Nonlinear mixed effects pharmacokinetic/pharmacodynamic analysis of the anticonvulsant ameltolide (LY201116) in a canine seizure model.

The anticonvulsant ameltolide (LY201116) is a novel potential therapy for the treatment of canine epilepsy. Eight dogs were administered five different oral doses of ameltolide and clinical scoring of the maximal electroshock (MES) induced seizures at 3 and 24 h postdosing were determined in two separate crossover design studies. Plasma ameltolide concentrations were determined at the time of seizures in all dogs and complete plasma concentration-time profiles were also determined in a separate study. A nonlinear mixed effects PK/PD model was fit to the resulting data. A one compartment open model with first order absorption was determined to best fit the ameltolide pharmacokinetics. An effect compartment with a cumulative logistic regression equation was used to establish the PK/PD relationship. The mean bioavailability normalized volume of distribution and the elimination half-life were estimated at 1.20 L/kg and 5.46 h, respectively. The fitted model estimated that from 2 to 15 h following a single 3 mg/kg oral ameltolide dose the mean probability of obtaining a 1 unit reduction in the seizure clinical score severity was greater than 0.80. The utilized PK/PD analysis combined with the canine MES model allowed for the rapid and efficient determination of the plasma ameltolide concentration-anticonvulsant relationship preclinically in dogs.

Success factors for implementing and sustaining a mature electronic medical record in a low-resource setting: a case study of iSanté in Haiti.

Electronic health information systems, including electronic medical records (EMRs), have the potential to improve access to information and quality of care, among other things. Success factors and challenges for novel EMR implementations in low-resource settings have increasingly been studied, although less is known about maturing systems and sustainability. One systematic review identified seven categories of implementation success factors: ethical, financial, functionality, organizational, political, technical and training. This case study applies this framework to iSanté, Haiti's national EMR in use in more than 100 sites and housing records for more than 750 000 patients. The author group, consisting of representatives of different agencies within the Haitian Ministry of Health (MSPP), funding partner the Centers for Disease Control and Prevention (CDC) Haiti, and implementing partner the International Training and Education Center for Health (I-TECH), identify successes and lessons learned according to the seven identified categories, and propose an additional cross-cutting category, sustainability. Factors important for long-term implementation success of complex information systems are balancing investments in hardware and software infrastructure upkeep, user capacity and data quality control; designing and building a system within the context of the greater eHealth ecosystem with a plan for interoperability and data exchange; establishing system governance and strong leadership to support local system ownership and planning for system financing to ensure sustainability. Lessons learned from 10 years of implementation of the iSanté EMR system are relevant to sustainability of a full range of increasingly interrelated information systems (e.g. for laboratory, supply chain, pharmacy and human resources) in the health sector in low-resource settings.

Challenges in data quality: the influence of data quality assessments on data availability and completeness in a voluntary medical male circumcision programme in Zimbabwe.

OBJECTIVES: To assess availability and completeness of data collected before and after a data quality audit (DQA) in voluntary medical male circumcision (VMMC) sites in Zimbabwe to determine the effect of this process on data quality. SETTING: 4 of 10 VMMC sites in Zimbabwe that received a DQA in February, 2015 selected by convenience sampling. PARTICIPANTS: Retrospective reviews of all client intake forms (CIFs) from November, 2014 and May, 2015. A total of 1400 CIFs were included from those 2 months across four sites. PRIMARY AND SECONDARY OUTCOMES: Data availability was measured as the percentage of VMMC clients whose CIF was on file at each site. A data evaluation tool measured the completeness of 34 key CIF variables. A comparison of pre-DQA and post-DQA results was conducted using χ2 and t-tests. RESULTS: After the DQA, high record availability of over 98% was maintained by sites 3 and 4. For sites 1 and 2, record availability increased by 8.0% (p=0.001) and 9.7% (p=0.02), respectively. After the DQA, sites 1, 2 and 3 improved significantly in data completeness across 34 key indicators, increasing by 8.6% (p<0.001), 2.7% (p=0.003) and 3.8% (p<0.001), respectively. For site 4, CIF data completeness decreased by 1.7% (p<0.01) after the DQA. CONCLUSIONS: Our findings suggest that CIF data availability and completeness generally improved after the DQA. However, gaps in documentation of vital signs and adverse events signal areas for improvement. Additional emphasis on data completeness would help support high-quality programme implementation and availability of reliable data for decision-making.

Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial.

BACKGROUND: Evidence has accumulated from observational studies that people eating more fruits and vegetables, which are rich in beta-carotene (a violet to yellow plant pigment that acts as an antioxidant and can be converted to vitamin A by enzymes in the intestinal wall and liver) and retinol (an alcohol chemical form of vitamin A), and people having higher serum beta-carotene concentrations had lower rates of lung cancer. The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the combination of 30 mg beta-carotene and 25,000 IU retinyl palmitate (vitamin A) taken daily against placebo in 18314 men and women at high risk of developing lung cancer. The CARET intervention was stopped 21 months early because of clear evidence of no benefit and substantial evidence of possible harm; there were 28% more lung cancers and 17% more deaths in the active intervention group (active = the daily combination of 30 mg beta-carotene and 25,000 IU retinyl palmitate). Promptly after the January 18, 1996, announcement that the CARET active intervention had been stopped, we published preliminary findings from CARET regarding cancer, heart disease, and total mortality. PURPOSE: We present for the first time results based on the pre-specified analytic method, details about risk factors for lung cancer, and analyses of subgroups and of factors that possibly influence response to the intervention. METHODS: CARET was a randomized, double-blinded, placebo-controlled chemoprevention trial, initiated with a pilot phase and then expanded 10-fold at six study centers. Cigarette smoking history and status and alcohol intake were assessed through participant self-report. Serum was collected from the participants at base line and periodically after randomization and was analyzed for beta-carotene concentration. An Endpoints Review Committee evaluated endpoint reports, including pathologic review of tissue specimens. The primary analysis is a stratified logrank test for intervention arm differences in lung cancer incidence, with weighting linearly to hypothesized full effect at 24 months after randomization. Relative risks (RRs) were estimated by use of Cox regression models; tests were performed for quantitative and qualitative interactions between the intervention and smoking status or alcohol intake. O'Brien-Fleming boundaries were used for stopping criteria at interim analyses. Statistical significance was set at the .05 alpha value, and all P values were derived from two-sided statistical tests. RESULTS: According to CARET's pre-specified analysis, there was an RR of 1.36 (95% confidence interval [CI] = 1.07-1.73; P = .01) for weighted lung cancer incidence for the active intervention group compared with the placebo group, and RR = 1.59 (95% CI = 1.13-2.23; P = .01) for weighted lung cancer mortality. All subgroups, except former smokers, had a point estimate of RR of 1.10 or greater for lung cancer. There are suggestions of associations of the excess lung cancer incidence with the highest quartile of alcohol intake (RR = 1.99; 95% CI = 1.28-3.09; test for heterogeneity of RR among quartiles of alcohol intake has P = .01, unadjusted for multiple comparisons) and with large-cell histology (RR = 1.89; 95% CI = 1.09-3.26; test for heterogeneity among histologic categories has P = .35), but not with base-line serum beta-carotene concentrations. CONCLUSIONS: CARET participants receiving the combination of beta-carotene and vitamin A had no chemopreventive benefit and had excess lung cancer incidence and mortality. The results are highly consistent with those found for beta-carotene in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study in 29133 male smokers in Finland.

The beta-carotene and retinol efficacy trial (CARET) for chemoprevention of lung cancer in high risk populations: smokers and asbestos-exposed workers.

CARET is a multicenter, two-armed, double-masked randomized chemoprevention trial in Seattle, Portland, San Francisco, Baltimore, Connecticut, and Irvine, to test whether oral administration of beta-carotene (30 mg/day) plus retinyl palmitate (25,000 IU/day) can decrease the incidence of lung cancer in high risk populations, namely, heavy smokers and asbestos-exposed workers. The intervention combines the antioxidant action of beta-carotene and the tumor suppressor mechanism of vitamin A. As of April 30, 1993, CARET had randomized 1,845 participants in the 1985-1988 pilot phase plus 13,260 "efficacy" participants since 1989; of these, 4,000 are asbestos-exposed males and 11,105 are smokers and former smokers (44% female). Accrual is complete everywhere except Irvine, which was the last center added (1991), and the safety profile of the regimen to date has been excellent. With 14,420 smokers, 4,010 asbestos-exposed participants, and 114,100 person-years through February 1998, we expect CARET to be capable of detecting a 23% reduction in lung cancer incidence in the two populations combined and 27, 49, 32, and 35% reductions in the smokers, female smokers, male smokers, and asbestos-exposed subgroups, respectively. CARET is highly complementary to the alpha-tocopherol-beta-carotene study in Finland and the Harvard Physicians Health Study (beta-carotene alone) in the National Cancer Institute portfolio of major cancer chemoprevention trials.

An assessment of data quality in a multi-site electronic medical record system in Haiti.

OBJECTIVES: Strong data quality (DQ) is a precursor to strong data use. In resource limited settings, routine DQ assessment (DQA) within electronic medical record (EMR) systems can be resource-intensive using manual methods such as audit and chart review; automated queries offer an efficient alternative. This DQA focused on Haiti's national EMR - iSanté - and included longitudinal data for over 100,000 persons living with HIV (PLHIV) enrolled in HIV care and treatment services at 95 health care facilities (HCF). METHODS: This mixed-methods evaluation used a qualitative Delphi process to identify DQ priorities among local stakeholders, followed by a quantitative DQA on these priority areas. The quantitative DQA examined 13 indicators of completeness, accuracy, and timeliness of retrospective data collected from 2005 to 2013. We described levels of DQ for each indicator over time, and examined the consistency of within-HCF performance and associations between DQ and HCF and EMR system characteristics. RESULTS: Over all iSanté data, age was incomplete in <1% of cases, while height, pregnancy status, TB status, and ART eligibility were more incomplete (approximately 20-40%). Suspicious data flags were present for <3% of cases of male sex, ART dispenses, CD4 values, and visit dates, but for 26% of cases of age. Discontinuation forms were available for about half of all patients without visits for 180 or more days, and >60% of encounter forms were entered late. For most indicators, DQ tended to improve over time. DQ was highly variable across HCF, and within HCFs DQ was variable across indicators. In adjusted analyses, HCF and system factors with generally favorable and statistically significant associations with DQ were University hospital category, private sector governance, presence of local iSante server, greater HCF experience with the EMR, greater maturity of the EMR itself, and having more system users but fewer new users. In qualitative feedback, local stakeholders emphasized lack of stable power supply as a key challenge to data quality and use of the iSanté EMR. CONCLUSIONS: Variable performance on key DQ indicators across HCF suggests that excellent DQ is achievable in Haiti, but further effort is needed to systematize and routinize DQ approaches within HCFs. A dynamic, interactive "DQ dashboard" within iSanté could bring transparency and motivate improvement. While the results of the study are specific to Haiti's iSanté data system, the study's methods and thematic lessons learned holdgeneralized relevance for other large-scale EMR systems in resource-limited countries.

The Carotene and Retinol Efficacy Trial (CARET) to prevent lung cancer in high-risk populations: pilot study with asbestos-exposed workers.

Pilot studies are an essential component for major chemoprevention trials. Prior to initiating the multicenter Carotene and Retinol Efficacy Trial to assess the effectiveness of beta-carotene and retinol for preventing lung cancer, we conducted pilot studies in Seattle between 1985 and 1988 in two high risk populations: current and former heavy smokers and asbestos-exposed workers. The Asbestos Workers Pilot Study for the Carotene and Retinol Efficacy Trial demonstrated that recruitment of asbestos-exposed participants with relevant risk factors was feasible from identified sources. We documented negligible toxicity and high adherence with the protocol, schedule, and intervention. Results from the pilot led to extension of the placebo run-in period, changes in the eligibility criteria, improvements in recruitment strategies and scheduling, elimination of stratification by risk factors in randomization, modifications of study vitamin dosage and of side effects monitoring, and refinement of trial design parameters for Carotene and Retinol Efficacy Trial. The Smokers Pilot is reported in the accompanying article (G. E. Goodman et al., Cancer Epidemiol., Biomarkers & Prev., 2: 389-396, 1993).

Cadmium chemical pneumonitis.

Metal fume exposures are common to a number of trades and may result in the self-limited acute toxic syndrome of metal fume fever. Acute inhalational cadmium toxicity may mimic metal fume fever on initial presentation, but may have a markedly different clinical course. We report a case of cadmium-induced chemical pneumonitis in a welder who, over four years, has shown persistent pulmonary function abnormalities. The potential for acute cadmium toxicity needs to be considered in any patient suspected of having metal fume fever.

Longitudinal pattern of reported respiratory symptoms and accelerated ventilatory loss in asbestos-exposed workers.

Studies investigating the relation between respiratory symptoms and change in ventilatory function have been limited by use of reported symptoms at a single point in time. To assess the relation between the longitudinal pattern of reported cough, phlegm, wheeze, and dyspnea and ventilatory loss, we prospectively investigated changes in FVC and FEV1 associated with development, resolution, or persistence of these symptoms over a 3- to 5-year period in 446 asbestos-exposed workers. Longitudinally reported symptoms changed frequently, with 52 to 61% of subjects reporting a specific symptom noting resolution or development of that symptom during follow-up. Initially reported symptoms were not predictive of accelerated loss of FVC or FEV1. In contrast, development of any new respiratory symptom, and to a lesser extent persistence of symptoms during follow-up, were associated with significantly greater ventilatory losses compared with asymptomatic individuals, ranging from 28 mL/yr in FEV1 for newly developed dyspnea, to 67 mL/yr in FVC for developed wheeze (p < 0.01). We conclude that development or persistence of respiratory symptoms over time, rather than the presence of symptoms per se, is predictive of future ventilatory loss. Recognition of interval changes in symptom reporting during surveillance of asbestos-exposed workers may effectively identify groups at risk for progressive ventilatory impairment.

Total lung capacity. An insensitive measure of impairment in patients with asbestosis and chronic obstructive pulmonary disease?

The total lung capacity (TLC) is frequently used as a measure of respiratory impairment in patients with asbestosis. Because asbestosis and chronic obstructive pulmonary disease (COPD) exert opposite effects on the TLC, it may be an insensitive measure of impairment in patients with both abnormalities. To assess this, we compared asbestos-exposed patients with functional evidence of COPD and radiographic evidence of interstitial fibrosis (group 1) to those with interstitial fibrosis alone (group 2). Despite the two groups being comparable in degree of radiographic "fibrosis," no case of restrictive impairment (reduced TLC) was identified among those with both interstitial fibrosis and COPD (group 1), compared to 33 percent of those with interstitial fibrosis alone (group 2). In addition, those patients with both interstitial fibrosis and COPD, compared to those with interstitial fibrosis alone, were found to have greater impairment as measured by alveolar-arterial oxygen difference and diffusing capacity. We conclude that the TLC is an insensitive measure of impairment due to asbestosis in patients with the common setting of coexistent asbestosis and COPD.

The validity of radiographic estimation of total lung capacity in patients with respiratory disease.

STUDY OBJECTIVE: To evaluate the validity of a state-of-the-art computerized planimetry technique for estimation of total lung capacity (TLC) from chest radiographs, when applied to patients with clinical lung disease receiving routine chest radiographs. DESIGN: Retrospective clinical survey. SETTING: An occupational medicine diagnostic clinic. PATIENTS: A convenience sample of 40 subjects with asbestos-related lung disease, 5 patients with nonasbestos-related restrictive defects, 15 subjects with occupational asthma, and 10 subjects with irritant tracheobronchitis. RESULTS: Estimation of TLC using state-of-the-art computerized algorithms demonstrated limited agreement with conventional measures of TLC when applied to patients with occupational lung disease receiving routine chest radiographs. The most pronounced differences occurred in patients with asbestos-related lung disease and restrictive defects, where the radiographic method of measurement significantly overestimated helium dilution TLC by 986 mL (r=0.73, p<0.001) and 1,135 mL (r=0.82, p<0.05), respectively. Good inspiratory effort was associated with significantly increased radiographic TLC relative to helium dilution TLC; however, radiographic features did not fully account for the observed differences between radiographic and helium dilution techniques. CONCLUSIONS: Our findings suggest that this planimetric technique should not be used as a substitute for conventional measures of TLC in clinic populations receiving routine radiographs. The large diagnostic group specific mean differences observed between radiographic and conventional measures of TLC also suggest that this method is of limited utility in clinical evaluation of occupational lung disease.

Disorders of proprioceptive responses in monkeys after cerebellar lesions: an analysis using the Denny-Brown Collection.

We used the Denny-Brown Research Collection to study in detail the reflex responses of monkeys after ablation of the anterior lobe, posterior lobe or the entire cerebellum. The Collection includes written, film and histological records, and photographs of the brain at autopsy. Large cerebellar ablations severely suppress proprioceptive responses, thereby significantly impairing the capacity to stand, walk, and hop. Cutaneous reflexes are also impaired, although more selectively, permitting expression of normally suppressed responses such as magnet reactions and tactile avoiding responses. Enhancement (release) of responses to truncal cutaneous stimulation, along with suppression of opposing proprioceptive responses, leads to postures of persistent flexion. Large cerebellar lesions also interfere with reflex responses mediated by visual and vestibular systems. More limited cerebellar ablations have similar, but less severe effects.

Tuberculosis in health care settings and the estimated benefits of engineering controls and respiratory protection.

Intra-institutional spread of tuberculosis (Tb) has re-emerged as a substantial public and occupational health threat. To characterize the person-hours and lifetime risks of Tb-related morbidity and mortality, we performed a risk assessment for health care workers (HCWs) developing Tb-related morbidity and mortality at varying levels of exposure, engineering controls, and respiratory protection. Under average conditions of exposure, one Tb skin-test conversion is estimated to occur for every 2650 person-hours of work by unprotected workers. With higher exposures, a skin-test conversion for an unprotected worker may occur in as few as 3 person-hours. Use of respiratory protection is estimated to reduce risks by the following proportions: surgical mask, 2.4-fold; disposable dust, fume, mist, or disposable high-efficiency particulate air filtering (HEPA) mask, 17.5-fold; elastomeric HEPA cartridge respirator, 45.5-fold; or powered air-purifying respirator (PAPR), 238-fold. Assuming a lifetime exposure of 250 hours, the risk of a skin-test conversion is estimated to be 9%. We conclude that HCWs are at substantial risk for Tb-related morbidity and mortality, and that administrative controls, engineering controls, and respirators offer substantial benefits in risk reduction.

Structure and function of occupational health services within selected Department of Energy sites.

The mission of the United States Department of Energy sites has recently changed from nuclear weapons production to site remediation. Considering the mass of radiological and chemical contaminants at these sites, ensuring the health and safety of workers is a major challenge. This study used the findings from a written survey to describe occupational health services at 10 Department of Energy sites. The study aims were to describe and compare: (1) the primary hazards associated with the site activities; (2) the occupational safety and health structure, including service providers; and (3) the occupational health and safety functions, including surveillance, training, and service provision. Although explosions and radiological agents were identified as the hazards with the greatest associated risks, workers at these sites were most likely to be exposed to physical hazards, ergonomic hazards, and/or chemicals, including asbestos. Physicians accounted for 2.4% of service providers, nurses for 5.5%, industrial hygienists for 12.2%, safety personnel for 11.8%, and health physicists for 64.9%. It was concluded that there is an imbalance between the most important hazards and the types of health and safety personnel at these sites.

Carpal tunnel syndrome among ski manufacturing workers.

Carpal tunnel syndrome is a common disorder marked by pain and dysesthesias of the upper extremities. As a test of the hypothesis that carpal tunnel syndrome is associated with occupational risk factors, jobs at a ski assembly plant were classified as repetitive and nonrepetitive. The prevalence of carpal tunnel syndrome among 106 employees with repetitive jobs was compared with that among 67 employees with nonrepetitive jobs. The data collection included a questionnaire, a physical examination, and the measurement of distal sensory latencies of the median and ulnar nerves. Carpal tunnel syndrome was present in either or both hands in 15.4% of those workers with repetitive jobs, but only in 3.1% of those workers with nonrepetitive jobs (crude prevalence ratio 4.92, 95% confidence interval 1.17-20.7). The conclusion was drawn that carpal tunnel syndrome is associated with jobs requiring frequent and sustained hand work.

The structure and function of the occupational health system in Thailand.

This article describes the challenges facing the Thai occupational health system as a result of the enormous growth in the manufacturing sector. It contains a brief history of recent developments in the occupational health system, including the redistribution of responsibilities among government ministries and the enactment of new occupational health regulations.

The respiratory effects of volatile organic compounds.

Volatile organic compounds (VOCs) have been implicated as causative agents in asthma and building-related illness. To determine whether a mixture of VOCs could impair lung function or cause airway inflammation among subjects without bronchial hyperresponsiveness, the authors conducted a randomized, crossover-design trial of controlled human exposures to filtered air for four hours, VOCs at 25 mg/m(3) for four hours, and VOCs at 50 mg/m(3) for four hours, using a VOC mixture based on sampling of indoor environments. VOC exposures caused dose-related increases in lower respiratory, upper respiratory, and non-respiratory symptoms, with no significant change in lung function (FEV(1);, FVC, or FEF(25-75), nasal lavage cellularity or differential cell counts, induced sputum cellularity or differential cell counts, or biomarkers of airway inflammation, including IL-8, LTB(4), or albumin in nasal lavage or induced sputum samples. Atopic individuals had significantly reduced FEE(25-75 following exposure to VOCs at 50 mg/m(3), suggesting that these individuals may be more sensitive to the health effects of VOCs. The authors conclude that reductions in levels of VOCs to substantially less than 25 mg/m(3) are required if a "non-irritating" work environment is desired.

Hyperventilation following a large-scale hazardous-materials incident.

Actual or perceived exposure to hazardous materials may result in physiologic and psychological effects. However, hyperventilation following such exposures has not previously been reported. After a large-scale industrial release of oxides of nitrogen, five (29%) of 17 patients evaluated at a major trauma center were hyperventilating, as defined by arterial PCO2 <33 mm Hg, and nine patients (53%) had arterial PCO2 <37 mm Hg. First responders (rescue team members and paramedics) had a higher rate of hyperventilation than other occupational groups. Age, gender, marital status, decontamination, and mode of arrival were not significantly associated with hyperventilation, although marital status approached significance. This study suggests that hyperventilation may be a common reaction after hazardous-materials incidents, and that certain populations may be at increased risk for this condition.

Pediatric environmental health: perceptions from a survey questionnaire.

To expand the base of knowledge regarding perceptions about potential environmental threats to children's health, a survey was conducted in the Northwest United States. Samples of Head Start parents, PTA presidents, public health officials, school nurses, naturopathic physicians, family practitioners, and pediatricians were mailed a questionnaire inquiring into the nature and degree of concerns about pediatric environmental health. The response rate was 24%. Trends in the data showed disparities in perceptions regarding levels of concern and exposure concerns between respondent categories. Disparities also existed regarding information resources used for children's environmental health. Recognizing differences in perceptions of children's environmental health, as demonstrated in these results, may be useful for risk communication and resource allocation, especially in the context of the wide variety of health belief models. Such knowledge may help clarity situations with environmental health risk concerns, including clinical, public health, and educational circumstances.

An occupational risk survey of a refractory brick company in Ha Noi, Viet Nam.

Viet Nam has an increasing need for building materials, including refractory bricks. Little is known regarding the occupational hazards incurred in brick manufacturing. To determine the occupational health hazards posed by a refractory brick operation in Ha Noi, Viet Nam, a cross-sectional occupational risk survey was conducted, focusing on respirable dust hazards. It included an industrial hygiene walk-through and gravimetric dust analysis. Noise, heat, lack of head protection, and dust exposure were hazards identified at the brick-manufacturing site. Respiratory protection involved a three-layer cloth mask that had not been tested for efficacy. Silica dust exposure levels exceeded the Vietnamese permissible exposure level by almost fivefold based on gravimetric assessment and estimated silica content. This brick manufacturing site contains significant injury and respiratory illness hazards. Further investigations are necessary to begin to develop occupational safety measures at the site.