Search

Objective Refractory autoimmune diseases remain a significant challenge in clinical practice and new therapeutic options are needed. This systematic review evaluates the existing reported data on the CD38-targeting antibody daratumumab as a new therapeutic approach in autoantibody-mediated autoimmune diseases.Methods A protocolised systematic literature review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed. Two databases (Medline and Embase) were searched for suitable studies. Usage of daratumumab in non-oncological or non-transplantation associated diseases with autoimmune pathophysiology was analysed including patient characteristics, therapeutic regimen, adverse events and patient outcome.Results 38 publications reporting the clinical course of 83 patients met the inclusion criteria. Daratumumab usage was reported in therapy-refractory cases (median of 5 different previous therapies) in 24 different autoimmune diseases. The median number of applications of daratumumab was 4, mainly via intravenous applications (87%). Concomitant treatment included glucocorticoids in 64% of patients, intravenous immunoglobulins (33%) and rituximab (17%). Remission or improvement of disease was reported in 81% of patients. Autoantibody depletion or reduction was stated in 52% of patients. Death occurred in three patients (3%). Adverse events were reported in 45% of patients including application-associated reaction (20%), infection (19%) and hypogammaglobulinaemia (33%).Conclusion Targeting CD38 via daratumumab is a new promising therapeutic option in therapy refractory autoimmune diseases. Efficacy as well as optimal therapeutic regimen and management or prevention of adverse events require further investigation. Therefore, systematic clinical trials of this therapeutic approach are needed.

The first search for ultra-rare K+ decays into the π+e+e−e+e− final state is reported, using a dataset collected by the NA62 experiment at CERN in 2017–2018. An upper limit of 1.4×10−8 at 90% CL is obtained for the branching ratio of the K+→π+e+e−e+e− decay, predicted in the Standard Model to be (7.2±0.7)×10−11. Upper limits at 90% CL are obtained at the level of 10−9 for the branching ratios of two prompt decay chains involving pair-production of hidden-sector mediators: K+→π+aa, a→e+e− and K+→π+S, S→A′A′, A′→e+e−.

RationaleThe mechanisms underlying atrial fibrillation (AF), the most common clinical arrhythmia, are poorly understood. Nucleoplasmic Ca2+ regulates gene expression, but the nature and significance of nuclear Ca2+-changes in AF are largely unknown.ObjectiveTo elucidate mechanisms by which AF alters atrial-cardiomyocyte nuclear Ca2+ ([Ca2+]Nuc) and CaMKII (Ca2+/calmodulin-dependent protein kinase-II)-related signaling.Methods and resultsAtrial cardiomyocytes were isolated from control and AF dogs (kept in AF by atrial tachypacing [600 bpm × 1 week]). [Ca2+]Nuc and cytosolic [Ca2+] ([Ca2+]Cyto) were recorded via confocal microscopy. Diastolic [Ca2+]Nuc was greater than [Ca2+]Cyto under control conditions, while resting [Ca2+]Nuc was similar to [Ca2+]Cyto; both diastolic and resting [Ca2+]Nuc increased with AF. IP3R (Inositol-trisphosphate receptor) stimulation produced larger [Ca2+]Nuc increases in AF versus control cardiomyocytes, and IP3R-blockade suppressed the AF-related [Ca2+]Nuc differences. AF upregulated nuclear protein expression of IP3R1 (IP3R-type 1) and of phosphorylated CaMKII (immunohistochemistry and immunoblot) while decreasing the nuclear/cytosolic expression ratio for HDAC4 (histone deacetylase type-4). Isolated atrial cardiomyocytes tachypaced at 3 Hz for 24 hours mimicked AF-type [Ca2+]Nuc changes and L-type calcium current decreases versus 1-Hz-paced cardiomyocytes; these changes were prevented by IP3R knockdown with short-interfering RNA directed against IP3R1. Nuclear/cytosolic HDAC4 expression ratio was decreased by 3-Hz pacing, while nuclear CaMKII phosphorylation was increased. Either CaMKII-inhibition (by autocamtide-2-related peptide) or IP3R-knockdown prevented the CaMKII-hyperphosphorylation and nuclear-to-cytosolic HDAC4 shift caused by 3-Hz pacing. In human atrial cardiomyocytes from AF patients, nuclear IP3R1-expression was significantly increased, with decreased nuclear/nonnuclear HDAC4 ratio. MicroRNA-26a was predicted to target ITPR1 (confirmed by luciferase assay) and was downregulated in AF atrial cardiomyocytes; microRNA-26a silencing reproduced AF-induced IP3R1 upregulation and nuclear diastolic Ca2+-loading.ConclusionsAF increases atrial-cardiomyocyte nucleoplasmic [Ca2+] by IP3R1-upregulation involving miR-26a, leading to enhanced IP3R1-CaMKII-HDAC4 signaling and L-type calcium current downregulation. Graphic Abstract: A graphic abstract is available for this article.

The COVID-19 pandemic has had devastating direct consequences on the health of affected patients. It has also had a significant impact on the ability of unaffected children to be physically active. We evaluated the effect of deconditioning from social distancing and school shutdowns implemented during the COVID-19 pandemic on the cardiovascular fitness of healthy unaffected children. This is a single-center, retrospective case-control study performed in an urban tertiary referral center. A cohort of 10 healthy children that underwent cardiopulmonary exercise testing after COVID-19 hospital restrictions were lifted was compared to a matched cohort before COVID-19-related shutdowns on school and after-school activities. Comparisons of oxygen uptake (VO2) max and VO2 at anaerobic threshold between the pre- and post-COVID-19 cohorts were done. The VO2 max in the post-COVID cohort was significantly lower than in the pre-COVID cohort (39.1 vs. 44.7, p = 0.031). Only one out of ten patients had a higher VO2 max when compared to their matched pre-COVID control and was also the only patient with a documented history of participation in varsity-type athletics. The percentile of predicted VO2 was significantly lower in the post-COVID cohort (95% vs. 105%, p = 0.042). This study for the first time documented a significant measurable decline in physical fitness of healthy children as a result of the COVID-19 pandemic and its associated restrictions. Measures need to be identified that encourage and facilitate regular exercise in children in a way that are not solely dependent on school and organized after-school activities.

We describe a 16-year-old asymptomatic male who presented with coronary artery dilation (z score + 2.3) identified on echo performed solely for presence of COVID-19 antibodies. This case raises the question of whether cardiac screening should be considered for all patients with a history of COVID-19.

Abstract With the changing epidemiology of COVID-19 and its impact on our daily lives, there is still an unmet need of COVID-19 therapies treating early infections to prevent progression. The current study was a randomized, parallel, double-blind, placebo-controlled trial. Ninety SARS-CoV-2 positive patients were randomized into 3 groups receiving placebo, 0.02% or 0.1% azelastine nasal spray for 11 days, during which viral loads were assessed by quantitative PCR. Investigators assessed patients’ status throughout the trial including safety follow-ups (days 16 and 60). Symptoms were documented in patient diaries. Initial viral loads were log10 6.85 ± 1.31 (mean ± SD) copies/mL (ORF 1a/b gene). After treatment, virus load was reduced in all groups (p

Abstract In vivo, the force–velocity relation (F–v–r) is typically derived from the torque–angular velocity relation (T–ω–r), which is subject to two factors that may influence resulting measurements: tendon compliance and preload prior to contraction. The in vivo plantar flexors’ T–ω–r was determined during preloaded maximum voluntary shortening contractions at 0–200°/s. Additionally, we used a two factor block simulation study design to independently analyze the effects of preload and tendon compliance on the resulting T–ω–r. Therefore, we replicated the in vivo experiment using a Hill-type muscle model of the gastrocnemius medialis. The simulation results matched a key pattern observed in our recorded in vivo experimental data: during preloaded contractions, torque output of the muscle was increased when compared with non-preloaded contractions from literature. This effect increased with increasing contraction velocity and can be explained by a rapidly recoiling tendon, allowing the contractile element to contract more slowly, thus developing higher forces compared with non-preloaded contractions. Our simulation results also indicate that a more compliant tendon results in increased ankle joint torques. The simulation and the experimental data clearly show that the deduction of the in vivo F–v–r from the T–ω–r is compromised due to the two factors preloading and tendon compliance.

Abstract Apicomplexan parasites have immense impacts on humanity, but their basic cellular processes are often poorly understood. Where endocytosis occurs in these cells, how conserved this process is with other eukaryotes, and what the functions of endocytosis are across this phylum are major unanswered questions. Using the apicomplexan model Toxoplasma, we identified the molecular composition and behavior of unusual, fixed endocytic structures. Here, stable complexes of endocytic proteins differ markedly from the dynamic assembly/disassembly of these machineries in other eukaryotes. We identify that these endocytic structures correspond to the ‘micropore’ that has been observed throughout the Apicomplexa. Moreover, conserved molecular adaptation of this structure is seen in apicomplexans including the kelch-domain protein K13 that is central to malarial drug-resistance. We determine that a dominant function of endocytosis in Toxoplasma is plasma membrane homeostasis, rather than parasite nutrition, and that these specialized endocytic structures originated early in infrakingdom Alveolata likely in response to the complex cell pellicle that defines this medically and ecologically important ancient eukaryotic lineage.

Abstract In order to achieve its ultra-low vertical emittance (1 pm) and high luminosity (of up to 230 × 10 34 cm − 2 s − 1 $230 \times 10^{34}\text{ cm}^{-2}\text{ s}^{-1}$ per collision point), the e+e− Future Circular Collider (FCC-ee) requires a well-informed alignment strategy, powerful correction methods, and good understanding of the impact of vibrations. The large ring size, high natural chromaticity, small β ∗ $\beta ^{*}$ , and the low coupling ratio make the FCC-ee design susceptible to misalignment and field errors, which if not properly addressed, threaten to increase the horizontal and vertical emittances and adversely affect the luminosity. Tight alignment tolerances around the 100 km ring would be a major cost driver and therefore alignment and stability need to be carefully studied. In this paper we present a status update, in which we apply analytical estimate methods, verified with simulation data, to determine the influence of the alignment of specific magnet types with the result informing the relative alignment tolerances. This is followed by simulations of a correction strategy that includes a large set of magnet misalignments and field errors. Finally, we also consider the tolerances on vibrations of quadrupoles through evaluating three cases: coherent vibration due to external seismic motion, vibrations resonant with the betatron frequency, and non-resonant, incoherent vibration.

Abstract The NA62 experiment at CERN targets the measurement of the ultra-rare K + → π + ν ν ¯ $$ {K}^{+}\to {\pi}^{+}\nu \overline{\nu} $$ decay, and carries out a broad physics programme that includes probes for symmetry violations and searches for exotic particles. Data were collected in 2016–2018 using a multi-level trigger system, which is described highlighting performance studies based on 2018 data.

Abstract The environmental DNA (eDNA) metabarcoding approach has become a useful tool for detecting the species diversity of different animal groups, including parasites. Myxozoa (Malacosporea and Myxosporea) represent a unique group of morphologically simplified endoparasites that mainly infest fish and whose diversity remains largely unexplored. Metabarcoding of DNA from the aquatic environment is a promising non‐invasive method that allows us to assess myxozoan biodiversity at a given site. This is essential not only for describing myxozoan communities, but also for the development of disease control methods. Using an alignment of 330 sequences, we employed in silico PCR to score primer pairs, designed to amplify the V4 region of the SSU rDNA of different myxosporean sublineages comprising the entire diversity of oligochaete‐infecting (freshwater) myxosporeans. We selected eight clade‐specific primer sets for metabarcoding, avoiding amplification of DNA from other organisms present in eutrophic freshwaters. The metabarcoding approach used in the analysis of eDNA sediment samples detected a high myxosporean diversity even in small sample volumes (in total 44 OTUs). Furthermore, metabarcoding analysis of myxosporeans in fish tissue samples selected for primer testing revealed 91 different myxosporean OTUs, more than double the number obtained by classical PCR screening and Sanger sequencing with general myxozoan primers and almost seven times higher detection than by microscopic examination. Our results further suggest quantitative sampling requirements for realistic future diversity estimates by comparing OTUs from fish tissue metabarcoding and eDNA samples. The use of specific primer sets enabled the detection of a high proportion of myxosporean reads (63–100%) in all datasets, even in highly eutrophic habitats. This shows our metabarcoding approach as an excellent tool for non‐invasive and sensitive detection of myxosporean biodiversity in aquatic sediments, potentially useful for monitoring myxozoan disease agents that threaten economically important fish in aquaculture.

Introduction: Sexual assault is a public health problem that affects many Americans and has multiple long-lasting effects on victims. Medical evaluation after sexual assault frequently occurs in the emergency department, and documentation of the visit plays a significant role in decisions regarding prosecution and outcomes of legal cases against perpetrators. The American College of Emergency Physicians recommends coding such visits as sexual assault rather than adding modifiers such as “alleged.”Methods: This study reviews factors associated with coding of visits as sexual assault compared to suspected sexual assault using the 2016 Nationwide Emergency Department Sample.Results: Younger age, female gender, a larger number of procedure codes, urban hospital location, and lack of concurrent alcohol use are associated with coding for confirmed sexual assault.Conclusion: Implications of this coding are discussed.

Ecosystems in the Sacramento–San Joaquin Delta are changing rapidly, as are ecosystems around the world. Extreme events are becoming more frequent and thresholds are likely to be crossed more often, creating greater uncertainty about future conditions. The accelerating speed of change means that ecological systems may not remain stable long enough for scientists to understand them, much less use their research findings to inform policy and management. Faced with these challenges, those involved in science, policy, and management must adapt and change and anticipate what the ecosystems may be like in the future. We highlight several ways of looking ahead—scenario analyses, horizon scanning, expert elicitation, and dynamic planning—and suggest that recent advances in distributional ecology, disturbance ecology, resilience thinking, and our increased understanding of coupled human–natural systems may provide fresh ways of thinking about more rapid change in the future. To accelerate forward-looking science, policy, and management in the Delta, we propose that the State of California create a Delta Science Visioning Process to fully and openly assess the challenges of more rapid change to science, policy, and management and propose appropriate solutions, through legislation, if needed.

The purpose of this systematic review is to explore the literature on emotional intelligence related to school leadership using Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The authors searched the electronic databases of Eric education, PsycINFO, Scopus and Psychology Database to find relevant articles. They used search criteria to identify a total of 110 references. Using rigorous selection methods, 35 articles were systematically reviewed. The results revealed that emotional intelligence is key for effective leadership and that the most commonly used skills/competences are self-awareness, self-management and empathy. Additionally, the literature makes it clear that the extent to which the leader builds trusting relationships contributes greatly to the development of teacher satisfaction and performance. These findings can help to inform the design of successful pre-service programmes for aspiring leaders and in-service programmes for school principals. Limitations and future lines of research are discussed.

The central pedagogical principle on which the "Next Generation Science Standards" (NGSS) are built is that of three-dimensional learning. This principle posits that it is through meaningful integration of the disciplinary core ideas (DCIs), science and engineering practices (SEPs), and crosscutting concepts (CCCs) that students will attain an understanding of both the knowledge and processes of science. The purpose of this article is to bring the value of CCCs to the foreground and to provide suggestions and resources for purposefully integrating them into curricula and instruction. As such, this article will supplement previous entries in this journal (Duschl 2012; Metz 2013; Talanquer 2019) that have specifically addressed CCCs and focused more on what they generally represent and how, in a broad sense, they can be utilized by teachers. Science Scope also has included several articles (Fick, Arias, and Baek 2017; German 2017; Mohl et al. 2017; Plonczak and Zwirn 2015) that support teachers in employing the CCCs. To augment these previous works, for each CCC, this article offers: (1) specific facets of the CCCs that teachers should consider explicitly addressing; (2) resources that support use of the CCCs, and (3) sample activities that show the CCCs in action.

In the last fifteen years, several groups have investigated metal injection moulding (MIM) of NdFeB powder to produce isotropic or anisotropic rare earth magnets of greater geometric complexity than that achieved by the conventional pressing and sintering approach. However, due to the powder’s high affinity for oxygen and carbon uptake, sufficient remanence and coercivity remains difficult. This article presents a novel approach to producing NdFeB magnets from recycled material using Powder Extrusion Moulding (PEM) in a continuous process. The process route uses powder obtained from recycling rare earth magnets through Hydrogen Processing of Magnetic Scrap (HPMS). This article presents the results of tailored powder processing, the production of mouldable feedstock based on a special binder system, and moulding with PEM to produce green and sintered parts. The magnetic properties and microstructures of debinded and sintered samples are presented and discussed, focusing on the influence of filling ratio and challenging processing conditions on interstitial content as well as density and magnetic properties.

Aryl and heteroaryl iodides have been efficiently converted into the corresponding thioacetates in cyclopentyl methyl ether (CPME), a green solvent, under Cu catalysis. The chemoselectivity of the reaction is mainly controlled by electronic factors, enabling the conversion of both electron-rich and electron-deficient substrates into the corresponding thioacetates in good to excellent yields. The products can be easily deprotected to the corresponding thiolates to carry out additional synthetic transformations in situ. Surprisingly, despite CPME’s relatively low dielectric constant, the reaction rate significantly increased when conducted under microwave irradiation conditions. This synthetic methodology exhibits a remarkable tolerance to functional groups, mild reaction conditions, and a wide substrate scope, utilizing a safe and inexpensive CuI pre-catalyst in the green solvent CPME. A non-aqueous workup allowing for the complete recovery of both catalyst and solvent makes this approach an environmentally sustainable protocol for C(sp2) sulfur functionalization. Additionally, the reaction shows selective cross-coupling with iodides in competition with chlorides and bromides, allowing its use in multistep syntheses. To demonstrate the potential of this methodology, it was applied to the high-yield synthesis of a photochromic dithienylethene, where a selective synthesis had not been reported before.

Powder injection molding is an established, cost effective and often near-net-shape mass production process for metal or ceramic parts with complex geometries. This paper deals with the extension of the powder injection molding process chain towards the usage of a commercially available borosilicate glass and the realization of glass compounds with huge densities. The whole process chain consists of the individual steps of compounding, molding, debinding, and sintering. The first part, namely, the search for a suitable feedstock composition with a very high solid load and reliable molding properties, is mandatory for the successful manufacture of a dense glass part. The most prominent feature is the binder composition and the related comprehensive rheological characterization. In this work, a binder system consisting of polyethylene glycol and polymethylmethacrylate with stearic acid as a surfactant was selected and its suitability for glass injection molding was evaluated. The influence of all feedstock components on processing and of the process steps on the final sintered part was investigated for sintered glass parts with densities around 99% of the theoretical value.

The vascularized fibula transfer is a well-established technique for extremity reconstruction, but operative planning and patient selection remains crucial. Although recently developed techniques for bone reconstruction, such as bone segment transfer, are becoming increasingly popular, bone defects may still require vascularized bone grafts under certain circumstances. In this study, 41 cases, 28 (68%) men and 13 (32%) women (median age: 40 years), were retrospectively analyzed. Therapy-specific data (flap vascularity [free vs. pedicled] size in cm and configuration [single- vs. double-barrel], mode of fixation [internal/external]) and potential risk factors were ascertained. Indications for reconstruction were osteomyelitis at host site (n = 23, 55%), pseudarthrosis (n = 8, 20%), congenital deformity (n = 6, 15%), traumatic defect, and giant cell tumor of the bone (n = 2, 5% each). Complete healing occurred in 34 (83%) patients after a median time of 6 months. Confounders for prolonged healing were female gender (p = 0.002), reconstruction in the lower limb (p = 0.011), smoking (p = 0.049), and the use of an external fixator (p = 0.009). Six (15%) patients required secondary limb amputation due to reconstruction failure, and one patient had persistent pseudarthrosis at last follow-up. The only risk factor for amputation assessed via logistic regression analysis was preexisting PAOD (peripheral artery occlusive disease; p = 0.008) The free fibula is a reliable tool for extremity reconstruction in various cases, but time to full osseous integration may exceed six months. Patients should be encouraged to cease smoking as it is a modifiable risk factor.

Background: Multiple interventions have been tested to promote well-being in high school students, often focusing on depression prevention. Aims: To test the impact of a one-semester active learning curriculum covering the modern science and philosophy of well-being and happiness on attitudinal measures related to the curriculum and standard measures of depression and well-being. Sample: Subjects were first-year students in an urban high school in Beijing, China (equivalent to US tenth grade). Methods: Nine classrooms were randomly assigned to the intervention curriculum (n = 252), and nine classrooms were randomly assigned to a traditional psychology curriculum (n = 263). Students completed questionnaires pre- and post-semester including a Positive Attitude Scale (PAS, concerning Relatedness, Competence, Autonomy, Gratitude, Calmness, Mindfulness, and Hope), Positive and Negative Affect Scale (PANAS), Centers for Epidemiological Studies Depression Scale (CES-D), Life Satisfaction Scale (LS), Subjective Happiness Scale (SHS), Meaning in Life Questionnaire (MLQ), and a test of knowledge about well-being (Knowledge Test, KT). Results: In a hierarchical linear model, there were statistically significant intervention effects on six of the seven subscales of the PAS, on PANAS balance, and on the KT. CES-D, LS, SHS, and MLQ were improved but not significantly so. Notable overall secular trends in measures of well-being were observed, with a peak in September and nadir in April. Conclusions: A one-semester course for high school students regarding well-being and happiness demonstrated significant changes in positive attitudes, affective balance, and knowledge about happiness. Circannual trends in well-being measures over the academic year have implications for those designing school intervention studies.

The causes of nigrostriatal cell death in idiopathic Parkinson’s disease are unknown, but exposure to toxic chemicals may play some role. We followed up here on suggestions that bacterial secondary metabolites might be selectively cytotoxic to dopaminergic neurons. Extracts from Streptomyces venezuelae were found to kill human dopaminergic neurons (LUHMES cells). Utilizing this model system as a bioassay, we identified a bacterial metabolite known as aerugine (C10H11NO2S; 2-[4-(hydroxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]phenol) and confirmed this finding by chemical re-synthesis. This 2-hydroxyphenyl-thiazoline compound was previously shown to be a product of a wide-spread biosynthetic cluster also found in the human microbiome and in several pathogens. Aerugine triggered half-maximal dopaminergic neurotoxicity at 3–4 µM. It was less toxic for other neurons (10–20 µM), and non-toxic (at

IntroductionBeing faced with multimorbidity (i.e., being diagnosed with at least two chronic conditions), is not only demanding in terms of following complicated medical regimes and changing health behaviors. The changes and threats involved also provoke emotional responses in the patients but also in their romantic partners. This study aims at exploring the ways of emotional co-regulation that couples facing multimorbidity express when interviewed together.MethodN = 15 opposite sex couples with one multimorbid patient after an acute health crisis that led to hospitalization were asked in a semi-structured interview about how they found ways to deal with the health situation, what they would recommend to other couples in a similar situation, and how they regulated their emotional responses. Interviews were analyzed qualitatively following open, axial, and selective coding, as in the grounded theory framework.ResultsEmerging categories from the romantic partners’ and the patients’ utterances revealed three main categories: First, overlapping cognitive appraisals about the situation (from fighting spirit to fatalism) and we-ness (construing the couple self as a unit) emerged as higher order factor from the utterances. Second, relationship-related strategies including strategies aimed at maintaining high relationship quality in spite of the asymmetric situation like strengthening the common ground and balancing autonomy and equity in the couple were often mentioned. Third, some couples mentioned how they benefit from individual strategies that involve fostering individual resources of the partners outside the couple relationship (such as cultivating relationships with grandchildren or going outdoors to nature).DiscussionResults underline the importance of a dyadic perspective not only on coping with disease but also on regulating the emotional responses to this shared challenging situation. The utterances of the couples were in line with earlier conceptualizations of interpersonal emotion regulation and dyadic perspectives on we-disease. They broaden the view by integrating the interplay between individual and interpersonal regulation strategies and underline the importance of balancing individual and relational resources when supporting couples faced with chronic diseases.

TURBOMOLE is a collaborative, multi-national software development project aiming to provide highly efficient and stable computational tools for quantum chemical simulations of molecules, clusters, periodic systems, and solutions. The TURBOMOLE software suite is optimized for widely available, inexpensive, and resource-efficient hardware such as multi-core workstations and small computer clusters. TURBOMOLE specializes in electronic structure methods with outstanding accuracy-cost ratio, such as density functional theory including local hybrids and the random phase approximation (RPA), GW-Bethe-Salpeter methods, second-order Møller-Plesset theory, and explicitly correlated coupled-cluster methods. TURBOMOLE is based on Gaussian basis sets and has been pivotal for the development of many fast and low-scaling algorithms in the past three decades, such as integral-direct methods, fast multipole methods, the resolution-of-the-identity approximation, imaginary frequency integration, Laplace transform, and pair natural orbital methods. This review focuses on recent additions to TURBOMOLE's functionality, including excited-state methods, RPA and Green's function methods, relativistic approaches, high-order molecular properties, solvation effects, and periodic systems. A variety of illustrative applications along with accuracy and timing data are discussed. Moreover, available interfaces to users as well as other software are summarized. TURBOMOLE's current licensing, distribution, and support model are discussed, and an overview of TURBOMOLE's development workflow is provided. Challenges such as communication and outreach, software infrastructure, and funding are highlighted.

Abstract Background Hyperphosphorylation and intraneuronal aggregation of the microtubule-associated protein tau is a major pathological hallmark of Alzheimer’s disease (AD) brain. Of special interest is the effect of cerebral amyloid beta deposition, the second main hallmark of AD, on human tau pathology. Therefore, studying the influence of cerebral amyloidosis on human tau in a novel human tau knock-in (htau-KI) mouse model could help to reveal new details on their interplay. Methods We studied the effects of a novel human htau-KI under fast-progressing amyloidosis in 5xFAD mice in terms of correlation of gene expression data with human brain regions, development of Alzheimer’s-like pathology, synaptic transmission, and behavior. Results The main findings are an interaction of human beta-amyloid and human tau in crossbred 5xFADxhtau-KI observed at transcriptional level and corroborated by electrophysiology and histopathology. The comparison of gene expression data of the 5xFADxhtau-KI mouse model to 5xFAD, control mice and to human AD patients revealed conspicuous changes in pathways related to mitochondria biology, extracellular matrix, and immune function. These changes were accompanied by plaque-associated MC1-positive pathological tau that required the htau-KI background. LTP deficits were noted in 5xFAD and htau-KI mice in contrast to signs of rescue in 5xFADxhtau-KI mice. Increased frequencies of miniature EPSCs and miniature IPSCs indicated an upregulated presynaptic function in 5xFADxhtau-KI. Conclusion In summary, the multiple interactions observed between knocked-in human tau and the 5xFAD-driven progressing amyloidosis have important implications for future model development in AD.

Background Existing data on predictors of late mortality and prevention of sudden cardiac death after atrial switch repair surgery for D-transposition of the great arteries (D-TGA) are heterogeneous and limited by statistical power. Methods and Results We conducted a systematic review and meta-analysis of 29 observational studies, comprising 5035 patients, that reported mortality after atrial switch repair with a minimum follow-up of 10 years. We also examined 4 additional studies comprising 105 patients who reported rates of implantable cardioverter-defibrillator therapy in this population. Average survival dropped to 65% at 40 years after atrial switch repair, with sudden cardiac death accounting for 45% of all reported deaths. Mortality was significantly lower in cohorts that were more recent and operated on younger patients. Patient-level risk factors for late mortality were history of supraventricular tachycardia (odds ratio [OR] 3.8, 95% CI 1.4-10.7), Mustard procedure compared with Senning (OR 2.9, 95% CI 1.9-4.5) and complex D-TGA compared with simple D-TGA (OR 4.4, 95% CI 2.2-8.8). Significant risk factors for sudden cardiac death were history of supraventricular tachycardia (OR 4.7, 95% CI 2.2-9.8), Mustard procedure (OR 2.2, 95% CI 1.1-4.1), and complex D-TGA (OR 5.7, 95% CI 1.8-18.0). Out of a total 124 implantable cardioverter-defibrillator discharges over 330 patient-years in patients with implantable cardioverter-defibrillators for primary prevention, only 8% were appropriate. Conclusions Patient-level risk of both mortality and sudden cardiac death after atrial switch repair are significantly increased by history of supraventricular tachycardia, Mustard procedure, and complex D-TGA. This knowledge may help refine current selection practices for primary prevention implantable cardioverter-defibrillator implantation, given disproportionately high rates of inappropriate discharges.

Invasive listeriosis, caused by Listeria (L.) monocytogenes, is a severe foodborne infection, especially for immunocompromised individuals. The aim of our investigation was the identification and analysis of listeriosis outbreaks in Germany with smoked and graved salmon products as the most likely source of infection using whole-genome sequencing (WGS) and patient interviews. In a national surveillance programme, WGS was used for subtyping and core genome multi locus sequence typing (cgMLST) for cluster detection of L. monocytogenes isolates from listeriosis cases as well as food and environmental samples in Germany. Patient interviews were conducted to complement the molecular typing. We identified 22 independent listeriosis outbreaks occurring between 2010 and 2021 that were most likely associated with the consumption of smoked and graved salmon products. In Germany, 228 cases were identified, of 50 deaths (22%) reported 17 were confirmed to have died from listeriosis. Many of these 22 outbreaks were cross-border outbreaks with further cases in other countries. This report shows that smoked and graved salmon products contaminated with L. monocytogenes pose a serious risk for listeriosis infection in Germany. Interdisciplinary efforts including WGS and epidemiological investigations were essential to identifying the source of infection. Uncooked salmon products are high-risk foods frequently contaminated with L. monocytogenes. In order to minimize the risk of infection for consumers, food producers need to improve hygiene measures and reduce the entry of pathogens into food processing. Furthermore, susceptible individuals should be better informed of the risk of acquiring listeriosis from consuming smoked and graved salmon products.

Abstract A sample of 2.8 × 104 K + → π + μ + μ − candidates with negligible background was collected by the NA62 experiment at the CERN SPS in 2017–2018. The model-independent branching fraction is measured to be (9.15 ± 0.08) × 10 −8, a factor three more precise than previous measurements. The decay form factor is presented as a function of the squared dimuon mass. A measurement of the form factor parameters and their uncertainties is performed using a description based on Chiral Perturbation Theory at O $$ \mathcal{O} $$ (p 6).

Objective: We estimated the correlations between the "pathways" chosen by community college students--in terms of desired credentials and fields of study, as well as other choices and outcomes along the paths--and the attainment of credentials with labor market value. We focused on the extent to which there were recorded changes in students' choices over time, whether students made choices informed by their chances of success and by labor market value of credentials, and the impacts of choices on outcomes. Method: Using micro-longitudinal administrative data on a full cohort of Kentucky community college students, we provide summary data on a range of pathway characteristics and outcomes, as well as binomial and multinomial logit estimates of how pathway characteristics affect the odds of completing different kinds of credentials. Some of the logit estimates were based on random or fixed effects models. Results: We found that several characteristics of chosen pathways, such as field of study and desired credential as well as early "momentum," affected outcomes. Student choices of pathways--and especially differences by gender and academic readiness--sometimes ran strongly counter to information about later chances of success in terms of probabilities of completing programs and attaining strong earnings. Students also changed pathways quite frequently, making it harder to accumulate the credits needed in their fields. Contributions: Attainment of credentials with greater market value by community college students could likely be improved by appropriate guidance and supports for them along the way and perhaps by broader institutional changes as well.