bluuebunny/crossref_metadata_2025_split huggingface dataset:
New-Onset Cancer Cases in FDA's Sentinel System: A Large Distributed System of US Electronic Healthcare Data
Authors: Haug Nicole R. , Wagner Anita K. , McGlynn Katherine A. , Leonard Charles E. , Nguyen Michael D. , Major Jacqueline M. 
Published: July 2022

Abstract

Background:
Evaluations of cancer etiology and safety and effectiveness of cancer treatments are predicated on large numbers of patients with sufficient baseline and follow-up data. To assess feasibility of FDA's Sentinel System's electronic healthcare data for surveillance of malignancy onset and examination of product safety, this study examined patterns of enrollment surrounding new-onset cancers.

Methods:
Using a retrospective cohort of patients based on administrative claims, we identified incident events of 19 cancers among 292.5 million health plan members from January 2000 to February 2020 using International Classification of Diseases (ICD) diagnosis codes. Annual incident cases were stratified by sex, age, medical and drug coverage, and insurer type. Descriptive statistics were calculated for observable time prior to and following diagnosis.

Results:
We identified 10,697,573 incident cancer events among members with medical coverage. When drug coverage was additionally required, number of incident cancers was reduced by 41%. Medicare data contributed 61% of cases, with similar duration trends as other insurers. Mean duration of follow-up prior to diagnosis ranged from 4.0 to 4.6 years, whereas follow-up post diagnosis ranged from 1.1 to 3.3 years. Approximately a third (36.1%) had at least 2 years both prior to and following diagnosis.

Conclusions:
The FDA Sentinel System's electronic healthcare data may be useful for characterizing relatively short latency cancer risk, examining cancer drug utilization and safety after diagnosis, and conducting surveillance for acute adverse events among patients with cancers.

Impact:
A national distributed system with electronic health data, the Sentinel system provides opportunity for rapid pharmacoepidemiologic assessments relevant in oncology.
RASGRF1 Fusions Activate Oncogenic RAS Signaling and Confer Sensitivity to MEK Inhibition
Authors: Hunihan Lisa , Zhao Dejian , Lazowski Heather , Li Man , Qian Yuping , Abriola Laura , Surovtseva Yulia V. , Muthusamy Viswanathan , Tanoue Lynn T. , Rothberg Bonnie E. Gould , Schalper Kurt A. , Herbst Roy S. , Wilson Frederick H. 
Published: July 2022

Abstract

Purpose:
The identification of actionable oncogenic alterations has enabled targeted therapeutic strategies for subsets of patients with advanced malignancies, including lung adenocarcinoma (LUAD). We sought to assess the frequency of known drivers and identify new candidate drivers in a cohort of LUAD from patients with minimal smoking history.

Experimental Design:
We performed genomic characterization of 103 LUADs from patients with ≤10 pack-year smoking history. Tumors were subjected to targeted molecular profiling and/or whole-exome sequencing and RNA sequencing in search of established and previously uncharacterized candidate drivers.

Results:
We identified an established oncogenic driver in 98 of 103 tumors (95%). From one tumor lacking a known driver, we identified a novel gene rearrangement between OCLN and RASGRF1. The encoded OCLN-RASGRF1 chimera fuses the membrane-spanning portion of the tight junction protein occludin with the catalytic RAS-GEF domain of the RAS activator RASGRF1. We identified a similar SLC4A4-RASGRF1 fusion in a pancreatic ductal adenocarcinoma cell line lacking an activating KRAS mutation and an IQGAP1-RASGRF1 fusion from a sarcoma in The Cancer Genome Atlas. We demonstrate these fusions increase cellular levels of active GTP-RAS, induce cellular transformation, and promote in vivo tumorigenesis. Cells driven by RASGRF1 fusions are sensitive to targeting of the RAF-MEK-ERK pathway in vitro and in vivo.

Conclusions:
Our findings credential RASGRF1 fusions as a therapeutic target in multiple malignancies and implicate RAF-MEK-ERK inhibition as a potential treatment strategy for advanced tumors harboring these alterations.
See related commentary by Moorthi and Berger, p. 2983
Membrane-Anchored and Tumor-Targeted IL12 (attIL12)-PBMC Therapy for Osteosarcoma
Authors: Yang Qing , Hu Jiemiao , Jia Zhiliang , Wang Qi , Wang Jing , Dao Long Hoang , Zhang Wendong , Zhang Sheng , Xia Xueqing , Gorlick Richard , Li Shulin 
Published: July 2022

Abstract

Purpose:
Chimeric antigen receptor (CAR) T-cell therapy has shown great promise for treating hematologic malignancies but requires a long duration of T-cell expansion, is associated with severe toxicity, and has limited efficacy for treating solid tumors. We designed experiments to address those challenges.

Experimental Design:
We generated a cell membrane-anchored and tumor-targeted IL12 (attIL12) to arm peripheral blood mononuclear cells (PBMC) instead of T cells to omit the expansion phase for required CAR T cells.

Results:
This IL12-based attIL12-PBMC therapy showed significant antitumor efficacy in both heterogeneous osteosarcoma patient-derived xenograft tumors and metastatic osteosarcoma tumors with no observable toxic effects. Mechanistically, attIL12-PBMC treatment resulted in tumor-restricted antitumor cytokine release and accumulation of attIL12-PBMCs in tumors. It also induced terminal differentiation of osteosarcoma cells into bone-like cells to impede tumor growth.

Conclusions:
In summary, attIL12-PBMC therapy is safe and effective against osteosarcoma. Our goal is to move this treatment into a clinical trial. Owing to the convenience of the attIL12-PBMC production process, we believe it will be feasible.
Uma história de amor pela terra: o fenômeno literário de Torto arado – entrevista com Itamar Vieira Junior
Authors: Noro Natália Souza , Gonçalves Marta Aparecida Garcia 
Published: July 2022

Bibiana e Belonísia, irmãs protagonistas do romance Torto Arado, têm suas vidas entrelaçadas por um trágico incidente. O enredo se passa no interior da Bahia, na Chapada Diamantina, uma região que recebeu um contingente grande de trabalhadores, submetidos a situação degradante de trabalho, análoga à escravidão, terra que o escritor baiano Itamar Vieira Junior percorreu como servidor do Incra e que o inspirou a escrever uma história de resistência, de insubordinação social, pela força do povo, pela força da paisagem e das histórias de vida das pessoas que ali habitam: uma verdadeira saga épica, conforme reitera o próprio autor nesta entrevista. O romance é narrado em primeira pessoa por três narradoras, que se alternam, uma em cada um dos três capítulos que compõem o livro, uma força de vozes femininas que vai dar vida e poder à narrativa. É essa narrativa de resistência, intrigante e atemporal, premiada no Brasil e no exterior, que constitui o tema da entrevista realizada com Itamar Vieira Junior.
Contribution of Excessive Gestational Weight Gain to the Increased Risk of Autism Spectrum Disorder Occurrence in Offspring
Authors: Kheirouri Sorayya , Farazkhah Tohid 
Published: July 2022

Background: According to epidemiological studies, the number of children affected by autism spectrum disorder (ASD) has elevated notably in recent years, which increases the importance of identifying and controlling modifiable risk factors of ASD. Aim: We aim to explore the association of maternal gestational weight gain (GWG) with the risk of ASD in offspring. Methods: This case-control study was conducted in Tabriz, Iran, from October 2019 to July 2020. Data of 426 children (208 with ASD and 218 healthy) were collected using medical records and face-to-face interviews with their mothers. Results: Maternal GWG was significantly higher in the ASD group ( P = .002). The percentage of inadequate (3.4% vs 0.5%) and excess (85.6% vs 56.0%) GWG was significantly higher in the ASD group ( P < .001). Maternal ( P < .001) and paternal ( P = .004) ages were significantly lower in the ASD group compared with the healthy group. Boys were shown to be more affected by ASD than girls ( P < .001). Results of multivariate regression indicated that maternal GWG [OR (95% CI): 1.10 (1.03, 1.19), P = .005], gestational age [OR (95% CI): 1.21 (1.05, 1.41), P= .009], maternal age [OR (95% CI): 0.82 (0.73, 0.91), P < .001], child male sex [OR (95% CI): 3.82 (2.31, 6.30), P < .001], and low education of father [OR (95% CI): 4.96 (1.56, 15.72), P = .006] were independently associated with increased risk of ASD. Conclusion: The results indicate that maternal excessive GWG, maternal and gestational age, parental low education level, and male sex of infant may independently increase the risk of ASD in offspring.
The Addition of Chemoradiation to Adjuvant Chemotherapy is Associated With Improved Survival Following Upfront Surgical Resection for Pancreatic Cancer With Nodal Metastases
Authors: Altman Ariella M. , White McKenzie J. , Marmor Schelomo , Shukla Dip , Chang Katherine , Lou Emil , LaRocca Christopher J. , Hui Jane Y.C. , Tuttle Todd M. , Jensen Eric H. , Denbo Jason W. 
Published: July 2022

Background It is unclear whether the addition of chemoradiation (CRT) to adjuvant chemotherapy (CT) following upfront resection of pancreatic ductal adenocarcinoma (PDAC) provides any benefit. While some studies have suggested a benefit to combined modality therapy (CMT) (adjuvant CT plus CRT), it is not clear if this benefit was related to increased CT usage in patients who received CMT. We sought to clarify the use of CMT in patients who underwent upfront resection of PDAC. Methods Patients with non-metastatic PDAC were retrospectively identified from the linked SEER-Medicare database. Those who underwent upfront resection were identified and divided into two cohorts – patients who received adjuvant CT and patients who received adjuvant CMT. Cohorts were compared. Univariate analysis described patient characteristics. Kaplan-Meier and multivariable Cox proportional hazards modeling were used to estimate overall survival (OS). Results 3555 patients were identified; 856 (24%) received CT and 573 (16%) received CMT. The median number of CT doses was 11 for both groups. Patients who received CMT were younger, diagnosed in the earlier time frame, and had fewer comorbidities. The median OS was 21 months and 18 months for those treated with CMT and CT ( P < .0001), respectively, but when stratified by nodal status, the association with improved OS in the CMT cohort was only observed in node-positive patients. On multivariable analysis, receipt of CMT and removal of >15 lymph nodes decreased the risk of death ( P < .05). Discussion Receipt of CMT following upfront resection for PDAC was associated with improved survival, which was confined to node-positive patients. The role of adjuvant CMT in PDAC with nodal metastases warrants further study.
Smartphone ophthalmoscopy versus slit-lamp biomicroscopy for optic nerve head evaluation: A digital apparatus into medical education
Authors: Muhsen Sana , Roto Allaa , Al-Sabbagh Mohammed Qussay , Al-Huneidy Leen , AlRamahi Nura , Alhalaybeh Naja , Kotkot Duaa , Alkiswani Somaya , Al-Ani Abdallah , Abu-Yaghi Nakhleh 
Published: July 2022

Objective Th aim of this study is to explore the diagnostic accuracy of smartphone-based D-EYE ophthalmoscopy in the diagnosis of optic nerve head (ONH) abnormalities and screening for glaucoma. Methods This is a prospective clinical-based validation study performed on 90 patients recruited from a tertiary teaching hospital. Patients underwent dilated fundus examination by slit-lamp and smartphone-based D-EYE fundoscopy operated by two experienced ophthalmologists. Results The diagnostic accuracy of smartphone-based D-EYE ophthalmoscopy of normal vertical cup-to-disc ratio (VCDR) was acceptable (sensitivity 85.8%–96.4%; specificity 51.4%–96.4%). The D-EYE would often underestimate VCDR values as mean VCDR was significantly lower among overall and glaucoma cohorts (all p-value <0.001) for D-EYE in comparison with slit-lamp. In terms of ONH abnormalities, the D-EYE adequately demonstrated high sensitivity in the identification of only margins-related abnormalities (sensitivity 92.5%–96.6%). Overall, the diagnostic accuracy and agreement between expert ophthalmologists using the D-EYE and the reference slit-lamp examination were significantly poor. Conclusion We demonstrated that the D-EYE is a highly specific tool for VCDR within the normal range but not in patients with glaucoma. Despite being an easy and portable tool to measure VCDR, it is limited in terms of diagnosing ONH and blood vessel abnormalities.
Complications and predictors of morbidity for hip fracture surgery in patients with chronic liver disease
Authors: Szapary Hannah J , Monárrez Rubén , Varady Nathan H , Hanna Philip , Chen Antonia F , Rodriguez Edward K 
Published: July 2022

Background: Despite the fact that patients with chronic liver disease (CLD) are at increased risk of complications after a fracture of the hip, there remains little information about the risk factors for acute postoperative complications and their overall outcome. The aim of this study was to describe inpatient postoperative complications and identify predictors of postoperative morbidity. Methods: Patients with CLD who had been treated for a fracture of the hip between April 2005 and August 2019 were identified from a retrospective search of an intramural trauma registry based in the Northeastern United States. Medical records were reviewed for baseline demographics, preoperative laboratory investigations, and outcomes. Results: The trauma registry contained 110 patients with CLD who had undergone surgery for a fracture of the hip. Of these, patients with a platelet-count of ⩽100,000/µL were 3.81 (95% CI, 1.59–9.12) times more likely to receive a transfusion than those with a platelet-count of >100,000/µL. Those with a Model for End-stage Liver Disease (MELD) score of >9 were 5.54 (2.33–13.16) times more likely to receive a transfusion and 3.97 (1.06–14.81) times more likely to develop postoperative delirium than those with a MELD score of ⩽9. Of patients without chronic kidney disease, those with a creatinine of ⩾1.2 mg/dL were 6.80 (1.79–25.87) times more likely to develop acute renal failure (ARF) than those with a creatinine of <1.2 mg/dL. In a multivariable model, as MELD score was increased, the odds of developing a composite postoperative complication, which included transfusion, ARF, delirium, or deep wound infection, were 1.29 (1.01–1.66). Other tools used to assess surgical risks, Charlson Comorbidity Index, Elixhauser, and American Society of Anesthesiologist scores, were not predictive. Conclusions: Patients with CLD who undergo surgery for a hip fracture have a high rate of postoperative complications which can be predicted by the preoperative laboratory investigations identified in this study and MELD scores, but not by other common comorbidity indices.
In-hospital outcomes and recurrence of stroke during pregnancy and puerperium
Authors: Garg Aayushi , Roeder Hannah , Leira Enrique C 
Published: July 2022

Background: There are limited data regarding the best management and outcomes of acute stroke during pregnancy and the puerperium. Methods: Pregnancy-related hospitalizations with age > 18 years were identified from the Nationwide Readmissions Database 2016–2018. The study cohort consisted of all patients with acute stroke and a 5% random sample of the remaining non-stroke hospitalizations. Logistic regression and survival analyses were used to compare the in-hospital outcomes and readmissions in patients with and without acute stroke. Results: There were 11,829,044 pregnancy-related hospitalizations, of which 4057 had acute stroke. The mean ± SD age of the study cohort was 29.0 ± 5.7 years. Among patients with acute ischemic stroke, 60 (3.7%) patients received intravenous thrombolysis and 112 (6.8%) patients underwent endovascular thrombectomy. Among patients with intracranial hemorrhage, 205 (10.5%) patients underwent ventriculostomy and 18 (0.9%) patients underwent decompressive craniotomy. Patients with stroke had longer length of stay (mean: 10.7 vs 2.7 days), higher in-hospital mortality (4.6% vs 0.0001%) and were less likely to discharge home (73.0% vs 98.6%). Non-elective readmission within 90 days of discharge occurred in 14.8% of patients with stroke versus in 3.9% of patients without stroke. Readmissions due to cerebrovascular events occurred in 2.3% of patients with stroke versus in 0.007% of patients without stroke within 1 year of discharge, with mean ± SD time to readmission 66.2 ± 78.0 days. Conclusion: Stroke is a serious complication of pregnancy, associated with high morbidity and mortality. Recurrence of stroke occurs in a small proportion of patients, and the risk is highest during the initial 3 months.
Efficacy and Safety of Dupilumab Versus Omalizumab in Chronic Rhinosinusitis With Nasal Polyps and Asthma: EVEREST Trial Design
Authors: De Prado Gomez, PharmD, MSc Lucia , Khan, MBBS, MPH Asif H. , Peters, MD Anju T. , Bachert, MD, PhD Claus , Wagenmann, MD Martin , Heffler, MD, PhD Enrico , Hopkins, BMBCh Claire , Hellings, MD, PhD Peter W. , Zhang, PhD Mei , Xing, PhD Jun , Rowe, MD Paul , Jacob-Nara, MD, MPH, DHSc Juby A. 
Published: July 2022

Background Chronic rhinosinusitis with nasal polyps (CRSwNP) and asthma are chronic type 2 inflammatory diseases that are frequently associated with each other. Dupilumab inhibits the dual signaling pathways of interleukin (IL)-4 and IL-13, which are key and central drivers of type 2 inflammation in CRSwNP. Omalizumab blocks the action of immunoglobulin E. Head-to-head studies are required to investigate the comparative efficacy and safety of these interventions. EVEREST (EValuating trEatment RESponses of dupilumab vs omalizumab in Type 2 patients) trial is designed to evaluate whether the efficacy of dupilumab is superior to omalizumab in treating patients with CRSwNP and comorbid asthma (ClinicalTrials.gov Identifiers: NCT04998604). Objective Here, we describe the EVEREST study design to compare the efficacy and safety of dupilumab compared to omalizumab over 24 weeks of treatment in patients with severe CRSwNP and comorbid asthma. Methods EVEREST is a global, phase 4 multicenter, randomized (1:1), double-blind, active-controlled trial. Approximately 422 adult patients with severe CRSwNP, symptoms of nasal congestion and loss of smell, and coexisting asthma will be recruited across 15 countries. The primary objective is to assess the efficacy of dupilumab compared to omalizumab in reducing the nasal polyp size and improving the sense of smell. The key secondary objectives are to evaluate the comparative efficacy in improving CRSwNP symptoms (eg, nasal congestion) and lung function. The safety will be evaluated in terms of treatment-emergent adverse events (AEs), serious AEs, and AEs of special interest. Conclusions EVEREST is the first head-to-head trial assessing the comparative efficacy and safety of 2 biologics in patients with severe CRSwNP and comorbid asthma. The study will provide evidence to help optimize treatment plans for patients that suffer from severe CRSwNP and comorbid asthma.
Outcomes of Biceps Tenotomy Versus Tenodesis During Arthroscopic Rotator Cuff Repair: An Analysis of Patients From a Large Multicenter Database
Authors: Srinivasan Ramesh C. , Hao Kevin A. , Wright Thomas W. , Farmer Kevin W. , Wright Jonathan O. , Roach Ryan P. , Moser Michael W. , Freidl Michael C. , Pazik Marissa , King Joseph J. 
Published: July 2022

Background: Studies to date evaluating biceps tenotomy versus tenodesis in the setting of concomitant rotator cuff repair (RCR) have demonstrated relatively equivalent pain and functional outcomes. Hypothesis: It was hypothesized that a significant difference could be demonstrated for pain and functional outcome scores comparing biceps tenotomy versus tenodesis in the setting of RCR if the study was adequately powered. Study Design: Cohort study; Level of evidence, 3. Methods: The Arthrex Surgical Outcomes System database was queried for patients who underwent arthroscopic biceps tenotomy or tenodesis and concomitant RCR between 2013 and 2021; included patients had a minimum of 2 years of follow-up. Outcomes between treatment types were assessed using the American Shoulder and Elbow Surgeons Shoulder (ASES), Single Assessment Numeric Evaluation (SANE), visual analog scale (VAS) for pain, and Veterans RAND 12-Item Health Survey (VR-12) scores preoperatively and at 3 months, 6 months, 1 year, and 2 years postoperatively. Results were stratified by age at surgery (3 groups: <55, 55-65, >65 years) and sex. Results: Overall, 1936 primary RCRs were included for analysis (1537 biceps tenodesis and 399 biceps tenotomy patients). Patients who underwent tenotomy were older and more likely to be female. A greater proportion of female patients aged <55 years and 55 to 65 years received a biceps tenotomy compared with tenodesis ( P = .012 and .026, respectively). All scores were comparable between the treatment types preoperatively and at 3 months, 6 months, and 1 year postoperatively. At 2-year follow-up, patients who received a biceps tenodesis had statistically more favorable ASES, SANE, VAS pain, and VR-12 scores ( P ≤ .031); however, the differences did not exceed the minimal clinically important difference (MCID) for these measures. Conclusion: Our findings indicate that surgeons are more likely to perform a biceps tenotomy in female and older patients. Biceps tenodesis provided improved pain and functional scores compared with tenotomy at 2-year follow-up; however, the benefit did not exceed previously reported MCID for the outcome scores. Both procedures provided improvement in outcomes; thus, the choice of procedure should be a shared decision between the surgeon and patient.
Epigenetic regulator genes direct lineage switching in MLL/AF4 leukemia
Authors: Tirtakusuma Ricky , Szoltysek Katarzyna , Milne Paul , Grinev Vasily V. , Ptasinska Anetta , Chin Paulynn S. , Meyer Claus , Nakjang Sirintra , Hehir-Kwa Jayne Y. , Williamson Daniel , Cauchy Pierre , Keane Peter , Assi Salam A. , Ashtiani Minoo , Kellaway Sophie G. , Imperato Maria R. , Vogiatzi Fotini , Schweighart Elizabeth K. , Lin Shan , Wunderlich Mark , Stutterheim Janine , Komkov Alexander , Zerkalenkova Elena , Evans Paul , McNeill Hesta , Elder Alex , Martinez-Soria Natalia , Fordham Sarah E. , Shi Yuzhe , Russell Lisa J. , Pal Deepali , Smith Alex , Kingsbury Zoya , Becq Jennifer , Eckert Cornelia , Haas Oskar A. , Carey Peter , Bailey Simon , Skinner Roderick , Miakova Natalia , Collin Matthew , Bigley Venetia , Haniffa Muzlifah , Marschalek Rolf , Harrison Christine J. , Cargo Catherine A. , Schewe Denis , Olshanskaya Yulia , Thirman Michael J. , Cockerill Peter N. , Mulloy James C. , Blair Helen J. , Vormoor Josef , Allan James M. , Bonifer Constanze , Heidenreich Olaf , Bomken Simon 
Published: July 2022

Abstract
The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukemia, resulting in poor clinical outcomes caused by resistance to chemotherapies and immunotherapies. In this study, the myeloid relapses shared oncogene fusion breakpoints with their matched lymphoid presentations and originated from various differentiation stages from immature progenitors through to committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programs, including alternative splicing. These findings indicate that the execution and maintenance of lymphoid lineage differentiation is impaired. The relapsed myeloid phenotype is recurrently associated with the altered expression, splicing, or mutation of chromatin modifiers, including CHD4 coding for the ATPase/helicase of the nucleosome remodelling and deacetylation complex. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4+ cell models, indicating that lineage switching in MLL/AF4 leukemia is driven and maintained by disrupted epigenetic regulation.