Focused VHEE (very high energy electron) beams and dose delivery for radiotherapy applications.

This paper presents the first demonstration of deeply penetrating dose delivery using focused very high energy electron (VHEE) beams using quadrupole magnets in Monte Carlo simulations. We show that the focal point is readily modified by linearly changing the quadrupole magnet strength only. We also present a weighted sum of focused electron beams to form a spread-out electron peak (SOEP) over a target region. This has a significantly reduced entrance dose compared to a proton-based spread-out Bragg peak (SOBP). Very high energy electron (VHEE) beams are an exciting prospect in external beam radiotherapy. VHEEs are less sensitive to inhomogeneities than proton and photon beams, have a deep dose reach and could potentially be used to deliver FLASH radiotherapy. The dose distributions of unfocused VHEE produce high entrance and exit doses compared to other radiotherapy modalities unless focusing is employed, and in this case the entrance dose is considerably improved over existing radiations. We have investigated both symmetric and asymmetric focusing as well as focusing with a range of beam energies.

Measuring angles on digitalized radiographic images using Microsoft PowerPoint.

OBJECTIVE: To introduce the "virtual goniometer", a method of measuring angles on digital images using Microsoft PowerPoint, a readily available and inexpensive software programme. METHODS: Twenty-six X-rays of scoliosis curves were photographed with a digital camera. Six examiners measured the angles of curvature on their computers using the goniometer (Set 1). Under a blinded protocol, repeated measurements on these digitalized X-rays were done three weeks later (Set 2). Intra-observer differences were analyzed. To assess validity, four examiners also measured the angles using the Cobb method. Measurements achieved by both methods were analyzed by the paired samples t-test. To assess inter-observer differences, the Pearson correlation coefficient was calculated. RESULTS: Pearson correlation coefficients were significant, r (24) > or = 0.975, p < 0.001. For intraobserver variability, the average 95% CI range was 2.23 degrees between Set 1 and Set 2. The average 95% CI range was 2.38 degrees for the difference between the digital and Cobb methods. CONCLUSIONS: Clinicians using this technique can reliably assume that repeated measurements of scoliosis curvatures will vary in the range of less than 3 degrees. The 95% CI range for intra-observer variability, an index of the technique's repeatability, was > or = 2.4 degrees. A high correlation of measurements can also be expected between different observers with the goniometer. This new technique allows practitioners to utilize an easily accessible computer programme to evaluate angular deformities on digitalized radiographic images accurately and hence reliably make clinical decisions based on these measurements.

The Institute of Medicine's report on drug safety: constructive and ambitious, but does it go far enough?

In September 2004, controversy surrounded the Food and Drug Administration (FDA). It climaxed more than a decade of safety concerns involving legitimate and perceived problems with FDA-approved drugs. In response, the FDA's Center for Drug Evaluation and Research (CDER) asked the Institute of Medicine (IOM) to examine the current systems for ensuring drug safety and recommend specific actions and improvements.

Mortality of patients following hip fractures in Barbados.

A retrospective study of all patients admitted with hip fractures to the Queen Elizabeth Hospital in Barbados from January 1996 to December 1998 was conducted. There were 110 patients who had sustained either a femoral neck or peri-trochanteric fracture. The mean age was 80.7 years and 71.8% of the patients were women. Mortality at six months in 110 patients was 32.7% and 41.2% at 12 months in 102 patients. Forty-nine patients had open reduction and internal fixation of their fractures, forty-five patients were treated with Austin Moore prostheses and one patient had excisional arthroplasty. Patients with pre-operative cardiac abnormalities had a significantly higher mortality (60%) at 12 months (p = 0.028). There was a linear correlation between age and mortality with mortality increasing with age. The length of time from admission to surgical procedure had no significant influence on mortality. Hip-fracture patients with cardiac abnormalities should be carefully evaluated and stabilized pre-operatively.

Mortality of patients following hip fractures in Barbados

A retrospective study of all patients admitted with hip fractures to the Queen Elizabeth Hospital in Barbados from January 1996 to December 1998 was conducted. There were 110 patients who had sustained either a femoral neck or peri-trochanteric fracture. The mean age was 80.7 years and 71.8 of the patients were women. Mortality at six months in 110 patients was 32.7 and 41.2 at 12 months in 102 patients. Forty-nine patients had open reduction and internal fixation of their fractures, forty-five patients were treated with Austin Moore prostheses and one patient had excisional arthroplasty. Patients with pre-operative cardiac abnormalities had a significantly higher mortality (60) at 12 months (p = 0.028). There was a linear correlation between age and mortality with mortality increasing with age. The length of time from admission to surgical procedure had no significant influence on mortality. Hip-fracture patients with cardiac abnormalities should be carefully evaluated and stabilized pre-operatively

A survey of cutlass ("Collins") injuries seen in the emergency department of the Queen Elizabeth Hospital in Barbados.

For the period March to November 1998 inclusive, a prospective survey was conducted of all patients who sustained injuries with a cutlass or machete and were admitted to the Accident and Emergency Department of the Queen Elizabeth Hospital. Of the 77 patient admissions, 81% (62/77) were male. The average age was 28.8 years (range 8 to 73 years; standard deviation 13.1). Twenty-two per cent of the patients were less than 20 years old. The most common locations of the lacerations were upper extremity (59 lacerations) and scalp (16 lacerations). Thirty-four per cent of the patients (26/77) sustained lacerations to two or more anatomical locations. There were 23 fractures in 21 patients; skull fractures were the most common fractures (11). Of the 63 patients who responded to the question on whether they knew the identity of their assailants, 51 reported that they were attacked by someone known to them; eight were assaulted by a spouse or known family member. Eighty-six per cent of patients (66/77) were treated in the emergency room and discharged. Of the 11 patients admitted, eight required treatment in the operating theatre. The average length of stay was 3.6 days. There were no amputations or deaths. One patient sustained loss of vision in one eye. In Barbados, most victims of cutlass injuries are males who know their assailants and the morbidity is most often related to head injuries and to short-term physical disability due especially to lacerations of the hand and forearm.

A survey of cutlass ("Collins") injuries seen in the emergency department of the Queen Elizabeth Hospital in Barbados

For the period March to November 1998 inclusive, a prospective survey was conducted of all patients who sustained injuries with a cutlass or machete and were admitted to the Accident and Emergency Department of the Queen Elizabeth Hospital. Of the 77 patient admissions, 81 (62/77) were male. The average age was 28.8 years (range 8 to 73 years; standard deviation 13.1). Twenty-two per cent of the patients were less than 20 years old. The most common locations of the lacerations were upper extremity (59 lacerations) and scalp (16 lacerations). Thirty-four per cent of the patients (26/77) sustained lacerations to two or more anatomical locations. There were 23 fractures in 21 patients; skull fractures were the most common fractures (11). Of the 63 patients who responded to the question on whether they knew the identity of their assailants, 51 reported that they were attacked by someone known to them; eight were assaulted by a spouse or known family member. Eighty-six per cent of patients (66/77) were treated in the emergency room and discharged. Of the 11 patients admitted, eight required treatment in the operating theatre. The average length of stay was 3.6 days. There were no amputations or deaths. One patient sustained loss of vision in one eye. In Barbados, most victims of cutlass injuries are males who know their assailants and the morbidity is most often related to head injuries and to short-term physical disability due especially to lacerations of the hand and forearm.

Coprescribing and codispensing of cisapride and contraindicated drugs.

CONTEXT: Cisapride, an oral prokinetic drug indicated for the symptomatic treatment of nocturnal heartburn due to gastroesophageal reflux disease, was approved by the US Food and Drug Administration in July 1993. After reports of serious cardiac arrhythmias and deaths during administration of cisapride, most involving concomitant exposure to another drug, a series of label changes and warnings were issued in February 1995, October 1995, June 1998, and June 1999. Cisapride was removed from general distribution in July 2000. OBJECTIVE: To determine the frequency of contraindicted coprescribing and codispensings, in which cisapride and a contraindicated drug were prescribed or dispensed to the same patient for overlapping periods, and the proportion of contraindicated coprescribing by the same physicians and codispensing by the same pharmacies. DESIGN AND SETTING: Retrospective study of prescription claims from a managed care organization database for all patients with cisapride prescriptions between July 1993 and December 1998. PARTICIPANTS: A total of 38 757 adult and pediatric patients who had a cisapride prescription immediately preceded by at least 60 days of insurance eligibility. MAIN OUTCOME MEASURE: Proportion of cisapride prescriptions or dispensing occurring during the same treatment period as a drug contraindicated at that time prescribed by the same physicians or dispensed by the same pharmacies. RESULTS: Of 131 485 cisapride prescriptions dispensed after the warnings began, 4414 (3.4%) overlapped with at least 1 drug contraindicated in the labeling at the time of the prescription. Of all overlapping prescription pairs, 2190 (50%) were by the same physicians, 3908 (89%) were by the same pharmacies, and 765 (17%) were dispensed on the same day. CONCLUSION: Prescriptions dispensed by the same pharmacies accounted for a far higher proportion of contraindicated medication pairs than prescriptions from the same physicians. The pharmacy may be an important and underutilized intervention point to prevent contraindicated drugs from being used together.

An evaluation of medical school education in musculoskeletal medicine at the University of the West Indies, Barbados.

At the University of the West Indies, Cave Hill campus, the Freedman and Bernstein musculoskeletal competency examination was administered to 22 medical students during the last month of their final year. Eighty-two per cent (82%) of the students failed to score above the passing score of 73.1%. Nineteen of the twenty-two students had taken an orthopaedic elective or rotation during their final two years. The questions were also categorized as Anatomy, Trauma and General Orthopaedics. All students failed to score above the passing score in Anatomy. Sixty-four per cent (64%) failed in Trauma and 45% failed in General Orthopaedics. This study suggests that inadequacies in medical school preparation do exist at this campus of the University of the West Indies and the findings mirror those at medical schools in the United States of America.

Postmarketing surveillance of new food ingredients: design and implementation of the program for the fat replacer olestra.

Following U.S. Food and Drug Administration (FDA) approval for the use of olestra, a noncaloric fat substitute (brand name Olean) in food snacks, the manufacturer agreed to provide safety updates on market experience to the FDA. However, guidelines for food product postmarketing surveillance (PMS) are not available and those typically used with medical products were only partly applicable. In modeling the Olean program, we drew from experience with consumer products and incorporated elements typical of medical product PMS. A cooperative effort was established with Olean snack manufacturers and a two-tiered, multidisciplinary approach enlisting Consumer Relations and Medical Affairs personnel was used to maximize use of specialized skills. The result of this effort was implementation of a reliable PMS system which could handle a high volume of reports from consumers while providing pertinent data required for medical interpretation of these reports. Summaries of data for the Olean snack manufacturers and FDA were generated in timely fashion. In addition to collection of the spontaneous reports from consumers, a clinical studies program was undertaken and an independent medical advisory panel was established. Through these, we gained perspective on the spontaneous reports and additional confirmation of the safety of olestra in savory snacks.

An evaluation of medical school education in musculoskeletal medicine at the University of the West Indies, Barbados

At the University of the West Indies, Cave Hill campus, the Freedman and Bernstein musculoskeletal competency examination was administered to 22 medical students during the last month of their final year. Eighty-two per cent (82) of the students failed to score above the passing score of 73.1. Nineteen of the twenty-two students had taken an orthopaedic elective or rotation during their final two years. The questions were also categorized as Anatomy, Trauma and General Orthopaedics. All students failed to score above the passing score in Anatomy. Sixty-four per cent (64) failed in Trauma and 45 failed in General Orthopaedics. This study suggests that inadequacies in medical school preparation do exist at this campus of the University of the West Indies and the findings mirror those at medical schools in the United States of America.

Pharmacogenetics and pharmacoepidemiology.

This paper seeks to stimulate consideration of the short- and long-term possibilities raised by research into pharmacogenetics and pharmacoepidemiology, to identify potential tissue databanks linked to population data, and to summarize our ethical responsibilities. Short term, we might identify selected disorders or risk factors, such as for drug-associated serious events, and might find selected target populations. Long term, we might incorporate genomics techniques into population data and map genetic risk factors for diseases and drug responses. Tissue specimens that might be linked to clinical data lie in certain data resources: clinical trials, ad hoc cohorts, case registries, and cross-sectional and longitudinal population samples. Specific areas must be addressed in research using human tissue and genetic material, including the ethical threat to privacy. We must avoid misuse of genetic information by breaching confidentiality and putting at risk specific genetically identifiable groups. The National Bioethics Advisory Commission recently addressed the issue of serum and tissue data banks in a published report summarized in this paper. Social, methodologic, and ethical issues relate to any protocol using serum and tissue, and indicate a need for broad educational efforts. We must set guidelines as pharmacogenetics research becomes a dimension of pharmacoepidemiology.

Microspore culture in Corchorus olitorius: effect of growth regulators, temperature and sucrose on callus formation.

Culture of isolated microspores and of anthers on media containing IAA directed free microspore development to an embryogenic pathway in C. olitorius. The first division of microspores on transfer to culture media was symmetrical in contrast to the asymmetrical division seen in normal development in vivo. Initially, 10-30% microspores divided symmetrically, but only 0.2-1% of the dividing microspores continued dividing and produced multicellular microcalli. About 30% of these microcalli produced callus but only on medium with 2.0 mg/L zeatin and 0.1 mg/L IAA. Incubation in the dark at temperatures of 35 degrees C for 1 day and then 25 degrees C was found effective for induction of first embryonic division in Corchorus. The frequency of microspore callus formation was higher on medium containing either 3% or 5% sucrose. Addition of colchicine and addition of activated charcoal to the above medium did not enhance microspore division in Corchorus olitorius. On transfer to different media most calli produced roots but regeneration of shoots and embryos was not induced.

Reason for discontinuation of newly prescribed antihypertensive medications: methods of a pilot study using computerized patient records.

Objective-The purpose of this pilot study was to examine the feasibility of using computerized medical records retrospectively to identify patients and their physicians for subsequent survey to examine discontinuation of a newly prescribed antihypertensive medication in primary care, while maintaining patient confidentiality.Design-A case - control study utilizing UKPCD (formerly MediPlus(R)), a large automated database of computerized medical records, and direct collection of information from patients and their physicians.Setting-Eight selected general practices in the United Kingdom.Participants-Thirty-two patients, identified with a newly prescribed antihypertensive (index) medication and classified by their treatment status (discontinuer vs continuer) and five physicians were surveyed.Results-The participation rate was low among physicians (19%), likely to be due to recruitment during the holiday season, but higher among eligible patients (70%). A higher proportion of discontinuers (37%) refused or failed to respond to the invitation to participate compared with continuers (27%). For most patients, self-reported treatment status matched the UKPCD-based classification of discontinuer or continuer (kappa = 0.67); agreement of UKPCD data with physicians was moderate (kappa = 0.53). The extent and accuracy of the information collected from patients demonstrated that they were able and willing to report detailed knowledge of their medications and recent symptoms. Discontinuers, however, had difficulty recalling the discontinued medication on their own, possibly due to the amount of time elapsed between the event and the questionnaire administration.Conclusion-This pilot study demonstrates the feasibility of examining medication discontinuation in an ambulatory setting by utilizing a large automated database of computerized records to identify and recruit eligible physicians and their hypertensive patients for study, while maintaining patient and physician privacy. Modifications to the methodology to increase physician and patient participation and recall, and to decrease the time between the index event and patient query would increase its utility in larger studies. Copyright (c) 2000 John Wiley & Sons, Ltd.

Selective serotonin reuptake inhibitors have broadened the utilisation of antidepressant treatment in accordance with recommendations. Findings from a Swedish prescription database.

BACKGROUND: With the advent of the selective serotonin reuptake inhibitors (SSRIs), the use of antidepressants has increased drastically in Sweden. The use of tricyclic antidepressants (TCAs) has, however, decreased. METHODS: We surveyed a prescription database in the Swedish county of Jämtland and compared prescription patterns for patients prescribed SSRIs with those prescribed TCAs. RESULTS: The incidence of treatments of antidepressants increased from 0.76% to 1.33% during the period 1991-1996. There were no significant differences between SSRIs and TCAs with regard to patients having only one prescription dispensed within three months from the index prescription, or patients who switched class of antidepressant. Only a minority of the treatments were continued for at least six months, but significantly more SSRI than TCA treatments (42% and 27%). A second treatment period suggesting recurrence was three-times more common in the TCA group than in the SSRI group. CONCLUSION: Provided that the increased use of SSRIs is mainly for depression, these drugs appear, despite a lower efficacy in severe depression, to have enabled a broader utilisation of antidepressants with regard to incidence, dosage and duration, in accordance with recommendations. Further analyses of this phenomenon relative to diagnostic criteria and outcome measures are required.

Presence of laminin fragments in cyst fluid from patients with autosomal dominant polycystic kidney disease (ADPKD): role in proliferation of tubular epithelial cells.

Cyst fluid samples obtained from eight patients with autosomal dominant polycystic kidney disease (ADPKD) were analysed for the presence of the basement membrane component laminin and its breakdown products, using ELISA and immunoblotting techniques. Whole laminin was not detected, whereas laminin fragments of 270, 155, 87, 56, and 14 kDa were detected at a mean total value of approximately 0.5 microgram/ml. The laminin fragments were assessed for their effect on cultured normal and ADPKD epithelial cells. Both cell types showed accelerated growth under these conditions. These findings suggest that basement membrane degradative fragments present in cyst fluid may contribute to cystic epithelial cell proliferation and may therefore be important in the pathogenesis of ADPKD.

Antidepressant use and resource utilization in the general practitioner setting in The Netherlands.

OBJECTIVE: To assess antidepressant use and resource utilization in the general practitioner (GP) setting in the Netherlands following initiation of antidepressant therapy. DESIGN: Longitudinal study in a retrospective database. PARTICIPANTS: Sample of 869 patients from a new database in the Netherlands who initiated therapy on a selective serotonin re-uptake inhibitor (SSRI) or a tricyclic antidepressant (TCA). MAIN OUTCOME MEASURES: Mean length of antidepressant therapy within the first 90 days and resource utilization in the GP setting in the first 180 days following therapy initiation. RESULTS: (1) patients who initiated therapy on an SSRI were younger (48.6 years old versus 54.1 years old, p<0.01) and more likely to have a depression diagnosis (58% versus 30%, p<0.01) than patients who initiated therapy on a TCA; (2) patients who initiated therapy on an SSRI were more likely than patients who initiated therapy on a TCA (65% versus 52%, p<0.01) to have more than 30 days of therapy within the first 90 days and to receive antidepressant doses consistent with Dutch guidelines; (3) patients with greater than 30 days of antidepressant therapy within the first 90 days had more general practitioner visits than patients with 30 days of therapy or less (TCA patients: 9.6 versus 7.0; SSRI patients: 8.8 versus 6.9, p<0.01). CONCLUSIONS: Patients in the GP setting in the Netherlands who initiate therapy on SSRIs are more likely than patients who initiate therapy on TCAs to receive recommended doses and duration of therapy consistent with Dutch antidepressant treatment guidelines.

Value of epidemiologic studies in determining the true incidence of adverse events. The nonsteroidal anti-inflammatory drug story.

BACKGROUND: Evidence supporting differential toxic effects of nonsteroidal anti-inflammatory drugs (NSAIDs) often is derived from spontaneous reports of adverse events to the US Food and Drug Administration (FDA). These reports represent observations from an undefined, exposed population that are not collected in a standardized manner and therefore are subject to reporting biases. Epidemiologic studies, in which the numbers of patients experiencing an adverse event and exposed to the drug are known, provide more reliable measures of risk and can place spontaneous reports in perspective. OBJECTIVE: To compare both data sources with regard to NSAID-associated gastrointestinal, liver, and skin events. METHODS: We obtained spontaneous reports of these adverse events for diclofenac, nabumetone, naproxen, and piroxicam. Published epidemiologic studies of these events were reviewed. RESULTS: Spontaneous reports did not mirror reliably the results of epidemiologic studies. Spontaneous reports showed higher associations of gastrointestinal and skin events with nabumetone and piroxicam and hepatic events with diclofenac. Epidemiologic studies generally did not show differential risk among these NSAIDs. CONCLUSIONS: When the 4 NSAIDs are compared in epidemiologic studies, there is no quantitative basis for identifying 1 as more or less toxic than the others, underlining the hazard of deriving quantitative conclusions from spontaneous reports. Spontaneous reports are an unreliable measure of risk; rather, they may provide evidence of the relative awareness of specific toxic effects among physicians.

Prescribing of selective serotonin reuptake inhibitors, anxiolytics, and sedative-hypnotics by general practitioners in The Netherlands: a multivariate analysis.

A study of the prescribing of anxiolytics and sedative-hypnotics and the occurrence of anxiety or sleep disorders before and after the initiation of selective serotonin reuptake inhibitor (SSRI) therapy may provide insight into differences in individual SSRIs. The purpose of our study was to evaluate whether and in what way the likelihood of being prescribed an anxiolytic or sedative-hypnotic or receiving a diagnosis of an anxiety or sleep disorder differed in patients prescribed either fluoxetine or paroxetine by a general practitioner (GP) in the Netherlands, where these two agents are the most commonly prescribed SSRIs. Episodes of SSRI treatment were constructed from a recently available GP database in the Netherlands. Logistic regression analysis was used to determine whether, after controlling for other observable factors, the receipt of paroxetine or fluoxetine was a statistically significant determinant for receipt of an anxiolytic or sedative-hypnotic or a diagnosis of an anxiety or sleep disorder. We found that patients who were prescribed fluoxetine as their index drug were less likely to receive a concomitant sedative-hypnotic on their index date compared with patients receiving paroxetine. After controlling for other observable factors, such as use of anxiolytics and sedative-hypnotics before SSRI therapy or on the index date or the existence of comorbid anxiety or sleep disorders, patients starting fluoxetine therapy were no more likely than patients starting paroxetine therapy to receive an anxiolytic or sedative-hypnotic or a diagnosis of an anxiety or sleep disorder during the 60-day post period. The likelihood of a patient's being diagnosed with or receiving a prescription for an anxiety or sleep disorder does not appear to be a differentiating factor between the prescribing of fluoxetine or paroxetine by GPs in the Netherlands.