A Prospective Study on Deep Inspiration Breath Hold Thoracic Radiation Therapy Guided by Bronchoscopically Implanted Electromagnetic Transponders.

BACKGROUND: Electromagnetic transponders bronchoscopically implanted near the tumor can be used to monitor deep inspiration breath hold (DIBH) for thoracic radiation therapy (RT). The feasibility and safety of this approach require further study. METHODS: We enrolled patients with primary lung cancer or lung metastases. Three transponders were implanted near the tumor, followed by simulation with DIBH, free breathing, and 4D-CT as backup. The initial gating window for treatment was ±5 mm; in a second cohort, the window was incrementally reduced to determine the smallest feasible gating window. The primary endpoint was feasibility, defined as completion of RT using transponder-guided DIBH. Patients were followed for assessment of transponder- and RT-related toxicity. RESULTS: We enrolled 48 patients (35 with primary lung cancer and 13 with lung metastases). The median distance of transponders to tumor was 1.6 cm (IQR 0.6-2.8 cm). RT delivery ranged from 3 to 35 fractions. Transponder-guided DIBH was feasible in all but two patients (96% feasible), where it failed because the distance between the transponders and the antenna was >19 cm. Among the remaining 46 patients, 6 were treated prone to keep the transponders within 19 cm of the antenna, and 40 were treated supine. The smallest feasible gating window was identified as ±3 mm. Thirty-nine (85%) patients completed one year of follow-up. Toxicities at least possibly related to transponders or the implantation procedure were grade 2 in six patients (six incidences, cough and hemoptysis), grade 3 in three patients (five incidences, cough, dyspnea, pneumonia, and supraventricular tachycardia), and grade 4 pneumonia in one patient (occurring a few days after implantation but recovered fully and completed RT). Toxicities at least possibly related to RT were grade 2 in 18 patients (41 incidences, most commonly cough, fatigue, and pneumonitis) and grade 3 in four patients (seven incidences, most commonly pneumonia), and no patients had grade 4 or higher toxicity. CONCLUSIONS: Bronchoscopically implanted electromagnetic transponder-guided DIBH lung RT is feasible and safe, allowing for precise tumor targeting and reduced normal tissue exposure. Transponder-antenna distance was the most common challenge due to a limited antenna range, which could sometimes be circumvented by prone positioning.

Detecting Hachimoji DNA: An Eight-Building-Block Genetic System with MoS2 and Janus MoSSe Monolayers.

In the pursuit of personalized medicine, the development of efficient, cost-effective, and reliable DNA sequencing technology is crucial. Nanotechnology, particularly the exploration of two-dimensional materials, has opened different avenues for DNA nucleobase detection, owing to their impressive surface-to-volume ratio. This study employs density functional theory with van der Waals corrections to methodically scrutinize the adsorption behavior and electronic band structure properties of a DNA system composed of eight hachimoji nucleotide letters adsorbed on both MoS2 and MoSSe monolayers. Through a comprehensive conformational search, we pinpoint the most favorable adsorption sites, quantifying their adsorption energies and charge transfer properties. The analysis of electronic band structure unveils the emergence of flat bands in close proximity to the Fermi level post-adsorption, a departure from the pristine MoS2 and MoSSe monolayers. Furthermore, leveraging the nonequilibrium Green's function approach, we compute the current-voltage characteristics, providing valuable insights into the electronic transport properties of the system. All hachimoji bases exhibit physisorption with a horizontal orientation on both monolayers. Notably, base G demonstrates high sensitivity on both substrates. The obtained current-voltage (I-V) characteristics, both without and with base adsorption on MoS2 and the Se side of MoSSe, affirm excellent sensing performance. This research significantly advances our understanding of potential DNA sensing platforms and their electronic characteristics, thereby propelling the endeavor for personalized medicine through enhanced DNA sequencing technologies.

High potential for biomass-degrading CAZymes revealed by pine forest soil metagenomics.

The undisturbed environment in Netarhat, with its high levels of accumulated lignocellulosic biomass, presents an opportunity to identify microbes for biomass digestion. This study focuses on the bioprospecting of native soil microbes from the Netarhat forest in Jharkhand, India, with the potential for lignocellulosic substrate digestion. These biocatalysts could help overcome the bottleneck of biomass saccharification and reduce the overall cost of biofuel production, replacing harmful fossil fuels. The study used metagenomic analysis of pine forest soil via whole genome shotgun sequencing, revealing that most of the reads matched with the bacterial species, very low percentage of reads (0.1%) belongs to fungal species, with 13% of unclassified reads. Actinobacteria were found to be predominant among the bacterial species. MetaErg annotation identified 11,830 protein family genes and 2 metabolic marker genes in the soil samples. Based on the Carbohydrate Active EnZyme (CAZy) database, 3,996 carbohydrate enzyme families were identified, with family Glycosyl hydrolase (GH) dominating with 1,704 genes. Most observed GH families in the study were GH0, 3, 5, 6. 9, 12. 13, 15, 16, 39, 43, 57, and 97. Modelling analysis of a representative GH 43 gene suggested a strong affinity for cellulose than xylan. This study highlights the lignocellulosic digestion potential of the native microfauna of the lesser-known pine forest of Netarhat.Communicated by Ramaswamy H. Sarma.

T cell epitope based vaccine design while targeting outer capsid proteins of rotavirus strains infecting neonates: an immunoinformatics approach.

Gastrointestinal diarrhea is majorly caused by the rotavirus (RV) in the children who generally are under the age group of 5 years. WHO estimates that ∼95% of the children contract RV infection, by this age. The disease is highly contagious; notably in many cases, it is proven fatal with high mortality rates especially in the developing countries. In India alone, an estimated 145,000 yearly deaths occurs due to RV related gastrointestinal diarrhea. WHO pre-qualified vaccines that are available for RV are all live attenuated vaccines with modest efficacy range between 40 and 60%. Further, the risk of intussusceptions has been reported in some children on RV vaccination. Thus, in a quest to develop alternative candidate to overcome challenges associated with these oral vaccines, we chose immunoinformatics approach to design a multi-epitope vaccine (MEV) while targeting the outer capsid viral proteinsVP4 and VP7 of the neonatal strains of rotavirus. Interestingly, ten epitopes, that is, six CD8+T-cells and four CD4+T-cell epitopes were identified which were predicted to be antigenic, non-allergic, non-toxic and stable. These epitopes were then linked to adjuvants, linkers, and PADRE sequences to create a multi-epitope vaccine for RV. The in silico designed RV-MEV and human TLR5 complex displayed stable interactions during molecular dynamics simulations. Further, the immune simulation studies of RV-MEV corroborated that the vaccine candidate emerges as a promising immunogen. Future investigations while performing in vitro and in vivo analyses with designed RV-MEV construct are highly desirable to warrant the potential of this vaccine candidate in protective immunity against different strains of RVs infecting neonates.Communicated by Ramaswamy H. Sarma.

Toward α-1,3/4 fucosyltransferases targeted drug discovery: In silico uncovering of promising natural inhibitors of fucosyltransferase 6.

Sialyl Lewis X (sLex ) antigen is a fucosylated cell-surface glycan that is normally involved in cell-cell interactions. The enhanced expression of sLex on cell surface glycans, which is attributed to the upregulation of fucosyltransferase 6 (FUT6), has been implicated in facilitating metastasis in human colorectal, lung, prostate, and oral cancers. The role that the upregulated FUT6 plays in the progression of tumor to malignancy, with reduced survival rates, makes it a potential target for anticancer drugs. Unfortunately, the lack of experimental structures for FUT6 has hampered the design and development of its inhibitors. In this study, we used in silico techniques to identify potential FUT6 inhibitors. We first modeled the three-dimensional structure of human FUT6 using AlphaFold. Then, we screened the natural compound libraries from the COCONUT database to sort out potential natural products (NPs) with best affinity toward the FUT6 model. As a result of these simulations, we identified three NPs for which we predicted binding affinities and interaction patterns quite similar to those we calculated for two experimentally tested FUT6 inhibitors, that is, fucose mimetic-1 and a GDP-triazole derived compound. We also performed molecular dynamics (MD) simulations for the FUT6 complexes with identified NPs, to investigate their stability. Analysis of the MD simulations showed that the identified NPs establish stable contacts with FUT6 under dynamics conditions. On these grounds, the three screened compounds appear as promising natural alternatives to experimentally tested FUT6 synthetic inhibitors, with expected comparable binding affinity. This envisages good prospects for future experimental validation toward FUT6 inhibition.

Randomized Phase 2 Placebo-Controlled Trial of Nintedanib for the Treatment of Radiation Pneumonitis.

PURPOSE: Radiation pneumonitis (RP) is the most common dose-limiting toxicity for thoracic radiation therapy. Nintedanib is used for the treatment of idiopathic pulmonary fibrosis, which shares pathophysiological pathways with the subacute phase of RP. Our goal was to investigate the efficacy and safety of nintedanib added to a prednisone taper compared with a prednisone taper alone in reducing pulmonary exacerbations in patients with grade 2 or higher (G2+) RP. METHODS AND MATERIALS: In this phase 2, randomized, double-blinded, placebo-controlled trial, patients with newly diagnosed G2+ RP were randomized 1:1 to nintedanib or placebo in addition to a standard 8-week prednisone taper. The primary endpoint was freedom from pulmonary exacerbations at 1 year. Secondary endpoints included patient-reported outcomes and pulmonary function tests. Kaplan-Meier analysis was used to estimate the probability of freedom from pulmonary exacerbations. The study was closed early due to slow accrual. RESULTS: Thirty-four patients were enrolled between October 2015 and February 2020. Of 30 evaluable patients, 18 were randomized to the experimental Arm A (nintedanib + prednisone taper) and 12 to the control Arm B (placebo + prednisone taper). Freedom from exacerbation at 1 year was 72% (confidence interval, 54%-96%) in Arm A and 40% (confidence interval, 20%-82%) in Arm B (1-sided, P = .037). In Arm A, there were 16 G2+ adverse events possibly or probably related to treatment compared with 5 in the placebo arm. There were 3 deaths during the study period in Arm A due to cardiac failure, progressive respiratory failure, and pulmonary embolism. CONCLUSIONS: There was an improvement in pulmonary exacerbations by the addition of nintedanib to a prednisone taper. Further investigation is warranted for the use of nintedanib for the treatment of RP.

Secreted Aspartyl Proteinases Targeted Multi-Epitope Vaccine Design for Candida dubliniensis Using Immunoinformatics.

Candida dubliniensis is an opportunistic pathogen associated with oral and invasive fungal infections in immune-compromised individuals. Furthermore, the emergence of C. dubliniensis antifungal drug resistance could exacerbate its treatment. Hence, in this study a multi-epitope vaccine candidate has been designed using an immunoinformatics approach by targeting C. dubliniensis secreted aspartyl proteinases (SAP) proteins. In silico tools have been utilized to predict epitopes and determine their allergic potential, antigenic potential, toxicity, and potential to elicit interleukin-2 (IL2), interleukin-4 (IL4), and IFN-γ. Using the computational tools, eight epitopes have been predicted that were then linked with adjuvants for final vaccine candidate development. Computational immune simulation has depicted that the immunogen designed emerges as a strong immunogenic candidate for a vaccine. Further, molecular docking and molecular dynamics simulation analyses revealed stable interactions between the vaccine candidate and the human toll-like receptor 5 (TLR5). Finally, immune simulations corroborated the promising candidature of the designed vaccine, thus calling for further in vivo investigation.

Feasibility of shape-sensing robotic-assisted bronchoscopy for biomarker identification in patients with thoracic malignancies.

OBJECTIVE: Molecular diagnostic assays require samples with high nucleic acid content to generate reliable data. Similarly, programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) requires samples with adequate tumor content. We investigated whether shape-sensing robotic-assisted bronchoscopy (ssRAB) provides adequate samples for molecular and predictive testing. METHODS: We retrospectively identified diagnostic samples from a prospectively collected database. Pathologic reports were reviewed to assess adequacy of samples for molecular testing and feasibility of PD-L1 IHC. Tumor cellularity was quantified by an independent pathologist using paraffin-embedded sections. Univariable and multivariable linear regression models were constructed to assess associations between lesion- and procedure-related variables and tumor cellularity. RESULTS: In total, 128 samples were analyzed: 104 primary lung cancers and 24 metastatic lesions. On initial pathologic assessment, ssRAB samples were deemed to be adequate for molecular testing in 84% of cases; on independent review of cellular blocks, median tumor cellularity was 60% (interquartile range, 25%-80%). Hybrid capture-based next-generation sequencing was successful for 25 of 26 samples (96%), polymerase chain reaction-based molecular testing (Idylla; Biocartis) was successful for 49 of 52 samples (94%), and PD-L1 IHC was successful for 61 of 67 samples (91%). Carcinoid and small cell carcinoma histologic subtype and adequacy on rapid on-site evaluation were associated with higher tumor cellularity. CONCLUSIONS: The ssRAB platform provided adequate tissue for next-generation sequencing, polymerase chain reaction-based molecular testing, and PD-L1 IHC in >80% of cases. Tumor histology and adequacy on intraoperative cytologic assessment might be associated with sample quality and suitability for downstream assays.

Solitary Lung Nodule: CT-Guided Transthoracic Biopsy vs Transbronchial Biopsy With Endobronchial Ultrasound and Flexible Bronchoscope, a Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Transbronchial lung biopsy with radial endobronchial ultrasound (rEBUS-TBB) and Computed tomography (CT) scan-guided transthoracic biopsy (CT-TTB) are commonly used to investigate peripheral lung nodules but high-quality data are still not clear about the diagnostic and safety profile comparison of these two modalities. METHOD: We included all randomized controlled trials (RCT) comparing rEBUS-TBB with a flexible bronchoscope and CT-TTB for solitary lung nodules. Two reviewers extracted data independently on diagnostic performance and complication rates. RESULTS: 170 studies were screened, 4 RCT with a total of 325 patients were included. CT-TTB had a higher diagnostic yield than rEBUS-TBB (83.45% vs 68.82%, risk difference - 0.15, 95% CI, [- 0.24, - 0.05]), especially for lesion size 1-2 cm (83% vs 50%, risk difference - 0.33, 95% CI, [- 0.51, - 0.14]). For malignant diseases, rEBUS-TBB had a diagnostic yield of 75.75% vs 87.7% of CT-TTB. rEBUS-TBB had a significant better safety profile with lower risks of pneumothorax (2.87% vs 21.43%, OR = 0.12, 95% CI [0.05-0.32]) and combined outcomes of hospital admission, hemorrhage, and pneumothorax (8.62% vs 31.81%, OR 0.21, 95% CI, [0.11-0.40]). Factors increasing diagnostic yield of rEBUS were lesion size and localization of the probe but not the distance to the chest wall and hilum. CONCLUSION: CT-TTB had a higher diagnostic yield than rEBUS-TBB in diagnosing peripheral lung nodules, particularly for lesions from 1 to 2 cm. However, rEBUS-TBB was significantly safer with five to eight times less risk of pneumothorax and composite complications of hospital admission, hemorrhage, and pneumothorax. The results of this study only apply to flexible bronchoscopy with radial ebus without navigational technologies. More data are needed for a comparison between CT-TTB with rEBUS-TBB combined with advanced navigational modalities.

Immunoinformatics-aided rational design of a multi-epitope vaccine targeting feline infectious peritonitis virus.

Feline infectious peritonitis (FIP) is a grave and frequently lethal ailment instigated by feline coronavirus (FCoV) in wild and domestic feline species. The spike (S) protein of FCoV assumes a critical function in viral ingress and infection, thereby presenting a promising avenue for the development of a vaccine. In this investigation, an immunoinformatics approach was employed to ascertain immunogenic epitopes within the S-protein of FIP and formulate an innovative vaccine candidate. By subjecting the amino acid sequence of the FIP S-protein to computational scrutiny, MHC-I binding T-cell epitopes were predicted, which were subsequently evaluated for their antigenicity, toxicity, and allergenicity through in silico tools. Our analyses yielded the identification of 11 potential epitopes capable of provoking a robust immune response against FIPV. Additionally, molecular docking analysis demonstrated the ability of these epitopes to bind with feline MHC class I molecules. Through the utilization of suitable linkers, these epitopes, along with adjuvants, were integrated to design a multi-epitope vaccine candidate. Furthermore, the stability of the interaction between the vaccine candidate and feline Toll-like receptor 4 (TLR4) was established via molecular docking and molecular dynamics simulation analyses. This suggests good prospects for future experimental validation to ascertain the efficacy of our vaccine candidate in inducing a protective immune response against FIP.

Occurrence and stability of anion-π interactions between phosphate and nucleobases in functional RNA molecules.

We present a systematic structural and energetic characterization of phosphate(OP)-nucleobase anion…π stacking interactions in RNAs. We observed OP-nucleobase stacking contacts in a variety of structural motifs other than regular helices and spanning broadly diverse sequence distances. Apart from the stacking between a phosphate and a guanine or a uracil two-residue upstream in specific U-turns, such interactions in RNA have been scarcely characterized to date. Our QM calculations showed an energy minimum at a distance between the OP atom and the nucleobase plane centroid slightly below 3 Å for all the nucleobases. By sliding the OP atom over the nucleobase plane we localized the optimal mutual positioning of the stacked moieties, corresponding to an energy minimum below -6 kcal•mol-1, for all the nucleobases, consistently with the projections of the OP atoms over the different π-rings we observed in experimental occurrences. We also found that the strength of the interaction clearly correlates with its electrostatic component, pointing to it as the most relevant contribution. Finally, as OP-uracil and OP-guanine interactions represent together 86% of the instances we detected, we also proved their stability under dynamic conditions in model systems simulated by state-of-the art DFT-MD calculations.

Immunoinformatics-Aided Design of a Peptide Based Multiepitope Vaccine Targeting Glycoproteins and Membrane Proteins against Monkeypox Virus.

Monkeypox is a self-limiting zoonotic viral disease and causes smallpox-like symptoms. The disease has a case fatality ratio of 3-6% and, recently, a multi-country outbreak of the disease has occurred. The currently available vaccines that have provided immunization against monkeypox are classified as live attenuated vaccinia virus-based vaccines, which pose challenges of safety and efficacy in chronic infections. In this study, we have used an immunoinformatics-aided design of a multi-epitope vaccine (MEV) candidate by targeting monkeypox virus (MPXV) glycoproteins and membrane proteins. From these proteins, seven epitopes (two T-helper cell epitopes, four T-cytotoxic cell epitopes and one linear B cell epitopes) were finally selected and predicted as antigenic, non-allergic, interferon-γ activating and non-toxic. These epitopes were linked to adjuvants to design a non-allergic and antigenic candidate MPXV-MEV. Further, molecular docking and molecular dynamics simulations predicted stable interactions between predicted MEV and human receptor TLR5. Finally, the immune-simulation analysis showed that the candidate MPXV-MEV could elicit a human immune response. The results obtained from these in silico experiments are promising but require further validation through additional in vivo experiments.

Immunoinformatics Aided Design and In-Vivo Validation of a Cross-Reactive Peptide Based Multi-Epitope Vaccine Targeting Multiple Serotypes of Dengue Virus.

Dengue virus (DENV) is an arboviral disease affecting more than 400 million people annually. Only a single vaccine formulation is available commercially and many others are still under clinical trials. Despite all the efforts in vaccine designing, the improvement in vaccine formulation against DENV is very much needed. In this study, we used a roboust immunoinformatics approach, targeting all the four serotypes of DENV to design a multi-epitope vaccine. A total of 13501 MHC II binding CD4+ epitope peptides were predicted from polyprotein sequences of four dengue virus serotypes. Among them, ten conserved epitope peptides that were interferon-inducing were selected and found to be conserved among all the four dengue serotypes. The vaccine was formulated using antigenic, non-toxic and conserved multi epitopes discovered in the in-silico study. Further, the molecular docking and molecular dynamics predicted stable interactions between predicted vaccine and immune receptor, TLR-5. Finally, one of the mapped epitope peptides was synthesized for the validation of antigenicity and antibody production ability where the in-vivo tests on rabbit model was conducted. Our in-vivo analysis clearly indicate that the imunogen designed in this study could stimulate the production of antibodies which further suggest that the vaccine designed possesses good immunogenicity.

Four-Dimensional Computed Tomography-Based Correlation of Respiratory Motion of Lung Tumors With Implanted Fiducials and an External Surrogate.

PURPOSE: Our purpose was to assess the suitability of airway-implanted internal fiducial markers and an external surrogate of respiratory motion for motion management during radiation therapy of lung tumors. METHODS AND MATERIALS: We analyzed 4-dimensional computed tomography scans acquired during radiation therapy simulation for 28 patients with lung tumors who had anchored fiducial markers bronchoscopically implanted inside small airways in or near the tumor in a prospective trial. We used a linear mixed model to build population-based correlative models of tumor and surrogate motion. The first 24 of the 28 patients were used to build correlative models, and 4 of the 28 consecutive patients were excluded and used as an internal validation cohort. Of the 24 patients from the model building cohort, all were used for the models based on the internal fiducial. The external surrogate was completely visualized in 11 patients from the model building cohort, so only those were used for the models based on the external surrogate. Furthermore, we determined the predicted residual error sum of squares for our correlative models, which may serve as benchmarks for future research. RESULTS: The motion of the internal fiducials was significantly associated with the tumor motion in the anterior-posterior (P < .0001) and superior-inferior (SI) directions (P < .0001). We also observed a strong correlation of the external surrogate anterior-posterior motion to the tumor dominant SI motion (P < .0001). In the validation cohort, the internal fiducial SI motion was the only reliable predictor of lung tumor motion. CONCLUSIONS: The internal fiducials appear to be more reliable predictors of lung tumor motion than the external surrogate. The suitability of such airway-implanted internal fiducial markers for advanced motion management techniques should be further investigated. Although the external surrogate seems to be less reliable, its wide availability and noninvasive application support its clinical utility, albeit the greater uncertainty will need to be compensated for.

Can bronchoscopically implanted anchored electromagnetic transponders be used to monitor tumor position and lung inflation during deep inspiration breath-hold lung radiotherapy?

PURPOSE: To evaluate the efficacy of using bronchoscopically implanted anchored electromagnetic transponders (EMTs) as surrogates for 1) tumor position and 2) repeatability of lung inflation during deep-inspiration breath-hold (DIBH) lung radiotherapy. METHODS: Forty-one patients treated with either hypofractionated (HF) or conventional (CF) lung radiotherapy on an IRB-approved prospective protocol using coached DIBH were evaluated for this study. Three anchored EMTs were bronchoscopically implanted into small airways near or within the tumor. DIBH treatment was gated by tracking the EMT positions. Breath-hold cone-beam-CTs (CBCTs) were acquired prior to every HF treatment or weekly for CF patients. Retrospectively, rigid registrations between each CBCT and the breath-hold planning CT were performed to match to 1) spine, 2) EMTs and 3) tumor. Absolute differences in registration between EMTs and spine were analyzed to determine surrogacy of EMTs for lung inflation. Differences in registration between EMTs and the tumor were analyzed to determine surrogacy of EMTs for tumor position. The stability of the EMTs was evaluated by analyzing the difference between inter-EMT displacements recorded at treatment from that of the plan for the CF patients, as well as the geometric residual (GR) recorded at the time of treatment. RESULTS: A total of 219 CBCTs were analyzed. The average differences between EMT centroid and spine registration among all CBCTs were 0.45±0.42 cm, 0.29±0.28 cm, and 0.18±0.15 cm in superior-inferior (SI), anterior-posterior (AP) and lateral directions, respectively. Only 59% of CBCTs had differences in registration < 0.5 cm for EMT centroid compared to spine, indicating that lung inflation is not reproducible from simulation to treatment. The average differences between EMT centroid and tumor registration among all CBCTs were 0.13±0.13 cm, 0.14±0.13 cm and 0.12±0.12 cm in SI, AP and lateral directions, respectively. Ninety-five percent of CBCTs resulted in a < 0.5 cm change between EMT centroid and tumor registration, indicating that EMT positions correspond well with tumor position during treatments. Six out of the seven recorded CF patients had average differences in inter-EMT displacements ≤0.26 cm and average GR ≤0.22 cm, indicating that the EMTs are stable throughout treatment. CONCLUSIONS: Bronchoscopically implanted anchored EMTs are good surrogates for tumor position and are reliable for maintaining tumor position when tracked during DIBH treatment, as long as the tumor size and shape are stable. Large differences in registration between EMTs and spine for many treatments suggest that lung inflation achieved at simulation is often not reproduced.

Shape-Sensing Robotic-Assisted Bronchoscopy in the Diagnosis of Pulmonary Parenchymal Lesions.

BACKGROUND: The landscape of guided bronchoscopy for the sampling of pulmonary parenchymal lesions is evolving rapidly. Shape-sensing robotic-assisted bronchoscopy (ssRAB) recently was introduced as means to allow successful sampling of traditionally challenging lesions. RESEARCH QUESTION: What are the feasibility, diagnostic yield, determinants of diagnostic sampling, and safety of ssRAB in patients with pulmonary lesions? STUDY DESIGN AND METHODS: Data from 131 consecutive ssRAB procedures performed at a US-based cancer center between October 2019 and July 2020 were captured prospectively and analyzed retrospectively. Definitions of diagnostic procedures were based on prior standards. Associations of procedure- and lesion-related factors with diagnostic yield were examined by univariate and multivariate generalized linear mixed models. RESULTS: A total of 159 pulmonary lesions were targeted during 131 ssRAB procedures. The median lesion size was 1.8 cm, 59.1% of lesions were in the upper lobe, and 66.7% of lesions were beyond a sixth-generation airway. The navigational success rate was 98.7%. The overall diagnostic yield was 81.7%. Lesion size of ≥ 1.8 cm and central location were associated significantly with a diagnostic procedure in the univariate analysis. In the multivariate model, lesions of ≥ 1.8 cm were more likely to be diagnostic compared with lesions < 1.8 cm, after adjusting for lung centrality (OR, 12.22; 95% CI, 1.66-90.10). The sensitivity and negative predictive value of ssRAB for primary thoracic malignancies were 79.8% and 72.4%, respectively. The overall complication rate was 3.0%, and the pneumothorax rate was 1.5%. INTERPRETATION: This study was the first to provide comprehensive evidence regarding the usefulness and diagnostic yield of ssRAB in the sampling of pulmonary parenchymal lesions. ssRAB may represent a significant advancement in the ability to access and sample successfully traditionally challenging pulmonary lesions via the bronchoscopic approach, while maintaining a superb safety profile. Lesion size seems to remain the major predictor of a diagnostic procedure.

Hemoptysis associated with percutaneous transthoracic needle biopsy: Development of critical events checklist and procedure outcomes.

BACKGROUND: A percutaneous transthoracic needle biopsy (PTNB) is performed to obtain tissue for a pathologic diagnosis. A PTNB is necessary prior to the initiation of many cancer treatments. There is a risk of hemoptysis, the expectoration of blood, with the possibility for adverse, life-threatening outcomes. A critical event checklist is a cognitive aid used in an emergency to ensure critical steps are followed. To date, there are no known checklists published for management of PTNB-related, life-threatening hemoptysis. The purpose of this report is to describe the development and implementation of a critical event checklist and the adoption of the checklist into hemoptysis management. METHODS: In March 2017, a process improvement team convened to evaluate the hemoptysis response using the Plan-Do-Study-Act (PDSA) methodology. The checklist was evaluated and updated through September 2019. The team educated Interventional Radiology (IR) clinicians on the new checklist and conducted simulations on its use. A retrospective chart review was performed on hemoptysis events between the ten-year period of October 1, 2008 and September 30, 2018 to evaluate the adoption of the checklist into practice. RESULTS: There were 231 hemoptysis events occurring in 229 patients (2 with repeat biopsies). Prior to implementing the protocol and checklist, there were 166 (71.9%) hemoptysis events. After implementation there were 65 (28.1%) events. The median amount of documented blood expectorated with hemoptysis was 100 mL (IQR 20.0-300.0). Twenty-six patients were admitted after PTNB for reasons related to the hemoptysis event (11.3%). During the procedure, four (1.7%) patients with hemoptysis suffered a cardiac arrest. Prior to implementation of the protocol and critical events checklist, nurses positioned patients in the lateral decubitus (LD) position in 40 out of 162 (24.7%) cases. After implementation of the critical events checklist, nurses positioned patients in the LD position 42 out of 65 cases (64.6%) (OR=5.57(95% CI 2.99-10.367), p<0.001). DISCUSSION: Interventional Radiology nurses successfully adopted the checklist into management of hemoptysis events. The reported incidence of hemoptysis suggests a need for IR teams to prepare for and simulate hemoptysis events. Future research is needed to evaluate the change in patient outcomes before and after critical events checklist implementation.

Structural Insights in Mammalian Sialyltransferases and Fucosyltransferases: We Have Come a Long Way, but It Is Still a Long Way Down.

Mammalian cell surfaces are modified with complex arrays of glycans that play major roles in health and disease. Abnormal glycosylation is a hallmark of cancer; terminal sialic acid and fucose in particular have high levels in tumor cells, with positive implications for malignancy. Increased sialylation and fucosylation are due to the upregulation of a set of sialyltransferases (STs) and fucosyltransferases (FUTs), which are potential drug targets in cancer. In the past, several advances in glycostructural biology have been made with the determination of crystal structures of several important STs and FUTs in mammals. Additionally, how the independent evolution of STs and FUTs occurred with a limited set of global folds and the diverse modular ability of catalytic domains toward substrates has been elucidated. This review highlights advances in the understanding of the structural architecture, substrate binding interactions, and catalysis of STs and FUTs in mammals. While this general understanding is emerging, use of this information to design inhibitors of STs and FUTs will be helpful in providing further insights into their role in the manifestation of cancer and developing targeted therapeutics in cancer.

An evolving role for endobronchial ultrasonography in the intensive care unit.

Endobronchial ultrasound (EBUS) bronchoscopy is an established minimally-invasive modality for visualization, characterization, and guidance of sampling of paratracheal and parabronchial structures and tissues. In the intensive care unit (ICU), rapidly obtaining an accurate diagnosis is paramount to the management of critically ill patients. In some instances, diagnosing and confirming terminal illness in a critically ill patient provides needed closure for patients and their loved ones. Currently available data on feasibility, safety, and yield of EBUS bronchoscopy in critically ill patients is based on single center experiences. These data suggest that in select ICU patients convex and radial probe-EBUS bronchoscopy can serve as useful tools in the evaluation of mediastinal lymphadenopathy, central airway obstruction, pulmonary embolism, and peripheral lung lesions. Barriers to the use of EBUS bronchoscopy in the ICU include: (I) requirement for dedicated equipment, prolonged procedure time, and bronchoscopy team expertise that may not be available; (II) applicability to a limited number of patients and conditions in the ICU; and (III) technical difficulty related to the relatively large outer diameter of the convex probe-EBUS bronchoscope and an increased risk for adverse cardiopulmonary consequences due to intermittent obstruction of the artificial airway. While the prospects for EBUS bronchoscopy in critically ill patients appear promising, judicious patient selection in combination with bronchoscopy team expertise are of utmost importance when considering performance of EBUS bronchoscopy in the ICU setting.