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PubMed2006

[New licensing regulations for physicians. Main areas of reform and first results of the implementation process].

Since October 2003 medical education in Germany has been given a new more up-to-date basis, the "New Licensing Regulations for Physicians". They represent a reform of both the structure and the content of medical education making great demands on medical faculties and medical students; e.g. elective courses during the first and second cycles of the curriculum, interdisciplinary courses (so-called 'cross-sectional courses'), practical clinical courses of several weeks in five specialties, and family medicine as an option for choice during the last year are central issues of the reform. The number of state-controlled medical examinations has been reduced from four to two. It is now the responsibility of medical faculties to assess the knowledge, clinical skills and professional attitudes of students with respect to the numerous specialties which are part of medical education. This paper presents the essential innovations and describes the current state of the implementation process. It also points out problems that deserve reconsideration. Although the full implementation of the new licensing regulations is still in progress, it might be said that they have already initiated important changes in medical education in Germany.

Curriculum↗
PubMed2004

Cancer mortality in a cohort of licensed herbicide applicators.

OBJECTIVES: In order to expand our knowledge on the possible long-term health effects of exposure to herbicides, we updated the follow-up of a cohort of 1341 licensed herbicide applicators in the Netherlands. The earlier report indicated that there might be an increased risk for multiple myeloma in this group. Although that finding was statistically significant, the result was based on a small number of cases. METHODS: We expanded the follow-up from 1 January 1988 to 1 January 2001, which added 13 years to the follow-up. We now report on the causes of death of 196 exposed workers. RESULTS: Our findings indicate that licensed herbicide applicators were at an increased risk for skin cancer mortality [standardized mortality ratio (SMR)=357.4, 95% confidence interval (CI) 115.1-827.0]. It is not clear if this excess of skin cancer should be attributed to herbicide exposure or to excess exposure to sunlight.

Follow-Up Studies↗
PubMed2005

Mathematical modeling and pharmaceutical pricing: analyses used to inform in-licensing and developmental go/No-Go decisions.

In the face of significant real healthcare cost inflation, pressured budgets, and ongoing launches of myriad technology of uncertain value, payers have formalized new valuation techniques that represent a barrier to entry for drugs. Cost-effectiveness analysis predominates among these methods, which involves differencing a new technological intervention's marginal costs and benefits with a comparator's, and comparing the resulting ratio to a payer's willingness-to-pay threshold. In this paper we describe how firms are able to model the feasible range of future product prices when making in-licensing and developmental Go/No-Go decisions by considering payers' use of the cost-effectiveness method. We illustrate this analytic method with a simple deterministic example and then incorporate stochastic assumptions using both analytic and simulation methods. Using this strategic approach, firms may reduce product development and in-licensing risk.

Cost-Benefit Analysis↗
PubMed1996

Does license disqualification reduce reoffence rates?

A review was conducted of the subsequent driving records of over 25,000 Queensland drivers cited for a drink driving offence in 1988 who received at least one subsequent license restriction. The interval of follow-up was at least 3 years, average 3.9 years. Periods of driving disqualification were identified and, for each driver, the total amount of time during restricted and unrestricted driving was computed; the numbers of events, i.e. crashes and traffic offences, recorded during these periods were counted. Rates under disqualification and during legal driving, expressed per thousand person-years were derived by dividing total numbers of events by total time during which they could occur. Three categories of traffic violation were considered: drink driving offences; traffic offences unassociated with drink driving, and any offence involving driving. Since only 12% of the offenders and 9% of the reoffenders were female, detailed analyses are presented for men only; results for women were little different. Statistical inference assumed a Poisson model for crashes and a negative binomial model for offences, and analyses were performed after stratification by number of drink driving offences. Calculated rates during periods of disqualification were about one third of the rates during legal driving for crashes and all three categories of traffic offence, ranging from 25% in the case of unassociated offences to 35% for any driving offence. There were differences, some statistically significant, by age and between metropolitan, provincial city and rural regions of the State, but most were relatively minor. Drivers were apprehended more frequently earlier in the disqualification period than later. It is impossible from these data to distinguish between reduced driving levels and more cautious traffic behaviour during periods of license restriction. It is nonetheless clear that while such penalties are in operation, they substantially reduce the negative impact of convicted drink-drivers on the road. Unfortunately the data do not permit one to say whether or for how long the effect persists.

Accidents, Traffic↗
PubMed1994

Mortality study on a cohort of Italian licensed pesticide users.

This study describes the mortality experience in a cohort of 23,401 farmers, residing in southern Piedmont, Italy, and licensed to use pesticides. From 1970 to 1986 the cohort included 340,794 person-years and 2683 deaths were observed. A strong attenuation of the death risk was found due to the healthy worker effect (seen as an active role in the application for the license by the members of the cohort) and due to the limited comparability of the cohort with respect to the reference population. The standardized mortality ratios (SMRs) were remarkably < 100 for all causes (SMR = 59; 95% confidence interval = 57-61) and for all tumors (SMR = 60; 95% CI 55-64), but they increased with the increasing duration of the follow-up. A risk increase was observed with respect to melanomas and eye tumors in the entire cohort and lymphoma and tumors of the connective tissue in the subcohort of subjects living in villages with mainly arable land.

Adolescent↗
PubMed2005

Parent-imposed limits on high-risk adolescent driving: are they stricter with graduated driver licensing?

The purpose of this study was to determine whether parent-imposed limits on 16-year-old high-risk driving are stricter in Maryland (MD), a state with graduated driver licensing (GDL) than in Connecticut (CT), a non-GDL state. In both states, parents and adolescents completed telephone surveys about the restrictions that parents placed on their adolescents' driving at night, with adolescent passengers, and at high speeds. In Maryland, surveys took place 1 month (294 parent-adolescent pairs) and 4 months (292 parent-adolescent pairs) after provisional licensure. In Connecticut, surveys took place the first month (132 pairs) and the third month (108 pairs) after adolescent licensure. The findings indicated that after controlling for demographic characteristics, Maryland parents and adolescents reported stricter parent-imposed limits for adolescent passengers, high-speed roads, weekend night driving, and overall limits. Parents in GDL states appear better able to establish and enforce adolescent driving restrictions when the licensing state stipulates, favors, and supports regulated adolescent driving.

Adolescent↗
PubMed2004

"Off-license" use of recombinant activated factor VII.

Recombinant factor VIIa (rFVIIa) has been widely used in the treatment of bleeding episodes in haemophiliac patients with inhibitors. In haemostatic circles it has also been assessed in reversing oral anticoagulant therapy. Over the last few years, it has been used "off-label" in patients with uncontrolled bleeding due to haemostatic abnormalities due to trauma and/or massive blood loss, thrombocytopenia, platelet dysfunction or liver dysfunction. This review examines the proposed mechanism of action of rFVIIa in the context of current concepts of haemostasis and its pharmacological properties. The "off-license" use of rFVIIa is reviewed. The latter are reported mainly as case reports, case series. There is an overwhelming need for randomized controlled trials to assess rFVIIa's efficacy, dosing and safety in current "off-license" use.

Blood Coagulation Disorders↗
PubMed2006

Regulating the licensing of DNA replication origins in metazoa.

Eukaryotic DNA replication is a highly conserved process; the proteins and sequence of events that replicate animal genomes are remarkably similar to those that replicate yeast genomes. Moreover, the assembly of prereplication complexes at DNA replication origins ('DNA licensing') is regulated in all eukaryotes so that no origin fires more than once in a single cell cycle. And yet there are significant differences between species both in the selection of replication origins and in the way in which these origins are licensed to operate. Moreover, these differences impart advantages to multicellular animals and plants that facilitate their development, such as better control over endoreduplication, flexibility in origin selection, and discrimination between quiescent and proliferative states.

Animals↗
PubMed2004

Scc2 couples replication licensing to sister chromatid cohesion in Xenopus egg extracts.

The cohesin complex is a central player in sister chromatid cohesion, a process that ensures the faithful segregation of chromosomes in mitosis and meiosis. Previous genetic studies in yeast show that Scc2/Mis4, a HEAT-repeat-containing protein, is required for the loading of cohesin onto chromatin. In this study, we have identified two isoforms of Scc2 in humans and Xenopus (termed Scc2A and Scc2B), which are encoded by a single gene but have different carboxyl termini created by alternative splicing. Both Scc2A and Scc2B bind to chromatin concomitant with cohesin during DNA replication in Xenopus egg extracts. Simultaneous immunodepletion of Scc2A and Scc2B from the extracts impairs the association of cohesin with chromatin, leading to severe defects in sister chromatid pairing in the subsequent mitosis. The loading of Scc2 onto chromatin is inhibited in extracts treated with geminin but not with p21(CIP1), suggesting that this step depends on replication licensing but not on the initiation of DNA replication. Upon mitotic entry, Scc2 is removed from chromatin through a mechanism that requires cdc2 but not aurora B or polo-like kinase. Our results suggest that vertebrate Scc2 couples replication licensing to sister chromatid cohesion by facilitating the loading of cohesin onto chromatin.

Amino Acid Sequence↗
PubMed2005

Susceptibility patterns for amoxicillin/clavulanate tests mimicking the licensed formulations and pharmacokinetic relationships: do the MIC obtained with 2:1 ratio testing accurately reflect activity against beta-lactamase-producing strains of Haemophilus influenzae and Moraxella catarrhalis?

Amoxicillin/clavulanate has recently undergone formulation changes (XR and ES-600) that represent 14:1 and 16:1 ratios of amoxicillin/clavulanate. These ratios greatly differ from the 2:1 ratio used in initial formulations and in vitro susceptibility testing. The objective of this study was to determine if the reference method using a 2:1 ratio accurately reflects the susceptibility to the various clinically used amoxicillin/clavulanate formulations and their respective serum concentration ratios. A collection of 330 Haemophilus influenzae strains (300 beta-lactamase-positive and 30 beta-lactamase-negative) and 40 Moraxella catarrhalis strains (30 beta-lactamase-positive and 10 beta-lactamase-negative) were tested by the broth microdilution method against eight amoxicillin/clavulanate combinations (4:1, 5:1, 7:1, 9:1, 14:1, and 16:1 ratios; 0.5 and 2 microg/mL fixed clavulanate concentrations) and the minimum inhibitory concentration (MIC) results were compared with those obtained with the reference 2:1 ratio testing. For the beta-lactamase-negative strains of both genera, there was no demonstrable change in the MIC values obtained for all ratios analyzed (2:1 to 16:1). For the beta-lactamase-positive strains of H. influenzae and M. catarrhalis, at ratios >or=4:1 there was a shift in the central tendency of the MIC scatterplot compared with the results of testing 2:1 ratio. As a result, there was a 2-fold dilution increase in the MIC(50) and MIC(90) values, most evident for H. influenzae and BRO-1-producing M. catarrhalis strains. For beta-lactamase-positive strains of H. influenzae, the shift resulted in a change in the interpretive result for 3 isolates (1.0%) from susceptible using the reference method (2:1 ratio) to resistant (8/4 microg/mL; very major error) at the 16:1 ratio. In addition, the number of isolates with MIC values at or 1 dilution lower than the breakpoint (4/2 microg/mL) increased from 5% at 2:1 ratio to 32-33% for ratios 14:1 and 16:1. Our results indicate that, for the beta-lactamase-positive strains of H. influenzae and M. catarrhalis, the results of the amoxicillin/clavulanate reference 2:1 ratio testing do not accurately represent all the currently licensed formulations. Pharmacokinetic/pharmacodynamic (PK/PD) target attainment might be compromised when higher amoxicillin/clavulanate ratios are used clinically. With a better understanding of PK/PD parameters, reevaluation of the amoxicillin/clavulanate in vitro susceptibility testing should be considered by the standardizing authorities to reflect the licensed formulations and accurately predict clinical outcomes.

Amoxicillin-Potassium Clavulanate Combination↗
PubMed2005

Graduated driver licensing and teen traffic fatalities.

Over the last 8 years, nearly every state has introduced graduated driver licensing (GDL) for teens. These new licensing procedures require teen drivers to advance through distinct stages where they are subject to a variety of restrictions (e.g., adult supervision, daytime driving, passenger limits). In this study, we present evidence on whether these restrictions have been effective in reducing traffic fatalities among teens. These evaluations are based on state-by-year panel data from 1992 to 2002. We assess the reliability of our basic inferences in several ways including an examination of contemporaneous data for older cohorts who were not directly affected by these policies. Our results indicate that GDL regulations reduced traffic fatalities among 15-17-year-olds by at least 5.6%. We also find that the life-saving benefits of these regulations were plausibly related to their restrictiveness. And we find no evidence that these benefits were attenuated by an increase in fatality risks during the full-licensure period available to older teens.

Accidents, Traffic↗
PubMed2004

Effects of the California graduated driver licensing program.

PROBLEM: On July 1, 1998, in an effort to ameliorate the problem of high teenage driver crash rates, California implemented a graduated driver licensing system (GDLS). METHOD: Data on injury crashes of 16- and 17-year-old drivers from a pre-GDLS year were compared with data from two post-GDLS years. Per-capita crash rate ratios were adjusted for changes in crash rates of 25- to 34-year-old drivers, who were unaffected by the GDLS. Prevented numbers and 95% confidence intervals were estimated. RESULTS: Fatal or severe injury crash rates were significantly lower during each of the two post-GDLS years (adjusted rate ratios (RR)=0.72 and 0.83, for 2000 vs. 1997 and 2001 vs. 1997, respectively). Significant rate reductions were observed for all crash types, particularly for struck object (RR=0.71 and 0.80, for 2000 vs. 1997 and 2001 vs. 1997, respectively) and non-collision (RR=0.63 and 0.72, for 2000 vs. 1997 and 2001 vs. 1997, respectively). Minor injury crash rates were also lower during post-GDLS years (RR=0.87 and 0.90, for 2000 vs. 1997 and 2001 vs. 1997, respectively). Percent reductions were notably larger during the hours of the late night driving restriction (midnight-5 a.m.) (RR=0.79 and 0.87, for 2000 vs. 1997 and 2001 vs. 1997, respectively). SUMMARY: The implementation of the California GDLS was followed by large reductions in the rate of injury-producing motor-vehicle crashes. IMPACT ON INDUSTRY: This evaluation supports previous evidence that GDLS is an effective countermeasure to adolescent motor-vehicle crashes and their associated injuries. States with a traditional licensing system may prevent adolescent driver crashes by adopting a GDLS. Future studies should examine factors that influence teenager compliance with GDLS provisions and identify approaches to improving compliance.

Accidents, Traffic↗
PubMed2005

Graduated driver licensing research in 2004 and 2005.

This is the second update of research on graduated driver licensing (GDL) and teenage drivers. It briefly summarizes research in progress and research published since the January 2004 update (Hedlund, J. & Compton, R. [2004]. Graduated driver licensing research in 2003 and beyond. Journal of Safety Research 35(1), 5-11). Research has been very active, especially on teenage driver risk factors, GDL program evaluations, the role of parents in managing and training their teenage drivers, and driver education. Results have strengthened the case for GDL, for nighttime and passenger restrictions, and for extended supervised driving practice.

Adolescent↗
PubMed2006

Graduated driver licensing and teenage driver research in 2006.

This is the third update of research on graduated driver licensing (GDL) and related teenage driver issues. It briefly summarizes research published since or not included in the 2005 update (Hedlund, J., & Compton, R. (2005). Graduated driver licensing research in 2004 and 2005. Journal of Safety Research, 36(2), 109-119.), describes research in progress of which the authors are aware, and announces plans for a symposium on teenage driving and GDL to be held in February 2007.

Accidents, Traffic↗
PubMed2005

Expression of Ki67, PCNA and the chromosome replication licensing protein Mcm2 in glial cells of the ageing human hippocampus increases with the burden of Alzheimer-type pathology.

Cell-cycle mechanisms may be aberrantly reactivated in the ageing brain and associated with the development of pathology, including Alzheimer's disease. Activation of cell-cycle mechanisms in glia has, however, been little studied. Our aim was to determine whether expression of a marker for chromosomal replication licensing, Mcm2, occurs in glia of the ageing hippocampus, and to compare its expression to that of Ki67 and PCNA. Blocks of hippocampus were obtained from 19 elderly brains derived from the MRC-CFAS neuropathology cohort, which included a spectrum of Alzheimer-type pathology, semi-quantified using the Braak scoring system for neurofibrillary tangles. Mcm2, PCNA and Ki67 were detected immunohistochemically. Expression of Mcm2, Ki67 and PCNA was observed in glial cells and neurons, with a trend to increased expression in association with higher burdens of Alzheimer-type pathology. Mcm2 expression in glial cells showed a significant linear trend across Braak stages (P = 0.043). This study demonstrates that grey and white matter glial cells show expression of cell-cycle markers in the ageing brain and that re-licensing for chromosomal replication is a component of the mechanisms activated. A quantitative relationship to the burden of Alzheimer-type pathology suggests that cell-cycle re-entry in glial cells may be important in the pathogenesis of age-related neurodegeneration.

Aged↗
PubMed2006

The impact of incomplete vaccination schedules on the magnitude and duration of protective antigen-specific IgG responses in recipients of the US licensed anthrax vaccine.

Using a cross-sectional analysis design, we measured serum anti-protective antigen (PA) concentrations in individuals receiving six or fewer US licensed anthrax vaccinations. Samples were collected from 363 individuals with a mean of 29.6+/-8.42 months after their last vaccination (range 3-57 months). An enzyme-linked immunosorbent assay (ELISA) developed and validated by the Centers for Disease Control and Prevention (CDC) was used to evaluate the range and status of anthrax vaccine-induced serum antibody concentrations. A significant correlation (r=0.73, P< or =0.001) was found to exist between the number of vaccinations received and specific anti-PA immunoglobulin G (IgG) concentrations. We observed two discrete groups comprised of one to three doses (5.9-11.7 microg/ml) and four to six doses (26.2-30.2 microg/ml). These data indicate that anti-PA IgG is present at low but detectable levels after as few as two vaccinations (5.9+/-6.43 microg/ml). These findings may have significance for anthrax vaccine recipients who are unable to complete the primary or full regimen with this licensed product.

Anthrax↗
PubMed2005

Enhanced immunogenicity and protective effect conferred by vaccination with combinations of modified vaccinia virus Ankara and licensed smallpox vaccine Dryvax in a mouse model.

Significant adverse events are associated with vaccination with the currently licensed smallpox vaccine. Candidate new-generation smallpox vaccines such as the replication-defective modified vaccinia virus Ankara (MVA) produce very few adverse events in experimental animals and in limited human clinical trials conducted near the end of the smallpox eradication campaign. Efficacy evaluation of such new-generation vaccines will be extraordinarily complex, however, since the eradication of smallpox precludes a clinical efficacy trial and the correlates of protection against smallpox are unknown. A combination of relevant animal efficacy studies along with thorough comparative immunogenicity studies between traditional and new-generation smallpox vaccines will be necessary for vaccine licensure. In the present study, a variety of immune responses elicited by MVA and the licensed smallpox vaccine Dryvax in a murine model were compared, with a focus on mimicking conditions and strategies likely to be employed in human vaccine trials. Immunization of mice with MVA, using several relevant vaccination routes including needle-free delivery, elicited humoral and cellular immune responses qualitatively similar to those elicited by vaccination with Dryvax. Similar levels of vaccinia-specific IgG and neutralizing antibody were elicited by Dryvax and MVA when higher doses (approximately 1 log) of MVA were used for immunization. Antibody levels peaked at about 6 weeks post-immunization and remained stable for at least 15 weeks. A booster immunization of either MVA or Dryvax following an initial priming immunization with MVA resulted in an enhanced IgG titer and neutralizing antibody response. In addition, both Dryvax and various MVA vaccination protocols elicited antibody responses to the extracellular enveloped form of the virus and afforded protection against a lethal intranasal challenge with vaccinia virus WR.

Animals↗
PubMed2004

Cell cycle regulation of the licensing activity of Cdt1 in Xenopus laevis.

Cdt1 is a conserved replication factor required in licensing the chromosome for a single round of DNA synthesis. The activity of Cdt1 is inhibited by geminin. The mechanism by which geminin interferes with Cdt1 activity is unknown. It is thought that geminin binds to and sequestrate Cdt1. We show that geminin does not interfere with the chromatin association of Cdt1 and that inhibition of DNA synthesis by geminin is observed following its accumulation on chromatin. The binding of geminin to chromatin has been investigated during S phase. We demonstrate that loading of geminin onto chromatin requires Cdt1, suggesting that geminin is targeted at replication origins. We also show that geminin binds chromatin at the transition from the pre-replication to pre-initiation complexes, which overlaps with the release of Cdt1. This regulation is strikingly different from that observed in somatic cells where the chromatin binding of these proteins is mutually exclusive. In contrast to somatic cells, we further show that geminin is stable during the early embryonic cell cycles. These results suggest a specific regulation of origin firing adapted to the rapid cell cycles of Xenopus and indicate that periodic degradation of geminin is not relevant to licensing during embryonic development.

Animals↗