Novel Corona Virus Disease 2019 (COVID-19) continue to sweep various nations causing more than 4.5 million confirmed cases and close to 300,000 deaths. Current pharmacotherapy largely fall short of controlling the pandemic. In this letter, we critically appraise the hydroxychloroquine plus azithromycin regimen recommended by Gautret et al and provide rationale for new treatments.

On 11/3/2020, the World Health Organization declared that COVID-19 is a pandemic emergency. In this scenario, cancer patients are to be considered at higher risk, being fragile and often with disease-related or treatment-induced immunodepression. Furthermore, this health emergency generates a harmful psychological impact on these patients, who fear a lot about losing the continuity of cancer therapy. This fact must be carefully considered by health personnel, especially in countries where heavy risk containment and social distancing measures, the only epidemiological strategies currently considered adequate, are in force. In short, this is a very delicate challenge for health professionals engaged in oncology. Here, we report some insights and challenges that healthcare professionals face daily in caring for cancer patients.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has spread worldwide and caused widespread devastation. In the absence of definitive therapy, symptomatic management remains the standard of care. Repurposing of many existing drugs including several anti-viral drugs is being attempted to tackle the COVID-19 pandemic. However, most of them have failed to show significant benefit in clinical trials. An attractive approach may be to target host proteases involved in SARS-CoV-2 pathogenesis. The priming of the spike (S) protein of the virus by proteolytic cleavage by the trans-membrane serine protease-2 (TMPRSS2) is necessary for it to bind to its receptor, angiotensin converting enzyme-2 (ACE2) and subsequently enter the cell. There are other proteases with varying spatiotemporal locations that may be important for viral entry and subsequent replication inside the cells, and these include trypsin, furin and cathepsins. In this report, we discuss the tentative therapeutic role of inhibitors of TMPRSS2, cathepsin, trypsin, furin, plasmin, factor X and elastase in infection caused by SARS-CoV-2. Both available evidence as well as hypotheses are discussed, with emphasis on drugs which are approved for other indications such as bromhexine, ammonium chloride, nafamostat, camostat, tranexamic acid, epsilon amino-caproic acid, chloroquine, ulinastatin, aprotinin and anticoagulant drugs. Simultaneously, novel compounds being tested and problems with using these agents are also discussed.

High expression of the inhibitory receptor programmed death ligand 1 (PD-L1) on the surface of tumor cells have been found play a key role in tumor immune evasion in several human malignancies. However, the expression of PD-L1 on bone marrow mesenchymal stem cells (BMSCs) and whether the PD-1/PD-L1 axis is involved in the BMSCs versus T cell immune response in Multiple Myeloma (MM) remain poorly defined. In this study, we explored the expression of PD-L1 on BMSCs from MM patients and the role of PD-1/PD-L1 pathway in BMSCs-mediated regulation of CD8+T cells. We observed that the expression of PD-L1 on BMSCs was significantly higher in NDMM group, compared with the NC group (18.81±1.61% vs. 2.78±0.70 %; P<0.001). Furthermore, the expression of PD-1 on CD8+ T cells in NDMM group was significantly higher than that in control group (43.22±2.98% vs. 20.71±1.08%; P<0.001). However, there was no significant difference in PD-1 expression of CD4+ T cells and NK cells between NDMM group and NC group. Additionally, the co-culture assays revealed that BMSCs significantly promoted CD8+ T cell apoptosis and suppressed CD8+ T cell function. However, PD-L1 inhibitor effectively reversed BMSCs-mediated suppression in CD8+ T cells. We also found that the combination of PD-L1 inhibitor and pomalidomide can further enhance the killing effect of CD8+ T cells on MM cells. In summary, our findings demonstrated that BMSCs may induce apoptosis and functional imbalance of CD8+ T cells via PD-1/PD-L1 pathway and promote the immunity escape of MM.

Benzoic acid is one of the most commonly used food preservatives, but currently exclusively produced in petrochemical processes. In this study, we describe a bio-based production pathway using an engineered strain of Pseudomonas taiwanensis. In a phenylalanine-overproducing strain, we heterologously expressed bacterial, yeast, and plant genes to achieve production of benzoate via a β-oxidation pathway. Strategic disruption of the native Pseudomonas benzoate degradation pathway further allowed the production of catechol and cis,cis-muconate. Taken together, this work demonstrates new routes for the microbial production of these industrially relevant chemicals from renewable resources.

Adeno-associated viral vectors (AAV) are one of the most efficient engineered tools for delivering genetic material into host cells. The commercialization of AAV-based drugs goes hand in hand with the need to increase manufacturing capacities and to develop appropriate quality controls. In particular, accurate methods to assess the level of residual DNA in AAV vector stocks are needed, considering the potential risk of co-transferring oncogenic or immunogenic sequences with the therapeutic vectors. Our laboratory has developed an assay based on high-throughput sequencing (HTS) to exhaustively identify and quantify DNA species in recombinant AAV batches. Compiled with a computational analysis of the single nucleotide variants (SNV), Single-Stranded Virus Sequencing (SSV-Seq) also provides information regarding rAAV genome identity. In this study, we show that the PCR amplification of regions with high GC content and including mononucleotide stretches can be biased during the DNA library preparation, leading to drops in the sequencing coverage along the AAV vector genome. To circumvent this problem, we have developed a PCR-free protocol, named SSV-Seq 2.0, that is optimized for the sequencing of rAAV genomes that contain sequences with a high percentage of GC and homopolymers, such as the CAG promoter. HTS-based assays are indispensable to provide accurate data to the regulatory agencies regarding nucleic acids content in AAV vector batches and to improve the safety and efficacy of these viral vectors.

Vitamin D has long been known to be a major regulator for both the endocrine and the immune system. With the advent of COVID-19 pandemic, there has been a growing interest in looking at the feasibility of using vitamin D as a preventative and therapeutic option in the management of the disease. A low serum level of vitamin D is linked to higher incidence of respiratory tract infection and disease progression. Vitamin D supplementation has proven to be effective in enhancing the immune system, strengthen lung epithelial barrier, and prevention of unchecked inflammatory response. Previous studies on the roles of vitamin D in managing influenza and other enveloped virus infection could shed light on the possible roles of vitamin D in the current pandemic. More randomised controlled trials are needed to explore the effects of vitamin D supplementation on COVID-19 infection.

Background In transcatheter aortic valve replacement (TAVR), accurate aortic annulus measurements are essential for prosthesis sizing to ensure procedural success. Although multi-slice computed tomography (MSCT) is considered the gold standard for aortic annulus measurement pre TAVR, MSCT might be contraindicated in some patients. Aim In patients undergoing TAVR, we sought to correlate manual and newer semi-automated three-dimensional (3D) transesophageal echocardiography (TEE) aortic annular measurements to MSCT measurements. In addition, we assessed the reproducibility of these 3D TEE methods. Methods Retrospective, single centre trial involving 39 patients with severe symptomatic aortic stenosis (AS) planned for TAVR, who underwent both pre-procedural MSCT and pre/peri- procedural manual and semi-automated 3D TEE. Results Mean age was 85.3 ± 4.7 years. Both 3D TEE methods highly correlated with MSCT for annular diameters (semi-automated r =0.96, p<0.0001 and manual r=0.84, p<0.0001) and for annular areas (semi-automated r=0.96, p<0.0001 and manual r=0.82, p<0.0001). Inter-observer reproducibility was high for both 3D TEE methods for annular diameters (semi-automated r=0.96, p<0.001 and manual r=0.91, p<0.001) and annular area (semi-automated r=0.96, p<0.0001 and manual was 0.95 p<0.0001). Conclusion Both semi-automated and manual 3D TEE for sizing of the aortic annulus for TAVR is comparable to MSCT. 3D TEE methods are easily reproducible. Newer semi-automated 3D TEE has the best correlation to MSCT. 3D TEE is an excellent alternative imaging modality for TAVR planning in patients whom MSCT is contraindicated.

On March 11, 2020, the World Health Organization (WHO) declared the SARS-CoV-2 outbreak a pandemic: it took a toll of more than 300.000 deaths and more than 4.5 million cases, worldwide. The initial data pointed out the tight bond between cardiovascular diseases and worse outcomes in COVID19-patients. Epidemiologically speaking, there is an overlap between the age-groups more affected by COVID-related death and the age-groups in which Cardiac Surgery has its usual base of patients. The Cardiac Surgery Departments have to think to a new normal: since the virus will remain endemic in the society, dedicated pathways or even dedicated Teams are pivotal to treat safely the patients, in respect of the safety of the health care workers. Moreover, we need a keen eye on deciding which pathologies have to be treated with priority: Coronary Artery Disease (CAD) showed a higher mortality rate in patients affected by COVID19, but it’s however reasonable to think that all the cardiac pathologies affecting the lung circulation - such as symptomatic severe mitral diseases or aortic stenosis - might deserve a priority access to treatment, in order to increase the survival rate in case of an acquired-Coronavirus infection later on.

This study experimentally investigated the flexural fatigue behaviors of honeycomb sandwich composites subjected to low velocity impact damage by considering the type and thickness of the face sheet material, the cell size and the core height parameters. First, the static strength of undamaged specimens was determined by three-point bending loads, and calculating their fatigue lives; secondly, the fatigue lives of the specimens damaged by low velocity impact tests were then determined. Increasing the face sheet thickness and core height increased the flexural strength, while increasing the cell size decreased the flexural strength. Low velocity impact damage decreased the flexural strength and fatigue lives but increased the damping ratio for all specimens.

Summary. Diseases of the paranasal sinuses (DPN) are the most common pathology in otorhinolaryngology. According to the literature, it is known that cystic sinusitis is an infectious and allergic disease, and the formation of cysts is considered as the result of an allergic reaction to infection in sensitized patients. Adverse environmental impact on the immunological system of the human body, reducing natural resistance, increasing the degree of allergization of the population contributes to a high level of General respiratory diseases. In this regard, it is relevant to study the indicators of General and local immunity in patients with chronic cystic sinusitis. We examined 138 patients with chronic cystic sinusitis aged 17 to 64 years. Conducted immunological study of the state of cellular and humoral immunity in accordance with the recommendations Of the Institute of immunology. A comprehensive immunological examination revealed a sharp imbalance of immunological parameters in blood serum, nasal flushes and cystic fluid in patients with chronic cystic sinusitis. In the complex of etiological and pathogenetic treatment in patients suffering from chronic cystic sinusitis, it is necessary to include immunodulators and immunostimulators.Introduction . Diseases of the paranasal sinuses (DPN), sinusitis-are among the most common pathologies in otorhinolaryngology[3,6]. This is facilitated by changes in the environmental situation in the world, the wide prevalence of both allergic and viral respiratory diseases, the irrational use of antibacterial drugs, and a decrease in local and General immune mechanisms. According to the literature, it is known that cystic sinusitis is an infectious and allergic disease. The formation of cysts is considered as a result of an allergic reaction to infection in sensitized patients[10]. To date, the causes of cysts have not been clarified, so it remains relevant to further in-depth study of various factors that may affect the course of the inflammatory process. In a modern city, a person is exposed to a complex of environmental factors that adversely affect their health. The leading one is multi-complex air pollution, which occurs as a result of intensive development of industry and transport [2]. We have identified an adverse effect of environment on the immune system of the human body - the formation of secondary immunosuppression, reduced natural resistance, increase the degree of allergization of the population, resulting in high rates of overall morbidity and, in the first place, the defeat of the respiratory tract that is characterized by high radiation, dust and fumes in the environment.Currently, the influence of three factors - dust, carbon monoxide and sulfur dioxide-on the incidence of acute respiratory infections, bronchitis and pneumonia has been reliably proven. These agents and their various combinations affect the incidence of angina, pharyngitis, rhinitis, and sinusitis [5,8]. The increased content of harmful substances in the inhaled air has not only a General adverse effect on the body, but also leads to a violation of their normal functioning of the nasal cavity, i.e. weakens its protective capabilities, which increases the risk of rhinitis and sinusitis.In connection with the above, it was considered relevant to study the indicators of General and local immunity in patients with chronic cystic sinusitis [2,4,7,9].The aim of the study was the state of immunological reactivity in patients with chronic cystic sinusitis.Materials and methods of research. 138 patients with chronic cystic sinusitis aged 17 to 64 years were examined, including 65 women (47%) and 73 men (53%) who applied to the clinic No. 1 of the Samarkand medical Institute. The number of workers and employees was about the same. For examination, patients with chronic cystic sinusitis were selected with a prescription of this pathology for at least 2 years and there were no concomitant inflammatory diseases. The diagnosis was made on the basis of patient complaints, anamnesis data documented in outpatient records, clinical manifestations of the disease, x-ray, computed tomography examination of the paranasal sinuses (PNS) and the results of maxillary sinus puncture. To determine the regional physiological norm, all the indicators used were determined in 54 clinically healthy donors aged 17 to 50 years of both sexes from the number of volunteers with no history of chronic inflammatory diseases. Immunological indicators of the physiological norm in flushes from the maxillary sinuses were determined in 23 healthy persons from the number of military conscripts. The conducted immunological study included a detailed determination of 3 links of the immune system: all stages of phagocytosis (% of phagocytic cells, phagocytic number and phagocytosis completion index - PCI) and nst-test, rosette formation reactions - active, spontaneous, and with loads of levamizol and theophylline, concentrations of immunoglobulins of classes A, M, G and sec - rotary Ig A, as well as the content of lysozyme and circulating immune complexes (CIC).We studied the state of cellular and humoral immunity according to the recommendations Of the Institute of immunology. Blood for research was taken in the morning on an empty stomach from the ulnar vein. To determine the cellular level of immunity, blood was placed in a heparinized test tube at the rate of 20 units of heparin per 1 ml of blood. The isolation of immunocompetent cells was performed by a conventional method using a ficol-verografin gradient. Mononuclear suspension was studied in a cell concentration of at least 1 million cells per 1 ml.To study the state of local immunity, cystic fluid was used, which was obtained by means of a diagnostic puncture of the maxillary sinus and was aspirated into a sterile syringe. Further calculations took into account the 1:10 dilution.Results and discussion. A comprehensive immunological examination revealed a sharp imbalance of immunological parameters in blood serum in patients with chronic cystic sinusitis. First of all, attention is drawn to the marked decrease in all indicators of serum immunoglobulin content, as well as secretory Ig A (table 1). It should be noted that the physiological norm of the content of immunoglobulins in blood serum is located within a fairly wide range. For example, the amplitude of ”normal” values for Ig A is from 1.7 to 2.55 g / l, and for SIgA-from 1.65 to 2.65. The same significant fluctuation in their indicators is observed in patients with chronic cystic sinusitis. It seems more convenient to use this indicator in the form of the Ig a/ SIgA index in practical health care . In healthy patients, it is equal to 1, i.e. 1: 1, and in patients with chronic cystic sinusitis, it changes significantly and is 3:1.in all the examined patients, this index was the most constant value, i.e. its fluctuations were minimal.Analyzing the phenomenon of a sharp decrease in the content of immunoglobulins of all classes in the examined patients, it can be assumed that this is a manifestation of a fairly common congenital immunodeficiency condition in all classes of immunoglobulins. In the literature, this category of patients is described as a group of frequently and long-term patients. In most cases, the anamnesis data corresponds to this description.When further analyzing the results of immunological examination of individuals with chronic cystic sinusitis, the following Genesis of the phenomenon of deficiency in all classes of immunoglobulins seems more likely, namely: characterizing the indicators of the macrophage system, it should be noted that the percentage of phagocytic cells is usually increased, which is quite consistent with the classical course of the inflammatory process, but the ability of phagocytes to capture and digest the pathogenic object is reduced (table 2).In this case, we are probably dealing with a congenital defect of the a-link of the immune system, which entails, according to the theory of the three-link immune system, a weak immunological signal to the B-link. Thus, the decrease in serum levels of immunoglobulins of all classes in patients with chronic cystic sinusitis appears to be mediated.This assumption is supported by such an increase in the value of the nst test to 56.5+3.4 (with a norm of 22.5-2.3).Defect A-link - bad recognition, capture and digestion of pathogen - creates conditions for the transition of the inflammatory process in chronic, since it entails a high concentration of this agent in the patient’s body, i.e., a high degree of sensitization, as manifested in the examined in the reaction of immunoparalysis.The high percentage of phagocytic cells and the increased values of the nst test are obviously compensatory. Describing the indicators of the T-system in chronic purulent sinusitis (table 3), it should be noted that the number of active test on the formation of the rosette in the resection reaction in these patients is slightly increased compared to the norm, but statistically unreliable.During stress tests, a decrease in test on the formation of the rosette with theophylline was detected, while the indicators of spontaneous tissue-forming test on the formation of the rosette cells with levamisole almost coincide with the lower limit of the norm, i.e. they are statistically unreliable.The most interesting indicator here is already known and actively used by immunologists index-the ratio of T-helper /T-suppressor: normally in healthy people, it is 0.5+0.03 or 1:2, and in patients with chronic purulent sinusitis, its indicator was significantly changed and took the value of 1.16+0.04, which corresponds to the ratio of 1:1 .Analyzing the state of non-specific resistance, we noted a significantly increased concentration of CIC in the blood serum in patients with chronic cystic sinusitis (98.7+8.2 units of opt.pl) compared to the norm (25:3.2 units of opt. pl). A high level of CIC corresponds to the immunological manifestations of chronic inflammation in the body and may reflect the failure of the phagocytosis process.The detected decrease in the lysozyme index in blood serum - 3.28+0.18 mkg/l (at the norm of 3.7±0.09 mkg/l) may be a sign of exhaustion of this system due to the age and severity of the inflammatory process occurring against the background of a defect in the a-link of the immune system. The immunological characteristics of patients with chronic cystic sinusitis are supplemented by a study from the maxillary sinuses, the results of which are presented in table 4.In cystic fluid in chronic cystic sinusitis, there is an almost double increase in the content of serum Ig A, Ig G and a noticeable decrease in serum Ig and secretory lgA compared to the same indicators in healthy volunteers. This ratio of serum immunoglobulins is quite consistent with the reaction of the B-link immunity to chronic inflammatory process, but a significant decrease in the content of SigA, apparently, pathognomonic for this category of patients, because it reflects the initial weakness of the local immune system of the nasal cavity and paranasal sinuses.In flushes, as in blood, with a wide range of values of Ig A and SigA, the ratio of Ig A/Slg a was the least subject to fluctuations and at the same time the most constant. In healthy patients, it was 0.98+0.032, and in patients-1.86-0.04. For convenience, we have expressed this ratio in the form of an ”immunoglobulin” index, which is 1:1 in healthy people and 2:1 in patients.Indicators of non-specific resistance in cystic fluid from the maxillary sinuses in chronic cystic sinusitis are presented in table 5.An increase of almost twice the normal CIC content in flushes from inflamed maxillary sinuses corresponds to immunological manifestations of the inflammatory process.The fact that in the body of patients with chronic cystic sinusitis, the level of CIC is increased both in the blood serum and in sinus flushes, suggests a possible participation of the autoimmune process in the pathogenesis of this disease.The content of lysozyme in flushes from the maxillary sinuses, as well as in the blood serum, is reduced. Obviously, this phenomenon is still systemic. It is possible that the reduced antibacterial capabilities of local immune factors in the maxillary sinus-secretory immunoglobulin and lysozyme are a predisposing factor in the formation of a chronic process in this organ.

Background: High intensity focused ultrasound (HIFU) is a non-invasive procedure that has been recently studied in management of placenta accreta spectrum (PAS). Objective: To appraise efficacy and safety of HIFU in management of PAS and to highlight restrictions of transitioning uterus-preserving studies to clinical practice. Search Strategy: A search on Scopus, Cochrane, PubMed and Web of Science was conducted from date of database inception to January 31st, 2020. Selection Criteria: Studies on use of HIFU in management of PAS were eligible. Review articles, conference papers, animal studies, and case reports were excluded. Data Collection and Analysis: A standardized data collection sheet was used to abstract data from eligible studies. CON-PAS registry was used to include studies on other conservative modalities of management of PAS. Results: Out of 30 studies, four were eligible (399 patients). Average residual placental volume was 61.74 cm3 (6.01-339). Treatment was successful in all patients. Normal menstruation recovered after 48.8 days (15-150). Average time for normalization of β-HCG was 16.5 (1-82) days. No major complications were encountered. Sixty-one studies were retrieved from CON-PAS registry; uterine artery embolization (23 studies), Prophylactic balloon placement (15), compression sutures (10), leaving placenta in situ (7), and uterine wall excision (6) were successful in 83.7% 92.9% 87.9%, 85.2%, and 79.3% of patients, respectively. Conclusions: HIFU yields promising success and safety profile in management of PAS in certain clinical situations. A global research strategy is recommended to incorporate conservative approaches in selected patients within a comprehensive protocol to manage PAS.

Aspirin as an old drug extracted from willow bark and widely used in the prevention and treatment of cardiovascular diseases. Increasing evidence have shown that aspirin use may significantly reduce the angiogenesis of cancer, while the mechanism of the association between angiogenesis and aspirin is complex. Although COX-1 is widely known as a target of aspirin, several studies reveal other antiangiogenic targets of aspirin, such as angiotensin II, Glucose transporter 1, heparanase, and matrix metalloproteinase. In addition, some evidence indicates that aspirin may produce antiangiogenic effects after acting in different cell types, such as endothelial cell, platelet, pericyte, and macrophage. In this review, we concentrate on recent researches on the antiangiogenic effects of aspirin in cancer, and analyze the molecular mechanisms of aspirin and its metabolites. Moreover, we discuss some mechanisms through which aspirin treatment may normalise existing blood vessels, including preventing disintegration of endothelial adheren junctions and recruiting pericytes. We also address the antiangiogenic effects and the underlying mechanisms of aspirin derivatives, which aim to improve safety and efficacy.

Approximately 13 patients with hemophilia A or B have been reported to be diagnosed with acute leukemia in childhood [1, 2]. This rarity appeared again in a 13 year old male with severe hemophilia with inhibitors who presented with worsening bone pain, weight loss, and leukocytosis. Coexistence of these life-threatening disorders, hemophilia and acute leukemia, pose practical challenges in providing standard care as the former has a propensity of bleeding and the latter requires intensive treatment with systemic and intrathecal chemotherapy. Our discussion aims at highlighting critical care strategies in management of severe hemophilia and hematologic malignancies.

CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1) is a rare entity recently described. Thirteen CNS HGNET-MN1 patients were identified using genome wide methylation arrays/RT-PCR across 7 institutions and were correlated with treatment and outcome. All patients had surgery (GTR:9/STR:4) as initial management followed by radiotherapy (focal:5/craniospinal:2/CyberKnife:1) and systemic chemotherapy in 3 patients. Seven patients relapsed; 5 local and 2 metastatic despite complete resection and radiotherapy. Three patients died due to their tumor relapse after 24 months despite upfront radiotherapy. Treatment of CNS HGNET-MN1 remains a major challenge with multiple failures, despite aggressive surgical resections and upfront radiotherapy.

IntroductionA spontaneous premature rupture of membranes in the early 2nd trimester considerably impairs the formation of the fetal skeletal system, as well as inhibiting the maturation of the lungs and kidneys due to the absence of amniotic fluid. Intrauterine infections can occur, which can also endanger the mother. This often leaves no other option than to advise the mother to terminate the pregnancy. Loss of amniotic fluid is observed in rare cases even after amniocentesis. In most cases, the defect is self-locking. In two-thirds of cases, abortion occurs, especially if larger amounts of amniotic fluid (15 ml) have been removed1. The termination of pregnancy is usually associated with considerable psychological stress for the patient.After Szendi 2 initially described total cervical occlusion, Saling 3,4 modified it in a prophylactic approach to habitual abortion. We successfully applied this method for many years in a prophylactic and therapeutic approach, modified it and always combined it with McDonald cerclage 5. The experience we had gained here placed us in a position to perform complete occlusion of the cervical canal and external os in two cases of ruptured membranes at 14 and 16 weeks of pregnancy, respectively.

Background: Six cell surface receptors, human epidermal growth factor receptor (Her)-2, platelet-derived growth factor receptor (PDGFR)-β, insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (IR), c-Met, and vascular endothelial growth factor receptor (VEGFR)-3, previously demonstrated variable expression across varying osteosarcoma (OS) cell lines. The current study sought to validate previous expression patterns and evaluate whether these receptors offer prognostic and therapeutic value. Methods: Patient-derived OS samples (n = 52) were labeled with antibodies to Her-2, PDGFR-β, IGF-1R, IR, c-Met, and VEGFR-3. Expression was characterized using flow cytometry. The geometric mean fluorescent intensity (geoMFI) for each receptor was calculated relative to a negative control. The event-free survival (EFS) and overall survival for patients with positive receptor expression were estimated by the Kaplan-Meier method. Differences in hazard for EFS event and overall survival event for patients with positive receptor expression were assessed using the log-rank test. Results: All 6 receptors were variably expressed in the majority of cell lines. None of the 6 receptors, were found to be significant predictors of EFS or overall survival. The sum total number of positive receptors per cell line also failed to predict EFS or overall survival. Conclusion: The six cell surface receptors demonstrated variable expression across the majority of patient-derived OS samples tested. While receptor expression did not provide prognostic value, their consistent expression makes them attractive targets for future therapeutic approaches.

During the COVID-19 pandemic, labour and delivery are not going to be put on hold. Managing anaesthesia for patients with COVID-19 will be a challenge, but there is little available data. Having reviewed the literature and the recommendations of experts, and the knowledge gained from the SARS epidemic, this article examines contemporary thinking regarding COVID-19 and pregnancy, the advantages and difficulties of various forms of anaesthesia, and a number of practical considerations related to the management of obstetric analgesia and anaesthesia for pregnant women with the disease.

Objective - Determine what is the best initial clinical score to evaluate and propose adequate management to pregnant women with suspicion of COVID-19 infection. Design – setting – population: Retrospective study in one center (Lille, France) from 15 March 2020 to 15 April 2020. Were included all pregnant consulting in our emergency center for a suspicion of COVID-19 infection. Methods – main outcome measures: Women had a clinical, radiologic and biologic first evaluation to adapt management at home or in hospitalization. The National Early Warning Score (NEWS) and the NEWS-PREG, which is an adaptation including trimester of pregnancy, were calculated in posteriori for each patient. Sensitivity, specificity, predictive positive and negative value of these scores to propose adequate management were calculated. Results: 63 women were included. Seventeen were hospitalized (27%) among 4 in intensive care (6,5%). Sensitivity, specificity, predictive positive value and predictive negative value to predict hospitalization of the NEWS were respectively 52.9%, 100%, 100% and 85.2%. There were respectively 82.4%, 93.5%, 82.4% and 93.4% for the NEWS-PREG. Areas under the curve to predict hospitalization of the two scores were 0.77 for the NEWS and 0.88 for the NEWS-PREG. No woman was readmitted or had to be transferred from conventionel hospitalization to intensive care within 48 hours of her initial assessment and orientation. Conclusion: The NEWS-PREG is an interesting initial clinical score which can be used in case of suspicion of COVID-19 infection to propose adequate management. It will be interesting to evaluate in a prospective study.

OBJECTIVE: To evaluate the efficacy and safety of up to 24 weeks of triptorelin treatment after conservative surgery for deep infiltrating endometriosis (DIE). DESIGN: Multicentre, prospective, non-interventional. SETTING: 18 tertiary hospitals in China. POPULATION: Premenopausal women aged ≥ 18 years treated with triptorelin 3.75 mg once every 28 days for up to 24 weeks after conservative surgery for DIE METHODS: Endometriosis symptoms were assessed, using a visual analogue scale (0–10 cm) or numerical range (0–10), at baseline (pre-surgery) and routine visits 3, 6, 9, 12, 18 and 24 months after surgery. MAIN OUTCOME MEASURES: Change in symptom intensity over time. RESULTS: A total of 384 women were analysed (mean [SD] age, 33.4 [6.2] years). Scores for all symptoms assessed (pelvic pain, dysmenorrhoea, ovulation pain, dyspareunia, menorrhagia, metrorrhagia and gastrointestinal and urinary symptoms) decreased from baseline over 24 months. Cumulative improvement rates in pelvic pain, dysmenorrhoea, ovulation pain and dyspareunia were 74.4%, 83.6%, 55.1% and 66.9%, respectively. The 24-month cumulative recurrence rate (≥ 1 symptom) was 22.2%. The risk of symptom recurrence was higher in patients with ≥ 2 versus 1 lesion (odds ratio [OR] 2.539; 95% CI: 1.458–4.423; p = 0.001) and patients with moderate (OR 5.733; 95% CI: 1.623–20.248; p = 0.007) or severe (OR 8.259; 95% CI: 2.449–27.851; p = 0.001) pain versus none/mild pain. Triptorelin was well tolerated. CONCLUSIONS: Triptorelin after conservative surgery for DIE improved symptoms over 24 months of follow up. FUNDING: Sponsored by Ipsen

Background and Purpose Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by cytotoxicity of mutant huntingtin protein (mHTT). Decrease of mHTT will be a potential strategy for therapeutic purpose of HD. VCP has been reported and functioned in HD. Finding of novel small molecules specifically regulates the activity of VCP, which may be benefited to HD patients. Experimental Approach In-house screening drug library against VCP enzymatic activity was performed and a leading candidate was studied for its mechanism of the degradation of mHTT and its effect on HD animal models. Key Results We identified gossypol, a clinical approved drug in China, as a novel modulator of VCP. Gossypol acetate acted through a gain-of-function way to induce the formation of VCP-LC3-mHTT ternary complex, triggering autophagic degradation of mHTT. Gossypol interfered with VCP’s enzymatic activity through its direct binding to interface between VCP’s N and D1 domains. Gossypol acetate not only lowered mHTT levels and rescued HD-relevant phenotypes in patient induced pluripotent stem cell (iPS)-derived neurons and HD knockin mouse striatal cell, but also improved motor function deficits in both Drosophila and mouse HD models. Conclusions and Implications Taken together, these findings revealed a new strategy for treating HD by gossypol that targets mHTT through VCP and LC3 to the autophagic pathway and raised the possibility that an existing drug can be repurposed as a new treatment of HD.

Objectives To describe a cohort of Italian women with confirmed COVID-19 infection admitted during pregnancy for out or inpatient hospital care, in order to provide rapid feedback for clinicians and policymakers. Design National population-based cohort study. Setting 297 Italian public and private maternity units. Population Pregnant women with COVID-19 infection confirmed by RT-PCR testing through nasopharyngeal swab and/or chest RX or CT findings and/or antibody response from maternal blood. Exclusion criteria: age <18 years, refusal to participate and inability to give consent to participation. Methods A network of 351 trained reference clinicians enrols eligible women after acquiring an informed consent and completes a data entry form through a secure web-based system. Main outcome measures COVID-19 pneumonia, invasive respiratory support, ICU admission, women’s severe morbidity and mortality Results Over 80% of the 65 cases occurred in Northern Italy. Women’s mean age is 33.8 years. Gestational age at presentation is ≤14 weeks in 15.6% of the cases, 15-27 weeks in 51.6% and ≥28 weeks in 32.8% women. Pneumonia affects 41.5% of the cohort; three women have severe complications and are admitted to ICU. None has died. Conclusions The study describes the course of COVID-19 infection in a cohort of pregnant women, providing valuable information to improve clinical and logistical management of these cases. Questions arising from the study deserve further research.

Approximately 20–40% of pediatric patients with anaplastic large-cell lymphoma (ALCL) develop recurrent disease. Here, we report a pilot experience using single-drug weekly vinorelbine (25 mg/m2/wk) as a salvage re-induction regimen in 4 consecutive pediatric patients with relapsed ALCL. All 4 patients achieved complete remission after 2 cycles of weekly vinorelbine and were disease-free alive at last evaluation. The main toxicity was hematologic. Only one week of vinorelbine administration was withheld for a grade 4 neutropenia in one patient. The results suggest that weekly vinorelbine has good efficacy and safety in the treatment of relapsed pediatric ALCL.

Redo multiple valve replacement is known to carry additional risk of morbidity and mortality. Currently, a transcatheter-based valve-in-valve approach could be useful in reducing potential serious consequences. On the other hand, this approach poses several technical challenges regarding the device and procedural aspects of the procedure. We present the case of a 78-year-old man who presented with symptoms of heart failure due to mitro-aortic bioprosthesis degenerations who was deemed to be at extremely high risk for conventional redo surgery. A two-steps single admission transcatheter-based approach was planned with a transfemoral aortic valve-in-valve procedure followed by a trans-apical mitral valve-in-valve implantation. The outcome was good and the recovery was fast.