Adverse events to antiretrovirals in the Swiss HIV Cohort Study: effect on mortality and treatment modification

BACKGROUND: Antiretroviral therapy (ART) decreases morbidity and mortality in HIV-infected patients but is associated with considerable adverse events (AEs). METHODS: We examined the effect of AEs to ART on mortality, treatment modifications and drop-out in the Swiss HIV Cohort Study. A cross-sectional evaluation of prevalence of 13 clinical and 11 laboratory parameters was performed in 1999 in 1,078 patients on ART. AEs were defined as abnormalities probably or certainly related to ART. A score including the number and severity of AEs was defined. The subsequent progression to death, drop-out and treatment modification due to intolerance were evaluated according to the baseline AE score and characteristics of individual AEs. RESULTS: Of the 1,078 patients, laboratory AEs were reported in 23% and clinical AEs in 45%. During a median follow up of 5.9 years, laboratory AEs were associated with higher mortality with an adjusted hazard ratio (HR) of 1.3 (95% confidence interval [CI] 1.2-1.5; P < 0.001) per score point. For clinical AEs no significant association with increased mortality was found. In contrast, an increasing score for clinical AEs (HR 1.11,95% CI 1.04-1.18; P = 0.002), but not for laboratory AEs (HR 1.07, 95% CI 0.97-1.17; P = 0.17), was associated with antiretroviral treatment modification. AEs were not associated with a higher drop-out rate. CONCLUSIONS: The burden of laboratory AEs to antiretroviral drugs is associated with a higher mortality. Physicians seem to change treatments to relieve clinical symptoms, while accepting laboratory AEs. Minimizing laboratory drug toxicity seems warranted and its influence on survival should be further evaluated.

Is right coronary artery hypoplasia and sudden death an underdiagnosed association?

Determining whether hypoplasia of a coronary artery has caused or contributed to death is often complicated by an absence of histologic evidence of myocardial ischemia in the area of the heart supplied by the affected artery and also by the lack of data for assessing coronary artery size at autopsy. A 45-year-old woman is reported who collapsed and died and who was found at autopsy to have a dominant, small-caliber, right coronary artery, with acute and chronic ischemic changes in the posterior interventricular septum supplied by the diminutive vessel. This case provides evidence that small-caliber coronary arteries may be associated with a lethal outcome. Given the difficulties that may occur in determining whether there is a causal link between small coronary artery caliber and death, it is possible that this may be an underdiagnosed cause of sudden cardiac death, rather than a coincidental finding of minimal significance.

Life and death partners: apoptosis, autophagy and the cross-talk between them

It is not surprising that the demise of a cell is a complex well-controlled process. Apoptosis, the first genetically programmed death process identified, has been extensively studied and its contribution to the pathogenesis of disease well documented. Yet, apoptosis does not function alone to determine a cell's fate. More recently, autophagy, a process in which de novo-formed membrane-enclosed vesicles engulf and consume cellular components, has been shown to engage in a complex interplay with apoptosis. In some cellular settings, it can serve as a cell survival pathway, suppressing apoptosis, and in others, it can lead to death itself, either in collaboration with apoptosis or as a back-up mechanism when the former is defective. The molecular regulators of both pathways are inter-connected; numerous death stimuli are capable of activating either pathway, and both pathways share several genes that are critical for their respective execution. The cross-talk between apoptosis and autophagy is therefore quite complex, and sometimes contradictory, but surely critical to the overall fate of the cell. Furthermore, the cross-talk is a key factor in the outcome of death-related pathologies such as cancer, its development and treatment.

Using technology to teach technology: design and evaluation of bilingual online physician education about electronic medical records.

The "EMR Tutorial" is designed to be a bilingual online physician education environment about electronic medical records. After iterative assessment and redesign, the tutorial was tested in two groups: U.S. physicians and Mexican medical students. Split-plot ANOVA revealed significantly different pre-test scores in the two groups, significant cognitive gains for the two groups overall, and no significant difference in the gains made by the two groups. Users rated the module positively on a satisfaction questionnaire.

Factors influencing the attitudes of cattle veterinarians, farmers, and claw trimmers towards the pain associated with the treatment of sole ulcers and the sensitivity to pain of dairy cows

This study assessed the attitudes of personnel involved in therapeutic claw trimming of dairy cattle in Switzerland towards pain associated with sole ulcers and their treatment. Data from 77 farmers, 32 claw trimmers, and 137 cattle veterinarians were used. A large range of factors were associated with whether the respondents thought that anaesthesia during the treatment of sole ulcers was beneficial; these included year of graduation, work experience, attitude to costs of analgesia, perception of competition between veterinarians and claw trimmers, estimation of pain level associated with treatment, estimated sensitivity of dairy cows to pain, knowledge of the obligation to provide analgesia, and whether the respondent thought lesion size and occurrence of defensive behaviour by the cow were important. Respondents' estimation of the pain level associated with sole ulcer treatment was linked to frequency of therapeutic claw trimming, age, farmers' income, estimated knowledge of the benefits of analgesia, and estimated sensitivity of dairy cows to pain. The latter factor was associated with profession, frequency of therapeutic claw trimming, capability of pain recognition, opinion on the benefits of analgesia, knowledge of the obligation to provide analgesia, and self-estimation of the ability to recognise pain. Improving the knowledge of personnel involved in therapeutic claw trimming with regard to pain in dairy cows and how to alleviate it is crucial if management of pain associated with treatment of sole ulcer and the welfare of lame cows are to be optimised.

A case-control study of the association between corneal arcus and death by cardiovascular disease among cornea donors

The cornea of the human eye can develop deposits of lipids in the periphery known as corneal arcus. [2, 10] For over a century, these deposits have been of interest as possible indicators of the accumulation of lipids in arterial walls of the heart and body with implications for heart disease. [2, 10, 11, 29] Heart disease is currently the leading cause of death in this country. [5, 29] There have been several publications suggesting an association between the development of atherosclerotic lesions and corneal arcus. [2, 12, 29] Investigators have differed in their interpretation of the relevance of corneal arcus to coronary heart disease or cardiovascular disease. However, there is widespread consensus that the presence of corneal arcus in patients under the age of 50 should prompt physicians to further investigate for dyslipidemia or heart disease. [2, 3, 6, 8, 19] Earlier studies have often suffered from difficulty in determining the presence or severity of atherosclerosis and from inconsistencies in evaluating corneal arcus. This study involves the review of mortality data, medical and social history and standardized slit lamp examination of corneal tissue donors to evaluate the prevalence of corneal arcus in relation to death by CHD or CVD. The prevalence of arcus, odds ratio, and logistic regression was utilized for statistical analysis.^

Bayesian and survival model for tumor relapse status and disease-specific survival, with applications to breast cancer

Breast cancer is the most common non-skin cancer and the second leading cause of cancer-related death in women in the United States. Studies on ipsilateral breast tumor relapse (IBTR) status and disease-specific survival will help guide clinic treatment and predict patient prognosis.^ After breast conservation therapy, patients with breast cancer may experience breast tumor relapse. This relapse is classified into two distinct types: true local recurrence (TR) and new ipsilateral primary tumor (NP). However, the methods used to classify the relapse types are imperfect and are prone to misclassification. In addition, some observed survival data (e.g., time to relapse and time from relapse to death)are strongly correlated with relapse types. The first part of this dissertation presents a Bayesian approach to (1) modeling the potentially misclassified relapse status and the correlated survival information, (2) estimating the sensitivity and specificity of the diagnostic methods, and (3) quantify the covariate effects on event probabilities. A shared frailty was used to account for the within-subject correlation between survival times. The inference was conducted using a Bayesian framework via Markov Chain Monte Carlo simulation implemented in softwareWinBUGS. Simulation was used to validate the Bayesian method and assess its frequentist properties. The new model has two important innovations: (1) it utilizes the additional survival times correlated with the relapse status to improve the parameter estimation, and (2) it provides tools to address the correlation between the two diagnostic methods conditional to the true relapse types.^ Prediction of patients at highest risk for IBTR after local excision of ductal carcinoma in situ (DCIS) remains a clinical concern. The goals of the second part of this dissertation were to evaluate a published nomogram from Memorial Sloan-Kettering Cancer Center, to determine the risk of IBTR in patients with DCIS treated with local excision, and to determine whether there is a subset of patients at low risk of IBTR. Patients who had undergone local excision from 1990 through 2007 at MD Anderson Cancer Center with a final diagnosis of DCIS (n=794) were included in this part. Clinicopathologic factors and the performance of the Memorial Sloan-Kettering Cancer Center nomogram for prediction of IBTR were assessed for 734 patients with complete data. Nomogram for prediction of 5- and 10-year IBTR probabilities were found to demonstrate imperfect calibration and discrimination, with an area under the receiver operating characteristic curve of .63 and a concordance index of .63. In conclusion, predictive models for IBTR in DCIS patients treated with local excision are imperfect. Our current ability to accurately predict recurrence based on clinical parameters is limited.^ The American Joint Committee on Cancer (AJCC) staging of breast cancer is widely used to determine prognosis, yet survival within each AJCC stage shows wide variation and remains unpredictable. For the third part of this dissertation, biologic markers were hypothesized to be responsible for some of this variation, and the addition of biologic markers to current AJCC staging were examined for possibly provide improved prognostication. The initial cohort included patients treated with surgery as first intervention at MDACC from 1997 to 2006. Cox proportional hazards models were used to create prognostic scoring systems. AJCC pathologic staging parameters and biologic tumor markers were investigated to devise the scoring systems. Surveillance Epidemiology and End Results (SEER) data was used as the external cohort to validate the scoring systems. Binary indicators for pathologic stage (PS), estrogen receptor status (E), and tumor grade (G) were summed to create PS+EG scoring systems devised to predict 5-year patient outcomes. These scoring systems facilitated separation of the study population into more refined subgroups than the current AJCC staging system. The ability of the PS+EG score to stratify outcomes was confirmed in both internal and external validation cohorts. The current study proposes and validates a new staging system by incorporating tumor grade and ER status into current AJCC staging. We recommend that biologic markers be incorporating into revised versions of the AJCC staging system for patients receiving surgery as the first intervention.^ Chapter 1 focuses on developing a Bayesian method to solve misclassified relapse status and application to breast cancer data. Chapter 2 focuses on evaluation of a breast cancer nomogram for predicting risk of IBTR in patients with DCIS after local excision gives the statement of the problem in the clinical research. Chapter 3 focuses on validation of a novel staging system for disease-specific survival in patients with breast cancer treated with surgery as the first intervention. ^

An orthodontic information package designed to increase patient awareness

BACKGROUND: Most patients and their parents experience difficulty in fully appreciating the implications and demands of orthodontic treatment. This is largely because of inadequate understanding of the process of treatment or the commitment required. OBJECTIVES: To determine if a specifically developed video information package could significantly increase patient awareness of the implications of a full course of orthodontic treatment. Changes in attitude to orthodontic treatment after viewing the package were also measured. METHODS: Year 7 (12 year-old) students in two primary schools in the City of Gold Coast, Australia were randomly allocated to either a study group or a control group. Knowledge of and attitude to orthodontic treatment were measured with self-administered questionnaires before and after viewing the information package. RESULTS: The intervention group showed a 15 per cent gain in knowledge (p < 0.001). There was no gain in knowledge for the 45 students in the control group. There was no measured change in perception of need for orthodontic treatment in the study group. There was, however, an increase in potential compliance and positive attitude to the appearance of orthodontic appliances. There was a small increase in willingness to undertake treatment, but this was not statistically significant. CONCLUSIONS: The information package developed for this study increased awareness of the implications and practical difficulties which may be encountered during a course of orthodontic treatment, and produced some changes in attitude to treatment.

Differential expression of the NMDA NR2B receptor subunit in motoneuron populations susceptible and resistant to amyotrophic lateral sclerosis

We have compared the expression pattern of NMDA receptor subunits (NR1 and NR2A-D)and NRI splice variants (NR1-1a/1b,-2a/2b,-3a/3b,4a/4b) in motor neuron populations from adult Wistar rats that are vulnerable (hypoglossal, XII) or resistant (oculomotor, III) to death in amyotrophic lateral sclerosis (ALS). The major finding was higher levels of expression of the NR2B subunit in the hypoglossal nucleus. Quantitative real-time PCR showed that NR1 was expressed at a greater level than any of the NR2 subunits (> 15 fold greater, P

Comparative susceptibility of indigenous and improved pig breeds to Classical swine fever virus infection: Practical and epidemiological implications in a subsistence-based, developing country setting

This study investigated the comparative susceptibility of indigenous Moo Laat and improved Large White/Landrace pig breeds to infection with classical swine fever virus (CSFV) under controlled conditions in the Lao People's Democratic Republic (Lao PDR). The Moo Laat (ML) and Large White/Landrace crossbreed (LWC) pigs were inoculated with a standard challenge strain designated Lao/Kham225 (infectivity titre of 10(2.75) TCID50/ml). The results demonstrated that both the native breed and an improved pig breed are fully susceptible to CSFV infection and the mortality rate is high. LWC pigs demonstrated lower (or shorter) survival times (50% survival time: 11 days), earlier and higher pyrexia and earlier onset of viraemia compared to ML pigs (50% survival time: 18 days). In the context of village-based pig production, the longer time from infection to death in native ML pigs means that incubating or early sick pigs are likely to be sold once an outbreak of CSF is recognized in a village. This increased longevity probably contributes to the maintenance and spread of disease in a population where generally the contact rate is low.

Attitudes of young people with diabetes to an Internet-based virtual clinic

We assessed the feasibility of developing a virtual diabetes clinic for young people, using the Internet. The proposed content of the site would be based on self-efficacy theory, aiming to develop confidence in self-management of diabetes. A questionnaire about the proposed Website was delivered to 72 patients who attended a young person’s outpatient clinic in a district hospital. Thirty-nine replies were received, a response rate of 54%. The mean age of the respondents was 13 years. A positive attitude to the potential clinic was reported by 95% of respondents. The items rated as most useful were: quick and easy access to up-todate information about diabetes; the opportunity to ask an expert; good graphics; easy navigation; interactivity. Responses to open questions indicated that 24-hour access and anonymity in asking questions were also valued. A virtual clinic appears to be a possible method of health-care delivery to young people with diabetes.

Macro determinants of FDI inflows to Japan:an analysis of source country characteristics

This paper examines the source country determinants of FDI into Japan. The paper highlights certain methodological and theoretical weaknesses in the previous literature and offers some explanations for hitherto ambiguous results. Specifically, the paper highlights the importance of panel data analysis, and the identification of fixed effects in the analysis rather than simply pooling the data. Indeed, we argue that many of the results reported elsewhere are a feature of this mis-specification. To this end, pooled, fixed effects and random effects estimates are compared. The results suggest that FDI into Japan is inversely related to trade flows, such that trade and FDI are substitutes. Moreover, the results also suggest that FDI increases with home country political and economic stability. The paper also shows that previously reported results, regarding the importance of exchange rates, relative borrowing costs and labour costs in explaining FDI flows, are sensitive to the econometric specification and estimation approach. The paper also discusses the importance of these results within a policy context. In recent years Japan has sought to attract FDI, though many firms still complain of barriers to inward investment penetration in Japan. The results show that cultural and geographic distance are only of marginal importance in explaining FDI, and that the results are consistent with the market-seeking explanation of FDI. As such, the attitude to risk in the source country is strongly related to the size of FDI flows to Japan. © 2007 The Authors Journal compilation © 2007 Blackwell Publishing Ltd.

The two-dose measles, mumps, and rubella (MMR) immunisation schedule: factors affecting maternal intention to vaccinate

BACKGROUND: In the light of sub-optimal uptake of the measles, mumps, and rubella (MMR) vaccination, we investigated the factors that influence the intentions of mothers to vaccinate. METHOD: A cross-sectional survey of 300 mothers in Birmingham with children approaching a routine MMR vaccination was conducted using a postal questionnaire to measure: intention to vaccinate, psychological variables, knowledge of the vaccine, and socioeconomic status. The vaccination status of the children was obtained from South Birmingham Child Health Surveillance Unit. RESULTS: The response rate was 59%. Fewer mothers approaching the second MMR vaccination (Group 2) intended to take their children for this vaccination than Group 1 (mothers approaching the first MMR vaccination) (Mann-Whitney U = 2180, P < 0.0001). Group 2 expressed more negative beliefs about the outcome of having the MMR vaccine ('vaccine outcome beliefs') (Mann-Whitney U = 2155, P < 0.0001), were more likely to believe it was 'unsafe' (chi 2 = 9.114, P = 0.004) and that it rarely protected (chi 2 = 6.882, P = 0.014) than Group 1. The commonest side-effect cited was general malaise, but 29.8% cited autism. The most trusted source of information was the general practitioner but the most common source of information on side-effects was television (34.6%). Multiple linear regression revealed that, in Group 1, only 'vaccine outcome beliefs' significantly predicted intention (77.1% of the variance). In Group 2 'vaccine outcome beliefs', attitude to the MMR vaccine, and prior MMR status all predicted intention (93% of the variance). CONCLUSION: A major reason for the low uptake of the MMR vaccination is that it is not perceived to be important for children's health, particularly the second dose. Health education from GPs is likely to have a considerable impact.

A pilot study to evaluate the self-medication system for liver transplant patients at the Queen Elizabeth Hospital in Birmingham

Background and Objective: Medication non-compliance is a considerable obstacle in achievinga therapeutic goal, whichcan result in poorerhealthcare outcomes, increased expenditure, wastage and potential for medication resistance. The UK Government’s Audit Commission’s publication ‘A Spoonful of Sugar’1 addresses these issues and promotes self-medication systems as a possible solution. The self-medication system within the Liver Transplant Unit (LTU) was implemented to induct patients onto new post- transplantation medication regimes ready for discharge. The system involves initial consultations with both the Liver Transplant Pharmacist and Trans- plant Co-ordinator, supported with additional advice as and when necessary. Design: Following ethical approval, evaluation of the self-medication sys- tem for liver transplant patients was conducted between January and March 2004 via two methods: audit and structured post-transplantation interview. The audit enabled any discrepancies between current Hospital guidelines and Liver Transplant Unit (LTU) practices to be highlighted. Patient interviews generated a retrospective insight into patient acceptance of the self-medication system. Setting: LTU, Queen Elizabeth Hospital, Birmingham, England. Main Outcome Measures: LTU compliance with Hospital self-medication guidelines and patient insight into self-medication system. Results: A total of seven patients were audited. Findings illustrated that self- medication by transplant patients is a complex process which was not fully addressed by current Hospital self-medication guidelines. Twenty-three patients were interviewed, showing an overwhelming positive attitude to- wards participating in their own care and a high level of understanding towards their individual medication regimes. Following a drugs counselling session, 100% of patients understood why they were taking their medica- tion, and their doses, 95% understood how to take their medication and 85% were aware of potential side effects. Conclusions: From this pilot evaluation it can be stated that the LTU self-medication system is appreciated by patients and assists them in fully understanding their medication regimes. There appear to be no major defects in the system. However areas such as communication barriers and on-going internet education were illustrated as areas for possible future investigation. References: 1. Audit Commission. A spoonful of sugar – medicines management in NHS hospitals. London: Audit Commission; 2001.

The role of death qualification in venirepersons' evaluations of aggravating and mitigating circumstances in capital trials

Death qualification is a part of voir dire that is unique to capital trials. Unlike all other litigation, capital jurors must affirm their willingness to impose both legal standards (either life in prison or the death penalty). Jurors who assert they are able to do so are deemed “death-qualified” and are eligible for capital jury service: jurors who assert that they are unable to do so are deemed “excludable” or “scrupled” and are barred from hearing a death penalty case. During the penalty phase in capital trials, death-qualified jurors weigh the aggravators (i.e., arguments for death) against the mitigators (i.e., arguments for life) in order to determine the sentence. If the aggravating circumstances outweigh the mitigating circumstances, then the jury is to recommend death; if the mitigating circumstances outweigh the aggravating circumstances, then the jury is to recommend life. The jury is free to weigh each aggravating and mitigating circumstance in any matter they see fit. Previous research has found that death qualification impacts jurors' receptiveness to aggravating and mitigating circumstances (e.g., Luginbuhl & Middendorf, 1988). However, these studies utilized the now-defunct Witherspoon rule and did not include a case scenario for participants to reference. The purpose of this study was to investigate whether death qualification affects jurors' endorsements of aggravating and mitigating circumstances when Witt, rather than Witherspoon, is the legal standard for death qualification. Four hundred and fifty venirepersons from the 11 th Judicial Circuit in Miami, Florida completed a booklet of stimulus materials that contained the following: two death qualification questions; a case scenario that included a summary of the guilt and penalty phases of a capital case; a 26-item measure that required participants to endorse aggravators, nonstatutory mitigators, and statutory mitigators on a 6-point Likert scale; and standard demographic questions. Results indicated that death-qualified venirepersons, when compared to excludables, were more likely to endorse aggravating circumstances. Excludable participants, when compared to death-qualified venirepersons, were more likely to endorse nonstatutory mitigators. There was no significant difference between death-qualified and excludable venirepersons with respect to their endorsement of 6 out of 7 statutory mitigators. It would appear that the Furman v. Georgia (1972) decision to declare the death penalty unconstitutional is frustrated by the Lockhart v. McCree (1986) affirmation of death qualification. ^