Defining the biogeography of bacterial populations in human body habitats is a high priority for understanding microbial-host relationships in health and disease. The healthy lung was traditionally ...considered sterile, but this notion has been challenged by emerging molecular approaches that enable comprehensive examination of microbial communities. However, studies of the lung are challenging due to difficulties in working with low biomass samples.
Our goal was to use molecular methods to define the bacterial microbiota present in the lungs of healthy individuals and assess its relationship to upper airway populations.
We sampled respiratory flora intensively at multiple sites in six healthy individuals. The upper tract was sampled by oral wash and oro-/nasopharyngeal swabs. Two bronchoscopes were used to collect samples up to the glottis, followed by serial bronchoalveolar lavage and lower airway protected brush. Bacterial abundance and composition were analyzed by 16S rDNA Q-PCR and deep sequencing.
Bacterial communities from the lung displayed composition indistinguishable from the upper airways, but were 2 to 4 logs lower in biomass. Lung-specific sequences were rare and not shared among individuals. There was no unique lung microbiome.
In contrast to other organ systems, the respiratory tract harbors a homogenous microbiota that decreases in biomass from upper to lower tract. The healthy lung does not contain a consistent distinct microbiome, but instead contains low levels of bacterial sequences largely indistinguishable from upper respiratory flora. These findings establish baseline data for healthy subjects and sampling approaches for sequence-based analysis of diseases.
We propose a new experiment at the Large Hadron Collider (LHC) that offers a powerful and model-independent probe for milli-charged particles. This experiment could be sensitive to charges in the ...range 10−3e–10−1e for masses in the range 0.1–100 GeV, which is the least constrained part of the parameter space for milli-charged particles. This is a new window of opportunity for exploring physics beyond the Standard Model at the LHC. The key new ingredients of the proposal are the identification of an optimal location for the detector and a telescopic/coincidence design that greatly reduces the background.
To determine the outcomes of patients undergoing tracheostomy for COVID-19 and of healthcare workers performing these procedures.
Tracheostomy is often performed for prolonged endotracheal intubation ...in critically ill patients. However, in the context of COVID-19, tracheostomy placement pathways have been altered due to the poor prognosis of intubated patients and the risk of transmission to providers through this highly aerosolizing procedure.
A prospective single-system multi-center observational cohort study was performed on patients who underwent tracheostomy after acute respiratory failure secondary to COVID-19.
Of the 53 patients who underwent tracheostomy, the average time from endotracheal intubation to tracheostomy was 19.7 days ± 6.9 days. The most common indication for tracheostomy was acute respiratory distress syndrome, followed by failure to wean ventilation and post-extracorporeal membrane oxygenation decannulation. Thirty patients (56.6%) were liberated from the ventilator, 16 (30.2%) have been discharged alive, 7 (13.2%) have been decannulated, and 6 (11.3%) died. The average time from tracheostomy to ventilator liberation was 11.8 days ± 6.9 days (range 2-32 days). Both open surgical and percutaneous dilational tracheostomy techniques were performed utilizing methods to mitigate aerosols. No healthcare worker transmissions resulted from performing the procedure.
Alterations to tracheostomy practices and processes were successfully instituted. Following these steps, tracheostomy in COVID-19 intubated patients seems safe for both patients and healthcare workers performing the procedure.
This phase I study investigated the safety and activity of lentiviral-transduced chimeric antigen receptor (CAR)-modified autologous T cells redirected against mesothelin (CART-meso) in patients with ...malignant pleural mesothelioma, ovarian carcinoma, and pancreatic ductal adenocarcinoma. Fifteen patients with chemotherapy-refractory cancer (n = 5 per indication) were treated with a single CART-meso cell infusion. CART-meso cells were engineered by lentiviral transduction with a construct composed of the anti-mesothelin single-chain variable fragment derived from the mouse monoclonal antibody SS1 fused to intracellular signaling domains of 4-1BB and CD3zeta. Patients received 1–3 × 107 or 1–3 × 108 CART-meso cells/m2 with or without 1.5 g/m2 cyclophosphamide. Lentiviral-transduced CART-meso cells were well tolerated; one dose-limiting toxicity (grade 4, sepsis) occurred at 1–3 × 107/m2 CART-meso without cyclophosphamide. The best overall response was stable disease (11/15 patients). CART-meso cells expanded in the blood and reached peak levels by days 6–14 but persisted transiently. Cyclophosphamide pre-treatment enhanced CART-meso expansion but did not improve persistence beyond 28 days. CART-meso DNA was detected in 7/10 tumor biopsies. Human anti-chimeric antibodies (HACA) were detected in the blood of 8/14 patients. CART-meso cells were well tolerated and expanded in the blood of all patients but showed limited clinical activity. Studies evaluating a fully human anti-mesothelin CAR are ongoing.
Haas et al. studied lentiviral-transduced chimeric antigen receptor (CAR)-modified T cells recognizing mesothelin in patients with solid cancers, including mesothelioma, ovarian cancer, and pancreatic cancer. They show that mesothelin-specific CAR T cells are well tolerated when administered systemically but produce limited clinical activity. Although a cyclophosphamide preconditioning regimen improved CAR T cell expansion in patients, it did not prolong their persistence in the blood. Their findings provide the framework for subsequent studies testing next generation CAR T cells targeting mesothelin in solid tumors.
Lung cancer remains the leading cause of death worldwide. Because many patients with non-small cell lung cancer are elderly and have multiple comorbid conditions, many with potentially curable ...disease are unfit to undergo definitive surgical resection. Stereotactic body radiation therapy (SBRT) is increasingly being used to treat patients with medically inoperable stage I non-small cell lung cancer. SBRT combines reproducible and accurate anatomic targeting with the delivery of a very high dose per fraction of radiation to a target. Planning and delivery of SBRT is a coordinated effort between the radiation oncology team and consulting services. Clinical outcomes, toxicity profiles, treatment delivery, and indications for SBRT are reviewed. Services currently billed during planning and treatment of SBRT are detailed. This article introduces to consulting specialists and subspecialists a new Current Procedural Terminology code that has been proposed to more accurately reflect work performed during SBRT by these consulting providers. This code is described, and its implications for patient care are discussed.
Long-term survival after lung transplantation is limited by infectious complications and by bronchiolitis obliterans syndrome (BOS), a form of chronic rejection linked in part to microbial triggers.
...To define microbial populations in the respiratory tract of transplant patients comprehensively using unbiased high-density sequencing.
Lung was sampled by bronchoalveolar lavage (BAL) and upper respiratory tract by oropharyngeal wash (OW). Bacterial 16S rDNA and fungal internal transcribed spacer sequencing was used to profile organisms present. Outlier analysis plots defining taxa enriched in lung relative to OW were used to identify bacteria enriched in lung against a background of oropharyngeal carryover.
Lung transplant recipients had higher bacterial burden in BAL than control subjects, frequent appearance of dominant organisms, greater distance between communities in BAL and OW indicating more distinct populations, and decreased respiratory tract microbial richness and diversity. Fungal populations were typically dominated by Candida in both sites or by Aspergillus in BAL but not OW. 16S outlier analysis identified lung-enriched taxa indicating bacteria replicating in the lower respiratory tract. In some cases this confirmed respiratory cultures but in others revealed enrichment by anaerobic organisms or mixed outgrowth of upper respiratory flora and provided quantitative data on relative abundances of bacteria found by culture.
Respiratory tract microbial communities in lung transplant recipients differ in structure and composition from healthy subjects. Outlier analysis can identify specific bacteria replicating in lung. These findings provide novel approaches to address the relationship between microbial communities and transplant outcome and aid in assessing lung infections.
Variation in sediment yield may reflect a signal of disturbances in the upstream landscape, modified by sediment routing. This study, conducted in a forested drainage basin in the inland Pacific ...Northwest, USA, sought to generate a better insight into the interdecadal variability of sediment yield in mountain landscapes in response to environmental change during the last century. To this end, we examined: (1) sediment yield fluctuations; and (2) their association with streamflow and land use changes; as well as (3) streamflow links to climate variability modes; and (4) the influence of sediment delivery from hillslope sources to streams (lateral connectivity) and its downstream routing through the stream network (longitudinal connectivity) on land use signal at the basin's outlet. Sediment yield between 1910 and 2017, estimated based on reconstructed fluvial delta growth, displayed an order of magnitude variability, which indicates a substantial geomorphic sensitivity. The interpretation of temporal patterns and an exploratory statistical analysis pointed to land use-related sediment supply changes as the primary driver of these fluctuations, dominating system behavior before changes in environmental regulations and practices in the mid-1970s. Hydroclimatically controlled streamflow variability appeared to be more prominent in the subsequent period. Our connectivity analysis suggested that a considerable portion of coarse sediment mobilized by harvest and road construction may still reside within the channel network. In light of previous research in this landscape system, we speculate that, despite limited anthropogenic pressures in the recent decades, its characteristics and behavior continue to be conditioned by land use legacies. Overall, this study contributes to the growing understanding of profound anthropogenic transformation of the earth surface. Specifically, it demonstrates that historical resource extraction may have left a lasting imprint even in relatively remote mountain landscapes. Given the ongoing rapid environmental change, such understanding is crucial for watershed management, conservation, and restoration.
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•A study in a forested mountain drainage basin in the inland Pacific Northwest (USA)•Sediment yield, streamflow, and land use change over the last century reconstructed.•Land use seemed to be a primary control of interdecadal sediment yield variability.•Flow variability (hydroclimate) had more a prominent effect in the recent decades.•Long-term land use legacies can affect even remote mountain landscape systems.
Cryotherapy is an evolving therapeutic and diagnostic tool used during bronchoscopy. Through rapid freeze-thaw cycles, cryotherapy causes cell death and tissue necrosis or tissue adherence that can ...be used via the flexible or rigid bronchoscope. This extreme cold can be used through the working channel of the bronchoscope via a specialized cryoprobe or directly with the use of spray cryotherapy. These properties allow for multiple bronchoscopic techniques, each with its own equipment and procedural, safety, and efficacy considerations. Bronchoscopic cryotherapy can be used in a variety of clinical scenarios, including the treatment of malignant and benign central airway obstruction and low-grade airway malignancy, foreign body removal or cryoextraction, endobronchial biopsy, and transbronchial biopsy. The bulk of the experience with bronchoscopic cryotherapy consists of uncontrolled case series of malignant central airway obstruction. There are also controlled data supporting the use of cryoadhesion for endobronchial biopsies, albeit with an increased risk of controllable bleeding. The use of cryoadhesion for transbronchial biopsies is an active area of investigation with limited controlled data. In addition, there are promising future directions using bronchoscopic cryotherapy, including chemosensitizing malignancy with cryotherapy and capitalizing on the synergy between cryotherapy and radiation.
Off-target toxicity due to the expression of target antigens in normal tissue represents a major obstacle to the use of chimeric antigen receptor (CAR)-engineered T cells for treatment of solid ...malignancies. To circumvent this issue, we established a clinical platform for engineering T cells with transient CAR expression by using in vitro transcribed mRNA encoding a CAR that includes both the CD3-ζ and 4-1BB co-stimulatory domains. We present two case reports from ongoing trials indicating that adoptive transfer of mRNA CAR T cells that target mesothelin (CARTmeso cells) is feasible and safe without overt evidence of off-tumor on-target toxicity against normal tissues. CARTmeso cells persisted transiently within the peripheral blood after intravenous administration and migrated to primary and metastatic tumor sites. Clinical and laboratory evidence of antitumor activity was demonstrated in both patients and the CARTmeso cells elicited an antitumor immune response revealed by the development of novel anti-self antibodies. These data demonstrate the potential of utilizing mRNA engineered T cells to evaluate, in a controlled manner, potential off-tumor on-target toxicities and show that short-lived CAR T cells can induce epitope-spreading and mediate antitumor activity in patients with advanced cancer. Thus, these findings support the development of mRNA CAR-based strategies for carcinoma and other solid tumors.
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