Production and characterization of a custom-made 228Th source with reduced neutron source strength for the Borexino experiment

A custom-made 228Th source of several MBq activity was produced for the Borexino experiment for studying the external background of the detector. The aim was to reduce the unwanted neutron emission produced via (alpha,n) reactions in ceramics used typically for commercial 228Th sources. For this purpose a ThCl4 solution was converted chemically into ThO2 and embedded into a gold foil. The paper describes the production and the characterization of the custom-made source by means of gamma-activity, dose rate and neutron source strength measurements. From gamma-spectroscopic measurements it was deduced that the activity transfer from the initial solution to the final source was >91% (at 68% C.L.) and the final activity was (5.41+-0.30) MBq. The dose rate was measured by two dosimeters yielding 12.1 mSv/h and 14.3 mSv/h in 1 cm distance. The neutron source strength of the 5.41 MBq 228Th source was determined as (6.59+-0.85)/sec.

Impact of left ventricular hypertrophy late after aortic valve replacement for aortic stenosis on cardiovascular morbidity and mortality

AIMS: The goal of this study was to assess the prevalence of left ventricular (LV) hypertrophy in patients with aortic stenosis late (>6 months) after aortic valve replacement and its impact on cardiac-related morbidity and mortality. METHODS AND RESULTS: In a single tertiary centre, echocardiographic data of LV muscle mass were collected. Detailed information of medical history and angiographic data were gathered. Ninety-nine of 213 patients (46%) had LV hypertrophy late (mean 5.8 +/- 5.4 years) after aortic valve replacement. LV hypertrophy was associated with impaired exercise capacity, higher New York Heart Association dyspnoea class, a tendency for more frequent chest pain expressed as higher Canadian Cardiovascular Society class, and more rehospitalizations. 24% of patients with normal LV mass vs. 39% of patients with LV hypertrophy reported cardiac-related morbidity (p = 0.04). In a multivariate logistic regression model, LV hypertrophy was an independent predictor of cardiac-related morbidity (odds ratio 2.31, 95% CI 1.08 to 5.41), after correction for gender, baseline ejection fraction, and coronary artery disease and its risk factors. Thirty seven deaths occurred during a total of 1959 patient years of follow-up (mean follow-up 9.6 years). Age at aortic valve replacement (hazard ratio 1.85, 95% CI 1.39 to 2.47, for every 5 years increase in age), coexisting coronary artery disease at the time of surgery (hazard ratio 3.36, 95% CI 1.31 to 8.62), and smoking (hazard ratio 4.82, 95% CI 1.72 to 13.45) were independent predictors of overall mortality late after surgery, but not LV hypertrophy. CONCLUSIONS: In patients with aortic valve replacement for isolated aortic stenosis, LV hypertrophy late after surgery is associated with increased morbidity.

Randomised trial of clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid hemorrhage undergoing surgical clipping (CONSCIOUS-2)

We report here results of a randomized, double-blind, placebo-controlled study ( http://www.ClinicalTrials.gov , NCT00558311) that investigated the effect of clazosentan (5 mg/h, n = 768) or placebo (n = 389) administered for up to 14 days in patients with aneurysmal subarachnoid hemorrhage (SAH) repaired by surgical clipping. The primary endpoint was a composite of all-cause mortality, new cerebral infarction or delayed ischemic neurological deficit due to vasospasm, and rescue therapy for vasospasm. The main secondary endpoint was the Glasgow Outcome Scale Extended (GOSE), which was dichotomized. Twenty-one percent of clazosentan- compared to 25% of placebo-treated patients met the primary endpoint (relative risk reduction [RRR] [95% CI]: 17% [-4% to 33%]; p = 0.10). Poor outcome (GOSE score ≤ 4) occurred in 29% of clazosentan- and 25% of placebo-treated patients (RRR: -18% [-45% to 4%]; p = 0.10). In prespecified subgroups, mortality/vasospasm-related morbidity was reduced in clazosentan-treated patients by 33% (8-51%) in poor WFNS (World Federation of Neurological Surgeons) grade (≥III) and 25% (5-41%) in patients with diffuse, thick SAH. Lung complications, anemia and hypotension occurred more frequently with clazosentan. Mortality (week 12) was 6% in both groups. The results showed that clazosentan nonsignificantly decreased mortality/vasospasm-related morbidity and nonsignificantly increased poor functional outcome in patients with aneurysmal SAH undergoing surgical clipping.

Plasma homocysteine levels increase following stress in older but not younger men

BACKGROUND: The incidence and prevalence of cardiovascular disease (CVD) increases with age. Some evidence suggests that mental stress may increase plasma homocysteine (Hcy), an amino acid relating to CVD. However, none of these studies assessed age effects on Hcy stress reactivity, nor did they control for age. The objective of this study was (a) to investigate whether Hcy reactivity to psychosocial stress differs between younger and middle-aged to older men and (b) to study whether psychosocial stress induces Hcy increases independent of age. METHODS: Twenty eight younger (20-30 years) and 22 middle-aged to older (47-65 years) apparently healthy men underwent an acute standardized psychosocial stress task combining public speaking and mental arithmetic in front of an audience. Blood samples for Hcy measurements were obtained immediately before and after, as well as 10 and 20min after stress. Moreover, salivary cortisol was repeatedly measured to test the effectiveness of the stress task in triggering a neuroendocrine stress response. RESULTS: Hcy reactivity to stress differed between age groups (F(1.4, 60.7)=5.41, p=.014). While the older group displayed an increase in the Hcy response to stress (F(2.5, 39.8)=3.86, p=.022), Hcy levels in the younger group did not change (p=.27). Psychosocial stress per se did not change Hcy levels independent of age (p=.53). CONCLUSIONS: Our findings suggest that psychosocial stress does not evoke an Hcy response per se, but only in interaction with age pointing to a mechanism by which mental stress may increase CVD risk in older individuals.

Prognostic role of FGFR1 amplification in early-stage non-small cell lung cancer.

Background:Recently, fibroblast growth factor receptor 1 (FGFR1) was discovered in squamous cell carcinomas (SCC) of the lung with FGFR1 amplification described as a promising predictive marker for anti-FGFR inhibitor treatment. Only few data are available regarding prevalence, prognostic significance and clinico-pathological characteristics of FGFR1-amplified and early-stage non-small cell lung carcinomas (NSCLC). We therefore investigated the FGFR1 gene status in a large number of well-characterised early-stage NSCLC.Methods:FGFR1 gene status was evaluated using a commercially available fluorescent in situ hybridisation (FISH) probe on a tissue microarray (TMA). This TMA harbours 329 resected, formalin-fixed and paraffin-embedded, nodal-negative NSCLC with a UICC stage I-II. The FISH results were correlated with clinico-pathological features and overall survival (OS).Results:The prevalence of an FGFR1 amplification was 12.5% (41/329) and was significantly (P<0.0001) higher in squamous cell carcinoma (SCC) (20.7%) than in adenocarcinoma (2.2%) and large cell carcinoma (13%). Multivariate analysis revealed significantly (P=0.0367) worse 5-year OS in patients with an FGFR1-amplified NSCLC.Conclusions:FGFR1 amplification is common in early-stage SCC of the lung and is an independent and adverse prognostic marker. Its potential role as a predictive marker for targeted therapies or adjuvant treatment needs further investigation.

Health-related quality of life in young survivors of childhood cancer

PURPOSE Childhood cancer and its treatment may affect health-related quality of life (HRQoL) in childhood cancer survivors, but population-based studies in young survivors are scarce. We aimed to: (1) compare HRQoL between young survivors and population norms and (2) find factors that influence parent-reported HRQoL in survivors. METHODS As part of the Swiss Childhood Cancer Survivor Study, a questionnaire was mailed to parents of survivors aged 8-16 years, registered in the Swiss Childhood Cancer Registry, ≥5 years after diagnosis. We used the KIDSCREEN-27 instrument to compare self- and parent-reported HRQoL between survivors (N = 425) and standardized norms in the five dimensions of physical well-being, psychological well-being, autonomy, peers and school environment (mean = 50, SD = 10). We then used multivariable linear regressions to test the influence of socio-demographic and cancer-related factors on HRQoL. RESULTS Self-reported physical well-being was comparable to norms. Other HRQoL dimensions were higher than norms, with the highest mean = 52.2 (p < 0.001) for school environment. Parent-reported HRQoL in survivors was comparable to population norms; only physical well-being was lower (mean = 47.1, p < 0.001), and school environment was higher (mean = 51.1, p = 0.035). Parent-reported HRQoL was lower for survivors of CNS tumors (physical well-being: β = -5.27, p = 0.007; psychological well-being: β = -4.39, p = 0.044; peers β = -5.17, p = 0.028), survivors of neuroblastoma (psychological well-being β = -5.20, p = 0.047), and survivors who had had a relapse (physical well-being β = -5.41, p = 0.005). CONCLUSIONS Assessing HRQoL during follow-up care, with a focus on physical well-being, specific diagnoses (e.g., CNS tumor) and late complications (e.g., relapse) might help to early identify problems and offer support to survivors with reduced HRQoL.

Publication activities of German junior researchers in academic medicine: which factors impact impact factors?

Previous studies have shown medical students in Germany to have little interest in research while at the same time there is a lack of physician scientists. This study’s aim is to investigate factors influencing publication productivity of physicians during and after finishing their medical doctorate. We conducted a PubMed search for physicians having received their doctoral degree at Ludwig-Maxmilians-University Munich Faculty of Medicine between 2011 and 2013 (N = 924) and identified the appropriate impact factor (IF) for each journal the participants had published in. Gender, age, final grade of the doctorate, participation in a structured doctoral study program and joint publication activities between graduate and academic supervisor were defined as factors. For analyses we used nonparametric procedures. Men show significantly more publications than women. Before their doctoral graduation men publish 1.98 (SD ± 3.64) articles on average, women 1.15 (±2.67) (p < 0.0001, d = 0.27). After completion of the doctorate (up to 06/2015), 40 % of men still publish, while only 24.3 % of women (p < 0.0001, φ = 0.17) continue to publish. No differences were found concerning the value of IFs. Similar results were found regarding the variable ‘participation in a structured doctoral study program’. Until doctoral graduation, program participants publish 2.82 (±5.41) articles, whereas participants doing their doctorate individually only publish 1.39 (±2.87) articles (p < 0.0001, d = 0.46). These differences persist in publication activities after graduation (45.5 vs. 29.7 %, p = 0.008, φ = 0.09). A structured doctorate seems to have positive influence on IFs (4.33 ± 2.91 vs. 3.37 ± 2.82, p = 0.006, d = 0.34). Further significant results concern the variables ‘final grade’ and ‘age’: An early doctoral graduation and an excellent or very good grade for the doctoral thesis positively influence publication productivity. Finally, joint publication activities between the graduate and his/her academic supervisor result in significantly higher IFs (3.64 ± 3.03 vs. 2.84 ± 2.25, p = 0.007, d = 0.28). The study’s results support the assumption about women’s underrepresentation in science as well as the relevance of structured doctoral study programs for preparing and recruiting young academics in medicine for scientific careers. Promoting women and further development of structured doctoral study programs are highly recommended.

Long-term stability of contour augmentation with early implant placement following single tooth extraction in the esthetic zone: a prospective, cross-sectional study in 41 patients with a 5- to 9-year follow-up

BACKGROUND Early implant placement with simultaneous contour augmentation is documented with short- and medium-term studies. The long-term stability of contour augmentation is uncertain. METHODS In this prospective, cross-sectional study, 41 patients with an implant-borne single crown were examined twice, in 2006 and 2010. Clinical, radiologic, and esthetic parameters were assessed at both examinations. In addition, a cone beam computed tomographic (CBCT) image was obtained during the second examination to assess the dimensions of the facial bone wall. RESULTS All 41 implants demonstrated ankylotic stability without signs of peri-implant infection at both examinations. The clinical parameters remained stable over time. Satisfactory esthetic outcomes were noted, as assessed by the pink and white esthetic score (PES/WES) indices. Overall, the PES scores were slightly higher than the WES scores. None of the implants developed mucosal recession over time, as confirmed by values of the distance between implant shoulder and mucosal margin and cast measurements. The periapical radiographs yielded stable peri-implant bone levels, with a mean distance between implant shoulder and first visible bone-implant contact value of 2.18 mm. The CBCT analysis demonstrated a mean thickness of the facial bone wall ≈2.2 mm. In two implants (4.9%) no facial bone wall was detectable radiographically. CONCLUSIONS This prospective cross-sectional study demonstrates stable peri-implant hard and soft tissues for all 41 implants examined and satisfactory esthetic outcomes overall. The follow-up of 5 to 9 years confirmed again that the risk for mucosal recession is low with early implant placement. In addition, contour augmentation with guided bone regeneration was able to establish and maintain a facial bone wall in 95% of patients.

Primary tumors of the submandibular glands: a retrospective study based on 41 cases

We report our experience on the diagnostic approach, treatment, and follow-up of primary submandibular gland tumors. Retrospective review. Tertiary referral center. Forty-one adult patients, 22 male and 19 female, with primary submandibular gland tumors, 20 benign and 21 malignant. Age, gender, clinical findings, cyto- and histopathology, treatment and outcome were analyzed. Most tumors presented as a painless submandibular mass. Thirty three patients underwent a fine needle aspiration, the sensitivity, specificity and accuracy of which--in detecting malignant tumors--were 79%, 100% and 88%, respectively. Preoperative radiological imaging was performed in 30 cases. Patients with benign tumors were treated with surgery. Most malignant tumors were treated with a combined modality, including neck dissection and radiation therapy. Five patients developed a postoperative complication. Recurrent disease was encountered in 5 malignant tumors. The 2, 5 and 10 year disease-specific survival of patients with malignancy were 84%, 75% and 41%, respectively. The preoperative assessment of the nature of submandibular gland tumors remains challenging. Aggressive treatment of patients with malignant disease may help to avoid poor prognosis.

A systematic review of the survival and complication rates of resin-bonded bridges after an observation period of at least 5 years

OBJECTIVES: The objectives of this systematic review were to assess the 5-year survival of resin-bonded bridges (RBBs) and to describe the incidence of technical and biological complications. METHODS: An electronic Medline search complemented by manual searching was conducted to identify prospective and retrospective cohort studies on RBBs with a mean follow-up time of at least 5 years. Patients had to have been examined clinically at the follow-up visit. Assessment of the identified studies and data extraction were performed independently by two reviewers. Failure and complication rates were analyzed using random-effects Poissons regression models to obtain summary estimates of 5-year proportions. RESULTS: The search provided 6110 titles and 214 abstracts. Full-text analysis was performed for 93 articles, resulting in 17 studies that met the inclusion criteria. Meta-analysis of these studies indicated an estimated survival of RBBs of 87.7% (95% confidence interval (CI): 81.6-91.9%) after 5 years. The most frequent complication was debonding (loss of retention), which occurred in 19.2% (95% CI: 13.8-26.3%) of RBBs over an observation period of 5 years. The annual debonding rate for RBBs placed on posterior teeth (5.03%) tended to be higher than that for anterior-placed RBBs (3.05%). This difference, however, did not reach statistical significance (P=0.157). Biological complications, like caries on abutments and RBBs lost due to periodontitis, occurred in 1.5% of abutments and 2.1% of RBBs, respectively. CONCLUSION: Despite the high survival rate of RBBs, technical complications like debonding are frequent. This in turn means that a substantial amount of extra chair time may be needed following the incorporation of RBBs. There is thus an urgent need for studies with a follow-up time of 10 years or more, to evaluate the long-term outcomes.

1.0-M gadobutrol versus 0.5-M gadoterate for peripheral magnetic resonance angiography: a prospective randomized controlled clinical trial

PURPOSE: To perform a quantitative and qualitative comparison of gadobutrol and gadoterate in three-station contrast enhanced magnetic resonance angiography (CE-MRA) of the lower limbs. MATERIALS AND METHODS: In this prospective randomized controlled trial, 52 patients with leg ischemia were randomly assigned to one of two groups receiving either gadobutrol (1.0 mmol Gd/mL, 15 mL) or gadoterate (0.5 mmol Gd/mL, 30 mL). Three-station 3D CE-MRAs from the pelvis to the ankles were performed with moving-table technique on a 1.5T MR scanner. Injection time was identical in both groups. Signal-to-noise (SNR) and contrast-to-noise ratios (CNR) were calculated for 816 arteries. Contrast quality in 1196 vessel segments was evaluated separately by two blinded readers on a three-point scale. RESULTS: Mean SNR (61.8 +/- 7.8 for gadobutrol vs. 61.9 +/- 9.1 for gadoterate, P = 0.257), CNR (52.8 +/- 9.1 vs. 52.8 +/- 10.7, P = 0.154), and qualitative ranking (1.41 vs. 1.44, P = 0.21) for all vessels did not differ significantly between the two patient groups. The overall quality was good in 90.4% with gadoterate and 94.2% with gadobutrol (P = 0.462). CONCLUSION: High-concentration gadobutrol allows neither a higher CNR nor any qualitative advantage over the ordinary unspecific Gd agent gadoterate when the same Gd load and injection times are used in multistation CE-MRA of the peripheral arteries.

Reanalysis-driven climate simulation over CORDEX North America domain using the Canadian Regional Climate Model, version 5: model performance evaluation

The performance of reanalysis-driven Canadian Regional Climate Model, version 5 (CRCM5) in reproducing the present climate over the North American COordinated Regional climate Downscaling EXperiment domain for the 1989–2008 period has been assessed in comparison with several observation-based datasets. The model reproduces satisfactorily the near-surface temperature and precipitation characteristics over most part of North America. Coastal and mountainous zones remain problematic: a cold bias (2–6 °C) prevails over Rocky Mountains in summertime and all year-round over Mexico; winter precipitation in mountainous coastal regions is overestimated. The precipitation patterns related to the North American Monsoon are well reproduced, except on its northern limit. The spatial and temporal structure of the Great Plains Low-Level Jet is well reproduced by the model; however, the night-time precipitation maximum in the jet area is underestimated. The performance of CRCM5 was assessed against earlier CRCM versions and other RCMs. CRCM5 is shown to have been substantially improved compared to CRCM3 and CRCM4 in terms of seasonal mean statistics, and to be comparable to other modern RCMs.

Neoadjuvant chemoradiotherapy with or without panitumumab in patients with wild-type KRAS, locally advanced rectal cancer (LARC): a randomized, multicenter, phase II trial SAKK 41/07

BACKGROUND We conducted a randomized, phase II, multicenter study to evaluate the anti-epidermal growth factor receptor (EGFR) mAb panitumumab (P) in combination with chemoradiotherapy (CRT) with standard-dose capecitabine as neoadjuvant treatment for wild-type KRAS locally advanced rectal cancer (LARC). PATIENTS AND METHODS Patients with wild-type KRAS, T3-4 and/or N+ LARC were randomly assigned to receive CRT with or without P (6 mg/kg). The primary end-point was pathological near-complete or complete tumor response (pNC/CR), defined as grade 3 (pNCR) or 4 (pCR) histological regression by Dworak classification (DC). RESULTS Forty of 68 patients were randomly assigned to P + CRT and 28 to CRT. pNC/CR was achieved in 21 patients (53%) treated with P + CRT [95% confidence interval (CI) 36%-69%] versus 9 patients (32%) treated with CRT alone (95% CI: 16%-52%). pCR was achieved in 4 (10%) and 5 (18%) patients, and pNCR in 17 (43%) and 4 (14%) patients. In immunohistochemical analysis, most DC 3 cells were not apoptotic. The most common grade ≥3 toxic effects in the P + CRT/CRT arm were diarrhea (10%/6%) and anastomotic leakage (15%/4%). CONCLUSIONS The addition of panitumumab to neoadjuvant CRT in patients with KRAS wild-type LARC resulted in a high pNC/CR rate, mostly grade 3 DC. The results of both treatment arms exceeded prespecified thresholds. The addition of panitumumab increased toxicity.

Outcome of patients with occlusions of the internal carotid artery or the main stem of the middle cerebral artery with NIHSS score of less than 5: comparison between thrombolysed and non-thrombolysed patients

BACKGROUND AND PURPOSE The use of thrombolysis in patients with minor neurological deficits and large vessel occlusion is controversial. METHODS We compared the outcome of patients with low National Institutes of Health Stroke Scale (NIHSS) scores and large vessel occlusions between thrombolysed and non-thrombolysed patients. RESULTS 88 (1.7%) of 5312 consecutive patients with acute (within 24 h) ischaemic stroke had occlusions of the internal carotid or the main stem of the middle cerebral artery and baseline NIHSS scores ≤5.47 (53.4%) were treated without thrombolysis, and 41 (46.6%) received intravenous thrombolysis, endovascular therapy or both. Successful recanalisation on MR or CT angiography at 24 h was more often observed in thrombolysed than in non-thrombolysed patients (78.9% versus 10.5%; p<0.001). Neurological deterioration (increase of NIHSS score ≥1 compared to baseline) was observed in 22.7% of non-thrombolysed versus 10.3% of thrombolysed after 24 h (p=0.002), in 33.3% versus 12.5% at hospital discharge (p=0.015) and in 41.4% versus 15% at 3 months (p<0.001). Symptomatic intracerebral haemorrhage occurred in two (asymptomatic in five) thrombolysed and in none (asymptomatic in three) non-thrombolysed. Thrombolysis was an independent predictor of favourable outcome (p=0.030) but not survival (p=0.606) at 3 months. CONCLUSIONS Non-thrombolysed patients with mild deficits and large vessel occlusion deteriorated significantly more often within 3 months than thrombolysed patients. Symptomatic intracerebral haemorrhages occurred in less than 5% of patients in both groups. These data suggest that thrombolysis is safe and effective in these patients. Therefore, randomised trials in patients with large vessel occlusions and mild or rapidly improving symptoms are needed.

The Antimalarial Drug Proguanil Is An Antagonist at 5-HT3 Receptors

Proguanil is an antimalarial prodrug that is metabolized to 4-chlorophenyl-1-biguanide (CPB) and the active metabolite cycloguanil (CG). These compounds are structurally related to meta-chlorophenyl biguanide (mCPBG), a 5-hydroxytryptamine 3 (5-HT3) receptor agonist. Here we examine the effects of proguanil and its metabolites on the electrophysiology and ligand-binding properties of human 5-HT3A receptors expressed in Xenopus oocytes and human embryonic kidney 293 cells, respectively. 5-HT3 receptor responses were reversibly inhibited by proguanil, with an IC50 of 1.81 μM. Competitive antagonism was shown by a lack of voltage-dependence, Schild plot (Kb = 1.70 μM), and radioligand competition (Ki = 2.61 μM) with the 5-HT3 receptor antagonist [3H]granisetron. Kinetic measurements (kon = 4.0 × 104 M−1 s−1; koff = 0.23 s−1) were consistent with a simple bimolecular reaction scheme with a Kb of 4.35 μM. The metabolites CG and CPB similarly inhibited 5-HT3 receptors as assessed by IC50 (1.48 and 4.36 μM, respectively), Schild plot (Kb = 2.97 and 11.4 μM), and radioligand competition (Ki = 4.89 and 0.41 μM). At higher concentrations, CPB was a partial agonist (EC50 = 14.1 μM; I/Imax = 0.013). These results demonstrate that proguanil competitively inhibits 5-HT3 receptors, with an IC50 that exceeds whole-blood concentrations following its oral administration. They may therefore be responsible for the occasional gastrointestinal side effects, nausea, and vomiting reported following its use. Clinical development of related compounds should therefore consider effects at 5-HT3 receptors as an early indication of possible unwanted gastrointestinal side effects.