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Background: Static cold storage (SCS) remains the gold standard for preserving donor hearts before transplantation but is associated with ischaemia, anaerobic metabolism, and organ injuries, leading to patient morbidity and mortality. We aimed to evaluate whether continuous, hypothermic oxygenated machine perfusion (HOPE) of the donor heart is safe and superior compared with SCS., Methods: We performed a multinational, multicentre, randomised, controlled, open-label clinical trial with a superiority design at 15 transplant centres across eight European countries. Adult candidates for heart transplantation were eligible and randomly assigned in a 1:1 ratio. Donor inclusion criteria were age 18-70 years with no previous sternotomy and donation after brain death. In the treatment group, the preservation protocol involved the use of a portable machine perfusion system ensuring HOPE of the resting donor heart. The donor hearts in the control group underwent ischaemic SCS according to standard practices. The primary outcome was time to first event of a composite of either cardiac-related death, moderate or severe primary graft dysfunction (PGD) of the left ventricle, PGD of the right ventricle, acute cellular rejection at least grade 2R, or graft failure (with use of mechanical circulatory support or re-transplantation) within 30 days after transplantation. We included all patients who were randomly assigned, fulfilled inclusion and exclusion criteria, and received a transplant in the primary analysis and all patients who were randomly assigned and received a transplant in the safety analyses. This trial was registered with ClicalTrials.gov (NCT03991923) and is ongoing., Findings: A total of 229 patients were enrolled between Nov 25, 2020, and May 19, 2023. The primary analysis population included 204 patients who received a transplant. There were no patients who received a transplant lost to follow-up. All 100 donor hearts preserved with HOPE were transplantable after perfusion. The primary endpoint was registered in 19 (19%) of 101 patients in the HOPE group and 31 (30%) of 103 patients in the SCS group, corresponding to a risk reduction of 44% (hazard ratio 0·56; 95% CI 0·32-0·99; log-rank test p=0·059). PGD was the primary outcome event in 11 (11%) patients in the HOPE group and 29 (28%) in the SCS group (risk ratio 0·39; 95% CI 0·20-0·73). In the HOPE group, 63 (65%) patients had a reported serious adverse event (158 events) versus 87 (70%; 222 events) in the SCS group. Major adverse cardiac transplant events were reported in 18 (18%) and 33 (32%) patients in the HOPE and SCS group (risk ratio 0·56; 95% CI 0·34-0·92)., Interpretation: Although there was not a significant difference in the primary endpoint, the 44% risk reduction associated with HOPE was suggested to be a clinically meaningful benefit. Post-transplant complications, measured as major adverse cardiac transplant events, were reduced. Analysis of secondary outcomes suggested that HOPE was beneficial in reducing primary graft dysfunction. HOPE in donor heart preservation addresses the existing challenges associated with graft preservation and the increasing complexity of donors and heart transplantation recipients. Future investigation will help to further elucidate the benefit of HOPE., Funding: XVIVO Perfusion., Competing Interests: Declaration of interests The sponsor provided the investigational devices and financial support for trial-specific investigational site costs to all participating centres. FR reports institutional research grants from XVIVO outside of the submitted work and receiving speakers fees from Atricure. GL reports receiving study materials from XVIVO as investigator in another clinical trial. SM reports research grants from German Center for Lung Research and German Research Foundation and honoraria from Berlin Heart. GD reports research grants from Astellas and Abbot and being a programme chair for ISHLT and a board member of XVIVO. AW is employed by the trial sponsor and may retain stock or stock options. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Introduction: Penile amputation is a rare urological emergency with varying etiologies, ranging from psychiatric disorders to traumatic injuries, and requires precise microsurgical replantation techniques to restore function and appearance. The popularization of microsurgery has greatly improved outcomes by enabling accurate vascular and nerve reattachments, which are crucial for erectile function and sensation. This comprehensive study reviews advancements in microsurgical penile replantation, perioperative, and postoperative care, focusing on the nuances of surgical interventions and potential complications such as ischemia and necrosis. Methods: The PubMed, EMBASE, and Cochrane databases, were queried for studies published between 2015 and 2023 that discussed preoperative conditions, surgical techniques, and postoperative outcomes in penile replantation cases. Resulting studies that reported preoperative and postoperative outcomes of at least one case of penile replantation after amputation were included. Case parameters of interest were then extracted and categorized to determine the most common complications as well as solutions utilized in penile replantation. Results: Our findings from 46 cases across 37 studies revealed a common occurrence of postoperative necrosis (56.5%) and highlighted the importance of timely vascular reconnection and innovative surgical strategies to manage complications. Three cases were complicated by scrotal hematomas and 23 cases reported at least one psychiatric comorbidity. Some innovative solutions mentioned include hyperbaric oxygen therapy, laser angiography, leech therapy, PDE inhibitors, and penile splints. Conclusion: The outcomes suggest a critical need for standardized protocols and further research into optimizing techniques and therapies to enhance the success rates as well as quality of life post-replantation. This review aims to guide future practices and encourage collaborative efforts to refine the complex microsurgical procedures involved in penile replantation., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2024 The Author(s).)

Introduction: Our goal was to compare the perceived readiness of graduating urologic residents and fellows to program directors (PDs) in U.S.-based postgraduate training programs. Additionally, we set out to assess the impact of COVID-19 on postgraduation plans to pursue fellowship training., Methods: Graduating residents, fellows, and PDs of accredited residency/fellowship programs in the U.S. were surveyed. The ranked preparedness of trainees to perform common urologic procedures was measured using a Likert scale from 1 (not comfortable) to 5 (fully proficient). The impact of COVID-19 was measured using a three-point Likert scale. Chi-squared and Kruskal-Wallis analyses were used to compare the groups., Results: From 93 responders, 21 were residents, 19 were fellows, 24 were residency PDs, and 29 were fellowship PDs. The median levels of comfort for trans-urethral resection of the prostate, hydrocelectomy, vasectomy, and urethral sling were at or above (≥3) moderate for both PDs and trainees. PDs were more likely to report underperformance for hypospadias repair (60% vs. 39%), penile prosthesis implantation (39% vs. 26%), and orthotopic neobladder formation (57% vs. 18%) than the trainees. Fifty-three (57.0%) of the surveyors felt that COVID-19 did not impact the trainees' comfort in performing general urologic procedures. COVID-19 influenced trainees' decision to pursue a fellowship or opt to practice as general urologists (p=0.002)., Conclusions: Our study suggests there may be a self-reported discrepancy between graduating trainees and their PDs regarding trainees' comfort levels performing general urologic procedures.

Heart failure (HF) is a common disease associated with high morbidity and mortality rates despite advanced pharmacological therapies. Heart transplantation remains the gold standard therapy for end-stage heart failure; however, its application is curtailed by the persistent shortage of donor organs. Over the past two decades, mechanical circulatory support, notably Left Ventricular Assist Devices (LVADs), have been established as an option for patients waiting for a donor organ. This comprehensive review focuses on elucidating the benefits and barriers associated with this application. We provide an overview of landmark clinical trials that have evaluated the use of LVADs as a bridge to transplantation therapy, with a particular focus on post-transplant outcomes. We discuss the benefits of stabilizing patients with these systems, weighing associated complications and limitations. Further technical advancements and research on optimal implantation timing are critical to ultimately improve outcomes and securing quality of life. In a world where the availability of donor organs remains constrained, LVADs are an increasingly important piece of patient care, bridging the critical gap to transplantation in advanced heart failure management., Competing Interests: PL and EP receive financial support from Abiomed Inc. and Abbott. The other authors of this manuscript have no conflicts of interest., (Copyright: © 2024 The Author(s). Published by IMR Press.)

Objective: Acute kidney injury (AKI) requiring renal-replacement therapy (RRT) after heart transplantation (OHT) is common and impairs outcomes. This study aimed to identify independent donor and recipient risk factors associated with RRT after OHT., Design: A retrospective data analysis., Setting: Data were collected from clinical routines in a maximum-care university hospital., Participants: Patients who underwent OHT., Interventions: The authors retrospectively analyzed data from 264 patients who underwent OHT between 2012 and 2021; 189 patients were eligible and included in the final analysis., Measurements and Main Results: The mean age was 48.0 ± 12.3 years, and 71.4% of patients were male. Ninety (47.6%) patients were on long-term mechanical circulatory support (lt-MCS). Posttransplant AKI with RRT occurred in 123 (65.1%) patients. In a multivariate analysis, preoperative body mass index >25 kg/m² (odds ratio [OR] 4.74, p < 0.001), elevated preoperative creatinine levels (OR for each mg/dL increase 3.44, p = 0.004), administration of red blood cell units during transplantation procedure (OR 2.31, p = 0.041) and ischemia time (OR for each hour increase 1.77, p = 0.004) were associated with a higher incidence of RRT. The use of renin-angiotensin-aldosterone system blockers before transplantation was associated with a reduced risk of RRT (OR 0.36, p = 0.013). The risk of mortality was 6.9-fold higher in patients who required RRT (hazard ratio 6.9, 95% CI: 2.1-22.6 p = 0.001). Previous lt-MCS, as well as donor parameters, were not associated with RRT after OHT., Conclusions: The implementation of guideline-directed medical therapy, weight reduction, minimizing ischemia time (ie, organ perfusion systems, workflow optimization), and comprehensive patient blood management potentially influences renal function and outcomes after OHT., Competing Interests: Declaration of competing interest S.O. declares payment to his institution and personally in the form of speaker fees, honoraria, and advisory board fees from Abiomed, speaker fees from Edwards Life Science and Novartis, departmental or institutional research funding from Novartis, and institutional educational grants from Abiomed. I.A.J. received speaker fees from AstraZeneca outside the submitted work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Transgender and nonbinary (TGNB) patients are a population with unique urologic needs that are often overlooked in urologic training. Most urology residents think that learning to take care of this population is important in their training; however, there is much variation in this educational content within urology residency programs. This review provides information on the current state of teaching regarding the unique needs of caring for TGNB patients as urologists and overviews some basic principles that every urologist should know., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Mouse models are a critical tool for studying human diseases, particularly developmental disorders 1 . However, conventional approaches for phenotyping may fail to detect subtle defects throughout the developing mouse 2 . Here we set out to establish single-cell RNA sequencing of the whole embryo as a scalable platform for the systematic phenotyping of mouse genetic models. We applied combinatorial indexing-based single-cell RNA sequencing 3 to profile 101 embryos of 22 mutant and 4 wild-type genotypes at embryonic day 13.5, altogether profiling more than 1.6 million nuclei. The 22 mutants represent a range of anticipated phenotypic severities, from established multisystem disorders to deletions of individual regulatory regions 4,5 . We developed and applied several analytical frameworks for detecting differences in composition and/or gene expression across 52 cell types or trajectories. Some mutants exhibit changes in dozens of trajectories whereas others exhibit changes in only a few cell types. We also identify differences between widely used wild-type strains, compare phenotyping of gain- versus loss-of-function mutants and characterize deletions of topological associating domain boundaries. Notably, some changes are shared among mutants, suggesting that developmental pleiotropy might be 'decomposable' through further scaling of this approach. Overall, our findings show how single-cell profiling of whole embryos can enable the systematic molecular and cellular phenotypic characterization of mouse mutants with unprecedented breadth and resolution., (© 2023. The Author(s).)

Background and Objective: Transgender and gender diverse (TGD) individuals may seek gender-affirming phalloplasty with specific functional goals, including erectile function sufficient for penetrative sexual intercourse. Individuals seeking penile prosthesis placement must accept the potential risks to their phallic anatomy., Methods: We review current practices at our center and narrative review of literature discussing techniques for penile prosthesis and testicular prosthesis placement after phalloplasty and scrotoplasty, as well as surgical outcomes, and quality of life outcomes where available., Key Content and Findings: Early discussion of a staged approach to phallic construction with a last step of implant placement is important during initial phalloplasty counseling. Pre-operative counseling at our multi-disciplinary center includes: discussion of surgical history, complications, goals and priorities; physical exam to evaluate phallic size and position, scrotal size, and other anatomic findings that may influence prosthesis selection; urinary evaluation, including uroflowmetry with post-void residual, and a cystoscopy with retrograde urethrogram if indicated based on symptoms or urinary studies, and discussion of surgical risks, benefits and alternatives. Although none of the commercially available penile prosthesis devices in the United States are designed for phalloplasty, modern inflatable and malleable prostheses are adapted for use in the post-phalloplasty setting. Due to the lack of native corpora cavernosa, highly variable phallic anatomy, and the need to adapt implants designed for natal penile anatomy, complication rates of prosthesis placement after phalloplasty remain high, with reported ranges of complications from 20% to 80%., Conclusions: Major complications requiring surgical revision are common relative to implant placement in natal penile anatomy, and include: infection requiring explantation, device extrusion, erosion, migration or malposition, inadequate rigidity, poor aesthetic result, pain, decrease or loss of erogenous and/or tactile sensation, device failure, injury to the urethra, and injury to the neurovascular supply of the penis with resultant partial or complete flap loss. This broad range of complication rates represents the variability with which results are reported and reflect a lack of clear reporting guidelines, significant variability in techniques, and need for more standardization. To optimize outcomes, it is important that surgeons have an in-depth understanding of phalloplasty anatomy and are equipped to manage potential complications in the short- and long-term., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-23-122/coif). The series “Complex Penile Prosthesis Surgery” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare., (2023 Translational Andrology and Urology. All rights reserved.)

Ex vivo machine perfusion (EVMP) is an emerging technique for preserving explanted solid organs with primary application in allogeneic organ transplantation. EVMP has been established as an alternative to the standard of care static-cold preservation, allowing for prolonged preservation and real-time monitoring of organ quality while reducing/preventing ischemia-reperfusion injury. Moreover, it has paved the way to involve expanded criteria donors, e.g., after circulatory death, thus expanding the donor organ pool. Ongoing improvements in EVMP protocols, especially expanding the duration of preservation, paved the way for its broader application, in particular for reconditioning and modification of diseased organs and tumor and infection therapies and regenerative approaches. Moreover, implementing EVMP for in vivo -like preclinical studies improving disease modeling raises significant interest, while providing an ideal interface for bioengineering and genetic manipulation. These approaches can be applied not only in an allogeneic and xenogeneic transplant setting but also in an autologous setting, where patients can be on temporary organ support while the diseased organs are treated ex vivo , followed by reimplantation of the cured organ. This review provides a comprehensive overview of the differences and similarities in abdominal (kidney and liver) and thoracic (lung and heart) EVMP, focusing on the organ-specific components and preservation techniques, specifically on the composition of perfusion solutions and their supplements and perfusion temperatures and flow conditions. Novel treatment opportunities beyond organ transplantation and limitations of abdominal and thoracic EVMP are delineated to identify complementary interdisciplinary approaches for the application and development of this technique., 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., (© 2023 Iske, Schroeter, Knoedler, Nazari-Shafti, Wert, Roesel, Hennig, Niehaus, Kuehn, Ius, Falk, Schmelzle, Ruhparwar, Haverich, Knosalla, Tullius, Vondran and Wiegmann.)

Wilson's disease (WD, MIM#277900) is an autosomal recessive disorder resulting in copper excess caused by biallelic variants in the ATP7B gene (MIM#606882) encoding a copper transporting P-type ATPase. ATP7B variants of unknown significance (VUS) are detected frequently, sometimes impeding a clear diagnosis. Functional analyses can help to classify these variants as benign or pathogenic. Additionally, variants already classified as (likely) pathogenic benefit from functional analyses to understand their pathomechanism, thus contribute to the development of personalized treatment approaches in the future. We described clinical features of six WD patients and functionally characterized five ATP7B missense variants (two VUS, three yet uncharacterized likely pathogenic variants), detected in these patients. We determined the protein level, copper export capacity, and cellular localization in an in vitro model and potential structural consequences using an ATP7B protein model based on AlphaFold. Our analyses give insight into the pathomechanism and allowed reclassification for the two VUS to likely pathogenic and for two of the three likely pathogenic variants to pathogenic., (© 2023 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Pulmonary hypertension worsens outcome in left heart disease. Stiffening of the pulmonary artery may drive this pathology by increasing right ventricular dysfunction and lung vascular remodeling. Here we show increased stiffness of pulmonary arteries from patients with left heart disease that correlates with impaired pulmonary hemodynamics. Extracellular matrix remodeling in the pulmonary arterial wall, manifested by dysregulated genes implicated in elastin degradation, precedes the onset of pulmonary hypertension. The resulting degradation of elastic fibers is paralleled by an accumulation of fibrillar collagens. Pentagalloyl glucose preserves arterial elastic fibers from elastolysis, reduces inflammation and collagen accumulation, improves pulmonary artery biomechanics, and normalizes right ventricular and pulmonary hemodynamics in a rat model of pulmonary hypertension due to left heart disease. Thus, targeting extracellular matrix remodeling may present a therapeutic approach for pulmonary hypertension due to left heart disease., (© 2023. The Author(s).)

Background: Diabetic retinopathy (DR) is a leading cause of blindness. Our objective was to evaluate the performance of an artificial intelligence (AI) system integrated into a handheld smartphone-based retinal camera for DR screening using a single retinal image per eye., Methods: Images were obtained from individuals with diabetes during a mass screening program for DR in Blumenau, Southern Brazil, conducted by trained operators. Automatic analysis was conducted using an AI system (EyerMaps™, Phelcom Technologies LLC, Boston, USA) with one macula-centered, 45-degree field of view retinal image per eye. The results were compared to the assessment by a retinal specialist, considered as the ground truth, using two images per eye. Patients with ungradable images were excluded from the analysis., Results: A total of 686 individuals (average age 59.2 ± 13.3 years, 56.7% women, diabetes duration 12.1 ± 9.4 years) were included in the analysis. The rates of insulin use, daily glycemic monitoring, and systemic hypertension treatment were 68.4%, 70.2%, and 70.2%, respectively. Although 97.3% of patients were aware of the risk of blindness associated with diabetes, more than half of them underwent their first retinal examination during the event. The majority (82.5%) relied exclusively on the public health system. Approximately 43.4% of individuals were either illiterate or had not completed elementary school. DR classification based on the ground truth was as follows: absent or nonproliferative mild DR 86.9%, more than mild (mtm) DR 13.1%. The AI system achieved sensitivity, specificity, positive predictive value, and negative predictive value percentages (95% CI) for mtmDR as follows: 93.6% (87.8-97.2), 71.7% (67.8-75.4), 42.7% (39.3-46.2), and 98.0% (96.2-98.9), respectively. The area under the ROC curve was 86.4%., Conclusion: The portable retinal camera combined with AI demonstrated high sensitivity for DR screening using only one image per eye, offering a simpler protocol compared to the traditional approach of two images per eye. Simplifying the DR screening process could enhance adherence rates and overall program coverage., (© 2023. The Author(s).)

Faced with a chronic donor shortage, clinicians and regulators both struggle to develop allocation systems which balance the challenges of waitlist mortality and donor availability. Most organ allocation systems across the globe have prioritized transplantation of patients supported on temporary mechanical circulatory support (tMCS) with regional variations. There are concerns that this approach might not produce optimal outcomes and is not without major drawbacks including lack of strict criteria for tMCS as bridge strategy, choice of optimal devices and wait time on tMCS. The current manuscript outlines characteristics and limitations of current devices used for tMCS as a bridging strategy. The outcomes of transplantation following device support are evolving and are highlighted as well. Lastly, the allocation schema for heart transplantation in various countries are reviewed and compared. Additionally, we propose key principles to guide changes in next iteration of donor allocation systems to balance waitlist mortality with optimal post-transplant outcomes. First, allocation should be on the basis of calculated scores which take into account a variety of pre-and post-transplant factors and cannot be easily manipulate by choice of support therapy. Next, time at high urgency statuses should be time-limited with strict criteria for renewal. Emphasis should be placed on the further refinement of durable mechanical support therapies. Patients on durable support need a pathway to qualify for transplantation in the absence of complications, and lastly, peer review of exceptions to organ allocation policy are critically important to ensure the appropriate allocation of donor organs., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: A point mutation in sickle cell disease (SCD) alters one amino acid in the β-globin subunit of hemoglobin, with resultant anemia and multiorgan damage that typically shortens lifespan by decades. Because SCD is caused by a single mutation, and hematopoietic stem cells (HSCs) can be harvested, manipulated, and returned to an individual, it is an attractive target for gene correction., Results: An optimized Cas9 ribonucleoprotein (RNP) with an ssDNA oligonucleotide donor together generated correction of at least one β-globin allele in more than 30% of long-term engrafting human HSCs. After adopting a high-fidelity Cas9 variant, efficient correction with minimal off-target events also was observed. In vivo erythroid differentiation markedly enriches for corrected β-globin alleles, indicating that erythroblasts carrying one or more corrected alleles have a survival advantage., Significance: These findings indicate that the sickle mutation can be corrected in autologous HSCs with an optimized protocol suitable for clinical translation., Competing Interests: The authors have no conflicts of interest. MCW is medical director of All Cells, Inc., from which some of the human CD34+ cells for the studies were purchased. Matthew S.McNeill, Garrett R. Rettig, Yongming Sun, Yu Wang, and Mark A. Behlke are employees of IDT, Inc. Mark A. De-Witt is a consultant for Synthego Inc. and CellFE Inc. Synthego Inc. did not contribute to this work. MCW is medical director of All Cells, Inc., from which some of the human CD34+ cells for the studies were purchased. Matthew S.McNeill, Garrett R. Rettig, Yongming Sun, Yu Wang, and Mark A. Behlke are employees of IDT, Inc. Mark A. De-Witt is a consultant for Synthego Inc. and CellFE Inc. Synthego Inc. did not contribute to this work. GRR is an employee of Integrated DNA Technologies and Danaher Corp and shareholder of Danaher Corp A single patent application was filed from this project: USPAT APPLICATION NUMBER: 17047025 - Methods for Treating Sickle Cell Disease. Products and tools supplied by IDT are for research use only and not intended for diagnostic or therapeutic purposes. Purchaser and/or user is solely responsible for all decisions regarding the use of these products and any associated regulatory or legal obligations., (© 2022.)

Background: Surgical ventricular restoration (SVR) leads to functional improvement by volume reduction and restoration of left ventricular (LV) geometry. Our purpose was to refine the planning for SVR using cardiac computed tomography (CCT)., Methods: The possibility to anticipate the postoperative residual LV volume was assessed using CCT in 205 patients undergoing SVR combined with coronary artery bypass grafting (77%), mitral valve repair/replacement (19%) and LV thrombectomy (19%). The potential of CCT to guide the procedure was evaluated. Additionally, the predictive value of CCT characteristics on survival was addressed., Results: 30-day, 1- and 5-year survival was 92.6, 82.7, and 72.1%, respectively, with a marked reduction of NYHA class III-IV quota after surgery (95.1% vs. 20.5% in the follow-up). Both pre- and postoperative LV end-systolic volume index (LVESVI) were predictive of all defined endpoints according to the following tertiles: preoperative: <74 ml/m 2 , 74-114 ml/m 2 and >114 ml/m 2 ; postoperative: <58 ml/m 2 , 58-82 ml/m 2 and >82 ml/m 2 . On average, a 50 ml/m 2 increase of preoperative LVESVI was associated with a 35% higher hazard of death ( p = 0.043). Aneurysms limited to seven antero-apical segments (1-7) were associated with a lower death risk ( n = 60, HR 0.52, CI 0.28-0.96, p = 0.038). LVESVI predicted by CCT was found to correlate significantly with effectively achieved LVESVI ( r = 0.87 and r = 0.88, respectively, p < 0.0001)., Conclusions: CCT-guided SVR can be performed with good mid-term survival and significant improvement in HF severity. CCT-based assessment of achievable postoperative LV volume helps estimate the probability of therapeutic success in individual patients., Competing Interests: VF disclosed financial relationships with the following entities: Medtronic GmbH, Biotronik SE & Co, Abbott GmbH & Co KG, Boston Scientific, Edwards Lifesciences, Berlin Heart, Novartis Pharma GmbH, JOTEC GmbH, and Zurich Heart. The remaining 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 © 2022 Solowjowa, Nemchyna, Hrytsyna, Meyer, Hennig, Falk and Knosalla.)

Objectives: Parameters of left ventricular (LV) mechanics, obtained from speckle-tracking echocardiography (STE), were found to be of prognostic value in patients with heart failure and those who underwent cardiac surgery. This study aimed to assess the value of STE in patients scheduled to undergo surgical ventricular restoration (SVR)., Methods: A total of 158 consecutive patients with baseline STE who underwent SVR due to an LV anteroapical aneurysm were included in the analysis. Preoperative longitudinal STE parameters were evaluated for their association with an outcome, defined as all-cause mortality, LV assist device implantation, or heart transplantation. The echocardiographic follow-up to assess the change in the regional function of the segments remote from the aneurysm was performed in 43 patients at a median of 10 months [interquartile range (IQR): 6-12.7 months] after SVR., Results: During a median follow-up of 5.1 years (IQR: 1.6-8.7 years), events occurred in 68 patients (48%). Less impaired mean basal end-systolic longitudinal strain (BLS) with a cutoff value ≤ -10.1 % demonstrated a strong association with event-free survival, also in patients with an LV shape corresponding to an intermediate shape between aneurysmal and globally akinetic. Initially hypo- or akinetic basal segments with preoperative end-systolic strain ≤ -7.8% showed a greater improvement in wall motion at the short-term follow up., Conclusion: Patients with less impaired preoperative BLS exhibited a better event-free survival after SVR, also those with severe LV remodeling. The preserved preoperative segmental longitudinal strain was associated with a greater improvement in regional wall motion after SVR. BLS assessment may play a predictive role in patients with an LV anteroapical aneurysm who are scheduled to undergo SVR., 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 © 2022 Nemchyna, Solowjowa, Dandel, Hrytsyna, Stein, Knierim, Schoenrath, Hennig, Falk and Knosalla.)

Purpose: Lymphovascular invasion (LV1) and presence of > 50% embryonal carcinoma (> 50% EC) represent risk factors for progression in patients with clinical stage 1 (CS1) nonseminomatous (NS) testicular germ cell tumours. As serum levels of microRNA-371a-3p (M371) are capable of detecting small amounts of GCT, we evaluated if LV1 and > 50% EC are associated with M371 levels., Methods: M371 serum levels were measured postoperatively in 153 NS CS1 patients and both pre- and postoperatively in 131 patients. We registered the following factors: age, tumour size, LV status, > 50% EC, teratoma in primary, preoperative elevation of classical tumour markers. M371 expression was compared among subgroups. The ability of M371 to predict LV1 was calculated by receiver operating characteristics (ROC) curves. Multiple regression analysis was used to look for associations of M371 levels with other factors., Results: Postoperatively elevated M371 levels were found in 29.4% of the patients, but were neither associated with LV status nor with > 50% EC. Likewise, relative decrease of M371 was not associated. ROC analysis of postoperative M371 levels revealed an AUC of 0.5 for the ability to predict LV1 while preoperative M371 had an AUC of 0.732. Multiple regression analysis revealed significant associations of preoperative M371 levels with LV status (p = 0.003), tumour size (p = 0.001), > 50% EC (p = 0.004), and teratoma component (p = 0.045)., Conclusion: Postoperatively elevated M371 levels are not associated with risk factors for progression in NS CS1 patients. However, the significant association of preoperative M371 expression with LV1 deserves further evaluation., (© 2021. The Author(s).)

Background: Despite the risk for complications, allograft surveillance after orthotopic heart transplantation (OHT) is performed by cardiac catheterization and biopsies. We investigated the diagnostic and prognostic value of a TDI-derived systolic wall motion analysis of the posterobasal wall of the left ventricle (Sm) as a screening modality in OHT aftercare., Methods: We examined data of 210 eligible patients who underwent OHT between 2010 and 2020. Forty-four patients who had died within the initial hospital stay were excluded. For 166 patients, baseline and follow-up data were analyzed. The mean age at OHT was 46.2 (±11.4) years; 76.5% were male., Results: Within the observational period, 22 (13.3%) patients died. In total, 170 episodes of acute cellular or humoral rejections occurred (84 ISHLT1R; 13 ISHLT2R; 8 ISHLT3R; 65 AMR), and 29 catheterizations revealed cardiac allograft vasculopathy (5 CAV1; 4 CAV2; 20 CAV3). Individual Sm radial/longitudinal remained stable within the follow-up period (11.5 ± 2.2 cm/s; 10.9 ± 2.1 cm/s). Patients with acute rejections and CAV3 showed significant Sm radial/longitudinal reductions (AMR1: 1.6 ± 1.9 cm/s, confidence interval (CI) 0.77-0.243, p < 0.001; 1.8 ± 2.0 cm/s, CI 0.92-0.267, p < 0.001. ISHLT1R: 1.7 ± 1.8 cm/s, CI 1.32-2.08, p < 0.001; 2.0 ± 1.6 cm/s, CI 1.66-2.34, p < 0.001. CAV3: 1.3 ± 2.5 cm/s, CI 0.23-2.43, p < 0.017; 1.4 ± 2.8 cm/s, CI 0.21-2.66, p < 0.021). Lower Sm was associated with a threefold increase in all-cause mortality (hazard ratio (HR) 3.24, CI 1.2-8.76, p = 0.020; HR 2.92, CI 1.19-7.18, p = 0.019). Overall, Sm-triggered surveillance led to 0.75 invasive diagnostics per patient post-OHT year., Conclusions: Sm remained stable in the post-OHT course. Reductions indicated ISHLT1R, AMR1 and CAV3 and were associated with higher all-cause mortality. Sm-triggered surveillance may be referred to as a safe, high-yield screening modality in OHT aftercare.

Multiple genes are known to be associated with osteogenesis imperfecta (OI), a phenotypically and genetically heterogenous bone disorder, marked predominantly by low bone mineral density and increased risk of fractures. Recently, mutations affecting MESD, which encodes for a chaperone required for trafficking of the low-density lipoprotein receptors LRP5 and LRP6 in the endoplasmic reticulum, were described to cause autosomal-recessive OI XX in homozygous children. In the present study, whole-exome sequencing of three stillbirths in one family was performed to evaluate the presence of a hereditary disorder. To further characterize the skeletal phenotype, fetal autopsy, bone histology, and quantitative backscattered electron imaging (qBEI) were performed, and the results were compared with those from an age-matched control with regular skeletal phenotype. In each of the affected individuals, compound heterozygous mutations in MESD exon 2 and exon 3 were detected. Based on the skeletal phenotype, which was characterized by multiple intrauterine fractures and severe skeletal deformity, OI XX was diagnosed in these individuals. Histological evaluation of MESD specimens revealed an impaired osseous development with an altered osteocyte morphology and reduced canalicular connectivity. Moreover, analysis of bone mineral density distribution by qBEI indicated an impaired and more heterogeneous matrix mineralization in individuals with MESD mutations than in controls. In contrast to the previously reported phenotypes of individuals with OI XX, the more severe phenotype in the present study is likely explained by a mutation in exon 2, located within the chaperone domain of MESD, that leads to a complete loss of function, which indicates the relevance of MESD in early skeletal development. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).., (© 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

The development of driveline infections following left ventricular assist device (LVAD) implantation remains a major problem. We investigated the impact of fluorescence in situ hybridization (FISH) combined with 16S rRNA gene sequencing on the diagnosis of driveline infections. LVAD drivelines (n = 61) from 60 consecutive patients were obtained during LVAD explantation and subjected to FISH analysis. 16S rRNA gene polymerase chain reaction (PCR) and sequencing to identify the microorganisms were performed. Results were compared with those of a standard microbiological culture. The reasons for pump removal were heart transplantation (n = 22), weaning (n = 14), pump exchange due to pump thrombosis (n = 12), technical problems (n = 7), or death (n = 5). Of the 60 patients, 26 exhibited clinical signs of a VAD-specific infection, while 34 (with 35 drivelines) showed no clinical signs of infection before explantation. The spectrum of identified pathogens differed between FISH/PCR and conventional microbiological diagnostics. In general, the bacterial spectrum was more diverse in FISH/PCR as compared with conventional microbiology, which more often showed only typical skin flora (coagulase-negative staphylococci and Corynebacteriaceae). In addition to identifying the species, FISH/PCR provided information about the spatial distribution and invasiveness of the microorganisms. Cultures usually represent the only source of microbiological information for clinicians and often prove to be unsatisfactory in complex LVAD cases. FISH/PCR not only identified a greater number and variety of microorganisms than standard culture did, but it also provided information about the number, localization, and biofilm state of the pathogens, making it a useful tool for diagnosing the specific cause of LVAD driveline infections., (Copyright © ASAIO 2020.)

Background: Residential exposure to air pollution (AP) has been shown to activate the immune system (IS). Although innate immune responses to AP have been studied extensively, investigations on the adaptive IS are scarce., Objectives: The aim of this study was to investigate the association between short- to long-term AP exposure and polyclonal free light chains (FLC) produced by plasma cells., Methods: We used repeated data from three examinations ( t 0 : 2000-2003; t 1 : 2006-2008; and t 2 : 2011-2015) of the population-based German Heinz Nixdorf Recall cohort of initially 4,814 participants (45-75 y old). Residential exposure to total and source-specific particulate matter (PM) with an aerodynamic diameter of 10 or 2.5 μ m ( PM 10 and PM 2.5 respectively), nitrogen dioxide ( NO 2 ), and particle number concentrations (accumulation mode; PN AM ) was estimated using a chemistry transport model with different time windows (1- to 365-d mean ± standard deviation) before blood draw. We applied linear mixed models with a random participant intercept to estimate associations between total, traffic- and industry-related AP exposures and log-transformed FLC, controlling for examination time, sociodemographic and lifestyle variables, estimated glomerular filtration rate and season., Results: Analyzing 9,933 observations from 4,455 participants, we observed generally positive associations between AP exposures and FLC. We observed strongest associations with middle-term exposures, e.g., 3.0% increase in FLC (95% confidence interval: 1.8%, 4.3%) per interquartile range increase in 91-d mean of NO 2 ( 14.1 μ g / m ³ ). Across the different pollutants, NO 2 showed strongest associations with FLC, followed by PM 10 and PN AM . Effect estimates for traffic-related exposures were mostly higher compared with total exposures. Although NO 2 and PN AM estimates remained stable upon adjustment for PM, PM estimates decreased considerably upon adjustment for NO 2 and PN AM ., Discussion: Our results suggest that middle-term AP exposures in particular might be positively associated with activation of the adaptive IS. Traffic-related PM, PN AM , and NO 2 showed strongest associations. https://doi.org/10.1289/EHP7164.

Background: MicroRNA-371a-3p (miR-371), the novel serum biomarker of testicular germ cell tumours (GCTs), is produced by undifferentiated subtypes of GCTs but not by teratoma. Cystic teratoma developing from retroperitoneal metastases of GCT subsequent to chemotherapy had been shown to contain high levels of classical serum tumour markers of GCT in the presence of normal marker levels in serum. To date, no information is available regarding the presence of miR-371 in the cystic fluid of residual teratoma after chemotherapy., Methods: Four patients (age 18-26 years) undergoing retroperitoneal lymph node dissection (RPLND) for cystic residual masses resulting from chemotherapy of bulky retroperitoneal GCT had measurements of miR-371 in both serum and cystic fluid aspirated from surgical specimens. Measurement of the miR was performed with quantitative real-time PCR using miR-30b-5p as reference. Results were tabulated and analysed in a descriptive manner., Results: Histologically, all of the surgical specimens involved teratoma only with no evidence of vital undifferentiated GCT tissue. All patients were cured. Prior to RPLND, miR-371 serum levels were not measurable or close to zero in all of the patients. Cystic fluid revealed elevated levels of miR-371 in 3 patients and traces of miR in one., Conclusions: The detection of miR-371 in the cystic fluid of teratoma is somewhat enigmatic since this GCT subtype usually does not express the miR. Two hypotheses may explain the finding: First, miR-371 molecules were released into the cystic fluid by active GCT tissue prior to chemotherapy. High levels were kept after regression of vital GCT tissue because the cystic lumen is without a specific drainage system. Second, teratoma cells lining the interior cyst wall may shed small amounts of miR-371 into the lumen. Because of the lacking drainage system, even small levels may accumulate. The present finding adds to the understanding of the biology of the novel biomarker of GCT., (© 2020 S. Karger AG, Basel.)

Introduction: While cardiac tumors are rare, their identification and differentiation has wide clinical implications. Recent cardiac magnetic resonance (CMR) parametric mapping techniques allow for quantitative tissue characterization. Our aim was to examine the range of values encountered in cardiac myxomas in correlation to histological measurements. Methods and Results: Nine patients with histologically proven cardiac myxomas were included. CMR (1.5 Tesla, Philips) including parametric mapping was performed in all patients pre-operatively. All data are reported as mean ± standard deviation. Compared to myocardium, cardiac myxomas demonstrated higher native T1 relaxation times (1,554 ± 192 ms vs. 1,017 ± 58 ms, p < 0.001), ECV (46.9 ± 13.0% vs. 27.1 ± 2.6%, p = 0.001), and T2 relaxation times (209 ± 120 ms vs. 52 ± 3 ms, p = 0.008). Areas with LGE showed higher ECV than areas without (54.3 ± 17.8% vs. 32.7 ± 18.6%, p = 0.042), with differences in native T1 relaxation times (1,644 ± 217 ms vs. 1,482 ± 351 ms, p = 0.291) and T2 relaxation times (356 ± 236 ms vs. 129 ± 68 ms, p = 0.155) not reaching statistical significance. Conclusions: Parametric CMR showed elevated native T1 and T2 relaxation times and ECV values in cardiac myxomas compared to normal myocardium, reflecting an increased interstitial space and fluid content. This might help in the differentiation of cardiac myxomas from other tumor entities., (Copyright © 2020 Nasser, Doeblin, Doltra, Schnackenburg, Wassilew, Berger, Gebker, Bigvava, Hennig, Pieske and Kelle.)

Objectives: Due to inconsistent epidemiological evidence on health effects of air pollution on progression of atherosclerosis, we investigated several air pollutants and their effects on progression of atherosclerosis, using carotid intima media thickness (cIMT), coronary calcification (CAC), and thoracic aortic calcification (TAC)., Methods: We used baseline (2000-2003) and 5-y follow-up (2006-2008) data from the German Heinz Nixdorf Recall cohort study, including 4,814 middle-aged adults. Residence-based long-term air pollution exposure, including particulate matter (PM) with aerodynamic diameter ≤ 2.5 μ m ( PM 2.5 ), ( PM 10 ), and nitrogen dioxide ( NO 2 ) was assessed using chemistry transport and land use regression (LUR) models. cIMT was quantified as side-specific median IMT assessed from standardized ultrasound images. CAC and TAC were quantified by computed tomography using the Agatston score. Development (yes/no) and progression of atherosclerosis (change in cIMT and annual growth rate for CAC/TAC) were analyzed with logistic and linear regression models, adjusting for age, sex, lifestyle variables, socioeconomic status, and traffic noise., Results: While no clear associations were observed in the full study sample (mean age 59.1 ( ± 7.6 ) y; 53% female), most air pollutants were marginally associated with progression of atherosclerosis in participants with no or low baseline atherosclerotic burden. Most consistently for CAC, e.g., a 1.5   μ g / m 3 higher exposure to PM 2.5 (LUR) yielded an estimated odds ratio of 1.19 [95% confidence interval (CI): 1.03, 1.39] for progression of CAC and an increased annual growth rate of 2% (95% CI: 1%, 4%)., Conclusion: Our study suggests that development and progression of subclinical atherosclerosis is associated with long-term air pollution in middle-aged participants with no or minor atherosclerotic burden at baseline, while overall no consistent associations are observed. https://doi.org/10.1289/EHP7077.

Objectives: Traffic noise is negatively associated with cognitive function, and its perception can differ between depressed and non-depressed people. We studied the role of depressive symptoms in the association between traffic noise and cognitive function. We studied the role of depressive symptoms in the association between traffic noise and cognitive function., Methods: During the first follow-up examination (2006-2008) of the German Heinz Nixdorf Recall study, cognitive function (five subtests and an additive global summary score, GCS) and depressive symptoms (CES-D score) were assessed in 2745 participants (aged 50-80, 49.8% women). Mild cognitive impairment (MCI) was diagnosed according to the Petersen criteria in 380 participants. Long-term exposure to traffic noise was modeled as weighted 24-h mean (L DEN ) and night-time mean (L NIGHT ) at the façade of the baseline addresses, and was corrected for indoors (L DEN&#95;IN and L NIGHT&#95;IN ). We developed multiple linear and logistic regression models adjusted for individual-level characteristics to investigate cross-sectionally the role of depressive symptoms in the association of traffic noise with cognitive function., Results: Overall, 8.6% participants had depressive symptoms. The median noise values were L DEN 52.1 dB(A) and L DEN&#95;IN 34.7 dB(A). Associations were slightly stronger for cognitive subtests in those with severe depression (CES-D>21), i.e., per 10 dB(A) L DEN and verbal fluency: β = -0.04 [-0.11; 0.03] for CES-D≤21 and β = -0.09 [-0.24; -0.06] for CES-D>21. Additional adjustment of the main model for CES-D did not change the association between noise and cognitive outcomes. Estimates using indoor noise exposure were generally stronger and more precise., Conclusions: Depressed people may be more susceptible to adverse effects of noise than non-depressed. Modeled estimates of indoor noise exposure is possibly a more appropriate measure of exposure., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Background: Few studies have examined the risk of long-term exposure to source-specific airborne pollutants on incidence of cerebrovascular and cardiovascular events., Objectives: We aimed to estimate the effect of long-term exposure to source-specific air pollution and particulate matter (PM) components on incidence of stroke, coronary heart disease (CHD), and total cardiovascular events (CVE) in the population-based Heinz Nixdorf Recall study (HNR)., Methods: We used baseline (2000-2003) and 14-year follow-up data of the HNR Study, an ongoing population-based prospective cohort study in Western Germany. Participants' residential mean exposures to NO 2 and total and source-specific PM 10 , PM 2.5 , accumulation mode particle number concentration (PN AM ), and PM components were modelled using a dispersion and chemical transport model. We used Cox regression to evaluate the effect of pollutants (per 1 μg/m 3 increase and per interquartile range - IQR) on risk of stroke and CHD, adjusting for socio-demographic characteristics, lifestyle risk factors and nighttime traffic noise exposure., Results: In 4,105 included participants (aged 45-76 at baseline, 52.5% women), we observed 118 cases of first stroke and 373 cases of first CHD during 46,748 person-years under risk. The median survival time within the cohort was 13.3 years. No effect of exposure to ambient air pollution on risk of CHD was observed, but distinct effects were observed for stroke. Ambient traffic-specific PM showed a stronger effect on stroke than industry-specific PM: hazard ratios (95% confidence interval) for total, traffic-specific, and industry-specific PM 2.5 were 1.16 (1.02-1.34), 2.53 (1.07-5.97), and 1.27 (1.03-1.56) per 1 μg/m 3 increase, respectively. PM components showed no substantially different effects from those of total PM per IQR, but higher associations were observed for NH 4 and SO 4 per 1 μg/m 3 . However, the exposure contrast of ammonium and sulfate components was very low., Conclusion: Traffic-specific PM exhibited stronger effects than total and industry-specific PM on risk of stroke. Among components, NH 4 and SO 4 showed higher effects. No effect was observed for PM and CHD., 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 © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: Tricuspid insufficiency (TI) is the most common valvular complication following orthotopic heart transplantation (HTx) and in serious cases is associated with increased mortality. In this study, we analyze the possible variables influencing TI following HTx and aim to identify the most important risk factors and mechanisms responsible for functional TI development and progression., Methods: We identified the incidence of TI within our institute in 857 of 1515 patients who underwent HTx using the biatrial anastomosis technique in the years between 1986 and 2010. The risk factors that could influence TI were retrospectively analyzed in detail in a representative group of 152 patients with identical TI distribution as found in the entire program. Patients of the group were subdivided into 2 groups according to the severity of TI: patients with TI grade ≤2 and those with TI grade >2. Impact on long-term survival (>15 years) was assessed., Results: In univariable analysis, study variables such as age of recipient ( P  = .027), donor to recipient right atrium anterior wall ratio ( P <  .001), tricuspid annulus anterior to septal leaflet excursion ratio ( P  = .001), dialysis ( P  = .026), and total biopsy number ( P  = .003) showed significant differences. The variables, height of recipient ( P  = .080), body mass index donor to body mass index recipient ratio ( P  = .080), and number of biopsies with more than moderate grade ( P  = .067) showed a trend toward significance in the development of severe TI after HTx. In multivariable analysis, we found an independent significant association between TI after HTx and donor to recipient right atrium anterior wall ratio, number of biopsies, and dialysis., Conclusions: Changes in tricuspid annulus geometry, number of biopsies, and dialysis are the most important risk factors for the development and progression of TI following cardiac transplantation. It could be prevented using modified operative techniques, noninvasive diagnostic modalities, and intensified ultrafiltration. In patients with biatrial anastomosis technique with generous atrial cuff, the presence of TI greater than grade 2 did not impact long-term survival., (© 2020 The Authors.)

Aims: Air pollution and noise are potential risk factors for subclinical atherosclerosis. Longitudinal analyses, especially on the interplay of these environmental factors, are scarce and inconsistent. Hence we investigated long-term traffic-related exposure to air pollution and noise with the development and progression of thoracic aortic calcification, a marker of subclinical atherosclerosis., Methods: We used baseline (2000-2003) and follow-up (2006-2008) data from the German Heinz Nixdorf Recall cohort study, including 4814 middle-aged adults. Residence-based air pollution (PM 2.5 (aerodynamic diameter ≤ 2.5 µm), PM 10 , nitrogen dioxide and particle number), and noise was assessed with dispersion models. Thoracic aortic calcification was quantified from non-contrast enhanced electron beam computed tomography. The presence and extent of thoracic aortic calcification progression were analysed with multiple logistic and linear regression models, respectively, adjusting for age, sex, lifestyle variables, socioeconomic status and respective co-exposure., Results: We observed no association in the full study sample ( n  = 3155, mean age 59.1 (±7.6) years, 52.8% women). While an interquartile range in particle number and night-time noise yielded odds ratios of 1.20 (1.03, 1.40) and 1.21 (1.00, 1.46) for binary thoracic aortic calcification progression, and 0.02 (-0.01, 0.05) and 0.04 (0.00, 0.07) higher growth rates of thoracic aortic calcification in participants with baseline thoracic aortic calcification less than 10, negative findings were observed in those with baseline thoracic aortic calcification of 10 or greater. Results were similar for other pollutants and daytime noise., Conclusion: Our study shows no overall associations. Subgroup analyses suggest independent associations of traffic-related air pollution and noise with the development and progression of subclinical atherosclerosis in participants with no or minor thoracic aortic calcification at baseline, in contrast to negative findings in those with advanced calcification.

Background: Serum levels of microRNA-371a-3p represent a specific tumor marker of testicular germ cell tumors (GCTs) but the origin of circulating miR-371a-3p is not finally resolved. The correlation between miR-levels in tissue and serum is unclear. Results: MiR-levels in GCT tissue are 399-fold higher than in contralateral testicular tissue and 5843-fold higher than in non-testicular tissue. MiR tissue levels correlate with corresponding serum levels (r 2 = 0.181). ISH detected miR-371a-3p intracellularly in GCT cells except teratoma. A low expression was also detected in normal testicular germ cells. Conclusions: Circulating miR-371a-3p is specifically derived from GCT tissue. The miR is present in GCT cells except teratoma. A low expression is also found in normal testicular tissue but not in non-testicular tissue. MiR-371a-3p levels in tissue and serum correlate significantly. This study underscores the usefulness of serum miR-371a-3p as tumor marker of GCT. Patients and methods: Expression levels of miR-371a-3p were concurrently measured in tissues of GCT, contralateral testes ( n = 38), and in serum ( n = 36) with real time PCR. For control, 5 healthy testicles and 4 non-testicular tissue samples were examined. MiR-levels were compared using descriptive statistical methods. We also performed in situ hybridization (ISH) of GCT tissue with a probe specific for miR-371a-3p., Competing Interests: CONFLICTS OF INTEREST Gazanfer Belge and Klaus-Peter Dieckmann each possess 9.7% ownership shares of miRdetect GmbH, Bremen, a start-up company aiming to develop a commercially available test for measuring microRNAs in serum. MiRdetect holds a patent for the measurement of miRNA in body fluids at the limit of detection. All other authors declare no competing interests towards this report. A further patent for the use of miR-371a-3p as a marker for GCNis was filed by miRdetect/University of Bremen on November, 2nd 2016. Arlo Radtke is an employee of miRdetect GmbH, Bremen since January 2019., (Copyright: © 2020 Belge et al.)

Adaptive immunity vitally depends on major histocompatibility complex class I (MHC I) molecules loaded with peptides. Selective loading of peptides onto MHC I, referred to as peptide editing, is catalyzed by tapasin and the tapasin-related TAPBPR. An important catalytic role has been ascribed to a structural feature in TAPBPR called the scoop loop, but the exact function of the scoop loop remains elusive. Here, using a reconstituted system of defined peptide-exchange components including human TAPBPR variants, we uncover a substantial contribution of the scoop loop to the stability of the MHC I-chaperone complex and to peptide editing. We reveal that the scoop loop of TAPBPR functions as an internal peptide surrogate in peptide-depleted environments stabilizing empty MHC I and impeding peptide rebinding. The scoop loop thereby acts as an additional selectivity filter in shaping the repertoire of presented peptide epitopes and the formation of a hierarchical immune response., Competing Interests: LS, FH, CT, RT No competing interests declared, (© 2020, Sagert et al.)

Background: An increasing number of studies have been published recently on the association between ambient air pollution (AP) and incident diabetes mellitus (DM), but studies investigating source-specific AP toxicity and potential mediating pathways are rare. We investigated the associations of all-source, traffic-specific, and industry-specific outdoor AP exposure with 10-year incidence of DM and potential mediation via inflammation-associated biomarkers., Methods: Data from participants of the prospective Heinz Nixdorf Recall cohort study who attended the baseline (t 0 ; 2000-2003), 5-year follow-up (t 1 ; 2006-2008), and 10-year follow-up (t 2 ; 2011-2015) examinations was used. For participants without DM at baseline (determined using information on physician diagnosis and glucose-lowering medication), residential long-term exposure (total, traffic-specific, and industry-specific) to particulate matter (PM 2.5 , PM 10 ), nitrogen dioxide (NO 2 ), and accumulation mode particle number concentration (PN AM ) were estimated using a chemistry transport model. Covariate-adjusted modified Poisson regression models with robust standard errors were applied to estimate relative risks (RR) for the associations between baseline AP and incident DM at t 2 . Mediation analyses for adiponectin, high-sensitivity C-reactive protein (hsCRP), and interleukin-1 receptor antagonist (IL-1RA) were conducted to estimate natural direct and indirect effects., Results: Of the 4,814 participants at t 0 , 2,451 participants (mean baseline age: 58.2 years) were included in the main analysis. Interquartile range (IQR) increases in total PM 10 and PN AM were associated with increased risk of DM (e.g., RR: 1.25 [95% Confidence Interval (CI): 1.02, 1.53] per 3.8 µg/m 3 PM 10 ). Whereas traffic-specific exposures were associated with DM risk for all air pollutants (e.g., RR: 1.24 [95% CI: 1.06, 1.46] per 0.3 µg/m 3 PM 10 ), significant associations for industry exposures were limited to NO 2 and PN AM (e.g., RR: 1.24 [95% CI: 1.03, 1.49] per 230 particles/mL PN AM ). Potential mediation of the association between AP and DM was observed for adiponectin but not for hsCRP and IL-1RA., Conclusion: Our study shows that long-term exposure to total and source-specific ambient AP may increase DM risk, with consistent results observed across traffic-specific exposures. Decreases in adiponectin may play a potential role along the causal pathway., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Pathogenic variants in the X-linked gene ZC4H2, which encodes a zinc-finger protein, cause an infrequently described syndromic form of arthrogryposis multiplex congenita (AMC) with central and peripheral nervous system involvement. We present genetic and detailed phenotypic information on 23 newly identified families and simplex cases that include 19 affected females from 18 families and 14 affected males from nine families. Of note, the 15 females with deleterious de novo ZC4H2 variants presented with phenotypes ranging from mild to severe, and their clinical features overlapped with those seen in affected males. By contrast, of the nine carrier females with inherited ZC4H2 missense variants that were deleterious in affected male relatives, four were symptomatic. We also compared clinical phenotypes with previously published cases of both sexes and provide an overview on 48 males and 57 females from 42 families. The spectrum of ZC4H2 defects comprises novel and recurrent mostly inherited missense variants in affected males, and de novo splicing, frameshift, nonsense, and partial ZC4H2 deletions in affected females. Pathogenicity of two newly identified missense variants was further supported by studies in zebrafish. We propose ZC4H2 as a good candidate for early genetic testing of males and females with a clinical suspicion of fetal hypo-/akinesia and/or (neurogenic) AMC., (© 2019 Wiley Periodicals, Inc.)

Objectives: Particulate air pollution is linked to adverse cardiovascular effects, including arterial stiffness. The aim of the study was to investigate the effect of short-term exposure to indoor fine and ultrafine particles on augmentation index (AIx), augmentation pressure (AP), and pulse wave velocity (PWV), early signs of vascular damage., Methods: We analyzed the association of particle emissions from typical indoor sources (candle burning - CB, toasting bread - TB, and frying sausages - FS) with changes in pulse wave analysis indices in 55 healthy adults in a randomized cross-over controlled exposure study. Particle mass concentration (PMC), size-specific particle number concentration (PNC) and lung-deposited particle surface area concentration (PSC) were measured during the 2 h exposure. AIx and AP were measured before, directly, 2, 4 and 24 h after exposure. PWV was measured directly and 24 h after exposure. We performed multiple mixed linear regression analyses of different particle metrics and AIx, AP and PWV., Results: The highest mean PMC was observed during FS reaching a maximum of 210 μg/m 3 PM 10 . The maximal PNC for UFP <100 nm was reached during CB with 2.3 million particles/cm 3 . PSC was similar across all three exposures (about 3000 μm 2 /cm³). Strongest associations between different particles metrics and arterial stiffness indices could be observed for UFP from CB and FS and for PMC from TB. The highest mean increase could be observed for the UFP fraction <10 nm, measured during CB, and AIx with an increase of 9.5%-points (95%-CI: 3.1; 15.9). PSC seemed to follow the pattern of PNC. PM 10 and PM 2.5 from TB led to clear changes in AIx with biggest increases for PM 10 of 5.8%-points (95%-CI: 3.2; 8.4) 2 h after exposure and for PM 2.5 of 8.1%-points (95%-CI: 2.5; 13.7) directly after exposure., Conclusions: Our study indicates effects of indoor exposure to fine and ultrafine particles on systemic arterial stiffness indices that depend on the indoor source as well as on particle metric. Differences in size-specific physical characteristics of source-specific particles might account for these differential effects. We did not observe clear and stable associations of indoor particle exposure and PWV., (Copyright © 2019. Published by Elsevier GmbH.)

Myeloid cells are important sites of lytic and latent infection by human cytomegalovirus (CMV). We previously showed that only a small subset of myeloid cells differentiated from CD34 + hematopoietic stem cells is permissive to CMV replication, underscoring the heterogeneous nature of these populations. The exact identity of resistant and permissive cell types, and the cellular features characterizing the latter, however, could not be dissected using averaging transcriptional analysis tools such as microarrays and, hence, remained enigmatic. Here, we profile the transcriptomes of ∼7000 individual cells at day 1 post-infection using the 10× genomics platform. We show that viral transcripts are detectable in the majority of the cells, suggesting that virion entry is unlikely to be the main target of cellular restriction mechanisms. We further show that viral replication occurs in a small but specific sub-group of cells transcriptionally related to, and likely derived from, a cluster of cells expressing markers of Colony Forming Unit - Granulocyte, Erythrocyte, Monocyte, Megakaryocyte (CFU-GEMM) oligopotent progenitors. Compared to the remainder of the population, CFU-GEMM cells are enriched in transcripts with functions in mitochondrial energy production, cell proliferation, RNA processing and protein synthesis, and express similar or higher levels of interferon-related genes. While expression levels of the former are maintained in infected cells, the latter are strongly down-regulated. We thus propose that the preferential infection of CFU-GEMM cells may be due to the presence of a pre-established pro-viral environment, requiring minimal optimization efforts from viral effectors, rather than to the absence of specific restriction factors. Together, these findings identify a potentially new population of myeloid cells permissive to CMV replication, and provide a possible rationale for their preferential infection.

Background: While prior studies have linked air pollution (AP) to diabetes prevalence and incidence, few have investigated whether AP exposure is also associated with alterations in diabetes-related biomarkers in metabolically healthy adults., Objective: To evaluate the associations between short-, medium-, and long-term AP and diabetes-related biomarkers (adiponectin, interleukin-1 receptor antagonist [IL-1RA], high sensitivity C-reactive protein [hsCRP], fibrinogen) in persons without diabetes., Methods: Adiponectin, IL-1RA, hsCRP, and fibrinogen were measured in blood samples collected at the baseline (t 0 ; 2000-2003) and first follow-up (t 1 ; 2006-2008) examinations of the prospective Heinz Nixdorf Recall (HNR) cohort study in Germany. Participants' residential mean exposures to PM 10 , PM 2.5 , NO 2 , and accumulation mode particle number concentration (PN AM ) were estimated for several time windows (1- to 365-day) prior to examination using a dispersion and chemistry transport model. We fitted covariate-adjusted linear mixed effects models using a random participant intercept and investigated effect modification by obesity status., Results: We analyzed 6727 observations (n t0  = 3626, n t1  = 3101) from 4052 participants of the HNR study (52% women; ages 45-76 years at t 0 ). For all air pollutants, medium-term exposures (60- to 120-day) were negatively associated with adiponectin (e.g., 91-day PN AM : -2.51% change [-3.40%, -1.53%] per interquartile [IQR] increase). Several short-, medium-, and long-term AP exposures were positively associated with IL-1RA (e.g., 365-day PM 10 : 2.64% change [1.25%, 4.22%] per IQR increase). Long-term exposures were positively associated with hsCRP level while no consistent patterns were observed for fibrinogen. Stronger associations for adiponectin were observed among non-obese participants., Conclusion: In persons without diabetes, we observed differing patterns of association between AP and diabetes-related biomarkers across a range of exposure windows, supporting the hypothesis that AP may play a role in the development of diabetes., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Road traffic noise affects a large number of people in urbanized areas. Recent epidemiological evidence indicates that environmental noise exposure may not only be associated with cardiovascular but also with cardio-metabolic outcomes. This prospective cohort study investigated the effect of outdoor and indoor residential road traffic noise on incident type 2 diabetes mellitus (T2DM)., Methods: We used data from 3,396 participants of age 45-75 years of the Heinz Nixdorf Recall study being non-diabetic at baseline (2000-2003). T2DM was defined via blood glucose level, incident intake of an anti-diabetic drug during follow-up or self-reported physician diagnosis at follow-up examination (2005-2008). Weighted 24-h (L den ) and night-time (L night ) mean road traffic noise was assessed according to the European Union directive 2002/49/EC. Road traffic noise exposure indoors was modeled taking into account the participants' room orientation, ventilation behavior and window insulation (n = 2,697). We applied Poisson regression analyses to estimate relative risks (RRs) of incident T2DM, adjusting for demographic characteristics, lifestyle factors, and air pollution exposure (NO 2 or PM 2.5 )., Results: A 10-dB(A) increase in outdoor road traffic noise (L den ) was associated with an RR of 1.09 (95% confidence interval, 0.96-1.24) for T2DM in the fully adjusted model. Models including PM 2.5 or NO 2 yielded RRs of 1.09 (0.96-1.24) and 1.11 (0.97-1.27), respectively. In analyses with road traffic noise (L den ) exposure indoors, we observed similar RRs with smaller confidence intervals (1.11 [1.01-1.21])., Conclusions: Our analyses suggest that long-term exposure to indoor and outdoor road traffic noise may increase the risk of developing T2DM, independent of air pollution exposure., Competing Interests: The authors declare that they have no conflicts of interest with regard to the content of this report., (Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of Environmental Epidemiology. All rights reserved.)

Background: Temporary mechanical circulatory support (MCS) offers a valuable option for treatment of refractory heart failure. We present our experience with selected MCS devices in cardiogenic shock of different etiologies., Methods: We retrospectively studied patients who were treated in our institution between 01/2016 and 07/2018. Patients receiving only veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support were excluded. Left ventricular support patients received Impella; right ventricular support was conducted using Levitronix CentriMag., Results: Thirty-seven patients received an Impella left ventricular assist device (LVAD). Etiology was: acute on chronic ischemic cardiomyopathy (ICMP; n=12), acute myocardial infarction (AMI; n=11), dilated cardiomyopathy (DCMP; n=7) and toxic cardiomyopathy (TCMP; n=2). Two patients presented with postcardiotomy shock and acute myocarditis, respectively. In one case, Takotsubo cardiomyopathy was diagnosed. Impella was used solely in 28 patients (Impella group) with an in-hospital survival of 37%. In nine patients, Impella was used in combination with extracorporeal life support (ECLS) implantation (ECMELLA group)-in-hospital survival was 33%. In the Impella group six patients recovered, six received a long-term VAD and 16 died on device. In the ECMELLA group one patient recovered, three received a long-term VAD and five died. The majority of CentriMag implantations as a right ventricular assist device (RVAD) were necessary after LVAD implantation (n=52); of these patients, 14 recovered, eight received long-term VAD and 30 died. The remaining 17 patients were supported by RVAD due to AMI (n=7); postcardiotomy (n=7); right heart failure after heart transplantation (n=2) and ICMP (n=1). Six of these patients recovered, two required long-term VAD and nine died., Conclusions: Survival after MCS implantation for left as well as right heart failure in cardiogenic shock remains low, but is superior to that of patients without mechanical support. Short-term MCS remains an option of choice if right, left or biventricular support is needed., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: Fractures of the anterior chest wall are rare among the total number of fractures. They include sternal fractures (SF) and the adjacent cartilaginous structures of the ribs. The accident mechanism can allow conclusions to be drawn about which further accompanying injuries may be present, e.g. rib and spinal fractures., Objective: The present work is intended to give an overview of injuries of the anterior chest wall. It includes clinical aspects as well as imaging and popular literature., Material and Methods: Included are injury constellations of the anterolateral chest wall, in particular of the sternum in combination with injuries of the spinal column in the sense of a sternovertebral injury (SVI). Possible treatment strategies were reviewed and the corresponding advantages and disadvantages are presented., Results: In symptomatic fractures of the anterior chest wall, their operative stabilization should be considered in order to restore the stability of the trunk. In addition, rib fractures in direct trauma and spinal injuries in indirect trauma are often included in the treatment., Conclusion: In the case of injuries of the thoracic trunk, this must always be regarded as a unit and must therefore be clarified in the context of the clinical examination and diagnostic apparatus. The possible accident mechanism can allow conclusions to be drawn about possible injury patterns, e.g. in the sense of SVIs.

Background: Combinations of sternal and spinal fractures often occur due to high velocity accidents and are associated with a high incidence of concomitant injuries. The anterior thoracic wall is described as the fourth column of torso stability, which is why sternovertebral injuries (SVI) present a high risk of sagittal deformation of the trunk, in particular injuries of the thoracic spine. To date, no studies have been published on the frequency distribution of the involved vertebral bodies in large patient groups., Objectives: This study was intended to elaborate a frequency distribution of vertebral fractures accompanying sternal fractures (SF) and examine the risk of a vertebral fracture accompanying a SF., Material and Methods: A total of 48,193 cases with the main or secondary diagnosis of a SF and 897,963 cases with vertebral fractures based on routine data of German hospitals from the years 2005-2012 were evaluated. A concomitant injury to the spinal column was examined for each vertebral body and then evaluated statistically., Results and Conclusions: Of all patients with a SF 30.96% also suffered from a vertebral fracture. Of these 3.11% were SF as the main diagnosis and 60.89% the secondary diagnosis. While vertebral fractures generally occurred most frequently in the region of the thoracolumbar transition and the second cervical vertebral body, the SVI showed a further frequency peak in the range from the lower cervical spine to the middle thoracic spine. The present study was able to show a frequency distribution of accompanying vertebral body injuries in a large and representative collective in the case of SF for the first time.

Background: Flail chest wall injuries (FCI) are common in younger patients due to high-speed trauma and in older patients due to low-energy trauma or falls from a low height. They show a high incidence of concomitant injuries and are therefore associated with high morbidity and mortality. If there is also an ipsilateral clavicular fracture (CF), the outcome is significantly poorer. The skeleton of the shoulder and chest loses stability and can lead to a loss of function of the shoulder and a pronounced deformation of the chest wall., Objective: This article shows the origin and clinical importance of FCI. What importance does a concomitant ipsilateral CF have and how can these costoclavicular injuries (CCI) be managed conservatively and operatively?, Material and Methods: After primary emergency care of the patients with appropriate diagnostics, in the presence of CCI operative stabilization was carried out by means of locked plate osteosynthesis of the clavicle and the affected ribs via minimally invasive approaches with the patient under general anesthesia. Patients were followed up postoperatively. Various minimally invasive posterolateral approaches to the chest wall were previously performed in a corpse study and then put into practice., Results and Conclusion: This study presents therapeutic options for the reconstruction of the chest wall based on the established literature and clinical examples. An ipsilateral CF combined with fractures of the 2nd-4th ribs can be treated through an innovative clavipectoral approach. For the other fractures, standard approaches to the anterolateral and posterolateral chest wall are performed, which are associated with a good outcome in clinical practice. An operative stabilization should be performed at the latest when FCI or CCI together with a dislocating fracture and a marked deformation of the thoracic wall are present. Remaining misalignments are associated with a simultaneous loss of function of the chest wall and shoulder.

Introduction: Recently, epidemiological studies have found a link between air pollution (AP) and individual components of the metabolic syndrome (MetS), a condition predisposing to cardiometabolic diseases. However, very few studies have explored a possible association between air pollution and MetS., Objective: We analyzed the effects of long-term exposure to airborne particulate matter and NO 2 on prevalence and incidence of MetS., Methods: We used data of the population-based prospective Heinz Nixdorf Recall study (baseline 2000-2003) to investigate the association(s) between AP exposure and MetS prevalence at baseline (n = 4457) and MetS incidence at first follow-up visit (n = 3074; average follow-up: 5.1 years). Mean annual exposure to size-fractioned particulate matter (PM 10 , PM 2.5 , PM coarse , and PM 2.5 abs) and nitrogen dioxide (NO 2 ) was assessed using a land use regression model. MetS was defined as central obesity plus two out of four additional risk factors (i.e., elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure or elevated plasma glucose). We estimated odds ratios (ORs) of MetS prevalence and incidence per interquartile range (IQR) of exposure, adjusting for demographic and lifestyle variables., Results: We observed a MetS prevalence of 20.7% (n = 922) and an incidence of 9.7% (n = 299). NO 2 was positively associated with MetS prevalence, with an OR increase per IQR of 1.12 (95%-CI 1.02-1.24, IQR = 6.1 μg/m 3 ). PM 10 and PM 2.5 were both borderline positively associated with MetS incidence, with ORs of 1.14 (95%-CI 0.99-1.32, IQR = 2.1 μg/m 3 ) and 1.19 (95%-CI 0.98-1.44, IQR = 1.5 μg/m 3 ) per IQR, respectively., Conclusion: In summary, we found a weak positive association between air pollution and MetS. The strongest and most consistent effects were observed between NO 2 and prevalent MetS., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Although epidemiological studies have reported associations between mortality and both ambient air pollution and air temperature, it remains uncertain whether the mortality effects of air pollution are modified by temperature and vice versa. Moreover, little is known on the interactions between ultrafine particles (diameter ≤ 100 nm, UFP) and temperature., Objective: We investigated whether the short-term associations of particle number concentration (PNC in the ultrafine range (≤100 nm) or total PNC ≤ 3000 nm, as a proxy for UFP), particulate matter ≤ 2.5 μm (PM 2.5 ) and ≤ 10 μm (PM 10 ), and ozone with daily total natural and cardiovascular mortality were modified by air temperature and whether air pollution levels affected the temperature-mortality associations in eight European urban areas during 1999-2013., Methods: We first analyzed air temperature-stratified associations between air pollution and total natural (nonaccidental) and cardiovascular mortality as well as air pollution-stratified temperature-mortality associations using city-specific over-dispersed Poisson additive models with a distributed lag nonlinear temperature term in each city. All models were adjusted for long-term and seasonal trend, day of the week, influenza epidemics, and population dynamics due to summer vacation and holidays. City-specific effect estimates were then pooled using random-effects meta-analysis., Results: Pooled associations between air pollutants and total and cardiovascular mortality were overall positive and generally stronger at high relatively compared to low air temperatures. For example, on days with high air temperatures (>75th percentile), an increase of 10,000 particles/cm 3 in PNC corresponded to a 2.51% (95% CI: 0.39%, 4.67%) increase in cardiovascular mortality, which was significantly higher than that on days with low air temperatures (<25th percentile) [-0.18% (95% CI: -0.97%, 0.62%)]. On days with high air pollution (>50th percentile), both heat- and cold-related mortality risks increased., Conclusion: Our findings showed that high temperature could modify the effects of air pollution on daily mortality and high air pollution might enhance the air temperature effects., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Despite the importance of understanding the connection between air pollution exposure and diabetes, studies investigating links between air pollution and glucose metabolism in nondiabetic adults are limited., Objective: We aimed to estimate the association of medium-term air pollution exposures with blood glucose and glycated hemoglobin A1c (HbA1c) among nondiabetics., Methods: This study included observations from nondiabetic participants (n obs =7,108) of the population-based Heinz Nixdorf Recall study at baseline (2000–2003) and follow-up examination (2006–2008). Daily fine particulate matter (aerodynamic diameter≤2.5 μm, PM 2.5 ; aerodynamic diameter≤10 μm, PM 10 ), accumulation mode particle number (PN AM ), and nitrogen dioxide (NO 2 ) exposures were estimated at participants’ residences using the spatiotemporal European Air Pollution Dispersion (EURAD) chemistry transport model. We evaluated the associations between medium-term air pollution exposures (28- and 91-d means) and glucose metabolism measures using mixed linear regression and adjusting for season, meteorology, and personal characteristics. A range of other exposure windows (1-, 2-, 3-, 7-, 14-, 45-, 60-, 75-, 105-, 120-, and 182-d means) were also evaluated to identify potentially relevant biological windows., Results: We observed positive associations between PM 2.5 and PN AM exposures and blood glucose levels [e.g., 28-d PM 2.5 : 0.91 mg/dL (95% CI: 0.38, 1.44) per 5.7 μg/m 3 ]. PM 2.5 , PM 10 , and PN AM exposures were positively associated with HbA1c [e.g., 91-d PM 2.5 : 0.07 p.p. (95% CI: 0.04, 0.10) per 4.0 μg/m 3 ]. Mean exposures during longer exposure windows (75- to 105-d) were most strongly associated with HbA1c, whereas 7- to 45-d exposures were most strongly associated with blood glucose. NO 2 exposure was not associated with blood glucose or with HbA1c., Conclusions: Medium-term PM and PN AM exposures were positively associated with glucose measures in nondiabetic adults. These findings indicate that reducing ambient air pollution levels may decrease the risk of diabetes. https://doi.org/10.1289/EHP2561.

Background: Although epidemiologic studies have shown associations between particle mass and daily mortality, evidence on other particle metrics is weak., Objectives: We investigated associations of size-specific particle number concentration (PNC) and lung-deposited particle surface area concentration (PSC) with cause-specific daily mortality in contrast to PM 10 ., Methods: We used time-series data (March 2009-December 2014) on daily natural, cardiovascular, and respiratory mortality (NM, CVM, RM) of three adjacent cities in the Ruhr Area, Germany. Size-specific PNC (electric mobility diameter of 13.3-750 nm), PSC, and PM 10 were measured at an urban background monitoring site. In single- and multipollutant Poisson regression models, we estimated percentage change (95% confidence interval) [% (95% CI)] in mortality per interquartile range (IQR) in exposure at single-day (0-7) and aggregated lags (0-1, 2-3, 4-7), accounting for time trend, temperature, humidity, day of week, holidays, period of seasonal population decrease, and influenza., Results: PNC 100-750 and PSC were highly correlated and had similar immediate (lag0-1) and delayed (lag4-7) associations with NM and CVM, for example, 1.12% (95% CI: 0.09, 2.33) and 1.56% (95% CI: 0.22, 2.92) higher NM with IQR increases in PNC 100-750 at lag0-1 and lag4-7, respectfully, which were slightly stronger then associations with IQR increases in PM 10 . Positive associations between PNC and NM were strongest for accumulation mode particles (PNC 100-500 nm), and for larger UFPs (PNC 50-100 nm). Associations between NM and PNC <100 changed little after adjustment for O 3 or PM 10 , but were more sensitive to adjustment for NO 2 ., Conclusion: Size-specific PNC (50-500 nm) and lung-deposited PSC were associated with natural and cardiovascular mortality in the Ruhr Area. Although associations were similar to those estimated for an IQR increase in PM 10 , particle number size distributions can be linked to emission sources, and thus may be more informative for potential public health interventions. Moreover, PSC could be used as an alternative metric that integrates particle size distribution as well as deposition efficiency. https://doi.org/10.1289/EHP2054.

Background: Accumulating evidence suggests serum levels of microRNA (miR)-371a-3p to be a novel tumour marker of testicular germ cell tumours (GCTs). Presently, there is only limited information regarding the velocity of decline of serum levels in response to treatment., Patients and Methods: Twenty-four patients with testicular GCT (20 seminoma, 4 nonseminoma, median age 40 years) with clinical stage 1 had measurements of serum levels of miR-371a-3p preoperatively and repeatedly on the following 3 days. Three had additional tests done within 24 h after surgery. Measurement results were analysed using descriptive statistical methods., Results: Serum levels dropped to 2.62, 1.27, and 0.47% of the preoperative level within 1, 2, and 3 days, respectively. The computed half-life amounts to 3.7-7 h. The velocity of decay is significantly associated with tumour size., Conclusions: Serum-levels of miR-371a-3p have a short half-life of less than 12 h. The rapid decay after treatment represents a valuable feature confirming the usefulness of miR-371a-3p as a valuable serum biomarker of GCT., (© 2018 S. Karger AG, Basel.)

Objective: To provide new insights into the interpretation of genetic variants in a rare neurologic disorder, CDKL5 deficiency, in the contexts of population sequencing data and an updated characterization of the CDKL5 gene., Methods: We analyzed all known potentially pathogenic CDKL5 variants by combining data from large-scale population sequencing studies with CDKL5 variants from new and all available clinical cohorts and combined this with computational methods to predict pathogenicity., Results: The study has identified several variants that can be reclassified as benign or likely benign. With the addition of novel CDKL5 variants, we confirm that pathogenic missense variants cluster in the catalytic domain of CDKL5 and reclassify a purported missense variant as having a splicing consequence. We provide further evidence that missense variants in the final 3 exons are likely to be benign and not important to disease pathology. We also describe benign splicing and nonsense variants within these exons, suggesting that isoform hCDKL5&#95;5 is likely to have little or no neurologic significance. We also use the available data to make a preliminary estimate of minimum incidence of CDKL5 deficiency., Conclusions: These findings have implications for genetic diagnosis, providing evidence for the reclassification of specific variants previously thought to result in CDKL5 deficiency. Together, these analyses support the view that the predominant brain isoform in humans (hCDKL5&#95;1) is crucial for normal neurodevelopment and that the catalytic domain is the primary functional domain.