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Chronic obstructive pulmonary disease (COPD) is one of the prevalent causes of worldwide mortality and encompasses two major clinical phenotypes, i.e., chronic bronchitis (CB) and emphysema. The most common cause of COPD is chronic tobacco inhalation. Research focused on the chronic bronchitic phenotype of COPD has identified several pathological processes that drive disease initiation and progression. For example, the lung’s mucociliary clearance (MCC) system performs the critical task of clearing inhaled pathogens and toxic materials from the lung. MCC efficiency is dependent on: (1) the ability of apical plasma membrane ion channels such as the cystic fibrosis transmembrane conductance regulator (CFTR) and the epithelial Na⁺ channel (ENaC) to maintain airway hydration; (2) ciliary beating; and (3) appropriate rates of mucin secretion. Each of these components is impaired in CB and likely contributes to the mucus stasis/accumulation seen in CB patients. This review highlights the cellular components responsible for maintaining MCC and how this process is disrupted following tobacco exposure and with CB. We shall also discuss existing therapeutic strategies for the treatment of chronic bronchitis and how components of the MCC can be used as biomarkers for the evaluation of tobacco or tobacco-like-product exposure.

The coronavirus disease 2019 (COVID-19) pandemic continues to spread globally, highlighting the urgent need for safe and effective vaccines that could be rapidly mobilized to immunize large populations. We report the preclinical development of a self-amplifying mRNA (SAM) vaccine encoding a prefusion stabilized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein and demonstrate strong cellular and humoral immune responses at low doses in mice and rhesus macaques. The homologous prime-boost vaccination regimen of SAM at 3, 10 and 30 μg induced potent neutralizing antibody (nAb) titers in rhesus macaques following two SAM vaccinations at all dose levels, with the 10 μg dose generating geometric mean titers (GMT) 48-fold greater than the GMT of a panel of SARS-CoV-2 convalescent human sera. Spike-specific T cell responses were observed with all tested vaccine regimens. SAM vaccination provided protective efficacy against SARS-CoV-2 challenge as both a homologous prime-boost and as a single boost following ChAd prime, demonstrating reduction of viral replication in both the upper and lower airways. The SAM vaccine is currently being evaluated in clinical trials as both a homologous prime-boost regimen at low doses and as a boost following heterologous prime. Self-amplifying mRNA vaccines offer the benefit of driving potent immune responses at low doses, as the mRNA replicates intracellularly. Here, the authors report the preclinical evaluation of a self-amplifying mRNA SARS-CoV-2 vaccine in non-human primates.

Mucus clearance on airway surfaces is a primary form of pulmonary defense. The efficiency of mucus clearance in large part depends on the volume of the airway surface liquid components, including both the periciliary liquid (PCL) layer and the mucus layer. Studies with in vitro model systems suggest that the mucus layer acts as a passive reservoir to redistribute water to and from, as needed, the PCL layer. In contrast, the overall volume of airway surface liquid is determined by active transepithelial salt transport. Data from in vitro systems suggest that airway epithelia have the capacity to both absorb and secrete liquid in response to the volume requirements on the apical surface. At present, the nature of the signals that transmit information about airway surface liquid volume to epithelia and their sensors are unknown. However, progress in elucidation of this system is important, because it appears that these systems are deranged in the genetic disease cystic fibrosis, which is characterized by airway surface liquid volume depletion, mucus stasis, and chronic infection. Thus, insights into these systems may offer novel therapeutic opportunities to correct this physiologic dysfunction of airway epithelia.

Airway diseases, including cigarette smoke-induced chronic bronchitis, cystic fibrosis, and primary ciliary dyskinesia are associated with decreased mucociliary clearance (MCC). However, it is not known whether a simple reduction in MCC or concentration-dependent mucus adhesion to airway surfaces dominates disease pathogenesis or whether decreasing the concentration of secreted mucins may be therapeutic. To address these questions, Scnn1b-Tg mice, which exhibit airway mucus dehydration/adhesion, were compared and crossed with Muc5b- and Muc5ac-deficient mice. Absence of Muc5b caused a 90% reduction in MCC, whereas Scnn1b-Tg mice exhibited an ∼50% reduction. However, the degree of MCC reduction did not correlate with bronchitic airway pathology, which was observed only in Scnn1b-Tg mice. Ablation of Muc5b significantly reduced the extent of mucus plugging in Scnn1b-Tg mice. However, complete absence of Muc5b in Scnn1b-Tg mice was associated with increased airway inflammation, suggesting that Muc5b is required to maintain immune homeostasis. Loss of Muc5ac had few phenotypic consequences in Scnn1b-Tg mice. These data suggest that: (i) mucus hyperconcentration dominates over MCC reduction alone to produce bronchitic airway pathology; (ii) Muc5b is the dominant contributor to the Scnn1b-Tg phenotype; and (iii) therapies that limit mucin secretion may reduce plugging, but complete Muc5b removal from airway surfaces may be detrimental.

BackgroundAnaerobic bacteria are increasingly regarded as important in cystic fibrosis (CF) pulmonary infection. The aim of this study was to determine the effect of antibiotic treatment on aerobic and anaerobic microbial community diversity and abundance during exacerbations in patients with CF.MethodsSputum was collected at the start and completion of antibiotic treatment of exacerbations and when clinically stable. Bacteria were quantified and identified following culture, and community composition was also examined using culture-independent methods.ResultsPseudomonas aeruginosa or Burkholderia cepacia complex were detected by culture in 24/26 samples at the start of treatment, 22/26 samples at completion of treatment and 11/13 stable samples. Anaerobic bacteria were detected in all start of treatment and stable samples and in 23/26 completion of treatment samples. Molecular analysis showed greater bacterial diversity within sputum samples than was detected by culture; there was reasonably good agreement between the methods for the presence or absence of aerobic bacteria such as P aeruginosa (κ=0.74) and B cepacia complex (κ=0.92), but agreement was poorer for anaerobes. Both methods showed that the composition of the bacterial community varied between patients but remained relatively stable in most individuals despite treatment. Bacterial abundance decreased transiently following treatment, with this effect more evident for aerobes (median decrease in total viable count 2.3×107 cfu/g, p=0.005) than for anaerobes (median decrease in total viable count 3×106 cfu/g, p=0.046).ConclusionAntibiotic treatment targeted against aerobes had a minimal effect on abundance of anaerobes and community composition, with both culture and molecular detection methods required for comprehensive characterisation of the microbial community in the CF lung. Further studies are required to determine the clinical significance of and optimal treatment for these newly identified bacteria.

Purpose Despite benefits of total knee arthroplasty (TKA) on function and quality of life, obese patients have less improved functional outcomes following TKA compared to their normal weight counterparts. Furthermore, obesity is a risk factor for aseptic loosening and revision surgery following TKA. With known benefits of robotic-assisted TKA (RaTKA) in precision and patient satisfaction, we aimed to evaluate the differences in patient reported outcome and early complication rates for patients undergoing RaTKA versus conventional TKA among patients of varying BMI groups. Methods This study was a retrospective cohort study of patients who underwent conventional versus RaTKA. Patients were grouped by BMI range (< 30 kg/m2, 30–40 kg/m2, and > 40 kg/m2). Patient-reported outcomes were measured by Oxford Knee Scores and 12-Item Short Form Survey scores preoperatively, 6-month, 1-year, and 2-year postoperatively. Mixed-effects linear models were built for each patient-reported outcome to assess the interaction between type of surgery and BMI while adjusting for known confounders such as demographic variables. Results A total of 350 patients ( n  = 186 RaTKA, n  = 164 conventional TKA) met inclusion criteria. SF-12 physical scores were significantly higher at 2-year follow-up among non-obese patients compared to obese and morbidly obese patients ( p  = 0.047). There was no statistically significant interaction between the type of surgery performed (RaTKA versus conventional TKA) and obesity regarding their effects on patient reported outcomes. Conclusions This study demonstrates no differences in functional outcomes among patients undergoing RaTKA compared to conventional TKA. Furthermore, obesity had no significant effect on this association. Level of evidence III.

This article provides a methodological bridge leading from the well‐developed theory of credit rationing to the less developed territory of empirically identifying credit constraints. We begin by developing a simple model showing that credit constraints may take three forms: quantity rationing, transaction cost rationing, and risk rationing. Each form adversely affects household resource allocation and thus should be accounted for in empirical analyses of credit market performance. We outline a survey strategy to directly elicit households’ status as unconstrained or constrained in the credit market and, if constrained, to further identify which of the three nonprice rationing mechanisms is at play. We discuss several practical issues that arise due to the use of a combination of “factual” and “interpretative” survey questions. Finally, using a farm‐level data set from Peru, we illustrate how the methodology can be used to estimate the impacts of credit constraints.

Purpose Hormone replacement therapy (HRT) causes a significant increase in the risk of venous thrombosis. The risk of medical and surgery-related complications among women taking HRT following total hip arthroplasty (THA) is poorly understood, and there are currently no guidelines in place regarding venous thromboembolism prophylaxis in this patient population. The purpose of this study was to evaluate the frequency of early medical and surgery-related complications following THA among women taking HRT. Methods Women aged > 40 years of age who underwent primary THA were identified from a retrospective database review. A control group of non-HRT users was matched using propensity scoring to HRT users. Rates of 90-day medical complications and 1-year surgery-related complications were compared between cohorts using odds ratios. Postoperative anticoagulation regimens were also compared. Results There were 3,936 patients in the HRT cohort who were matched to 39,360 patients not taking HRT. There were no significant differences in rates of DVT (OR 0.94, p  = 0.6601) or PE (OR 0.80, p  = 0.4102) between cohorts. Patients on HRT were more likely to sustain a dislocation (OR 1.35, p  = 0.0269) or undergo revision surgery (OR 1.23, p  = 0.0105). HRT patients were more likely to be prescribed warfarin (OR 1.21, p  = 0.0001) or enoxaparin (OR 1.18, p  = 0.0022) and less likely to be prescribed rivaroxaban (OR 0.62, p  < 0.0001) compared to controls. Conclusions HRT was not found to be an independent risk factor for thromboembolism following THA. Further research is warranted to better delineate the ideal perioperative medical management of HRT users undergoing THA.

Therapeutic vaccines that elicit cytotoxic T cell responses targeting tumor-specific neoantigens hold promise for providing long-term clinical benefit to patients with cancer. Here we evaluated safety and tolerability of a therapeutic vaccine encoding 20 shared neoantigens derived from selected common oncogenic driver mutations as primary endpoints in an ongoing phase 1/2 study in patients with advanced/metastatic solid tumors. Secondary endpoints included immunogenicity, overall response rate, progression-free survival and overall survival. Eligible patients were selected if their tumors expressed one of the human leukocyte antigen-matched tumor mutations included in the vaccine, with the majority of patients (18/19) harboring a mutation in KRAS . The vaccine regimen, consisting of a chimp adenovirus (ChAd68) and self-amplifying mRNA (samRNA) in combination with the immune checkpoint inhibitors ipilimumab and nivolumab, was shown to be well tolerated, with observed treatment-related adverse events consistent with acute inflammation expected with viral vector-based vaccines and immune checkpoint blockade, the majority grade 1/2. Two patients experienced grade 3/4 serious treatment-related adverse events that were also dose-limiting toxicities. The overall response rate was 0%, and median progression-free survival and overall survival were 1.9 months and 7.9 months, respectively. T cell responses were biased toward human leukocyte antigen-matched TP53 neoantigens encoded in the vaccine relative to KRAS neoantigens expressed by the patients’ tumors, indicating a previously unknown hierarchy of neoantigen immunodominance that may impact the therapeutic efficacy of multiepitope shared neoantigen vaccines. These data led to the development of an optimized vaccine exclusively targeting KRAS-derived neoantigens that is being evaluated in a subset of patients in phase 2 of the clinical study. ClinicalTrials.gov registration: NCT03953235 . In an interim analysis of a phase 1/2 trial, a heterologous prime boost vaccine comprised of a chimpanzee adenovirus and self-amplifying mRNA that encodes neoantigens derived from common oncogenic driver mutations in combination with immune checkpoint blockade was safe and elicited neoantigen-specific T cell responses in patients with advanced solid tumors.

It has been postulated that mucus stasis is central to the pathogenesis of obstructive lung diseases. In Scnn1b-transgenic (Scnn1b-Tg+) mice, airway-targeted overexpression of the epithelial Na+ channel β subunit causes airway surface dehydration, which results in mucus stasis and inflammation. Bronchoalveolar lavage from neonatal Scnn1b-Tg+ mice, but not wild-type littermates, contained increased mucus, bacteria, and neutrophils, which declined with age. Scnn1b-Tg+ mice lung bacterial flora included environmental and oropharyngeal species, suggesting inhalation and/or aspiration as routes of entry. Genetic deletion of the Toll–interleukin-1 receptor adapter molecule MyD88 in Scnn1b-Tg+ mice did not modify airway mucus obstruction, but caused defective neutrophil recruitment and increased bacterial infection, which persisted into adulthood. Scnn1b-Tg+ mice derived into germ-free conditions exhibited mucus obstruction similar to conventional Scnn1b-Tg+ mice and sterile inflammation. Collectively, these data suggest that dehydration-induced mucus stasis promotes infection, compounds defects in other immune mechanisms, and alone is sufficient to trigger airway inflammation.