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Objectives Bipolar disorder (BD) has a highly heterogeneous clinical course that is characterized by relapses and increased health care utilization in a significant fraction of patients. A thorough understanding of factors influencing illness course is essential for predicting disorder severity and developing targeted therapies. Methods We performed polygenic score analyses in four cohorts (N = 954) to test whether the genetic risk for BD, schizophrenia, or major depression is associated with a severe course of BD. We analyzed BD patients with a minimum illness duration of five years. The severity of the disease course was assessed by using the number of hospitalizations in a mental health facility and a composite measure of longitudinal illness severity (OPCRIT item 90). Results Our analyses showed that higher polygenic scores for BD (β = 0.11, SE = 0.03, p = 1.17 × 10-3) and schizophrenia (β = 0.09, SE = 0.03, p = 4.24 × 10-3), but not for major depression, were associated with more hospitalizations. None of the investigated polygenic scores was associated with the composite measure of longitudinal illness severity (OPCRIT item 90). Limitations We could not account for non-genetic influences on disease course. Our clinical sample contained more severe cases. Conclusions This study demonstrates that the genetic risk burden for psychiatric illness is associated with increased health care utilization, a proxy for disease severity, in BD patients. The findings are in line with previous observations made for patients diagnosed with schizophrenia or major depression. Therefore, in the future psychiatric disorder polygenic scores might become helpful for stratifying patients with high risk of a chronic manifestation and predicting disease course.

Aims: Neither the long-term development of ablation lesions nor the capability of late gadolinium enhancement (LGE)-MRI to detect ablation-induced fibrosis at late stages of scar formation have been defined. We sought to assess the development of atrial ablation lesions over time using LGE-MRI and invasive electroanatomical mapping (EAM). Methods and results: Ablation lesions and total atrial fibrosis were assessed in serial LGE-MRI scans 3 months and >12 months post pulmonary vein (PV) isolation. High-density EAM performed in subsequent repeat ablation procedures served as a reference. Serial LGE-MRI of 22 patients were analyzed retrospectively. The PV encircling ablation lines displayed an average LGE, indicative of ablation-induced fibrosis, of 91.7% ± 7.0% of the circumference at 3 months, but only 62.8% ± 25.0% at a median of 28 months post ablation (p < 0.0001). EAM performed in 18 patients undergoing a subsequent repeat procedure revealed that the consistent decrease in LGE over time was owed to a reduced detectability of ablation-induced fibrosis by LGE-MRI at time-points > 12 months post ablation. Accordingly, the agreement with EAM regarding detection of ablation-induced fibrosis and functional gaps was good for the LGE-MRI at 3 months (κ .74; p < .0001), but only weak for the LGE-MRI at 28 months post-ablation (κ .29; p < .0001). Conclusion: While non-invasive lesion assessment with LGE-MRI 3 months post ablation provides accurate guidance for future redo-procedures, detectability of atrial ablation lesions appears to decrease over time. Thus, it should be considered to perform LGE-MRI 3 months post-ablation rather than at later time-points > 12 months post ablation, like for example, prior to a planned redo-ablation procedure.

Despite substantial technological and procedural advances that have improved the efficacy and safety of AF ablation in recent years, the long‐term durability of ablation lesions is still not satisfactory. There also remains concern regarding rare but potentially life‐threatening procedure‐related complications like cardiac tamponade and atrioesophageal fistulae. Current ablation strategies are aiming to optimize the trade‐off between efficacy and safety, where more extensive ablation appears to inevitably increase the risk of collateral injury. However, new forms of energy application may have the potential to resolve this quandary. The emerging concept of high power‐short duration radiofrequency ablation features a more favorable lesion geometry that appears ideally suited to create contiguous lesions in the thin‐walled atrium. Moreover, novel non‐thermal ablation methods based on electroporation appear to provide a unique selectivity for cardiomyocytes and to spare surrounding tissues composed of other cell types. Both, high power‐short duration and electroporation ablation might have the potential to break the trade‐off between effective lesions and collateral damage and to substantially improve risk‐benefit ratios in AF ablation. In addition, both approaches lead to considerable reductions in ablation times. However, their putative benefits regarding efficacy, efficiency, and safety remain to be proven in randomized controlled trials.

Die Katheterablation von Herzrhythmusstorungen hat sich fur die meisten tachykarden Arrhythmieformen als primare Behandlungsform etabliert. Hierbei ist die interventionelle Behandlung eines symptomatischen Vorhofflimmerns der medikamentosen Therapie uberlegen, sodass die Durchfuhrung einer Katheterablation zunehmend zum klinischen Alltag vieler Kliniken gehort. Die elektrische Isolation der Pulmonalvenen (PVI) stellt den Eckpfeiler der interventionellen Therapie sowohl von paroxysmalem als auch von persistierendem Vorhofflimmern dar. Dieser Artikel beschreibt die Durchfuhrung einer Pulmonalvenenisolation mittels Radiofrequenzablation in Punkt-fur-Punkt-Technik und soll eine praktische Anleitung fur die Arbeit im Herzkatheterlabor sein. Diese Arbeit setzt eine Reihe von Artikeln fort, die fur eine Weiterbildung im Bereich der speziellen Rhythmologie erstellt worden sind.

Aufgrund guter Ergebnisse, zunehmender Standardisierung und Fehlen von gleichwertigen Alternativen gehort die Durchfuhrung einer Katheterablation zunehmend zum klinischen Alltag vieler Kliniken. Dieser Artikel beschreibt die Durchfuhrung haufiger oder notwendiger Punktionen (Punktion der Leistengefase, transseptale Punktion, Perikardpunktion) im Rahmen einer Katheterablation und soll eine praktische Anleitung fur die Arbeit im Herzkatheterlabor darstellen. Diese Arbeit setzt eine Reihe von Artikeln fort, die fur eine Weiterbildung im Bereich der speziellen Rhythmologie konzipiert sind.

PURPOSE Contrast-free lung MRI based on Fourier decomposition is an attractive method to monitor various lung diseases. However, the accuracy of the current perfusion quantification is limited. In this study, a new approach for perfusion quantification based on voxel-wise proton density and median signal decay toward the steady state for Fourier decomposition-based techniques is proposed called QQuantified (QQuant ). METHODS Twenty patients with chronic obstructive pulmonary disease and 18 patients with chronic thromboembolic pulmonary hypertension received phase-resolved functional lung-MRI (PREFUL) and dynamic contrast-enhanced (DCE)-MRI. Nine healthy participants received phase-resolved functional lung-MRI only. Median values of QQuant were compared to a Fourier decomposition perfusion quantification presented by Kjorstad et al (QKjorstad ) and validated toward pulmonary blood flow derived by DCE-MRI (PBFDCE ). Blood fraction maps determined by the new approach were calculated. Regional and global correlation coefficients were calculated, and Bland-Altman plots were created. Histogram analyses of all cohorts were created. RESULTS The introduced parameter QQuant showed only 2 mL/min/100 mL mean deviation to PBFDCE in the patient cohort and showed less bias than QKjorstad . Significant increases of regional correlation with PBFDCE were achieved (r = 0.3 vs. r = 0.2, P < .01*). The trend of global correlation toward PBFDCE is not uniform, showing higher values for QKjorstad in the chronic obstructive pulmonary disease cohort than for QQuant and vice versa in the chronic thromboembolic pulmonary hypertension cohort. In contrast to QKjorstad , QQuant perfusion maps indicate a physiologic dorsoventral gradient in supine position similar to PBFDCE with similar value distribution in the histograms. CONCLUSION We proposed a new approach for perfusion quantification of phase-resolved functional lung measurements. The developed parameter QQuant reveals a higher accuracy compared to QKjorstad .

Ein infracochlear gelegenes Cholesteatom der Felsenbeinspitze, welches direkten Kontakt zur A. carotidea interna (ACI) hat, ist selten anzutreffen. Aufgrund der Gefahr der Eroffnung der Cochlea mit konsekutiver Ertaubung und der Verletzung der ACI erfordert es eine grundliche praoperative Zugangsplanung, ausfuhrliche Aufklarung und Information des Patienten. Der dargestellte Fall zeigt das navigierte endoskopisch kontrollierte transtympanale Vorgehen bei einem solchen infracochlearen Cholesteatomrezidiv. Das Horvermogen des Patienten wurde nicht beeintrachtigt, und es zeigte sich kein Anhalt fur ein Rezidiv.

BACKGROUND Regional flow volume loop ventilation-weighted noncontrast-enhanced proton lung MRI in free breathing has emerged as a novel technique for assessment of regional lung ventilation, but has yet not been validated with 129 Xenon MRI (129 Xe-MRI), a direct visualization of ventilation in healthy volunteers, cystic fibrosis (CF), and chronic obstructive pulmonary disease (COPD) patients. PURPOSE To compare regional ventilation and regional flow volume loops measured by noncontrast-enhanced ventilation-weighted phase-resolved functional lung MRI (PREFUL-MRI) with 129 Xe-MRI ventilation imaging and with lung function test parameters. STUDY TYPE Retrospective study. POPULATION Twenty patients with COPD, eight patients with CF, and six healthy volunteers. FIELD STRENGTH/SEQUENCE PREFUL and 129 Xe-MRI gradient echo sequences were acquired at 1.5T. ASSESSMENT Coronal slices of PREFUL-MRI (free breathing) and 129 Xe-MRI (single breath-hold) were acquired on the same day, matched by their ventrodorsal position and coregistered for evaluation. Ventilation defect percentage (VDP) was calculated based on regional ventilation (RV), regional flow volume loops (RFVL), or 129 Xe-MRI with two different threshold methods. A combined VDP was calculated for RV and RFVL. Additionally, lung function testing was performed (such as the forced expiratory volume in 1 second [FEV1 ]) was used. STATISTICAL TESTS The obtained parameters were compared using Wilcoxon tests, correlated using Spearman's correlation coefficient (r), and agreement between PREFUL and 129 Xe-MRI parameters was assessed using Bland-Altman analysis and Dice coefficients. RESULTS VDP measured by PREFUL and 129 Xe were significantly correlated with both thresholding techniques (r = 0.62-0.69, P

Aims Myocardial fibrosis is a hallmark of atrial fibrillation (AF) and its characterization could be used to guide ablation procedures. Late gadolinium enhanced-magnetic resonance imaging (LGE-MRI) detects areas of atrial fibrosis. However, its accuracy remains controversial. We aimed to analyse the accuracy of LGE-MRI to identify left atrial (LA) arrhythmogenic substrate by analysing voltage and conduction velocity at the areas of LGE. Methods and results Late gadolinium enhanced-magnetic resonance imaging was performed before ablation in 16 patients. Atrial wall intensity was normalized to blood pool and classified as healthy, interstitial fibrosis, and dense scar tissue depending of the resulting image intensity ratio. Bipolar voltage and local conduction velocity were measured in LA with high-density electroanatomic maps recorded in sinus rhythm and subsequently projected into the LGE-MRI. A semi-automatic, point-by-point correlation was made between LGE-MRI and electroanatomical mapping. Mean bipolar voltage and local velocity progressively decreased from healthy to interstitial fibrosis to scar. There was a significant negative correlation between LGE with voltage (r = −0.39, P Conclusions Areas with higher LGE show lower voltage and slower conduction in sinus rhythm. The enhancement intensity correlates with bipolar voltage and conduction velocity in a point-by-point analysis. The performance of LGE-MRI in assessing local velocity might be reduced in patients with dilated atria (LA diameter ≥45).

OBJECTIVE Choice of electrode array (EA) design and differences in outcome are major concerns both to patients with single-sided deafness (SSD) and to surgeons before cochlear implant (CI) surgery. The present work investigates the effects of EA design on 1) insertion depths, and 2) audiological outcomes of SSD CI recipients. STUDY DESIGN Retrospective study. SETTING Tertiary academic center. PATIENTS Forty patients with acquired SSD matched according to duration of deafness MAIN OUTCOME MEASURES:: Fourteen CI recipients were implanted with a perimodiolar electrode (cochlear perimodiolar [CPM]), 12 with a shorter lateral wall electrode (cochlear lateral wall [CLW]), and 14 with a longer lateral wall electrode array (medEl lateral wall [MLW]). Postoperative rotational tomography was evaluated to determine cochlear size and EA angle of insertion depth (AID). Binaural speech comprehension in noise (in three configuration presentations) and localization ability were assessed 12 months postoperatively with CI. RESULTS AID was significantly deeper in MLW (mean 527.94 degrees) compared with the CPM (mean 366.35 degrees) and CLW groups (mean 367.01 degrees). No significant difference in AID was seen between the CPM and CLW groups (difference 0.66 degrees). Cochlear sizes revealed no significant differences between any groups. All three groups showed significant improvement in head shadow effect (difference on average CPM: 6.3 dB SPL, CLW 5 dB SPL, and MLW 4.05 dB SPL) and localization ability at 12 months postoperatively (difference on average CPM: 19.72 degrees, CLW: 24 degrees, and MLW: 12.9 degrees). No significant difference in the extent of audiological benefit was observed between any groups. CONCLUSION No effect on binaural benefit was apparent from the selection of the three EA designs in SSD CI recipients. Further studies focusing on subjective results, sound quality, and music perception depending on EA design in SSD CI recipients are needed.

Propensity to psychiatric disease involves the contribution of multiple genetic variants with small individual effects (i. e., polygenicity). This contribution can be summarized using polygenic scores (PGSs). The present article discusses the methodological foundations of PGS calculation, together with the limitations and caveats of their use. Furthermore, we show that in terms of using genetic information to address the complexities of mental disorders, PGSs have become a standard tool in psychiatric research. PGS also have the potential for translation into clinical practice. Although PGSs alone do not allow reliable disease prediction, they have major potential value in terms of risk stratification, the identification of disorder subtypes, functional investigations, and case selection for experimental models. However, given the stigma associated with mental illness and the limited availability of effective interventions, risk prediction for common psychiatric disorders must be approached with particular caution, particularly in the non-regulated consumer context.

BACKGROUND: Buruli ulcer is a neglected tropical disease caused by Mycobacterium ulcerans infection that damages the skin and subcutis. It is most prevalent in western and central Africa and Australia. Standard antimicrobial treatment with oral rifampicin 10 mg/kg plus intramuscular streptomycin 15 mg/kg once daily for 8 weeks (RS8) is highly effective, but streptomycin injections are painful and potentially harmful. We aimed to compare the efficacy and tolerability of fully oral rifampicin 10 mg/kg plus clarithromycin 15 mg/kg extended release once daily for 8 weeks (RC8) with that of RS8 for treatment of early Buruli ulcer lesions.METHODS: We did an open-label, non-inferiority, randomised (1:1 with blocks of six), multicentre, phase 3 clinical trial comparing fully oral RC8 with RS8 in patients with early, limited Buruli ulcer lesions. There were four trial sites in hospitals in Ghana (Agogo, Tepa, Nkawie, Dunkwa) and one in Benin (Pobè). Participants were included if they were aged 5 years or older and had typical Buruli ulcer with no more than one lesion (caterories I and II) no larger than 10 cm in diameter. The trial was open label, and neither the investigators who took measurements of the lesions nor the attending doctors were masked to treatment assignment. The primary clinical endpoint was lesion healing (ie, full epithelialisation or stable scar) without recurrence at 52 weeks after start of antimicrobial therapy. The primary endpoint and safety were assessed in the intention-to-treat population. A sample size of 332 participants was calculated to detect inferiority of RC8 by a margin of 12%. This study was registered with ClinicalTrials.gov, NCT01659437.FINDINGS: Between Jan 1, 2013, and Dec 31, 2017, participants were recruited to the trial. We stopped recruitment after 310 participants. Median age of participants was 14 years (IQR 10-29) and 153 (52%) were female. 297 patients had PCR-confirmed Buruli ulcer; 151 (51%) were assigned to RS8 treatment, and 146 (49%) received oral RC8 treatment. In the RS8 group, lesions healed in 144 (95%, 95% CI 91 to 98) of 151 patients, whereas lesions healed in 140 (96%, 91 to 99) of 146 patients in the RC8 group. The difference in proportion, -0·5% (-5·2 to 4·2), was not significantly greater than zero (p=0·59), showing that RC8 treatment is non-inferior to RS8 treatment for lesion healing at 52 weeks. Treatment-related adverse events were recorded in 20 (13%) patients receiving RS8 and in nine (7%) patients receiving RC8. Most adverse events were grade 1-2, but one (1%) patient receiving RS8 developed serious ototoxicity and ended treatment after 6 weeks. No patients needed surgical resection. Four patients (two in each study group) had skin grafts.INTERPRETATION: Fully oral RC8 regimen was non-inferior to RS8 for treatment of early, limited Buruli ulcer and was associated with fewer adverse events. Therefore, we propose that fully oral RC8 should be the preferred therapy for early, limited lesions of Buruli ulcer.FUNDING: WHO with additional support from MAP International, American Leprosy Missions, Fondation Raoul Follereau France, Buruli ulcer Groningen Foundation, Sanofi-Pasteur, and BuruliVac.

The shape of the left atrium (LA) and left atrial appendage (LAA) have been shown to predict stroke in patients with atrial fibrillation (AF). Prior studies rely on qualitative assessment of shape, which limits reproducibility and clinical utility. Statistical shape analysis (SSA) allows for quantitative assessment of shape. We use this method to assess the shape of the LA and LAA and predict stroke in patients with AF. From a database of AF patients who had previously undergone MRI of the LA, we identified 43 patients with AF who subsequently had an ischemic stroke. We also identified a cohort of 201 controls with AF who did not have a stroke after the MRI. We performed SSA of the LA and LAA shape to quantify the shape of these structures. We found three of the candidate LAA shape parameters to be predictive of stroke, while none of the LA shape parameters predicted stroke. When the three predictive LAA shape parameters were added to a logistic regression model that included the CHA

Fatigue, depression, and pain affect the majority of multiple sclerosis (MS) patients, which causes a substantial burden to patients and society. The pathophysiology of these symptoms is not entirely clear, and current treatments are only partially effective. Clinically, these symptoms share signs of anhedonia, such as reduced motivation and a lack of positive affect. In the brain, they are associated with overlapping structural and functional alterations in areas involved in reward processing. Moreover, neuroinflammation has been shown to directly impede monoaminergic neurotransmission that plays a key role in reward processing. Here, we review recent neuroimaging and neuroimmunological findings, which indicate that dysfunctional reward processing might represent a shared functional mechanism fostering the symptom cluster of fatigue, depression, and pain in MS. We propose a framework that integrates these findings with a focus on monoaminergic neurotransmission and discuss its therapeutic implications, limitations, and perspectives.

As early detection of symptoms in the subclinical to clinical psychosis spectrum may improve health outcomes, knowing the probabilistic susceptibility of developing a disorder could guide mitigation measures and clinical intervention. In this context, polygenic risk scores (PRSs) quantifying the additive effects of multiple common genetic variants hold the potential to predict complex diseases and index severity gradients. PRSs for schizophrenia (SZ) and bipolar disorder (BD) were computed using Bayesian regression and continuous shrinkage priors based on the latest SZ and BD genome-wide association studies (Psychiatric Genomics Consortium, third release). Eight well-phenotyped groups (n = 1580; 56% males) were assessed: control (n = 305), lower (n = 117) and higher (n = 113) schizotypy (both groups of healthy individuals), at-risk for psychosis (n = 120), BD type-I (n = 359), BD type-II (n = 96), schizoaffective disorder (n = 86), and SZ groups (n = 384). PRS differences were investigated for binary traits and the quantitative Positive and Negative Syndrome Scale. Both BD-PRS and SZ-PRS significantly differentiated controls from at-risk and clinical groups (Nagelkerke’s pseudo-R2: 1.3–7.7%), except for BD type-II for SZ-PRS. Out of 28 pairwise comparisons for SZ-PRS and BD-PRS, 9 and 12, respectively, reached the Bonferroni-corrected significance. BD-PRS differed between control and at-risk groups, but not between at-risk and BD type-I groups. There was no difference between controls and schizotypy. SZ-PRSs, but not BD-PRSs, were positively associated with transdiagnostic symptomology. Overall, PRSs support the continuum model across the psychosis spectrum at the genomic level with possible irregularities for schizotypy. The at-risk state demands heightened clinical attention and research addressing symptom course specifiers. Continued efforts are needed to refine the diagnostic and prognostic accuracy of PRSs in mental healthcare.

Telacebec (Q203) is a new antituberculosis drug in clinical development that has extremely potent activity against Mycobacterium ulcerans, the causative agent of Buruli ulcer (BU). The potency of Q203 has prompted investigation of its potential role in ultrashort, even single-dose, treatment regimens for BU in mouse models. However, the relationships of Q203 dose, dose schedule, duration, and host immune status to treatment outcomes remain unclear, as does the risk of emergence of drug resistance with Q203 monotherapy. Here, we used mouse footpad infection models in immunocompetent BALB/c and immunocompromised SCID-beige mice to compare different Q203 doses, different dosing schedules, and treatment durations ranging from 1 day to 2 weeks, on long-term outcomes. We also tested whether combining Q203 with a second drug can increase efficacy. Overall, efficacy depended on total dose more than on duration. Total doses of 5 to 20 mg/kg rendered nearly all BALB/c mice culture negative by 13 to 14 weeks posttreatment, without selection of Q203-resistant bacteria. Addition of a second drug did not significantly increase efficacy. Although less potent in SCID-beige mice, Q203 still rendered the majority of footpads culture negative at total doses of 10 to 20 mg/kg. Q203 resistance was identified in relapse isolates from some SCID-beige mice receiving monotherapy but not in isolates from those receiving Q203 combined with bedaquiline or clofazimine. Overall, these results support the potential of Q203 monotherapy for single-dose or other ultrashort therapy for BU, although highly immunocompromised hosts may require higher doses or durations and/or combination therapy.

Buruli ulcer (BU) is a neglected tropical disease caused by infection with Mycobacterium ulcerans. Unclear transmission, no available vaccine, and suboptimal treatment regimens hamper the control of this disease. Carefully designed preclinical research is needed to address these shortcomings. In vivo imaging (IVIS®, Perkin Elmer, Waltham, MA) of infection is an emerging tool that permits monitoring of disease progression and reduces the need to using large numbers of mice at different time-points during the experiment, as individual mice can be imaged at multiple time-points. We aimed to further describe the use of in vivo imaging (IVIS) in BU. We studied the detection of M. ulcerans in experimentally infected BALB/c mouse tails and the subsequent histopathology and immune response in this pilot study. IVIS-monitoring was performed weekly in ten infected BALB/c mice to measure light emitted as a proxy for bacterial load. Nine of 10 (90%) BALB/c mice infected subcutaneously with 3.3 × 105 M. ulcerans JKD8049 (containing pMV306 hsp16+luxG13) exhibited light emission from the site of infection, indicating M. ulcerans growth in vivo, whereas only five of 10 (50%) animals developed clinical signs of the disease. Specific antibody titers were detected within 2 weeks of the infection. Interferon (IFN)-γ and interleukin (IL)-10 were elevated in animals with pathology. Histopathology revealed clusters of acid-fast bacilli in the subcutaneous tissue, with macrophage infiltration and granuloma formation resembling human BU. Our study successfully showed the utility of M. ulcerans IVIS monitoring and lays a foundation for further research.

Buruli ulcer is a neglected tropical disease caused by Myocobacterium ulcerans; it manifests as a skin lesion, nodule, or ulcer that can be extensive and disabling. To assess the global burden and the progress on disease control, we analyzed epidemiologic data reported by countries to the World Health Organization during 2010–2017. During this period, 23,206 cases of Buruli ulcer were reported. Globally, cases declined to 2,217 in 2017, but local epidemics seem to arise, such as in Australia and Liberia. In 2013, the World Health Organization formulated 4 programmatic targets for Buruli ulcer that addressed PCR confirmation, occurrence of category III (extensive) lesions and ulcerative lesions, and movement limitation caused by the disease. In 2014, only the movement limitation goal was met, and in 2019, none are met, on a global average. Our findings support discussion on future Buruli ulcer policy and post-2020 programmatic targets.

Purpose Surgical management, including the extent of surgery, for patients with parotid malignant tumors has been challenging. The aims of the present study were to identify the factors associated with survival, estimate the incidence of occult nodal and intraglandular metastases, and determine the predictive influence on overall and disease-free survival, with consideration of the surgical extent. Patients and Methods We implemented a retrospective cohort study and identified incident cases with parotid malignant tumors from 2003 to 2016 at a single quaternary medical care and cancer center. A medical record analysis was performed retrospectively of the patient and histopathologic data. The predictor variables were age; tumor grade; T stage; N stage; facial nerve palsy; perineural, vascular, and lymphovascular invasion; completion parotidectomy; elective neck dissection; and pN0 versus pN+. Overall and disease-free survival were evaluated as primary and secondary outcome variables. Data analysis was performed as a time-to-event analysis (Kaplan-Meier method). Results A total of 102 patients with parotid carcinoma had undergone surgery from 2003 to 2016 at the University Hospital Freiburg, Germany; 69 patients had undergone completion parotidectomy (total, 36; radical, 33). A total of 13 patients had occult intraparotideal lymph node metastases after elective completion parotidectomy. All the patients who had undergone elective neck dissection and clinically had had no nodal involvement (cN0) had had no pathologic lymph node metastases found (pN0). However, the predictive factors for cervical nodal involvement were high-grade tumors, locally advanced tumors (cT3-cT4), and the presence of intraparotideal nodal metastases. Conclusions The rate of occult cervical metastases in the present study was surprisingly low (0%). However, owing to the various predictive factors, elective neck dissection should be performed for high-grade or locally advanced (stage T3-T4) parotid malignoma. Moreover, we highly recommend performing completion parotidectomy for all high-grade tumors and also for locally advanced (stage T3-T4) low-grade tumors, owing to the >12% of occult intraparotideal metastases found in the present study.

The identification of generalizable treatment response classes (TRC[s]) in major depressive disorder (MDD) would facilitate comparisons across studies and the development of treatment prediction algorithms. Here, we investigated whether such stable TRCs can be identified and predicted by clinical baseline items. We analyzed data from an observational MDD cohort (Munich Antidepressant Response Signature [MARS] study, N = 1017), treated individually by psychopharmacological and psychotherapeutic means, and a multicenter, partially randomized clinical/pharmacogenomic study (Genome-based Therapeutic Drugs for Depression [GENDEP], N = 809). Symptoms were evaluated up to week 16 (or discharge) in MARS and week 12 in GENDEP. Clustering was performed on 809 MARS patients (discovery sample) using a mixed model with the integrated completed likelihood criterion for the assessment of cluster stability, and validated through a distinct MARS validation sample and GENDEP. A random forest algorithm was used to identify prediction patterns based on 50 clinical baseline items. From the clustering of the MARS discovery sample, seven TRCs emerged ranging from fast and complete response (average 4.9 weeks until discharge, 94% remitted patients) to slow and incomplete response (10% remitted patients at week 16). These proved stable representations of treatment response dynamics in both the MARS and the GENDEP validation sample. TRCs were strongly associated with established response markers, particularly the rate of remitted patients at discharge. TRCs were predictable from clinical items, particularly personality items, life events, episode duration, and specific psychopathological features. Prediction accuracy improved significantly when cluster-derived slopes were modelled instead of individual slopes. In conclusion, model-based clustering identified distinct and clinically meaningful treatment response classes in MDD that proved robust with regard to capturing response profiles of differently designed studies. Response classes were predictable from clinical baseline characteristics. Conceptually, model-based clustering is translatable to any outcome measure and could advance the large-scale integration of studies on treatment efficacy or the neurobiology of treatment response.

Background Chronic obstructive pulmonary disease (COPD) is associated with high morbidity and mortality. Identification of imaging biomarkers for phenotyping is necessary for future treatment and therapy monitoring. However, translation of visual analytic pipelines into clinics or their use in large-scale studies is significantly slowed by time-consuming postprocessing steps. Purpose To implement an automated tool chain for regional quantification of pulmonary microvascular blood flow in order to reduce analysis time and user variability. Study type Prospective. Population In all, 90 MRI scans of 63 patients, of which 31 had a COPD with a mean Global Initiative for Chronic Obstructive Lung Disease status of 1.9 ± 0.64 (μ ± σ). Field strength/sequence 1.5T dynamic gadolinium-enhanced MRI measurement using 4D dynamic contrast material-enhanced (DCE) time-resolved angiography acquired in a single breath-hold in inspiration. [Correction added on August 20, 2019, after first online publication: The field strength in the preceding sentence was corrected.] ASSESSMENT: We built a 3D convolutional neural network for semantic segmentation using 29 manually segmented perfusion maps. All five lobes of the lung are denoted, including the middle lobe. Evaluation was performed on 61 independent cases from two sites of the Multi-Ethnic Study of Arteriosclerosis (MESA)-COPD study. We publish our implementation of a model-free deconvolution filter according to Sourbron et al for 4D DCE MRI scans as open source. Statistical test Cross-validation 29/61 (# training / # testing), intraclass correlation coefficient (ICC), Spearman ρ, Pearson r, Sorensen-Dice coefficient, and overlap. Results Segmentations and derived clinical parameters were processed in ~90 seconds per case on a Xeon E5-2637v4 workstation with Tesla P40 GPUs. Clinical parameters and predicted segmentations exhibit high concordance with the ground truth regarding median perfusion for all lobes with an ICC of 0.99 and a Sorensen-Dice coefficient of 93.4 ± 2.8 (μ ± σ). Data conclusion We present a robust end-to-end pipeline that allows for the extraction of perfusion-based biomarkers for all lung lobes in 4D DCE MRI scans by combining model-free deconvolution with deep learning. Level of evidence 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;51:571-579.

Background Chronic lung allograft dysfunction (CLAD) is a major cause for the low long-term survival rates after lung transplantation (LTx). Early detection of CLAD may enable providing medical treatment before a nonreversible graft dysfunction has occurred. MRI is advantageous to pulmonary function testing (PFT) in the ability to assess regional function changes, and thus have the potential in detecting very early stages of CLAD before changes in global forced expiratory volume during the first second (FEV1%) occur. Purpose To examine whether early stages of CLAD (diagnosed based on PFT values) could also be detected using MRI-derived parameters of regional flow-volume dynamics. Study type Retrospective. Population 62 lung transplantation recipients were included in the study, 29 of which had been diagnosed with CLAD at various stages. Field strength/sequence MRI datasets were acquired with a 1.5T Siemens scanner using a spoiled gradient echo sequence. Assessment MRI datasets were retrospectively preprocessed and analyzed by a blinded radiologist according to the phase resolved functional lung MRI (PREFUL-MRI) approach, resulting in fractional ventilation (FV) maps and regional flow-volume loops (rFVL). FV- and rFVL-based parameters of regional lung ventilation were estimated. Statistical tests Differences between groups were compared by Mann-Whitney U-test with a Bonferroni correction for multiple comparisons (n = 2). Results rFVL-CC-based parameters discriminated significantly between the presence or absence of CLAD (P Data conclusion Using the contrast media-free PREFUL-MRI technique, parameters of ventilation dynamics and its regional heterogeneity were shown to be sensitive for the detection of early CLAD stages. Level of evidence 3 TECHNICAL EFFICACY: Stage 3 J. Magn. Reson. Imaging 2019;50:1873-1882.

RATIONALE AND OBJECTIVES To assess the repeatability of global and regional lung ventilation quantification in both healthy subjects and patients with chronic obstructive pulmonary disease (COPD) using fluorinated (19F) gas washout magnetic resonance (MR) imaging in free breathing. MATERIAL AND METHODS In this prospective institutional review board-approved study, 12 healthy nonsmokers and eight COPD patients were examined with 19F dynamic gas washout MR imaging in free breathing and with lung function testing. Measurements were repeated within 2 weeks. Lung ventilation was quantified using 19F gas washout time. Repeatability was analyzed for the total lung and on a regional basis using the coefficient of variation (COV) and Bland-Altman plots. RESULTS In healthy subjects and COPD patients, a good repeatability was found for lung ventilation quantification using dynamic 19F gas washout MR imaging on a global (COV < 8%) and regional (COV < 15%) level. Gas washout time was significantly increased in the COPD group compared to the healthy subjects. CONCLUSION 19F gas washout MR imaging provides a good repeatability of lung ventilation quantification and appears to be sensitive to early changes of regional lung function alterations such as normal aging.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Instituto de Salud Carlos III, Spanish Government, Madrid, Spain [FIS_PI16/00435 Background Late gadolinium enhancement MRI (LGE-MRI) is increasingly used to detect native as well as ablation-induced atrial fibrosis in the context of atrial fibrillation (AF). However, cardiac fibrotic tissue including ablation lesions is subject to sustained remodeling, and neither the development of ablation-induced fibrosis over time nor the capability of LGE-MRI to detect it at different stages of scar formation have been defined. We sought to define the long-term development of ablation-induced atrial fibrosis and to validate LGE-MRI for the assessment of ablation lesions at different time points. Methods Patients with first-time AF ablation and an early follow-up LGE-MRI (3 months post ablation) and a late follow-up LGE-MRI (>12 months post ablation) were included. LGE-MRI data were postprocessed for quantification of fibrotic tissue using the ADAS 3D software. In the majority of patients high-density electroanatomical mapping (EAM), performed in a repeat procedure served as a reference. Results 22 consecutive patients fulfilling the inclusion criteria were analysed retrospectively. In the LGE-MRI 3 months post ablation an average of 91.7 ± 7.0% of the ablation lines" circumference displayed late gadolinium enhancement (LGE) reflecting ablation-induced fibrosis, whereas in the late follow-up LGE-MRI, at a median of 28 months post ablation, only 62.8 ± 25.0% of the ablation lines" circumference was covered by LGE (p Conclusions Our results indicate that while ablation-induced atrial fibrosis appears to remain rather constant over time, LGE-MRI loses some of its capability to detect it. Thus, LGE-MRI 3 months post ablation may be more accurate in the detection of durable ablation lesions than LGE-MRI at later time points more than 12 months after ablation. Abstract Figure

BackgroundStudying the phenotypic and genetic characteristics of age and polarity at onset (AAO, PAO) in bipolar disorder (BD) can provide new insights into disease pathology and facilitate the development of screening tools.AimsTo examine the genetic architecture of AAO and PAO and their association with BD disease characteristics.MethodsGenome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (N=12977) and PAO (N=6773) were conducted in BD patients of 34 cohorts and a replication sample (N=2237). The association of onset with disease characteristics was investigated in two of these cohorts.ResultsEarlier AAO was associated with an increased risk of psychotic symptoms, suicidality, and fewer episodes. A depressive onset correlated with lifetime suicidality and a manic onset with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in SNV-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased polygenic scores for autism spectrum disorder (β=-0.34 years, SE=0.08), major depression (β=-0.34 years, SE=0.08), schizophrenia (β=-0.39 years, SE=0.08), and educational attainment (β=-0.31 years, SE=0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.ConclusionsAAO and PAO are associated with indicators of BD severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents, and phenotype definitions introduce significant heterogeneity, affecting analyses.RELEVANCE STATEMENTIn the largest study to systematically characterize age at onset (N=12977) and polarity at onset (N=6773) in bipolar disorder, we describe an association between illness onset characteristics and indicators of severity, confirming their clinical relevance. Our study shows that that early illness onset is associated with genetic liability for a broad range of psychiatric disorders. However, we also highlight systematic differences in age at onset across cohorts, continents, and phenotype definitions. This heterogeneity results in reduced heritability and affects genetic analyses, underscoring the need for the development of standardized phenotype definitions.

Publisher's version, Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development., The study was supported by the German Federal Ministry of Education and Research (BMBF), through the Integrated Network IntegraMent, under the auspices of the e:Med programme (grants 01ZX1314A to MMN and SC; 01ZX1314G to MR; 01ZX1614J to BMM) through grants 01EE1406C to MR and 01EE1409C to MR and SHW, and through ERA-NET NEURON, “SynSchiz—Linking synaptic dysfunction to disease mechanisms in schizophrenia—a multilevel investigation” (01EW1810 to MR) and BMBF grants 01EE1409C and 01EE1406C to MR and SHW; by the German Research Foundation (DFG grants FOR2107; RI908/11-2 to MR; NO246/10-2 to MMN; MU1315/8-2 to BMM; WI 3439/3-2 to SHW), by the Andalusian regional Health and Innovation Government (grants PI-0060-2017, RC-0006-2015 the Nicolas Monarde Programme for YDO and CTS-546) and by the Swiss National Science Foundation (SNSF grant 156791 to SC). MMN is a member of the DFG-funded cluster of excellence ImmunoSensation. The PGC has received major funding from the US National Institute of Mental Health and the US National Institute of Drug Abuse (U01 MH109528 and U01 MH1095320). We thank the research participants and employees of 23andMe, Inc. for their contribution to the MDD meta-analysis published in [14]. We thank the International Genomics of Alzheimer's Project (IGAP) for providing summary results data for the present analyses. See the Supplementary Data for extended Acknowledgements.

Psychiatric disorders show heterogeneous clinical manifestations and disease trajectories, with current classification systems not accurately reflecting their molecular etiology. This heterogeneity impedes timely and targeted treatment. Our study aimed to identify diagnostically mixed psychiatric patient clusters that share clinical and genetic features and may profit from similar therapeutic interventions. We used unsupervised high-dimensional data clustering on deep clinical data to identify transdiagnostic groups in a discovery sample (N=1250) of healthy controls and patients diagnosed with depression, bipolar disorder, schizophrenia, schizoaffective disorder, and other psychiatric disorders. We observed five diagnostically mixed clusters and ordered them based on severity. The least impaired cluster 0, containing most healthy controls, was characterized by general well-being. Clusters 1-3 differed predominantly regarding levels of maltreatment, depression, daily functioning, and parental bonding. Cluster 4 contained most patients diagnosed with psychotic disorders and exhibited the highest severity in many dimensions, including medication load. MDD patients were present in all clusters, indicating that we captured different disease stages or subtypes. We replicated all but the smallest cluster 1 in an independent sample (N=622). Next, we analyzed genetic differences between clusters using polygenic scores (PGS) and the psychiatric family history. These genetic variables differed mainly between clusters 0 and 4 (prediction AUC=81%; significant PGS: cross-disorder psychiatric risk, schizophrenia, and educational attainment). Our results confirm that psychiatric disorders consist of heterogeneous subtypes sharing molecular factors and symptoms. The identification of transdiagnostic clusters advances our understanding of the heterogeneity of psychiatric disorders and may support the development of personalized treatment regimes.

OBJECTIVE: Many multiple sclerosis (MS) genetic susceptibility variants have been identified, but understanding disease heterogeneity remains a key challenge. Relapses are a core feature of MS and a common primary outcome of clinical trials, with prevention of relapses benefiting patients immediately and potentially limiting long-term disability accrual. We aim to identify genetic variation associated with relapse hazard in MS by analyzing the largest study population to date. METHODS: We performed a genomewide association study (GWAS) in a discovery cohort and investigated the genomewide significant variants in a replication cohort. Combining both cohorts, we captured a total of 2,231 relapses occurring before the start of any immunomodulatory treatment in 991 patients. For assessing time to relapse, we applied a survival analysis utilizing Cox proportional hazards models. We also investigated the association between MS genetic risk scores and relapse hazard and performed a gene ontology pathway analysis. RESULTS: The low-frequency genetic variant rs11871306 within WNT9B reached genomewide significance in predicting relapse hazard and replicated (meta-analysis hazard ratio (HR) = 2.15, 95% confidence interval (CI) = 1.70-2.78, p = 2.07 × 10-10 ). A pathway analysis identified an association of the pathway "response to vitamin D" with relapse hazard (p = 4.33 × 10-6 ). The MS genetic risk scores, however, were not associated with relapse hazard. INTERPRETATION: Genetic factors underlying disease heterogeneity differ from variants associated with MS susceptibility. Our findings imply that genetic variation within the Wnt signaling and vitamin D pathways contributes to differences in relapse occurrence. The present study highlights these cross-talking pathways as potential modulators of MS disease activity. ANN NEUROL 2021;89:884-894. ispartof: ANNALS OF NEUROLOGY vol:89 issue:5 pages:884-894 ispartof: location:United States status: published

Aims Left atrial (LA) fibrosis is present in patients with atrial fibrillation (AF) and can be visualized by magnetic resonance imaging with late gadolinium enhancement (LGE-MRI). Previous studies have shown that LA fibrosis is not randomly distributed, being more frequent in the area adjacent to the descending aorta (DAo). The objective of this study is to analyse the relationship between fibrosis in the atrial area adjacent to the DAo and the distance to it, as well as the prognostic implications of this fibrosis. Methods and results Magnetic resonance imaging with late gadolinium enhancement was obtained in 108 patients before AF ablation to analyse the extent of LA fibrosis and the distance DAo-to-LA. A high-density electroanatomic map was performed in a subgroup of 16 patients to exclude the possibility of an MRI artifact. Recurrences after ablation were analysed at 1 year of follow-up. The extent of atrial fibrosis in the area adjacent to the DAo was inversely correlated with the distance DAo-to-LA (r = −0.34, P Conclusions Atrial fibrosis was predominantly located in the area adjacent to the DAo, and increased with the proximity between the two structures. Furthermore, this regional fibrosis better predicted recurrence after AF ablation than total atrial fibrosis.

Objectives To evaluate the agreement in detecting pulmonary perfusion defects in patients with chronic thromboembolic pulmonary hypertension using dual-energy CT and dynamic contrast-enhanced MRI. Second, to compare both imaging modalities in monitoring lung perfusion changes in these patients after undergoing pulmonary endarterectomy. Methods 20 patients were examined with CT and MRI before and/or after pulmonary endarterectomy. Estimated perfusion defect percentage from both modalities was compared in a lobe-based analysis. Spatial agreement of perfusion defect maps was also assessed. Results A significant correlation between CT and MRI based perfusion defect percentage was calculated in all lung lobes (r > 0.78; p < 0.001). In addition, a good spatial agreement between perfusion defect maps was found (mean spatial overlap for the whole lung was 68.2%; SD = 6.9). Both CT and MRI detected improvements in pulmonary perfusion after pulmonary endarterectomy: 8% and 7% decrease in whole lung perfusion defect percentage (p = 0.007 and 0.004), respectively. In a lobe-wise analysis, improvements were statistically significant only in lower lobes using both modalities (reduction in defect percentage ranged from 16–29%; p < 0.02). Conclusions Dual-energy CT is an alternative to MRI in monitoring chronic thromboembolic pulmonary hypertension. Both imaging modalities provided comparable estimations of perfusion defects and could detect similar improvement in lung perfusion after pulmonary endarterectomy.

Psychiatric disorders show heterogeneous symptoms and trajectories, with current nosology not accurately reflecting their molecular etiology and the variability and symptomatic overlap within and between diagnostic classes. This heterogeneity impedes timely and targeted treatment. Our study aimed to identify psychiatric patient clusters that share clinical and genetic features and may profit from similar therapies. We used high-dimensional data clustering on deep clinical data to identify transdiagnostic groups in a discovery sample (N = 1250) of healthy controls and patients diagnosed with depression, bipolar disorder, schizophrenia, schizoaffective disorder, and other psychiatric disorders. We observed five diagnostically mixed clusters and ordered them based on severity. The least impaired cluster 0, containing most healthy controls, showed general well-being. Clusters 1–3 differed predominantly regarding levels of maltreatment, depression, daily functioning, and parental bonding. Cluster 4 contained most patients diagnosed with psychotic disorders and exhibited the highest severity in many dimensions, including medication load. Depressed patients were present in all clusters, indicating that we captured different disease stages or subtypes. We replicated all but the smallest cluster 1 in an independent sample (N = 622). Next, we analyzed genetic differences between clusters using polygenic scores (PGS) and the psychiatric family history. These genetic variables differed mainly between clusters 0 and 4 (prediction area under the receiver operating characteristic curve (AUC) = 81%; significant PGS: cross-disorder psychiatric risk, schizophrenia, and educational attainment). Our results confirm that psychiatric disorders consist of heterogeneous subtypes sharing molecular factors and symptoms. The identification of transdiagnostic clusters advances our understanding of the heterogeneity of psychiatric disorders and may support the development of personalized treatments.

The discovery of novel natural products (NPs) that will serve as lead structures has to be an ongoing effort to fill the respective development pipelines. However, identification of NPs, which possess a potential for application in e.g., the pharma or agro sector, must be as cost effective and fast as possible. Furthermore, the amount of sample available for initial testing is usually very limited, not least because of the fact that the impact on the environment, i.e., the sampled biosystem, should be kept minimal. Here, our pipeline SeaPEPR is described, in which a primary bioactivity screening of crude extracts is combined with the analysis of their metabolic fingerprint. This enabled prioritization of samples for subsequent microfractionation and dereplication of the active compounds early in the workflow. As a case study, 76 marine sponge-derived extracts were screened against a microbial screening panel. Thereunder, human pathogenic bacteria (Escherichia coli ATCC35218 and Staphylococcus aureus ATCC33592) and yeast (Candida albicans FH2173), as well as the phytopathogenic fungus Septoria tritici MUCL45407. Overall, nine extracts revealed activity against at least one test organism. Metabolic fingerprinting enabled assigning four active extracts into one metabolic group, therefore, one representative was selected for subsequent microfractionation. Dereplication of the active fractions showed a new dibrominated aplysinopsin and a hypothetical chromazonarol stereoisomer derivative. Furthermore, inhibitory activity against the common plant pest Septoria tritici was discovered for NPs of marine origin.

Background Previous research demonstrated benefits of adaptive digital microphone technologies (ADMTs) in adults with single-sided deafness (SSD) having a cochlear implant (CI). Children with SSD are especially affected by background noise because of their noise exposure in kindergarten and school. Purpose This article aims to evaluate possible effects of ADMT on speech recognition in background noise in children with SSD who use a CI. Study Sample Ten children between 5 and 11 years of age were included. Data Collection and Analysis Speech recognition in noise was assessed for one frontal distant and two lateral speakers. The speech stimulus was presented at a speech level of 65 dB(A) and noise at a level of 55 dB(A). For the presentation condition with one frontal speaker, four listening conditions were assessed: (1) normal-hearing (NH) ear and CI turned off; (2) NH ear and CI; (3) NH ear and CI with ADMT; and (4) NH ear with ADMT and CI. Listening conditions (2) to (4) were also tested for each lateral speaker. The frontal speaker was positioned directly in front of the participant, whereas the lateral speakers were positioned at angles of 90 degrees and –90 degrees to the participant's head. Results Children with SSD who use a CI significantly benefit from the application of ADMT in speech recognition in noise for frontal distant and for lateral speakers. Speech recognition improved significantly with ADMT at the CI and the NH ears. Conclusion Application of ADMT significantly improves speech recognition in noise in children with SSD who use a CI and can therefore be highly recommended. The decision of whether to apply ADMT at the CI NH ear or bilaterally should be made for each child individually.

Background: Lesions of brain white matter (WM) and atrophy of brain gray matter (GM) are well-established surrogate parameters in multiple sclerosis (MS), but it is unclear how closely these parameters relate to each other. Objective: To assess across the whole cerebrum whether GM atrophy can be explained by lesions in connecting WM tracts. Methods: GM images of 600 patients with relapsing-remitting MS (women = 68%; median age = 33.0 years, median expanded disability status scale score = 1.5) were converted to atrophy maps by data from a healthy control cohort. An atlas of WM tracts from the Human Connectome Project and individual lesion maps were merged to identify potentially disconnected GM regions, leading to individual disconnectome maps. Across the whole cerebrum, GM atrophy and potentially disconnected GM were tested for association both cross-sectionally and longitudinally. Results: We found highly significant correlations between disconnection and atrophy across most of the cerebrum. Longitudinal analysis demonstrated a close temporal relation of WM lesion formation and GM atrophy in connecting fibers. Conclusion: GM atrophy is associated with WM lesions in connecting fibers. Caution is warranted when interpreting group differences in GM atrophy exclusively as differences in early neurodegeneration independent of WM lesion formation.

Purpose The aim of the study was to compare long-term results after 1 year in patients with single-sided deafness (SSD) who were fitted with different hearing aids. The participants tested contralateral routing of signals (CROS) hearing aids and bone-anchored hearing systems (BAHS). They were also informed about the possibility of a cochlear implant (CI) and chose one of the three devices. We also investigated which factors influenced the choice of device. Methods Prospective study with 89 SSD participants who were divided into three groups by choosing BAHS, CROS, or CI. All participants received test batteries with both objective hearing tests (speech perception in noise and sound localisation) and subjective questionnaires. Results 16 participants opted for BAHS-, 13 for CROS- and 30 for CI-treatment. The greater the subjective impairment caused by SSD, the more likely patients were to opt for surgical treatment (BAHS or CI). The best results in terms of speech perception in noise (especially when sound reaches the deaf ear and noise the hearing ear), sound localization, and subjective results were achieved with CI. Conclusion The best results regarding the therapy of SSD are achieved with a CI, followed by BAHS. This was evident both in objective tests and in the subjective questionnaires. Nevertheless, an individual decision is required in each case as to which SSD therapy option is best for the patient. Above all, the patient's subjective impairment and expectations should be included in the decision-making process.

An infracochlear cholesteatoma of the petrous apex with direct contact to the internal carotid artery (ICA) is rare. Due to the risk of cochlear injury with consecutive deafness or injury of the ICA, precise preoperative planning of the approach and strategy is recommended, as well as thorough preoperative counseling of the patient for their informed consent. This case report presents navigated endoscopically controlled transtympanic resection of such a cholesteatoma recurrence. Hearing capacity was not impaired and the patient shows no signs of recurrence.

Magnetic resonance imaging (MRI) is an emerging tool for diagnosis and treatment monitoring of chronic thromboembolic pulmonary hypertension (CTEPH). The current study aims to identify central pulmonary arterial hemodynamic parameters that reflect clinical, cardiac and pulmonary changes after PEA. 31 CTEPH patients, who underwent PEA and received pre- and postoperative MRI, were analyzed retrospectively. Central pulmonary arterial blood flow, lung perfusion and right heart function data were derived from MRI. Mean pulmonary arterial pressure (mPAP) and 5-month follow-up six-minute walk-distance (6MWD) were assessed. After PEA, mPAP decreased significantly and patients achieved a higher 6MWD. Central pulmonary arterial blood flow velocities, pulmonary blood flow (PBF) and right ventricular function increased significantly. Two-dimensional (2D) phase-contrast (PC) MRI-derived average mean velocity, maximum mean velocity and deceleration volume changes after PEA correlated with changes of 6MWD and right heart ejection fraction (RVEF). Deceleration volume is a novel 2D PC MRI parameter showing further correlation with PBF changes. In conclusion, 2D PC MRI-derived main pulmonary hemodynamic changes reflect changes of RVEF, PBF and 5-month follow-up 6MWD and may be used for future CTEPH patient monitoring after PEA.

Hypothesis Before modern imaging was introduced, revision surgery was the only way to evaluate possible reasons for inadequate improvement in hearing after ossicular replacement during reconstructive middle ear surgery. Background The aim of this study was to evaluate freely navigable virtual tympanoscopy using different computed tomographic modalities. We compared cone-beam computed tomography (CBCT), flat panel computed tomography (FPCT), and conventional computed tomography in helical mode (CTH), volume mode (CTV), and ultra high resolution mode (CTD). Methods Four temporal bone specimens were reconstructed with partial or total ossicular replacement prostheses. The best functional results for prosthetic coupling were achieved under the control of laser Doppler vibrometry (LDV). Afterward, a progressive step-by-step decoupling of the prostheses was carried out. Different prosthesis positions were evaluated by LDV as well as different computed tomographic modalities with 3D reconstruction of each dataset. Results Anatomical structures were better depicted and the best position and coupling of inserted prostheses were achieved using CBCT. All imaging techniques could be used to control the position of middle ear prostheses, but CBCT provided the highest resolution and the best image quality in both 2D and 3D reformations and in 3D-animated video representation. Conclusion Compared with several other imaging modalities, CBCT was best at depicting miscellaneous coupling problems. Noninvasive detection of coupling problems caused by minimal loss of contact between prostheses and middle ear ossicles will influence the clinical outcome. This early detection will help to determine whether revision surgery is needed.

ObjectiveIn this observational study, we investigated the impact of genetic factors at the immunoglobulin heavy chain constant locus on chromosome 14 and the major histocompatibility complex region on intrathecal immunoglobulin G, A, and M levels as well as on B cells and plasmablasts in the CSF and blood of patients with multiple sclerosis (MS).MethodsUsing regression analyses, we tested genetic variants on chromosome 14 and imputed human leukocyte antigen (HLA) alleles for associations with intrathecal immunoglobulins in 1,279 patients with MS or clinically isolated syndrome and with blood and CSF B cells and plasmablasts in 301 and 348 patients, respectively.ResultsThe minor alleles of variants on chromosome 14 were associated with higher intrathecal immunoglobulin G levels (β = 0.58 [0.47 to 0.68], lowest adjusted p = 2.32 × 10−23), and lower intrathecal immunoglobulin M (β = −0.56 [−0.67 to −0.46], p = 2.06 × 10−24) and A (β = −0.42 [−0.54 to −0.31], p = 7.48 × 10−11) levels. Alleles from the HLA-B*07:02-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype were associated with higher (lowest p = 2.14 × 10−7) and HLA-B*44:02 with lower (β = −0.35 [−0.54 to −0.17], p = 1.38 × 10−2) immunoglobulin G levels. Of interest, different HLA alleles were associated with lower intrathecal immunoglobulin M (HLA-C*02:02, β = −0.45 [−0.61 to −0.28], p = 1.01 × 10−5) and higher immunoglobulin A levels (HLA-DQA1*01:03-DQB1*06:03-DRB1*13:01 haplotype, β = 0.40 [0.21 to 0.60], p = 4.46 × 10−3). The impact of HLA alleles on intrathecal immunoglobulin G and M levels could mostly be explained by associations with CSF B cells and plasmablasts.ConclusionAlthough some HLA alleles seem to primarily drive the extent of humoral immune responses in the CNS by increasing CSF B cells and plasmablasts, genetic variants at the immunoglobulin heavy chain constant locus might regulate intrathecal immunoglobulins levels via different mechanisms.

Purpose We investigated the long-term results of cochlear implant (CI) recipients with asymmetric hearing loss (AHL) or single-sided deafness (SSD). We focused on wearing behavior, audiometric hearing rehabilitation, and subjective benefits of the CI. CI is expected to improve audiological results, subjective hearing perception, and tinnitus burden. Methods Speech recognition in background noise and sound localization were assessed preoperatively and after at least six years of CI experience. Validated questionnaires determined the subjective benefit of CI use and the subjective evaluation of tinnitus. Results Over 80% of the included AHL and SSD CI recipients used their CI between 6 and 10 h daily; four subjects with SSD were non-users. Speech recognition in background noise and sound localization improved significantly compared with the unaided preoperative situation. Additionally, CI improved subjective speech intelligibility and spatial hearing impression while reducing tinnitus burden. Conclusion Subjects with AHL and SSD benefit from CI, subjectively and audiologically. Cochlear implant is a successful long-term treatment for AHL and SSD.

Telacebec (Q203) is a new antitubercular drug with extremely potent activity against Mycobacterium ulcerans. Here, we explored the treatment-shortening potential of Q203 alone or in combination with rifampin (RIF) in a mouse footpad infection model. The first study compared Q203 at 5 and 10 mg/kg doses alone and with rifampin. Q203 alone rendered most mouse footpads culture negative in 2 weeks. Combining Q203 with rifampin resulted in a relapse-free cure 24 weeks after completing 2 weeks of treatment, compared to a 25% relapse rate in mice receiving RIF with clarithromycin, the current standard of care, for 4 weeks. The second study explored the dose-ranging activity of Q203 alone and with RIF, including the extended activity of Q203 after treatment discontinuation. The bactericidal activity of Q203 persisted for > 4 weeks beyond the last dose. All mice receiving just 1 week of Q203 at 2 to 10 mg/kg were culture negative 4 weeks after stopping treatment. Mice receiving 2 weeks of Q203 at 0.5, 2, and 10 mg/kg were culture negative 4 weeks after treatment. RIF did not increase the efficacy of Q203. A pharmacokinetics substudy revealed that Q203 doses of 2 to 10 mg/kg in mice produce plasma concentrations similar to those produced by 100 to 300 mg doses in humans, with no adverse effect of RIF on Q203 concentrations. These results indicate the extraordinary potential of Q203 to reduce the duration of treatment necessary for a cure to < 1 week (or 5 doses of 2 to 10 mg/kg) in our mouse footpad infection model and warrant further evaluation of Q203 in clinical trials.

Background: Upon treatment with biopharmaceuticals, the immune system may produce anti-drug antibodies (ADA) that inhibit the therapy. Up to 40% of multiple sclerosis patients treated with interferon β (IFNβ) develop ADA, for which a genetic predisposition exists. Here, we present a genome-wide association study on ADA and predict the occurrence of antibodies in multiple sclerosis patients treated with different interferon β preparations. Methods: We analyzed a large sample of 2,757 genotyped and imputed patients from two cohorts, split between a discovery and a replication dataset. Binding ADA (bADA) levels were measured by capture-ELISA, neutralizing ADA (nADA) titers using a bioassay. Genome-wide association analyses were conducted stratified by cohort and treatment preparation, followed by fixed-effects meta-analysis. Results: Binding ADA levels and nADA titers were correlated and showed a significant heritability (47% and 50%, respectively). The risk factors differed strongly by treatment preparation: The top-associated and replicated variants for nADA presence were the HLA-associated variants rs77278603 in IFNβ-1a s.c.- (odds ratio (OR)=3.55 (95% confidence interval=2.81-4.48), p=2.1x10-26) and rs28366299 in IFNβ-1b s.c.-treated patients (OR=3.56 (2.69-4.72), p=6.6x10-19). The rs77278603-correlated HLA haplotype DR15-DQ6 conferred risk specifically for IFNβ-1a s.c. (OR=2.88 (2.29-3.61), p=7.4x10-20) while DR3-DQ2 was protective (OR=0.37 (0.27-0.52), p=3.7x10-09). The haplotype DR4-DQ3 was the major risk haplotype for IFNβ-1b s.c. (OR=7.35 (4.33-12.47), p=1.5x10-13). These haplotypes exhibit large population-specific frequency differences. In a cohort of IFNβ-1a s.c.-treated patients, prediction models for nADA reached an AUC of 0.91 (0.85-0.95), a sensitivity of 0.78, and a specificity of 0.90. Patients with the top 30% of genetic risk had, compared to patients in the bottom 30%, an OR of 73.9 (11.8 463.6, p=4.4x10-06) of developing nADA. Conclusions: We identified several HLA-associated genetic risk factors for ADA against interferon β, which were specific for treatment preparations and population backgrounds. Genetic prediction models could robustly identify patients at risk for developing ADA and might be used for personalized therapy recommendations and stratified ADA screening in clinical practice. These analyses serve as a roadmap for genetic characterizations of ADA against other biopharmaceutical compounds.

Aims While the CLOSE protocol proposes a maximally tolerable interlesion distance (ILD) of 6 mm for ablation index ablation index-guided atrial fibrillation (AF) ablation, a target ILD has never been defined. This randomized study sought to establish a target ILD for ablation index-guided AF ablation. Methods and results Consecutive patients scheduled for first-time pulmonary vein (PV) isolation (PVI) were randomly assigned to ablation protocols with a target ILD of 5.0–6.0 mm or 3.0–4.0 mm, with the primary endpoint of first-pass PVI. In compliance with the CLOSE protocol, the maximum tolerated ILD was 6.0 mm in both study protocols. A target ablation index of ≥550 (anterior) or ≥400 (posterior) was defined for the ‘5–6 mm’ protocol and ≥500 (anterior) or ≥350 (posterior) for the ‘3–4 mm’ protocol. The study was terminated early for superiority of the ‘3–4 mm’ protocol. Forty-two consecutive patients were randomized and 84 ipsilateral PV pairs encircled according to the study protocol. First-pass PVI was accomplished in 35.0% of the ‘5–6 mm’ group and 90.9% of the ‘3–4 mm’ group (P Conclusion In ablation index-guided AF ablation, an ILD of 3.0–4.0 mm should be targeted rather than 5.0–6.0 mm. Moreover, the lower target ILD may allow for less extensive ablation at each given point.

Background Stressful life events influence the course of affective disorders, however, the mechanisms by which they bring about phenotypic change are not entirely known. Methods We explored the role of DNA methylation in response to recent stressful life events in a cohort of bipolar patients from the longitudinal PsyCourse study (n = 96). Peripheral blood DNA methylomes were profiled at two time points for over 850,000 methylation sites. The association between impact ratings of stressful life events and DNA methylation was assessed, first by interrogating methylation sites in the vicinity of candidate genes previously implicated in the stress response and, second, by conducting an exploratory epigenome-wide association analysis. Third, the association between epigenetic aging and change in stress and symptom measures over time was investigated. Results Investigation of methylation signatures over time revealed just over half of the CpG sites tested had an absolute difference in methylation of at least 1% over a 1-year period. Although not a single CpG site withstood correction for multiple testing, methylation at one site (cg15212455) was suggestively associated with stressful life events (p −5). Epigenetic aging over a 1-year period was not associated with changes in stress or symptom measures. Conclusions To the best of our knowledge, our study is the first to investigate epigenome-wide methylation across time in bipolar patients and in relation to recent, non-traumatic stressful life events. Limited and inconclusive evidence warrants future longitudinal investigations in larger samples of well-characterized bipolar patients to give a complete picture regarding the role of DNA methylation in the course of bipolar disorder.

Telacebec (Q203) is a new anti-tubercular drug with extremely potent activity against Mycobacterium ulcerans. Here, we explored the treatment-shortening potential of Q203 alone or in combination with rifampin (RIF) in a mouse footpad infection model. The first study compared Q203 at 5 and 10 mg/kg doses alone and with rifampin. Q203 alone rendered most mouse footpads culture-negative in 2 weeks. Combining Q203 with rifampin resulted in relapse-free cure 24 weeks after completing 2 weeks of treatment, compared to a 25% relapse rate in mice receiving RIF+clarithromycin, the current standard of care, for 4 weeks.The second study explored the dose-ranging activity of Q203 alone and with RIF, including the extended activity of Q203 after treatment discontinuation. The bactericidal activity of Q203 persisted for ≥ 4 weeks beyond the last dose. All mice receiving just 1 week of Q203 at 2-10 mg/kg were culture-negative 4 weeks after stopping treatment. Mice receiving 2 weeks of Q203 at 0.5, 2 and 10 mg/kg were culture-negative 4 weeks after treatment. RIF did not increase the efficacy of Q203. A pharmacokinetics sub-study revealed that Q203 doses of 2-10 mg/kg in mice produce plasma concentrations similar to those produced by 100-300 mg doses in humans, with no adverse effect of RIF on Q203 concentrations.These results indicate the extraordinary potential of Q203 to reduce the duration of treatment necessary for cure to ≤ 1 week (or 5 doses of 2-10 mg/kg) in our mouse footpad infection model and warrant further evaluation of Q203 in clinical trials.