Knowledge, attitude and practice regarding standard precautions among nurses in Teaching Hospital Batticaloa

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Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells

Autologous T cells engineered to express chimeric antigen receptor against the B cell antigen CD19 (CAR19) are achieving marked leukemic remissions in early-phase trials but can be difficult to manufacture, especially in infants or heavily treated patients. We generated universal CAR19 (UCART19) T cells by lentiviral transduction of non-human leukocyte antigen-matched donor cells and simultaneous transcription activator-like effector nuclease (TALEN)-mediated gene editing of T cell receptor α chain and CD52 gene loci. Two infants with relapsed refractory CD19(+) B cell acute lymphoblastic leukemia received lymphodepleting chemotherapy and anti-CD52 serotherapy, followed by a single-dose infusion of UCART19 cells. Molecular remissions were achieved within 28 days in both infants, and UCART19 cells persisted until conditioning ahead of successful allogeneic stem cell transplantation. This bridge-to-transplantation strategy demonstrates the therapeutic potential of gene-editing technology

Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR

Chimeric antigen receptor (CAR)-modified T cells targeting CD19 demonstrate unparalleled responses in relapsed/refractory acute lymphoblastic leukemia (ALL)1,2,3,4,5, but toxicity, including cytokine-release syndrome (CRS) and neurotoxicity, limits broader application. Moreover, 40–60% of patients relapse owing to poor CAR T cell persistence or emergence of CD19− clones. Some factors, including the choice of single-chain spacer6 and extracellular7 and costimulatory domains8, have a profound effect on CAR T cell function and persistence. However, little is known about the impact of CAR binding affinity. There is evidence of a ceiling above which increased immunoreceptor affinity may adversely affect T cell responses9,10,11. We generated a novel CD19 CAR (CAT) with a lower affinity than FMC63, the high-affinity binder used in many clinical studies1,2,3,4. CAT CAR T cells showed increased proliferation and cytotoxicity in vitro and had enhanced proliferative and in vivo antitumor activity compared with FMC63 CAR T cells. In a clinical study (CARPALL, NCT02443831), 12/14 patients with relapsed/refractory pediatric B cell acute lymphoblastic leukemia treated with CAT CAR T cells achieved molecular remission. Persistence was demonstrated in 11 of 14 patients at last follow-up, with enhanced CAR T cell expansion compared with published data. Toxicity was low, with no severe CRS. One-year overall and event-free survival were 63% and 46%, respectivel

RNAi Effector Diversity in Nematodes

While RNA interference (RNAi) has been deployed to facilitate gene function studies in diverse helminths, parasitic nematodes appear variably susceptible. To test if this is due to inter-species differences in RNAi effector complements, we performed a primary sequence similarity survey for orthologs of 77 Caenorhabditis elegans RNAi pathway proteins in 13 nematode species for which genomic or transcriptomic datasets were available, with all outputs subjected to domain-structure verification. Our dataset spanned transcriptomes of Ancylostoma caninum and Oesophagostomum dentatum, and genomes of Trichinella spiralis, Ascaris suum, Brugia malayi, Haemonchus contortus, Meloidogyne hapla, Meloidogyne incognita and Pristionchus pacificus, as well as the Caenorhabditis species C. brenneri, C. briggsae, C. japonica and C. remanei, and revealed that: (i) Most of the C. elegans proteins responsible for uptake and spread of exogenously applied double stranded (ds)RNA are absent from parasitic species, including RNAi-competent plant-nematodes; (ii) The Argonautes (AGOs) responsible for gene expression regulation in C. elegans are broadly conserved, unlike those recruited during the induction of RNAi by exogenous dsRNA; (iii) Secondary Argonautes (SAGOs) are poorly conserved, and the nuclear AGO NRDE-3 was not identified in any parasite; (iv) All five Caenorhabditis spp. possess an expanded RNAi effector repertoire relative to the parasitic nematodes, consistent with the propensity for gene loss in nematode parasites; (v) In spite of the quantitative differences in RNAi effector complements across nematode species, all displayed qualitatively similar coverage of functional protein groups. In summary, we could not identify RNAi effector deficiencies that associate with reduced susceptibility in parasitic nematodes. Indeed, similarities in the RNAi effector complements of RNAi refractory and competent nematode parasites support the broad applicability of this research genetic tool in nematodes

Geoeconomic variations in epidemiology, ventilation management, and outcomes in invasively ventilated intensive care unit patients without acute respiratory distress syndrome: a pooled analysis of four observational studies

Background: Geoeconomic variations in epidemiology, the practice of ventilation, and outcome in invasively ventilated intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) remain unexplored. In this analysis we aim to address these gaps using individual patient data of four large observational studies. Methods: In this pooled analysis we harmonised individual patient data from the ERICC, LUNG SAFE, PRoVENT, and PRoVENT-iMiC prospective observational studies, which were conducted from June, 2011, to December, 2018, in 534 ICUs in 54 countries. We used the 2016 World Bank classification to define two geoeconomic regions: middle-income countries (MICs) and high-income countries (HICs). ARDS was defined according to the Berlin criteria. Descriptive statistics were used to compare patients in MICs versus HICs. The primary outcome was the use of low tidal volume ventilation (LTVV) for the first 3 days of mechanical ventilation. Secondary outcomes were key ventilation parameters (tidal volume size, positive end-expiratory pressure, fraction of inspired oxygen, peak pressure, plateau pressure, driving pressure, and respiratory rate), patient characteristics, the risk for and actual development of acute respiratory distress syndrome after the first day of ventilation, duration of ventilation, ICU length of stay, and ICU mortality. Findings: Of the 7608 patients included in the original studies, this analysis included 3852 patients without ARDS, of whom 2345 were from MICs and 1507 were from HICs. Patients in MICs were younger, shorter and with a slightly lower body-mass index, more often had diabetes and active cancer, but less often chronic obstructive pulmonary disease and heart failure than patients from HICs. Sequential organ failure assessment scores were similar in MICs and HICs. Use of LTVV in MICs and HICs was comparable (42\ub74% vs 44\ub72%; absolute difference \u20131\ub769 [\u20139\ub758 to 6\ub711] p=0\ub767; data available in 3174 [82%] of 3852 patients). The median applied positive end expiratory pressure was lower in MICs than in HICs (5 [IQR 5\u20138] vs 6 [5\u20138] cm H2O; p=0\ub70011). ICU mortality was higher in MICs than in HICs (30\ub75% vs 19\ub79%; p=0\ub70004; adjusted effect 16\ub741% [95% CI 9\ub752\u201323\ub752]; p&lt;0\ub70001) and was inversely associated with gross domestic product (adjusted odds ratio for a US$10 000 increase per capita 0\ub780 [95% CI 0\ub775\u20130\ub786]; p&lt;0\ub70001). Interpretation: Despite similar disease severity and ventilation management, ICU mortality in patients without ARDS is higher in MICs than in HICs, with a strong association with country-level economic status. Funding: No funding

Risk Prediction for Acute Kidney Injury in Acute Medical Admissions in the UK

Background Acute Kidney Injury (AKI) is associated with adverse outcomes; identifying patients who are at risk of developing AKI in hospital may lead to targeted prevention. This approach is advocated in national guidelines but is not well studied in acutely unwell medical patients. We therefore aimed to undertake a UK-wide study in acute medical units (AMUs) with the following aims: to define the proportion of acutely unwell medical patients who develop hospital-acquired AKI (hAKI); to determine risk factors associated with the development of hAKI; and to assess the feasibility of using these risk factors to develop an AKI risk prediction score. Methods In September 2016, a prospective multicentre cohort study across 72 UK AMUs was undertaken. Data were collected from all patients who presented over a 24-hour period. Chronic dialysis, community-acquired AKI (cAKI) and those with fewer than two creatinine measurements were subsequently excluded. The primary outcome was the development of h-AKI. Results 2,446 individuals were admitted to the AMUs of the 72 participating centres. 384 patients (16%) sustained AKI of whom 287 (75%) were cAKI and 97 (25%) were hAKI. After exclusions, 1,235 participants remained in whom chronic kidney disease (OR 3.08, 95% CI 1.96-4.83), diuretic prescription (OR 2.33, 95% CI 1.5-3.65), a lower haemoglobin concentration and an elevated serum bilirubin were independently associated with development of hAKI. Multivariable model discrimination was moderate (c-statistic 0.75), and this did not support the development of a robust clinical risk prediction score. Mortality was higher in those with hAKI (adjusted OR 5.22; 95% CI 2.23-12.20). Conclusion AKI in AMUs is common and associated with worse outcomes, with the majority of cases community acquired. The smaller proportion of hAKI cases, only moderate discrimination of prognostic risk factor modelling and the resource implications of widespread application of an AKI clinical risk score across all AMU admissions suggests that this approach is not currently justified. More targeted risk assessment or automated methods of calculating individual risk may be more appropriate alternatives

Diversity Assessment of Annonamuricata L. Through Molecular Characterization using SSR Markers

Annona muricata L. (Magnoliales: Annonaceae) is a tropical fruit tree with a long history of traditional use. The object of this research was to determine the genetic diversity of the Annona muricata L. species using SSR markers. Thirty-four accessions of A.muricata leave samples and a leaf sample of A.cherimola as a control were collected from different locations in Sri Lanka. Genetic diversity of A.muricata was evaluated using eight microsatellites markers developed in Annona cherimola. Optimum annealing temperature of each primer was selected after the gradient PCR. Total nine genotypes were detected with 1.125 alleles per locus. The low levels of mean observed and expected heterozygosity ranged from 0.0147 and from 0.0140, respectively. The average Polymorphic Information Content (PIC) value for all markers used was 0.0131, the highest PIC value 0.1046 was obtained for the primer LMCH9.The high level of PIC value and polymorphism indicate that the primer LMCH9 is well suited for diversity assessment of Annona muricata germplasm. Accessions 168, 25, 82 amp 49 were gave heterozygous alleles band for primer LMCH9. As a result, it was revealed a relatively limited genetic diversity within selected Annona accessions with respect to Annona cherimola markers

Screening of segregating F2 progenies and validation of DNA markers through bulk segregant analysis for phosphorous deficiency tolerance in rice

Phosphorous deficiency (PD) tolerance is a polygenic trait. The underlying genetics of PD tolerance trait is important to provide the basis for detecting Quantitative Trait Loci (QTLs) and validating markers that could be used in Marker Assisted Breeding (MAB) in rice. The PD tolerance of Sri Lankan rice germplasm has been characterized. However, no attempts were taken to develop and validate the DNA markers for the breeding purposes and to understand the genetic basis of the traits. The present research project was conducted to assess the PD related traits and to validate internationally published DNA markers that are linked to PD tolerance using Sri Lankan rice cultivars. A total of 84 crosses were made and advanced to F2 and higher generations. Out of these crosses, an important subset of three crosses was selected based on the overall PD tolerance and sensitivity, importance as mega production varieties and pedigree connections between the cultivars. The plant height, number of tillers, shoot dry weight, leaf width, flag leaf width and the color metrics L*, a*, b*, hue (h*) and chroma (C*) were measured from 200 individuals each from the three populations grown under P deficient (Po) soil conditions. Except color traits, other traits were normally distributed and exhibited higher broad sensitivity. The color metrics indicate the presence of possible epistatic interactions between the major underlying loci. From each population, two extreme bulks were selected from the highest and lowest ends of shoot dry weight (SDW) for bulk segregant analyses (BSA) to validate the DNA markers for PD tolerance. It was observed that, DNA marker K46-K1 can be used for MAB of rice for PD tolerance. The genetic information generated in the present study can also be used for larger scale genomic studies such as SNPs, GBS and GWAS mapping