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PURPOSE To assess a new polynomial regression formula integrating the refractive prediction error of the first operated eye in order to improve the intraocular lens (IOL) power calculation of the second eye in cataract surgery. SETTING Centre Hospitalier Universitaire, Toulouse, France. DESIGN Retrospective multicentric dataset study. METHODS A polynomial regression formula called WeOptimeye2nd (WO2nd) was developed using a machine-learning algorithm trained on a dataset of 534 patients who underwent sequential bilateral cataract surgery. A separate multicentric dataset was used to retrospectively calculate predicted refraction with WO2nd, SRK/T, Barrett Universal II, and 3 other methods of constant factors (CF) second eye refinement (CF0.38, CF0.35 and CF0.5). Mean absolute errors (MAE) and percentage of eyes within ±0.25, 0.5, and 1.0 diopters (D) from predicted spherical equivalent were compared between formulas. RESULTS The study comprised data on 722 patients. In the overall population, WO2nd had the lowest MAE: 0.339 versus 0.347 (p=0.137), 0.340 (p=0.956), 0.350 (p=0.066), 0.399 (p

The high cytotoxic activity of Vγ9Vδ2 T lymphocytes against tumor cells makes them useful candidates in anticancer therapies. However, the molecular mechanism of their activation by phosphoantigens (PAgs) is not completely known. Many studies have depicted the mechanism of Vγ9Vδ2 T-cell activation by PAg-sensed accessory cells, such as immune presenting cells or tumor cells. In this study, we demonstrated that pure resting Vγ9Vδ2 T lymphocytes can self-activate through exogenous PAgs, involving their TCR and the butyrophilins BTN3A1 and BTN2A1. This is the first time that these three molecules, concurrently expressed at the plasma membrane of Vγ9Vδ2 T cells, have been shown to be involved together on the same and unique T cell during PAg activation. Moreover, the use of probucol to stimulate the inhibition of this self-activation prompted us to propose that ABCA-1 could be implicated in the transfer of exogenous PAgs inside Vγ9Vδ2 T cells before activating them through membrane clusters formed by γ9TCR, BTN3A1 and BTN2A1. The self-activation of Vγ9Vδ2 T cells, which leads to self-killing, can therefore participate in the failure of γδ T cell-based therapies with exogenous PAgs and should be taken into account.

PURPOSE: To evaluate the efficacy and safety of transepithelial corneal cross-linking (CXL) with supplemental oxygen. METHODS: This was a prospective, non-comparative, pilot cohort study conducted at the National Reference Center for Keratoconus (Toulouse, France) on patients with progressive keratoconus. Transepithelial, pulsed, accelerated CXL was performed in an oxygen-rich atmosphere. Oxygen goggles were applied to the eyes to maintain a high level of oxygen during treatment. The main efficacy outcome was the mean change from baseline in maximum keratometry (Kmax) and the secondary outcomes were the mean changes in flat keratometry (K1), steep keratometry (K2), mean keratometry (Km), corrected distance visual acuity (CDVA), uncorrected distance visual acuity (UDVA), and demarcation line depth. The safety outcomes were the incidence of adverse events, the mean change in pachymetry, and endothelial cell count. RESULTS: Thirty-four eyes of 34 patients were included. At 12 months postoperatively, the Kmax decreased by 1.56 ± 1.71 diopters (D) ( P < .0001) and CDVA improved by 0.093 ± 0.193 logMAR ( P < .02). The K2 and Km decreased by 0.51 ± 1.03 D ( P < .02) and 0.40 ± 0.78 D ( P < .01), respectively. There was no change in K1 and UDVA. The most frequent adverse event was corneal haze (64.78%). There were neither cases of infectious keratitis or loss of more than two lines in CDVA nor changes in pachymetry or endothelial cell count. CONCLUSIONS: Transepithelial CXL performed in an oxygen-rich atmosphere results in improved Kmax and CDVA with good safety. These promising findings suggest that this procedure could be safe and capable of halting the progression of keratoconus. [ J Refract Surg . 2021;37(1):42–48.]

Avian influenza virus (AIV) subtypes H5N1 and H9N2 co-circulate in poultry in Bangladesh, causing significant bird morbidity and mortality. Despite their importance to the poultry value chain, the role of farms in spreading and maintaining AIV infections remains poorly understood in most disease-endemic settings. To address this crucial gap, we conducted a cross-sectional study between 2017 and 2019 in the Chattogram Division of Bangladesh in clinically affected and dead chickens in farms with suspected AIV infection. Viral prevalence of each subtype was approximately 10% among farms for which veterinary advice was sought, indicating high levels of virus circulation in chicken farms despite the low number of reported outbreaks. Co-circulation of both subtypes was common in farms, with our findings suggest that in the field, the co-circulation of H5N1 and H9N2 can modulate disease severity, which could facilitate an underestimated level of AIV transmission in the poultry value chain. Finally, using newly generated whole-genome sequences, we investigate the evolutionary history of a small subset of H5N1 and H9N2 viruses. Our analyses revealed that for both subtypes, the sampled viruses were genetically most closely related to other viruses isolated in Bangladesh and represented multiple independent incursions. However, due to lack of longitudinal surveillance in this region, it is difficult to ascertain whether these viruses emerged from endemic strains circulating in Bangladesh or from neighbouring countries. We also show that amino acids at putative antigenic residues underwent a distinct replacement during 2012 which coincides with the use of H5N1 vaccines.

Micronutrient deficiencies and stunting rates are high in many low-income countries. Increasing and diversifying food intake are often challenging for small-scale farmers in lowland areas as flooding often results in crop losses and drowning of livestock. A cluster-randomised controlled trial was conducted over 12-months in Bangladesh, involving 150 small-scale duck rearing households, including 50 control, and 50 households each in two intervention arms. Interventions focussing on improving duck health and duck nutrition were applied on a village level. Data analysis focussed on assessing the impact of interventions on duck mortality, sales and consumption, and on dietary diversity of household members. Improved duck rearing increased the consumption and the sales of ducks. Household selling more ducks were more likely to purchase and consume milk products, contributing to an improved households’ dietary diversity. Our results suggest that improving duck rearing can provide a suitable and sustainable alternative to maintain and improve dietary diversity of households in flood-prone areas.

Follicular lymphoma (FL) is the most common indolent lymphoma. Despite the clear benefit of CD20-based therapy, a subset of FL patients still progress to aggressive lymphoma. Thus, identifying early biomarkers that incorporate positron emission tomography metrics could be helpful to identify patients with a high risk of treatment failure with rituximab. We retrospectively included a total of 132 untreated FL patients separated into training and validation cohorts. Optimal threshold of baseline whole-body maximum standardized uptake (SUVmax) was first determined in the training cohort (n=48) to predict progression-free survival (PFS). The PET results were investigated along with the tumor and immune microenvironment, which were determined by immunochemistry and transcriptome studies involving gene set enrichment analyses and immune cell deconvolution, together with the tumor mutation profile. We report that baseline SUVmax>14.5 was associated with poorer PFS than baseline SUVmax≤14.5 (hazard ratio =0.28; P=0.00046). Neither immune T-cell infiltration nor immune checkpoint expression were associated with baseline PET metrics. By contrast, FL samples with Ki-67 staining ≥10% showed enrichment of cell cycle/DNA genes (P=0.013) and significantly higher SUVmax values (P=0.007). Despite similar oncogenic pathway alterations in both SUVmax groups of FL samples, four out of five cases harboring the infrequent FOXO1 transcription factor mutation were seen in FL patients with SUVmax>14.5. Thus, high baseline SUVmax reflects FL tumor proliferation and, together with Ki-67 proliferative index, can be used to identify patients at risk of early relapse with rituximab chemotherapy.

International audience; Cytomegalovirus (CMV) infection is responsible for significant morbidity and mortality in immunocompromised patients, namely solid organ and hematopoietic cell transplant recipients, and can induce congenital infection in neonates. There is currently an unmet need for new management and treatment strategies. Establishment of an anti-CMV immune response is critical in order to control CMV infection. The two main human T cells involved in HCMV-specific response are αβ and non-Vγ9Vδ2 T cells that belong to γδ T cell compartment. CMV-induced non-Vγ9Vδ2 T cells harbor a specific clonal expansion and a phenotypic signature, and display effector functions against CMV. So far, only two main molecular mechanisms underlying CMV sensing have been identified. Non-Vγ9Vδ2 T cells can be activated either by stress-induced surface expression of the γδT cell receptor (TCR) ligand annexin A2, or by a multimolecular stress signature composed of the γδTCR ligand endothelial protein C receptor and co-stimulatory signals such as the ICAM-1-LFA-1 axis. All this basic knowledge can be harnessed to improve the clinical management of CMV infection in at-risk patients. In particular, non-Vγ9Vδ2 T cell monitoring could help better stratify the risk of infection and move forward a personalized medicine. Moreover, recent advances in cell therapy protocols open the way for a non-Vγ9Vδ2 T cell therapy in immunocompromised patients.

BACKGROUND Dupilumab is approved for use in moderate-to-severe atopic dermatitis (AD) and as an add-on maintenance treatment in patients suffering from severe asthma with type 2 inflammation. Ocular adverse events (OAEs) have been reported with dupilumab almost exclusively in patients treated for AD. OBJECTIVES The objectives of this study were to describe the incidence and nature of dupilumab-induced OAEs and to assess the potential predisposing factors. PATIENTS AND METHODS We conducted a prospective, single-centre, real-life study in adult AD patients treated with dupilumab, who were systematically examined by an ophthalmologist before and during treatment. RESULTS Forty-six patients were included prospectively with a median age of 41.1 years and a median initial SCOring Atopic Dermatitis of 46.0 (IQR: 34.5-55.5). OAEs concerned 34.8% of patients and were mostly of mild to moderate severity. Two patients had to discontinue treatment due to OAE. The majority of patients developed or aggravated dry eye disease, with superficial punctate keratitis (SPK). Six patients developed conjunctivitis. Dupilumab-induced OAEs were associated with the following pre-existing parameters: dry eye disease with SPK (Odds ratio (OR); 6.3 [95% confidence interval (CI): 1.3-31.6]), eyelid eczema (OR: 8.7 [95%CI: 1.8-40.6]), history of food allergy (OR 3.8 (95% CI: 1.002-14,070) and IgE serum level> 1000 kU/L (OR:10.6 [CI 95%: 1.2-91.3]). CONCLUSION Atopic dermatitis patients with eyelid eczema or dry eye disease symptoms may be referred to an ophthalmologist before starting dupilumab to consider initiating preventive eye hydration measures. Further multicentric and translational studies are warranted to better explain OAEs pathophysiology.

The finding that γδ T cells are present among tumor-infiltrating lymphocytes in humans suggests they participate in tumor immune surveillance, but their relevance is unclear because the relative abundance of tumor-infiltrating γδ T cells correlates with positive or negative, or even do not correlate with prognosis. This likely depends on the fact that tumor-infiltrating γδ T cells may play substantially different effector or regulatory functions, and correlation with patient's prognosis relies on distinct γδ T cell subsets in the context of the tumor. There is interest to exploit γδ T cells in tumor immunotherapy, but to make this approach successful there is urgent need to fully understand the biological functions of γδ T cells and of how they can be manipulated in vivo and ex vivo to safely provide benefit to the host. This review focuses on our previous and ongoing studies of tumor-infiltrating γδ T lymphocytes in different types of human cancer. Moreover, we discuss the interaction of tumor-infiltrating γδ T cells with other cells and molecules present in the tumor microenvironment, and their clinical relevance on the ground, that deep knowledge in this field can be used further for better immunotherapeutic intervention in cancer.

In order to control Highly Pathogenic Avian Influenza (HPAI) H5N1 and Low Pathogenic Avian Influenza (LPAI) H9N2 virus spread in endemically infected countries, a detailed understanding of infection patterns is required. We conducted cross-sectional studies in Bangladesh in 2016 and 2017, on 144 backyard, 106 broiler and 113 layer chicken farms. Although all sampled birds were negative for H5 virus by RT-PCR, H5 antibodies were detected in unvaccinated birds on all three farming systems. Higher H5 antibody prevalence was observed in ducks raised on backyard farms, 14.2% (95% CI: 10.0%-19.8%), compared to in-contact backyard chickens, 4.2% (95% CI: 2.8%-6.1%). The H5 antibody prevalence was lower in broiler chickens, 1.5% (95% CI: 0.9%-2.5%), compared to layer chickens, 7.8% (95% CI: 6.1%-9.8%). H9 viruses were detected by RT-PCR in 0.5% (95% CI: 0.2%-1.3%) and 0.6% (95% CI: 0.3%-1.5%) of broilers and layers, respectively, and in 0.2% (95% CI: 0.0%-1.2%) of backyard chickens. Backyard chickens and ducks showed similar H9 antibody prevalence, 16.0% (95% CI: 13.2%-19.2%) and 15.7% (95% CI: 11.3%-21.4%), which was higher compared to layers, 5.8% (95% CI: 4.3%-7.6%), and broilers, 1.5% (95% CI: 0.9%-2.5%). Over the course of a production cycle, H5 and H9 antibody prevalence increased with the age of backyard and layer chickens. Usually, multiple ducks within a flock were H5 antibody positive, in contrast to backyard chickens, broilers and layers where only individual birds within flocks developed H5 antibodies. Our findings highlight low virus circulation in healthy chickens of all production systems in Bangladesh, which is in contrast to high virus circulation reported from live bird markets. Data generated in this project can be used to adopt risk-based surveillance approaches in different chicken production systems in Bangladesh and to inform mathematical models exploring HPAI infection dynamics in poultry from the source of production.

The presence of free-grazing ducks (FGD) has consistently been shown to be associated with highly pathogenic avian influenza virus (HPAIV) H5N1 outbreaks in South-East Asia. However, the lack of knowledge about the transmission pathways limits the effectiveness of control efforts. To address this gap, we developed a probabilistic transmission model of HPAIV H5N1 in the nomadic FGD production system in Viet Nam, assuming different scenarios to address parameter uncertainty. Results suggested that HPAIV H5N1 could spread within the nomadic FGD production system, with an estimated flock-level effective reproduction number (re) ranging from 2.16 (95% confidence interval (CI): 1.39-3.49) to 6.10 (95%CI: 3.93-9.85) depending on the scenario. Indirect transmission via boats and trucks was shown to be the main transmission route in all scenarios. Results suggest that re could be reduced below one with 95% confidence if 86% of FGD flocks were vaccinated in the best-case scenario or 95% in the worst-case scenario. If vaccination was combined with cleaning and disinfection of transport vehicles twice a week, vaccination coverage could be lowered to 60% in the best-case scenario. These findings are of particular relevance for prioritising interventions for effective control of HPAIV in nomadic free-grazing duck production systems.

International audience; Tumor antigen-specific CD4 T cells accumulate at tumor sites, evoking their involvement in antitumor effector functions in situ. Contrary to CD8 cytotoxic T lymphocyte exhaustion, that of CD4 T cells remains poorly appreciated. Here, using phenotypic, transcriptomic, and functional approaches, we characterized CD4 T cell exhaustion in patients with head and neck, cervical, and ovarian cancer. We identified a CD4 tumor-infiltrating lymphocyte (TIL) population, defined by high PD-1 and CD39 expression, which contained high proportions of cytokine-producing cells, although the quantity of cytokines produced by these cells was low, evoking an exhausted state. Terminal exhaustion of CD4 TILs was instated regardless of TIM-3 expression, suggesting divergence with CD8 T cell exhaustion. scRNA-Seq and further phenotypic analyses uncovered similarities with the CD8 T cell exhaustion program. In particular, PD-1hiCD39+ CD4 TILs expressed the exhaustion transcription factor TOX and the chemokine CXCL13 and were tumor antigen specific. In vitro, PD-1 blockade enhanced CD4 TIL activation, as evidenced by increased CD154 expression and cytokine secretion, leading to improved dendritic cell maturation and consequently higher tumor-specific CD8 T cell proliferation. Our data identify exhausted CD4 TILs as players in responsiveness to immune checkpoint blockade.

Most Chinese provinces have a daily-updated database of live animal movements; however, the data are not efficiently utilized to support interventions to control H7N9 and other avian influenzas. Based on official records, this study assessed the spatio-temporal patterns of live broilers moved out of and within Guangxi in 2017. The yearly and monthly networks were analyzed for inter- and intra-provincial movements, respectively. Approximately 200,000 movements occurred in 2017, involving the transport of 200 million live broilers from Guangxi. Although Guangxi exported to 24 out of 32 provinces of China, 95% of inter-provincial movements occurred with three bordering provinces. Within Guangxi, counties were highly connected through the live broiler movements, creating conditions for rapid virus spreading throughout the province. Interestingly, a peak in movements during the Chinese Lunar New Year celebrations, late January in 2017, was not observed in this study, likely due to H7N9-related control measures constraining live bird trading. Both intra- and inter-provincial movements in March 2017 were significantly higher than in other months of that year, suggesting that dramatic price changes may influence the movement's network and reshape the risk pathways. However, despite these variations, the same small proportion of counties (less than 20%) exporting/importing more than 90% of inter- and intra-provincial movements remains the same throughout the year. Interventions, particularly surveillance and improving biosecurity, targeted to those counties are thus likely to be more effective for avian influenza risk mitigation than implemented indiscriminately. Additionally, simulations further demonstrated that targeting counties according to their degree or betweenness in the movement network would be the most efficient way to limit disease transmission via broiler movements. The study findings provide evidence to support the design of risk-based control interventions for H7N9 and all other avian influenza viruses in broiler value chains in Guangxi.

Therapy resistance represents a major clinical challenge in acute myeloid leukemia (AML). Here we define a ‘MitoScore’ signature, which identifies high mitochondrial oxidative phosphorylation in vivo and in patients with AML. Primary AML cells with cytarabine (AraC) resistance and a high MitoScore relied on mitochondrial Bcl2 and were highly sensitive to venetoclax (VEN) + AraC (but not to VEN + azacytidine). Single-cell transcriptomics of VEN + AraC-residual cell populations revealed adaptive resistance associated with changes in oxidative phosphorylation, electron transport chain complex and the TP53 pathway. Accordingly, treatment of VEN + AraC-resistant AML cells with electron transport chain complex inhibitors, pyruvate dehydrogenase inhibitors or mitochondrial ClpP protease agonists substantially delayed relapse following VEN + AraC. These findings highlight the central role of mitochondrial adaptation during AML therapy and provide a scientific rationale for alternating VEN + azacytidine with VEN + AraC in patients with a high MitoScore and to target mitochondrial metabolism to enhance the sensitivity of AML cells to currently approved therapies. Sarry and colleagues demonstrate that adaptive resistance to venetoclax + cytarabine therapy in acute myeloid leukemia relies on mitochondrial respiration and show that combination with electron transport chain complex inhibitors delays relapse in patient-derived xenograft models in vivo.

International audience; T cells responding to persistent tumor or viral antigens progressively lose their functional properties, a feature known as exhaustion. This state is also characterized by cell-surface expression of multiple inhibitory immune checkpoint receptors (IRs). Cancer immunotherapy by immune checkpoint targeting has shown impressive clinical outcomes, but requires substantial improvement given the limited number of patients who benefit from the treatment. Targeting the mechanisms controlling immune checkpoint expression could represent a step towards this aim. Accumulating data indicate that this strategy can limit immune checkpoint expression, in some instances simultaneously inhibiting several immune checkpoints. This review discusses various mechanisms through which IRs are activated or regulated, and ways these mechanisms could be exploited to develop more effective future immunotherapies.

Vietnamese poultry are host to co‐circulating subtypes of avian influenza viruses, including H5N1 and H9N2, which pose a great risk to poultry productivity and to human health. AIVs circulate throughout the poultry trade network in Vietnam, with live bird markets being an integral component to this network. Traders at LBMs exhibit a variety of trading practices, which may influence the transmission of AIVs. We identified trading practices that impacted on AIV prevalence in chickens marketed in northern Vietnamese LBMs. We generated sequencing data for 31 H9N2 and two H5N6 viruses. Viruses isolated in the same LBM or from chickens sourced from the same province were genetically closer than viruses isolated in different LBMs or from chickens sourced in different provinces. The position of a vendor in the trading network impacted on their odds of having AIV‐infected chickens. Being a retailer and purchasing chickens from middlemen was associated with increased odds of infection, whereas odds decreased if vendors purchased chickens directly from large farms. Odds of infection were also higher for vendors having a greater volume of ducks unsold per day. These results indicate how the spread of AIVs is influenced by the structure of the live poultry trading network.

Ocular cicatricial pemphigoid (OCP) is a rare systemic autoimmune disease and a potentially blinding subepithelial blistering disorder. The purpose of this study was to describe the clinical spectrum of the disease and to assess the efficacy and safety of immunosuppressive agents in a cohort of patients with OCP.We conducted a monocentric retrospective cross-sectional cohort study of all unselected consecutive patients diagnosed with progressive OCP. Ocular and extra ophthalmological involvement as well as histological findings were gathered. Other outcomes were exposures to immunosuppressive agents defined by the use of a particular treatment. For each exposure, success in controlling ocular inflammation was graded as a complete response, response, or failure. Relapses and adverse events (AE) were also recorded.Seventeen patients (34 affected eyes), 35% of whom were women, were included, with an age at diagnosis of 75 ± 11 years. Corneal involvement was diagnosed in 30 of 34 eyes, and 22 of 34 eyes had progressive fibrosing conjunctival involvement. Sixty-two exposures to immunosuppressive agents or biologics were recorded: dapsone, n = 26; mycophenolate mofetil, n = 6; azathioprine, n = 4; cyclophosphamide, n = 10; rituximab, n = 14; and intravenous immunoglobulin, n = 2. Rates of response and of complete response achievement during the first 3 months were 84% and 45%, respectively. Response rates were 100%, 100%, 86%, 85%, and 80% for intravenous immunoglobulin, mycophenolate mofetil, rituximab, dapsone, and cyclophosphamide, respectively. Thirteen percent of those drugs were discontinued because of an adverse event in 4 patients.This study describes the efficacy of immunosuppressants or biologics with an acceptable safety profile for OCP.

A cross-sectional observation and an intervention study were conducted in Chittagong, Bangladesh in 2015 to assess the status of antimicrobial residues in chicken and fish. The samples were tested for selected antimicrobials (amoxicillin, ciprofloxacin, oxytetracycline and enrofloxacin) using thin-layer chromatography (TLC). The TLC-based overall prevalence of residues was 87.9% in chicken (N = 182) and 56.9% in fish (N = 153). The prevalences in chicken in June (N = 91) and in October (N = 91), respectively, were 91.2% and 83.5% (amoxicillin), 1.1% and 1.1% (enrofloxacin), 1.1% and 0% (ciprofloxacin), and 0% and 6.6% (oxytetracycline). In fish, the prevalence in September (N = 74) and in October (N = 79) was 52.7% and 44.3% (amoxicillin) and 1.4% and 27.8% (oxytetracycline), respectively. The mean concentration of amoxicillin residue was evaluated by ultra-high-performance liquid chromatography to be 508.4 mg/kg (chicken) and 515.4 mg/kg (fish). The random effect model identified market (Chawkbazar vs. Boalkhali: OR 5.7; Steelmill bazar vs. Boalkhali: OR 5.6) as significant factors for amoxicillin residue in chicken. Amoxicillin concentration was significantly reduced in chicken of Kazirhat (β= - 1.3) and Chawkbazar (β= - 1.1) and increased in October (β= 0.77) based on a generalized linear model (GLM). Climbing perch fish had significantly more risk of having amoxicillin residue than that of Bombay duck (OR = 0.05). All samples were treated by washing, boiling and cooking with spices, and then, TLC-based screening of amoxicillin residues was done. A subset of each treated group was evaluated by UHPLC. Treatment reduced amoxicillin residue levels significantly.

In this paper, we identify behaviours in live bird commodity chains in Chattogram, Bangladesh, which may influence the risk of pathogen emergence and transmission: the nature of poultry trade, value appropriation and selling sick or infected birds. Examining the reasons why actors engage in these behaviours, we emphasise the politics of constraints within a context of real-world decisions, governed by existential and pragmatic agency. Focusing on contact zones and entanglement, analysing patron-client relationships and precarious circumstances, we argue that agency and structure specific to the Bangladeshi context produce a risk environment. Structural constraints may reinforce risky occupational practises and limit individual agency. Structural constraints need to be addressed in order to tackle animal and zoonotic disease risk along live animal commodity chains.

Background Heart rate variability biofeedback (HRVB) is a non-pharmacological intervention used in the management of chronic diseases. Method A systematic search was performed according to eligibility criteria including adult chronic patients, HRVB as main treatment with or without control conditions, and psychophysiological outcomes as dependent variables. Results In total, 29 articles were included. Reported results showed the feasibility of HRVB in chronic patients without adverse effects. Significant positive effects were found in various patient profiles on hypertension and cardiovascular prognosis, inflammatory state, asthma disorders, depression and anxiety, sleep disturbances, cognitive performance and pain, which could be associated with improved quality of life. Improvements in clinical outcomes co-occurred with improvements in heart rate variability, suggesting possible regulatory effect of HRVB on autonomic function. Conclusions HRVB could be effective in managing patients with chronic diseases. Further investigations are required to confirm these results and recommend the most effective method.

Commercial broiler and layer farming represents an important livestock industry in Bangladesh. Adequate biosecurity practices are considered to be an effective method to prevent infectious disease occurrence on commercial poultry farms, but antimicrobials are also frequently administered to reduce disease risk. We conducted a cross-sectional study on 57 commercial layer and 83 broiler farms in eight subdistricts of the Chattogram district in Bangladesh to investigate the relationship between implemented biosecurity practices and the use of antimicrobials on these farms. We used a causal diagram framework to inform multi-level mixed effects logistic regression models to explore the total and direct effects of biosecurity practices implemented on commercial farms on prophylactic versus therapeutic antimicrobial usage on these farms. Overall, inadequate biosecurity was more common on broiler compared to layer farms and on farms rearing smaller flock sizes. For example, separation of sick from healthy birds was more common on layer farms (85.2 %, 46/54) compared to broiler farms (38.6 %, 32/83) (p = 0.001). Prophylactic administration (compared to therapeutic use) of antimicrobials was less common on farms that were separating sick birds from the healthy birds (total and direct effect OR = 0.1, 95 % CI: 0.1−0.6, p = 0.006) and less common on farms that used a poorer quality source of water for drinking, cooling, cleaning, and washing (total and direct effect OR = 0.3, 95 % CI: 0.1−0.9, p = 0.036). In contrast, farmers that used washing facilities (versus non-usage of washing facilities) were more likely to administer antimicrobials prophylactically (total and direct effect OR = 3.9, 95 % CI: 1.3−11.3, p = 0.012). The null model ICC indicated significant clustering at the subdistrict level (ICC = 0.20, 95 % CI: 0.04−0.60, p = 0.013), but the ICC was reduced after including flock size and farm type, and the biosecurity practices as fixed effects (ICC = 0.14, 95 % CI: 0.02−0.59, p = 0.0661). Overall, our study highlighted that a large proportion of commercial chicken farmers mediated poor biosecurity practices by prophylactic application of antimicrobials. The results of our research can be used to inform awareness programs for commercial poultry farmers emphasizing the importance of improving biosecurity rather than using antimicrobials to reduce the risk of poultry disease occurrence.

γδ T lymphocytes represent ∼1% of human peripheral blood mononuclear cells and even more cells in most tissues of vertebrates. Although they have important anticancer functions, most current single-cell RNA sequencing (scRNA-seq) studies do not identify γδ T lymphocytes because their transcriptomes at the single-cell level are unknown. Here we show that high-resolution clustering of large scRNA-seq datasets and a combination of gene signatures allow the specific detection of human γδ T lymphocytes and identification of their T cell receptor (TCR)Vδ1 and TCRVδ2 subsets in large datasets from complex cell mixtures. In t -distributed stochastic neighbor embedding plots from blood and tumor samples, the few γδ T lymphocytes appear collectively embedded between cytotoxic CD8 T and NK cells. Their TCRVδ1 and TCRVδ2 subsets form close yet distinct subclusters, respectively neighboring NK and CD8 T cells because of expression of shared and distinct cytotoxic maturation genes. Similar pseudotime maturation trajectories of TCRVδ1 and TCRVδ2 γδ T lymphocytes were discovered, unveiling in both subsets an unattended pool of terminally differentiated effector memory cells with preserved proliferative capacity, a finding confirmed by in vitro proliferation assays. Overall, the single-cell transcriptomes of thousands of individual γδ T lymphocytes from different CMV + and CMV − donors reflect cytotoxic maturation stages driven by the immunological history of donors. This landmark study establishes the rationale for identification, subtyping, and deep characterization of human γδ T lymphocytes in further scRNA-seq studies of complex tissues in physiological and disease conditions.

International audience; High-definition transcriptomic studies through single-cell RNA sequencing (scRNA-Seq) have revealed the heterogeneity and functionality of the various microenvironments across numerous solid tumors. Those pioneer studies have highlighted different cellular signatures correlated with clinical response to immune checkpoint inhibitors. scRNA-Seq offers also a unique opportunity to unravel the intimate heterogeneity of the ecosystems across different lymphoma entities. In this review, we will first cover the basics and future developments of the technology, and we will discuss its input in the field of translational lymphoma research, from determination of cell-of-origin and functional diversity, to monitoring of anti-cancer targeted drugs response and toxicities, and how new improvements in both data collection and interpretation will further foster precision medicine in the upcoming years.

Purpose Hematologic patients have a poorer health-related quality of life due to the disease and its treatments. Non-pharmacological interventions represent an opportunity in tertiary cancer prevention to manage persistent symptoms and support patients in their return to active daily living. This interventional study aimed to evaluate the feasibility of a program combining physical exercise (PE) and heart rate variability biofeedback (HRVB) in hematologic patients. Method Hematologic patients in remission within 6 months participated in a 12-week rehabilitation program including 24 supervised sessions of PE associated with 10 supervised sessions of HRVB and daily home-based practice of paced breathing. We assessed patient adherence, fatigue, physical function, and heart rate variability. Results Twenty patients were included, 17 completed the protocol and 3 dropped out due to disease progression or time constraints; no adverse events or incidents were reported. Participation rates were 85% for PE and 98% for HRVB-supervised sessions. Significant improvements of physical capacity (6-min walk test, p p p p p p p p > 0.05). Conclusion A rehabilitation program combining PE and HRVB is feasible in hematologic patients and effective on physical function. Further research with a larger sample size is needed to investigate effectiveness on patients’ autonomic functions and their impacts on symptomatology.

Commercial poultry production is growing rapidly in Bangladesh to address the increasing demand for poultry meat and eggs. Challenges faced by producers include the occurrence of poultry diseases, which are usually treated or controlled by antimicrobials. A cross-sectional study was conducted on 57 commercial layer and 83 broiler farms in eight subdistricts of the Chattogram district, Bangladesh, to assess antimicrobial usage in relation to clinical signs observed in chicken flocks on these farms. Of the 140 commercial chicken farms, 137 (97.9%) used antimicrobials and 24 different antimicrobial agents were administered. On layer farms, the most commonly used antimicrobials were ciprofloxacin (37.0% of farms, 20/54), amoxicillin (33.3%, 18/54), and tiamulin (31.5%, 17/54), while on broiler farms, colistin (56.6%, 47/83), doxycycline (50.6%, 42/83), and neomycin (38.6%, 32/83) were most commonly administered. Only 15.3% (21/137) of farmers used antimicrobials exclusively for therapeutic purposes, while 84.7% (116/137) of farmers used them prophylactically, administering them either for prophylactic purposes only (22.6% of farmers, 31/137) or in combination with therapeutic purposes (62.1% of farmers, 85/137). About 83.3% (45/54) of layer farmers were selling eggs while antimicrobials were being administered compared to 36.1% (30/83) of the broiler farmers selling broiler chickens while administering antimicrobials. Overall, 75.2% (103/137) of farmers reported clinical signs for which they administered antimicrobials, while 24.8% (34/137) of farmers reported no clinical signs but still administered antimicrobials. Respiratory signs (71.8% of farms with clinical signs, 74/103) were most commonly reported, followed by enteric signs (32.0%, 33/103) and increased mortality (16.5%, 17/103). About 37.2% (51/137) of farmers bought antimicrobials exclusively from feed and chick traders, followed by veterinary medical stores (35.0%, 48/137). Purchasing antimicrobials from feed and chick traders was more common among broiler than layer farmers. It is recommended that commercial poultry farmers should keep records of antimicrobials used with dosage and duration of administration along with indication of use. This would allow farmers and veterinarians to review if antimicrobial usage had the desired effects and to evaluate the appropriate use of antimicrobial agents under an antimicrobial stewardship approach.

Purpose To assess the keratoconus (KC) prevalence among first-degree relatives of affected subjects. Methods We performed large epidemiological, prospective, and observational cohort, which took place in the French KC National Reference Centre, in Bordeaux. We studied data from 94 unrelated patients with KC and at least 2 first-degree relatives assessable. Each subject had a thorough ocular examination including visual acuity, refraction, slitlamp biomicroscopy, indirect ophthalmoscopy, keratometry, corneal topography and tomographer (Topographic Modeling System; Tomey Corporation, Japan; and Galilei G4, Ziemer, Switzerland, respectively), pachymetry, and biomechanical properties of cornea (Ocular Response Analyzer; Reichert, Depew, NY). Additional data were collected about atopy, smoking, and eye-rubbing habits. KC prevalence, multivariate analysis, and familial correlation analysis have been studied. Results Of the 221 relatives, 9.05% (n = 20) had clinically manifest KC, and 15.4% (n = 31) had subclinical KC. The prevalence of KC was estimated equal to 0.14 [95% confidence interval (CI), 0.07-0.22] among parents, 0.03 (95% CI, 0-0.10) among offspring, and 0.10 (95% CI, 0.04-0.20) among siblings. In multivariable analysis, age and eye-rubbing were associated with an increased risk of KC. The familial correlation of KC among probands' first-degree relatives was estimated at 0.55 among parents, 0.29 among offspring, and 0.49 among siblings. Conclusions Being a first-degree relative of a subject with KC remains a risk factor for developing KC. This should be taken into account especially when screening for KC in pediatric patients, for refractive surgery candidates, and for patients being evaluated for cataract surgery.

In mice, IFNγ-producing γδ T cells that express the co-stimulatory molecule, CD27, play a critical role in host defence and anti-tumour immunity. However, their phenotypic diversity, composition in peripheral and secondary lymphoid organs, similarity to αβ T cells as well as homology with human γδ T cells is poorly understood. Here, using single cell RNA sequencing, we show that CD27+ γδ T cells consist of two major clusters, which are distinguished by expression of Ly6C. We demonstrate that CD27+Ly6C— γδ T cells exhibit a naïve T cell-like phenotype, whereas CD27+Ly6C+ γδ T cells display a memory-like phenotype, produce several NK cell-related and cytotoxic molecules and are highly similar to both mouse CD8+ T cells and mature human γδ T cells. In a breast cancer mouse model, depletion of CD27+ γδ T cells failed to affect tumour growth, but these cells could be coerced into killing cancer cells after expansion ex vivo. These results identify novel subsets of γδ T cells in mice that are comparable to human γδ T cells, opening new opportunities for γδ T cell-based cancer immunotherapy research.

Bone morphogenetic protein 1 (BMP-1) is an important metalloproteinase that synchronizes growth factor activation with extracellular matrix assembly during morphogenesis and tissue repair. The mechanisms by which BMP-1 exerts these effects are highly context dependent. Because BMP-1 overexpression induces marked phenotypic changes in two human cell lines (HT1080 and 293-EBNA cells), we investigated how BMP-1 simultaneously affects cell-matrix interactions and growth factor activity in these cells. Increasing BMP-1 led to a loss of cell adhesion that depended on the matricellular glycoprotein thrombospondin-1 (TSP-1). BMP-1 cleaved TSP-1 between the VWFC/procollagen-like domain and the type 1 repeats that mediate several key TSP-1 functions. This cleavage induced the release of TSP-1 C-terminal domains from the extracellular matrix and abolished its previously described multisite cooperative interactions with heparan sulfate proteoglycans and CD36 on HT1080 cells. In addition, BMP-1-dependent proteolysis potentiated the TSP-1-mediated activation of latent transforming growth factor-β (TGF-β), leading to increased signaling through the canonical SMAD pathway. In primary human corneal stromal cells (keratocytes), endogenous BMP-1 cleaved TSP-1, and the addition of exogenous BMP-1 enhanced cleavage, but this had no substantial effect on cell adhesion. Instead, processed TSP-1 promoted the differentiation of keratocytes into myofibroblasts and stimulated production of the myofibroblast marker α-SMA, consistent with the presence of processed TSP-1 in human corneal scars. Our results indicate that BMP-1 can both trigger the disruption of cell adhesion and stimulate TGF-β signaling in TSP-1-rich microenvironments, which has important potential consequences for wound healing and tumor progression.