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Objectives: Spinal muscular atrophy (SMA) is a rare genetic disorder that causes progressive muscle weakness and paralysis. In its most common and severe form, the majority of untreated infants die before 2 years of age. Early detection and treatment, ideally before symptom onset, maximize survival and achievement of age-appropriate motor milestones, with potentially substantial impact on health-related quality of life. Therefore, SMA is an ideal candidate for inclusion in newborn screening (NBS) programs. We evaluated the cost-effectiveness of including SMA in the NBS program in The Netherlands., Methods: We developed a cost-utility model to estimate lifetime health effects and costs of NBS for SMA and subsequent treatment versus a treatment pathway without NBS (ie, diagnosis and treatment after presentation with overt symptoms). Model inputs were based on literature, local data, and expert opinion. Sensitivity and scenario analyses were conducted to assess model robustness and validity of results., Results: After detection of SMA by NBS in 17 patients, the number of quality-adjusted life-years gained per annual birth cohort was estimated at 320 with NBS followed by treatment compared with treatment after clinical SMA diagnosis. Total healthcare costs, including screening, diagnostics, treatment, and other healthcare resource use, were estimated to be €12 014 949 lower for patients identified by NBS., Conclusions: NBS for early identification and treatment of SMA versus later symptomatic treatment after clinical diagnosis improves health outcomes and is less costly and, therefore, is a cost-effective use of resources. Results were robust in sensitivity and scenario analyses., (Copyright © 2022. Published by Elsevier Inc.)

Objectives: To assess the vertical discrepancy between implant-supported crowns and adjacent teeth in the maxillary anterior region at least 8 years after implant placement and to evaluate the influence of this discrepancy on the level of aesthetic awareness of patients., Material and Methods: The sample consisted of 23 adult individuals evaluated at least 8 years after placement of an implant-supported central or lateral single tooth-fixed partial denture. Patients had their crowns delivered at a mean age of 47.8 years (range: 18.9-65.8). The vertical discrepancy was measured by comparing initial and follow-up periapical radiographs using the implant as a stable structure. The patients' satisfaction with their anterior teeth condition and awareness of the possible vertical problem were evaluated using a questionnaire. The aesthetic outcome and patient awareness were related to the objective measurement of the vertical discrepancy., Results: The implant showed a mean infraocclusion of 0.62 mm (range: 0.15-1.63 mm). The vertical discrepancy was not associated with the patient's gender, age at implant placement, and duration between initial and recall radiograph. Patients were generally satisfied with the long-term aesthetic outcome of their smile (mean: 3.9 on a 1-5 scale, 1 unsatisfied, and 5 completely satisfied). Out of 23 patients, 8 noticed the implant infraocclusion and 4 of them found the problem severe enough to be willing to improve the situation. The amount of vertical discrepancy was not associated with the patient's perception of the discrepancy and the pink aesthetic score., Conclusion: Implant-supported crowns in the anterior region may suffer infraocclusion over the long term. The amount of vertical discrepancy was not dependent on the gender and age of the patient. Patients were generally satisfied with the aesthetic result of the restoration. The amount of vertical discrepancy, at least in the range we have measured, was not perceived by the patients as a complication., (© 2022 The Authors. Clinical and Experimental Dental Research published by John Wiley & Sons Ltd.)

Introduction: The global rise of urbanization has much triggered scientific interest in how nature impacts on human health. Natural environments, such as alpine landscapes, forests, or urban green spaces, are potential high-impact health resources. While there is a growing body of evidence to reveal a positive influence of these natural environments on human health and well-being, further investigations guided by rigorous evidence-based medical research are very much needed., Objective: The present study protocol aims at testing research methodologies in the context of a prospective clinical trial on nature-based interventions. This shall improve the standards of medical research in human-nature interactions., Methods: The ANKER Study investigates the influence of two novel types of nature-based therapy-mountain hiking and forest therapy-on physiological, psychological, and immunological parameters of couples with a sedentary lifestyle. Two intervention groups were formed and spent a seven-day holiday in Algund, Italy. The "forest therapy group" participated in daily guided low-power nature connection activities. The "hiking group", by contrast, joined in a daily moderate hiking program. Health-related quality of life and relationship quality are defined as primary outcomes. Secondary outcomes include nature connection, balance, cardio-respiratory fitness, fractional exhaled nitric oxide, body composition and skin hydration. Furthermore, a new approach to measure health-related quality of life is validated. The so-called "intercultural quality of life" comic assesses the health-related quality of life with a digitally animated comic-based tool.

Introduction: Spinal muscular atrophy (SMA) is a rare, genetic neuromuscular disorder caused by deletion/mutation of the survival motor neuron 1 gene, characterized by progressive loss of motor neurons, resulting in increasing muscular weakness, deteriorating motor function, and, in its most severe form, death before 2 years. Nusinersen, an antisense oligonucleotide that increases expression of the functional SMN protein, was approved for SMA by US and European regulatory agencies in 2016 and 2017, respectively. The indicated regimen requires intrathecal injections every 4 months, following the first four injections during the loading phase. Adherence is integral to treatment success. Adherence to nusinersen may pose particular challenges as most patients with SMA are young children who require complex multidisciplinary care (including ongoing intrathecal treatment administration and potential specialized anesthetic and surgical procedures) at specialized centers. However, real-world data on adherence to nusinersen are limited., Methods: We conducted a retrospective claims database analysis from December 23, 2016, to November 20, 2019, to study nusinersen adherence and discontinuation/persistence in US patients with SMA types 1-3 who completed the loading phase, and to determine the impact of non-adherence or treatment discontinuation on SMA-related comorbidities, health care resource utilization (HCRU), and costs., Results: We identified 23 patients with SMA type 1, 41 patients with SMA type 2, and 260 patients with SMA type 3 who had completed the loading phase. Deviations from the indicated nusinersen treatment schedule were frequent in real-world usage, with most patients receiving ≥1 dose outside the scheduled interval. Across SMA types, non-adherent patients were more likely to have had SMA-related comorbidities (e.g., feeding difficulties, dyspnea and respiratory anomalies, and muscle weakness) and greater HCRU. Persistence rates 12 months after treatment initiation for patients with SMA types 1, 2, and 3 were 55.2%, 42.4%, and 54.6%, respectively. Patients who discontinued nusinersen and those who did not had generally similar comorbidity profiles. Discontinuation was associated with greater health care costs across SMA types., Conclusion: Our analysis of claims data indicated that discontinuation and non-adherence to nusinersen treatment were prevalent, and associated with greater frequency of comorbidities, greater HCRU, and increased costs for patients., (© 2021. The Author(s).)

Negative symptoms in schizophrenia are conceptualised as loading onto two factors: amotivation and diminished expression, which relate to different behavioural and neural markers. This distinction has proven useful for understanding the cognitive, motivational and neural mechanisms involved in negative symptoms, and for the development of treatments. Recently, it has been advocated that an even finer distinction into five subdomains is needed to understand the mechanisms underlying negative symptoms, and to prevent masking specific treatment and intervention effects. However, it is currently unclear whether such a fine-grained approach offers additional insights grounded in theory. In the present work, we focused on the factor amotivation, which has been shown to selectively correlate with the propensity to discount rewards in the face of effort and with the activity in the ventral striatum during reward anticipation. In a reanalysis of these studies we explored whether subdomains of amotivation - avolition, asociality, anhedonia - showed preferential correlation with these previously identified behavioural and neural markers. We show that for both behavioural and neural markers, a fine-grained model with the three subdomains did not better explain the data than a model with the amotivation factor only. Moreover, none of the three subdomains correlated significantly more or less with the behavioural or neural markers. Thus, no additional information was gained on amotivation in schizophrenia by selectively looking at its three subdomains. Consequently, the two-factor solution currently remains a valid option for the study of negative symptoms and further research is needed for behavioural and neural validation of the five-factor model., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Onasemnogene abeparvovec, a one-time intravenous gene replacement therapy, and nusinersen, an antisense oligonucleotide that requires ongoing intrathecal administration, have been evaluated as treatments for spinal muscular atrophy (SMA) type 1 in separate Phase III trials, but no head-to-head comparison studies have been conducted. Onasemnogene abeparvovec was compared with nusinersen using a matching-adjusted indirect comparison (MAIC) to estimate the treatment effect of onasemnogene abeparvovec relative to nusinersen for the treatment of symptomatic patients with SMA type 1 for up to 24 months of follow-up., Methods: In the absence of studies for both onasemnogene abeparvovec and nusinersen with a common comparator, a Bayesian naïve indirect treatment comparison (ITC) and MAIC between onasemnogene abeparvovec and nusinersen were conducted to compare efficacy and safety of onasemnogene abeparvovec with nusinersen. Outcomes of interest were event-free survival (EFS), overall survival (OS), and motor milestone achievements (independent sitting and independent walking). Relative treatment effects were expressed as relative risk (RR) and risk difference., Results: Pooled and weighted patient-level data illustrated a favorable effect toward onasemnogene abeparvovec, suggesting longer EFS for patients compared with nusinersen (HR of onasemnogene abeparvovec vs. nusinersen: 0.19 [95% CI: 0.07-0.54; 99% CI: 0.05-0.74]). At 24 months of follow-up, patients receiving onasemnogene abeparvovec were statistically significantly more likely to achieve the motor milestone of sitting independently compared with patients treated with nusinersen. Although statistically significant differences were not observed at 6 to 18 months between treatment options, the likelihood of sitting independently at 12 and 18 months numerically favored onasemnogene abeparvovec. A numerically greater likelihood of walking by 18 and 24 months was also observed for patients treated with onasemnogene abeparvovec compared with nusinersen. Onasemnogene abeparvovec therapy was also associated with a favorable (but statistically nonsignificant) outcome for OS and may be associated with prolonged survival compared with nusinersen (HR of onasemnogene abeparvovec vs. nusinersen: 0.35 [95% CI: 0.09-1.32; 99% CI: 0.06-2.01]). Bayesian naïve ITC results were similar to the MAIC analysis for EFS, OS, and motor milestone achievements. Small sample size limited covariate matching to baseline CHOP INTEND and nutritional support requirement, leading to wider CIs and statistically inconclusive outcomes for some of the results., Conclusions: Despite limitations of the current MAIC analysis (mainly a small sample size for statistical testing, even for the pooled onasemnogene abeparvovec trials, and potential differences in prognostic and predictive factors between studies), the relative treatment effects in EFS, OS, and motor milestone achievement indicate that onasemnogene abeparvovec may offer continued benefit compared with nusinersen through 24 months of follow-up.

Background : Recent cost-utility analysis (CUA) models for onasemnogene abeparvovec (Zolgensma®, formerly AVXS-101) in spinal muscular atrophy type 1 (SMA1) differ on key assumptions and results. Objective : To compare the manufacturer's proprietary CUA model to the model published by the Institute for Clinical and Economic Review (ICER), and to update the manufacturer's model with long-term follow-up data and some key ICER assumptions. Study design : We updated a recent CUA evaluating value for money in cost per incremental Quality-adjusted Life Year (QALY) of onasemnogene abeparvovec versus nusinersen (Spinraza®) or best supportive care (BSC) in symptomatic SMA1 patients, and compared it to the ICER model. Setting/Perspective : USA/Commercial payer Participants : Children aged <2 years with SMA1. Interventions : Onasemnogene abeparvovec, a single-dose gene replacement therapy, versus nusinersen, an antisense oligonucleotide, versus BSC. Main outcome measure : Incremental-cost effectiveness ratio and value-based price using traditional thresholds for general medicines in the US. Results : Updated survival (undiscounted) predicted by the model was 37.60 years for onasemnogene abeparvovec compared to 12.10 years for nusinersen and 7.27 years for BSC. Updated quality-adjusted survival using ICER's utility scores and discounted at 3% were 13.33, 2.85, and 1.15 discounted QALYs for onasemnogene abeparvovec, nusinersen, and BSC, respectively. Using estimated net prices, the discounted lifetime cost/patient was $3.93 M for onasemnogene abeparvovec, $4.60 M for nusinersen, and $1.96 M for BSC. The incremental cost per QALY gained for onasemnogene abeparvovec was dominant against nusinersen and $161,648 against BSC. These results broadly align with the results of the ICER model, which predicted a cost per QALY gained of $139,000 compared with nusinersen, and $243,000 compared with BSC (assuming a placeholder price of $2 M for onasemnogene abeparvovec), differences in methodology notwithstanding. Exploratory analyses in presymptomatic patients were similar. Conclusion : This updated CUA model is similar to ICER analyses comparing onasemnogene abeparvovec with nusinersen in the symptomatic and presymptomatic SMA populations. At a list price of $2.125 M, onasemnogene abeparvovec is cost-effective compared to nusinersen for SMA1 patients treated before age 2 years. When compared to BSC, cost per QALY of onasemnogene abeparvovec is higher than commonly used thresholds for therapies in the USA ($150,000 per QALY)., Competing Interests: Rebecca Dean, Ivar Jensen, Phil Cyr and Beckley Miller are employees of PRECISIONheor and PRECISIONheor received funding for the analysis from Novartis Gene Therapies. Benit Maru and Thomas Wiesner are employees of SSI Strategy, who were contracted to support Novartis Gene Therapies. Douglas M. Sproule, Douglas E. Feltner are former employees of Novartis Gene Therapies. Omar Dabbous, Matthias Bischof and Walter Toro are employees of Novartis Gene Therapies. Daniel C. Malone is a consultant to Novartis., (© The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

In response to the COVID-19 pandemic, a protocol was designed for mail-out devices and educational materials created to teach patients how to install a device for 2 weeks of continuous ambulatory ECG monitoring. We compared data collection from two sequential patient populations; one who received standard device application in the same clinic in the months before the pandemic response, and another, who received their device by mail for self-installation. Patients received a single phone call when the device was mailed and were able to contact the manufacturer as needed for support. A total of 47 devices were assessed from each group. Each group was similar in age (70 vs 65 years), and clinical indication for monitoring. Noise signal magnitude (22.34 vs 26.28%), symptom based manual activation (10 vs 8 events) and APB/recorded hour burden measurements (37.05 vs 23.36%) were similar in both groups (all comparisons were statistically non-significant). Both groups had a similar mean of hours recorded (240.37 vs. 245.05 h). Zero patient kits were lost, and all reports were delivered. Overall, it was found that a mail-delivered home-based recording platform can be reliably used to acquire clinical data with similar data quality and patient compliance as a conventional in-clinic model for long term ambulatory ECG monitoring., (Copyright © 2020 Elsevier Inc. All rights reserved.)

TRPV3 is a Ca 2+ -permeable cation channel, prominently expressed by keratinocytes where it contributes to maintaining the skin barrier, skin regeneration, and keratinocyte differentiation. However, much less is known about its physiological function in other tissues and there is still a need for identifying novel and efficient TRPV3 channel blockers. By screening a compound library, we identified 26E01 as a novel TRPV3 blocker. 26E01 blocks heterologously expressed TRPV3 channels overexpressed in HEK293 cells as assessed by fluorometric intracellular free Ca 2+ assays (IC 50  = 8.6 μM) but does not affect TRPV1, TRPV2 or TRPV4 channels. Electrophysiological whole-cell recordings confirmed the reversible block of TRPV3 currents by 26E01, which was also effective in excised inside-out patches, hinting to a rather direct mode of action. 26E01 suppresses endogenous TRPV3 currents in the mouse 308 keratinocyte cell line and in the human DLD-1 colon carcinoma cell line (IC 50  = 12 μM). In sections of the gastrointestinal epithelium of mice, the expression of TRPV3 mRNA follows a gradient along the gastrointestinal tract, with the highest expression in the distal colon. 26E01 efficiently attenuates 2-aminoethoxydiphenyl borate-induced calcium influx in primary colonic epithelial cells isolated from the distal colon. As 26E01 neither shows toxic effects on DLD-1 cells at concentrations of up to 100 μM in MTT assays nor on mouse primary colonic crypts as assessed by calcein-AM/propidium iodide co-staining, it may serve as a useful tool to further study the physiological function of TRPV3 in various tissues., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The sinus elevation procedure is a safe and predictable technique that allows the placement of implants in atrophic posterior maxillae. However, some recommendations have to be followed by the patient to ensure reliable healing. It is particularly important to avoid inducing trauma in the region concerned and through the sinuses. This report describes a rare complication that occurred after the grafting of a sinus, which was attributed to a violent sneeze a few hours after the intervention. The diagnosis of emphysema following air entry was confirmed by the suddenness of the swelling and associated crepitation, and by the radiographic observation of a delimited radiolucent zone in the grafted sinus. The immediate diagnosis and subsequent management prevented further adverse events. This case report supports the need for complete comprehensive instruction of patients after oral surgery, swift diagnosis, and management of emphysema., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2020 Marc El Hage et al.)

Negative symptoms in schizophrenia have been suggested to map onto two distinct factors - amotivation and diminished expression. Only recently, two-factor solutions for measuring negative symptoms have been proposed for the Positive and Negative Symptom Scale (PANSS), the most commonly used scale to assess the psychopathology of patients with schizophrenia. We aimed to validate the PANSS two-factor structure on a clinical, behavioural and neural level. For this multi-level validation, we reanalysed several datasets with patients for whom both the Brief Negative Symptom Assessment Scale (BNSS) and PANSS data were collected. We used a clinical dataset (n = 120) as well as behavioural data from an effort-based decision making task (n = 31) and functional neuroimaging data from a monetary incentive delay task (n = 41). Both tasks have previously been shown to be associated with BNSS amotivation. On the clinical level, the PANSS amotivation and diminished expression were highly correlated with their BNSS counterparts. On the behavioural level, we found that the PANSS amotivation factor but not the diminished expression factor specifically associated with willingness to invest effort to obtain a reward. On the neural level, PANSS amotivation was specifically related to reduced ventral striatal activation during reward anticipation. Our data confirm that the PANSS clearly allows distinguishing amotivation from diminished expression, as it relates selectively to specific aspects of behaviour and brain function. Our results will allow a re-analysis and sharing of existing datasets that used the PANSS to further substantiate the distinction between the two factors in neuroscientific studies and clinical trials., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Surface modification may yield enhanced soft tissue adhesion to transmucosal titanium implant necks., Aim: To evaluate and compare changes in soft tissues around implants with a modified hydrophilic sandblasted and acid-etched neck (mSLA; test) to those with a machined neck (M; control)., Materials and Methods: Implants with a diameter of 4.1 mm and a neck height of 1.8 mm were randomly inserted in healed sites with pristine bone of the posterior maxilla or mandible. The modified Sulcus Bleeding Index (mSBI) (primary outcome) was assessed at baseline (BL) and 6, 12 and 36 months. Secondary outcomes included the assessment of pocket probing depth (PPD), mucosal recession (REC) and clinical attachment level (CAL). Standardized radiographs were taken at time of implant placement, at BL and after 12 and 36 months., Results: Of the 43 randomized subjects, 38 (19 test and 19 controls) completed the 36-month follow-up. Implant survival rates amounted to 95.5% (test) and 100% (control) (p > .05). At 36 months, 77.6% of test implants and 78.9% of control implants were without any bleeding sites (mSBI = 0; p > .05). The 36-month success rate was 86.4% in the test and 85.7% in the control group, respectively (p > .05). At 36 months, the mean radiographic bone level change from BL was 0.33 ± 0.69 mm at test implants and 0.12 ± 0.3 mm at control implants (p > .05)., Conclusion: Tissue level implants with a hydrophilic mSLA transmucosal neck failed to yield clinical and radiographic benefits compared with implants with a machined neck up to 3 years., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

It has been suspected that abnormalities in social inference (e.g., learning others' intentions) play a key role in the formation of persecutory delusions (PD). In this study, we examined the association between subclinical PD and social inference, testing the prediction that proneness to PD is related to altered social inference and beliefs about others' intentions. We included 151 participants scoring on opposite ends of Freeman's Paranoia Checklist (PCL). The participants performed a probabilistic advice-taking task with a dynamically changing social context (volatility) under one of two experimental frames. These frames differentially emphasised possible reasons behind unhelpful advice: (i) the adviser's possible intentions (dispositional frame) or (ii) the rules of the game (situational frame). Our design was thus 2 × 2 factorial (high vs. low delusional tendencies, dispositional vs. situational frame). We found significant group-by-frame interactions, indicating that in the situational frame high PCL scorers took advice less into account than low scorers. Additionally, high PCL scorers believed more frequently that incorrect advice was delivered intentionally and that such misleading behaviour was directed towards them personally. Overall, our results suggest that social inference in individuals with subclinical PD tendencies is shaped by negative prior beliefs about the intentions of others and is thus less sensitive to the attributional framing of adviser-related information. These findings may help future attempts of identifying individuals at risk for developing psychosis and understanding persecutory delusions in psychosis., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: Surgically facilitated orthodontic treatment is increasingly being used, especially for adults, to facilitate tooth movements and reduce the duration of orthodontic treatment. The present article reports on an innovative, safe, and minimally invasive technique to perform flapless corticotomies using a dedicated surgical guide produced with a complete digital intraoral and laboratory workflow., Materials and Methods: A 51-year-old man presented with maxillary and mandibular anterior crowding. He required rapid treatment with limited use of braces. Corticotomies were planned for both arches before the use of orthodontic appliances. The matching of the stereolithographic files obtained from the digital prints of the full arches and the cone beam computed tomography images allowed for the positioning of the cutting planes for corticisions. The guide was printed with a transparent, biocompatible, and photopolymerizable resin, and cold sterilized. Minimally invasive corticotomies were performed using a piezoelectric instrument. The orthodontic treatment started immediately after surgery., Results: No adverse events were recorded during surgery. The piezoelectric instrument was guided accurately, and precise application of the corticisions prevented all the anatomical elements from being injured. The healing was uneventful and the patient experienced no pain., Conclusion: The present report shows that a surgical guide specifically and digitally produced for corticotomies allowed for the performance of a minimally invasive flapless technique and accurate piezosurgery. The use of such a guide was easy to implement, made the procedure safer, and reduced postoperative pain.

The primary tool used currently for preventing pesticide drift from entering streams is a no-spray buffer zone. Riparian hedgerows may provide an additional option; however, quantitative information on their effectiveness is limited. To quantify the potential benefit of riparian hedgerows for drift reduction, aerial malathion {diethyl 2-[(dimethoxyphosphorothioyl)sulfanyl]butanedioate} applications on blueberry ( L.) farms with fields adjacent to streams or ditches were monitored. Drift from fields with extensive dense woody riparian vegetation was compared with drift from fields with no dense woody riparian vegetation. Overall, total instream malathion deposition was 96.1% lower at vegetated sites compared with nonvegetated sites. Univariable models identified six variables that were significantly related to decreasing instream total malathion deposition: increasing bank canopy cover, increasing average site canopy cover, increasing canopy angle, increasing the distance between the field edge and vegetation edge, increasing the distance between the field edge and center of stream, and decreasing bank slope. For the variables most feasible for landowners to alter, the following increases could result, on average, in a 26% decrease in the total instream malathion deposition: bank canopy cover (7%), distance between field and vegetation (0.3 m), and distance between field and center of stream (0.9 m). No-spray buffer sizes needed for significant deposition reductions may be large, but for nonvegetated or minimally vegetated streams similar to those studied here, increasing bank canopy cover may give comparable advantages while allowing the use of the entire field area and conferring additional ecosystem benefits such as shading streams and improving habitat., (© 2019 The Author(s).)

Purpose: The aim of this study was to evaluate the performance of implants placed for 5 years in grafted vs nongrafted sinuses in relation to crown-to-implant ratio. The measurements of crown and implant lengths took into account changes in both endo-sinus and crestal bone levels over 5 years., Materials and Methods: Enrolled patients required one or two implants in at least one sinus and presented a residual bone height of posterior maxilla ≤ 4 mm. Individual sinuses were randomly allocated either to be grafted or not before surgery. Implants of 8 mm in length were placed using osteotome sinus floor elevation (OSFE). After 10 weeks of healing, they were loaded functionally using definitive single crowns. Radiographic measurements were made on periapical radiographs taken at surgery, prosthetic steps, and 5 years. The implant length was measured between the most apical and coronal contact of bone and implant, and the crown length was measured between the most occlusal point of the crown and the crestal bone. Data were analyzed using mixed linear models., Results: Twenty implants were placed in grafted sinuses and 17 in native bone (12 patients). One of the 35 restored implants failed. Immediately after surgery, the mean lengths of the implants placed in grafted and nongrafted sites were 2.4 ± 0.8 and 2.7 ± 0.9 mm, respectively (P = .351). At loading, the mean crown-to-implant ratios were 3.8 ± 0.8 and 4.6 ± 2.0 (P = .033), respectively, whereas at 5 years, they were 2.0 ± 0.8 and 2.1 ± 0.4, respectively (P = .341)., Conclusion: The use of grafting material is not necessary to restore posterior maxilla ≤ 4 mm with OSFE and simultaneous implant placement. Over 5 years, all restored implants but one were functional. Despite unfavorable conditions in terms of initial bone anchorage and height of single crown restoration, a high initial crown-to-implant ratio did not compromise the long-term survival of implants placed in grafted or nongrafted sinuses.

This position statement is based on current evidence available on the safety and benefits of continuous subcutaneous insulin infusion therapy (CSII, pump therapy) in diabetes with an emphasis on the effects of CSII on glycemic control, hypoglycaemia rates, occurrence of ketoacidosis, quality of life and the use of insulin pump therapy in pregnancy. The current article represents the recommendations of the Austrian Diabetes Association for the clinical praxis of insulin pump treatment in children, adolescents and adults.

This position statement represents the recommendations of the Austrian Diabetes Association regarding the clinical diagnostic and therapeutic application, safety and benefits of continuous subcutaneous glucose monitoring systems in patients with diabetes, based on current evidence.

This article aims to evaluate and compare the 10-year bone anchorage and protrusion of implants into the sinus using cone beam computerized tomography (CBCT) and periapical radiography. Implants (≤ 10 mm) were placed with osteotome sinus floor elevation (OSFE) without grafting in maxillae with bone height ≤ 8 mm. After 10 years, the CBCT analysis showed bone presence at the buccal and palatal implant sides and corroborated the results obtained using periapical radiographs. In the absence of any symptom or complication, the use of two-dimensional radiography is sufficient for routine long-term follow-up of implants after OSFE without grafting.

Objective: Negative symptoms are currently viewed as having a 2-dimensional structure, with factors reflecting diminished expression (EXP) and motivation and pleasure (MAP). However, several factor-analytic studies suggest that the consensus around a 2-dimensional model is premature. The current study investigated and cross-culturally validated the factorial structure of BNSS-rated negative symptoms across a range of cultures and languages., Method: Participants included individuals diagnosed with a psychotic disorder who had been rated on the Brief Negative Symptom Scale (BNSS) from 5 cross-cultural samples, with a total N = 1691. First, exploratory factor analysis was used to extract up to 6 factors from the data. Next, confirmatory factor analysis evaluated the fit of 5 models: (1) a 1-factor model, 2) a 2-factor model with factors of MAP and EXP, 3) a 3-factor model with inner world, external, and alogia factors; 4) a 5-factor model with separate factors for blunted affect, alogia, anhedonia, avolition, and asociality, and 5) a hierarchical model with 2 second-order factors reflecting EXP and MAP, as well as 5 first-order factors reflecting the 5 aforementioned domains., Results: Models with 4 factors or less were mediocre fits to the data. The 5-factor, 6-factor, and the hierarchical second-order 5-factor models provided excellent fit with an edge to the 5-factor model. The 5-factor structure demonstrated invariance across study samples., Conclusions: Findings support the validity of the 5-factor structure of BNSS-rated negative symptoms across diverse cultures and languages. These findings have important implications for the diagnosis, assessment, and treatment of negative symptoms., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Osteotome sinus floor elevation (OSFE) is a technique aimed at simplifying implant placement in the posterior atrophic maxilla. The necessity of bone grafting under the elevated sinus membrane has been widely debated. The aim was to compare the evolution over 5 years of implant stability in sites grafted or left ungrafted., Materials and Methods: A total of 12 patients (9 female and 3 male) presenting ≤ 4 mm initial bone height (IBH) in the posterior maxillary sites were recruited. Implants (n = 37) were placed using OSFE. According to the randomisation, the sinuses received either bone graft (n = 20, control group) or no graft (n = 17, test group). Patients received both these treatments when both sinuses fulfilled the inclusion criteria. Control assessments were performed 1 week, 10 weeks, 12 weeks, and then 1 year, 3 years and 5 years after the implant placement. Periapical radiographs were taken and the implant stability quotient (ISQ) was measured at different time points., Results: At implant surgery, the mean ISQ was 58.9 ± 11.2 for the test group and 53.8 ± 10.2 for the control group; it plummeted 10 weeks after the implant placement and rose thereafter. Five years after the implant placement, the mean ISQ reached 80.8 ± 4.2 for the control group, and 79.7 ± 4.3 for the test group. The difference between the groups was not significant. The IBH significantly affected implant stability at implant insertion and 5 years after the implant insertion, but not at the other time points., Conclusions: The implants performed using OSFE in ungrafted sites were as stable as the implants placed in grafted sites., Competing Interests: Conflict of interest statement: All authors report no conflict of interest.

Purpose: To evaluate the thickness of the sinus membrane in contact with implants inserted 10 years before using an augmentation procedure without grafting material, and to identify adverse events correlated with implant protrusion in the sinus., Materials and Methods: Osteotome sinus floor elevations were performed without grafting material. The implants (Straumann AG, Basel, Switzerland) were placed simultaneously, all protruded into the sinus. After 10 years, implants were considered viable in the absence of mobility, pain, infection, or continued radiolucency. Sinus health was assessed using cone-beam computed tomography and by the way of a questionnaire in which patients reported symptoms of sinusitis they might have had., Results: Controlled implants (21 implants, 13 patients) were osseointegrated. The membrane thickness was <2 mm in 11 patients and 2 to 3 mm with flat thickening in 2 patients. No patients exhibited any clinical or radiographic signs of sinusitis., Conclusions: No sinus complications were observed after 10 years. The initial protrusion of implants into the sinus did not influence long-term sinus health. The maintenance of successful integration is thus the key to avoiding sinus complication.

Background: Apathy can be defined as a reduction of goal-directed behavior and is a strong predictor for poor functional outcome in schizophrenia. However, no objective measure of apathy has been identified and assessment is limited to retrospective interview-based ratings. Here we aimed to identify more precise objective readouts of apathy for translational research and clinical practice., Methods: We employed a combined approach including interview-based ratings of the two negative symptom factors apathy and diminished expression, actigraphy based measures of spontaneous motor activity and the evaluation of daily activities using ecological momentary assessment. Furthermore, a functional magnetic resonance imaging task for reward anticipation was applied to investigate shared and divergent neural correlates of interview-based and behaviorally measured apathy., Results: We found in 18 schizophrenia patients with high interview-based apathy levels that motor activity was negatively correlated with apathy but not with diminished expression. In contrast, measures of daily activities were not associated with apathy. Neural activation during reward anticipation revealed an association between hypoactivation of the ventral striatum and interview-based apathy as well as hypoactivation of the inferior frontal gyrus and motor activity level., Conclusions: Spontaneous motor activity is an objective readout of apathy, which was specific and not present for diminished expression. On a neural level, interview-based and objective measures of apathy showed divergent neural correlates in the cortical-striatal network, which suggests dissociable neural processes. Finally, motor activity provides a promising readout for quantifying apathy in both translational research and clinical practice., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Striatal abnormalities play a crucial role in the pathophysiology of schizophrenia. Growing evidence suggests an association between aberrant striatal activity during reward anticipation and symptom dimensions in schizophrenia. However, it is not clear whether this holds across the psychosis continuum. The aim of the present study was to investigate alterations of ventral striatal activation during reward anticipation and its relationship to symptom expression in persons with schizotypal personality traits (SPT) and first-episode psychosis. Twenty-six individuals with high SPT, 26 patients with non-affective first-episode psychosis (including 13 with brief psychotic disorder (FEP-BPD) and 13 with first-episode schizophrenia [FEP-SZ]) and 25 healthy controls underwent event-related functional magnetic resonance imaging while performing a variant of the Monetary Incentive Delay task. Ventral striatal activation was positively correlated with total symptom severity, in particular with levels of positive symptoms. This association was observed across the psychosis continuum and within each subgroup. Patients with FEP-SZ showed the strongest elevation of striatal activation during reward anticipation, although symptom levels did not differ between groups in the psychosis continuum. While our results provide evidence that variance in striatal activation is mainly explained by dimensional symptom expression, patients with schizophrenia show an additional dysregulation of striatal activation. Trans-diagnostic approaches are promising in order to disentangle dimensional and categorical neural mechanisms in the psychosis continuum., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Patients with a history of intravenous drug abuse included in an official opioid substitution program represent an important subgroup of patients with chronic hepatitis C. The objective of this study was to assess the efficacy of and adherence to treatment with peginterferon and ribavirin in Austrian patients on stable opioid substitution therapy (OST)., Methods: This prospective, multicenter, observational, non-interventional trial (clinicaltrials.gov identifier, NCT01416610) included treatment-naïve patients with chronic hepatitis C on OST. Treatment consisted of peginterferon alpha-2a (PEGASYS®, 180 µg/week) plus ribavirin (COPEGUS®, 1000/1200 mg/day in genotypes (GT) 1/4 and 800 mg/day in GT 2/3) for 24-72 weeks, according to GT and viral response., Results: The intention-to-treat (ITT) population comprised 88 patients. Mean duration of therapy was 6.0 ± 2.8 months. Treatment was discontinued earlier than planned in 34 out of 88 patients (39%), mainly because of poor adherence or side effects of treatment. At the end of treatment 65/88 patients (74%) were PCR negative. During follow-up, 5 patients relapsed. Only 44/88 patients (50%) could be evaluated 24 weeks after the end of treatment. Sustained virologic response 24 weeks after end of therapy (SVR24) was documented in 39/88 patients (44%). If only patients were considered who finished treatment as planned and for whom results at follow-up week 24 were available, the SVR24 rate was 89% (32/36)., Conclusion: Despite favorable prognostic factors, such as young age and a high proportion of GT3, SVR rates were low in this cohort of patients receiving OST, the main reason being poor adherence; however, in those patients completing treatment, the SVR rate was high.

Background: Climate change affects human health. The respective consequences are predicted to increase in the future. Patients with chronic lung disease are particularly vulnerable to the involved environmental alterations. However, their subjective perception and reactions to these alterations remain unknown., Methods: In this pilot study, we surveyed 172 adult patients who underwent pulmonary rehabilitation and 832 adult tourists without lung disease in the alpine region about their perception of being affected by climate change and their potential reaction to specific consequences. The patients' survey also contained the COPD Assessment Test (CAT) to rate the severity of symptoms., Results: Most of the patients stated asthma (73.8%), COPD (9.3%) or both (11.0%) as underlying disease while 5.8% suffered from other chronic lung diseases. Patients and tourists feel equally affected by current climate change in general, while allergic subjects in both groups feel significantly more affected (p = 0.04). The severity of symptoms assessed by CAT correlates with the degree of feeling affected (p<0.01). The main disturbing consequences for patients are decreased air quality, increasing numbers of ticks and mosquitos and a rising risk for allergy and extreme weather events such as thunderstroms, while tourists are less disturbed by these factors. Increasing number of heat-days is of little concern to both groups., Conclusion: Overall patients are more sensitive to health-related consequences of climate change. Yet, the hazard of heat-days seems underestimated and awareness should be raised.

Objectives: Over 5 years, (i) to evaluate the clinical efficiency of 8-mm implants placed with osteotome sinus floor elevation (OSFE) in extremely atrophic maxillae and (ii) to compare bone levels around implants placed with and without grafting., Material and Methods: TE ® SLActive ® implants (Institut Straumann AG, Basel, Switzerland) were placed in sites with a residual bone height (RBH) of ≤4 mm. Before surgery, sinuses were randomized to receive anorganic bovine bone (control) or no graft (test). After 10 weeks of healing, implants were functionally loaded with single crowns. Bone levels were measured from standardized peri-apical radiographs., Results: Thirty-seven (17 test, 20 control) implants were placed in 12 patients (RBH: 2.4 ± 0.9 mm). Two early and one late failures occurred. The success rate was 91.9% (94.1% test, 90.0% control). All implants gained endo-sinus bone (3.8 ± 1.0 mm test, 4.8 ± 1.2 mm control; P = 0.004). Mean crestal bone loss (CBL) was 0.6 ± 1.1 mm, without a significant difference between the groups (P = 0.527). Mean bone gain and CBL did not change significantly between 1 and 5 years (P = 0.249 and P = 0.293, respectively)., Conclusions: Atrophic posterior maxillae can be predictably rehabilitated using OSFE with a simultaneous implant placement. The new bone formed around implants after 1 year was stable after 5 years, irrespective of the presence or the absence of graft. Grafting was unnecessary to achieve an average bone augmentation of 3.8 mm, but more bone was gained with grafting., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Nuclear orphan receptor NR4A1 exerts an essential tumor suppressor function in aggressive lymphomas. In this study, we investigated the hypothesized contribution of the related NR4A family member NR4A3 to lymphomagenesis. In aggressive lymphoma patients, low expression of NR4A3 was associated with poor survival. Ectopic expression or pharmacological activation of NR4A3 in lymphoma cell lines led to a significantly higher proportion of apoptotic cells. In a mouse NSG xenograft model of lymphoma (stably transduced SuDHL4 cells), NR4A3 expression abrogated tumor growth, compared with vector control and uninduced cells that formed massive tumors. Transcript analysis of four different aggressive lymphoma cell lines overexpressing either NR4A3 or NR4A1 revealed that apoptosis was driven similarly by induction of BAK, Puma, BIK, BIM, BID, and Trail. Overall, our results showed that NR4A3 possesses robust tumor suppressor functions of similar impact to NR4A1 in aggressive lymphomas. Cancer Res; 77(9); 2375-86. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Oroantral communication (OAC) rarely occurs long after implant placement. The present report describes the rare etiology and the difficulty of the diagnosis of an uncommon OAC occurring 10 years after the implant placement in the posterior maxilla. The difficulty of the diagnosis lies in the absence of clinical symptoms of sinusitis and presence of multiunit prosthesis hiding implant failure. This case report supports the need for sinus check-up during a routine implant examination.

Background: Negative symptoms are considered core symptoms of schizophrenia. The Brief Negative Symptom Scale (BNSS) was developed to measure this symptomatic dimension according to a current consensus definition. The present study examined the psychometric properties of the German version of the BNSS. To expand former findings on convergent validity, we employed the Temporal Experience Pleasure Scale (TEPS), a hedonic self-report that distinguishes between consummatory and anticipatory pleasure. Additionally, we addressed convergent validity with observer-rated assessment of apathy with the Apathy Evaluation Scale (AES), which was completed by the patient's primary nurse., Methods: Data were collected from 75 in- and outpatients from the Psychiatric Hospital, University Zurich diagnosed with either schizophrenia or schizoaffective disorder. We assessed convergent and discriminant validity, internal consistency and inter-rater reliability., Results: We largely replicated the findings of the original version showing good psychometric properties of the BNSS. In addition, the primary nurses evaluation correlated moderately with interview-based clinician rating. BNSS anhedonia items showed good convergent validity with the TEPS., Conclusions: Overall, the German BNSS shows good psychometric properties comparable to the original English version. Convergent validity extends beyond interview-based assessments of negative symptoms to self-rated anhedonia and observer-rated apathy.

Background: An economic analysis from the perspective of the UK National Health Service (NHS) evaluated the cost effectiveness of lisdexamfetamine dimesylate (LDX) compared with atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder who have had an inadequate response to methylphenidate., Methods: A 1-year decision-analytic model was constructed, with the health outcomes "response", "nonresponse", and "unable to tolerate". Clinical data were taken from a head-to-head, randomized controlled trial in inadequate responders to methylphenidate. Response to treatment was defined as a score of 1 (very much improved) or 2 (much improved) on the Clinical Global Impression-Improvement subscale. Tolerability was assessed by discontinuation rates owing to adverse events. Utility weights were identified via a systematic literature review. Healthcare resource use estimates were obtained via a survey of clinicians. Daily drug costs were derived from British National Formulary 2012 costs and mean doses reported in the trial. One-way and probabilistic sensitivity analyses (PSAs) were performed., Results: The comparison of LDX with atomoxetine resulted in an estimate of an incremental cost-effectiveness ratio of £1802 per quality-adjusted life-year (QALY). The result was robust in a wide range of sensitivity analyses; results were most sensitive to changes in drug costs and efficacy. In the PSA, assuming a maximum willingness to pay of £20,000 per QALY, LDX versus atomoxetine had an 86 % probability of being cost effective. In 38 % of PSA runs, LDX was more effective and less costly than atomoxetine., Conclusions: From the perspective of the UK NHS, LDX provides a cost-effective treatment option for children and adolescents who are inadequate responders to methylphenidate., Competing Interests: Compliance with Ethical Standards Ethical standards This was a non-interventional cost-utility analysis; therefore, institutional review board approval and informed consent were deemed unnecessary. This article does not contain any studies with human participants/animals performed by any of the authors. Funding This study was funded by Shire Development LLC. Funding was provided to RTI Health Solutions to develop the model. Open access was funded by Shire International GmbH. Conflict of interest EAZ and JAM are employees of RTI Health Solutions. MB is an employee of Shire. PH and JS were employees of Shire when this work was conducted. SMB was an employee of RTI when this work was conducted and is now employed by BresMed Health Solutions, Sheffield, UK.

Objectives The role of postoperative mediastinal radiotherapy in completely resected non-small cell lung cancer (NSCLC) and pathological N2 disease is controversial. In clinical practice, not all lung cancer patients with histologically confirmed N2 disease and a high risk for local recurrence are able to undergo postoperative concurrent radio/chemotherapy due to their physical condition or postoperative morbidities. Mediastinal radiotherapy is less compromising than a combination of radio/chemotherapy and seems likely to be tolerable for limited patients to achieve better local tumor control. Materials and Methods All patients included in this retrospective analysis were excluded from postoperative adjuvant combination chemo/radiotherapy due to their comorbidity, advanced age, or a complicated postoperative course. Three-dimensional conformal radiotherapy of the mediastinal lymph node stations (mean dose: 50 Gy; range: 50-54 Gy) in patients with R0 resection, additional boost of 10 Gy in patients with R1 or R2 resection, was performed postoperatively. Results A total of 110 patients were included in this analysis. Mean survival was 25.5 ± 19.2 months. The 1-, 3-, and 5-year survival was 75.4, 38.7, and 26.2%, respectively. Postoperative complications and the development of distant metastases did not correlate (p = 0.7). Distant metastases proved to be a significant prognostic factor of survival (p < 0.0001). Local recurrence was seen in a total of three patients (2.7%). Five-year survival of patients developing major postoperative complications was significantly inferior (p = 0.04) to those without postoperative complications. The extent of surgery had a significant impact on survival-5-year survival after lobectomy was significantly longer than after pneumonectomy (p = 0.029). R1 resection had no significant impact on the survival rates (p = 0.67). Discussion Stage III-N2 NSCLC patients with multiple comorbidities or a complicated postoperative course after surgery may benefit from modern mediastinal radiotherapy. Surgery and postoperative mediastinal radiotherapy can achieve local tumor control. Distant metastases have the highest impact on the prognosis. Pneumonectomy, however, should be avoided in stage III NSCLC, when possible., (Georg Thieme Verlag KG Stuttgart · New York.)

Theoretical principles of information processing and empirical findings suggest that to efficiently represent all possible rewards in the natural environment, reward-sensitive neurons have to adapt their coding range dynamically to the current reward context. Adaptation ensures that the reward system is most sensitive for the most likely rewards, enabling the system to efficiently represent a potentially infinite range of reward information. A deficit in neural adaptation would prevent precise representation of rewards and could have detrimental effects for an organism's ability to optimally engage with its environment. In schizophrenia, reward processing is known to be impaired and has been linked to different symptom dimensions. However, despite the fundamental significance of coding reward adaptively, no study has elucidated whether adaptive reward processing is impaired in schizophrenia. We therefore studied patients with schizophrenia (n=27) and healthy controls (n=25), using functional magnetic resonance imaging in combination with a variant of the monetary incentive delay task. Compared with healthy controls, patients with schizophrenia showed less efficient neural adaptation to the current reward context, which leads to imprecise neural representation of reward. Importantly, the deficit correlated with total symptom severity. Our results suggest that some of the deficits in reward processing in schizophrenia might be due to inefficient neural adaptation to the current reward context. Furthermore, because adaptive coding is a ubiquitous feature of the brain, we believe that our findings provide an avenue in defining a general impairment in neural information processing underlying this debilitating disorder.

Background: Little is known about the long-term outcome of implants placed in the atrophic maxilla using osteotome sinus floor elevation (OSFE) without grafting., Purpose: The study aims to evaluate the long-term efficiency of the procedure and stability of the peri-implant bone formed following implant placement without grafting into resorbed posterior maxilla., Materials and Methods: Twenty-five implants (≤10 mm in length) were placed in 17 patients using OSFE without grafting. The mean residual bone height was 5.4 ± 2.3 mm. Bone levels were evaluated at 1, 3, 5, and 10 years using periapical radiographs., Results: Fifteen patients (23 implants) participated in the 10-year examination. All implants fulfilled the survival criteria. Following surgery, the implant sites gained endo-sinus bone (mean: 3.0 ± 1.4 mm). The mean crestal bone loss (CBL) was limited to 1.0 ± 0.9 mm. The difference in mean endo-sinus bone gain and CBL was statistically significant between 1 and 10 years, but not between 3 and 5, 3 and 10, and 5 and 10 years., Conclusions: At 10 years, the implant survival rate was 100%. Endo-sinus bone was mainly gained during the first year. This study demonstrates the long-term predictability of OSFE without grafting and simultaneous implant placement., (© 2015 Wiley Periodicals, Inc.)

This position statement is based on the current evidence available on the safety and benefits of continuous subcutaneous insulin pump therapy (CSII) in diabetes with an emphasis on the effects of CSII on glycemic control, hypoglycaemia rates, occurrence of ketoacidosis, quality of life and the use of insulin pump therapy in pregnancy. The current article represents the recommendations of the Austrian Diabetes Association for the clinical praxis of insulin pump treatment in children, adolescents and adults.

Background: Negative symptoms of schizophrenia can be grouped in 2 dimensions: apathy and diminished expression. Increasing evidence suggests that negative symptoms are associated with altered neural activity of subcortical and cortical regions in the brain reward system. However, the neurobiological basis of the distinct symptom dimensions within negative symptoms is still poorly understood. The primary aim of our study was to examine the neural correlates of the negative symptom dimensions apathy and diminished expression during a reward processing task., Methods: Patients with schizophrenia and healthy controls underwent event-related fMRI while performing a variant of the Monetary Incentive Delay Task. We assessed negative symptom dimensions using the Brief Negative Symptom Scale., Results: We included 27 patients and 25 controls in our study. Both groups showed neural activation indicated by blood oxygen-level dependent signal in the ventral striatum during reward anticipation. Ventral striatal activation during reward anticipation showed a strong negative correlation with apathy. Importantly, this effect was not driven by cognitive ability, medication, depressive or positive symptoms. In contrast, no significant correlation with the diminished expression dimension was observed., Limitations: Although the results remain significant when controlling for chlorpromazine equivalents, we cannot fully exclude potential confounding effects of medication with atypical antipsychotics., Conclusion: The specific correlation of ventral striatal hypoactivation during reward anticipation with apathy demonstrates a differentiation of apathy and diminished expression on a neurobiological level and provides strong evidence for different pathophysiological mechanisms underlying these 2 negative symptom dimensions. Our findings contribute to a multilevel framework in which apathy and motivational impairment in patients with schizophrenia can be described on psychopathological, behavioural and neural levels.

Background and Purpose: To report our experience with limb-sparing surgery, IOERT and EBRT in extremity STS., Materials and Methods: 183 patients were retrospectively analyzed. 78% presented in primary situation, with 80% located in the lower limb. Stage at presentation was: I: 6%, IIa: 25%, IIb: 21%, III: 42%, IV: 7%. The majority showed high-grade lesions (grade 1: 5%, 2: 31%, 3: 64%). IOERT was applied to the tumor bed (median 15Gy) and preceded (9%) or followed (91%) by EBRT (median 45Gy) in all patients., Results: Median follow-up was 64months (78months in survivors). Surgery was complete in 68%, while 32% had microscopic residual disease. 5- and 10-year-LC was 86% and 84%, respectively. LC was significantly higher in primary compared to recurrent disease and tended to be higher after complete resection. Estimated 5- and 10-year-DC was 68% and 66%, while corresponding OS was 77% and 66%, respectively. OS was significantly affected by grading and stage. Severe postoperative complications and late toxicities were observed in 19% and 20%, respectively. Limb-preservation rate was 95% with good function in 83%., Conclusions: Combination of limb-sparing surgery, IOERT and EBRT achieved encouraging LC and OS in this unfavorable patient group with acceptable postoperative complications and low rates of late toxicities resulting in a high limb-preservation rate and good functional outcome., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

This position statement represents the recommendations of the Austrian Diabetes Association regarding the clinical diagnostic and therapeutic application, safety and benefits of continuous subcutaneous glucose monitoring systems in patients with diabetes mellitus, based on current evidence.

Background: The question whether a minimal maxillary residual bone height (RBH) allows the predictable use of osteotome sinus floor elevation (OSFE) remains unresolved., Purpose: To evaluate the efficacy of short implants placed with OSFE in an RBH of ≤4 mm and to compare bone levels around implants placed with (control) or without (test) grafting after 3 years., Materials and Methods: Eight-millimeter implants were placed by OSFE in sinuses randomized to receive anorganic bovine bone or no grafting material. Healing time before prosthetic rehabilitation was 10 weeks. Peri-implant bone levels were measured on standardized periapical radiographs., Results: Thirty-seven implants (17 test, 20 control) were placed at a mean RBH of 2.4 ± 0.9 mm. Three implants failed during the 3-year follow-up. After 3 years, all implants had gained endosinus bone (test: 4.1 ± 1.0 mm; control: 5.1 ± 1.2 mm; p = .001). Mean bone gain was stable between 1 and 3 years in both groups., Conclusions: Grafting is unnecessary to achieve bone augmentation of 4.1 mm; however, more bone is gained with grafting. Bone gained over 1 year was retained. Atrophic posterior maxillae can be predictably rehabilitated using OSFE and simultaneous placement of 8-mm implants., (© 2015 Wiley Periodicals, Inc.)

Aims: Spinal muscular atrophy (SMA) is a rare genetic disorder characterized by progressive muscle weakness, atrophy, respiratory failure, and in severe cases, infantile death. Early detection and treatment before symptom onset may substantially improve outcomes, allowing patients to achieve age-appropriate motor milestones and longer survival. We assessed the cost-utility of newborn screening (NBS) for SMA in Japan., Materials and Methods: A cost-utility model (decision tree and Markov model) compared lifetime health effects and costs between "NBS" for SMA (presymptomatic treatment) or "no NBS" (treatment initiated at symptom onset). Model inputs were sourced from literature, local data, and expert opinion. Sensitivity and scenario analyses were conducted to assess model robustness and data validity., Results: Based on the 1:10,000 SMA incidence, it was estimated that 43 newborns/year would have SMA, and a total of 39 patients with SMA would initiate presymptomatic treatment after NBS. An estimated 736 quality-adjusted life-years were gained per annual birth cohort with NBS. NBS for SMA was dominant compared with no NBS (i.e. less costly and more effective), with ¥8,856,960,096 reduced total costs with NBS versus no NBS (base-case). Sensitivity and scenario analyses supported cost effectiveness of NBS for SMA versus no NBS. A greater percentage of patients was estimated to enjoy longer survival and be without permanent assisted ventilation with NBS versus no NBS., Limitations: Real-world observations may differ from single-arm clinical trial outcomes. It was assumed that patients with SMA identified via NBS were asymptomatic and would receive treatment prior to symptoms. Best supportive care was not considered, and Japan-specific variations in gene replacement therapy protocol were not fully reflected., Conclusion: NBS for SMA allows for early identification of patients with SMA and treatment initiation before symptom onset, improving health outcomes and reducing total costs than without NBS.

Purpose: Current guidelines recommend postoperative radiation therapy (PORT) for incompletely resected non-small cell lung cancer (NSCLC). However, there is still a paucity of evidence for this approach. Hence, we analyzed survival in 78 patients following radiotherapy for incompletely resected NSCLC (R1) and investigated prognostic factors., Patients and Methods: All 78 patients with incompletely resected NSCLC (R1) received PORT between December 2001 and September 2014. The median total dose for PORT was 60 Gy (range 44-68 Gy). The majority of patients had locally advanced tumor stages (stage IIA (2.6%), stage IIB (19.2%), stage IIIA (57.7%) and stage IIIB (20.5%)). 21 patients (25%) received postoperative chemotherapy., Results: Median follow-up after radiotherapy was 17.7 months. Three-year overall (OS), progression-free (PFS), local (LPFS) and distant progression-free survival (DPFS) rates were 34.1, 29.1, 44.9 and 51.9%, respectively. OS was significantly prolonged at lower nodal status (pN0/1) and following dose-escalated PORT with total radiation doses >54 Gy (p=0.012, p=0.013). Furthermore, radiation doses >54 Gy significantly improved PFS, LPFS and DPFS (p=0.005; p=0.050, p=0.022). Interestingly, survival was neither significantly influenced by R1 localization nor by extent (localized vs. diffuse). Multivariate analyses revealed lower nodal status and radiation doses >54.0 Gy as the only independent prognostic factors for OS (p=0.021, p=0.036)., Conclusion: For incompletely resected NSCLC, PORT is used for improving local tumor control. Local progression is still the major pattern of failure. Radiation doses >54 Gy seem to support improved local control and were associated with better OS in this retrospective study., (Copyright © 2015. Published by Elsevier Ireland Ltd.)

Negative symptoms can be grouped into the two dimensions of diminished expression and apathy, which have been shown to be dissociable regarding external validators, such as functional outcome. Here, we investigated whether these two dimensions differentially relate to neurocognitive impairment in schizophrenia. 47 patients with schizophrenia or schizoaffective disorder and 33 healthy control participants were subjected to a neurocognitive test battery assessing multiple cognitive domains (processing speed, working memory, verbal fluency, verbal learning and memory, mental planning), which are integrated into a composite cognition score. Negative symptoms in patients were assessed using the Brief Negative Symptom Scale. We found that diminished expression significantly related to neurocognitive impairment, while severity of apathy symptoms was not directly associated with neurocognition. Other assessed clinical variables include chlorpromazine equivalents, positive symptoms, and depressive symptoms and did not influence the results. Our results are in line with a cognitive resource limitation model of diminished expression in schizophrenia and indicate that cognitive remediation therapy might be helpful to ameliorate expressive deficits., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The negative symptoms of schizophrenia have been associated with altered neural activity during both reward processing and cognitive processing. Even though increasing evidence suggests a strong interaction between these two domains, it has not been studied in relation to negative symptoms. To elucidate neural mechanisms of the reward-cognition interaction, we applied a letter variant of the n-back working memory task and varied the financial incentives for performance. In the interaction contrast, we found a significantly activated cluster in the rostral anterior cingulate cortex (ACC), the middle frontal gyrus, and the bilateral superior frontal gyrus. The interaction did not differ significantly between the patient group and a healthy control group, suggesting that patients with schizophrenia are on average able to integrate reward information and utilize this information to maximize cognitive performance. However within the patient group, we found a significant inverse correlation of ACC activity with the factor diminished expression. This finding is consistent with the model that a lack of available cognitive resources leads to diminished expression. We therefore argue that patients with diminished expression have difficulties in recruiting additional cognitive resources (as implemented in the ACC) in response to an anticipated reward. Due to this lack of cognitive resources, less processing capacity is available for effective expression, resulting in diminished expressive behavior., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Reducing the scale of etched nanostructures below the 10 nm range eventually will require an atomic scale understanding of the entire fabrication process being used in order to maintain exquisite control over both feature size and feature density. Here, we demonstrate a method for tracking atomically resolved and controlled structures from initial template definition through final nanostructure metrology, opening up a pathway for top-down atomic control over nanofabrication. Hydrogen depassivation lithography is the first step of the nanoscale fabrication process followed by selective atomic layer deposition of up to 2.8 nm of titania to make a nanoscale etch mask. Contrast with the background is shown, indicating different mechanisms for growth on the desired patterns and on the H passivated background. The patterns are then transferred into the bulk using reactive ion etching to form 20 nm tall nanostructures with linewidths down to ~6 nm. To illustrate the limitations of this process, arrays of holes and lines are fabricated. The various nanofabrication process steps are performed at disparate locations, so process integration is discussed. Related issues are discussed including using fiducial marks for finding nanostructures on a macroscopic sample and protecting the chemically reactive patterned Si(100)-H surface against degradation due to atmospheric exposure.

Purpose: The purpose of this study was to evaluate postoperative radiotherapy regarding outcome and toxicity in patients with thymic epithelial tumors (TET) after surgery., Materials and Methods: We retrospectively analyzed medical records of 41 patients with TET treated with postoperative radiotherapy at our institution between 1995 and 2012. The impact of prognostic factors (e.g., Masaoka stage, histological subtype) was investigated and radiation-related toxicity was assessed., Results: Median age was 59.8 years and median follow-up was 61 months. In 24.4 %, TETs were associated with paraneoplastic syndromes. The 5-year overall survival (OS) was 89.5 % and the 5-year disease-free survival (DFS) was 88.9 %. Masaoka stage had a significant impact on OS (p = 0.007). Locally limited stages I + II had a 5-year OS of 100 % compared to 80 % for stage III and 66.7 % for stage IV. The 5-year DFS was excellent with 100 % for both WHO groups A/AB/B1 and B2, respectively, and significantly (p = 0.005) differed from B3/C-staged patients with a 5-year DFS of 63.6 %. Resection status, paraneoplastic association, radiation dose, or tumor size did not influence survival. There were no high-grade acute or late side effects caused by radiotherapy., Conclusion: Masaoka stage has a significant impact on OS as WHO type has on DFS in patients with TETs after surgery and adjuvant irradiation. Postoperative radiotherapy with doses around 50 Gy is safe and not likely to cause high-grade toxicity. Further prospective trials are necessary to separate patient subgroups that benefit from radiotherapy from those that do not.

Objectives: Acute chest pain (ACP) is a leading cause of hospital emergency unit consultation. As there are various underlying conditions, ranging from musculoskeletal disorders to acute coronary syndrome (ACS), thorough clinical diagnostics are warranted. The aim of this prospective study was to assess whether reproducible chest wall tenderness (CWT) on palpation in patients with ACP can help to rule out ACS., Methods: In this prospective, double-blinded diagnostic study, all consecutive patients assessed in the emergency unit at the University Hospital Zurich because of ACP between July 2012 and December 2013 were included when a member of the study team was present. Reproducible CWT on palpation was the initial step and was recorded before further examinations were initiated. The final diagnosis was adjudicated by a study-independent physician., Results: 121 patients (60.3% male, median age 47 years, IQR 34-66.5 years) were included. The prevalence of ACS was 11.6%. Non-reproducible CWT had a high sensitivity of 92.9% (95% CI 66.1% to 98.8%) for ACS and the presence of reproducible CWT ruled out ACS (p=0.003) with a high negative predictive value (98.1%, 95% CI 89.9% to 99.7%). Conversely non-reproducible CWT ruled in ACS with low specificity (48.6%, 95% CI 38.8% to 58.5%) and low positive predictive value (19.1%, 95% CI 10.6% to 30.5%)., Conclusions: This prospective diagnostic study supports the concept that reproducible CWT helps to rule out ACS in patients with ACP in an early stage of the evaluation process. However, ACS and other diagnoses should be considered in patients with a negative CWT test., Trial Registration Number: ClinicalTrial.gov: NCT01724996., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Myelinating Schwann cells in the vertebrate peripheral nervous system rely on Brg1 (Smarca4) for terminal differentiation. Brg1 serves as central ATP-hydrolyzing subunit of the chromatin remodelling BAF complexes and is recruited during myelination as part of these complexes by the transcription factor Sox10 in Schwann cells. Here, we analyzed the role of Brg1 during development of myelinating oligodendrocytes in the CNS of the mouse. Following Brg1 deletion in oligodendrocyte precursors, these cells showed normal survival, proliferation, and migration. A mild but significant reduction in the number of oligodendrocytes with myelin gene expression in the absence of Brg1 points to a contribution to oligodendroglial differentiation but also shows that the role of Brg1 is much less prominent than during Schwann cell differentiation. Additionally, we failed to obtain evidence for a genetic interaction between Brg1 and Sox10 comparable with the one in Schwann cells. This argues that similarities exist between the regulatory networks and mechanisms in both types of myelinating glia but that the exact mode of action and the relevance of functional interactions differ, pointing to a surprising degree of variability in the control of myelination., (Copyright © 2015 the authors 0270-6474/15/350021-15$15.00/0.)

Background: The best therapy for patients with stage I non-small cell lung cancer (NSCLC) who are medically unfit for lobectomy or prefer not to undergo surgery has not yet been demonstrated., Objectives: We analyzed data from our prospective database to evaluate the recurrence and survival rates and assess the extent to which the type of treatment explains outcome differences., Methods: This study included 116 patients with histologically proven clinical stage I NSCLC who were treated with sublobar resection (SLR; n = 42), radiofrequency ablation (RFA; n = 25) or radiotherapy (RT; n = 49) between 2009 and 2013. The primary end point was the time to primary tumor recurrence (PR). Kaplan-Meier curves and Cox regression were used to compare the recurrence patterns and survivals after adjustments for potential confounders., Results: The SLR patients were younger and exhibited better performance status. The RT patients had larger tumors. After adjusting for age and tumor size, there were differences between the different treatments in terms of the PR rate, but no differences were observed in overall (OS) or disease-free survival. The hazard ratio for PR comparing SLR versus RT adjusted for age and tumor size was 2.73 (95% confidence interval, CI, 0.72-10.27) and that for SLR versus RFA was 7.57 (95% CI 1.94-29.47)., Conclusions: Our study suggests that SLR was associated with a higher primary tumor control rate compared to RFA or RT, although the OSs were not different. These results should be confirmed in prospective trials., (© 2015 S. Karger AG, Basel.)