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To evaluate whether an educational intervention based on collegial discussions on patient cases could increase interns’ professional confidence in prescribing. In a randomized controlled study at Sahlgrenska University Hospital, Gothenburg, Sweden, 69 interns (median age: 29 years, 54% female) were allocated to an intervention or control group. The intervention consisted of two 3-h seminars based on collegial discussions of patient cases focused on performing medication reviews. This included reconciling the drug treatment and ascertaining that it is reasonable given the patient’s current health status, as well as tips on practical handling of the medical records system and integrated decision support. Self-assessed confidence in performing medication reviews was evaluated with questionnaires distributed at baseline and at 6-month follow-up. Fifty-seven (83%) interns completed the questionnaires. Although the opposite was found at baseline, intervention interns, in comparison with controls, at follow-up, were more confident in performing medication reviews (4.3 ± 0.9 vs. 3.6 ± 1.3, P = 0.034; 1 = completely disagree to 5 = completely agree). At follow-up, the intervention participants had increased their confidence in prescribing to a greater extent compared with the control participants, including performing medication reviews as well as taking responsibility for the medication list at discharge: + 1.5/+ 1 vs ± 0 on the 5-point agreement scale (all P ≤ 0.01). Among other positive outcomes, the intervention increased the interns’ awareness of adverse effects as a potential cause of symptoms and their confidence in withdrawing a medication. Structured collegial discussions on pharmacotherapy, even of a relatively short duration, can increase junior physicians’ professional confidence in prescribing medicines.

Background and purpose Aneurysmal subarachnoid haemorrhage (aSAH) is associated with high morbidity and mortality despite novel treatments. Genetic variability may explain outcome differences. Apolipoprotein E (ApoE) is a glycoprotein with a major role in brain lipoprotein metabolism. It has three isoforms encoded by distinct alleles: APOEe2, APOEe3 and APOEe4. The APOEe4 allele is associated with Alzheimer's disease and worse outcome after traumatic brain injury and ischaemic stroke. This prospective blinded study explored the influence of the APOEe4 polymorphism on the risk of aSAH, risk of cerebral vasospasm (CVS) and 1-year neurological outcome. Methods The APOEe4 polymorphism was analysed in 147 patients with aSAH. Allele and genotype frequencies were compared to those found in a gender- and area-matched control group of healthy individuals (n = 211). Early CVS was identified and treated according to neurointensive care unit (NICU) guidelines. Neurological deficit(s) at admittance and at 1-year follow-up visit was recorded. Neurological outcome was assessed by the National Institute of Health Stroke Scale, Barthel Index and the Extended Glasgow Outcome Scale. Results APOEe4 and non-APOEe4 allele frequencies were similar in aSAH patients and healthy individuals. The presence of APOEe4 was not associated with the development of early CVS. We could not find an influence of the APOE polymorphism on 1-year neurological outcome between groups. Subgroup analyses of patients treated with surgical clipping vs endovascular coiling did not reveal any associations. Conclusions The APOEe4 polymorphism has no major influence on risk of aSAH, the occurrence of CVS or long-term neurological outcome after aSAH.

Object Family studies have suggested a role of genetic factors in susceptibility to aneurysmal subarachnoid hemorrhage (aSAH), but the underlying genetic risk factors remain poorly defined. There is an activation of the fibrinolytic system in aSAH, and fibrinolytic markers may be useful in predicting outcome. The authors investigate associations between putative functional variants in genes of importance for fibrinolysis and aSAH and/or outcome following aSAH. Methods One hundred eighty-three patients presenting with aSAH at a neurointensive care unit were consecutively recruited. Two healthy controls per case, matched for age, sex, and geographic region, were randomly recruited. Outcome was assessed after 1 year according to the extended Glasgow Outcome Scale. Single nucleotide polymorphisms (SNPs) in the tissue-type plasminogen activator (tPA), plasminogen activator inhibitor type 1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI), and factor XIII (FXIII) genes were investigated. Results Participants carrying the FXIII 34Leu allele showed an increased risk of aSAH. When adjusting for smoking and hypertension, 2 haplotypes, differing on either the FXIII Val34Leu or the Pro564Leu position, showed an association to aSAH. No significant association was observed for the tPA -7351 C > T, PAI-1 -675 4G > 5G, or TAFI Ala147Thr SNPs. No specific SNP or haplotype was associated with outcome after aSAH, whereas a weak association was observed for a tPA/PAI-1 genotype combination. Conclusions Polymorphisms in the FXIII gene showed association to aSAH. The finding of an increased risk of bleeding in FXIII 34Leu carriers is biologically plausible.

BACKGROUND Traumatic brain injury (TBI) is one of the most common causes of death and dismal outcome among children and young adults. The morbidity and mortality differ but more aggressive monitoring and more designated neuro intensive care units have improved the results. Studies have demonstrated a connection between apolipoprotein E (APOE) genotype and outcome after TBI, but few are prospective and none is from northern Europe. APOE has three alleles: epsilon2, epsilon3 and epsilon4. METHODS A total of 96 patients with Glasgow coma score (GCS) < or =8 were prospectively and consecutively included. APOE genotypes were all analyzed at the same laboratory from blood samples by polymerase chain reaction-restriction fragment length polymorphism. RESULTS All patients were assessed at 1 year with Glasgow outcome scale extended (GOSE), National Institute of Health Stroke Scale (NIHSS) and the Barthel daily living index. The genotype was available in all patients. Twenty-six patients expressed APOE epsilon4 while 70 patients did not. Outcome demonstrated that patients with APOE epsilon4 had worse outcome vs. those lacking this allele. When subdividing patients into gender, males with APOE epsilon4 did worse, a difference not detected among female patients. CONCLUSIONS APOE epsilon4 correlated to worse outcome in TBI patients. We also found that males with APOE epsilon4 had poor outcome while females did not. Thus, the results indicate that genetic polymorphism may influence outcome after TBI.

S100B is an established marker of brain damage. Used in the context as a biochemical marker, S100B denotes a measurement of all S100 proteins, including at least one S100B monomer, i.e. the sum of the two dimers S100A1B and S100BB. Almost all published studies are based on this "sum concentration". However, the brain specificity of S100B has been questioned and increased serum levels have also been reported after trauma without head injury. Since the S100B monomer dominates in the brain, we hypothesised that the S100BB dimer should be better related to outcome after severe traumatic brain injury than S100A1B or the "sum concentration".Daily serum samples were collected from 59 patients with severe traumatic brain injury. Three different ELISA methods were used for measurements of S100B, S100A1B and S100BB respectively. Outcome was assessed after one year and categorised according to the Glasgow Outcome Scale.Serum levels of S100B, S100A1B and S100BB followed the same temporal course, with early maximum and rapidly decreasing values over the first days after the trauma. Maximum serum concentrations of each of the parameters were increased in the patient group with an unfavourable outcome compared with those with a favourable outcome (p = 0.01, 0.006 and 0.004, respectively).Both S100A1B and S100BB were related to outcome after severe traumatic brain injury. Even though this study is small, it seems unlikely that separate analyses of the dimers are of any advantage compared with measuring S100B alone.

Subarachnoid haemorrhage (SAH) is a serious condition that has a young age onset and poor outcome [1]. Approximately 75% of the cases of SAH are due to the rupture of an intracranial aneurysm (IA) [1]. The most important risk factors are smoking, hypertension, and excessive alcohol intake [1]. In addition, genetic factors have been shown to play an important role [2]. The matrix metalloproteinases (MMP) can degrade extracellular matrix (ECM) components, and alteration of the ECM leads to changes of the vessel wall. There is evidence that matrix remodelling plays a role in the formation and rupture of IA. MMP9 levels has been found to be increased in the aneurysmal wall [3], and both MMP2 and MMP9 was found to be overexpressed in cerebral ruptured aneurysms compared with unruptured aneurysms [4]. To evaluate the role of genetic variants in MMP2 and MMP9 in SAH due to ruptured IA (aSAH), the genes were tagged using HapMap CEU data (Rel 23a) and Haploview (r = 0.8 and MAF = 0.1), resulting in 11 tagSNPs. SNPs in the promoter region of MMP2 (rs243865) and in the 30UTR of MMP9 (rs20544) were also genotyped. Consecutive patients (n = 183) presenting with aSAH admitted to the Neurointensive Care Unit at the Sahlgrenska University Hospital in Gothenburg, Sweden and 366 matched controls were recruited. A detailed description of the inclusion criteria has been published [5, 6]. All participants gave written informed consent, and the Medical Ethics Committee at the University of Gothenburg approved the study. Genotyping was performed by TaqMan SNP Genotyping Assays. The assay for rs243865 failed and was replaced by an assay for rs243864. All genotype frequencies were in Hardy–Weinberg equilibrium, and genotyping success rates were above 98%. Haplotype analyses were conducted using HelixTree 6.4.3 (Golden Helix). Association between single SNPs and case–control status was investigated with logistic regression using an additive model. The study has 80% power to detect an OR of 1.45 at the 5% level for SNPs with a MAF of 0.3 for the risk allele. Mean age of patients and controls was 55 years and 74% were females. As expected, smokers were more frequent in cases compared to controls. Baseline characteristics have been presented previously [6]. Genotype frequencies are presented in Table 1. No SNP showed association to aSAH, and haplotype analysis did not add any further information (data not shown). As SAH is more common in women [1] we conducted a sex-stratified subanalysis. Two strongly linked SNPs in MMP9 (rs3918256 and rs20544, r = 0.99 in our material) showed significant associations with aSAH in men, both with OR 1.6 (95% CI 1.00–2.60). These associations did not remain after adjustment for smoking and hypertension. No association was found in the female subgroup. However, the effect of the SNPs did not differ significantly between men and women. In line with previous studies on aSAH, hemorrhagic stroke, and IA [7–10], we did not detect any association with genetic variants in MMP9, although conflicting results has been reported for rs20544 and IA [11]. Furthermore, in concordance with the present study, a lack of association between genetic variants in MMP2 and IA has been reported [11]. S. Olsson (&) L. Z. Csajbok K. Jood K. Nylen B. Nellgard C. Jern Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Box 403, SE-405 30 Gothenburg, Sweden e-mail: sandra.olsson@neuro.gu.se

Aims Medication reviews by a third party have been introduced as a method to improve drug treatment in older people. We assessed whether this intervention reduces mortality and hospitalization for nursing home residents. Methods Systematic literature searches were performed (from January 1990 to June 2012) in Medline, EMBASE, Cochrane Library, ProQuest Nursing & Allied Health Sources and Health Technology Assessment databases. We included randomized and nonrandomized controlled trials (RCTs and non-RCTs) of medication reviews compared with standard care or other types of medication reviews in nursing home residents. The outcome variables were mortality and hospitalization. Study quality was assessed systematically. We performed meta-analyses using random-effects models. Results Seven RCTs and five non-RCTs fulfilled the inclusion criteria. The mean age of included patients varied between 78 and 86 years. They were treated with a mean of 4–12 drugs. The study quality was assessed as high (n = 1), moderate (n = 4) or low (n = 7). Eight studies compared medication reviews with standard care. In six of them, pharmacists were involved in the intervention. Meta-analyses of RCTs revealed a risk ratio (RR) for mortality of 1.03 [medication reviews vs. standard care; five trials; 95% confidence interval (CI) 0.85–1.23]. The corresponding RR for hospitalization was 1.07 (two trials; 95% CI 0.61–1.87). Conclusions Our findings indicate that medication reviews for nursing home residents do not reduce mortality or hospitalization. More research in the setting of controlled trials remains to be done in order to clarify how drug treatment can be optimized for these patients.

Background and aim Genetic factors play a role in susceptibility to subarachnoid haemorrhage, but little is known about which genes are involved. Recently, genome wide association studies have identified the 9p21 region as a risk locus for intracranial aneurysms (IA). The aim of the present study was to examine the possible association between 9p21 and ruptured IA—that is, aneurysmal subarachnoid haemorrhage (aSAH)—in a Swedish population. There is one study showing an association between 9p21 and arterial stiffness, and arterial stiffness plays a role in the development of hypertension. Therefore, a second aim was to investigate whether a putative association is independent of hypertension. Methods The study comprised 183 patients presenting with aSAH to the Neurointensive Care Unit at Sahlgrenska University Hospital and 366 healthy, age and sex matched population based controls. As the causative functional variant in the region has not yet been identified, a 44 kbp region on 9p21 was tagged using HapMap. Six single nucleotide polymorphism (SNPs) were genotyped. Results Two SNPs, rs10757278 and rs1333045, showed significant associations with aSAH in univariate analyses. After adjustment for hypertension as well as for smoking, the association between aSAH and rs10757278 remained significant with an OR for aSAH of 1.42 (95% CI 1.08 to 1.87; p=0.01) for the uncommon G allele. Conclusions These data confirm earlier results showing that 9p21 is a susceptibility locus for IA, and that this association is present in a Swedish sample restricted to ruptured IA. For the first time, it has been demonstrated that this association is independent of hypertension.

Family studies have suggested a role of genetic factors in susceptibility to aneurysmal subarachnoid hemorrhage (aSAH), but the underlying genetic risk factors remain poorly defined. There is an activation of the fibrinolytic system in aSAH, and fibrinolytic markers may be useful in predicting outcome. The authors investigate associations between putative functional variants in genes of importance for fibrinolysis and aSAH and/or outcome following aSAH.One hundred eighty-three patients presenting with aSAH at a neurointensive care unit were consecutively recruited. Two healthy controls per case, matched for age, sex, and geographic region, were randomly recruited. Outcome was assessed after 1 year according to the extended Glasgow Outcome Scale. Single nucleotide polymorphisms (SNPs) in the tissue-type plasminogen activator (tPA), plasminogen activator inhibitor type 1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI), and factor XIII (FXIII) genes were investigated.Participants carrying the FXIII 34Leu allele showed an increased risk of aSAH. When adjusting for smoking and hypertension, 2 haplotypes, differing on either the FXIII Val34Leu or the Pro564Leu position, showed an association to aSAH. No significant association was observed for the tPA -7351 CT, PAI-1 -675 4G5G, or TAFI Ala147Thr SNPs. No specific SNP or haplotype was associated with outcome after aSAH, whereas a weak association was observed for a tPA/PAI-1 genotype combination.Polymorphisms in the FXIII gene showed association to aSAH. The finding of an increased risk of bleeding in FXIII 34Leu carriers is biologically plausible.

Background and Purpose— Aneurysmal subarachnoid hemorrhage (aSAH) stands out from other subtypes of stroke because of the high early mortality and the risk of complications. Serum glial fibrillary acidic protein (s-GFAP) concentrations are increased after stroke. The aim of this study was to investigate whether s-GFAP could be used as a marker of brain damage and outcome after aSAH. Methods— Serum samples were obtained on a regular basis from 116 adults during a 2-week period after aSAH and analyzed using an enzyme-linked immunosorbent assay. The World Federation of Neurological Surgeons scale was used for neurological evaluation. Outcome was assessed after 1 year and categorized according to the Extended Glasgow Outcome Scale. Results— Increased s-GFAP levels were seen in 81 of the 116 patients. Maximum s-GFAP correlated with World Federation of Neurological Surgeons scale on arrival and on days 10 to 15 ( r =0.37, P r =0.47, P P P r =−0.48, P Conclusions— s-GFAP provides information about brain injury severity and outcome after aSAH, which can be useful as a complement to clinical data.

We investigated if tau, microtubular binding protein, in serum and ventricular CSF (vCSF) in patients with severe traumatic brain injury (TBI) during the initial posttraumatic days correlated to 1-year outcome.Patients with severe TBI (n = 39, Glasgow Coma Scale scoreor=8) were included. We measured serum and vCSF total tau on days 0 to 14, using ELISA. vCSF total tau correlated to 1-year Extended Glasgow Outcome Scale (GOSE), the NIH Stroke Scale (NIHSS) neurologic status, and the Bartel Daily Living Index. Patients (n = 20) with normal pressure hydrocephalus (NPH) served as reference.Higher levels of tau were found in TBI patients vs patients with NPH. A correlation was found between initial vCSF total tau and GOSE levels (R = 0.42, p0.001) but not between vCSF total tau and NIHSS or Bartel scores at 1 year. A vCSF total tau level of2,126 pg/mL on days 2 to 3 discriminated between dead and alive (sensitivity of 100% and a specificity of 81%). A vCSF total tau level of702 pg/mL on days 2 to 3 discriminated between bad (GOSE 1 to 4) and good (GOSE 5 to 8) outcome (sensitivity of 83% and a specificity of 69%). Patients with GOSE 1 (dead) had higher vCSF total tau levels on days 2 to 3 (p0.001) vs both surviving patients (GOSE 2 to 8) and those with NPH. Total tau was not detected in serum throughout the study.The increase in ventricular CSF (vCSF) total tau probably reflects axonal damage, known to be a central pathologic mechanism in traumatic brain injury (TBI). These results suggest that vCSF total tau may be an important early biochemical neuromarker for predicting long-term outcome in patients with a severe TBI.

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating event. Following the bleeding, a number of pathophysiological changes and clinical factors determine outcome. Not surprisingly, attempts to predict outcome based on a single factor have failed. The neurological status graded at admission to hospital and distributions of the blood on CT are the strongest predictors. There is evidence that cerebrospinal fluid (CSF) proteins may serve as markers of the extent of brain damage. The present study is focused on the light unit of neurofilament protein (NFL), previously not evaluated in aSAH. Lumbar puncture (LP), neurological grading according to World Federation of Neurological Surgeons (WFNS) and neurological examination according to the National Institute of Health Stroke Scale (NIHSS) were performed in 48 consecutive patients with aSAH 10–14 days after the hemorrhage. CSF–NFL concentrations were analyzed using an ELISA. Outcome was assessed after 1 year and categorised according to the extended Glasgow Outcome Scale (GOSE). A significant correlation between CSF–NFL and GOSE was detected at follow up after 1 year. CSF–NFL also correlated with WFNS and NIHSS on the day of the lumbar puncture. CSF–NFL is a biochemical marker of brain damage correlating to neurological status and long-term outcome after aneurysmal subarachnoid hemorrhage.

Several studies have established the relevance of S-100 in blood as a marker of brain damage after traumatic brain injury. However, a more specific marker is required and glial fibrillary acidic protein (GFAP) is considered to be a good candidate.In order to assess the increase of GFAP in serum (s-GFAP) after a severe traumatic brain injury (TBI) we collected daily serum samples from 59 patients with severe TBI starting on the day of the trauma. S-GFAP was measured using a sandwich ELISA. The Glasgow outcome scale (GOS) assessed outcome after 1 year.All but one patient had maximal s-GFAP values above the laboratory reference value (median increased 10-fold). The highest detected levels were seen during the first days after TBI and then decreased gradually. Patients with unfavourable outcome had significantly (p0.001) higher maximal s-GFAP values in the acute phase compared with patients with favourable outcome. All patients (n=5) with s-GFAP15.04 microg /L died (reference level0.15 microg/L). We found no significant difference in the maximal s-GFAP levels of patients with isolated brain injury in comparison with patients with multiple traumas.Serum-GFAP is increased during the first days after a severe traumatic brain injury and related to clinical outcome.

Severe traumatic brain injury (TBI) may result in widespread damage to axons, termed diffuse axonal injury. Alzheimer's disease (AD) is characterised by synaptic and axonal degeneration together with senile plaques (SP). SP are mainly composed of aggregated beta-amyloid (Abeta), which are peptides derived from the amyloid precursor protein (APP). Apart from TBI in itself being considered a risk factor for AD, severe head injury seems to initiate a cascade of molecular events that are also associated with AD. We have therefore analysed the 42 amino acid forms of Abeta (Abeta1-42) and two soluble forms of APP (alpha-sAPP and ss-sAPP) in ventricular cerebrospinal fluid (VCSF) and Abeta(1-42) in plasma from 28 patients in a serial samples 0-11 days after TBI. The levels of alpha-sAPP, ss-sAPP and Abeta(1-42) were determined using ELISA assays. After TBI, there was a significant stepwise increase in VCSF-Abeta(1-42) up to 1173 % from day 0-1 to day 5-6 and in VCSF-beta-sAPP up to 2033 % increase from day 0-1 to day 7-11. There was also a slight but significant increase of VCSF-beta-sAPP from day 0-1 to day 5-6 and day 7-11. By contrast, the plasma- Abeta(1-42) level is unchanged after injury. The marked increase in VCSFAbeta(1-42) implies that increased Abeta expression may occur as a secondary phenomenon after TBI with axonal damage. The unchanged level of plasma-Abeta(1-42) in contrast to the marked increase in VCSF-Abeta(1-42) after severe TBI, supports the suggestion that plasma Abeta(1-42) does not reflect Abeta metabolism in the central nervous system (CNS).