IntroductionOut-of-hospital cardiac arrest is one of the leading causes of death in industrialised countries. Survival depends on prompt identification of cardiac arrest and on the quality and timing ...of cardiopulmonary resuscitation (CPR) and defibrillation. For laypeople, there has been a growing interest on hands-only CPR, meaning continuous chest compression without interruption to perform ventilations. It has been demonstrated that intentional interruptions in hands-only CPR can increase its quality. The aim of this randomised trial is to compare three CPR protocols performed with different intentional interruptions with hands-only CPR.Methods and analysisThis is a prospective randomised trial performed in eight training centres. Laypeople who passed a basic life support course will be randomised to one of the four CPR protocols in an 8 min simulated cardiac arrest scenario on a manikin: (1) 30 compressions and 2 s pause; (2) 50 compressions and 5 s pause; (3) 100 compressions and 10 s pause; (4) hands-only. The calculated sample size is 552 people. The primary outcome is the percentage of chest compression performed with correct depth evaluated by a computerised feedback system (Laerdal QCPR).Ethics and dissemination. Due to the nature of the study, we obtained a waiver from the Ethics Committee (IRCCS Policlinico San Matteo, Pavia, Italy). All participants will sign an informed consent form before randomisation. The results of this study will be published in peer-reviewed journal. The data collected will also be made available in a public data repository.Trial registration number NCT02632500.
The Tracks survey of people who inject drugs (PWID) collected data in 14 sentinel sites across Canada (2017-2019). These findings describe the prevalence of human immunodeficiency virus (HIV), ...hepatitis C and associated risk behaviours among Indigenous participants.
Information regarding socio-demographics, social determinants of health, use of prevention services and testing, drug use, risk behaviours, and HIV and hepatitis C testing, care and treatment was collected through interviewer-administered questionnaires. Biological samples were tested for HIV, hepatitis C antibodies and hepatitis C ribonucleic acid (RNA). Descriptive statistics were calculated and reviewed by an Indigenous-led advisory group using the Two-Eyed Seeing approach.
Of the 2,383 participants, 997 were Indigenous (82.9% First Nations, 14.9% Métis, 2.2% Inuit). Over half (54.5%) were cisgender male and the average age was 38.9 years. A large proportion (84.0%) reported their mental health as "fair to excellent". High proportions experienced stigma and discrimination (90.2%) and physical, sexual and/or emotional abuse in childhood (87.5%) or with a sexual partner (78.6%). Use of a needle/syringe distribution program (90.5%) and testing for HIV (87.9%) and hepatitis C (87.8%) were high. Prevalence of HIV was 15.4% (78.2% were aware of infection status) and 36.4% were hepatitis C RNA-positive (49.4% were aware of infection status).
High rates of HIV and hepatitis C were identified. Challenges in access to and maintenance of HIV and hepatitis C care and treatment were noted. This information informs harm reduction strategies, including the need to scale-up awareness of prophylaxis in a culturally relevant manner.
Contexte : L’enquête Track auprès des utilisateurs de drogues injectables a permis de recueillir des données dans quatorze sites sentinelles au Canada (2017 à 2019). Ces résultats décrivent la ...prévalence du virus de l’immunodéficience humaine (VIH), de l’hépatite C et des comportements à risque associés à ceux-ci chez les participants autochtones. Méthodes : Des informations sur les caractéristiques sociodémographiques, les déterminants sociaux de la santé, le recours aux services de prévention et au dépistage, la consommation de drogues, les comportements à risque, ainsi que le dépistage, les soins et le traitement du VIH et de l’hépatite C ont été recueillies par l’entremise de questionnaires administrés par un intervieweur. Les échantillons biologiques ont été analysés pour y détecter la présence d’anticorps anti-VIH et anti-hépatite C et l’acide ribonucléique (ARN) de l’hépatite C. Les statistiques descriptives ont été calculées et examinées par un groupe consultatif dirigé par des autochtones, selon l’approche à double perspective (Two-Eyed Seeing). Résultats : Parmi les 2 383 participants, 997 étaient des autochtones (82,9 % étaient des membres des Premières Nations, 14,9 % étaient des Métis et 2,2 % étaient des Inuits). Plus de la moitié (54,5 %) étaient des hommes cisgenres et l’âge moyen était de 38,9 ans. Une grande proportion (84,0 %) des participants ont déclaré que leur santé mentale était de « passable excellente ». Une forte proportion d’entre eux ont été victimes de stigmatisation et de discrimination (90,2 %) ainsi que de violences physiques, sexuelles et/ou psychologiques durant l’enfance (87,5 %) ou de la part d’un partenaire sexuel (78,6 %). Un pourcentage élevé d’entre eux ont déclaré utiliser un programme de distribution de seringues (90,5 %) et avoir été dépisté pour le VIH (87,9 %) et l’hépatite C (87,8 %). La prévalence du VIH était de 15,4 % (78,2 % d’entre eux avaient connaissance de leur statut infectieux) et 36,4 % d’entre eux étaient séropositifs pour l’ARN de l’hépatite C (49,4 % d’entre eux avaient connaissance de leur statut infectieux). Conclusion : L’enquête a révélé des taux élevés de VIH et d’hépatite C. Elle a également révélé des défis liés à l’accès et au maintien des soins et des traitements liés au VIH et à l’hépatite C. Ces renseignements éclairent les stratégies de réduction des méfaits, y compris la nécessité d’accroître la sensibilisation à la prophylaxie d’une manière culturellement pertinente.
Cartilage lesions and osteoarthritis (OA) presents an ever-increasing clinical and socioeconomic burden. Synovial inflammation and articular inflammatory environment are the key factor for ...chondrocytes apoptosis and hypertrophy, ectopic bone formation and OA progression. To effectively treat OA, it is critical to develop a drug that skews inflammation toward a pro-chondrogenic microenvironment. In this narrative and critical review, we aim to see the potential use of immune cells modulation or cell therapy as therapeutic alternatives to OA patients. Macrophages are immune cells that are present in synovial lining, with different roles depending on their subtypes. These cells can polarize to pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes, being the latter associated with wound-healing by the production of ARG-1 and pro-chondrogenic cytokines, such as IL-10, IL-1RA, and TGF-b. Emerging evidence reveals that macrophage shift can be determined by several stimuli, apart from the conventional
IL-4, IL-13, and IL-10. Evidences show the potential of physical exercise to induce type 2 response, favoring M2 polarization. Moreover, macrophages in contact with oxLDL have effect on the production of anabolic mediators as TGF-b. In the same direction, type II collagen, that plays a critical role in development and maturation process of chondrocytes, can also induce M2 macrophages, increasing TGF-b. The mTOR pathway activation in macrophages was shown to be able to polarize macrophages
, though further studies are required. The possibility to use mesenchymal stem cells (MSCs) in cartilage restoration have a more concrete literature, besides, MSCs also have the capability to induce M2 macrophages. In the other direction, M1 polarized macrophages inhibit the proliferation and viability of MSCs and impair their ability to immunosuppress the environment, preventing cartilage repair. Therefore, even though MSCs therapeutic researches advances, other sources of M2 polarization are attractive issues, and further studies will contribute to the possibility to manipulate this polarization and to use it as a therapeutic approach in OA patients.
Drug resistance and relapse remain key challenges in pancreatic cancer. Here, we have used RNA sequencing (RNA-seq), chromatin immunoprecipitation (ChIP)-seq, and genome-wide CRISPR analysis to map ...the molecular dependencies of pancreatic cancer stem cells, highly therapy-resistant cells that preferentially drive tumorigenesis and progression. This integrated genomic approach revealed an unexpected utilization of immuno-regulatory signals by pancreatic cancer epithelial cells. In particular, the nuclear hormone receptor retinoic-acid-receptor-related orphan receptor gamma (RORγ), known to drive inflammation and T cell differentiation, was upregulated during pancreatic cancer progression, and its genetic or pharmacologic inhibition led to a striking defect in pancreatic cancer growth and a marked improvement in survival. Further, a large-scale retrospective analysis in patients revealed that RORγ expression may predict pancreatic cancer aggressiveness, as it positively correlated with advanced disease and metastasis. Collectively, these data identify an orthogonal co-option of immuno-regulatory signals by pancreatic cancer stem cells, suggesting that autoimmune drugs should be evaluated as novel treatment strategies for pancreatic cancer patients.
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•Map of PDAC dependencies using RNA-seq, ChIP-seq, and genome-wide CRISPR screening•Expression and direct utilization of cytokine and immune signals in PDAC stem cells•Nuclear hormone receptor RORγ regulates mouse and human pancreatic cancer•Pharmacologic blockade of RORγ reduces tumor burden and improves survival
Pancreatic cancer stem cells co-opt immuno-regulatory pathways, a vulnerability that could be exploited therapeutically by agents currently in trials for autoimmune diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Healthy individuals exhibit blood pressure variation over a 24-hour period with higher blood pressure during wakefulness and lower blood pressure during sleep. Loss or disruption of the blood ...pressure circadian rhythm has been linked to adverse health outcomes, for example, cardiovascular disease, dementia, and chronic kidney disease. However, the current diagnostic and therapeutic approaches lack sufficient attention to the circadian rhythmicity of blood pressure. Sleep patterns, hormone release, eating habits, digestion, body temperature, renal and cardiovascular function, and other important host functions as well as gut microbiota exhibit circadian rhythms, and influence circadian rhythms of blood pressure. Potential benefits of nonpharmacologic interventions such as meal timing, and pharmacologic chronotherapeutic interventions, such as the bedtime administration of antihypertensive medications, have recently been suggested in some studies. However, the mechanisms underlying circadian rhythm-mediated blood pressure regulation and the efficacy of chronotherapy in hypertension remain unclear. This review summarizes the results of the National Heart, Lung, and Blood Institute workshop convened on October 27 to 29, 2021 to assess knowledge gaps and research opportunities in the study of circadian rhythm of blood pressure and chronotherapy for hypertension.
During the southern summer season of 2015 and 2016, South Africa experienced one of the most severe meteorological droughts since the start of climate recording, due to an exceptionally strong El ...Niño event. To investigate spatiotemporal dynamics of surface moisture and vegetation structure, data from ESA’s Copernicus Sentinel-1/-2 and NASA’s Landsat-8 for the period between March 2015 and November 2017 were utilized. In combination, these radar and optical satellite systems provide promising data with high spatial and temporal resolution. Sentinel-1 C-band data was exploited to derive surface moisture based on a hyper-temporal co-polarized (vertical-vertical—VV) radar backscatter change detection approach, describing dynamics between dry and wet seasons. Vegetation information from a TLS (Terrestrial Laser Scanner)-derived canopy height model (CHM), as well as the normalized difference vegetation index (NDVI) from Sentinel-2 and Landsat-8, were utilized to analyze vegetation structure types and dynamics with respect to the surface moisture index (SurfMI). Our results indicate that our combined radar–optical approach allows for a separation and retrieval of surface moisture conditions suitable for drought monitoring. Moreover, we conclude that it is crucial for the development of a drought monitoring system for savanna ecosystems to integrate land cover and vegetation information for analyzing surface moisture dynamics derived from Earth observation time series.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
•PARP1-dependent PARylation post-translationally modifies and regulates STAT5.•Catalytic PARP inhibition reduces STAT5 stability.•PARP1 loss results in reduced STAT5 signaling and activation of ...downstream targets.•STAT5-activated cancers are sensitive to PARP inhibition.•PARP inhibition overcomes TKI-resistance in FLT3-ITD AML.
Signal transducer and activator of transcription 5 (STAT5) signaling plays a pathogenic role in both hematologic malignancies and solid tumors. In acute myeloid leukemia (AML), internal tandem duplications of fms-like tyrosine kinase 3 (FLT3-ITD) constitutively activate the FLT3 receptor, producing aberrant STAT5 signaling, driving cell survival and proliferation. Understanding STAT5 regulation may aid development of new treatment strategies in STAT5-activated cancers including FLT3-ITD AML. Poly ADP-ribose polymerase (PARP1), upregulated in FLT3-ITD AML, is primarily known as a DNA repair factor, but also regulates a diverse range of proteins through PARylation. Analysis of STAT5 protein sequence revealed putative PARylation sites and we demonstrate a novel PARP1 interaction and direct PARylation of STAT5 in FLT3-ITD AML. Moreover, PARP1 depletion and PARylation inhibition decreased STAT5 protein expression and activity via increased degradation, suggesting that PARP1 PARylation of STAT5 at least in part potentiates aberrant signaling by stabilizing STAT5 protein in FLT3-ITD AML. Importantly for translational significance, PARPis are cytotoxic in numerous STAT5-activated cancer cells and are synergistic with tyrosine kinase inhibitors (TKI) in both TKI-sensitive and TKI-resistant FLT3-ITD AML. Therefore, PARPi may have therapeutic benefit in STAT5-activated and therapy-resistant leukemias and solid tumors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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