Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding.

The ability of circulating tumor cells (CTCs) to form clusters has been linked to increased metastatic potential. Yet biological features and vulnerabilities of CTC clusters remain largely unknown. Here, we profile the DNA methylation landscape of single CTCs and CTC clusters from breast cancer patients and mouse models on a genome-wide scale. We find that binding sites for stemness- and proliferation-associated transcription factors are specifically hypomethylated in CTC clusters, including binding sites for OCT4, NANOG, SOX2, and SIN3A, paralleling embryonic stem cell biology. Among 2,486 FDA-approved compounds, we identify Na+/K+ ATPase inhibitors that enable the dissociation of CTC clusters into single cells, leading to DNA methylation remodeling at critical sites and metastasis suppression. Thus, our results link CTC clustering to specific changes in DNA methylation that promote stemness and metastasis and point to cluster-targeting compounds to suppress the spread of cancer.

Neutrophils escort circulating tumour cells to enable cell cycle progression.

A better understanding of the features that define the interaction between cancer cells and immune cells is important for the development of new cancer therapies1. However, focus is often given to interactions that occur within the primary tumour and its microenvironment, whereas the role of immune cells during cancer dissemination in patients remains largely uncharacterized2,3. Circulating tumour cells (CTCs) are precursors of metastasis in several types of cancer4-6, and are occasionally found within the bloodstream in association with non-malignant cells such as white blood cells (WBCs)7,8. The identity and function of these CTC-associated WBCs, as well as the molecular features that define the interaction between WBCs and CTCs, are unknown. Here we isolate and characterize individual CTC-associated WBCs, as well as corresponding cancer cells within each CTC-WBC cluster, from patients with breast cancer and from mouse models. We use single-cell RNA sequencing to show that in the majority of these cases, CTCs were associated with neutrophils. When comparing the transcriptome profiles of CTCs associated with neutrophils against those of CTCs alone, we detect a number of differentially expressed genes that outline cell cycle progression, leading to more efficient metastasis formation. Further, we identify cell-cell junction and cytokine-receptor pairs that define CTC-neutrophil clusters, representing key vulnerabilities of the metastatic process. Thus, the association between neutrophils and CTCs drives cell cycle progression within the bloodstream and expands the metastatic potential of CTCs, providing a rationale for targeting this interaction in treatment of breast cancer.

The Effects of Race, Ethnicity, and Maternal Education on Infant Mortality.

BACKGROUND: The state of New Jersey has a large Black/African American (AA) versus White racial disparity in infant mortality and educational level at childbirth. This disparity, measured by rate ratio, increases with greater maternal education among varied racial-ethnic groups. The nature of this disparity measured by rate differences has not been explored. OBJECTIVES: Infant birth and mortality data were used to examine whether racial or ethnic disparities in infant mortality increased with greater maternal education, comparing rate differences and rate ratios. Racial and ethnic variations in the association between maternal education and infant mortality were examined. METHODS: Data were from the New Jersey State Health Assessment Data for all New Jersey births between 2014 and 2018 stratified by race and ethnicity, maternal education, and infant mortality ( n = 481,333). R software was used to create a data set and estimate additive and multiplicative interactions, rate differences, and rate ratios for infant mortality by maternal race/ethnicity and educational levels among four racial-ethnic groups. RESULTS: Infant mortality was significantly greater for Black/AA and Hispanic mothers than for White mothers. At all educational levels, Black/AA mothers had the highest prevalence of infant mortality compared to other racial or ethnic groups. Rate differences in infant mortality showed a decrease in Black/AA-White differences for mothers with a high school education or less compared to mothers with a college degree. However, rate ratios showed an increase in Black/AA-White ratio with increasing education levels for mothers with high school education or less than mothers with a college degree. Risk ratios comparing infant mortality for Black/AA versus Hispanic or Asian mothers showed more than a twofold greater risk at all education levels for Black/AA infants. Finally, college-educated Black/AA mothers had significantly higher rates of infant mortality than White or Hispanic mothers with a high school education or less. DISCUSSION/IMPLICATIONS: Black/AA mothers with a college degree had a higher infant mortality rate than White, Hispanic, or Asian mothers with a high school education or less. Future research should address contextual/systemic contributors to this disparity.

Interactions Between Forced Sexual Intercourse Victimization and Gender on Violent Behaviors: Youth Risk Behavior Survey 2017-2019.

In recent years, the United States has seen an increase in gun-related violence and school shootings. The Centers for Disease Control and Prevention (CDC) estimates that the incidence of gun carrying among high-school students has declined. Nevertheless, an examination of the underlying factors that increase the risk of violence-related behaviors is necessary to develop interventions to decrease gun use among high-school students. General Strain Theory (GST) predicts that victims of violence are (a) significantly more likely to engage in violent behaviors and (b) the increased risk of violent behavior by persons who experience violence is significantly greater among male victims. This research aims to test these predictions of the strain theory with data from the Youth Risk Behavior Survey (YRBS). To that end, it investigates whether the relationship between forced sexual intercourse victimization (FSIV) and gun or weapon carrying or physical fighting is significantly greater among male students. Using R and pooled data from the nationally representative YRBS (2017 and 2019), additive interactions were estimated according to Strengthening the Reporting of Observational Studies in Epidemiology guidelines to determine the association between FSIV and weapon carry, gun carry, or physical fighting. Multiplicative interactions and odds ratios were also estimated for comparison. Results show a high risk of gun and weapon carrying and physical fighting among both male and female students who experience FSIV and a significant relationship between FSIV and increased risk of these violence-related behaviors. Additive interactions show that the relationship between FSIV and these violent behaviors is each significantly greater among male students than female students. Results confirm the predictions of GST and show that FSIV significantly increases the risk of gun carrying and other violence-related behaviors among male and female U.S. high-school students; the increased risk is significantly greater among male students.

Remarkable sex-specific differences at single-cell resolution in neonatal hyperoxic lung injury.

Exposure to supraphysiological concentrations of oxygen (hyperoxia) predisposes to bronchopulmonary dysplasia (BPD), which is characterized by abnormal alveolarization and pulmonary vascular development, in preterm neonates. Neonatal hyperoxia exposure is used to recapitulate the phenotype of human BPD in murine models. Male sex is considered an independent predictor for the development of BPD, but the main mechanisms underlying sexually dimorphic outcomes are unknown. Our objective was to investigate sex-specific and cell-type specific transcriptional changes that drive injury in the neonatal lung exposed to hyperoxia at single-cell resolution and delineate the changes in cell-cell communication networks in the developing lung. We used single-cell RNA sequencing (scRNAseq) to generate transcriptional profiles of >35,000 cells isolated from the lungs of neonatal male and female C57BL/6 mice exposed to 95% [Formula: see text] between PND1-5 (saccular stage of lung development) or normoxia and euthanized at PND7 (alveolar stage of lung development). ScRNAseq identified 22 cell clusters with distinct populations of endothelial, epithelial, mesenchymal, and immune cells. Our data identified that the distal lung vascular endothelium (composed of aerocytes and general capillary endothelial cells) is exquisitely sensitive to hyperoxia exposure with the emergence of an intermediate capillary endothelial population with both general capillaries (gCap) and aerocytes or alveolar capillaries (aCap) markers. We also identified a myeloid-derived suppressor cell population from the lung neutrophils. Sex-specific differences were evident in all lung cell subpopulations but were striking among the lung immune cells. Finally, we identified that the specific intercellular communication networks and the ligand-receptor pairs that are impacted by neonatal hyperoxia exposure.

Structural architecture and brain network efficiency link polygenic scores to intelligence.

Intelligence is highly heritable. Genome-wide association studies (GWAS) have shown that thousands of alleles contribute to variation in intelligence with small effect sizes. Polygenic scores (PGS), which combine these effects into one genetic summary measure, are increasingly used to investigate polygenic effects in independent samples. Whereas PGS explain a considerable amount of variance in intelligence, it is largely unknown how brain structure and function mediate this relationship. Here, we show that individuals with higher PGS for educational attainment and intelligence had higher scores on cognitive tests, larger surface area, and more efficient fiber connectivity derived by graph theory. Fiber network efficiency as well as the surface of brain areas partly located in parieto-frontal regions were found to mediate the relationship between PGS and cognitive performance. These findings are a crucial step forward in decoding the neurogenetic underpinnings of intelligence, as they identify specific regional networks that link polygenic predisposition to intelligence.

The association between history of prenatal loss and maternal psychological state in a subsequent pregnancy: an ecological momentary assessment (EMA) study.

BACKGROUND: Prenatal loss which occurs in approximately 20% of pregnancies represents a well-established risk factor for anxiety and affective disorders. In the current study, we examined whether a history of prenatal loss is associated with a subsequent pregnancy with maternal psychological state using ecological momentary assessment (EMA)-based measures of pregnancy-specific distress and mood in everyday life. METHOD: This study was conducted in a cohort of N = 155 healthy pregnant women, of which N = 40 had a history of prenatal loss. An EMA protocol was used in early and late pregnancy to collect repeated measures of maternal stress and mood, on average eight times per day over a consecutive 4-day period. The association between a history of prenatal loss and psychological state was estimated using linear mixed models. RESULTS: Compared to women who had not experienced a prior prenatal loss, women with a history of prenatal loss reported higher levels of pregnancy-specific distress in early as well as late pregnancy and also were more nervous and tired. Furthermore, in the comparison group pregnancy-specific distress decreased and mood improved from early to late pregnancy, whereas these changes across pregnancy were not evident in women in the prenatal loss group. CONCLUSION: Our findings suggest that prenatal loss in a prior pregnancy is associated with a subsequent pregnancy with significantly higher stress and impaired mood levels in everyday life across gestation. These findings have important implications for designing EMA-based ambulatory, personalized interventions to reduce stress during pregnancy in this high-risk group.

Inactivation of SARS-CoV-2 on salt-coated surfaces: an in vitro study.

In the COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), face masks have become a very important safety measure against the main route of transmission of the virus: droplets and aerosols. Concerns that masks contaminated with SARS-CoV-2 infectious particles could be a risk for self-contamination have emerged early in the pandemic as well as solutions to mitigate this risk. The coating of masks with sodium chloride, an antiviral and non-hazardous to health chemical, could be an option for reusable masks. To assess the antiviral properties of salt coatings deposited onto common fabrics by spraying and dipping, the present study established an in vitro bioassay using three-dimensional airway epithelial cell cultures and SARS-CoV-2 virus. Virus particles were given directly on salt-coated material, collected, and added to the cell cultures. Infectious virus particles were measured by plaque forming unit assay and in parallel viral genome copies were quantified over time. Relative to noncoated material, the sodium chloride coating significantly reduced virus replication, confirming the effectiveness of the method to prevent fomite contamination with SARS-CoV-2. In addition, the lung epithelia bioassay proved to be suitable for future evaluation of novel antiviral coatings.

Spatiotemporal evolution of COVID-19 in Portugal's Mainland with self-organizing maps.

BACKGROUND: Self-Organizing Maps (SOM) are an unsupervised learning clustering and dimensionality reduction algorithm capable of mapping an initial complex high-dimensional data set into a low-dimensional domain, such as a two-dimensional grid of neurons. In the reduced space, the original complex patterns and their interactions can be better visualized, interpreted and understood. METHODS: We use SOM to simultaneously couple the spatial and temporal domains of the COVID-19 evolution in the 278 municipalities of mainland Portugal during the first year of the pandemic. Temporal 14-days cumulative incidence time series along with socio-economic and demographic indicators per municipality were analyzed with SOM to identify regions of the country with similar behavior and infer the possible common origins of the incidence evolution. RESULTS: The results show how neighbor municipalities tend to share a similar behavior of the disease, revealing the strong spatiotemporal relationship of the COVID-19 spreading beyond the administrative borders of each municipality. Additionally, we demonstrate how local socio-economic and demographic characteristics evolved as determinants of COVID-19 transmission, during the 1st wave school density per municipality was more relevant, where during 2nd wave jobs in the secondary sector and the deprivation score were more relevant. CONCLUSIONS: The results show that SOM can be an effective tool to analysing the spatiotemporal behavior of COVID-19 and synthetize the history of the disease in mainland Portugal during the period in analysis. While SOM have been applied to diverse scientific fields, the application of SOM to study the spatiotemporal evolution of COVID-19 is still limited. This work illustrates how SOM can be used to describe the spatiotemporal behavior of epidemic events. While the example shown herein uses 14-days cumulative incidence curves, the same analysis can be performed using other relevant data such as mortality data, vaccination rates or even infection rates of other disease of infectious nature.

Modeling dynamic personality theories in a continuous-time framework: An illustration.

OBJECTIVE: Personality psychology has traditionally focused on stable between-person differences. Yet, recent theoretical developments and empirical insights have led to a new conceptualization of personality as a dynamic system (e.g., Cybernetic Big Five Theory). Such dynamic systems comprise several components that need to be conceptually distinguished and mapped to a statistical model for estimation. METHOD: In the current work, we illustrate how common components from these new dynamic personality theories may be implemented in a continuous time-modeling framework. RESULTS: As an empirical example, we reanalyze experience sampling data with N = 180 persons (with on average T = 40 [SD = 8] measurement occasions) to investigate four different effects between momentary happiness, momentary extraverted behavior, and the perception of a situation as social: (1) between-person effects, (2) contemporaneous effects, (3) autoregressive effects, and (4) cross-lagged effects. CONCLUSION: We highlight that these four effects must not necessarily point in the same direction, which is in line with assumptions from dynamic personality theories.

Identifying Gender-Related Differences in Graduate Medical Education with the Use of a Web-Based Professionalism Monitoring Tool.

OBJECTIVES: Medical education is required to ensure a healthy training and learning environment for resident physicians. Trainees are expected to demonstrate professionalism with patients, faculty, and staff. West Virginia University Graduate Medical Education (GME) initiated a Web-based professionalism and mistreatment form ("button") on our Web site for reporting professionalism breaches, mistreatment, and exemplary behavior events. The purpose of this study was to identify characteristics in resident trainees who had a "button push" activation about their behavior to better understand ways to improve professionalism in GME. METHODS: This West Virginia University institutional review board-approved quality improvement study is a descriptive analysis of GME button push activations from July 2013 through June 2021. We compared characteristics of all of those trainees who had specific button activation(s) about their behavior. Data are reported as frequency and percentage. Nominal data and interval data were analyzed using the χ2 and the t test, respectively. P < 0.05 was significant. Logistic regression was used to analyze those differences that were significant. RESULTS: In the 8-year study period, there were 598 button activations, and 54% (n = 324) of the activations were anonymous. Nearly all of the button reports (n = 586, 98%) were constructively resolved within 14 days. Of the 598 button activations, 95% (n = 569) were identified as involving one sex, with 66.3% (n = 377) identified as men and 33.7% (n = 192) as women. Of the 598 activations, 83.7% (n = 500) involved residents and 16.3% (n = 98) involved attendings. One-time offenders comprised 90% (n = 538), and 10% (n = 60) involved individuals who had previous button pushes about their behavior. CONCLUSIONS: Implementation of a professionalism-monitoring tool, such as our Web-based button push, identified gender differences in the reporting of professionalism breaches, because twice as many men as women were identified as the instigator of a professionalism breech. The tool also facilitated timely interventions and exemplary behavior recognition.

Tobacco Alkaloid Assessment in a DSS-Induced Colitis Mouse Model with a Fully Humanized Immune System.

Inflammatory bowel disease (IBD) refers to chronic intestinal immune-mediated diseases including two main disease manifestations: ulcerative colitis (UC) and Crohn's disease (CD). Epidemiological, clinical, and preclinical evidence has highlighted the potential anti-inflammatory properties of naturally occurring alkaloids. In the present study, we investigated the potential anti-inflammatory activities of the tobacco alkaloids nicotine and anatabine in a dextran sulfate sodium (DSS)-induced UC mouse model with a fully humanized immune system. Our results show that nicotine significantly reduced all acute colitis symptoms and improved colitis-specific endpoints, including histopathologically assessed colon inflammation, tissue damage, and mononuclear cell infiltration. The tobacco alkaloid anatabine showed similar effectiveness trends, although they were generally weaker or not significant. Gene expression analysis in the context of biological network models of IBD further pinpointed a possible mechanism by which nicotine attenuated DSS-induced colitis in humanized mice. The current study enables further investigation of possible molecular mechanisms by which tobacco alkaloids attenuate UC symptoms.

Crowdsourced benchmarking of taxonomic metagenome profilers: lessons learned from the sbv IMPROVER Microbiomics challenge.

BACKGROUND: Selection of optimal computational strategies for analyzing metagenomics data is a decisive step in determining the microbial composition of a sample, and this procedure is complex because of the numerous tools currently available. The aim of this research was to summarize the results of crowdsourced sbv IMPROVER Microbiomics Challenge designed to evaluate the performance of off-the-shelf metagenomics software as well as to investigate the robustness of these results by the extended post-challenge analysis. In total 21 off-the-shelf taxonomic metagenome profiling pipelines were benchmarked for their capacity to identify the microbiome composition at various taxon levels across 104 shotgun metagenomics datasets of bacterial genomes (representative of various microbiome samples) from public databases. Performance was determined by comparing predicted taxonomy profiles with the gold standard. RESULTS: Most taxonomic profilers performed homogeneously well at the phylum level but generated intermediate and heterogeneous scores at the genus and species levels, respectively. kmer-based pipelines using Kraken with and without Bracken or using CLARK-S performed best overall, but they exhibited lower precision than the two marker-gene-based methods MetaPhlAn and mOTU. Filtering out the 1% least abundance species-which were not reliably predicted-helped increase the performance of most profilers by increasing precision but at the cost of recall. However, the use of adaptive filtering thresholds determined from the sample's Shannon index increased the performance of most kmer-based profilers while mitigating the tradeoff between precision and recall. CONCLUSIONS: kmer-based metagenomic pipelines using Kraken/Bracken or CLARK-S performed most robustly across a large variety of microbiome datasets. Removing non-reliably predicted low-abundance species by using diversity-dependent adaptive filtering thresholds further enhanced the performance of these tools. This work demonstrates the applicability of computational pipelines for accurately determining taxonomic profiles in clinical and environmental contexts and exemplifies the power of crowdsourcing for unbiased evaluation.

White matter microglia heterogeneity in the CNS.

Microglia, the resident myeloid cells in the central nervous system (CNS) play critical roles in shaping the brain during development, responding to invading pathogens, and clearing tissue debris or aberrant protein aggregations during ageing and neurodegeneration. The original concept that like macrophages, microglia are either damaging (pro-inflammatory) or regenerative (anti-inflammatory) has been updated to a kaleidoscope view of microglia phenotypes reflecting their wide-ranging roles in maintaining homeostasis in the CNS and, their contribution to CNS diseases, as well as aiding repair. The use of new technologies including single cell/nucleus RNA sequencing has led to the identification of many novel microglia states, allowing for a better understanding of their complexity and distinguishing regional variations in the CNS. This has also revealed differences between species and diseases, and between microglia and other myeloid cells in the CNS. However, most of the data on microglia heterogeneity have been generated on cells isolated from the cortex or whole brain, whereas white matter changes and differences between white and grey matter have been relatively understudied. Considering the importance of microglia in regulating white matter health, we provide a brief update on the current knowledge of microglia heterogeneity in the white matter, how microglia are important for the development of the CNS, and how microglial ageing affects CNS white matter homeostasis. We discuss how microglia are intricately linked to the classical white matter diseases such as multiple sclerosis and genetic white matter diseases, and their putative roles in neurodegenerative diseases in which white matter is also affected. Understanding the wide variety of microglial functions in the white matter may provide the basis for microglial targeted therapies for CNS diseases.

Levels and dynamics of estimated glomerular filtration rate and recurrent vascular events and death in patients with minor stroke or transient ischemic attack.

BACKGROUND AND PURPOSE: Impaired kidney function is associated with an increased risk of vascular events in acute stroke patients, when assessed by single measurements of estimated glomerular filtration rate (eGFR). It is unknown whether repeated measurements provide additional information for risk prediction. METHODS: The MonDAFIS (Systematic Monitoring for Detection of Atrial Fibrillation in Patients with Acute Ischemic Stroke) study randomly assigned 3465 acute ischemic stroke patients to either standard procedures or an additive Holter electrocardiogram. Baseline eGFR (CKD-EPI formula) were dichotomized into values of < versus ≥60 ml/min/1.73 m2 . eGFR dynamics were classified based on two in-hospital values as "stable normal" (≥60 ml/min/1.73 m2 ), "increasing" (by at least 15% from baseline, second value ≥ 60 ml/min/1.73 m2 ), "decreasing" (by at least 15% from baseline of ≥60 ml/min/1.73 m2 ), and "stable decreased" (<60 ml/min/1.73 m2 ). The composite endpoint (stroke, major bleeding, myocardial infarction, all-cause death) was assessed after 24 months. We estimated hazard ratios in confounder-adjusted models. RESULTS: Estimated glomerular filtration rate at baseline was available in 2947 and a second value in 1623 patients. After adjusting for age, stroke severity, cardiovascular risk factors, and randomization, eGFR < 60 ml/min/1.73 m2 at baseline (hazard ratio [HR] = 2.2, 95% confidence interval [CI] = 1.40-3.54) as well as decreasing (HR = 1.79, 95% CI = 1.07-2.99) and stable decreased eGFR (HR = 1.64, 95% CI = 1.20-2.24) were independently associated with the composite endpoint. In addition, eGFR < 60 ml/min/1.732 at baseline (HR = 3.02, 95% CI = 1.51-6.10) and decreasing eGFR were associated with all-cause death (HR = 3.12, 95% CI = 1.63-5.98). CONCLUSIONS: In addition to patients with low eGFR levels at baseline, also those with decreasing eGFR have increased risk for vascular events and death; hence, repeated estimates of eGFR might add relevant information to risk prediction.

Autophagy in white matter disorders of the CNS: mechanisms and therapeutic opportunities.

Autophagy is a constitutive process that degrades, recycles and clears damaged proteins or organelles, yet, despite activation of this pathway, abnormal proteins accumulate in neurons in neurodegenerative diseases and in oligodendrocytes in white matter disorders. Here, we discuss the role of autophagy in white matter disorders, including neurotropic infections, inflammatory diseases such as multiple sclerosis, and in hereditary metabolic disorders and acquired toxic-metabolic disorders. Once triggered due to cell stress, autophagy can enhance cell survival or cell death that may contribute to oligodendrocyte damage and myelin loss in white matter diseases. For some disorders, the mechanisms leading to myelin loss are clear, whereas the aetiological agent and pathological mechanisms are unknown for other myelin disorders, although emerging studies indicate that a common mechanism underlying these disorders is dysregulation of autophagic pathways. In this review we discuss the alterations in the autophagic process in white matter disorders and the potential use of autophagy-modulating agents as therapeutic approaches in these pathological conditions. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

SIRT1 activation and its circadian clock control: a promising approach against (frailty in) neurodegenerative disorders.

With the increase in life expectancy, the incidence of neurodegenerative disorders and their impact worldwide has been increasing in recent years. Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, have complex and varied mechanisms of pathogenesis. Importantly, they share the common feature of disrupted circadian rhythms. This hallmark is believed to underlie the symptoms of such diseases and even potentially contribute to their onset. In addition, the association of physical frailty with dementia and neurodegenerative disorders has been demonstrated. In fact, frail persons are 8 times more likely to have some form of dementia and population studies report a significant prevalence for frailty in older patients with AD and PD. SIRT1 regulates the acetylation status of clock components and controls circadian amplitude of clock genes. However, the mechanisms responsible for this circadian clock control have been the subject of contradictory findings. Importantly, the activation of SIRT1 has been shown to have very relevant therapeutic potential against neurodegeneration. Nevertheless, few studies have attempted to connect the therapeutic reestablishing of SIRT1 as an approach against circadian disruption in neurodegenerative diseases. In this review, we address: circadian rhythms as an important early biomarker of neurodegenerative disorders; mechanisms for SIRT1 activation and the novel sirtuin-activating compounds (STACs); SIRT1 circadian paradox and subsequent studies in an unprecedented way in the literature; the beneficial role of SIRT1 activation in neurodegeneration; innovative proposals of how circadian-based interventions (e.g., SIRT1 activators) may become an important therapeutic approach against neurodegenerative disorders and how non-pharmacologic interventions (e.g., Mediterranean-style diet) might help in the prevention and/or treatment of these high-burden disorders, while tackling frailty and enhancing robustness.

Bone-anchored hearing system, contralateral routing of signals hearing aid or cochlear implant: what is best in single-sided deafness?

PURPOSE: The aim of the study was to compare long-term results after 1 year in patients with single-sided deafness (SSD) who were fitted with different hearing aids. The participants tested contralateral routing of signals (CROS) hearing aids and bone-anchored hearing systems (BAHS). They were also informed about the possibility of a cochlear implant (CI) and chose one of the three devices. We also investigated which factors influenced the choice of device. METHODS: Prospective study with 89 SSD participants who were divided into three groups by choosing BAHS, CROS, or CI. All participants received test batteries with both objective hearing tests (speech perception in noise and sound localisation) and subjective questionnaires. RESULTS: 16 participants opted for BAHS-, 13 for CROS- and 30 for CI-treatment. The greater the subjective impairment caused by SSD, the more likely patients were to opt for surgical treatment (BAHS or CI). The best results in terms of speech perception in noise (especially when sound reaches the deaf ear and noise the hearing ear), sound localization, and subjective results were achieved with CI. CONCLUSION: The best results regarding the therapy of SSD are achieved with a CI, followed by BAHS. This was evident both in objective tests and in the subjective questionnaires. Nevertheless, an individual decision is required in each case as to which SSD therapy option is best for the patient. Above all, the patient's subjective impairment and expectations should be included in the decision-making process.

Smart Manufacturing and Digitalization of Metrology: A Systematic Literature Review and a Research Agenda.

Smart manufacturing comprises fully integrated manufacturing systems that respond in real time to meet the changing demands and conditions in industrial activities, supply networks and customer needs. A smart manufacturing environment will face new challenges, including those concerning metrological issues, i.e., analysis of large quantities of data; communication systems for digitalization; measurement standards for automated process control; digital transformation of metrological services; and simulations and virtual measurement processes for the automatic assessment of measured data. Based on the assumption that the interplay between smart manufacturing and digitalization of metrology is an emerging research field, this paper aims to present a systematic literature review (SLR) based on a bibliographic data collection of 160 scientific articles retrieved from the Web of Science and Scopus databases over the 2016-2022 time frame. The findings presented in this review and recommendations for building a research agenda can help policy makers, researchers and practitioners by providing directions for the evolution of digital metrology and its role in the digitalization of the economy and society.

Disorder of Sex Development Due to 17-Beta-Hydroxysteroid Dehydrogenase Type 3 Deficiency: A Case Report and Review of 70 Different HSD17B3 Mutations Reported in 239 Patients.

The 17-beta-hydroxysteroid dehydrogenase type 3 (17-ß-HSD3) enzyme converts androstenedione to testosterone and is encoded by the HSD17B3 gene. Homozygous or compound heterozygous HSD17B3 mutations block the synthesis of testosterone in the fetal testis, resulting in a Disorder of Sex Development (DSD). We describe a child raised as a female in whom the discovery of testes in the inguinal canals led to a genetic study by whole exome sequencing (WES) and to the identification of a compound heterozygous mutation of the HSD17B3 gene (c.608C>T, p.Ala203Val, and c.645A>T, p.Glu215Asp). Furthermore, we review all HSD17B3 mutations published so far in cases of 17-ß-HSD3 deficiency. A total of 70 different HSD17B3 mutations have so far been reported in 239 patients from 187 families. A total of 118 families had homozygous mutations, 63 had compound heterozygous mutations and six had undetermined genotypes. Mutations occurred in all 11 exons and were missense (55%), splice-site (29%), small deletions and insertions (7%), nonsense (5%), and multiple exon deletions and duplications (2%). Several mutations were recurrent and missense mutations at codon 80 and the splice-site mutation c.277+4A>T each represented 17% of all mutated alleles. These findings may be useful to those involved in the clinical management and genetic diagnosis of this disorder.