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The digitization of health records and growing availability of tumour DNA sequencing provide an opportunity to study the determinants of cancer outcomes with unprecedented richness. Patient data are often stored in unstructured text and siloed datasets. Here we combine natural language processing annotations 1,2 with structured medication, patient-reported demographic, tumour registry and tumour genomic data from 24,950 patients at Memorial Sloan Kettering Cancer Center to generate a clinicogenomic, harmonized oncologic real-world dataset (MSK-CHORD). MSK-CHORD includes data for non-small-cell lung (n = 7,809), breast (n = 5,368), colorectal (n = 5,543), prostate (n = 3,211) and pancreatic (n = 3,109) cancers and enables discovery of clinicogenomic relationships not apparent in smaller datasets. Leveraging MSK-CHORD to train machine learning models to predict overall survival, we find that models including features derived from natural language processing, such as sites of disease, outperform those based on genomic data or stage alone as tested by cross-validation and an external, multi-institution dataset. By annotating 705,241 radiology reports, MSK-CHORD also uncovers predictors of metastasis to specific organ sites, including a relationship between SETD2 mutation and lower metastatic potential in immunotherapy-treated lung adenocarcinoma corroborated in independent datasets. We demonstrate the feasibility of automated annotation from unstructured notes and its utility in predicting patient outcomes. The resulting data are provided as a public resource for real-world oncologic research., Competing Interests: Competing interests: S.B.M. declares professional services and activities for Amgen, Clinical Care Options, Daiichi Sankyo, Elevation Oncology, MedPage Today, Novartis, Physicians’ Education Resource, Pinetree Therapeutics, Purple Biotech and Vindico Medical Education; and equity in McKesson. L.B. declares professional services and activities for the Cancer Prevention & Research Institute of Texas. M.R. declares professional services and activities (uncompensated) for Artios Pharma, AstraZeneca, Foundation Medicine, Pfizer and Tempus Labs; and professional services and activities for Change Healthcare, Clinical Education Alliance, Genome Quebec, MJH Associates and myMedEd. M.L. declares equity in and professional services and activities (uncompensated) for Paige.AI. D.B.S. declares professional services and activities for American Association for Cancer Research, BridgeBio, Fog Pharmaceuticals, Paige.AI, Pfizer, Rain Therapeutics; and equity in and professional services and activities for Elsie Biotechnologies, Fore Biotherapeutics, Function Oncology, Pyramid Biosciences and Scorpion Therapeutics. D.R.J. declares professional services and activities for AstraZeneca, Dava Oncology and MORE Health; and professional services and activities (uncompensated) for Merck & Co. D.G. declares professional services and activities for AstraZeneca, Grail, Johnson & Johnson, Med Learning Group, Medtronic and Varian Medical Systems. H.Y. declares professional services and activities for AbbVie, AstraZeneca, Black Diamond Therapeutics, Blueprint Medicines, C4 Therapeutics, Daiichi Sankyo, Ipsen Pharma, Janssen Pharmaceuticals, Taiho and Takeda Pharmaceuticals. R.Y. declares professional services and activities for Mirati Therapeutics and Zai Lab. W.A. declares professional services and activities for AstraZeneca, Clinical Education Alliance, Janssen Oncology and Touch Independent Medical Education. W.P. declares professional services and activities for Astellas. J.G.-A. declares professional services and activities for Ethicon; and equity in and professional services and activities for Intuitive Surgical. P.D.S. declares professional services and activities for the National Comprehensive Cancer Network and the National Institutes of Health. R. Levine declares equity, a fiduciary role or position and intellectual property rights in and professional services and activities (uncompensated) for Ajax Therapeutics; equity in Anovia Biosciences, Bakx Therapeutics, Epiphanes, Imago Biosciences and Syndax; professional services and activities for AstraZeneca, Genome Quebec, Goldman Sachs, Incyte, Janssen Pharmaceuticals and Jubilant Therapeutics; equity in and professional services and activities (uncompensated) for Auron Therapeutics and the Isoplexis Corporation; equity in and professional services and activities for C4 Therapeutics, Kurome Therapeutics, Mana Therapeutics, Mission Bio, Prelude Therapeutics, Scorpion Therapeutics, Zentalis Pharmaceuticals; intellectual property rights in the Cure Breast Cancer Foundation and Epizyme; professional services and activities (uncompensated) for the ECOG-ACRIN Cancer Research Group; equity and a fiduciary role or position in and professional services and activities (uncompensated) for Qiagen; and a fiduciary role or position in and professional services and activities for The Mark Foundation. C.M.R. declares professional services and activities for Amgen, AstraZeneca, Bridge Medicines, D2G Oncology, Harpoon Therapeutics and Jazz Pharmaceuticals; intellectual property rights in Daiichi Sankyo; and equity in Earli. M.F.B. declares professional services and activities for AstraZeneca and Paige.AI; professional services and activities (uncompensated) for JCO Precision Oncology and the Journal of Molecular Diagnostics; and intellectual property rights in SOPHiA GENETICS. P.R. declares professional services and activities for Biovica, Inivata, Novartis, Prelude Therapeutics and SAGA Diagnostics; professional services and activities (uncompensated) for Guardant Health, Paige.AI and Tempus Labs; and equity, a fiduciary role or position and intellectual property rights in Odyssey Biosciences. B.T.L. declares professional services and activities (uncompensated) for Amgen, the Asia Society, AstraZeneca, Bolt Biotherapeutics and Daiichi Sankyo; and intellectual property rights in Karger Publishers and Shanghai Jiao Tong University Press. G.J.R. declares professional services and activities (uncompensated) for the American Association for Cancer Research, the American Society of Clinical Oncology, Mirati Therapeutics, Pfizer, Takeda Pharmaceuticals and Verastem; and professional services and activities for Harborside Press, MJH Associates, the National Comprehensive Cancer Network, Phillips Gilmore Oncology Communications, Research to Practice and Triptych Health Partners. H.S. declares professional services and activities for Bayer, Pfizer, Regeneron Pharmaceuticals, Sanofi and WCG Oncology; and intellectual property rights in Elucida Oncology. J.S.R.-F. is an employee of AstraZeneca, has served as a consultant for Goldman Sachs, Paige.AI and REPARE Therapeutics; and has served as an adviser for Roche, Genentech, Roche Tissue Diagnostics, Ventana, Novartis, InVicro, GRAIL, Goldman Sachs, Paige.AI and Volition RX. J. Gao and M.C. are employees of Caris., (© 2024. The Author(s).)

Objectives: The purpose of this study was to identify the 50 most-cited publications relating to lacrosse since 1990 and conduct a bibliometric analysis of the identified studies., Methods: Clarivate Analytics Web of Science database was queried to identify all publication titles, abstracts, and keywords for the term 'lacrosse' on 9 June 2023. The resulting articles were sorted by total number of citations. Titles and abstracts were included based on their relevance to lacrosse. Once the 50 most cited articles were identified, each article was further analyzed to obtain author name, publication year, country of origin, journal name, article type, research topic, competition level, total number of citations, and the level of evidence. Citation density (total number of citations/years since publication) was calculated and recorded for each of the most-cited studies., Results: The 50 most-cited articles were cited 4237 of times with an average of 84 citations per article. The most cited article was cited 637 (15.0%) times. The articles came from 2 different countries, with the United States and Australia comprising 49 and 1 articles, respectively. All articles were published in English. The American Journal of Sports Medicine published the most articles ( n  = 21, 42.0%). The most studied topic was concussion/traumatic brain injury ( n  = 18) followed by studies assessing all injuries ( n  = 7). Collegiate-level lacrosse was the most studied level of competition ( n  = 22), while high school-level followed ( n  = 12)., Conclusions: The majority of the 50 most-cited articles related to lacrosse since 1990 focus on the prevalence, diagnosis and identification of concussion/traumatic brain injury in high school and collegiate-level athletes. These articles are predominantly epidemiological or cohort studies with Level III or IV evidence that almost unanimously originate from the United States.

The norcembranoid and cembranoid diterpenoids represent an intriguing class of natural products isolated from marine sources. Their chemical synthesis has been a challenging and exciting field of research over the past two decades, owing largely to their structural complexity. We recently disclosed a total synthesis of a member of this class, ineleganolide, in a 23 step longest linear sequence. In search of a shorter, more efficient route, we have devised a new strategy for the synthesis of a key bicyclic enone. Disclosed herein is our improved synthesis of this strained intermediate, completing the formal synthesis of ineleganolide in only 14 steps, thereby shortening our previous synthesis by 9 steps. Dedicated to Prof. Thomas Maimone on his receipt of the Tetrahedron Young Investigator Award 2024.

Purpose: The utilization of reverse total shoulder arthroplasty now exceeds the incidence of anatomic shoulder arthroplasty. Previous mid-to-long-term studies on rTSA have reported a decrease in shoulder function as follow-up increased. The purpose of this study was to provide data on mid-term outcomes and implant survival in a series focusing on reverse total shoulder arthroplasty., Materials and Methods: Demographic information such as age at surgery, revision surgery status, BMI, and smoking status were recorded. The clinical endpoints measured in this study were range of motion scores (forward elevation, external rotation, internal rotation) and patient reported outcomes (VAS, ASES, SST). Radiographic variables captured included preoperative glenoid morphology, humeral lucency, and glenoid loosening., Results: Fifty-six shoulders were included in this study. The overall mean age at surgery was 72.5 ± 7.2 years with an average follow-up time of 6.8 ± 3.5 years. The mean BMI was 28.1 ± 5.5. All measurements of range of motion saw significant and sustained improvements. Overall, forward elevation improved from 82° preoperatively to 133° postoperatively (p < 0.01). External rotation improved from 23° preoperatively to 36° (p < 0.01), while internal rotation improved from L3 to L1 (p = 0.05). ASES scores improved from 31 preoperatively to 70 postoperatively (p < 0.01). SST scores improved from 2 preoperatively to 7 (p < 0.01). VAS pain index scores improved from 6 to 2 following surgery (p < 0.01). Postoperative scapular notching was seen in 18 patients at final follow-up. Glenoid loosening was seen in 3 shoulders. Humeral loosening was seen in 18 shoulders. Tuberosity resorption was seen in 8 shoulders. The 5 year survival estimate was 98%, and the 10 year survival estimate was 83%., Conclusion: In this series, we found that rTSA provides mid-term improvements in range of motion in patients while reducing pain levels. When considered together, this demonstrates that most patients undergoing rTSA can have excellent use of their shoulder from age at surgery to end-of-life., (© 2023. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Background: The purpose of this study was to assess outcomes after spinal anesthesia (SA) versus general anesthesia (GA) in patients undergoing thoracic endograft placement and to evaluate the adjunctive use of cerebrospinal fluid drainage (CSFD) placement., Methods: A single-center retrospective review of patients that underwent thoracic endograft placement from 2001 to 2019 was performed. Patients were stratified based on the type of anesthesia they received: GA, SA or epidural, GA with CSFD, and SA with CSFD. Primary outcomes included 30-day mortality and length of stay (LOS). Baseline characteristics were analyzed with Student's t-test and Pearson's chi-squared test. Multivariate logistic regression analysis was performed to identify risk factors for 30-day mortality and longer LOS., Results: A total of 333 patients underwent thoracic endograft placement; 104 patients received SA, 180 patients received GA, 30 patients received GA and CSFD, and 19 patients received SA and CSFD. Of the total patients, 16.2% underwent thoracic endograft placement for type B aortic dissection, 3.3% for type A aortic dissection, and 12.3% for penetrating ulcer. The mean age of the study population was 68.7 years old. Patients undergoing SA were older with a mean age of 73.4 years versus 64.7 years for patients undergoing GA (P < 0.001). Spinal anesthesia (SA) was preferred in patients at high risk for GA (>75 years old: 52.9% vs. 33.3%, P < 0.001; renal comorbidities: 20.6% vs. 10.6%, P = 0.03, and current smokers: 26.7% vs. 9.6%, P < 0.001). Length of stay (LOS) was decreased in the SA group (4.29 days vs. 9.70 days, P < 0.001). There was a lower incidence of spinal cord ischemia in the SA group (1.0% vs. 2.2%, P = 0.44), as well as significantly decreased 30-day mortality (0% vs. 5.6%, P = 0.01), reintervention (19.2% vs. 26.8%, P = 0.02), and return to the operating room (6.8% vs. 12.7%, P = 0.02). Of the 19 patients that had SA + CSFD, there were no signs and symptoms of spinal cord ischemia and decreased incidence of perioperative complications (0% vs. 33.3%, P = 0.01). There was no difference in the risk for intraoperative complications, neurologic complications, or 30-day mortality between GA + CSFD patients versus SA + CSFD patients. Age >75 (P = 0.002), intraoperative complications (P < 0.001), and perioperative complications (P = 0.02) were associated with increased mortality after thoracic endograft placement per multivariate logistic regression analysis., Conclusions: Spinal anesthesia (SA) in select high-risk patients was associated with reduced 30-day mortality, neurologic complications, and LOS compared to GA. The concurrent use of spinal drainage and SA had satisfactory results compared to spinal drainage and GA., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background/aims: Understanding the factors that lead to poor outcomes after reverse total shoulder arthroplasty (rTSA) is important to appropriate patient counseling. While patient-reported allergies (PRAs) have been shown to be associated with poorer outcomes after both TKA and THA, their effect on rTSA outcomes remains unclear. This study investigated the effect of zero, one, and two or more preoperative PRAs on clinical outcomes after rTSA at over two years follow-up in a cohort of fifty-two patients from our institution., Methods: Patients who underwent rTSA and had a minimum follow-up time of two years were identified from an institutional database. Patients were split into cohorts of zero, one, and two or more PRAs. Range of motion (ROM) was assessed by degrees of forward elevation, external rotation, and internal rotation. Patient-reported outcomes (PROs) were assessed by the Visual Analog Scale (VAS), American Shoulder and Elbow Surgeon (ASES) score, and Simple Shoulder Test (SST) score., Results: Fifty-two patients, 10 of whom reported one allergy and 11 of whom reported two or more allergies, were included in our analysis. Mean ROM and PROs improved after rTSA in each cohort. Differences in ROM and PROs between cohorts did not reach statistical significance; however, patients with PRAs tended to have worse preoperative forward elevation, VAS score, and ASES score. Two patients in the zero-allergy cohort required revision (6 %)., Conclusion: This study found no statistically significant difference in clinical outcomes among cohorts of patients with zero, one, or two or more preoperative PRAs after rTSA at over two years follow-up. However, patients with PRAs tended to have lower preoperative functional scores. We postulate that this may be the result of psychosomatic factors at play in these patients. PRAs should not dissuade patients or clinicians from pursuing rTSA., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Paul J. Cagle, MD Stryker: Consultant Johnson & Johnson: Consultant Arthrex: Consultant. Evan L. Flatow, MD American Shoulder and Elbow Surgeons: Board or committee member Health Association of NY: Board or committee member Innomed: IP royalties Springer: Publishing royalties, financial or material support Zimmer: IP royalties; Unpaid consultant. The following individuals have no conflicts of interest or sources of support that require acknowledgement: Andrew A. Palosaari, Christopher A. White, Benjamin D. Gross, Akshar Patel, Troy Li., (© 2024 Professor P K Surendran Memorial Education Foundation. Published by Elsevier B.V. All rights reserved.)

International cancer registries make real-world genomic and clinical data available, but their joint analysis remains a challenge. AACR Project GENIE, an international cancer registry collecting data from 19 cancer centers, makes data from >130,000 patients publicly available through the cBioPortal for Cancer Genomics (https://genie.cbioportal.org). For 25,000 patients, additional real-world longitudinal clinical data, including treatment and outcome data, are being collected by the AACR Project GENIE Biopharma Collaborative using the PRISSMM data curation model. Several thousand of these cases are now also available in cBioPortal. We have significantly enhanced the functionalities of cBioPortal to support the visualization and analysis of this rich clinico-genomic linked dataset, as well as datasets generated by other centers and consortia. Examples of these enhancements include (i) visualization of the longitudinal clinical and genomic data at the patient level, including timelines for diagnoses, treatments, and outcomes; (ii) the ability to select samples based on treatment status, facilitating a comparison of molecular and clinical attributes between samples before and after a specific treatment; and (iii) survival analysis estimates based on individual treatment regimens received. Together, these features provide cBioPortal users with a toolkit to interactively investigate complex clinico-genomic data to generate hypotheses and make discoveries about the impact of specific genomic variants on prognosis and therapeutic sensitivities in cancer., Significance: Enhanced cBioPortal features allow clinicians and researchers to effectively investigate longitudinal clinico-genomic data from patients with cancer, which will improve exploration of data from the AACR Project GENIE Biopharma Collaborative and similar datasets., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: Citation analyses have been used to understand the impact that a group of publications has on its field. As the techniques and indications of reverse total shoulder arthroplasty (RTSA) continue to expand, it is important to identify articles that can orient readers to the history, evolution, and current status of the body of RTSA literature. The purpose of this study was to identify and analyze the 50 most-cited articles related to RTSA., Methods: Various Boolean queries were searched on the Clarivate Analytics Web of Science. Information collected included author name, publication year, country of origin, journal name, article type, total number of citations, and level of evidence., Results: Top 50 most-cited articles amassed a total of 10,521 citations. The most-cited article was cited a total of 766 times. The most common study designs were case series (28) and cohort studies (9). Authors from the United States (24) contributed the most to included papers, followed by France (19) and Switzerland (8)., Discussion: The most-cited articles on RTSA are expert opinions, case studies, and cohort studies published by American authors. As RTSA continues to grow over the next decade, studies with higher levels-of-evidence may overtake articles included in this analysis., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Background: Current discussion centers around the appropriateness of shoulder arthroplasty in elderly patients, and whether anatomic and reverse total shoulder arthroplasty yield acceptable results in this population. The purpose of this study was to examine midterm outcomes in patients 75 years and older who underwent either procedure., Methods: A retrospective review was performed on patients who underwent anatomic total shoulder arthroplasty (aTSA) or reverse total shoulder arthroplasty (rTSA) between 2000 and 2018. Inclusion criteria was patient age ≥75 years at time of surgery and ≥1 years postoperative follow-up. Primary outcomes were differences in Simple Shoulder Test (SST), American Shoulder and Elbow Surgeons (ASES) score, Visual Analog Scale (VAS) pain score, and range of motion. A secondary outcome was revision surgery., Results: 22 patients who underwent aTSA and 17 patients who underwent rTSA were included. Mean age at surgery was 79 and 80 in the aTSA and rTSA groups, respectively. Mean postoperative follow-up was 6.6 years across both cohorts. Anatomic TSA patients experienced improvements in VAS (7 preop vs. 1 postop; p < 0.001), ASES (16 vs. 75; p < 0.001), and SST (2 vs. 8; p < 0.001) scores. Reverse TSA patients also experienced improvements in VAS (7 vs. 1; p < 0.001), ASES (29 vs. 74; p < 0.001), and SST (1 vs. 7; p < 0.001) scores. Anatomic TSA patients experienced improved external rotation (17° vs. 53°; p < 0.001), forward elevation (108° vs. 155°; p < 0.001), and internal rotation (L5 vs. T10; p < 0.001). Reverse TSA patients experienced improved forward elevation (52° vs. 126°; p < 0.001). 21 aTSA patients (100%) and 16 rTSA patients (94%) experienced survival free from revision. 100% of aTSA and rTSA patients experienced survival free from loosening., Conclusion: Both aTSA and rTSA can be performed in the elderly population with acceptable midterm outcomes, suggesting that implant survival and patient satisfaction have the potential to endure through the end of life., Level of Evidence: IV., Competing Interests: Please see ICJME forms for more details., (© 2023 Professor P K Surendran Memorial Education Foundation. Published by Elsevier B.V. All rights reserved.)

Objective/introduction: Increased vascular tortuosity may be an independent marker of generalized aortic pathology. This study investigates the association between descending thoracic aortic tortuosity, aneurysm pathophysiology, and outcomes following EVAR in AAA patients., Methods: Patients who underwent elective EVAR between 2004 and 2018 were reviewed. Thoracic tortuosity index (TTI) was measured using 3D reconstruction software. Patients were dichotomized across the median TTI into high tortuosity [HT] (TTI >1.27, Figure1(a)) and low tortuosity [LT] (TTI ≤1.27, Figure 1(b)) groups. Perioperative complications, postoperative outcomes, and CT-based features of thoracic aortic wall degeneration (Figure 1(c)-(e)) were collected and analyzed., Results: 136 patients underwent treatment: 70 HT patients, including 54 males and 16 females (mean age: 77 years), and 66 LT patients, including 62 males and 4 females (mean age: 70 years) (age; P < .001). LT patients exhibited greater prevalence of hypercholesterolemia and diabetes (P = .045, P = .01). Presence of degenerative aortic wall markers was greater in HT patients (P = .045). HT patients had higher incidence of multiple aneurysms concurrently present in their aorta compared to LT (32.8% vs 11.3%; P = .002). Frequency of AAA rupture/dissection was 4.3% for HT and 1.5% for LT (P = .339). A trend was observed in all cause 30-day mortality in the HT group (P = .061). Other perioperative complications and postoperative outcomes were similar between groups., Conclusion: High TTI was associated with older age at time of EVAR, greater prevalence of degenerative markers in the descending thoracic aortic wall, and widespread aorto-iliac dilation. While not predictive of EVAR outcomes, TTI can provide valuable information regarding aneurysm pathophysiology.

Introduction: Interpretation of high-resolution CT images plays an important role in the diagnosis and management of interstitial lung diseases. However, interreader variation may exist due to varying levels of training and expertise. This study aims to evaluate interreader variation and the role of thoracic radiology training in classifying interstitial lung disease (ILD)., Methods: This is a retrospective study where seven physicians (radiologists, thoracic radiologists, and a pulmonologist) classified the subtypes of ILD of 128 patients from a tertiary referral center, all selected from the Interstitial Lung Disease Registry which consists of patients from November 2014 to January 2021. Each patient was diagnosed with a subtype of interstitial lung disease by a consensus diagnosis from pathology, radiology, and pulmonology. Each reader was provided with only clinical history, only CT images, or both. Reader sensitivity and specificity and interreader agreements using Cohen's κ were calculated., Results: Interreader agreement based only on clinical history, only on radiologic information, or combination of both was most consistent amongst readers with thoracic radiology training, ranging from fair (Cohen's κ: 0.2-0.46), moderate to almost perfect (Cohen's κ: 0.55-0.92), and moderate to almost perfect (Cohen's κ: 0.53-0.91) respectively. Radiologists with any thoracic training showed both increased sensitivity and specificity for NSIP as compared to other radiologists and the pulmonologist when using only clinical history, only CT information, or combination of both (p < 0.05)., Conclusions: Readers with thoracic radiology training showed the least interreader variation and were more sensitive and specific at classifying certain subtypes of ILD., Summary Sentence: Thoracic radiology training may improve sensitivity and specificity in classifying ILD based on HRCT images and clinical history., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: As of 2018, upwards of 42% of the US adult population was considered obese based on body mass index (BMI) scales. With the annual number of total joint replacements increasing, this study aimed to evaluate the impact BMI has on anatomic total shoulder arthroplasty (aTSA) outcomes., Methods: This was a retrospective analysis of 128 shoulders requiring primary aTSA. Patients were stratified into 3 cohorts based on their BMI at surgery: underweight/normal weight (U/NW; BMI ≤25.0), overweight (25.0 < BMI ≤ 30.0), and obese (BMI >30.0). BMI was separately analyzed as a continuous variable. Clinical endpoints were range of motion scores, including forward elevation, external rotation, and internal rotation, and patient-reported outcomes, including visual analog scale (VAS) scores, American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) scores, and the Simple Shoulder Test (SST). Survivorship curves were calculated using Kaplan-Meier analysis., Results: Forty-four, 50, and 34 patient shoulders were in the U/NW, overweight, and obese cohorts, respectively. The mean follow-up time was 11.4 years. The U/NW cohort had more females (73%) compared with the overweight (34%; P = .0030) and obese (35%; P = .0015) groups; no differences were seen in revision rates. BMI was negatively correlated with age at surgery (r = -0.19, P = .014); it was not correlated with any of the 6 postoperative clinical endpoints. All 3 cohorts saw significant improvements in forward elevation, external rotation, internal rotation and VAS, ASES, and SST scores when compared preoperatively to postoperatively (P < .001). There were no significant differences between the 3 cohorts with respect to postoperative range of motion. Postoperative ASES scores were higher for the overweight cohort (82.6 ± 18.6) compared with both the U/NW (63.0 ± 25.1) and obese cohorts (70.5 ± 26.8) (P < .001). The overweight cohort also had higher SST (P = .0012) postoperative scores compared with the U/NW and obese cohorts; VAS scores were comparable between groups (P = .12). The nonobese (BMI <30) group (n = 94) showed 5-, 10-, and 15-year implant survival of 98.9%, 94.9%, and 83.9%, respectively compared to 97.1%, 93.7%, and 87.0% in the obese (BMI ≥30) group (n = 34). The log rank test revealed no significant difference in survival curves (P = .82)., Conclusion: To our knowledge, this is the longest follow-up study analyzing clinical endpoints stratified by BMI for aTSA. We saw that patients with a higher BMI required shoulder replacement at a significantly younger age. However, we also report that regardless of BMI, all patients saw significant improvements in patient-reported outcomes and range of motion scores postoperatively., (Copyright © 2022 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

For accurate diagnosis of interstitial lung disease (ILD), a consensus of radiologic, pathological, and clinical findings is vital. Management of ILD also requires thorough follow-up with computed tomography (CT) studies and lung function tests to assess disease progression, severity, and response to treatment. However, accurate classification of ILD subtypes can be challenging, especially for those not accustomed to reading chest CTs regularly. Dynamic models to predict patient survival rates based on longitudinal data are challenging to create due to disease complexity, variation, and irregular visit intervals. Here, we utilize RadImageNet pretrained models to diagnose five types of ILD with multimodal data and a transformer model to determine a patient's 3-year survival rate. When clinical history and associated CT scans are available, the proposed deep learning system can help clinicians diagnose and classify ILD patients and, importantly, dynamically predict disease progression and prognosis., (© 2023. The Author(s).)

We report the total synthesis of the furanobutenolide-derived diterpenoid (+)-ineleganolide. The synthetic approach relies on a convergent strategy based on the coupling of two enantioenriched fragments, which are derived from (-)-linalool and (+)-norcarvone, respectively. A high-yielding, one-step Michael addition and aldol cascade furnishes a pentacyclic framework as a single diastereomer, thereby overcoming previous challenges in controlling stereochemistry. The endgame features an O 2 -facilitated C-H oxidation and a samarium diiodide-induced semipinacol rearrangement to furnish the highly rigid central seven-membered ring.

Background: Hypersensitivity pneumonitis (HP) is a type of interstitial lung disease (ILD) with a variable disease course and prognosis ranging from inflammatory and self-limiting to irreversible and progressive pulmonary fibrosis. Comorbidities are common in HP and may have an impact on prognosis. Due to the heterogeneity of HP presentation and progression, the identification of specific phenotypes in relationship to disease course and outcome is essential. The aim of this study was to identify clusters of comorbidities which could represent phenotypes in fibrotic HP and examine their impact on prognosis., Methods: Patients diagnosed with fibrotic HP at a tertiary referral center for ILD were included. Comorbidities were systematically registered and clusters of comorbidities were identified using cluster analyses. Disease progression and survival was estimated for each cluster., Results: The cohort comprised 211 patients with 53.6% males, mean age 63.0, baseline FVC 72.7%, DLCO 44.1%. Median follow-up time was 1.8 years (IQR 0.7-3.9). Three clusters with distinct comorbidity profiles and clinical characteristics were identified. One cluster dominated by elder male patients with predominantly cardiovascular diseases was associated with more respiratory hospitalizations and a worse prognosis. Differences in pulmonary function or exercise capacity trajectories between clusters were not observed., Conclusions: Three clusters with distinct comorbidities were identified and could represent phenotypes in fibrotic HP not previously recognized. The worst prognosis was observed in a cluster dominated by elder males with cardiovascular diseases. Increased focus on prevention and treatment of comorbidities could potentially improve the prognosis of patients with fibrotic HP., (© 2022. The Author(s).)

Introduction: Implementing novel tools that identify contributors to the cost of orthopedic procedures can help hospitals maximize efficiency, minimize waste, improve surgical decision-making, and practice value-based care. The purpose of this study was to develop and internally validate a machine learning algorithm to identify key drivers of total charges after ambulatory arthroscopic rotator cuff repair and compare its performance with a state-of-the-art statistical learning model., Methods: A retrospective review of the New York State Ambulatory Surgery and Services Database was performed to identify patients who underwent elective outpatient rotator cuff repair (RCR) from 2015 to 2016. Initial models were constructed using patient characteristics (age, gender, insurance status, patient income, Elixhauser Comorbidity Index) as well as intraoperative variables (concomitant procedures and services, operative time). These were subsequently entered into 5 separate machine learning algorithms and a generalized additive model using natural splines. Global variable importance and partial dependence curves were constructed to identify the greatest contributors to cost., Results: A total of 33,976 patients undergoing ambulatory RCR were included. Median total charges after ambulatory RCR were $16,017 (interquartile range: $11,009-$22,510). The ensemble model outperformed the generalized additive model and demonstrated the best performance on internal validation (root mean squared error: $7112, 95% confidence interval: 7036-7188; logarithmic root mean squared error: 0.354, 95% confidence interval: 0.336-0.373, R 2 : 0.53), and identified major drivers of total charges after RCR as increasing operating room time, patient income level, number of anchors used, use of local infiltration anesthesia/peripheral nerve blocks, non-White race/ethnicity, and concurrent distal clavicle excision. The model was integrated into a web-based open-access application capable of providing individual predictions and explanations on a case-by-case basis., Conclusion: This study developed an ensemble supervised machine learning algorithm that outperformed a sophisticated statistical learning model in predicting total charges after ambulatory RCR. Important contributors to total charges included operating room time, duration of care, number of anchors used, type of anesthesia, concomitant distal clavicle excision, community characteristics, and patient demographic factors. Generation of a patient-specific payment schedule based on the Agency for Healthcare Research and Quality risk of mortality highlighted the financial risk assumed by physicians in flat episodic reimbursement schedules given variable patient comorbidities and the importance of an accurate prediction algorithm to appropriately reward high-value care at low costs., (Copyright © 2022 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Purpose: A total proctocolectomy with subsequent creation of an ileal-pouch, such as a J-pouch or a Kock pouch, has been the most common surgery performed for ulcerative colitis (UC). A small portion of these patients will develop complications with the inflow limb into the pouch requiring operative intervention. The objective was to establish a better understanding as to the pathological mechanism by which these pouch inflow limb problems develop., Methods: This was a retrospective cohort study conducted at a single tertiary care inflammatory bowel disease (IBD) center. A database was created of all the patients who underwent pouch-related procedures, following completion of their original pouch, between 2006 and 2018. The patients requiring operative resection for inflow limb complications were identified among this cohort. Operative and pathological data were collected., Results: One hundred seventy-eight UC patients underwent surgeries on their pouches between 2006 and 2018. Sixteen patients required operative resection for inflow limb problems. Reoperations for inflow limb problems included inflow limb resection with pouch excision (n = 4) and inflow limb resection with pouch revision (n = 12). The pathology findings of the inflow limb were consistent with Crohn's disease in 9 patients (56%). Two other patients (total 69%) were eventually diagnosed with Crohn's disease due to other pathological specimens or perianal pathology. The remaining patients had chronic, non-specific enteritis/serositis., Conclusions: A small proportion of pouch patients will eventually require surgery for inflow limb complications. Among these, there was a high rate of Crohn's disease of the inflow limb and overall change in diagnosis to Crohn's disease (Plietz et al. in Official Journal of the American College of Gastroenterology | ACG 114:S453, 2019)., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Interpretation of genomic variants in tumor samples still presents a challenge in research and the clinical setting. A major issue is that information for variant interpretation is fragmented across disparate databases, and aggregation of information from these requires building extensive infrastructure. To this end, we have developed Genome Nexus, a one-stop shop for variant annotation with a user-friendly interface for cancer researchers and clinicians., Methods: Genome Nexus (1) aggregates variant information from sources that are relevant to cancer research and clinical applications, (2) allows high-performance programmatic access to the aggregated data via a unified application programming interface, (3) provides a reference page for individual cancer variants, (4) provides user-friendly tools for annotating variants in patients, and (5) is freely available under an open source license and can be installed in a private cloud or local environment and integrated with local institutional resources., Results: Genome Nexus is available at https://www.genomenexus.org. It displays annotations from more than a dozen resources including those that provide variant effect information (variant effect predictor), protein sequence annotation (Uniprot, Pfam, and dbPTM), functional consequence prediction (Polyphen-2, Mutation Assessor, and SIFT), population prevalences (gnomAD, dbSNP, and ExAC), cancer population prevalences (Cancer hotspots and SignalDB), and clinical actionability (OncoKB, CIViC, and ClinVar). We describe several use cases that demonstrate the utility of Genome Nexus to clinicians, researchers, and bioinformaticians. We cover single-variant annotation, cohort analysis, and programmatic use of the application programming interface. Genome Nexus is unique in providing a user-friendly interface specific to cancer that allows high-performance annotation of any variant including unknown ones., Conclusion: Interpretation of cancer genomic variants is improved tremendously by having an integrated resource for annotations. Genome Nexus is freely available under an open source license., Competing Interests: Robert SheridanStock and Other Ownership Interests: Agios, Alnylam (I), Alphabet (I), Amazon Inc, Amgen (I), Biogen (I), Bluebird Bio, Bristol Myers Squibb (I), Clementia Pharmaceuticals (I), General Electric Company, Johnson & Johnson (I), Merck (I), Northwest Biotherapeutics (I), Pfizer (I), Portola Pharmaceuticals, Viatris, Organon & Co, ClearPoint Neuro Inc, 2Seventy Bio Inc Angelica OchoaStock and Other Ownership Interests: Infinity Pharmaceuticals, AstraZeneca/MedImmune Avery WangStock and Other Ownership Interests: Gilead Sciences, CVS, Brickell Biotech, Zomedica, Bristol Myers Squibb Adam AbeshouseStock and Other Ownership Interests: Ligand Pharmaceuticals Cyriac KandothEmployment: Thermo Fisher Scientific (I)Stock and Other Ownership Interests: Massive Bio Sander RodenburgConsulting or Advisory Role: The Hyve Sander TanEmployment: myTomorrows Sjoerd van HagenStock and Other Ownership Interests: Galapagos NV Remond J. A. FijnemanResearch Funding: Merck BV (Inst), Personal Genome (Inst), Delfi Diagnostics (Inst), Cergentis (Inst)Patents, Royalties, Other Intellectual Property: several patents pending (Inst) Gerrit A. MeijerStock and Other Ownership Interests: crcBioscreen BVResearch Funding: Exact Sciences (Inst), Sysmex (Inst), Sentinel Diagnostics (Inst), Personal Genome Diagnostics (Inst), Hartwig Medical Foundation (Inst)Patents, Royalties, Other Intellectual Property: Several patents pending (Inst)No other potential conflicts of interest were reported.

When COVID-19 prevented scholars from traveling to libraries, archives, and museums, staff at those institutions devised creative strategies for providing remote access to their holdings. This article examines one such initiative launched by the Linda Hall Library of Science, Engineering, and Technology in Kansas City, Missouri. The Library's prioritization of print over archival materials, experience fulfilling document delivery requests, and investments in digitization infrastructure facilitated the transition to a completely virtual fellowship program during the 2021-22 academic year. Although virtual fellowships could not replicate every aspect of in-person residencies, they nonetheless supplied scholars with much-needed funding, research materials, and membership in a scholarly community. Based on the program's initial success, the Library plans to continue offering virtual fellowships to scholars otherwise unable to conduct research on site.

Objective  The COVID-19 pandemic led to an unprecedented pause in elective surgeries, including shoulder arthroplasty. We sought to determine whether clinical and/or demographic differences would be seen between patients who presented for shoulder arthroplasty during the pandemic compared with the previous year (2019). Methods  Institutional records were queried for patients who underwent shoulder replacement between March 1 and July 1 of 2019 and 2020. Demographics, range of motion, surgical duration, hospitalization time, discharge disposition, and postoperative management were analyzed. Results  The mean duration of surgery was 160 ± 50 minutes in 2020 and 179 ± 54 minutes in 2019 ( p  = 0.13). The mean hospitalization time was 36 ± 13 hours in 2020 and 51 ± 40 hours in 2019 ( p  = 0.04). In 2019, 96% of the patients participated in physical therapy, while 71% did it in 2020 ( p  = 0.003). A total of 100% of the 2019 patients and 86% of the 2020 patients participated in an in-person postoperative follow-up ( p  = 0.006). The 2019 patients reported for an office visit on average 14 ± 11 days after surgery; the 2020 patients waited 25 ± 25 days to return for a follow-up ( p  = 0.10). Range of motion, age, American Society of Anesthesiologists (ASA) scores, and complication rates did not differ between the cohorts. Conclusion  Patients presenting for surgery during the initial phase of the pandemic were demographically and clinically similar to 2019 patients. However, the length of stay was significantly reduced during the COVID-19 pandemic. Postoperative follow-up and physical therapy were delayed in 2020, but this did not lead to differences in complication or readmission rates compared with those of the 2019 cohort. Level of Evidence  III., Competing Interests: Conflitos de Interesses Paul J. Cagle, MD Stryker: Consultor Johnson & Johnson: Consultor Bradford O. Parsons, MD Arthrex: Consultor Os seguintes profissionais não têm conflitos de interesse ou fontes de financiamento que precisem ser mencionados: Kevin C. Wang, Akshar V. Patel, Christopher A. White e Benjamin D. Gross, (Sociedade Brasileira de Ortopedia e Traumatologia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

The power of cation-initiated cyclizations of polyenes for the synthesis of polycyclic terpenoids cannot be overstated. However, a major limitation is the intolerance of many relevant reaction conditions toward the inclusion in the substrate of polar functionality, particularly in unprotected form. Radical polycyclizations are important alternatives to bioinspired cationic variants, in part owing to the range of possible initiation strategies, and in part for the functional group tolerance of radical reactions. In this article, we demonstrate that Co-catalyzed MHAT-initiated radical bicyclizations are not only tolerant of oxidation at virtually every position in the substrate, oftentimes in unprotected form, but these functional groups can also contribute to high levels of stereochemical control in these complexity-generating transformations. Specifically, we show the effects of protected or unprotected hydroxy groups at six different positions and their impact on stereoselectivity. Further, we show how multiply oxidized substrates perform in these reactions, and finally, we document the utility of these reactions in the synthesis of three aromatic abietane diterpenoids.

Purpose: Cancer classification is foundational for patient care and oncology research. Systems such as International Classification of Diseases for Oncology (ICD-O), Systematized Nomenclature of Medicine Clinical Terms (SNOMED-CT), and National Cancer Institute Thesaurus (NCIt) provide large sets of cancer classification terminologies but they lack a dynamic modernized cancer classification platform that addresses the fast-evolving needs in clinical reporting of genomic sequencing results and associated oncology research., Methods: To meet these needs, we have developed OncoTree, an open-source cancer classification system. It is maintained by a cross-institutional committee of oncologists, pathologists, scientists, and engineers, accessible via an open-source Web user interface and an application programming interface., Results: OncoTree currently includes 868 tumor types across 32 organ sites. OncoTree has been adopted as the tumor classification system for American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE), a large genomic and clinical data-sharing consortium, and for clinical molecular testing efforts at Memorial Sloan Kettering Cancer Center and Dana-Farber Cancer Institute. It is also used by precision oncology tools such as OncoKB and cBioPortal for Cancer Genomics., Conclusion: OncoTree is a dynamic and flexible community-driven cancer classification platform encompassing rare and common cancers that provides clinically relevant and appropriately granular cancer classification for clinical decision support systems and oncology research.

Aim: Hartmann's procedure is commonly performed emergently for infectious, inflammatory, or malignant processes. Most patients historically do not undergo reversal, and those who do have been found to suffer significant morbidity. The aim of this study was to study factors associated with complications after Hartmann's reversal and to provide information and guidance to surgeons., Method: A retrospective review of patients undergoing Hartmann's reversal between May 2002 and October 2017 was conducted at a tertiary medical center. Data included patient characteristics at the time of surgery and intra- and postoperative complications. Chi-square test was used for categorical variables. The Wilcoxon signed rank or t test where appropriate was used for multivariate analysis., Results: Two hundred forty-nine patients were included. Mean age at reversal was 58.8 years, and 114 (58%) were male. Sixty-two (31.8%) patients experienced a major complication following reversal. Eight (4%) patients had an anastomotic leak. Thirteen (6.67%) patients had an intra-abdominal abscess which required either IR or operative drainage. Patients who experienced a major complication were more likely to have an ASA 4 at time of reversal (14.3% vs. 4.24%, p = 0.019), liver disease (6.6% vs. 0.8%, p = 0.021), and BMI < 30 (35% vs. 17.3%, p = 0.020)., Conclusions: Nearly one-third of patients who had reversal surgery experienced a major complication. Four percent of patients undergoing reversal had an anastomotic leak, comparable to previously reported rates. Patients with ASA 4, liver disease, and BMI < 30 were at higher risk of a major complication following reversal. Patients who underwent laparoscopic reversal had no significant difference in outcomes., Aim: What does this paper add to the literature? The decision of whether to reverse a colostomy after Hartmann's procedure. Our study aims to identify risk factors associated with complications after Hartmann's reversal to better guide surgeon's facing the dilemma of whether or not to reverse the stoma.

Purpose: To compare the efficacy of a subacromial injection (SAI) with a single-shot interscalene block (ISB) for immediate postoperative pain relief after outpatient arthroscopic rotator cuff repair (ARCR)., Methods: We performed a retrospective chart review of consecutive patients who underwent ARCR. Patients received either an ISB before the procedure or an SAI after the procedure. Preoperative baseline patient characteristics were collected and compared. Visual analog scale (VAS) pain scores were recorded preoperatively, at 15-minute intervals over a 120-minute period in the postanesthesia care unit (PACU), and at discharge. Differences in VAS scores between groups were compared with known values of the minimal clinically important difference, and the percentage of patients with VAS scores below the patient acceptable symptom state was tabulated. Differences between preoperative characteristics were assessed using the Mann-Whitney U, Fisher exact, or χ 2 test. The Mann-Whitney U test was also used to evaluate VAS scores and total time spent in the PACU between groups., Results: The median VAS score was significantly lower in the ISB group at PACU admission, at all intervals throughout the PACU stay, and at discharge (P < .0001). The median total time in the PACU was 107 minutes (25th percentile-75th percentile, 90-120 minutes) and 210 minutes (25th percentile-75th percentile, 175-274 minutes) in the ISB and SAI groups, respectively (P < .0001). Between-group differences in VAS scores were greater than the values of the minimal clinically important difference at each measured interval. A total of 98% and 67% of patients in the ISB and SAI groups, respectively, were discharged with VAS scores below the patient acceptable symptom state of 3., Conclusions: Patients receiving an ISB experience significantly less pain than those receiving an SAI. In addition, they are discharged home from the PACU in half the time as patients receiving an SAI. On the basis of the comparative efficacy, an SAI cannot replace an ISB after ARCR. The ISB should therefore remain the standard of care as an adjunct to postoperative analgesia for patients who undergo outpatient ARCR., Level of Evidence: Level III, retrospective, comparative therapeutic trial., (Copyright © 2020 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

AKT inhibitors have promising activity in AKT1 E17K -mutant estrogen receptor (ER)-positive metastatic breast cancer, but the natural history of this rare genomic subtype remains unknown. Utilizing AACR Project GENIE, an international clinicogenomic data-sharing consortium, we conducted a comparative analysis of clinical outcomes of patients with matched AKT1 E17K -mutant ( n = 153) and AKT1 -wild-type ( n = 302) metastatic breast cancer. AKT1 -mutant cases had similar adjusted overall survival (OS) compared with AKT1 -wild-type controls (median OS, 24.1 vs. 29.9, respectively; P = 0.98). AKT1 -mutant cases enjoyed longer durations on mTOR inhibitor therapy, an observation previously unrecognized in pivotal clinical trials due to the rarity of this alteration. Other baseline clinicopathologic features, as well as durations on other classes of therapy, were broadly similar. In summary, we demonstrate the feasibility of using a novel and publicly accessible clincogenomic registry to define outcomes in a rare genomically defined cancer subtype, an approach with broad applicability to precision oncology. SIGNIFICANCE: We delineate the natural history of a rare genomically distinct cancer, AKT1 E17K -mutant ER-positive breast cancer, using a publicly accessible registry of real-world patient data, thereby illustrating the potential to inform drug registration through synthetic control data. See related commentary by Castellanos and Baxi, p. 490 ., (©2020 American Association for Cancer Research.)

A method for the synthesis of benzylsilanes starting from the corresponding ammonium triflates is reported. Silyl boronic esters are employed as silicon pronucleophiles, and the reaction is catalyzed by copper(I) salts. Enantioenriched benzylic ammonium salts react stereospecifically through an S N 2-type displacement of the ammonium group to afford α-chiral silanes with inversion of the configuration. A cyclopropyl-substituted substrate does not undergo ring opening, thus suggesting an ionic reaction mechanism with no benzyl radical intermediate., (© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Introduction: Chronic Hypersensitivity Pneumonitis (cHP) is a fibrotic interstitial lung disease (ILD) resulting from repeated exposure to an offending antigen. Prognostication in cHP remains challenging, and the relationship between comorbidities and survival has yet to be characterized. The aim of this study was to describe the relationship between comorbid conditions and survival in patients with cHP., Methods: The prospective database from a tertiary referral centre for ILD was reviewed for patient-reported comorbidities, their frequency, and relationship with survival in cHP patients. Comorbidities were assessed by direct questioning of the patient at the baseline visit and by a standardized questionnaire for the diagnosis of interstitial lung diseases. During the follow-up examinations, patients were asked about newly diagnosed comorbidities., Results: Two hundred eleven patients with cHP were identified (mean age 63 years, 53% male, mean FVC 73%), with mean follow-up of 32 months. The mean number of comorbidities was 3 (10% had 0, 59% 1-3 and 31% ≥4 comorbidities). Most frequent comorbidities groups were cardiovascular (65%) and respiratory (26%), most common comorbidities were hypertension (56%), gastro-esophageal reflux disease (GERD) (24%), diabetes (20%) and coronary heart disease (18%). In general, deceased patients had more comorbidities than survivors (p = 0.005), yet there was no association between the absolute number of comorbidities and survival. Pulmonary hypertension (30.8% versus 5.7%, p = 0.001;), diastolic dysfunction (26.9% versus 6.4%, p = 0.004) and cerebrovascular disease were more frequent in non-survivors (23.1% versus 7.6%, p = 0.026). Lung cancer was not observed, and neither GERD nor antacid drugs were associated with outcome (p = 0.357 and p = 0.961, respectively)., Conclusions: Comorbidities are common in cHP are associated with survival. Further work should determine whether interventions for these specific comorbidities can positively affect survival.

Pathway Commons (https://www.pathwaycommons.org) is an integrated resource of publicly available information about biological pathways including biochemical reactions, assembly of biomolecular complexes, transport and catalysis events and physical interactions involving proteins, DNA, RNA, and small molecules (e.g. metabolites and drug compounds). Data is collected from multiple providers in standard formats, including the Biological Pathway Exchange (BioPAX) language and the Proteomics Standards Initiative Molecular Interactions format, and then integrated. Pathway Commons provides biologists with (i) tools to search this comprehensive resource, (ii) a download site offering integrated bulk sets of pathway data (e.g. tables of interactions and gene sets), (iii) reusable software libraries for working with pathway information in several programming languages (Java, R, Python and Javascript) and (iv) a web service for programmatically querying the entire dataset. Visualization of pathways is supported using the Systems Biological Graphical Notation (SBGN). Pathway Commons currently contains data from 22 databases with 4794 detailed human biochemical processes (i.e. pathways) and ∼2.3 million interactions. To enhance the usability of this large resource for end-users, we develop and maintain interactive web applications and training materials that enable pathway exploration and advanced analysis., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Transbronchial cryobiopsy (cTBB) may offer an alternative to surgical lung biopsy (SLB) for histopathological diagnosis of interstitial lung diseases (ILDs). However, real-life experience is limited, although case series are increasingly reported., Objectives: We aimed to evaluate the value of cTBB performed under real-life conditions in a tertiary care center for ILDs., Methods: Data on all patients undergoing a cTBB for evaluation of suspected ILD between October 2015 and January 2017 were included in this retrospective case series. Procedure details, complication rates, histopathological results, and diagnostic consensus reached by a multidisciplinary team (MDT) discussion were collated and evaluated., Results: A total of 109 patients (mean age 64 years, range 19-85; 66% male, 38% never smokers) referred to our center with features suggestive of ILD underwent cTBB. The mean FVC% predicted was 77% (range 41-131), with a mean DLCO of 51% (range 20-86), and a 6-min walking test (6MWT) of 402 m (range 100-642). On average, 4 samples were taken from each patient (range 1-8), with a mean biopsy diameter of 5 mm (range 2-12). Complications included pneumothorax (11.9%), all treated with chest drain. Moderate bleeding occurred in 28.4% (all resolved without active measures). No acute disease exacerbations and no deaths occurred. A histopathological pattern diagnosis was possible in 80 cases (73.4%), and 26.6% of cases were considered nonspecific. An MDT consensus diagnosis was reached in 83.5% of cases. Subsequent SLB was proposed in 13 cases and performed in 8 cases., Conclusions: In the real-world setting, cTBB has a meaningful diagnostic value in the context of a MDT approach and may enable histopathological assessment even in patients with more advanced disease unsuitable for SLB., (© 2018 S. Karger AG, Basel.)

Driven by the recent advances of next generation sequencing (NGS) technologies and an urgent need to decode complex human diseases, a multitude of large-scale studies were conducted recently that have resulted in an unprecedented volume of whole transcriptome sequencing (RNA-seq) data, such as the Genotype Tissue Expression project (GTEx) and The Cancer Genome Atlas (TCGA). While these data offer new opportunities to identify the mechanisms underlying disease, the comparison of data from different sources remains challenging, due to differences in sample and data processing. Here, we developed a pipeline that processes and unifies RNA-seq data from different studies, which includes uniform realignment, gene expression quantification, and batch effect removal. We find that uniform alignment and quantification is not sufficient when combining RNA-seq data from different sources and that the removal of other batch effects is essential to facilitate data comparison. We have processed data from GTEx and TCGA and successfully corrected for study-specific biases, enabling comparative analysis between TCGA and GTEx. The normalized datasets are available for download on figshare.

Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy., (Copyright © 2018. Published by Elsevier Inc.)

The incidence of esophagogastric cancer is rapidly rising, but only a minority of patients derive durable benefit from current therapies. Chemotherapy as well as anti-HER2 and PD-1 antibodies are standard treatments. To identify predictive biomarkers of drug sensitivity and mechanisms of resistance, we implemented prospective tumor sequencing of patients with metastatic esophagogastric cancer. There was no association between homologous recombination deficiency defects and response to platinum-based chemotherapy. Patients with microsatellite instability-high tumors were intrinsically resistant to chemotherapy but more likely to achieve durable responses to immunotherapy. The single Epstein-Barr virus-positive patient achieved a durable, complete response to immunotherapy. The level of ERBB2 amplification as determined by sequencing was predictive of trastuzumab benefit. Selection for a tumor subclone lacking ERBB2 amplification, deletion of ERBB2 exon 16, and comutations in the receptor tyrosine kinase, RAS, and PI3K pathways were associated with intrinsic and/or acquired trastuzumab resistance. Prospective genomic profiling can identify patients most likely to derive durable benefit to immunotherapy and trastuzumab and guide strategies to overcome drug resistance. Significance: Clinical application of multiplex sequencing can identify biomarkers of treatment response to contemporary systemic therapies in metastatic esophagogastric cancer. This large prospective analysis sheds light on the biological complexity and the dynamic nature of therapeutic resistance in metastatic esophagogastric cancers. Cancer Discov; 8(1); 49-58. ©2017 AACR. See related commentary by Sundar and Tan, p. 14 See related article by Pectasides et al., p. 37 This article is highlighted in the In This Issue feature, p. 1 ., (©2017 American Association for Cancer Research.)

A key feature of age-related hearing loss is a reduction in the expression of inhibitory neurotransmitters in the central auditory system. This loss is partially responsible for changes in central auditory processing, as inhibitory receptive fields play a critical role in shaping neural responses to sound stimuli. Vigabatrin (VGB), an antiepileptic agent that irreversibly inhibits γ-amino butyric acid (GABA) transaminase, leads to increased availability of GABA throughout the brain. This study used multi-channel electrophysiology measurements to assess the excitatory frequency response areas in old CBA mice to which VGB had been administered. We found a significant post-VGB reduction in the proportion of V-type shapes, and an increase in primary-like excitatory frequency response areas. There was also a significant increase in the mean maximum driven spike rates across the tonotopic frequency range of all treated animals, consistent with observations that GABA buildup within the central auditory system increases spike counts of neural receptive fields. This increased spiking is also seen in the rate-level functions and seems to explain the improved low-frequency thresholds., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Tumor molecular profiling is a fundamental component of precision oncology, enabling the identification of genomic alterations in genes and pathways that can be targeted therapeutically. The existence of recurrent targetable alterations across distinct histologically defined tumor types, coupled with an expanding portfolio of molecularly targeted therapies, demands flexible and comprehensive approaches to profile clinically relevant genes across the full spectrum of cancers. We established a large-scale, prospective clinical sequencing initiative using a comprehensive assay, MSK-IMPACT, through which we have compiled tumor and matched normal sequence data from a unique cohort of more than 10,000 patients with advanced cancer and available pathological and clinical annotations. Using these data, we identified clinically relevant somatic mutations, novel noncoding alterations, and mutational signatures that were shared by common and rare tumor types. Patients were enrolled on genomically matched clinical trials at a rate of 11%. To enable discovery of novel biomarkers and deeper investigation into rare alterations and tumor types, all results are publicly accessible.

Our objectives was to create an initiative to change the culture of a small community to improve quality of life as it relates to health for the residents through the use of health-related educational sessions, a coordinated fitness and nutrition program, and the construction of community fitness trails. We compared the use of a health-focused community driven program to the status quo in seeking opportunities to improve perception and understanding of one's health and overall quality of life for participants. Among the various techniques identified to improve a community's health outcomes, dissemination of information through the use of educational sessions empowered citizens to take control of their health status, and ultimately, their quality of life. This came with zero negative impacts for those providing the education, as well as those participating in the sessions. Although the application of these methods depends on local resources, leadership, and partnerships, programs similar to those presented here can help to improve quality of life for citizens in communities across the country facing the challenges secondary to a sedentary lifestyle.

Database Url: https://ctd2-dashboard.nci.nih.gov/., (© The Author(s) 2017. Published by Oxford University Press.)

Metal-reducing bacteria gain energy by extracellular electron transfer to external solids, such as naturally abundant minerals, which substitute for oxygen or the other common soluble electron acceptors of respiration. This process is one of the earliest forms of respiration on earth and has significant environmental and technological implications. By performing electron transfer to electrodes instead of minerals, these microbes can be used as biocatalysts for conversion of diverse chemical fuels to electricity. Understanding such a complex biotic-abiotic interaction necessitates the development of tools capable of probing extracellular electron transfer down to the level of single cells. Here, we describe an experimental platform for single cell respiration measurements. The design integrates an infrared optical trap, perfusion chamber, and lithographically fabricated electrochemical chips containing potentiostatically controlled transparent indium tin oxide microelectrodes. Individual bacteria are manipulated using the optical trap and placed on the microelectrodes, which are biased at a suitable oxidizing potential in the absence of any chemical electron acceptor. The potentiostat is used to detect the respiration current correlated with cell-electrode contact. We demonstrate the system with single cell measurements of the dissimilatory-metal reducing bacterium Shewanella oneidensis MR-1, which resulted in respiration currents ranging from 15 fA to 100 fA per cell under our measurement conditions. Mutants lacking the outer-membrane cytochromes necessary for extracellular respiration did not result in any measurable current output upon contact. In addition to the application for extracellular electron transfer studies, the ability to electronically measure cell-specific respiration rates may provide answers for a variety of fundamental microbial physiology questions.

Type 2 diabetes mellitus (T2DM) carries a high prevalence in the United States and worldwide. Therefore, the number of medication classes being developed and studied has grown. The individualized management of diabetes is accomplished by evaluating a medication's efficacy, safety, and cost, along with the patient's preference and tolerance to the medication. Sodium glucose co-transporter 2 inhibitors are a new therapeutic class indicated for the treatment of diabetes and have a unique mechanism of action, independent of beta-cell function. The first agent approved by the Food and Drug Administration (FDA) was canagliflozin in March 2013. Two agents - dapagliflozin and empagliflozin - were FDA-approved in January and July 2014, respectively. A clear understanding of the new class is needed to identify its appropriate use in clinical practice. Members of the American College of Clinical Pharmacy Endocrine and Metabolism Practice and Research Network reviewed available literature regarding this therapeutic class. The article addresses the advantages, disadvantages, emerging role, and patient education for sodium glucose co-transporter 2 inhibitors. Key limitations for this article include limited access to clinical trial data not published by the pharmaceutical company and limited data on products produced outside the United States.

Adenoid cystic carcinomas (ACCs) are among the most enigmatic of human malignancies. These aggressive salivary gland cancers frequently recur and metastasize despite definitive treatment, with no known effective chemotherapy regimen. Here we determined the ACC mutational landscape and report the exome or whole-genome sequences of 60 ACC tumor-normal pairs. These analyses identified a low exonic somatic mutation rate (0.31 non-silent events per megabase) and wide mutational diversity. Notably, we found mutations in genes encoding chromatin-state regulators, such as SMARCA2, CREBBP and KDM6A, suggesting that there is aberrant epigenetic regulation in ACC oncogenesis. Mutations in genes central to the DNA damage response and protein kinase A signaling also implicate these processes. We observed MYB-NFIB translocations and somatic mutations in MYB-associated genes, solidifying the role of these aberrations as critical events in ACC. Lastly, we identified recurrent mutations in the FGF-IGF-PI3K pathway (30% of tumors) that might represent new avenues for therapy. Collectively, our observations establish a molecular foundation for understanding and exploring new treatments for ACC.

Background: Multiple complications can arise secondary to poor control of glucose, blood pressure, and cholesterol in a patient with diabetes., Objective: To evaluate the effect of a pharmacist-physician collaboration on attainment of diabetes-related measures of control., Methods: This was a prospective, multicenter, cohort study. Patients were enrolled from 7 practice sites throughout Tennessee if they had been diagnosed with type 2 diabetes, were aged 18 years or older with a life expectancy greater than 1 year, and were English speaking. Pregnant women were excluded. Patients were followed for 12 months following enrollment by informed consent. The pharmacist-physician collaboration method was established prior to study initiation. Primary outcomes included hemoglobin A1c (A1C), number of patients with A1C less than 7%, and percentage of patients with A1C greater than 9%., Results: Of the 206 patients enrolled, the mean age was 59.73 years, and most were male (59.71%) and white (66.02%). The A1C was reduced by an average of 1.16% (p < 0.0001). The proportion of patients with A1C less than 7% increased from 12.75% at baseline to 36.76% at study conclusion (p = 0.0002). The proportion of patients with A1C greater than 9% decreased from 34.15% to 16.50%, (p < 0.0001)., Conclusions: Pharmacist-physician collaborative management at multiple practice locations and types of setting (eg, private, academic, Veterans Affairs medical center) has a positive impact on glycemic control and diabetes-related health maintenance. This was accomplished without increasing the total number of antihyperglycemic agents prescribed and without an increase in patient-reported episodes of hypoglycemia.

The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.

This review presents clinical pearls for initiating liraglutide (Victoza®, Novo Nordisk Inc) therapy for the management of type 2 diabetes and selecting patients who will benefit from liraglutide therapy. Liraglutide, a once-daily glucagon-like peptide 1 receptor agonist, is Food and Drug Administration approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Liraglutide is effective for reducing hemoglobin A1c levels by 0.8% to 1.5% in patients with type 2 diabetes as monotherapy or in combination with other diabetic medications (such as metformin, sulfonylureas, rosiglitazone, or basal insulin) when compared with placebo and these other diabetic medications, including exenatide. Overweight or obese patients with type 2 diabetes or those with insulin resistance are good candidates for liraglutide therapy because liraglutide use is associated with weight loss (about 2%-4% of initial body weight) and improved β-cell function. The incidence of hypoglycemia with liraglutide is low; therefore, liraglutide would be a safe therapy choice for patients at risk or with a history of symptomatic or severe hypoglycemia. Nausea seems to be the most problematic adverse effect associated with liraglutide therapy, but it is usually transient and is minimized with dose titration.

A rapidly growing corpus of formal, computable pathway information can be used to answer important biological questions including finding non-trivial connections between cellular processes, identifying significantly altered portions of the cellular network in a disease state and building predictive models that can be used for precision medicine. Due to its complexity and fragmented nature, however, working with pathway data is still difficult. We present Paxtools, a Java library that contains algorithms, software components and converters for biological pathways represented in the standard BioPAX language. Paxtools allows scientists to focus on their scientific problem by removing technical barriers to access and analyse pathway information. Paxtools can run on any platform that has a Java Runtime Environment and was tested on most modern operating systems. Paxtools is open source and is available under the Lesser GNU public license (LGPL), which allows users to freely use the code in their software systems with a requirement for attribution. Source code for the current release (4.2.0) can be found in Software S1. A detailed manual for obtaining and using Paxtools can be found in Protocol S1. The latest sources and release bundles can be obtained from biopax.org/paxtools.

Induced pluripotent stem cells (iPSCs) have emerged as a promising basis for modeling pediatric genetic disorders, allowing the derivation, study, and genetic correction of disease and patient-specific cell lines in vitro. Similar to embryonic stem cells (ESCs), iPSCs are capable of unlimited in vitro expansion and derivation of many cell types, including hematopoietic stem cells (HSCs). These may not only allow large scale screenings to develop therapeutic compounds, but also help to overcome cross-species barriers of genetically engineered animal models, which do not adequately recapitulate the associated human phenotype. Here, we review the current state and emerging developments of iPSC research, which can be exploited as a tool in modeling pediatric hematopoietic disorders and could lead to new clinical applications in gene and cell therapies.

The cBio Cancer Genomics Portal (http://cbioportal.org) is an open-access resource for interactive exploration of multidimensional cancer genomics data sets, currently providing access to data from more than 5,000 tumor samples from 20 cancer studies. The cBio Cancer Genomics Portal significantly lowers the barriers between complex genomic data and cancer researchers who want rapid, intuitive, and high-quality access to molecular profiles and clinical attributes from large-scale cancer genomics projects and empowers researchers to translate these rich data sets into biologic insights and clinical applications., (© 2012 AACR.)

There are several interconnected metabolic pathways in bacteria essential for the conversion of carbon electron sources directly into electrical currents using microbial fuel cells (MFCs). This study establishes a direct exogenous method to increase power output from a Shewanella oneidensis MR-1 containing MFC by adding calcium chloride to the culture medium. The current output from each CaCl(2) concentration tested revealed that the addition of CaCl(2) to 1400 μM increased the current density by >80% (0.95-1.76 μA/cm(2)) using sodium lactate as the sole carbon source. Furthermore, polarization curves showed that the maximum power output could be increased from 157 to 330 μW with the addition of 2080 μM CaCl(2). Since the conductivity of the culture medium did not change after the addition of CaCl(2) (confirmed by EIS and bulk conductivity measurements), this increase in power was primarily biological and not based on ionic effects. Thus, controlling the concentration of CaCl(2) is a pathway to increase the efficiency and performance of S. oneidensis MR-1 MFCs., (Published by Elsevier B.V.)