Cytokine release syndrome in COVID-19 patients, a new scenario for an old concern. The fragile balance between infections and autoimmunity

On 7 January 2020, researchers isolated and sequenced in China from patients with severe pneumonitis a novel coronavirus, then called SARS-CoV-2, which rapidly spread worldwide, becoming a global health emergency. Typical manifestations consist of flu-like symptoms such as fever, cough, fatigue, and dyspnea. However, in about 20% of patients, the infection progresses to severe interstitial pneumonia and can induce an uncontrolled host-immune response, leading to a life-threatening condition called cytokine release syndrome (CRS). CRS represents an emergency scenario of a frequent challenge, which is the complex and interwoven link between infections and autoimmunity. Indeed, treatment of CRS involves the use of both antivirals to control the underlying infection and immunosuppressive agents to dampen the aberrant pro-inflammatory response of the host. Several trials, evaluating the safety and effectiveness of immunosuppressants commonly used in rheumatic diseases, are ongoing in patients with COVID-19 and CRS, some of which are achieving promising results. However, such a use should follow a multidisciplinary approach, be accompanied by close monitoring, be tailored to patient’s clinical and serological features, and be initiated at the right time to reach the best results. Autoimmune patients receiving immunosuppressants could be prone to SARS-CoV-2 infections; however, suspension of the ongoing therapy is contraindicated to avoid disease flares and a consequent increase in the infection risk

Targeting pediatric leukemia propagating cells using anti-CD200 antibody therapy.

Treating refractory pediatric acute lymphoblastic leukemia (ALL) remains a challenge despite impressive remission rates (>90%) achieved in the last decade. The use of innovative immunotherapeutic approaches such as anti-CD19 chimeric antigen receptor T cells does not ensure durable remissions, because leukemia-propagating cells (LPCs) that lack expression of CD19 can cause relapse, which signifies the need to identify new markers of ALL. Here we investigated expression of CD58, CD97, and CD200, which were previously shown to be overexpressed in B-cell precursor ALL (BCP-ALL) in CD34(+)/CD19(+), CD34(+)/CD19(–), CD34(–)/CD19(+), and CD34(–)/CD19(–) LPCs, to assess their potential as therapeutic targets. Whole-genome microarray and flow cytometric analyses showed significant overexpression of these molecules compared with normal controls. CD58 and CD97 were mainly co-expressed with CD19 and were not a prerequisite for leukemia engraftment in immune deficient mice. In contrast, expression of CD200 was essential for engraftment and serial transplantation of cells in measurable residual disease (MRD) low-risk patients. Moreover, these CD200(+) LPCs could be targeted by using the monoclonal antibody TTI-CD200 in vitro and in vivo. Treating mice with established disease significantly reduced disease burden and extended survival. These findings demonstrate that CD200 could be an attractive target for treating low-risk ALL, with minimal off-tumor effects that beset current immunotherapeutic approaches

Plasma and red blood cell pufas in home parenteral nutrition paediatric patients—effects of lipid emulsions

Background: Mixed lipid emulsions (LE) containing fish oil present several advantages compared to the sole soybean oil LE, but little is known about the safety of essential fatty acids (EFA) profile in paediatric patients on long-term Parenteral Nutrition (PN). Aim of the study: to assess glycerophosfolipid polyunsaturated fatty acids (PUFA) levels on plasma and red blood cell (RBC) membrane of children on long term PN with composite LE containing fish oil (SMOF), and to compare it with a group receiving olive oil LE (Clinoleic®) and to the reference range for age, previously determined on a group of healthy children. Results: A total of 38 patients were enrolled, median age 5.56 (0.9–21.86) years, 15 receiving Clinoleic®, 23 receiving SMOF. Patients on SMOF showed significantly higher levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), lower levels of arachidonic acid (ARA) and Mead acid (MEAD)/ARA ratio in plasma and RBC compared with patients on Clinoleic® and with healthy children. Triene:tetraene (T:T) ratio of both groups of patients did not differ from that of healthy children-median plasma (MEAD/ARA: 0.01, interquartile rage (IQR) 0.01, p = 0.61 and 0.02, IQR 0.02, p = 0.6 in SMOF and Clinoleic® patients, respectively), and was considerably lower than Holman index (>0.21). SMOF patients showed no statistically significant differences in growth parameters compared with Clinoleic® patients. Patients of both groups showed stiffness class F0-F1 of liver stiffness measure (LSM) 5.6 (IQR 0.85) in SMOF patients and 5.3 (IQR 0.90) in Clinoleic® patients, p = 0.58), indicating absence of liver fibrosis. Conclusions: Fatty acids, measured as concentrations (mg/L), revealed specific PUFA profile of PN patients and could be an accurate method to evaluate nutritional status and eventually to detect essential fatty acid deficiency (EFAD). SMOF patients showed significantly higher EPA, DHA and lower ARA concentrations compared to Clinoleic® patients. Both LEs showed similar hepatic evolution and growth

Targeting the IspD enzyme in the MEP pathway: identification of a novel fragment class

Enzymes of the 2-C-methylerythritol-d-erythritol 4-phosphate 2C-methyl-D-erythritol 4-phosphate (MEP) pathway (MEP pathway or non-mevalonate pathway) are responsible for the synthesis of universal precursors of the huge large and structurally diverse family of isoprenoids. This pathway is absent in humans, but present in many pathogenic organisms and plants, making it an attractive source of drug targets. Here, we present a high-throughput screening approach that led to the discovery of a novel fragment hit active against the third enzyme of the MEP pathway, PfIspD. A systematic SAR investigation afforded a novel chemical structure with a balanced activity-stability profile (16). Using a homology model of PfIspD, we proposed a putative binding mode for our newly identified inhibitors that sets the stage for structure-guided optimization

Analysis of Elliptically Polarized Maximally Entangled States for Bell Inequality Tests

When elliptically polarized maximally entangled states are considered, i.e., states having a non random phase factor between the two bipartite polarization components, the standard settings used for optimal violation of Bell inequalities are no longer adapted. One way to retrieve the maximal amount of violation is to compensate for this phase while keeping the standard Bell inequality analysis settings. We propose in this paper a general theoretical approach that allows determining and adjusting the phase of elliptically polarized maximally entangled states in order to optimize the violation of Bell inequalities. The formalism is also applied to several suggested experimental phase compensation schemes. In order to emphasize the simplicity and relevance of our approach, we also describe an experimental implementation using a standard Soleil-Babinet phase compensator. This device is employed to correct the phase that appears in the maximally entangled state generated from a type-II nonlinear photon-pair source after the photons are created and distributed over fiber channels.Comment: 8 page

Field test of a continuous-variable quantum key distribution prototype

We have designed and realized a prototype that implements a continuous-variable quantum key distribution protocol based on coherent states and reverse reconciliation. The system uses time and polarization multiplexing for optimal transmission and detection of the signal and phase reference, and employs sophisticated error-correction codes for reconciliation. The security of the system is guaranteed against general coherent eavesdropping attacks. The performance of the prototype was tested over preinstalled optical fibres as part of a quantum cryptography network combining different quantum key distribution technologies. The stable and automatic operation of the prototype over 57 hours yielded an average secret key distribution rate of 8 kbit/s over a 3 dB loss optical fibre, including the key extraction process and all quantum and classical communication. This system is therefore ideal for securing communications in metropolitan size networks with high speed requirements.Comment: 15 pages, 6 figures, submitted to New Journal of Physics (Special issue on Quantum Cryptography

Faecal calprotectin in suspected paediatric inflammatory bowel disease.

Objectives: The diagnostic accuracy of faecal calprotectin (FC) concentration for paediatric inflammatory bowel disease (IBD) is well described at the population level, but not at the individual level. We reassessed the diagnostic accuracy of FC in children with suspected IBD and developed an individual risk prediction rule using individual patient data. Methods: MEDLINE, EMBASE, DARE, and MEDION databases were searched to identify cohort studies evaluating the diagnostic performance of FC in paediatric patients suspected of having IBD. A standard study-level meta-analysis was performed. In an individual patient data meta-analysis, we reanalysed the diagnostic accuracy on a merged patient dataset. Using logistic regression analysis we investigated whether and how the FC value and patient characteristics influence the diagnostic precision. A prediction rule was derived for use in clinical practice and implemented in a spreadsheet calculator. Results: According to the study-level meta-analysis (9 studies, describing 853 patients), FC has a high overall sensitivity of 0.97 (95% confidence interval [CI] 0.92–0.99) and a specificity of 0.70 (0.59–0.79) for diagnosing IBD. In the patient-level pooled analysis of 742 patients from 8 diagnostic accuracy studies, we calculated that at an FC cutoff level of 50 mg/g there would be 17% (95% CI 15–20) false-positive and 2% (1–3) false-negative results. The final logistic regression model was based on individual data of 545 patients and included both FC level and age. The area under the receiver operating characteristic curve of this derived prediction model was 0.92 (95% CI 0.89–0.94). Conclusions: In high-prevalence circumstances, FC can be used as a noninvasive biomarker of paediatric IBD with only a small risk of missing cases. To quantify the individual patients’ risk, we developed a simple prediction model based on FC concentration and age. Although the derived prediction rule cannot substitute the clinical diagnostic process, it can help in selecting patients for endoscopic evaluation

Topological optimization of quantum key distribution networks

A Quantum Key Distribution (QKD) network is an infrastructure that allows the realization of the key distribution cryptographic primitive over long distances and at high rates with information-theoretic security. In this work, we consider QKD networks based on trusted repeaters from a topology viewpoint, and present a set of analytical models that can be used to optimize the spatial distribution of QKD devices and nodes in specific network configurations in order to guarantee a certain level of service to network users, at a minimum cost. We give details on new methods and original results regarding such cost minimization arguments applied to QKD networks. These results are likely to become of high importance when the deployment of QKD networks will be addressed by future quantum telecommunication operators. They will therefore have a strong impact on the design and requirements of the next generation of QKD devices.Comment: 25 pages, 4 figure