Cystic fibrosis is an autosomal recessive disease caused by CFTR gene mutations. Despite having the same mutation, CF patients may demonstrate clinical variability in severity and prognosis of the disease. In this study, we aimed to determine differentially expressed genes and associated molecular pathways between mild and severe siblings with same genotype. We performed targeted real-time PCR based transcriptomic analysis of nasal epithelial cells obtained from two families with two siblings with Class II mutations (F508del/F508del) and (F508del/G85E), one family with three siblings with Class IV mutation (I1234V/I1234V). In severe siblings with Class II mutations, TNFRSF11A, KCNE1, STX1A, SLC9A3R2 were found to be up regulated. CXCL1, CFTR, CXCL2 were found to be down regulated. Inflammation-immune response related signaling pathways such as IL-17, NF-kappa B, TNF, NOD-like receptor signaling were identified. In the severe sibling with Class IV mutation; inflammation and immune response-related pathways were discovered. Also, AGE-RAGE and TLR signaling were found to be specific to Class IV group. Comparison of CF patients to non-CF control; showed that ICAM1 was up regulated whereas EZR, TNFRSF1A, HSPA1A were down regulated in patients. In addition, a significant positive correlation was determined between differentially expressed genes in AGE-RAGE, cytokine-cytokine receptor interaction, insulin resistance and hepatic involvement in CF patients. As a result of this study, differentially expressed genes and associated pathways responsible for clinical severity among affected siblings carrying the same mutation were identified. The results will provide an opportunity for the development of novel target molecules for treatment of disease.

Montelukast therapy in asthmatic children with and without food allergyUmit Murat Sahiner1*, Ebru Arik Yilmaz1*, Sara Fontanella2, Sadia Haider2, Ozge Soyer1, Adnan Custovic2, Omer Kalayci1, Cansin Sackesen1,3*Equal contribution1 Hacettepe University School of Medicine, Division of Pediatric Allergy, Ankara, Turkey2 National Heart and Lung Institute, Imperial College London, UK3 Koc University School of Medicine, Division of Pediatric Allergy, Istanbul TukeyRunning Title: Montelukast in asthma and food allergyFunding Source: The study drugs, placebos and laboratory kits were provided by Merck Sharpe and Dohme Company. The protocol was developed by the corresponding author Prof Cansin Sackesen and reviewed by Merck Sharpe and Dohme Company. However, there is no contribution of Merck Sharpe and Dohme Company to the results and discussion of the article.Conflicts of Interest: The authors declare no conflicts of interest in relation to this study.

A Gynecologist's perspective on the limitations of telemedicine in the setting of early pregnancy diagnosis during the COVID-19 Pandemic.

Fully digital microscopes are becoming more and more common in surgical applications. In addition to high-resolution stereoscopic images of the operating field, which can be transmitted over long distances or stored directly, these systems offer further potentials by supporting the surgical workflow based on their fully digital image processing chain. For example, the image display can be adapted to the respective surgical scenario by adaptive color reproduction optimization or image overlays with additional information, such as the tissue topology. Knowledge of this topology can be used for computer-assisted or AR-guided microsurgical treatments and enables additional features such as spatially resolved spectral reconstruction of surface reflectance. In this work, a new method for high-resolution depth measurements in digital microsurgical applications is proposed, which is based on the principle of laser triangulation. Part of this method is a sensor data fusion procedure to properly match the laser scanner and camera data. In this context, a strategy based on RBF interpolation techniques is presented to handle missing or corrupt data, which, due to the measuring principle, can occur on steep edges and through occlusion. The proposed method is used for the acquisition of high-resolution depth profiles of various organic tissue samples, proving the feasibility of the proposed concept as a supporting technology in a digital microsurgical workflow.

Introduction: Catheter ablation (CA) of typical atrial flutter (AFl) is the preferred treatment for typical AFl due to excellent long-term success. However, current guidelines recommend oral anticoagulation (OAC) based on established indices of stroke regardless of the perceived success of ablation. Methods: We identified all patients who underwent typical AFl ablation at our institute from 2011-2017. All patients continued OAC for at least 6 weeks post CA and underwent 24-hour Holter monitoring. OAC was discontinued if there was no evidence of recurrence at 6 weeks. In patients with low LVEF or prior Atrial Fibrillation episodes, OAC was continued for 6 months with repeat Holter monitoring at 6 months. Results: A total of 106 patients were included in our analysis, mean age was 64±14 years and 78.3% were male. Mean CHADSVaSC score was 3±1. OAC was discontinued by 6 weeks in 17% and at 1 year in 55.7%. OAC was continued indefinitely in 44.3%. Over a mean follow up period of 28.6±27.3 months, there was one ischemic stroke in the OAC discontinuation group and no ischemic events in the continued OAC group. There was a total of 3 major bleeding events, all in the OAC group. Conclusion: In patients undergoing successful atrial flutter ablation, a strategy of OAC discontinuation with close rhythm monitoring appears feasible. Benefit of continued OAC in this cohort may be outweighed by the adverse risk of bleeding. Further studies examining rhythm guided OAC can minimize unnecessary exposure to long term anticoagulation.

Antimicrobial resistance (AMR) is a complex and global problem. Despite the growing literature on AMR in the medical and veterinary settings, there is still a lack of knowledge and research on the wildlife compartment. The main aim of this study was to report the global trends in AMR research in wildlife, through a bibliometric study of articles found in the Web of Science database. A total of 214 articles were obtained, published between 1979 and 2019. A rising interest in the last decades towards this topic becomes evident. During this period, the scientific literature was distributed among a broad range of scientific fields, however it became more multidisciplinary in the last years with a change of the spotlight into the “One Health” paradigm. There was a geographical bias in the research outputs. Most published documents were indisputably from the United States, followed by Spain, Portugal and the United Kingdom. The most productive institutions in terms of publication number were located in Portugal and Spain. An important level of international collaboration was identified. An analysis of the main keywords showed an overall dominance of “AMR”, “E. coli”, “genes”, “prevalence”, “bacteria”, “Salmonella spp.” and “wild birds”. This is the first study providing a global overview of the spatial and temporal trends of research related to AMR in wildlife. Given the growth tendency over the last years, it is envisaged that scientific production and research efforts will expand in the future. In addition to offering a broad view of the existing research trends, this study identifies research gaps both in terms of geographical incidence and also in relation to unexplored subtopics. Unearthing scientific areas that should be invested in and explored in the future is key to designing new strategic research agendas in AMR research in wildlife and to inform funding programs.

We present a timely evaluation of health effects of COVID-19 related lockdown events in Pakistan. Using parametric t tests and non-parametric Wilcoxon signed ranks tests we find that the coronavirus cases and deaths in the four-weeks after lockdown lifting are significantly greater than those reported over the same time periods during lockdown. This paper is meant to aid in handling interventions to manage COVID-19 outbreak across the Asia and Pacific region, especially to the ones that have similar settings of health care systems and economic development. However, the direct economic and environmental effects of imposing and easing lockdown measures remain a matter of further investigation.

Rice is one of the most susceptible plant to iron (Fe) deficiency under neutral and alkaline conditions. Alkaline stress induces H2O2 production and increases the deposition of Fe on roots surface, which causes leaf chlorosis and Fe deficiency in rice. Gene chip and qRT-PCR analysis indicated that the expression of nitrate reductase (NR) genes were down-regulated by alkaline treatment, which resulted in significantly decreased nitrate activities and nitric oxide (NO) production in epidermis and stele, where the H2O2 was accumulated. In contrast, treatment with sodium nitroprusside (SNP), a NO donor, strongly alleviates alkaline-induced Fe deficiency by limiting Fe plaque formation. Increasing the NO signal significantly reduces the accumulation of H2O2 and lignin barrier, but enhances phenolic acid secretion in root epidermis and stele under alkaline stress. The secreted phenolic acid effectively mobilized the apoplast Fe and increased Fe uptake in root, thus which alleviate the Fe deficiency response and down-regulate expression of Fe uptake genes under alkaline condition. In conclusion, alkaline stress inhibits the NR activity and NO production in roots of rice, which plays a vital role in mobilizing the apoplast Fe by regulation of H2O2 and phenolic acids concentrations.

Objectives: Multiple organ dysfunction syndrome (MODS) with secondary hemophagocytic lymphohistiocytosis (SHLH) causes significant mortality, while continuous renal replacement therapy (CRRT) is commonly conducted. The objective is to identify the predictor factors associated with poor outcomes in pediatric patients with SHLH-associated MODS who received CRRT. Design: A multicenter prospective nested case-control study. Setting: In four PICUs of tertiary university children’s hospital in Shanghai from September 2013 to August 2018. Patients: Pediatric patients receiving CRRT due to SHLH-associated MODS from September 2013 to August 2018. Interventions: None. Measurements and Main Results: Overall PICU mortality rate was 46.15% (24/52). Less respiratory (28.6% vs. 87.5%, P<0.001) or cardiovascular dysfunction (25.0% vs. 83.3%, P<0.001) caused in survivors at CRRT initiation, as well as reduced demands of mechanical ventilation and vasoactive agents (28.6% vs. 87.5%,17.9 % vs. 66.7 %, both P<0.001). Non-survivors had higher levels of serum LDH (1404.5 (713.25, 2793) vs. 982.7 (692, 1461) (U/L), P = 0.037), lactic acid (1.9 (1.3, 4.53) (mmol/L) vs. 1.65 (0.8, 2.45) , P=0.034), triglyceride (2.88 (1.94, 5.08) (mmol/L) vs. 2.41 (1.63, 3.32), P=0.032) and IL-6 (28.66 (17.77, 113.63) (pg/ml) vs.0.98 (0.1, 4.63) P=0.000). More than 3 organ dysfunction (Odd ratio [OR] : 3.464; 95% confidence interval [CI] [1.018-11.788], P = 0.047), and the serum IL-6 level higher than 13.12 pg/mL (OR:1.388; 95% CI [1.058-1.821], P = 0.018 ) were two independent risk factors for mortality. Conclusions: The number of organ dysfunction and IL-6 levels at CRRT initiation are the independent risk factors for mortality in SHLH-associated MODS patients.

Blastic plasmacytoid dendritic cell neoplasm is an aggressive and rare hematologic malignancy, exceptionally presented in children. This case reports an 11-year-old Peruvian boy, with a 2-year history of a purple-violate tumor in a leg, lymph node involvement, and histopathological study with immunohistochemistry: CD4+, CD56+, Tdt+, CD45+, TCL1+. An institutional treatment protocol for high-risk ALL was given. There was a diagnosis delay in a pediatric patient with a rare but very visible neoplasm in a low-middle income country. Despite this, the clinical course was of an indolent evolution. The institutional protocol was efficient to achieve complete oncological disease response.

Investigation of cooperative effect exhibited by purely C-H—O hydrogen bonded (H-bonded) networks in linear and cyclic clusters of (1,3-cyclohexanedione)n (n = 2 to 6) has been carried out using density functional theoretical calculations. Linear clusters were found to show anti-cooperative behavior, while the cyclic clusters showed positive cooperativity. H-bond strengths and binding energies per bimolecular interaction were found to decrease with increasing cluster size for the linear clusters whereas their cyclic counterparts showed opposite trends. The extent of cooperativity has been found to show monotonic behavior for both linear and cyclic clusters and was found to reach an asymptotic limit with increasing cluster size. Natural bond orbital (NBO) analysis and atoms in molecule (AIM) calculations were found to corroborate the obtained results.

Aims: To investigate current practices and problems of neurological prognostication in comatose cardiac arrest (CA) patients. Methods: An anonymous questionnaire was distributed to 1600 emergency physicians in 75 hospitals which were selected randomly from China between January and July 2018. Results: 92.1% respondents fulfilled the survey. The details of the neurological prognosis were not well understood. The predictive value of brain stem reflex, motor response and myoclonus was confirmed by 63.5%, 44.6% and 31.7% respondents respectively. Only 30.7% knew that GWR value <1.1 indicated poor prognosis and only 8.1% know the most commonly used SSEP N20. Epileptiform, burst suppression, and isoelectric was considered to predict poor outcome by 35.0%, 27.4% and 45.7% respondents. 46.7% knew NSE, and only 24.7% knew S-100β. Only a few respondents knew that neurological prognostication should be performed later than 72h from CA either in TTM or non-TTM patients. In practice, the most commonly used method was clinical examination (85.4%). 67.9% had used brain CT for prognosis, and 18.4% for MRI. NSE (39.6%) was a little more widely used than S-100β (18.0%). However, SSEP (4.4%) and EEG (11.4%) were occasionally performed. The survey may have been subject to bias ascertainment as only university affiliated hospitals and university teaching hospitals were selected, making it likely that the degree of neuroprognostication awareness and practice reflected in our survey is an optimistic perspective. Conclusions: Neurological prognostication in CA survivors had not been well understood and performed by emergency physicians in China. They were more likely to use clinical examination rather than objective tools, especially SSEP and EEG, which also illustrated that multimodal approach was not well performed in practice.

Uniaxial static and cyclic creep tests are carried out on a bainite 2.25Cr-1Mo steel at 455°C. The dependence of cyclic response on varied unloading conditions is investigated, with unloading rates from 0.6 MPa/s to 39 MPa/s and the valley stress duration from 0 to 30 min. Fracture surfaces of each specimen are analysed by using a scanning electron microscopy, and a systematic classification of strain components under cyclic creep is proposed to determine the actual damage. The results indicate that, the fracture modes under static and cyclic creep conditions both have ductile features. Due to the effect of anelastic strain recovery, the strain accumulation rate under cyclic creep is significantly retarded as compared with static creep, and the unloading conditions apparently influence the behaviour of anelastic strain recovery. Moreover, a life prediction method for cyclic creep tests based on mean actual strain deducted recovery strain is proposed.

Every organism on Earth depends on interactions with other organisms to survive. In each of these interactions, an organism must utilize the limited toolbox of genes and proteins it possesses to successfully manipulate or cooperate with another species, but it can also coopt the genome machinery of its partner. Insect-induced plant galls are an extreme example of this, wherein an insect hijacks the plant genome to direct the initiation and development of galls comprising of plant tissue. However, the mechanism(s) behind insect-induced gall induction and development remain elusive. Here we demonstrate that cynipid wasp Dryocosmus quercuspalustris create a complex and novel parasite-specific organ from red oak tissue via massive changes in host gene expression. Our results show that the gall wasp is not merely modifying oak leaf tissue but creating a novel organ, resulting in extensive changes in gene expression between galled and ungalled tissue (differential expression in 28% of genes) and distinct gall tissue types (20% of genes). The outer gall tissue showed increases in various plant defense systems, which is consistent with its predicted functional role of protecting the wasp larva. The inner larval capsule shows suppression of large parts of the plant innate immune system and evidence for the wasp utilizing the plant’s RNA interference mechanisms, which may be a potential mechanism of gall induction. We also find significant overlap between cynipid galls and agricultural gall pests, suggesting possible shared mechanisms for this complex species interaction even in disparate plants and insect galling guilds.

Background: Bacillus Calmette-Guérin (BCG) vaccination policies of countries are postulated to have effect on the course of coronavirus disease 2019 (COVID-19) pandemic. Methods: Retrospective cross-sectional study was conducted between March 11-June 10, 2020 in a chest clinic in a state hospital in Istanbul,Turkey. Adults with diagnosis of COVID-19 pneumonia confirmed with severe acute respiratory syndrome coronavirus 2 polymerase chain reaction positivity in a nasopharyngeal sample and pulmonary infiltrates in computed chest tomography were included consecutively. Sociodemographic characteristics, body-mass index, smoking status, comorbid diseases, income rates, and BCG-vaccination status were compared between severe and mild patients with COVID-19 pneumonia. Results: Study population consisted of 123 adults (mean age, 49.7 years [standard deviation, 13.3 years]; 82 (66.7%) male). The proportion of BCG-vaccinated cases was significantly lower among severe patients than mild patients with COVID-19 pneumonia (68.5% vs 88.2%; p=.026). Mean age (54.0 ± 11.5 years vs 38.3 ±10.7 years; p <.001), diabetes rate (32.6% vs 5.9%; p=.002) and low-income (84.3% vs 52.9% p<.001) are higher in patients with severe COVID-19 pneumonia than in patients with mild COVID-19 pneumonia. Multivariate logistic regression analysis showed that increasing age (odds ratio [OR], 1.112; 95% confidence interval [CI], 1.058 – 1.169; p<.001) and low income (OR, 3.369; 95% CI, 1.074 – 10.570; p =.037) are associated with severe COVID-19 pneumonia. Conclusion: Clinical data does not support that being vaccinated with BCG is associated with disease severity in COVID-19 pneumonia. Age and low-income are the major predictors for disease severity.

A document by Xiaohai Zheng. Click on the document to view its contents.

Background: This study aimed to investigate the Hospital-Acquired Conditions (HACs) and find deficits in our hospital, so as to improve the incidence of HACs in China from our retrospect. Methods: We conducted statistics on the incidence and the percentage of HACs, and managed the cost and length of stay of the 950 patients went through HACs in our hospital from 2016 to 2018. Results: The overall incidence was 0.571%. The two most common conditions with the most cost were deep vein thrombosis (DVT) and pulmonary embolisms (PE) (351), and surgical site infections (SSI) (143), which were followed closely by manifestations of poor glycemic control (53), vascular catheter–associated infections (VCAIs) (52), stage III and IV pressure ulcers (49), catheter-associated urinary tract infections (CAUTIs) (33), and falls and trauma (30). Iatrogenic pneumothorax with venous catheterization (7) only occupied small portions. Blood incompatibility and air embolism didn’t happen in the three years. Conclusions: From the comparison of three years, the condition decreased in 2017, while met a higher increase in 2018. This may relative to the launch of medical reform in 2017. Chinese hospitals still need to investigate the HACs, give adaptable emphasis and concern to improve, and promote the overall level of medical management.

Striking features of the COVID-19 pandemic are the rapid spread of the SARS-CoV-2 virus and the relatively narrow profile of patients adversely affected. SARS-CoV-2 enters human cells by means of ACE2, destroying the protein in the process. ACE2 maintains renin-angiotensin-aldosterone system (RAAS) homeostasis and is upregulated in the setting of chronic RAAS disequilibrium seen in COVID-19-susceptible patients. The ACE2-depletion effect on angiotensin II (AngII) levels likely contributes to the spectrum of cytokine responses found in COVID-19 patients. However, as most of the inflammatory effects of AngII are amplified through aldosterone-activated mineralocorticoid receptors (MRs), blocking MRs may provide much-needed benefit. The MR-blockers, spironolactone and eplerenone, are relatively selective in exerting downstream dampening effects on RAAS stress and target the pathophysiological processes in COVID-19-susceptible patients where acute viral-induced ACE2 depletion could be responsible for a catastrophic aldosterone surge in severely ill patients.

• Respirators are currently recommended for use for any aerosol generating procedure • Verbal communication is impeded by the use of respirators • The authors have trialled a simple throat mic speaker system • The system improves both volume and clarity of speech • The authors recommend this, or similar systems to improve communication in theatre

Objectives: To evaluate the safety of intratympanic and intravenous dexamethasone administration for the treatment of sudden sensorineural hearing loss(SSNHL) and hearing improvement at low, mid and high frequencies. Methods: SSNHL patients were randomly divided into two groups within 72 hours after onset and received 24 days of dexamethasone therapy.The group A patients only received intravenous dexamethasone once every other day.Patients in group B received 12 days intravenous dexamethasome and six injection of intratympanic dexamethasome from the 13th day to 24th day like in Group A.Side effects and hearing recovery were compared. Results: The discomfort of intratympanic injection were mild and transient, no tympanic membrane perforation and otitis media, whereas the systemic adverse effects increased cumulatively over the course of intratympanic dexamethasone treatment in group A.The systemic side effects were more serious in group B than in group A. On day 7 (D7),the average 3-frequency PTA (250, 500, and 1000 Hz) was 34.10±9.14 dBHL in group A and 25.70±6.88 dBHL in group B(P<0.05). Hearing recovery was better in group A than group B,but there are the same long-term efficacy at the 90-day follow-up.Group A had slightly better high-frequency hearing recovery than group B, but this difference was not statistically significant. There were no significant differences in the total effective rate of hearing improvement. Conclusions: Early intratympanic dexamethasone intervention led to the rapid recovery of hearing loss, with a good remedial effect on hearing at low-mid frequencies. Intratympanic dexamethasone was safer than intravenous dexamethasone for SSNHL, and high-frequency hearing recovery may have been better with intratympanic dexamethasone, but the difference was not statistically significant. Therefore, it is necessary to make individualized treatment decisions according to the patient’s condition.

Presented is an interesting case of a patient with diagnosis of central nervous system (CNS) malignancy and Hashimoto thyroiditis, who developed anaphylaxis to low sorb tubing which was used for chemotherapy and supportive care medication. The patient had no known drug allergies and an unremarkable work up for hereditary angioedema, rheumatological and immunodeficiency disorders. This hypersensitivity reaction (HSR) has not been previously reported in literature and delayed the patient’s cancer related treatment, which has the potential of impacting patient outcomes. We report this rare case, discuss differential diagnosis for HSR in patients with negative allergy history, and provide management guidelines.

Infant acute lymphoblastic leukemia (infant ALL) is known for its poor prognosis. Current treatment protocols include aggressive chemotherapy and allogeneic stem cell transplantation but prognosis remains poor. Immunotherapy is a new approach with promising results. CAR-T cell therapy has recently been approved for relapsed or refractory childhood ALL but lacks documentation regarding infant ALL. We describe here two cases of patients suffering from infant ALL who were treated with CAR-T cell therapy, the feasibility and efficiency of treatment and their outcome.

Background: The prevalence of tree nut allergy has increased worldwide, and cashew has become one of the most common food allergens. More critically, cashew allergy is frequently associated with severe anaphylaxis. Despite the high medical need, no approved treatment is available and strict avoidance and preparedness for prompt treatment of allergic reactions are considered dual standard of care. In the meantime, Phase III study results suggest investigational epicutaneous immunotherapy (EPIT) may be a relevant and safe treatment for peanut allergy and may improve the quality of life for many peanut allergic children. Objective: We aimed to evaluate the capacity of EPIT to provide protection against cashew-induced anaphylaxis in a relevant mouse model. Methods: A mouse model of IgE-mediated cashew anaphylaxis was first developed. Based upon this model, the efficacy of EPIT was evaluated by applying patches containing cashew allergens to cashew-sensitized mice. Cashew-specific antibody titers were measured throughout treatment. Treated mice were challenged orally to cashew and anaphylactic symptoms were monitored. Additionally, plasma levels of mast-cell proteases (mMCP)-1/7 were quantified from blood samples collected after challenge to evaluate IgE-induced mast-cell activation. Results: EPIT significantly decreased anaphylactic symptoms following challenge and increased cashew-specific IgG2a (equivalent of human IgG1). Interestingly, this protection was associated with a sharp decrease in mast-cell reactivity. Conclusion: We demonstrate that EPIT markedly reduced IgE-mediated allergic reactions in a mouse model of cashew allergy, which suggests that EPIT may be a relevant approach to treating cashew allergy.

Background. Sublingual allergen immunotherapy (SLIT) is recognized as both efficacious and safe, especially when using monomeric allergoids. Its mechanism of action is based on the differentiation, activation, and maturation of allergen-specific Regulatory T-cells (Tregs), fundamental for the activation and maintenance of immune tolerance. Tregs, originally identified as a subpopulation of Foxp3 expressing CD4+CD25high T-cells; however, under inflammatory conditions, they are conveniently identified by the surface antigen CD127 and are subtyped as Resting, Activated and Effector Tregs by surface expression of CD45RA, HLA-DR and CD39 that represent markers of differentiation status, inhibitory and recall potential. Hence, in this study, circulating Tregs were characterized in pediatric patients suffering from allergic rhinitis (AR) treated by SLIT and to verify the possible correlation between some Treg subsets with successful SLIT. Methods. Twenty children suffering from mite AR and/or asthma were enrolled. AR severity was assessed by evaluating ACT and ARIA scores at baseline and after 12-months of mite-SLIT. Treg analysis of PBMC pre- and post-SLIT, was based on cytofluorimetric determination of total Tregs, as CD4+CD25highCD39+CD127low/neg, further characterized for CD45RA, HLA-DR and CD39 expression. Results. After SLIT, Resting Tregs were significantly reduced whilst Activated/Effector Tregs CD45RAneg (memory Tregs) resulted increased; moreover, CD39 and HLA-DR expression on Tregs was significantly increased. Notably, the intensity of HLA-DR expression on Tregs positively correlated with the improvement of the clinical scores. Conclusions. Our findings suggest that effective SLIT is associated with re-patterning of the differentiation status of Tregs, particularly with the generation of allergen-specific memory effector Tregs.