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Peroxynitrite (ONOO - ) is a highly reactive nitrogen species that can cause significant damage to proteins, lipids, and DNA. Various enzymes, including metalloenzymes, play crucial roles in reducing ONOO - concentrations to protect cellular components. While the interaction of ONOO - with heme proteins is well known, the reduction by Cu-containing proteins is less studied. Amyloid precursor protein (APP), implicated in Alzheimer's disease, has an E2 domain that binds copper ions with a dissociation constant of K D ∼ 10 -12 M and is proposed to be involved in iron homeostasis, copper trafficking, and oxidative stress response. Our recent studies using EXAFS, UV-Vis, and EPR spectroscopy revealed a previously unidentified labile water ligand in the Cu(II) site of the E2 domain, suggesting reactivity with anionic substrates like ONOO - . Experimental data showed that Cu(I)-E2 reduces ONOO - at a significant rate (1.1 × 10 5 M -1 s -1 ), comparable to native peroxynitrite scavengers, while maintaining active site integrity through multiple redox cycles. This study further investigates the mechanism of ONOO - reduction by Cu(I)-E2 using the Griess assay, demonstrating that reduction occurs via single electron transfer, forming nitrite and nitrate. This process aligns with previous findings that Cu(I)-E2 is oxidized to Cu(II)-E2 upon ONOO - reduction. Mutations at Lys435, affecting secondary sphere interactions, revealed that factors beyond electrostatics are involved in substrate recruitment. MD simulations suggest that steric hindrance from a newly formed hydrogen bond also plays a role. Understanding ONOO - reduction by the E2 domain of APP expands our knowledge of copper proteins in mitigating oxidative stress and elucidates their physiological and pathological roles, particularly in Alzheimer's disease.

Asthma is a prevalent chronic respiratory disease affecting all age groups globally, causing significant morbidity and mortality. Small airway involvement, often undetected by traditional spirometry, has emerged as a critical aspect of asthma pathophysiology, especially in severe cases. This retrospective observational study aimed to assess small airway dysfunction using impulse oscillometry (IOS) in 94 severe asthma patients. Results indicated that 27.3% of patients had small airway obstruction. While spirometry showed no statistical differences between groups, IOS parameters were significantly different, highlighting its sensitivity in detecting small airway disease. Patients with small airway involvement exhibited poorer asthma control, emphasizing the clinical relevance of identifying and addressing small airway dysfunction. The study underscores the need for comprehensive evaluation tools like IOS alongside spirometry, especially in severe asthma management. Further large-scale studies are warranted to validate IOS's utility in optimizing therapeutic strategies and improving asthma control, particularly in resource-limited settings. Recognizing and addressing small airway involvement could lead to individualized management approaches and better outcomes in severe asthma patients.

TEMPUS is a new detector system being developed for photon science. It is based on the Timepix4 chip and, thus, it can be operated in two distinct modes: a photon-counting mode, which allows for conventional full-frame readout at rates up to 40 kfps; and an event-driven time-stamping mode, which allows excellent time resolution in the nanosecond regime in measurements with moderate X-ray flux. In this paper, the initial prototype, a single-chip device, is introduced, and the readout system described. Moreover, and in order to evaluate its capabilities, some tests were performed at PETRA III and ESRF for which results are also presented., (open access.)

Introduction: Colistin is used to treat hospital-acquired pneumonia and ventilator-associated pneumonia. However, direct drug deposition at the site of infection may improve its efficacy and reduce systemic exposure. The aim of this study was to assess the safety and tolerability of nebulized colistin among Indian patients diagnosed with pneumonia caused by multidrug-resistant gram-negative bacilli in real-world settings., Methodology: We retrospectively reviewed the medical records of patients treated with nebulized colistin for pneumonia. We assessed the adverse events and relevant abnormal laboratory findings of nebulized colistin therapy., Results: All enrolled patients (N=30, males: 22, females: 8; average age: 71.06 years) were treated for 13.36 days. Almost 80% of patients had a history of shortness of breath, which was a major symptom when they were admitted to the hospital. The patients were administered nebulized colistin for an average of six days (8 hours per day). The most common dosing schedule was 1 million international units (MIU)/8 hours. No serious adverse event was observed, and only one patient died while on the treatment but the death was not related to colistin treatment. The average sequential organ failure assessment score for all patients was 6.5., Conclusion: Our study demonstrated the efficient clinical utility and well-tolerated safety profile of nebulized colistin in the treatment of patients with pneumonia. Neurotoxicity and nephrotoxicity were not reported. Since a significant percentage of patients were with chronic respiratory diseases, our study further indicates the safety and effectiveness of nebulized colistin in chronic obstructive pulmonary disease (COPD) patients too., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Talwar et al.)

Here we report the evidence of an additional magnetic ordering and frequency dispersive magneto-dielectric (MD) permittivity besides multiferroic behavior in Te 4+ ( S = 0) doped FeVO 4 . Two antiferromagnetic transitions similar to FeVO 4 at ∼21.86 K (TN1) and 16.03 K (TN2) were observed in all samples. An additional novel defect clusters based magnetic ordering at relatively higher temperature (TAMO) ∼ 203 K is also observed from the magnetization. Evaluated magnetic moments show systematic decrease and the magnetic frustration factors show an increase with the increasing of Te 4+ ( S = 0) content. MD studies show stable ferroelectric ordering at spiral magnetic transition (TN2) and the multiferroic order persists to the largest doping of Te ( x = 0.10). The MD studies also reveal a magneto-capacitive (MC) behavior at TAMO(∼203 K) with a high dielectric constant and loss, and the possible reason for the magnetic ordering and MC behavior is ascribed to short range magnetic clustering arising out of defect based mechanisms. Mössbauer spectroscopic studies confirm local structural correlation with magnetic and ferroelectric ordering., (© 2023 IOP Publishing Ltd.)

Background: Identifying risk factors for poor outcomes can help with risk stratification and targeting of treatment. Risk factors for mortality and exacerbations have been identified in bronchiectasis but have been almost exclusively studied in European and North American populations. This study investigated the risk factors for poor outcome in a large population of bronchiectasis patients enrolled in India., Methods: The European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC) and Respiratory Research Network of India (EMBARC-India) registry is a prospective observational study of adults with computed tomography-confirmed bronchiectasis enrolled at 31 sites across India. Baseline characteristics of patients were used to investigate associations with key clinical outcomes: mortality, severe exacerbations requiring hospital admission, overall exacerbation frequency and decline in forced expiratory volume in 1 s., Results: 1018 patients with at least 12-month follow-up data were enrolled in the follow-up study. Frequent exacerbations (≥3 per year) at baseline were associated with an increased risk of mortality (hazard ratio (HR) 3.23, 95% CI 1.39-7.50), severe exacerbations (HR 2.71, 95% CI 1.92-3.83), future exacerbations (incidence rate ratio (IRR) 3.08, 95% CI 2.36-4.01) and lung function decline. Coexisting COPD, dyspnoea and current cigarette smoking were similarly associated with a worse outcome across all end-points studied. Additional predictors of mortality and severe exacerbations were increasing age and cardiovascular comorbidity. Infection with Gram-negative pathogens (predominantly Klebsiella pneumoniae ) was independently associated with increased mortality (HR 3.13, 95% CI 1.62-6.06), while Pseudomonas aeruginosa infection was associated with severe exacerbations (HR 1.41, 95% CI 1.01-1.97) and overall exacerbation rate (IRR 1.47, 95% CI 1.13-1.91)., Conclusions: This study identifies risk factors for morbidity and mortality among bronchiectasis patients in India. Identification of these risk factors may support treatment approaches optimised to an Asian setting., Competing Interests: Conflict of interest: M. Loebinger reports grants from AstraZeneca, Insmed and Grifols, outside the submitted work. F. Blasi reports grants from AstraZeneca, Bayer, Chiesi, GlaxoSmithKline, Menarini and Pfizer; consulting fees from Novartis, Pfizer, Zambon, Vertex, Viatris, AstraZeneca, Bayer, Chiesi, GlaxoSmithKline, Grifols, Guidotti, Insmed and Menarini, outside the submitted work. A. Shoemark reports grants from AstraZeneca, outside the submitted work. E. Polverino reports grants from Chiesi, Zambon, Shionogi, Teva, CSL Boehring, Insmed and Grifols, outside the submitted work. T. Welte reports grants from AstraZeneca and GlaxoSmithKline, outside the submitted work. M. Shteinberg reports grants from Trudell, GlaxoSmithKline, Novartis, Boehringer Ingelheim, AstraZeneca, Kamada, Vertex, Teva, Actelion and Rafa, outside the submitted work. S. Aliberti reports grants from Insmed, Chiesi and Fisher & Paykel; consulting fees from McGraw Hill, Insmed, Zambon, AstraZeneca, CSL Behring, Grifols, Fondazione Charta, Boehringer Ingelheim, Chiesi, Zcube, Menarini and GlaxoSmithKline, outside the submitted work. S. Limaye reports grants from Glenmark, supporting the present manuscript. J.D. Chalmers reports grants from AstraZeneca, Novartis, Boehringer Ingelheim, Insmed, GlaxoSmithKline and Gilead Sciences; consulting fees from AstraZeneca, Insmed, Boehringer Ingelheim, Janssen, Chiesi, Novartis, GlaxoSmithKline, Pfizer and Zambon, outside the submitted work. All other authors have nothing to disclose., (Copyright ©The authors 2023.)

Background and Objective: Severe asthma phenotyping based on invasive and non-invasive bio-markers assists in a better understanding of heterogeneity of clinical presentations and thereby using targeted therapies. Therefore, the current study was conducted to evaluate phenotypes based on non-invasive bio-markers of severe asthma patients attending a tertiary care hospital in North India., Methods: This was a retrospective, observational study conducted on the patients who visited the respiratory department of a tertiary care hospital in North India. Patients aged 18 years and above diagnosed with severe asthma were classified into distinct phenotypes, namely, atopic asthma, eosinophilic asthma, and Type 2 low asthma. Patients with their clinical and functional parameters were classified based on the levels of bio-chemical and hematological results [such as total/specific IgE, blood absolute eosinophil count (AEC)], skin prick tests, history of allergy, and the presence of allergic symptoms., Results: Out of total 100 severe asthmatics, the majority of the patients had an eosinophilic asthma (49%) phenotype, followed by atopic (allergic) asthma (36%) and Type 2 low asthma (15%) phenotypes. However, it was found that 29% of these patients had overlap of both atopy and eosinophilia. The atopic phenotype showed allergic symptoms, positive skin prick tests, and elevated IgE levels. The eosinophilic phenotype had high AEC (≥300 cells/uL) and low IgE (< 30 IU/ml) levels. The Type 2 low phenotype showed low AEC and IgE levels along with the absence of allergic symptoms. However, among these 100 patients, overlapping traits of both atopy and eosinophilia were labelled as overlap phenotypes. 50% of type 2 low severe asthma cases had eosinophils >150 cells/cmm and were eligible for mepolizumab., Conclusions: Identification of severe asthma pheno-endotypes based on simple non-invasive bio-markers is feasible in Indian settings, and it is of utmost importance for future treatment planning in these patients with available biologicals. Overlap of eosinophilic and atopic endotypes in one-third cases would challenge physicians to choose upfront appropriate biologicals in our country. Type 2 low asthma was least common with only <10% cases of severe asthma being ineligible for any biological., Competing Interests: None

Acute exacerbation (AE) in idiopathic pulmonary fibrosis (IPF) is unfortunate a deadly event with a very high mortality rate. Its occurrence is highly unpredictable, though few baseline risk factors have been identified. The revised definition of AE is more precise with clarity on defined parameters. However, no clear guidelines exist on treatment, with most therapies showing inconsistent benefits. Both the approved anti-fibrotic (pirfenidone and nintedanib) have shown equal efficacy in reducing the decline in lung functions, with few studies suggesting a drop in AE. We report a case of a patient with IPF with mildly impaired lung functions who was initiated on pirfenidone with dose titrated on a weekly basis but developed AE-IPF on day 10 of starting pirfenidone and after four days of doubling the dose from 600 mg/day to 1,200 mg/day. This raised the suspicion of whether pirfenidone played any role in this unfortunate event. With no response to conventional therapy of steroids and non-invasive ventilation for AE-IPF, initialization of nintedanib led to recovery with discharge of the patient in two weeks of hospitalization. This case highlights inadequacy in knowledge about the effects of these anti-fibrotics in IPF and recommends close monitoring in the future., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Kaushal et al.)

Background: Pulmonary renal syndrome (PRS) is a simultaneous occurrence of diffuse alveolar hemorrhage (DAH) and glomerulonephritis (GN). The diagnosis of PRS not only requires a high index of clinical suspicion and prompt management, but it is often fatal due to rapidly progressive clinical deterioration despite aggressive treatment. The authors, therefore, share the real-world experience of PRS presenting to tertiary care pulmonary center in north India., Aims: The objectives of the study were to identify etiology, clinical manifestations, treatment modalities and outcomes of patients presenting with PRS., Materials & Methods: This was a retrospective observational study undertaken at Metro Centre for Respiratory Diseases of patients diagnosed with PRS during the last two years between 2019 and 2021. The patients diagnosed with PRS based on clinical manifestations, serology and biopsies were included in the study. All cases of non-immunological causes of PRS were excluded from the study. Chi-square and Mann-Whitney U tests were done to look for associations obtained between survivors and non-survivors. Cox regression analysis was done to estimate the hazard ratios of clinical variables on survival in PRS patients., Results: A total of 12 patients of PRS were included in the study and diagnosis was made based on clinical manifestations, serology as well as biopsies. The mean age of presentation was 45.4 (± 17.8) years and 66.7% of the patients were females. The most common etiology was anti-nuclear cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) seen in 83.3% of the cases. The most common symptoms were coughing and fever (80%) followed by dyspnea and hemoptysis (70%) with the mean duration of symptoms being 17.1 (±8.9) days. The mortality of PRS patients in our study was 41.6% and these patients had a higher acute physiology and chronic health evaluation (APACHE) score (median-26) compared to those patients who survived (median - 15.8)., Conclusion: The occurrence of PRS, although rare, presents with rapid clinical deterioration leading to a high mortality rate. AAV was the most common cause of PRS as observed in our study. Early recognition and prompt aggressive management strategies with immunosuppressant therapies are essential for better outcomes for the patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Talwar et al.)

The present work reports polarization response and the effects of ac - & dc -fields on 30% Sn doped BaTiO 3 polycrystalline relaxor thin films as a function of temperature. Apart from the low temperature frequency dispersion in dielectric data, a frequency independent local maxima in dielectric constant and a concomitant peak in dielectric loss at T * ∼ 245 K is observed, which is unusual of bulk relaxor systems. Below T *, dispersion in dielectric constant becomes quite evident showing signatures of non-ergodic behavior. Subsequently, the dielectric and polarization responses in ergodic (> T *) and non-ergodic (< T *) states are studied to determine the polar state in the system. The ac -field dependence of permittivity indicates the presence of domain like dynamics, predominantly in non-ergodic state. Field induced transition to ferroelectric state, both in ergodic and non-ergodic phases, is demonstrated from the dc -field studies. Further, the dc -field and polarization hysteresis studies reveal the system resembles that of anti-ferroelectric systems below T *, a possible signature for the existence of incommensurate polar regions. These experimental results put together, provides key insights in understanding the field effects of relaxor behavior in doped barium titanate systems., (© 2021 IOP Publishing Ltd.)

We have investigated magnetic, structural and dielectric properties of Bi 5 FeTi 3 O 15 (BFTO) in the temperature range 5K-300 K. Using diffraction, Raman spectroscopy and x-ray absorption fine structure measurements, iso-structural modifications are observed at low temperatures (≈100 K). The analysis of dielectric constant data revealed signatures of dielectric relaxation, concomitant with these structural modifications in BFTO at the same temperatures. Further, employing complementary experimental methods, it is shown that the distribution of Fe/Ti ions in BFTO is random. With the help of techniques that probe magnetism at various length and time scales, it is shown that the phase-pure BFTO is non-magnetic down to the lowest temperatures., (© 2021 IOP Publishing Ltd.)

Amyloidosis is an uncommon heterogeneous and multi-systemic disease characterized by extracellular amyloid deposition. The size of proteins varies and forms a part of local disease or systemic process. Light chain amyloidosis (AL) is the most prevalent form of systemic amyloidosis which may also be seen in localized disease. Isolated tracheobronchial amyloidosis (TBA) is rather unusual with local amyloid deposition which may pose a diagnostic dilemma with subsequent therapeutic challenge. Awareness of such a presentation is crucial in the diagnosis of this rare disease. We describe three cases who presented with haemoptysis, which on further evaluation were diagnosed as isolated TBA, and a review of literature., (© 2020 The Authors. Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of Respirology.)

Background: Bronchiectasis is a common but neglected chronic lung disease. Most epidemiological data are limited to cohorts from Europe and the USA, with few data from low-income and middle-income countries. We therefore aimed to describe the characteristics, severity of disease, microbiology, and treatment of patients with bronchiectasis in India., Methods: The Indian bronchiectasis registry is a multicentre, prospective, observational cohort study. Adult patients (≥18 years) with CT-confirmed bronchiectasis were enrolled from 31 centres across India. Patients with bronchiectasis due to cystic fibrosis or traction bronchiectasis associated with another respiratory disorder were excluded. Data were collected at baseline (recruitment) with follow-up visits taking place once per year. Comprehensive clinical data were collected through the European Multicentre Bronchiectasis Audit and Research Collaboration registry platform. Underlying aetiology of bronchiectasis, as well as treatment and risk factors for bronchiectasis were analysed in the Indian bronchiectasis registry. Comparisons of demographics were made with published European and US registries, and quality of care was benchmarked against the 2017 European Respiratory Society guidelines., Findings: From June 1, 2015, to Sept 1, 2017, 2195 patients were enrolled. Marked differences were observed between India, Europe, and the USA. Patients in India were younger (median age 56 years [IQR 41-66] vs the European and US registries; p<0·0001]) and more likely to be men (1249 [56·9%] of 2195). Previous tuberculosis (780 [35·5%] of 2195) was the most frequent underlying cause of bronchiectasis and Pseudomonas aeruginosa was the most common organism in sputum culture (301 [13·7%]) in India. Risk factors for exacerbations included being of the male sex (adjusted incidence rate ratio 1·17, 95% CI 1·03-1·32; p=0·015), P aeruginosa infection (1·29, 1·10-1·50; p=0·001), a history of pulmonary tuberculosis (1·20, 1·07-1·34; p=0·002), modified Medical Research Council Dyspnoea score (1·32, 1·25-1·39; p<0·0001), daily sputum production (1·16, 1·03-1·30; p=0·013), and radiological severity of disease (1·03, 1·01-1·04; p<0·0001). Low adherence to guideline-recommended care was observed; only 388 patients were tested for allergic bronchopulmonary aspergillosis and 82 patients had been tested for immunoglobulins., Interpretation: Patients with bronchiectasis in India have more severe disease and have distinct characteristics from those reported in other countries. This study provides a benchmark to improve quality of care for patients with bronchiectasis in India., Funding: EU/European Federation of Pharmaceutical Industries and Associations Innovative Medicines Initiative inhaled Antibiotics in Bronchiectasis and Cystic Fibrosis Consortium, European Respiratory Society, and the British Lung Foundation., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Pulmonary mucormycosis is a life-threatening opportunistic fungal infection. It is considered as a disease of immunocompromised state and is rarely seen in immunocompetent patients. We here report a case of refractory bronchovascular pleuropulmonary mucormycosis, who despite early detection, optimal management with liposomal amphotericin B, and posaconazole therapy followed by surgery, progressed further and led to a fatal outcome. Dual antifungal therapy combined with surgery is the only definitive treatment option available in the literature. Many new therapeutic options for mucormycosis treatment have become available but none have shown promising results, and larger studies are required to assess their efficacy.

Hemoptysis is considered as a medical emergency which requires urgent stabilization with identification and correction of underlying etiology. Diagnosis of the cause of hemoptysis is not always readily identified after bronchoscopy and conventional computed tomography (CT) chest. Arteriovenous malformation (AVM) is a rare but important cause of massive hemoptysis which can be easily picked up by the use of double turn contrast CT chest. We here report a rare congenital AVM anomaly called Klippel-Trenaunay-Parks-Weber syndrome as a cause of massive hemoptysis and utility of double turn CT in diagnosing AVM as a cause of hemoptysis.

Literature on concurrent association of sarcoidosis with lymphoproliferative malignancies other than lymphoma e.g. multiple myeloma is meager. The rarity of the situation prompted us to report this patient who was a 51-year-old woman with a 2-years history of breathlessness, cough with expectoration, chest pain and backache. Initial evaluation revealed mild anemia, increased alkaline phosphatase with chest skiagram showing both lower zone non homogenous opacities with calcified hilar lymph nodes. CECT chest showed mediastinal with bilateral hilar lymphadenopathy, parenchymal fibrosis, traction bronchiectasis, ground glass opacities, septal and peribronchovascular thickening affecting mid and lower lung zones bilaterally. MRI Dorsolumbar spine was suggestive of marrow infiltrative disorder. EBUS FNA of intrathoracic nodes, EBB and TBLB confirmed sarcoidosis. PET CT revealed hyper metabolic activity in lung, multiple lymph nodes and lytic bone lesions. Serum protein electrophoresis and immunofixation revealed a monoclonal paraprotein, immunoglobulin IgG kappa type. Bone marrow biopsy revealed an increase in plasma cells (15%), but no granulomas. Diagnosis of Indolent or multiple myeloma with sarcoidosis was established. 12 cases of sarcoidosis and multiple myeloma have been reported in literature, and mostly preceding the onset of multiple myeloma by many years, in our case both were diagnosed concurrently.

A 47-year-old-female presented with dyspnea and unproductive cough for 4 months. General examination revealed pulsatile swelling in the midline below the thyroid cartilage present since childhood. Computed tomography-angiography of the neck showed right innominate artery dilated, elongated and coursing above downward, anterior to the trachea below the thyroid, compressing the trachea and origin of the right subclavian artery higher up. A case of anomalous innominate artery causing symptomatic compression of the trachea in adults is a rare entity.

A 62-year-old Black man was found to have a malignant hepatoma localized to the right lobe of the liver but multicentric in origin. Alpha-fetoprotein (AFP) was found to be present in the serum, but, after a right hemi-hepatectomy, it was no longer detectable. The implications are discussed.

Sixteen cases of perforated duodenal ulcer in Black patients admitted to Tembisa Hospital during a 1-year period are reviewed. They constitute 0,4% of all surgical admissions. Duodenal ulcer has been considered a rare disease in South African Blacks, but we believe that the incidence is increasing in Black urban populations. The literature is reviewed and possible aetiological factors are discussed.

The literature on Cushing's syndrome associated with pregnancy is reviewed, and a case of this rare association is reported. The patient had an adrenal adenoma. Investigations and interpretation of stimulation and suppression tests are discussed. Cortisol metabolism in normal pregnancy is referred to.