Role of Thymic Stromal Lymphopoietin in the Pathophysiology of Asthma and Clinical and Biological Effects of Blockade With Tezepelumab.

The airway epithelium is the first line of defense of the respiratory system against the external environment. It plays an active role in the initiation of immune and allergic responses against potential hazards. Among the various specialized cells and cytokines that participate in epithelium-induced responses, alarmins are particularly interesting, given their ample role in mediating T2 and non-T2 inflammatory mechanisms involved in the pathogenesis of asthma. Thymic stromal lymphopoietin (TSLP) is an alarmin with broad effects in asthma that result from its widespread action on multiple cell types, including eosinophils, mast cells, dendritic cells, and group-2 innate lymphoid cells. Its role in allergy-mediated responses, eosinophilic inflammation, airway hyperresponsiveness, mucus hyperproduction, viral tolerance, and airway remodeling is of the utmost importance, as more comprehensive asthma assessments have been developed to explore these pathogenic features. Therefore, blockade with targeting molecules, such as monoclonal antibodies, has emerged as a promising therapeutic option, particularly in patients with multiple pathogenic pathways. In this review, we examine the roles of alarmins (mainly TSLP) in the pathogenesis of asthma and clinical expression and discuss the effects of inhibiting TSLP on several inflammatory and clinical outcomes. We also review the literature supporting treatment with anti-TSLP biologics and the unanswered questions and unmet needs associated with targeting alarmins in asthma.

Soil carbon stock and stability under Eucalyptus-based silvopasture and other land-use systems in the Cerrado biodiversity hotspot.

During the past few decades, commercial silvopastoral systems (SPS) with exotic Eucalyptus (hybrid) trees have become popular in the Brazilian Cerrado (savanna). With the increasing awareness about the role of carbon (C) storage in soils as a climate-change mitigation strategy and the relationship between the nature of soil aggregates and the soil's carbon sequestration potential, it is important to understand the influence of such SPS systems on soil organic carbon (SOC) storage. We studied C content in three aggregate size classes in six land-use systems on Oxisols in Minas Gerais, Brazil. The systems were planted forest, native secondary forest, managed pasture, and three 8-year-old SPS, differing in their tree-planting configurations. Eucalyptus hybrid was the tree in SPS and planted forest treatments, and Urochloa decumbens was the grass in SPS and pasture treatments. From each treatment, replicated soil samples were collected from four depth-classes (0-10, 10-30, 30-60, and 60-100 cm), fractionated by wet sieving into the three aggregate-size classes, 2000 to 250 µm, 250 to 53 µm, and <53 µm size classes representing macroaggregates, microaggregates, and silt + clay, respectively, and their C contents determined. Down to 1 m, total SOC stock values ranged from 260 Mg ha-1 under pasture to 167 Mg ha-1 under native forest, with 174 Mg ha-1 for Eucalyptus plantation and about 195 Mg ha-1 for the three SPS. Compared to the degraded native forest, the pasture system had significantly higher SOC in the whole soil and the aggregate size fractions, especially in the lower soil-depth classes. The lower SOC stock of Eucalyptus hybrid SPS compared to open pasture differs from the general trend of SPS having higher stock. Given that the Cerrado biome is a biodiversity hotspot, the use of native nitrogen-fixing trees, of which there are several, is worth investigating. In addition, the conversion from Eucalyptus monocultures to SPS could be considered as a strategy to increase the SOC stock.

The 2020 International Alliance for the Control of Scabies Consensus Criteria for the Diagnosis of Scabies.

BACKGROUND: Scabies is a common parasitic skin condition that causes considerable morbidity globally. Clinical and epidemiological research for scabies has been limited by a lack of standardization of diagnostic methods. OBJECTIVES: To develop consensus criteria for the diagnosis of common scabies that could be implemented in a variety of settings. METHODS: Consensus diagnostic criteria were developed through a Delphi study with international experts. Detailed recommendations were collected from the expert panel to define the criteria features and guide their implementation. These comments were then combined with a comprehensive review of the available literature and the opinion of an expanded group of international experts to develop detailed, evidence-based definitions and diagnostic methods. RESULTS: The 2020 International Alliance for the Control of Scabies (IACS) Consensus Criteria for the Diagnosis of Scabies include three levels of diagnostic certainty and eight subcategories. Confirmed scabies (level A) requires direct visualization of the mite or its products. Clinical scabies (level B) and suspected scabies (level C) rely on clinical assessment of signs and symptoms. Evidence-based, consensus methods for microscopy, visualization and clinical symptoms and signs were developed, along with a media library. CONCLUSIONS: The 2020 IACS Criteria represent a pragmatic yet robust set of diagnostic features and methods. The criteria may be implemented in a range of research, public health and clinical settings by selecting the appropriate diagnostic levels and subcategories. These criteria may provide greater consistency and standardization for scabies diagnosis. Validation studies, development of training materials and development of survey methods are now required. What is already known about this topic? The diagnosis of scabies is limited by the lack of accurate, objective tests. Microscopy of skin scrapings can confirm the diagnosis, but it is insensitive, invasive and often impractical. Diagnosis usually relies on clinical assessment, although visualization using dermoscopy is becoming increasingly common. These diagnostic methods have not been standardized, hampering the interpretation of findings from clinical research and epidemiological surveys, and the development of scabies control strategies. What does this study add? International consensus diagnostic criteria for common scabies were developed through a Delphi study with global experts. The 2020 International Alliance for the Control of Scabies (IACS) Criteria categorize diagnosis at three levels of diagnostic certainty (confirmed, clinical and suspected scabies) and eight subcategories, and can be adapted to a range of research and public health settings. Detailed definitions and figures are included to aid training and implementation. The 2020 IACS Criteria may facilitate the standardization of scabies diagnosis.

Exacerbations of Severe Asthma While on Anti-IL-5 Biologics.

Anti-interleukin 5 (IL-5) and anti-IL-5 receptor α monoclonal antibodies markedly decrease airway and peripheral blood eosinophil numbers and are thus highly effective in reducing asthma exacerbations. Nonetheless, these biologics do not completely resolve exacerbations. There is very little information on the cellular nature of exacerbations during treatment with biologics. Using illustrative clinical case scenarios, we highlight the importance of carefully characterizing asthmatics at the time of exacerbation and recognizing neutrophilic causes of exacerbations to ensure optimal management. While an eosinophilic exacerbation may improve with more corticosteroids or by switching to another anti-IL-5 monoclonal antibody, a noneosinophilic exacerbation will likely not. An infective exacerbation needs to be recognized, and the pathogen must be identified and treated with the appropriate antimicrobial agent.

Exclusive Breast Milk vs. Hybrid Milk Feeding for Preterm Babies-A Randomized Controlled Trial Comparing Time to Full Feeds.

When breastmilk is insufficient to meet planned feed volumes, neonatologists need to continue parenteral nutrition (PN) or use formula. This trial conducted at a tertiary care unit in South India between August 2014 and April 2016 compared time to full feeds in preterms fed 'mother's milk alone(MM)' vs. 'hybrid feed-mother's milk supplemented with formula(HF)'. We also compared time to regain birth weights, duration of PN, feed intolerance, Necrotizing Enterocolitis stage 2 or more, all-cause mortality, Extrauterine growth restriction, Healthcare associated infections, exclusive breast milk feeding rates at discharge, Retinopathy of prematurity requiring laser therapy, abnormal neurosonogram and oxygen dependency at 28 days. Neonates between 27 and 32 weeks were randomized into MM/HF when breast milk was insufficient. HF received formula to reach targeted feed volumes. MM received more PN to meet fluid requirements. 54 babies were analyzed in MM and 58 in HF. Time to full feeds were similar-MM (14.1 ± 4 days); HF (13.5 ± 4 days), p = 0.45. Exclusive breast milk feeding rates at discharge were higher in MM when compared to HF (74% vs. 51%). Other secondary outcomes were similar between groups. When mother's milk is unavailable in sufficient quantities, preterm babies may receive hybrid feeds. (Clinical trials registry of India no. REF/2016/02/006622).

Scope of surface-modified molecular and nanomaterials in gel/liquid forms for developing mechanically flexible DSSCs/QDSSCs.

The advanced lifestyle of the human race involves heavy usage of various gadgets which require copious supplies of energy for uninterrupted functioning. Due to the ongoing depletion of fossil fuels and the accelerating demand for other energy resources, renewable energy sources, especially solar cells, are being extensively explored as viable alternatives. Flexible solar cells have recently emerged as an advanced member of the photovoltaic family; the flexibility and pliability of these photovoltaic materials are advantageous from a practical point of view. Conventional flexible solar cell materials, when dispersed in solvents, are usually volatile and create severe stability issues when incorporated in devices. Recently, non-volatile, less viscous functional molecular liquids/gels have been proposed as potential materials for use in foldable device applications. This perspective article discusses the scope of surface-modified non-volatile molecular and nanomaterials in liquid/gel forms in the manufacturing and deployment of flexible photovoltaics.

Emerging trends in sensors based on carbon nitride materials.

A new class of functional materials, carbon nitrides, has recently attracted the attention of researchers. Carbon nitride is a metal-free carbonaceous material, possessing a high N : C ratio with structure ranging from polymeric to graphitic form, constituting heptazine or triazine rings as structural motifs. It entered into the frame as a heterogeneous photocatalyst owing to its medium band gap, porosity, and high thermal and chemical inertness. Intensive research aimed towards exploring its inherent potentials has opened up a new area of study in the field of sensors; moreover, due to tunability of its electronic and optical properties, high stability, biocompatibility and low cost, it can be used in the area of sensing. In this review, we highlighted various strategies for the development of nanoscale morphological varieties of carbon nitrides and fabrication of sensors based on the luminescence properties of the carbon nitride materials. Herein, we exclusively envisioned new vistas for carbon nitrides as an imperative candidate for the fabrication of ideal sensors.

Cold-stored platelets: A product with function optimized for hemorrhage control.

Early administration of blood products following severe trauma is pivotal for establishing hemostasis and achieving successful outcomes. Platelet transfusions, in particular, provide rapid control of hemostasis and help to restore platelet dysfunction induced by trauma. In the U.S. platelets used for therapeutic purposes are stored at room temperature with a limited shelf life of 5-7 days. Issues with room temperature storage of platelets, including an increased risk of bacterial growth and a decline in platelet hemostatic function, have led to a resurgence in interest in cold-stored platelets for therapeutic transfusion. This review presents the current state of cold-stored platelets and cold-stored whole blood as treatment for actively bleeding patients. Usage of cold stored platelets in alternative areas, such as in the field of regenerative medicine, is also discussed.

Split-graft liver transplantation from an adult donor with an unrecognized UCD to a pediatric and adult recipient.

We report the outcomes of an adult and pediatric split liver transplant from an adult male donor who died due to an unrecognized UCD, OTC deficiency. Recognizing inborn errors of metabolism can be challenging, especially in adult centers where such disorders are rarely encountered. Shortage of donors for liver transplantation has led to procedures to maximize donor utilization, such as split and live donor grafts. The cause of death should be ascertained before accepting a cadaveric donor organ.

Revisiting Type 2-high and Type 2-low airway inflammation in asthma: current knowledge and therapeutic implications.

Asthma is a complex respiratory disorder characterized by marked heterogeneity in individual patient disease triggers and response to therapy. Several asthma phenotypes have now been identified, each defined by a unique interaction between genetic and environmental factors, including inflammatory, clinical and trigger-related phenotypes. Endotypes further describe the functional or pathophysiologic mechanisms underlying the patient's disease. type 2-driven asthma is an emerging nomenclature for a common subtype of asthma and is characterized by the release of signature cytokines IL-4, IL-5 and IL-13 from cells of both the innate and adaptive immune systems. A number of well-recognized biomarkers have been linked to mechanisms involved in type 2 airway inflammation, including fractional exhaled nitric oxide, serum IgE, periostin, and blood and sputum eosinophils. These type 2 cytokines are targets for pharmaceutical intervention, and a number of therapeutic options are under clinical investigation for the management of patients with uncontrolled severe asthma. Anticipating and understanding the heterogeneity of asthma and subsequent improved characterization of different phenotypes and endotypes must guide the selection of treatment to meet individual patients' needs.

Targeting PP2A and proteasome activity ameliorates features of allergic airway disease in mice.

BACKGROUND: Asthma is an allergic airway disease (AAD) caused by aberrant immune responses to allergens. Protein phosphatase-2A (PP2A) is an abundant serine/threonine phosphatase with anti-inflammatory activity. The ubiquitin proteasome system (UPS) controls many cellular processes, including the initiation of inflammatory responses by protein degradation. We assessed whether enhancing PP2A activity with fingolimod (FTY720) or 2-amino-4-(4-(heptyloxy) phenyl)-2-methylbutan-1-ol (AAL(S) ), or inhibiting proteasome activity with bortezomib (BORT), could suppress experimental AAD. METHODS: Acute AAD was induced in C57BL/6 mice by intraperitoneal sensitization with ovalbumin (OVA) in combination with intranasal (i.n) exposure to OVA. Chronic AAD was induced in mice with prolonged i.n exposure to crude house dust mite (HDM) extract. Mice were treated with vehicle, FTY720, AAL(S) , BORT or AAL(S) +BORT and hallmark features of AAD assessed. RESULTS: AAL(S) reduced the severity of acute AAD by suppressing tissue eosinophils and inflammation, mucus-secreting cell (MSC) numbers, type 2-associated cytokines (interleukin (IL)-33, thymic stromal lymphopoietin, IL-5 and IL-13), serum immunoglobulin (Ig)E and airway hyper-responsiveness (AHR). FTY720 only suppressed tissue inflammation and IgE. BORT reduced bronchoalveolar lavage fluid (BALF) and tissue eosinophils and inflammation, IL-5, IL-13 and AHR. Combined treatment with AAL(S) +BORT had complementary effects and suppressed BALF and tissue eosinophils and inflammation, MSC numbers, reduced the production of type 2 cytokines and AHR. AAL(S) , BORT and AAL(S) +BORT also reduced airway remodelling in chronic AAD. CONCLUSION: These findings highlight the potential of combination therapies that enhance PP2A and inhibit proteasome activity as novel therapeutic strategies for asthma.

Novel SPG20 mutation in an extended family with Troyer syndrome.

Troyer Syndrome (TRS) is a rare autosomal recessive complicated spastic paraplegia disorder characterized by various neurological and musculoskeletal manifestations. Pathogenicity stems from mutations in SPG20 which encodes Spartin, a multifunctional protein that is thought to be essential for neuron viability. Here we report on the clinical and molecular characterization of TRS in five patients from an extended consanguineous family in the United Arab Emirates. Molecular analysis involved Whole Exome Sequencing and Sanger sequencing for identification and confirmation of the causative variant respectively. In silico tools including CADD and Polyphen-2 were used to assess pathogenicity of the variant. The clinical description of these patients included spastic paraparesis, motor and cognitive delay, gait abnormalities, musculoskeletal features, as well as white matter abnormalities and emotional liability. Molecular analysis revealed a novel homozygous missense mutation in SPG20 (c.1324G > C; p.Ala442Pro) occurring at an evolutionarily conserved residue in the Plant-Related Senescence domain of Spartin. The mutation segregated with the clinical phenotype in all patients. In silico algorithms predict the mutation to be disease causing, and the variant had not been previously reported in public or ethnic specific variant repositories.

Human bronchial and parenchymal fibroblasts display differences in basal inflammatory phenotype and response to IL-17A.

BACKGROUND: Chronic inflammation, typified by increased expression of IL-17A, together with airway and parenchymal remodelling are features of chronic lung diseases. Emerging evidence suggests that phenotypic heterogeneity of repair and inflammatory capacities of fibroblasts may contribute to the differential structural changes observed in different regions of the lung. OBJECTIVE: To investigate phenotypic differences in parenchymal and bronchial fibroblasts, either in terms of inflammation and remodelling or the ability of these fibroblasts to respond to IL-17A. METHODS: Four groups of primary fibroblasts were used: normal human bronchial fibroblast (NHBF), normal human parenchymal fibroblast (NHPF), COPD human bronchial fibroblast (CHBF) and COPD human parenchymal fibroblast (CHPF). Cytokine and extracellular matrix (ECM) expression were measured at baseline and after stimulation with IL-17A. Actinomycin D was used to measure cytokine mRNA stability. RESULTS: At baseline, we observed higher protein production of IL-6 in NHPF than NHBF, but higher levels of IL-8 and GRO-α in NHBF. IL-17A induced a higher expression of GRO-α (CXCL1) and IL-6 in NHPF than in NHBF, and a higher level of IL-8 expression in NHBF. IL-17A treatment decreased the mRNA stability of IL-6 in NHBF when compared with NHPF. CHPF expressed higher protein levels of fibronectin, collagen-I and collagen-III than CHBF, NHBF and NHPF. IL-17A increased fibronectin and collagen-III protein only in NHPF and collagen-III protein production in CHBF and CHPF. CONCLUSIONS AND CLINICAL RELEVANCE: These findings provide insight into the inflammatory and remodelling processes that may be related to the phenotypic heterogeneity of fibroblasts from airway and parenchymal regions and in their response to IL-17A.

Role of local eosinophilopoietic processes in the development of airway eosinophilia in prednisone-dependent severe asthma.

BACKGROUND: In severe asthmatics with persistent airway eosinophilia, blockade of interleukin-5 has significant steroid-sparing effects and attenuates blood and sputum eosinophilia. The contribution of local maturational processes of progenitors within the airways relative to the recruitment of mature cells from the peripheral circulation to the development of airway eosinophilia is not known. We hypothesize that local eosinophilopoiesis may be the predominant process that drives persistent airway eosinophilia and corticosteroid requirement in severe asthmatics. OBJECTIVES: In a cross-sectional study, the number and growth potential of eosinophil-lineage-committed progenitors (EoP) were assayed in 21 severe eosinophilic asthmatics, 19 mild asthmatics, eight COPD patients and eight normal subjects. The effect of anti-IL-5 treatment on mature eosinophils and EoP numbers was made in severe eosinophilic asthmatics who participated in a randomized clinical trial of mepolizumab (substudy of a larger GSK sponsored global phase III trial, MEA115575) where subjects received mepolizumab (100 mg, n = 9) or placebo (n = 8), as six monthly subcutaneous injections. RESULTS: Mature eosinophil and EoP numbers were significantly greater in the sputum of severe asthmatics compared with all other subject groups. In colony-forming assays, EoP from blood of severe asthmatics demonstrated a greater response to IL-5 than mild asthmatics. Treatment of severe asthmatics with mepolizumab significantly attenuated blood eosinophils and increased EoP numbers consistent with blockade of systemic eosinophilopoiesis. There was however no significant treatment effect on mature eosinophils, sputum EoP numbers or the prednisone maintenance dose. CONCLUSIONS AND CLINICAL RELEVANCE: Patients with severe eosinophilic asthma have an exaggerated eosinophilopoeitic process in their airways. Treatment with 100 mg subcutaneous mepolizumab significantly attenuated systemic differentiation of eosinophils, but did not suppress local airway eosinophil differentiation to mature cells. Targeting IL-5-driven eosinophil differentiation locally within the lung maybe of relevance for optimal control of airway eosinophilia and asthma.

Histone deacetylase activity and recurrent bacterial bronchitis in severe eosinophilic asthma.

An increase in P13 Kinase activity and an associated reduction in histone deacetylase activity may contribute to both relative steroid insensitivity in patients with severe eosinophilic asthma and impaired macrophage scavenger function and susceptibility to recurrent infective bronchitis that may, in turn, contribute to further steroid insensitivity.

Nasal and pharyngeal eosinophil peroxidase levels in adults with poorly controlled asthma correlate with sputum eosinophilia.

The objective of the study was to compare nasal, pharyngeal, and sputum eosinophil peroxidase (EPX) levels with induced sputum eosinophil percentage in 10 adults with poorly controlled asthma and 10 normal controls. EPX was measured using an ELISA and normalized for grams of protein for nasal and pharynx specimens and for mL-gram of protein for sputum. Sputum EPX levels were statistically different between asthma and control subjects (P = 0.024). EPX levels measured in the nasal and pharyngeal swab samples derived from the same patients were also different between asthma and control subjects, each displaying a high degree of significance (P = 0.002). Spearman's correlation coefficients for nasal EPX and pharyngeal EPX levels compared to induced sputum eosinophil percentage were 0.81 (P = 0.0007) and 0.78 (P = 0.0017), respectively. Thus, there is a strong association in a given patient between both nasal and pharyngeal EPX levels and the eosinophil percentage of induced sputum.

Association of HLA-DQA1 and -DQB1 alleles with type I diabetes in Arabs: a meta-analyses.

This study aimed at assessing the nature and significance of associations between various alleles of HLA-DQA1, HLA-DQB1, and type I diabetes (T1D) in Arab populations. Evidence from literature (published before 20 April 2015) was amassed and analysed through multiple meta-analyses, which yielded effect summary odds ratios and 95% confidence intervals for 24 alleles and 4 haplotypes. A total of 1273 cases and 1747 controls from 16 studies were analysed. High levels of significance were obtained to support higher T1D risk when harbouring DQA1*03:01. The alleles DQB1*02:01 and *03:02 and the haplotypes DR3 and DR4 were significant risk factors, albeit with high publication heterogeneity. The protective effects of DQA1*01:01, DQB1*05:03, *06:02, *06:03, and *06:04 were robustly suggested by all indicators of meta-analyses. The haplotypes DR7 and DR11 were strongly suggested to be protective in Arabs. A relatively small number of studies have emerged from Arab countries, mostly with inadequate power on an individual basis. This study fills the gap by providing significant size effect of human leukocyte antigen (HLA) alleles and completes the continuum of global ethnic differences in this context.

Rennet-induced gelation of concentrated milk in the presence of sodium caseinate: differences between milk concentration using ultrafiltration and osmotic stressing.

Concentrating milk is a common unit operation in the dairy industry. With the reduction of water, the particles interact more frequently with each other and the functionality of the casein micelles may depend on the interactions occurring during concentration. The objective of this research was to investigate the effect of concentration on the renneting properties of the casein micelles by comparing 2 concentration methods: ultrafiltration and osmotic stressing. Both methods selectively concentrate the protein fraction of milk, while the composition of the soluble phase is unaltered. To evaluate possible differences in the rearrangements of the casein micelles during concentration, renneting properties were evaluated with or without the addition of soluble caseins, added either before or after concentration. The results indicate that casein micelles undergo rearrangements during concentration and that shear during membrane filtration may play a role in affecting the final properties of the milk.

Evaluation of Sialometric Analysis of Patients Suffering from Depressive Disorders.

BACKGROUND: Depressive disorders, worldwide, may rank second by the year 2020. In India; about 10 million people suffer from depressive disorders, the prevalence rate being recorded as 31.2 for every 1000 individuals. A significant impairment of all personal hygiene may occur due a depressive episode which in turn may result in altered salivary flow. OBJECTIVE: The present study was a hospital- based clinical cross-sectional study which was conducted in Bhopal, the heart of Madhya Pradesh, India. It was done to assess the relationship of bring about a comparison of sialometric alterations between normal and subjects with depressive disorders. METHOD: The survey period extended over a period of one year and two months, from May 2009 to July 2010. It was conducted in Bhopal, Madhya Pradesh, Central India. A sample size of 150 individuals, 50 of each group, was taken in the study. Whole salivary flow rates were determined by gravimetric method (i.e., in millilitres per minute). The Tenovuo criterion was used, to which numerical scores (SFI) were attributed. RESULT: Results showed that the unstimulated salivary flow rates between patients of Group I and Group III (p< 0.0001) and between Group II and Group III (p < 0.0001) were statistically significant. The study also showed statistically significant relation between subjective and objective oral dryness (chi 2= 55.789, df= 6 and p< 0.0001). CONCLUSION: It was observed that subjective sensation of dry mouth may exist even in the presence of normal salivary flow rates. This might be acknowledged as a psychophysiological expression of depression and may not necessarily reflect actual salivary gland function. The lack of secreted mucins rather than the quantity of saliva may play a role in the genesis of xerostomia.