FLT3-directed UniCAR T-cell therapy of acute myeloid leukaemia.

Adaptor chimeric antigen receptor (CAR) T-cell therapy offers solutions for improved safety and antigen escape, which represent main obstacles for the clinical translation of CAR T-cell therapy in myeloid malignancies. The adaptor CAR T-cell platform 'UniCAR' is currently under early clinical investigation. Recently, the first proof of concept of a well-tolerated, rapidly switchable, CD123-directed UniCAR T-cell product treating patients with acute myeloid leukaemia (AML) was reported. Relapsed and refractory AML is prone to high plasticity under therapy pressure targeting one single tumour antigen. Thus, targeting of multiple tumour antigens seems to be required to achieve durable anti-tumour responses, underlining the need to further design alternative AML-specific target modules (TM) for the UniCAR platform. We here present the preclinical development of a novel FMS-like tyrosine kinase 3 (FLT3)-directed UniCAR T-cell therapy, which is highly effective for in vitro killing of both AML cell lines and primary AML samples. Furthermore, we show in vivo functionality in a murine xenograft model. PET analyses further demonstrate a short serum half-life of FLT3 TMs, which will enable a rapid on/off switch of UniCAR T cells. Overall, the presented preclinical data encourage the further development and clinical translation of FLT3-specific UniCAR T cells for the therapy of AML.

[Development of a chatbot (conversational app) for cataract surgery patients]. / Développement d'un chatbot (agent conversationnel) pour les patients en parcours de chirurgie de la cataracte.

INTRODUCTION: The goal of this study was to create and promote a type of chatbot or conversational app, for patients who need cataract surgery and to evaluate its acceptability. METHODS: Multicentric prospective clinical study in two phases. Phase I : distribution of a questionnaire of 20 questions (evaluating patients' knowledge about cataracts and cataract surgery and their expectations in terms of patient education). Statistical analysis was performed through factorial analysis with factor rotation and Cronbach's alpha calculation. Phase II : creation of a chatbot with a repertoire of question-answer sets. An acceptability analysis was performed using a second questionnaire inspired by the « SUS Score ¼. RESULTS: One hundred and six initial questionnaires were collected. The patients were mostly women (56.6 %), aged 60 to 79 years (81 %), retired (77.4 %), with no high school diploma (33.0 %), had never used a chatbot before (95.3 %) and were accustomed to using a smartphone (66.0 %). Patients evaluated their knowledge about cataracts as insufficient (51.8 %) and felt the need to receive additional information (81.1 %). The comprehensibility score of the first questionnaire was 91 (middle school level). The baseline data of the chatbot was composed of 316 questions with a median comprehensibility score of 101 (middle school level). The first test of the chatbot included 18 patients. The median connection time was 4min and 40seconds (standard deviation 6.6). The median of number of questions asked for each connection was 6.5 (standard deviation 6.7). Acceptability was good, with a mean Sus Score of 78.6/100 (standard deviation 11.9). CONCLUSION: This study shows the importance of information for cataract surgery patients. The creation of a chatbot for patients undergoing cataract surgery appears to be relevant in achieving this goal.

[First- and second-line hospital management of ophthalmologic emergencies: Clinical pathway study of 1360 patients]. / Prise en charge des urgences ophtalmologiques en premier et second recours hospitaliers : analyse du parcours de 1360 patients.

The general practitioner (GP) might offer a good alternative for the management of certain ophthalmologic emergencies in his or her practice, given the increasing demand for ophthalmological care and difficulties with access to ophthalmologists. The main objective of the study was to describe ophthalmological complaints and their management in general emergency departments compared to ophthalmological emergency departments in order to assess which pathologies can be treated by the GP. This was a single-center retrospective study at the University Hospital of Reims, based on consultation data from the general and ophthalmological emergency departments for all adult patients presenting for an ophthalmological problem in September 2019 and September 2020. Consultations where patients were brought back following a first emergency consultation and consultations for another non-ophthalmological reason were excluded. Out of 1360 consultations recorded, 16% of patients had initially consulted their GP. The 4 most frequent diagnoses were: "ocular trauma," "conjunctivitis," "eye pain" and "visual impairment." A prescription for medication was issued in 77% of cases, 37% of which were for antibiotics. Only 29% of consultations carried out in general emergency departments led to a request for a complementary ophthalmology consultation. The GP might therefore be able to manage certain ophthalmological emergencies in his or her practice as a first line and refer certain ophthalmologic emergencies. However, the training of GPs in this specialty must be reinforced in collaboration with ophthalmologists.

Prediction of nitrogen excretion from data on dairy cows fed a wide range of diets compiled in an intercontinental database: A meta-analysis.

Manure nitrogen (N) from cattle contributes to nitrous oxide and ammonia emissions and nitrate leaching. Measurement of manure N outputs on dairy farms is laborious, expensive, and impractical at large scales; therefore, models are needed to predict N excreted in urine and feces. Building robust prediction models requires extensive data from animals under different management systems worldwide. Thus, the study objectives were (1) to collate an international database of N excretion in feces and urine based on individual lactating dairy cow data from different continents; (2) to determine the suitability of key variables for predicting fecal, urinary, and total manure N excretion; and (3) to develop robust and reliable N excretion prediction models based on individual data from lactating dairy cows consuming various diets. A raw data set was created based on 5,483 individual cow observations, with 5,420 fecal N excretion and 3,621 urine N excretion measurements collected from 162 in vivo experiments conducted by 22 research institutes mostly located in Europe (n = 14) and North America (n = 5). A sequential approach was taken in developing models with increasing complexity by incrementally adding variables that had a significant individual effect on fecal, urinary, or total manure N excretion. Nitrogen excretion was predicted by fitting linear mixed models including experiment as a random effect. Simple models requiring dry matter intake (DMI) or N intake performed better for predicting fecal N excretion than simple models using diet nutrient composition or milk performance parameters. Simple models based on N intake performed better for urinary and total manure N excretion than those based on DMI, but simple models using milk urea N (MUN) and N intake performed even better for urinary N excretion. The full model predicting fecal N excretion had similar performance to simple models based on DMI but included several independent variables (DMI, diet crude protein content, diet neutral detergent fiber content, milk protein), depending on the location, and had root mean square prediction errors as a fraction of the observed mean values of 19.1% for intercontinental, 19.8% for European, and 17.7% for North American data sets. Complex total manure N excretion models based on N intake and MUN led to prediction errors of about 13.0% to 14.0%, which were comparable to models based on N intake alone. Intercepts and slopes of variables in optimal prediction equations developed on intercontinental, European, and North American bases differed from each other, and therefore region-specific models are preferred to predict N excretion. In conclusion, region-specific models that include information on DMI or N intake and MUN are required for good prediction of fecal, urinary, and total manure N excretion. In absence of intake data, region-specific complex equations using easily and routinely measured variables to predict fecal, urinary, or total manure N excretion may be used, but these equations have lower performance than equations based on intake.

Symposium review: Effective nutritional strategies to mitigate enteric methane in dairy cattle.

Intensive research in the past decade has resulted in a better understanding of factors driving enteric methane (CH4) emissions in ruminants. Meta-analyses of large databases, developed through the GLOBAL NETWORK project, have identified successful strategies for mitigation of CH4 emissions. Methane inhibitors, alternative electron sinks, vegetable oils and oilseeds, and tanniferous forages are among the recommended strategies for mitigating CH4 emissions from dairy and beef cattle and small ruminants. These strategies were also effective in decreasing CH4 emissions yield and intensity. However, a higher inclusion rate of oils may negatively affect feed intake, rumen function, and animal performance, specifically milk components in dairy cows. In the case of nitrates (electron sinks), concerns with animal health may be impeding their adoption in practice, and potential emission trade-offs have to be considered. Tannins and tanniferous forages may have a negative effect on nutrient digestibility, and more research is needed to confirm their effects on overall animal performance in long-term experiments with high-producing animals. A meta-analysis of studies with dairy cows fed the CH4 inhibitor 3-nitrooxypropanol (3-NOP) at the Pennsylvania State University showed (1) a consistent 28 to 32% decrease in daily CH4 emissions or emissions yield and intensity; (2) no effect on dry matter intake, milk production, body weight, or body weight change, and a slight increase in milk fat concentration and yield (0.19 percentage units and 90 g/d, respectively); 3-NOP also appears to increase milk urea nitrogen concentration; (3) an exponential decrease in the mitigation effect of the inhibitor with increasing its dose (from 40 to 200 mg/kg of feed dry matter, corresponding to 3-NOP intake of 1 to 4.8 g/cow per day); and (4) a potential decrease in the efficacy of 3-NOP over time, which needs to be further investigated in long-term, full-lactation or multiple-lactation studies. The red macroalga Asparagopsis taxiformis has a strong CH4 mitigation effect, but studies are needed to determine its feasibility, long-term efficacy, and effects on animal production and health. We concluded that widespread adoption of mitigation strategies with proven effectiveness by the livestock industries will depend on cost, government policies and incentives, and willingness of consumers to pay a higher price for animal products with decreased carbon footprint.

[Setting up Objective Structured Clinical Examination (OSCE) in ophthalmology]. / Mise en place des examens cliniques objectifs structurés (ECOS) facultaires en ophtalmologie.

Obective Structured Clinical Examinations (OSCE) are a reproducible and objective way to evaluate medical students and have been used for many years in English-speaking countries, Canada and Switzerland. They evaluate candidates more on the basis of their practical skills, know-how and interpersonal skills than on their theoretical knowledge. From a nationally validated, limited list of typical clinical situations, stations are set up by the teaching team with standardized patients played by actors, designed to test a variety of problem solving, technical, diagnostic, therapeutic, communication, examination, and history taking skills, possibly with simulation tools. Setting up a station, as well as creating an OSCE cycle with several stations through which the candidates rotate, requires significant preparation prior to the examination: creating the station scenario with precise instruction sheets for the candidates, simulated patients and evaluators, multiple stages of proofreading, verifying the required equipment and adapting rating scales. OSCEs seek to evaluate students "objectively," as they are the only variable in this type of examination, in which the scripts, materials and rating scales have been standardized to limit subjectivity. This examination method is a flagship measure of the reform of the second cycle of French medical studies. OSCEs are now part of the testing modalities for the 2021-2022 academic year and will be integrated into the National Dematerialized Examination (NDE) starting in May 2023. They may also be useful in validating the achievements of students and residents in various stages of training, as well as in continuing medical education (CME). We present herein the key elements of these new evaluation tools and their practical applications in the evaluation of students in ophthalmology.

[Management of ocular toxoplasmosis in France: Results of a modified Delphi study]. / Prise en charge de la toxoplasmose oculaire en France : résultats d'une étude Delphi modifiée.

OBJECTIVE: To evaluate diagnostic and therapeutic practices and then establish a consensus on the management of ocular toxoplasmosis in France through a Delphi study. MATERIALS AND METHODS: Twenty-three French experts in ocular toxoplasmosis were invited to respond to a modified Delphi study conducted online, in the form of two questionnaires, in an attempt to establish a consensus on the diagnosis and management of this pathology. The threshold for identical responses to reach consensus was set at 70 %. RESULTS: The responses of 19 experts out of the 23 selected were obtained on the first questionnaire and 16 experts on the second. The main elements agreed upon by the experts were to treat patients with a decrease in visual acuity or an infectious focus within the posterior pole, to treat peripheral lesions only in the presence of significant inflammation, the prescription of first-line treatment with pyrimethamine-azithromycin, the use of corticosteroid therapy after a period of 24 to 48hours, the prophylaxis of frequent recurrences (more than 2 episodes per year) with trimethoprim-sulfamethoxazole as well as the implementation of prophylactic treatment of recurrences in immunocompromised patients. On the other hand, no consensus emerged with regard to the examinations to be carried out for the etiological diagnosis (anterior chamber paracentesis, fluorescein angiography, serology, etc.), second-line treatment (in the case of failure of first-line treatment), or treatment of peripheral foci. CONCLUSION: This study lays the foundations for possible randomized scientific studies to be conducted to clarify the management of ocular toxoplasmosis, on the one hand to confirm consensual clinical practices and on the other hand to guide practices for which no formal consensus has been demonstrated.

Intravitreal triamcinolone injections in non-arteritic anterior ischemic optic neuropathy - A retrospective report.

BACKGROUND: Non-arteritic anterior ischemic optic neuropathy (NAION) is a common cause of vision loss but no treatment has demonstrated its efficiency. A preliminary study showed an improvement on the visual acuity (VA) in a group of patients who received intravitreal administration of triamcinolone acetonide (IVTA) versus a non-treated group. In the present series, the visual outcome of IVTA in NAION was evaluated on a larger group of patients. METHODS: This retrospective, unmasked and non-randomized study took place at Reims University Hospital between 2009 and 2017. The data of consecutive patients presenting with isolated optic disc edema characteristic of recent NAION (<1month of visual acuity loss) were included. After informed consent, a single intravitreal injection of filtrated 4mg/0.1mL triamcinolone acetonide were administered. Twenty-seven control patients chose not to be injected and therefore served as controls. LogMar visual acuity (VA), VA rating (VAR) (1 line=0.1LogMAR=5 VAR letters), retinal nerve fiber layer thickness assessed by OCT and static visual field were evaluated at presentation, after 7days, after 3months and after 6months. RESULTS: Sixty-eight patients with NAION were evaluated. Forty-one received IVTA, 29 were injected within 15days after the onset of symptoms and 12 after 15days. There was a higher proportion of patients improving VA of 2 lines or more (10 or more VAR letters) in the injected group (49%) compared with the non-injected group (11%, P=0.019). Among the patients injected before 15days, the proportion improving for 2 lines or more (55% vs. 11%, respectively, P=0.013) and for 3 lines or more (45% vs. 11%, respectively, P=0.035) were significantly higher than in the non-injected group. Also, comparing the VA at presentation with the VA after 6months in the injected eyes, it improved significantly (P=0.003) and also in the subgroup injected within 15days (P=0.0007) but not in the injected group after 15days (P=0.801). Visual field improvement was only observed in the subgroup of patients injected within 15days with a significant improvement of the mean deviation (dB) within 6months (P=0.015). CONCLUSIONS: This follow-up study confirms the results of the previous series displaying an apparent benefit of intravitreal steroids injected in the acute phase of NAION. Only patients receiving IVTA within 15days from onset of NAION have a significant improvement of VA and visual field during the follow-up period of 6months.

[Retrospective evaluation of residencies in private ophthalmology practice from 2015 to 2018 in Champagne-Ardenne]. / Évaluation rétrospective de stages d'interne d'ophtalmologie en cabinet libéral de 2015 à 2018 en Champagne-Ardenne.

INTRODUCTION: Between 2010 and 2018, the quota for admission to ophthalmology residencies increased by 50 % (106 in 2010 vs 150 in 2018). In order to accommodate this increasing number of residents, the University Hospital of Reims formulated an agreement with the Regional Health Agency in May 2015 enabling certain ophthalmologists in the private sector to train a resident within their private practice for a semester. We will present the results of three and one half years of this experience. METHODS: Two retrospective questionnaires were created and completed. One was addressed to the host supervisor, the other to the resident. Their objective was to evaluate and standardize the experience from both points of view. The following aspects were explored: the extent to which the environment was welcoming, the resident's clinical ability and progress, the resident's surgical ability and progress, time-management, resident-patient relations and respective assessments. We also requested information on the number of residents hosted by each private practice as well as the positive and negative aspects of the internship for both the supervisor and the intern. RESULTS: Between May 2015 and October 2018 (seven semesters), 12 residents from the University Hospital of Reims did an internship with one of the six proposed private sector ophthalmologists in the Champagne-Ardennes region. The residents were between their second and eighth semesters of professional training. Seven residents did their first or second semester of ophthalmology training in a private practice. The survey results led to the conclusion of a positive experience for both trainer and trainee regarding the progress made by the resident, both clinically and surgically. CONCLUSION: Given the growing number of ophthalmology residents and the limits of the training capacity of hospital-based residencies, private sector internships with practitioners actively involved in teaching increase the training capacity for residents and complement the conventional hospital training.

Approche diagnostique et thérapeutique de la vasculopathie polypoïdale choroïdienne. Recommandations de la Fédération France Macula.

PURPOSE: To update the medical literature on the diagnostic and therapeutic approach to polypoidal choroidal vasculopathy (PCV) and to propose a treatment algorithm in agreement with French market approval, supported by the France Macula Federation (FFM). METHODS: Literature review and expert opinion. RESULTS: The diagnosis of PCV is based on multimodal imaging, including indocyanine green angiography (ICGA), which is considered the gold standard for the diagnosis of PCV. Regarding the therapeutic management of PCV, the FFM recommends treating PCV first-line either by monotherapy with intra-vitreal anti-vascular endothelial growth factor (anti-VEGF) injections, or by a combined treatment of photodynamic therapy (PDT) with Verteporfin and intra-vitreal anti-VEGF injections, depending on the location of the PCV.

Short-term methane emissions from 2 dairy farms in California estimated by different measurement techniques and US Environmental Protection Agency inventory methodology: A case study.

Reported estimates of CH4 emissions from ruminants and manure management are up to 2 times higher in atmospheric top-down calculations than in bottom-up (BU) inventories. We explored this discrepancy by estimating CH4 emissions of 2 dairy facilities in California with US Environmental Protection Agency (US EPA) methodology, which is used for BU inventories, and 3 independent measurement techniques: (1) open-path measurements with inverse dispersion modeling (hereafter open-path), (2) vehicle measurements with tracer flux ratio method, and (3) aircraft measurements with the closed-path method. All 3 techniques were used to estimate whole-facility CH4 emissions during 3 to 6 d per farm in the summer of 2016. In addition, open-path was used to estimate whole-facility CH4 emissions over 13 to 14 d per farm in the winter of 2017. Our objectives were to (1) compare whole-facility CH4 measurements utilizing the different measurement techniques, (2) compare whole-facility CH4 measurements to US EPA inventory methodology estimates, and (3) compare CH4 emissions between 2 dairies. Whole-facility CH4 estimates were similar among measurement techniques. No seasonality was detected for CH4 emissions from animal housing, but CH4 emissions from liquid manure storage were 3 to 6 times greater during the summer than during the winter measurement periods. The findings confirm previous studies showing that whole-facility CH4 emissions need to be measured throughout the year to estimate and evaluate annual inventories. Open-path measurements for liquid manure storage emissions were similar to monthly US EPA estimates during the summer, but not during the winter measurement periods. However, the numerical difference was relatively small considering yearly emission estimates. Manure CH4 emissions contributed 69 to 79% and 26 to 47% of whole-facility CH4 emissions during the summer and winter measurement periods, respectively. Methane yields from animal housing were similar between farms (on average 20.9 g of CH4/kg of dry matter intake), but CH4 emissions normalized by volatile solids (VS) loading from liquid manure storage (g of CH4 per day/kg of VS produced by all cattle per day) at 1 dairy were 1.7 and 3.5 times greater than at the other during the summer (234 vs. 137 g of CH4/kg of VS) and winter measurement periods (78 vs. 22 g of CH4/kg of VS), respectively. We attributed much of this difference to the proportion of manure stored in liquid (anaerobic) form, and suggest that manure management practices that reduce the amount of manure solids stored in liquid form could significantly reduce dairy CH4 emissions.