Platelet mitochondrial membrane depolarization reflects disease severity in patients with sepsis and correlates with clinical outcome

Introduction: Sepsis is still a leading cause of morbidity and mortality, even in modern times, and thrombocytopenia has been closely associated with unfavorable disease outcome. Decreases in mitochondrial membrane potential (depolarization) were found in different tissues during sepsis. Previous work suggests that mitochondrial dysfunction of platelets correlates with clinical disease activity in sepsis. However, platelet mitochondrial membrane potential (Mmp) has not been investigated in a clinical follow-up design and not with regard to disease outcome. Methods: In this study, platelet mitochondrial membrane depolarization was assessed by means of a fluorescent Mmp-Index with flow cytometry in 26 patients with sepsis compared with control patients. Platelet Mmp-Index on admission was correlated with the clinical disease scores Acute Physiology and Chronic Health Evaluation Score II (APACHE II), Sequential Organ Failure Score (SOFA), and Simplified Acute Physiology Score II (SAPS II). Finally, platelet Mmp-Index on admission and follow-up were compared in the group of sepsis survivors and nonsurvivors. Expression of the prosurvival protein Bcl-xL in platelets was quantified by immunoblotting. Results: Platelet mitochondrial membrane depolarization correlated significantly with the simultaneously assessed clinical disease severity by APACHE II (r = -0.867; P < 0.0001), SOFA (r = -0.857; P < 0.0001), and SAPS II score (r = -0.839; P < 0.0001). Patients with severe sepsis showed a significant reduction in platelet Mmp-Index compared with sepsis without organ failure (0.18 (0.12 to 0.25) versus 0.79 (0.49 to 0.85), P < 0.0006) or with the control group (0.18 (0.12 to 0.25) versus 0.89 (0.68 to 1.00), P < 0.0001). Platelet Mmp-Index remained persistently low in sepsis nonsurvivors (0.269 (0.230 to 0.305)), whereas we observed recovery of platelet Mmp-Index in the survivor group (0.9 (0.713 to 1.017)). Furthermore, the level of prosurvival protein Bcl-xL decreased in platelets during severe sepsis. Conclusion: In this study, we demonstrated that mitochondrial membrane depolarization in platelets correlates with clinical disease severity in patients with sepsis during the disease course and may be a valuable adjunct parameter to aid in the assessment of disease severity, risk stratification, and clinical outcome

Direct subthalamic nucleus stimulation influences speech and voice quality in Parkinson's disease patients

BACKGROUND DBS of the subthalamic nucleus (STN) considerably ameliorates cardinal motor symptoms in PD. Reported STN-DBS effects on secondary dysarthric (speech) and dysphonic symptoms (voice), as originating from vocal tract motor dysfunctions, are however inconsistent with rather deleterious outcomes based on post-surgical assessments. OBJECTIVE To parametrically and intra-operatively investigate the effects of deep brain stimulation (DBS) on perceptual and acoustic speech and voice quality in Parkinson's disease (PD) patients. METHODS We performed an assessment of instantaneous intra-operative speech and voice quality changes in PD patients (n = 38) elicited by direct STN stimulations with variations of central stimulation features (depth, laterality, and intensity), separately for each hemisphere. RESULTS First, perceptual assessments across several raters revealed that certain speech and voice symptoms could be improved with STN-DBS, but this seems largely restricted to right STN-DBS. Second, computer-based acoustic analyses of speech and voice features revealed that both left and right STN-DBS could improve dysarthric speech symptoms, but only right STN-DBS can considerably improve dysphonic symptoms, with left STN-DBS being restricted to only affect voice intensity features. Third, several subareas according to stimulation depth and laterality could be identified in the motoric STN proper and close to the associative STN with optimal (and partly suboptimal) stimulation outcomes. Fourth, low-to-medium stimulation intensities showed the most optimal and balanced effects compared to high intensities. CONCLUSIONS STN-DBS can considerably improve both speech and voice quality based on a carefully arranged stimulation regimen along central stimulation features

Validierung und Reliabilitätsprüfung des Nijmegen Cochlear Implant Questionnaire in deutscher Sprache

Hintergrund: Der Nijmegen Cochlear Implant Questionnaire (NCIQ) ist ein krankheitsspezifischer Fragebogen zur Erhebung der gesundheitsbezogenen Lebensqualität von Patienten vor und nach Cochleaimplantation. Ziel der Arbeit: Validierung und Reliabilitätsprüfung der deutschen Übersetzung des NCIQ. Material und Methoden: Es wurde eine prospektive Studie an 100 postlingual ertaubten oder hochgradig schwerhörigen Patienten durchgeführt, welche präoperativ sowie 3 und 6 Monate nach einer Cochleaimplantation mittels NCIQ, Abbreviated Profile of Hearing Aid Benefit (APHAB) und Hearing Participation Scale (HPS) untersucht wurden. Als Kontrolle fungierte ein postlingual ertaubtes oder hochgradig schwerhöriges, unbehandeltes Patientenkollektiv (n = 54). Cronbach‑α und Test-Retest-Reliabilität dienten der Reliabilitätsüberprüfung. Es wurde auf Inhalts‑, Übereinstimmungs- und auf diskriminative Validität getestet. Die Konstruktvaliditätsprüfung basiert auf kürzlich veröffentlichen Daten. Als Gütekriterien wurden die Sensitivität und eine ROC("Receiver Operating Characteristic")-Analyse, inklusive AUC("Area Under the ROC Curve")-Betrachtung, eingesetzt. Ergebnisse: Das Test-Retesting ergab nach 3 und 6 Monaten postoperativ stabile NCIQ-Werte. Die Cronbach-α-Werte wiesen auf eine gute interne Konsistenz hin. Der NCIQ diskriminierte valide zwischen behandelten und unbehandelten Patientengruppen. Es ergaben sich statistisch signifikante, wenn auch schwache, Korrelationen zwischen dem NCIQ und dem APHAB (r = -0,22; p = 0,04) und dem HPS (r = 0,30; p = 0,01). Sensitivitäts- und ROC-Analysen zeigten eine gute Messqualität des deutschsprachigen NCIQ. Schlussfolgerung: Die deutsche Übersetzung des NCIQ misst zuverlässig und valide die Lebensqualität vor und nach Cochleaimplantation und kann zur klinischen Erfolgskontrolle nach Cochleaimplantationen verwendet werden.Background: The Nijmegen Cochlear Implant Questionnaire (NCIQ) is a disease-specific questionnaire to determine the health-related quality of life (HRQoL) of patients before and after cochlear implantation. Objective: This study aimed to assess the validity and reliability of the German translation of the NCIQ. Materials and methods: A prospective study was performed in 100 postlingually deaf or severely hearing-impaired patients. HRQoL was assessed using the NCIQ, the Abbreviated Profile of Hearing Aid Benefit (APHAB), and the Hearing Participation Scale (HPS) before as well as 3 and 6 months after cochlear implantation. An untreated group of postlingually deaf or severely hearing-impaired patients (n = 54) served as a control. Cronbach's α and test–retest reliability were measured. The content, discrimination, and agreement validity were tested. The evaluation of construct validity was based on recently published data. Sensitivity and receiver operating curve (ROC) analysis, including consideration of the area under the curve (AUC), were used as quality criteria. Results: The test-retest analysis showed stable NCIQ values 3 and 6 months postoperatively. The Cronbach’s α values indicated good internal consistency. The NCIQ validly discriminated between treated and untreated patient groups. There were statistically significant albeit weak correlations between the NCIQ and the APHAB (r = -0.22; p = 0.04) and the HPS (r = 0.30; p = 0.01). Sensitivity and ROC analyses showed good measurement quality of the German-speaking NCIQ. Conclusion: The German translation of the NCIQ reliably and validly measures HRQoL before and after cochlear implantation and can be used for clinical monitoring after treatment with cochlear implants

Role of Pelvic Lymph Node Resection in Vulvar Squamous Cell Cancer:A Subset Analysis of the AGO-CaRE-1 Study

Background: As the population at risk for pelvic nodal involvement remains poorly described, the role of pelvic lymphadenectomy (LAE) in vulvar squamous cell cancer (VSCC) has been a matter of discussion for decades. Methods: In the AGO-CaRE-1 study, 1618 patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB or higher primary VSCC treated at 29 centers in Germany between 1998 and 2008 were documented. In this analysis, only patients with pelvic LAE (n = 70) were analyzed with regard to prognosis and correlation between inguinal and pelvic lymph node involvement. Results: The majority of patients had T1b/T2 tumors (n = 47; 67.1%), with a median diameter of 40 mm (2–240 mm); 54/70 patients (77.1%) who received pelvic LAE had positive groin nodes. For 42 of these 54 patients, the number of affected groin nodes had been documented as a median of 3; 14/42 (33.3%) of these patients had histologically confirmed pelvic nodal metastases (median number of affected pelvic nodes 3 [1–12]). In these 14 patients, the median number of affected groin nodes was 7 (1–30), with a groin metastases median maximum diameter of 42.5 mm (12–50). Receiver operating characteristic analysis showed an area under the curve of 0.85, with 83.3% sensitivity and 92.6% specificity for the prediction of pelvic involvement in cases of six or more positive groin nodes. No cases of pelvic nodal involvement without groin metastases were observed. Prognosis in cases of pelvic metastasis was poor, with a median progression-free survival of only 12.5 months. Conclusion: For the majority of node-positive patients with VSCC, pelvic nodal staging appears unnecessary since a relevant risk for pelvic nodal involvement only seems to be present in highly node-positive disease

Risk for pelvic metastasis and role of pelvic lymphadenectomy in node-positive vulvar cancer - results from the AGO-VOP.2 QS vulva study

Simple Summary In node-positive vulvar squamous cell cancer, questions of when and how to perform pelvic lymphadenectomy (LAE) as well as the optimal extent of pelvic treatment in general have been surrounded by considerable controversy. In Germany, systematic pelvic LAE is currently recommended as a staging procedure in patients at risk for pelvic nodal involvement in order to prevent morbidity caused by pelvic radiotherapy (RT) in patients without histologically-confirmed pelvic involvement. However, the population at risk for pelvic metastases remains insufficiently described, resulting in the potential overtreatment of a considerable proportion of patients with groin-positive disease. This applies to the indication to perform surgical staging but also to adjuvant RT of the pelvis without previous pelvic staging. Our study aims to describe the risk for pelvic lymph node metastasis with regard to positive groin nodes and to clarify the indication criteria for pelvic treatment in node-positive vulvar cancer. Abstract The need for pelvic treatment in patients with node-positive vulvar cancer (VSCC) and the value of pelvic lymphadenectomy (LAE) as a staging procedure to plan adjuvant radiotherapy (RT) is controversial. In this retrospective, multicenter analysis, 306 patients with primary node-positive VSCC treated at 33 gynecologic oncology centers in Germany between 2017 and 2019 were analyzed. All patients received surgical staging of the groins; nodal status was as follows: 23.9% (73/306) pN1a, 23.5% (72/306) pN1b, 20.4% (62/306) pN2a/b, and 31.9% (97/306) pN2c/pN3. A total of 35.6% (109/306) received pelvic LAE; pelvic nodal involvement was observed in 18.5%. None of the patients with nodal status pN1a or pN1b and pelvic LAE showed pelvic nodal involvement. Taking only patients with nodal status ≥pN2a into account, the rate of pelvic involvement was 25%. In total, adjuvant RT was applied in 64.4% (197/306). Only half of the pelvic node-positive (N+) patients received adjuvant RT to the pelvis (50%, 10/20 patients); 41.9% (122/291 patients) experienced recurrent disease or died. In patients with histologically-confirmed pelvic metastases after LAE, distant recurrences were most frequently observed (7/20 recurrences). Conclusions: A relevant risk regarding pelvic nodal involvement was observed from nodal status pN2a and higher. Our data support the omission of pelvic treatment in patients with nodal status pN1a and pN1b

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

The Crowdsourced Replication Initiative: Investigating Immigration and Social Policy Preferences. Executive Report.

In an era of mass migration, social scientists, populist parties and social movements raise concerns over the future of immigration-destination societies. What impacts does this have on policy and social solidarity? Comparative cross-national research, relying mostly on secondary data, has findings in different directions. There is a threat of selective model reporting and lack of replicability. The heterogeneity of countries obscures attempts to clearly define data-generating models. P-hacking and HARKing lurk among standard research practices in this area.This project employs crowdsourcing to address these issues. It draws on replication, deliberation, meta-analysis and harnessing the power of many minds at once. The Crowdsourced Replication Initiative carries two main goals, (a) to better investigate the linkage between immigration and social policy preferences across countries, and (b) to develop crowdsourcing as a social science method. The Executive Report provides short reviews of the area of social policy preferences and immigration, and the methods and impetus behind crowdsourcing plus a description of the entire project. Three main areas of findings will appear in three papers, that are registered as PAPs or in process

Backbone and methyl assignment of bacteriorhodopsin incorporated into nanodiscs

Resonance assignments are challenging for membrane proteins due to the size of the lipid/detergent-protein complex and the presence of line-broadening from conformational exchange. As a consequence, many correlations are missing in the triple-resonance NMR experiments typically used for assignments. Herein, we present an approach in which correlations from these solution-state NMR experiments are supplemented by data from 13C unlabeling, single-amino acid type labeling, 4D NOESY data and proximity of moieties to lipids or water in combination with a structure of the protein. These additional data are used to edit the expected peaklists for the automated assignment protocol FLYA, a module of the program package CYANA. We demonstrate application of the protocol to the 262-residue proton pump from archaeal bacteriorhodopsin (bR) in lipid nanodiscs. The lipid-protein assembly is characterized by an overall correlation time of 44 ns. The protocol yielded assignments for 62% of all backbone (H, N, Cα, Cβ, C’) resonances of bR, corresponding to 74% of all observed backbone spin systems, and 60 % of the Ala, Met, Ile (δ1), Leu and Val methyl groups, thus enabling to assign a large fraction of the protein without mutagenesis data. Most missing resonances stem from the extracellular half, likely due intermediate exchange line-broadening. Further analysis revealed that missing information of the amino acid type of the preceding residue is the largest problem, and that 4D NOESY experiments are particularly helpful to compensate for that information loss