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In order to rapidly develop C6 and C8 SAR of our reported tricyclic sulfone series of RORγt inverse agonists, a late-stage bromination was employed. Although not regioselective, the bromination protocol allowed us to explore new substitution patterns/vectors that otherwise would have to be incorporated at the very beginning of the synthesis. Based on the SAR obtained from this exercise, compound 15 bearing a C8 fluorine was developed as a very potent and selective RORγt inverse agonist. This analog's in vitro profile, pharmacokinetic (PK) data and efficacy in an IL-23 induced mouse acanthosis model will be discussed., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aim of the study was to examine the course of schizophrenia patients within 2 years after discharge. Within a multicenter study of the German Competence Network on Schizophrenia, patients suffering from a schizophrenia spectrum disorder were examined regarding their psychopathological improvement, tolerability, and the treatment regime applied during hospitalization and a 2-year follow-up period. Response, remission, the level of everyday functioning, and relapse were furthermore evaluated during the follow-up period using established definitions for these outcome domains. The psychopharmacological treatment was specifically evaluated in terms of a potential association with relapse. 149 patients were available for analysis, with 65% of the patients being in response, 52% in symptomatic remission, and 64% having a satisfiable everyday functioning 2 years after their discharge from hospital. Despite these favorable outcome rates, 63% of the patients suffered from a relapse within the 2-year follow-up period with 86% of these patients being rehospitalized. Discharge non-responder and non-remitter were twice as likely to relapse during follow-up. A significant decrease of side-effects was observed with negligible rates of extrapyramidal side-effects, sedation, and weight gain during follow-up. Patients receiving treatment with atypical antipsychotics were found to have the lowest risk to relapse (p < 0.0001). The results highlight the natural and unsteady course of schizophrenia in most patients underlining the need to develop more specific treatment strategies ensuring ongoing stability and preventing relapse.

Background: Nucleic acid testing is essential for the detection and quantification of HCV RNA in the diagnosis of HCV infection and treatment monitoring. The Alinity m HCV assay was recently developed by Abbott Molecular for rapid detection and quantification of HCV RNA on the fully automated, continuous, random-access Alinity m analyzer., Objectives: Our study assessed the performance of the new Alinity m HCV assay for detection and quantification of HCV RNA in a large series of patient samples of various genotypes. This international, multicentric study evaluated the linearity, precision, and reproducibility of the Alinity m HCV assay and its performance in comparison to three other HCV assays currently used in clinical practice., Results: The Alinity m HCV assay demonstrated high linearity (correlation coefficient r = 1.00), precision (coefficients of variation [CV] 6.6-13.5 %) and reproducibility (CV 1.7-4.3 % across three control lots). At a concentration near the lower limit of detection, the Alinity m HCV assay exhibited >98 % detectability. The Alinity m HCV assay showed excellent correlation with comparator HCV assays in serum (n = 406) and plasma (n = 1401) samples (correlation coefficients ≥0.96, bias 0.01 to 0.14 Log 10 IU/mL). More than 95 % of the quantified results with the Alinity m HCV assay were less than mean bias ± 1.96 SD different from those of the comparator assays., Conclusions: The newly developed Alinity m HCV assay is sensitive, reproducible, and accurately quantifies HCV RNA levels in serum and plasma samples from patients with chronic HCV infection, with no impact of HCV genotype on assay performance., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Accurate molecular methods to detect and quantify hepatitis B virus (HBV) DNA are essential to diagnose chronic infections, guide treatment decisions, assess response to treatment, and determine risk of HBV-related complications. New generations of real-time HBV DNA assay platforms provide results in less than 2-3 h, with continuous loading of specimens and true random-access capability., Objectives: We examined the clinical performance of the new Alinity m HBV assay, run on the fully automated, continuous, random-access Alinity m platform, to accurately detect and quantify HBV DNA in a large series of patient samples infected with different HBV genotypes frequently encountered in clinical practice., Study Design: This international, multisite study assessed the precision and reproducibility of the Alinity m HBV assay and compared its performance to four HBV assays currently in clinical use., Results: The Alinity m HBV assay demonstrated linear quantitation of HBV DNA in plasma samples, with high precision (coefficient of variation 4.1 %-8.8 %) and reproducibility. The Alinity m HBV assay showed excellent correlation (correlation coefficients ≥0.947) with comparator HBV assays, with an overall observed bias ranging from -0.07 to 0.17 Log 10 IU/mL. 97 % of quantifiable patient results were <1 Log 10 IU/mL different than the respective comparator assays, with comparable results across HBV genotypes., Conclusions: The newly developed real-time PCR-based Alinity m HBV assay is sensitive, reproducible, and accurately quantifies HBV DNA levels from HBsAg-positive patients across the full dynamic range of quantification., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Accurate, rapid detection of HIV-1 RNA is critical for early diagnosis, treatment decision making, and long-term management of HIV-1 infection., Objective: We evaluated the diagnostic performance of the Alinity m HIV-1 assay, which uses a dual target/dual probe design against highly conserved target regions of the HIV-1 genome and is run on the fully automated Alinity m platform., Study Design: This was an international, multisite study that compared the diagnostic performance of the Alinity m HIV-1 assay to four commercially available HIV-1 assays routinely used in nine independent clinical laboratories. Alinity m HIV-1 assay precision, detectability, and reproducibility was compared across four study sites., Results: The Alinity m HIV-1 assay produced comparable results to currently available HIV-1 assays (correlation coefficient >0.995), with an overall bias of -0.1 to 0.10 Log 10 copies/mL. The Alinity m HIV-1 assay and its predecessor m2000 HIV-1 assay demonstrated comparable detection of 16 different HIV-1 subtypes (R 2  = 0.956). A high level of agreement (>88 %) between all HIV-1 assays was seen near clinical decision points of 1.7 Log 10 copies/mL (50 copies/mL) and 2.0 Log 10 copies/mL (200 copies/mL). Alinity m HIV-1 assay precision was 0.08 and 0.21 Log 10 copies/mL at VLs of 1000 and 50 copies/mL, respectively, with a high level of detectability (≥97 % hit rate) and reproducibility across sites., Conclusions: The Alinity m HIV-1 assay provides comparable diagnostic accuracy to current HIV-1 assays, and when run on the Alinity m system, has the capacity to shorten the time between diagnosis and treatment., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Hepatitis C virus (HCV) antigen/antibody (Ag/Ab) assays offer the benefit of reducing the window period compared to assays that detect only HCV-Ab. In this study the performance of the Murex Ag/Ab (Murex, Abbott) and Monolisa Ag/Ab Ultra (Monolisa, Bio-Rad) ELISAs was compared for the use of filter dried serum/plasma spots (DS/PS) with a focus on the sensitivity and the percentage of correct positive test results. Correct positive ELISA results were assumed for samples that subsequently tested positive for HCV RNA by RT-qPCR, or RNA negative samples that tested positive in a Western blot (confirmed ELISA results). Sensitivity was evaluated from DS/PS eluates using HCV seroconversion panels [plasma samples of subtypes-(St) 1a, 2b)] and longitudinal HCV antibody positive serum panels (St 1b, 2b, 3a, and 4d). The proportion of correct positive test results was evaluated using 1102 newly diagnosed HIV positive clinical dried serum spots (DSS) eluates for screening of potential HCV co-infection. For the plasma HCV seroconversion samples, which were used as a reference for DSS eluates, the Murex became reactive earlier for antigen positive bleeds. However, for the HCV antibody positive eluates and dilutions thereof, the Monolisa demonstrated a superior sensitivity. Of the clinical DSS 22.8 % (28/123) of samples reactive in the Murex were negative in a subsequent RT-qPCR and Western blot, while only 1.9 % (2/105) of the samples reactive in the Monolisa were negative in these confirmatory assays. Our results indicate that the Monolisa provides fewer false positive results for HCV detection in DSS, whereas for undiluted plasma or serum samples, the Murex can serve as an additional diagnostic tool to narrow the window period., Competing Interests: Declaration of Competing Interest None, (Copyright © 2020 Elsevier B.V. All rights reserved.)

Monitoring recency of infection helps to identify current transmission in vulnerable populations for effective disease control. We have established an in-house avidity based hepatitis C virus (HCV) recency assay based on the Monolisa Anti-HCV PLUS Version 3 ELISA kit for use of dried serum/plasma spots (DS/PS) in order to distinguish recent and long-term infections. A first panel of DS/PS (n = 218; genotype 1 n = 170 and non-genotype 1 n = 48) consisting of primary and at least one follow up sample was used to analyze the temporal changes of the Avidity Index (AI) over time. Sub-panels of longitudinal DS/PS (n = 66) and acute cases (<26 weeks; n = 34) were taken to calculate the Mean Duration of Recent Infection (MDRI) and the False Long-term Rate (FLTR), respectively. A second panel of DS/PS >104 weeks (n = 132) and a third panel of DS/PS prepared from resolved infections (≥180 days since last positive; n = 32) were used to calculate the False Recent Rate (FRR). For all genotypes, the optimal AI cut-off was determined to be 40% resulting in an MDRI of 364 days (95% CI: 223-485). FLTR was 5.9% (95% CI: 0.7-19.7), 8.3% (95% CI: 1-27), and 0% (-) and FRR was 13.6% (95% CI: 8.3-20.7), 11.7% (95% CI: 6.6-19), and 30.6% (95% CI: 9.1-61.4) for all genotypes, genotype 1, and non-genotype 1 infections, respectively. For resolved infections, the FRR was 53.1% (95% CI: 35.8-70.4). Thus, this assay performs particularly well for genotype 1 reaching a high rate of correct discriminations between infections acquired less than a year before diagnosis and those acquired earlier by applying an AI cut-off of 40%. Due to a rapid decline in avidity post resolution of an HCV infection this assay is not recommended to be used in HCV RNA negative patients., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Novel tricyclic analogues were designed, synthesized, and evaluated as RORγt inverse agonists. Several of these compounds were potent in an IL-17 human whole blood assay and exhibited excellent oral bioavailability in mouse pharmacokinetic studies. This led to the identification of compound 5 , which displayed dose-dependent inhibition of IL-17F production in a mouse IL-2/IL-23 stimulated pharmacodynamic model. In addition, compound 5 was studied in mouse acanthosis and imiquimod-induced models of skin inflammation, where it demonstrated robust efficacy comparable to a positive control. As a result of this excellent overall profile, compound 5 (BMS-986251) was selected as a clinically viable developmental candidate., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Background: Fear of reinjury is common after anterior cruciate ligament reconstruction (ACLR) and often deters a return to preinjury sport participation. A better understanding of injury-related fear is needed to inform rehabilitation strategies., Purpose/hypothesis: The purpose of this study was to (1) identify individual fear-evoking tasks or situations, (2) compare the intensity and amount of change relative to other injury-related fears (reinjury, knee giving way, and knee pain) after completion of a return-to-sport training program, and (3) determine whether standardized questionnaires can identify the intensity of fear for the individual fear-evoking task or situation and for fear of reinjury. The hypothesis was that the task or situation that evokes fear would vary across patients and the intensity of that fear would be higher and show less change after return-to-sport training compared with other injury-related fears., Study Design: Case series; Level of evidence, 4., Methods: Participants included 33 patients (15 males; mean age, 18 years) with ACLR who enrolled in a group-format return-to-sport training program. Questionnaires completed before and after return-to-sport training included items to specify fear-evoking tasks or situations, items to rate the intensity of various injury-related fears, the Anterior Cruciate Ligament Return to Sport after Injury scale (ACL-RSI), and the Tampa Scale for Kinesiophobia (TSK-11)., Results: The most common fear-evoking task or situation was cutting, followed by contact, jumping, and other. Intensity of fear-evoking task or situation was higher than other injury-related fears, but all fears decreased in intensity after training. The ACL-RSI score better identified the intensity of fear for the individual fear-evoking task or situation and for fear of reinjury than did the TSK-11 score., Conclusion: Activities that evoke fear vary across patients, but fear of cutting is common. The intensity of common fears after ACLR decreased after advanced group training, and large effect sizes were seen for nearly all examined fears. Fear of reinjury and intensity of individually feared tasks may be better reflected in the ACL-RSI score than the TSK-11 score., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: B.J.N. has received research support from Histogenics and Regentis, educational support from Arthrex, and consulting fees from Marrow Access Technology. M.T. has received research support from DJO. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2020.)

Introduction : Antipsychotic-induced weight-gain (AIWG) is a very important, yet often neglected side-effect in the treatment with first and second generation antipsychotics. AIWG can increase the risk of developing metabolic syndrome, diabetes and cardiovascular disease. Meta-analyzes mostly concentrate on AIWG in schizophrenic and bipolar patients, even though antipsychotics are prescribed off-label across many other diagnostic groups (e.g. anxiety disorders, depression, autistic disorder). Areas covered : Pub Med and Web of Science were systematically searched for RCTs reporting on AIWG with a sample size of ≥ 100 published between 2014 and 2019. All diagnoses and ages were included. Expert opinion : Inclusion criteria were fulfilled by 27 RCTs. All antipsychotics led to significantly more weight-gain (p < .001) and most antipsychotics led to a significantly higher risk for a clinically relevant weight-gain of ≥7% compared to placebo (RR = 2.04). The results support previous findings that weight-gain occurs quickly. To efficaciously and efficiently tackle the problem of AIWG in clinical practice and trials, people at high risk need to be identified by predictive tools enabling the clinician to offer tailored adjunctive therapies (medication and/or lifestyle interventions). Most importantly, weight and metabolic monitoring ought to be consequently implemented in clinical routine in the treatment of any patient with any diagnosis when antipsychotics are prescribed.

Background: Despite being recommended for use in clinical trials, the consensus remission criteria were found to leave patients with persisting symptoms, relevant areas of functional impairment and a decreased sense of wellbeing. Therefore, to evaluate the appropriateness of the schizophrenia consensus criteria, a definition of remission based on the Clinical Global Impression Scale (CGI) was developed and remitter subgroups were compared., Methods: 239 patients with a schizophrenia spectrum disorder were evaluated regarding their remission status after inpatient treatment. Remission in schizophrenia was defined according to the symptom-severity component of the consensus criteria by Andreasen et al. and a CGI based definition was calculated using sensitivity and specificity using receiver operating curves (asymptomatic remitter). Both remitter groups (schizophrenia consensus versus asymptomatic remitters) were compared regarding different clinical variables at discharge as well as the likelihood to relapse within a 1-year follow-up period. Both schizophrenia remitter subgroups were compared to remitters in major depression as a reference value., Results: Following the consensus criteria, 63% of the schizophrenia patients were in remission compared to only 18% following the asymptomatic criterion. The schizophrenia consensus remitters were less likely to be concurrent treatment responders (p < 0.0001), had a significantly greater illness severity (p < 0.0001) and less functioning (p = 0.0358) as well as a significantly greater risk to relapse (p = 0.0174) compared to the schizophrenia asymptomatic remitters as well as the depressed remitters., Conclusion: It should be critically re-evaluated if the currently proposed consensus criteria are adequate to measure what is traditionally understood to be remission., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: The aim of this double-blind randomized study was to evaluate the response to antipsychotic treatment in schizophrenia patients with predicted high/low risk of nonresponse identified by applying a set of well-established scales and predictors of outcome and to compare efficacy between ziprasidone and haloperidol., Methods: One hundred twelve schizophrenia patients (ziprasidone: n=54; haloperidol: n=58) were rated weekly on the Positive and Negative Syndrome Scale for Schizophrenia (PANSS), the Global Assessment of Functioning Scale (GAF), the Social and Occupational Functioning Scale (SOFAS), the Simpson-Angus Scale (SAS), and Hillside Akathisia Scale (HAS)., Results: Ninety-two patients (82%) were predicted to have a high risk of nonresponse. No significant difference regarding PANSS improvement in this subsample was found comparing ziprasidone and haloperidol (p=0.563). Also, for the total patient sample, no significant difference was found regarding the course of the PANSS total score, GAF (p=0.921), and SOFAS (p=0.658) between ziprasidone and haloperidol. Haloperidol resulted in higher scores on the SAS (p=0.001) and HAS (p=0.011)., Discussion: An alarmingly high number of patients were at high risk of nonresponse to antipsychotic treatment., Competing Interests: The authors report no financial conflict of interests within the context of this article., (© Georg Thieme Verlag KG Stuttgart · New York.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

The reactivity of phosphanyl phosphonates toward diacetylenic ketones was studied. Reactions resulted in the selective formation of phospholones via phosphaalkene intermediates. Phospholones were obtained in yields of 37-96% depending on the substituent on the acetylenic unit. Reduction of the phenyl-substituted phospholone resulted in the formation of a persubstituted phosphole bearing a hydroxyl group in position 3 in 64% yield, and its oxidation led to oxaphospholone in 77% yield. Both of these modifications led to substantial changes in the optoelectronic properties of the compounds and bathochromic shifts of the longest wavelength absorption maximum.

High accuracy and precision at the lower end of quantification are crucial requirements of a modern HIV viral load (VL) assay, since some clinically relevant thresholds are located at 50 and 200 copies/ml. In this study, we compared the performance of two new fully automated HIV-1 VL assays, Aptima HIV-1 Quant Dx and Cobas HIV-1 (Cobas 6800), with the established RealTi m e m 2000 assay. Assay precision and accuracy were evaluated in a retrospective evaluation out of excess plasma material from four HIV-1+ individuals (subtypes B, C, CRF01&#95;AE, and CRF02&#95;AG). Native plasma samples were diluted to nominal concentrations at 50 and 200 copies/ml (according to the RealTi m e m 2000 assay). All dilutions were tested in triplicate in five independent runs over 5 days and in three labs per system. Assay concordance was determined using 1,011 surplus clinical routine samples, as well as selected retrospective longitudinal samples from 7 patients on treatment. The three assays yielded highly concordant results for individual clinical samples ( R 2 > 0.98; average difference, ≤0.2 log copies/ml) and retrospective longitudinal samples from patients on treatment. The Aptima and RealTi m e assays showed similar high precision, meeting the 5σ criterion for the majority of samples across all labs and subtypes. The Cobas assay was less precise, missing the 5σ criterion for the majority of samples at low concentrations. In this analysis, results from the Cobas assay appeared less reliable near the clinically relevant cutoff and should be interpreted with more caution in this context. Due to high precision, full automation, and high concordance with the RealTi m e assay, the Aptima assay represents a good alternative in routine VL monitoring., (Copyright © 2018 Wiesmann et al.)

Background: Application of autologous platelet-rich plasma in fibrin matrix (PRPFM) improves tendon healing in patients undergoing arthroscopic rotator cuff repair. We performed a prospective, randomized, single-blinded study of 76 patients, with an α level of 5% and power of 80%., Materials and Methods: Seventy-six patients were divided into 2 randomized groups. The treatment group underwent arthroscopic rotator cuff repair with PRPFM. The control group did not receive the PRPFM treatment. Patients were evaluated preoperatively and at 6 months and 24 months postoperatively with validated clinical outcome scores, and dynamometer examination. A magnetic resonance imaging scan was performed at 6 months postoperatively., Results: The 2 randomized groups were homogeneous. Western Ontario Rotator Cuff (WORC) scores were not statistically different at any time interval. The WORC scores changed from 1257 to 139 in the control group and from 1106 to 99 in the PRPFM group over the 24-month study period. On the Simple Shoulder Test, improvement over the study period was noted from 45% to 96% in the control group and from 49% to 96% in the PRPFM group. Strength of the supraspinatus at 24 months by dynamometer testing was 99.8% in the control group and 96.3% in the PRPFM group. Infraspinatus strength was 104% in the control group and 103% in the PRPFM group. The secondary outcome of retear occurred at a rate of 19% for the double-row technique and 7.4% for the PRPFM technique at 6 months. All our results were statistically insignificant., Conclusions: Our results showed no benefit from PRPFM used for rotator cuff repair according to the WORC Index, Simple Shoulder Test, and shoulder strength index., (Copyright © 2018 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Identifying resistance to antiretroviral drugs is crucial for ensuring the successful treatment of patients infected with viruses such as human immunodeficiency virus (HIV) or hepatitis C virus (HCV). In contrast to Sanger sequencing, next-generation sequencing (NGS) can detect resistance mutations in minority populations. Thus, genotypic resistance testing based on NGS data can offer novel, treatment-relevant insights. Since existing web services for analyzing resistance in NGS samples are subject to long processing times and follow strictly rules-based approaches, we developed geno2pheno[ngs-freq], a web service for rapidly identifying drug resistance in HIV-1 and HCV samples. By relying on frequency files that provide the read counts of nucleotides or codons along a viral genome, the time-intensive step of processing raw NGS data is eliminated. Once a frequency file has been uploaded, consensus sequences are generated for a set of user-defined prevalence cutoffs, such that the constructed sequences contain only those nucleotides whose codon prevalence exceeds a given cutoff. After locally aligning the sequences to a set of references, resistance is predicted using the well-established approaches of geno2pheno[resistance] and geno2pheno[hcv]. geno2pheno[ngs-freq] can assist clinical decision making by enabling users to explore resistance in viral populations with different abundances and is freely available at http://ngs.geno2pheno.org.

Antipsychotics are effective in treating schizophrenia but may lead to a higher cardiovascular risk due to QTc prolongation. Besides drugs, genetic and clinical factors may contribute to QTc prolongation. The aim of this study is to examine the effect of candidate genes known for QTc prolongation and their interaction with common antipsychotics. Thus, 199 patients were genotyped for nine polymorphisms in KCNQ1, KCNH2, SCN5A, LOC10537879, LOC101927066, NOS1AP and NUBPL. QTc interval duration was measured before treatment and weekly for 5 weeks while being treated with risperidone, quetiapine, olanzapine, amisulpride, aripiprazole and haloperidol in monotherapy. Antipsychotics used in this study showed a different potential to affect the QTc interval. We found no association between KCNH2, KCNQ1, LOC10537879, LOC101927066, NOS1AP and NUBPL polymorphisms and QTc duration at baseline and during antipsychotic treatment. Mixed general models showed a significant overall influence of SCN5A (H558R) on QTc duration but no significant interaction with antipsychotic treatment. Our results do not provide evidence for an involvement of candidate genes for QTc duration in the pathophysiology of QTc prolongation by antipsychotics during short-term treatment. Further association studies are needed to confirm our findings. With a better understanding of these interactions the cardiovascular risk of patients may be decreased.

Objectives: This in-vitro study was performed to compare the contact wear, fracture strength and failure mode of implant-supported all-ceramic single crowns manufactured with various fabrication and fixation concepts., Materials and Methods: Fifty dental implants (Conelog Ø 4,3mm/L11mm, Camlog Biotechnologies AG) were embedded and treated with all-ceramic molar single-crowns. Three groups received hand-layered zirconia crowns (IPS e.max Ceram/ IPS e.max ZirCAD, Ivoclar Vivadent AG): CZL (cement-retained zirconia-based layered) group crowns were cemented conventionally, SZL (screw-retained zirconia-based layered) group crowns were screw-retained, MZL (modified zirconia-based layered) group crowns showed a different coping design with screw retention. The specimens of SST (screw-retained sintering-technique) and SFL (screw-retained full-contour lithium-disilicate) group were CAD/CAM (Computer-aided design/computer-aided manufacturing) fabricated in the sintering technique (IPS e.max ZirCAD/IPS e.max CAD, Ivoclar Vivadent AG) and full-contour of lithium disilicate (IPS e.max CAD, Ivoclar Vivadent AG) respectively and screw-retained. All specimens underwent artificial aging, load until failure and a scanning electron microscopy (SEM) analysis. The received data were statistically compared (one-way ANOVA; Student-Newman-Keuls test; Mann-Whitney U-test) at a significance level of 5%., Results: Mouth-motion fatigue testing caused two abutment fractures (SST group and SZL group) and two chipping events (CZL group). Specimens of MZL group showed statistically significant less contact wear compared to the other groups (p<0.001). There was no statistical difference between the groups in terms of the maximum fracture load. SEM-analysis showed a more homogenous structure and surface of CAD/CAM fabricated specimens towards manually veneered components., Conclusions: The mode of retention did not influence the fracture resistance but the failure patterns of the specimens. CAD/CAM milled lithium-disilicate crowns seemed to be a preserving factor for dental implants., Clinical Relevance: The mode of retention and veneering influences the mechanical performance of implant-supported single crowns.

Acute hepatitis C virus infection remains a major health concern in human immunodeficiency virus(HIV)-infected men who have sex with men (MSM). New direct-acting antiviral agent (DAA) combination therapy has not yet been approved for the treatment for acute hepatitis C virus(HCV), thereby potentially causing deferral of HCV treatment. Therefore, we aimed to study the course of liver disease after an episode of acute HCV. This study is a retrospective single-centre cohort of HIV-positive MSM with acute HCV infection. Liver fibrosis was estimated by Fibroscan ® and Fibrotest ® . Liver-related and non-liver-related outcomes were documented. Overall 213 episodes of acute HCV infection in 178 men were documented. Median follow-up for all included patients was 38.7 months. Spontaneous HCV clearance was found in 10.8% of patients, which was significantly associated with older age, lower HCV RNA levels, and higher ALT levels upon initial acute HCV diagnosis. Treatment with interferon-based therapy was initiated in 86.3% of cases, resulting in a sustained virological response(SVR) rate of 70.7%. After 3 years' follow-up, significant liver fibrosis of METAVIR F2 stage or higher was found in 39.4% of patients after first acute HCV diagnosis. Higher age, physician-declared alcoholism, and nonresponse to acute HCV therapy were independently associated with higher fibrosis stages. Ten patients died during the observation period (IR 1.4/100 patient-years) and four during interferon treatment. Significant liver fibrosis is a common finding in HIV-positive MSM following acute HCV infection despite high treatment uptake and cure rates, suggesting the need for close liver disease monitoring particularly if HCV treatment is deferred., (© 2017 John Wiley & Sons Ltd.)

The aim of this study was to evaluate antidepressant add-on treatment within the acute treatment of schizophrenia spectrum disorder patients. Antidepressant add-on was evaluated in 365 patients within a naturalistic multicenter study. Patients with/without antidepressant add-on were compared regarding clinical and treatment-related variables, response and remission, and remission of depressive and negative symptoms. The efficacy of antidepressant add-on treatment was furthermore analyzed applying marginal structure models. Twenty-three percent of the patients received antidepressant add-on for a mean duration of 50.28 (33.42) days. Patients with the diagnosis of a schizoaffective disorder, multiple illness episodes, and a longer duration of their illness as well as those with significantly fewer baseline positive symptoms, more negative and depressive symptoms, more side effects, and less subjective well-being were augmented with antidepressants. At discharge no significant effect of antidepressant add-on treatment was observed in terms of a 25% improvement (p=0.2623), a 50% improvement (p=0.3946), remission (p=0.0552), or remission of depressive (p=0.6336) and negative symptoms (p=0.8756). Also, when analyzing marginal structure models considering the diagnostic subgroups, no significant effect was found. Add-on with antidepressants is common. A final recommendation in terms of this strategy's efficacy cannot be given., Competing Interests: Conflict of Interest: In terms of the study at hand the authors declare no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Introduction: NEUROD2 is a neurospecific helix-loop-helix transcription factor which has an impact on the regulation of glutamatergic and GABAergic genes. We investigated an association of NEUROD2 with neurocognitive dysfunctions in schizophrenia and schizoaffective disorder patients before and during treatment with different second-generation antipsychotics., Methods: Patients were genotyped for four different polymorphisms of the NEUROD2 gene ((rs9889354(A/G), rs1877032(C/T), rs12453682(C/T) and rs11078918(C/G)). Cognitive function was assessed at baseline and week 8. Results of individual neuropsychological tests were assigned to six cognitive domains (reaction time and quality; executive function; working, verbal and visual memory) and a general cognitive index., Results: 167 patients were included in the study. The NEUROD2 exonic polymorphism rs11078918 showed significant associations with verbal memory and executive functions, whereas the NEUROD2 polymorphism rs12453682 was significantly associated with working and verbal memory, executive functions and with a cognitive index. Significant associations were found at baseline and after eight weeks. Moreover, significant associations between the change in neuropsychological test results during antipsychotic treatment and the NEUROD2 polymorphisms rs11078918 and rs12453682 were observed., Conclusions: Our findings suggest that the NEUROD2 gene could play a role in the pathophysiology of neurocognitive dysfunctions as well as in the change of cognitive symptoms under antipsychotic treatment in schizophrenia and schizoaffective disorder.

Background: The major resistance-associated substitution for sofosbuvir (S282T) in HCV NS5B causes severe viral fitness costs and rapidly reverts back to prototype in the absence of selection pressure. Accordingly, resistance against sofosbuvir is rarely detected even in patients after treatment failure., Case Presentation: We report a case of a GT3a infected patient with viral breakthrough under SOF/DCV therapy. At the time of breakthrough the RAS S282T was predominant in NS5B and then rapidly disappeared during follow-up by week 12 after treatment. Interestingly, despite only serine was encoded in position 282 during follow-up, two distinct genetic pathways for reversion were detectable. In 31% of the quasispecies the original codon for serine was present whereas in the majority of the quasispecies an alternative codon was selected. This alternative codon usage was unique for all GT3a isolates from the HCV database and remained detectable as a genetic footprint for prior resistance selection at the RNA level for at least 6 months., Conclusions: Comparative analyses of viral sequences at the codon level before and after DAA treatment may help to elucidate the patient's history of resistance selection, which is particularly valuable for highly unfit substitutions that are detectable only for a short period of time. If such codon changes increase the risk of re-selection of resistance upon a second exposure to SOF remains to be addressed.

Objectives: Computer-aided technologies can help to minimize clinical complications of zirconia-based restorations such as veneering porcelain fractures. The aim of this study was to evaluate different veneering approaches for zirconia single crowns regarding contact wear, fracture strength, and failure mode., Methods: Six different types of computer-aided design (CAD) crowns were manufactured and conventionally cemented on 10 metal dies each: three groups with a zirconia framework and a CAD/CAM-fabricated veneering cap ("digital veneering system": DVS, CAD-on, Infix CAD), zirconia-based crowns with pressed veneering caps (Infix Press), zirconia framework containing the dentin layer with only the incisal enamel material added (dentin-core), and conventional substructure with powder buildup veneering porcelain (layering technique). All specimens were submitted to artificial aging (120,000 mechanical cycles, 50 N load, 0.7-mm sliding movement, 320 thermocycles). After contact wear was measured with a laser scanning system, fracture resistance and failure mode were examined using a universal testing machine and a scanning electron microscope. Statistical analysis was performed at a significance level of 5%., Results: No statistical difference was revealed regarding the contact wear of the restorations (P = 0.171; ANOVA). No significant difference was found regarding the fracture resistance of the crowns (P = 0.112; ANOVA). Failure analysis revealed three different failure patterns: cohesive veneering fracture, adhesive delamination, and total fracture, with a characteristic distribution between the groups., Significance: All tested specimens survived artificial aging and exhibited clinically acceptable wear resistance and fracture resistance. Digital veneering techniques offer a promising, time- and cost-effective manufacturing process for all-ceramic restorations and may usefully complement the digital workflow.

This letter describes the discovery, synthesis, SAR, and biological activity of [2.2.1]-bicyclic sultams as potent antagonists of the androgen receptor. Optimization of the series led to the identification of compound 25, which displayed robust pharmacodynamic effects in rats after oral dosing., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Bruton's tyrosine kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a critical role in multiple cell types responsible for numerous autoimmune diseases. This article will detail the structure-activity relationships (SARs) leading to a novel second generation series of potent and selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide 6 (BMS-935177) was selected to advance into clinical development.

During the postpartum period, women are at higher risk of developing a mental disorder such as postpartum depression (PPD), a disorder that associates with mother-infant bonding and child development. Oxytocin is considered to play a key role in mother-infant bonding and social interactions and altered oxytocin plasma concentrations were found to be associated with PPD. In the present study, we evaluated oxytocin plasma levels and depressive symptoms during pregnancy and the postpartum period in healthy women. We evaluated 100 women twice during pregnancy (weeks 35 and 38) and three times in the postpartum period (within 2 days and 7 weeks and 6 months after delivery) by measuring oxytocin plasma levels with enzyme-linked immunosorbent assay (ELISA) and assessing depressive symptoms with the Montgomery-Asberg Depression Rating Scale. Oxytocin plasma levels significantly increased from the 35th week of gestation to 6 months postpartum in all women. However, levels decreased from the 38th week of gestation to 2 days after delivery in participants with postpartum depressive symptoms, whereas they continuously increased in the group without postpartum depressive symptoms; the difference between the course of oxytocin levels in the two groups was significant (Δt2-t3: t = 2.14; p = 0.036*). Previous depressive episodes and breastfeeding problems predicted postpartum depressive symptoms. Our results indicate that alterations in the oxytocin system during pregnancy might be specific for women who develop postpartum depressive symptoms. Future studies should investigate whether oxytocin plasma levels might have predictive value in women at high risk for PPD.

Chronic hepatitis E has been described several times in strongly immunosuppressed HIV-patients. We describe the persistence of HEV-infection in an HIV-patient despite a restored immune response. This case demonstrates that HEV-infection can persist in formerly immunosuppressed individuals irrespective of the current immune status. Persisting HEV-infection can lead to chronic inflammation and liver cirrhosis. Physicians should be aware of the possibility of chronic hepatitis E even in patients that are not any longer immunocompromised. However, ribavirin is an efficient treatment option., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Background: Remission is a common outcome of short-term trials and the main goal of acute and longterm treatment. The longitudinal stability of remission has rarely been investigated under naturalistic treatment conditions., Methods: Naturalistic multisite follow-up study. Three-year symptomatic long-term outcome of initially hospitalized tertiary care patients (N = 784) with major depressive episodes. Remission rates as well as the switch rates between remission and non-remission were reported., Results: After one, two and three years 62 %, 59 % and 69 % of the observed patients met criteria for remission. During the follow-up 88 % of all patients achieved remission. 36 % of maintained remission from discharge to 3-years, 12 % of all patients never reached remission and 52 % percent showed a fluctuating course switching from remission to non-remission and vice versa. There was considerable transition between remission and non-remission. For example, from discharge to 1 year, from 1 to 2, and from 2 to 3 years 25 %, 21 % and 11 % lost remission., Conclusion: Cumulative outcome rates are encouraging. Absolute rates at predefined endpoints as well as the fluctuations between these outcomes reflect the variable and chronic nature of major depression.

The face of hepatitis C virus (HCV) therapy is changing dramatically. Direct-acting antiviral agents (DAAs) specifically targeting HCV proteins have been developed and entered clinical practice in 2011. However, despite high sustained viral response (SVR) rates of more than 90%, a fraction of patients do not eliminate the virus and in these cases treatment failure has been associated with the selection of drug resistance mutations (RAMs). RAMs may be prevalent prior to the start of treatment, or can be selected under therapy, and furthermore they can persist after cessation of treatment. Additionally, certain DAAs have been approved only for distinct HCV genotypes and may even have subtype specificity. Thus, sequence analysis before start of therapy is instrumental for managing DAA-based treatment strategies. We have created the interpretation system geno2pheno[HCV] (g2p[HCV]) to analyse HCV sequence data with respect to viral subtype and to predict drug resistance. Extensive reviewing and weighting of literature related to HCV drug resistance was performed to create a comprehensive list of drug resistance rules for inhibitors of the HCV protease in non-structural protein 3 (NS3-protease: Boceprevir, Paritaprevir, Simeprevir, Asunaprevir, Grazoprevir and Telaprevir), the NS5A replicase factor (Daclatasvir, Ledipasvir, Elbasvir and Ombitasvir), and the NS5B RNA-dependent RNA polymerase (Dasabuvir and Sofosbuvir). Upon submission of up to eight sequences, g2p[HCV] aligns the input sequences, identifies the genomic region(s), predicts the HCV geno- and subtypes, and generates for each DAA a drug resistance prediction report. g2p[HCV] offers easy-to-use and fast subtype and resistance analysis of HCV sequences, is continuously updated and freely accessible under http://hcv.geno2pheno.org/index.php. The system was partially validated with respect to the NS3-protease inhibitors Boceprevir, Telaprevir and Simeprevir by using data generated with recombinant, phenotypic cell culture assays obtained from patients' virus variants.

Significant changes of schizophrenia patients during inpatient treatment were evalutaed and compared to established outcome criteria. The concept of reliable and clinically significant change methods was applied to three hundred and ninety-six patients suffering from a schizophrenia spectrum disorder. First, information on whether or not the change of the patient's condition is sufficient in order to declare that it is beyond a measurement error or random effect (= reliable change) was evaluated and in a second step it was observed if the reliable change was clinically meaningful (= clinically significant change). Different Positive and Negative Syndrome Scale for Schizophrenia (PANSS) thresholds were applied to define the clinically significant change (40, 45 and 50 points). These changes were then compared to established outcome criteria such as response and remission. Seventy-nine of the 396 patients (20%) showed a reliable improvement of symptoms, whereas 70% improved without achieving a reliable change of their condition. Of the 79 patients achieving a reliable change during treatment 8-15% concurrently showed a clinically significant change depending on the respective PANSS threshold. In contrast, 56% of the patients achieved response and 60% were in remission at discharge when applying established outcome criteria. Our results showed that a rather small number of schizophrenia patients were found to reliably change during inpatient treatment, with even less patients achieving a clinically significant change. The concept of reliable and clinically significant changes revealed to be a lot more stringent than today's established outcome criteria and should be critically evaluated regarding its use in schizophrenia patients., (Copyright © 2015 John Wiley & Sons, Ltd.)

Lemna minor L., a widely used model plant for toxicity tests has raised interest for its application to phytoremediation due to its rapid growth and ubiquitous occurrence. In rural areas, the pollution of water bodies with heavy metals and agrochemicals poses a problem to surface water quality. Among problematic compounds, heavy metals (copper) and pesticides are frequently found in water bodies. To establish duckweed as a potential plant for phytoremediation, enzymatic and antioxidative stress responses of Lemna minor during exposure to copper and a chloroacetamide herbicide were investigated in laboratory studies. The present study aimed at evaluating growth and the antioxidative and glutathione-dependent enzyme activity of Lemna plants and its performance in a scenario for phytoremediation of copper and a chloroacetamide herbicide. Lemna minor was grown in Steinberg medium under controlled conditions. Plants were treated with CuSO4 (ion conc. 50 and 100 μg/L) and pethoxamide (1.25 and 2.5 μg/L). Measurements following published methods focused on plant growth, oxidative stress, and basic detoxification enzymes. Duckweed proved to survive treatment with the respective concentrations of both pollutants very well. Its growth was inhibited scarcely, and no visible symptoms occurred. On the cellular basis, accumulation of O2(-) and H2O2 were detected, as well as stress reactions of antioxidative enzymes. Duckweed detoxification potential for organic pollutants was high and increased significantly with incubation. Pethoxamide was found to be conjugated with glutathione. Copper was accumulated in the fronds at high levels, and transient oxidative defense reactions were triggered. This work confirms the significance of L. minor for the removal of copper from water and the conjugation of the selective herbicide pethoxamide. Both organic and inorganic xenobiotics induced different trends of enzymatic and antioxidative stress response. The strong increase of stress responses following copper exposure is well known as oxidative burst, which is probably different from the much more long-lasting responses found in plants exposed to pethoxamide. Lemna sp. might be used as a tool for phytoremediation of low-level contamination with metals and organic xenobiotics, however the authors recommend a more detailed analysis of the development of the oxidative burst following copper exposure and of the enzymatic metabolism of pethoxamide in order to elucidate the extent of its removal from water.

Background: Precise locations of chondral and meniscal damage with increased time to anterior cruciate ligament reconstruction (ACLR) have not been well described., Purpose/hypothesis: The purpose of the study was to determine the relationship between delay in primary ACLR and incidence of secondary intra-articular injury. The hypothesis was that patients with increased time between initial injury and ACLR will exhibit greater incidence of secondary intra-articular injury when compared with those who receive surgical intervention promptly after injury. A second hypothesis was that patients with higher preinjury activity levels or older age will exhibit greater secondary injury when compared with those with minimal preinjury activity levels and younger age., Study Design: Cohort study; Level of evidence, 3., Methods: A retrospective review was performed on 1434 patients with an anterior cruciate ligament deficiency who underwent primary ACLR at a single institution between 2009 and 2013. Patients were grouped according to time to surgery after initial injury: 0-3, 4-12, and >12 months. Operative notes were used to analyze 10 variables across time-to-surgery groups: cartilage damage in the patella, trochlea, medial femoral condyle, lateral femoral condyle, medial tibial plateau, and lateral tibial plateau; medial and lateral meniscal injury; and the incidence of procedures involving either the meniscus or cartilage. Patient age and preinjury activity level were also analyzed for the 10 variables based on time-to-surgery groups., Results: An association was noted between time to surgery and increased incidence of injury in the trochlea, lateral femoral condyle, medial tibial plateau, and medial meniscus (P < .001). Different significant findings within each age group were observed, but overall positive findings were seen in the same 4 locations described above. On the basis of preinjury activity level, the less active patients were most at risk for medial meniscal and trochlear injury, while the more active patients were most at risk for medial tibial plateau injury with increased time from injury to ACLR., Conclusion: Increasing time from injury to ACLR was associated with increased incidence of secondary injury seen in the trochlea, lateral femoral condyle, medial tibial plateau, and medial meniscus. Separate analyses of patient age and preinjury activity level showed similar findings, thus supporting the primary analysis., (© 2015 The Author(s).)

The aim of this study was to evaluate residual symptoms in patients achieving remission according to the consensus criteria and to analyze their potential influence on the patient's outcome one year after discharge. In total, 399 patients suffering from a schizophrenia spectrum disorder were evaluated within a naturalistic study. Remission status was examined using the consensus criteria. Residual symptoms were defined as any symptom present at the time-point of remission following analogous analyses performed in depressed patients. Therefore, a PANSS item with a symptom severity of >1 (= at least borderline mentally ill) was defined to be a residual symptom. Remitters with and without residual symptoms were compared regarding psychopathology, functioning and side effects. In total, 236 patients (59%) were remitters at discharge with 94% of them suffering from at least one residual symptom. The most common residual symptoms were blunted affect (49%), conceptual disorganization (42%) and social withdrawal (40%). A significant association was found between the presence of residual symptoms and the severity of side effects (p < 0.0001) and functioning (p = 0.0003) at discharge as well as between residual symptoms and the risk of relapse and chance of remission one year after discharge. Residual symptoms were highly prevalent in remitted schizophrenia inpatients following the suggested definition. Most residual symptoms were persistent baseline symptoms suggesting an ongoing illness severity. Also, the necessity to re-evaluate the consensus criteria questioning the status of remission in these patients is also pointed out.

Background: Affective disorders are associated with an increased risk of cardiovascular disease, which, at least partly, appears to be independent of psychopharmacological treatments used to manage these disorders. Reduced heart rate variability (SDNN) and a low Omega-3 Index have been shown to be associated with increased risk for death after myocardial infarction. Therefore, we set out to investigate heart rate variability and the Omega-3 Index in euthymic patients with bipolar disorders., Methods: We assessed heart rate variability (SDNN) and the Omega-3 Index in 90 euthymic, mostly medicated patients with bipolar disorders (Bipolar-I, Bipolar-II) on stable psychotropic medication, free of significant medical comorbidity and in 62 healthy controls. Heart rate variability was measured from electrocardiography under a standardized 30 minutes resting state condition. Age, sex, BMI, smoking, alcohol consumption and caffeine consumption as potential confounders were also assessed., Results: Heart rate variability (SDNN) was significantly lower in patients with bipolar disorders compared to healthy controls (35.4 msec versus 60.7 msec; P<0.0001), whereas the Omega-3 Index did not differ significantly between the groups (5.2% versus 5.3%). In a linear regression model, only group membership (patients with bipolar disorders versus healthy controls) and age significantly predicted heart rate variability (SDNN)., Conclusion: Heart rate variability (SDNN) may provide a useful tool to study the impact of interventions aimed at reducing the increased risk of cardiovascular disease in euthymic patients with bipolar disorders. The difference in SDNN between cases and controls cannot be explained by a difference in the Omega-3 Index., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Introduction: Second-generation antipsychotics (SGAs) are widely used in several psychiatric disease entities and exert to a different extent a risk for antipsychotic-induced weight gain (AIWG). As AIWG is associated with an increase in metabolic syndrome or cardiovascular events, knowledge of these risks is crucial for further monitoring and the initiation of counteractive measures., Areas Covered: We searched PubMed and Web of Sciences for randomized-controlled trials and naturalistic observational studies published between 2010 and 2014 with sample sizes exceeding 100, including all marketed SGAs apart from zotepine, and providing data on weight increase. We also summarized relevant systematic reviews and meta-analyses of head-to-head comparisons., Expert Opinion: Recently published data still support the hierarchical ranking of SGAs already proposed in previous reviews ranking clozapine and olanzapine as having the highest risk, followed by amisulpride, asenapine, iloperidone, paliperidone, quetiapine, risperidone and sertindole in the middle, and aripiprazole, lurasidone and ziprasidone with the lowest risk. Number needed to harm varied considerably in our meta-analysis. Younger patients and patients with a lower baseline body mass index are most vulnerable. The greatest amount of weight gain occurs within the first weeks of treatment. AIWG occurs in all diagnostic groups and is also common in treatment with first-generation antipsychotics; therefore, awareness of this adverse event is essential for anyone prescribing antipsychotics.

Background: Aim was to examine depressive symptoms in acutely ill schizophrenia patients on a single symptom basis and to evaluate their relationship with positive, negative and general psychopathological symptoms., Methods: Two hundred and seventy-eight patients suffering from a schizophrenia spectrum disorder were analysed within a naturalistic study by the German Research Network on Schizophrenia. Using the Calgary Depression Scale for Schizophrenia (CDSS) depressive symptoms were examined and the Positive and Negative Syndrome Scale (PANSS) was applied to assess positive, negative and general symptoms. Correlation and factor analyses were calculated to detect the underlying structure and relationship of the patient's symptoms., Results: The most prevalent depressive symptoms identified were depressed mood (80%), observed depression (62%) and hopelessness (54%). Thirty-nine percent of the patients suffered from depressive symptoms when applying the recommended cut-off of a CDSS total score of >6 points at admission. Negligible correlations were found between depressive and positive symptoms as well as most PANSS negative and global symptoms despite items on depression, guilt and social withdrawal. The factor analysis revealed that the factor loading with the PANSS negative items accounted for most of the data variance followed by a factor with positive symptoms and three depression-associated factors., Limitations: The naturalistic study design does not allow a sufficient control of study results for the effect of different pharmacological treatments possibly influencing the appearance of depressive symptoms., Conclusion: Results suggest that depressive symptoms measured with the CDSS are a discrete symptom domain with only partial overlap with positive or negative symptoms., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Introduction: The most recently approved antiretroviral, the integrase inhibitor dolutegravir (DTG), is described to be a very potent drug with a unique resistance profile, but a certain degree of cross-resistance to RAL or EVG induced drug resistance, which is mediated mainly by integrase mutations at positions 140 and 148. The impact of a single N155H mutation to DTG resistance is described to be minor. However, there is only rare data available about the impact of N155H in the context of secondary site integrase mutations. Here, we present a case of virological failure in a DTG treated patient based on N155H mutation background., Methods: Therapy monitoring of an HIV-HCV co-infected patient harbouring already an omni-drug-class resistant HIV-1 in consequence of more than 20 years ART history. Drug susceptibility testing was performed by RT-PCR from plasma and subsequent Sanger sequencing. Tropism testing was done from proviral DNA with FPR cut-offs according to the German recommendations., Results: In 2013, the patient harbouring a virus with high level resistance to all RTI and PI received a regimen containing FTC, TDF, DRV/r, RPV, T20, and RAL to handle a viral load of 5000 RNA copies/mL, but never achieved fully suppressed viral load. In June 2013, after S119R, N155H and E157Q mutations in viral integrase were detected, the patient received DTG, and RAL was stopped. One month later, when viral load was undetectable for the first time since 2007, ART was de-escalated by removing T20. Since February 2014, low-level viral load was re-detectable. Two new mutations T97A and S147G in the integrase and no other new resistance associated mutations in protease and reverse transcriptase in comparison to the sample analyzed in June 2013 were detected., Conclusions: Highly resistant HIV-1 strains have been a common problem in the past. Their frequencies were pushed back by highly potent ART, but the virus is still able to become resistant against all available antiretrovirals at once. The here documented strain became resistant to DTG without carrying mutations at the described positions 140 and 148, but in the context of integrase N155H. Since N155H alone is described not to contribute sufficient resistance to DTG, there seems to be a need to re-check viruses with N155H plus minor mutations (like T97A, S119R, S147G and E157Q) potentially contributing to DTG resistance.

Introduction: Due to drug-drug interactions of HIV- and HCV-specific antivirals when initiating an HCV-therapy, the antiretroviral therapy (ART) often has to be changed. The spectrum of applicable antiretrovirals is small, therefore many patients were switched to raltegravir/truvada (RAL/TVD) in our cohort. Due to the relatively low genetic barrier of RAL, this regimen may be endangered to fail, if the NRTI backbone is not fully active because of pre-existing NRTI resistance. We investigated the long-term follow-up and safety of RAL/TVD in co-infected patients after hepatitis C virus (HCV) therapy was stopped and the protective antiretroviral effect of interferon ended., Materials and Methods: Twenty patients initiated a direct-acting antiviral (DAA) containing HCV therapy (8x faldaprevir, 6x telaprevir, 2x daclatasvir and 4x simeprevir) between 11/2011 and 01/2013. Seventeen were switched to RAL/TVD, three patients were not treated before, but started with the regimen. Diagnosis of HIV infection was dated between 1985 and 2010. The HI-viral suppression was monitored retrospectively to date., Results: Thirteen of the twenty patients (65%) remained on RAL/TVD after finishing HCV treatment, for seven patients, no data about their ART continuation was available, after HCV therapy had stopped. All remaining thirteen patients showed an HI-viral load below detection limit up to date (for 15 to 22 months, median 20 months). Only for four patients, historic resistance data were available but none showed NRTI mutations., Conclusions: Switch to RAL/TVD as HIV ART due to initiating HCV therapy was safe for the observed small cohort even in long-term follow-up without switchback or a second ART switch. However, resistance data for the cohort was little, showing no NRTI mutations, indicating a relatively safe setting. Since no further data is available, physicians should keep in mind ART history, historical therapy failure and HIV-resistance while switching ART to treat HCV in co-infected patients. Further investigation in larger cohorts is needed, especially thinking of upcoming interferon-free HCV regimen in heavily pre-treated co-infected patients.

Introduction: Proven resistance against HIV drugs, either by phenotyping or genotyping is a rare event in clinical trials. The overall assumption of drug resistance disappearing is additionally driven by the recommendations to screen for transmitted drug resistance, leading to large numbers of examinations with relatively low rates of resistance. Goal of our analysis was to assess if drug resistance in treatment failure is also decreasing outside of clinical trials., Materials and Methods: The MIB database at timepoint of analysis consists of data from 2876 HIV infected patients. Besides various laboratory parameters, clinical data and treatment history is included. HIV-1 protease and reverse transcriptase sequences were analyzed using the HIV-GRADE drug resistance algorithm. As in only a small number of patients genotypic resistance testing for integrase inhibitors was performed, mainly due to reimbursement reasons, it was assumed that failing treatment on a previous integrase inhibitor containing regimen is equate to resistance., Results: Of the 2876 patients in the database, 220 had a treatment change due to treatment failure between 2009 and 2012, a genotypic resistance testing at an appropriate timepoint of maximum four weeks before treatment change and a treatment duration of at least six months before treatment failure. In 2009, 61% of patients showed no drug resistance while 39% showed resistance against one or more drug classes (two or more drug classes: 19.5%; three or more drug classes: 2.4%, four drug classes 2.4%). In 2012, no resistance was found in 52% of patients while resistance against three or more drug classes was found in nearly 14% of patients (one or more: 48%; two or more 23%; four classes: 4.5%)., Conclusions: Treatment failure with viral load sufficiently high for drug resistance testing was not frequently observed in our database. Nevertheless, treatment failure was often associated with drug resistance against at least one drug class. With more use of the newer drug classes, resistance against those new classes will become more common and rates of multiclass resistance will be increasing.

Introduction: Simeprevir, a new oral NS3/4A protease inhibitor, was recently approved by the FDA and the EMA for the treatment of patients with chronic HCV genotype 1, 4, 5 and 6 infection l. It has been recommended in the 2014 UK Consensus Guidelines as a possible treatment of previously untreated genotype 1a-infected patients. The antiviral efficacy of simeprevir is adversely affected by the mutation at the Q80K loci. There is controversial discussion that the incidence of Q80K in the European HCV 1a-infected community is very low and therefore testing of Q80K before starting a therapy including simeprevir is not necessary. We analyzed the appearance of Q80K in all sequenced HCV NS3A samples in 2014 in our laboratory., Materials and Methods: All in 2014 received orders for HCV resistance tests were analyzed with an in-house bulk sequencing method analyzing NS3A amino acids 1-181. Analysis was performed using geno2pheno HCV. The genotype 1a samples were selected, Q80K status and data of HIV co-infection were collected., Results: Forty-two HCV 1a samples were sent to us for resistance analyses from nine different medical centres in Berlin and Hannover, Germany. Nineteen (or 45%) of the sequences showed a Q80K mutation. Six extra clade I viruses had no Q80K mutation. Comparison between mono- and HIV-1 co-infected patients showed no difference in frequency of Q80K (mono-infected: 8 out of 19 patients; co-infected: 9 out of 23). For two 80K-positive patients, the HIV-status was not available., Conclusions: The incidence for Q80K mutation in HCV genotype 1a with overall 45% is substantially high in our cohort and does not differ between mono- and HIV-1 co-infected patients. Response to simeprevir is affected by the presence of viral Q80K. When treating HCV-infected patients with a simeprevir containing regimen, it is therefore important that HCV does not contain the Q80K mutation.

In randomized controlled trials, maintenance treatment for relapse prevention has been proven to be efficacious in patients responding in acute treatment, its efficacy in long-term outcome in "real-world patients" has yet to be proven. Three-year long-term data from a large naturalistic multisite follow-up were presented. Severe relapse was defined as suicide, severe suicide attempt, or rehospitalization. Next to relapse rates, possible risk factors including antidepressant medication were identified using univariate generalized log-rank tests and multivariate Cox proportional hazards model for time to severe relapse. Overall data of 458 patients were available for analysis. Of all patients, 155 (33.6%) experienced at least one severe relapse during the 3-year follow-up. The following variables were associated with a shorter time to a severe relapse in univariate and multivariate analyses: multiple hospitalizations, presence of avoidant personality disorder, continuing antipsychotic medication, and no further antidepressant treatment. In comparison with other studies, the observed rate of severe relapse during 3-year period is rather low. This is one of the first reports demonstrating a beneficial effect of long-term antidepressant medication on severe relapse rates in naturalistic patients. Concomitant antipsychotic medication may be a proxy marker for treatment resistant and psychotic depression.

Objectives: The incidence of sexually transmitted hepatitis C virus (HCV) reinfection is on the rise in HIV-infected men who have sex with men (MSM). Data on natural history of acute hepatitis C and possible factors associated with spontaneous clearance are limited. The aim of this study was to analyse the outcome of HCV reinfections in HIV-positive MSM., Methods: A retrospective analysis was carried out on patients with more than one sexually acquired HCV infection who were diagnosed at four major German HIV and hepatitis care centres. Reinfection was defined by genotype or phylogenetic clade switch, detectable HCV RNA after a sustained virological response (SVR) or after spontaneous clearance (SC)., Results: In total, 48 HIV-positive MSM were identified with HCV reinfection, among them 11 with a third episode and one patient with four episodes. At the first episode, 43 and five patients had an SVR and SC, respectively. The second episode was accompanied by a genotype switch in 29 patients (60%). Whereas 30 and nine patients showed an SVR and SC, respectively, eight patients developed chronic hepatitis. Neither HCV genotype switch nor interleukin-28B genotype was associated with SC. However, SC rates at the second episode were higher for patients with SC at the first episode compared with patients without SC (60 vs. 14%, respectively; P = 0.03). Two patients with SC at the first episode were reinfected with the same genotype., Conclusions: Multiple reinfections in HIV-infected MSM do occur, with or without genotype switch, and with prior SC of previous episodes. In this large case series, except for SC at the first episode, no factor was of value in clinical decision-making for early therapeutic intervention in acute HCV reinfection., (© 2014 British HIV Association.)

Objectives: Deep brain stimulation (DBS) for Tourette's syndrome (TS) in various targets has been in the focus for some years. However, there are hardly any data on "psychosocial" outcome after DBS for TS. The aim of the present study therefore was to focus on the functional outcome and "psychosocial changes" in TS patients after DBS., Methods: Six patients with treatment-refractory TS underwent GPi-DBS. The Yale Global Tic Severity Scale (YGTSS) was used to evaluate symptomatic outcome. Psychosocial changes were assessed applying the Global Assessment of Functioning Scale (GAF) and the Gilles-de-la-Tourette-Syndrome Quality-of-Life scale (GTS-QOL) with additionally documenting psychosocial changes. Follow-up ranged between 12 and 72 months., Results: In all symptomatic responders (4 of 6) we found a significant functional improvement (mean GAF increasing from 53.75 (± 7.5) pre-operatively to 83.75 (± 7.5) at last follow-up) along with a positive correlation with the course of GTS-QOL (R(2) = 0.62)., Conclusions: Treatment success should not only be assessed with the classic "tic-scales", but also with the GAF and GTS-QOL. Although improvement of tics seems to be positively correlated with improved functional outcome, symptomatic improvement may lead to unexpected major psychosocial changes - which both the patient and the clinicians in charge - should be prepared for.

Drug resistance testing, genotype analysis, and the determination of immune and vaccine escape variants support personalized antiviral treatment for hepatitis B patients. As phenotypic drug resistance testing for hepatitis B virus (HBV) is especially labor-intensive, due to the lack of simple cell culture systems, genotypic methods play a very pronounced role. The genetic structure of HBV allows the simultaneous analysis of two different genes by examination of a single region in the genome of HBV. Nevertheless, the overlapping open reading frames of the hepatitis B surface antigen (HBsAg) and the reverse transcriptase (RT) have to be interpreted separately. In diagnostic procedures, standard Sanger type sequencing (mostly performed as a dye-dideoxynucleotide terminator system) is still the most commonly used method. This allows using established techniques for interpreting those types of genetic information. Besides reviewing the foundation of drug resistance interpretation for HBV, different interpretation systems, either commercially available (TRUGENE, Abbott, ViroScore) or free to use (geno2pheno[HBV], HIV-GRADE HBV tool), are compared in this article., (© 2014 S. Karger AG, Basel.)

Background: Brain-derived neurotrophic factor (BDNF) plays an important role in differentiation and repair of neurons in the adult brain. BDNF serum levels have been found to be lower in depressed patients than in healthy subjects. In a couple of studies, effective antidepressant treatment including electroconvulsive therapy led to an increase in BDNF serum levels. As transcranial direct current stimulation (tDCS) is currently discussed as novel therapeutic intervention in major depression, we investigated BDNF serum levels during tDCS in therapy-resistant depression., Methods: Twenty-two patients with a major depressive episode participated in a double-blind placebo-controlled trial and received randomized cross over treatment with 2 weeks active and 2 weeks sham tDCS (1 or 2 mA for 20 min, anode over the left dorsolateral prefrontal cortex, cathode right supraorbital cortex)., Results: Clinical assessment only showed a modest and non-significant improvement in HAMD, BDI and CGI in both groups. BDNF serum levels were measured at baseline, after 2 and after 4 weeks. There was neither a significant change of BDNF levels following active tDCS, nor were severity of depressive symptoms and BDNF levels correlated., Limitations: The small sample size, its heterogeneity, the short observation period and a cross-over design without an interval between both conditions., Conclusions: tDCS did not change BDNF serum levels unlike other established antidepressant interventions in this treatment resistant sample. However, larger studies are needed., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The role of the brain-derived neurotrophic factor (BDNF) in the pathophysiology of major depressive disorder (MDD) remains to be elucidated. Recent post hoc analyses indicated a potential association of three polymorphisms in the BDNF gene with worse treatment outcome in patients with the subtype of melancholic depression. We aimed at replicating these findings in a German naturalistic multicenter follow-up. Three polymorphisms in the BDNF gene (rs7103411, rs6265 (Val66Met) and rs7124442) were genotyped in 324 patients with MDD and 470 healthy controls. We applied univariate tests and logistic regression models stratifying for depression subtype and gender. The three polymorphisms were not associated with MDD as diagnosis. Further, no associations were found in univariate tests. With logistic regression, we only found a tendency towards an association of the rs6265 (Val66Met) polymorphism with overall response to treatment (response rates: GG (val/val) < GA (val/met) < AA (met/met); p = 0.0129) and some gender differences for the rs6265 (Val66Met) and rs7103411 polymorphisms. Treatment outcome stratified for subtypes of depression did not differ significantly between the investigated polymorphisms or using haplotype analyses. However, results showed a tendency towards significance. At this stage, we cannot support an influence of these three polymorphisms. Further studies in larger patient samples to increase sample sizes of subgroups are warranted.