Monitoring anti-CD19 chimeric antigen receptor T cell population by flow cytometry and its consistency with digital droplet polymerase chain reaction.

Anti-CD19 chimeric antigen receptor (CAR19) T cell therapy has produced impressive clinical efficacy in patients with relapsed or refractory B-cell malignancies. As a living drug, monitoring the pharmacokinetics of CAR T cells in vivo is an important part of clinical work, which provides valuable information for assessing therapeutic response and related side effects. However, no guidelines are available regarding the detection and quantification of CAR T cells. Flow cytometry is a convenient and commonly used method in monitoring CAR T cell kinetics, but its performance remains to be validated. By using a commercial anti-idiotype antibody that detects unique epitopes on the most popular CAR19 construct, we evaluated important performance parameters, including specificity, lower limit of detection, lower limit of quantification, and precision of flow cytometry in the detection and quantification of CAR19 T cells. Consistency between the results generated by flow cytometry and droplet digital PCR was then investigated in 188 pairs of clinical data and in cell line experiments. Rabbit anti-mouse FMC63 monoclonal antibody possesses high specificity in the detection of CAR19 positive cells by FCM with a cut-off value of 0.05%. The results produced by flow cytometry and ddPCR were well correlated in the clinical samples and in cell lines, but the correlation deteriorated as the abundance of CAR19 positive cells decreased. This was especially evident with less than 0.5% of lymphocytes in clinical data, possibly due to reduced precision (indicated by intra- and inter-assay coefficients of variability) of both droplet digital PCR and flow cytometry. We demonstrated that flow cytometry using anti-idiotype antibody is a reliable and robust approach in the detection and quantification of CAR19 T cells in vivo and has good consistency with droplet digital PCR in monitoring CAR19 T cell kinetics.

TNF-α blockade may lead to improvement of vascular function in psoriasis patients.

Psoriasis is one of the most common chronic inflammatory skin diseases and at the same time a risk factor for cardiovascular disease. Interleukin-17A (IL-17A)-mediated inflammation in psoriasis may lead to vascular dysfunction. This study aimed at investigating whether anti-inflammatory treatment by tumor necrosis factor (TNF)-α blockade alters vascular function in psoriasis patients. A total of 11 patients with psoriasis who underwent treatment with either adalimumab (n = 8) or etanercept (n = 3), 10 healthy control individuals and 14 patients with coronary artery disease (CAD) were included in this study. Treatment response was assessed using the Psoriasis Area and Severity Index (PASI) score. Endothelial reactivity and resting endothelium-dependent vascular tone were assessed by ultrasound measurement of flow-mediated dilation (FMD) and low-flow-mediated constriction (l-FMC), respectively. FMD was slightly impaired in psoriasis patients compared to healthy controls. Anti-TNF-α treatment did not significantly change FMD levels. Psoriasis patients showed a trend towards increased baseline vascular activity compared to healthy controls. Anti-TNF-α treatment significantly improved l-FMC in psoriasis patients. Noteworthy, both FMD and l-FMC in psoriasis patients were comparable to those in patients with CAD; however, an important influence of age differences between the groups or co-existent classical cardiovascular risk factors on FMD and l-FMC cannot be ruled out by our small study. The results suggest that anti-inflammatory treatment with TNF-α blockade improves vascular function in patients with psoriasis, mainly by altering baseline vascular tone. Further studies will be necessary to establish the potentially protective impact of anti-inflammatory therapy on vascular function in patients with chronic inflammatory diseases.

Impact of COVID-19 pandemic on STEMI undergoing primary PCI treatment in Beijing, China.

OBJECTIVE: Strict control measures under the COVID epidemic have brought an inevitable impact on ST-segment elevation myocardial infarction (STEMI)'s emergency treatment. We investigated the impact of the COVID on the treatment of patients with STEMI undergoing primary PCI. METHODS: In this single center cohort study, we selected a time frame of 6 month after declaration of COVID-19 infection (Jan 24-July 24, 2020); a group of STEMI patients in the same period of 2019 was used as control. Finally, a total of 246 STEMI patients, who were underwent primary PCI, were enrolled into the study (136 non COVID-19 outbreak periods and 110 COVID-19 outbreak periods). The impact of COVID on the time of symptom onset to the first medical contact (symptom-to-FMC) and door to balloon (D-to-B) was investigated. Moreover, the primary outcome was in-hospital major adverse cardiac events (MACE), defined as a composite of cardiac death, heart failure and malignant arrhythmia. RESULTS: Compared with the same period in 2019, there was a 19% decrease in the total number of STEMI patients undergoing primary PCI at the peak of the pandemic in 2020. The delay in symptom-to-FMC was significantly longer in COVID Outbreak period (180 [68.75, 342] vs 120 [60,240] min, P = 0.003), and the D-to-B times increased significantly (148 [115-190] vs 84 [70-120] min, P < 0.001). However, among patients with STEMI, MACE was similar in both time periods (18.3% vs 25.7%, p = 0.168). On multivariable analysis, COVID was not independently associated with MACE; the history of diabetes, left main disease and age>65 years were the strongest predictors of MACE in the overall population. CONCLUSIONS: The COVID pandemic was not independently associated with MACE; suggesting that active primary PCI treatment preserved high-quality standards even when challenged by a severe epidemic. CLINICAL TRIAL REGISTRATION: URL: https://ClinicalTrials.gov Unique identifier: NCT04427735.

Can combined online and face-to-face continuing medical education improve the clinical knowledge and skills of family doctors in Vietnam? A cluster randomised controlled trial.

OBJECTIVES: To assess the effectiveness of a combined online and face-to-face continuing medical education (CME) programme, for improvement in clinical knowledge and skills of family doctors, in comparison with a control group; and to explore the self-reported satisfaction, competencies and confidence of those in the intervention group. METHODS: We used a cluster randomised controlled trial, with pre- and post-testing, and a feedback survey at the end of the 18-month CME programme. The measurements consisted of a multiple-choice test, an objective structured clinical examination test and an anonymously self-administered questionnaire. RESULTS: There were 58 family doctors from four provinces in the intervention group and 32 doctors from three provinces in control group, both in the Mekong Delta region in Vietnam. The mean age of participants was 47.8 years, and the female/male ratio was 1/2.9. After training, the intervention group had significantly higher scores on overall knowledge (mean difference = 1.4, 95% CI 1.0-1.86, P < 0.001; Cohen's d 1.36, Pearson's r 0.53), in four of the five education modules: peptic disorders, diabetes, hypertension and bone-muscle-joint diseases (Pearson's r 0.56, 0.56, 0.34 and 0.4, respectively), and in problem-solving skills (Pearson's r 0.27). Self-reports showed a positive learning attitude, strong interest and improved confidence and competency among doctors in the intervention group. CONCLUSIONS: A combined online and face-to-face CME programme proved applicable and effective for improving the clinical knowledge and problem-solving skills of family doctors in Vietnam.

OBJECTIFS: Evaluer l'efficacité d'une combinaison d'un programme de formation médicale continue (FMC), en ligne et en face-à-face pour l' amélioration des connaissances cliniques et les compétences des médecins de famille, par rapport à un groupe témoin et explorer la satisfaction, les compétences et la confiance autodéclarées des participants dans le groupe d'intervention. Méthodes Nous avons utilisé un essai contrôlé randomisé en grappes , avec pré et post-test, et une enquête de rétroaction à la fin du programme de FMC de 18 mois. Les mesures consistaient en un test à choix multiple, un test d'examen clinique objectif structuré et un questionnaire anonyme administré. Résultats Il y avait 58 médecins de famille de 4 provinces dans le groupe d'intervention et 32 médecins de 3 provinces dans le groupe témoin, tous deux dans la région du delta du Mékong au Vietnam. L'âge moyen des participants était de 47,8 ans, et le ratio femmes/hommes était de 1/2,9. Après la formation, le groupe d'intervention avaient des scores significativement plus élevés sur l' ensemble des connaissances (moyenne de différence = 1,4 ; IC95%: 1,0 à 1,86 ; p < 0,001 ; d de Cohen: 1,36 ; r de Pearson 0,53), dans 4 des 5 modules d'éducation: troubles gastro-duodénaux, diabète, hypertension et maladies des os-muscles- articulaires (r de Pearson 0,56 ; 0,56 ; 0,34 et 0,4, respectivement), et dans les compétences à résoudre des problèmes (r de Pearson: 0,2 7). Les auto-évaluations ont montré une attitude d'apprentissage positive, un vif intérêt et une amélioration de la confiance et des compétences chez les médecins du groupe d'intervention. CONCLUSIONS: Une FMC combiné basé sur Internet et en direct est applicable et efficace pour l'amélioration des connaissances cliniques et les compétences à résoudre les problèmes chez les médecins de famille au Vietnam.

Identification of Potent CD19 scFv for CAR T Cells through scFv Screening with NK/T-Cell Line.

CD19 is the most promising target for developing chimeric-antigen receptor (CAR) T cells against B-cell leukemic cancer. Currently, two CAR-T-cell products, Kymriah and Yescarta, are approved for leukemia patients, and various anti-CD19 CAR T cells are undergoing clinical trial. Most of these anti-CD19 CAR T cells use FMC63 single-chain variable fragments (scFvs) for binding CD19 expressed on the cancer cell surface. In this study, we screened several known CD19 scFvs for developing anti-CD19 CAR T cells. We used the KHYG-1 NK/T-cell line for screening of CD19 scFvs because it has advantages in terms of cell culture and gene transduction compared to primary T cells. Using our CAR construct backbone, we made anti-CD19 CAR constructs which each had CD19 scFvs including FMC63, B43, 25C1, BLY3, 4G7, HD37, HB12a, and HB12b, then made each anti-CD19 CAR KHYG-1 cells. Interestingly, only FMC63 CAR KHYG-1 and 4G7 CAR KHYG-1 efficiently lysed CD19-positive cell lines. In addition, in Jurkat cell line, only these two CAR Jurkat cell lines secreted IL-2 when co-cultured with CD19-positive cell line, NALM-6. Based on these results, we made FMC63 CAR T cells and 4G7 CAR T cells from PBMC. In in vitro lysis assay, 4G7 CAR T cells lysed CD19-positive cell line as well as FMC63 CAR T cells. In in vivo assay with NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice, 4G7 CAR T cells eradicated NALM-6 as potently as FMC63 CAR T cells. Therefore, we anticipate that 4G7 CAR T cells will show as good a result as FMC63 CAR T cells for B-cell leukemia patients.

Reliability of low-flow vasoreactivity in the brachial artery of adolescents.

PURPOSE: Macrovascular endothelial function is commonly assessed using flow-mediated dilation (FMD) and is nitric oxide (NO) dependent. However, the vasoreactivity to low flow during the FMD protocol may complement FMD interpretation. This study aimed to investigate in adolescents: (1) the day-to-day reliability of low-flow-mediated constriction (L-FMC) and composite vessel reactivity (CVR); and (2) the relationship between L-FMC and FMD. METHODS: A retrospective analysis of data on 27 adolescents (14.3 ± 0.6 year, 12 males) was performed. Participants had two repeat measures, on separate days, of macrovascular function using high-resolution ultrasound for assessment of L-FMC, FMD, and CVR. RESULTS: On average, the L-FMC response was vasoconstriction on both days (-0.59 ± 2.22% and -0.16 ± 1.50%, respectively). In contrast, an inconsistent response to low flow (vasoconstriction, dilation, or no change) was observed on an individual level. Cohen's Kappa revealed poor agreement for classifying the L-FMC measurement between visits (k = 0.04, P > .05). Assessment of the actual vessel diameter was robust with a coefficient of variation of 1.7% (baseline and peak) and 2.7% (low-flow). The between-day correlation coefficient between measures was r = .18, r = .96 and r = .52 for L-FMC, FMD, and CVR, respectively. No significant correlation between FMD and L-FMC was observed for either visit (r = -.06 and r = -.07, respectively; P > .05). CONCLUSION: In adolescents, the low-flow vasoreactivity is inconsistent between days. Whereas the actual vessel diameter is reproducible, the measurement of L-FMC and CVR has poor between-day reliability compared to FMD. Finally, L-FMC, and FMD are not significantly correlated.

Unbiased compound screening with a reporter gene assay highlights the role of p13 in the cardiac cellular stress response.

We recently showed that a 13-kDa protein (p13), the homolog protein of formation of mitochondrial complex V assembly factor 1 in yeast, acts as a potential protective factor in pancreatic islets under diabetes. Here, we aimed to identify known compounds regulating p13 mRNA expression to obtain therapeutic insight into the cellular stress response. A luciferase reporter system was developed using the putative promoter region of the human p13 gene. Overexpression of peroxisome proliferator-activated receptor gamma coactivator 1α, a master player regulating mitochondrial metabolism, increased both reporter activity and p13 expression. Following unbiased screening with 2320 known compounds in HeLa cells, 12 pharmacological agents (including 8 cardiotonics and 2 anthracyclines) that elicited >2-fold changes in p13 mRNA expression were identified. Among them, four cardiac glycosides decreased p13 expression and concomitantly elevated cellular oxidative stress. Additional database analyses showed highest p13 expression in heart, with typically decreased expression in cardiac disease. Accordingly, our results illustrate the usefulness of unbiased compound screening as a method for identifying novel functional roles of unfamiliar genes. Our findings also highlight the importance of p13 in the cellular stress response in heart.

The Maximum Entropy Method in Ultrasonic Non-Destructive Testing-Increasing the Resolution, Image Noise Reduction and Echo Acquisition Rate.

The use of linear methods, for example, the Combined Synthetic Aperture Focusing Technique (C-SAFT), does not allow one to obtain images with high resolution and low noise, especially structural noise in all cases. Non-linear methods should improve the quality of the reconstructed image. Several examples of the application of the maximum entropy (ME) method for ultrasonic echo processing in order to reconstruct the image of reflectors with Rayleigh super-resolution and a high signal-to-noise ratio are considered in the article. The use of the complex phase-shifted Barker code signal as a probe pulse and the compression of measured echoes by the ME method made it possible to increase the signal-to-noise ratio by more than 20 dB for the image of a flat-bottom hole with a diameter of 1 mm in a model experiment. A modification of the ME method for restoring the reflector image by the time-of-flight diffraction (TOFD) method is considered, taking into account the change of the echo signal shape, depending on the depth of the reflector. Using the ME method, 2.5D-images of models of dangling cracks in a pipeline with a diameter of 800 mm were obtained, which make it possible to determine their dimensions. In the object with structural noise, using the ME method, it was possible to increase the signal-to-noise ratio of the reflector image by more than 12 dB. To accelerate the acquisition of echoes in the dual scan mode, it is proposed to use code division multiple access (CDMA) technology based on simultaneous emission by all elements of the array of pseudo-orthogonal signals. The model experiment showed the effectiveness of applying the ME method.

Gut morphology and hepatic oxidative status of European sea bass (Dicentrarchus labrax) juveniles fed plant feedstuffs or fishmeal-based diets supplemented with short-chain fructo-oligosaccharides and xylo-oligosaccharides.

The effects of short-chain fructo-oligosaccharides (scFOS) and xylo-oligosaccharides (XOS) on gut morphology and hepatic oxidative status were studied in European sea bass juveniles weighing 60 g. Fish were fed diets including fishmeal (FM diets) or plant feedstuffs (PF diets; 30 FM:70 PF) as main protein sources (control diets). Four other diets were formulated similar to the control diets but including 1 % scFOS or 1 % XOS. At the end of the trial, fish fed PF-based diets presented histomorphological alterations in the distal intestine, whereas only transient alterations were observed in the pyloric caeca. Comparatively to fish fed FM-based diets, fish fed PF diets had higher liver lipid peroxidation (LPO), superoxide dismutase (SOD) and catalase (CAT) activities, and lower glutathione peroxidase, glutathione reductase and glucose 6-phosphate dehydrogenase activities. In fish fed the PF diets, prebiotic supplementation decreased SOD activity and XOS supplementation further decreased CAT activity. In fish fed the FM diets, XOS supplementation promoted a reduction of all antioxidant enzyme activities. Overall, dietary XOS and scFOS supplementation had only minor effects on gut morphology or LPO levels. However, dietary XOS reduced antioxidant enzymatic activity in both PF and FM diets, which indicate a positive effect on reduction of hepatic reactive oxygen species production.

Sustainable treatment of aquaculture water employing fungi-microalgae consortium: Nutrients removal enhancement, bacterial communities optimization, emerging contaminants elimination, and mechanism analysis.

Fungi-microalgae consortium (FMC) has emerged as a promising system for advanced wastewater treatment due to its high biomass yield and environmental sustainability. This study aimed to investigate the nutrients removal, bacterial community shift, emerging contaminants elimination, and treatment mechanism of a FMC composed of Cordyceps militaris and Navicula seminulum for aquaculture pond water treatment. The fungi and microalgae were cultured and employed either alone or in combination to evaluate the treatment performance. The results demonstrated that the FMC could improve water quality more significantly by reducing nutrient pollutants and optimizing the bacterial community structures. Furthermore, it exhibited stronger positive correlation between the enrichment of functional bacteria for water quality improvement and pollutants removal performance than the single-species treatments. Moreover, the FMC outperformed other groups in eliminating emerging contaminants such as heavy metals, antibiotics, and pathogenic Vibrios. Superiorly, the FMC also showed excellent symbiotic interactions and cooperative mechanisms for pollutants removal. The results collectively corroborated the feasibility and sustainability of using C. militaris and N. seminulum for treating aquaculture water, and the FMC would produce more mutualistic benefits and synergistic effects than single-species treatments.

AUStralian Indigenous Chronic Disease Optimisation Study (AUSI-CDS) prospective observational cohort study to determine if an established chronic disease health care model can be used to deliver better heart failure care among remote Indigenous Australians: Proof of concept-study rationale and protocol.

BACKGROUND: The congestive heart failure syndrome has increased to epidemic proportions and is cause for significant morbidity and mortality. Indigenous patients suffer a greater prevalence with greater severity. Upon diagnosis patients require regular follow-up with medical and allied health services. Patients are prescribed life saving, disease modifying and symptom relieving therapies. This can be an overwhelming experience for patients. To compound this, remoteness, differentials in conventional health care and services pose special problems for Indigenous clients in accessing care. Additional barriers of language, culture, socio-economic disadvantage, negative attitudes towards establishment, social stereotyping, stigma and discrimination act as barriers to improved care. Recent focus supported by clinical evidence support the role of chronic disease self-management programs. A patient focused, problem identification, goal setting and psychosocial modification based program should in principal highlight these issues and help tailor a patient focused comprehensive care plan to complement guideline based care. At present there are no Indigenous focused chronic disease self-management programs. There is a need for research on ways to provide chronic disease management to this group. We therefore designed a study to assess a model of patient focussed comprehensive care for Indigenous Australians with heart failure. STUDY DESIGN: AUSI-CDS is a prospective, cohort, observational study to evaluate the efficacy of the standard "Flinders Program of Chronic Condition Management" for Indigenous patients with chronic heart failure. Eligible patients will be Indigenous, suffering from chronic heart failure, in the Northern Territory. The primary end-point is the satisfaction score based on the PACIC. The study will recruit 20 patients and is expected to last 12 months. SUMMARY: The rationale and design of the AUSI-CDS using the Flinders Model is described.

Clinical Impact of Single Nucleotide Polymorphism in CD-19 on Treatment Outcome in FMC63-CAR-T Cell Therapy.

Chimeric antigen receptor (CAR)-T cell therapy is effective in patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) with response rates of 63-84% and complete response observed in 43-54%. Common germline variants of the target antigen CD19 may elicit different responses to CAR-T cell therapy. The CD19 gene single nucleotide polymorphism rs2904880 encoding leucine or valine at amino acid position 174 of the CD19 antigen was prevalent in 51% of the studied DLBCL patients. In a retrospective comparative analysis of clinical outcome, there were significant differences in CD19 L174 versus V174 carriers: the median time of progression-free survival was 22 vs. 6 months (p = 0.06), overall survival was 37 vs. 8 months (p = 0.11), complete response rates were 51% vs. 30% (p = 0.05), and refractory disease rates were 14% vs. 32% (p = 0.04). The single nucleotide polymorphism in CD19 was shown to influence the treatment outcome in FMC63-anti-CD19-CAR-T cell therapy, and the CD19 minor allele L174 predicted a favorable treatment outcome.

Validity of regional network systems on reperfusion therapy in diabetes mellitus and non-diabetes mellitus patients with ST-segment elevation myocardial infarction.

Background: Patients with ST-segment elevation myocardial infarction (STEMI) with diabetes mellitus (DM) had higher mortality and poorer prognosis than those without DM. Previous studies had demonstrated the effectiveness of regional network systems (RNS) for reperfusion therapy in patients with STEMI. However, the differences in nursing care with RNS in subgroups of patients with DM with STEMI were unclear. Our study aimed to evaluate the validity of RNS in reperfusion therapy in patients with STEMI with or without DM. Methods: We retrospectively enrolled patients with STEMI who received reperfusion therapy at the chest pain center of the 920th Hospital in Kunming City, Yunnan Province from 2019 to 2021. Personal information and hospitalization information for patients with STEMI were collected through the chest pain center registration system. Univariate and multivariate logistic regression were used to analyze factors associated with outcomes in patients with STEMI who received RNS. Wilcoxon rank-sum test and chi-squared test were used to analyze the differences in reperfusion therapy times and clinical outcomes between RNS and non-RNS in patients with STEMI with or without DM. Results: This study enrolled 1,054 patients with STEMI, including 148 patients with DM and 906 patients without DM. Logistic regression analysis indicated that DM was associated with patients with STEMI who received RNS [OR 1.590 95% CI (1.034-2.446), P = 0.035]. RNS may decrease the reperfusion therapy time in patients with STEMI and patients without DM with STEMI, including the first medical contact (FMC) to door, FMC to wire and FMC to catheterization laboratory activity (all P < 0.05). However, we found no significant difference in reperfusion therapy times with and without RNS in patients with DM (all P > 0.05). Conclusion: Regional network systems may decrease the reperfusion therapy time in patients without DM with STEMI, but no decrease was found in patients with DM with STEMI.

10-Year Temporal Trends of In-Hospital Mortality and Emergency Percutaneous Coronary Intervention for Acute Myocardial Infarction.

Background: The mortality rate of acute myocardial infarction (AMI) has improved dramatically because of reperfusion therapy during the last 40 years; however, recent temporal trends for AMI have not been fully clarified in Japan. Objectives: The purpose of this study was to elucidate the temporary trend in in-hospital mortality and treatment of AMI for the last decade in the Tokyo Metropolitan area. Methods: We enrolled 30,553 patients from the Tokyo Cardiovascular Care Unit Network Registry, diagnosed with AMI from 2007 to 2016, as part of an ongoing, multicenter, cohort study. We analyzed the temporal trends in basic characteristics, treatment, and in-hospital mortality of AMI. Results: The overall emergency percutaneous coronary intervention (PCI) rate significantly increased (P < 0.001). In particular, it remarkably increased in patients older than 80 years of age (58.3% to 70.3%, P < 0.001) and patients with Killip III or IV (Killip III, 46.9% to 65.7%; Killip IV, 65.2% to 76.6%, P < 0.001 for both). The crude and age-adjusted in-hospital mortality remained low (5.2% to 8.2% and 3.4% to 5.5%, respectively) and significantly decreased during the decade (P < 0.001). The in-hospital mortality remarkably decreased in patients older than 80 years of age (17.3% to 12.7%, P < 0.001) and in those with cardiogenic shock (38.5% to 27.3%, P < 0.001). Conclusions: This large cohort study from Tokyo revealed that in-hospital mortality of AMI significantly decreased with the increase in emergency percutaneous coronary intervention rate over the decade, particularly for high-risk patients such as older patients and those with cardiogenic shock.

Before the door: Comparing factors affecting symptom onset to first medical contact for STEMI patients between a high and low-middle income country.

Background: Early reperfusion in patients with ST-segment elevation myocardial infarction (STEMI) has been associated with preservation of left ventricular function and decrease in mortality. Symptom onset to first medical contact (FMC) time consumes the majority of total ischemic time, and remains one of the main reasons that patients do not receive timely care. With FMC to reperfusion time being effectively reduced in many parts of the world, the focus is now shifting to reducing symptom onset to FMC times. Methods: This mixed-methods observational study was designed to elucidate factors affecting symptom onset to FMC time at a regional cardiac center in a low-middle income country (LMIC) and a high-income country (HIC). A review of the Aswan Heart Center and Hamilton General Hospital STEMI registry in Egypt and Canada was conducted, and retrospective semi-structured questionnaires carried out for a convenience sample of 158 patients. Results: Gender, symptom type and severity were none-modifiable factors found between early and late presenters. Modifiable factors found were actions of bystanders, actions of patients, transportation method and time. Emotional factors also showed differences between the two groups. Conclusion: While some concepts are generalizable, contextual differences in demographics, risk factors, access and knowledge are identified. These factors can be used to inform tailored knowledge translation strategies to help reduce symptom onset to FMC in both LMIC and HIC.

An outlook of FMC's current and future herbicide-resistance management strategies.

Herbicide resistance has emerged globally as a serious threat to profitable crop production. FMC promotes integrated weed management approaches including responsible use of existing herbicides, use of non-herbicide weed control tools, awareness about herbicide resistance issues, and support to herbicide resistance management initiatives. FMC is dedicated to developing sustainable weed control solutions through the discovery of new herbicides with novel sites-of-action, effective formulations, advanced application technology, and proactive monitoring for herbicide resistance. © 2020 Society of Chemical Industry.

Directed Evolution of Stabilized Monomeric CD19 for Monovalent CAR Interaction Studies and Monitoring of CAR-T Cell Patients.

CD19 is among the most relevant targets in cancer immunotherapy. However, its extracellular domain (ECD) is prone to aggregation and misfolding, representing a major obstacle for the development and analysis of CD19-targeted therapeutics. Here, we engineered stabilized CD19-ECD (termed SuperFolder) variants, which also showed improved expression rates and, in contrast to the wild type protein, they could be efficiently purified in their monomeric forms. Despite being considerably more stable, these engineered mutants largely preserved the wild type sequence (>98.8%). We demonstrate that the variant SF05 enabled the determination of the monovalent affinity between CD19 and a clinically approved FMC63-based CAR, as well as monitoring and phenotypic characterization of CD19-directed CAR-T cells in the blood of lymphoma patients. We anticipate that the SuperFolder mutants generated in this study will be highly valuable tools for a range of applications in basic immunology and CD19-targeted cancer immunotherapy.

Is Cd11c and Fmc7 Negativity in Chronic Lymphocytic Leukemia Poor Prognostic?

Chronic lymphocytic leukemia (CLL) is a common hematological malignancy. This study is aimed to investigate the prognostic effect of clinic, laboratory and flow cytometric analysis in CLL patients. Newly diagnosed 55 CLL cases were divided into two groups, as stable disease (Group 1) and progressive disease (Group 2). Group 1 included those who did not require any treatment since diagnosis and those who did not progress after receiving the first step anti CLL treatment. Group 2 included the patients who received ≥ 2 steps treatment. The relation between the two groups was analyzed statistically in terms of clinical, laboratory and flow cytometric findings. Twenty patients (36.3%) required treatment at the time of diagnosis, four patients (3.8%) received first-line treatment during follow-up and 31 (56.3%) patients were followed without any treatment. Thirteen patients required second step treatment after a median of 26.3 months. The risk of progression was found to be increased 5-fold (p = 0.015) in the CD38 positive patient group, 4.2-fold (p = 0.0147) in the FMC7 negative patient group and 2.8-fold in the CD11c negative patient group. FMC 7 negativity decreased total survival 5.9-fold (p = 0.051). Unlike similar publications, we found that patients with CD11c or FMC7 negativity were in a higher need for ≥ 2 step treatment. This suggests that CD11c or FMC7 negativity may be used as a poor prognostic marker in CLL.

The impact of Community intervention on the time from Symptom onset to first medical contact with acute coronary syndrome.

OBJECTIVE: Patient delay in the recognition of and response to the symptoms of acute coronary syndrome (ACS) is a worldwide problem. A community education program about chest pain was implemented in China, and was aimed at providing better community intervention. In this study, the impact of this program on the time of symptom onset to the first medical contact (SO-to-FMC) in ACS patients was investigated, as was the incidence of major adverse cardiac and cerebrovascular events (MACCE) in these patients. METHODS: A total of 10 local communities were included in this study. A 9-month intensive community education program about chest pain was conducted in these communities. The data on the demographics, mode of transportation, procedures, clinical outcomes, and discharge diagnoses of all ACS patients in these communities were collected. RESULTS: The study communities had a combined population of 361,609, and all community population sizes ranged from 12,823 to 66,127. The average SO-to-FMC time of the control period was 510 min, whereas, following community intervention, the average SO-to-FMC time was 256 min (P <  0.001). Furthermore, comparative analyses revealed that, following discharge from the hospital, the 1.5-year MACCE-free survival rate was higher in the community intervention group than in the control group (95.0 % vs. 90.5 %, P =  0.025), and the 1.5-year mortality rate was lower in the community intervention group than in the control group (3.3 % vs. 6.3 %, P =  0.03). CONCLUSIONS AND PRACTICAL IMPLICATIONS: The Hangzhou Chest Pain Science Education Project(HCPSEP) was found to reduce the SO-to-FMC time and improve the outcome of ACS patients. This indicates that a scientific, educational program on chest pain can be effective in improving the knowledge and alertness of the local residents about chest pain. This type of program may be recognized and carried out in other regions.