Interleukin 2 restores CD3-zeta chain expression but fails to generate tumour-specific lytic activity in tumour-infiltrating lymphocytes derived from human colorectal hepatic metastases.

Metastatic colorectal cancer is usually progressive despite infiltration of the tumours by T lymphocytes, suggesting that these tumour-infiltrating lymphocytes (TILs) are functionally deficient. Recently, TILs from other tumours have been shown to express reduced levels of the T-cell receptor signal-transducing CD3-zeta chain. We were interested to determine whether a similar abnormality existed in TILs from human colorectal hepatic metastasis (CHM) and, if so, whether correcting the abnormality in vitro would restore anti-tumour activity and provide support for the development of immunotherapy for colorectal hepatic metastases. Twelve of 19 TILs from colorectal hepatic metastases were successfully expanded in vitro in high-dose recombinant interleukin 2 (rlL-2) and their specific anti-tumour cytolytic activity was determined. CD3-positive (CD3+) TILs were HLA-Drhigh and CD69high, suggesting that they had been activated by exposure to antigen but expressed low levels of CD25, CD71 and the nuclear proliferation antigen Ki-67. Furthermore, they showed reduced expression of CD3-zeta compared with autologous peripheral blood T cells (PBTs) and failed to proliferate in the absence of high-dose rIL-2. Expansion of TILs in rIL-2 resulted in restoration of CD3-zeta expression and the ability to lyse K562 and Daudi cells but not autologous tumour cells. The absence of autologous tumour-specific cytolytic T-cell (CTL) activity may be due to the poor immunogenicity of colorectal tumour cells, which we found expressed only low levels of MHC I antigens and CD54 and failed to express MHC II antigens or the co-stimulatory molecules CD80, CD86 or CD106. The inability of rIL-2 to generate tumour-specific CTLs despite restoration of CD3-zeta expression and the presence of an intact lytic mechanism suggests that successful immunotherapy may require the development of strategies to increase the immunogenicity of this tumour

The effect of door-to-balloon delay in primary percutaneous coronary intervention on clinical outcomes of STEMI: a systematic review and meta-analysis protocol

BACKGROUND: Acute myocardial infarction (AMI) is a medical emergency in which sudden occlusion of coronary artery(ies) results in ischemia and necrosis of the cardiac tissues. Reperfusion therapies that aim at reopening the occluded artery remain the mainstay of treatment for AMI. Primary percutaneous coronary intervention (PCI), which enables the restoration of blood flow by reopening the occluded artery(ies) via a catheter with an inflatable balloon, is currently the preferred treatment for AMI with ST segment elevation (STEMI). The door-to-balloon (D2B) delay refers to the time interval counting from the arrival of a patient with STEMI at a hospital to the time of the balloon inflation (or stent deployment) that reopens the occluded artery(ies). Reducing this delay in primary PCI is thought to be an important strategy toward achieving better patient outcomes. Unfortunately, significant reduction of D2B delay in the USA over the last decade has not been shown to be associated with improved STEMI mortality. It has been suggested that the lack of impact could be due to the expanding use of primary PCI in STEMI as well as the survival cohort effect, leading to a shift toward a higher risk population receiving the procedure. Others have suggested that reduction in D2B delay may not be as impactful as expected, given that it only represents a small fraction of the total ischemic time. Although most existing evidence have pointed to the presence of a beneficial effect of shorter D2B delay, some inconsistencies however exist. This study aims to synthesize available evidence in order to answer the following questions: (1) what is the overall effect of D2B delay on clinical outcomes in patients with STEMI treated with primary PCI? (2) What factors explain the differences of the effect estimates among the studies? (3) What are the important strength and limitation of the existing body of evidence? METHOD: We will search PubMed/MEDLINE, EMBASE, ClinicalTrials.gov, WHO International Clinical Trials Registry, CINAHL Database, and the Cochrane Library using a predefined search strategy. Other sources of literature will include proceedings from the European Society of Cardiology, the American College of Cardiology, the American Heart Association, the EUROPCR, and the ProQuest Dissertations and Theses Database. We will include data from observational studies (case-control and cohort study design) and randomized control trials (that have investigated the relationship of D2B time and clinical outcome(s) in an adult (older than 18) STEMI population). Mortality (cardiac related and all-cause) and incidence heart failure (HF) have been prioritized as the primary outcomes. All eligible studies will be assessed for risk of bias using the Risk Of Bias in Non-randomized Studies - of Interventions tool. The Grading of Recommendations, Assessment, and Evaluation (GRADE) framework will be used to report the quality of evidence and strength of recommendations. We will proceed to analyze the data quantitatively if the pre-specified conditions are satisfied. DISCUSSION: Recent discussion on the negative findings of improved D2B delay over time being unrelated to better STEMI outcomes at the population level has reminded us of an important knowledge gap we have on this domain. This systematic review will serve to address some of these key questions not previously examined. Answers to these questions could clarify the controversies and offer empirical support for or against the suggested hypotheses. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015026069 ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13643-016-0304-7) contains supplementary material, which is available to authorized users

Removal of steroid estrogens in carbonaceous and nitrifying activated sludge processes

This is the post-print version of the final paper published in Chemosphere. The published article is available from the link below. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. Copyright @ 2010 Elsevier B.V.A carbonaceous (heterotrophic) activated sludge process (ASP), nitrifying ASP and a nitrifying/denitrifying ASP have been studied to examine the role of process type in steroid estrogen removal. Biodegradation efficiencies for total steroid estrogens (ΣEST) of 80 and 91% were recorded for the nitrifying/denitrifying ASP and nitrifying ASP respectively. Total estrogen biodegradation (ΣEST) was only 51% at the carbonaceous ASP, however, the extent of biodegradation in the absence of nitrification clearly indicates the important role of heterotrophs in steroid estrogen removal. The low removal efficiency did not correlate with biomass activity for which the ASPcarbonaceous recorded 80 μg kg−1 biomass d−1 compared to 61 and 15 μg kg−1 biomass d−1 at the ASPnitrifying and ASPnitrifying/denitrifying respectively. This finding was explained by a moderate correlation (r2 = 0.55) between total estrogen loading (ΣEST mg m−3 d−1) and biomass activity (μg ΣEST degraded kg−1 d−1) and has established the impact of loading on steroid estrogen removal at full-scale. At higher solids retention time (SRT), steroid estrogen biodegradation of >80% was observed, as has previously been reported. It is postulated that hydraulic retention time (HRT) is as important as SRT as this governs both reaction time and loading. This observation is based on the high specific estrogen activity determined at the ASPcarbonaceous plant, the significance of estrogen loading and the positive linear correlation between SRT and HRT.Public Utilities Board of Singapore, Anglian Water Ltd., Severn Trent Water Ltd., Thames Water Utilities Ltd., United Utilities Plc., and Yorkshire Water Services Ltd

The application of useless Japanese inventions for requirements elicitation in information security

Rules of requirements elicitation in security are broken through the use of Chindōgu, by designing impractical security countermeasures in the first instance, then using these to create usable security requirements. We present a process to conceive the requirements in Chindōgu form. We evaluate the usefulness of this process by applying it in three workshops with data gathered from a European rail company, and comparing requirements elicited by this process with a set of control requirements

The combined diabetes and renal control trial (C-DIRECT) - a feasibility randomised controlled trial to evaluate outcomes in multi-morbid patients with diabetes and on dialysis using a mixed methods approach

Background: This cluster randomised controlled trial set out to investigate the feasibility and acceptability of the “Combined Diabetes and Renal Control Trial” (C-DIRECT) intervention, a nurse-led intervention based on motivational interviewing and self-management in patients with coexisting end stage renal diseases and diabetes mellitus (DM ESRD). Its efficacy to improve glycaemic control, as well as psychosocial and self-care outcomes were also evaluated as secondary outcomes. Methods: An assessor-blinded, clustered randomised-controlled trial was conducted with 44 haemodialysis patients with DM ESRD and ≥ 8% glycated haemoglobin (HbA1c), in dialysis centres across Singapore. Patients were randomised according to dialysis shifts. 20 patients were assigned to intervention and 24 were in usual care. The C-DIRECT intervention consisted of three weekly chair-side sessions delivered by diabetes specialist nurses. Data on recruitment, randomisation, and retention, and secondary outcomes such as clinical endpoints, emotional distress, adherence, and self-management skills measures were obtained at baseline and at 12 weeks follow-up. A qualitative evaluation using interviews was conducted at the end of the trial. Results: Of the 44 recruited at baseline, 42 patients were evaluated at follow-up. One patient died, and one discontinued the study due to deteriorating health. Recruitment, retention, and acceptability rates of C-DIRECT were generally satisfactory HbA1c levels decreased in both groups, but C-DIRECT had more participants with HbA1c < 8% at follow up compared to usual care. Significant improvements in role limitations due to physical health were noted for C-DIRECT whereas levels remained stable in usual care. No statistically significant differences between groups were observed for other clinical markers and other patient-reported outcomes. There were no adverse effects. Conclusions: The trial demonstrated satisfactory feasibility. A brief intervention delivered on bedside as part of routine dialysis care showed some benefits in glycaemic control and on QOL domain compared with usual care, although no effect was observed in other secondary outcomes. Further research is needed to design and assess interventions to promote diabetes self-management in socially vulnerable patients

Differential Dynamics of Transposable Elements during Long-Term Diploidization of Nicotiana Section Repandae (Solanaceae) Allopolyploid Genomes

PubMed ID: 23185607This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Cost-minimization analysis of oral versus intravenous antibiotic treatment for Klebsiella pneumoniae liver abscess

A cost-minimization analysis was conducted for Klebsiella pneumoniae liver abscess (KLA) patients enrolled in a randomized controlled trial which found oral ciprofloxacin to be non-inferior to intravenous (IV) ceftriaxone in terms of clinical outcomes. Healthcare service utilization and cost data were obtained from medical records and estimated from self-reported patient surveys in a non-inferiority trial of oral ciprofloxacin versus IV ceftriaxone administered to 152 hospitalized adults with KLA in Singapore between November 2013 and October 2017. Total costs were evaluated by category and payer, and compared between oral and IV antibiotic groups over the trial period of 12 weeks. Among the subset of 139 patients for whom cost data were collected, average total cost over 12 weeks was $16,378 (95$14,620-$18,136) for the oral ciprofloxacin group and$20,569 (95% CI, $18,296-$22,842) for the IV ceftriaxone group, largely driven by lower average outpatient costs, as the average number of outpatient visits was halved for the oral ciprofloxacin group. There were no other statistically significant differences, either in inpatient costs or in other informal healthcare costs. Oral ciprofloxacin is less costly than IV ceftriaxone in the treatment of Klebsiella liver abscess, largely driven by reduced outpatient service costs.Trial registration: ClinicalTrials.gov Identifier NCT01723150 (7/11/2012)

The effectiveness of lunchbox interventions on improving the foods and beverages packed and consumed by children at centre-based care or school: a systematic review and meta-analysis

Objective: To assess the effectiveness of lunchbox interventions aiming to improve the foods and beverages packed and consumed by children at centre-based care or school; and subsequent impact on children’s adiposity. Methods: Systematic search of nine databases for controlled trials published in English between 1995-January 2017. Where appropriate, data were pooled in a random effects meta-analysis. Results: Of the 1601 articles identified, ten studies (centre-based care n = 4, school n = 6) were included of which eight were RCTs. The impact of interventions on the packing of discretionary foods, sugar-sweetened drinks and other core foods was inconsistent. Meta-analysis of four RCTs trials found a moderate increase in provision of vegetables (SMD = 0.40 95% CI 0.16 to 0.64, p = 0.001, I2 = 82%; equivalent to a mean difference of 0.28 serves) but not fruit. Four studies reported impact on children’s dietary intake, one reported no significant effect on consumption of discretionary foods, one reported improvements in the consumption of sugar-sweetened drinks and water, and two reported improvements in consumption of vegetables and fruit. Two studies, that were broader obesity prevention interventions, reported no significant impact on adiposity. Conclusions: There is some evidence that lunchbox interventions are effective in improving the packing of vegetables in children’s lunchboxes, however more robust research is required to determine the impact on children’s dietary intake and adiposity. Trial registration: PROSPERO 2016: CRD4201603564

Retrospective observational RT-PCR analyses on 688 babies born to 843 SARS-CoV-2 positive mothers, placental analyses and diagnostic analyses limitations suggest vertical transmission is possible

Research question: Is there vertical transmission (from mother to baby antenatally or intrapartum) after SARS-CoV-2 (COVID-19) infected pregnancy? Study design: A systematic search related to SARS-CoV-2 (COVID-19), pregnancy, neonatal complications, viral and vertical transmission. The duration was from December 2019 to May 2020. Results: A total of 84 studies with 862 COVID positive women were included. Two studies had ongoing pregnancies while 82 studies included 705 babies, 1 miscarriage and 1 medical termination of pregnancy (MTOP). Most publications (50/84, 59.5%), reported small numbers (&lt;5) of positive babies. From 75 studies, 18 babies were COVID-19 positive. The first reverse transcription polymerase chain reaction (RT-PCR) diagnostic test was done in 449 babies and 2 losses, 2nd RT-PCR was done in 82 babies, IgM tests were done in 28 babies, and IgG tests were done in 28 babies. On the first RT-PCR, 47 studies reported time of testing while 28 studies did not. Positive results in the first RT-PCR were seen in 14 babies. Earliest tested at birth and the average time of the result was 22 hours. Three babies with negative first RT-PCR became positive on the second RT-PCR at day 6, day 7 and at 24 hours which continued to be positive at 1 week. Four studies with a total of 4 placental swabs were positive demonstrating SARS-CoV-2 localised in the placenta. In 2 studies, 10 tests for amniotic fluid were positive for SARS-CoV-2. These 2 babies were found to be positive on RT-PCR on serial testing. Conclusion: Diagnostic testing combined with incubation period and placental pathology indicate a strong likelihood that intrapartum vertical transmission of SARS-CoV-2 (COVID-19) from mother to baby is possible