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Atrial fibrillation is the most common cardiac arrhythmia, leading to progressive dilation of cardiac chambers, abnormal contraction patterns of the atria and ventricles and, potentially, atrioventricular valvular insufficiency. Moreover, heart failure with preserved ejection fraction is often present and closely intertwined with disease initiation and progression. Surgical valve repair with a true-sized ring annuloplasty is a well-established treatment option in atrial functional mitral regurgitation. While early results are good, recent studies have brought the durability of this repair approach into question, highlighting the need for further refinement of the surgical strategy. In particular, repair strategies that simultaneously target the mitral valve as well as the left ventricle could provide improved repair durability., (© The Author 2024. Published by MMCTS on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

The treatment of secondary mitral regurgitation (SMR) remains challenging despite the implementation of modern heart failure medication and established catheter-based techniques. Only a subgroup of SMR patients benefit from mitral valve (MV) intervention, and the long-term prognostic benefit of different therapeutic approaches in SMR remains controversial. A literature search was conducted through PubMed and Embase databases to identify relevant studies addressing the pathophysiological background for papillary muscle maneuvers in SMR and currently available surgical techniques. Furthermore, the studies evaluating patients' selection criteria for papillary muscle maneuvers were specifically considered. Articles were selected based on quality and relevance. Over the last two decades, papillary muscle maneuvers have evolved as a pathophysiology-based treatment strategy to address left ventricular (LV) remodeling in SMR. In particular, patients with severe leaflet tenting and moderate heart failure phenotype seem to benefit most from papillary muscle maneuvers that improve LV geometry and thereby the durability of MV repair. We conclude that papillary muscle maneuvers are an evolving pathophysiology-based treatment strategy of ventricular SMR which target papillary muscle displacement due to LV remodeling., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2024 The Author(s). Published by IMR Press.)

Cold atmospheric plasma (CAP) is a promising alternative to antibiotics and chemical substances in dentistry that can reduce the risk of unwanted side effects and bacterial resistance. AmbiJet is a device that can ignite and deliver plasma directly to the site of action for maximum effectiveness. The aim of the study was to investigate its antimicrobial efficacy and the possible development of bacterial resistance. The antimicrobial effect of the plasma was tested under aerobic and anaerobic conditions on bacteria (five aerobic, three anaerobic (Gram +/-)) that are relevant in dentistry. The application times varied from 1 to 7 min. Possible bacterial resistance was evaluated by repeated plasma applications (10 times in 50 days). A possible increase in temperature was measured. Plasma effectively killed 10 6 seeded aerobic and anaerobic bacteria after an application time of 1 min per 10 mm 2 . Neither the development of resistance nor an increase in temperature above 40 °C was observed, so patient discomfort can be ruled out. The plasma treatment proved to be effective under anaerobic conditions, so the influence of ROS can be questioned. Our results show that AmbiJet efficiently eliminates pathogenic oral bacteria. Therefore, it can be advocated for clinical therapeutic use.

Background: Individuals with persistent impairments due to Coronavirus disease 2019 (COVID-19) can receive pulmonary rehabilitation in Germany. To date, there is no evidence of the medium- or long-term effects of pulmonary rehabilitation on Long COVID., Aim: This study examined changes in health and occupational outcomes over time and described the therapeutic content of pulmonary rehabilitation and aftercare. This analysis also compared two rehabilitation groups after COVID-19 who had different levels of access to rehabilitation., Design: Longitudinal observational study with multicenter and prospective data collection., Setting: Pulmonary rehabilitation in four different rehabilitation facilities in Germany., Population: Individuals with a mild course of disease and long-lasting impairments (inpatient rehabilitation, IR) and patients with a severe course after hospitalization (follow-up rehabilitation, FuR). Participants had to be between 18 and 65 years of age., Methods: Written questionnaires were administered at the beginning and end of rehabilitation, as well as six and twelve months after rehabilitation. Health-related quality of life (HrQoL), fatigue, participation restrictions, COVID-19 symptoms, mental and physical health were assessed, as well as occupational outcomes and questions about rehabilitation and aftercare., Results: IR patients were predominantly female (68.0%) and 52 years of age on average, while 66.1% of Long COVID rehabilitees in FuR were male and three years older. Over the course of rehabilitation, most COVID-19 symptoms decreased with statistical significance. The subjective health scales showed improvements with medium to large effect sizes (ES) over time in IR (P<0.01; ES between 0.55 (cognitive fatigue) and 1.40 (physical fatigue)) and small to large effects in FuR (P<0.01; ES between 0.45 (anxiety) and 1.32 (physical fatigue)). One year after rehabilitation, most effects remained at a moderate level. After twelve months, an increase in neurocognitive symptoms was observed in FuR patients. More than 80% of employed people returned to work one year after rehabilitation, although FuR patients returned to work a median of four weeks later (P<0.01)., Conclusions: The comparative analysis showed that rehabilitees in different forms of rehabilitation attended rehabilitation with different impairments and rehabilitation goals, which are partly considered in treatment and aftercare., Clinical Rehabilitation Impact: To provide needs-based rehabilitation to different rehabilitation groups with Long COVID, knowledge of their health histories and preferences is necessary.

Background: This study provides comparative evidence of the selective MET inhibitor capmatinib versus standard of care (SOC) in first-line (1 L) and second-line (2 L) non-small cell lung cancer (NSCLC) patients with METex14 mutations in German routine care., Methods: SOC data were collected from German routine care via retrospective chart review. Analyses were conducted as naive and propensity score adjusted (PSA) comparisons to capmatinib-treated patients within the GEOMETRY mono-1 trial. Effectiveness endpoints included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), time to CNS progression (CNSprog), and exploratory safety endpoints., Results: The SOC arm included 119 patients in 1 L and 46 in 2 L versus 60 patients in 1 L and 81 in 2 L treated with capmatinib, with balanced baseline characteristics after PSA. In 1 L, the naive comparison showed a significant benefit of capmatinib versus SOC for OS (median: 25.49 vs 14.59 months; HR 0.58; 95 % CI 0.39-0.87; P = 0.011), PFS (median: 12.45 vs 5.03 months; HR: 0.44; 95 % CI: 0.31-0.63; P < 0.001), and ORR (event rate: 68.3 vs 26.9 %; RR 2.54; 95 % CI 1.80-3.58; P < 0.001). In 2 L, OS, PFS, and ORR showed positive trends favoring capmatinib over SOC. Capmatinib treatment in the 1 L and 2 L led to significant benefit in CNSprog. PSA analyses showed consistent results to naive analysis. Exploratory safety endpoints indicated a manageable safety profile for capmatinib., Conclusions: The present study demonstrates the important role of capmatinib in providing robust clinically meaningful benefit to patients with NSCLC harboring METex14 mutations and its significant role in preventing the development of brain metastases., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AK reports study support from Novartis. MS reports an advisory role/speaker fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Novartis, Pfizer, Roche, Sanofi-Aventis, Siemens Healthineers, Takeda. MS has also received research support for his institution from Amgen, Dracen Pharmaceuticals, Janssen, Novartis; and travel support from AstraZeneca, Boehringer Ingelheim, Janssen, Pfizer. MW reports institutional support from Takeda; consulting fees from Daiichi Sankyo, GlaxoSmithKline, Amgen, AstraZeneca, Janssen, Novartis, Pfizer, Roche; personal honoraria from Takeda, Roche, Amgen, and AstraZeneca; travel grant support from Amgen, and Janssen. MW also participated on data safety monitoring board for Boehringer Ingelheim. HDH reports advisory role/ personal honoraria from Amgen, Boehringer Ingelheim, Bristol-Myers Squibb; institutional financial support as local principal investigator from Amgen, AstraZeneca, AvenCell Europe GmbH, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Dracen, Merck, Novartis, Revolution Medicines; support as steering committee member and coordinating principal investigator from Amgen. JK reports advisory support on behalf of institution from Lilly Deutschland, Merck Sharp & Dohme, Amgen, Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, Pfizer, Roche Pharma AG, Merck Serono GmbH and Janssen-Cilag GmbH. TG reports study support from Novartis; and participation on data safety monitoring board for Bristol-Myers Squibb. SK received personal honoraria from Boehringer Ingelheim and GlaxoSmithKline; and also received grants from Deutsche Forschungsgesellschaft. SMB reports grants or contracts from Roche and Quality Initiative Pathology; and received consulting fees and personal honoraria from AstraZeneca, Bayer, Bristol Myers Squibb, Discovery Life Science, Janssen, Menarini, Merck, Novartis and Quality Initiative Pathology. AT received grants from AstraZeneca and Lilly; consulting fees from Amgen, AstraZeneca, Pierre Fabre, Sanofi, Daiichi, Merck Sharp & Dohme, Roche, Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, Lilly, Takeda, Novartis; honoraria for lectures from Amgen, AstraZeneca, Pierre Fabre, Sanofi, Daiichi, Merck Sharp & Dohme, Roche, Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, Lilly, Takeda, Novartis; support for attending meetings/travel from Sanofi, AstraZeneca and Pfizer; leadership role in AIO and ERS. AT also participated on the data safety monitoring board study ROSE study (AIO-YMO/TRK-0120 / ROSE). DKG received consulting fees from Boehringer Ingelheim, Pfizer, Merck Sharp & Dohme, Janssen, Bristol-Myers Squibb, Sanofi and Roche; and received support for meeting and/or travel from Takeda and Boehringer Ingelheim. KO, MZ and UJ are employees of Novartis. JW received personal honoraria/consulting fees, support for meetings and/or travel from and participated on data safety monitoring board from Amgen, AstraZeneca, Bayer, Blueprint, Bristol-Myers Squibb, Boehringer-Ingelheim, Chugai, Daiichi Sankyo, Janssen, Lilly, Loxo, Merck, Mirati, Merck Sharp & Dohme, Novartis, Nuvalent, Pfizer, Pierre-Fabre, Roche, Seattle Genetics, Takeda, Turning Point; and received research support for institution from Bristol-Myers Squibb, Janssen Pharmaceutica, Novartis, Pfizer. JK, SG, CS, MCD, MJ, CW have no conflicts of interest to disclose outside of the submitted work., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Whole Exome Sequencing (WES) has emerged as an efficient tool in clinical cancer diagnostics to broaden the scope from panel-based diagnostics to screening of all genes and enabling robust determination of complex biomarkers in a single analysis., Methods: To assess concordance, six formalin-fixed paraffin-embedded (FFPE) tissue specimens and four commercial reference standards were analyzed by WES as matched tumor-normal DNA at 21 NGS centers in Germany, each employing local wet-lab and bioinformatics. Somatic and germline variants, copy-number alterations (CNAs), and complex biomarkers were investigated. Somatic variant calling was performed in 494 diagnostically relevant cancer genes. The raw data were collected and re-analyzed with a central bioinformatic pipeline to separate wet- and dry-lab variability., Results: The mean positive percentage agreement (PPA) of somatic variant calling was 76 % while the positive predictive value (PPV) was 89 % in relation to a consensus list of variants found by at least five centers. Variant filtering was identified as the main cause for divergent variant calls. Adjusting filter criteria and re-analysis increased the PPA to 88 % for all and 97 % for the clinically relevant variants. CNA calls were concordant for 82 % of genomic regions. Homologous recombination deficiency (HRD), tumor mutational burden (TMB), and microsatellite instability (MSI) status were concordant for 94 %, 93 %, and 93 % of calls, respectively. Variability of CNAs and complex biomarkers did not decrease considerably after harmonization of the bioinformatic processing and was hence attributed mainly to wet-lab differences., Conclusion: Continuous optimization of bioinformatic workflows and participating in round robin tests are recommended., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MMT reports speaker and travel Expenses from Twist. JS reports speaker honoraria from DLS, Molecular Health, AstraZeneca and Biocartis, outside the submitted work. UL reports speaker fees from AstraZeneca, GSK, Novartis, Menarini, advisory board from AstraZeneca and Novartis. DH reports speaker honorary AstraZeneca, adboard BMS, WD speaker honoraries BMS & Novartis. SMB reports speaker honoraria, advisory board fees and research grants from AstraZeneca, Daiichi, Menarini, Novartis, Roche, BMS, Pfizer, Bayer, MSD, Merck, Amgen, Molecular Health, Targos, DLS, Janssen, GSK, QuIP, outside the submitted work. SL reports research grant from BMS, advisory board/speaker invitation from AstraZeneca, Eli Lilly, Roche and Takeda outside of this work. NTG reports research support from Janssen-Cilag and Advisory Boards from Janssen-Cilag, AstraZeneca, Daiichi-Sankyo and BMS outside the submitted work. WW reports research grants from Roche, MSD, BMS and AstraZeneca. Advisory board, lectures and speaker bureau fees from Roche, MSD, BMS, AstraZeneca, Pfizer, Merck, Lilly, Boehringer, Novartis, Takeda, Bayer, Janssen, Amgen, Astellas, Illumina, Eisai, Siemens, Agilent, ADC, GSK und Molecular Health. SO received reimbursement for travel expenses and payment for conference presentations from Illumina Inc. and Oxford Nanopore Technologies. CS reports research funding from BMS Stiftung Immunonkologie and institutional grants from Illumina outside the submitted work. CPS reports an investigator-initiated grant from Illumnia outside of the submitted work. PS reports grants from Inctye, BMS, Gilead, Falk, speakers bureau/advisory board from MSD, BMS, AstraZeneca, Incyte, Astellas, Janssen, Eisai, Amgen, Boehringer Ingelheim. DK reports personal fees for speaker honoraria from AstraZeneca, and Pfizer, personal fees for Advisory Board from Bristol-Myers Squibb, outside the submitted work. NP reports speaker fees from Novartis, Bayer, Roche, AstraZeneca, Illumina, BMS, MSD, PGDX/Labcorp, advisory board from Novartis, Lilly, Roche, Janssen, travel expenses from Novartis, AstraZeneca, Illumina, BMS, MSD, PGDX/Labcorp, Research grants from Illumina. JB reports grants from German Cancer Aid and consulting from MSD, outside the submitted work. AS reports participation in Advisory Board/Speaker’s Bureau for Astra Zeneca, AGCT, Bayer, Bristol-Myers Squibb, Eli Lilly, Illumina, Janssen, MSD, Novartis, Pfizer, Roche, Seattle Genetics, Takeda, and Thermo Fisher, grants from Bayer, Bristol-Myers Squibb, and Chugai, outside the submitted work. All other authors report no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Forensic genetic analyses aim to retrieve as much information as possible from biological trace material recovered from crime scenes. While standard short tandem repeat (STR) profiling is essential to individualize biological traces, its significance is diminished in crime scenarios where the presence of a suspect's DNA is acknowledged by all parties. In such cases, forensic (m)RNA analysis can provide crucial contextualizing information on the source level about a trace's composition, i.e., body fluids/tissues, and has therefore emerged as a powerful tool for modern forensic investigations. However, the question which of several suspects contributed a specific component (body fluid) to a mixed trace cannot be answered by RNA analysis using conventional methods. This individualizing information is stored within the sequence of the mRNA transcripts. Massively parallel sequencing (MPS) represents a promising alternative, offering not only higher multiplex capacity, but also the typing of individual coding region SNPs (cSNPs) to enable the assignment of contributors to mixture components, thereby reducing the risk of association fallacies. Herein, we describe the development of an extensive mRNA/cSNP panel for targeted sequencing on the IonTorrent S5 platform. Our panel comprises 30 markers for the detection of six body fluids/tissues (blood, saliva, semen, skin, vaginal and menstrual secretion), along with 70 linkage-controlled cSNPs for contributor assignment. It exhibited high reliable detection sensitivity with RNA inputs down to 0.75 ng and a conservatively calculated probability of identity of 0.03 - 6 % for individual body fluid-specific cSNP profiles. Limitations and areas for future work include RNA-related allele imbalances, inclusion of markers to correctly identify rectal mucosa and the optimization of specific markers. In summary, our new panel is intended to be a major step forward to interpret biological evidence at sub-source and source level based on cSNP attribution of a body fluid component to a suspect and victim, respectively., Competing Interests: Declaration of Competing Interest All authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Autoantibodies are a hallmark of lupus nephritis (LN), but their association with LN classes and treatment response are not adequately known. In this study, we quantified circulating autoantibodies in the Accelerating Medicines Partnership LN longitudinal cohort to identify serological biomarkers of LN histologic classification and treatment response and how these biomarkers change over time based on treatment response., Methods: Peripheral blood samples were collected from 279 patients with systemic lupus erythematosus undergoing diagnostic kidney biopsy based on proteinuria. Of these, 268 were diagnosed with LN. Thirteen autoantibody specificities were measured by bead-based assays (Bio-Rad Bioplex 2200) and anti-C1q by enzyme-linked immunosorbent assay at the time of biopsy (baseline) and at 3, 6, and 12 months after biopsy. Clinical response was determined at 12 months., Results: Proliferative LN (International Society of Nephrology/Renal Pathology Society class III/IV±V, n = 160) was associated with higher concentrations of anti-C1q, anti-chromatin, anti-double-stranded DNA (dsDNA), and anti-ribosomal P autoantibodies compared to nonproliferative LN (classes I/II/V/VI, n = 108). Anti-C1q and-dsDNA were independently associated with proliferative LN. In proliferative LN, higher baseline anti-C1q levels predicted complete response (area under the curve [AUC] 0.72; P = 0.002) better than baseline proteinuria (AUC 0.59; P = 0.21). Furthermore, all autoantibody levels except for anti-La/SSB decreased over 12 months in patients with proliferative, but not membranous, LN with a complete response., Conclusion: Baseline levels of anti-C1q and anti-dsDNA may serve as noninvasive biomarkers of proliferative LN, and anti-C1q may predict complete response at the time of kidney biopsy. In addition, tracking autoantibodies over time may provide further insights into treatment response and pathogenic mechanisms in patients with proliferative LN., (© 2024 The Author(s). Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: Reports of adverse reactions to metal debris contributed in part to a decline in use of large-bearing metal-on-metal total hip devices. We hypothesize an optimal trunnion design may reduce risk of this failure mode in large-bearing total hip arthroplasty systems. The purpose of this study is to report mid- to long-term outcomes for a single-surgeon series of 211 total hip arthroplasties using the large-bearing Biomet Magnum metal-on-metal system., Materials and Methods: Between December 2004 and January 2016, the primary surgeon performed 211 uncemented Magnum total hip arthroplasties in 181 patients. The average length of follow-up was 10.1 ± 3.5 years (range 8-18 years)., Results: Using failure of any component as the endpoint, the overall survivorship rate was 98.1% at 10 years and 97.4% at 18 years. These eight failures (3.8% of cohort) included one case of adverse wear-related failure (0.5%), two cases of acetabular ingrowth failure (0.9%), three cases of trunnion corrosion (1.4%), one failure of late infection (0.5%), and one inappropriate revision of components for trochanteric nonunion without instability (0.5%). Excluding failed cases, all components were radiographically stable with no radiolucencies. Except for the one wear failure, ion testing revealed that 97.2% of cases were within optimal whole blood metal ion levels with the remaining ion test results within acceptable levels., Conclusions: With the uncemented Magnum metal-on-metal total hip, we achieved 97.4% 18-year implant survivorship, exceeding the NICE criteria and registry benchmarks for implant survivorship. We observed a trunnion corrosion rate of 1.4% and no cases of instability. The single case of adverse wear-related failure was caused by acetabular component malposition., (© 2024. The Author(s).)

Cholestatic injuries are accompanied by ductular reaction, initiated by proliferation and activation of biliary epithelial cells (BECs), leading to fibrosis. Sortilin (encoded by Sort1) facilitates IL-6 secretion and leukemia inhibitory factor (LIF) signaling. This study investigated the interplay between sortilin and IL-6 and LIF in cholestatic injury-induced ductular reaction, morphogenesis of new ducts, and fibrosis. Cholestatic injury was induced by bile duct ligation (BDL) in wild-type and Sort1 -/- mice, with or without augmentation of IL-6 or LIF. Mice with BEC sortilin deficiency (hGFAP cre .Sort1 fl/fl ) and control mice were subjected to BDL and 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet (DDC) induced cholestatic injury. Sort1 -/- mice displayed reduced BEC proliferation and expression of BEC-reactive markers. Administration of LIF or IL-6 restored BEC proliferation in Sort1 -/- mice, without affecting BEC-reactive or inflammatory markers. Sort1 -/- mice also displayed impaired morphogenesis, which was corrected by LIF treatment. Similarly, hGFAP cre .Sort1 fl/fl mice exhibited reduced BEC proliferation, but similar reactive and inflammatory marker expression. Serum IL-6 and LIF were comparable, yet liver pSTAT3 was reduced, indicating that sortilin is essential for co-activation of LIF receptor/gp130 signaling in BECs, but not for IL-6 secretion. hGFAP cre .Sort fl/fl mice displayed impaired morphogenesis and diminished fibrosis after BDL and DDC. In conclusion, sortilin-mediated engagement of LIF signaling in BECs promoted ductular reaction and morphogenesis during cholestatic injury. This study indicates that BEC sortilin is pivotal for the development of fibrosis., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Monitoring urban structure and development requires high-quality data at high spatio-temporal resolution. While traditional censuses have provided foundational insights into demographic and socio-economic aspects of urban life, their pace may not always align with the pace of urban development. To complement these traditional methods, we explore the potential of analysing alternative big-data sources, such as human mobility data. However, these often noisy and unstructured big data pose new challenges. Here, we propose a method to extract meaningful explanatory variables and classifications from such data. Using movement data from Beijing, which are produced as a by-product of mobile communication, we show that meaningful features can be extracted, revealing, for example, the emergence and absorption of subcentres. This method allows the analysis of urban dynamics at a high-spatial resolution (here 500 m) and near real-time frequency, and high computational efficiency, which is especially suitable for tracing event-driven mobility changes and their impact on urban structures.

Complete remission of BRAF V600E-driven ACC CUP by BRAF/MEK inhibition underscores importance of precision oncology.

Analysis across a growing number of single-cell perturbation datasets is hampered by poor data interoperability. To facilitate development and benchmarking of computational methods, we collect a set of 44 publicly available single-cell perturbation-response datasets with molecular readouts, including transcriptomics, proteomics and epigenomics. We apply uniform quality control pipelines and harmonize feature annotations. The resulting information resource, scPerturb, enables development and testing of computational methods, and facilitates comparison and integration across datasets. We describe energy statistics (E-statistics) for quantification of perturbation effects and significance testing, and demonstrate E-distance as a general distance measure between sets of single-cell expression profiles. We illustrate the application of E-statistics for quantifying similarity and efficacy of perturbations. The perturbation-response datasets and E-statistics computation software are publicly available at scperturb.org. This work provides an information resource for researchers working with single-cell perturbation data and recommendations for experimental design, including optimal cell counts and read depth., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

NUT carcinomas (NC) are very rare and highly aggressive tumors, molecularly defined by an aberrant gene fusion involving the NUTM1 gene. NCs preferentially arise intrathoracically or in the head and neck region, having a highly adverse prognosis with almost no long-term survivors. Here, we report on a cohort of 35 adult NC patients who were evaluated at University Hospital Tuebingen in an eight year time span, i.e. between 2016 and 2023. Primary objectives were overall survival (OS) and influence of primary tumor locations, fusion gene types and staging on OS. Secondary objectives were patient baseline characteristics, risk factors, tumor markers, treatment decisions and responses to therapy comparing thoracic vs non-thoracic origins. Further, data from tumor genome sequencing were analyzed. In this monocentric German cohort, 54 % of patients had thoracic tumors and 65 % harbored a BRD4-NUTM1 fusion gene. Median OS was 7.5 months, being significantly dependent on primary tumor location and nodal status. Initial misdiagnosis was a problem in 31 % of the cases. Surgery was the first treatment in most patients (46 %) and 80 % were treated with polychemotherapies, showing longer progression free survival (PFS) with ifosfamide-based than with platinum-based regimens. Patients treated with an immune checkpoint inhibitor (ICI) in addition to first-line chemotherapy tended to have longer OS. Initial LDH levels could be identified as a prognostic measure for survival prognosis. Sequencing data highlight aberrant NUTM1 fusion genes as unique tumor driver genes. This is the largest adult European cohort of this orphan tumor disease, showing epidemiologic and molecular features as well as relevant clinical data. Awareness to prevent misdiagnosis, fast contact to a specialized nation-wide center and referral to clinical studies are essential as long-term survival is rarely achieved with any of the current therapeutic regimes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Airway management is a cornerstone of emergency medical care. This project aimed to create evidence-based guidelines based on the systematic review recently conducted by the Agency for Healthcare Research and Quality (AHRQ). A technical expert panel was assembled to review the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The panel made specific recommendations on the different PICO (population, intervention, comparison, outcome) questions reviewed in the AHRQ review and created good practice statements that summarize and operationalize these recommendations. The recommendations address the use of ventilation with bag-valve mask ventilation alone vs. supraglottic airways vs. endotracheal intubation for adults and children with cardiac arrest, medical emergencies, and trauma. Additional recommendations address the use of video laryngoscopy and drug-assisted airway management. These recommendations, and the associated good practice statements, offer EMS agencies and clinicians an opportunity to review the available evidence and incorporate it into their airway management strategies.

Background: Some people suffering from Covid-19 can be affected by persistent symptoms and long-term consequences of the disease (Long Covid) beyond their acute phase. Consequently, this can lead to restrictions in participation. Therefore, the focus is on medical rehabilitation in which Long Covid is treated as a new challenge., Methods: A prospective, exploratory observational study will be conducted. The written survey of Long Covid rehabilitants takes place at the beginning and end of the pneumological rehabilitation. The aim of the study is to describe the rehabilitation contents and goals, the subjective burdens, the social and occupational participation as well as the health-related changes. Among other factors, disease-specific symptoms, quality of life, participation, psychological impairments, fatigue, and performance were recorded., Results: Long Covid rehabilitants (N=221) participate in the written survey. At the end of rehabilitation, the questionnaire survey indicated significant improvements in almost all outcome parameters with a large effect (p<0.01; ES between 0.76 (anxiety) and 1.30 (fatigue)). All corona symptoms, such as breathlessness on exertion, fatigue or lack of strength improved significantly at the end of rehabilitation. Moreover, the rehabilitants most frequently name the improvement of their health (92%), the increase of their performance (92%) and the improvement of the respiratory muscle strength (78%) as rehabilitation goals. In fact, these goals are achieved by 60 to 70%, significantly fewer rehabilitation patients reach the restoration of their ability to work (32%) or a better ability to concentrate (17%). Respiratory physiotherapy, endurance training and medical training therapy are described as most helpful. At the end of rehabilitation, 76% rated their rehabilitation success as good to excellent based on a single question., Conclusion: The first data of the study reveal that Long Covid rehabilitants are exposed to substantial burdens. Through medical rehabilitation, the patients experience medical and social support and experience significant improvements in all recorded health-related outcomes., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

For large libraries of small molecules, exhaustive combinatorial chemical screens become infeasible to perform when considering a range of disease models, assay conditions, and dose ranges. Deep learning models have achieved state-of-the-art results in silico for the prediction of synergy scores. However, databases of drug combinations are biased toward synergistic agents and results do not generalize out of distribution. During 5 rounds of experimentation, we employ sequential model optimization with a deep learning model to select drug combinations increasingly enriched for synergism and active against a cancer cell line-evaluating only ∼5% of the total search space. Moreover, we find that learned drug embeddings (using structural information) begin to reflect biological mechanisms. In silico benchmarking suggests search queries are ∼5-10× enriched for highly synergistic drug combinations by using sequential rounds of evaluation when compared with random selection or ∼3× when using a pretrained model., Competing Interests: Declaration of interests All authors affiliated with Relation Therapeutics receive equity-based compensation in the company. N.V. holds stock in Glyde Bio, Inc., and Innovac Therapeutics, Inc., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cellular differentiation requires extensive alterations in chromatin structure and function, which is elicited by the coordinated action of chromatin and transcription factors. By contrast with transcription factors, the roles of chromatin factors in differentiation have not been systematically characterized. Here, we combine bulk ex vivo and single-cell in vivo CRISPR screens to characterize the role of chromatin factor families in hematopoiesis. We uncover marked lineage specificities for 142 chromatin factors, revealing functional diversity among related chromatin factors (i.e. barrier-to-autointegration factor subcomplexes) as well as shared roles for unrelated repressive complexes that restrain excessive myeloid differentiation. Using epigenetic profiling, we identify functional interactions between lineage-determining transcription factors and several chromatin factors that explain their lineage dependencies. Studying chromatin factor functions in leukemia, we show that leukemia cells engage homeostatic chromatin factor functions to block differentiation, generating specific chromatin factor-transcription factor interactions that might be therapeutically targeted. Together, our work elucidates the lineage-determining properties of chromatin factors across normal and malignant hematopoiesis., (© 2023. The Author(s).)

Abstract: Injury is the leading cause of death in children older than 1 year, and children make up 22% of the population. Pediatric readiness (PR) of the nation's emergency departments and state trauma and emergency medical services (EMS) systems is conceptually important and vital to mitigate mortality and morbidity in this population. The extension of PR to the trauma community has become a focused area for training, staffing, education, and equipment at all levels of trauma center designation, and there is evidence that a higher level of emergency department PR is independently associated with long-term survival among injured children. Although less well studied, there is an associated need for EMS PR, which is relevant to the injured child who needs assessment, treatment, triage, and transport to a trauma center. We outline a blueprint along with recommendations for incorporating PR into trauma system development in this opinion from the EMS Committee of the American College of Surgeons Committee on Trauma. These recommendations are particularly pertinent in the rural and underserved areas of the United States but are directed toward all levels of professionals who care for an injured child along the trauma continuum of care., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

In soccer, the offensive style of play describes characteristic behavioral features of the players at team level during the offensive phase of matches. This study aimed to investigate the effect of offensive playing style (i.e., while in ball possession) on physical and technical match performance during offensive play as well as success-related factors. The sample consisted of official tracking and event data of 153 matches of the 2020/21 German Bundesliga season. For every team in every match an offensive playing style coefficient was calculated to locate teams on a continuum between ball possession and counter-attacking style. This calculation contains 11 technical and physical performance parameters and has already been validated. In addition, dependent physical (e.g., sprinting distance), technical (e.g., passes), and success-related (e.g., goals) variables were examined. A separate linear mixed model was calculated for each dependent variable. While teams with lower playing style coefficient values (= counter-attacking style) covered more high-intensity ( p ≤ 0.01; R 2 = 0.13) and sprinting distances per second in possession ( p ≤ 0.01; R 2 = 0.14), teams with higher playing style coefficient values (= ball possession style) were physically more demanded over a whole match (e.g., more accelerations ( p ≤ 0.01; R 2 = 0.69), decelerations ( p ≤ 0.01; R 2 = 0.69), high-intensity ( p ≤ 0.01; R 2 = 0.36), sprint distance ( p = 0.03; R 2 = 0.08)). Furthermore, teams with higher playing style coefficient values played more horizontal passes ( p ≤ 0.01; R 2 = 0.73) and revealed better passing success rates ( p ≤ 0.01; R 2 = 0.17). In contrast, teams with lower playing style coefficient values played more long passes ( p < 0.01; R 2 = 0.58). The influence of the playing style coefficient on success-related variables was smaller ( p ≤ 0.36; R 2 = 0.10-0.13). Concluding, offensive playing style affects physical and technical match performance, but has limited influence on success. Hence, coaches can use the findings to optimize training contents to prepare players for the physical demands of a match., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Forcher, Forcher, Wäsche, Jekauc, Woll, Gross and Altmann.)

Progress in molecular methods has enabled the monitoring of bacterial populations in time. Nevertheless, understanding community dynamics and its links with ecosystem functioning remains challenging due to the tremendous diversity of microorganisms. Conceptual frameworks that make sense of time series of taxonomically rich bacterial communities, regarding their potential ecological function, are needed. A key concept for organizing ecological functions is the niche, the set of strategies that enable a population to persist and define its impacts on the surroundings. Here we present a framework based on manifold learning to organize genomic information into potentially occupied bacterial metabolic niches over time. Manifold learning tries to uncover low-dimensional data structures in high-dimensional data sets that can be used to describe the data in reduced dimensions. We apply the method to re-construct the dynamics of putatively occupied metabolic niches using a long-term bacterial time series from the Baltic Sea, the Linnaeus Microbial Observatory (LMO). The results reveal a relatively low-dimensional space of occupied metabolic niches comprising groups of taxa with similar functional capabilities. Time patterns of occupied niches were strongly driven by seasonality. Some metabolic niches were dominated by one bacterial taxon, whereas others were occupied by multiple taxa, depending on the season. These results illustrate the power of manifold learning approaches to advance our understanding of the links between community composition and functioning in microbial systems. IMPORTANCE The increase in data availability of bacterial communities highlights the need for conceptual frameworks to advance our understanding of these complex and diverse communities alongside the production of such data. To understand the dynamics of these tremendously diverse communities, we need tools to identify overarching strategies and describe their role and function in the ecosystem in a comprehensive way. Here, we show that a manifold learning approach can coarse grain bacterial communities in terms of their metabolic strategies and that we can thereby quantitatively organize genomic information in terms of potentially occupied niches over time. This approach, therefore, advances our understanding of how fluctuations in bacterial abundances and species composition can relate to ecosystem functions and it can facilitate the analysis, monitoring, and future predictions of the development of microbial communities., Competing Interests: The authors declare no conflict of interest.

Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory disorder with high prevalence among middle-aged women. Collagen-induced arthritis (CIA) is the most widely used animal model of RA, however, sex differences and long-term effects of CIA in mice are poorly described in the literature. Aim: Therefore, the present study aimed to analyze the long-term effects of CIA on the joints of middle-aged mice of both sexes and to describe potential sex differences. Materials and methods: CIA was induced in middle-aged DBA/1J mice by immunization with bovine type II collagen and complete Freund's adjuvant. Saline was administered to control mice. Arthritis score assessment, plethysmometry, and thermal imaging of the joints were performed weekly for 15 weeks. Locomotor activity, micro-computed tomography, joint histology and biochemical analyses were performed at the end of the experiment. Results: Our results indicate a similar prevalence of arthritis in both sexes of mice-67% (8/12) of females and 89% (8/9) males with an earlier onset in males (day 14 vs. day 35). After the arthritis scores peaked on day 56 for males and day 63 for females, they steadily declined until the end of the experiment on day 105. A similar dynamics was observed in paw volume and temperature analyzing different aspects of joint inflammation. Long-term consequences including higher proteinuria (by 116%), loss of bone density (by 33.5%) and joint damage in terms of synovial hyperplasia as well as bone and cartilage erosions were more severe in CIA males compared to CIA females. There were no significant differences in locomotor activity between CIA mice and CTRL mice of any sex. Conclusion: This is the first study to describe the long-term effects of the CIA model in terms of sex differences in DBA/1J mice. Our results indicate sex differences in the dynamics, but not in the extent of arthritis. An earlier onset of arthritis and more severe consequences on joints, bones and kidneys were found in males. The underlying immune pathomechanisms responsible for the limited duration of the arthritis symptoms and the opposite sex difference in comparison to RA patients require further investigation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Schuh, Macáková, Feješ, Groß, Belvončíková, Janko, Juskanič, Hollý, Borbélyová, Šteňová, Pastorek, Vlková and Celec.)

It has been postulated that the brain operates in a self-organized critical state that brings multiple benefits, such as optimal sensitivity to input. Thus far, self-organized criticality has typically been depicted as a one-dimensional process, where one parameter is tuned to a critical value. However, the number of adjustable parameters in the brain is vast, and hence critical states can be expected to occupy a high-dimensional manifold inside a high-dimensional parameter space. Here, we show that adaptation rules inspired by homeostatic plasticity drive a neuro-inspired network to drift on a critical manifold, where the system is poised between inactivity and persistent activity. During the drift, global network parameters continue to change while the system remains at criticality.

Changes in transcription factor binding sites (TFBSs) can alter the spatiotemporal expression pattern and transcript abundance of genes. Loss and gain of TFBSs were shown to cause shifts in expression patterns in numerous cases. However, we know little about the evolution of extended regulatory sequences incorporating many TFBSs. We compare, across the crucifers (Brassicaceae, cabbage family), the sequences between the translated regions of Arabidopsis Bsister (ABS)-like MADS-box genes (including paralogous GOA-like genes) and the next gene upstream, as an example of family-wide evolution of putative upstream regulatory regions (PURRs). ABS-like genes are essential for integument development of ovules and endothelium formation in seeds of Arabidopsis thaliana. A combination of motif-based gene ontology enrichment and reporter gene analysis using A. thaliana as common trans-regulatory environment allows analysis of selected Brassicaceae Bsister gene PURRs. Comparison of TFBS of transcriptionally active ABS-like genes with those of transcriptionally largely inactive GOA-like genes shows that the number of in silico predicted TFBS) is similar between paralogs, emphasizing the importance of experimental verification for in silico characterization of TFBS activity and analysis of their evolution. Further, our data show highly conserved expression of Brassicaceae ABS-like genes almost exclusively in the chalazal region of ovules. The Arabidopsis-specific insertion of a transposable element (TE) into the ABS PURRs is required for stabilizing this spatially restricted expression, while other Brassicaceae achieve chalaza-specific expression without TE insertion. We hypothesize that the chalaza-specific expression of ABS is regulated by cis-regulatory elements provided by the TE., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

The VISAGE Enhanced Tool for Appearance and Ancestry (ET) has been designed to combine markers for the prediction of bio-geographical ancestry plus a range of externally visible characteristics into a single massively parallel sequencing (MPS) assay. We describe the development of the ancestry panel markers used in ET, and the enhanced analyses they provide compared to previous MPS-based forensic ancestry assays. As well as established autosomal single nucleotide polymorphisms (SNPs) that differentiate sub-Saharan African, European, East Asian, South Asian, Native American, and Oceanian populations, ET includes autosomal SNPs able to efficiently differentiate populations from Middle East regions. The ability of the ET autosomal ancestry SNPs to distinguish Middle East populations from other continentally defined population groups is such that characteristic patterns for this region can be discerned in genetic cluster analysis using STRUCTURE. Joint cluster membership estimates showing individual co-ancestry that signals North African or East African origins were detected, or cluster patterns were seen that indicate origins from central and Eastern regions of the Middle East. In addition to an augmented panel of autosomal SNPs, ET includes panels of 85 Y-SNPs, 16 X-SNPs and 21 autosomal Microhaplotypes. The Y- and X-SNPs provide a distinct method for obtaining extra detail about co-ancestry patterns identified in males with admixed backgrounds. This study used the 1000 Genomes admixed African and admixed American sample sets to fully explore these enhancements to the analysis of individual co-ancestry. Samples from urban and rural Brazil with contrasting distributions of African, European, and Native American co-ancestry were also studied to gauge the efficiency of combining Y- and X-SNP data for this purpose. The small panel of Microhaplotypes incorporated in ET were selected because they showed the highest levels of haplotype diversity amongst the seven population groups we sought to differentiate. Microhaplotype data was not formally combined with single-site SNP genotypes to analyse ancestry. However, the haplotype sequence reads obtained with ET from these loci creates an effective system for de-convoluting two-contributor mixed DNA. We made simple mixture experiments to demonstrate that when the contributors have different ancestries and the mixture ratios are imbalanced (i.e., not 1:1 mixtures) the ET Microhaplotype panel is an informative system to infer ancestry when this differs between the contributors., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Native American (NA) populations have higher rates of rheumatic disease and present with overlapping disease symptoms and nontraditional serologic features, thus presenting an urgent need for better biomarkers in NA diagnostics. This study used a machine learning approach to identify immune signatures that more effectively stratify NA patients with rheumatic disease., Methods: Adult NA patients with autoantibody-positive (AAB+) rheumatoid arthritis (RA; n = 28), autoantibody negative (AAB-) RA (n = 18), systemic autoimmune rheumatic disease (n = 28), arthralgia/osteoarthritis (n = 28), or polyarthritis/undifferentiated connective tissue disease (n = 28), and control patients (n = 28) provided serum samples for cytokine, chemokine, and AAB assessment. Random forest clustering and soluble mediator groups were used to identify patients and control patients with similar biologic signatures. The American College of Rheumatology criteria specific for systemic disease and RA identified differences in disease manifestations across clusters., Results: Serum soluble mediators were not homogenous between different NA rheumatic disease diagnostic groups, reflecting the heterogeneity of autoimmune diseases. Clustering by serum biomarkers created 5 analogous immune phenotypes. Soluble mediators and pathways associated with chronic inflammation and involvement of the innate, B cell, T follicular helper cell, and interferon-associated pathways, along with regulatory signatures, distinguished the 5 immune signatures among patients. Select clinical features were associated with individual immune profiles. Patients with low inflammatory and higher regulatory signatures were more likely to have few clinical manifestations, whereas those with T cell pathway involvement had more arthritis., Conclusion: Serum protein signatures distinguished NA patients with rheumatic disease into distinct immune subsets. Following these immune profiles over time may assist with earlier diagnoses and help guide more personalized treatment approaches., (© 2021 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

The aim of this study was to conduct a systematic literature review on the influence of dietary and nutraceutical interventions as an adjunct to non-surgical periodontal therapy (NSPT). A literature search for randomized, controlled clinical trials (RCTs) was performed in PubMed, the Cochrane Library, and the Web of Science. Trial inclusion criteria included the application of a defined nutritional intervention (food, beverages, or supplements) adjunctive to NSPT compared to NSPT alone with at least one measured periodontal parameter (pocket probing depths (PPD) or clinical attachment level (CAL)). Of 462 search results, 20 clinical trials relating to periodontitis and nutritional interventions were identified, of which, in total, 14 studies could be included. Eleven studies examined supplements containing lycopene, folate, chicory extract, juice powder, micronutrients and plant extracts, omega-3 fatty acids, vitamin E, or vitamin D. Three studies examined food-based interventions (kiwifruit, green or oolong tea). Due to limited information on within-group differences in the studies, results were descriptively analyzed. A significant positive effect on periodontal parameters (PPD, bleeding on probing) was found for vitamin E, chicory extract, juice powder, green tea, and oolong tea. Heterogeneous effects were found for lycopene, folate, omega-3 fatty acids, and vitamin D. No effects on PPD were found for adjunct kiwifruit (in combination with NSPT). Risk of bias via RoB2 revealed a low risk of bias with some concerns. There was a high heterogeneity in the type of nutritional interventions. The adjunctive use of various supplements and green/oolong tea led to positive and significant effects of the nutritional interventions on clinical periodontal outcome parameters. In the context of non-surgical periodontal therapy, an adjunctive intake of micronutrients, omega-3 fatty acids, green/oolong tea, and polyphenols and flavonoids could be beneficial. Long-term clinical studies with full data reports (especially within-group differences) are needed for conducting a meta-analysis.

Dental pulp regeneration strategies frequently result in hard tissue formation and pulp obliteration. The aim of this study was to investigate whether dental pulp stem cells (DPSCs) can be directed toward soft tissue differentiation by extracellular elasticity. STRO-1-positive human dental pulp cells were magnetically enriched and cultured on substrates with elasticities of 1.5, 15, and 28 kPa. The morphology of DPSCs was assessed visually. Proteins relevant in mechanobiology ACTB, ITGB1, FAK, p-FAK, TALIN, VINCULIN, PAXILLIN, ERK 1/2, and p-ERK 1/2 were detected by immunofluorescence imaging. Transcription of the pulp marker genes BMP2, BMP4, MMP2, MMP3, MMP13, FN1, and IGF2 as well as the cytokines ANGPT1, VEGF, CCL2, TGFB1, IL2, ANG, and CSF1 was determined using qPCR. A low stiffness, i.e., 1.5 kPa, resulted in a soft tissue-like phenotype and gene expression, whereas DPSCs on 28 kPa substrates exhibited a differentiation signature resembling hard tissues with a low cytokine expression. Conversely, the highest cytokine expression was observed in cells cultured on intermediate elasticity, i.e., 15 kPa, substrates possibly allowing the cells to act as "trophic mediators". Our observations highlight the impact of biophysical cues for DPSC fate and enable the design of scaffold materials for clinical pulp regeneration that prevent hard tissue formation.

Following fixation of a trochanteric femoral fracture with a TFNA© and despite correct fracture reduction and fixation, a 96-year-old patient suffered a complete cut-in, i.e. a medialization of the entire femoral neck blade through the nail into the hip joint. Against the background of implant development and current literature, this increasingly frequent type of complication is described and distinguished from other fixation failures such as the cut-out. Attempts to explain this phenomenon as well as research options are presented and a pragmatic approach to avoid this problem is outlined., (© 2022. The Author(s).)

Post-transplant Lymphoproliferative Disease (PTLD) remains a major complication of solid organ transplantation (SOT) in pediatric patients. The majority are Epstein-Barr Virus (EBV) driven CD20 + B-cell proliferations responsive to reduction to immunosuppression and anti-CD20 directed immunotherapy. This review focusses on the epidemiology, role of EBV, clinical presentation, current treatment strategies, adoptive immunotherapy and future research in EBV + PTLD in pediatric patients., Competing Interests: Declaration of competing interest None of the authors have any conflict of interests to declare., (Copyright © 2023. Published by Elsevier Ltd.)

Proton-coupled electron-transfer (PCET) processes play a key role in biocatalytic energy conversion and storage, for example, photosynthesis or nitrogen fixation. Here, we report a series of bipyridine-containing di- to tetranuclear Ru(bda) macrocycles 2 C-4 C (bda: 2,2'-bipyridine-6,6'-dicarboxylate) to promote O-O bond formation. In photocatalytic water oxidation under neutral conditions, all complexes 2 C-4 C prevail in a folded conformation that support the water nucleophilic attack (WNA) pathway with remarkable turnover frequencies of up to 15.5 s -1 per Ru unit respectively. Single-crystal X-ray analysis revealed an increased tendency for intramolecular π-π stacking and preorganization of the proximal bases close to the active centers for the larger macrocycles. H/D kinetic isotope effect studies and electrochemical data demonstrate the key role of the proximal bipyridines as proton acceptors in lowering the activation barrier for the crucial nucleophilic attack of H 2 O in the WNA mechanism., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Background: In 2017, the Health Resources and Services Administration's Maternal Child and Health Bureau's Emergency Medical Services for Children program implemented a performance measure for State Partnership grants to increase the percentage of EMS agencies within each state that have designated individuals who coordinate pediatric emergency care, also called a pediatric emergency care coordinator (PECC). The PECC Learning Collaborative (PECCLC) was established to identify best practices to achieve this goal. This study's objective is to report on the structure and outcomes of the PECCLC conducted among nine states., Methods: This study used quantitative and qualitative methods to evaluate outcomes from the PECCLC. Participating state representatives engaged in a 6-month collaborative that included monthly learning sessions with subject matter experts and support staff and concluded with a two-day in-person meeting. Outcomes included reporting the number of PECCs recruited, identifying barriers and enablers to PECC recruitment, characterizing best practices to support PECCs, and identifying barriers and enablers to enhance and sustain the PECC role. Outcomes were captured by self-report from participating state representatives and longitudinal qualitative interviews conducted with representative PECCs at 6 and 18 months after conclusion of the PECCLC., Results: During the 6-month collaborative, states recruited 341 PECCs (92% of goal). Follow up at 5 months post-collaborative revealed an additional recruitment of 184 for a total of 525 PECCs (142% of the goal). Feedback from state representatives and PECCs revealed the following barriers: competition from other EMS responsibilities, budgetary constraints, lack of incentive for agencies to create the position, and lack of requirement for establishing the role. Enablers identified included having an EMS agency recognition program that includes the PECC role, train-the-trainer programs, and inclusion of the PECC role in agency licensure requirements. Longitudinal interviews with PECCs identified that the most common activity associated with their role was pediatric-specific education and the most important need for PECC success was agency-level support., Conclusion: Over the 6-month Learning Collaborative, nine states were successful in recruiting a substantial number of PECCs. Financial and time constraints were significant barriers to statewide PECC recruitment, yet these can be potentially addressed by EMS agency recognition programs.

Existing measures of health care access were inadequate for guiding policy decisions in West Virginia, as they identified the entire state as having limited access. To address this, we compiled a comprehensive database of primary health care providers and facilities in the state, developed a modified E2SFCA tool to measure spatial access in the context of West Virginia's rural and mountainous nature, and integrated this with an index of socio-economic barriers to access. The integrated index revealed that the rural areas, especially in the southern part of the state, have especially limited access to primary health care. 1. Introduction. An emerging public health issue which has been exacerbated by the COVID-19 pandemic, is that of healthcare deserts , which are places where basic affordable health care is not accessible for residents. This problem has become worse in rural areas as rural hospitals close. In these areas, including West Virginia, scattered populations suffer from limited access to primary healthcare services. Uneven geographic and socio-economic barriers to accessing primary health care are major contributing factors to these health disparities. West Virginia's unique rural and mountainous settlement patterns, aging population, and economic crisis over the past two decades have resulted in unequal access to the primary healthcare services for its residents. The rural nature of the state makes it difficult to maintain medical facilities accessible to much of the population, especially as rural hospitals have been closing, such as the one in Williamson, WV (Jarvie, 2020). The mountainous terrain slows down travel across winding roads, lengthening travel times to the nearest hospital, while an aging population has increased health care needs. Lastly, an economic crisis and higher poverty rate makes West Virginians less able to pay for health care. As a result, West Virginians are confronting a health crisis. According to a recent report by the West Virginia Health Statistics Center (2019), West Virginians rank first in the country for heart attacks, have the second-highest obesity rate and prevalence of mental health problems in the country, along with the fourth-highest rate of diabetes and fifth-highest rate of cancer. An issue faced by West Virginia's policymakers is the limitations of tools for identifying and assessing healthcare deserts, as they are poorly suited for the unique challenges in West Virginia. Academic research has not analyzed comprehensive primary healthcare accessibility in WV, although previous studies have focused on Appalachia (e.g., Behringer & Friedell 2006; Smith & Holloman, 2011; Elnicki et al., 1995; Donohoe et al., 2015, 2016a, 2016b), and others focus on access to more specialized services (Valvi et al., 2019; Donohoe, 2016a). Existing approaches to identify the healthcare deprived areas, such as Health Professional Shortage Areas (HPSA), are not suitable for guiding West Virginia policies, because every one of the 55 counties within the state has several HPSAs, which makes prioritizing resources difficult. The lack of easily accessible, comprehensive, and up-to-date physician and healthcare facility database creates additional difficulties. Physician license datasets were found to often include inconsistent, misleading, and out-of-date information. The last limitation of the HPSA designation is that it is based on zip code areas and census tracts, which are not ideal as zip code areas lack spatial context and much covariate data, while rural census tracts are too large to capture spatial variation of access. In this context, the WV HealthLink project was begun with joint effort with WV Rural Health Initiative (RHI) to fill gaps in research and support decision making for primary healthcare access in West Virginia. The goals of the projects are: (1) to help West Virginia's three medical schools provide specialized professional training in rural healthcare; (2) to address health disparities by investing in clinical projects in underserved areas; and (3) to retain health professionals in WV. In 2018, to support these goals, HealthLink was invited by the RHI's leadership to analyze disparities in primary health care access in West Virginia and develop tools for rural healthcare decision-making. These goals also create a comprehensive and up-to-date physician and facility database, new analysis tools, and new visualization tools for decision support. The goals of this paper are to assess the spatial and social accessibility of primary health care in West Virginia, and to understand spatial and social determinants that shape this access. To achieve these goals, this paper completes the following objectives: (1) define primary healthcare and access; (2) build an extensive and up-to-date primary healthcare database; (3) develop an assessment framework for WV; and (4) visualize the results for policy makers and practitioners. The structure of this paper is as follows. First, we describe three methodological problems encountered as we define primary health care access. Second, we present the methods used to resolve these problems, and conclude by presenting our modified enhanced two-step floating catchment area (E2FCA hereafter) approach and its results for WV. Our foci in this modification were improving the accuracy of the analysis regarding measuring distance, considering distance decay effect, and more precisely representing the location of supply and demand., (© The Author(s), under exclusive licence to Springer Nature B.V. 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Background: In patients with extremity soft tissue sarcoma (eSTS), we describe outcomes of preoperative external beam radiation therapy (EBRT), limb-sparing surgery (LSS), and intraoperative electron radiation therapy (IOERT)., Methods: One hundred and eighteen patients with eSTS treated between October 17, 2002 and July 28, 2021 were identified. EBRT was delivered preoperatively followed by LSS and IOERT., Results: The median follow-up was 24.9 months. The presentation was primary in 102 (94%) patients and recurrent in 6 (6%) patients. Tumor location was lower extremity in 82 (76%) patients and upper extremity in 26 (24%) patients. Stage distribution was as follows: 3 (3%) IA, 24 (22%) IB, 31 (29%) II, 24 (22%) IIIA, and 25 (23%) IIIB. Final surgical margins were negative in 96 (89%) patients. The 5-year local control, failure-free survival, and overall survival were 94%, 75%, and 64%, respectively. Univariate analysis identified age >50, lower extremity, and higher grade as significant negative prognostic factors for overall survival. Grade 3 fracture or osteoradionecrosis requiring surgical fixation, neuropathy, and lymphedema occurred in 7 (6%), 1 (1%), and 0 patients, respectively., Conclusions: This study represents one of the largest series using preoperative EBRT, LSS, and IOERT for eSTS, with high local control and a low rate of late severe toxicity., (© 2022 Wiley Periodicals LLC.)

Responding to the growing scientific and practical interest in forensic DNA phenotyping, the VISible Attributes through GEnomics (VISAGE) Consortium was founded in 2017 with the main goal of developing and validating new and reliable molecular and statistical tools to predict appearance, ancestry and age from DNA. Here, we describe the development and inter-laboratory evaluation and validation of the VISAGE Enhanced Tool for Appearance and Ancestry inference from DNA. The VISAGE Enhanced Tool for Appearance and Ancestry is the first forensic-driven genetic laboratory tool that comprises well-established markers for eye, hair and skin color with more recently discovered DNA markers for eyebrow color, freckling, hair shape and male pattern baldness and bio-geographic ancestry informative DNA markers. The bio-geographic ancestry markers include autosomal SNPs (bi- and tri-allelic SNPs), X-SNPs, Y-SNPs and autosomal Microhaplotypes. In total, primers targeting 524 SNPs (representing a 97.6% assay conversion rate) were successfully designed using AmpliSeq into a single primer pool (i.e., one multiplex assay) and sequenced with the Ion S5. In a collaborative framework, five VISAGE laboratories tested the VISAGE Enhanced Tool for Appearance and Ancestry on reproducibility, sensitivity, genotyping concordance, mixtures, species specificity and performance in relevant forensic conditions, including inhibitor-spiked, mock casework and artificially degraded samples. Based on our results, the VISAGE Enhanced Tool for Appearance and Ancestry is a robust, reproducible, and - for the large SNP number - fairly sensitive MPS assay with high concordance rates. With the VISAGE Enhanced Tool for Appearance and Ancestry introduced here, the VISAGE Consortium delivers the first single DNA-test for combined appearance prediction based on seven traits together with bio-geographic ancestry inference based on major continental regions for separated bi-parental and paternal ancestry, which represents the most comprehensive validated laboratory tool currently available for Forensic DNA Phenotyping., Competing Interests: Conflict of interest statement The authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The twin crises of climate change and biodiversity loss define a strong need for functional diversity monitoring. While the availability of high-quality ecological monitoring data is increasing, the quantification of functional diversity so far requires the identification of species traits, for which data are harder to obtain. However, the traits that are relevant for the ecological function of a species also shape its performance in the environment and hence, should be reflected indirectly in its spatiotemporal distribution. Thus, it may be possible to reconstruct these traits from a sufficiently extensive monitoring dataset. Here, we use diffusion maps, a deterministic and de facto parameter-free analysis method, to reconstruct a proxy representation of the species' traits directly from monitoring data and use it to estimate functional diversity. We demonstrate this approach with both simulated data and real-world phytoplankton monitoring data from the Baltic Sea. We anticipate that wider application of this approach to existing data could greatly advance the analysis of changes in functional biodiversity.

Human dental pulp stem cells (hDPSCs) are promising for oral/craniofacial regeneration, but their purification and characterization is not yet standardized. hDPSCs from three donors were purified by magnetic activated cell sorting (MACS)-assisted STRO-1-positive cell enrichment (+), colony derivation (c), or a combination of both (c/+). Immunophenotype, clonogenicity, stemness marker expression, senescence, and proliferation were analyzed. Multilineage differentiation was assessed by qPCR, immunohistochemistry, and extracellular matrix mineralization. To confirm the credibility of the results, repeated measures analysis and post hoc p -value adjustment were applied. All hDPSC fractions expressed STRO-1 and were similar for several surface markers, while their clonogenicity and expression of CD10/44/105/146, and 166 varied with the purification method. (+) cells proliferated significantly faster than (c/+), while (c) showed the highest increase in metabolic activity. Colony formation was most efficient in (+) cells, which also exhibited the lowest cellular senescence. All hDPSCs produced mineralized extracellular matrix. Regarding osteogenic induction, (c/+) revealed a significant increase in mRNA expression of COL5A1 and COL6A1 , while osteogenic marker genes were detected at varying levels. (c/+) were the only population missing BDNF gene transcription increase during neurogenic induction. All hDPSCs were able to differentiate into chondrocytes. In summary, the three hDPSCs populations showed differences in phenotype, stemness, proliferation, and differentiation capacity. The data suggest that STRO-1-positive cell enrichment is the optimal choice for hDPSCs purification to maintain hDPSCs stemness. Furthermore, an (immuno) phenotypic characterization is the minimum requirement for quality control in hDPSCs studies.

Objectives: Papillary muscle repositioning in functional mitral regurgitation (FMR) alleviates mitral valve (MV) tenting by reducing the distance between papillary muscle tips and MV annular plane, i.e. apical left ventricular (LV) displacement. We aimed to quantify the effect of papillary muscle repositioning on papillary muscle geometry and to evaluate whether improved papillary muscle geometry after papillary muscle repositioning translates into the global LV reverse remodelling in FMR type IIIb., Methods: Patients with severe FMR type IIIb were prospectively enrolled and underwent pre- and postoperative 1.5-T cardiac magnetic resonance imaging. A new variable was defined, the papillary muscle to mitral annulus distance, which quantifies the distance between papillary muscle tips and MV annular plane. All parameters were measured by 2 independent investigators., Results: A total of 63 patients were enrolled. In all patients, papillary muscle to mitral annulus distance correlated significantly with established markers of LV remodelling and MV tenting severity. In patients who underwent subannular papillary muscle repositioning procedure (surgical cohort, n = 23), preoperative median papillary muscle to mitral annulus distance was 30 mm [interquartile range (IQR): 27-34 mm] and was significantly reduced postoperatively to 25 mm (IQR: 21-27 mm) (P = 0.001). LV end-diastolic diameter was reduced from 66 mm (IQR: 60-71) preoperatively to 58 mm (IQR: 53-67) after the surgery (P = 0.001)., Conclusions: MV repair with papillary muscle repositioning results in a papillary muscle to mitral annulus distance reduction and significantly improved MV tenting parameters. Improved papillary muscle geometry after papillary muscle repositioning is associated with a global LV reverse remodelling and may, thereby, improve the prognosis of FMR patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

There is growing clinical need and interest to implement novel risk prediction tools in bicuspid aortic valve-associated proximal aortic disease, so-called bicuspid aortic valve aortopathy. Inherent limitations of the diameter-based risk stratification for adverse aortic events in bicuspid aortic valve aortopathy patients have recently been recognized. Therefore, alternative diagnostic tools and subsequent adjustments in the treatment guidelines are urgently needed. Herein, we summarize the current evidence on recent diagnostic developments to improve risk stratification in bicuspid aortic valve aortopathy, including circulating microRNAs as biomarkers to predict the progression of aortic disease.

Cancer treatment with immune checkpoint blockade (ICB) often induces immune-related adverse events (irAEs). We hypothesized that proteins coexpressed in tumors and normal cells could be antigenic targets in irAEs and herein described DITAS (discovery of tumor-associated self-antigens) for their identification. DITAS computed transcriptional similarity between lung tumors and healthy lung tissue based on single-sample gene set enrichment analysis. This identified 10 lung tissue-specific genes highly expressed in the lung tumors. Computational analysis was combined with functional T cell assays and single-cell RNA sequencing of the antigen-specific T cells to validate the lung tumor self-antigens. In patients with non-small cell lung cancer (NSCLC) treated with ICB, napsin A was a self-antigen that elicited strong CD8 + T cell responses, with ICB responders harboring higher frequencies of these CD8 + T cells compared with nonresponders. Human leukocyte antigen (HLA) class I ligands derived from napsin A were present in human lung tumors and in nontumor lung tissues, and napsin A tetramers confirmed the presence of napsin A-specific CD8 + T cells in blood and tumors of patients with NSCLC. Napsin A-specific T cell clonotypes were enriched in lung tumors and ICB-induced inflammatory lung lesions and could kill immortalized HLA-matched NSCLC cells ex vivo. Single-cell RNA sequencing revealed that these T cell clonotypes expressed proinflammatory cytokines and cytotoxic markers. Thus, DITAS successfully identified self-antigens, including napsin A, that likely mediate effective antitumor T cell responses in NSCLC and may simultaneously underpin lung irAEs.