Search

Es wird eine modulare Entwicklungsplattform für miniaturisierte photoakustische Gassensoren vorgestellt. Durch physikalische Modelle und angepasste Algorithmen zur Datenanalyse ist es möglich, einen konfigurierbaren Gassensor entsprechend den gewünschten Anforderungen selbst zu entwerfen. Zielgase, Sensorempfindlichkeit, Ansprechzeit und Robustheit gegenüber Störeinflüssen können berücksichtigt werden. Die Plattform wurde erfolgreich implementiert, wie die Prototypen für verschiedene Gase zeigen., A modular development platform for miniaturized photoacoustic gas sensors is presented. Using physical models and adapted algorithms for data analysis, it is possible to self-design a configurable gas sensor according to the desired requirements. Target gases, sensor sensitivity, response time, and robustness to interferences can be considered. The platform has been successfully implemented, as shown by the prototypes for various gases.

Background Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year. Methods We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants. Results We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume. Conclusions Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies., Background: Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year. Methods: We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants. Results: We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume. Conclusions: Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.

Aim: Assess the prognostic ability of a non-highly malignant and reactive EEG to predict good outcome after cardiac arrest (CA). Methods: Prospective observational multicentre substudy of the "Targeted Hypothermia versus Targeted Normothermia after Out-of-hospital Cardiac Arrest Trial", also known as the TTM2-trial. Presence or absence of highly malignant EEG patterns and EEG reactivity to external stimuli were prospectively assessed and reported by the trial sites. Highly malignant patterns were defined as burst-suppression or suppression with or without superimposed periodic discharges. Multimodal prognostication was performed 96 h after CA. Good outcome at 6 months was defined as a modified Rankin Scale score of 0-3. Results: 873 comatose patients at 59 sites had an EEG assessment during the hospital stay. Of these, 283 (32%) had good outcome. EEG was recorded at a median of 69 h (IQR 47-91) after CA. Absence of highly malignant EEG patterns was seen in 543 patients of whom 255 (29% of the cohort) had preserved EEG reactivity. A non-highly malignant and reactive EEG had 56% (CI 50-61) sensitivity and 83% (CI 80-86) specificity to predict good outcome. Presence of EEG reactivity contributed (p < 0.001) to the specificity of EEG to predict good outcome compared to only assessing background pattern without taking reactivity into account. Conclusion: Nearly one-third of comatose patients resuscitated after CA had a non-highly malignant and reactive EEG that was associated with a good long-term outcome. Reactivity testing should be routinely performed since preserved EEG reactivity contributed to prognostic performance., Funding Agencies|Swedish Research Council; Swedish Heart-Lung Foundation; Knutsson Foundation, Laerdal Foundation; (Hans-Gabriel and Alice Trolle-Wachtmeister Foundation for Medical Research, and Regional Research Support in Region Skane); Laerdal Foundation; Hans-Gabriel and Alice Trolle-Wachtmeister Foundation for Medical Research; Regional Research Support in Region Skane; Swedish National Health Service

AIM: Assess the prognostic ability of a non-highly malignant and reactive EEG to predict good outcome after cardiac arrest (CA). METHODS: Prospective observational multicentre substudy of the "Targeted Hypothermia versus Targeted Normothermia after Out-of-hospital Cardiac Arrest Trial", also known as the TTM2-trial. Presence or absence of highly malignant EEG patterns and EEG reactivity to external stimuli were prospectively assessed and reported by the trial sites. Highly malignant patterns were defined as burst-suppression or suppression with or without superimposed periodic discharges. Multimodal prognostication was performed 96 h after CA. Good outcome at 6 months was defined as a modified Rankin Scale score of 0-3. RESULTS: 873 comatose patients at 59 sites had an EEG assessment during the hospital stay. Of these, 283 (32%) had good outcome. EEG was recorded at a median of 69 h (IQR 47-91) after CA. Absence of highly malignant EEG patterns was seen in 543 patients of whom 255 (29% of the cohort) had preserved EEG reactivity. A non-highly malignant and reactive EEG had 56% (CI 50-61) sensitivity and 83% (CI 80-86) specificity to predict good outcome. Presence of EEG reactivity contributed (p < 0.001) to the specificity of EEG to predict good outcome compared to only assessing background pattern without taking reactivity into account. CONCLUSION: Nearly one-third of comatose patients resuscitated after CA had a non-highly malignant and reactive EEG that was associated with a good long-term outcome. Reactivity testing should be routinely performed since preserved EEG reactivity contributed to prognostic performance.

The biomedical sciences must maintain and enhance a research culture that prioritizes rigour and transparency. The US National Institute of Neurological Disorders and Stroke convened a workshop entitled Catalyzing Communities of Research Rigor Champions that brought together a diverse group of leaders in promoting research rigour and transparency (identified as rigour champions) to discuss strategies, barriers and resources for catalyzing technical, cultural and educational changes in the biomedical sciences. This article summarizes 2 days of panels and discussions and provides an overview of critical barriers to research rigour, perspectives behind reform initiatives and considerations for stakeholders across science. Additionally, we describe applications of network science to foster, maintain and expand cultural changes related to scientific rigour and opportunities to embed rigourous practices into didactic courses, training experiences and degree programme requirements. We hope this piece provides a primer for the wider research community on current discussions and actions and inspires individuals to build, join or expand collaborative networks within their own institutions that prioritize rigourous research practices.

In dieser Arbeit werden integrierte, siliziumbasierte Mikropumpen und darauf abgestimmte, miniaturisierte Strömungssensoren von Grund auf neu konzeptioniert und entwickelt. Die Entwicklungsphase wird durch virtuelle Produktentwicklung und durch die Adaptierung vorhandener Fertigungsprozesse beschleunigt. Nach der Entwicklung geeigneter Prüfstände können durch experimentelle Charakterisierung die Vorteile der Mikropumpen und Strömungssensoren gegenüber dem Stand der Technik nachgewiesen werden., In this work, integrated silicon-based micropumps and matched miniaturized flow sensors are conceptualized and developed from scratch. The development phase is accelerated by virtual product development and by adapting existing manufacturing processes. After the development of suitable test rigs, the advantages of the micropumps and flow sensors compared to the state of the art can be demonstrated by experimental characterization.

Micropumps and microvalves are essential components of modern medical microfluidic systems for novel treatments of diseases, restoration of lost body functions, and increased patient comfort. To date, microfluidic device technology lacks safe, reliable, and efficient pumps and valves that readily fulfill biocompatibility, system hermeticity, and economic requirements. To address this demand, this work develops a versatile metal-based microfluidic platform of pumps and valves for medical applications., Mikropumpen und Mikroventile sind zentrale Elemente von modernen medizinischen Mikrofluidiksystemen, die neuartige Therapien von Krankheiten, Wiederherstellung von Körperfunktionen oder Verbesserung des Patientenkomforts ermöglichen. Jedoch fehlt es an sicheren, zuverlässigen und effizienten Pumpen und Ventilen, die die Anforderungen an Biokompatibilität, Hermetizität und Kosteneffizienz erfüllen. Diese Arbeit widmet sich daher der Entwicklung einer anpassungsfähigen, metallbasierten Plattform von Pumpen und Ventilen für medizinische Anwendungen.

Specifically tailored medical applications can potentially enable several new diagnoses or therapies. Medical implants for recovery of certain actuators, e.g., artificial sphincter or penile prosthesis, can profit from extremely small micropumps that allow to restore patients’ actuators. This thesis investigates micropumps for high-flow applications and derives several guidelines to optimize them. The methods of investigation range from experimental analysis to theoretical modeling., Angepasste medizinische Anwendungen können viele neue Diagnosen oder Therapien ermöglichen. Medizinische Implantate zur Wiederherstellung bestimmter Aktorik, z. B. künstliche Schließmuskeln oder Penisprothesen, können durch extrem kleine Mikropumpen ermöglicht werden. In dieser Arbeit werden Mikropumpen für Hochflussanwendungen untersucht und viele Möglichkeiten zu deren Optimierung abgeleitet. Die Untersuchungsmethoden reichen von der experimentellen Analyse bis zur theoretischen Modellierung.

This resource manual presents information on mediation practices in special education disagreements between the school and parents. The manual provides an overview of requirements in the Individuals with Disabilities Education Act (IDEA) and gives definitions for alternative dispute resolution processes, such as arbitration and litigation. A chart shows the differences between mediation, due process hearings, and litigation. The manual explains the benefits of mediation and the qualifications, skills, and abilities a mediator should possess. Information is provided on how to prepare for mediation and how to conduct the mediation. The different phases of the mediation are described. They include: (1) the introduction/opening statement (a sample is provided); (2) fact finding, with statements by each mediation party; (3) collaboration and discussion; (4) the caucus; and (5) reconvening the joint session. Finally, information on how to conclude the mediation is provided. Commonly asked questions about mediation are answered. Appendices include sample mediation agreements, sample evaluation forms, and rules of mediation. (Contains 15 references.) (CR)

BACKGROUND: It remains elusive how the characteristics, the course of disease, the clinical management and the outcomes of critically ill COVID-19 patients admitted to intensive care units (ICU) worldwide have changed over the course of the pandemic. METHODS: Prospective, observational registry constituted by 90 ICUs across 22 countries worldwide including patients with a laboratory-confirmed, critical presentation of COVID-19 requiring advanced organ support. Hierarchical, generalized linear mixed-effect models accounting for hospital and country variability were employed to analyse the continuous evolution of the studied variables over the pandemic. RESULTS: Four thousand forty-one patients were included from March 2020 to September 2021. Over this period, the age of the admitted patients (62 [95% CI 60-63] years vs 64 [62-66] years, p < 0.001) and the severity of organ dysfunction at ICU admission decreased (Sequential Organ Failure Assessment 8.2 [7.6-9.0] vs 5.8 [5.3-6.4], p < 0.001) and increased, while more female patients (26 [23-29]% vs 41 [35-48]%, p < 0.001) were admitted. The time span between symptom onset and hospitalization as well as ICU admission became longer later in the pandemic (6.7 [6.2-7.2| days vs 9.7 [8.9-10.5] days, p < 0.001). The PaO2/FiO2 at admission was lower (132 [123-141] mmHg vs 101 [91-113] mmHg, p < 0.001) but showed faster improvements over the initial 5 days of ICU stay in late 2021 compared to early 2020 (34 [20-48] mmHg vs 70 [41-100] mmHg, p = 0.05). The number of patients treated with steroids and tocilizumab increased, while the use of therapeutic anticoagulation presented an inverse U-shaped behaviour over the course of the pandemic. The proportion of patients treated with high-flow oxygen (5 [4-7]% vs 20 [14-29], p < 0.001) and non-invasive mechanical ventilation (14 [11-18]% vs 24 [17-33]%, p < 0.001) throughout the pandemic increased concomitant to a decrease in invasive mechanical ventilation (82 [

[Background and Purpose] This update of the treatment guidelines was commissioned by the European Academy of Neurology and the European section of the Movement Disorder Society. Although these treatments are initiated usually in specialized centers, the general neurologist and general practitioners taking care of PD patients should know the therapies and their place in the treatment pathway., [Methods] Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the spectrum of approved interventions including deep brain stimulation (DBS) or brain lesioning with different techniques (radiofrequency thermocoagulation, radiosurgery, magnetic resonance imaging–guided focused ultrasound surgery [MRgFUS] of the following targets: subthalamic nucleus [STN], ventrolateral thalamus, and pallidum internum [GPi]). Continuous delivery of medication subcutaneously (apomorphine pump) or through percutaneous ileostomy (intrajejunal levodopa/carbidopa pump [LCIG]) was also included. Changes in motor features, health-related quality of life (QoL), adverse effects, and further outcome parameters were evaluated. Recommendations were based on high-class evidence and graded in three gradations. If only lower class evidence was available but the topic was felt to be of high importance, clinical consensus of the guideline task force was gathered., [Results] Two research questions have been answered with eight recommendations and five clinical consensus statements. Invasive therapies are reserved for specific patient groups and clinical situations mostly in the advanced stage of Parkinson's disease (PD). Interventions may be considered only for special patient profiles, which are mentioned in the text. Therapy effects are reported as change compared with current medical treatment. STN-DBS is the best-studied intervention for advanced PD with fluctuations not satisfactorily controlled with oral medications; it improves motor symptoms and QoL, and treatment should be offered to eligible patients. GPi-DBS can also be offered. For early PD with early fluctuations, STN-DBS is likely to improve motor symptoms, and QoL and can be offered. DBS should not be offered to people with early PD without fluctuations. LCIG and an apomorphine pump can be considered for advanced PD with fluctuations not sufficiently managed with oral treatments. Unilateral MRgFUS of the STN can be considered for distinctly unilateral PD within registries. Clinical consensus was reached for the following statements: Radiosurgery with gamma radiation cannot be recommended, unilateral radiofrequency thermocoagulation of the pallidum for advanced PD with treatment-resistant fluctuations and unilateral radiofrequency thermocoagulation of the thalamus for resistant tremor can be recommended if other options are not available, unilateral MRgFUS of the thalamus for medication-resistant tremor of PD can be considered only within registries, and unilateral MRgFUS of the pallidum is not recommended., [Conclusions] Evidence for invasive therapies in PD is heterogeneous. Only some of these therapies have a strong scientific basis. They differ in their profile of effects and have been tested only for specific patient groups.

Vorgestellt wird ein bionischer, mikrofluidischer Aktor, basierend auf dem Prinzip schwimmender Fische. Der abstrahierte Bewegungsablauf wird in ein piezoelektrisch angetriebenes, mikroelektromechanisches System übertragen. Mittels einer detaillierten Auswertemethodik, basierend auf Simulationen und Messungen, wird ein tiefgreifendes Verständnis über die zugrunde liegenden fluidischen Prozesse generiert, die Performanz der Bauteile bewertet und mögliche industrielle Anwendungen diskutiert., A bionic, microfluidic actuator based on the principle of swimming fish is presented. The abstracted motion scheme is transferred to a piezoelectrically driven, microelectromechanical system (MEMS). Using a comprehensive methodology based on simulations and measurements, a profound understanding of the underlying fluidic processes is generated, the performance of the actuator is evaluated and possible industrial applications are discussed.

4H-SiC JBS-diodes and PiN-diodes were investigated and characterized under extreme operating conditions. To this end, a high temperature test setup was built, and four different measurement configurations were implemented. Investigations on JBS-diodes demonstrated the bipolar activation as well as their blocking capability in dependence of structural variations of the devices. Measurements on PiN-diodes served to calibrate TCAD-simulation models between 300K and 770K, which describe the impact of carbon vacancies on the electron-hole recombination rates., Es wurden 4H-SiC-JBS-Dioden und PiN-Dioden unter extremen Betriebsbedingungen untersucht und charakterisiert. Hierzu wurde ein Hochtemperatur-Prüfstand aufgebaut, in dem vier verschiedene Messkonfigurationen implementiert sind. Untersuchungen an JBS-Dioden zeigten deren bipolare Aktivierung sowie deren Sperrfähigkeit in Abhängigkeit von strukturellen Variationen der Baulemente. Messungen an PiN-Dioden dienten dazu, TCAD-Simulationsmodelle im Temperaturbereich von 300K bis 770K zu kalibrieren, welche den Einfluß von Kohlenstoff-Leerstellen auf die Elektron-Loch-Rekombinationsraten beschreiben.

IMPORTANCE: The Targeted Hypothermia vs Targeted Normothermia After Out-of-Hospital Cardiac Arrest (TTM2) trial reported no difference in mortality or poor functional outcome at 6 months after out-of-hospital cardiac arrest (OHCA). This predefined exploratory analysis provides more detailed estimation of brain dysfunction for the comparison of the 2 intervention regimens. OBJECTIVES: To investigate the effects of targeted hypothermia vs targeted normothermia on functional outcome with focus on societal participation and cognitive function in survivors 6 months after OHCA. DESIGN, SETTING, AND PARTICIPANTS: This study is a predefined analysis of an international multicenter, randomized clinical trial that took place from November 2017 to January 2020 and included participants at 61 hospitals in 14 countries. A structured follow-up for survivors performed at 6 months was by masked outcome assessors. The last follow-up took place in October 2020. Participants included 1861 adult (older than 18 years) patients with OHCA who were comatose at hospital admission. At 6 months, 939 of 1861 were alive and invited to a follow-up, of which 103 of 939 declined or were missing. INTERVENTIONS: Randomization 1:1 to temperature control with targeted hypothermia at 33 °C or targeted normothermia and early treatment of fever (37.8 °C or higher). MAIN OUTCOMES AND MEASURES: Functional outcome focusing on societal participation assessed by the Glasgow Outcome Scale Extended ([GOSE] 1 to 8) and cognitive function assessed by the Montreal Cognitive Assessment ([MoCA] 0 to 30) and the Symbol Digit Modalities Test ([SDMT] z scores). Higher scores represent better outcomes. RESULTS: At 6 months, 836 of 939 survivors with a mean age of 60 (SD, 13) (range, 18 to 88) years (700 of 836 male [84%]) participated in the follow-up. There were no differences between the 2 intervention groups in functional outcome focusing on societal participation (GOSE score, odds ratio, 0.91; 95% CI, 0.71-1.17; P =

The optimal management of locally advanced rectal cancer is rapidly evolving. The National Cancer Institute Rectal-Anal Task Force convened an expert panel to develop consensus on the design of future clinical trials of patients with rectal cancer. A series of 82 questions and subquestions, which addressed radiation and neoadjuvant therapy, patient perceptions, rectal cancer populations of special interest, and unique design elements, were subject to iterative review using a Delphi analytical approach to define areas of consensus and those in which consensus is not established. The task force achieved consensus on several areas, including the following: 1) the use of total neoadjuvant therapy with long-course radiation therapy either before or after chemotherapy, as well as short-course radiation therapy followed by chemotherapy, as the control arm of clinical trials; 2) the need for greater emphasis on patient involvement in treatment choices within the context of trial design; 3) efforts to identify those patients likely, or unlikely, to benefit from nonoperative management or minimally invasive surgery; 4) investigation of the utility of circulating tumor DNA measurements for tailoring treatment and surveillance; and 5) the need for identification of appropriate end points and recognition of challenges of data management for patients who enter nonoperative management trial arms. Substantial agreement was reached on priorities affecting the design of future clinical trials in patients with locally advanced rectal cancer.

BACKGROUND: Descriptions of changes in invasive bacterial disease (IBD) epidemiology during the coronavirus disease 2019 (COVID-19) pandemic in the United States are limited. METHODS: We investigated changes in the incidence of IBD due to Streptococcus pneumoniae, Haemophilus influenzae, group A Streptococcus (GAS), and group B Streptococcus (GBS). We defined the COVID-19 pandemic period as 1 March to 31 December 2020. We compared observed IBD incidences during the pandemic to expected incidences, consistent with January 2014 to February 2020 trends. We conducted secondary analysis of a health care database to assess changes in testing by blood and cerebrospinal fluid (CSF) culture during the pandemic. RESULTS: Compared with expected incidences, the observed incidences of IBD due to S. pneumoniae, H. influenzae, GAS, and GBS were 58%, 60%, 28%, and 12% lower during the pandemic period of 2020, respectively. Declines from expected incidences corresponded closely with implementation of COVID-19-associated nonpharmaceutical interventions (NPIs). Significant declines were observed across all age and race groups, and surveillance sites for S. pneumoniae and H. influenzae. Blood and CSF culture testing rates during the pandemic were comparable to previous years. CONCLUSIONS: NPIs likely contributed to the decline in IBD incidence in the United States in 2020; observed declines were unlikely to be driven by reductions in testing.

Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders., Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders.

Contains fulltext : 291641.pdf (Publisher’s version ) (Open Access), Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders.

Genetic engineering and gene therapy are greatly disputed in our time. With the advancement of technology, one has the power to manipulate genes in the body, which raises the questions: What is our role in this? Is there a limit to this power, or should there be? This paper reviews the uses of this technology and evaluates the ethics from a scientific and Biblical point of view. It is concluded that using gene therapy to help cure diseases is very beneficial in both the scientific and Biblical realm as it is restoring individuals back to health and wholeness.

Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders.

The essential handbook for doing historical research in the twenty-first centuryThe Princeton Guide to Historical Research provides students, scholars, and professionals with the skills they need to practice the historian's craft in the digital age, while never losing sight of the fundamental values and techniques that have defined historical scholarship for centuries.Zachary Schrag begins by explaining how to ask good questions and then guides readers step-by-step through all phases of historical research, from narrowing a topic and locating sources to taking notes, crafting a narrative, and connecting one's work to existing scholarship. He shows how researchers extract knowledge from the widest range of sources, such as government documents, newspapers, unpublished manuscripts, images, interviews, and datasets. He demonstrates how to use archives and libraries, read sources critically, present claims supported by evidence, tell compelling stories, and much more.Featuring a wealth of examples that illustrate the methods used by seasoned experts, The Princeton Guide to Historical Research reveals that, however varied the subject matter and sources, historians share basic tools in the quest to understand people and the choices they made. Offers practical step-by-step guidance on how to do historical research, taking readers from initial questions to final publication Connects new digital technologies to the traditional skills of the historian Draws on hundreds of examples from a broad range of historical topics and approaches Shares tips for researchers at every skill level

In dieser Arbeit wurde ein alternatives Konzept eines MEMS-Mikrofons entworfen, um das Signal-Rausch-Verhältnis zu verbessern. Im neuen Bauelementkonzept wird das Schallsignal durch die Kapazitätsänderung in einer mikromechanischen Kammstruktur detektiert. Zur Unterstützung des Entwurfsprozesses wurde ein physikalisch basiertes modulares Simulationsmodell abgeleitet, das die gesamte Mikrofonfunktion prädiktiv abbildet. Die erfolgreiche Umsetzung des Konzepts zeigt sich in den realisierten Prototypen, die zusammen mit umfassenden theoretischen Untersuchungen das Potential des neuartigen Mikrofonkonzepts unterstreichen., In this work, an alternative concept of a MEMS microphone was designed to improve the signal-to-noise ratio. In the new concept, the sound signal is detected by the capacitance change in a micromechanical comb drive. To support the design process, a physically based modular simulation model was derived that predictively maps the entire microphone function. The successful implementation of the concept is reflected in the realized prototypes, which, together with comprehensive theoretical investigations, underline the potential of the new microphone concept.

Item does not contain fulltext, BACKGROUND: Patients in the late stages of parkinsonism are highly dependent on others in their self-care and activities of daily living. However, few studies have assessed the physical, psychological and social consequences of caring for a person with late-stage parkinsonism. PATIENTS AND METHODS: Five hundred and six patients and their caregivers from the Care of Late Stage Parkinsonism (CLaSP) study were included. Patients' motor and non-motor symptoms were assessed using the UPDRS and Non-motor symptom scale (NMSS), Neuropsychiatric inventory (NPI-12), and caregivers' health status using the EQ-5D-3 L. Caregiver burden was assessed by the Zarit Burden Interview (ZBI). RESULTS: The majority of caregivers were the spouse or life partner (71.2%), and were living with the patient at home (67%). Approximately half of caregivers reported anxiety/depression and pain/discomfort (45% and 59% respectively). The factors most strongly associated with caregiver burden were patients' neuropsychiatric features on the total NPI score (r = 0.38, p < 0.0001), total NMSS score (r = 0.28, p < 0.0001), caring for male patients and patients living at home. Being the spouse, the hours per day assisting and supervising the patient as well as caregivers' EQ-5D mood and pain scores were also associated with higher ZBI scores (all p < 0.001). CONCLUSION: The care of patients with late stage parkinsonism is associated with significant caregiver burden, particularly when patients manifest many neuropsychiatric and non-motor features and when caring for a male patient at home.

4H-SiC JBS-diodes and PiN-diodes were investigated and characterized under extreme operating conditions. To this end, a high temperature test setup was built, and four different measurement configurations were implemented. Investigations on JBS-diodes demonstrated the bipolar activation as well as their blocking capability in dependence of structural variations of the devices. Measurements on PiN-diodes served to calibrate TCAD-simulation models between 300K and 770K, which describe the impact of carbon vacancies on the electron-hole recombination rates., Es wurden 4H-SiC-JBS-Dioden und PiN-Dioden unter extremen Betriebsbedingungen untersucht und charakterisiert. Hierzu wurde ein Hochtemperatur-Prüfstand aufgebaut, in dem vier verschiedene Messkonfigurationen implementiert sind. Untersuchungen an JBS-Dioden zeigten deren bipolare Aktivierung sowie deren Sperrfähigkeit in Abhängigkeit von strukturellen Variationen der Baulemente. Messungen an PiN-Dioden dienten dazu, TCAD-Simulationsmodelle im Temperaturbereich von 300K bis 770K zu kalibrieren, welche den Einfluß von Kohlenstoff-Leerstellen auf die Elektron-Loch-Rekombinationsraten beschreiben.

BackgroundAs severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination coverage increases in the United States, there is a need to understand the real-world effectiveness against severe coronavirus disease 2019 (COVID-19) and among people at increased risk for poor outcomes.MethodsIn a multicenter case-control analysis of US adults hospitalized March 11-May 5, 2021, we evaluated vaccine effectiveness to prevent COVID-19 hospitalizations by comparing odds of prior vaccination with a messenger RNA (mRNA) vaccine (Pfizer-BioNTech or Moderna) between cases hospitalized with COVID-19 and hospital-based controls who tested negative for SARS-CoV-2.ResultsAmong 1212 participants, including 593 cases and 619 controls, median age was 58 years, 22.8% were Black, 13.9% were Hispanic, and 21.0% had immunosuppression. SARS-CoV-2 lineage B0.1.1.7 (Alpha) was the most common variant (67.9% of viruses with lineage determined). Full vaccination (receipt of 2 vaccine doses ≥14 days before illness onset) had been received by 8.2% of cases and 36.4% of controls. Overall vaccine effectiveness was 87.1% (95% confidence interval [CI], 80.7-91.3). Vaccine effectiveness was similar for Pfizer-BioNTech and Moderna vaccines, and highest in adults aged 18-49 years (97.4%; 95% CI, 79.3-9.7). Among 45 patients with vaccine-breakthrough COVID hospitalizations, 44 (97.8%) were ≥50 years old and 20 (44.4%) had immunosuppression. Vaccine effectiveness was lower among patients with immunosuppression (62.9%; 95% CI,20.8-82.6) than without immunosuppression (91.3%; 95% CI, 85.6-94.8).ConclusionDuring March-May 2021, SARS-CoV-2 mRNA vaccines were highly effective for preventing COVID-19 hospitalizations among US adults. SARS-CoV-2 vaccination was beneficial for patients with immunosuppression, but effectiveness was lower in the immunosuppressed population.

Item does not contain fulltext, BACKGROUND: Non-motor fluctuations (NMF) in people with Parkinson's disease (PwP) are clinically important yet understudied. OBJECTIVE: To study NMF in PwP using both the Movement Disorder Society Non-Motor Rating Scale (MDS-NMS) NMF subscale and wearable sensors. METHODS: We evaluated differences in overall burden of NMF and of specific NMF across disease durations: <2 years (n = 33), 2-5 years (n = 35), 5-10 years (n = 33), and > 10 years (n = 31). In addition, wearable triaxial sensor output was used as an exploratory outcome for early morning "off" periods. RESULTS: Significant between-group differences were observed for MDS-NMS NMF total scores (P < 0.001), and specifically for depression, anxiety, fatigue and cognition, with both NMF prevalence and burden increasing in those with longer disease duration. Whereas only 9.1% with a short disease duration had NMF (none of whom had dyskinesia), in PwP with a disease duration of >10 years this was 71.0% (P < 0.001). From a motor perspective, dyskinesia severity increased evenly with increasing disease duration, while NMF scores in affected individuals showed an initial increase with largest differences between 2-5 years disease duration (P < 0.001), with plateauing afterwards. Finally, we observed that the most common NMF symptoms in patients with sensor-confirmed early morning "off" periods were fluctuations in cognitive capabilities, restlessness, and excessive sweating. CONCLUSIONS: Non-motor fluctuations prevalence in PwP increases with disease duration, but in a pattern different from motor fluctuations. Moreover, NMF can occur in PwP without dyskinesia, and in those with NMF the severity of NMF increases most during years 2-5 after diagnosis.

Current understanding of global temperature and sea-level change over the Plio-Pleistocene remains poorly constrained and highly uncertain. We address these issues by reconstructing regional and global temperature evolution using ~120 published SST records that span some to all of the last 4.5 Myr. We use the resulting globally averaged SST difference to derive differences in global mean surface temperature and mean ocean temperature. We subtract reconstructed changes in mean ocean temperature from a global benthic oxygen isotope stack to derive the oxygen isotopic composition of seawater. We then reconstruct global mean sea level from our seawater isotope record by accounting for temperature effects on the isotopic composition of the main global ice sheets. Our reconstructions suggest that global cooling between 4.0-0.8 Ma was accompanied by intensification of Northern Hemisphere glaciation by 2.5 Ma, with subsequent fluctuations of large, LGM-like ice sheets occurring under a range of temperatures and temperature variability. These results present fundamental challenges to our understanding of ice sheet-climate interactions, including controls on ice-sheet inception and growth, and require a reassessment of hypotheses for the middle Pleistocene transition that invoke an increase in ice-sheet volume.

Vaccine effectiveness (VE) against COVID-19 hospitalization was evaluated among immunocompetent adults (≥18 years) during March-August 2021 using a case-control design. Among 1669 hospitalized COVID-19 cases (11% fully vaccinated) and 1950 RT-PCR-negative controls (54% fully vaccinated), VE was 96% (95% confidence interval [CI], 93%-98%) among patients with no chronic medical conditions and 83% (95% CI, 76%-88%) among patients with ≥ 3 categories of conditions. VE was similar between those aged 18-64 years versus ≥65 years (P > .05). VE against severe COVID-19 was very high among adults without chronic conditions and lessened with increasing comorbidity burden.

ObjectivesTo characterize the clinical severity of covid-19 associated with the alpha, delta, and omicron SARS-CoV-2 variants among adults admitted to hospital and to compare the effectiveness of mRNA vaccines to prevent hospital admissions related to each variant.DesignCase-control study.Setting21 hospitals across the United States.Participants11 690 adults (≥18 years) admitted to hospital: 5728 with covid-19 (cases) and 5962 without covid-19 (controls). Patients were classified into SARS-CoV-2 variant groups based on viral whole genome sequencing, and, if sequencing did not reveal a lineage, by the predominant circulating variant at the time of hospital admission: alpha (11 March to 3 July 2021), delta (4 July to 25 December 2021), and omicron (26 December 2021 to 14 January 2022).Main outcome measuresVaccine effectiveness calculated using a test negative design for mRNA vaccines to prevent covid-19 related hospital admissions by each variant (alpha, delta, omicron). Among patients admitted to hospital with covid-19, disease severity on the World Health Organization's clinical progression scale was compared among variants using proportional odds regression.ResultsEffectiveness of the mRNA vaccines to prevent covid-19 associated hospital admissions was 85% (95% confidence interval 82% to 88%) for two vaccine doses against the alpha variant, 85% (83% to 87%) for two doses against the delta variant, 94% (92% to 95%) for three doses against the delta variant, 65% (51% to 75%) for two doses against the omicron variant; and 86% (77% to 91%) for three doses against the omicron variant. In-hospital mortality was 7.6% (81/1060) for alpha, 12.2% (461/3788) for delta, and 7.1% (40/565) for omicron. Among unvaccinated patients with covid-19 admitted to hospital, severity on the WHO clinical progression scale was higher for the delta versus alpha variant (adjusted proportional odds ratio 1.28, 95% confidence interval 1.11 to 1.46), and lower for the omicron versus delta varian

David Merola,1,2 Jessica Young,2,3 Deborah Schrag,4 Kueiyu Joshua Lin,1,2,5 Nicholas Robert,6 Sebastian Schneeweiss1,2 1Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 2Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA; 3Department of Population Medicine, Harvard Medical School & Harvard Pilgrim Healthcare Institute, Boston, MA, USA; 4Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical School New York, New York, NY, USA; 5Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; 6Ontada, Irving, TX, USACorrespondence: David Merola, Email davemerola@gmail.comBackground: The use of electronic health records (EHR) data to assess drug effectiveness in clinical oncology practice is of great interest to regulators, clinicians, and payers. However, the utility of EHR data in clinical effectiveness studies may be limited by missing data, unmeasured confounding, and imperfect outcome surveillance. This study sought to emulate and compare the results of a randomized controlled trial investigating the efficacy of palbociclib with fulvestrant vs letrozole in advanced breast cancer.Methods: This was a cohort study using longitudinal EHR data derived from outpatient oncology practices in the United States. Eligibility criteria from the PARSIFAL trial were emulated as closely as possible. Patients were included if they had hormone-positive, human epidermal growth factor receptor – 2 (HER-2) negative metastatic breast cancer and had no record of prior treatment for metastatic disease. Patients initiating first-line treatment with palbociclib and fulvestrant following their first record of metastasis were compared to those initiating palbociclib and letrozole on the same day. Treatments were ascertained by oncology medication ordering records in the data source. The p

[Background and Objectives] The goal of this work was to investigate the association between group A streptococcal (GAS) infections and tic incidence among unaffected children with a family history of chronic tic disorders (CTDs)., [Methods] In a prospective cohort study, children with no history for tics who were 3 to 10 years of age with a first-degree relative with a CTD were recruited from the European Multicentre Tics in Children Study (EMTICS) across 16 European centers. Presence of GAS infection was assessed with throat swabs, serum anti–streptolysin O titers, and anti-DNAse titers blinded to clinical status. GAS exposure was defined with 4 different definitions based on these parameters. Cox regression analyses with time-varying GAS exposure were conducted to examine the association of onset of tics and GAS exposure during follow-up. Sensitivity analyses were conducted with Cox regression and logistic regression analyses., [Results] A total of 259 children were recruited; 1 child was found to have tic onset before study entry and therefore was excluded. Sixty-one children (23.6%) developed tics over an average follow-up period of 1 (SD 0.7) year. There was a strong association of sex and onset of tics, with girls having an ≈60% lower risk of developing tics compared to boys (hazard ratio [HR] 0.4, 95% confidence interval [CI] 0.2–0.7). However, there was no statistical evidence to suggest an association of any of the 4 GAS exposure definitions with tic onset (GAS exposure definition 1: HR 0.310, 95% CI 0.037–2.590; definition 2: HR 0.561, 95% CI 0.219–1.436; definition 3: HR 0.853, 95% CI 0.466–1.561; definition 4: HR 0.725, 95% CI 0.384–1.370)., [Discussion] These results do not suggest an association between GAS exposure and development of tics.

This work focusses on the optimization of 4.5kV SiC MPS diodes, with a view to the trade-off between the nominal and the surge current operation modes. An analytical compact model describing the impact of the geometrical and physical parameters on this trade-off has been developed. Based on this compact model, we propose several novel device structures. We provide physical explanations for the impact of non-ideal Ohmic contact on the fabricated diodes. We performed numerical simulations of the robustness against cosmic radiation comparing Si and SiC PiN diodes with the same blocking voltage of 1.5kV., Diese Arbeit beschäftigt sich mit der Optimierung von 4.5kV-SiC-MPS Dioden hinsichtlich ihres Verhaltens im Nenn- und im Stoßstrombetrieb. Mit Hilfe eines in dieser Arbeit entwickelten analytischen Kompaktmodells wird der Einfluss geometrischer und physikalischer Parameter auf das Bauelementverhalten untersucht und hieraus neuartige, verbesserte Konzepte abgeleitet. Desweiteren wurde mit Hilfe von Computersimulationen der Einfluss nichtidealer ohmscher Kontakte untersucht und die Robustheit von Si- und SiC-PiN-Dioden gegenüber kosmischer Strahlung bei gleicher Sperrspannung von 1.5kV verglichen.

ObjectiveTo investigate the association between Group-A streptococcal (GAS) infections and tic incidence among unaffected children with a family history of chronic tic disorders (CTD).MethodsIn a prospective cohort study, children with no history for tics aged 3 to 10 years with a first-degree relative with CTD were recruited from the European Multicentre Tics in Children Study (EMTICS) across 16 European centres. Presence of GAS infection was assessed using throat swabs, serum Anti-streptolysin O titres (ASOT) and Anti-DNAse B (ADB) titres blinded to clinical status. GAS exposure was defined using four different definitions based on these parameters. Cox regression analyses with time-varying GAS exposure were conducted to examine the association of onset of tics and GAS exposure during follow-up. Sensitivity analyses were conducted using Cox regression and logistic regression analyses.ResultsA total of 260 children were recruited whilst one subject was found to have tic onsets before study entry and therefore was excluded. 61 children (23.6%) developed tics over an average follow-up period of 1 (SD 0.7) year. There was a strong association of sex and onset of tics, with girls having an approximately 60% lower risk of developing tics compared to boys (HR: 0.4, 95% CI 0.2-0.7). However, there was no statistical evidence to suggest an association of any of the four GAS exposure definitions with tic onset (GAS exposure definition 1: HR=0.310, 95% CI: 0.037-2.590; definition 2: HR=0.561, 95% CI: 0.219-1.436; definition 3: HR=0.853, 95% CI: 0.466-1.561; definition 4: HR=0.725, 95% CI: 0.384-1.370).ConclusionThese results do not suggest an association of GAS exposure and development of tics.Classification of EvidenceThis study provides Class I evidence that Group-A streptococcal exposure does not associate with the development of tics in children with first-degree relatives with chronic tic disorder.

Der Einsatz von modellbasierten, virtuellen Prototypen ermöglicht den zeit- und kosteneffizienten Entwurf von Mikrosystemen. Diese Arbeit stellt ein modulares, physikalisch basiertes Modellierungskonzept vor, mit dem Modelle für die vielfältigen Mikrosysteme auf die jeweilige Problemstellung im Entwurf maßgeschneidert und so optimal eingesetzt werden können. Anhand von zwei sehr unterschiedlichen Mikrobauelementen – einem Hochfrequenz-Mikroschalter und einem Silizium-Mikrofon – wird dieses Konzept veranschaulicht und bewertet., Model-based, virtual prototyping enables the cost- and time-efficient design of microsystems. This work introduces a modular, physics-based modelling approach, which faces the diversity of microsystems with models tailored to the specific device and design task. This concept is exemplified by applying it to two different micro devices – a radio-frequency microswitch and a silicon microphone – and evaluated with respect to a general use in microsystem design.

With increasing numbers of infants in need of child care, the demand for infant care programs has grown. This handbook was designed to meet the need for technical assistance regarding program components and workable practices geared specifically to infant and toddler care. Part 1 of the handbook, "Considerations in Infant and Toddler Care," contains the chapters: (1) "What Are Parents Concerned About?" (Kleinman); (2) "Helping the Child Adjust to the Setting" (Lauritzen); (3) "Ensuring Health and Safety" (Chu); (4) "Providing Learning and Growth Experiences for Children" (Bromwich); (5) "Caring for Children with Special Needs" (Bromwich and Kleinman); (6) "Helping Children Accept Limits--Discipline" (Godwin); (7) "Helping Children Learn to Use the Toilet" (Lauritzen and Tullis); and (8) "Building Relationships with Parents" (Bromwich). Part 2 of the handbook, "Infant and Toddler Care in Centers" contains chapters: (9) "Setting Up the Environment" (Gordon, Khokha, Schrag, and Weeks); (10) "Staffing Programs for Infants and Toddlers" (Gordon); (11) "Staff Satisfaction, Rights, and Status" (Gordon); and (12) "Staff Meetings, Inservice Training, and Continuing Education" (Godwin). Part 3 of the handbook, "Infant and Toddler Care in Family Child Care Homes," contains chapters: (13) "Infants and Toddlers in Family Child Care" (Lauritzen); (14) "Designing the Family Child Care Environment" (Tishler); (15) "Business Aspects of Setting Up a Child Care Home" (McHale); and (16) "Family Child Care Systems and Satellite Homes" (Lauritzen). The handbook includes a section on finding help in the community. Appendices contain charts and sample forms. Contains a 90-item bibliography. (EV)

Addressed to parents, this publication discusses issues and offers recommendations on the preparation of providers of services to infants and their families. Section I discusses parents as consumers of infant/family services. Section II discusses parents as leaders in policy development, including policies affecting the training of infant/family practitioners. Section III discusses parents as trainers of infant/family practitioners. Providing an agenda for action, section IV suggests priorities for collaborative action among parents, policymakers, educators, and professionals to improve the training of those who work with infants, toddlers, and their families. An appendix lists resources for further information. (RH)