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Abstract InGaN/GaN micro-light-emitting diodes (micro-LEDs) with a metal–insulator-semiconductor (MIS) structure on the sidewall are proposed to improve efficiency. In this MIS structure, a sidewall electrode is deposited on the insulating layer-coated sidewall of the device mesa between a cathode on the bottom and an anode on the top. Electroluminescence (EL) measurements of fabricated devices with a mesa diameter of 10 μm show that the application of negative biases on the sidewall electrode can increase the device external quantum efficiency (EQE). In contrast, the application of positive biases can decrease the EQE. The band structure analysis reveals that the EQE is impacted because the application of sidewall electric fields manipulates the local surface electron density along the mesa sidewall and thus controls surface Shockley–Read–Hall (SRH) recombination. Two suggested strategies, reducing insulator layer thickness and exploring alternative materials, can be implemented to further improve the EQE of MIS micro-LEDs in future fabrication. Graphical Abstract

Introduction: NSCLC with MET exon 14 skipping mutation (METex14) is associated with poor outcomes. Integration of novel targeted therapies is challenging because of barriers in testing and drug access. We, therefore, sought to characterize the treatment patterns, outcomes, and emerging issues of treatment sequencing in patients with METex14-mutant NSCLC. Methods: We reviewed all NSCLC cases with METex14 alterations between 2014 and 2020 across four Canadian cancer centers. Demographics, disease characteristics, systemic therapy, overall response rates (ORRs), survival, and toxicity were summarized. Results: Among 64 patients with METex14-mutant NSCLC, the median overall survival was 23.1 months: 127.0 months in stage 1, 27.3 months in resected stage 2 and 3, and 16.6 months in unresectable stage 3 or 4 disease, respectively. In patients with advanced disease, 22% were too unwell for systemic treatment. MET tyrosine kinase inhibitors (TKIs) were administered to 28 patients with an ORR of 33%, median progression-free survival of 2.7 months, and 3.8 months for selective TKIs. Programmed cell death protein-1 (PD-1) inhibitors were given to 25 patients—the ORR was 44% and progression-free survival was 10.6 months. No responses were seen with subsequent MET TKIs after initial TKI treatment. Grade 3 or higher toxicities occurred in 64% of patients who received MET TKI after PD-1 inhibitors versus 8% in those who did not receive PD-1 inhibitors. Conclusions: Many patients with advanced METex14 NSCLC were too unwell to receive treatment. PD-1 inhibitors seem effective as an initial treatment, although greater toxicity was seen with subsequent MET TKIs. Thus, timely testing for METex14 skipping and initial therapy are imperative to improving patient survival.

Background: Coronaviral infection-induced acute lung injury has become a major threat to public health, especially through the ongoing pandemic of COVID-19. Apta-1 is a newly discovered Aptamer that has anti-inflammatory effects on systemic septic responses. The therapeutic effects of Apta-1 on coronaviral infection-induced acute lung injury and systemic responses were evaluated in the present study. Methods: Female A/J mice (at 12–14 weeks of age) were challenged with murine hepatitis virus 1 (MHV-1), a coronavirus, at 5000 PFU intranasally, followed by Apta-1 intravenously administered (100 mg/kg, twice) 1.5 h or 2 days after viral delivery. Animals were sacrificed at Day 2 or Day 4. Lung tissues were examined with H&E, immunohistochemistry staining, and western blotting. RT-qPCR was used for cytokine gene expression. Serum and plasma were collected for laboratory assessments. Results: Apta-1 treatment reduced viral titers, prevented MHV-1-induced reduction of circulating blood volume and hemolysis, reduced alveolar space hemorrhage, and protease-activated receptor 1 (PAR-1) cleavage. Apta-1 treatment also significantly reduced chemokine (MKC, MCP-1, and RANTES) levels, as well as AST, ALT, total bilirubin, and reduced unconjugated bilirubin levels in the serum. Conclusion: Apta-1 showed therapeutic benefits in coronaviral infection-induced hemorrhage and PAR-1 cleavage in the lung. It also has anti-inflammatory effects systemically.

Abstract Background It is now possible to comprehensively characterize the microbiota of the lungs using culture-independent, sequencing-based assays. Several sample types have been used to investigate the lung microbiota, each presenting specific challenges for preparation and analysis of microbial communities. Bronchoalveolar lavage fluid (BALF) enables the identification of microbiota specific to the lower lung but commonly has low bacterial density, increasing the risk of false-positive signal from contaminating DNA. The objectives of this study were to investigate the extent of contamination across a range of sample densities representative of BALF and identify features of contaminants that facilitate their removal from sequence data and aid in the interpretation of BALF sample 16S sequencing data. Results Using three mock communities across a range of densities ranging from 8E+ 02 to 8E+ 09 16S copies/ml, we assessed taxonomic accuracy and precision by 16S rRNA gene sequencing and the proportion of reads arising from contaminants. Sequencing accuracy, precision, and the relative abundance of mock community members decreased with sample input density, with a significant drop-off below 8E+ 05 16S copies/ml. Contaminant OTUs were commonly inversely correlated with sample input density or not reproduced between technical replicates. Removal of taxa with these features or physical concentration of samples prior to sequencing improved both sequencing accuracy and precision for samples between 8E+ 04 and 8E+ 06 16S copies/ml. For the lowest densities, below 8E+ 03 16S copies/ml BALF, accuracy and precision could not be significantly improved using these approaches. Using clinical BALF samples across a large density range, we observed that OTUs with features of contaminants identified in mock communities were also evident in low-density BALF samples. Conclusion Relative abundance data and community composition generated by 16S sequencing of BALF samples across the range of density commonly observed in this sample type should be interpreted in the context of input sample density and may be improved by simple pre- and post-sequencing steps for densities above 8E+ 04 16S copies/ml.

Purpose. To examine the surgical outcomes and graft conditions in patients receiving micropulse transscleral cyclophotocoagulation (MP-TSCPC) to treat post-keratoplasty ocular hypertension. Methods. This retrospective observational study included 30 eyes of 28 consecutive glaucoma patients with a history of penetrating keratoplasty (PKP) or Descemet’s stripping automated endothelial keratoplasty (DSAEK) who underwent MP-TSCPC at the University of California, San Francisco from 09/2015 to 08/2018. Using the Wilcoxon signed-rank test, we compared preoperative and postoperative intraocular pressure (IOP), number of glaucoma medications, visual acuity, and central corneal thickness at 1, 3, 6, and 12 months. Postoperative complications, additional surgeries, and graft failures were also recorded at these follow-up times. Linear regression model was used to study whether PKP vs. DSAEK affects the effectiveness of MP-TSCPC. Results. Thirty eyes from 28 patients were followed for 12 months. IOP was significantly decreased from preop at all follow-up points (P

Background/Purpose: The aim of this study is to determine the best dosing strategy for vancomycin by studying the associated factors and examining correlations between the area under the plasma concentration-time curve (AUC) values and trough concentrations in children. Methods: Children aged 3 months to 18 years were included if they received vancomycin for more than three doses between January 1, 2010 and December 31, 2012 and had one or more serum vancomycin trough concentrations. Vancomycin clearance (CL) was calculated using the following model: CL = 0.248*Wt0.75*(0.48/serum creatinine)0.361*[ln (age)/7.8]0.995. The AUC (mg-h/L) was calculated by 24-hour dose (mg/kg/d)/CL(L/h). The value of AUC divided by the minimum inhibitory concentration (MIC) of vancomycin was AUC/MIC. Results: A total of 218 children were included. The mean age was 6.0 ± 5.1 years and the mean body weight was 20 ± 11.7 kg. Vancomycin trough concentrations were moderately correlated with AUC values (r2 = 0.232, p

Abstract Additive manufacturing/3D printing of medical devices is becoming more commonplace, a 3D printed drug is now commercially available, and bioprinting is poised to transition from laboratory to market. Despite the variety of technologies enabling these products, the US Food and Drug Administration (FDA) is charged with protecting and promoting the public health by ensuring these products are safe and effective. To that end, we are presenting the FDA’s current perspective on additive manufacturing/3D printing of medical products ranging from those regulated by the Center for Devices and Radiological Health (CDRH), the Center for Drug Evaluation and Research (CDER), and the Center for Biologics Evaluation and Research (CBER). Each Center presents an overview of the additively manufactured products in their area and the specific concerns and thoughts on using this technology in those product spaces.

The present article is the second in a series on rare lung diseases. It focuses on pulmonary alveolar proteinosis (PAP), a disorder in which lipoproteinaceous material accumulates in the alveolar space. PAP was first described in 1958, and for many years the nature of the material accumulating in the lungs was unknown. Major insights into PAP have been made in the past decade, and these have led to the notion that PAP is an autoimmume disorder in which autoantibodies interfere with signalling through the granulocyte-macrophage colony-stimulating factor receptor, leading to macrophage and neutrophil dysfunction. This has spurred new therapeutic approaches to this disorder. The discussion of PAP will begin with a case report, then will highlight the classification of PAP and review recent insights into the pathogenesis of PAP. The approach to therapy and the prognosis of PAP will also be discussed.

The present article is the first in a series that will review selected rare lung diseases. The objective of this series is to promote a greater understanding and awareness of these unusual conditions among respirologists. Each article will begin with a case that serves as a focal point for a discussion of the pathophysiology and management of the particular condition. The first article is on lymphangioleiomyomatosis (LAM); subsequent articles will focus on pulmonary alveolar proteinosis, alpha-1-antitrypsin deficiency and primary ciliary dyskinesia.

Desquamative interstitial pneumonia (DIP) is a rare form of interstitial lung disease (ILD) commonly found among healthy smokers. ILD is a rare manifestation of systemic lupus erythematosus (SLE), and typically associated with a histopathological pattern of nonspecific interstitial pneumonia (NSIP). The present article describes an unusual case of DIP in a non-smoking patient with SLE presenting as NSIP. DIP can occur in the context of SLE in patients with a negative smoking history, and clinicians should consider lung biopsy to correctly classify ILD with unusual presentation on computed tomography scan.

Pulmonary disease in otherwise healthy patients can occur by secondary exposure to nontuberculous mycobacteria from hot tubs. The pathology of hot tub lung may be related to an infection, a hypersensitivity reaction or both. Previous reports of hot tub lung have highlighted distinct pathological features that have distinguished this entity from classic hypersensitivity pneumonitis. Two cases of hot tub lung in Ontario, which presented at very different time points in their disease course, are reported; one patient presented more fulminantly with a clinical picture resembling subacute hypersensitivity pneumonitis, and the other presented with chronic disease. Both cases exhibited clinical, radiological and pathological findings closely mimicking classic subacute and chronic hypersensitivity pneumonitis.

BACKGROUND: Barrett's esophagus (BE) is one of the most common premalignant lesions and can progress to esophageal adenocarcinoma (EA). The numerous molecular events may play a role in the neoplastic transformation of Barrett's mucosa such as the change of DNA ploidy, p53 mutation and alteration of adhesion molecules. However, the molecular mechanism of the progression of BE to EA remains unclear and most studies of mitochondrial DNA (mtDNA) mutations in BE have performed on BE with the presence of dysplasia. METHODS/FINDINGS: Thus, the current study is to investigate new molecular events (Barrett's esophageal tissue-specific-mtDNA alterations/instabilities) in mitochondrial genome and causative factors for their alterations using the corresponding adjacent normal mucosal tissue (NT) and tissue (BT) from 34 patients having Barrett's metaplasia without the presence of dysplasia. Eighteen patients (53%) exhibited mtDNA mutations which were not found in adjacent NT. mtDNA copy number was about 3 times higher in BT than in adjacent NT. The activity of the mitochondrial respiratory chain enzyme complexes in tissues from Barrett's metaplasia without the presence of dysplasia was impaired. Reactive oxygen species (ROS) level in BT was significantly higher than those in corresponding samples. CONCLUSION/SIGNIFICANCE: High ROS level in BT may contribute to the development of mtDNA mutations, which may play a crucial role in disease progression and tumorigenesis in BE.

Pulmonary Langerhans’ cell histiocytosis (PLCH) is an unusual cystic lung disease that is also characterized by extrapulmonary manifestations. The current review discusses the presenting features and relevant diagnostic testing and treatment options for PLCH in the context of a clinical case. While the focus of the present article is adult PLCH and its pulmonary manifestations, it is important for clinicians to distinguish the adult and pediatric forms of the disease, as well as to be alert for possible extrapulmonary complications. A major theme of the current series of articles on rare lung diseases has been the translation of insights gained from fundamental research to the clinic. Accordingly, the understanding of dendritic cell biology in this disease has led to important advances in the care of patients with PLCH.

Decline in insulin action is a metabolic feature of aging and is involved in the development of age-related diseases including Type 2 Diabetes Mellitus (T2DM) and Alzheimer's disease (AD). A novel mitochondria-associated peptide, Humanin (HN), has a neuroprotective role against AD-related neurotoxicity. Considering the association between insulin resistance and AD, we investigated if HN influences insulin sensitivity.Using state of the art clamp technology, we examined the role of central and peripheral HN on insulin action. Continuous infusion of HN intra-cerebro-ventricularly significantly improved overall insulin sensitivity. The central effects of HN on insulin action were associated with activation of hypothalamic STAT-3 signaling; effects that were negated by co-inhibition of hypothalamic STAT-3. Peripheral intravenous infusions of novel and potent HN derivatives reproduced the insulin-sensitizing effects of central HN. Inhibition of hypothalamic STAT-3 completely negated the effects of IV HN analog on liver, suggesting that the hepatic actions of HN are centrally mediated. This is consistent with the lack of a direct effect of HN on primary hepatocytes. Furthermore, single treatment with a highly-potent HN analog significantly lowered blood glucose in Zucker diabetic fatty rats. Based upon the link of HN with two age-related diseases, we examined if there were age associated changes in HN levels. Indeed, the amount of detectable HN in hypothalamus, skeletal muscle, and cortex was decreased with age in rodents, and circulating levels of HN were decreased with age in humans and mice.We conclude that the decline in HN with age could play a role in the pathogenesis of age-related diseases including AD and T2DM. HN represents a novel link between T2DM and neurodegeneration and along with its analogues offers a potential therapeutic tool to improve insulin action and treat T2DM.

This paper presents optimized implementations of two different pipeline FFT processors on Xilinx Spartan-3 and Virtex-4 FPGAs. Different optimization techniques and rounding schemes were explored. The implementation results achieved better performance with lower resource usage than prior art. The 16-bit 1024-point FFT with the R22SDF architecture had a maximum clock frequency of 95.2 MHz and used 2802 slices on the Spartan-3, a throughput per area ratio of 0.034 Msamples/s/slice. The R4SDC architecture ran at 123.8 MHz and used 4409 slices on the Spartan-3, a throughput per area ratio of 0.028 Msamples/s/slice. On Virtex-4, the 16-bit 1024-point R22SDF architecture ran at 235.6 MHz and used 2256 slice, giving a 0.104 Msamples/s/slice ratio; the 16-bit 1024-point R4SDC architecture ran at 219.2 MHz and used 3064 slices, giving a 0.072 Msamples/s/slice ratio. The R22SDF was more efficient than the R4SDC in terms of throughput per area due to a simpler controller and an easier balanced rounding scheme. This paper also shows that balanced stage rounding is an appropriate rounding scheme for pipeline FFT processors.