Does the EU's Paediatric Regulation work for new medicines for children in Denmark, Finland, Norway and Sweden? : A cross-sectional study

Objective The aim of this study was to assess the marketing status of the new paediatric medicinal products listed in the 10-year report as initially authorised between 2007 and 2016, reflecting the product availability in four Nordic countries. Design This is a cross-sectional study. Setting Analysis of the national medicine agency's databases in Denmark, Finland, Norway and Sweden. Data source New medicinal products with paediatric indications and new paediatric formulations listed in the Annex of European Medicines Agency's EU Paediatric Regulation 10-year report. Data analysis The products were classified according to national marketing status between January 2019 and March 2019, whether a product was authorised and whether the product was marketed. Main outcome measures The percentages of the new medicinal products with paediatric indications and new paediatric formulations having a valid marketing authorisation and being marketed, both in terms of the sums of all countries and separately for each country. Results Across the four countries, 21%-32% (16/76-24/76) of the new medicinal products were not marketed. Of the new formulations relevant to children, 29%-50% (16/56-28/56) were not marketed, and a significant proportion of these products had never been marketed. Conclusions This study reflects the reality of the implementation of the Paediatric Regulation. The results show that several new paediatric medicines and new formulations are not marketed. This affects the product availability. Similar data from other countries are needed to evaluate the overall European status to find remedies to current situation and increase the availability of the medicines for children. ©Peer reviewe

Treatment of proximal humerus fractures in the elderly : A systematic review of 409 patients

Background and purpose - There is no consensus on the treatment of proximal humerus fractures in the elderly. Patients and methods - We conducted a systematic search of the medical literature for randomized controlled trials and controlled clinical trials from 1946 to Apr 30, 2014. Predefined PICOS criteria were used to search relevant publications. We included randomized controlled trials involving 2- to 4-part proximal humerus fractures in patients over 60 years of age that compared operative treatment to any operative or nonoperative treatment, with a minimum of 20 patients in each group and a minimum follow-up of 1 year. Outcomes had to be assessed with functional or disability measures, or a quality-of-life score. Results - After 2 independent researchers had read 777 abstracts, 9 publications with 409 patients were accepted for the final analysis. No statistically significant differences were found between nonoperative treatment and operative treatment with a locking plate for any disability, for quality-of-life score, or for pain, in patients with 3- or 4-part fractures. In 4-part fractures, 2 trials found similar shoulder function between hemiarthroplasty and nonoperative treatment. 1 trial found slightly better health related quality of life (higher EQ-5D scores) at 2-year follow-up after hemiarthroplasty. Complications were common in the operative treatment groups (10-29%). Interpretation - Nonoperative treatment over locking plate systems and tension banding is weakly supported. 2 trials provided weak to moderate evidence that for 4-part fractures, shoulder function is not better with hemiarthroplasty than with nonoperative treatment. 1 of the trials provided limited evidence that health-related quality of life may be better at 2-year follow-up after hemiarthroplasty. There is a high risk of complications after operative treatment.Peer reviewe

Operative versus non-operative treatment for 2-part proximal humerus fracture: A multicenter randomized controlled trial

Background Although increasingly used, the benefit of surgical treatment of displaced 2-part proximal humerus fractures has not been proven. This trial evaluates the clinical effectiveness of surgery with locking plate compared with non-operative treatment for these fractures. Methods and findings The NITEP group conducted a superiority, assessor-blinded, multicenter randomized trial in 6 hospitals in Finland, Estonia, Sweden, and Denmark. Eighty-eight patients aged 60 years or older with displaced (more than 1 cm or 45 degrees) 2-part surgical or anatomical neck proximal humerus fracture were randomly assigned in a 1:1 ratio to undergo either operative treatment with a locking plate or non-operative treatment. The mean age of patients was 72 years in the non-operative group and 73 years in the operative group, with a female sex distribution of 95% and 87%, respectively. Patients were recruited between February 2011 and April 2016. The primary outcome measure was Disabilities of Arm, Shoulder, and Hand (DASH) score at 2-year follow-up. Secondary outcomes included Constant–Murley score, the visual analogue scale for pain, the quality of life questionnaire 15D, EuroQol Group’s 5- dimension self-reported questionnaire EQ-5D, the Oxford Shoulder Score, and complications. The mean DASH score (0 best, 100 worst) at 2 years was 18.5 points for the operative treatment group and 17.4 points for the non-operative group (mean difference 1.1 [95% CI −7.8 to 9.4], p = 0.81). At 2 years, there were no statistically or clinically significant between-group differences in any of the outcome measures. All 3 complications resulting in secondary surgery occurred in the operative group. The lack of blinding in patient-reported outcome assessment is a limitation of the study. Our assessor physiotherapists were, however, blinded. Conclusions This trial found no significant difference in clinical outcomes at 2 years between surgery and non-operative treatment in patients 60 years of age or older with displaced 2-part fractures of the proximal humerus. These results suggest that the current practice of performing surgery on the majority of displaced proximal 2-part fractures of the humerus in older adults may not be beneficial. Trial registration ClinicalTrials.gov NCT01246167.Peer reviewe

Remote Ischemic Preconditioning Protects the Brain Against Injury After Hypothermic Circulatory Arrest

Background-Ischemic preconditioning (IPC) is a mechanism protecting tissues from injury during ischemia and reperfusion. Remote IPC (RIPC) can be elicited by applying brief periods of ischemia to tissues with ischemic tolerance, thus protecting vital organs more susceptible to ischemic damage. Using a porcine model, we determined whether RIPC of the limb is protective against brain injury caused by hypothermic circulatory arrest (HCA).Methods and Results-Twelve piglets were randomized to control and RIPC groups. RIPC was induced in advance of cardiopulmonary bypass by 4 cycles of 5 minutes of ischemia of the hind limb. All animals underwent cardiopulmonary bypass followed by 60 minutes of HCA at 18 degrees C. Brain metabolism and electroencephalographic activity were monitored for 8 hours after HCA. Assessment of neurological status was performed for a week postoperatively. Finally, brain tissue was harvested for histopathological analysis.Study groups were balanced for baseline and intraoperative parameters. Brain lactate concentration was significantly lower (P < 0.0001, ANOVA) and recovery of electroencephalographic activity faster (P < 0.05, ANOVA) in the RIPC group. RIPC had a beneficial effect on neurological function during the 7-day follow-up (behavioral score; P < 0.0001 versus control, ANOVA). Histopathological analysis demonstrated a significant reduction in cerebral injury in RIPC animals (injury score; mean [interquartile range]: control 5.8 [3.8 to 7.5] versus RIPC 1.5 [0.5 to 2.5], P < 0.001, t test).Conclusions-These data demonstrate that RIPC protects the brain against HCA-induced injury, resulting in accelerated recovery of neurological function. RIPC might be neuroprotective in patients undergoing surgery with HCA and improve long-term outcomes. Clinical trials to test this hypothesis are warranted. (Circulation. 2011; 123: 714-721.

Depression in Primary care: Interpersonal Counseling vs Selective serotonin reuptake inhibitors. The DEPICS Study. A multicenter randomized controlled trial. Rationale and design

<p>Abstract</p> <p>Background</p> <p>Depression is a frequently observed and disabling condition in primary care, mainly treated by Primary Care Physicians with antidepressant drugs. Psychological interventions are recommended as first-line treatment by the most authoritative international guidelines but few evidences are available on their efficacy and effectiveness for mild depression.</p> <p>Methods/Design</p> <p>This multi-center randomized controlled trial was conducted in 9 Italian centres with the aim to compare the efficacy of Inter-Personal Counseling, a brief structured psychological intervention, to that of Selective Serotonin Reuptake Inhibitors. Patients with depressive symptoms referred by Primary Care Physicians to psychiatric consultation-liaison services were eligible for the study if they met the DSM-IV criteria for major depression, had a score ≥13 on the 21-item Hamilton Depression Rating Scale, and were at their first or second depressive episode. The primary outcome was remission of depressive symptoms at 2-months, defined as a HDRS score ≤ 7. Secondary outcome measures were improvement in global functioning and recurrence of depressive symptoms at 12-months. Patients who did not respond to Inter-Personal Counseling or Selective Serotonin Reuptake Inhibitors at 2-months received augmentation with the other treatment.</p> <p>Discussion</p> <p>This trial addresses some of the shortcomings of existing trials targeting major depression in primary care by evaluating the comparative efficacy of a brief psychological intervention that could be easily disseminated, by including a sample of patients with mild/moderate depression and by using different outcome measures.</p> <p>Trial registration</p> <p>Australian New Zealand Clinical Trials Registry ACTRN12608000479303</p

Placebo Response of Non-Pharmacological and Pharmacological Trials in Major Depression: A Systematic Review and Meta-Analysis

Background: Although meta-analyses have shown that placebo responses are large in Major Depressive Disorder (MDD) trials; the placebo response of devices such as repetitive transcranial magnetic stimulation (rTMS) has not been systematically assessed. We proposed to assess placebo responses in two categories of MDD trials: pharmacological (antidepressant drugs) and non-pharmacological (device- rTMS) trials. Methodology/Principal Findings: We performed a systematic review and meta-analysis of the literature from April 2002 to April 2008, searching MEDLINE, Cochrane, Scielo and CRISP electronic databases and reference lists from retrieved studies and conference abstracts. We used the keywords placebo and depression and escitalopram for pharmacological studies; and transcranial magnetic stimulation and depression and sham for non-pharmacological studies. All randomized, double-blinded, placebo-controlled, parallel articles on major depressive disorder were included. Forty-one studies met our inclusion criteria - 29 in the rTMS arm and 12 in the escitalopram arm. We extracted the mean and standard values of depression scores in the placebo group of each study. Then, we calculated the pooled effect size for escitalopram and rTMS arm separately, using Cohen's d as the measure of effect size. We found that placebo response are large for both escitalopram (Cohen's d - random-effects model - 1.48; 95%C.I. 1.26 to 1.6) and rTMS studies (0.82; 95%C.I. 0.63 to 1). Exploratory analyses show that sham response is associated with refractoriness and with the use of rTMS as an add-on therapy, but not with age, gender and sham method utilized. Conclusions/Significance: We confirmed that placebo response in MDD is large regardless of the intervention and is associated with depression refractoriness and treatment combination (add-on rTMS studies). The magnitude of the placebo response seems to be related with study population and study design rather than the intervention itself

Intraobserver and interobserver reliability of recategorized Neer classification in differentiating 2-part surgical neck fractures from multi-fragmented proximal humeral fractures in 116 patients

Background: Optimal fracture classification should be simple and reproducible and should guide treatment. For proximal humeral. fractures, the Neer classification is commonly used. However, intraobserver and interobserver reliability of the Neer classification has been shown to be poor. In clinical practice. it is essential to differentiate 2-part surgical neck fractures from multi-fragmented fractures. Thus, the aim of this study was to evaluate whether surgeons can differentiate 2-part surgical neck fractures from multifragmented fractures using plain radiographs and/or computed tomography (CT). Methods: Three experienced upper limb specialists and trauma surgeons (B.O.S., A.P.L., and V.L.) independently reviewed and classified blinded plain radiographs and CT scans of 116 patients as showing 2-part surgical neck fractures or multi-fragmented fractures. Each imaging modality was reviewed and classified separately by each surgeon, after which each surgeon reviewed both modalities at the same time. This process was repeated by all surgeons after 24 weeks. Intraobserver and interobserver analyses were conducted using Cohen and Reiss K values, respectively. Results: The K coefficient for interobserver reliability showed substantial correlation (0.61-0.73) and was as follows: 0.73 for radiographs alone, 0.61 for CT scans alone, and 0.72 for radiographs and CT scans viewed together. After 24 weeks, the process was repeated and intraobserver reliability was calculated.The K coefficient for intraobserver reliability showed substantial correlation (0.62-0.75) and was as follows: 0.62 for radiographs alone, 0.64 for CT scans alone, and 0.75 for radiographs and CT scans viewed together. Conclusion: Clinicians were able to differentiate 2-part surgical neck fractures from multi-fragmented fractures based on plain radiographs reliably. (C) 2018 The Author(s).Peer reviewe

Distal Biceps Tendon Rupture Surgery : Changing Incidence in Finnish and Swedish Men Between 1997 and 2016

Purpose Distal biceps tendon rupture is a relatively rare injury usually occurring with excess external extension force applied to a flexed elbow. The aim of this study was to examine the incidence of distal biceps tendon rupture surgery in the Finnish and Swedish adult population between the years 1997 and 2016. A secondary aim was to investigate the distal biceps rupture incidence in the Swedish population in 2001 to 2016. Methods We assessed the number and rate of distal biceps tendon rupture surgery using the Finnish and Swedish Hospital Discharge Register as databases. The study included the entire Finnish and Swedish adult population aged 18 years and older between January 1, 1997 and of December 31, 2016. Results During the study period, 2,029 patients had a distal biceps tendon rupture in Finland, and the corresponding figure was 2,000 in Sweden. The rate of distal biceps tendon rupture surgery increased steeply, but equally, in both countries, in Finnish men from 1.3 per 100,000 person-years in 1997 to 9.6 in 2016, and in Swedish men from 0.2 in 1997 to 5.6 in 2016. The incidence of distal biceps tendon rupture in Sweden increased in men from 1.6 to 10.0 per 100,000 person-years from 2001 to 2016. Conclusions There was a 7-fold and a 28-fold increase in the incidence of distal biceps tendon rupture surgery in Finnish and Swedish men during 1997 to 2016. The incidence of distal biceps tendon rupture rose 6-fold in Swedish men in 2001 to 2016. Copyright (C) 2020 by the American Society for Surgery of the Hand. Published by Elsevier Inc.Peer reviewe