Metabolomics of asthma, COPD, and asthma-COPD overlap: an overview.

The two common progressive lung diseases, asthma and chronic obstructive pulmonary disease (COPD), are the leading causes of morbidity and mortality worldwide. Asthma-COPD overlap, referred to as ACO, is another complex pulmonary disease that manifests itself with features of both asthma and COPD. The disease has no clear diagnostic or therapeutic guidelines, thereby making both diagnosis and treatment challenging. Though a number of studies on ACO have been documented, gaps in knowledge regarding the pathophysiologic mechanism of this disorder exist. Addressing this issue is an urgent need for improved diagnostic and therapeutic management of the disease. Metabolomics, an increasingly popular technique, reveals the pathogenesis of complex diseases and holds promise in biomarker discovery. This comprehensive narrative review, comprising 99 original research articles in the last five years (2017-2022), summarizes the scientific advances in terms of metabolic alterations in patients with asthma, COPD, and ACO. The analytical tools, nuclear magnetic resonance (NMR), gas chromatography-mass spectrometry (GC-MS), and liquid chromatography-mass spectrometry (LC-MS), commonly used to study the expression of the metabolome, are discussed. Challenges frequently encountered during metabolite identification and quality assessment are highlighted. Bridging the gap between phenotype and metabotype is envisioned in the future.

Unsuspected Subclinical Left Ventricular Dysfunction in Post-COVID Patients: A Real-world Observation.

BACKGROUND: Subclinical myocardial dysfunction may exist in post-COVID-19 patients and may carry significance in long term. METHODOLOGY: Subjects of long-COVID-19 with historically and radiologically significant pulmonary involvement (without documented cardiac involvement) were evaluated on outpatient follow-up echocardiographically when they had disproportionate shortness of breath (SOB), fatigue, or high pulse rate as perceived by the physicians. The common acute-phase symptoms were noted and scored retrospectively. The assessment included spirometry and measurement of chronic obstructive pulmonary disease (COPD) assessment test (CAT) score with measurement of the left ventricular (LV) and right ventricular (RV) free wall global longitudinal strain as an adjunct to routine two-dimensional and Doppler echocardiography and spirometry. The results were evaluated statistically with respect to the history of hospitalization. RESULTS: The hospitalized (n = 15) and nonhospitalized (n = 10) patients were demographically similar. However, the nonhospitalized patients had higher total symptom score (p = 0.03), anosmia (p = 0.017), and ageusia (p = 0.0019). At follow-up (>3 months of acute illness), the nonhospitalized patients had a better CAT score (p = 0.04), higher change in max pulse rate (p = 0.03), and higher forced expiratory volume in 1 second (FEV1) (p = 0.002), tricuspid annular plane systolic excursion (TAPSE) (p = 0.02), and left ventricular global longitudinal strain (LVGLS) (-17.15 ± 1.19 vs -13.11 ± 1.91) (p = 0.0001). Overall, the two groups formed distinct clusters. The LVGLS and the maximum pulse rate difference in the two chair test (2CT) seem to contribute maximally to the variance between the two groups in multivariate analysis. CONCLUSION: The subclinical myocardial dysfunction persisting in post-COVID patients (without suspected cardiac affection and lower neuroinflammatory symptoms in the acute phase) with significant pulmonary affection needs further evaluation. They demonstrate a higher max pulse rate difference in the 2CT. This real-world observation demands further investigations.

Identification of novel metabolic signatures potentially involved in the pathogenesis of COPD associated pulmonary hypertension.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) associated pulmonary hypertension (COPD-PH), one of the most prevalent forms of PH, is a major burden on the healthcare system. Although PH in COPD is usually of mild-to-moderate severity, its presence is associated with shorter survival, more frequent exacerbations and worse clinical outcomes. The pathophysiologic mechanisms responsible for PH development in COPD patients remain unclear. It is envisioned that a better understanding of the underlying mechanism will help in diagnosis and future treatment strategies. OBJECTIVES: The present study aims to determine metabolomic alterations in COPD-PH patients as compared to healthy controls. Additionally, to ensure that the dysregulated metabolites arise due to the presence of PH per se, an independent COPD cohort is included for comparison purposes. METHODS: Paired serum and exhaled breath condensate (EBC) samples were collected from male patients with COPD-PH (n = 60) in accordance with the 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines. Age, sex and BMI matched healthy controls (n = 57) and COPD patients (n = 59) were recruited for comparison purposes. All samples were characterized using 1H nuclear magnetic resonance (NMR) spectroscopy. RESULTS: Fifteen serum and 9 EBC metabolites were found to be significantly altered in COPD-PH patients as compared to healthy controls. Lactate and pyruvate were dysregulated in both the biofluids and were further correlated with echocardiographic systolic pulmonary artery pressure (sPAP). Multivariate analysis showed distinct class separation between COPD-PH and COPD. CONCLUSIONS: The findings of this study indicate an increased energy demand in patients with COPD-PH. Furthermore, both lactate and pyruvate correlate with sPAP, indicating their importance in the clinical course of the disease.

Impact of long-term doxycycline on lung function & exacerbations: A real-world open, prospective pilot observation on chronic obstructive pulmonary disease.

BACKGROUND & OBJECTIVES: Upregulation of matrix metalloproteinases (MMPs) is related to the pathogenesis of chronic obstructive pulmonary disease (COPD). We aimed at assessing the tolerability and impact of long-term use of MMP inhibitor doxycycline in COPD. METHODS: A cohort of COPD patients was randomized to continue a uniform COPD treatment with or without add-on long-term oral doxycycline. The lung exacerbations (spirometry), adverse events and health status (COPD Assessment Test score) were noted at 3, 6, 9 and 12 months of therapy. Measurement of the serum MMP-2, and 9 and high-sensitive C-reactive protein (hs-CRP) levels was done at the start of the study and at three months, whenever possible. RESULTS: There were 27, 19, 13 and 10 patients with add-on doxycycline group and 22, 19, 11 and 7 patients with COPD treatment alone at 3, 6, 9 and 12 months of treatment respectively. The improvement was obvious and mostly (at 6 and 12 months) significant (P >0.05) for lung function parameters [forced expiratory volume in one second (FEV1), FEV1/forced vital capacity (FVC) and forced expiratory flow at 25-75% of FVC (FEF25-75)] and universal for health status at all measurements, with an overall 26.69 per cent reduction in exacerbations. The analysis with the lung function changes in the available population with protocol violation also supported the same trend. The concomitant reduction in serum MMP-9 (P =0.01), MMP-2 (P =0.01) and hs-CRP (P =0.0001) levels (n=21) at three months was also significant. The adverse reactions with add-on doxycycline appeared acceptable. INTERPRETATION & CONCLUSIONS: Long-term doxycycline appears well tolerated and seems to improve lung function, health status and exacerbations in COPD. The claim needs further scientific validations.

Metabolomic fingerprinting and systemic inflammatory profiling of asthma COPD overlap (ACO).

BACKGROUND: Asthma-COPD overlap (ACO) refers to a group of poorly studied and characterised patients reporting with disease presentations of both asthma and COPD, thereby making both diagnosis and treatment challenging for the clinicians. They exhibit a higher burden in terms of both mortality and morbidity in comparison to patients with only asthma or COPD. The pathophysiology of the disease and its existence as a unique disease entity remains unclear. The present study aims to determine whether ACO has a distinct metabolic and immunological mediator profile in comparison to asthma and COPD. METHODS: Global metabolomic profiling using two different groups of patients [discovery (D) and validation (V)] were conducted. Serum samples obtained from moderate and severe asthma [n = 34(D); n = 32(V)], moderate and severe COPD [n = 30(D); 32(V)], ACO patients [n = 35(D); 40(V)] and healthy controls [n = 33(D)] were characterized using gas chromatography mass spectrometry (GC-MS). Multiplexed analysis of 25 immunological markers (IFN-γ (interferon gamma), TNF-α (tumor necrosis factor alpha), IL-12p70 (interleukin 12p70), IL-2, IL-4, IL-5, IL-13, IL-10, IL-1α, IL-1ß, TGF-ß (transforming growth factor), IL-6, IL-17E, IL-21, IL-23, eotaxin, GM-CSF (granulocyte macrophage-colony stimulating factor), IFN-α (interferon alpha), IL-18, NGAL (neutrophil gelatinase-associated lipocalin), periostin, TSLP (thymic stromal lymphopoietin), MCP-1 (monocyte chemoattractant protein- 1), YKL-40 (chitinase 3 like 1) and IL-8) was also performed in the discovery cohort. RESULTS: Eleven metabolites [serine, threonine, ethanolamine, glucose, cholesterol, 2-palmitoylglycerol, stearic acid, lactic acid, linoleic acid, D-mannose and succinic acid] were found to be significantly altered in ACO as compared with asthma and COPD. The levels and expression trends were successfully validated in a fresh cohort of subjects. Thirteen immunological mediators including TNFα, IL-1ß, IL-17E, GM-CSF, IL-18, NGAL, IL-5, IL-10, MCP-1, YKL-40, IFN-γ, IL-6 and TGF-ß showed distinct expression patterns in ACO. These markers and metabolites exhibited significant correlation with each other and also with lung function parameters. CONCLUSIONS: The energy metabolites, cholesterol and fatty acids correlated significantly with the immunological mediators, suggesting existence of a possible link between the inflammatory status of these patients and impaired metabolism. The present findings could be possibly extended to better define the ACO diagnostic criteria, management and tailoring therapies exclusively for the disease.

Multisystem Inflammatory Syndrome of Children Related to SARS-CoV-2: A Novel Experience in Children with a Novel Virus.

Severe acute respiratory syndrome-coronavirus-2 (SARS CoV-2) is a novel virus. There has been an increasing number of case reports on multisystem inflammatory syndrome in children (MIS-C) but the global and population-specific incidence of MIS-C particularly in Asian countries, its causal relationship with SARS-CoV-2 and its immunopathogenesis remain unknown. Emerging questions on how the pathophysiology of MIS-C differs from that of Kawasaki disease (KD) and non-KD inflammatory syndromes need to be answered. Genetic factors influencing the incidence of MIS-C in the different ethnic populations are to be explored. What happens to the children with MIS-C, in the long run, remains unknown to date. Multicenter clinical trials are needed to establish optimal treatment and follow-up for MIS-C. HOW TO CITE THIS ARTICLE: Bhattacharyya P. Multisystem Inflammatory Syndrome of Children Related to SARS-CoV-2: A Novel Experience in Children with a Novel Virus. Indian J Crit Care Med 2020;24(11):1010-1011.

Metabolomic signatures of asthma-COPD overlap (ACO) are different from asthma and COPD.

INTRODUCTION: Asthma-chronic obstructive pulmonary disease (COPD) overlap, termed as ACO, is a complex heterogeneous disease without any clear diagnostic or therapeutic guidelines. The pathophysiology of the disease, its characteristic features, and existence as a unique disease entity remains unclear. Individuals with ACO have a faster lung function decline, more frequent exacerbations, and worse quality of life than those with COPD or asthma alone. OBJECTIVES: The present study aims to determine whether ACO has a distinct metabolic profile in comparison to asthma and COPD. METHODS: Two different groups of patients were recruited as discovery (D) and validation (V) cohorts. Serum samples obtained from moderate and severe asthma patients diagnosed as per GINA guidelines [n = 34(D); n = 32(V)], moderate and severe COPD cases identified by GOLD guidelines [n = 30(D); 32(V)], ACO patients diagnosed by joint GOLD and GINA guidelines [n = 35(D); 40(V)] and healthy controls [n = 33(D)] were characterized using nuclear magnetic resonance (NMR) spectrometry. RESULTS: Multivariate and univariate analysis indicated that 12 metabolites [lipid, isoleucine, N-acetylglycoproteins (NAG), valine, glutamate, citric acid, glucose, L-leucine, lysine, asparagine, phenylalanine and histidine] were dysregulated in ACO patients when compared with both asthma and COPD. These metabolites were further validated in a fresh cohort of patients, which again exhibited a similar expression pattern. CONCLUSIONS: Our findings suggest that ACO has an enhanced energy and metabolic burden associated with it as compared to asthma and COPD. It is anticipated that our results will stimulate researchers to further explore ACO and unravel the pathophysiological complexities associated with the disease.

Effect of doxycyline in chronic obstructive pulmonary disease - An exploratory study.

PURPOSE: Various mechanisms, including oxidative stress, inflammation, and protease-antiprotease imbalance are proposed for the progressive decline in lung function in chronic obstructive pulmonary disease (COPD). Doxycycline, a broad spectrum tetracycline antibiotic, is reported to have non-antimicrobial matrix metalloproteinases (MMP) inhibitory action in various inflammatory conditions. The effect of doxycycline in COPD is hereby assessed in the present randomized prospective study. PATIENTS AND METHODS: The first group of COPD patients (n = 30; mild (n = 3), moderate (n = 6), severe (n = 7), very severe (n = 14) as per GOLD II & III criteria was prescribed the standard therapy, a combination of (i) short acting anti-muscarinic agent (SAMA) + short acting ß2 agonist (SABA) inhaled and (ii) corticosteroid inhaled (ICS) + long acting ß2 agonist (LABA) (iii) ICS + LABA + LAMA. Whereas doxycycline (100 mg), was used daily once or twice as per Body Mass Index (BMI), as an add-on to existing standard therapy for the second group of patients (n = 30; mild (n = 2), moderate (n = 7), severe (n = 8), very severe (n = 13). All recruited patients were followed-up after 3 months of treatment. Lung function index FEV1(%) predicted, FEV1/FVC (%), quality of life status including COPD Assessment Test (CAT), St. George's Respiratory Questionnaire (SGRQ) were assessed. Routine blood cell count also was performed. RESULTS: Biochemical analysis included estimation of oxidative stress markers, inflammatory cytokines and proteases in plasma of both the groups. Reduction in oxidative stress is evidenced by a significant decrease in Lipid hydro peroxides (LPO), total oxidative stress (TOS) and increase in glutathione peroxidase (GSH-PX), reduced glutathione (GSH) and total anti-oxidant capacity (TAO) nitrite and nitrate (NOx) along with peroxynitrate following 3 months of add-on doxycycline treatment. Reduced levels of cytokines such as interleukin IL-6, TNF-α, IL-8 were also observed. Multivariate analysis identified TNF-α major effective discriminant among pre and post doxycycline treated COPD patients. The expression of TNF-α was inversely correlated with FEV1/FVC (%) changes. The levels of MMP-2 and MMP-9/tissue inhibitors of metalloproteinases (TIMP)-1 ratio (MMP-9/ TIMP-1), also decreased significantly and the decline could be associated with TOS. A significant increase in bilirubin and reduced glutathione (GSH) level was noticed in standard therapy group. CONCLUSION: These data suggest that the improvement in lung function and quality of life in COPD patients may probably be attributed to the antioxidant, anti-inflammatory and anti-MMP activity of doxycycline. The potential therapeutic role of long-term doxycycline, in addition to its traditional antibiotic effect, definitely warrants further attention.

Novel algorithm to identify and differentiate specific digital signature of breath sound in patients with diffuse parenchymal lung disease.

BACKGROUND AND OBJECTIVE: Auscultation is an important part of the clinical examination of different lung diseases. Objective analysis of lung sounds based on underlying characteristics and its subsequent automatic interpretations may help a clinical practice. METHODS: We collected the breath sounds from 8 normal subjects and 20 diffuse parenchymal lung disease (DPLD) patients using a newly developed instrument and then filtered off the heart sounds using a novel technology. The collected sounds were thereafter analysed digitally on several characteristics as dynamical complexity, texture information and regularity index to find and define their unique digital signatures for differentiating normality and abnormality. For convenience of testing, these characteristic signatures of normal and DPLD lung sounds were transformed into coloured visual representations. The predictive power of these images has been validated by six independent observers that include three physicians. RESULTS: The proposed method gives a classification accuracy of 100% for composite features for both the normal as well as lung sound signals from DPLD patients. When tested by independent observers on the visually transformed images, the positive predictive value to diagnose the normality and DPLD remained 100%. CONCLUSIONS: The lung sounds from the normal and DPLD subjects could be differentiated and expressed according to their digital signatures. On visual transformation to coloured images, they retain 100% predictive power. This technique may assist physicians to diagnose DPLD from visual images bearing the digital signature of the condition.

Chronic lung disease and detection of pulmonary artery dilatation in high resolution computerized tomography of chest in chronic arsenic exposure.

Lung affection in chronic arsenicosis developing from chronic ingestion of arsenic contaminated groundwater has been known but little is known on its effect on pulmonary arterial system. A cross sectional study was carried out at two geographically similar areas and demographically similar populations with or without evidence of chronic arsenic exposure in West Bengal, India. The willing participants in both the groups with chronic respiratory symptoms were evaluated with High Resolution Computerized Tomography (HRCT) of Chest. Evaluation of High Resolution Computerized Tomography of chest followed clinical assessment of lung disease in194 and 196 subjects from the arsenic exposed and unexposed people; the former had a higher prevalence of cough OR(Odds Ratio) 3.23 (95% CI(Confidence Interval): 1.72-6.07) and shortness of breath OR1.76 (95% CI: 0.84-3.71), respectively. The arsenic exposed individuals showed higher score for bronchiectasis [mean ± SD(Standard Deviation)] as 2.41 ± 2.32 vs. 1.22 ± 1.48 (P <0.001), pulmonary artery branch dilatation (PAD) as 2.48 ± 2.33 vs. 0.78 ± 1.56, (P <0.001) and pulmonary trunk dilatation as 0.26 ± 0.45 vs. nil. Age-adjusted prevalence odds ratio (POR) for Pulmonary Artery Dilatation Found in HRCT comparing those exposed to arsenic (Group 1) to unexposed participants (Group 2) was found to be 6.98 (CI: 2.26-16.48). There was a strong dose-response relationship between the PAD (Pulmonary Artery Dilatation) and cumulative arsenic exposure. Pulmonary trunk and branch dilatation in chronic arsenicosis is a frequent abnormality seen in HRCT Chest of arsenicosis patients. The significance of such finding needs further investigation.

Understanding pulmonary hypertension: the need for an integrative metabolomics and transcriptomics approach.

Pulmonary hypertension (PH), characterised by mean pulmonary arterial pressure (mPAP) >20 mm Hg at rest, is a complex pathophysiological disorder associated with multiple clinical conditions. The high prevalence of the disease along with increased mortality and morbidity makes it a global health burden. Despite major advances in understanding the disease pathophysiology, much of the underlying complex molecular mechanism remains to be elucidated. Lack of a robust diagnostic test and specific therapeutic targets also poses major challenges. This review provides a comprehensive update on the dysregulated pathways and promising candidate markers identified in PH patients using the transcriptomics and metabolomics approach. The review also highlights the need of using an integrative multi-omics approach for obtaining insight into the disease at a molecular level. The integrative multi-omics/pan-omics approach envisaged to help in bridging the gap from genotype to phenotype is outlined. Finally, the challenges commonly encountered while conducting omics-driven studies are also discussed.

Bioinformatics analysis of hypoxia associated genes and inflammatory cytokine profiling in COPD-PH.

Pulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD) is associated with worse clinical outcomes and decreased survival rates. In absence of disease specific diagnostic/therapeutic targets and unclear pathophysiology, there is an urgent need for the identification of potential genetic/molecular markers and disease associated pathways. The present study aims to use a bioinformatics approach to identify and validate hypoxia-associated gene signatures in COPD-PH patients. Additionally, hypoxia-related inflammatory profile is also explored in these patients. Microarray dataset obtained from the Gene Expression Omnibus repository was used to identify differentially expressed genes (DEGs) in a hypoxic PH mice model. The top three hub genes identified were further validated in COPD-PH patients, with chemokine (C-X-C motif) ligand 9 (CXCL9) and CXCL12 showing significant changes in comparison to healthy controls. Furthermore, multiplexed analysis of 10 inflammatory cytokines, tumor necrosis factor alpha (TNF-α), transforming growth factor ß (TGF-ß), interleukin 1-beta (IL-1ß), IL-4, IL-5, IL-6, IL-13, IL-17, IL-18 and IL-21 was also performed. These markers showed significant changes in COPD-PH patients as compared to controls. They also exhibited the ability to differentially diagnose COPD-PH patients in comparison to COPD. Additionally, IL-6 and IL-17 showed significant positive correlation with systolic pulmonary artery pressure (sPAP). This study is the first report to assess the levels of CXCL9 and CXCL12 in COPD-PH patients and also explores their link with the inflammatory profile of these patients. Our findings could be extended to better understand the underlying disease mechanism and possibly used for tailoring therapies exclusive for the disease.

Leucocytosis in a case of sarcoidosis with pleural involvement--an unknown association.

A case of biopsy-proven sarcoidosis with pleural and lung parenchymal involvement is reported. The resolution of neutrophilia and other disease manifestations with azathioprine points towards sarcoidosis being the probable cause. GG, 45 years old male, presented with fever and right-sided chest pain with biochemical features of granulomatous hepatitis and apparently unexplained leucocytosis. Azathioprine 100 mg daily was started; he improved dramatically within 3 weeks with disappearance of pain and normalization of alkaline phosphatase and leucocytosis. All clinical, biochemical and hematological parameters improved subsequently. There were no significant side effects and the patient is doing well after more than three years on azathioprine. The resolution of neutrophilia on treatment of sarcoidosis suggests a causal relationship. However, further follow-up is essential to screen for future hematological abnormalities.

The impact of lockdown on symptoms and health status of patients with chronic airway diseases: An appraisal of patient perceived impressions.

Background: The pandemic-specific lockdown may influence the health status of patients with chronic airflow obstruction (CAO) as COPD, COPD-PH, and chronic asthma. Objectives: To find the impact of the lockdown on symptoms, and the degree of perceived change in physical activity and emotional health with possible reasons including the indicators of ambient air pollution. Methods: A cohort of CAO patients was telephonically enquired regarding their perceived well-being in symptom status, physical activity, and emotional health with the perceived contribution from plausible reasons (regular medication, simple food, no pollution, and family attention) for the change; all being expressed in percentages. The change in symptom scores as 0-39, 40-79, and 80-100 were regarded as 'low', 'medium', and 'high' respectively. The impact of the individual contributing factor was calculated statistically. The assessment of the CAT (COPD assessment test) score and the ambient air pollution (PM2.5 and PM10) was also done for their association with well-being. Results: There was a universal improvement (p < 0.5) in COPD (n = 113), COPD-PH, (n = 40), and chronic asthma, (n = 19) as regards symptoms, physical activity, and emotional health that tallies to overall and individual change in CAT score. There were concomitant reductions in PM10 and PM2.5 levels during the lockdown compared to the same period of the previous year. All the four listed factors contributed with the 'no/low pollution' and 'simple food being the most important; on acting together, they reduced the moderate and severe symptoms impressively. Conclusion: Reduced air pollution and simple food appear most important for the improvement of CAO patients during the lockdown period.

COPD and glycopyrronium responsiveness assessment: An appraisal.

Clinical Trial Registration: ECR/159/Inst/WB/2013/RR-20. Background: Glycopyrronium bromide (a long-acting antimuscarinic agent: LAMA) appears pharmacokinetically suitable for testing bronchodilator responsiveness as salbutamol (short-acting ß2-agonist: SABA). Exploring the feasibility, acceptability, degree of reversibility with glycopyrronium, and its comparison with that of salbutamol may be intriguing. Methods: New, consecutive, and willing outpatient attendees in the same season of the two consecutive years with chronic obstructive pulmonary disease (FEV1/FVC <0.07; FEV1 <80% of predicted) were subjected to serial responsiveness with inhalation of salbutamol first followed by 50 µg dry powder glycopyrronium [Salbutamol- Glycopyrronium] (phase-1) in the first year and glycopyrronium followed by salbutamol [Glycopyrronium- Salbutamol] (phase-2) in the following year. We looked for the acceptability, adverse reactions, and degree of changes in FEV1, FVC, FEV1/FVC, and FEF25-75 with comparison between the two groups. Results: The [Salbutamol- Glycopyrronium] group (n = 86) were similar in age, body mass index, and FEV1 to the [Glycopyrronium- Salbutamol] group (n = 88). Both the agents could make a significant (P <.0001) improvement in the parameters independently or as add-on when used serially in alternate orders. The intergroup difference at no stage was significant. The sensitive patients to salbutamol (n = 48), glycopyrronium (n = 44), and both (n = 12) have improvement of 165, 189, and 297 mL while a both-insensitive group (n = 70) had barely 44 mL of improvement. The protocol was universally accepted without any adverse events. Conclusion: Serial testing of salbutamol and glycopyrronium responsiveness in alternate orders provides an insight regarding the independent and the add-on effects of these two agents. About 40% of our chronic obstructive pulmonary disease patients had no clinically appreciable difference in FEV1 with the salbutamol + glycopyrronium combination inhalation.

Conformational perturbation of SARS-CoV-2 spike protein using N-acetyl cysteine: an exploration of probable mechanism of action to combat COVID-19.

The infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) resulted in a pandemic with huge death toll and economic consequences. The virus attaches itself to the human epithelial cells through noncovalent bonding of its spike protein with the angiotensin-converting enzyme-2 (ACE2) receptor on the host cell. Based on in silico studies we hypothesized that perturbing the functionally active conformation of spike protein through the reduction of its solvent accessible disulfide bonds, thereby disintegrating its structural architecture, may be a feasible strategy to prevent infection by reducing the binding affinity towards ACE2 enzyme. Proteomics data showed that N-acetyl cysteine (NAC), an antioxidant and mucolytic agent been widely in use in clinical medicine, forms covalent conjugates with solvent accessible cysteine residues of spike protein that were disulfide bonded in the native state. Further, in silico analysis indicated that the presence of the selective covalent conjugation of NAC with Cys525 perturbed the stereo specific orientations of the interacting key residues of spike protein that resulted in threefold weakening in the binding affinity of spike protein with ACE2 receptor. Interestingly, almost all SARS-CoV-2 variants conserved cystine residues in the spike protein. Our finding results possibly provides a molecular basis for identifying NAC and/or its analogues for targeting Cys-525 of the viral spike protein as fusion inhibitor and exploring in vivo pharmaco-preventive and its therapeutic potential activity for COVID-19 disease. However, in-vitro assay and animal model-based experiment are required to validate the probable mechanism of action.Communicated by Ramaswamy H. Sarma.

Development and pilot testing of PROACTIVE: A pediatric onco-critical care capacity and quality assessment tool for resource-limited settings.

BACKGROUND: Nearly 90% children with cancer reside in low- and middle-income countries, which face multiple challenges delivering high-quality pediatric onco-critical care (POCC). We recently identified POCC quality and capacity indicators for PROACTIVE (PediatRic Oncology cApaCity assessment Tool for IntensiVe carE), a tool that evaluates strengths and limitations in POCC services. This study describes pilot testing of PROACTIVE, development of center-specific reports, and identification of common POCC challenges. METHODS: The original 119 consensus-derived PROACTIVE indicators were converted into 182 questions divided between 2 electronic surveys for intensivists and oncologists managing critically ill pediatric cancer patients. Alpha-testing was conducted to confirm face-validity with four pediatric intensivists. Eleven centers representing diverse geographic regions, income levels, and POCC services conducted beta-testing to evaluate usability, feasibility, and applicability of PROACTIVE. Centers' responses were scored and indicators with mean scores ≤75% in availability/performance were classified as common POCC challenges. RESULTS: Alpha-testing ensured face-validity and beta-testing demonstrated feasibility and usability of PROACTIVE (October 2020-June 2021). Twenty-two surveys (response rate 99.4%) were used to develop center-specific reports. Adjustments to PROACTIVE were made based on focus group feedback and surveys, resulting in 200 questions. Aggregated data across centers identified common POCC challenges: (1) lack of pediatric intensivists, (2) absence of abstinence and withdrawal symptoms monitoring, (3) shortage of supportive care resources, and (4) limited POCC training for physicians and nurses. CONCLUSIONS: PROACTIVE is a feasible and contextually appropriate tool to help clinicians and organizations identify challenges in POCC services across a wide range of resource-levels. Widespread use of PROACTIVE can help prioritize and develop tailored interventions to strengthen POCC services and outcomes globally.

A new measure for multi-professional medical team communication: design and methodology for multilingual measurement development.

Background: As implementation science in global health continues to evolve, there is a need for valid and reliable measures that consider diverse linguistic and cultural contexts. A standardized, reproducible process for multilingual measure development may improve accessibility and validity by participants in global health settings. To address this need, we propose a rigorous methodology for multilingual measurement development. We use the example of a novel measure of multi-professional team communication quality, a determinant of implementation efforts. Methods: The development and translation of this novel bilingual measure is comprised of seven steps. In this paper, we describe a measure developed in English and Spanish, however, this approach is not language specific. Participants are engaged throughout the process: first, an interprofessional panel of experts and second, through cognitive interviewing for measure refinement. The steps of measure development included: (1) literature review to identify previous measures of team communication; (2) development of an initial measure by the expert panel; (3) cognitive interviewing in a phased approach with the first language (English); (4): formal, forward-backward translation process with attention to colloquialisms and regional differences in languages; (5) cognitive interviewing repeated in the second language (Spanish); (6) language synthesis to refine both instruments and unify feedback; and (7) final review of the refined measure by the expert panel. Results: A draft measure to assess quality of multi-professional team communication was developed in Spanish and English, consisting of 52 questions in 7 domains. This measure is now ready for psychometric testing. Conclusions: This seven-step, rigorous process of multilingual measure development can be used in a variety of linguistic and resource settings. This method ensures development of valid and reliable tools to collect data from a wide range of participants, including those who have historically been excluded due to language barriers. Use of this method will increase both rigor and accessibility of measurement in implementation science and advance equity in research and practice.

CritCom: assessment of quality of interdisciplinary communication around deterioration in pediatric oncologic patients.

Background: High-quality clinical care requires excellent interdisciplinary communication, especially during emergencies, and no tools exist to evaluate communication in critical care. We describe the development of a pragmatic tool focusing on interdisciplinary communication during patient deterioration (CritCom). Methods: The preliminary CritCom tool was developed after a literature review and consultation with a multidisciplinary panel of global experts in communication, pediatric oncology, and critical care to review the domains and establish content validity iteratively. Face and linguistic validity were established through cognitive interviews, translation, and linguistic synthesis. We conducted a pilot study among an international group of clinicians to establish reliability and usability. Results: After reviewing 105 potential survey items, we identified 52 items across seven domains. These were refined through cognitive interviews with 36 clinicians from 15 countries. CritCom was piloted with 433 clinicians (58% nurses, 36% physicians, and 6% other) from 42 hospitals in 22 countries. Psychometric testing guided the refinement of the items for the final tool. CritCom comprised six domains with five items each (30 total). The final tool has excellent reliability (Cronbach's alpha 0.81-0.86), usability (93% agree or strongly agree that the tool is easy to use), and similar performance between English and Spanish tools. Confirmatory factor analysis was used to establish the final 6-domain structure. Conclusions: CritCom is a reliable and pragmatic bilingual tool to assess the quality of interdisciplinary communication around patient deterioration for children in diverse resource levels globally. Critcom results can be used to design and evaluate interventions to improve team communication.

Left ventricular diastolic dysfunction in COPD may manifest myocardial ischemia.

BACKGROUND: Left ventricular diastolic dysfunction (LVDD) is observed frequently in advanced COPD and it appears unrelated to the co-presence of its common risk factors as hypertension, diabetes, ischemic heart disease, etc. The patho-physiology of this association is yet unclear. We postulated that ischemia not apparent in the routine clinical evaluation could be the cause of such LVDD. METHOD: Advanced COPD (GOLD III & IV) patients being excluded of concomitant presence of hypertension, diabetes, ischemic heart disease, and hypothyroidism by conventional evaluations were looked for the presence of LVDD by tissue Doppler echocardiography. The subjects having LVDD were further evaluated with 99(m)Tc MIBI stress myocardial perfusion imaging to detect the presence of ischemia. RESULTS: 7 out of 14 patients of advanced COPD sufferers without any known risk factors for LVDD had reversible perfusion defect in the stress perfusion imaging predominantly involving the inferior wall myocardium (71.43%). Most of the defects, though significant, were not picked up by stress ECG. CONCLUSION: Reversible ischemic defects are quite common (50%) in advanced COPD patients with LVDD without the presence of common risk factors. This association needs further evaluation.