Search

Purpose of Review: A global study of multimorbidity in schizophrenia, especially of the association with physical conditions, might offer much needed etiological insights. Recent Findings: Our review suggests that life-style factors and medication related to schizophrenia are only part of the explanation of the increase in risk for cardiovascular, metabolic, pulmonary disorders, and some cancers. Positive associations with autoimmune disorders (with the exception of rheumatoid arthritis) and epilepsy are promising avenues of research but to date have not been fully exploited. The same holds for the negative comorbidity seen for rheumatoid arthritis and some cancers (e.g., prostate). Summary: As a whole, our review suggests that most of the explored conditions have a different prevalence in schizophrenia than in the general population. Several hypotheses emerged from this review such as the role of immune and genetic factors, of sex hormones, and of more general variability factors. [ABSTRACT FROM AUTHOR]

Paracetamol is the most widely used analgesic drug in the world. However, the risk and the severity of poisoning with this medication are often underestimated. A simple and cost-effective method for screening paracetamol poisoning by using thin-layer chromatography (TLC) and a smartphone has been developed. Successful liquid‒liquid extraction of the drug from plasma was carried out. Then, samples were spotted on a TLC plate and eluted by a mobile phase of acetone‒hexane‒ammonia (4:5:0.1, V/V). JustTLC software was used to analyze and quantify paracetamol spots. The results of the analytical validation showed that our method is linear in the range of 80–180 µg/mL with a correlation coefficient of R2 > 0.99. The precision, the accuracy, and the robustness of the method were also verified. The limits of detection and quantification were 8.79 and 26.65 µg/mL, respectively. The comparison with an enzyme immunoassay and high-performance liquid chromatography (HPLC) method was satisfactory. This methodology opens up new promising perspectives in toxicology laboratories. [ABSTRACT FROM AUTHOR]

Simple Summary: Foot diseases are a widespread issue in dairy herds that lead to economic losses and cow welfare alteration. Time is a limited key resource for farmers in herd management and especially for the control of lameness. The aim of this study is to determine the most effective time to be allocated for digital dermatitis management and to quantify the marginal economic gain for extra time devoted to digital dermatitis management in dairy herds. This study shows that allocating less time to lameness detection and more to footbath application is more profitable for both farmers and animal welfare. The optimal time to spend on footbath application ranges from 17.8 to 22.3 h/month. The objective of this study is to determine the most effective time allocation for digital dermatitis management and to quantify the marginal economic gain from extra time devoted to digital dermatitis management. The model simulating foot disease occurrence and the associated management was Dairy Health Simulator©. Then, an econometric model was applied to identify the relationship between the dairy workshop's gross margin and time for lameness management as well as the hourly marginal gain curve associated with lameness management. The gross margin was optimized under two constraints, i.e., the overall time spent for lameness management and the mean lameness duration (mimicking cow welfare). The results show that allocating less time to lameness detection and more to footbath application can contribute as follows: (i) reduces time spent for lameness management, (ii) maintains the best welfare level, and (iii) obtains the highest gross margin. The optimal time to devote to footbath application ranged from 17.8 to 22.3 h/month. A hiring strategy was investigated, and the break-even point ranged from 16.1 to 19.8 h/month. The recommended time to spend on footbath application is relatively important; therefore, stakeholders should consider the importance of lameness to the dairy industry and should devote enough time for footbath applications. [ABSTRACT FROM AUTHOR]

Background New generation ultra-fast fluorescence confocal microscopy allows the ex vivo intraoperative analysis of fresh tissue. The High resolution Imaging for Breast carcInoma detection in ex vivo Specimens after breast Conserving sUrgery by hiStolog Scanner (HIBISCUSS) project aimed to develop an online learning program to recognize the main breast tissue features on ultra-fast fluorescence confocal microscopy images and to evaluate the performance of surgeons and pathologists in diagnosing cancerous and non-cancerous breast tissue in ultra-fast fluorescence confocal microscopy images. Methods Patients who underwent conservative surgery or mastectomy for breast carcinoma (invasive or in situ lesions) were included. The fresh specimens were stained with a fluorescent dye and imaged using a large field-of-view (20 cm2) ultra-fast fluorescence confocal microscope. Results One hundred and eighty-one patients were included. The images from 55 patients were annotated to generate learning sheets and images from 126 patients were blindly interpreted by seven surgeons and two pathologists. The time for tissue processing and ultra-fast fluorescence confocal microscopy imaging was between 8 and 10 min. The training program was composed of 110 images divided into nine learning sessions. The final database for blind performance assessment comprised 300 images. The mean duration for one training session and one performance round was 17 and 27 min respectively. The performance of pathologists was almost perfect with 99.6 per cent (standard deviation (s.d.) 5.4 per cent) accuracy. Surgeons' accuracy significantly increased (P = 0.001) from 83 per cent (s.d. 8.4 per cent) in round 1 to 98 per cent (s.d. 4.1 per cent) in round 7 as well as the sensitivity (P = 0.004). Specificity increased without significance from 84 per cent (s.d. 16.7 per cent) in round 1 to 87 per cent (s.d. 16.4 per cent) in round 7 (P = 0.060). Conclusion Pathologists and surgeons showed a short learning curve in differentiating breast cancer from non-cancerous tissue in ultra-fast fluorescence confocal microscopy images. Performance assessment for both specialties supports ultra-fast fluorescence confocal microscopy evaluation for intraoperative management. Registration number NCT04976556 (http://www.clinicaltrials.gov). [ABSTRACT FROM AUTHOR]

Summary: Low baseline NK‐cell counts (NKCCs) in patients with diffuse large B‐cell lymphoma (DLBCL) are associated with a poor prognosis. The REMARC phase III trial (NCT01122472) showed that lenalidomide maintenance prolonged PFS in rituximab–chemotherapy responders. We conducted a REMARC ancillary study analysing the impact of lenalidomide maintenance on the prognostic value of low NKCCs. Blood samples from 335 elderly French patients enrolled in the REMARC trial were analysed by flow cytometry to obtain NKCCs at diagnosis (n = 220), at randomization (n = 186) and/or six months after randomization (n = 184). Baseline NKCCs < 100 cells/μl were associated with shorter PFS and OS (HRs = [2.2 (1.4, 3.3), p < 0.001] and [2.8 (1.7, 4.5), p < 0.001], respectively), independently of aaIPI. In a competing risk analysis, low NKCCs at baseline were associated with a higher risk of relapse/progression (p = 0.0025), but not of death without progression (p = 0.33). Lenalidomide did not affect the prognosis value of low baseline NKCCs (p = 0.6349). Similar results were obtained for low NKCCs at randomization. Our results demonstrate that low NKCCs at baseline and post rituximab–chemotherapy are robust prognostic factors in DLBCL and reveal that lenalidomide has no impact on this parameter. Other therapeutic strategies aiming at improving NK‐cell function could improve outcomes in DLBCL. [ABSTRACT FROM AUTHOR]

Establishing long-term microbiome-based monitoring programs is critical for managing and conserving wild fish populations in response to climate change. In most cases, these studies have been conducted on gut and, to a lesser extent, skin (mucus) microbiomes. Here, we exploited the concept of liquid biopsy to study the circulating bacterial microbiome of two Northern halibut species of economic and ecological importance. Amplification and sequencing of the 16S rRNA gene were achieved using a single drop of blood fixed on FTA cards to identify the core blood microbiome of Atlantic and Greenland halibut populations inhabiting the Gulf of St. Lawrence, Canada. We provide evidence that the circulating microbiome DNA (cmDNA) is driven by genetic and environmental factors. More specifically, we found that the circulating microbiome signatures are species-specific and vary according to sex, size, temperature, condition factor, and geographical localization. Overall, our study provides a novel approach for detecting dysbiosis signatures and the risk of disease in wild fish populations for fisheries management, most notably in the context of climate change. [ABSTRACT FROM AUTHOR]

Our understanding of how microbiome signatures are modulated in wild fish populations remains poorly developed and has, until now, mostly been inferred from studies in commercial and farmed fish populations. Here, for the first time, we have studied changes in the skin and blood microbiomes of the Salmo trutta population of the volcanic Kerguelen archipelago located at the northern limit of the Antarctic Ocean. The Kerguelen Islands present a natural framework of population expansion and reveal a likely situation representing further climate change in distribution areas. Our results showed that S. trutta of the Kerguelen Islands has a microbiome signature distinct from those of salmonids of the Northern Hemisphere. Our study also revealed that the skin and blood microbiomes differ between sedentary and migratory S. trutta. While 18 phyla were shared between both groups of trout, independent of the compartment, 6 phyla were unique to migratory trout. Further analyses showed that microbiome signatures undergo significant site-specific variations that correlate, in some cases, with the peculiarity of specific ecosystems. Our study also revealed the presence of potential pathogens at particular sites and the impact of abiotic factors on the microbiome, most notably due to the volcanic nature of the environment. This study contributes to a better understanding of the factors that modulate the microbiome signatures of migratory and sedentary fish populations. It will also help to better monitor the impacts of climate change on the colonization process in the sub-Antarctic region. [ABSTRACT FROM AUTHOR]

Simple Summary: The present work proposes an original approach for antimicrobial (AM) resistance reduction based on marginal abatement cost. The optimal use of AMs for dairy cows is defined, and the costs of decreasing antimicrobial use (AMU) below the optimal level and increasing AMU above the optimal level are assessed. Maintaining udder health is the primary indication for antimicrobial use (AMU) in dairy production, and modulating this application is a key factor in decreasing AMU. Defining the optimal AMU and the associated practical rules is challenging since AMU interacts with many parameters. To define the trade-offs between decreased AMU, labor and economic performance, the bioeconomic stochastic simulation model DairyHealthSim (DHS)© was applied to dairy cow mastitis management and coupled to a mean variance optimization model and marginal abatement cost curve (MACC) analysis. The scenarios included three antimicrobial (AM) treatment strategies at dry-off, five types of general barn hygiene practices, five milking practices focused on parlor hygiene levels and three milk withdrawal strategies. The first part of economic results showed similar economic performances for the blanked dry-off strategy and selective strategy but demonstrated the trade-off between AMU reduction and farmers' workload. The second part of the results demonstrated the optimal value of the animal level of exposure to AM (ALEA). The MACC analysis showed that reducing ALEA below 1.5 was associated with a EUR 10,000 loss per unit of ALEA on average for the farmer. The results call for more integrative farm decision processes and bioeconomic reasoning to prompt efficient public interventions. [ABSTRACT FROM AUTHOR]

To respond to the antimicrobial resistance (AMR) threat, public health entities implement policies aiming to reduce antimicrobial use (AMU) in livestock systems, in which policy success and sustainability might be subject to the social acceptability of the novel regulatory environment. Therefore, consistent methods that gather and synthesize preferences of stakeholder groups are needed during the policy design. The objective of this study was to present a methodology for evaluating the acceptability of potential strategies to reduce AMU using multi-criteria decision analysis (MCDA) using French dairy industry as a model. Preference-ranking organization methods for enrichment evaluations were applied to rank stakeholders' acceptance of four different potential AMU reduction strategies: 1. Baseline AMU regulations in France; 2. Total interdiction of AMU; 3. Interdiction of prophylaxis and metaphylaxis AMU; and 4. Subsidies to reduce AMU by 25%. A total of 15 stakeholders (consumers, n = 10; farmers, n = 2; public health representatives, n = 3) representing the French dairy sector and public health administration participated in the acceptance weighting of the strategies in relation with their impact on environmental, economic, social, and political criteria. We established a MCDA methodology and result-interpretation approach that can assist in prioritizing alternatives to cope with AMR in the French dairy industry or in other livestock systems. Our MCDA framework showed that consumers and public health representatives preferred alternatives that consider the restriction of AMU, whereas farmers preferred to maintain baseline policy. [ABSTRACT FROM AUTHOR]

Impacts of climate changes are particularly severe in polar regions where warmer temperatures and reductions in sea-ice covers threaten the ecological integrity of marine coastal ecosystems. Because of their wide distribution and their ecological importance, mussels are currently used as sentinel organisms in monitoring programs of coastal ecosystems around the world. In the present study, we exploited the concept of liquid biopsy combined to a logistically friendly sampling method to study the hemolymphatic bacterial microbiome in two mussel species (Aulacomya atra and Mytilus platensis) in Kerguelen Islands, a remote Subantarctic volcanic archipelago. We found that the circulating microbiome signatures of both species differ significantly even though their share the same mussel beds. We also found that the microbiome differs significantly between sampling sites, often correlating with the particularity of the ecosystem. Predictive models also revealed that both species have distinct functional microbiota, and that the circulating microbiome of Aulacomya atra was more sensitive to changes induced by acute thermal stress when compared to Mytilus platensis. Taken together, our study suggests that defining circulating microbiome is a useful tool to assess the health status of marine ecosystems and to better understand the interactions between the sentinel species and their habitat. [ABSTRACT FROM AUTHOR]

Impacts of climate changes are particularly severe in polar regions where warmer temperatures and reductions in sea-ice covers threaten the ecological integrity of marine coastal ecosystems. Because of their wide distribution and their ecological importance, mussels are currently used as sentinel organisms in monitoring programs of coastal ecosystems around the world. In the present study, we exploited the concept of liquid biopsy combined to a logistically friendly sampling method to study the hemolymphatic bacterial microbiome in two mussel species (Aulacomya atra and Mytilus platensis) in Kerguelen Islands, a remote Subantarctic volcanic archipelago. We found that the circulating microbiome signatures of both species differ significantly even though their share the same mussel beds. We also found that the microbiome differs significantly between sampling sites, often correlating with the particularity of the ecosystem. Predictive models also revealed that both species have distinct functional microbiota, and that the circulating microbiome of Aulacomya atra was more sensitive to changes induced by acute thermal stress when compared to Mytilus platensis. Taken together, our study suggests that defining circulating microbiome is a useful tool to assess the health status of marine ecosystems and to better understand the interactions between the sentinel species and their habitat. [ABSTRACT FROM AUTHOR]

Objectives: Probe-based confocal laser endomicroscopy (pCLE) is a noninvasive and real-time imaging technique allowing acquisition of in situ images of the tissue microarchitecture during oral surgery. We aimed to assess the diagnostic performance of pCLE combined with patent blue V (PB) in improving the management of early oral cavity, oro/hypopharyngeal, and laryngeal cancer by imaging squamous cell carcinoma in vivo. Materials and methods: The prospective study enrolled 44 patients with early head and neck lesions. All patients underwent white-light inspection or panendoscopy depending on the lesion's location, followed by pCLE imaging of the tumor core and its margins after topical application of PB. Each zone imaged by pCLE was interpreted at distance of the exam by three pathologists blinded to final histology. Results: Most imaged zones could be presented to pathologists; the final sensitivity and specificity of pCLE imaging in head and neck cancers was 73.2–75% and 30–57.4%, respectively. During imaging, head and neck surgeons encountered some challenges that required resolving, such as accessing lesions with the flexible optical probe, achieving sufficiently precise imaging on the targeted tissues, and heterogeneous tissue staining by fluorescent dye. Conclusion: Final sensitivity scores were reasonable but final specificity scores were low. pCLE zones used to calculate specificity were acquired in areas of tumor margins, and the poor quality of the images acquired in these areas explains the final low specificity scores. Clinical relevance: Practical adjustments and technical training are needed to analyze head and neck lesions in various anatomical sites in real-time by pCLE. [ABSTRACT FROM AUTHOR]

Aims: Gene x environment (G×E) interactions, i.e. genetic modulation of the sensitivity to environmental factors and/or environmental control of the gene expression, have not been reliably established regarding aetiology of psychotic disorders. Moreover, recent studies have shown associations between the polygenic risk scores for schizophrenia (PRS-SZ) and some risk factors of psychotic disorders, challenging the traditional gene v. environment dichotomy. In the present article, we studied the role of GxE interaction between psychosocial stressors (childhood trauma, stressful life-events, self-reported discrimination experiences and low social capital) and the PRS-SZ on subclinical psychosis in a population-based sample. Methods: Data were drawn from the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study, in which subjects without psychotic disorders were included in six countries. The sample was restricted to European descendant subjects (n = 706). Subclinical dimensions of psychosis (positive, negative, and depressive) were measured by the Community Assessment of Psychic Experiences (CAPE) scale. Associations between the PRS-SZ and the psychosocial stressors were tested. For each dimension, the interactions between genes and environment were assessed using linear models and comparing explained variances of 'Genetic' models (solely fitted with PRS-SZ), 'Environmental' models (solely fitted with each environmental stressor), 'Independent' models (with PRS-SZ and each environmental factor), and 'Interaction' models (Independent models plus an interaction term between the PRS-SZ and each environmental factor). Likelihood ration tests (LRT) compared the fit of the different models. Results: There were no genes-environment associations. PRS-SZ was associated with positive dimensions (β = 0.092, R 2 = 7.50%), and most psychosocial stressors were associated with all three subclinical psychotic dimensions (except social capital and positive dimension). Concerning the positive dimension, Independent models fitted better than Environmental and Genetic models. No significant GxE interaction was observed for any dimension. Conclusions: This study in subjects without psychotic disorders suggests that (i) the aetiological continuum hypothesis could concern particularly the positive dimension of subclinical psychosis, (ii) genetic and environmental factors have independent effects on the level of this positive dimension, (iii) and that interactions between genetic and individual environmental factors could not be identified in this sample. [ABSTRACT FROM AUTHOR]

The influence of psychosocial stressors on psychosis risk has usually been studied in isolation and after the onset of the disorder, potentially ignoring important confounding relationships or the fact that some stressors that may be the consequence of the disorder rather than preexisting. The study of subclinical psychosis could help to address some of these issues. In this study, we investigated whether there was (i) an association between dimensions of subclinical psychosis and several psychosocial stressors including: childhood trauma, self-reported discrimination experiences, low social capital, and stressful life experiences, and (ii) any evidence of environment–environment (ExE) interactions between these factors. Data were drawn from the EUGEI study, in which healthy controls (N = 1497) and siblings of subjects with a psychotic disorder (N = 265) were included in six countries. The association between psychosocial stressors and subclinical psychosis dimensions (positive, negative and depressive dimension as measured by the Community Assessment of Psychic Experiences (CAPE) scale) and possible ExE interactions were assessed using linear regression models. After adjusting for sex, age, ethnicity, country, and control/sibling status, childhood trauma (β for positive dimension: 0.13, negative: 0.49, depressive: 0.26) and stressful life events (positive: 0.08, negative: 0.16, depressive: 0.17) were associated with the three dimensions. Lower social capital was associated with the negative and depression dimensions (negative: 0.26, depressive: 0.13), and self-reported discrimination experiences with the positive dimension (0.06). Our findings are in favor of independent, cumulative and non-specific influences of social adversities in subclinical psychosis in non-clinical populations, without arguments for E × E interactions. [ABSTRACT FROM AUTHOR]

Keywords: AL amyloidosis; cardiac amyloidosis; venetoclax; BH3 mimetics; apoptosis EN AL amyloidosis cardiac amyloidosis venetoclax BH3 mimetics apoptosis 674 677 4 05/03/21 20210501 NES 210501 Systemic light-chain (AL) amyloidosis has a poor prognosis, especially when progressive heart failure occurs. Venetoclax induces profound and sustained responses in patients with relapsed/refractory light-chain amyloidosis We report here the results of a single-centre retrospective study on consecutive R/R AL amyloidosis patients treated off-label with venetoclax in a French academic referral centre between February 2017 and January 2020. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18-22 April 2004. [Extracted from the article]

Background The recent success achieved with the use of B cell-depleting agents in some patients with minimal change nephrotic syndrome (MCNS) suggests an unexpected role for B lymphocytes in the pathogenesis of this immune-mediated glomerular disease. Nevertheless, no extensive B-cell phenotyping analysis has ever been performed in untreated adult patients soon after MCNS diagnosis. Methods We investigated the distribution of the different B-cell subpopulations in 22 untreated adult patients with biopsy-proven MCNS [MCNS relapse (MCNS-Rel)]. We compared these data with those for 24 healthy controls, 13 MCNS patients in remission (with no specific treatment) and 19 patients with idiopathic membranous nephropathy (IMN). Results Patients with MCNS-Rel or IMN had higher proteinuria and lower serum albumin and gammaglobulin levels (P < 0.0001 for all comparisons) than MCNS patients in remission. Plasmablasts were the only B-cell subsets present at significantly higher levels in MCNS-Rel patients than in the patients of the other three groups (P < 0.05 for all comparisons). The lower albumin levels and higher proteinuria levels were positively correlated with the percentage of circulating plasmablasts (Spearman test's ρ = −0.54, P = 0.01 and ρ = 0.65, P = 0.002, respectively). Similarly, the increase of immunoglobulin M (IgM) and the decrease of IgG levels were significantly associated with the percentage of plasmablasts in MCNS-Rel patients (Spearman's ρ = 0.36, P = 0.01 and Spearman's ρ = −0.60, P = 0.01, respectively). Increased production of interleukin (IL)-21, IL-6 and B-cell activating factor (BAFF) in the serum of MCNS-Rel patients was found significantly correlated with the percentage of plasmablasts (ρ = 0.72, P = 0.0002, ρ = 0.49, P = 0.04 and ρ = 0.62, P = 0.009, respectively). Conclusions An increase in the proportion of circulating plasmablasts seems to be a hallmark of untreated MCNS in adult patients. Further studies are required to more precisely determine the phenotype and functions of these cells. [ABSTRACT FROM AUTHOR]

Eighteen patients received a dose of 20 mg at each daratumumab infusions, three patients received 10 mg and four patients did not receive dexamethasone because of dexamethasone induced cardiac failure. Systemic light-chain (AL) amyloidosis is a plasma cell disorder characterized by extracellular deposition of monoclonal immunoglobulin light chains leading to organ dysfunction. We assessed the efficacy of daratumumab in such AL patients with severe cardiac involvement by performing a single-center retrospective study that included consecutive patients with Mayo Clinic stage III AL treated with daratumumab from May 2017 to August 2019. However, patients with severe cardiac amyloidosis involvement, defined as stage IIIb by the Mayo classification with European modification, have been excluded from these studies and little data on daratumumab use are available for patients with severe cardiac involvement. [Extracted from the article]

Background: Biomarkers of disease severity might help individualizing the management of patients with the acute respiratory distress syndrome (ARDS). Whether the alveolar compartmentalization of biomarkers has a clinical significance in patients with pneumonia-related ARDS is unknown. This study aimed at assessing the interrelation of ARDS/sepsis biomarkers in the alveolar and blood compartments and explored their association with clinical outcomes.Methods: Immunocompetent patients with pneumonia-related ARDS admitted between 2014 and 2018 were included in a prospective monocentric study. Bronchoalveolar lavage (BAL) fluid and blood samples were obtained within 48 h of admission. Twenty-two biomarkers were quantified in BAL fluid and serum. HLA-DR+ monocytes and CD8+ PD-1+ lymphocytes were quantified using flow cytometry. The primary clinical endpoint of the study was hospital mortality. Patients undergoing a bronchoscopy as part of routine care were included as controls.Results: Seventy ARDS patients were included. Hospital mortality was 21.4%. The BAL fluid-to-serum ratio of IL-8 was 20 times higher in ARDS patients than in controls (p < 0.0001). ARDS patients with shock had lower BAL fluid-to-serum ratio of IL-1Ra (p = 0.026), IL-6 (p = 0.002), IP-10/CXCL10 (p = 0.024) and IL-10 (p = 0.023) than others. The BAL fluid-to-serum ratio of IL-1Ra was more elevated in hospital survivors than decedents (p = 0.006), even after adjusting for SOFA and driving pressure (p = 0.036). There was no significant association between alveolar or alveolar/blood monocytic HLA-DR or CD8+ lymphocytes PD-1 expression and hospital mortality.Conclusions: IL-8 was the most compartmentalized cytokine and lower BAL fluid-to-serum concentration ratios of IL-1Ra were associated with hospital mortality in patients with pneumonia-associated ARDS. [ABSTRACT FROM AUTHOR]

Rationale: Uncontrolled inflammatory innate response and impaired adaptive immune response are associated with clinical severity in patients with coronavirus disease (COVID-19).Objectives: To compare the immunopathology of COVID-19 acute respiratory distress syndrome (ARDS) with that of non-COVID-19 ARDS, and to identify biomarkers associated with mortality in patients with COVID-19 ARDS.Methods: Prospective observational monocenter study. Immunocompetent patients diagnosed with RT-PCR-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and ARDS admitted between March 8 and March 30, 2020, were included and compared with patients with non-COVID-19 ARDS. The primary clinical endpoint of the study was mortality at Day 28. Flow cytometry analyses and serum cytokine measurements were performed at Days 1-2 and 4-6 of ICU admission.Measurements and Main Results: As compared with patients with non-COVID-19 ARDS (n = 36), those with COVID-19 (n = 38) were not significantly different regarding age, sex, and Sequential Organ Failure Assessment and Simplified Acute Physiology Score II scores but exhibited a higher Day-28 mortality (34% vs. 11%, P = 0.030). Patients with COVID-19 showed profound and sustained T CD4+ (P = 0.002), CD8+ (P < 0.0001), and B (P < 0.0001) lymphopenia, higher HLA-DR expression on monocytes (P < 0.001) and higher serum concentrations of EGF (epithelial growth factor), GM-CSF, IL-10, CCL2/MCP-1, CCL3/MIP-1a, CXCL10/IP-10, CCL5/RANTES, and CCL20/MIP-3a. After adjusting on age and Sequential Organ Failure Assessment, serum CXCL10/IP-10 (P = 0.047) and GM-CSF (P = 0.050) were higher and nasopharyngeal RT-PCR cycle threshold values lower (P = 0.010) in patients with COVID-19 who were dead at Day 28.Conclusions: Profound global lymphopenia and a "chemokine signature" were observed in COVID-19 ARDS. Increased serum concentrations of CXCL10/IP-10 and GM-CSF, together with higher nasopharyngeal SARS-CoV-2 viral load, were associated with Day-28 mortality. [ABSTRACT FROM AUTHOR]

In his PhD thesis Shih characterized the relationship between two graphs, where the cycle space of the first is included in the cycle space of the second and the dimension of the cycle spaces differ by one [7]. However, this result never appeared in a refereed publication. As a consequence this theorem has not received the attention it deserves. We give a simpler and shorter proof of this result as well as several restatements that are of independent interest. In addition, we mention applications to even-cycle matroids, even-cut matroids and frame matroids. [ABSTRACT FROM AUTHOR]

The rising public health threat of antimicrobial resistance, the influence of food service companies, as well as the overall lack of positive image of using medical products in intensive farming are major drivers curbing antimicrobial use. In the future, government policies may affect practices of antimicrobial use in beef production in feedlots, a prominent current user of antimicrobials in animal agriculture, but also the agricultural industry generating the highest cash receipt in the U.S. Our objective was to estimate the cost effect from the following policies in feedlots: 1) using antimicrobials for disease prevention, control, and treatment; 2) using antimicrobials only for treatment of disease; and 3) not using antimicrobials for any reason. We modelled a typical U.S. feedlot, where high risk cattle may be afflicted by diseases requiring antimicrobial therapy, namely respiratory diseases, liver abscesses and lameness. We calculated the net revenue loss under each policy of antimicrobial use restriction. With moderate disease incidence, the median net revenue loss was $66 and $96 per animal entering the feedlot, for not using antimicrobials for disease prevention and control, or not using any antimicrobials, respectively, compared to using antimicrobials for disease prevention, control, and treatment. Losses arose mainly from an increase of fatality and morbidity rates, almost doubling for respiratory diseases in the case of antimicrobial use restrictions. In the case of antimicrobial use prohibition, decreasing the feeder cattle price by 9%, or alternatively, increasing the slaughter cattle price by 6.3%, would offset the net revenue losses for the feedlot operator. If no alternatives to antimicrobial therapy for prevention, control and treatment of current infectious diseases are implemented, policies that economically incentivize adoption of non-antimicrobial prevention and control strategies for infectious diseases would be necessary to maintain animal welfare and the profitability of beef production while simultaneously curbing antimicrobial use. [ABSTRACT FROM AUTHOR]

The induction of specific and sustainable tolerance is a challenging issue in organ transplantation. The discovery of the immunosuppressive properties of apoptotic cells in animal models has paved the way for their use in human transplantation. In this work, we aimed to define a stable, reproducible, and clinically compatible production procedure of human apoptotic cells (Apo-cells). Using a clinically approved extracorporeal photopheresis technique, we have produced and characterized phenotypically and functionally human apoptotic cells. These Apo-cells have immunosuppressive properties proved in vitro and in vivo in NOD/SCID/γC mice by their capacity to modulate an allogeneic response following both a direct and an indirect antigen presentation. These results brought the rationale for the use of Apo-cells in tolerance induction protocol for organ transplantation. [ABSTRACT FROM AUTHOR]

We compared the characteristics of the 13 patients with CNS involvement (CNS+) with 62 patients without evidence of active CNS disease (CNS-). B Introduction: b Central nervous system (CNS) involvement in patients with refractory or relapsed large B-cell lymphoma (LBCL) is associated with an extremely poor prognosis. Treatment with anti CD19 CAR-T cells is safe and effective in patients with relapsed refractory large B-cell lymphoma with active central nervous system involvement. [Extracted from the article]

Background: The Community Assessment of Psychic Experiences (CAPE) is a 42-item self-report questionnaire that has been developed and validated to measure the dimensions of psychosis in the general population. The CAPE has a three-factor structure with dimensions of positive, negative and depression. Assessing the cross-national equivalence of a questionnaire is an essential prerequisite before pooling data from different countries. In this study, our aim was to investigate the measurement invariance of the CAPE across different countries. Methods: Data were drawn from the European Union Gene-Environment Interaction (EU-GEI) study. Participants (incident cases of psychotic disorder, controls and siblings of cases) were recruited in Brazil, France, Italy, the Netherlands, Spain and UK. To analyse the measurement invariance across these samples, we tested configural invariance (i.e. identical structures of the factors), metric invariance (i.e. equivalence of the factor loadings) and scalar invariance (i.e. equivalence of the thresholds) of the three CAPE dimensions using multigroup categorical confirmatory factor analysis methods. Results: The configural invariance model fits well, providing evidence for identical factorial structure across countries. In comparison with the configural model invariance, the fit indices were very similar in the metric and scalar invariance models, indicating that factor loadings and thresholds did not differ across the six countries. Conclusion: We found that, across six countries, the CAPE showed equivalent factorial structure, factor loadings and thresholds. Thus, differences observed in scores between individuals from different countries should be considered as reflecting different levels of psychosis. [ABSTRACT FROM AUTHOR]

Summary: Chemotherapy plus rituximab has been the mainstay of treatment for follicular lymphoma (FL) for two decades but is associated with immunosuppression and relapse. In phase 2 studies, lenalidomide combined with rituximab (R2) has shown clinical synergy in front‐line and relapsed/refractory FL. Here, we show that lenalidomide reactivated dysfunctional T and Natural Killer (NK) cells ex vivo from FL patients by enhancing proliferative capacity and T‐helper cell type 1 (Th1) cytokine release. In combination with rituximab, lenalidomide improved antibody‐dependent cellular cytotoxicity in sensitive and chemo‐resistant FL cells, via a cereblon‐dependent mechanism. While single‐agent lenalidomide and rituximab increased formation of lytic NK cell immunological synapses with primary FL tumour cells, the combination was superior and correlated with enhanced cytotoxicity. Immunophenotyping of FL patient samples from a phase 3 trial revealed that R2 treatment increased circulating T‐ and NK‐cell counts, while R‐chemotherapy was associated with reduced cell numbers. Finally, using an in vitro model of myeloid differentiation, we demonstrated that lenalidomide caused a reversible arrest in neutrophil maturation that was distinct from a cytotoxic chemotherapeutic agent, which may help explain the lower rates of neutropenia observed with R2versus R‐chemotherapy. Taken together, we believe these data support a paradigm shift in the treatment of FL – moving from combination immunochemotherapy to chemotherapy‐free immunotherapy. [ABSTRACT FROM AUTHOR]

The development of cancer and chronic infections is facilitated by many subversion mechanisms, among which enhanced expression of immune checkpoints molecules, such as programmed death-1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), on exhausted T cells. Recently, immune checkpoint inhibitors have shown remarkable efficiency in the treatment of a number of cancers. However, expression of immune checkpoints on natural killer (NK) cells and its functional consequences on NK cell effector functions are much less explored. In this review, we focus on the current knowledge on expression of various immune checkpoints in NK cells, how it can alter NK cell-mediated cytotoxicity and cytokine production. Dissecting the role of these inhibitory mechanisms in NK cells is critical for the full understanding of the mode of action of immunotherapies using checkpoint inhibitors in the treatment of cancers and chronic infections. [ABSTRACT FROM AUTHOR]

Sustained activation of JAK/STAT3 signaling pathway is classically described in Multiple Myeloma (MM). One explanation could be the silencing of the JAK/STAT suppressor genes, through the hypermethylation of SHP-1 and SOCS-1, previously demonstrated in MM cell lines or in whole bone marrow aspirates. The link between such suppressor gene silencing and the degree of bone marrow invasion or the treatment response has not been evaluated in depth. Using real-time RT-PCR, we studied the expression profile of three JAK/STAT suppressor genes: SHP-1, SHP-2 and SOCS-1 in plasma cells freshly isolated from the bone marrows of MM patients and healthy controls. Our data demonstrated an abnormal repression of such genes in malignant plasma cells and revealed a significant correlation between such defects and the sustained activation of the JAK/STAT3 pathway during MM. The repressed expression of SHP-1 and SHP-2 correlated significantly with a high initial degree of bone marrow infiltration but was, unexpectedly, associated with a better response to the induction therapy. Collectively, our data provide new evidences that substantiate the contribution of JAK/STAT suppressor genes in the pathogenesis of MM. They also highlight the possibility that the decreased gene expression of SHP-1 and SHP-2 could be of interest as a new predictive factor of a favorable treatment response, and suggest new potential mechanisms of action of the therapeutic molecules. Whether such defect helps the progression of the disease from monoclonal gammopathy of unknown significance to MM remains, however, to be determined. [ABSTRACT FROM AUTHOR]

Background: Primary upper aerodigestive tract malignancy remains a cancer having a poor prognosis, despite current progress in treatment, due to a generally late diagnosis.Objectives: We conducted a preliminary assessment of five dyes approved for human use for the imaging of head and neck tissues at the cellular level, which could be considered for clinical examination.Methods: We investigated fluorescence endomicroscopic images on fresh samples obtained from head and neck surgeries after staining with hypericin, methylene blue, toluidine blue, patent blue or indocyanine green to provide a preliminary consideration as to whether these images contain enough information for identification of non-pathologic and pathologic tissues. The distribution pattern of dye has been examined using probe-based confocal laser endomicroscopy (pCLE) in ex vivo specimens and compared with corresponding histology.Results: In most samples, the image quality provided by pCLE with both dyes allowed pathologists to recognize histological characteristics to identify the tissues.Conclusion: The combination of pCLE imaging with these dyes provides interpretable images close to conventional histology; a promising clinical tool to assist physicians in examination of upper aerodigestive tract, as long as depth imaging issues can be overcome. [ABSTRACT FROM AUTHOR]

Antenatal renal vein thrombosis is a rarely described diagnostic finding, with variable consequences on kidney function. We present the case of an affected fetus, born at 35-week gestation, with intrauterine oligohydramnios and two small kidneys. A renal ultrasound carried out after birth confirmed the presence of prenatal abnormalities. Renal vein thrombosis was not diagnosed at the time. The baby died 20 days later of kidney failure, metabolic acidosis, and polypnea with severe hypotrophy. Autopsy revealed atrophied kidneys and adrenal glands. The vena cava had thrombosis occupying most of its length. The right renal vein was normal, while the left renal vein was threadlike and not permeable. Histologically, there was necrosis of the left adrenal gland with asymmetrical bilateral renal impairment and signs of ischemic and hemorrhagic lesions. A review of thrombophilia was carried out and a heterozygous mutation in Factor V was found in both the mother and the child. [ABSTRACT FROM AUTHOR]

BRCA2 mutation carriers typically develop luminal B breast cancers. Data on the effectiveness of neoadjuvant chemotherapy in these patients are limited because of small patient numbers and lack of prospective studies. We used our 15-year genetic clinic database to compare retrospectively the pathological complete response rates (pCR) and rates of post-chemotherapy nodal involvement among BRCA2 carriers and BRCA1/2-negative (WT) patients with luminal B tumours, all treated with neoadjuvant anthracyclines ± taxanes-based chemotherapy. Twenty-nine BRCA2 carriers and 67 WT patients fulfilled the inclusion criteria and were analysed. Patients and treatment characteristics were represented. A pCR occurred in 3 (10 %) BRCA2 patients and 13 (19 %) WT patients ( p = 0.43). Twenty (69 %) BRCA2 carriers and 34 (51 %) WT patients remained node-positive at surgery ( p = 0.17). BRCA2 germline mutations are associated with a low probability of pCR and a high risk of axillary invasion. Alternative treatments are highly expected, and clinical trials are needed to set the best treatment regimen in this population. [ABSTRACT FROM AUTHOR]

Background: When any atypical feature is identified on a percutaneous biopsy specimen of a suspicious breast lesion, surgical excision is mandatory, leading to unnecessary surgeries in 70-90 % of the cases. The purpose of this study was to develop a model to predict the presence of cancer at surgery that would be applicable to all atypical lesions. Methods: We collected complete clinical, radiological, and double-reading histological data concerning all patients with a diagnosis of a pure atypical lesion on image-guided biopsy performed at the One-Stop Breast Care Unit between 2004 and 2011. Results: Among the 204 eligible patients, 49 cancers (24 %) had been diagnosed at definitive surgery (20 ductal carcinoma in situ, 20 invasive ductal, and 9 invasive lobular carcinoma). The univariate analysis retrieved age ( p = 0.03), the focus size in mm ( p = 0.02), the number of biopsy cores ( p = 0.02), the disappearance of radiological anomalies after biopsy ( p = 0.05), the mean number of atypical foci ( p = 0.05) and the percentage of atypical lobules and ducts for lobular neoplasia ( p = 0.04) as factors associated with cancer at surgery, whereas neither Ki67 nor ALDH1 expression was significantly correlated. The final most informative nomogram comprised information on patient age, the disappearance of radiological anomalies after biopsy and a focus size >15 mm. For the optimal threshold (risk of cancer = 21 %), sensitivity, specificity, positive predictive value, and negative predictive value were 78, 66, 36, and 90 %, respectively. Conclusions: After validation, this model could help to identify a subset of patients with premalignant disease who could be spared surgery. [ABSTRACT FROM AUTHOR]

Summary Auto-reactive cytotoxic T lymphocytes play a key role in the progressive loss or destruction of melanocytes in vitiligo but the mechanism underlying the loss of self-tolerance is unknown. A deregulation of regulatory T-cell biology has recently been suggested. The analysis of the suppressive effects of peripheral T regulatory cells in vitiligo patients revealed a functional defect in seven of 15 cases. This defect was strongly correlated with disease activity. The evaluation of the percentage of peripheral regulatory T lymphocytes did not reveal any intrinsic quantitative defect. Yet, a decrease in the percentage of such cells was noted in patients with progressive forms, suggesting a recruitment of regulatory T cells from the peripheral blood to the site of injury. This was further corroborated by the significant increase of Forkhead box P3 expression in the vitiliginous skin of patients. Our data support the involvement of a functional defect of peripheral regulatory T cells in the pathogenesis of vitiligo and open new possibilities to advance therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: The mechanisms underlying the loss of self-tolerance in systemic lupus erythematosus (SLE) are incompletely deciphered. TGF-β plays a key role in self-tolerance demonstrated by the onset of a fatal autoimmune syndrome associated with lupus autoantibodies in mice lacking a functional TGF-β receptor. The present work aims to define whether resistance to TGF-β might contribute to the pathogenesis of SLE. Methods: Twenty-two patients with active SLE, 16 with other connective tissue diseases, and 10 healthy controls were prospectively included in this study. The effects of exogenous TGF-β1 on IL-2-dependent T-cell proliferation, IFN-γ secretion, and target gene transcription were analyzed on peripheral blood mononuclear cells. Results: Our results showed that 75% of patients with SLE or other connective tissue diseases were totally or partially resistant to the effects of TGF-β1. The responses to the anti-proliferative and transcriptional effects of TGF-β were, however, discordant in a high proportion of our patients. Hence, we distinguish three distinct profiles of resistance to TGF-β1 and suggest that patients may exhibit different defects affecting distinct points of TGF-β1 signaling pathways. Conclusion: Our data demonstrate the presence of an impaired response of peripheral cells to TGF-β1 in patients with active SLE that may participate to the pathogenesis of the disease. Further studies will be necessary to delineate the mechanisms underlying the lymphocyte resistance to TGF-β1 in SLE. [ABSTRACT FROM AUTHOR]

Biomarkers of disease severity might help with individualizing the management of patients with acute respiratory distress syndrome (ARDS). During sepsis, a sustained decreased expression of the antigen-presenting molecule human leucocyte antigen-DR (HLA-DR) on circulating monocytes is used as a surrogate marker of immune failure. This study aimed at assessing whether HLA-DR expression on alveolar monocytes in the setting of a severe lung infection is associated with their functional alterations. BAL fluid and blood from immunocompetent patients with pneumonia-related ARDS admitted between 2016 and 2018 were isolated in a prospective monocentric study. Alveolar and blood monocytes were immunophenotyped using flow cytometry. Functional tests were performed on alveolar and blood monocytes after in vitro lipopolysaccharide (LPS) stimulation. Phagocytosis activity and intracellular tumor necrosis factor (TNF) production were quantified using fluorochrome-conjugated-specific antibodies. Ten ARDS and seven non-ARDS control patients were included. Patients with pneumonia-related ARDS exhibited significantly lower HLA-DR expression both on circulating (p < 0.0001) and alveolar (p = 0.0002) monocytes. There was no statistically significant difference observed between patient groups (ARDS vs. non-ARDS) regarding both alveolar and blood monocytes phagocytosis activity. After LPS stimulation, alveolar (p = 0.027) and blood (p = 0.005) monocytes from pneumonia-related ARDS patients had a significantly lower intracellular TNF expression than non-ARDS patients. Monocytes from pneumonia-related ARDS patients have a deactivated status and an impaired TNF production capacity but display potent phagocytic activity. HLA-DR level expression should not be used as a surrogate marker of the phagocytic activity or the TNF production capacity of alveolar monocytes. [ABSTRACT FROM AUTHOR]

The aim of this paper is to examine the indirect effects of new housing construction on the redistribution of old housing stock in developing countries. The basic data for the study comes from the author's work in Tunisia, with comparative illustration from similar studies in Mexico, and is used to test a certain number of conclusions on filtering derived from empirical studies undertaken in developed countries. The conclusions are that dwellings in the middle range of values initiated the longest chains of moves, but that as even these chains end before reaching the poorest families, filtering strategies need to be complemented by a positive programme of slum-upgrading. [ABSTRACT FROM PUBLISHER]

In France, veterinarians can both prescribe and deliver veterinary medicines, which is a questionable situation from the perspective of antimicrobial use (AMU) reduction to avoid antimicrobial resistance (AMR). This situation places veterinarians in direct commercial relationships with the pharmaceutical industry as purchase contracts are signed between veterinarians and pharmaceutical companies. The aim of the present work is to analyse the relationships between veterinarians and pharmaceutical firms in the oligopoly market context of French veterinary medicine to determine whether the prescription behaviour of practitioners can be biased by joint prescription and delivery. Therefore, we develop an analysis based on principal-agent theory. Contracts between pharmaceutical companies and veterinarians during the 2008–2014 period were analysed based on 382 contracts related to 47 drugs belonging to eight main pharmaceutical firms (2320 observations). The price per unit after rebate of each drug and contract was calculated. The descriptive analysis demonstrated high disparity among the contracts across pharmaceutical firms with regard to the provisions of the contracts and how they are presented. Then, linear regression was used to explain the price per unit after rebate based on the explanatory variables, which included the yearly purchase objective, year, type of drug and type of rebate. The decrease in price per unit after rebate for each extra €1000 purchase objective per drug category was established to be €0.061 per 100 kg body weight for anticoccidiosis treatments, €0.029 per 100 kg body weight for anti-inflammatories, €0.0125 per 100 kg body weight and €0.0845 per animal for antiparasitics, and €0.031 per animal for intramammary antimicrobials. Applying agency theory reveals that veterinarians can be considered agents in the case of monopolistic situations involving pharmaceutical firms; otherwise, veterinarians are considered principals (oligopolistic situations in which at least several medicines have similar indications). The present study does not provide evidence suggesting that joint prescription and delivery may introduce any potential prescription bias linked to conflicts of interest under the market conditions during the 2008–2014 period. [ABSTRACT FROM AUTHOR]

Background: Several have suggested a link between discrimination phenomena and psychotic disorders. Since this is a potentially modifiable factor, it seems important to clarify the links between discrimination and psychotic disorders. In the hypothesis of the psychotic continuum, schizotypal features in the general population are intermediate phenotypes in schizophrenia studies. In this study, the aim was to study the links between discrimination and level of schizotypy in the general population. We assumed that exposure to discrimination experiences is associated with increased levels of schizotypy. Methods: Subjects from the general population (N = 1456), without psychotic disorders, were recruited in 17 cities and 6 countries (Brazil, Spain, France, Holland, Italy, UK). Each subject completed the Community Assessment of Psychic Experiences (CAPE), a autoquestionaire considered to assess the level of psychometric schizotypy (with positive, negative and depressive dimensions) and the 20-item Perceived Discrimination Scale developed by Williams et al. Linear regression analyzes were used with discrimination as an explanatory variable and CAPE scores as variables to be explained. Results: We show that an increase in the perceived discrimination score was associated with significantly higher levels of schizotypy, in the positive (p = 1.7.10-10), negative (p = 3.4.10-10) and the depressed dimensions (p = 2.1.10-10). In more than half of the subjects who reported discrimination experiences, the reason for the discrimination invoked was not one of the reasons given. Ethnicity remains, however, a major cause of reported discrimination. Discussion: The stress-vulnerability model could explain the link between discrimination and schizotypy, though dysregulation of the hypothalamopituitary axis and cortisol secretion in subjects with schizotypy, preventing them from responding adaptively to social stress. Psychological and social factors also seem to play a role in stress management. [ABSTRACT FROM AUTHOR]