and had better 6-month survival (OR, 2.8; 95% CL, 2.06, 3.88), and patients younger than 85 years had fewer in-hospital complications (11% vs 4%, P < .001). CONCLUSION: Surgical repair within the first 2 days of hospitalization and more than 5 PT/OT sessions per week were associated with better health outcomes in a nationally representative sample of elderly patients with hip fracture.

Racial variations in the rates of carotid angiography and endarterectomy in patients with stroke and transient ischemic attack.

BACKGROUND: Carotid endarterectomy is emerging as the treatment of choice for patients with symptomatic carotid artery stenosis at low operative risk. We sought to determine if racial variations in the rate of carotid angiography and endarterectomy exist in the Veteran Affairs health care system among patients who are insulated from the cost of their care. METHODS: From a national database of all hospitalizations at Veterans Affairs medical centers, we identified a cohort of patients with diagnoses of stroke or transient ischemic attack who were likely to be candidates for carotid angiography and endarterectomy. We used logistic regression to determine if the patient's race was associated with receiving carotid angiography and endarterectomy, after adjusting for patient's age, degree of eligibility for Veterans Affairs care, socioeconomic status, comorbidities associated with hospital admission, and geographic region of the hospital. RESULTS: Of the 35 922 veterans in the cohort, 3535 (9.8%) underwent angiography during the study period and 1249 (3.5%) had carotid endarterectomy. Blacks constituted 18.2% of the patients with a history of stroke or transient ischemic attack, 9.8% of the patients having angiography, but only 4.2% of the patients undergoing carotid endarterectomy. Whites constituted 77.1% of the patients with a history of stroke or transient ischemic attack, 86.1% of the patients receiving angiography, and 93.0% of those having carotid endarterectomies. After adjusting for confounding variables, black patients continued to have a significantly lower likelihood than white patients of undergoing angiography (risk ratio = 0.47; 95% confidence interval = 0.42, 0.53) and subsequent endarterectomy (risk ratio = 0.28; 95% confidence interval = 0.20, 0.38). CONCLUSIONS: Socioeconomic status and access to care within a large managed health care system do not fully explain racial differences in the rate of carotid angiography and endarterectomy. Either referral bias for evaluation for carotid endarterectomy or racial differences in the extent and location of cerebrovascular disease are more important explanations for the observed racial variations.

Primary care clinicians' performance for detecting actinic keratoses and skin cancer.

BACKGROUND: If skin cancer screening is to become widely adopted, its effectiveness depends on the ability of primary care clinicians to detect cutaneous malignancies. OBJECTIVE: To assess primary care clinicians' proficiency for detecting skin cancers and actinic keratoses in a clinic population. METHODS: A convenience sample of 190 white male patients aged 40 years or older presenting to a university-affiliated Veterans Affairs general internal medicine or dermatology clinic were included in the study. Each patient was independently examined by a primary care clinician and a dermatologist to measure interobserver agreement. We compared the ability of primary care clinicians to diagnose actinic keratoses and skin cancers using dermatologists' examinations as a pragmatic reference standard. RESULTS: Agreement was moderate as to whether a patient had single actinic keratosis (kappa, 0.36; 95% confidence interval [CI], 0.22-0.50), multiple actinic keratoses (kappa, 0.48; 95% CI, 0.34-0.61), or skin cancer (kappa, 0.48; 95% CI, 0.34-0.62). Agreement decreased when individual lesions were the unit of analysis. When the patient was the unit of analysis, primary care clinicians identified the presence of skin cancer with a sensitivity of 57% (95% CI, 44%-68%), specificity of 88% (95% CI, 81%-93%), positive likelihood ratio of 4.9 (95% CI, 3.0-8.3), and negative likelihood ratio of 0.48 (95% CI, 0.35-0.63). When the lesion was the unit of analysis the sensitivity was 38% (95% CI, 29%-47%), the specificity was 95% (95% CI, 93%-96%), the positive likelihood ratio was 7.1 (95% CI, 4.8-10.3), and the negative likelihood ratio was 0.66 (95% CI, 0.56-0.75). CONCLUSIONS: Examinations performed by primary care clinicians for diagnosing skin cancer lacked sensitivity. Without improved diagnostic skills, primary care clinicians' examinations may be ineffective as a screening test.

Racial differences in care among hospitalized patients with Pneumocystis carinii pneumonia in Chicago, New York, Los Angeles, Miami, and Raleigh-Durham.

BACKGROUND: While strategies for medical care for human immunodeficiency virus-related Pneumocystis carinii pneumonia (PCP) are well established, racial variations in care have not been evaluated. OBJECTIVE: To determine whether sociodemographic characteristics influence patterns of care and patient outcomes, by analyzing the use of diagnostic tests and anti-PCP medications and in-hospital mortality rates for persons who were hospitalized with human immunodeficiency virus-related PCP. METHODS: Retrospective chart review of a cohort of 627 Veterans Administration (VA) patients and 1547 non-VA patients with empirically treated or cytologically confirmed PCP who were hospitalized from 1987 to 1990. Outcomes included representative aspects of the process of care for PCP and short-term mortality rates. RESULTS: Among VA patients, black and Hispanic patients were not significantly different from white patients with regard to in-hospital mortality rates, use and timing of a bronchoscopy, or receipt of timely anti-PCP medications. Among non-VA patients, black and Hispanic patients were more likely to die in the hospital and less likely to undergo a diagnostic bronchoscopy in the first 2 days of hospitalization. These racial and ethnic group differences in the use of a bronchoscopy and in-hospital mortality among non-VA patients were almost fully accounted for by differences in health insurance status and hospital characteristics. CONCLUSIONS: Racial factors do not appear to be an important determinant of the intensity of diagnostic or therapeutic care among patients who are hospitalized with PCP. Variations in care are largely attributable to differences in health insurance and admitting hospital characteristics.

Depression and other determinants of values placed on current health state by stroke patients: evidence from the VA Acute Stroke (VASt) study.

BACKGROUND AND PURPOSE: This prospective study examined the determinants of the utility (value) placed on health status among a sample of patients with acute ischemic and intracerebral hemorrhagic stroke. METHODS: Data were from the VA Acute Stroke (VASt) study, a nationwide prospective cohort of 1073 acute stroke patients admitted at any of 9 Department of Veterans Affairs Medical Center sites between April 1, 1995, and March 31, 1997. The primary outcome was the patient's health status utility as measured by the time-tradeoff method. Data were obtained by telephone interviews at 1, 6, and 12 months and by medical record review. General linear mixed modeling was used to assess the effects of social, psychological, and physical factors on patients' valuations of their current health state. The analysis was confined to the 327 patients who were able to provide self-reports at >/=2 time points. RESULTS: Patients' valuations of their health state status over the initial 12 months after stroke were very stable over time, with only a slight improvement at 6 months, followed by a slight decline at 12 months. In adjusted analyses, living alone, being institutionalized, decreased physical function, and depression were independently associated with lower levels of patient health status utility over time. CONCLUSIONS: Stroke patient health status utilities are relatively stable during the initial year after stroke. In addition to physical function, psychological health and social environment are important determinants of patient health status utility. These factors need to be considered when conducting stroke decision analyses if more accurate conclusions are to be drawn regarding preferred patterns of care.

Improving the reliability of stroke subgroup classification using the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria.

BACKGROUND AND PURPOSE: We sought to improve the reliability of the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification of stroke subtype for retrospective use in clinical, health services, and quality of care outcome studies. The TOAST investigators devised a series of 11 definitions to classify patients with ischemic stroke into 5 major etiologic/pathophysiological groupings. Interrater agreement was reported to be substantial in a series of patients who were independently assessed by pairs of physicians. However, the investigators cautioned that disagreements in subtype assignment remain despite the use of these explicit criteria and that trials should include measures to ensure the most uniform diagnosis possible. METHODS: In preparation for a study of outcomes and management practices for patients with ischemic stroke within Department of Veterans Affairs hospitals, 2 neurologists and 2 internists first retrospectively classified a series of 14 randomly selected stroke patients on the basis of the TOAST definitions to provide a baseline assessment of interrater agreement. A 2-phase process was then used to improve the reliability of subtype assignment. In the first phase, a computerized algorithm was developed to assign the TOAST diagnostic category. The reliability of the computerized algorithm was tested with a series of synthetic cases designed to provide data fitting each of the 11 definitions. In the second phase, critical disagreements in the data abstraction process were identified and remaining variability was reduced by the development of standardized procedures for retrieving relevant information from the medical record. RESULTS: The 4 physicians agreed in subtype diagnosis for only 2 of the 14 baseline cases (14%) using all 11 TOAST definitions and for 4 of the 14 cases (29%) when the classifications were collapsed into the 5 major etiologic/pathophysiological groupings (kappa=0.42; 95% CI, 0.32 to 0.53). There was 100% agreement between classifications generated by the computerized algorithm and the intended diagnostic groups for the 11 synthetic cases. The algorithm was then applied to the original 14 cases, and the diagnostic categorization was compared with each of the 4 physicians' baseline assignments. For the 5 collapsed subtypes, the algorithm-based and physician-assigned diagnoses disagreed for 29% to 50% of the cases, reflecting variation in the abstracted data and/or its interpretation. The use of an operations manual designed to guide data abstraction improved the reliability subtype assignment (kappa=0.54; 95% CI, 0.26 to 0.82). Critical disagreements in the abstracted data were identified, and the manual was revised accordingly. Reliability with the use of the 5 collapsed groupings then improved for both interrater (kappa=0.68; 95% CI, 0.44 to 0.91) and intrarater (kappa=0.74; 95% CI, 0.61 to 0.87) agreement. Examining each remaining disagreement revealed that half were due to ambiguities in the medical record and half were related to otherwise unexplained errors in data abstraction. CONCLUSIONS: Ischemic stroke subtype based on published TOAST classification criteria can be reliably assigned with the use of a computerized algorithm with data obtained through standardized medical record abstraction procedures. Some variability in stroke subtype classification will remain because of inconsistencies in the medical record and errors in data abstraction. This residual variability can be addressed by having 2 raters classify each case and then identifying and resolving the reason(s) for the disagreement.

Benzodiazepine use and cognitive function among community-dwelling elderly.

OBJECTIVE: To evaluate the relation between benzodiazepine use and cognitive function among community-dwelling elderly. METHODS: This prospective cohort study included 2765 self-reporting subjects from the Duke Established Populations for Epidemiologic Studies of the Elderly. The subjects were cognitively intact at baseline (1986-1987) and alive at follow-up data collection 3 years later. Cognitive function was assessed with the Short Portable Mental Status Questionnaire (unimpaired versus impaired and change in score) and on the basis of the number of errors on the individual domains of the Orientation-Memory-Concentration Test. Benzodiazepine use was determined during in-home interviews and classified by dose, half-life, and duration. Covariates included demographic characteristics, health status, and health behaviors. RESULTS: After control for covariates, current users of benzodiazepine made more errors on the memory test (beta coefficient, 0.35; 95% confidence interval [CI], 0.10 to 0.61) than nonusers. Further assessment of the negative effects on memory among current users suggested a dose response in which users taking the recommended or higher dose made more errors (beta coefficient, 0.57; 95% CI, 0.26 to 0.88) and a duration response in which long-term users made more errors (beta coefficient, 0.39; 95% CI, 0.05 to 0.73) than nonusers. Users of agents with long half-lives and users of agents with short half-lives both had increased memory impairment (beta coefficient, 0.32; 95% CI, 0.01 to 0.64 and beta coefficient, 0.38; 95% CI, 0.02 to 0.75, respectively) relative to nonusers. Previous benzodiazepine use was unrelated to memory problems, and current and previous benzodiazepine use was unrelated to level of cognitive functioning as measured with the other 4 tests. CONCLUSIONS: The results suggested that current benzodiazepine use, especially in recommended or higher doses, is associated with worse memory among community-dwelling elderly.