Risk Factors and Treatment Outcome Analysis Associated with Second-Line Drug-Resistant Tuberculosis

The present study aimed at analyzing the treatment outcomes and risk factors associated with fluoroquinolone drug resistance having mutations in the gyrA and gyrB genes. A total of 258 pulmonary tuberculosis samples with first-line drug-resistant (H, R, or HR) were subjected to GenoType MTBDRsl assay for the molecular detection of mutations. Among the 258 samples, 251 were drug-resistant tuberculosis and seven were sensitive to all first-line TB drugs. Out of 251 DR-TB cases, 42 cases were MDR TB, 200 were INH mono-resistant and nine cases were RIF mono-resistant tuberculosis. Out of 251 DR-TB cases performed with a MTBDRsl assay, 14 had Pre-XDR-FQ, one patient had pre-XDR-SLID, one had extensively drug-resistant tuberculosis (XDR-TB) and 235 cases were sensitive to both FQ and SLID drugs. The study group had a mean average of 42.7 ± 16.4 years. The overall successful treatment outcomes among the MDR, INH mono-resistant, and pre-XRD patients were 70.6%, 82.0%, and 51%, respectively. The percentage of risk for the unfavorable outcomes in the pre-XDR, INH -mono-resistant, and XDR cases were 113.84% increased risk with RR 2.14; 95% CI 0.7821–5.8468. The independent risk factor associated with the unfavorable outcomes to failure was 77.78% increased risk with RR 1.78; 95% CI 0.3375–9.3655. Logistic regression analysis revealed that the percentage relative risk among MDR-TB patients for gender, male (RR: 1.85), age ≥ 61 years (RR: 1.96), and diabetics (RR: 1.05) were 84.62%, 95.83%, and 4.76%, respectively. The independent risk factors associated with INH mono-resistant cases of age 16–60 (RR: 1.86), ≥61 year (RR: 1.18), and treated cases (RR: 5.06). This study presaged the significant risk of INH mono-resistant, pre-XDR, and MDR among males, young adults, diabetics, and patients with previous treatment failure. Timely identification of high-risk patients will give pronounced advantages to control drug resistance tuberculosis diseases.

Role of Macrophage Polarization in Acute Respiratory Distress Syndrome

Acute Respiratory Distress Syndrome is a familiar and destructive clinical condition characterized by progressive, swift and impaired pulmonary state. It leads to mortality if not managed in a timely manner. Recently the role of imbalanced macrophage polarization has been reported in ARDS. Macrophages are known for their heterogeneity and plasticity. Under different microenvironmental stimuli, they (M0) can switch between classically activated macrophage (M1) and alternatively activated (M2) states. This switch is regulated by several signaling pathways and epigenetic changes. In this review, the importance of macrophage M1 and M2 has been discussed in the arena of ARDS citing the phase-wise impact of macrophage polarization. This will provide a further understanding of the molecular mechanism involved in ARDS and will help in developing novel therapeutic targets. Various biomarkers that are currently used concerning this pathophysiological feature have also been summarized.

Immune Correlates of Non-Necrotic and Necrotic Granulomas in Pulmonary Tuberculosis: A Pilot Study

A granuloma, a pathologic hallmark of tuberculosis (TB), is a complex cellular structure that develops at the site of Mycobacterium tuberculosis (Mtb) infection and is comprised of different immune cell types. Severe pulmonary TB in humans is characterized by the presence of heterogeneous granulomas, ranging from highly cellular to solid/non-necrotic and necrotic lesions, within the lungs. The host-Mtb interactions within the granulomas dictate the containment of Mtb infection or its progression into a necrotic, cavitary disease. However, the immune environment in various granulomas is poorly understood. The myeloid-derived suppressor cells (MDSCs) are key immune cells that regulate the protective versus permissive host responses against Mtb infection. However, their contexture within the lung granulomas remains unclear. In this study, using single and multiplex immunohistochemical staining, we analyzed the distribution of MDSCs, macrophages, CD4+ T cells and their immunometabolic and effector function states in the solid/non-necrotic and necrotic granulomas in patients with active pulmonary TB. We found increased MDSCs with elevated expression of immunosuppressive molecules in the solid/non-necrotic granulomas. In contrast, cells in the solid and necrotic granulomas produced similar levels of IL-6 and IL-10. Our findings suggest that MDSCs are present in solid/non-necrotic granuloma, which may play an essential role in the progression into a necrotic lesion, thus exacerbating disease pathology and transmission.

Three-Dimensional Airway Spheroids and Organoids for Cystic Fibrosis Research

Cystic fibrosis (CF) is an autosomal recessive multi-organ disease caused by mutations in the CF Transmembrane Conductance Regulator (CFTR) gene, with morbidity and mortality primacy related to the lung disease. The CFTR protein, a chloride/bicarbonate channel, is expressed at the apical side of airway epithelial cells and is mainly involved in appropriate ion and fluid transport across the epithelium. Although many animal and cellular models have been developed to study the pathophysiological consequences of the lack/dysfunction of CFTR, only the three-dimensional (3D) structures termed “spheroids” and “organoids” can enable the reconstruction of airway mucosa to model organ development, disease pathophysiology, and drug screening. Airway spheroids and organoids can be derived from different sources, including adult lungs and induced pluripotent stem cells (iPSCs), each with its advantages and limits. Here, we review the major features of airway spheroids and organoids, anticipating that their potential in the CF field has not been fully shown. Further work is mandatory to understand whether they can accomplish better outcomes than other culture conditions of airway epithelial cells for CF personalized therapies and tissue engineering aims.

Programmed Cell Death in SARS-CoV-2 Infection: A Short Review

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the latest variant in the coronavirus family, causing COVID-19, has resulted in global pandemic since early 2020 leading to severe public health concern. So far, the pandemic has caused more than 200 million infections and 4 million deaths worldwide. Most of the studies are focused on developing prevention, intervention, and therapeutic strategies. However, underlying pathophysiology of the disease is important as well, which needs further attention. Cell death is one of the major causative mechanisms that leads to severe inflammation, and it is also an a posteriori consequence of the hyperinflammatory storm that renders poor prognosis of the disease. Substantial cell death has been reported in biopsy samples from post mortem patients. Among the distinct cell death pathways, apoptosis, the regulated programmed cell death plays an important role in the pathogenesis of the disease. Understanding the role of SARS-CoV-2 infection in apoptosis is critical to linearize the pathogenesis of the virus as well as the resultant disease, that may uncover novel therapeutic targets in treatment of COVID-19 patients. Here, we review the current progress on the underlying molecular mechanism(s) of SARS-CoV-2-induced apoptosis, not only at the level of the virus but also at its individual proteins.

A Qualitative Study Exploring the Impact and Effects Following Hospital Discharge of COVID-19

Introduction: Research into the long-term effects of coronavirus disease 2019 (COVID-19) continues at an unprecedented pace. Many physical long-term symptoms of COVID-19 have been reported and include headache, fatigue, muscle pain and breathlessness, etc. Psychological effects are not dissimilar to survivors of SARS. There is limited qualitative research exploring the mental health impacts and experiences of hospitalized COVID-19 inpatients. Methods: A prospective qualitative study is planned to explore patient experiences post hospital discharge following a diagnosis of COVID-19. The research aims to gain an understanding of how COVID-19 affects quality of life (QoL) and functional abilities. Patients discharged from the hospital will be invited to take part in semi-structured interviews discussing their experiences of hospitalization and the impact of COVID-19 on their QoL. Interviews will be conducted at three and six months following discharge from hospital. This study will provide important qualitative insight and may inform clinical interventions and commissioning decisions. Trial registration: The study has Research Ethics Committee (REC) and Health Research Authority (HRA) approvals obtained from Health and Care Research Wales (HCRW) [IRAS project ID 293196].

Differential Effects of Oleuropein and Hydroxytyrosol on Aggregation and Stability of CFTR NBD1-ΔF508 Domain

Cystic Fibrosis (CF) is caused by loss of function mutations in the Cystic Fibrosis transmembrane conductance regulator (CFTR). The folding and assembly of CFTR is inefficient. Deletion of F508 in the first nucleotide binding domain (NBD1-ΔF508) further disrupts protein stability leading to endoplasmic reticulum retention and proteasomal degradation. Stabilization and prevention of NBD1-ΔF508 aggregation is critical to rescuing the folding and function of the entire CFTR channel. We report that the phenolic compounds Oleuropein and Hydroxytryosol reduce aggregation of NBD1-ΔF508. The NBD1-ΔF508 aggregate size was smaller in the presence of Hydroxytryosol as determined by dynamic light scattering. Neither phenolic compound increased the thermal stability of NBD1-ΔF508 as measured by differential scanning fluorimetry. Interestingly, Hydroxytyrosol inhibited the stabilizing effect of the indole compound BIA, a known stabilizer, on NBD1-ΔF508. Molecular docking studies predicted that Oleuropein preferred to bind in the F1-type core ATP-binding subdomain in NBD1. In contrast, Hydroxytyrosol preferred to bind in the α4/α5/α6 helical bundle of the ABCα subdomain of NBD1 next to the putative binding site for BIA. This result suggests that Hydroxytyrosol interferes with BIA binding, thus providing an explanation for the antagonistic effect on NBD1 stability upon incubation with both compounds. To our knowledge, these studies are the first to explore the effects of these two phenolic compounds on the aggregation and stability of NBD1-ΔF508 domain of CFTR.

The Effect of High Flow Nasal Cannula Therapy in Exercised-Induced Asthma of Children

High flow nasal cannula (HFNC) therapy is a non-invasive oxygen delivery mode which is safe and well tolerated by adults and children with respiratory distress. HFNC is increasingly used in children with respiratory distress due to mucus retention, such as bronchiolitis and acute asthma. However, he effectiveness of this therapy in acute asthma has not been well researched. To evaluate HFNC for acute childhood asthma, we designed a randomized prospective crossover trial. In the trial, children aged 6–18 years, with a forced expiratory volume in one second (FEV1) lability of ≥30% during an exercise challenge test (ECT) are included. The time of fully recovered lung function within 10% of the baseline after peak fall of FEV1 is compared with and without HFNC therapy. A 50% reduction of recovery time during HFNC therapy compared to recovery time without HFNC is considered clinically relevant, with a power of 80% and a significance level of 5%. Secondly, the pressure used by the HFNC device to deliver the constant present flow is evaluated. A relationship between the measured pressure and the degree of recovery may reveal a working mechanism behind HFNC.

Evaluation of a Meta-Analysis of Ambient Air Quality as a Risk Factor for Asthma Exacerbation

Background: An irreproducibility crisis currently afflicts a wide range of scientific disciplines, including public health and biomedical science. A study was undertaken to assess the reliability of a meta-analysis examining whether air quality components (carbon monoxide, particulate matter 10 µm and 2.5 µm (PM10 and PM2.5), sulfur dioxide, nitrogen dioxide and ozone) are risk factors for asthma exacerbation. Methods: The number of statistical tests and models were counted in 17 randomly selected base papers from 87 used in the meta-analysis. Confidence intervals from all 87 base papers were converted to p-values. p-value plots for each air component were constructed to evaluate the effect heterogeneity of the p-values. Results: The number of statistical tests possible in the 17 selected base papers was large, median = 15,360 (interquartile range = 1536–40,960), in comparison to results presented. Each p-value plot showed a two-component mixture with small p-values < 0.001 while other p-values appeared random (p-values > 0.05). Given potentially large numbers of statistical tests conducted in the 17 selected base papers, p-hacking cannot be ruled out as explanations for small p-values. Conclusions: Our interpretation of the meta-analysis is that random p-values indicating null associations are more plausible and the meta-analysis is unlikely to replicate in the absence of bias.

Association between Obstructive Lung Disease and Cardiovascular Disease: Results from the Vermont Diabetes Information System

The association between obstructive lung disease and cardiovascular disease (CVD) has been suggested previously, but few studies have looked at this association in a diabetic cohort, a population highly susceptible to both comorbidities. A total of 1003 subjects in community practice settings were interviewed at home at the time of enrolment into the Vermont Diabetes Information System, a clinical decision support program. Patients self-reported their personal and clinical characteristics, including any obstructive lung disease. Laboratory data were obtained directly from the clinical laboratory. We performed a cross-sectional analysis of the interviewed subjects to assess a possible association between obstructive lung disease and CVD. In a multivariate logistic regression model, obstructive lung disease was significantly associated with CVD, even after correcting for potential confounders, including gender, obesity, low income, cigarette smoking, alcohol problems, and high comorbidity (odds ratio = 1.96; 95% confidence interval 1.37–2.81; p < 0.01). All components of CVD, including coronary artery disease (CAD), congestive heart failure (CHF), peripheral vascular disease (PVD), and cerebrovascular accidents (CVA), were also significantly associated with obstructive lung disease. These data suggest an association between obstructive lung disease and CVD in patients with diabetes. Future studies are needed to identify the mechanism supporting this association