A multidisciplinary approach to promoting a Baby Friendly environment at an urban university medical center.
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Academic Medical Centers↗
Biomedical subjects
R Williams
Publications and source records attributed to R Williams.
Daily variation of particulate air pollution and poor cardiac autonomic control in the elderly.
examined the cardiac autonomic response to daily variations in PM in 26 elderly (mean age 81) individuals for 3 consecutive weeks. Several standardized methods were used to measure 24-hr average PM concentrations prior to the clinical test inside (indoor PM2.5) and immediately outside (outdoor PM2.5 and PM2.5-10) of participants' residences. Resting, supine, 6-min R wave to R wave (R-R) interval data were collected to estimate high frequency (0.15-0.40 Hz) and low frequency (0.04-0.15 Hz) powers and standard deviation of normal R-R intervals (SDNN) as cardiac autonomic control indices. Participant-specific lower heart rate variability days were defined as days for which the high-frequency indices fell below the first tertile of the individual's high-frequency distribution over the study period. Indoor PM2.5 > 15 microg/m3 was used to define high pollution days. Results show that the odds ratio (95% confidence interval) of low heart rate variability high frequency for high (vs. not high) pollution days was 3.08 (1.43, 6.59). The ss-coefficients (standard error) from mixed models to assess the quantitative relationship between variations in indoor PM2.5 and the log-transformed high frequency, low frequency, and SDNN were: -0.029 (0.010), -0.027 (0.009), and -0.004 (0.003), respectively. This first study of cardiac autonomic control response to daily variations of PM2.5 indicates that increased levels of PM2.5 are associated with lower cardiac autonomic control, suggesting a possible mechanistic link between PM and cardiovascular disease mortality.
Aged↗
Population pharmacokinetics. A regulatory perspective.
The application of population approaches to drug development is recommended in several US Food and Drug Administration (FDA) guidance documents. Population pharmacokinetic (and pharmacodynamic) techniques enable identification of the sources of inter- and intra-individual variability that impinge upon drug safety and efficacy. This article briefly discusses the 2-stage approach to the estimation of population pharmacokinetic parameters, which requires serial multiple measurements on each participant, and comprehensively reviews the nonlinear mixed-effects modelling approach, which can be applied in situations where extensive sampling is not done on all or any of the participants. Certain preliminary information, such as the compartment model used in describing the pharmacokinetics of the drug, is required for a population pharmacokinetic study. The practical design considerations of the location of sampling times, number of samples/participants and the need to sample an individual more than once should be borne in mind. Simulation may be useful for choosing the study design that will best meet study objectives. The objectives of the population pharmacokinetic study can be secondary to the objectives of the primary clinical study (in which case an add-on population pharmacokinetic protocol may be needed) or primary (when a stand-alone protocol is required). Having protocols for population pharmacokinetic studies is an integral part of 'good pharmacometric practice'. Real-time data assembly and analysis permit an ongoing evaluation of site compliance with the study protocol and provide the opportunity to correct violations of study procedures. Adequate policies and procedures should be in place for study blind maintenance. Real-time data assembly creates the opportunity for detecting and correcting errors in concentration-time data, drug administration history and covariate data. Population pharmacokinetic analyses may be undertaken in 3 interwoven steps: exploratory data analysis, model development and model validation (i.e. predictive performance). Documentation for regulatory purposes should include a complete inventory of key runs in the analyses undertaken (with flow diagrams if possible), accompanied by articulation of objectives, assumptions and hypotheses. Use of diagnostic analyses of goodness of fit as evidence of reliability of results is advised. Finally, the use of stability testing or model validation may be warranted to support label claims. The opinions expressed in this article were revised by incorporating comments from various sources and published by the FDA as 'Guidance for Industry: Population Pharmacokinetics' (see the FDA home page http:/(/)www.fda.gov for further information).
Data Interpretation, Statistical↗
Fasting proinsulin concentrations predict the development of type 2 diabetes.
OBJECTIVE: The development of specific assays allows the different molecules in the proinsulin processing pathway to be measured separately. 32,33 Split proinsulin is the predominant form of proinsulin and accounts for the disproportionate hyperproinsulinemia seen in individuals with prevalent type 2 diabetes. This study was established to examine whether the concentration of this molecule predicts diabetes. RESEARCH DESIGN AND METHODS: A population-based longitudinal cohort study was conducted in Ely, Cambridgeshire. At baseline, 1,122 individuals completed a 75-g oral glucose tolerance test (OGTT). At the 4.5-year follow-up study, repeat OGTTs were performed on 937 of the cohort of 1,071 individuals who had been nondiabetic at baseline. RESULTS: A total of 26 people progressed to diabetes as determined by the OGTTs. The risk of progression was strongly related to the fasting glucose concentration (relative risk [RR] comparing top with bottom quartile 17.6 [95% CI 2.4-130.4]) and fasting 32,33 split proinsulin (RR 16.4 [2.2-121.9]), but less strongly to the fasting insulin (RR 4.41 [1.5-12.9]) or intact proinsulin (RR 5.2 [1.5-17.3]). In multivariate analyses, these associations were independent of age, sex, BMI, and baseline glucose tolerance category. Subjects in the top quartile for fasting glucose and total proinsulin with a family history of diabetes were a high-risk subgroup (incidence 65.8 per 1,000 person-years of follow-up [pyfu]); 30% of them progressed to diabetes at follow-up. CONCLUSIONS: Fasting 32,33 split proinsulin independently predicts the development of diabetes. This prediction was better than that observed for either the insulin or intact proinsulin concentrations. The combination of family history, fasting glucose, and total proinsulin identified a subgroup of individuals at high risk of progression who might benefit from targeted interventions.
Adult↗
Perinatal and neonatal determinants of childhood type 1 diabetes. A case-control study in Yorkshire, U.K.
OBJECTIVE: To identify environmental factors that exert their effect in the perinatal and neonatal period and influence the subsequent onset of insulin dependent (type 1) diabetes during childhood. RESEARCH DESIGN AND METHODS: A population-based case-control study of data abstracted from the hospital obstetric and neonatal records of 196 children with type 1 diabetes and 325 age- and sex-matched control subjects. Analysis of matched sets by conditional logistic regression was conducted for a range of perinatal and neonatal factors. RESULTS: A significantly raised risk was observed for illnesses in the neonatal period (OR 1.61, 95% CI 1.06-2.44), the majority of which were infections and respiratory difficulties. Exclusive breast feeding as the initial feeding method was significantly protective (OR 0.65, 95% CI 0.45-0.94). There were no significant associations with high- or low-birth weight, being firstborn or small-for-dates. All factors significant (5% level) for the entire dataset, that is, maternal age, type 1 diabetes in mothers, preeclampsia, delivery by cesarean section, neonatal illnesses, and initial breast feeding were modeled and the OR remained significant for all variables other than cesarean section. CONCLUSIONS: The findings are based on medical record data that cannot be subject to biased recall of mothers. Neonatal illnesses increased and initial breast feeding decreased the risk of childhood type 1 diabetes. Further determinants of risk are mothers with type 1 diabetes, older mothers, and preeclampsia during pregnancy.
Adolescent↗
Temporary extracorporeal liver support for severe acute alcoholic hepatitis using the BioLogic-DT.
Patients with severe acute alcoholic hepatitis develop multiple organ failure which is associated with production of inflammatory cytokines and a poor prognosis. The aim of the present pilot study was to evaluate the effects of the BioLogic-DT sorption-suspension dialyser in patients with severe acute alcoholic hepatitis. Ten patients with encephalopathy (grade II-IV) were entered into the study, 5 received treatment with the BioLogic-DT for 6 hours daily for 3 days and 5 received conventional treatment as controls. The system was biocompatible with no adverse effects on blood pressure or platelet counts, factor V, fibrinogen or antithrombin III. No bleeding episodes were observed even with the use of small doses of heparin. After 3 days, blood ammonia was lower in the BioLogic-DT treated patients than in the controls, although blood lactate was higher. There were slight increases in plasma TNF and IL-8 during treatment over and above the higher levels present initially, possibly as a result of activation of white cells in the extracorporeal circuit. The further development of the BioLogic-DT dialyser with the addition of a plasma treatment module capable of removing cytokines would be worth evaluating in acute alcoholic hepatitis.
Acute Disease↗
Splanchnic and systemic haemodynamic response to volume changes in patients with cirrhosis and portal hypertension.
We investigated the haemodynamic response to volume depletion and subsequent repletion in patients with cirrhosis and portal hypertension. Twelve patients with compensated cirrhosis and portal hypertension were included in the study. The haemodynamic changes occurring after removal of approx. 15% of the blood volume, and subsequently after isovolume repletion with colloid, were assessed. Baseline haemodynamic measurements showed increased cardiac output and a systemic vascular resistance at the lower limit of normal. The hepatic venous pressure gradient (HVPG) was increased, at 18 mmHg. After depletion, arterial pressure, cardiac output and all right-heart-sided pressures decreased, and systemic vascular resistance increased. HVPG decreased to 16.0 mmHg. All the above changes were statistically significant. After blood volume restitution, the haemodynamic values returned to baseline. In particular, an increase in HVPG was shown in four out of the twelve patients (two with ascites and two without), which was small in three of them. However, HVPG remained the same as or lower than the baseline in the other eight patients. Patients with cirrhosis and portal hypertension exhibit an abnormal haemodynamic response to blood volume depletion. After volume repletion, no increase in the portal pressure was noted in this group of patients as a whole, although four out of the twelve patients did show an increase, possibly due to extensive collateral circulation.
Adult↗
Hepatitis B and C: carrier to cancer--current trends.
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Hepatitis B, Chronic↗
Trefoil factor-2, human spasmolytic polypeptide, promotes branching morphogenesis in MCF-7 cells.
Members of the trefoil factor (TFF) family are highly expressed in endodermal ulcerative wound healing and selectively in neoplastic proliferation of various glandular epithelia. There is some evidence that TFF1 and TFF3 affect cell motility, are indirectly involved in growth suppression, and are associated with mucin expression. TFF2 is co-expressed with TFF1 in gastric surface epithelial cells, but its potential role in vivo is unclear. We analyzed potential effects on cell proliferation and morphogenesis of TFF2 on a panel of epithelial and mesenchymal cell lines. TFF2 had no measurable effect on the proliferation of any of the cell lines tested. In type 1 collagen lattices, TFF2 at a low concentration (25-100 nM) induced the formation of highly complex branched structures in the breast carcinoma cell line MCF-7 over a period of 14 to 42 days. No significant effect was shown with other cell lines. This morphogenic effect was abolished by monoclonal antibodies specific for either TFF2 or TFF1. TFF2 did not affect cell motility in MCF-7 cells as measured by videomicroscopy, in contrast to previous studies using TFF1. TFF2-treated MCF-7 colonies showed a 30% reduction in the number of apoptotic bodies, corroborated by trypan blue exclusion and DNA fragmentation ELISA, indicating TFF2 promotes cell survival via inhibition of apoptosis and can act as a morphogen in the presence of TFF1. These properties may complement the actions of TFF1 as a motogen and may explain differential expression in endodermal wound healing.
Antibodies, Monoclonal↗
Evolution of wild-type and precore mutant HBV infection after liver transplantation.
Recurrence of hepatitis B virus (HBV) infection after liver transplantation is associated with varying degree of graft damage. The aim of the study was to investigate longitudinally the changes of wild-type and precore A1896HBV mutant viral populations after reinfection and their impact on liver graft damage. The wild-type HBV and A1896HBV strains were quantitated before and serially after orthotopic liver transplantation (OLT) in 14 hepatitis B surface antigen (HBsAg)-positive liver graft recipients (4 hepatitis B e antigen [HBeAg]+; 10 anti-HBe+). Before OLT, the wild-type precore HBV was present in all 4 HBeAg-positive patients and in 2/10 anti-HBe-positive patients; a mixed virus population was present in 6 patients; and A1896HBV mutant alone in 2 patients. After OLT, A1896HBV mutant appeared and gradually accumulated in 5/6 patients who had the wild-type HBV before OLT and 1 of these patients seroconverted from HBeAg to anti-HBe 52 months after transplantation. A mixed HBV population was present continuously in 6 patients before and after OLT. Of the 2 patients with A1896HBV only pre-OLT, the wild type appeared in one patient and the other patient retained persistently the A1896HBV mutant. There was no relationship between liver graft histology and the type of viral population at reinfection or at the end of follow up. Changes in the HBV population occur during follow up of recurrent hepatitis B in liver transplant recipients with frequent accumulation of precore A1896HBV mutants, but the type of viral population does not determine the severity of hepatitis B in the graft.
Adult↗
A change in treatment process with a modern record and verify system.
PURPOSE: With the introduction of new treatment devices, such as a multileaf collimator (MLC) and dynamic wedge (DW), therapists have an increased responsibility to ensure correct treatment. Simultaneously, three-dimensional treatment planning (3DTP) has led to an increased number of portals and table movements. To counteract this challenge and maintain efficiency, a comprehensive record and verify (R&V) system is mandatory. We evaluated a commercial system (Varis) for reliability, ease of use, efficiency, and integration with our planning systems. METHODS AND MATERIALS: Some key elements of the Varis system are: integration of MLC and DW; auto setup for MLC, jaw, collimator, gantry, and limited table parameters; direct download of simulation beam data; and a regimented field scheduling system that prescribes all beam data for particular fractions. Evaluation of the system was driven by treatment time analysis, error rates, and an increased workload. These issues were governed by how we disseminated duties and how the system accommodated or changed our processes. RESULTS: Most data entry is performed by our dosimetry staff. Data can be downloaded from the simulator, but more patients now move from CT simulation and/or 3DTP to the treatment machine. Varis does not link to these systems. The physics staff confirms all entries to correct data entry errors. The workload for dosimetrists increased by an average of 8 minutes/patient entry; physics time increased by 7 minutes/patient entry; the weekly electronic chart check takes approximately 3 minutes/patient. Therapists who used Varis efficiently showed a slight decrease in treatment times, attributed to MLC integration and auto-setup. Some therapists experienced a decrease in efficiency, because of unfamiliarity and excess intervention. On a positive note, notable events have decreased by a factor of 10 since full initiation. Unfortunately, the remaining errors are often the result of a therapist relying on incorrect electronic information. CONCLUSION: The Varis R&V system has had an impact on our clinic's process and efficiency. Checking of all beam data and related field scheduling have helped reduce errors and misconceptions. We feel a dual-energy machine can be operated with two experienced therapists and an up-to-date R&V system more accurately and efficiently than with three therapists working without an integrated R&V. We anticipate future Varis releases will further promote efficiency and accuracy.
Computer Communication Networks↗
Sex differences in the use of asthma drugs: cross sectional study.
OBJECTIVES: To assess the use of asthma drugs by men and women with asthma and to identify sex specific predictors for the use of oral steroids. DESIGN: Cross sectional study. SETTING: Six general practices in East Anglia. SUBJECTS: 103 men and 134 women aged 20-54 with asthma. MAIN OUTCOME MEASURES: Self reported use of agonists, inhaled steroids, and oral steroids. RESULTS: No sex difference was found in use of agonists or inhaled steroids. However a strong association existed between sex and oral steroid use. 40 (30%) women reported using oral steroids compared with nine (9%) men. Women were more than five times (odds ratio=5.5, 95% confidence interval 2.2 to 13.7) more likely to report use of oral steroids than men after asthma symptoms, age, visits to the general practitioner in previous six months, and time since diagnosis of asthma were controlled for. Women who had visited the general practitioner for asthma one or more times in the previous six months were four times (3.9, 1.6 to 9.5) as likely to report use of oral steroids. In addition, more frequent visits to the general practitioner for asthma were related in a dose-response manner to a greater likelihood of using oral steroids among women after asthma symptoms, age, and time since diagnosis were controlled for. This relation was not observed among men. CONCLUSION: Women used oral steroids more than men. The more frequent consultations with a doctor by women may result in more requests for oral steroids or doctors may preferentially prescribe oral steroids to women.
Adrenergic beta-Antagonists↗
Progressive cardiac amyloidosis following liver transplantation for familial amyloid polyneuropathy: implications for amyloid fibrillogenesis.
BACKGROUND: Circulating transthyretin (TTR) is derived from the liver, and orthotopic liver transplantation (OLT) is widely performed for variant TTR-associated familial amyloid polyneuropathy (FAP). The effect of OLT on FAP-related cardiac amyloid is of particular interest because wild-type TTR can itself be deposited as senile cardiac amyloid. METHODS: Serial echocardiography was performed in 20 FAP patients, 14 of whom underwent OLT, and 10 other liver transplant patients. Follow-up included serum amyloid P component scintigraphy and measurement of plasma TTR before and after OLT. RESULTS: Cardiac amyloidosis progressed rapidly in three FAP patients (TTR Pro52 and Thr84 mutations) after OLT, even though the deposits elsewhere had stabilized or regressed. Results of echocardiography improved in three transplant patients with TTR Met30 and remained normal in seven other patients. Plasma TTR levels were altered substantially after OLT, but they did not reflect the cardiac findings. CONCLUSIONS: Although amyloid deposition in FAP is generally inhibited after OLT, cardiac amyloidosis can be exacerbated, probably due to enhanced deposition of wild-type TTR on a template of amyloid derived from variant TTR. The phenomenon may be mutation-dependent. These findings suggest that amyloid formation de novo and its subsequent accumulation can be promoted by different factors, which may be organ-specific.
Amyloid Neuropathies↗
Presence of a newly described human DNA virus (TTV) in patients with liver disease.
BACKGROUND: A newly described DNA virus, named transfusion-transmitted virus (TTV), was recently detected with high prevalence in Japanese patients with fulminant hepatitis and chronic liver disease of unknown aetiology. We investigated the presence of this virus in patients with liver disease in the UK to find out whether TTV infection is associated with liver damage. METHODS: We used semi-nested PCR to amplify TTV DNA from serum samples from 126 adults, of whom 72 were patients with a range of chronic liver diseases, 24 had spontaneous resolution of infection with hepatitis C virus (HCV), and 30 were normal controls. Direct DNA sequencing and phylogenetic analysis were used to characterise the TTV isolates. FINDINGS: We detected TTV DNA in 18 (25%) of the 72 patients with chronic liver disease, which was not different from the 10% prevalence in normal controls (p=0.15). The rate of TTV DNA was similar among patients with various liver diseases. The majority of TTV-positive cases had no biochemical or histological evidence of significant liver damage. TTV DNA sequencing of nine isolates showed the same genotypic groups as in Japan: three patients were infected with genotype 1, which showed 4% nucleotide divergence, and six patients were infected with genotype 2 with 15-27% divergence. INTERPRETATION: The high prevalence of active TTV infection in the general population, both in the UK and in Japan, and the lack of significant liver damage, suggest that TTV, similar to hepatitis G virus (HGV), may be an example of a human virus with no clear disease association.
Adult↗
Domino hepatic transplantation using the liver from a patient with familial amyloid polyneuropathy.
BACKGROUND: In transplantation, novel methods are required to augment the supply of donor organs. We report the first domino liver transplant in which a patient with familial amyloid polyneuropathy (FAP) received an orthotopic split liver graft, and her explanted liver was donated to another patient. Three successful liver transplants were thus achieved from the one cadaver liver. PATIENTS AND METHODS: A cadaveric donor liver was split and the left lobe was grafted into a child with biliary atresia. The right lobe was transplanted into a woman with FAP associated with the transthyretin Met30 variant. Her own otherwise healthy liver was donated to a patient with cirrhosis and hepatocellular carcinoma. RESULTS: Fifteen months after transplantation, all three recipients are well with normal liver function. The domino recipient developed inferior vena cava stricturing at the level of anastomosis after surgery with resultant ascites, requiring dilatation and LeVeen shunt insertion. Serum amyloid P component scintigraphy showed amyloid regression in the domino donor and to date has not identified any amyloid deposits in the recipient, who also remains free of tumor recurrence. CONCLUSIONS: Domino transplantation using the livers from patients with FAP may be justified for patients whose disease condition precludes a long spell on the waiting list, including those with hepatic malignancies and those for whom palliation rather than long-term cure is the aim.
Adult↗
Deaths from low dose paracetamol poisoning.
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Acetaminophen↗
Epidemiological issues in health needs assessment.
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Epidemiologic Methods↗
Development and importance of health needs assessment.
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Health Care Costs↗