Mucociliary clearance augmenting drugs block SARS-CoV-2 replication in human airway epithelial cells.

The coronavirus disease (COVID-19) pandemic, caused by SARS-CoV-2 coronavirus, is devastatingly impacting human health. A prominent component of COVID-19 is the infection and destruction of the ciliated respiratory cells, which perpetuates dissemination and disrupts protective mucociliary transport (MCT) function, an innate defense of the respiratory tract. Thus, drugs that augment MCT could improve the barrier function of the airway epithelium and reduce viral replication and, ultimately, COVID-19 outcomes. We tested five agents known to increase MCT through distinct mechanisms for activity against SARS-CoV-2 infection using a model of human respiratory epithelial cells terminally differentiated in an air/liquid interphase. Three of the five mucoactive compounds tested showed significant inhibitory activity against SARS-CoV-2 replication. An archetype mucoactive agent, ARINA-1, blocked viral replication and therefore epithelial cell injury; thus, it was further studied using biochemical, genetic, and biophysical methods to ascertain the mechanism of action via the improvement of MCT. ARINA-1 antiviral activity was dependent on enhancing the MCT cellular response, since terminal differentiation, intact ciliary expression, and motion were required for ARINA-1-mediated anti-SARS-CoV2 protection. Ultimately, we showed that the improvement of cilia movement was caused by ARINA-1-mediated regulation of the redox state of the intracellular environment, which benefited MCT. Our study indicates that intact MCT reduces SARS-CoV-2 infection, and its pharmacologic activation may be effective as an anti-COVID-19 treatment.

Effects of Intrathecal Morphine Administration in Patients Undergoing Primary Total Hip Arthroplasty Under Spinal Anesthesia With Quadratus Lumborum Block for Postoperative Analgesia.

Introduction Quadratus lumborum (QL) block has previously been shown to provide improved analgesia in patients undergoing primary total hip arthroplasty (THA) under spinal anesthesia when compared to spinal anesthesia alone. Additionally, recent studies have shown the addition of intrathecal morphine (ITM) to provide superior postoperative analgesia in patients undergoing various surgical interventions including total knee arthroplasty under spinal anesthesia with peripheral nerve blockade. At this time, however, there has not been a study evaluating the effects of intrathecal morphine in patients undergoing THA under spinal anesthesia with QL block. This study aims to assess if the addition of intrathecal morphine can provide adequate or even superior postoperative analgesia in patients undergoing primary THA. Methods This retrospective study included 26 patients in the spinal/QL block/intrathecal morphine (SA+QLB+ITM) group, 31 patients in the spinal/QL block group (SA+QLB), and 28 patients in the spinal only (SA or control) group. Twenty-six patients undergoing primary THA under a combination of spinal anesthesia and peripheral nerve blockade (quadratus lumborum block) were given a dose of 100 mcg of intrathecal morphine. Various parameters were evaluated including Post-Anesthesia Care Unit (PACU) and 24-hour visual analog scale (VAS) scores, time to first opioid use, 24- and 48-hour total opioid use as oral morphine equivalents (OME), 24-hour ambulation distance, and time from block placement to hospital discharge. The results were analyzed and compared to patients undergoing primary THA under spinal anesthesia with QL block (no intrathecal morphine) and compared to a control group of patients undergoing primary THA under spinal anesthesia only. Results The study analysis included 26 patients in the SA+QLB+ITM group, 31 patients in the SA+QLB group, and 28 patients in the SA (control) group. When compared with the control group, the SA+QLB+ITM had lower 24-hour total opioid usage (mean difference 20.80 OME, CI 6.454 to 35.15, p-value 0.0025), longer time to 1st opioid use (mean difference -20.51 hours later, p-value .0052), lower 24-hr VAS (difference 2.421, p-value 0.0012, CI 0.8559 to 3.987), and faster time to discharge (16.00 hr earlier, p-value 0.0459). When compared to the SA+QLB group, the SA+QLB+ITM group only showed a statistically significant difference in faster time to discharge (19.46 hr earlier, p-value 0.0068). However, while there was no statistically significant difference in time to 1st opioid use between the control and SA+QLB group, the difference did become significant when comparing the control to the SA+QLB+ITM group (mean difference -20.51 hours later (p-value .0052). There was no significant difference in either of the three groups in ambulation distance at 24 hours, PACU VAS, or 48-hour total opioid use. Conclusion Our study concludes that the addition of 100 mcg ITM for total hip arthroplasty under spinal anesthesia improved postoperative analgesia compared to the control group. Also, the ITM group did better with respect to delay in first opioid use and decreased hospital stay compared to the control and block-only groups. Our study warrants no more concerns of PONV, pruritus, or respiratory depression with this dose of ITM and requires standard postoperative care.

Efficacy of Erector Spinae Plane (ESP) Block for Non-cardiac Thoracic and Upper Abdominal Surgery: A Single Institute Comparative Retrospective Case Series.

Introduction Erector spinae plane (ESP) block was first introduced for the management of thoracic pain but has become increasingly popular for the treatment of abdominal surgical pain. Previous studies have shown the ESP block can be easily adapted to abdominal procedures at the corresponding dermatome level and provide postoperative analgesia. Though the versatility, simplicity, and safety of the ESP block have been demonstrated, there is a gap in the literature regarding its comparison between thoracic and abdominal surgeries. This study aims to evaluate the efficacy of the ESP block in treating acute postoperative pain in patients undergoing thoracic and abdominal surgeries. Methods This retrospective study included 50 patients in the non-cardiac thoracic surgery group (bilateral breast mastectomy with reconstruction) and 50 patients in the abdominal surgery group (robotic or laparoscopic sleeve gastrectomy). Data was obtained via the acute pain service records at a tertiary care center from 2018 to 2022. All patients received bilateral ESP blocks, performed under ultrasound guidance. Various parameters were evaluated including oral morphine equivalents (OMEs) and visual analog scale (VAS) scores during post-anesthesia care unit (PACU), 6, 12, and 24 hours postop. The use of abortive antiemetic medications within 24 hours was also measured to evaluate the incidence of nausea and vomiting. The results were analyzed and compared. No control group is included, as all patients at our institution receive a peripheral nerve block as a part of the institution's enhanced recovery pathway (ERP). Results This retrospective study included 50 patients in the non-cardiac thoracic surgery group (bilateral breast mastectomy with reconstruction) and 50 patients in the abdominal surgery group (robotic or laparoscopic sleeve gastrectomy). Compared to the thoracic group, the abdominal group had a statistically higher VAS score in PACU with mean difference (MD) 1.3 VAS, 95% confidence interval (CI) 0.03-2.56, p-value 0.0443, statistically higher OME consumption in the PACU (difference 13.35 OME, 95% CI 4.97-21.73, p-value 0.0003), and required significantly more antiemetic pharmacotherapy (mean 1.4 antiemetics administered, 95% CI 0.84-2.04, p-value <0.0001). Despite the abdominal group having more OME utilization in the PACU, there was no difference in cumulative OME use in the first 24 hours (95% CI -9.745-24.10, p-value 0.4021). Conclusion In this study, we demonstrated that ESP blocks are an effective regional anesthesia technique to reduce postoperative pain and opioid consumption. The ESP block can serve as a useful and safe alternative to either thoracic epidural or paravertebral block techniques in thoracic and upper abdominal surgeries for perioperative pain management.

Pulmonary Fibrosis Ferret Model Demonstrates Sustained Fibrosis, Restrictive Physiology, and Aberrant Repair.

Rationale: The role of MUC5B mucin expression in IPF pathogenesis is unknown. Bleomycin-exposed rodent models do not exhibit sustained fibrosis or airway remodeling. Unlike mice, ferrets have human-like distribution of MUC5B expressing cell types and natively express the risk-conferring variant that induces high MUC5B expression in humans. We hypothesized that ferrets would consequently exhibit aberrant repair to propagate fibrosis similar to human IPF. Methods: Bleomycin (5U/kg) or saline-control was micro-sprayed intratracheally then wild-type ferrets were evaluated through 22 wks. Clinical phenotype was assessed with lung function. Fibrosis was assessed with µCT imaging and comparative histology with Ashcroft scoring. Airway remodeling was assessed with histology and quantitative immunofluorescence. Results: Bleomycin ferrets exhibited sustained restrictive physiology including decreased inspiratory capacity, decreased compliance, and shifted Pressure-Volume loops through 22 wks. Volumetric µCT analysis revealed increased opacification of the lung bleomycin-ferrets. Histology showed extensive fibrotic injury that matured over time and MUC5B-positive cystic structures in the distal lung suggestive of honeycombing. Bleomycin ferrets had increased proportion of small airways that were double-positive for CCSP and alpha-tubulin compared to controls, indicating an aberrant 'proximalization' repair phenotype. Notably, this aberrant repair was associated with extent of fibrotic injury at the airway level. Conclusions: Bleomycin-exposed ferrets exhibit sustained fibrosis through 22 wks and have pathologic features of IPF not found in rodents. Ferrets exhibited proximalization of the distal airways and other pathologic features characteristic of human IPF. MUC5B expression through native cell types may play a key role in promoting airway remodeling and lung injury in IPF.

What the future holds: cystic fibrosis and aging.

Cystic fibrosis (CF) is one of the most common genetic diseases with around 70,000 affected patients worldwide. CF is a multisystem disease caused by a mutation in the CF transmembrane conductance regulator gene, which has led to a significant decrease in life expectancy and a marked impairment in the quality of life for people with CF (pwCF). In recent years, the use of highly effective CFTR modulator therapy (HEMT) has led to improved pulmonary function, fewer CF exacerbations, lower symptom burden, and increased weight. This has coincided with an increased life expectancy for pwCF, with mean age of survival being now in the 50s. This being a major breakthrough, which the CF population has hoped for, pwCF are now facing new challenges by growing old with a chronic respiratory disease. In this mini review, we are attempting to summarize the current knowledge of the aging process and its effect on CF disease and its manifestations including new developments, the current research gaps and potential future developments in the field to allow healthy aging for the CF community.

Comparison of Pericapsular Nerve Group (PENG) Block Versus Quadratus Lumborum (QL) Block for Analgesia After Primary Total Hip Arthroplasty Under Spinal Anesthesia: A Retrospective Study.

BACKGROUND: Total hip arthroplasty (THA) is one of the most common operative procedures performed. Controlling postoperative pain following THA remains a challenge due to the complex innervation of the hip joint and the recent desire to preserve motor function following nerve blockade. Several nerve block techniques have been used for THA in the past, but the quadratus lumborum (QL) block and the blockade of the pericapsular nerve group (PENG) have emerged as opiate-sparing regional anesthesia techniques that preserve motor function. To date, little data comparing the two block techniques exists. The purpose of our study was to compare outcomes following these techniques in patients undergoing primary THA. MATERIALS AND METHODS: This retrospective analysis utilized data from three distinct groups who underwent primary THA at our institution: 45 patients who received PENG block, 38 patients who received QL block, and 77 control patients. Chart review analysis was performed by authorized personnel to obtain cumulative oral morphine equivalent (OME) data at 24 and 48 hours postoperatively (primary outcomes). In addition, visual analog pain scale (VAS) scores in the post-anesthesia care unit (PACU) and at 12, 24, and 48 hours, ambulation distance, and length of hospital stay data were obtained (secondary outcomes). Group comparisons were conducted using either analysis of variance (ANOVA) with Tukey's multiple comparison test for parametric data or Krustal-Wallis with Dunn's multiple comparison tests for nonparametric endpoints. RESULTS: This study found a statistically significant difference in cumulative OME usage across all groups at 24 and 48 hours. Significant difference in OMEs was found between QL and control and PENG and control; however, no difference was found in OMEs between PENG and QL groups at either time point. There was a statistically significant difference in VAS scores in the PACU across all groups; QL showed significantly lower VAS scores in the PACU compared to PENG and control, while PENG only showed significantly lower VAS scores compared to control. There was a statistically significant difference in VAS scores at 24 hours across all groups; however, only QL showed significantly lower VAS scores compared to control at 24 hours. QL was associated with a statistically significant increase in the length of hospital stay compared to PENG. CONCLUSION: This study showed no difference between OME usage in patients who received PENG or QL nerve blocks for primary THA. VAS scores were similar between groups with the exception of QL outperforming PENG in the PACU. Optimizing postoperative pain via multi-approach strategies should remain a priority for patients undergoing THA. Future research is warranted in order to provide guidance on best practice for these patients.

The Dose Comparison of Intrathecal Morphine for Postoperative Analgesia in Total Knee Arthroplasty Under Spinal Anesthesia: A Single Institute Retrospective Study.

Background and purpose of the study Intrathecal morphine (ITM) provides effective postoperative analgesia in patients undergoing total knee arthroplasty (TKA) under spinal anesthesia. However, the ideal dose at which maximal analgesic effects can be delivered with minimal side effects is not clearly known. This retrospective study is aimed to compare two different doses of ITM with respect to analgesia benefits and side effects. Methods This is a retrospective, descriptive, single-center study approved by the Institutional Review Board (IRB) at the University of Alabama at Birmingham. Three patient groups were selected: a control group receiving continuous adductor canal block (CCACB) under spinal anesthesia, and two experimental groups receiving single-dose adductor canal block (SSACB) under spinal anesthesia with either 100 mcg or 150 mcg of ITM. The sample size included 75 patients (25 per group) who were 18 years and older, American Society of Anesthesiology (ASA) class 1-3 who were undergoing primary TKA. Patients with chronic pain or opioid use exceeding 30 days and those undergoing surgeries other than primary TKA were excluded. Outcome data, including opioid use (from which post-operative oral morphine equivalents (OME) were calculated), antiemetic use, visual analog pain scale (VAS) scores, distance ambulated at 24 hours, and length of hospital stay, were extracted by chart review. Results In the post-anesthesia care unit (PACU), patients in both ITM groups experienced significantly lower opioid consumption and pain scores compared to the control group (p<.001). Furthermore, cumulative OME at 24 hours was significantly less in the ITM groups compared to the control, but there was no difference between ITM doses (p=0.004; mean cumulative OME for control was 77.2 OME vs 43.4 OME for 100 mcg ITM vs 42.6 OME for 150 mcg ITM). Antiemetic usage did not increase in the ITM groups. Although there was no statistically significant difference in ambulation at 24 hours, both ITM groups exhibited a trend toward greater average ambulation distance compared to the control group (p=0.095; mean distance walked for control was 67.6 feet, 76.6 feet for 100 mcg ITM vs 98.8 feet for 150 mcg ITM). Hospital length of stay did not significantly differ between the groups. Conclusion ITM doses of 100 mcg and 150 mcg provide effective analgesia for patients undergoing lower extremity total knee arthroplasty under spinal anesthesia. Patients receiving ITM had better pain scores in the immediate post-operative period and had overall less oral morphine equivalent consumption when compared to control. In addition, the safety and side effect profile for ITM is similar for both doses as there was no incidence of respiratory depression and antiemetic usage did not differ between all study arms. Future studies should explore the use of higher ITM doses and consider a broader patient population to further understand the advantages and potential drawbacks of ITM in TKA surgery.

A high-resolution 3D atlas of the spectrum of tuberculous and COVID-19 lung lesions.

Our current understanding of the spectrum of TB and COVID-19 lesions in the human lung is limited by a reliance on low-resolution imaging platforms that cannot provide accurate 3D representations of lesion types within the context of the whole lung. To characterize TB and COVID-19 lesions in 3D, we applied micro/nanocomputed tomography to surgically resected, postmortem, and paraffin-embedded human lung tissue. We define a spectrum of TB pathologies, including cavitary lesions, calcium deposits outside and inside necrotic granulomas and mycetomas, and vascular rearrangement. We identified an unusual spatial arrangement of vasculature within an entire COVID-19 lobe, and 3D segmentation of blood vessels revealed microangiopathy associated with hemorrhage. Notably, segmentation of pathological anomalies reveals hidden pathological structures that might otherwise be disregarded, demonstrating a powerful method to visualize pathologies in 3D in TB lung tissue and whole COVID-19 lobes. These findings provide unexpected new insight into the spatial organization of the spectrum of TB and COVID-19 lesions within the framework of the entire lung.

Ataluren/ivacaftor combination therapy: Two N-of-1 trials in cystic fibrosis patients with nonsense mutations.

Premature termination codons (PTCs) in cystic fibrosis transmembrane conductance regulator (CFTR) produce nonfunctional protein. No approved therapies exist for PTC mutations, including W1282X. We hypothesized that ivacaftor, combined with readthrough therapy, may benefit W1282X patients. Two N-of-1 clinical trials were conducted with ataluren and ivacaftor in various combinations. No meaningful clinical benefit was observed in either patient with ivacaftor alone or ataluren/ivacaftor combination. However, isolated improvements of uncertain significance were noted by a nasal potential difference (NPD) and FEV1 % with ivacaftor in Patient-1 and with ataluren/ivacaftor combination by NPD and body mass index in Patient-2. Drug regimen composed of readthrough agents and potentiators warrant further development for W1282X and other CFTR nonsense mutations.

Exercise Physiology Across the Lifespan in Cystic Fibrosis.

Cystic fibrosis (CF), a severe life-limiting disease, is associated with multi-organ pathologies that contribute to a reduced exercise capacity. At present, the impact of, and interaction between, disease progression and other age-related physiological changes in CF on exercise capacity from child- to adult-hood is poorly understood. Indeed, the influences of disease progression and aging are inherently linked, leading to increasingly complex interactions. Thus, when interpreting age-related differences in exercise tolerance and devising exercise-based therapies for those with CF, it is critical to consider age-specific factors. Specifically, changes in lung function, chronic airway colonization by increasingly pathogenic and drug-resistant bacteria, the frequency and severity of pulmonary exacerbations, endocrine comorbidities, nutrition-related factors, and CFTR (cystic fibrosis transmembrane conductance regulator protein) modulator therapy, duration, and age of onset are important to consider. Accounting for how these factors ultimately influence the ability to exercise is central to understanding exercise impairments in individuals with CF, especially as the expected lifespan with CF continues to increase with advancements in therapies. Further studies are required that account for these factors and the changing landscape of CF in order to better understand how the evolution of CF disease impacts exercise (in)tolerance across the lifespan and thereby identify appropriate intervention targets and strategies.