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Software development for applications in computational science and engineering has become complex in recent years. This is mainly due to the increasing parallelism and heterogeneity in modern computer architectures and to the more realistic physical and mathematical models that have to be processed. One idea to address this issue is to use code generation techniques. In contrast to manual implementations in a general-purpose computing language, they allow to integrate automatic code transforms to produce efficient code for different models and platforms. As an example the numerical solution of an elliptic partial differential equation via generated geometric multigrid solvers is considered. We present three code generation approaches for it and discuss their advantages and disadvantages with respect to performance, portability, and productivity.

Nanoparticles (NP) have specific catalytic properties, which are influenced by parameters like their size, shape, or composition. Bimetallic NPs, composed of two metal elements can show an improved catalytic activity compared to the monometallic NPs. We, herein, report on the selective aerobic oxidation of benzyl alcohol catalyzed by unsupported Pd/Au and Pd NPs at atmospheric pressure. NPs of varying compositions were synthesized and characterized by UV/Vis spectroscopy, transmission electron microscopy (TEM), and small-angle X-ray scattering (SAXS). The NPs were tested in the model reaction regarding their catalytic activity, stability, and recyclability in batch and continuous procedure. Additionally, in situ extended X-ray absorption fine structure (EXAFS) measurements were performed in order to get insight in the process during NP catalysis.

Ultrafast spectroscopy on a series of Fe(II) complexes finds an increase of the 3MLCT lifetime with increasing number of N-heterocyclic carbene (NHC) donor functions revealing a promising route for the design of Fe photosensitizers.

The paper presents the problem of pedestrian safety at stops, with stops designed for opposite directions. Stop areas with a predominantly pedestrian traffic, where pedestrians cross tram tracks, are not protected by traffic signals. The article presents a method for conducting a study to identify types of pedestrian and tram driver behaviour, developed on the basis of a pilot study. This method helps to evaluate, inter alia, the tendency of pedestrians to risk going across the tram track before an oncoming tram, depending on how far it is from the pedestrian crossing. It also helps to determine the probability of the tram slowing down or emergency braking when crossing the pedestrian crossing, and the probability of difficulties with the departure of the tram, caused by pedestrians.

Abstract Background The i-gel™, LMA-Supreme (LMA-S) and Laryngeal Tube Suction-D (LTS-D) are single-use supraglottic airway devices with an inbuilt drainage channel. We compared them with regard to their position in situ as well as to clinical performance data during elective surgery. Methods Prospective, randomized, comparative study of three groups of 40 elective surgical patients each. Speed of insertion and success rates, leak pressures (LP) at different cuff pressures, dynamic airway compliance, and signs of postoperative airway morbidity were recorded. Fibreoptic evaluation was used to determine the devices’ position in situ. Results Leak pressures were similar (i-gel™ 25.9, LMA-S 27.1, LTS-D 24.0 cmH2O; the latter two at 60 cmH2O cuff pressure) as were insertion times (i-gel™ 10, LMA-S 11, LTS-D 14 sec). LP of the LMA-S was higher than that of the LTS-D at lower cuff pressures (p p p <0.05). Airway morbidity was more pronounced with the LTS-D (p <0.01). Conclusion All devices were suitable for ventilating the patients’ lungs during elective surgery. Trial registration German Clinical Trial Register DRKS00000760

Abstract Background Breast cancer treatment is based on a combination of adjuvant chemotherapy followed by radiotherapy effecting intracellular signal transduction. With the tyrosine kinase inhibitors new targeted drugs are available. Imatinib mesylate is a selective inhibitor of bcr-abl, PRGFR alpha, beta and c-kit. The purpose of this study was to determine whether Imatinib has an influence on the effectiveness of radiotherapy in breast cancer cell lines and if a combination of imatinib with standard chemotherapy could lead to increased cytoreduction. Methods Colony-forming tests of MCF 7 and MDA MB 231 were used to study differences in cell proliferation under incubation with imatinib and radiation. Changes in expression and phosphorylation of target receptors were detected using western blot. Cell proliferation, migration and apoptosis assays were performed combining imatinib with doxorubicin. Results The combination of imatinib and radiotherapy showed a significantly stronger inhibition of cell proliferation compared to single radiotherapy. Differences in PDGFR expression could not be detected, but receptor phosphorylation was significantly inhibited when treated with imatinib. Combination of imatinib with standard chemotherapy lead to an additive effect on cell growth inhibition compared to single treatment. Conclusions Imatinib treatment combined with radiotherapy leads in breast cancer cell lines to a significant benefit which might be influenced through inhibition of PDGFR phosphorylation. Combining imatinib with chemotherapy enhances cytoreductive effects. Further in vivo studies are needed to evaluate the benefit of Imatinib in combination with radiotherapy and chemotherapy on the treatment of breast cancer.

Abstract Background Occult organizational structures in DNA sequences may hold the key to understanding functional and evolutionary aspects of the DNA molecule. Such structures can also provide the means for identifying and discriminating organisms using genomic data. Species specific genomic signatures are useful in a variety of contexts such as evolutionary analysis, assembly and classification of genomic sequences from large uncultivated microbial communities and a rapid identification system in health hazard situations. Results We have analyzed genomic sequences of eukaryotic and prokaryotic chromosomes as well as various subtypes of viruses using an information theoretic framework. We confirm the existence of a species specific average mutual information (AMI) profile. We use these profiles to define a very simple, computationally efficient, alignment free, distance measure that reflects the evolutionary relationships between genomic sequences. We use this distance measure to classify chromosomes according to species of origin, to separate and cluster subtypes of the HIV-1 virus, and classify DNA fragments to species of origin. Conclusion AMI profiles of DNA sequences prove to be species specific and easy to compute. The structure of AMI profiles are conserved, even in short subsequences of a species' genome, rendering a pervasive signature. This signature can be used to classify relatively short DNA fragments to species of origin.

Abstract Background We describe the use of a conceptual framework and implementation protocol to prepare effective health services interventions for implementation in community-based (i.e., non-academic-affiliated) settings. Methods The framework is based on the experiences of the U.S. Centers for Disease Control and Prevention (CDC) Replicating Effective Programs (REP) project, which has been at the forefront of developing systematic and effective strategies to prepare HIV interventions for dissemination. This article describes the REP framework, and how it can be applied to implement clinical and health services interventions in community-based organizations. Results REP consists of four phases: pre-conditions (e.g., identifying need, target population, and suitable intervention), pre-implementation (e.g., intervention packaging and community input), implementation (e.g., package dissemination, training, technical assistance, and evaluation), and maintenance and evolution (e.g., preparing the intervention for sustainability). Key components of REP, including intervention packaging, training, technical assistance, and fidelity assessment are crucial to the implementation of effective interventions in health care. Conclusion REP is a well-suited framework for implementing health care interventions, as it specifies steps needed to maximize fidelity while allowing opportunities for flexibility (i.e., local customizing) to maximize transferability. Strategies that foster the sustainability of REP as a tool to implement effective health care interventions need to be developed and tested.

Abstract Background The discovery of functional non-coding RNA sequences has led to an increasing interest in algorithms related to RNA analysis. Traditional sequence alignment algorithms, however, fail at computing reliable alignments of low-homology RNA sequences. The spatial conformation of RNA sequences largely determines their function, and therefore RNA alignment algorithms have to take structural information into account. Results We present a graph-based representation for sequence-structure alignments, which we model as an integer linear program (ILP). We sketch how we compute an optimal or near-optimal solution to the ILP using methods from combinatorial optimization, and present results on a recently published benchmark set for RNA alignments. Conclusion The implementation of our algorithm yields better alignments in terms of two published scores than the other programs that we tested: This is especially the case with an increasing number of input sequences. Our program LARA is freely available for academic purposes from http://www.planet-lisa.net.

Abstract Background The chromosome 22q11 region is proposed as a major candidate locus for susceptibility genes to schizophrenia. Recently, the gene ZDHHC8 encoding a putative palmitoyltransferase at 22q11 was proposed to increase liability to schizophrenia based on both animal models and human association studies by significant over-transmission of allele rs175174A in female, but not male subjects with schizophrenia. Methods Given the genetic complexity of schizophrenia and the potential genetic heterogeneity in different populations, we examined rs175174 in 204 German proband-parent triads and in an independent case-control study (schizophrenic cases: n = 433; controls: n = 186). Results In the triads heterozygous parents transmitted allele G preferentially to females, and allele A to males (heterogeneity χ2 = 4.43; p = 0.035). The case-control sample provided no further evidence for overall or gender-specific effects regarding allele and genotype frequency distributions. Conclusion The findings on rs175174 at ZDHHC8 are still far from being conclusive, but evidence for sexual dimorphism is moderate, and our data do not support a significant genetic contribution of rs175174 to the aetiopathogenesis of schizophrenia.

Abstract Background In the emerging field of environmental genomics, direct cloning and sequencing of genomic fragments from complex microbial communities has proven to be a valuable source of new enzymes, expanding the knowledge of basic biological processes. The central problem of this so called metagenome-approach is that the cloned fragments often lack suitable phylogenetic marker genes, rendering the identification of clones that are likely to originate from the same genome difficult or impossible. In such cases, the analysis of intrinsic DNA-signatures like tetranucleotide frequencies can provide valuable hints on fragment affiliation. With this application in mind, the TETRA web-service and the TETRA stand-alone program have been developed, both of which automate the task of comparative tetranucleotide frequency analysis. Availability: http://www.megx.net/tetra Results TETRA provides a statistical analysis of tetranucleotide usage patterns in genomic fragments, either via a web-service or a stand-alone program. With respect to discriminatory power, such an analysis outperforms the assignment of genomic fragments based on the (G+C)-content, which is a widely-used sequence-based measure for assessing fragment relatedness. While the web-service is restricted to the calculation of correlation coefficients between tetranucleotide usage patterns of submitted DNA sequences, the stand-alone program generates a much more detailed output, comprising all raw data and graphical plots. The stand-alone program is controlled via a graphical user interface and can batch-process a multitude of sequences. Furthermore, it comes with pre-computed tetranucleotide usage patterns for 166 prokaryote chromosomes, providing a useful reference dataset and source for data-mining. Conclusions Up to now, the analysis of skewed oligonucleotide distributions within DNA sequences is not a commonly used tool within metagenomics. With the TETRA web-service and stand-alone program, the method is now accessible in an easy to use manner for a broad audience. This will hopefully facilitate the interrelation of genomic fragments from metagenome libraries, ultimately leading to new insights into the genetic potentials of yet uncultured microorganisms.

Die wettbewerbspolitische Analyse zeigt, dass sich der vollversorgende pharmazeutische Großhandel in einem äußerst wettbewerbsintensiven Marktumfeld bewegt. Insbesondere fokussiert sich dieser Wettbewerb auf den Parameter Preis und nimmt hier z. T. ruinöse Züge an. Aufgrund spezifischer Marktgegebenheiten auf der Angebots- wie Nachfrageseite (sog. Marktversagen) können sich die Arzneimittelgroßhändler aus diesem wettbewerblichen Dilemma aus eigener Kraft nicht wirksam befreien. Im Ergebnis könnte dies dazu führen, dass die Unternehmen die Auskömmlichkeit ihres Geschäftsbetriebs absehbar nicht mehr in der Weise sicherstellen können, wie es der gesetzliche Sicherstellungs- und Versorgungsauftrag verlangt. Insofern besteht ein hohes Gemeinwohlinteresse dahin gehend, die ökonomischen Rahmenbedingungen so zu gestalten, dass sich hier ein funktionsfähiger Wettbewerb einstellen kann. Auf diesem Wege können letztlich effiziente und nachhaltige Strukturen zur Sicherstellung einer flächendeckenden Arzneimittelversorgung über und durch den vollversorgenden pharmazeutischen Großhandel gewährleistet werden. Aus der durchgeführten Analyse leitet sich daher unmittelbar ein gesundheits- und wirtschaftspolitischer Handlungsbedarf ab.

There is an emerging population of older adults living with HIV, and among them, Black older adults experience the greatest burden of the disease. This is a growing public health concern, as older adults are disproportionately diagnosed at a later stage of the disease, while reporting similar risk factors as younger adults. It has also been shown that the Black Church is well positioned to offer health screenings. Thus, this study aimed to assess HIV knowledge, beliefs, and risk behaviors of older church-affiliated Black adults. Data were collected from a sample of Black adults ( N = 543) from four predominately Black churches in Kansas City, MO. Participants were surveyed on measures assessing demographic characteristics, HIV knowledge and attitudes, and HIV testing and risk behaviors. Results indicated that compared to younger Black adults, Black older adults were less knowledgeable about the transmission of HIV and were less willing to be tested for HIV in church settings. However, there was no significant difference on the perceived seriousness of HIV in the community. Results further showed that Black older adults were less likely to use condoms/barriers during the past 6 months and over their lifetime. We discuss the implications of results for HIV intervention programs.

Tumor immune microenvironmental alterations occur early in multiple myeloma (MM) development. In this study, we aim to systematically characterize the tumor immune microenvironment (TME) and the tumor-immune interactions from precursor stages, i.e., monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), to newly diagnosed MM, comparing these to healthy donors. Using CIBERSORT, mass cytometry (CyTOF), and single-cell RNA sequencing (scRNA-Seq), we examined innate and adaptive immune changes across these stages. We found a decrease in granulocytes in the TME predicts MM outcomes. HLA-DR is reduced in CD16 + monocytes and plasmacytoid dendritic cells, while myeloid dendritic cells show decreased expression of stress and immune-response genes. NK cells and CD8 + T cells shift from a GZMK + to a GZMB + cytotoxic phenotype in the TME, with increased inhibitory markers TIM3 and TIGIT. In paired samples, the proportion and gene expression pattern in patient-specific GZMB + CD8 + T cells remain largely unchanged despite MM progression. Our findings provide a comprehensive immune landscape of MM and its precursors, offering insights into therapeutic strategies. Enhancing neutrophil and NK cell cytotoxicity, tumor antigen presentation, and CD8 + T cell versatility in precursor stages may prevent MM progression., (© 2024. The Author(s).)

Background: Low-dose CT (LDCT) is underused in Arkansas for lung cancer screening, a rural state with a high incidence of lung cancer. The objective was to determine whether offering free LDCT increased the number of high-risk individuals screened in a rural catchment area., Methods: There were 5,402 patients enrolled in screening at Highlands Oncology, a community oncology clinic in Northwest Arkansas, from 2013 to 2020. Screenings were separated into time periods: period 1 (10 months for-fee), period 2 (10 months free with targeted advertisements and primary care outreach), and period 3 (62 months free with only primary care outreach). In all, 5,035 high-risk participants were eligible for analysis based on National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Enrollment rates, incidence densities (IDs), Cox proportional hazard models, and Kaplan-Meier curves were performed to investigate differences between enrollment periods and high-risk groups., Results: Patient volume increased drastically once screenings were offered free of charge (period 1 = 4.6 versus period 2 = 66.0 and period 3 = 69.8 average patients per month). Incidence density per 1,000 person-years increased through each period (ID Period 1  = 17.2; ID Period 2  = 20.8; ID Period 3  = 25.5 cases). Cox models revealed significant differences in lung cancer risk between high-risk groups (P = .012) but not enrollment periods (P = .19). Kaplan-Meier lung cancer-free probabilities differed significantly between high-risk groups (log-rank P = .00068) but not enrollment periods (log-rank P = .18)., Conclusions: This study suggests that eligible patients are more receptive to free LDCT screening, despite most insurances not having a required copay for eligible patients., (Copyright © 2023 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

This paper presents results from the Smart Healthy Campus 2.0 study/smartphone app, developed and used to collect mental health-related lifestyle data from 86 Canadian undergraduates January-August 2021. Objectives of the study were to 1) address the absence of longitudinal mental health overview and lifestyle-related data from Canadian undergraduate students, and 2) to identify associations between these self-reported mental health overviews (questionnaires) and lifestyle-related measures (from smartphone digital measures). This was a longitudinal repeat measures study conducted over 40 weeks. A 9-item mental health questionnaire was accessible once daily in the app. Two variants of this mental health questionnaire existed; the first was a weekly variant, available each Monday or until a participant responded during the week. The second was a daily variant available after the weekly variant. 6518 digital measure samples and 1722 questionnaire responses were collected. Mixed models were fit for responses to the two questionnaire variants and 12 phone digital measures (e.g. GPS, step counts). The daily questionnaire had positive associations with floors walked, installed apps, and campus proximity, while having negative associations with uptime, and daily calendar events. Daily depression had a positive association with uptime. Daily resilience appeared to have a slight positive association with campus proximity. The weekly questionnaire variant had positive associations with device idling and installed apps, and negative associations with floors walked, calendar events, and campus proximity. Physical activity, weekly, had a negative association with uptime, and a positive association with calendar events and device idling. These lifestyle indicators that associated with student mental health during the COVID-19 pandemic suggest directions for new mental health-related interventions (digital or otherwise) and further efforts in mental health surveillance under comparable circumstances., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Brogly et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Gene expression of formalin-fixed paraffin-embedded (FFPE) tissue may serve for molecular studies on cardiovascular diseases. Chemotherapeutics, such as doxorubicin (DOX) may cause heart injury, but the mechanisms of these side effects of DOX are not well understood. This study aimed to investigate whether DOX-induced gene expression in archival FFPE heart tissue in experimental rats would correlate with the gene expression in fresh-frozen heart tissue by applying RNA sequencing technology. The results showed RNA from FFPE samples was degraded, resulting in a lower number of uniquely mapped reads. However, DOX-induced differentially expressed genes in FFPE were related to molecular mechanisms of DOX-induced cardiotoxicity, such as inflammation, calcium binding, endothelial dysfunction, senescence, and cardiac hypertrophy signaling. Our data suggest that, despite the limitations, RNA sequencing of archival FFPE heart tissue supports utilizing FFPE tissues from retrospective studies on cardiovascular disorders, including DOX-induced cardiotoxicity., Competing Interests: Declaration of Competing Interest The authors have no interests to declare., (Copyright © 2024. Published by Elsevier GmbH.)

The naturally occurring amino acid, l-ergothioneine (EGT), has immense potential as a therapeutic, having shown promise in the treatment of other disease models, including neurological disorders. EGT is naturally uptaken into cells via its specific receptor, OCTN1, to be utilized by cells as an antioxidant and anti-inflammatory. In our current study, EGT was administered over a period of 6 months to 25-26-month-old CBA/CaJ mice as a possible treatment for age-related hearing loss (ARHL), since presbycusis has been linked to higher levels of cochlear oxidative stress, apoptosis, and chronic inflammation. Results from the current study indicate that EGT can prevent aging declines of some key features of ARHL. However, we found a distinct sex difference for the response to the treatments, for hearing - Auditory Brainstem Responses (ABRs) and Distortion Product Otoacoustic Emissions (DPOAEs). Males exhibited lower threshold declines in both low dose (LD) and high dose (HD) test groups throughout the testing period and did not display some of the characteristic aging declines in hearing seen in Control animals. In contrast, female mice did not show any therapeutic effects with either treatment dose. Further confirming this sex difference, EGT levels in whole blood sampling throughout the testing period showed greater uptake of EGT in males compared to females. Additionally, RT-PCR results from three tissue types of the inner ear confirmed EGT activity in the cochlea in both males and females. Males and females exhibited significant differences in biomarkers related to apoptosis (Cas-3), inflammation (TNF-a), oxidative stress (SOD2), and mitochondrial health (PGC1a).These changes were more prominent in males as compared to females, especially in stria vascularis tissue. Taken together, these findings suggest that EGT has the potential to be a naturally derived therapeutic for slowing down the progression of ARHL, and possibly other neurodegenerative diseases. EGT, while effective in the treatment of some features of presbycusis in aging males, could also be modified into a general prophylaxis for other age-related disorders where treatment protocols would include eating a larger proportion of EGT-rich foods or supplements. Lastly, the sex difference discovered here, needs further investigation to see if therapeutic conditions can be developed where aging females show better responsiveness to EGT., Competing Interests: Declaration of competing interest The authors do not have any competing or financial interests for this article., (Copyright © 2024. Published by Elsevier B.V.)

Chronological age represents the time that passes between birth and a given date. To understand the complex network of factors contributing to chronological lifespan, a variety of model organisms have been implemented. One of the best studied organisms is the yeast Saccharomyces cerevisiae, which has greatly contributed toward identifying conserved biological mechanisms that act on longevity. Here, we discuss high- und low-throughput protocols to monitor and characterize chronological lifespan and chronological aging-associated cell death in S. cerevisiae. Included are propidium iodide staining with the possibility to quantitatively assess aging-associated cell death via flow cytometry or qualitative assessments via microscopy, cell viability assessment through plating and cell counting and cell death characterization via propidium iodide/AnnexinV staining and subsequent flow cytometric analysis or microscopy. Importantly, all of these methods combined give a clear picture of the chronological lifespan under different conditions or genetic backgrounds and represent a starting point for pharmacological or genetic interventions., (Copyright © 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Multiple myeloma (MM) growth is supported by an immune-tolerant bone marrow microenvironment. Here, we find that loss of Never in mitosis gene A (NIMA)-related kinase 2 (NEK2) in tumor microenvironmental cells is associated with MM growth suppression. The absence of NEK2 leads to both fewer tumor-associated macrophages (TAMs) and inhibitory T cells. NEK2 expression in myeloid progenitor cells promotes the generation of functional TAMs when stimulated with MM conditional medium. Clinically, high NEK2 expression in MM cells is associated with increased CD8 + T effector memory cells, while low NEK2 is associated with an IFN-γ gene signature and activated T cell response. Inhibition of NEK2 upregulates PD-L1 expression in MM cells and myeloid cells. In a mouse model, the combination of NEK2 inhibitor INH154 with PD-L1 blockade effectively eliminates MM cells and prolongs survival. Our results provide strong evidence that NEK2 inhibition may overcome tumor immune escape and support its further clinical development., Competing Interests: Declaration of interests The authors declare that they have filed for patents related to this work. M.C. and P.L.B have rights to Vκ∗MYC technology licensing. S.A.H reports receiving honorarium from Jansen and Sanofi., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: COVID-19 vaccines play a critical role in reducing the morbidity and mortality associated with SARS-CoV-2 infection and despite vaccine availability, disparities in COVID-19 vaccine uptake among Canadian subgroups exist. Community organizations are uniquely situated to relay important vaccine messaging around all vaccines, understand components of vaccine hesitancy, and facilitate vaccine uptake within the communities they serve. The objective of this research was to solicit community organizations perspectives specific to COVID-19 vaccines and explore strategies of increasing vaccine uptake within their communities., Methods: A qualitative focus group study was held in the spring of 2021 with 40 community organizations from across the country. Discussions focused on COVID-19 vaccine communication and awareness within their communities, vaccine misinformation, and strategies to increase vaccine acceptance and access. Data were analyzed utilizing thematic and inductive techniques., Results: Vaccine hesitancy was identified among staff and clients. Vaccine confidence, complacency, convenience, and mistrust in government and authorities were identified as contributors to vaccine hesitancy. Community organizations utilized innovative and novel methods to encourage vaccine uptake and increase vaccine confidence. Leveraging established trusting relationships was key to successful messaging within communities., Conclusion: Community organizations used innovative methods, built on established trust, to increase vaccine confidence within their communities and among their staff. Community agencies played an important role in COVID-19 vaccine uptake within subgroups of the Canadian population. Community organizations are key public health partners and play a critical role in increasing COVID-19 vaccine confidence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial of financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2023 Ashfield, Donelle, Uppal, Bauer and Kothari.)

Purpose: Traumatic Brain Injury (TBI) is a major cause of death and disability worldwide. Mounting evidence suggests that even mild TBI injuries, which comprise >75% of all TBIs, can cause chronic post-concussive neurological symptoms, especially when experienced repetitively (rTBI). The most common post-concussive symptoms include auditory dysfunction in the form of hearing loss, tinnitus, or impaired auditory processing, which can occur even in the absence of direct damage to the auditory system at the time of injury. The mechanism by which indirect damage causes loss of auditory function is poorly understood, and treatment is currently limited to symptom management rather than preventative care. We reasoned that secondary injury mechanisms, such as inflammation, may lead to damage of the inner ear and parts of the brain used for hearing after rTBI. Herein, we established a model of indirect damage to the auditory system induced by rTBI and characterized the pathology of hearing loss., Methods: We established a mouse model of rTBI in order to determine a timeline of auditory pathology following multiple mild injuries. Mice were subject to controlled cortical impact at the skull midline once every 48 h, for a total of 5 hits. Auditory function was assessed via the auditory brainstem response (ABR) at various timepoints post injury. Brain and cochleae were collected to establish a timeline of cellular pathology., Results: We observed increased ABR thresholds and decreased (ABR) P1 amplitudes in rTBI vs sham animals at 14 days post-impact (dpi). This effect persisted for up to 60 days (dpi). Auditory temporal processing was impaired beginning at 30 dpi. Spiral ganglion degeneration was evident at 14 dpi. No loss of hair cells was detected at this time, suggesting that neuronal loss is one of the earliest notable events in hearing loss caused by this type of rTBI., Conclusions: We conclude that rTBI results in chronic auditory dysfunction via damage to the spiral ganglion which occurs in the absence of any reduction in hair cell number. This suggests early neuronal damage that may be caused by systemic mechanisms similar to those leading to the spread of neuronal death in the brain following TBI. This TBI-hearing loss model provides an important first step towards identifying therapeutic targets to attenuate damage to the auditory system following head injury., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing financial interests or personal relationships that could have influenced the research described in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Introduction: Alterations in DNA methylation profiles have been associated with cancer, and can be influenced by environmental factors such as smoking. A small but growing literature indicates there are reproducible and robust differences in methylation levels among smokers, never smokers, and ex-smokers. Here, we compared differences in salivary DNA methylation levels among current and ex-smokers (at least 2 years abstinent)., Methods: Smokers (n=26) and ex-smokers (n=30) provided detailed smoking histories, completed the Paced Auditory Serial Addition Test (PASAT), and submitted a saliva sample. Whole-genome DNA methylation from saliva was performed, and ANCOVA models and a receiver operating characteristic (ROC) curve were used for the differences between groups and the performance of significant CpG sites., Results: After controlling for race, age, and gender, smokers had significantly lower methylation levels than ex-smokers in two CpG sites: cg05575921 (AHRR) and cg21566642 (ALPPL2). Based on the ROC analyses, both CpGs had strong classification potentials (cg05575921 AUC=0.97 and cg21566642 AUC=0.93) in differentiating smoking status. Across all subjects, the percent methylation of cg05575921 (AHRR) and cg21566642 (ALPPL2) positively correlated with the length of the last quit attempt (r=0.65 and 0.64, respectively, p<0.001) and PASAT accuracy (r=0.29 and 0.30, respectively, p<0.05)., Conclusions: In spite of the small sample size and preliminary research, our results replicate previously reported differences in AHRR hypomethylation among smokers. Furthermore, we show that the duration of smoking abstinence is associated with a recovery of methylation in ex-smokers, which may be linked to a reduced risk of smoking-associated diseases. The association with cognitive performance suggests that the hypomethylation of AHRR in saliva may reflect systemic exposure to cigarette-related toxicants that negatively affect cognitive performance, and should be validated in larger studies., Competing Interests: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors declare that they have no competing interests, financial or otherwise, related to the current work. M. Addicott reports that since the initial planning of the work, support for the present manuscript has been received from NIH NIDA R21 DA045970 (PI: Addicott), NIGMS P20 GM109005 (PL: Hsu), and Winthrop P. Rockefeller Cancer Institute Shared Resource Voucher Award. She also reports that in the past 36 months, she has received the following Grants: NIAAA R01 AA027705 Addicott (MPI), NIDA R01 DA048948-01 Addicott (PI), NIDA R21 DA055426 Addicott (MPI), NIDA R21 DA053393 Addicott (PI), and NIDA R01 DA044471. P.C. Hsu reports that since the initial planning of the work, support for the present manuscript has been received from the National Institute of General Medical Sciences [P20 GM109005 (PI/PL: Boerma/Hsu)]. She also reports that in the past 36 months, she has had the role of the Secretary at the Metabolomics Quality Assurance and quality Control Consortium (mQACC)., (© 2023 Hsu P.C. et al.)

Background: Trauma is the leading cause of death among persons aged 1-44 years. Trauma recidivism occurs when an individual experiences more than one significant injury in a 5-year period. The relationship between a trauma recidivist's perception of recurrent injury has been unclear., Objective: To describe the association between select sociodemographic and clinical variables, threat orientation, and the perceived likelihood of recurrent injury of individuals recently experiencing a significant injury., Methods: A prospective cross-sectional study was conducted with Level II trauma inpatients ( n = 84) in Southern California from October 2021 to January 2022. Participants completed surveys prior to discharge. Clinical variables were extracted from the electronic health record., Results: The trauma recidivism rate was 31%. Mental illness and length of hospital stay were associated with trauma recidivism. In individuals with two or more mental illness diagnoses, the odds of trauma recidivism were approximately 6.5 times higher than in those with no mental illness (odds ratio = 6.48, 95% confidence interval: 1.7-24.6)., Conclusion: Trauma is a preventable health care concern with timely recognition of risk factors and intervention. This study confirms mental illness as a predominant factor in injury and should be addressed in clinical practice. This study builds upon previous research and emphasizes the necessity of targeting injury prevention and education in the mentally ill. Trauma providers seeking to practice with an upstream mentality have a responsibility in screening patients for mental illness to help prevent further injury and death., Competing Interests: The authors have no conflicts of interest or funding to declare., (Copyright © 2023 Society of Trauma Nurses.)

Deciphering Multiple Myeloma evolution in the whole bone marrow is key to inform curative strategies. Here, we perform spatial-longitudinal whole-exome sequencing, including 140 samples collected from 24 Multiple Myeloma patients during up to 14 years. Applying imaging-guided sampling we observe three evolutionary patterns, including relapse driven by a single-cell expansion, competing/co-existing sub-clones, and unique sub-clones at distinct locations. While we do not find the unique relapse sub-clone in the baseline focal lesion(s), we show a close phylogenetic relationship between baseline focal lesions and relapse disease, highlighting focal lesions as hotspots of tumor evolution. In patients with ≥3 focal lesions on positron-emission-tomography at diagnosis, relapse is driven by multiple distinct sub-clones, whereas in other patients, a single-cell expansion is typically seen (p < 0.01). Notably, we observe resistant sub-clones that can be hidden over years, suggesting that a prerequisite for curative therapies would be to overcome not only tumor heterogeneity but also dormancy., (© 2022. The Author(s).)

Deciphering genomic architecture is key to identifying novel disease drivers and understanding the mechanisms underlying myeloma initiation and progression. In this work, using the CoMMpass dataset, we show that structural variants (SV) occur in a nonrandom fashion throughout the genome with an increased frequency in the t(4;14), RB1, or TP53 mutated cases and reduced frequency in t(11;14) cases. By mapping sites of chromosomal rearrangements to topologically associated domains and identifying significantly upregulated genes by RNAseq we identify both predicted and novel putative driver genes. These data highlight the heterogeneity of transcriptional dysregulation occurring as a consequence of both the canonical and novel structural variants. Further, it shows that the complex rearrangements chromoplexy, chromothripsis and templated insertions are common in MM with each variant having its own distinct frequency and impact on clinical outcome. Chromothripsis is associated with a significant independent negative impact on clinical outcome in newly diagnosed cases consistent with its use alongside other clinical and genetic risk factors to identify prognosis., (© 2022. The Author(s).)

Sensorineural Hearing Loss (SNHL) is a highly prevalent disorder involving permanent damage or loss to the inner ear's mechano-sensory hair cells and nerve fibers. Major contributing causes are ototoxic drugs, loud noises, and aging. Drug-induced hearing loss (DIHL), affects over 25% of patients treated with common therapeutics such as aminoglycoside antibiotics, loop diuretics or chemotherapeutics. A commonly used chemotherapeutic agent, cisplatin, is very effective for treating malignant tumors, but results in a majority of patients experiencing irreversible hearing loss and/or tinnitus. Additionally, since there is currently no FDA-approved treatments for SNHL, attenuation of ototoxicity is a major area of investigation in oncology, otolaryngology and hearing research. Several potential otoprotective agents have been investigated at the clinical trial stage, but none have progressed to a full FDA-approval. In this study, we investigated a combinatorial approach comprised of an antioxidant, a p53 inhibitor and a neurotrophin, as a multifactorial otoprotective treatment for cisplatin exposure. In vitro, HEI-OC1 cells, an immortalized organ of Corti epithelial cell line, pre-treated with this biotherapeutic cocktail had significantly reduced cisplatin-induced cell death, DNA fragmentation, and apoptotic activation. In an ex vivo study, rat pup D2-D3 organ of Corti explants, significant protection against cisplatin-based hair cell and neuronal loss was achieved by delivery of the same combinatorial pretreatment. Interestingly, the hair cell protection was localized to the basal and middle regions of the organ of Corti. Together, these findings highlight a novel approach to attenuate cisplatin ototoxicity and potentially prevent DIHL by addressing biological mechanisms of cisplatin ototoxicity., (Copyright © 2022. Published by Elsevier B.V.)

Chemotherapy with doxorubicin (DOX) may cause unpredictable cardiotoxicity. This study aimed to determine whether the methylation signature of peripheral blood mononuclear cells (PBMCs) prior to and after the first cycle of DOX-based chemotherapy could predict the risk of cardiotoxicity in breast cancer patients. Cardiotoxicity was defined as a decrease in left ventricular ejection fraction (LVEF) by >10%. DNA methylation of PBMCs from 9 patients with abnormal LVEF and 10 patients with normal LVEF were examined using Infinium HumanMethylation450 BeadChip. We have identified 14,883 differentially methylated CpGs at baseline and 18,718 CpGs after the first cycle of chemotherapy, which significantly correlated with LVEF status. Significant differentially methylated regions (DMRs) were found in the promoter and the gene body of SLFN12, IRF6 and RNF39 in patients with abnormal LVEF. The pathway analysis found enrichment for regulation of transcription, mRNA splicing, pathways in cancer and ErbB2/4 signaling. The preliminary results from this study showed that the DNA methylation profile of PBMCs may predict the risk of DOX-induced cardiotoxicity prior to chemotherapy. Further studies with larger cohorts of patients are needed to confirm these findings.

Introduction: Hearing impairment, or hearing loss, can be caused by several factors and the implications vary according to the type, degree, cause and age of occurrence. Hearing screening should be a common procedure, allowing the pre-clinical identification and necessary referrals, avoiding the consequences of auditory deprivation. Mobile apps have shown to be a good alternative for hearing assessment., Objective: The objective was to develop an app and assess its performance in identifying hearing loss by comparing it with another validated screening tool., Methods: The application, called Ouviu, was created using audiological knowledge and tools available on the iOS platform. We evaluated 185 people, aged between 6 and 96 years, distributed into 5 age groups, performing audiometry and hearing screening using two tools: HearCheck and the application., Results: The results showed that the sensitivity of the application in identifying hearing loss was approximately 97%, while that of HearCheck was 79%. The positive predictive value of the application showed that the probability of a person being identified with this tool and actually having a hearing loss was 94%, while for HearCheck it was 96%. False negatives, which failed hearing loss identification, were fewer in the app (3%) than in HearCheck (21%)., Conclusion: Consequently, the developed application was shown to be effective as a hearing screening tool, surpassing HearCheck in identifying mild hearing loss. In addition to being portable, easy to apply, low cost and rapidly performed, the application has the advantage of assessing environmental noise to perform the exam, as well as the fact that it is not necessary to attach any hardware to the mobile device., (Copyright © 2020 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.)

The slow accumulation of inflammatory biomarker levels in the body-also known as inflammaging-has been linked to a myriad of age-related diseases. Some of these include neurodegenerative conditions such as Parkinson's disease, obesity, type II diabetes, cardiovascular disease, and many others. Though a direct correlation has not been established, research connecting age-related hearing loss (ARHL)-the number one communication disorder and one of the most prevalent neurodegenerative diseases of our aged population-and inflammaging has gained interest. Research, thus far, has found that inflammatory markers, such as IL-6 and white blood cells, are associated with ARHL in humans and animals. Moreover, studies investigating ion channels and mitochondrial involvement have shown promising relationships between their functions and inflammaging in the cochlea. In this review, we summarize key findings in inflammaging within the auditory system, the involvement of ion channels and mitochondrial functions, and lastly discuss potential treatment options focusing on controlling inflammation as we age.

Objectives: This study aims to examine the feasibility of an intergenerational remote intervention program designed to promote the wellbeing and social connection of vulnerable older adults, mainly people with aphasia and dementia during the COVID-19 pandemic in the south of Brazil. Undergraduate students were guided to lead weekly sessions of clowning, storytelling, dancing, and cooking-related activities for 3 months (from November/2020 to February/2021)., Method: The mixed-method design of the study addresses the implementation and feasibility of the program. Data analysis considered both quantitative-number of individuals who accepted the invitation to participate, voluntary dropouts, attendance-and qualitative data-participative observation and thematic analysis of evaluative conversations. An inclusive group of 34 older adults with stroke-induced cognitive impairments, dementia and individuals without any neurological conditions enrolled in the program based on social and racial equity principles. Feasibility and acceptability were addressed in terms of recruitment, implementation, remote evaluation, delivery of remote intervention, adherence, and attendance. Activities and participants' perceptions are described., Results: The initial period of the program achieved 83.7% of adherence and sustainability for additional 3 months. Preliminary results suggest feasibility and acceptability, considering formal and informal support in digital inclusion. Participatory observations describe that the structure of sessions and activities were well received. The analysis of participants' perceptions detects the thematic saliency of feelings of social connection and a sense of having learned with the group., Conclusions: Preliminary results of this study demonstrate the feasibility and acceptability of the program, pointing to its potential mental health benefits., (© 2021 John Wiley & Sons Ltd.)

Background: The COVID-19 pandemic is a public health emergency that poses challenges to the mental health of approximately 1.4 million university students in Canada. Preliminary evidence has shown that the COVID-19 pandemic had a detrimental impact on undergraduate student mental health and well-being; however, existing data are predominantly limited to cross-sectional survey-based studies. Owing to the evolving nature of the pandemic, longer-term prospective surveillance efforts are needed to better anticipate risk and protective factors during a pandemic., Objective: The overarching aim of this study is to use a mobile (primarily smartphone-based) surveillance system to identify risk and protective factors for undergraduate students' mental health. Factors will be identified from weekly self-report data (eg, affect and living accommodation) and device sensor data (eg, physical activity and device usage) to prospectively predict self-reported mental health and service utilization., Methods: Undergraduate students at Western University (London, Ontario, Canada), will be recruited via email to complete an internet-based baseline questionnaire with the option to participate in the study on a weekly basis, using the Student Pandemic Experience (SPE) mobile app for Android/iOS. The app collects sensor samples (eg, GPS coordinates and steps) and self-reported weekly mental health and wellness surveys. Student participants can opt in to link their mobile data with campus-based administrative data capturing health service utilization. Risk and protective factors that predict mental health outcomes are expected to be estimated from (1) cross-sectional associations among students' characteristics (eg, demographics) and key psychosocial factors (eg, affect, stress, and social connection), and behaviors (eg, physical activity and device usage) and (2) longitudinal associations between psychosocial and behavioral factors and campus-based health service utilization., Results: Data collection began November 9, 2020, and will be ongoing through to at least October 31, 2021. Retention from the baseline survey (N=427) to app sign-up was 74% (315/427), with 175-215 (55%-68%) app participants actively responding to weekly surveys. From November 9, 2020, to August 8, 2021, a total of 4851 responses to the app surveys and 25,985 sensor samples (consisting of up to 68 individual data items each; eg, GPS coordinates and steps) were collected from the 315 participants who signed up for the app., Conclusions: The results of this real-world longitudinal cohort study of undergraduate students' mental health based on questionnaires and mobile sensor metrics is expected to show psychosocial and behavioral patterns associated with both positive and negative mental health-related states during pandemic conditions at a relatively large, public, and residential Canadian university campus. The results can be used to support decision-makers and students during the ongoing COVID-19 pandemic and similar future events. For comparable settings, new interventions (digital or otherwise) might be designed using these findings as an evidence base., International Registered Report Identifier (irrid): DERR1-10.2196/30504., (©Chris Brogly, Michael A Bauer, Daniel J Lizotte, MacLean L Press, Arlene MacDougall, Mark Speechley, Erin Huner, Marc Mitchell, Kelly K Anderson, Eva Pila. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 17.09.2021.)

The auditory system is a fascinating sensory organ that overall, converts sound signals to electrical signals of the nervous system. Initially, sound energy is converted to mechanical energy via amplification processes in the middle ear, followed by transduction of mechanical movements of the oval window into electrochemical signals in the cochlear hair cells, and finally, neural signals travel to the central auditory system, via the auditory division of the 8th cranial nerve. The majority of people above 60 years have some form of age-related hearing loss, also known as presbycusis. However, the biological mechanisms of presbycusis are complex and not yet fully delineated. In the present article, we highlight ion channels and transport proteins, which are integral for the proper functioning of the auditory system, facilitating the diffusion of various ions across auditory structures for signal transduction and processing. Like most other physiological systems, hearing abilities decline with age, hence, it is imperative to fully understand inner ear aging changes, so ion channel functions should be further investigated in the aging cochlea. In this review article, we discuss key various ion channels in the auditory system and how their functions change with age. Understanding the roles of ion channels in auditory processing could enhance the development of potential biotherapies for age-related hearing loss.

Both arsenic and cadmium are reported to be toxic to humans. The use of saliva as a biomarker of low-level exposures to these elements has not been adequately explored, and the putative relationship between exposure and obesity is unclear. This cross-sectional study aims to investigate the relationship between salivary arsenic and cadmium concentrations and their association with obesity. Arsenic and cadmium concentrations were analyzed in human saliva samples by Inductively Coupled Plasma-Mass Spectrometry on 270 randomly selected women who participated in the Arkansas Rural Community Health Study. Multivariable logistic regression was performed to evaluate the association between heavy metal concentrations and obesity. Stratified logistic regression was performed based on menopausal status. Generalized linear models were used to evaluate weight gain velocity. Significant positive associations were observed in postmenopausal women for both arsenic (OR = 4.43, 95% CI 1.91-10.28) and cadmium (OR = 2.72, 95% CI 1.23-5.99) concentrations, as well as significant trends among tertiles ( p < 0.01 and p = 0.01, respectively). No relationship with obesity was evident among premenopausal women for either metal. A dose-response relationship was observed between increasing weight gain velocity and increasing metal concentrations. At concentrations well below governmental and industrial standards for acute toxicity, significant associations between obesity and concentration of these heavy metals are evident. The rate at which individuals gain weight is affected by metal concentrations and may play a role in the rapid increase in weight in postmenopausal women. These results might explain, in part, the missing variability in the increasing obesity pandemic in certain population exposed to these environmental toxicants., Competing Interests: Compliance with Ethical Standards Conflict of interest The authors declare that they have no conflict of interest.

Disruption of the normal splicing patterns of RNA is a major factor in the pathogenesis of a number of diseases. Increasingly research has shown the strong influence that splicing patterns can have on cancer progression. Multiple Myeloma is a molecularly heterogeneous disease classified by the presence of key translocations, gene expression profiles and mutations but the splicing patterns in MM remains largely unexplored. We take a multifaceted approach to define the extent and impact of alternative splicing in MM. We look at the spliceosome component, SF3B1, with hotspot mutations (K700E and K666T/Q) shown to result in an increase in alternative splicing in other cancers. We discovered a number of differentially spliced genes in comparison of the SF3B1 mutant and wild type samples that included, MZB1, DYNLL1, TMEM14C and splicing related genes DHX9, CLASRP, and SNRPE. We identified a broader role for abnormal splicing showing clear differences in the extent of novel splice variants in the different translocation groups. We show that a high number of novel splice loci is associated with adverse survival and an ultra-high risk group. The enumeration of patterns of alternative splicing has the potential to refine MM classification and to aid in the risk stratification of patients.

Background: Somatic variant callers are used to find mutations in sequencing data from cancer samples. They are very sensitive and have high recall, but also may produce low precision data with a large proportion of false positives. Further ad hoc filtering is commonly performed after variant calling and before further analysis. Improving the filtering of somatic variants in a reproducible way represents an unmet need. We have developed Filters for Next Generation Sequencing (FiNGS), software written specifically to address these filtering issues., Results: Developed and tested using publicly available sequencing data sets, we demonstrate that FiNGS reliably improves upon the precision of default variant caller outputs and performs better than other tools designed for the same task., Conclusions: FiNGS provides researchers with a tool to reproducibly filter somatic variants that is simple to both deploy and use, with filters and thresholds that are fully configurable by the user. It ingests and emits standard variant call format (VCF) files and will slot into existing sequencing pipelines. It allows users to develop and implement their own filtering strategies and simple sharing of these with others.

Smoldering myeloma (SMM) is associated with a high-risk of progression to myeloma (MM). We report the results of a study of 82 patients with both targeted sequencing that included a capture of the immunoglobulin and MYC regions. By comparing these results to newly diagnosed myeloma (MM) we show fewer NRAS and FAM46C mutations together with fewer adverse translocations, del(1p), del(14q), del(16q), and del(17p) in SMM consistent with their role as drivers of the transition to MM. KRAS mutations are associated with a shorter time to progression (HR 3.5 (1.5-8.1), p = 0.001). In an analysis of change in clonal structure over time we studied 53 samples from nine patients at multiple time points. Branching evolutionary patterns, novel mutations, biallelic hits in crucial tumour suppressor genes, and segmental copy number changes are key mechanisms underlying the transition to MM, which can precede progression and be used to guide early intervention strategies.

Natural polyamines (spermidine and spermine) are small, positively charged molecules that are ubiquitously found within organisms and cells. They exert numerous (intra)cellular functions and have been implicated to protect against several age-related diseases. Although polyamine levels decline in a complex age-dependent, tissue-, and cell type-specific manner, they are maintained in healthy nonagenarians and centenarians. Increased polyamine levels, including through enhanced dietary intake, have been consistently linked to improved health and reduced overall mortality. In preclinical models, dietary supplementation with spermidine prolongs life span and health span. In this review, we highlight salient aspects of nutritional polyamine intake and summarize the current knowledge of organismal and cellular uptake and distribution of dietary (and gastrointestinal) polyamines and their impact on human health. We further summarize clinical and epidemiological studies of dietary polyamines.

Purpose: Copy-number changes and translocations have been studied extensively in many datasets with long-term follow-up. The impact of mutations remains debated given the short time to follow-up of most datasets., Experimental Design: We performed targeted panel sequencing covering 125 myeloma-specific genes and the loci involved in translocations in 223 newly diagnosed myeloma samples recruited into one of the total therapy trials., Results: As expected, the most commonly mutated genes were NRAS, KRAS , and BRAF , making up 44% of patients. Double-Hit and BRAF and DIS3 mutations had an impact on outcome alongside classical risk factors in the context of an intensive treatment approach. We were able to identify both V600E and non-V600E BRAF mutations, 58% of which were predicted to be hypoactive or kinase dead. Interestingly, 44% of the hypoactive/kinase dead BRAF -mutated patients showed co-occurring alterations in KRAS, NRAS , or activating BRAF mutations, suggesting that they play a role in the oncogenesis of multiple myeloma by facilitating MAPK activation and may lead to chemoresistance., Conclusions: Overall, these data highlight the importance of mutational screening to better understand newly diagnosed multiple myeloma and may lead to patient-specific mutation-driven treatment approaches., (©2020 American Association for Cancer Research.)