PLoS Pathog

Human Papillomaviruses (HPV) cause widespread infections in humans, resulting in latent infections or diseases ranging from benign hyperplasia to cancers. HPV-induced pathologies result from complex interplays between viral proteins and the host proteome. Given the major public health concern due to HPV-associated cancers, most studies have focused on the early proteins expressed by HPV genotypes with high oncogenic potential (designated high-risk HPV or HR-HPV). To advance the global understanding of HPV pathogenesis, we mapped the virus/host interaction networks of the E2 regulatory protein from 12 genotypes representative of the range of HPV pathogenicity. Large-scale identification of E2-interaction partners was performed by yeast two-hybrid screenings of a HaCaT cDNA library. Based on a high-confidence scoring scheme, a subset of these partners was then validated for pair-wise interaction in mammalian cells with the whole range of the 12 E2 proteins, allowing a comparative interaction analysis. Hierarchical clustering of E2-host interaction profiles mostly recapitulated HPV phylogeny and provides clues to the involvement of E2 in HPV infection. A set of cellular proteins could thus be identified discriminating, among the mucosal HPV, E2 proteins of HR-HPV 16 or 18 from the non-oncogenic genital HPV. The study of the interaction networks revealed a preferential hijacking of highly connected cellular proteins and the targeting of several functional families. These include transcription regulation, regulation of apoptosis, RNA processing, ubiquitination and intracellular trafficking. The present work provides an overview of E2 biological functions across multiple HPV genotypes

The impact of the temporal sequence of cranial radiotherapy and platin-based chemotherapy on hearing impairment in pediatric and adolescent CNS and head-and-neck cancer patients: A report from the PanCareLIFE consortium.

The impact of the temporal sequence by which cranial radiotherapy (CRT) and platin-based chemotherapy (PCth) are administered on sensorineural hearing loss (SNHL) in pediatric and adolescent central nervous system (CNS) and head-and-neck (HN) cancer patients has not yet been studied in detail. We examined the ototoxic effects of sequentially applied CRT and PCth. This study included children and adolescents with CNS and HN tumors who participated in the multicountry PanCareLIFE (PCL) consortium. Audiological outcomes were compared between patients who received CRT prior to PCth and those who received it afterwards. The incidence, degree and posttreatment progression of SNHL, defined as Muenster classification grade ≥MS2b, were evaluated in 141 patients. One hundred and nineteen patients were included in a time-to-onset analysis. Eighty-eight patients received CRT prior to PCth (Group 1) and 53 patients received PCth before CRT (Group 2). Over a median follow-up time of 1.6 years, 72.7% of patients in Group 1 experienced SNHL ≥ MS2b compared to 33.9% in Group 2 (P < .01). A time-to-onset analysis was performed for 74 patients from Group 1 and 45 patients from Group 2. Median time to hearing loss (HL) ≥ MS2b was 1.2 years in Group 1 and 4.4 years in Group 2 (P < .01). Thus, audiological outcomes were better for patients who received CRT after PCth than before. This finding should be further evaluated and considered within clinical practice in order to minimize hearing loss in children and adolescents with CNS and HN tumors

T Cell Cancer Therapy Requires CD40-CD40L Activation of Tumor Necrosis Factor and Inducible Nitric-Oxide-Synthase-Producing Dendritic Cells

Effective cancer immunotherapy requires overcoming immunosuppressive tumor microenvironments. We\ua0found that local nitric oxide (NO) production by tumor-infiltrating myeloid cells is important for adoptively transferred CD8(+) cytotoxic T\ua0cells to destroy tumors. These myeloid cells are phenotypically similar to inducible nitric oxide synthase (NOS2)- and tumor necrosis factor (TNF)-producing dendritic cells (DC), or Tip-DCs. Depletion of immunosuppressive, colony stimulating factor 1 receptor (CSF-1R)-dependent arginase 1(+) myeloid cells enhanced NO-dependent tumor killing. Tumor elimination via NOS2 required the CD40-CD40L pathway. We also uncovered a strong correlation between survival of colorectal cancer patients and NOS2, CD40, and TNF expression in their tumors. Our results identify a network of pro-tumor factors that can be targeted to boost cancer immunotherapies

Supporting work practices through telehealth: impact on nurses in peripheral regions

<p>Abstract</p> <p>Background</p> <p>In Canada, workforce shortages in the health care sector constrain the ability of the health care system to meet the needs of its population and of its health care professionals. This issue is of particular importance in peripheral regions of Quebec, where significant inequalities in workforce distribution between regions has lead to acute nursing shortages and increased workloads. Information and communication technologies (ICTs) are innovative solutions that can be used to develop strategies to optimise the use of available resources and to design new nursing work practices. However, current knowledge is still limited about the real impact of ICTs on nursing recruitment and retention. Our aim is to better understand how work practice reorganization, supported by ICTs, and particularly by telehealth, may influence professional, educational, and organizational factors relating to Quebec nurses, notably those working in peripheral regions.</p> <p>Methods/Design</p> <p>First, we will conduct a descriptive study on the issue of nursing recruitment. Stratified sampling will be used to select approximately twenty innovative projects relating to the reorganization of work practices based upon ICTs. Semi-structured interviews with key informants will determine professional, educational, and organizational recruitment factors. The results will be used to create a questionnaire which, using a convenience sampling method, will be mailed to 600 third year students and recent graduates of two Quebec university nursing faculties. Descriptive, correlation, and hierarchical regression analyses will be performed to identify factors influencing nursing graduates' intentions to practice in peripheral regions. Secondly, we will conduct five case studies pertaining to the issue of nursing retention. Five ICT projects in semi-urban, rural, and isolated regions have been identified. Qualitative data will be collected through field observation and approximately fifty semi-structured interviews with key stakeholders.</p> <p>Discussion</p> <p>Data from both parts of this research project will be jointly analysed using triangulation of researchers, theoretical approaches, methods, and results. Continuous exchanges with decision makers and periodic knowledge transfer activities are planned to facilitate the dissemination and utilization of research results in policies regarding the nursing recruitment and retention.</p

Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci

Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: “Some College” (yes/no, for any education beyond high school) and “Graduated College” (yes/no, for completing a 4-year college degree). Genome-wide significant (p &lt; 5 × 10−8) and suggestive (p &lt; 1 × 10−6) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.</p

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

From the value of mindfulness in the field of mental health to the impact of meditation on Western care practices

La méditation de pleine conscience est en expansion depuis une quarantaine d’années. En définissant plus précisément les contextes d’émergences de deux de types de pratique méditative, le protocole MBSR et la méditation assise selon le courant zen, nous interrogerons le discours anthropologique de ces pratiques. Ce bénéfice réflexif questionnera le possible lien entre la méditation et les pratiques du care en Occident et cela afin d’apporter des réponses structurées à la problématique : en quoi la MPC, remise dans l’un de ses contextes culturels d’émergence, peut-elle être un élément de soutien de la pratique du care en Occident ? Deux études ont été effectuées auprès de deux populations : des soignants et des enseignants. L’objet de ces études est de questionner les effets de la méditation de pleine conscience sur les qualités de savoir-être. Les résultats montrent que l’entraînement à une attitude de sollicitude, permet de prendre la mesure du réajustement de l’engagement affectif dans le rapport au care : le seul exercice de la méditation assise entraine concrètement une disponibilité et non un supplément de disposition pour la pratique du « prendre soin ».Mindfulness meditation has been expanding over the past forty years. By defining more precisely the contexts of emergence of two types of meditative practice, the MBSR protocol and Zen sitting meditation, we will question the anthropological discourse of these practices. This reflexive benefit will question the possible link between meditation and care practices in the West in order to provide structured answers to the following question: in what way can GPA, put back into one of its cultural contexts of emergence, be an element of support for care practices in the West? Two studies were conducted with two populations : caregivers and teachers. The purpose of these studies is to question the effects of mindfulness meditation on the qualities of being. The results show that training in an attitude of care allows us to measure the readjustment of the affective commitment in the relationship to care: the sole exercise of sitting meditation concretely leads to an availability and not to an additional disposition for the practice of "taking care"

From the value of mindfulness in the field of mental health to the impact of meditation on Western care practices

La méditation de pleine conscience est en expansion depuis une quarantaine d’années. En définissant plus précisément les contextes d’émergences de deux de types de pratique méditative, le protocole MBSR et la méditation assise selon le courant zen, nous interrogerons le discours anthropologique de ces pratiques. Ce bénéfice réflexif questionnera le possible lien entre la méditation et les pratiques du care en Occident et cela afin d’apporter des réponses structurées à la problématique : en quoi la MPC, remise dans l’un de ses contextes culturels d’émergence, peut-elle être un élément de soutien de la pratique du care en Occident ? Deux études ont été effectuées auprès de deux populations : des soignants et des enseignants. L’objet de ces études est de questionner les effets de la méditation de pleine conscience sur les qualités de savoir-être. Les résultats montrent que l’entraînement à une attitude de sollicitude, permet de prendre la mesure du réajustement de l’engagement affectif dans le rapport au care : le seul exercice de la méditation assise entraine concrètement une disponibilité et non un supplément de disposition pour la pratique du « prendre soin ».Mindfulness meditation has been expanding over the past forty years. By defining more precisely the contexts of emergence of two types of meditative practice, the MBSR protocol and Zen sitting meditation, we will question the anthropological discourse of these practices. This reflexive benefit will question the possible link between meditation and care practices in the West in order to provide structured answers to the following question: in what way can GPA, put back into one of its cultural contexts of emergence, be an element of support for care practices in the West? Two studies were conducted with two populations : caregivers and teachers. The purpose of these studies is to question the effects of mindfulness meditation on the qualities of being. The results show that training in an attitude of care allows us to measure the readjustment of the affective commitment in the relationship to care: the sole exercise of sitting meditation concretely leads to an availability and not to an additional disposition for the practice of "taking care"