Prevalence and correlates of perceived ethnic discrimination in the Hispanic Community Health Study/Study of Latinos Sociocultural Ancillary Study.

Empirical studies examining perceived ethnic discrimination in Latinos of diverse background groups are limited. This study examined prevalence and correlates of discrimination in a diverse sample of U.S. Latinos (N=5,291) from the multi-site Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and HCHS/SOL Sociocultural Ancillary Study. The sample permitted an examination of differences across seven groups (Central American, Cuban, Dominican, Mexican, Puerto Rican, South American, and Other/Multiple Background). Most participants (79.5%) reported lifetime discrimination exposure and prevalence rates ranged from 64.9% to 98% across groups. Structural Equation Models (SEM) indicated that after adjusting for sociodemographic covariates most group differences in reports of discrimination were eliminated. However, Cubans reported the lowest levels of discrimination, overall among all groups. Furthermore, regional effects were more important than group effects. Participants from Chicago reported the highest levels of discrimination in comparison to other regions. Group differences among Latinos appear to be primarily a function of sociodemographic differences in education, income, and acculturation. In addition, differences in exposure to discrimination may be tied to variables associated with both immigration patterns and integration to U.S. culture. Results highlight the importance of considering historical context and the intersection of discrimination and immigration when evaluating the mental health of Latinos

Synergistic Antimicrobial Effects of Silver/Transition-metal Combinatorial Treatments

Due to the emergence of multi-drug resistant strains, development of novel antibiotics has become a critical issue. One promising approach is the use of transition metals, since they exhibit rapid and significant toxicity, at low concentrations, in prokaryotic cells. Nevertheless, one main drawback of transition metals is their toxicity in eukaryotic cells. Here, we show that the barriers to use them as therapeutic agents could be mitigated by combining them with silver. We demonstrate that synergism of combinatorial treatments (Silver/transition metals, including Zn, Co, Cd, Ni, and Cu) increases up to 8-fold their antimicrobial effect, when compared to their individual effects, against E. coli and B. subtilis. We find that most combinatorial treatments exhibit synergistic antimicrobial effects at low/ non-toxic concentrations to human keratinocyte cells, blast and melanoma rat cell lines. Moreover, we show that silver/(Cu, Ni, and Zn) increase prokaryotic cell permeability at sub-inhibitory concentrations, demonstrating this to be a possible mechanism of the synergistic behavior. Together, these results suggest that these combinatorial treatments will play an important role in the future development of antimicrobial agents and treatments against infections. In specific, the cytotoxicity experiments show that the combinations have great potential in the treatment of topical infections

Commissioning of a synchrotron-based proton beam therapy system for use with a Monte Carlo treatment planning system

This work tackles the commissioning and validation of a novel combination of a synchrotron-based proton beam therapy system (Hitachi, Ltd.) for use with a Monte Carlo treatment planning system (TPS). Four crucial aspects in this configuration have been investigated: (1) Monte Carlo-based correction performed by the TPS to the measured integrated depth-dose curves (IDD), (2) circular spot modelling with a single Gaussian function to characterize the synchrotron physical spot, which is elliptical, (3) the modelling of the range shifter that enables using only one set of measurements in open beams, and (4) the Monte Carlo dose calculation model in small fields. Integrated depth-dose curves were measured with a PTW Bragg peak chamber and corrected, with a Monte Carlo model, to account for energy absorbed outside the detector. The elliptical spot was measured by IBA Lynx scintillator, EBT3 films and PTW microDiamond. The accuracy of the TPS (RayStation, RaySearch Laboratories) at spot modelling with a circular Gaussian function was assessed. The beam model was validated using spread-out Bragg peak (SOBP) fields. We took single-point doses at several depths through the central axis using a PTW Farmer chamber, for fields between 2 × 2cm and 30 × 30cm. We checked the range-shifter modelling from open-beam data. We tested clinical cases with film and an ioni- zation chamber array (IBA Matrix). Sigma differences for spots fitted using 2D images and 1D profiles to elliptical and circular Gaussian models were below 0.22 mm. Differences between SOBP measurements at single points and TPS calculations for all fields between 5 × 5 and 30 × 30cm were below 2.3%. Smaller fields had larger differences: up to 3.8% in the 2 × 2cm field. Mean differences at several depths along the central axis were generally below 1%. Differences in range- shifter doses were below 2.4%. Gamma test (3%, 3 mm) results for clinical cases were generally above 95% for Matrix and film. Approaches for modelling synchrotron proton beams have been validated. Dose values for open and range- shifter fields demonstrate accurate Monte Carlo correction for IDDs. Elliptical spots can be successfully modelled using a circular Gaussian, which is accurate for patient calculations and can be used for small fields. A double-Gaussian spot can improve small-field calculations. The range-shifter modelling approach, which reduces clinical commissioning time, is adequat

Adaptive multi-interventional trial platform to improve patient care for fibrotic interstitial lung diseases

BACKGROUND Fibrotic interstitial lung diseases (fILDs) are a heterogeneous group of lung diseases associated with significant morbidity and mortality. Despite a large increase in the number of clinical trials in the last 10 years, current regulatory-approved management approaches are limited to two therapies that prevent the progression of fibrosis. The drug development pipeline is long and there is an urgent need to accelerate this process. This manuscript introduces the concept and design of an innovative research approach to drug development in fILD: a global Randomised Embedded Multifactorial Adaptive Platform in fILD (REMAP-ILD). METHODS Description of the REMAP-ILD concept and design: the specific terminology, design characteristics (multifactorial, adaptive features, statistical approach), target population, interventions, outcomes, mission and values, and organisational structure. RESULTS The target population will be adult patients with fILD, and the primary outcome will be a disease progression model incorporating forced vital capacity and mortality over 12 months. Responsive adaptive randomisation, prespecified thresholds for success and futility will be used to assess the effectiveness and safety of interventions. REMAP-ILD embraces the core values of diversity, equity, and inclusion for patients and researchers, and prioritises an open-science approach to data sharing and dissemination of results. CONCLUSION By using an innovative and efficient adaptive multi-interventional trial platform design, we aim to accelerate and improve care for patients with fILD. Through worldwide collaboration, novel analytical methodology and pragmatic trial delivery, REMAP-ILD aims to overcome major limitations associated with conventional randomised controlled trial approaches to rapidly improve the care of people living with fILD

Adaptive multi-interventional trial platform to improve patient care for fibrotic interstitial lung diseases

BACKGROUND: Fibrotic interstitial lung diseases (fILDs) are a heterogeneous group of lung diseases associated with significant morbidity and mortality. Despite a large increase in the number of clinical trials in the last 10 years, current regulatory-approved management approaches are limited to two therapies that prevent the progression of fibrosis. The drug development pipeline is long and there is an urgent need to accelerate this process. This manuscript introduces the concept and design of an innovative research approach to drug development in fILD: a global Randomised Embedded Multifactorial Adaptive Platform in fILD (REMAP-ILD). METHODS: Description of the REMAP-ILD concept and design: the specific terminology, design characteristics (multifactorial, adaptive features, statistical approach), target population, interventions, outcomes, mission and values, and organisational structure. RESULTS: The target population will be adult patients with fILD, and the primary outcome will be a disease progression model incorporating forced vital capacity and mortality over 12 months. Responsive adaptive randomisation, prespecified thresholds for success and futility will be used to assess the effectiveness and safety of interventions. REMAP-ILD embraces the core values of diversity, equity, and inclusion for patients and researchers, and prioritises an open-science approach to data sharing and dissemination of results. CONCLUSION: By using an innovative and efficient adaptive multi-interventional trial platform design, we aim to accelerate and improve care for patients with fILD. Through worldwide collaboration, novel analytical methodology and pragmatic trial delivery, REMAP-ILD aims to overcome major limitations associated with conventional randomised controlled trial approaches to rapidly improve the care of people living with fILD

At the beginnings of the funerary Megalithism in Iberia at Campo de Hockey necropolis

[EN] The excavations undertaken at the Campo de Hockey site in 2008 led to the identification of a major Neolithic necropolis in the former Island of San Fernando (Bay of Cadiz). This work presents the results of the latest studies, which indicate that the site stands as one of the oldest megalithic necropolises in the Iberian Peninsula. The main aim of this work is to present with precision the chronology of this necropolis through a Bayesian statistical model that confirms that the necropolis was in use from c. 4300 to 3800 cal BC. The presence of prestige grave goods in the earliest and most monumental graves suggest that the Megalithism phenomenon emerged in relation to maritime routes linked to the distribution of exotic products. We also aim to examine funerary practices in these early megalithic communities, and especially their way of life and the social reproduction system. As such, in addition to the chronological information and the Bayesian statistics, we provide the results of a comprehensive interdisciplinary study, including anthropological, archaeometric and genetic data.We wish to express our gratitude to Antonio Saez Espligares (Historical Museum of San Fernando) and Lourdes Lorenzo (Figlina, s.l.) for their support during the archaeological excavation. This research was conducted in the framework of the following research projects: "Analysis of prehistoric societies from the Middle Palaeolithic to the Late Neolithic at both sides of the Strait of Gibraltar: relations and contacts", funded by the State Research Agency (SRA) and the European Regional Development Fund (ERDF). Ref.: HAR2017-87324-P. (2018-2021). "Analisis interdisciplinar para el conocimiento del poblamiento humano de la Bahia de Cadiz durante la Prehistoria Reciente (VI-II milenios a.n.e.)", funded by 2014-2020 ERDF Operational Programme and the Department of Economy, Knowledge, Business and University of the Regional Government of Andalusia. Ref.: FEDER-UCA18-106917 (2020-2023). "Analisis de los isotopos de oxigeno en conchas y de los isotopos estables de oxigeno y carbono en huesos humanos en el poblado neolitico insular de Campo de Hockey (San Fernando, Cadiz)", authorised and funded by CEIMAR. Ref.: CEIJ-015 (2018-2019). Eduardo Molina Piernas acknowledges co-funding from European Social Fund (D1113102E3) and Junta de Andalucia

Effect of ABCB1 and ABCC3 Polymorphisms on Osteosarcoma Survival after Chemotherapy: A Pharmacogenetic Study

Background: Standard treatment for osteosarcoma patients consists of a combination of cisplatin, adriamycin, and methotrexate before surgical resection of the primary tumour, followed by postoperative chemotherapy including vincristine and cyclophosphamide. Unfortunately, many patients still relapse or suffer adverse events. We examined whether common germline polymorphisms in chemotherapeutic transporter and metabolic pathway genes of the drugs used in standard osteosarcoma treatment may predict treatment response. Methodology/Principal Findings: In this study we screened 102 osteosarcoma patients for 346 Single Nucleotide Polymorphisms (SNPs) and 2 Copy Number Variants (CNVs) in 24 genes involved in the metabolism or transport of cisplatin, adriamycin, methotrexate, vincristine, and cyclophosphamide. We studied the association of the genotypes with tumour response and overall survival. We found that four SNPs in two ATP-binding cassette genes were significantly associated with overall survival: rs4148416 in ABCC3 (per-allele HR = 8.14, 95%CI = 2.73-20.2, p-value = 5.1×10 -5), and three SNPs in ABCB1, rs4148737 (per-allele HR = 3.66, 95%CI = 1.85-6.11, p-value = 6.9×10 -5), rs1128503 and rs10276036 (r 2 = 1, per-allele HR = 0.24, 95%CI = 0.11-0.47 p-value = 7.9×10 -5). Associations with these SNPs remained statistically significant after correction for multiple testing (all corrected p-values [permutation test] ≤0.03). Conclusions: Our findings suggest that these polymorphisms may affect osteosarcoma treatment efficacy. If these associations are independently validated, these variants could be used as genetic predictors of clinical outcome in the treatment of osteosarcoma, helping in the design of individualized therapyThis work was supported by the AECC (Asociación Española contra el Cáncer), FIS (Fondo de Investigación Sanitaria-Instituto de Salud Carlos III) and the ‘‘Inocente Inocente’’ Foundatio

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

A Taxonomically-informed Mass Spectrometry Search Tool for Microbial Metabolomics Data

MicrobeMASST, a taxonomically-informed mass spectrometry (MS) search tool, tackles limited microbial metabolite annotation in untargeted metabolomics experiments. Leveraging a curated database of >60,000 microbial monocultures, users can search known and unknown MS/MS spectra and link them to their respective microbial producers via MS/MS fragmentation patterns. Identification of microbial-derived metabolites and relative producers, without a priori knowledge, will vastly enhance the understanding of microorganisms’ role in ecology and human health

The Helicobacter pylori Genome Project : insights into H. pylori population structure from analysis of a worldwide collection of complete genomes

Helicobacter pylori, a dominant member of the gastric microbiota, shares co-evolutionary history with humans. This has led to the development of genetically distinct H. pylori subpopulations associated with the geographic origin of the host and with differential gastric disease risk. Here, we provide insights into H. pylori population structure as a part of the Helicobacter pylori Genome Project (HpGP), a multi-disciplinary initiative aimed at elucidating H. pylori pathogenesis and identifying new therapeutic targets. We collected 1011 well-characterized clinical strains from 50 countries and generated high-quality genome sequences. We analysed core genome diversity and population structure of the HpGP dataset and 255 worldwide reference genomes to outline the ancestral contribution to Eurasian, African, and American populations. We found evidence of substantial contribution of population hpNorthAsia and subpopulation hspUral in Northern European H. pylori. The genomes of H. pylori isolated from northern and southern Indigenous Americans differed in that bacteria isolated in northern Indigenous communities were more similar to North Asian H. pylori while the southern had higher relatedness to hpEastAsia. Notably, we also found a highly clonal yet geographically dispersed North American subpopulation, which is negative for the cag pathogenicity island, and present in 7% of sequenced US genomes. We expect the HpGP dataset and the corresponding strains to become a major asset for H. pylori genomics