Biomaterial Property Effects on Platelets and Macrophages: An in Vitro Study

The purpose of this study was to evaluate the effects of surface properties of bone implants coated with hydroxyapatite (HA) and beta-tricalcium phosphate (beta-TCP) on platelets and macrophages upon implant installation and compare them to grit-blasted Ti and Thermanox used as a control. Surface properties were characterized using scanning electron microscopy, profilometry, crystallography, Fourier transform infrared spectroscopy, and coating stability. For platelets, platelet adherence and morphology were assessed. For macrophages, morphology, proliferation, and polarization were evaluated. Surface characterization showed similar roughness of similar to 2.5 mu m for grit-blasted Ti discs, both with and without coating. Coating stability assessment showed substantial dissolution of HA and beta-TCP coatings. Platelet adherence was significantly higher for grit-blasted Ti, Ti-HA, and Ti-beta-TCP coatings compared to that of cell culture control Thermanox. Macrophage cultures revealed a decreased proliferation on both HA and beta-TCP coated discs compared to both Thermanox and grit-blasted Ti. In contrast, secretion of pro-inflammatory cytokine TNF-alpha and anti-inflammatory cytokine TGF-beta were marginal for grit-blasted Ti and Thermanox, while a coating-dependent increased secretion of pro- and anti-inflammatory cytokines was observed for HA and beta-TCP coatings. The results demonstrated a significantly upregulated pro-inflammatory and anti-inflammatory cytokine secretion and marker gene expression of macrophages on HA and beta-TCP coatings. Furthermore, HA induced an earlier M1 macrophage polarization but more M2 phenotype potency than beta-TCP. In conclusion, our data showed that material surface affects the behaviors of first cell types attached to implants. Due to the demonstrated crucial roles of platelets and macrophages in bone healing and implant integration, this information will greatly aid the design of metallic implants for a higher rate of success in patients.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Radboudumc, Dept Biomat, POB 9101, NL-6500 HB Nijmegen, NetherlandsFed Univ Sao Paulo UNIFESP, Dept Biosci, 136 Silva Jardim St, BR-11015021 Santos, SP, BrazilFed Univ Sao Paulo UNIFESP, Dept Biosci, 136 Silva Jardim St, BR-11015021 Santos, SP, BrazilCAPES: 9424/2014-08Web of Scienc

An Examination of Discrimination on Stress, Depression, and Oppression-Based Trauma During the COVID-19 Pandemic and the Racial Awakening of 2020

Background Discrimination is a pervasive societal issue that monumentally impacts people of color (POC). Many Black, Asian, and Hispanic/Latinx individuals report experiencing race-based discrimination in their lifetime. Discrimination has previously been linked to adverse health outcomes among POC, including stress, depressive, and posttraumatic stress disorder symptoms. These health disparities are posited to have become exacerbated by COVID-19 and the racial awakening of 2020. The current study examined the short- and long-term effects of discrimination on stress, depression, and oppression-based trauma among POC. Methods Participants were (n = 398) who identified as Black, Indigenous, Hispanic/Latinx, and Asian completed an online self-report survey assessing discrimination, depression, stress, and oppression-based trauma collected at 3 time points: (T1) beginning of the COVID-19 pandemic (May 2020), (T2) 6 weeks later during the racial awakening of 2020 (June 2020), (T3) one year later (June 2021). Results Significant positive paths were revealed from T1 discrimination to T2 depression, T2 stress, and T3 oppression-based trauma. The association between T1 discrimination and T3 oppression-based trauma was partially mediated by T2 depression, but not by stress; total and total indirect effects remained significant. The final model accounted for a significant proportion of the variance in T3 oppression-based trauma, T2 depression, and T2 stress. Conclusion Findings are consistent with prior research linking discriminatory experiences with mental health symptomatology and provide evidence that race-based discrimination poses harmful short-and long-term mental health consequences. Further research is necessary to better understand oppression-based trauma to improve the accuracy of clinical diagnosis and treatment of POC

Genetic modifiers of Duchenne muscular dystrophy and dilated cardiomyopathy

OBJECTIVE: Dilated cardiomyopathy (DCM) is a major complication and leading cause of death in Duchenne muscular dystrophy (DMD). DCM onset is variable, suggesting modifier effects of genetic or environmental factors. We aimed to determine if polymorphisms previously associated with age at loss of independent ambulation (LoA) in DMD (rs28357094 in the SPP1 promoter, rs10880 and the VTTT/IAAM haplotype in LTBP4) also modify DCM onset. METHODS: A multicentric cohort of 178 DMD patients was genotyped by TaqMan assays. We performed a time-to-event analysis of DCM onset, with age as time variable, and finding of left ventricular ejection fraction 70 mL/m2 as event (confirmed by a previous normal exam < 12 months prior); DCM-free patients were censored at the age of last echocardiographic follow-up. RESULTS: Patients were followed up to an average age of 15.9 \ub1 6.7 years. Seventy-one/178 patients developed DCM, and median age at onset was 20.0 years. Glucocorticoid corticosteroid treatment (n = 88 untreated; n = 75 treated; n = 15 unknown) did not have a significant independent effect on DCM onset. Cardiological medications were not administered before DCM onset in this population. We observed trends towards a protective effect of the dominant G allele at SPP1 rs28357094 and recessive T allele at LTBP4 rs10880, which was statistically significant in steroid-treated patients for LTBP4 rs10880 (< 50% T/T patients developing DCM during follow-up [n = 13]; median DCM onset 17.6 years for C/C-C/T, log-rank p = 0.027). CONCLUSIONS: We report a putative protective effect of DMD genetic modifiers on the development of cardiac complications, that might aid in risk stratification if confirmed in independent cohorts

Prognostic role of circulating tumor cell trajectories in metastatic colorectal cancer

Abstract: Background: A large amount of evidence from clinical studies has demonstrated that circulating tumor cells are strong predictors of outcomes in many cancers. However, the clinical significance of CTC enumeration in metastatic colorectal cancer is still questioned. The aim of this study was to evaluate the clinical value of CTC dynamics in mCRC patients receiving first-line treatments. Materials and methods: Serial CTC data from 218 patients were used to identify CTC trajectory patterns during the course of treatment. CTCs were evaluated at baseline, at a first-time point check and at the radiological progression of the disease. CTC dynamics were correlated with clinical endpoints. Results: Using a cut-off of ≥1 CTC/7.5 mL, four prognostic trajectories were outlined. The best prognosis was obtained for patients with no evidence of CTCs at any timepoints, with a significant difference compared to all other groups. Lower PFS and OS were recognized in group 4 (CTCs always positive) at 7 and 16 months, respectively. Conclusions: We confirmed the clinical value of CTC positivity, even with only one cell detected. CTC trajectories are better prognostic indicators than CTC enumeration at baseline. The reported prognostic groups might help to improve risk stratification, providing potential biomarkers to monitor first-line treatments

A new case of limb girdle muscular dystrophy 2g in a greek patient, founder effect and review of the literature

Limb girdle muscular dystrophy (LGMD) type 2G is a rare form of muscle disease, described only in a few patients worldwide, caused by mutations in TCAP gene, encoding the protein telethonin. It is characterised by proximal limb muscle weakness associated with distal involvement of lower limbs, starting in the first or second decade of life. We describe the case of a 37-year-old woman of Greek origin, affected by disto-proximal lower limb weakness. No cardiac or respiratory involvement was detected. Muscle biopsy showed myopathic changes with type I fibre hypotrophy, cytoplasmic vacuoles, lipid overload, multiple central nuclei and fibre splittings; ultrastructural examination showed metabolic abnormalities. Next generation sequencing analysis detected a homozygous frameshift mutation in the TCAP gene (c.90_91del), previously described in one Turkish family. Immunostaining and Western blot analysis showed complete absence of telethonin. Interestingly, Single Nucleotide Polymorphism analysis of the 10 Mb genomic region containing the TCAP gene showed a shared homozygous haplotype of both the Greek and the Turkish patients, thus suggesting a possible founder effect of TCAP gene c.90_91del mutation in this part of the Mediterranean area. (C) 2018 Elsevier B.V. All rights reserved.Peer reviewe

Timed rise from floor as a predictor of disease progression in Duchenne muscular dystrophy: An observational study

The role of timed items, and more specifically, of the time to rise from the floor, has been reported as an early prognostic factor for disease progression and loss of ambulation. The aim of our study was to investigate the possible effect of the time to rise from the floor test on the changes observed on the 6MWT over 12 months in a cohort of ambulant Duchenne boys.A total of 487 12-month data points were collected from 215 ambulant Duchenne boys. The age ranged between 5.0 and 20.0 years (mean 8.48 ±2.48 DS).The results of the time to rise from the floor at baseline ranged from 1.2 to 29.4 seconds in the boys who could perform the test. 49 patients were unable to perform the test at baseline and 87 at 12 month The 6MWT values ranged from 82 to 567 meters at baseline. 3 patients lost the ability to perform the 6mwt at 12 months. The correlation between time to rise from the floor and 6MWT at baseline was high (r = 0.6, p<0.01).Both time to rise from the floor and baseline 6MWT were relevant for predicting 6MWT changes in the group above the age of 7 years, with no interaction between the two measures, as the impact of time to rise from the floor on 6MWT change was similar in the patients below and above 350 m. Our results suggest that, time to rise from the floor can be considered an additional important prognostic factor of 12 month changes on the 6MWT and, more generally, of disease progression

Clinical Multigene Panel Sequencing Identifies Distinct Mutational Association Patterns in Metastatic Colorectal Cancer

Extensive molecular characterization of human colorectal cancer (CRC) via Next Generation Sequencing (NGS) indicated that genetic or epigenetic dysregulation of a relevant, but limited, number of molecular pathways typically occurs in this tumor. The molecular picture of the disease is significantly complicated by the frequent occurrence of individually rare genetic aberrations, which expand tumor heterogeneity. Inter- and intratumor molecular heterogeneity is very likely responsible for the remarkable individual variability in the response to conventional and target-driven first-line therapies, in metastatic CRC (mCRC) patients, whose median overall survival remains unsatisfactory. Implementation of an extensive molecular characterization of mCRC in the clinical routine does not yet appear feasible on a large scale, while multigene panel sequencing of most commonly mutated oncogene/oncosuppressor hotspots is more easily achievable. Here, we report that clinical multigene panel sequencing performed for anti-EGFR therapy predictive purposes in 639 formalin-fixed paraffin-embedded (FFPE) mCRC specimens revealed previously unknown pairwise mutation associations and a high proportion of cases carrying actionable gene mutations. Most importantly, a simple principal component analysis directed the delineation of a new molecular stratification of mCRC patients in eight groups characterized by non-random, specific mutational association patterns (MAPs), aggregating samples with similar biology. These data were validated on a The Cancer Genome Atlas (TCGA) CRC dataset. The proposed stratification may provide great opportunities to direct more informed therapeutic decisions in the majority of mCRC cases

A Força Aérea, Enquanto Agente de Protecção Civil, no Combate ao Terrorismo

Este estudo pretende determinar de que forma a Força Aérea Portuguesa (FAP), na sua condição de agente primário de proteção civil, poderá contribuir para a capacidade de resposta nacional perante ações terroristas com recurso a materiais nucleares, radiológicos, biológicos e químicos (NRBQ). Complementarmente será abordado o enquadramento doutrinário da defesa NRBQ (DNRBQ) na FAP e analisadas as suas capacidades reais de intervenção numa resposta a uma situação de terrorismo que envolva este tipo de produtos, relacionando-as com as competências dos outros agentes primários de proteção civil. Nesta perspetiva, aborda-se a estrutura de atuação implementada em alguns países europeus, que servirá como modelo de análise comparativa entre sistemas de resposta a incidentes desta natureza. Caracteriza-se o conceito de terrorismo associado a este tipo de dispositivos e as ações desenvolvidas por organizações internacionais, das quais Portugal é membro, objetivando a criação de mecanismos de resposta capazes de fazer face a este tipo de situações. Para procurar enquadrar a equipa que a FAP disponibiliza ao Estado-Maior General das Forças Armadas (EMGFA), apresenta-se a estrutura de DNRBQ e o modelo de organização da Equipa de Alerta NRBQ, entidade da FAP responsável pela atuação num cenário desta natureza, analisando o sistema nacional de proteção civil e traduzindo para a realidade nacional a capacidade de resposta que os agentes primários dispõem para atuarem em incidentes desta natureza. A forma como este objetivo é atingido é através da formulação de hipóteses que são sujeitas a validação, recorrendo a entrevistas, pesquisa bibliográfica e análise documental. Identifica-se a necessidade da criação de valências que cubram a DNRBQ, como garantia da segurança dos militares destacados em teatros de operações onde esta ameaça seja uma realidade, e adicionalmente a sua utilização pela Força Aérea, enquanto agente de proteção civil, no combate ao terrorismo. Identifica-se também a necessidade de reestruturar a diretiva que regula a DNRBQ, no sentido de a operacionalizar face à realidade da FAP e de traduzir a doutrina a ser adotada. Conclui-se que a DNRBQ deverá ser caracterizada por uma estrutura simples, centralizada num único local, que envolva as áreas operacional e de instrução, constituída por pequenas equipas especializadas que assegurem todas as componentes e, desta forma contribuam para a missão da FAP. No final deste estudo apresentam-se algumas recomendações que poderão contribuir para a reflexão sobre a utilidade das conclusões. Abstract: This study aims to determine how the Portuguese Air Force (PRTAF), in its capability as initial reaction element, may contribute to the national response capability in case of terrorist acts using chemical, biological, radiological and nuclear (CBRN) devices. In addition, the framework of the PRTAF guidelines for CBRN defence is evaluated and the actual response to terrorism acts involving such kind of materials is analyzed, linking them with the skills of the other elements. In this perspective, the response structure implemented in some European countries is discussed to serve as a model for a comparative analysis of the response systems to such incidents. The terrorism concept associated with such devices and the actions taken by the international organizations of which Portugal is a member are characterized aiming the creation of response mechanisms able to cope with such incidents. In order to frame the PRTAF CBRN Response Team available to the Armed Forces General Staff (EMGFA), the CBRN defence structure and the CBRN Response Team organization are presented. The national civil protection system is also considered and the first response capability to act in such incidents is also considered, bearing in mind the national reality. In this work, the hypotheses created were validated using interviews, literature research and document analysis. It is undeniable that there is a need for the CBRN defence capability in the PRTAF to ensure the safety of the troops which are deployed to areas of operations where this threat is a reality. In addition, this capability may be used to combat terrorism in the homeland. There is, also, a need to restructure the FAP CBRN defence directive in order to adjust it to nowadays situations and a need to translate the doctrine to be adopted. As a conclusion, the CBRN defence should be characterised by a simple structure, centralized in one place, involving operational and educational areas, consisting of small specialized teams that will ensure all components and thus contribute to the PRTAF’s main mission. At the end of the present study, there are some recommendations that may contribute to the debate on the usefulness of the findings

Long-term natural history data in Duchenne muscular dystrophy ambulant patients with mutations amenable to skip exons 44, 45, 51 and 53

The aim of this international collaborative effort was to report 36-month longitudinal changes using the 6MWT in ambulant patients affected by Duchenne muscular dystrophy amenable to skip exons 44, 45, 51 or 53