Objectives: Correct use of inhaler devices is critical in ensuring the optimal lung bioavailability of the inhaled drug. The study aimed to assess inhaler technique used in patients with using metered-dose inhalers (MDI) by correlating with urinary salbutamol excretion post inhalation and its correlation with disease control. Methods: Thirty patients with obstructive pulmonary diseases attending outpatients’ services inhaled two doses of salbutamol 100 µg and urine samples were collected after 30 min. Inhaler technique scores were assessed using a standardized 8-point checklist. The 30-minute concentration of urinary salbutamol is then correlated with inhaler technique scores and control status of the disease. Key findings: The mean age of the subjects was 60.8 (SD ± 9.338). The mean (SD) 30 min urinary salbutamol concentration was 3.6±1.6 µg/ml. The mean concentration of salbutamol was found to be 2.3 µg/ml (n=1), 2.3 µg/ml (n=5), 3.1 µg/ml (n=7), 3.9 µg/ml (n=8), 4.7 µg/ml (n=5), 5.3 µg/ml (n=3), and 5.0 µg/ml (n=1) among patients performing 1, 2, 3, 4, 5, 6, 7, 8 steps correctly, respectively. There was a statistically significant correlation (p=0.028) witnessed between the mean 30 min urinary salbutamol concentration and total correct steps. The frequency of exacerbation, use of antibiotics, and oral corticosteroids (OCS) were more in patients with poor inhaler technique scores, although statistical significance was achieved only for frequency of antibiotics use (p=0.032). Conclusions: The 30 min salbutamol urinary concentration evaluation may help to identify patients who were underdosed due to poor handling of inhaler devices. Being a complex procedure, it can at least be initiated in patients reporting frequent exacerbations, hospitalization, and those who need multiple drugs for disease control.

Elucidation of signalling events in a pathogen is potentially important to tackle the infection caused by it. Such events mediated by protein phosphorylation play important roles in infection and therefore to predict the phosphosites and substrates of the serine/threonine protein kinases, we have developed a Machine learning based approach and predicted the phosphosites for Mycobacterium tuberculosis serine/threonine protein kinases using kinase-peptide structure-sequence data. This approach utilizes features derived from kinase 3D-structure environment and known phosphosite sequences to generate Support Vector Machine based kinase specific predictions of phosphosites making it suitable for prediction of phosphosites of STPKs with no or scarce data of their phosphosites. Support vector machine outperformed the four machine learning algorithms we tried (random forest, logistic regression, support vector machine and k-nearest neighbours) with aucROC value of 0.88 on the independent testing dataset and a ten-fold cross validation accuracy of ~81.6% for the final model. Our predicted phosphosites of M. tuberculosis STPKs form an useful resource for experimental biologists enabling elucidation of STPK mediated post-translational regulation of important cellular processes. The training features file and model files, together with usage instructions file, are available at: https://github.com/vipulbiocoder/Mtb-KSPP

In order to further elucidate the role of mesolimbic peptides in the expression of alcohol reward, the present study investigated the effects of ghrelin and glucagon-like peptide-1 (GLP-1) on alcohol intake, in addition to alcohol intake stimulated by systemic d-amphetamine or cocaine treatment. All rats were initially habituated to a 6% alcohol solution. We then demonstrated that intraperitoneal injections of d-amphetamine and cocaine increased alcohol compared to the vehicle condition. In subsequent testing we examined the effects of ventral tegmental area (VTA) ghrelin or vehicle paired with a fixed dose of d-amphetamine or vehicle. In separate rats we then investigated the impact of the GLP-1 agonist exendin-4 (Ex-4), injected into the VTA, on alcohol intake alone, or when Ex-4 was co-administered with d-amphetamine or cocaine. Our results indicated that VTA ghrelin significantly increased alcohol intake, and most importantly, potentiated the effect of d-amphetamine and cocaine on alcohol consumption. Conversely, VTA Ex-4 inhibited alcohol intake and antagonized the stimulatory effect of d-amphetamine and cocaine on alcohol consumption. In a final study we further demonstrated that VTA Ex-4 treatment significantly inhibited the combined stimulatory effects of ghrelin paired with d-amphetamine or ghrelin paired with cocaine. Overall our findings are consistent with a critical role for both ghrelin and GLP-1 receptor mechanisms in mesolimbic alcohol reward circuitry. Moreover, our results further suggest that ghrelin and GLP-1 modulate the stimulatory effect of psychostimulants on alcohol intake.

Chemotherapeutic drugs have been widely used in the treatment of cancer disease for about 70 years and, even with the development of new therapies, they are still prescribed by oncologists, alone or in combination with other antineoplastic agents. All chemotherapies are able to provoke hypersensitivity reactions, even with different incidences, depending on the different class of these drugs, and these reactions are the third leading cause of fatal drug-induced anaphylaxis in the United States. In Europe deaths related to chemotherapy have also been reported. In particular, most reactions are provoked by platinum compounds, taxanes, epipodophyllotoxins and asparaginase. However, currently there are different points of view about the best procedures for the diagnosis, treatment and prevention of these reactions. Thus, the European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology organized a task force to provide data and recommendations regarding the allergological work up in this field of drug hypersensitivity reactions. The aims of this position paper were to provide consensus on the investigation of HSRs to chemotherapeutic drugs and to give practical suggestions for clinicians that treat these patients, such as oncologists, allergologists and internists. Key sections cover: risk factors, pathogenesis, symptoms, role of skin tests, in vitro tests, indications and contraindications of drug provocation tests and desensitization of neoplastic patients with allergic reactions to chemotherapeutic drugs. Statements, recommendations and unmet needs were discussed and proposed at the end of each section.

Aim: To investigate the correlation between the clinical characteristics of myalgia-arthralgia, disease anxiety, and blood parameters in COVID-19. Methods: Patients diagnosed with COVID-19 via computed tomography and polymerase chain reaction were included. Disease-related anxiety was evaluated using the Impact of Event Scale-Revised (IES-R). Pain character were evaluated using the Pain Quality Assessment Scale. Laboratory parameters were checked for all patients. The correlation between clinical and laboratory parameters was examined. Results: The sample consisted of 70 (42.9%) females and 93 (57.1%) males. The prevalence of muscle-joint pain was 63.2% (n=103). The most common pains were back pain (n=52, 50.5%). The pain was mostly temporary, intense, and dull. It spread locally to sensitive surrounding areas. Patients with muscle-joint pain were found to have a higher prevalence and severity of disease anxiety (p <0.05). Those with high muscle-joint pain and disease anxiety had high CK and low lymphocyte (p <0.05). Conclusion: Muscle-joint pains are highly frequent in COVID-19 disease. Pain is most commonly in the back. This pain spreads locally to sensitive surrounding tissues. Pain severity and frequency are higher in those with higher disease anxiety. Muscle pain is particularly associated with low lymphocyte and high CK. What’s known • It is known that myalgia and fatigue are most common complaints in COVID-19. • However, the characters of these symptoms has not been systematically evaluated. • In addition to this, there is no sufficient data evaluating its relationship with laboratory findings and emotional state What’s new • Arthralgia and myalgia are very common and spreads locally to sensitive surrounding tissues, particularly in the back. • Severity and frequency of pain are higher in patients with more disease anxiety. • Muscle pain is associated with low levels of lymphocytes and high levels of creatine kinase.

Objectives This article focuses on massive epistaxis and pseudoaneurysm in patients with NPC after radiotherapy and discusses clinically relevant treatment strategies. Design Retrospective the medical data of NPC patients with massive epistaxis after radiotherapy and review the English literature over the past 10 years. Setting Otorhinolaryngology department in the First Affiliated Hospital of Nanchang University. Participants 21 patients with massive epistaxis after radiotherapy for NPC. Main outcome measures Characteristics and related causes of massive epistaxis or pseudoaneurysms were analyzed in terms of the clinical stage of NPC, course of radiotherapy, and affected artery. An analysis was performed on the methods of endovascular interventional treatment of such pseudoaneurysms. Results 19 cases were accompanied with bone destruction of the skull base; 13 cases were found tumor recurrence; 15 cases were in stage III or IV of NPC; 14 cases were combined with pseudoaneurysms. Analysis with the imaging of pseudoaneurysms, we found that the petrous ICA was the most predilection site. There were 11 out of 14 pseudoaneurysms had sentinel hemorrhage in the initial phase. All 14 pseudoaneurysm patients were underwent endovascular interventional therapy, but one died from hemorrhagic shock during the procedure. There were no rebleeding again among other patients. Conclusions Pseudoaneurysm could cause massive epistaxis with high mortality. The formation of a pseudoaneurysm was closely associated with a high carcinoma stage, re-radiotherapy, and local bone destruction and infection. Most cases had sentinel epistaxis. The imaging material prompted that pseudoaneurysm had a predisposition to the petrous part of the ICA, while the preferred therapy was endovascular embolization treatment. Key poits 1.Patients with massive epistaxis mean a single nasal bleeding volume exceeded 100 ml, or cumulative bleeding volume was more than 300 ml. 2.Patients who presented with active oronasal bleeding should be rapidly managed by nasal packing. 3.When there is hemorrhagic shock, patients should undergo endotracheal intubation and blood transfusion before being transferred to the otorhinolaryngology department. 4.CTA and DSA are recommended for patients with massive epistaxis associated with NPC after radiotherapy. 5.Interventional embolization is recommended to patients with pseudoaneurysm.

Background and Purpose: Dexamethasone is widely used in preterm labor and related diseases. However, prenatal dexamethasone exposure (PDE) can cause multi-organ developmental toxicities in offspring. Our previous study found the occurrence of fetal-originated diseases were associated with adrenal developmental programming alteration in offspring. Here, we investigated the effects of PDE on the adrenal function in offspring and its intrauterine programming mechanism. Experimental Approach: A rat model of PDE was established to observe the alteration of adrenal steroidogenesis in offspring. Further, we confirmed the gender difference of adrenal steroidogenesis and its molecular mechanism combined with in vivo and in vitro experiment. Key Results: PDE caused a decrease in adrenal steroidogenic function in fetal rats, but decreased in males and increased in females after birth. Meanwhile, the adrenal H3K14ac level and expression of 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) in PDE offspring were decreased in males and increased in females, suggesting 11β-HSD2 might mediate gender difference of adrenal function. We further confirmed dexamethasone inhibited the H3K14ac level and expression of 11β-HSD2 through GR/SP1/p300 pathway. After bilateral testectomy or ovariectomy in adult PDE offspring rats, adrenal 11β-HSD2 expression and steroidogenic function were both reduced. Using rat primary fetal adrenal cells, the differential expression in AR and ERβ were proved to involve in regulating the gender difference of 11β-HSD2 expression. Conclusion and Implications: This study demonstrated the gender difference in adrenal steroidogenic function of PDE offspring after birth, and elucidates a sex hormone receptor-dependent epigenetically regulating mechanism for adrenal 11β-HSD2 programming alteration.

Anthropogenic changes affect biological communities of host and vectors driving arbovirus activity. In general, urban and agricultural ecosystems harbor less avian and mosquito diversity than native ecosystems and are dominated by few species. Human activities have led to the emergence / re-emergence of different infectious pathogens particularly arboviruses representing a threat to both public health and biodiversity. Saint Louis encephalitis (SLEV) and West Nile viruses (WNV) are transmitted by Culex spp. mosquitoes as main vectors and several bird species as hosts. With the aim to study the exposure of free-ranging bird communities to SLEV and WNV in Pampean agroecosystems as well as to evaluate the environmental/ biological factors potentially associated we collected and bleed free ranging birds in 12 sites. Serum samples were analyzed by Plaque Reduction Neutralization Test (PRNT) for both viruses. Generalized Linear Mixed Models (GLMM) were performed to analyze the association between environmental / biological variables from each sampled site and avian exposition. A total of 1019 birds were sampled during 2017 - 2019. Overall, we found SLEV NTAb in 60 out of 1019 samples (5.8%) while WNV seroprevalence was 2.1% (21/1019). SLEV and WNV seroprevalence were different among the sampled sites. Agricultural area was positively associated with the SLEV-WNV infection risk for an avian host. Forested area also had a strong association but in a negative way. Our results suggest that open agricultural area increase the infection risk of free ranging birds to SLEV and WNV while forested area diminishes the infection risk maybe through a dilution effect of vector and host communities.

Objective To compare the pre-operative use of GnRH analogue and/or intra-operative use of tourniquets to determine which intervention best reduces the intraoperative blood loss at open myomectomy. Design Randomised controlled trial, partially blinded (clinician and participant) Setting Single tertiary centre Population Women requiring open myomectomy in our gynaecology outpatient clinic Methods Patients were allocated to receive either pre-operative GnRHa, intra-operative mechanical tourniquet or a combination of preoperative GnRHa and intra-operative mechanical tourniquet. Main Outcome Measure Mean intraoperative blood loss Results There was a difference in mean intra-operative blood loss of groups GnRHa (n=14) versus Tourniquet (n=12) (752ml, 95% CI 148ml-1355ml, p=0.01) and groups GnRHa versus GnRHa+ Tourniquet (n=17) (804ml, 95% CI 250ml-1357ml, p=0.002). No significant difference in intra-operative blood loss between groups Tourniquet and GnRHa+ Tourniquet (52ml, 95% CI -630ml-526ml, p=1) were detected. A sub-analysis showed that there is no statistical significance (p=0.45) between mean blood loss at surgery and uterine size across the groups. Conclusions The use of a mechanical tourniquet with or without pre-operative gonadotrophin releasing hormone analogues is significantly more effective at reducing intraoperative blood loss at open myomectomy than the use of pre-operative gonadotrophin releasing hormone analogues alone Tweetable Abstract Mechanical tourniquet with or without GnRHa significantly reduces intraoperative blood loss at open myomectomy EudraCT Number 2010-019810-26

This study investigated the behavior of lipid mixtures of beeswax with avocado oil or Brazil nut oil in supercritical CO2 processing. It entailed the measurements of melting temperature (Tm), solidification temperature (Ts), volumetric expansion (Ve), solubility of supercritical CO2, and solubility of the lipid mixtures in supercritical CO2 at fixed pressures. The Tm and Ts of lipid mixtures decreased progressively to a lower level (closer to 150 bar) that were then increased with increasing pressure. The volumetric expansion, solubility of supercritical CO2, and solubility of the lipid mixtures in supercritical CO2 increased as pressure increased. On the basis of the results, particle formation using these lipid mixtures as carrier materials could be feasible with supercritical CO2 at a temperature of 60 °C and pressures from 150 to 300 bar. The moderate temperature of the process could allow its application with thermally labile bioactive compounds.

Objective • Prioritising normal birth has led to harm in some instances in the UK • Australian organisations have also promoted normal birth in maternity practice • The negative impact of normal birth appears less well understood in Australia • The study explores this impact of normal birth promotion and the quality of clinical incident investigations Design • Survey-based research design Setting • Online survey Population or Sample • Australian maternity health care providers Methods • Open and close-ended questions on the survey • The survey received 1278 responses • Data analysed using SPSS software Main Outcome Measures • Perceptions on bias against or delay in interventions • Perceptions on systemic attempts to reduce caesarean rates • Perceptions on clinical incident investigations and the engagement of women in these processes Results • Promoting normal birth may by introduce bias against or delay interventions • Attempts to reduce caesarean section rates may reduce the agency of the woman to choose how she births • Incident investigations appear to be independent and improve outcomes for mothers and babies • Women with birth trauma appear to lack support and follow up postnatally Conclusions • Current regulatory standards for maternity services may need to be re-evaluated • Key performance indicators for maternity services need to change to reflect core ethical and legal obligations around informed consent

T regulatory cells from people with asthma show a Th2-like phenotypeKirstin Jansen1, Oliver F. Wirz1, Willem van de Veen1,2, Ge Tan1,3, Milena Sokolowska1, Simon D. Message4, Tatiana Kebadze4, Nicholas Glanville4, Patrick Mallia4, Cezmi A. Akdis1,2, Sebastian L. Johnston4, Kari Nadeau5 and Mübeccel Akdis1*1 Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.2 Christine Kühne – Center for Allergy Research and Education (CK-CARE), Davos, Switzerland.3 Functional Genomics Center Zürich, ETH Zürich/University of Zürich, Zürich, Switzerland.4 National Heart and Lung Institute, Imperial College London, United Kingdom.5 Sean N. Parker Center for Allergy and Asthma Research, Department of Medicine, Stanford University, Palo Alto, CA, USA.* Corresponding author:Mübeccel Akdis, MD, PhD.Swiss Institute of Allergy and Asthma Research (SIAF)Herman-Burchard-Strasse 9CH-7265 Davos-Wolfgang, SwitzerlandE-mail: akdism@siaf.uzh.chTel.: +41 81 410 08 48Declaration of fundingM. Akdis has received research support from the Swiss National Science Foundation No. 320030-159870/310030-179428 and PREDICTA (No: 260895) and the Sean N Parker Center for Allergy and Asthma Research at Stanford University. C.A. Akdis is employed by the Swiss Institute of Allergy and Asthma Research, University of Zurich; the Swiss National Science Foundation No. 310030-156823, and the Christine Kühne – Center for Allergy Research and Education (CK-CARE). M. Sokolowska received research grant from the Swiss National Science Foundation No. 310030_189334/1 and from the GSK. The experimental infection study was supported by a Medical Research Council Clinical Research Fellowship (to S.D.M.), a British Medical Association H.C. Roscoe Fellowship (to S.D.M.), British Lung Foundation/Severin Wunderman Family Foundation Lung Research Program Grant P00/2, Asthma UK Grants 02/027 and 05/067, Welcome Trust Grants 063717 and 083567/Z/07/Z for the Centre for Respiratory Infection, Imperial College, and the National Institute for Health Research (NIHR) Biomedical Research Center funding scheme. S. L. Johnston is the Asthma UK Clinical Professor (grant CH11SJ), is an NIHR Emeritus Senior Investigator and was supported by MRC Centre Grant G1000758, Asthma UK Centre Grant AUK-BC-2015-01 and European Research Council Advanced Grant 788575. K.C. Nadeau is supported by NIH grant U19 AI104209 (Asthma and Allergic Diseases Cooperative Research Center), U01 AI140498 and R01 AI140134 and the Naddisy Foundation.To the editor,Asthma is the most common chronic inflammatory disease of the lung, characterised by wheezing, shortness of breath and variable airflow obstruction. It is a heterogeneous disease that can be classified into different endotypes of which T2-high - allergic asthma is one of the most common forms, especially in children. Allergic asthma is characterised by increased IgE and type-2 cytokines, including IL-5, IL-4 and IL-131.Thus far, it is not completely understood why these type-2 responses are poorly controlled in asthma. T regulatory cells (Treg cells) are key mediators in controlling type 2 responses. However, under certain conditions, Treg cells can display a pathogenic and proinflammatory phenotype and contribute to disease pathogenesis2. Treg cells of food allergic children showed a T helper 2 (Th2)-like phenotype. Whether this Th2-like phenotype of Treg cells is also present in asthmatic individuals is unknown.Therefore, in this exploratory study, we compared the gene-expression profile of Tregs from people with stable allergic-asthma to non-allergic controls without asthma. We isolated PBMCs from 5 people with asthma and 4 controls (Table S1) and sorted Treg cells with flow cytometry (CD3+CD4+D25hiCD127low). Then, we isolated RNA from the sorted Treg cells and performed RNA-seq (See Supplemental information for detailed methods). In total, 369 genes were differentially expressed between Treg cells from asthmatic individuals and controls (P<0.01) (Supplemental Figure 1). We clustered the genes into different groups: Treg cell markers, cytokine receptors, virus related, transcription factors, cytokines and others (Figure 1A). Interestingly, we found that the expression of FOXP3was reduced in Treg cells from asthmatic individuals (Figure 1B). This is in line with a previous study that observed a lower expression ofFOXP3 in Treg cells from individuals with asthma3. Interestingly FOXP3 expression inversely correlated with the IgE levels found in the serum (Figure 2A), supporting the finding that Treg cells can suppress IgE production4.In addition, we found a significant upregulation of IL13 mRNA expression and a trend to increased expression of IL4 andIL5 mRNAs in Tregs in asthma, indicating a Th2-like phenotype as was reported in Tregs from children with food allergies2. Furthermore, we found an upregulation of the prostaglandin D2 receptor (PTGDR2 ) or CRTH2, in line with a previous study that reported an increased amount of CRTH2+ Tregs in asthma5.Interestingly, several cytokine receptors were differentially expressed between Tregs from asthmatic individuals compared to controls. The IL-4 receptor alpha transcript IL4RA was significantly reduced in asthma. The expression of IL4RA also strongly correlated with the levels of IgE in the serum (Figure 2A). Previously, it was shown in mice that IL-4 receptor signalling is essential in controlling Th2 responses and airway inflammation6. Our data suggest a similar role of IL4RA in humans. Likewise, we observed a downregulation of TNF receptor superfamily member 25 (TNFRSF25 ), which was shown to contribute to preventing allergic lung inflammation7 and downregulation of OX40 (TNFRSF4 ).Additionally, we observed a difference in virus/type-I interferon(IFN)-related genes in asthma, which was also observed in single-cell transcriptomic data of allergen-specific Tregs from individuals with asthma8. Curiously, the expression of the type 1 IFN receptors IFNAR1/2 were lower expressed in asthma, which could indicate a deficiency against respiratory viruses and chronicity.Lastly, we performed an enrichment analysis to see up or downregulation of pathway maps, process networks and go processes with MetaCore (Table 1). The pathway maps and process networks included upregulation of pathways related to immune functions already described. However, the affected GO processes were mostly related to epigenetic mechanisms including nucleosome organisation, nucleosome assembly and chromatin organisation. With the tool STRING, we performed a pathway analysis that showed a cluster of histone genes (Figure 2B). So far, there is no data reporting the function of histone genes in Tregs or related to asthma, but perhaps this finding could be related to changes in epigenetics. It was reported that in asthma Tregs have increased CpG methylation of theFOPX3 locus compared to individuals without asathma3.In conclusion, Tregs from individuals with asthma show reduced expression of several molecules related to Treg suppressive functionality, while having increased expression of Th2-like characteristics that could lead to their reduced control of allergic airway inflammation. Further studies are needed to confirm these findings in a larger population and investigate their contribution to disease pathology.References1. Kuruvilla, M. E., Lee, F. E. H. & Lee, G. B. Understanding Asthma Phenotypes, Endotypes, and Mechanisms of Disease. Clinical Reviews in Allergy and Immunology (2019). doi:10.1007/s12016-018-8712-12. Noval Rivas, M. & Chatila, T. A. Regulatory T cells in allergic diseases. Journal of Allergy and Clinical Immunology138 , 639–652 (2016).3. Runyon, R. S. et al. Asthma Discordance in Twins Is Linked to Epigenetic Modifications of T Cells. PLoS One (2012). doi:10.1371/journal.pone.00487964. Meiler, F., Klunker, S., Zimmermann, M., Akdis, C. A. & Akdis, M. Distinct regulation of IgE, IgG4 and IgA by T regulatory cells and toll-like receptors. Allergy Eur. J. Allergy Clin. Immunol.(2008). doi:10.1111/j.1398-9995.2008.01774.x5. Boonpiyathad, T. et al. Impact of high-altitude therapy on type-2 immune responses in asthma patients. Allergy Eur. J. Allergy Clin. Immunol. 75 , 84–94 (2020).6. Khumalo, J., Kirstein, F., Hadebe, S. & Brombacher, F. IL-4Rα signaling in CD4+CD25+FoxP3+ T regulatory cells restrains airway inflammation via limiting local tissue IL-33. JCI Insight (2020). doi:10.1172/jci.insight.1362067. Schreiber, T. H. et al. Therapeutic Treg expansion in mice by TNFRSF25 prevents allergic lung inflammation. J. Clin. Invest.(2010). doi:10.1172/JCI429338. Seumois, G. et al. Single-cell transcriptomic analysis of allergen-specific T cells in allergy and asthma. Sci. Immunol.(2020). doi:10.1126/SCIIMMUNOL.ABA60879. Message, S. D. et al. Rhinovirus-induced lower respiratory illness is increased in asthma and related to virus load and Th1/2 cytokine and IL-10 production. Proc Natl Acad Sci U S A105 , 13562–13567 (2008).10. Dobin, A. et al. STAR: Ultrafast universal RNA-seq aligner.Bioinformatics 29 , 15–21 (2013).11. Liao, Y., Smyth, G. K. & Shi, W. The Subread aligner: Fast, accurate and scalable read mapping by seed-and-vote. Nucleic Acids Res. 41 , e108 (2013).12. Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: A Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26 , 139–140 (2009).13. Szklarczyk, D. et al. The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res 45 , D362-d368 (2017).Figure 1: Tregs from asthmatic individuals show a distinct phenotype compared to controls. (A) Genes that are significantly changed in Tregs cells from asthmatic individuals compared to controls (log 2 ratio)– clustered in the groups: Treg markers, cytokine receptors, virus related, transcription factors, cytokines and others. (B) Fragments per kilo base per million mapped reads (FPKM) values of genes of interest (FOXP3, IL13, IL5, IL4, IL4R, PTGDR2, TNFRSF25, TNFRSF4, IFNAR1, IFNAR2) of all donors. N = 4 (healthy), 5 (asthma). *** p<0.001 , ** p<0.01, * p<0.05Figure 2: Phenotype of Tregs might be associated to Treg function . (A) Correlation between expression of FOXP3 (left) and IL4RA (right) with IgE serum levels. (B) Satellite plot showing a cluster of known interactions related to nucleosome assembly. Genes higher expressed in asthmatic individuals are shown in red, and lower expression in blue.

Aims: The role of urodynamic studies in the diagnosis and prognosis of interstitial cystitis/bladder pain syndrome (IC/BPS) remains controversial. We evaluated the correlation of baseline voiding dysfunctions with long-term treatment outcome in a large cohort of patients with IC/BPS. Methods: We studied 211 patients with nonulcerative IC/BPS. All patients underwent video urodynamic examination at baseline to identify their voiding conditions and they received subsequent treatments. The primary endpoint was the global response assessment (GRA) at the current interview. Secondary endpoints included O’Leary-Sant score (OSS), Visual Analog Scale (VAS) for pain, and the rate of IC symptom flare-up. Results: Mean patient age was 56.8 ± 12.8 years and mean IC symptom duration was 16.0 ± 9.9 years. At baseline, 83 (39.3%) patients had a voiding problem and 62.7% had one to three comorbidities. The duration, comorbidity, treatments, changes in OSS and VAS, maximum bladder capacity (MBC), glomerulations, GRA, and flare-up rate were not significantly different among the different voiding subtypes. When we divided the patients by their voiding conditions of normal (n = 32) and hypersensitive bladder with (n = 76) and without (n = 103) voiding dysfunctions, only MBC (P = 0.002) and glomerulation (P = 0.021) demonstrated a significant difference. When we analyzed subgroups by GRA, patients with a GRA ≥ 2 had a significantly shorter disease duration. There also were significant associations between GRA and the changes in OSS and VAS (P < 0.001). Conclusions: Voiding dysfunctions in patients with non-Hunner IC/BPS do not affect long-term treatment outcome.

Background: Currently there is no clear consensus on the use, value, benefits, and impact of serology testing as part of a comprehensive SARS-CoV-2 testing strategy. The lack of clarity on the use of this strategy in policies and guidelines may have serious implications on the efforts to curb the pandemic. The aim of this paper is to elaborate an experts and community consensus on the use of serology testing as an effective method to respond to and mitigate the impact of the pandemic. The recommendations herein can help build community awareness and guide advocacy strategies.Methods: A desk review was conducted to inform a working document that was subject to a multistage process of validation and feedback by a group of renowned experts. The multi-stakeholder group of experts, representing the European and international levels, convened to inform and validate the recommendations.Results: The consensus offered eight policy recommendations organized in two main themes. The first group of recommendations provides guidance on the role and value of serology testing to contain and understand the COVID-19 pandemic. The second group targets health system strengthening aspects necessary to support the appropriate delivery of serology testing.Conclusions: Recommendations seek to indicate how SARS-CoV-2 serology testing may positively impact national health systems, country economies and local communities. The pertinence of the recommendations is to communities in Europe, and beyond, and relevant to multiple stakeholders. Given the rapidly changing scenario, this set of recommendations should be considered a live document.

Maintenance of a desirable mixture of shrubs and grasses is a key issue in sustainable grazing management. The aim of this study was to explore the effect of long-term sheep grazing on desert steppe shrubs. Based on a long-term controlled sheep stocking rate experiment in a desert steppe of north China, combined with long-term random sampling monitoring of above-ground vegetation standing crop (14 years) and short-term systematic sampling monitoring of vegetation cover and individual characteristics of shrubs (3 years), we analyzed plant community changes, the current situation of shrubs and the response of individual shrub characteristics to stocking rate. We found that low stocking rates have increased the cumulative above-ground standing crop of shrubs and herbaceous plants, but the cumulative above-ground standing crop of shrubs under high grazing rates tends to be flat. The cover and height of four shrub species generally showed a decrease with increasing stocking rate, while the response of the four shrubs to the stocking rate gradient varied. Among four shrub species, Artemisia frigida was the most sensitive to stocking rate, followed by Ceratoides latens and Caragana microphylla, while Kochia prostrata was relatively insensitive to stocking rate. These results suggest that grassland managers can use an appropriate stocking rate to maintain desirable plant community composition and configuration in the temperate grassland.

Introduction Inter-professional education (IPE) is becoming an integral part of many professional programmes throughout the UK, ensuring health professionals are competent to work as part of an inter-professional team upon entry into their profession. IPE has become a fundamental component of curriculum content in health and social care degrees. Aims Research aim - to evaluate a simulated IPE intervention. Methods A one day IPE intervention, ‘Evening On-Call’ was run involving nursing and medical students and pre-registration pharmacists (student pharmacists in year 5 of training) in an on-call setting. This IPE incorporated manikin and actor patients in a simulated ward. During the intervention, the 3 groups of students are assessed under observation on their clinical, prioritisation and communication skills. Participants perceptions of this intervention were evaluated by completion of a questionnaire to capture their perceptions regarding the experience, the pre-IPL briefing and post-IPL feedback and perceived relevance of this training. Free text sections collected additional comments and a follow-up questionnaire was sent six months later. Results Initial questionnaire feedback was predominantly positive for each professional group. The majority perceived the simulated IPL had given them a greater understanding of other professionals’ roles, had enhanced their professional confidence and would help them prioritise workload once qualified. The 6 months follow up questionnaire supported the initial questionnaire findings. Some responses highlighted participants believed the simulated IPL had helped them work more effectively with other healthcare professionals, communicate more effectively and better prioritise their workload. There may be some evidence of sustained self-reported effectiveness in teaching certain professional and clinical skills to participants using this type of simulated intervention.

Background: An emerging body of evidence has highlighted the protective role of spirulina in human health. Thus, we conducted a randomized controlled trial to discern the effects of spirulina supplementation on anthropometric indices, blood pressure, sleep quality, mood, fatigue status, and quality of life among ulcerative colitis patients. Methods: Eighty participants with ulcerative colitis were randomly allocated to receive, either, 1 g/day (two 500 mg capsules) spirulina (n=40) or placebo (n=40), in a clinical trial for eight weeks. Dietary intake, physical activity, sleep quality, mental health, fatigue status, and quality, were assessed for each participant at baseline and trial cessation. Anthropometric indices and blood pressure were also assessed. Results: Seventy-three participants completed the intervention. Our results revealed that spirulina supplementation significantly reduced sleep disturbances (p=0.03), while no significant changes occurred in the sleep quality score or other sleep parameters, vs. the placebo group (p> 0.05). Furthermore, a significant reduction in stress score (p=0.04) and increase in quality of life (p=0.03) was detected, but not anxiety, depression, or fatigue scores (p> 0.05). Additionally, anthropometric indices and blood pressure did not significantly change (p> 0.05). Conclusion: An improved quality of life was observed among ulcerative colitis patients following spirulina supplementation, which could be attributed to improved sleep disturbance and stress status. Further clinical studies, with longer duration interventions and suitably powered sample sizes, are necessary to p elucidate the veracity of our findings.

Because of their selectivity, biologicals are crucial therapeutic agents in oncological, immunological, and inflammatory diseases and their use in clinical practice is broadening. Biologicals are among the most common drugs that can cause hypersensitivity reactions (HSRs), and this is primarily attributed to an explosion in new treatment options that has developed through personalized and precision medicine. Patients can develop HSRs to these agents during the first lifetime exposure or after repeated exposure. Despite its relatively high prevalence, the underlying mechanisms and optimal management of HSRs to biologicals remain incompletely explained. In this position paper, the authors provided evidence-based recommendations for the diagnosis and management of HSRs to biologicals. Additionally, the document defines unmet needs, which should be topics of future studies.

A document by Lara Lemon. Click on the document to view its contents.

Adaptations to anthropogenic domestic habitats contribute to the success of mosquito Aedes aegypti as a major global vector of several arboviral diseases. The species inhabited African forests before expanding into domestic habitats and spreading to the rest of the world. Despite a well-studied evolutionary history, how this species initially moved into human settlements in Africa remains unclear. During this initial habitat transition, Ae. aegypti switched from using natural containers like tree holes as larval breeding sites to using artificial containers like clay pots. Little is known about how these natural versus artificial containers differ in their environments, or whether Ae. aegypti in forest versus domestic habitats evolved any corresponding incipient behavioral divergence, such as in oviposition. To address these gaps, we first characterized physical characteristics, larval density, microbial density, bacterial composition, and volatile profiles of natural versus artificial containers used as mosquito larval breeding sites. We focused on two localities in Africa, La Lopé, Gabon and Rabai, Kenya. In both localities, our data showed that the two habitat-specific container types had significantly different characteristics. We then examined whether such containers differed in their attractiveness for oviposition, a key behavior affecting larval distribution. Forest Ae. aegypti readily accepted artificial containers in our field experiments, and laboratory choice experiments did not find distinct oviposition preference between forest and village Ae. aegypti colonies. These results suggested that African Ae. aegypti were likely generalists in their oviposition site choice. This flexibility to accept different containers might play a vital role during the initial domestication of Ae. aegypti, allowing the mosquitoes to use human-stored water as fallback breeding sites during dry seasons. Although ovipositional changes were not present initially, after longer domestic habitat breeding, the mosquitoes did evolve divergence oviposition preference, as suggested by previous comparisons of African Ae. aegypti and human-specialized non-African Ae. aegypti.

Background Dental caries can be affected or altered by the body’s oxidant / antioxidant balance and oxidative stress. Aim/Hypothesis To examine the relationship between dental caries and Total Oxidant Status (TOS), Total Antioxidant Status (TAS), and Oxidative Stress Index (OSI). Design The study group consisted of 52 children with dental caries (DMFS/dfs ≥ 5), and the control group consisted of 42 healthy children (DMFS/dfs = 0). The saliva samples, unstimulated and mid-morning, were collected from all children. Participants’ saliva samples were acquired by spitting for 5 minutes, after which the samples were frozen and stored at 4 ° C and kept at -80 ° C until analysis. NCSS (Number Cruncher Statistical System) 2007 (Kaysville, Utah, USA) was used for the statistical analysis. Results TOS of the patient group cases were statistically significantly higher than those of the control group (p=0,004; p<0,01). OSI values of the patient group cases were statistically significantly higher than those of the control group (p=0,008; p<0,01). Conclusion OSI and TOS as markers of oxidative stress levels were found to be significantly higher in the group of patients with dental caries than in the healthy group.

Abstract Introduction The COVID-19 pandemic has resulted in a significant burden on healthcare systems causing disruption to medical and surgical training of doctors globally. Aims and objectives This is the first international survey assessing the perceived impact of the COVID-19 pandemic on training of doctors of all grades and specialties. Methods An online global survey was disseminated using Survey Monkey® between 4th August 2020 and 17th November 2020. A global network of collaborators facilitated participant recruitment. Data was collated anonymously with informed consent and analysed using univariate and adjusted multivariable analysis. Results 743 doctors of median age 27 (IQR: 25-30) were included with the majority (56.8%, n=422) being male. Two-thirds of doctors were in a training post (66.5%, n=494), 52.9% (n=393) in a surgical specialty and 53.0% (n= 394) in low- and middle-income countries. 69.2% (n=514) reported an overall perceived negative impact of the COVID-19 pandemic on their training. A significant decline was noted among non-virtual teaching methods such as face-to-face lectures, tutorials, ward-based teaching, theatre sessions, conferences, simulation sessions and morbidity and mortality meetings (p≤0.05). Doctors from low or middle-income countries were associated with perceived inadequate supervision while performing invasive procedures under general, local or regional anaesthetic. (p≤0.05) Conclusion In addition to the detrimental impact of the COVID-19 pandemic on healthcare infrastructure, there has been an indirect consequence of disrupted training within medical and surgical subspecialties. A focus on reconfiguration of training programs through a variety of additional resources will become imperative to reduce the long-term sequalae of COVID-19 on doctors’ training.

Aims: Metabolic Syndrome has become the greatest health hazard in the modern world, along with infectious diseases. We aimed to evaluate the effects of metabolic syndrome on disease course, laboratory values and mortality in patients with COVID 19 pneumonia. Methods: COVID 19 pneumonia patients with and without metabolic syndrome were compared in terms of laboratory parameters, clinical results and mortality rates retrospectively. Results: A total of 194 patients hospitalized with COVID 19 pneumonia (with and without metabolic syndrome n = 93 and 101, respectively) were included in the study. Patients with metabolic syndrome had lower oxygen saturation at the time of admission (88.76 vs 93.66 p <0.0001), higher neutrophil (5.85 vs 4.81 p = 0.02) and CRP levels (88.36 vs 62.93 p = 0.009) and COVID 19 involvement was more common in lung tomography (12.3 vs 7.7 p <0.0001). Total length of stay (12.3 vs 6.5 days p <0.0001) and clinical length of stay (7.8 vs 5.9 days p = 0.003) were longer in patients with metabolic syndrome. Requirement of intensive care (45.2% vs 4.9% p <0.0001) and mortality rates (24.7% vs 0.9% p <0.0001) were higher in patients with metabolic syndrome. Presence of metabolic syndrome (OR 32.86, 95% CI 4.34 to 249 p<0.05) were significantly associated with increased mortality. Discussion and conclusion: Our results demonstrated that patients with metabolic syndrome that were hospitalized with COVID 19 pneumonia had significantly higher mortality and intensive care requirement. They have lower oxygen saturations, higher CRP levels and more widespread radiological involvement. Keywords: Covid 19 - Metabolic syndrome – Pneumonia - Mortality

Immunopreventable diseases are a public health reality in Brazil and worldwide. Objectives and Methods: A population, observational, descriptive, retrospective study was conducted with secondary information from DATASUS to discriminate the hospitalizations associated with immunopreventable diseases in Brazil and their care costs, within the Scope of the SUS, between 2008 and 2018, in the economically active population (20 to 59 years). Results: It was analyzed for 457,479 hospitalizations, total of 127,746 hospitalizations (27.92% of all hospitalizations) were observed for immunopreventable diseases in the adult population, totaled R$115,682,097.54 (29.72% of the total values. The trend analysis of the time series of hospitalizations in this population showed a stationary trend. Conclusions: It were identified an opportunity of increasing the immunization coverage in the workforce population, for avoided hospitalizations and their costs for the health system.