Cox regression survival analysis with compositional covariates: Application to modelling mortality risk from 24-h physical activity patterns.

Survival analysis is commonly conducted in medical and public health research to assess the association of an exposure or intervention with a hard end outcome such as mortality. The Cox (proportional hazards) regression model is probably the most popular statistical tool used in this context. However, when the exposure includes compositional covariables (that is, variables representing a relative makeup such as a nutritional or physical activity behaviour composition), some basic assumptions of the Cox regression model and associated significance tests are violated. Compositional variables involve an intrinsic interplay between one another which precludes results and conclusions based on considering them in isolation as is ordinarily done. In this work, we introduce a formulation of the Cox regression model in terms of log-ratio coordinates which suitably deals with the constraints of compositional covariates, facilitates the use of common statistical inference methods, and allows for scientifically meaningful interpretations. We illustrate its practical application to a public health problem: the estimation of the mortality hazard associated with the composition of daily activity behaviour (physical activity, sitting time and sleep) using data from the U.S. National Health and Nutrition Examination Survey (NHANES).

Emergency department non-invasive cardiac output study (EDNICO): a feasibility and repeatability study.

BACKGROUND: There is little published data investigating non-invasive cardiac output monitoring in the emergency department (ED). We assessed six non-invasive fluid responsiveness monitoring methods which measure cardiac output directly or indirectly for their feasibility and repeatability of measurements in the ED: (1) left ventricular outflow tract echocardiography derived velocity time integral, (2) common carotid artery blood flow, (3) suprasternal aortic Doppler, (4) bioreactance, (5) plethysmography with digital vascular unloading method, and (6) inferior vena cava collapsibility index. METHODS: This is a prospective observational study of non-invasive methods of assessing fluid responsiveness in the ED. Participants were non-ventilated ED adult patients requiring intravenous fluid resuscitation. Feasibility of each method was determined by the proportion of clinically interpretable measurements from the number of measurement attempts. Repeatability was determined by comparing the mean difference of two paired measurements in a fluid steady state (after participants received an intravenous fluid bolus). RESULTS: 76 patients were recruited in the study. A total of 207 fluid responsiveness measurement sets were analysed. Feasibility rates were 97.6% for bioreactance, 91.3% for vascular unloading method with plethysmography, 87.4% for common carotid artery blood flow, 84.1% for inferior vena cava collapsibility index, 78.7% for LVOT VTI, and 76.8% for suprasternal aortic Doppler. The feasibility rates difference between bioreactance and all other methods was statistically significant. CONCLUSION: Our study shows that non-invasive fluid responsiveness monitoring in the emergency department may be feasible with selected methods. Higher repeatability of measurements were observed in non-ultrasound methods. These findings have implications for further studies specifically assessing the accuracy of such non-invasive cardiac output methods and their effect on patient outcome in the ED in fluid depleted states such as sepsis.

Differences in physical activity time-use composition associated with cardiometabolic risks.

This study investigates the association between the overall physical activity composition of the day (sedentary behavior (SB), light intensity physical activity (LIPA) and moderate-to-vigorous physical activity (MVPA)) and cardiometabolic health, and examines whether improved health can be associated with replacing SB with LIPA. A cross-sectional analysis of the Health Survey for England 2008 on N = 1411 adults was undertaken using a compositional analysis approach to examine the relationship between cardiometabolic risk biomarkers and physical activity accounting for co-dependency between relative amounts of time spent in different behavior. Daily time spent in SB, LIPA and MVPA was determined from waist-mounted accelerometry data (Actigraph GT1M) and modelled against BMI, waist circumference, waist-to-hip ratio, blood pressure, total and HDL cholesterol, HbA1c, and VO2 maximum. The composition of time spent in SB, LIPA and MVPA was statistically significantly associated with BMI, waist circumference, waist-to-hips ratio, HDL cholesterol and VO2 maximum (p < 0.001), but not HbA1c, systolic and diastolic blood pressure, or total cholesterol. Increase of relative time spent in MVPA was beneficially associated with obesity markers, HDL cholesterol, and VO2 maximum, and SB with poorer outcomes. The association of changes in LIPA depended on whether it displaced MVPA or SB. Increasing the proportion of MVPA alone may have the strongest potential association with adiposity outcomes and HDL cholesterol but similar outcomes could also be associated with a lower quantity of MVPA provided a greater quantity of SB is replaced overall with LIPA (around 10.5 min of LIPA is equivalent to 1 min of MVPA).

Evidence-practice gaps in lung cancer: A scoping review.

Lung cancer is a significant international health problem. Aligning clinical practice with evidence-based guideline recommendations has the potential to improve patient outcomes. This scoping review describes evidence-practice gaps across the diagnostic and management care pathway for lung cancer. We conducted searches of online databases Medline, PsychInfo, Cinahl and the Cochrane Library to identify studies published between 2008 and 2012. Of 614 articles screened, 65 met inclusion criteria. We identified seven evidence-practice gaps: (1) delays in timely diagnosis and referral; (2) curative and (3) palliative treatments are under-utilised; (4) older age and co-morbidities influence the use of treatments; (5) the benefits of multidisciplinary team review are not available to all lung cancer patients; (6) psychosocial needs are unmet; and (7) early referral to palliative care services is under-utilised. The scoping review highlighted three key messages: (1) there are significant challenges in the timely diagnosis and referral of lung cancer; (2) curative and palliative treatments, psychosocial support and palliative care are under-utilised in lung cancer management; and (3) variations in treatment utilisation appear to be associated with non-disease factors such as patient characteristics, provider practices and the organisation of health care services. Future research should focus on designing interventions to overcome variations in care.

Presence or absence of intestinal metaplasia but not its burden is associated with prevalent high-grade dysplasia and cancer in Barrett's esophagus.

Universal agreement on the inclusion of intestinal metaplasia to diagnose Barrett's esophagus (BE) is lacking. Our aim was to determine the association of intestinal metaplasia and its density with the prevalence of dysplasia/cancer in columnar lined esophagus (CLE). Patients with CLE but no intestinal metaplasia (CLE-no IM) were identified by querying the clinical pathology database using SNOMED codes for distal esophageal biopsies. CLE-IM patients were identified from a prospectively maintained database of BE patients. Subsequently, relative risks for prevalent dysplasia and cancer were calculated. Since patients with CLE-no IM are not usually enrolled in surveillance, only prevalent dysplasia/cancer on index endoscopy was analyzed. Goblet cell density and percent intestinal metaplasia were estimated. All biopsy slides were reviewed for dysplasia by two experienced gastrointestinal pathologists. Two hundred sixty-two CLE-IM and 260 CLE-no IM patients were included (age 64±12 vs. 60±11 years, P=0.001; whites 92% vs. 82%, P=0.001; males 99.7% vs. 99.3%, P=NS; CLE length 3.4±3.2 vears 1.4±0.4 cm, P=0.001 and hiatus hernia 64% vs. 56%, P=0.013). The odds of finding low-grade dysplasia and of high-grade dysplasia (HGD)/cancer were 12.5-fold (2.9-53.8, P=0.007) and 4.2-fold (95% CI 1.4-13, P=0.01) higher, respectively, in the CLE-IM group. Reanalysis after controlling for important variables of age, race, and length did not significantly alter the overall results. In CLE-IM group, when patients with high (>50/LPF) versus low goblet cell density (<50/LPF) and <10% versus >10% intestinal metaplasia were compared, the odds of HGD/cancer, OR 1.5 (0.5-4.9, P=0.5) and 1.97 (0.54-7.22), respectively, were not significantly higher. Demonstration of intestinal metaplasia continues to be an essential element in the definition of BE, but its quantification may not be useful for risk stratification of HGD/cancer in BE.

Evaluation of the updated confocal laser endomicroscopy criteria for Barrett's esophagus among gastrointestinal pathologists.

Previously developed novel probe-based confocal laser endomicroscopy (pCLE) criteria have been found to have high accuracy and substantial interobserver agreement (IOA) for diagnosing dysplasia in Barrett's esophagus (BE) when used by endoscopists. These updated criteria are: (i) epithelial surface: saw toothed, (ii) cells: enlarged, (iii) cells: pleomorphic, (iv) glands: not equidistant, (v) glands: unequal in size and shape, and (vi) goblet cells: not easily identified. The accuracy and IOA among pathologists in the diagnosis of dysplasia using the novel pCLE criteria is not known. The primary objective of the study was to evaluate the accuracy, overall IOA and learning curve among three gastrointestinal (GI) pathologists in diagnosing dysplasia in BE using the updated pCLE criteria. The secondary aim was to compare the accuracy and IOA between GI pathologists and gastroenterology endoscopists. Ninety pCLE videos and respective histology were retrieved from a previously conducted multicenter, prospective, randomized, controlled trial evaluating the utility of pCLE in BE patients. Videos were obtained from 101 BE patients previously enrolled for surveillance or endoscopic treatment of high-grade dysplasia or early esophageal adenocarcinoma. Three GI pathologists reviewed 90 pCLE video clips for dysplasia versus no dysplasia, confidence in their diagnosis, and image quality. The overall accuracy for the diagnosis of dysplasia (low-grade dysplasia/high-grade dysplasia/esophageal adenocarcinoma) was 77.8% (95% confidence interval [CI]: 72.4-82.3). The accuracy was higher when pathologists had 'high confidence' in their assessment of the videos (93.8% vs. 69.3%, P < 0.001). There was no significant difference in accuracy between the first set of 30 and second set of 60 videos (84% vs. 74%, P = 0.065). IOA among GI pathologists was substantial, k = 0.65 (95% CI: 0.53-0.73). The sensitivity for detecting dysplasia was 85% (95% CI: 78.1-90.7) and the specificity was 70% (95% CI: 61.91-77.92). These results were comparable with the evaluation of the same set of videos by endoscopists. GI pathologists have high accuracy and substantial IOA for diagnosing BE dysplasia with pCLE. Pathologists appear to have similar accuracy and IOA as endoscopists. These results provide further support of endoscopists accurately interpreting the in vivo optical histology provided by pCLE.

Breath ammonia and trimethylamine allow real-time monitoring of haemodialysis efficacy.

Non-invasive monitoring of breath ammonia and trimethylamine using Selected-ion-flow-tube mass spectroscopy (SIFT-MS) could provide a real-time alternative to current invasive techniques. Breath ammonia and trimethylamine were monitored by SIFT-MS before, during and after haemodialysis in 20 patients. In 15 patients (41 sessions), breath was collected hourly into Tedlar bags and analysed immediately (group A). During multiple dialyses over 8 days, five patients breathed directly into the SIFT-MS analyser every 30 min (group B). Pre- and post-dialysis direct breath concentrations were compared with urea reduction, Kt/V and creatinine concentrations. Dialysis decreased breath ammonia, but a transient increase occurred mid treatment in some patients. Trimethylamine decreased more rapidly than reported previously. Pre-dialysis breath ammonia correlated with pre-dialysis urea in group B (r(2) = 0.71) and with change in urea (group A, r(2) = 0.24; group B, r(2) = 0.74). In group B, ammonia correlated with change in creatinine (r(2) = 0.35), weight (r(2) = 0.52) and Kt/V (r(2) = 0.30). The ammonia reduction ratio correlated with the urea reduction ratio (URR) (r(2) = 0.42) and Kt/V (r(2) = 0.38). Pre-dialysis trimethylamine correlated with Kt/V (r(2) = 0.21), and the trimethylamine reduction ratio with URR (r(2) = 0.49) and Kt/V (r(2) = 0.36). Real-time breath analysis revealed previously unmeasurable differences in clearance kinetics of ammonia and trimethylamine. Breath ammonia is potentially useful in assessment of dialysis efficacy.

The impact of a temporary ice rink on a local emergency department service.

Ice skating is becoming more popular throughout the UK, with temporary ice rinks opening in many city centres during holiday periods, especially during Christmas. Data were collected from patients who presented to the local emergency department with injuries sustained on a nearby city-centre temporary ice rink. Injuries related to ice rinks accounted for 0.76% of all emergency department attendances and represented 0.29% of ice rink participants (2.9 per 1000). Women in the older age range sustained the most significant injuries. Our study has shown that the rate of injuries per 1000 ice rink participants is comparable with data recorded when a new ice rink is opened.

Pneumococcal meningitis in Jamaican children / La meningitis pneumocócica en niños jamaicanos

OBJECTIVE: To describe the clinical features and outcome of pneumococcal meningitis in Jamaican children. METHODS: All patients admitted to the Bustamante Hospital for Children, during the period 1995-1999, who had pneumococcus isolated from cerebrospinal fluid (CSF) or pleocytosis in association with a blood culture isolate of pneumococcus were selected. Demographic, clinical and laboratory data were collected. RESULTS: Twenty-five (23%) of 111 patients with pneumococcal infections satisfied criteria for meningitis. The median age was 8 months (range 0.5-60 months). There were 4 (16%) cases of sickle cell disease, 2 (50%) of whom were first diagnosed during the current illness. This represents a 53-fold increased risk of pneumoccocal meningitis in patients with Sickle-cell disease based on population prevalence rates. Oxacillin resistance occurred in 3 (12%) patients, one of whom died. Mortality rate was 12% (3) with all deaths occurring in infants < 1 year. Poor outcome occurred in 36% (9) of the patients. Of the (35%) 8 survivors who had follow-up evaluation, (38%) 3 had documented hearing loss. CONCLUSIONS: Meningitis is a common clinical syndrome of invasive pneumococcal disease, occurring in 23% of cases resulting in mortality and high morbidity among Jamaican children. Local seroepidemiological studies are urgently needed to inform national vaccine decisions. As an interim plan, policymakers should consider a risk-based strategy to vaccine prophylaxis that will ensure that high risk groups such as children with sickle cell disease are offered currently available conjugate pneumococcal vaccines.

OBJETIVO: Describir las características clínicas y evolución de la meningitis meningocócica en niños jamaicanos. MÉTODOS: Se escogieron todos los pacientes que ingresaron al Hospital Infantil Bustamante, durante el período de 1995-1999, y que tuvieron pneumococos aislados del líquido cefalorraquídeo (LCR) o pleocitosis asociada con un aislado de pneumococos en un cultivo de sangre. Se recogieron los datos demográficos y clínicos, así como los datos de laboratorio. RESULTADOS: Veinticinco (23%) de los pacientes con infecciones pneumocócicas correspondían a los criterios de la meningitis. La edad promedio fue de 8 meses (rango 0.5 - 60 meses). Hubo 4 (16%) casos de anemia falciforme, 2 (50%) de los cuales fueron diagnosticados primeramente durante la enfermedad corriente. Esto representa un aumento de riesgo de meningitis meningocócica 53 veces mayor en pacientes con anemia ciclémica, teniendo en cuenta las tasas de prevalencia poblacional. Se halló resistencia a la oxacilina en 3 (12%) pacientes, uno de los cuales murió. La tasa de mortalidad fue del 12% (3), correspondiendo todas las muertes a infantes < 1 año. Resultados pobres se produjeron en (9) 36% de los pacientes. De los 8 (35%) supervivientes que tuvieron evaluación de seguimiento, 3 (38%) tuvieron pérdida de la audición documentada. CONCLUSIONES: La meningitis es un síndrome clínico común de la enfermedad pneumocócica invasiva, que tiene lugar en 23 % de los casos, y que trae por consecuencia mortalidad y una alta morbilidad entre los niños jamaicanos. Se requieren con urgencia estudios seroepidemiológicos locales a fin de tener información para las decisiones nacionales sobre las vacunas. A modo de plan provisional, los encargados de trazar las políticas deben considerar una estrategia de riesgo para la profilaxis de vacuna, a fin de asegurar que los grupos de alto riesgo, tales como los niños con anemia falciforme, puedan tener a su alcance las vacunas pneumocócicas conjugadas actualmente disponibles.

Pneumococcal meningitis in Jamaican children.

OBJECTIVE: To describe the clinical features and outcome of pneumococcal meningitis in Jamaican children. METHODS: All patients admitted to the Bustamante Hospital for Children, during the period 1995-1999, who had pneumococcus isolated from cerebrospinal fluid (CSF) or pleocytosis in association with a blood culture isolate of pneumococcus were selected. Demographic, clinical and laboratory data were collected. RESULTS: Twenty-five (23%) of 111 patients with pneumococcal infections satisfied criteria for meningitis. The median age was 8 months (range 0.5-60 months). There were 4 (16%) cases of sickle cell disease, 2 (50%) of whom were first diagnosed during the current illness. This represents a 53-fold increased risk of pneumoccocal meningitis in patients with Sickle-cell disease based on population prevalence rates. Oxacillin resistance occurred in 3 (12%) patients, one of whom died. Mortality rate was 12% (3) with all deaths occurring in infants < 1 year. Poor outcome occurred in 36% (9) of the patients. Of the (35%) 8 survivors who had follow-up evaluation, (38%) 3 had documented hearing loss. CONCLUSIONS: Meningitis is a common clinical syndrome of invasive pneumococcal disease, occurring in 23% of cases resulting in mortality and high morbidity among Jamaican children. Local seroepidemiological studies are urgently needed to inform national vaccine decisions. As an interim plan, policymakers should consider a risk-based strategy to vaccine prophylaxis that will ensure that high risk groups such as children with sickle cell disease are offered currently available conjugate pneumococcal vaccines.

Career paths of alumni of the Cornell Leadership Program for veterinary students.

The Cornell Leadership Program at Cornell University, usa, aims to assist talented veterinary students to embark on careers in research, academia, government agencies or industry. Over 400 students have participated since the Program began in 1990 and their subsequent careers have been followed. In this study, five sources of data were analysed: application documents of the participants; audio recordings of interviews with each participant from 2000 to 2007; annual tracking records of alumni after graduating with a veterinary degree; spontaneous comments from alumni about how the Program influenced their career plans; and a list of published scientific papers by alumni. Analysis revealed that about 50 per cent of veterinary graduates were establishing themselves in careers envisaged by the Program, although many of them experienced conflicts between a vocational commitment to clinical practice and a desire to solve problems through research. Many alumni asserted that the Program had influenced their career plans, but they had difficulty in accepting that rigorous scientific training was more important in acquiring research skills than working directly on a veterinary research problem. One career of great appeal to alumni was that of veterinary translational science, in which disease mechanisms are defined through fundamental research. It is concluded from the data that there are three challenging concepts for recently qualified veterinarians aiming to advance the knowledge of animal disease: research careers are satisfying and rewarding for veterinarians; a deep understanding of the chosen field of research is needed; and a high standard of scientific training is required to become an effective veterinary scientist.

Interventions for preventing bone disease in kidney transplant recipients.

BACKGROUND: Patients with chronic kidney disease have significant abnormalities of bone remodeling and mineral homeostasis and are at increased risk of fracture. The fracture risk for a kidney transplant recipient is four times that of the general population and higher than for a patient on dialysis. Randomised controlled trials (RCTs) report the use of bisphosphonates, vitamin D sterols, calcitonin, and hormone replacement therapy to treat bone disease following transplantation. OBJECTIVES: To evaluate the use of interventions for treating bone disease following kidney transplantation. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL in The Cochrane Library), Cochrane Renal Group's specialised register, MEDLINE, EMBASE, reference lists, and conference proceedings abstracts without language restriction. Date of last search: May 2006 SELECTION CRITERIA: RCTs and quasi-RCTs comparing different treatments for kidney transplant recipients of any age were selected. We excluded all other transplant recipients, including kidney-pancreas transplant recipients. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. Statistical analyses were performed using the random effects model and the results expressed as relative risk (RR) with 95% confidence intervals (CI) for dichotomous variables and mean difference (MD) for continuous outcomes. MAIN RESULTS: Twenty-four trials (1,299 patients) were included. No individual intervention (bisphosphonates, vitamin D sterol or calcitonin) was associated with a reduction in fracture risk compared with placebo. Combining results for all active interventions against placebo demonstrated any treatment of bone disease was associated with a reduction in the RR of fracture (RR 0.51, 95% CI 0.27 to 0.99). Bisphosphonates (any route), vitamin D sterol, and calcitonin all had a beneficial effect on the bone mineral density at the lumbar spine. Bisphosphonates and vitamin D sterol also had a beneficial effect on the bone mineral density at the femoral neck. Bisphosphonates had greater efficacy for preventing bone mineral density loss when compared head-to-head with vitamin D sterols. Few or no data were available for combined hormone replacement, testosterone, selective oestrogen receptor modulators, fluoride or anabolic steroids. Other outcomes including all-cause mortality and drug-related toxicity were reported infrequently. AUTHORS' CONCLUSIONS: Treatment with a bisphosphonate, vitamin D sterol or calcitonin after kidney transplantation may protect against immunosuppression-induced reductions in bone mineral density and prevent fracture. Adequately powered trials are required to determine whether bisphosphonates are better than vitamin D sterols for fracture prevention in this population. The optimal route, timing, and duration of administration of these interventions remains unknown.

Withholding and withdrawing of life sustaining treatment in the newborn.

The rapid progress of medical technology has resulted in more opportunities to maintain the life of infants in serious and potentially life threatening situations. Whether to treat such infants is a common dilemma. The burden of these difficult decisions rests almost equally on distraught parents and relatives and on the professional staff of neonatal units. Sometimes, either parents or care teams choose to seek a decision from the courts. Ways of reaching the best possible and most inclusive consensus decisions are examined in this review.

Interventions for preventing bone disease in kidney transplant recipients.

BACKGROUND: Patients with chronic kidney disease have significant abnormalities of bone remodelling and calcium homeostasis and are at increased risk of fracture. The fracture risk for a kidney transplant recipient is four times that of the general population and higher than that for a patient on dialysis. Trials reporting the use of bisphosphonates, vitamin D analogues, calcitonin, and hormone replacement therapy to treat bone disease following engraftment exist. OBJECTIVES: To evaluate the use of interventions for the treatment of bone disease following kidney transplantation. SEARCH STRATEGY: The Cochrane CENTRAL Register of Controlled Trials (The Cochrane Library - Issue 3 2004), MEDLINE (1966 to August 2004), EMBASE (1980- August 2004) and reference lists were searched without language restriction. SELECTION CRITERIA: Randomised trials of treatment of bone disease following kidney transplantation were included. Trials of recipients of any transplant other than a kidney transplant including trials of kidney-pancreas transplants were excluded. DATA COLLECTION AND ANALYSIS: Two authors assessed independently trial quality and extracted data. Statistical analyses were performed using the random effects model and the results expressed as relative risk (RR) with 95% confidence intervals (CI) for dichotomous variables. For continuous variables the weighted mean difference (WMD) and its 95% CI was used. MAIN RESULTS: Twenty-three eligible trials (1,209 patients) were identified. Seven trials compared more than two interventions. Nineteen trials compared active treatment with placebo, five vitamin D analogue and calcium, six vitamin D analogue alone, twelve bisphosphonates, and four nasal calcitonin. Eight trials compared two active treatments, one 17-beta oestradiol and medroxyprogesterone versus vitamin D analogue, five bisphosphonate versus vitamin D analogue, two vitamin D analogue and calcium versus calcium and one bisphosphonate versus calcitonin. Methodological quality was suboptimal. There were no significant differences between any treatment group for risk of fracture. Bisphosphonate, administered by any route, vitamin D analogue and calcitonin all had a beneficial effect on the bone mineral density at the lumbar spine. Bisphosphonates and vitamin D analogue had a beneficial effect on the bone mineral density at the femoral neck. Few or no data were available for combined hormone replacement, testosterone, selective oestrogen receptor modulators, fluoride or anabolic steroids. All-cause mortality and drug-related toxicity were reported infrequently and there was no statistical difference between treatment groups. AUTHORS' CONCLUSIONS: No benefit from any intervention known to reduce risk of fracture from bone disease could be demonstrated to reduce fracture incidence in kidney transplant recipients.

The implication of follicular lymphoma patients receiving allogeneic stem cell transplantation from donors carrying t(14;18)-positive cells.

We performed real-time quantitative polymerase chain reaction (RQ-PCR) in peripheral blood (PB) and/or bone marrow (BM) samples collected pre- and post transplant from 23 recipient-donor pairs receiving allogeneic stem cell transplantation (allo-SCT) for follicular lymphoma (FL). Of 23 donors, 11 had a PB and/or BM sample positive for t(14;18) (BCL2/IGH fusion) at low levels (

INRS activities on risk assessment of glycol ethers.

The occupational exposure assessment uses data from published sources, from Industry (most often from the producers), and from dedicated occupational exposure data bases, as well as evaluations using the EASE model (Estimation and Assessment of Substance Exposure). Atmospheric concentrations and characteristics of skin contacts are evaluated in different scenarios (such as manufacturing, formulating, main and most polluting uses) and sub-scenarios (e.g. warm water dilution). Air concentrations of EGBE are low during production (most often <0.5 mg/m(3)), incidental excursions being <50 mg/m(3); the "worst-case" mean concentration is proposed as 9 mg/m(3). Skin contact, according to EASE, may be in the range of 0-0.1 mg/cm(2)(day), and should be mitigated by the use of suitable gloves. For formulations of products containing EGBE, air concentrations are evaluated as 10 mg/m(3) and skin contact as 0.19 mg/cm(2)(day). The "reasonable worst case" air concentrations (8-Hr TWA) are assessed at around 11 mg/m(3) (coating industry), from 5 to 20 mg/m(3) in printing activities (depending on the task), and in the 20-70 mg/m(3) range (upper limit 40 mg/m(3) in better controlled situations) for cleaning activities. Skin contact would be around twice the preceding level, i.e., 0.4 mg/cm(2)(day) for coating as well as cleaning activities. EGBE and its major metabolites, 2-butoxyacetaldehyde (2-BAL) and 2-butoxyacetic acid (2-BAA) have been subjected to tests for genetic toxicity tests both in vitro and in vivo. While some positive responses have been obtained, the balance of the evidence indicates that EGBE does not express significant genotoxic activity. There are no epidemiological data investigating a relationship between exposure to EGBE and human cancer. Two carcinogenicity inhalation bioassays have been conducted in rodents, one in rats and one in mice. Significant increases were found in forestomach tumours in female mice and haemangiosarcomas in male mice. No increases in tumour incidences were found in either male or female rats. Mechanistic studies have suggested the crucial involvement in the pathogenesis of haemangiosarcomas of a chain of events consisting of (1) haemolysis due to BAA, followed by (2) hepatic haemosiderin deposition and (3) the subsequent generation of reactive oxygen species within the endothelial cells from which haemangiosarcomas arise. Since human erythrocytes are particularly resistant to the haemolytic effects of BAA, it is extremely unlikely, according to this model, that the haemangiosarcomas observed in male mice will have human significance. Similarly, mechanistic studies on the female mouse forestomach tumours have suggested that these also are not important as an indication of human risk. In vivo, EGBE tested in a continuous breeding study and in repeated dose toxicity tests, did not produced specific effects on reproductive organs or fertility parameters. For developmental toxicity, rats, mice and rabbits were dosed via oral and/or inhalation routes. Foeto- and embryo-toxicity was observed in presence or maternal toxicity (haemolytic anaemia). The data available give plausible support to the hypothesis that this developmental toxicity is a direct consequence of maternal toxicity. There are no epidemiological data investigating a relationship between exposure to EGBE alone and human reproductive effects.

The mutagenicity testing of tertiary-butyl alcohol, tertiary-butyl acetate and methyl tertiary-butyl ether in Salmonella typhimurium.

Tertiary-Butyl alcohol (TBA), tertiary-butyl acetate (TBAc) and methyl tertiary-butyl ether (MTBE) are chemicals to which the general public may be exposed either directly or as a result of their metabolism. There is little evidence that they are genotoxic; however, an earlier publication reported that significant results were obtained in Salmonella typhimurium TA102 mutagenicity tests with both TBA and MTBE. We now present results of testing these chemicals and TBAc against S. typhimurium strains in two laboratories. The emphasis was placed on testing with S. typhimurium TA102 and the use of both dimethyl sulphoxide and water as vehicles. Dose levels up to 5000 microg/plate were used and incubations were conducted in both the presence and absence of liver S9 prepared from male rats treated with either Arochlor 1254 or phenobarbital-beta-naphthoflavone. The experiments were replicated, but in none of them was a significant mutagenic response observed, thus the current evidence indicates the TBA, TBAc and MTBE are not mutagenic in bacteria.

Trigonelline is not responsible for the acute increase in plasma homocysteine following ingestion of instant coffee.

OBJECTIVE: To determine whether trigonelline contributes to the effect of coffee on homocysteine (Hcy). DESIGN AND INTERVENTIONS: This was a randomised crossover study. Subjects consumed 50 mg trigonelline, 5 g of instant coffee (approximately 50 mg trigonelline) or water, consumed as a single dose in 100 ml, with 1 week between each treatment. Blood samples were drawn fasting and hourly for 8 h. Urine samples were collected pretreatment and every 2 h for 8 h. SETTING: Christchurch Clinical Studies Trust, Christchurch, New Zealand. SUBJECTS: Eight healthy male subjects. RESULTS: Instant coffee raised plasma Hcy concentrations compared with water (P=0.019) and trigonelline (P=0.037). Plasma Hcy concentrations were not different between water and trigonelline treatments (P=0.789). The change in plasma Hcy concentration was higher (mean+/-s.e.) 4 h (0.7+/-0.2 micromol/l, P=0.006), 5 h (0.7+/-0.2 micromol/l, P=0.013) and 7 h (0.7+/-0.2 micromol/l, P=0.024) following coffee consumption. Urinary glycine betaine excretion was increased by coffee but not by trigonelline. CONCLUSION: Ingestion of instant coffee acutely elevated plasma Hcy; however, trigonelline is not responsible for this rise. SPONSORSHIP: Supported by the Health Research Council, the Canterbury Medical Foundation, the Foundation of Research, Science and Technology.

Invasive pneumococcal disease in Jamaican children.

A 5-year retrospective review of cases of invasive pneumococcal disease admitted to the Bustamante Hospital for Children, Jamaica was conducted. A total of 111 cases were identified. The estimated incidence of invasive pneumococcal disease in Kingston and St Andrew was 21/100,000 children under the age of 10 years. The majority of cases (76%) were in the under-2-years age group. All four deaths were of infants. Pre-existing medical conditions included sickle cell disease, HIV and undernutrition. The rate of resistance to penicillin was 13.8%. Meningitis accounted for three of the four deaths identified and poor outcome was identified in 28% of cases of meningitis. We conclude that invasive pneumococcal disease causes significant morbidity and mortality in young Jamaican children. Strategies directed at preventing HIV infection and malnutrition and improving the care of children with sickle cell disease and HIV infection would significantly reduce disease incidence.