Enhancing the Measure of Participation Burden in Protocol Design to Incorporate Logistics, Lifestyle, and Demographic Characteristics.

BACKGROUND: Growing interest in improving patient participation convenience and the feasible execution of clinical trials has increased demand for new approaches to leverage patient input in the protocol design process. METHODS: This study builds on prior work conducted by the Tufts Center for the Study of Drug Development in collaboration with ZS. A comprehensive participant burden algorithm based on protocol procedures, participation requirements and lifestyle preferences was developed and tested. Clinical trial preferences and perceptions from 3002 global patients were analyzed to inform and derive the algorithm. It was next tested against a convenience sample of 266 completed protocols. Descriptive statistics, significance tests, and regression analyses were performed. RESULTS: Mean participant burden scores were highly associated with, and predictive (p < 0.01) of, screen failure rates, overall clinical trial duration and the number of substantial protocol amendments; and predictive (p < 0.05) of protocol treatment duration. Of 11 subgroups assessed, those that most influenced the algorithm and drove higher overall burden scores included disease condition, caregiver reliance, race, prior experience as a clinical trial participant and participant age. Geographic area and participant sex showed only minimal influence. CONCLUSION: This study presents advancement and refinement in measuring participation burden that will assist drug development teams and protocol authors in retrospectively understanding clinical trial performance outcomes and in prospectively informing protocol design decisions.

The prevalence of two 'commonly' encountered synthetic target fibres within a large urban environment.

A target fibre study was carried out to assess the random prevalence of two ostensibly commonly encountered synthetic fibre types; black acrylic and blue polyester. The study was performed in an environment which maximised the number of random contacts between textile garments in the population and specific surfaces, namely; seating relating to buses, public houses and cinemas found within a large urban conurbation. Surface debris tapings were collected from samples of bus seats (30), pub seats (54) and cinema seats (53). Using low power stereomicroscopy, a total of 114 and 68 fibres, superficially similar to the respective black acrylic and blue polyester target fibres, were recovered from these tapings. The full range of comparative microscopical and instrumental analysis used in operational forensic laboratories was performed on the recovered fibres. No matches were found with either of the target fibres. These findings are in accordance with similar studies which show that the probability of an 'adventitious' match with a particular fibre type/colour combination is extremely low. In addition, the findings demonstrate that the current techniques and instrumentation employed by operational forensic laboratories are fit for purpose. Importantly, the findings demonstrate that databases and surveys (e.g. fibre population studies) which do not consider the analytical/comparison processes, must not be used in isolation when evaluating fibre evidence at source level.

The development of vaccination perspectives among chiropractic, naturopathic and medical students: a case study of professional enculturation.

An important influence on parents' decisions about pediatric vaccination (children under 6 years of age) is the attitude of their health care providers, including complementary and alternative medicine (CAM) providers. Very limited qualitative research exists, however, on how attitudes towards vaccination develop among healthcare professionals in-training. We explored perspective development among three groups of students: medical, chiropractic, and naturopathic. We conducted focus group sessions with participants from each year of study at three different healthcare training programs in Ontario, Canada. Semi-structured and open-ended questions were used to elicit dynamic interaction among participants and explore how they constructed their attitudes toward vaccination at the beginning and part way through their professional training. Analyses of verbatim transcripts of audiotaped interviews were conducted both inductively and deductively using questions structured by existing literature on learning, professional socialization and interprofessional relations. We found five major themes and each theme was illustrated with representative quotes. Numerous unexpected insights emerged within these themes, including students' general open-mindedness towards pediatric vaccination at the beginning of their training; the powerful influence of both formal education and informal socialization; uncritical acceptance of the vaccination views of senior or respected professionals; students' preference for multiple perspectives rather than one-sided, didactic instruction; the absence of explicit socio-cultural tensions among professions; and how divergences among professional students' perspectives result from differing emphases with respect to lifestyle, individual choice, public health and epidemiological factors-rather than disagreement concerning the biomedical evidence. This last finding implies that their different perspectives on pediatric vaccination may be complementary rather than irreconcilable. Our findings should be considered by developers of professional and interprofessional educational curricula and public health officials formulating policy on pediatric vaccination.

Three-dimensional computed tomography for determination of femoral anteversion in a cerebral palsy model.

BACKGROUND: Previous investigation has proven 3-dimensional (3D) computed tomography (CT) to be a poor method of assessing femoral anteversion in patients with cerebral palsy. However, new advancements in CT software yield the potential to improve upon those dated results. METHODS: CT was performed on 9 femoral models with varying amounts of anteversion (20 to 60 degrees) and varying neck-shaft angles (120 to 160 degrees). Each model was scanned in 2 holding devices. One holder placed the femur in an ideal position relative to the gantry. The other placed the femur in flexion, adduction, and internal rotation simulating a common lower extremity posture in cerebral palsy. Femoral anteversion was measured on 3D reconstructions by 4 observers on 2 separate occasions. Interobserver and intraobserver reliability, accuracy, and the effect of increasing neck-shaft angle of the measurements were examined and compared with previously published data using the same models. RESULTS: Pearson correlation coefficients between first and second measurements by the same examiner were all above 0.96 regardless of positioning of the femur in the gantry. The correlation coefficients among all examiners were 0.97 regardless of positioning of the femur in the gantry. Accuracy in measurements was comparable using 3D CT techniques with mean differences between the normal and cerebral palsy-positioned models of <3.6 degrees (SD, 3.1 to 3.3 degrees). Accuracy of the study's 3D CT technique in measuring femoral anteversion in cerebral palsy-positioned femurs was significantly more accurate than that of 2D CT (P<0.0001). CONCLUSIONS: Recent improvements in processing software and 3D reconstruction have made assessment of femoral anteversion with 3D CT accurate through the studied range of anteversion and neck-shaft angles. Using this technique, high intraobserver and interobserver reliability in the determination of femoral anteversion can be expected regardless of neck-shaft angle or postural deformity. LEVEL OF EVIDENCE: Level II.

Rosacea: a review of current topical, systemic and light-based therapies.

Rosacea is a common chronic inflammatory disorder of the facial skin characterized by periods of exacerbation, remission and possible progression. The principle subtypes include erythematotelangiectatic rosacea, papulopustular rosacea, phymatous rosacea and ocular rosacea. Although the pathogenesis is unknown, rosacea is largely recognized as an inflammatory disorder. Individual subtypes are likely a result of different pathogenic factors and respond best to different therapeutic regimens. The non-pharmacologic approach to therapy is adequate skin care, trigger avoidance and photoprotection; in addition, there are several topical, herbal, systemic and light based therapies available. Standard Food and Drug Administration (FDA) approved treatments include topical sodium sulfacetamide, metronidazole, and azelaic acid. Anti-inflammatory dose doxycycline, a controlled-release 40 mg formulation offers a non-antibiotic, anti-inflammatory treatment option. Combination of azelaic acid or topical metronidazole with anti-inflammatory doxycycline appears to have a synergistic effect. Oral isotretinoin may be effective for phymatous rosacea and treatment resistant rosacea. Light based therapies with pulsed dye laser and intense pulsed light are effective in treatment of erythema and telangiectasias. As our knowledge of rosacea and its therapeutic options expand, a multifaceted approach to treatment is warranted.

Mutation profile of the CDH23 gene in 56 probands with Usher syndrome type I.

Mutations in the human gene encoding cadherin23 (CDH23) cause Usher syndrome type 1D (USH1D) and nonsyndromic hearing loss. Individuals with Usher syndrome type I have profound congenital deafness, vestibular areflexia and usually begin to exhibit signs of RP in early adolescence. In the present study, we carried out the mutation analysis in all 69 exons of the CDH23 gene in 56 Usher type 1 probands already screened for mutations in MYO7A. A total of 18 of 56 subjects (32.1%) were observed to have one or two CDH23 variants that are presumed to be pathologic. Twenty one different pathologic genome variants were observed of which 15 were novel. Out of a total of 112 alleles, 31 (27.7%) were considered pathologic. Based on our results it is estimated that about 20% of patients with Usher syndrome type I have CDH23 mutations.

"Walk in to Work Out": a randomised controlled trial of a self help intervention to promote active commuting.

STUDY OBJECTIVE: To determine if a self help intervention, delivered via written interactive materials (the "Walk in to Work Out" pack), could increase active commuting behaviour (walking and cycling). DESIGN: Randomised controlled trial. The intervention group received the "Walk in to Work Out" pack, which contained written interactive materials based on the transtheoretical model of behaviour change, local information about distances and routes, and safety information. The control group received the pack six months later. Focus groups were also conducted after six months. SETTING: Three workplaces in the city of Glasgow, Scotland, UK. PARTICIPANTS: 295 employees who had been identified as thinking about, or doing some irregular, walking or cycling to work. MAIN RESULTS: The intervention group was almost twice as likely to increase walking to work as the control group at six months (odds ratio of 1.93, 95% confidence intervals 1.06 to 3.52). The intervention was not successful at increasing cycling. There were no distance travelled to work, gender, or age influences on the results. Twenty five per cent (95% confidence intervals 17% to 32%) of the intervention group, who received the pack at baseline, were regularly actively commuting at the 12 month follow up. CONCLUSION: The "Walk in to Work Out" pack was successful in increasing walking but not cycling. The environment for cycling must be improved before cycling will become a popular option.

Explaining the thinness of the fresh water lens in the Pleistocene carbonate aquifer on Andros Island, Bahamas.

Two hypotheses are explored to explain the thinness of the fresh water lens on Andros Island, Bahamas. The lens is an order of magnitude thinner than predicted by the Ghyben-Herzberg theory. One hypothesis previously posed in the literature is that the base of the lens is governed by the contact between the Lucayan Formation and the pre-Lucayan limestones. An alternate hypothesis, posed here, is that thinning is caused by the hydraulic influence of low-permeability paleosols in the Lucayan Formation. These hypotheses were explored, along with the influence of recharge and other factors, using a numerical model for variable-density flow and salt transport. In the layered system of grainstones/packstones and paleosols within the Lucayan Formation itself, the velocity vectors are nearly horizontal in the grainstones/packstones, and they are nearly vertical in the paleosols. These strata above the pre-Lucayan, all lower than it in permeability, draw the base of the lens upward to a position well above the contact by significantly reducing pressure within and below the strata relative to hydrostatic pressure. It is the loss of pressure across the paleosols that dramatically thins the fresh water lens, and thus the predominant hydraulic control on lens thickness arises from the existence of paleosols.

Transepithelial sodium absorption is increased in people of African origin.

Salt-sensitive hypertension is more common and has more severe consequences in urban black populations than in white populations. Increased renal sodium reabsorption through epithelial sodium channels may underlie the development of high blood pressure in black people. Increased sodium channel activity has been detected in subjects with Liddle's syndrome by nasal potential difference measurements. Nasal potential difference measurements were made in 39 black normotensive, 106 black hypertensive, 51 white normotensive, and 61 white hypertensive subjects. Blood pressure, body mass index, and 24-hour urinary sodium excretion were also measured. Maximum potential difference was significantly higher in black subjects than in white subjects (P=0.009) but was not significantly different between normotensive and hypertensive subjects after adjustment for age, gender, current smoking status, body mass index, and 24-hour urinary sodium excretion (black normotensive, -21.6+/-1.0 mV; black hypertensive, -21.5+/-0.7 mV; white normotensive, -18.5+/-1.0 mV; and white hypertensive subjects, -18.9+/-0.9 mV). Nasal potential difference did not correlate with blood pressure or biochemical variables within ethnic and blood pressure groups. Nasal potential difference, an index of nasal sodium channel activity, is greater in black than in white people but does not differ between normotensive and hypertensive groups. Increased nasal potential difference measurements may reflect generalized upregulation of sodium transport in black people compared with white people, which may help to explain the high prevalence of hypertension in black people but would not explain differences in blood pressure within separate ethnic groups.

Genetic heterogeneity of Usher syndrome: analysis of 151 families with Usher type I.

Usher syndrome type I is an autosomal recessive disorder marked by hearing loss, vestibular areflexia, and retinitis pigmentosa. Six Usher I genetic subtypes at loci USH1A-USH1F have been reported. The MYO7A gene is responsible for USH1B, the most common subtype. In our analysis, 151 families with Usher I were screened by linkage and mutation analysis. MYO7A mutations were identified in 64 families with Usher I. Of the remaining 87 families, who were negative for MYO7A mutations, 54 were informative for linkage analysis and were screened with the remaining USH1 loci markers. Results of linkage and heterogeneity analyses showed no evidence of Usher types Ia or Ie. However, one maximum LOD score was observed lying within the USH1D region. Two lesser peak LOD scores were observed outside and between the putative regions for USH1D and USH1F, on chromosome 10. A HOMOG chi(2)((1)) plot shows evidence of heterogeneity across the USH1D, USH1F, and intervening regions. These results provide conclusive evidence that the second-most-common subtype of Usher I is due to genes on chromosome 10, and they confirm the existence of one Usher I gene in the previously defined USH1D region, as well as providing evidence for a second, and possibly a third, gene in the 10p/q region.

The mercury sphygmomanometer should be abandoned before it is proscribed.

Both in clinical practice and medical research, blood pressure is still largely measured by auscultation using a mercury sphygmomanometer. Blood pressure is the most important predictor of life expectancy. Treatment of high blood pressure reduces strokes, heart attack and heart failure. Accurate measurement is therefore essential. At a large London teaching hospital, just under 500 mercury sphygmomanometers and their associated cuffs were examined. More than half had serious problems that would have rendered them inaccurate in measuring blood pressure. At the same time, assessment of the technical knowledge needed to measure blood pressure by the ausculatory technique was also carried out amongst medical and nursing staff. This showed a considerable level of ignorance. These results inevitably lead to inaccurate measurement of blood pressure with serious consequences. In addition mercury is a non-degradable pollutant, eventually accumulating on the sea bed. The use of mercury in sphygmomanometers is already in the process of being eliminated in Scandinavia and Holland and other countries are likely to follow. Our results suggest that mercury sphygmomanometers are not adequately maintained and require expertise that is not available for accurate measurement of blood pressure. Their use should be dispensed with on these grounds before a ban for other and, perhaps less justifiable reasons. Validated automatic devices, which are less liable to measurement and observer error should be used instead. At the same time a concerted effort is needed to instruct health care professionals on the importance of more accurate measurement of blood pressure. Journal of Human Hypertension (2000) 14, 31-36.

Conjugal loss and syndromal depression in a sample of elders aged 70 years or older.

OBJECTIVE: The goal of this study was to describe the association between conjugal loss and both syndromal depression and depressive symptoms in a prospective cohort study of people aged 70 years or older. METHOD: A measure of syndromal depression, the shortform Composite International Diagnostic Interview (CIDI), and a revised version of the Center for Epidemiologic Studies--Depression Scale (CES-D Scale) were administered to a group of 5,449 elders in a longitudinal cohort study. The authors compared the rates of syndromal depression (CIDI diagnosis) and depressive symptoms (six CES-D Scale symptoms) in married participants and those who lost spouses between the first and second waves of assessment. RESULTS: The rate of syndromal depression in the newly bereaved was nearly nine times as high as the rate for married individuals, and the rate of depressive symptoms was nearly four times as high. The percentage of the bereaved respondents who had scores above threshold on the revised CES-D Scale was higher for those interviewed up to 2 years after loss of a spouse than for married respondents. Age, sex, prior psychiatric history, and the expectedness of the death did not differ between depressed and nondepressed newly bereaved subjects. CONCLUSIONS: Recent bereavement is a significant risk factor for syndromal depression in the elderly. Some widows and widowers experienced high levels of depressive symptoms up to 2 years after the loss of their spouses. Neither demographic variables nor variables concerning the nature of the spouse's death predicted bereavement-related depression.

BDNF and NT4/5 promote survival and neurite outgrowth of pontocerebellar mossy fiber neurons.

The neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), and NT4/5 are all found in the developing cerebellum. Granule cells, the major target neurons of mossy fibers, express BDNF during mossy fiber synaptogenesis. To determine whether neurotrophins contribute to the development of cerebellar afferent axons, we characterized the effects of neurotrophins on the growth of mossy fiber neurons from mice and rats in vitro. For a mossy fiber source, we used the basilar pontine nuclei (BPN), the major source of cerebellar mossy fibers in mammals. BDNF and NT4/5 increased BPN neuron survival, neurite outgrowth, growth cone size, and elongation rate, while neither NT3 nor NGF increased survival or outgrowth. In addition, BDNF and NT4/5 reduced the size of neurite bundles. Consistent with these effects, in situ hybridization on cultured basilar pontine neurons revealed the presence of mRNA encoding the TrkB receptor which binds both BDNF and NT4/5 with high affinity. We detected little or no message encoding the TrkC receptor which preferentially binds NT3. BDNF and NT4/5 also increased TrkB mRNA levels in BPN neurons. In addition to previously established functions as an autocrine/paracrine trophic factor for granule cells, the present results indicate that cerebellar BDNF may also act as a target-derived trophic factor for basilar pontine mossy fibers.

Prehospital care--a UK perspective.

In the UK, emergency ambulances are responding to astonishing increases in levels of emergency calls, in the order of a 40% increase nationally in the last 5 years. Pressures in primary care service out-of-hours provision, and increasing community-based care of elderly patients, as well as increased expectation by the public are contributory causes. Services are also being pressed to improve response times, particularly to life-threatening cases. These various aspects are discussed below.

Psychiatrists' and internists' knowledge and attitudes about delivery of clinical preventive medical services.

OBJECTIVE: Changes in the health care environment have placed a greater responsibility on psychiatrists to deliver basic primary care services. The study assessed baseline knowledge and attitudes about clinical preventive medical services among psychiatric faculty and psychiatric residents at a tertiary care medical center. METHODS: Residents and faculty in psychiatry and general internal medicine completed a structured questionnaire, including 20 case scenarios, that assessed their baseline knowledge of clinical preventive medical services, their attitudes concerning delivery of those services, and their beliefs about the effectiveness of those services in changing patients' behavior. The case scenarios and knowledge questions were based on the clinical preventive medical services recommendations outlined by the U. S. Preventive Services Task Force. RESULTS: Psychiatrists reported more frequent assessment of and counseling about the use of illicit drugs and weapons, and internists were more likely to query about measures related to physical health such as cancer screening and immunizations. The two groups reported similar attitudes toward the need for and the efficacy of preventive medical services. Commonly cited barriers to the delivery of preventive care included lack of time and education. Psychiatrists scored reasonably well on baseline knowledge about guidelines for preventive medical services, particularly given their recent lack of specific education in these matters. CONCLUSIONS: Psychiatrists believe clinical preventive services are important and express interest in their delivery. Additional educational interventions are needed to train psychiatrists in clinical preventive services to avoid missed clinical opportunities for intervention in psychiatric populations that may have poor access to other medical care.

The evaluation of eating and weight symptoms. A comparison of medically ill and eating disorder patients.

The purpose of this study was to determine the utility of hospitalization in a medical-psychiatry unit for eating disorder patients. A retrospective chart review of 48 patients given an International Classification of Disease-9 diagnosis of an eating disorder was conducted. Presenting symptoms, functional status using the Karnofsky Index, medical and psychiatric evaluation, diagnosis, treatment, and outcome were evaluated. Patients fell into 1 of 3 groups: those with an active eating disorder and comorbid medical complications (Eating Disorder [ED] positive [POS], n = 25), those with a history of an eating disorder admitted for some other reason (ED history [HX], n = 8), and those with eating or weight symptoms ultimately found to be related to a noneating disorder or primary medical process (ED negative [NEG], n = 15). The ED POS patients were younger (28.1 vs. 49.1 years, P = 0.0001) but had a lower functional status on admission compared with the ED NEG patients (Karnofsky score 51 vs. 72, P = 0.0002). They were more likely to binge eat, restrain intake, and abuse laxatives (P = 0.0001, P = 0.024, P = 0.037, respectively) but did not differ with respect to history of vomiting (P = 0.113). The ED POS patients were more likely to be transferred to a general psychiatry or eating disorder unit. Overall length of stay was greater in this group (44.6 vs. 20.4 days, P = 0.031). Initial evaluation of patients presenting with eating or weight symptoms may be difficult given similarities between the patients with primary eating disorders and those with other underlying medical causes. The medical-psychiatry unit provides comprehensive initial evaluation and treatment of patients with eating and weight symptoms.