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Thiago De Marchi,1,2 Fabiano Frâncio,1,3 João Vitor Ferlito,3 Renata Weigert,3 Cristiane de Oliveira,3 Ana Paula Merlo,3 Délcio Luis Pandini,3 Bolivar Antônio Pasqual-Júnior,3 Daniela Giovanella,3 Shaiane Silva Tomazoni,4,5 Ernesto Cesar Leal-Junior2,4,5 1University Center of Bento Gonçalves (UNICNEC), Bento Gonçalves, Rio Grande do Sul, Brazil; 2Laboratory of Phototherapy and Innovative Technologies in Health (LaPIT), Post-graduate Program in Rehabilitation Sciences, Nove de Julho University, São Paulo, Brazil; 3Hospital Tacchini, Bento Gonçalves, Rio Grande do Sul, Brazil; 4Physiotherapy Research Group, Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway; 5ELJ Consultancy, Scientific Consultants, São Paulo, BrazilCorrespondence: Shaiane Silva TomazoniPhysiotherapy Research Group, Department of Global Public Health and Primary Care, University of Bergen, Alrek helseklynge, blokk D, Årstadveien 17, Bergen, NO-5020, NorwayEmail shaiane.tomazoni@eljconsultancy.comPurpose: We aimed to investigate the effects of photobiomodulation therapy combined with static magnetic field (PBMT-sMF) on the length of intensive care unit (ICU) stay and mortality rate of severe COVID-19 patients requiring invasive mechanical ventilation and assess its role in preserving respiratory muscles and modulating inflammatory processes.Patients and Methods: We conducted a prospectively registered, triple-blinded, randomized, placebo-controlled trial of PBMT-sMF in severe COVID-19 ICU patients requiring invasive mechanical ventilation. Patients were randomly assigned to receive either PBMT-sMF or a placebo daily throughout their ICU stay. The primary outcome was length of ICU stay, defined by either discharge or death. The secondary outcomes were survival rate, diaphragm muscle function, and the changes in blood parameters, ventilatory parameters, and arterial blood gases.Results: Thirty patients were included and equally randomized into the two groups. There were no significant differences in the length of ICU stay (mean difference, MD = − 6.80; 95% CI = − 18.71 to 5.11) between the groups. Among the secondary outcomes, significant differences were observed in diaphragm thickness, fraction of inspired oxygen, partial pressure of oxygen/fraction of inspired oxygen ratio, C-reactive protein levels, lymphocyte count, and hemoglobin (p < 0.05).Conclusion: Among severe COVID-19 patients requiring invasive mechanical ventilation, the length of ICU stay was not significantly different between the PBMT-sMF and placebo groups. In contrast, PBMT-sMF was significantly associated with reduced diaphragm atrophy, improved ventilatory parameters and lymphocyte count, and decreased C-reactive protein levels and hemoglobin count.Trial Registration Number (Clinical Trials.gov): NCT04386694.Keywords: COVID-19, photobiomodulation, intensive care unit, respiratory muscles, ventilatory parameters, mechanical ventilation

Introduction: Assessment of patient satisfaction following an aesthetic surgery has shown an increasing trend over the past years. To date, there is no prospective and comprehensive study evaluating this aspect after surgical facial and neck rejuvenation. The aim of the current work was to address patient satisfaction after face and neck lift surgery using a validated questionnaire.Patients and Methods: We present a prospective and multicenter study (five regional centers) involving all patients undergoing face and neck lift surgery between April 2015 and April 2017 in several French centers for aesthetic surgery. All subjects assessed the FACE-Q scales before the procedure, and furtherly at 3-month, 6-month and 12-month follow-ups.Results: Thirty-six patients were included with a median age of 58.5 years old [IQR 54.0-66.0]. The FACE-Q outcomes were significantly higher at 3-month follow-up (p < 0.001). Seventy-five percent of the patients underwent an additional surgical procedure associated with face and neck lift. Particularly, a combined blepharoplasty led to a significant increase in the score of global facial appearance. The patients considered themselves a mean of 6 years younger in the third month after surgery. These results remained constant at six and twelve postoperative months.Conclusion: A statistically significant improvement of the FACE-Q scores could be highlighted on every scale, with permanent results at 6 and 12 months postsurgery. We hereby present the first study with evidence that appearance and quality of life outcomes can be reliably assessed after rhytidectomy.Level of Evidence IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. [ABSTRACT FROM AUTHOR]

We report our experience with the use of Integra® for the management of severe traumatic wounds of the hand. Fifteen patients were treated with follow-up ranging from 10 to 37 months. Wounds were associated with an osseous and/or joint and/or tendon exposure. Following Integra® placement, patients were managed with dressings and subsequent split-thickness skin grafting an average of 26 days later. Integra® was successful in achieving durable, functional and aesthetic definitive coverage in 13 of 15 applications while allowing a satisfying pollicidigital prehension. Regarding our clinical experience, Integra® is an effective technique to deal with severe wounds of the hand with exposed tendon and/or bone and/or joint, even in the absence of paratenon or periosteum. This can potentially lessen the need for local rotational or free flap coverage and should be taken into consideration as a viable alternative in traumatic reconstruction of the hand. [ABSTRACT FROM PUBLISHER]

Tumor cells can co-opt the promigratory activity of chemokines and their cognate G protein- coupled receptors (GPCRs) to metastasize to regional lymph nodes or distant organs. Indeed, the migration toward SDF-1 (stromal cell-derived factor 1) of tumor cells bearing CXCR4 [chemokine (C-X-C motif) receptor 4] has been implicated in the lymphatic and organ-specific metastasis of various human malignancies, including breast cancer. The downstream mechanisms of CXCR4-mediated migration are not fully elucidated. The study of the precise signaling pathways involved in cell migration and metastasis in each tumor type may help identify novel therapeutic targets for improving cancer therapy. Here we show that blockade of mTOR complex 1 (mTORC1) by Rapamycin or knocking down Raptor decreases CXCR4-Gai mediated cell migration. Moreover, using a spontaneous lymph node metastasis model, we were able to show that pharmacological blockade of mTORC1 decreases lymph node metastasis in vivo. Taken together our data suggest that Rapamycin, a FDA-approved drug, could be beneficial to prevent tumor cells spreading from the primary tumor and metastasize. Molecular events underlying the effects of Rapamycin on CXCR4-induced migration will be presented. This research was supported [in part] by the Intramural Research Program of the NIH, NIDCR. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential cancer therapeutic that induces apoptosis in cancer cells while sparing the non-malignant cells in preclinical models. However, its efficacy in clinical trials has been limited, suggesting unknown modulatory mechanisms responsible for the lack of TRAIL activity in patients. Here, we hypothesized that TRAIL treatment elicits transcriptional changes in triple negative breast cancer (TNBC) cells that alter the immune milieu. To test this, we performed an RNAseq analysis of MDA-MB-231 cells treated with TRAIL, followed by validation in additional TNBC cell lines. TRAIL significantly induces expression of multiple cytokines such as CXCLs 1, 2, 3, 8,11 and IL-6, which are known to modify neutrophil function. Mechanistically, the induction of these cytokines was predominantly mediated by death receptor 5, caspase 8 (but not caspase 8 enzymatic activity), and the non-canonical NFKB2 pathway. The cytokines produced by the TRAIL-treated TNBC cells enhanced chemotaxis of healthy human donor isolated neutrophils. In vivo , TRAIL treated TNBC murine xenograft tumors showed activation of the NFKB2 pathway, elevated production of CXCLs and IL-6, and increased neutrophil recruitment into the tumors. Moreover, donor isolated neutrophils preincubated in supernatants from TRAIL-treated TNBC cells exhibited impaired cytotoxic effect against TNBC cells. Transcriptomic analysis of neutrophils incubated with either TRAIL alone or supernatant of TRAIL-treated TNBC cells revealed increased expression of inflammatory cytokines, immune modulatory genes, immune checkpoint genes, and genes implicated in delayed neutrophil apoptosis. Functional studies with these neutrophils confirmed their suppressive effect on T cell proliferation and an increase in Treg suppressive phenotype. Collectively, our study demonstrates a novel role of TRAIL-induced NFKB2-dependent cytokine production that promotes neutrophil chemotaxis and immune suppression.

PAX3/7 fusion-negative rhabdomyosarcoma (FN-RMS) is a childhood mesodermal lineage malignancy with a poor prognosis for metastatic or relapsed cases. Limited understanding of advanced FN-RMS is partially attributed to the absence of sequential invasion and dissemination events and the challenge in studying cell behavior, using, for example, non-invasive intravital microscopy (IVM), in currently used xenograft models. Here, we developed an orthotopic tongue xenograft model of FN-RMS to study cell behavior and the molecular basis of invasion and metastasis using IVM. FN-RMS cells are retained in the tongue and invade locally into muscle mysial spaces and vascular lumen, with evidence of hematogenous dissemination to the lungs and lymphatic dissemination to lymph nodes. Using IVM of tongue xenografts reveals shifts in cellular phenotype, migration to blood and lymphatic vessels, and lymphatic intravasation. Insight from this model into tumor invasion and metastasis at the tissue, cellular, and subcellular level can guide new therapeutic avenues for advanced FN-RMS., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Membrane remodeling drives a broad spectrum of cellular functions, and it is regulated through mechanical forces exerted on the membrane by cytoplasmic complexes. Here, we investigate how actin filaments dynamically tune their structure to control the active transfer of membranes between cellular compartments with distinct compositions and biophysical properties. Using intravital subcellular microscopy in live rodents we show that a lattice composed of linear filaments stabilizes the granule membrane after fusion with the plasma membrane and a network of branched filaments linked to the membranes by Ezrin, a regulator of membrane tension, initiates and drives to completion the integration step. Our results highlight how the actin cytoskeleton tunes its structure to adapt to dynamic changes in the biophysical properties of membranes., (© 2024 Heydecker et al.)

X-chromosome inactivation (XCI) balances gene expression between the sexes in female mammals. Shortly after fertilization, upregulation of Xist RNA from one X chromosome initiates XCI, leading to chromosome-wide gene silencing. XCI is maintained in all cell types, except the germ line and the pluripotent state where XCI is reversed. The mechanisms triggering Xist upregulation have remained elusive. Here we identify GATA transcription factors as potent activators of Xist. Through a pooled CRISPR activation screen in murine embryonic stem cells, we demonstrate that GATA1, as well as other GATA transcription factors can drive ectopic Xist expression. Moreover, we describe GATA-responsive regulatory elements in the Xist locus bound by different GATA factors. Finally, we show that GATA factors are essential for XCI induction in mouse preimplantation embryos. Deletion of GATA1/4/6 or GATA-responsive Xist enhancers in mouse zygotes effectively prevents Xist upregulation. We propose that the activity or complete absence of various GATA family members controls initial Xist upregulation, XCI maintenance in extra-embryonic lineages and XCI reversal in the epiblast., (© 2023. The Author(s).)

Objectives: To document the level of vaccine hesitancy in caregivers' of children younger than 12 years of age over the course of the pandemic in Pediatric Emergency Departments (ED). Study design Ongoing multicenter, cross-sectional survey of caregivers presenting to 19 pediatric EDs in the USA, Canada, Israel, and Switzerland during first months of the pandemic (phase1), when vaccines were approved for adults (phase2) and most recently when vaccines were approved for children (phase3)., Results: Willingness to vaccinate rate declined over the study period (59.7%, 56.1% and 52.1% in the three phases). Caregivers who are fully vaccinated, who have higher education, and those worried their child had COVID-19 upon arrival to the ED, were more likely to plan to vaccinate in all three phases. Mothers were less likely to vaccinate early in the pandemic, but this hesitancy attenuated in later phases. Older caregivers were more willing to vaccinate, and caregivers of older children were less likely to vaccinate their children in phase 3. During the last phase, willingness to vaccinate was lowest in those who had a primary care provider but did not rely on their advice for medical decisions (34%). Those with no primary care provider and those who do and rely on their medical advice, had similar rates of willingness to vaccinate (55.1% and 52.1%, respectively)., Conclusions: COVID-19 vaccine hesitancy is widespread and growing over time, and public health measures should further try to leverage identified factors associated with hesitancy in order to enhance vaccination rates among children., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)