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IMPORTANCE: The ability to predict sudden cardiac death (SCD) in children and adolescents with hypertrophic cardiomyopathy (HCM) is currently inadequate. Late gadolinium enhancement (LGE) by cardiovascular magnetic resonance (CMR) imaging is associated with SCD events in adults with HCM. OBJECTIVE: To examine the prognostic significance of LGE in patients with HCM who are younger than 21 years. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, retrospective cohort study was conducted from April 8, 2015, to September 12, 2022, in patients with HCM who were younger than 21 years and had undergone CMR imaging across multiple sites in the US, Europe, and South America. Observers of CMR studies were masked toward outcomes and demographic characteristics. EXPOSURE: Natural history of HCM. MAIN OUTCOME AND MEASURES: The primary outcome was SCD and surrogate events, including resuscitated cardiac arrest and appropriate discharges from an implantable defibrillator. Continuous and categorical data are expressed as mean (SD), median (IQR), or number (percentage), respectively. Survivor curves comparing patients with and without LGE were constructed by the Kaplan-Meier method, and likelihood of subsequent clinical events was further evaluated using univariate and multivariable Cox proportional hazards models. RESULTS: Among 700 patients from 37 international centers, median (IQR) age was 14.8 (11.9-17.4) years, and 518 participants (74.0%) were male. During a median (IQR) [range] follow-up period of 1.9 (0.5-4.1) [0.1-14.8] years, 35 patients (5.0%) experienced SCD or equivalent events. LGE was present in 230 patients (32.9%), which constituted an mean (SD) burden of 5.9% (7.3%) of left ventricular myocardium. The LGE amount was higher in older patients and those with greater left ventricular mass and maximal wall thickness; patients with LGE had lower left ventricular ejection fractions and larger left atrial diameters. The presence and burden of LGE was associated with SCD, even after correcting for existing risk stratification tools. Patients with 10% or more LGE, relative to total myocardium, had a higher risk of SCD (unadjusted hazard ratio [HR], 2.19; 95% CI, 1.59-3.02; P < .001). Furthermore, the addition of LGE burden improved the performance of the HCM Risk-Kids score (before LGE addition: 0.66; 95% CI, 0.58-0.75; after LGE addition: 0.73; 95% CI, 0.66-0.81) and Precision Medicine in Cardiomyopathy score (before LGE addition: 0.68; 95% CI, 0.49-0.77; after LGE addition: 0.73; 95% CI, 0.64-0.82) SCD predictive models. CONCLUSIONS AND RELEVANCE: In this retrospective cohort study, quantitative LGE was a risk factor for SCD in patients younger than 21 years with HCM and improved risk stratification.

The debate about competition concerns in the digital economy cumulated in the adoption of new legislation, Section 19a GWB in Germany and the Digital Markets Act at the EU level. At around the same time, a new term gained prevalence in the competition law discourse—the ‘ecosystem’. Often, it is not quite clear, what is meant by it or what the economics behind it are. In this article, I look to the strategic management literature, whose scholars have developed a coherent ecosystem concept. I will explain the economic benefits of the ecosystem structure and the essential role governance plays in it. From the economics of the ecosystem, several insights can be won for competition law. These insights will be applied to the new legislation in the second part. It will be analysed to what extent the DMA and Section 19a GWB are based on the ecosystem concept, whether they identify the problematic actors as addressees, and whether they capture the restrictive conduct. Although both legislative responses do not build on the ecosystem concept, they do not completely fail to address the right issues. Their neglect of the concept, though, could lead to serious enforcement failures.

Thyroid hormone (TH) carrier proteins play an important role in distributing TH to target tissue as well as maintaining the balance of free versus bound TH in the blood. Interference with the TH carrier proteins has been identified as a potential mechanism of thyroid system disruption. To address the lack of data regarding chemicals binding to these carrier proteins and displacing TH, a fluorescence-based in vitroscreening assay was utilized to screen over 1,400 chemicals from the U.S. EPA’s ToxCast phase1_v2, phase 2, and e1k libraries for competitive binding to one of the carrier proteins, thyroxine-binding globulin. Initial screening at a single high concentration of 100 μM identified 714 chemicals that decreased signal of the bound fluorescent ligand by 20% or higher. Of these, 297 produced 50% or greater reduction in fluorescence and were further tested in concentration–response (0.004 to 150 μM) to determine relative potency. Ten chemicals were found to have EC50 values <1 μM, 63 < 10 μM, and 141 chemicals between 10 and 100 μM. Utilization of this assay contributes to expanding the number of in vitroassays available for identifying chemicals with the potential to disrupt TH homeostasis. These results support ranking and prioritization of chemicals to be tested in vivoto aid in the development of a framework for predicting in vivoeffects from in vitrohigh-throughput data.

Transthyretin (TTR) is one of the serum binding proteins responsible for transport of thyroid hormones (TH) to target tissue and for maintaining the balance of available TH. Chemical binding to TTR and subsequent displacement of TH has been identified as an end point in screening chemicals for potential disruption of the thyroid system. To address the lack of data regarding chemicals binding to TTR, we optimized an in vitroassay utilizing the fluorescent probe 8-anilino-1-napthalenesulfonic acid (ANSA) and the human protein TTR to screen over 1500 chemicals from the U.S. EPA’s ToxCast ph1_v2, ph2, and e1k libraries utilizing a tiered approach. Testing of a single high concentration (target 100 μM) resulted in 888 chemicals with 20% or greater activity based on displacement of ANSA from TTR. Of these, 282 chemicals had activity of 85% or greater and were further tested in 12-point concentration–response with target concentrations ranging from 0.015 to 100 μM. An EC50 was obtained for 276 of these 301 chemicals. To date, this is the largest set of chemicals screened for binding to TTR. Utilization of this assay is a significant contribution toward expanding the suite of in vitroassays used to identify chemicals with the potential to disrupt thyroid hormone homeostasis.

The risk of early recurrent events after stroke remains high despite currently established secondary prevention strategies1. Risk is particularly high in patients with atherosclerosis, with more than 10% of patients experiencing early recurrent events1,2. However, despite the enormous medical burden of this clinical phenomenon, the underlying mechanisms leading to increased vascular risk and recurrent stroke are largely unknown. Here, using a novel mouse model of stroke-induced recurrent ischaemia, we show that stroke leads to activation of the AIM2 inflammasome in vulnerable atherosclerotic plaques via an increase of circulating cell-free DNA. Enhanced plaque inflammation post-stroke results in plaque destabilization and atherothrombosis, finally leading to arterioarterial embolism and recurrent stroke within days after the index stroke. We confirm key steps of plaque destabilization also after experimental myocardial infarction and in carotid artery plaque samples from patients with acute stroke. Rapid neutrophil NETosis was identified as the main source of cell-free DNA after stroke and NET–DNA as the causative agent leading to AIM2 inflammasome activation. Neutralization of cell-free DNA by DNase treatment or inhibition of inflammasome activation reduced the rate of stroke recurrence after experimental stroke. Our findings present an explanation for the high recurrence rate after incident ischaemic events in patients with atherosclerosis. The detailed mechanisms uncovered here provide clinically uncharted therapeutic targets for which we show high efficacy to prevent recurrent events. Targeting DNA-mediated inflammasome activation after remote tissue injury represents a promising avenue for further clinical development in the prevention of early recurrent events.

In modern manufacturing systems, quality monitoring is crucial for efficient and cost-effective production. Conventional systems rely on thresholds and process windows, but machine learning (ML) techniques promise greater accuracy and efficiency.

A recent bathymetric survey of Lake Constance revealed ~ 170 mounds composed of loosely deposited rocks aligned in a ~ 10-km long chain along the southern Swiss shoreline in a water depth of 3–5 m. The mounds are 10–30 m in diameter and up to 1.5 m high. Over their entire length of occurrence, the mounds are estimated to be composed of ~ 60 million individual boulders, with a total weight of ~ 78,000 t. A ground penetrating radar (GPR) survey showed that the mounds are not linked to the glacial substrate but were rather deposited artificially on the edge of a prograding shelf composed of Holocene lake sediments. Here, we present the results of a coring campaign with four piston cores along a GPR transect across one of the mounds. The cores recovered the full Holocene sedimentary succession all the way into the basal till that is overlain by lacustrine sediments dating back to ~ 14,400 cal. yrs BP. The four cores are merged into a ~ 12.4-m long composite section reflecting continuous sedimentation from the siliciclastic-dominated Late Glacial to the carbonate-rich Late Holocene. The stratigraphic horizon representing the mound’s construction was radiocarbon-dated to ~ 5600–5300 cal. yrs BP, placing them in the Neolithic period. This age was confirmed by radiocarbon dating of wood samples collected during underwater excavation of the mounds. Geochemical analysis of the Holocene sedimentary succession shows generally high carbonate contents (average of 69%). The interval from 5750 to 4950 cal. yrs BP, a part of the mound period, is characterized by a Holocene minimum in carbonate content (average of 57%) and by larger mean grain sizes. Comparing these values to those from a recent surface-sediment depth transect indicates that this was a period of rather low lake levels, which might have favoured mound construction. Correlations to nearby archaeological sites and to the general West-Central European lake-level record indicates that the mounds likely were built during a short phase of low lake levels during a general trend of climatic cooling followed by a lake-level transgression.

Proximal humerus fractures are a common injury, predominantly affecting older adults. This study aimed to develop risk-prediction models for prolonged length of hospital stay (LOS), serious adverse complications, and readmission within 30 days of surgically treated proximal humerus fractures using machine learning (ML) techniques.

The seamless merging of the physical and digital worlds, has led to an unprecedented increase in the speed at which automation can be introduced into production. can be introduced. Smart manufacturing systems will, at a fundamental level, enable the use of artificial intelligence (AI) through machine learning (ML). This involves the alignment of information flows through suitable interfaces to humans is essential. is indispensable. This human-centered approach is referred to as Industry 5.0 (I5.0) or the human-centered approach (HCA) [1, 2]. The prioritization of people can be achieved prioritization can be achieved by placing the process-related interests of people at the at the center of production monitoring and relying on technologies that help employees by developing knowledge and skills, initiate optimizations.

Study Design SurveyObjective In March of 2020, an original study by Louie et al investigated the impact of COVID-19 on 902 spine surgeons internationally. Since then, due to varying government responses and public health initiatives to the pandemic, individual countries and regions of the world have been affected differently. Therefore, this follow-up study aimed to assess how the COVID-19 impact on spine surgeons has changed 1 year later.Methods A repeat, multi-dimensional, 90-item survey written in English was distributed to spine surgeons worldwide via email to the AO Spine membership who agreed to receive surveys. Questions were categorized into the following domains: demographics, COVID-19 observations, preparedness, personal impact, patient care, and future perceptions.Results Basic respondent demographics, such as gender, age, home demographics, medical comorbidities, practice type, and years since training completion, were similar to those of the original 2020 survey. Significant differences between groups included reasons for COVID testing, opinions of media coverage, hospital unemployment, likelihood to be performing elective surgery, percentage of cases cancelled, percentage of personal income, sick leave, personal time allocation, stress coping mechanisms, and the belief that future guidelines were needed (P<.05).Conclusion Compared to baseline results collected at the beginning of the COVID-19 pandemic in 2020, significant differences in various domains related to COVID-19 perceptions, hospital preparedness, practice impact, personal impact, and future perceptions have developed. Follow-up assessment of spine surgeons has further indicated that telemedicine and virtual education are mainstays. Such findings may help to inform and manage expectations and responses to any future outbreaks.

Die Anzahl von Soldat*innen der Bundeswehr mit einsatzspezifischen Traumafolgestörungen steigt stetig an. Voruntersuchungen zeigen, dass nur knapp die Hälfte der Betroffenen professionelle Hilfe in Anspruch nimmt. Über Einflussfaktoren auf die Entwicklung einer dem komplexen Krankheitsbild angemessenen Patientenkompetenz und die Versorgung Einsatzgeschädigter im interprofessionellen Netzwerk ist wenig bekannt.

What differs biochar from charcoal? The simple answer is that biochar is a carbon-rich product obtained from the thermal decomposition of organic material, at the presence of no or only a bit of oxygen. In principle, the production of biochar is comparable to the production of charcoal, one of the oldest and most established processes developed by mankind. While charcoal is made traditionally from wood, biochar can be based on a wide range of biomass and biomass residues. However, a variety of technologies for the production of biochar has been developed in recent years. The technologies are based on pyrolysis, gasification, or hydrothermal carbonization and are ranging from simple units, like heated steel drums to full automated and controlled processes. Therefore, the obtained products have tremendous differences in its properties and resulting qualities. The quality defines the field of application. To obtain the required quality for each application, the right process must be applied. Consequently, it is not enough only to enrich the carbon content by thermal decomposition of organic material. The production of tailor-made biochar for specific high added–value application is much more complex. In addition, side products like liquid biofuels make business cases stronger. If it is done in the right way, biochar production combined with advanced biofuels can be an economic solution to overcome the problems of climate change. “So for the future of mankind, this black matter might give the light at the end of the tunnel.”

Data driven strategies for acute pancreatitis (AP) in pediatrics are limited; adult data suggests lactated ringers (LR) compared to normal saline (NS) resulted in favorable outcomes, but has not been studied in pediatrics. Our objective was to evaluate the efficacy of LR during the first 48 h of an AP episode compared with NS. A multisite randomized controlled clinical trial, from 2015 to 2020 (Clinical Trials.govNCT03242473). Patients were randomized to exclusively LR or NS for the first 48 h. Primary outcomes were serial C‐reactive protein (CRP) values. Secondary outcomes included other lab values, time to feeds, length of stay (LOS), systemic inflammatory response syndrome (SIRS) development, and progression to severe AP (SAP). We studied 76 patients (38 LR, 38 NS). CRP at 24 and 48 h were not significantly different between LR or NS group. Additionally, there were no differences in trends of BUN, amylase, lipase, SIRS status, or SAP development between the LR and NS group at 24 and 48 h. A higher proportion of LR patients (32%, 12/38) were discharged before 48 h compared to NS (13%, 5/38). The LR group had a significantly higher rate of discharge within the first 72 h compared to the NS group (p= 0.02). The use of LR was associated with a faster rate of discharge during the intervention period and in the first 72 h, but no other differences compared to NS. This reduction in length of hospitalization has significant implications for patients and healthcare costs. Fluid resucistation with isotonic fluids has been shown to be helpful in pediatric acute pancreatitis (AP).Adult literature has favored lactated ringers (LR), but this has not been evaluated in pediatric AP. Fluid resucistation with isotonic fluids has been shown to be helpful in pediatric acute pancreatitis (AP). Adult literature has favored lactated ringers (LR), but this has not been evaluated in pediatric AP. This study shows that patients who exclusively received LR were discharged faster than patients who received normal saline.There were no other benefits or harms associated with the use of LR. This study shows that patients who exclusively received LR were discharged faster than patients who received normal saline. There were no other benefits or harms associated with the use of LR.

Chromatin architecture is a fundamental mediator of genome function. Fasting is a major environmental cue across the animal kingdom, yet how it impacts three-dimensional (3D) genome organization is unknown. Here we show that fasting induces an intestine-specific, reversible and large-scale spatial reorganization of chromatin in Caenorhabditis elegans. This fasting-induced 3D genome reorganization requires inhibition of the nutrient-sensing mTOR pathway, acting through the regulation of RNA Pol I, but not Pol II nor Pol III, and is accompanied by remodelling of the nucleolus. By uncoupling the 3D genome configuration from the animal’s nutritional status, we find that the expression of metabolic and stress-related genes increases when the spatial reorganization of chromatin occurs, showing that the 3D genome might support the transcriptional response in fasted animals. Our work documents a large-scale chromatin reorganization triggered by fasting and reveals that mTOR and RNA Pol I shape genome architecture in response to nutrients.

Zusammenfassung: Hintergrund: Seit 1983 werden am Klinikum Stuttgart, Krankenhaus Bad Cannstatt chirurgische Eingriffe bei Patienten zur Behandlung krankhafter Adipositas durchgeführt. Ziel dieser Arbeit war es, die Entwicklung der Adipositaschirurgie in einer Klinik der Maximalversorgung über einen Zeitraum von mehr als 20 Jahren zu untersuchen und darzustellen. Methoden: Die Daten zur Adipositaschirurgie wurden retrospektiv erfasst. Die Entwicklung der Adipositaschirurgie wurde anhand der Parameter Anzahl der Eingriffe, Eingriffsart, Krankenhausverweildauer und postoperative Komplikationsrate analysiert. Ergebnisse: Insgesamt wurden 1041 primäre adipositaschirurgische Eingriffe durchgeführt. Diese waren in frühen Jahren zunächst konventionelle Verfahren (horizontaler Bypass und vertikale Gastroplastik). 2003 wurden laparoskopische Verfahren eingeführt (Magenband und gastrojejunaler Bypass). Die Krankenhausverweildauer betrug durchschnittlich 14,7±5,1 Tage bei den konventionellen Eingriffen gegenüber 6,7±4,2 Tagen bei den laparoskopischen Eingriffen. Die 30-Tage-Mortalität lag bei 0,8% bzw. 0,0%. Frühe postoperative Komplikationen traten in 16,9% bzw. 7,8% der Fälle auf. Schlussfolgerung: Die perioperative Komplikationsrate und die stationäre Verweildauer konnten durch die Anwendung der laparoskopischen Verfahren signifikant reduziert werden. Unsere Untersuchung belegt klar die Vorteile der Laparoskopie in der Adipositaschirurgie, die mittlerweile die Standardmethode darstellt und sich nahtlos in das übrige Spektrum der Maximalversorgung einfügt.

Laser-plasma accelerators, have extremely high accelerating gradients and can generate ultra-short electron bunches with micrometer bunch lengths which makes them a prominent candidate to drive the next-generation compact light sources and free-electron lasers (FELs). To fully exploit the advantages of this novel accelerating technology and to compensate for large chromatic effects in the beam transport line, novel compact beam optic elements based on high-temperature superconductor technology are studied. Moreover, the limited mechanical properties of the HTS ceramic-structured superconductors lead to many manufacturing issues during the coil winding process and to ease this difficulty, designing magnets with simple shape coils is of interest. In this article, the magnet design as well as the fabrication and test of a demonstrator of a periodic iron-core miniature HTS quadrupole is discussed. This magnet features simple pancake coils that are capable of providing high field gradients and in the experiments were successfully powered in liquid nitrogen and liquid helium showing no degradation.

The aim of this research is the identification of a unified bookkeeping and evaluation scheme for the integrated performance analysis of a boundary layer ingesting (BLI) concept in the conceptual design phase. A thorough review and classification of existing performance bookkeeping schemes suits as a basis for the derivation of a bookkeeping scheme suitable for the initial sizing as well as detailed design analysis during the conceptual phase of a BLI concept. Figures of merit for the concept performance assessment are evaluated with regard to the requirements of aircraft multidisciplinary conceptual design. Based on the survey, the most practical integral momentum conservation approach is deduced and its application to integrated conceptual sizing and a subsequent design analysis is evaluated. The proposed scheme is universally applicable to coupled airframe–propulsion aircraft concepts, compatible with standard aircraft and propulsion system sizing tools and, under certain assumptions, deployable for low- and high-fidelity evaluation methods. Finally, several figures of merit are selected to cover a range of design aspects in the BLI evaluation.

Objective: To investigate the anatomical status of the round window niche and hearing outcome of cochlear implantation (CI) after explorative tympanotomy (ExT) with sealing of the round window membrane in patients with sudden sensorineural hearing loss at a tertiary referral medical center.Methods: Between January 1, 2007, and July 30, 2020, 1602 patients underwent CI at our department. Out of these, all patients previously treated by ExT with sealing of the round window membrane because of unilateral sudden hearing loss were included in the study. A retrospective chart review was conducted concerning method of round window membrane sealing, intraoperative findings during CI, postoperative imaging, and hearing results.Results: Twenty one patients (9 females; 8 right ears; 54.3 years [± 12.9 years]) underwent ExT with sealing of the round window membrane with subsequent CI after 26.6 months (± 32.9 mo) on average. During CI, in 76% of cases (n = 16), the round window niche was blocked by connective tissue due to the previous intervention but could be removed completely in all cases. The connective tissue itself and its removal had no detrimental effects on the round window membrane. Postoperative computed tomography scan showed no electrode dislocation. Mean postoperative word recognition score after 3 months was 57.4% (± 17.2%) and improved significantly to 73.1% (± 16.4%, P= .005) after 2 years.Conclusion: Performing CI after preceding ExT, connective tissue has to be expected blocking the round window niche. Remaining tissue can be removed safely and does not alter the round window membrane allowing for a proper electrode insertion. Short- and long-term hearing results are satisfactory. Consequently, ExT with sealing of the round window membrane in patients with sudden sensorineural hearing loss does not impede subsequent CI that can still be performed safely.

Objectives: The aims of our study were to investigate the clinical and audiometric outcome of the surgical treatment of postinflammatory medial meatal fibrosis (PIMMF) and to review the histopathologic changes in the specimens of the fibrotic plug, in order to try to shed light on the pathogenesis of the disease.Materials and Methods: The clinical records and the histopathologic specimens of all patients who underwent tympanomeatoplasty for PIMMF at the ENT Clinic of the University of Erlangen between 2006 and 2020 were evaluated retrospectively.Results: Thirty-four patients (41 primary surgical procedures) made up our study cohort. Of this, 28 cases were managed by means of meatoplasty and 13 cases with tympanomeatoplasty. The mean preoperative air–bone gap (ABG) was 27.8 dB (10-44 dB). Postoperative ABG was significantly improved compared to preoperative values at both short- and long-term follow-ups (P< .001 for both). No significant difference was noted between short-term and long-term ABG (P= .240). An ABG ≤20 dB was achieved in 65.8% of patients (short term) and 50% (long term). The overall rate of revision surgery for restenosis was 29.3% (12/41). Histopathologic reevaluation of the fibrotic plugs revealed a mosaic of patterns with frequent occurrence of secondary cholesteatoma-like lesions and keloid-like tissue changes. Lichenoid submucosal inflammation and increased ectopic ceruminous gland lobules were seen less frequently.Discussion: The moderate long-term outcome of surgical management and the identification of histologic changes with therapeutic implications might pave the way for alternative nonsurgical treatment options.

Post-ERCP pancreatitis (PEP) is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP). Limited existing data suggest that prophylactic pancreatic duct (PD) stenting in pediatric patients may increase the risk of PEP. The aim of this study is to identify factors associated with PEP in pediatric patients. Patients at a single institution who underwent ERCP between 2012 and 2020 were retrospectively reviewed. Patient and procedure-related factors were collected. Data were analyzed using Chi-square or Fisher exact tests as appropriate and Mann-Whitney-Wilcoxon tests. Seven hundred thirty-six ERCPs were performed for 402 unique patients. Ninety-four cases were complicated by PEP (12.8%), of which 91 were mild and 3 were moderately severe. Pancreatic indication, native major papilla, PD cannulation and injection, and higher American Society for Gastrointestinal Endoscopy (ASGE) complexity were associated with PEP. A higher proportion of patients who received rectal indomethacin (65% vs 47%, P= 0.002), or who had placement of a prophylactic (31% vs 20%, P= 0.01) or therapeutic PD stent (37% vs 27%, P= 0.04) developed PEP; however, in a subgroup analysis of high-risk patients, this association was not persistent. A smaller proportion of PEP patients had PRSS1mutation compared to non-PEP patients (22% vs 40%, P= 0.04). This study evaluates factors associated with developing PEP in a large pediatric cohort. A high rate of PEP was observed, likely secondary to higher rates of pancreatic indication and higher ASGE complexity scores compared to previously reported literature. Randomized prospective trials are needed to better define the utility of various interventions.