Use, timing and outcome of coronary angiography in patients with high-risk non-ST-segment elevation acute coronary syndrome in daily clinical practice: insights from a 'real world' prospective registry.

BACKGROUND: An early invasive strategy (EIS) is recommended in high-risk patients with non-ST-elevation acute coronary syndrome (NSTE-ACS), defined as coronary angiography (CAG), within 24 h of admission. The aim of the present study is to investigate guideline adherence, patient characteristics associated with timing of the intervention and clinical outcome. METHODS: In a prospective registry, the use and timing of CAG and the characteristics and clinical outcome associated with timing were evaluated in high-risk ACS patients. The outcome of early versus delayed invasive strategy (DIS) was compared. RESULTS: Between 2006 and 2014, 2,299 high-risk NSTE-ACS patients were included. The use of CAG increased from 77% in 2006 to 90% in 2014 (p trend <0.001) together with a decrease of median time to CAG from 23.3 to 14.5 h (p trend <0.001) and an increase of patients undergoing EIS from 50 to 60% (p trend = 0.002). Patient factors independently related to DIS were higher GRACE risk score, higher age and the presence of comorbidities. No difference was found in incidence of mortality, reinfarction or bleeding at 30-day follow-up. All-cause mortality at 1­year follow-up was 4.1% vs 7.0% in EIS and DIS respectively (hazard ratio 1.67, 95% confidence interval 1.12-2.49) but was comparable after adjustment for confounding factors. CONCLUSION: The percentage of high-risk NSTE-ACS patients undergoing CAG and EIS has increased in the last decade. In contrast to the guidelines, patients with a higher risk profile are less likely to undergo EIS. However, no difference in outcome after 30 days and 1 year was found after multivariate adjustment for this higher risk.

Is risk-taking in talented junior tennis players related to overuse injuries?

Overuse injuries are a serious problem in junior tennis. Gaining insight in age-specific risk factors can contribute to prevention. The developmental cognitive processes that take place during adolescence make talented players more inclined to take risks. This may be even more pronounced in the high performance culture in which they move. Therefore, this study focuses on the relationship between risk-taking and overuse injuries in talented tennis players. Seventy-three talented tennis players (45 boys and 28 girls, age 11-14 years) were monitored for 32 weeks, using the Oslo Sports Trauma Research Centre Questionnaire on Health Problems. Risk-taking was measured at the start of the season with the Iowa Gambling Task. Linear regression analyses were executed to predict (a) overuse injuries, (b) time loss overuse injuries and (c) overuse severity, by risk-taking, exposure time, and injury history. In boys, risk-taking contributed significantly to time loss overuse injuries [F(1,39) = 7.764, P = 0.008, R2  = 0.15] and to overuse severity [F(1,39) = 5.683, P = 0.022, with an R2 of 0.13] In girls, time loss overuse injuries [F(1,23) = 6.889, P = 0.018, R2  = 0.20] and overuse severity [F(1,23) = 7.287, P = 0.013, R2  = 0.24] were predicted by exposure time. Coaches and trainers should be aware that talented male tennis players who are inclined to take risks, are more likely to maintain risky behavioral patterns related to overuse injuries.

Anthropometric Injury Risk Factors in Elite-standard Youth Soccer.

The aim of the study was to investigate whether an increased risk of injury occurrence can be determined through frequent anthropometric measurements in elite-standard youth soccer players. Over the course of one season, we followed 101 male elite-standard youth soccer players between 11 and 19 years of age. Height and body mass were monitored at monthly measurement intervals and fat percentage was assessed every 3 months by use of the sum of skinfold method. Growth in height (cm), alternations in body mass index (kg/m(2)), fat percentage and fat-free mass index (kg/m(2)) were calculated. Injuries were recorded in accordance with the recommendations of the FIFA Consensus Model for Injury Registration. Odds ratio scores and 95% confidence intervals were calculated using binary logistic regression analyses. The following anthropometric injury risk factors were identified: ≥ 0.6 centimeter growth per month (p=0.03; OR=1.63; 95% CI: 1.06-2.52), ≥ 0.3 kg/m(2) increase of body mass index value per month (p=0.03; OR=1.61; 95% CI: 1.04-2.49) and low fat percentage; i. e., < 7% for players aged 11-16 and < 5% for players over 16 years (p=0.01; OR=1.81; 95% CI: 1.18-2.76). Individual monitoring of anthropometrics provides useful information to determine increased risk of injury occurrence in elite-standard youth soccer.

Importance of peak height velocity timing in terms of injuries in talented soccer players.

The purpose of this study was to identify differences in traumatic and overuse injury incidence between talented soccer players who differ in the timing of their adolescent growth spurt. 26 soccer players (mean age 11.9 ± 0.84 years) were followed longitudinally for 3 years around Peak Height Velocity, calculated according to the Maturity Offset Protocol. The group was divided into an earlier and later maturing group by median split. Injuries were registered following the FIFA consensus statement. Mann-Whitney tests showed that later maturing players had a significantly higher overuse injury incidence than their earlier maturing counterparts both in the year before Peak Height Velocity (3.53 vs.0.49 overuse injuries/1 000 h of exposure,U = 49.50, z = − 2.049, p < 0.05) and the year of Peak Height Velocity (3.97 vs. 1.56 overuse injuries/1 000 h of exposure, U = 50.5, z = − 1.796,p < 0.05). Trainers and coaches should be careful with the training and match load they put on talented soccer players, especially those physically not (yet) able to handle that load. Players appear to be especially susceptible to injury between 13.5 and 14.5 years of age. Training and match load should be structured relative to maturity such that athletic development is maximized and the risk of injury is minimized.

Sport injuries aligned to peak height velocity in talented pubertal soccer players.

In young athletes, demands of sports are superimposed on normal growth and maturation. It has been suggested that this causes a temporarily increased vulnerability for injuries. We followed 26 talented soccer players (mean age 11.9±0.84 years) longitudinally for 3 years around their adolescent growth spurt, called Peak Height Velocity, to identify differences in number of traumatic and overuse injuries and days missed due to injuries. Peak Height Velocity was calculated according to the Maturity Offset Protocol. The number of injuries was calculated for each player per year. A repeated measurement analysis showed that athletes had significantly more traumatic injuries in the year of Peak Height Velocity (1.41) than in the year before Peak Height Velocity (0.81). A moderate effect size of 0.42 was found for the difference in number of overuse injuries per player per year before (0.81) and after Peak Height Velocity (1.41), respectively. Finally, a moderate effect size of 0.55 was found for difference between days missed due to injuries before (7.27 days per player per year) and during Peak Height Velocity (15.69 days per player per year). Adolescent growth spurt seems to result in increased vulnerability for traumatic injuries. Afterwards athletes seem to be susceptible to overuse injuries.

Psychosocial factors influencing the recovery of athletes with anterior cruciate ligament injury: a systematic review.

This review describes the psychosocial factors that affect recovery following anterior cruciate ligament (ACL) injury and reconstructive surgery in athletes. A systematic search in literature with inclusion and exclusion criteria on PubMed, PsycINFO, and Embase was performed. Articles used in this review were divided in five different parts according to the biopsychosocial model of Wiese-Bjornstal, with the addition of intervention studies. The results showed that a high internal Health Locus of Control and a high self-efficacy were useful cognitive factors to facilitate the recovery. Athletes with a low level of fear of reinjury had the best knee outcome after the injury followed by a reconstruction. In addition, athletes who returned to sport had less fear of reinjury and were more experienced and established athletes compared with athletes who did not return to sport. Furthermore, researchers showed that there was a positive relation between goal setting and adherence, which in turn yielded a positive relation with the outcome of the rehabilitation of an ACL injury. There were several psychosocial interventions that appeared to be facilitating the rehabilitation process.

Taking immunogenicity assessment of therapeutic proteins to the next level.

Therapeutic proteins provide innovative and effective therapies for numerous diseases. However, some of these products are associated with unwanted immunogenicity that may lead to clinical consequences such as reduced or loss of efficacy, altered pharmacokinetics (PK), general immune and hypersensitivity reactions, and neutralisation of the natural counterpart (e.g. the physiological hormone). Regulatory guidance on immunogenicity assessment needs to take into consideration a great diversity of products, indications and patient populations as well as constantly advancing manufacturing technologies. Such guidance needs to be sufficiently specific while, at the same time, allowing interactive discussion and adjusted benefit-risk weighing of each product on a case-by-case basis, e.g. for a unique treatment of a life threatening disease acceptable treatment risks may differ considerably from the ones in case of less serious disease. This theme was the focus of the international conference "Taking immunogenicity assessment of therapeutic proteins to the next level", held at the Paul-Ehrlich-Institut in Langen, Germany, on the 10-11. June 2010. The objectives of the conference were to highlight how the field could move from that of a mere description of risk factors to a system of risk assessment and mitigation, as well as an understanding of the impact of unwanted immunogenicity on the overall benefit/risk consideration for a medicinal product. More than 150 experts from industry, academia and regulatory authorities worldwide discussed the phenomenon of undesired immunogenicity from different perspectives. The conference focussed on issues relevant to three areas: (1) new European guidelines that are currently the subject of discussion; (2) testing strategies for immunogenicity assessment; and (3) scientific progress on the product-related factors that may contribute to the development of pathogenesis of immunogenicity, in particular in the field of protein aggregation and post-translational modifications. This report provides an overview of issues, insights, and conclusions that were discussed and achieved during the meeting.

Miltefosine treatment of Leishmania major infection: an observational study involving Dutch military personnel returning from northern Afghanistan.

In a retrospective, observational study involving 34 patients with Leishmania major infection, 31 of whom had experienced unsuccessful treatment with intralesional antimony (ilSb(v)), miltefosine proved effective. Thirty patients experienced cure after receipt of miltefosine, 3 after receipt of additional ilSb(v), and 1 after 28 daily intravenous injections of antimony. Temporary diminution of ejaculate volume was reported by 21 patients.

Sub-visible particle quantitation in protein therapeutics.

Biologics represent a large and growing segment of the therapeutic medicinal market. Sub-visible particles present in these products are a product quality attribute and a potential patient safety concern yet to be fully explored. Early and consistent particle quantitation and control throughout the product life cycle of these drugs from development to commercial lot release is critical in mitigating any concerns. This requires appropriate analytical methods which can be applied to biopharmaceuticals across a large variety of protein concentrations and modes of administration. The compendial light obscuration method for quantitating sub-visible particles in small volume parenterals is not ideally suited for therapeutic biologics. Approaches to modify the current compendial method so that it is applicable to biologics, including appropriate sample preparation, reduced assay sample volume, increased sizing information, and development of an appropriate sampling plan, are presented in this article. Successful applications of a modified light obscuration method to therapeutic protein products are demonstrated, and a strategy to utilise complimentary methods and techniques at different phases of product development is discussed.

Predictors of course in obsessive-compulsive disorder: logistic regression versus Cox regression for recurrent events.

OBJECTIVE: Two methods for predicting remissions in obsessive-compulsive disorder (OCD) treatment are evaluated. Y-BOCS measurements of 88 patients with a primary OCD (DSM-III-R) diagnosis were performed over a 16-week treatment period, and during three follow-ups. METHOD: Remission at any measurement was defined as a Y-BOCS score lower than thirteen combined with a reduction of seven points when compared with baseline. Logistic regression models were compared with a Cox regression for recurrent events model. RESULTS: Logistic regression yielded different models at different evaluation times. The recurrent events model remained stable when fewer measurements were used. Higher baseline levels of neuroticism and more severe OCD symptoms were associated with a lower chance of remission, early age of onset and more depressive symptoms with a higher chance. CONCLUSION: Choice of outcome time affects logistic regression prediction models. Recurrent events analysis uses all information on remissions and relapses. Short- and long-term predictors for OCD remission show overlap.

Detection, measurement and characterization of unwanted antibodies induced by therapeutic biologicals.

Assessment of the unwanted immunogenicity of therapeutic biologicals in recipients is an important consideration in the evaluation of these medicinal products. Proper planning of immunogenicity studies with appropriately devised strategies is critical if valid and meaningful conclusions concerning the unwanted immunogenicity are to be derived. An essential requisite for such studies is the need for conducting carefully selected and validated procedures. Several techniques are available for detection, characterization and measurement of antibodies elicited in an immune response. These include various formats of immunoassays, surface plasmon resonance and biological assays. None of these assays alone can provide sufficient information on the characteristics of the induced antibodies. A combination of methods is therefore usually necessary for a detailed understanding of the quantity and type(s) of antibodies generated against a therapeutic product. This manuscript considers the benefits and limitations of the various techniques available for antibody detection and outlines a brief strategy for the assessment of unwanted immunogenicity of therapeutic products.

An overview of scientific and regulatory issues for the immunogenicity of biological products.

Immunogenicity of biological products can occur pre-clinically and clinically when products elicit immune responses in animals or humans receiving the products. This is a concern for manufacturers, regulatory agencies and clinicians as immune responses can result in effects on product effectiveness and safety. The clinical sequelae of immunogenicity range from no effects to serious, life-threatening syndromes. However, although many biological products are immunogenic to some extent, it is quite rare that immunogenicity leads to serious adverse events. Whilst there are methods to detect immunogenicity, they currently rely on detecting the humoral rather than the cellular response of the immune system. The design and validation of assays such as immuno-assays and bio-assays are critical for a meaningful assessment of immunogenicity. There are a growing number of computational and laboratory-based methods for the prediction of immunogenicity, as well as methods to reduce potential immunogenicity and these may lead to less immunogenic biological products in future.

Standardization of antibody preparations for use in immunogenicity studies: a case study using the World Health Organization International Collaborative Study for Islet Cell Antibodies.

The immunogenicity of biological therapeutic products is currently a high profile regulatory and biotechnology industry issue. The immune responses raised against biotechnology products range from the benign, to affecting product efficacy, to those that have serious deleterious clinical impact. The most widely used marker of immunogenicity is the detection and measurement of antibody responses induced in vivo to a product. This relies on assays that are sensitive and robust. In order to assess the parameters of an assay during its design, development and validation, it is extremely useful to have a reference standard to compare assay results. However, immune responses lead to polyclonal antibody preparations that can vary by affinity and avidity. This makes it extremely difficult to select a preparation that will behave similarly in different test systems and against different antibody samples. The case example of the WHO standardization of islet cell antibodies illustrates the difficulties in the process and the mechanisms required to produce a suitable antibody standard.

Immune responses to therapeutic proteins in humans--clinical significance, assessment and prediction.

There is a large and increasing number of therapeutic proteins approved for clinical use and many more undergoing preclinical studies and clinical trials in humans. Most of them are human or 'humanized' recombinant molecules. Virtually all therapeutic proteins elicit some level of antibody response, which in some cases, can lead to potentially serious side effects. Therefore, immunogenicity of therapeutic proteins is a concern for clinicians, manufacturers and regulatory agencies. In order to assess immunogenicity of these molecules, appropriate detection, quantitation and characterization of antibody responses are necessary. Immune responses to therapeutic proteins in conventional animal models has not been, except in rare cases, predictive of the response in humans. In recent years there has been a considerable progress in development of computational methods for prediction of epitopes in protein molecules that have the potential to induce an immune response in a recipient. Initial attempts to apply such tools in early development of therapeutic proteins have already been reported. It is expected that computer driven prediction followed by in vitro and/or in vivo testing of any potentially immunogenic epitopes will help in avoiding, or at least minimizing, immune responses to therapeutic proteins.

How to diagnose cardiac tamponade.

Malignant pericardial effusion is a potentially fatal complication of malignancy unless recognised and treated promptly. Patients with this condition are often difficult to diagnose. Physical examination, chest radiography and electrocardiography have poor diagnostic values in identification of patients with pericardial effusion. Echocardiography, which allows rapid confirmation of the presence of an effusion and precise assessment of its haemodynamic impact, is the gold standard for diagnosis.

Challenges with current technology for the detection, measurement and characterization of antibodies against biological therapeutics.

The primary concern with immunogenicity of biological products for manufacturers, regulatory agencies and clinicians is whether antibodies produced by patients receiving the product have clinical sequelae. However, the assessment of this concern is entirely dependent on the appropriate detection, measurement and characterisation of antibodies against biological therapeutics. The current assays for antibodies in biological fluids are prone to a wide range of technical difficulties in addition to scientific challenges in their interpretation. Problems such as matrix effects, selecting controls, antibody affinity, neutralizing capacity, antigen presentation and antigen/antibody complexes all require consideration in the design of antibody assays. Following the design of antibody assays, rigorous validation must be carried out to assure that the results they produce are meaningful. The relevance of quantitative measurement is particularly difficult to assess, as is the comparability of assay results between laboratories. Therefore considerable care is required in the design, execution, analysis and interpretation of antibody assays.

Setting specifications for potency assays--basic principles.

To develop any biological therapeutic successfully, it is necessary to characterise the product thoroughly, both physicochemically and biologically. To ensure that consistency of production is maintained, some level of control is required to limit the variability of the product from batch to batch. This premise forms the basis of specification setting. The biological activity or potency of the product must be appropriately assessed through a functional assay unless specifically justified otherwise e.g. for binding proteins where binding has been correlated with biological activity. Biological assays are particularly prone to assay variability and therefore it is necessary to design and execute the assay to reduce variability as much as possible while providing a statistically valid measure of the reproducibility of potency estimates. Therefore, specifications for potency should only be derived following establishment of a well validated and controlled bioassay and should include some measure of the variability of the estimate in addition to the actual potency estimate itself. The limits applied to those specifications need to reflect the true batch to batch consistency of the product, its nature and toxicity as well as its intended use.