Exploring the causes of adverse events in hospitals and potential prevention strategies

Objectives To examine the causes of adverse events (AEs) and potential prevention strategies to minimise the occurrence of AEs in hospitalised patients. Methods For the 744 AEs identified in the patient record review study in 21 Dutch hospitals, trained reviewers were asked to select all causal factors that contributed to the AE. The results were analysed together with data on preventability and consequences of AEs. In addition, the reviewers selected one or more prevention strategies for each preventable AE. The recommended prevention strategies were analysed together with four general causal categories: technical, human, organisational and patient-related factors. Results Human causes were predominantly involved in the causation of AEs (in 61% of the AEs), 61% of those being preventable and 13% leading to permanent disability. In 39% of the AEs, patient-related factors were involved, in 14% organisational factors and in 4% technical factors. Organisational causes contributed relatively often to preventable AEs (93%) and AEs resulting in permanent disability (20%). Recommended strategies to prevent AEs were quality assurance/peer review, evaluation of safety behaviour, training and procedures. For the AEs with human and patient-related causes, reviewers predominantly recommended quality assurance/peer review. AEs caused by organisational factors were considered preventable by improving procedures. Discussion Healthcare interventions directed at human causes are recommended because these play a large role in AE causation. In addition, it seems worthwhile to direct interventions on organisational causes because the AEs they cause are nearly always believed to be preventable. Organisational factors are thus relatively easy to tackle. Future research designs should allow researchers to interview healthcare providers that were involved in the event, as an additional source of information on contributing factors.

Standardising neonatal and paediatric antibiotic clinical trial design and conduct: the PENTA-ID network view.

Antimicrobial development for children remains challenging due to multiple barriers to conducting randomised clinical trials (CTs). There is currently considerable heterogeneity in the design and conduct of paediatric antibiotic studies, hampering comparison and meta-analytic approaches. The board of the European networks for paediatric research at the European Medicines Agency (EMA), in collaboration with the Paediatric European Network for Treatments of AIDS-Infectious Diseases network (www.penta-id.org), recently developed a Working Group on paediatric antibiotic CT design, involving academic, regulatory and industry representatives. The evidence base for any specific criteria for the design and conduct of efficacy and safety antibiotic trials for children is very limited and will evolve over time as further studies are conducted. The suggestions being put forward here are based on the adult EMA guidance, adapted for neonates and children. In particular, this document provides suggested guidance on the general principles of harmonisation between regulatory and strategic trials, including (1) standardised key inclusion/exclusion criteria and widely applicable outcome measures for specific clinical infectious syndromes (CIS) to be used in CTs on efficacy of antibiotic in children; (2) key components of safety that should be reported in paediatric antibiotic CTs; (3) standardised sample sizes for safety studies. Summarising views from a range of key stakeholders, specific criteria for the design and conduct of efficacy and safety antibiotic trials in specific CIS for children have been suggested. The recommended criteria are intended to be applicable to both regulatory and clinical investigator-led strategic trials and could be the basis for harmonisation in the design and conduct of CTs on antibiotics in children. The next step is further discussion internationally with investigators, paediatric CTs networks and regulators

Physicians' Experiences as Patients with Statin Side Effects: A Case Series.

Physicians are among those prescribed statins and therefore, subject to potential statin adverse effects (AEs). There is little information on the impact of statin AEs on physicians affected by them. We sought to assess the character and impact of statin AEs occurring in physicians and retired physicians, and to ascertain whether/how personal experience of AEs moderated physicians' attitude toward statin use. Seven active or retired physicians from the United States communicated with the Statin Effects Study group regarding their personal experience of statin AEs. AE characteristics, experience with (their own) physicians, and impact of AE was ascertained. We inquired whether or how their experience altered their own attitude toward statins or statin AEs. Patient A: Atorvastatin 40 then 80 mg was followed by cognitive problems, neuropathy, and glucose intolerance in a Radiologist in his 50s (Naranjo criteria: probable causality). Patient B: Atorvastatin 10 mg was followed in 2 months by muscle weakness and myalgia in an Internist in his 40s (probable causality). Patient C: Atorvastatin, ezetimibe/simvastatin, rosuvastatin at varying doses was followed shortly after by irritability, myalgia, and fatigue in a Cardiac Surgeon in his 40s (probable causality). Patient D: Simvastatin 20 then 40 mg was followed in 4 years by mitochondriopathy, myopathy, neuropathy, and exercise intolerance in an Emergency Medicine physician in his 50s (definite causality). Patient E: Simvastatin 20 mg and niacin 1000 mg was followed in one month by muscle weakness and myalgia in a Physical Medicine and Rehabilitation physician in his 50s (probable causality). Patient F: Lovastatin 20 mg then simvastatin 20 mg, atorvastatin 20 mg, rosuvastatin 5 mg, niacin 20 mg and ezetimbe 10 mg was followed by muscle weakness and myalgia in an Obstetrician/Gynecologist in his 70s (definite causality). Patient G: Ezetimibe/simvastatin and atorvastatin (dose unavailable) was followed shortly after by cognitive problems in a Radiologist in her 80s (probable causality). Thus AEs affected multiple quality-of-life relevant domains, often in combination, encompassing muscle (N = 5), fatigue (N = 2), peripheral neuropathy (N = 2), cognitive (N = 2), dysglycemia (N = 1) and behavioral manifestations (N = 1). In five, the AEs affected the physician professionally. Five physicians experienced dismissive attitudes in some of their own healthcare encounters. One noted that his experience helped not only his own attention to statin AEs, but that of other physicians in his community. Several stated that their experience altered their understanding of and/or attitude toward statin AEs, and/or their view of settings in which statin use is warranted. Statin AEs can have profound impact in high functioning professionals with implications to the individual, their professional life, and those whom they serve professionally

The addition of bevacizumab to standard chemotherapy in breast cancer : which patient benefits the most?

Bevacizumab, a humanized monoclonal antibody directed against vascular endothelial growth factor, is an effective and well-tolerated treatment option for patients with breast cancer. Bevacizumab has demonstrated a gain in progression-free survival and a trend towards an overall survival benefit in various subgroups of breast cancer. Given the lack of a predictive biomarker, we performed a literature search with regard to efficacy and tolerability of bevacizumab in different subgroups of breast cancer patients and in different settings. In the metastatic setting, the efficacy of bevacizumab has been most extensively studied and demonstrated in patients with triple-negative breast cancer, the most difficult-to-treat population among patients with advanced disease and also the group with the biggest need for new treatment options. Overall, bevacizumab is well tolerated with very few serious adverse events. Bevacizumab is also an active and feasible treatment option for patients above 70 years of age

Comparison of insulin detemir and insulin glargine in a Basal-Bolus regimen, with insulin aspart as the mealtime insulin, in patients with type 1 diabetes: A 52-week, multinational, randomized, open-label, parallel-group, treat-to-target noninferiority trial

Objective: The primary study objective was to determine whether insulin detemir (detemir) was noninferior to insulin glargine (glargine) as the basal insulin in a basal-bolus regimen, with insulin aspart as the mealtime insulin, in terms of glycemic control at the end of 52 weeks in patients with type I diabetes mellitus (T1DM). Methods: This multinational, open-label, parallel-group, treat-to-target, noninferiority trial enrolled patients aged >= 18 years who had had T1DM for at least 12 months, had been taking a basal-bolus insulin regimen for at least 3 months, and had a glycosylated hemoglobin (HbA(1c)) value <= 11.0% at screening. Patients were randomized in a 2:1 ratio to receive either detemir or glargine for 52 weeks. The basal insulin was initially administered once daily (in the evening) in both groups; if patients in the detemir group were achieving the plasma glucose (PG) target before breakfast but not before dinner, they were switched to twice-daily administration. Glargine was administered once daily throughout the trial, according to its approved labeling. Each patient attended 13 study visits and received 16 scheduled telephone calls from the trial site. The primary efficacy end point was glycemic control (HbA(1c)) after 52 weeks of treatment. Secondary end points included the number of patients achieving an HbAlc value <= 7.0%, with or without a major hypoglycemic episode in the last month of treatment; fasting PG (FPG); within-patient variation in self-monitored plasma glucose (SMPG) before breakfast and dinner; and 10-point SMPG profiles. The noninferiority margin was 0.4%, consistent with US Food and Drug Administration guidelines. Results: Four hundred forty-three patients (mean [SD] age, 42 [12] years; body mass index, 26.5 [4.0] kg/m(2); duration of diabetes, 17.2 [11.4] years; HbA(1c), 8.1% [1.1%]) received study treatment. After 52 weeks, the estimated mean HbA(1c) did not differ significantly between the detemir and glargine groups (7.57% and 7.56%, respectively; mean difference, 0.01%; 95% CI -0.13 to 0.16), consistent with the noninferiority of detemir to glargine. The corresponding estimated changes in HbA(1c) were -0.53% and -0.54%. In the 90 patients who completed the trial on once-dally detemir and the 173 patients who completed the trial on twice-daily detemir, the estimated changes in HbA(1c) were-0.49% and -0.58%, respectively. After 52 weeks, there were no significant differences in the proportions of those receiving detemir and glargine who achieved an HbA(1c) value <= 7.0% without major hypo-glycemia (31.9% and 28.9%, respectively). In addition, there were no significant differences in estimated mean FPG (8.58 and 8.81 rnmol/L; mean difference, -0.23 mmol/L; 95% CI, -1.04 to 0.58) or in basal insulin doses. The basal insulin dose was numerically higher in patients receiving detemir twice rather than once daily (0.47 vs 0.33 U/kg, respectively). The relative risks for total and nocturnal hypoglycemia with detemir versus glargine were 0.94 and 1.12, respectively (both, P = NS). Six patients (2.0%) randomized to the detemir group and 4 (2.7%) randomized to the glargine group withdrew due to adverse events. Conclusions: During 52 weeks of basal-bolus therapy in patients with T1DM, detemir was noninferior to glargine in terms of overall glycemic control (HbA(1c)). When used according to the approved labeling, detemir and glargine did not differ in tolerability or in terms of the occurrence of hypoglycemia. (Clin Ther. 2009; 31:2086-2097) (C) 2009 Excerpta Medica Inc

Everolimus dosing recommendations for tuberous sclerosis complex–associated refractory seizures

ObjectiveThe present analysis examined the exposure-response relationship by means of the predose everolimus concentration (C-min) and the seizure response in patients with tuberous sclerosis complex-associated seizures in the EXIST-3 study. Recommendations have been made for the target C-min range of everolimus for therapeutic drug monitoring (TDM) and the doses necessary to achieve this target C-min

Marginal Farmers and Agri-Environmental Schemes: Evaluating Policy Design Adequacy for the Environmental Fallow Measure

This paper examines the factors affecting farmer's participation in an agri-environmental scheme (AES) in marginal areas implying few changes in the traditional farm management (environmental fallow). The enrolment theoretical micro-economic model reveals that farmers` (extrinsic) factors as well as decision maker's (intrinsic) factors are important for farmer's participation, without disregarding the role of social capital. The farm and farmer characteristics (intrinsic factors) as well as the influence of the social capital have been tested trough the specification and estimation of an adoption model for dry-land marginal farmers in Granada (southern Spain). 300 farmers with cereal dry-land specialization have been surveyed in order to identify factors influencing their enrolment decision and to derive scheme design modifications to improve the AES success, understood as participation rate. Due to the fact that the effects of applying this measure do not have significant effect on the food and animal production, the participation decision is hypothesized to be mainly driven by the farmer's attitude reflecting the importance of the social capital in order to educate farmers. Nevertheless, AES interaction with other agricultural policies, such as LFA compensatory payments, restraints the possibility of this scheme's success specially when these payments imply greater financial resources. Further research is needed to see whether this same pattern holds when considering AES implying a more intensive change in the farm management.Agri-environmental policy, participation, marginal areas, policy design, Environmental Economics and Policy,

Nightly treatment of primary insomnia with prolonged release melatonin for 6 months: a randomized placebo controlled trial on age and endogenous melatonin as predictors of efficacy and safety

&lt;p&gt;Background: Melatonin is extensively used in the USA in a non-regulated manner for sleep disorders. Prolonged release melatonin (PRM) is licensed in Europe and other countries for the short term treatment of primary insomnia in patients aged 55 years and over. However, a clear definition of the target patient population and well-controlled studies of long-term efficacy and safety are lacking. It is known that melatonin production declines with age. Some young insomnia patients also may have low melatonin levels. The study investigated whether older age or low melatonin excretion is a better predictor of response to PRM, whether the efficacy observed in short-term studies is sustained during continued treatment and the long term safety of such treatment.&lt;/p&gt; &lt;p&gt;Methods: Adult outpatients (791, aged 18-80 years) with primary insomnia, were treated with placebo (2 weeks) and then randomized, double-blind to 3 weeks with PRM or placebo nightly. PRM patients continued whereas placebo completers were re-randomized 1:1 to PRM or placebo for 26 weeks with 2 weeks of single-blind placebo run-out. Main outcome measures were sleep latency derived from a sleep diary, Pittsburgh Sleep Quality Index (PSQI), Quality of Life (World Health Organzaton-5) Clinical Global Impression of Improvement (CGI-I) and adverse effects and vital signs recorded at each visit.&lt;/p&gt; &lt;p&gt;Results: On the primary efficacy variable, sleep latency, the effects of PRM (3 weeks) in patients with low endogenous melatonin (6-sulphatoxymelatonin [6-SMT] ≤8 μg/night) regardless of age did not differ from the placebo, whereas PRM significantly reduced sleep latency compared to the placebo in elderly patients regardless of melatonin levels (-19.1 versus -1.7 min; P = 0.002). The effects on sleep latency and additional sleep and daytime parameters that improved with PRM were maintained or enhanced over the 6-month period with no signs of tolerance. Most adverse events were mild in severity with no clinically relevant differences between PRM and placebo for any safety outcome.&lt;/p&gt; &lt;p&gt;Conclusions: The results demonstrate short- and long-term efficacy and safety of PRM in elderly insomnia patients. Low melatonin production regardless of age is not useful in predicting responses to melatonin therapy in insomnia. The age cut-off for response warrants further investigation.&lt;/p&gt