Quantitative Computed Tomography Assessment of Pectoralis and Erector Spinae Muscle Area and Disease Severity in Chronic Obstructive Pulmonary Disease Referred for Lung Volume Reduction.

Patients with advanced chronic obstructive pulmonary disease (COPD) develop skeletal muscle loss (sarcopenia) that is associated with adverse clinical outcomes including mortality. We evaluated if thoracic muscle area is associated with clinical outcomes in patients with severe COPD. We analyzed consecutive patients with severe COPD undergoing evaluation for lung volume reduction from 2015 to 2019 (n = 117) compared to current and former smoking controls undergoing lung cancer screening with normal lung function (n = 41). Quantitative assessments of pectoralis muscle (PM) and erector spinae muscle (ESM) cross sectional area (CSA) were related to clinical outcomes including composite endpoints. Our results showed a reduction in PM CSA but not ESM CSA was associated with the severity of GOLD stage of COPD. Current smokers demonstrated reduced PM CSA which was similar to that in COPD patients who were GOLD stages 3 and 4. PM CSA was associated positively with FEV1, FEV1% predicted, FVC, DLCO, and FEV1/FVC ratio, and was associated negatively with the degree of radiologic emphysema. ESM correlated positively with DLCO, RV/TLC (a marker of hyperinflation), and correlated negatively with radiologic severity of emphysema. Kaplan-Meier analysis showed that reductions in PM but not ESM CSA was associated with the composite end point of mortality, need for lung volume reduction, or lung transplant. In conclusion, in well-characterized patients with severe COPD referred for lung volume reduction, PM CSA correlated with severity of lung disease, mortality, and need for advanced therapies. In addition to predicting clinical outcomes, targeting sarcopenia is a potential therapeutic approach in patients with severe COPD.

Development of mRNA manufacturing for vaccines and therapeutics: mRNA platform requirements and development of a scalable production process to support early phase clinical trials.

The remarkable success of SARS CoV-2 mRNA-based vaccines and the ensuing interest in mRNA vaccines and therapeutics have highlighted the need for a scalable clinical-enabling manufacturing process to produce such products, and robust analytical methods to demonstrate safety, potency, and purity. To date, production processes have either not been disclosed or are bench-scale in nature and cannot be readily adapted to clinical and commercial scale production. To address these needs, we have advanced an aqueous-based scalable process that is readily adaptable to GMP-compliant manufacturing, and developed the required analytical methods for product characterization, quality control release, and stability testing. We also have demonstrated the products produced at manufacturing scale under such approaches display good potency and protection in relevant animal models with mRNA products encoding both vaccine immunogens and antibodies. Finally, we discuss continued challenges in raw material identification, sourcing and supply, and the cold chain requirements for mRNA therapeutic and vaccine products. While ultimate solutions have yet to be elucidated, we discuss approaches that can be taken that are aligned with regulatory guidance.

Lower lobe lung volume reduction surgery: a case report.

Lung volume reduction surgery (LVRS) is an option for select patients with advanced chronic obstructive pulmonary disease (COPD). Current guidelines recommend LVRS for patients with appropriate physiology and heterogeneous distribution of emphysema predominately involving upper lobes. We present an unusual case of a 72-year-old male with an advanced COPD who suffered with recurrent exacerbations despite optimal medical management. He underwent a two-stage bilateral lower lobe LVRS for heterogeneous lower lobe emphysema via video-assisted thoracoscopic (VATS) approach. This resulted in a significant subjective as well as objective improvement in his pulmonary functions, 6-min walk distance and subsequent discontinuation of supplemental oxygen.

Rapamycin Reduced Ischemic Brain Damage in Diabetic Animals Is Associated with Suppressions of mTOR and ERK1/2 Signaling.

The objectives of the present study are to investigate the activation of mTOR and ERK1/2 signaling after cerebral ischemia in diabetic rats and to examine the neuroprotective effects of rapamycin. Ten minutes transient global cerebral ischemia was induced in straptozotocin-induced diabetic hyperglycemic rats and non-diabetic, euglycemic rats. Brain samples were harvested after 16 h of reperfusion. Rapamycin or vehicle was injected 1 month prior to the induction of ischemia. The results showed that diabetes increased ischemic neuronal cell death and associated with elevations of p-P70S6K and Ras/ERK1/2 and suppression of p-AMPKα. Rapamycin ameliorated diabetes-enhanced ischemic brain damage and suppressed phosphorylation of P70S6K and ERK1/2. It is concluded that diabetes activates mTOR and ERK1/2 signaling pathways in rats subjected to transient cerebral ischemia and inhibition of mTOR by rapamycin reduces ischemic brain damage and suppresses the mTOR and ERK1/2 signaling in diabetic settings.

Role of flexible bronchoscopy in immunocompromised patients with lung infiltrates.

STUDY OBJECTIVE: To study the diagnostic role of flexible bronchoscopy (FB) in immunocompromised patients with pulmonary infiltrates. DESIGN: Prospective, observational study. SETTING: Tertiary care hospital. PATIENTS: A total of 104 consecutive non-HIV-infected immunocompromised patients with lung infiltrates in whom FB was performed. METHODS: The primary outcome measure was the diagnostic yield of FB, which was derived as the number of the diagnoses made using FB results divided by all final diagnoses. Final diagnoses were established using data from FB, surgical lung biopsy (SLB), and microbiology and serology testing, and by the clinical response to empiric therapy. We also studied the diagnostic yields of individual sampling procedures such as BAL, transbronchial biopsy (TBB), and protected-specimen brush (PSB) sampling. RESULTS: Overall, 128 diagnoses were made in 104 patients. The overall diagnostic yield of FB was 56.2% (95% confidence interval [CI], 47 to 64%). FB provided at least one diagnosis in 53 of 104 patients (51%; 95% CI, 40 to 62%). FB was more likely to establish the diagnosis when the lung infiltrate was due to an infectious agent (81%; 95% CI, 67 to 90%) than to a noninfectious process (56%; 95% CI, 43 to 67%; p = 0.011). The diagnostic yields of BAL (38%; 95% CI, 30 to 47%) and TBB (38%; 95% CI, 27 to 51%) were similar (p = 0.94). The diagnostic yield of PSB sampling was lower (13%; 95% CI 6 to 24%; p = 0.001) than that of BAL. The combined diagnostic yield of BAL and TBB (70%; 95% CI, 57 to 80%) was higher than that of BAL alone (p < 0.001). Finally, the diagnostic yield of FB with PSB sampling, BAL, and TBB was similar to that of FB with BAL and TBB. The complication rate from FB was 21% (95% CI, 15 to 31%). Minor bleeding (13%) and pneumothorax (4%) were the most common complications. CONCLUSIONS: FB has a high diagnostic yield in immunocompromised patients with pulmonary infiltrates. Based on our results, we recommend performing TBB in these patients, whenever possible.

Clinical characteristics and prediction of pulmonary hypertension in severe emphysema.

BACKGROUND: We explored the prevalence, clinical and physiologic correlates of pulmonary hypertension (PH), and screening strategies in patients with severe emphysema evaluated for the National Emphysema Treatment Trial (NETT). METHODS: Patients undergoing Doppler echocardiography (DE) and right heart catheterization were included. Patients with mean pulmonary arterial pressure ≥ 25 mmHg (PH Group) were compared to the remainder (non-PH Group). RESULTS: Of 797 patients, 302 (38%) had PH and 18 (2.2%) had severe PH. Compared to the non-PH Group, patients with PH had lower % predicted FEV1 (p < 0.001), % predicted diffusion capacity for carbon monoxide (p = 0.006), and resting room air PaO2 (p < 0.001). By multivariate analysis, elevated right ventricular systolic pressure, reduced resting room air PaO2, reduced post-bronchodilator % predicted FEV1, and enlarged pulmonary arteries on computed tomographic scan were the best predictors of PH. A strategy using % predicted FEV1, % predicted DLCO, PaO2, and RVSP was predictive of the presence of pre-capillary PH and was highly predictive of its absence. CONCLUSIONS: Mildly elevated pulmonary artery pressures are found in a significant proportion of patients with severe emphysema. However, severe PH is uncommon in the absence of co-morbidities. Simple non-invasive tests may be helpful in screening patients for pre-capillary PH in severe emphysema but none is reliably predictive of its presence.

Bronchoscopic approach to COPD.

Chronic obstructive pulmonary disease (COPD) is a highly prevalent condition that has frequent morbidity and mortality, with associated costs of US $ 2.5 billion annually and nearly 14,000 deaths each year. In the most advanced stages it causes debilitating breathlessness which is not improved despite maximal medical therapy including smoking cessation, bronchodilators, steroids and supplemental oxygen. Limitations of medical therapy led to the development of several surgical techniques to improve quality of life. However, surgical techniques still carry substantial morbidity even if the mortality is low at centers with larger experience; hence investigators are vigorously pursuing research into innovative, alternative methods for achieving lung volume reduction (LVR), in recent years. Endoscopic techniques for LVR are proposed, based on two main approaches, either closing of anatomical airway passages into destroyed lobe/segment of the lung to affect a collapse and reduction in volume or opening extra-anatomical airway passages, aimed at improving expiratory collateral flow from hyper-inflated areas bypassing the flow limited segments of the emphysematous airways. This article reviews the available endoscopic devises and the evidence supporting their use in the treatment of COPD.

NETT coordinators: researchers, caregivers, or both?

The National Emphysema Treatment Trial (NETT) required the coordinated evaluation and treatment of thousands of patients with emphysema simultaneous with data collection to evaluate the safety and efficacy of surgery versus medical treatment for emphysema. These tasks were performed by a multidisciplinary team led by the clinic coordinator at each NETT center. The clinic coordinators functioned as members of the research team as well as communicators, managers, and members of the patient care team. The clinic coordinators' ability to balance these roles was instrumental to the successful completion of NETT, as evidenced by randomization of 1,218 subjects with only 10 subjects being lost to follow-up. Striving to achieve recruitment goals and working to retain study subjects was very labor intensive. The coordinator role was complicated by the study population's severity of illness combined with the complexity of the NETT protocol. Management of the study subjects' medical condition had to be balanced with the management of a multicenter, randomized clinical trial to ensure quality data collection and protocol adherence.

Multidisciplinary care of the patient with chronic obstructive pulmonary disease.

The National Emphysema Treatment Trial used a multidisciplinary team approach to implement the maximum medical care protocol, including adjustment of medications and outpatient pulmonary rehabilitation for all patients and nutritional and psychological counseling as needed. This article discusses the benefits of such an approach in the care of the patient with chronic obstructive pulmonary disease. Team member roles complement each other and contribute to the goal of providing the highest-quality medical care. The primary focus of the team is to reinforce the medical plan and to provide patient education and support. This article reviews the elements of the initial patient assessment and the functional and nutritional assessment. Patient education focuses on medication use, recognition and management of chronic obstructive pulmonary disease exacerbation symptoms, smoking cessation, advance directives, and travel.

Lung volume reduction surgery in patients with emphysema and alpha-1 antitrypsin deficiency.

BACKGROUND: The role of lung volume reduction surgery (LVRS) for individuals with alpha-1 antitrypsin (AAT) deficiency is unclear. METHODS: To assess the role of LVRS in individuals with severe deficiency of AAT, outcomes within the National Emphysema Treatment Trial were analyzed. RESULTS: Of 1218 randomized subjects, 16 (1.3%) had severe AAT deficiency (serum level < 80 mg/dL) and a consistent phenotype (when available). Characteristics of these 16 patients include 87.5% male; median serum AAT level, 55.5 mg/dL; age, 66 years; forced expiratory volume in 1 second (FEV1), 27% predicted; and 50% had upper-lobe-predominant emphysema. All 10 subjects randomized to LVRS underwent the procedure. Although the small number of subjects hampered statistical analysis, 2-year mortality was higher with surgery (20% versus 0%) than with medical treatment. Comparison of outcomes between the 10 AAT-deficient and the 554 AAT-replete subjects undergoing LVRS showed a greater increase in exercise capacity at 6 months in replete subjects and a trend toward lower and shorter duration FEV1 rise in deficient individuals. CONCLUSIONS: This study extends to 49 cases the published experience of LVRS in severe AAT deficiency. Although the small number of subjects precludes firm conclusions, trends of lower magnitude and duration of FEV1 rise after surgery in AAT-deficient versus AAT-replete subjects and higher mortality in deficient individuals randomized to surgery versus medical treatment suggest caution in recommending LVRS in AAT deficiency.

Patient and surgical factors influencing air leak after lung volume reduction surgery: lessons learned from the National Emphysema Treatment Trial.

BACKGROUND: Although staple line buttressing is advocated to reduce air leak after lung volume reduction surgery (LVRS), its effectiveness is unknown. We sought to identify risk factors for air leak and its duration and to estimate its medical consequences for selecting optimal perioperative technique(s), such as buttressing technique, to preempt or treat post-LVRS air leak. METHODS: Detailed air leak data were available for 552 of 580 patients receiving bilateral stapled LVRS in the National Emphysema Treatment Trial. Risk factors for prevalence and duration of air leak were identified by logistic and hazard function analyses. Medical consequences were estimated in propensity-matched pairs with and without air leak. RESULTS: Within 30 days of LVRS, 90% of patients developed air leak (median duration = 7 days). Its occurrence was more common and duration prolonged in patients with lower diffusing capacity (p = 0.06), upper lobe disease (p = 0.04), and important pleural adhesions (p = 0.007). Duration was also protracted in Caucasians (p < 0.0001), patients using inhaled steroids (p = 0.004), and those with lower 1-second forced expiratory volume (p = 0.0003). Surgical approach, buttressing, stapler brand, and intraoperative adjunctive procedures were not associated with fewer or less prolonged air leaks (p >/= 0.2). Postoperative complications occurred more often in matched patients experiencing air leak (57% vs 30%, p = 0.0004), and postoperative stay was longer (11.8 +/- 6.5 days vs 7.6 +/- 4.4 days, p = 0.0005). CONCLUSIONS: Air leak accompanies LVRS in 90% of patients, is often prolonged, and is associated with a more complicated and protracted hospital course. Its occurrence and duration are associated with characteristics of patients and their disease, not with a specific surgical technique.