Markers of eosinophilic airway inflammation in patients with asthma and allergic rhinitis.

Background: Measurement of airway inflammation is an important step to determine phenotype of asthma and allergic rhinitis (AR). Objective: To assess the level of nitric oxide in exhaled air (FeNO), nasal fraction of nitric oxide (nasal NO), their relationship with clinical control and blood eosinophils in patients with steroid-naive mild and moderate asthma and AR. Methods: One hundred forty-seven patients (65 men), ages 26-49.5 years (mean age, 32 years) with AR (n = 81) or AR and concomitant asthma (n = 46) and 20 healthy subjects were included in a single-center cohort study. All the patients underwent spirometry with reversibility test. Control of asthma and AR was assessed by using the Asthma Control Questionnaire and the visual analog scale, respectively. Levels of FeNO and nasal NO were measured by chemiluminescent analyzer, peripheral blood eosinophils were counted by automatic analyzer. Results: The FeNO level was significantly elevated in the patients with asthma and concomitant AR compared with the healthy subjects and was associated with control of both asthma and AR. There was no correlation between nasal NO and control of AR. Receiver operating characteristic analysis revealed that the level of eosinophils of 150 cells/µL may be a cutoff for lower airway eosinophilic inflammation. Blood eosinophils count was unable to distinguish eosinophilic and non-eosinophilic upper airway inflammation. Conclusion: We confirm that FeNO but not nasal NO is a marker of eosinophilic airway inflammation in patients with mild-moderate steroid-naive AR and concomitant asthma. A blood eosinophil level of ≥150 cells/µL may be a simple marker of eosinophilic airway inflammation in patients with asthma. However, its low specificity requires repeated measurements and use in combination with other biomarkers.

APOLLO, a testis-specific Drosophila ortholog of importin-4, mediates the loading of protamine-like protein Mst77F into sperm chromatin.

DNA in sperm is packed with small, charged proteins termed SNBPs (sperm nuclear basic proteins), including mammalian and Drosophila protamines. During spermiogenesis, somatic-type chromatin is taken apart and replaced with sperm chromatin in a multistep process leading to an extraordinary condensation of the genome. During fertilization, the ova face a similarly challenging task of SNBP eviction and reassembly of nucleosome-based chromatin. Despite its importance for the animal life cycle, sperm chromatin metabolism, including the biochemical machinery mediating the mutual replacement of histones and SNBPs, remains poorly studied. In Drosophila, Mst77F is one of the first SNBPs loaded into the spermatid nuclei. It persists in mature spermatozoa and is essential for sperm compaction and male fertility. Here, by using in vitro biochemical assays, we identify chaperones that can mediate the eviction and loading of Mst77F on DNA, thus facilitating the interconversions of chromatin forms in the male gamete. Unlike NAP1 and TAP/p32 chaperones that disassemble Mst77F-DNA complexes, ARTEMIS and APOLLO, orthologs of mammalian importin-4 (IPO4), mediate the deposition of Mst77F on DNA or oligonucleosome templates, accompanied by the dissociation of histone-DNA complexes. In vivo, a mutation of testis-specific Apollo brings about a defect of Mst77F loading, abnormal sperm morphology, and male infertility. We identify IPO4 ortholog APOLLO as a critical component of sperm chromatin assembly apparatus in Drosophila. We discover that in addition to recognized roles in protein traffic, a nuclear transport receptor (IPO4) can function directly in chromatin remodeling as a dual, histone- and SNBP-specific, chaperone.

p16High senescence restricts cellular plasticity during somatic cell reprogramming.

Despite advances in four-factor (4F)-induced reprogramming (4FR) in vitro and in vivo, how 4FR interconnects with senescence remains largely under investigated. Here, using genetic and chemical approaches to manipulate senescent cells, we show that removal of p16High cells resulted in the 4FR of somatic cells into totipotent-like stem cells. These cells expressed markers of both pluripotency and the two-cell embryonic state, readily formed implantation-competent blastoids and, following morula aggregation, contributed to embryonic and extraembryonic lineages. We identified senescence-dependent regulation of nicotinamide N-methyltransferase as a key mechanism controlling the S-adenosyl-L-methionine levels during 4FR that was required for expression of the two-cell genes and acquisition of an extraembryonic potential. Importantly, a partial 4F epigenetic reprogramming in old mice was able to reverse several markers of liver aging only in conjunction with the depletion of p16High cells. Our results show that the presence of p16High senescent cells limits cell plasticity, whereas their depletion can promote a totipotent-like state and histopathological tissue rejuvenation during 4F reprogramming.

Global expert views on the diagnosis, classification and pharmacotherapy of allergic rhinitis in clinical practice using a modified Delphi panel technique.

Background: Diagnosis, classification, and treatment of allergic rhinitis (AR) varies considerably despite the availability of treatment guidelines. Objectives: We aimed to carry out a two-part modified Delphi panel study to elucidate global expert management of AR in real life. Methods: The modified Delphi panel study was composed of two ten-minute online questionnaires sent to global AR experts, aiming to identify areas of consensus (defined as >75% respondent agreement) on aspects of their real-world daily practice related to AR diagnosis, classification, and pharmacotherapy. A workshop discussion with respondents held after the first-round questionnaire informed the development of the second-round questionnaire. Results: Eighteen experts (from 7 countries across 3 continents) completed both questionnaires in September-October 2021 and January 2022, respectively. The majority of respondents agreed that diagnosis of AR is best confirmed using a mixture of observation and testing (n = 15) and collaborating with colleagues across other specialties (n = 14). Experts agreed that severity (n = 18), upper/lower respiratory tract involvement (n = 15) and symptom frequency (n = 14) are important factors when classifying AR, however consensus was not reached on which classification tool should be used. Although there were mixed opinions on the preferred pharmacotherapy treatment in the presented case studies, respondents largely agreed on which treatments require less monitoring (intranasal corticosteroid therapies [INCS]) and when treatments should be stepped down (≤3 months). Although opinions varied across respondents, some respondents considered as-needed INCS treatment and surgery to be viable treatment options. Conclusion: We identified clear differences between real-world practice and treatment guidelines related to the management of AR. Furthermore, we recognized differences among physicians concerning their clinical practice in the pharmacological treatment of AR. These findings highlight the need for greater research into the management of AR and further indicate there is still a major gap between treatment guidelines and daily practice, even among specialists, suggesting a need for local guideline adaptation and implementation plans.

Different approaches to target volume definition and boost delivery in surgery de-escalation clinical trial in breast cancer patients with pathological complete response.

PURPOSE: We evaluate various approaches to target volume definition and boost delivery in patients with complete response to neoadjuvant systemic therapy (NST) who were treated by radiotherapy without a surgery. MATERIALS AND METHODS: A pathological complete response (pCR) was diagnosed in 21 of 27 patients included in "surgery de-escalation" prospective observation study. Clips were placed in the primary tumor volume (PrTV) before NST and during the vacuum aspiration biopsy. Twenty patients with pCR underwent the whole breast irradiation and a boost to the PrTV. High-dose rate brachytherapy (HDRB) was the basic technique for boost delivery. Finally, we identified the value of fused images (computed tomography [CT] before NST with simulation CT), clips and their combination for an accurate boost delivery. RESULTS: A complete overlap between PrTV on pre-treatment CT with the localization of the clips on simulation CT was mentioned in 10, partial mismatch in three patients. In 12 of these 13 women, HDRB was successfully used for the boost delivery. In five cases we mentioned a marked discrepancy between the PrTV on fused images and the topography of the clips. In other two women we did not find clips on simulation CT. The fused images in five of these seven patients showed anatomical landmarks (scar, fibrosis) used for identification of the gross tumor volume. In all 20 women with pCR (average follow-up of 16.6 months), there were no locoregional recurrences. CONCLUSION: Combination of the clips with fusion of pre-NST and simulation CTs is important for an accurate boost delivery.

Drosophila SUMM4 complex couples insulator function and DNA replication control.

Asynchronous replication of chromosome domains during S phase is essential for eukaryotic genome function, but the mechanisms establishing which domains replicate early versus late in different cell types remain incompletely understood. Intercalary heterochromatin domains replicate very late in both diploid chromosomes of dividing cells and in endoreplicating polytene chromosomes where they are also underreplicated. Drosophila SNF2-related factor SUUR imparts locus-specific underreplication of polytene chromosomes. SUUR negatively regulates DNA replication fork progression; however, its mechanism of action remains obscure. Here, we developed a novel method termed MS-Enabled Rapid protein Complex Identification (MERCI) to isolate a stable stoichiometric native complex SUMM4 that comprises SUUR and a chromatin boundary protein Mod(Mdg4)-67.2. Mod(Mdg4) stimulates SUUR ATPase activity and is required for a normal spatiotemporal distribution of SUUR in vivo. SUUR and Mod(Mdg4)-67.2 together mediate the activities of gypsy insulator that prevent certain enhancer-promoter interactions and establish euchromatin-heterochromatin barriers in the genome. Furthermore, SuUR or mod(mdg4) mutations reverse underreplication of intercalary heterochromatin. Thus, SUMM4 can impart late replication of intercalary heterochromatin by attenuating the progression of replication forks through euchromatin/heterochromatin boundaries. Our findings implicate a SNF2 family ATP-dependent motor protein SUUR in the insulator function, reveal that DNA replication can be delayed by a chromatin barrier, and uncover a critical role for architectural proteins in replication control. They suggest a mechanism for the establishment of late replication that does not depend on an asynchronous firing of late replication origins.

Inside cells, molecules of DNA provide the instructions needed to make proteins. Cells carefully maintain and repair their DNA, and typically make a complete copy of the genome before they divide to ensure that after division, each daughter cell has a full set. Within human, fly and other eukaryotic nuclei, DNA is packaged into structures known as chromosomes. Cells follow precisely controlled programs to replicate distinct regions of chromosomes at different times. To start copying a particular region, the cell machinery that replicates DNA binds to a sequence known as the origin of replication. It is thought that as-yet unknown cues from the cell may lead the replication machinery to bind to different origins of replication at different times. In some circumstances, cells make extra copies of their DNA without dividing. For example, many cells in the larvae of fruit flies contain hundreds of extra DNA copies to sustain their increased sizes. However, the entire genome is not copied during this process, so cells end up with more copies of some regions of the genome than others. A protein called SUUR is required for hindering the replication of the 'underrepresented' regions, but it is not clear how it works. To address this question, Andreyeva, Emelyanov et al. developed a new approach based on liquid chromatography and quantitative proteomics to identify the native form of SUUR in fruit flies. This revealed that SUUR exists as a stable complex with a protein called Mod(Mdg4), which is needed to recruit SUUR to the chromosomes. Further experiments suggested that SUUR and Mod(Mdg4) work together to bind to regions of DNA known as gypsy insulator elements, creating a physical barrier that hinders the replication machinery from accessing some parts of the genome. The findings of Andreyeva, Emelyanov et al. provide an alternative explanation for how individual cells may stagger the process of copying their DNA without relying on the replication machinery binding to various replication origins at different times. Rather, late replication timing may be instructed by an insulator-born delay of the progression of replication over particular genomic regions. This mechanism adds to the list of nuclear processes (chromosome partitioning, transcriptional regulation, etc.) that are known to be directed by insulators and associated architectural proteins.

Treating chronic urticaria refractory to H1-antihistamines in Russia: data from the AWARE study.

Introduction: Data on burden and treatment outcomes of chronic spontaneous urticaria (CSU) in Russia are limited. Poor adherence to recommended treatments can lead to suboptimal management of CSU patients. Aim: To understand disease burden, treatment algorithms, and outcomes of CSU in the Russian cohort of the AWARE study. Material and methods: AWARE was a global prospective, non-interventional study of chronic urticaria in the real-world setting. Adult patients with H1-antihistamines (H1AH)-refractory CSU for ≥ 2 months were included. Disease characteristics, quality of life (QoL), healthcare resource utilisation (HRU), and pharmacological treatments were observed during the 2-year study period. Results: Of the 135 patients enrolled from Russia, 121 completed the study. Pre-baseline, ~37% of patients were managed with non-recommended treatments (33% treated with sedative H1AH; 4% with other non-recommended treatments) and 28.2% of patients were not treated for CSU. There was a reduction in the use of sedative H1AH during the study (0.9% of patients treated with sedative H1AHs at Year 2). Decreased disease activity was seen as early as 3 months and continued to improve over 2 years (Urticaria Activity Score over 7 days (UAS7): 20.2 at baseline (n = 124) to 10.1, 7.1, and 3.2 at month 3 (n = 118), 12 (n = 109), and 24 (n = 109), respectively). This corresponded with QoL improvements (dermatology life quality index (DLQI) score: 10.3 at baseline to 5.4, 3.6, and 2.3 at Month 3 (n = 75), 12 (n = 98), and 24 (n = 92), respectively), and reduced angioedema and hives throughout the study. Conclusions: The burden of CSU in Russia is high, contributing to increased HRU. Guideline-recommended treatments and systematic escalation of therapy to achieve complete symptom control can improve management of patients with CSU.

Manifesto on united airways diseases (UAD): an Interasma (global asthma association - GAA) document.

OBJECTIVE: The large amount of evidence and the renewed interest in upper and lower airways involvement in infectious and inflammatory diseases has led Interasma (Global Asthma Association) to take a position on United Airways Diseases (UAD). METHODS: Starting from an extensive literature review, Interasma executive committee discussed and approved this Manifesto developed by Interasma scientific network (INES) members. RESULTS: The manifesto describes the evidence gathered to date and defines, states, advocates, and proposes issues on UAD (rhinitis, rhinosinusitis and nasal polyposis), and concomitant/comorbid lower airways disorders (asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, obstructive sleep apnoea) with the aim of challenging assumptions, fostering commitment, and bringing about change. UAD refers to clinical pictures characterized by the coexistence of upper and lower airways involvement, driven by a common pathophysiological mechanism, leading to a greater burden on patient's health status and requiring an integrated diagnostic and therapeutic plan. The high prevalence of UAD must be taken into account. Upper and lower airways diseases influence disease control and patient's quality of life. CONCLUSIONS: Patients with UAD need to have a timely and adequate diagnosis, treatment, and, when recommended, referral for management in a specialized center. Diagnostic testing including skin prick or serum specific IgE, lung function, fractional exhaled nitric oxide (FeNO), polysomnography, allergen-specific immunotherapies, biological therapies and home based continuous positive airway pressure (CPAP) whenever these are recommended, should be part of the management plan for UAD. Education of medical students, physicians, health professionals, patients and caregivers on the UAD is needed.

Manifesto on inhaled triple therapy in asthma: an Interasma (Global Asthma Association - GAA) document.

Objective: The optimal use of drug combinations for the management of asthma is providing significant results. This has prompted Interasma (Global Asthma Association) to take a position on inhaled triple therapy in asthma.Methods: We performed an extensive literature research to clinical trials, meta-analyses, randomized controlled trials and systematic reviews.Results: Starting from an extensive literature review, Interasma executive committee discussed and approved this Manifesto, developed by Interasma scientific network (INES) members.Conclusions: The manifesto describes the evidence gathered to date and states, advocates, and proposes issues on inhaled corticosteroid (ICS) plus long-acting beta 2 agonist (LABA) and long-acting muscarinic antagonists (LAMA) with the aim of challenging assumptions, fostering commitment, and bringing about change.

ERS statement: a core outcome set for clinical trials evaluating the management of COPD exacerbations.

Clinical trials evaluating the management of acute exacerbations of COPD assess heterogeneous outcomes, often omitting those that are clinically relevant or more important to patients. We have developed a core outcome set, a consensus-based minimum set of important outcomes that we recommend are evaluated in all future clinical trials on exacerbations management, to improve their quality and comparability. COPD exacerbations outcomes were identified through methodological systematic reviews and qualitative interviews with 86 patients from 11 countries globally. The most critical outcomes were prioritised for inclusion in the core outcome set through a two-round Delphi survey completed by 1063 participants (256 patients, 488 health professionals and 319 clinical academics) from 88 countries in five continents. Two global, multi-stakeholder, virtual consensus meetings were conducted to 1) finalise the core outcome set and 2) prioritise a single measurement instrument to be used for evaluating each of the prioritised outcomes. Consensus was informed by rigorous methodological systematic reviews. The views of patients with COPD were accounted for at all stages of the project. Survival, treatment success, breathlessness, quality of life, activities of daily living, the need for a higher level of care, arterial blood gases, disease progression, future exacerbations and hospital admissions, treatment safety and adherence were all included in the core outcome set. Focused methodological research was recommended to further validate and optimise some of the selected measurement instruments. The panel did not consider the prioritised set of outcomes and associated measurement instruments to be burdensome for patients and health professionals to use.

Impact of the COVID-19 pandemic on the management of chronic noninfectious respiratory diseases.

Introduction: The COVID-19 pandemic has challenged health care across the world, not just by the severity of the disease and the high mortality rate but also by the consequences on the management of the patients with chronic diseases.Areas covered: This review summarizes the most up-to-date published data regarding the impact of COVID-19 on the management and outcomes of patients with chronic noninfectious respiratory illnesses including obstructive sleep apnea, asthma, chronic obstructive pulmonary disease, bronchiectasis, interstitial and pulmonary vascular diseases, and lung cancer.Expert opinion: Most of chronic respiratory diseases (except asthma and cystic fibrosis) are associated with more severe COVID-19 and poor outcomes but the mechanisms involved are not yet identified. The therapeutic management of the patients with chronic respiratory diseases and COVID-19 is similar to the other patients but the post-recovery course could be worse in this population and followed by the development of pulmonary fibrosis, bronchiectasis, and pulmonary hypertension. The pandemic highly impacted our usual medical activities by limiting the access to several diagnosis procedures, the necessity to develop new methods for the monitoring of the disease and adapt the therapeutic strategies. The long-term consequences of all these changes are still unknown.

TiLoop Bra Assisted Breast Reconstruction - Our Experience.

Additional covering of the lower pole with allomaterial or its synthetic analogues during immediate breast reconstruction is being perfomed at the N.N. Petrov National Medical Research Oncology Center, Ministry of Healthcare of Russian Federation for last 7 years. Initially, epidermal flap was the only option for lower pole coverage, later ADM was used as part of clinical approbation. Average complication rate ranges from 20-35% due to blood circulatory (supply) disorders. Since 2018, a titanized mesh (TiLoop Bra) been used as a additional coverage of the lower pole. Methods: From July 2018 to April 2019, 103 breast reconstructions were performed using TiLoop-BRA mesh. All operations were performed due to malignant tumors of breast, of which in 94 operations were performed for unilateral breast carcinoma, 9 for bilateral breast carcinoma.74 patients received neoadjuvant therapy, 31 received adjuvant therapy, 17 patients required radiation therapy. Results: Overall complications rates significally decreased. Complete loss of breast implant and mesh endoprosthesis 5.88%, Capsular contracture 17.65 %, Only mesh removal due to painful syndrome 5.88%,* Red breast * syndrome (by analogy with ADM) 5.88%.

Management of Cough in Patients with Chronic Obstructive Pulmonary Disease: Results of the Multicenter Randomized Placebo-Controlled Clinical Trial.

BACKGROUND: Chronic cough declines quality of life and increases risk of complications in patients with chronic obstructive pulmonary disease (COPD). Reducing cough severity and associated negative effects is important therapeutic goal in COPD. Rengalin with anti- and protussive activity is based on technologically processed antibodies to bradykinin, histamine and morphine. AIM: To evaluate efficacy and safety of Rengalin in treatment of cough in patients with COPD. METHODS: Patients (n=238, mean age 64.3±8.2 years) with stable COPD and persistent cough despite maintenance therapy (anticholinergics, beta-2-adrenergic agonists, inhaled corticosteroids) were included and randomized in the study. The severity of cough assessment (according to the "Cough Severity Score"), COPD impact on patient's life (COPD Assessment Test, CAT), and spirometry were performed at screening. Patients took Rengalin or Placebo 2 tablets 2 times daily for 4 weeks. The endpoints were proportion of patients who responded to treatment, dynamics of cough severity, and severity of COPD symptoms. Intention-to-treat (per protocol) analysis was performed. RESULTS: Positive response to Rengalin was recorded in 83.6 [85.7]% (vs 72.6 [72.7]% in Placebo group, p=0.0422 [p=0.0163]). Double decrease of cough severity was reported in 42.2 [43.8]% in Rengalin group (versus 32.7 [32.7]% in Placebo; p=0.1373 [p=0.0907]). The total CAT score decreased by 3.3±4.2 [3.6±3.9] points (versus 2.5±4.1 [2.5±4.2] in Placebo group); the difference between groups was 0.79±4.16 [1.04±4.02] points (p=0.0870 [p=0.0416]). The number of patients with adverse events (AEs) in Rengalin (n=13) and Placebo (n=12) groups did not have significant differences (p=1.00). No AEs with certain relationship with study drug were registered. CONCLUSION: Rengalin is an effective and safe drug in patients with stable COPD and persistent cough, despite stable doses of maintenance therapy according to the GOLD guidelines. Four-week therapy decreases severity of cough by two times in more than 40% of patients. TRIAL REGISTRATION: ClinicalTrials.gov (id: NCT03159091).

Camel regulates development of the brain ventricular system.

Development of the brain ventricular system of vertebrates and the molecular mechanisms involved are not fully understood. The developmental genes expressed in the elements of the brain ventricular system such as the ependyma and circumventricular organs act as molecular determinants of cell adhesion critical for the formation of brain ventricular system. They control brain development and function, including the flow of cerebrospinal fluid. Here, we describe the novel distantly related member of the zebrafish L1-CAM family of genes-camel. Whereas its maternal transcripts distributed uniformly, the zygotic transcripts demonstrate clearly defined expression patterns, in particular in the axial structures: floor plate, hypochord, and roof plate. camel expresses in several other cell lineages with access to the brain ventricular system, including the midbrain roof plate, subcommissural organ, organum vasculosum lamina terminalis, median eminence, paraventricular organ, flexural organ, and inter-rhombomeric boundaries. This expression pattern suggests a role of Camel in neural development. Several isoforms of Camel generated by differential splicing of exons encoding the sixth fibronectin type III domain enhance cell adhesion differentially. The antisense oligomer morpholino-mediated loss-of-function of Camel affects cell adhesion and causes hydrocephalus and scoliosis manifested via the tail curled down phenotype. The subcommissural organ's derivative-the Reissner fiber-participates in the flow of cerebrospinal fluid. The Reissner fiber fails to form upon morpholino-mediated Camel loss-of-function. The Camel mRNA-mediated gain-of-function causes the Reissner fiber misdirection. This study revealed a link between Chl1a/Camel and Reissner fiber formation, and this supports the idea that CHL1 is one of the scoliosis factors.

Battlefield Extracorporeal Cardiopulmonary Resuscitation for Out-of-Hospital Cardiac Arrest: A Feasibility Study During Military Exercises.

PURPOSE: To evaluate the feasibility of prehospital extracorporeal cardiopulmonary resuscitation (E-CPR) in the military exercise setting. METHODS: Three 40kg Sus scrofa (wild swine) underwent controlled 35% blood loss and administration of potassium chloride to achieve cardiac arrest (CA). During CPR, initiated 1 minute after CA, the animals were transported to Role 1. Femoral vessels were cannulated, followed by E-CPR using a portable perfusion device. Crystalloid and blood transfusions were initiated, followed by tactical evacuation to Role 2 and 4-hour observation. RESULTS: All animals developed sustained asystole. Chest compressions supported effective but gradually deteriorating blood circulation. Two animals underwent successful E-CPR, with restoration of perfusion pressure to 80mmHg (70-90mmHg) 25 and 23 minutes after the induction of CA. After transportation to Role 2, one animal developed abdominal compartment syndrome as a result of extensive (9L) fluid replacement. The other animal received a lower volume of crystalloids (4L), and no complications occurred. In the third animal, multiple attempts to cannulate arteries were unsuccessful because of spasm and hypotension. Open aortic cannulation enabled the circuit to commence. No return of spontaneous circulation was ultimately achieved in either of the remaining animals. CONCLUSION: Our study demonstrates both the potential feasibility of battlefield E-CPR and the evolving capability in the care of severey injured combat casualties.

Core outcome set for the management of acute exacerbations of chronic obstructive pulmonary disease: the COS-AECOPD ERS Task Force study protocol.

Randomised controlled trials (RCTs) on the management of COPD exacerbations evaluate heterogeneous outcomes, often omitting those that are clinically important and patient relevant. This limits their usability and comparability. A core outcome set (COS) is a consensus-based minimum set of clinically important outcomes that should be evaluated in all RCTs in specific areas of health care. We present the study protocol of the COS-AECOPD ERS Task Force, aiming to develop a COS for COPD exacerbation management, that could remedy these limitations. For the development of this COS we follow standard methodology recommended by the COMET initiative. A comprehensive list of outcomes is assembled through a methodological systematic review of the outcomes reported in relevant RCTs. Qualitative research with patients with COPD will also be conducted, aiming to identify additional outcomes that may be important to patients, but are not currently addressed in clinical research studies. Prioritisation of the core outcomes will be facilitated through an extensive, multi-stakeholder Delphi survey with a global reach. Selection will be finalised in an international, multi-stakeholder meeting. For every core outcome, we will recommend a specific measurement instrument and standardised time points for evaluation. Selection of instruments will be based on evidence-informed consensus. Our work will improve the quality, usability and comparability of future RCTs on the management of COPD exacerbations and, ultimately, the care of patients with COPD. Multi-stakeholder engagement and societal support by the European Respiratory Society will raise awareness and promote implementation of the COS.

Beliefs and preferences regarding biological treatments for severe asthma.

BACKGROUND: Severe asthma is a serious condition with a significant burden on patients' morbidity, mortality, and quality of life. Some biological therapies targeting the IgE and interleukin-5 (IL5) mediated pathways are now available. Due to the lack of direct comparison studies, the choice of which medication to use varies. We aimed to explore the beliefs and practices in the use of biological therapies in severe asthma, hypothesizing that differences will occur depending on the prescribers' specialty and experience. METHODS: We conducted an online survey composed of 35 questions in English. The survey was circulated via the INterasma Scientific Network (INESNET) platform as well as through social media. Responses from allergists and pulmonologists, both those with experience of prescribing omalizumab with (OMA/IL5) and without (OMA) experience with anti-IL5 drugs, were compared. RESULTS: Two hundred eighty-five (285) valid questionnaires from 37 countries were analyzed. Seventy-on percent (71%) of respondents prescribed biologics instead of oral glucocorticoids and believed that their side effects are inferior to those of Prednisone 5 mg daily. Agreement with ATS/ERS guidelines for identifying severe asthma patients was less than 50%. Specifically, significant differences were found comparing responses between allergists and pulmonologists (Chi-square test, p < 0.05) and between OMA/IL5 and OMA groups (p < 0.05). CONCLUSIONS: Uncertainties and inconsistencies regarding the use of biological medications have been shown. The accuracy of prescribers to correctly identify asthma severity, according to guidelines criteria, is quite poor. Although a substantial majority of prescribers believe that biological drugs are safer than low dose long-term treatment with oral steroids, and that they must be used instead of oral steroids, every effort should be made to further increase awareness. Efficacy as disease modifiers, biomarkers for selecting responsive patients, timing for outcomes evaluation, and checks need to be addressed by further research. Practices and beliefs regarding the use of asthma biologics differ between the prescriber's specialty and experience; however, the latter seems more significant in determining beliefs and behavior. Tailored educational measures are needed to ensure research results are better integrated in daily practice.

Progress in Occupational Asthma.

Occupational asthma (OA) represents one of the major public health problems due to its high prevalence, important social and economic burden. The aim of this review is to summarize current data about clinical phenotypes, biomarkers, diagnosis and management of OA, a subtype of work-related asthma. Most studies have identified two phenotypes of OA. One is sensitizer-induced asthma, occuring after a latency period and caused by hypersensitivity to high- or low-molecular weight agents. The other is irritant-induced asthma, which can occur after one or more exposures to high concentrations of irritants without latency period. More than 400 agents causing OA have been identified and its list is growing fast. The best diagnostic approach for OA is a combination of clinical history and objective tests. An important tool is a specific inhalation challenge. Additional tests include assessments of bronchial hyperresponsiveness to methacholine/histamine in patients without airflow limitations, monitoring peak expiratory flow at- and off-work, sputum eosinophil count, exhaled nitric oxide measurement, skin prick tests with occupational allergens and serum specific IgE. Treatment of OA implies avoidance of exposure, pharmacotherapy and education. OA is a heterogeneous disease. Mechanisms of its different phenotypes, their diagnosis, role of new biomarkers and treatment require further investigation.

Defined p16High Senescent Cell Types Are Indispensable for Mouse Healthspan.

The accumulation of senescent cells can drive many age-associated phenotypes and pathologies. Consequently, it has been proposed that removing senescent cells might extend lifespan. Here, we generated two knockin mouse models targeting the best-characterized marker of senescence, p16Ink4a. Using a genetic lineage tracing approach, we found that age-induced p16High senescence is a slow process that manifests around 10-12 months of age. The majority of p16High cells were vascular endothelial cells mostly in liver sinusoids (LSECs), and to lesser extent macrophages and adipocytes. In turn, continuous or acute elimination of p16High senescent cells disrupted blood-tissue barriers with subsequent liver and perivascular tissue fibrosis and health deterioration. Our data show that senescent LSECs are not replaced after removal and have important structural and functional roles in the aging organism. In turn, delaying senescence or replacement of senescent LSECs could represent a powerful tool in slowing down aging.

Toward personalization of asthma treatment according to trigger factors.

Asthma is a severe and chronic disabling disease affecting more than 300 million people worldwide. Although in the past few drugs for the treatment of asthma were available, new treatment options are currently emerging, which appear to be highly effective in certain subgroups of patients. Accordingly, there is a need for biomarkers that allow selection of patients for refined and personalized treatment strategies. Recently, serological chip tests based on microarrayed allergen molecules and peptides derived from the most common rhinovirus strains have been developed, which may discriminate 2 of the most common forms of asthma, that is, allergen- and virus-triggered asthma. In this perspective, we argue that classification of patients with asthma according to these common trigger factors may open new possibilities for personalized management of asthma.