Efficacy and Safety of Appropriate Shocks and Antitachycardia Pacing in Transvenous and Subcutaneous Implantable Defibrillators: Analysis of All Appropriate Therapy in the PRAETORIAN Trial.

BACKGROUND: The PRAETORIAN trial (A Prospective, Randomized Comparison of Subcutaneous and Transvenous Implantable Cardioverter Defibrillator Therapy) showed noninferiority of subcutaneous implantable cardioverter defibrillator (S-ICD) compared with transvenous implantable cardioverter defibrillator (TV-ICD) with regard to inappropriate shocks and complications. In contrast to TV-ICD, S-ICD cannot provide antitachycardia pacing for monomorphic ventricular tachycardia. This prespecified secondary analysis evaluates appropriate therapy and whether antitachycardia pacing reduces the number of appropriate shocks. METHODS: The PRAETORIAN trial was an international, investigator-initiated randomized trial that included patients with an indication for implantable cardioverter defibrillator (ICD) therapy. Patients with previous ventricular tachycardia <170 bpm or refractory recurrent monomorphic ventricular tachycardia were excluded. In 39 centers, 849 patients were randomized to receive an S-ICD (n=426) or TV-ICD (n=423) and were followed for a median of 49.1 months. ICD programming was mandated by protocol. Appropriate ICD therapy was defined as therapy for ventricular arrhythmias. Arrhythmias were classified as discrete episodes and storm episodes (≥3 episodes within 24 hours). Analyses were performed in the modified intention-to-treat population. RESULTS: In the S-ICD group, 86 of 426 patients received appropriate therapy, versus 78 of 423 patients in the TV-ICD group, during a median follow-up of 52 months (48-month Kaplan-Meier estimates 19.4% and 17.5%; P=0.45). In the S-ICD group, 83 patients received at least 1 shock, versus 57 patients in the TV-ICD group (48-month Kaplan-Meier estimates 19.2% and 11.5%; P=0.02). Patients in the S-ICD group had a total of 254 shocks, compared with 228 shocks in the TV-ICD group (P=0.68). First shock efficacy was 93.8% in the S-ICD group and 91.6% in the TV-ICD group (P=0.40). The first antitachycardia pacing attempt successfully terminated 46% of all monomorphic ventricular tachycardias, but accelerated the arrhythmia in 9.4%. Ten patients with S-ICD experienced 13 electrical storms, versus 18 patients with TV-ICD with 19 electrical storms. Patients with appropriate therapy had an almost 2-fold increased relative risk of electrical storms in the TV-ICD group compared with the S-ICD group (P=0.05). CONCLUSIONS: In this trial, no difference was observed in shock efficacy of S-ICD compared with TV-ICD. Although patients in the S-ICD group were more likely to receive an ICD shock, the total number of appropriate shocks was not different between the 2 groups. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01296022.

Device-related complications in subcutaneous versus transvenous ICD: a secondary analysis of the PRAETORIAN trial.

BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (S-ICD) is developed to overcome lead-related complications and systemic infections, inherent to transvenous ICD (TV-ICD) therapy. The PRAETORIAN trial demonstrated that the S-ICD is non-inferior to the TV-ICD with regard to the combined primary endpoint of inappropriate shocks and complications. This prespecified secondary analysis evaluates all complications in the PRAETORIAN trial. METHODS AND RESULTS: The PRAETORIAN trial is an international, multicentre, randomized trial in which 849 patients with an indication for ICD therapy were randomized to receive an S- ICD (N = 426) or TV-ICD (N = 423) and followed for a median of 49 months. Endpoints were device-related complications, lead-related complications, systemic infections, and the need for invasive interventions. Thirty-six device-related complications occurred in 31 patients in the S-ICD group of which bleedings were the most frequent. In the TV-ICD group, 49 complications occurred in 44 patients of which lead dysfunction was most frequent (HR: 0.69; P = 0.11). In both groups, half of all complications were within 30 days after implantation. Lead-related complications and systemic infections occurred significantly less in the S-ICD group compared with the TV-ICD group (P < 0.001, P = 0.03, respectively). Significantly more complications required invasive interventions in the TV-ICD group compared with the S-ICD group (8.3% vs. 4.3%, HR: 0.59; P = 0.047). CONCLUSION: This secondary analysis shows that lead-related complications and systemic infections are more prevalent in the TV-ICD group compared with the S-ICD group. In addition, complications in the TV-ICD group were more severe as they required significantly more invasive interventions. This data contributes to shared decision-making in clinical practice.

Six-lead device superior to single-lead smartwatch ECG in atrial fibrillation detection.

This was a head-to-head comparative study on different electrocardiogram (ECG)-based smartwatches and devices for atrial fibrillation detection. We prospectively included 220 patients scheduled for electrical cardioversion and recorded ECGs with 3 different devices (Withings Move ECG, Apple Watch 5, Kardia Mobile 6-leads) as well as the standard 12-lead ECG (gold standard), both before and after cardioversion. All atrial fibrillation detection algorithms had high accuracy (sensitivity and specificity: 91-99%) but were hampered by uninterpretable recordings (20-24%). In cardiologists' interpretation, the 6-lead device was superior (sensitivity 99%, specificity 97%) to both single-lead smartwatches (P < .05) for atrial fibrillation detection.

The European TeleCheck-AF project on remote app-based management of atrial fibrillation during the COVID-19 pandemic: centre and patient experiences.

AIMS: TeleCheck-AF is a multicentre international project initiated to maintain care delivery for patients with atrial fibrillation (AF) during COVID-19 through teleconsultations supported by an on-demand photoplethysmography-based heart rate and rhythm monitoring app (FibriCheck®). We describe the characteristics, inclusion rates, and experiences from participating centres according the TeleCheck-AF infrastructure as well as characteristics and experiences from recruited patients. METHODS AND RESULTS: Three surveys exploring centre characteristics (n = 25), centre experiences (n = 23), and patient experiences (n = 826) were completed. Self-reported patient characteristics were obtained from the app. Most centres were academic (64%) and specialized public cardiology/district hospitals (36%). Majority of the centres had AF outpatient clinics (64%) and only 36% had AF ablation clinics. The time required to start patient inclusion and total number of included patients in the project was comparable for centres experienced (56%) or inexperienced in mHealth use. Within 28 weeks, 1930 AF patients were recruited, mainly for remote AF control (31% of patients) and AF ablation follow-up (42%). Average inclusion rate was highest during the lockdown restrictions and reached a steady state at a lower level after easing the restrictions (188 vs. 52 weekly recruited patients). Majority (>80%) of the centres reported no problems during the implementation of the TeleCheck-AF approach. Recruited patients [median age 64 (55-71), 62% male] agreed that the FibriCheck® app was easy to use (94%). CONCLUSION: Despite different health care settings and mobile health experiences, the TeleCheck-AF approach could be set up within an extremely short time and easily used in different European centres during COVID-19.

Training-Induced Functional Gains following SCI.

We previously demonstrated that daily, hour-long training sessions significantly improved both locomotor (limb kinematics, gait, and hindlimb flexor-extensor bursting patterns) and nonlocomotor (bladder function and at-level mechanical allodynia) functions following a moderate contusive spinal cord injury. The amount of training needed to achieve this recovery is unknown. Furthermore, whether this recovery is induced primarily by neuronal activity below the lesion or other aspects related to general exercise is unclear. Therefore, the current study objectives were to (1) test the efficacy of 30 minutes of step training for recovery following a clinically relevant contusion injury in male Wistar rats and (2) test the efficacy of training without hindlimb engagement. The results indicate that as little as 30 minutes of step training six days per week enhances overground locomotion in male rats with contusive spinal cord injury but does not alter allodynia or bladder function. Thirty minutes of forelimb-only exercise did not alter locomotion, allodynia, or bladder function, and neither training protocol altered the amount of in-cage activity. Taken together, locomotor improvements were facilitated by hindlimb step training for 30 minutes, but longer durations of training are required to affect nonlocomotor systems.

Flood risk assessments at different spatial scales.

Managing flood risk, i.e. both the hazard and the potential consequences, is an important aspect of adapting to global change and has gained much traction in recent decades. As a result, a priori flood risk assessments have become an important part of flood management practices. Many methodologies have been set up, ranging from global risk assessments for the world as a whole, to local assessments for a particular stretch of a river/coast or small town. Most assessment frameworks generally follow a similar approach, but there are also notable differences between assessments at different spatial scales. This review article examines these differences, for instance those related to the methodology, use of assessments and uncertainties. From this review, future research needs are identified in order to improve flood risk assessments at different scales. At global/continental scale, there is a clear need for harmonised information on flood defences to improve assessments. Furthermore, inclusions of indirect economic effects at the macro-/meso-scale would give a better indication of the total effects of catastrophic flooding. At the meso-/micro-scale, there is an urgent need to improve our understanding of the effects of flooding on critical infrastructures, given their importance to society, the economy, emergency management and reconstruction. An overarching theme at all scales is the validation of flood risk assessments, which is often limited. More detailed post-disaster information would allow for improved calibration, validation and thus performance of flood risk models. Lastly, the link between spatial scales also deserves attention, for instance up- or downscaling methodologies.

Uncertainty and Bias in Global to Regional Scale Assessments of Current and Future Coastal Flood Risk.

This study provides a literature-based comparative assessment of uncertainties and biases in global to world-regional scale assessments of current and future coastal flood risks, considering mean and extreme sea-level hazards, the propagation of these into the floodplain, people and coastal assets exposed, and their vulnerability. Globally, by far the largest bias is introduced by not considering human adaptation, which can lead to an overestimation of coastal flood risk in 2100 by up to factor 1300. But even when considering adaptation, uncertainties in how coastal societies will adapt to sea-level rise dominate with a factor of up to 27 all other uncertainties. Other large uncertainties that have been quantified globally are associated with socio-economic development (factors 2.3-5.8), digital elevation data (factors 1.2-3.8), ice sheet models (factor 1.6-3.8) and greenhouse gas emissions (factors 1.6-2.1). Local uncertainties that stand out but have not been quantified globally, relate to depth-damage functions, defense failure mechanisms, surge and wave heights in areas affected by tropical cyclones (in particular for large return periods), as well as nearshore interactions between mean sea-levels, storm surges, tides and waves. Advancing the state-of-the-art requires analyzing and reporting more comprehensively on underlying uncertainties, including those in data, methods and adaptation scenarios. Epistemic uncertainties in digital elevation, coastal protection levels and depth-damage functions would be best reduced through open community-based efforts, in which many scholars work together in collecting and validating these data.

The photoplethysmography dictionary: practical guidance on signal interpretation and clinical scenarios from TeleCheck-AF.

Aims: Within the TeleCheck-AF project, numerous centres in Europe used on-demand photoplethysmography (PPG) technology to remotely assess heart rate and rhythm in conjunction with teleconsultations. Based on the TeleCheck-AF investigator experiences, we aimed to develop an educational structured stepwise practical guide on how to interpret PPG signals and to introduce typical clinical scenarios how on-demand PPG was used. Methods and results: During an online conference, the structured stepwise practical guide on how to interpret PPG signals was discussed and further refined during an internal review process. We provide the number of respective PPG recordings (FibriCheck®) and number of patients managed within a clinical scenario during the TeleCheck-AF project. To interpret PPG recordings, we introduce a structured stepwise practical guide and provide representative PPG recordings. In the TeleCheck-AF project, 2522 subjects collected 90 616 recordings in total. The majority of these recordings were classified by the PPG algorithm as sinus rhythm (57.6%), followed by AF (23.6%). In 9.7% of recordings, the quality was too low to interpret. The most frequent clinical scenarios where PPG technology was used in the TeleCheck-AF project was a follow-up after AF ablation (1110 patients) followed by heart rate and rhythm assessment around (tele)consultation (966 patients). Conclusion: We introduce a newly developed structured stepwise practical guide on PPG signal interpretation developed based on presented experiences from TeleCheck-AF. The present clinical scenarios for the use of on-demand PPG technology derived from the TeleCheck-AF project will help to implement PPG technology in the management of AF patients.

Cleavage of amyloid beta peptide during constitutive processing of its precursor.

The amyloid beta peptide (A beta P) is a small fragment of the much larger, broadly distributed amyloid precursor protein (APP). Abundant A beta P deposition in the brains of patients with Alzheimer's disease suggests that altered APP processing may represent a key pathogenic event. Direct protein structural analyses showed that constitutive processing in human embryonic kidney 293 cells cleaves APP in the interior of the A beta P, thus preventing A beta P deposition. A deficiency of this processing event may ultimately prove to be the etiological event in Alzheimer's disease that gives rise to senile plaque formation.

Modeling growth factor activity during proinflammatory stress: methodological considerations in assessing cytokine modulation of IGF binding proteins released by cultured bovine kidney epithelial cells.

The present research was conducted to model potential mechanisms through which IGFBPs might be affected by a key proinflammatory response initiating cytokine tumor necrosis factor (TNF-)-alpha. Madin-Darby bovine kidney epithelial (MDBK) cells, known to release IGFBPs in response to several stimuli, were grown under several conditions and challenged with forskolin (F) or recombinant TNF-alpha for 24h. Forskolin increased IGFBP-3 gene expression and media content of BP-3 protein. TNF-alpha increased basal and augmented F-mediated IGFBP-3 gene expression. However, TNF-alpha effects on the measurable media content of IGFBPs were influenced by culture conditions; in the absence of added protease inhibitors (PIs) or sufficient media albumin concentration (high BSA, 1mg/ml), the effect of TNF-alpha was to decrease (P<0.02) measurable IGFBPs. In the presence of PI and high BSA, media IGFBP-3 levels were shown to be increased by TNF-alpha consistent with the gene expression data. Changes in media IGFBP-3 protease activity were examined further to explain the observed effects of TNF-alpha on production and destruction of IGFBPs in media. When recombinant human IGFBP-3 (500 ng/ml) was added to PI-free, low BSA 100 microg/ml) media from TNF-treated MDBK cells, less than 10% of the BP-3 was recognizable by Western blot in 30 min; conversely, inclusion of High BSA and PI in media resulted in attenuation of the protease effect on the IGFBPs. The data suggest that the MDBK model of cellular response to proinflammatory stimulus is affected by culture conditions and that TNF-alpha affects media content of IGFBPs through effects on IGFBP gene expression coupled with degradation of IGFBPs via enhanced proteolytic enzyme release.

Water scarcity hotspots travel downstream due to human interventions in the 20th and 21st century.

Water scarcity is rapidly increasing in many regions. In a novel, multi-model assessment, we examine how human interventions (HI: land use and land cover change, man-made reservoirs and human water use) affected monthly river water availability and water scarcity over the period 1971-2010. Here we show that HI drastically change the critical dimensions of water scarcity, aggravating water scarcity for 8.8% (7.4-16.5%) of the global population but alleviating it for another 8.3% (6.4-15.8%). Positive impacts of HI mostly occur upstream, whereas HI aggravate water scarcity downstream; HI cause water scarcity to travel downstream. Attribution of water scarcity changes to HI components is complex and varies among the hydrological models. Seasonal variation in impacts and dominant HI components is also substantial. A thorough consideration of the spatially and temporally varying interactions among HI components and of uncertainties is therefore crucial for the success of water scarcity adaptation by HI.

The world's road to water scarcity: shortage and stress in the 20th century and pathways towards sustainability.

Water scarcity is a rapidly growing concern around the globe, but little is known about how it has developed over time. This study provides a first assessment of continuous sub-national trajectories of blue water consumption, renewable freshwater availability, and water scarcity for the entire 20th century. Water scarcity is analysed using the fundamental concepts of shortage (impacts due to low availability per capita) and stress (impacts due to high consumption relative to availability) which indicate difficulties in satisfying the needs of a population and overuse of resources respectively. While water consumption increased fourfold within the study period, the population under water scarcity increased from 0.24 billion (14% of global population) in the 1900s to 3.8 billion (58%) in the 2000s. Nearly all sub-national trajectories show an increasing trend in water scarcity. The concept of scarcity trajectory archetypes and shapes is introduced to characterize the historical development of water scarcity and suggest measures for alleviating water scarcity and increasing sustainability. Linking the scarcity trajectories to other datasets may help further deepen understanding of how trajectories relate to historical and future drivers, and hence help tackle these evolving challenges.

The inheritance of metabolic flux: expressions for the within-sibship mean and variance given the parental genotypes.

Recent developments have related quantitative trait expression to metabolic flux. The present paper investigates some implications of this for statistical aspects of polygenic inheritance. Expressions are derived for the within-sibship genetic mean and genetic variance of metabolic flux given a pair of parental, diploid, n-locus genotypes. These are exact and hold for arbitrary numbers of gene loci, arbitrary allelic values at each locus, and for arbitrary recombination fractions between adjacent gene loci. The within-sibship, genetic variance is seen to be simply a measure of parental heterozygosity plus a measure of the degree of linkage coupling within the parental genotypes. Approximations are given for the within-sibship phenotypic mean and variance of metabolic flux. These results are applied to the problem of attaining adequate statistical power in a test of association between allozymic variation and inter-individual variation in metabolic flux. Simulations indicate that statistical power can be greatly increased by augmenting the data with predictions and observations on progeny statistics in relation to parental allozyme genotypes. Adequate power may thus be attainable at small sample sizes, and when allozymic variation is scored at a only small fraction of the total set of loci whose catalytic products determine the flux.

Exploitation of phylogenetic distance in cell surface immune labeling: studies with beta 2-microglobulin.

Beta 2-microglobulin (beta 2M) is part of the HLA molecule, and is found on the cell surface of human nucleated cells. In certain skin tumors, malignant change has been associated with a loss of this surface beta 2M, indicating a possible diagnostic value for this marker. At present beta 2M is best identified in paraffin-embedded tissue by means of a triple-layer peroxidase-antiperoxidase technique, using mammalian polyclonal antisera. Recently a polyclonal antiserum against human beta 2M has been produced in chickens. Because of the phylogenetic differences between the species, the resulting antiserum is likely to recognize more epitopes on the beta 2M and show greater sensitivity than antisera raised in mammalian species. To confirm this hypothesis, the avian antiserum was compared to both mammalian polyclonal (rabbit) and monoclonal (mouse) antibody in vitro. beta 2M fixed to plastic surfaces combined with more avian than mammalian antibody. Furthermore, insolubilized chicken antibody could bind more secondary antibody-horseradish peroxidase conjugate than could insolubilized mammalian antibody, thus showing even greater enhancement with this system. Immunohistochemical analysis of these systems confirmed that the chicken strategy has greater sensitivity, and can be used in an indirect system with consequent reduction in nonspecific background activity. It is the most suitable technique for the investigation of the distribution of beta 2M in paraffin-embedded tissue.

Associated peptides isolated from human seminal fluid containing beta 2-microglobulin determinants.

Proteins in human semen that react with a monoclonal mouse antibody to human beta 2-microglobulin (h beta 2M) have been isolated using immunoaffinity chromatography. As well as material of the same size as h beta 2M, a peptide of approximately 18000 kdaltons was isolated. It is suggested that this substance either contains h beta 2-M sequences itself or, as is more likely, is non-covalently associated with an h beta 2M-like peptide chain.

Biochemistry and pharmacology of 7alpha-substituted androstenediones as aromatase inhibitors.

The inhibition of aromatase, the enzyme responsible for converting androgens to estrogens, is therapeutically useful for the endocrine treatment of hormone-dependent breast cancer. Research by our laboratory has focused on developing competitive and irreversible steroidal aromatase inhibitors, with an emphasis on synthesis and biochemistry of 7alpha-substituted androstenediones. Numerous 7alpha-thiosubstituted androst-4-ene-3,17-diones are potent competitive inhibitors, and several 1,4-diene analogs, such as 7alpha-(4'-aminophenylthio)-androsta-1,4-diene-3,17-di one (7alpha-APTADD), have demonstrated effective enzyme-activated irreversible inhibition of aromatase in microsomal enzyme assays. One focus of current research is to examine the effectiveness and biochemical pharmacology of 7alpha-APTADD in vivo. In the hormone-dependent 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary carcinoma model system, 7alpha-APTADD at a 50 mg/kg/day dose caused an initial decrease in mean tumor volume during the first week, and tumor volume remained unchanged throughout the remaining 5-week treatment period. This agent lowers serum estradiol levels and inhibits ovarian aromatase activity. A second research area has focused on the synthesis of more metabolically stable inhibitors by replacing the thioether linkage at the 7alpha position with a carbon-carbon linkage. Several 7alpha-arylaliphatic androst-4-ene-3,17-diones were synthesized by 1,6-conjugate additions of appropriate organocuprates to a protected androst-4,6-diene or by 1,4-conjugate additions to a seco-A-ring steroid intermediate. These compounds were all potent inhibitors of aromatase with apparent Kis ranging between 13 and 19 nM. Extension of the research on these 7alpha-arylaliphatic androgens includes the introduction of a C1-C2 double bond in the A-ring to provide enzyme-activated irreversible inhibitors. The desired 7alpha-arylaliphatic androsta-1,4-diene-3,17-diones were obtained from their corresponding 7alpha-arylaliphatic androst-4-ene-3,17-diones by oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). These inhibitors demonstrated enzyme-mediated inactivation of aromatase with apparent k(inact)s ranging from 4.4 x 10(-4) to 1.90 x 10(-3) s(-1). The best inactivator of the series was 7alpha-phenpropylandrosta-1,4-diene-3,17-dione, which exhibited a T(1/2) of 6.08 min. Aromatase inhibition was also observed in MCF-7 human mammary carcinoma cell cultures and in JAr human choriocarcinoma cell cultures, exhibiting IC50 values of 64-328 nM. The 7alpha-arylaliphatic androgens thus demonstrate potent inhibition of aromatase in both microsomal incubations and in choriocarcinoma cell lines expressing aromatase enzymatic activity. Additionally, the results from these studies provide further evidence for the presence of a hydrophobic binding pocket existing near the 7alpha-position of the steroid in the active site of aromatase. The size of the 7alpha-substituent influences optimal binding of steroidal inhibitors to the active site and affects the extent of enzyme-mediated inactivation observed with androsta-1,4-diene-3,17-dione analogs.

A double-blind comparison of meptazinol versus paracetamol and placebo in acute and chronic painful conditions presented to the general practitioner.

A double-blind study was carried out in 90 patients with acute or chronic painful musculoskeletal conditions of at least moderate severity to compare the effectiveness over a 72-hour period of oral treatment, 3 to 6 hourly, with 200 mg meptazinol, 1 g paracetamol and placebo. Assessments of pain by physicians and patients indicated that both active treatments produced effective analgesia compared with placebo. No significant differences were observed between meptazinol and paracetamol. The frequency of adverse effects reported was low and similar in all three treatment groups.

Verapamil SR and propranolol LA: a comparison of efficacy and side effects in the treatment of mild to moderate hypertension.

The efficacy, safety and toleration of sustained release verapamil (Securon SR, Knoll) and long acting propranolol (Inderal LA, ICI) in the treatment of mild to moderate hypertension were compared in a randomized, double-blind, parallel group study. Both drugs were of similar efficacy and were well tolerated in the majority of patients. However, in the verapamil SR treated group side-effects resulted in significantly fewer drug-related withdrawals.

The progression of an infundibulum to aneurysm formation and rupture: case report and literature review.

OBJECTIVE AND IMPORTANCE: Infundibula (IFs) are funnel-shaped symmetrical enlargements that occur at the origins of cerebral arteries and are apparent on 7 to 25% of otherwise normal angiograms. They are frequently considered as normal anatomic variants of no pathogenic significance. CLINICAL PRESENTATION: We report the case of a ruptured posterior communicating artery aneurysm that had developed at the site of a previously known IF in a 49-year-old hypertensive woman. She had a poor conscious level at admission, with widespread subarachnoid hemorrhage and obstructive hydrocephalus. INTERVENTION: The patient was immediately ventilated, and an external ventricular drain was inserted. The aneurysm was successfully clipped; however, secondary hemorrhage occurred both before and during craniotomy. She developed marked hypernatremia and subsequently died. CONCLUSION: This is the 11th case of IF-to-aneurysm progression reported. It suggests that in certain cases, serial investigations may be indicated with IFs to detect aneurysm formation and preempt rupture.

Overtaking road-accidents: differences in manoeuvre as a function of driver age.

Nine-hundred and seventy-three police road-accident files describing overtaking accidents were sampled from the headquarters of Nottinghamshire Constabulary, England, for the years 1989-1993. Salient facts were extracted from each case, including the exact manoeuvre involved, the principle explanatory factors, the driver(s) most at fault, and the drivers' ages. Two kinds of reliability measure for case interpretations. indicated high levels of consistency. Two induced exposure measures were used, comparing driver involvement in a given type of overtaking accident with involvement in overtaking accidents in general, and comparing the age profiles of the drivers most at fault with those of the other drivers involved. Ten types of overtaking accident were distinguished, and three are discussed in detail: collision with a right-turning vehicle (the most common injury-accident for overtakers), which tends to occur either because a young driver makes a faulty overtaking decision, or an older driver makes a faulty right turn; head-on collision, which affects all age groups roughly in proportion to exposure; and the 'return-and-lose-control' accident, which is associated particularly with young drivers. The study illustrates the 'structured judgement method' of accident causation research, in which human interpreters are used to ascribe causes and processes to individual cases, but orthodox research techniques are used to standardise procedures, and to assess and ensure reliability.