bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapid Identification and Evaluation of Neoantigen-reactive T-Cell Receptors From Single Cells
Authors: Paria Biman C. , Levin Noam , Lowery Frank J. , Pasetto Anna , Deniger Drew C. , Parkhurst Maria R. , Yossef Rami , Kim Sanghyun P. , Florentin Maria , Ngo Lien T. , Ray Satyajit , Krishna Sri , Robbins Paul F. , Rosenberg Steven A.
Published: October 2020

Engineered T cells expressing tumor-specific T-cell receptors (TCRs) are emerging as a mode of personalized cancer immunotherapy that requires identification of TCRs against the products of known driver mutations and novel mutations in a timely fashion. We present a nonviral and non–next-generation sequencing platform for rapid, and efficient neoantigen-specific TCR identification and evaluation that does not require the use of recombinant cloning techniques. The platform includes an innovative method of TCRα detection using Sanger sequencing, TCR pairings and the use of TCRα/β gene fragments for putative TCR evaluation. Using patients’ samples, we validated and compared our new methods head-to-head with conventional approaches used for TCR discovery. Development of a unique demultiplexing method for identification of TCRα, adaptation of synthetic TCRs for gene transfer, and a reliable reporter system significantly shortens TCR discovery time over conventional methods and increases throughput to facilitate testing prospective personalized TCRs for adoptive cell therapy.
Carpal Tunnel Syndrome: A New Adverse Effect of Immune Checkpoint Inhibitors, 11 Cases
Authors: Lechevalier Diane , Denis Daphné , Le Corre Yannick , Heidelberger Valentine , Brunet-Possenti Florence , Longvert Christine , Piot Jean M. , Maillard Hervé , Beneton Nathalie
Published: October 2020

This study aims at reporting 11 cases of carpal tunnel syndrome (CTS) occurring in patients on immunotherapy. The increasing use of immune checkpoint inhibitors in oncodermatology is associated with the appearance of immunologic adverse effects linked to nonspecific stimulation of the immune system. CTS has not been reported in this context. A retrospective multicenter review was performed on CTSs occurring on immunotherapy and confirmed with electroneuromyography. Data were collated from patients’ files. Most of the time, CTS was severe, bilateral, with a motor deficit and confirmed axonal damage on electroneuromyography. In 4 cases, it was associated with rheumatological adverse effects (arthralgia/inflammatory synovitis). The most effective treatment appeared to be general corticosteroid therapy, even at low doses (<15 mg/d), or surgery. An imputability of the CTS of these patients to immunotherapy was considered due to the unusual intensity of the symptoms and the absence of other predisposing factors (diabetes and dysthyroidism well-controlled). Its combination with other immunologic adverse effects and the efficacy of general corticosteroid therapy suggests an immunologic origin. CTS is probably an immunologic adverse effect of immunotherapy. It is often severe or misleading in presentation and affects quality of life. The recognition of this adverse effect should make it possible to provide patients with appropriate care.
Comparison of the anterior and posterior approach in treating four-level cervical spondylotic myelopathy
Authors: Zhai Ji-Liang , Guo Shi-Gong , Nie Li , Hu Jian-Hua
Published: October 2020

Background:

The optimal surgical approach for four-level cervical spondylotic myelopathy remains controversial. The purpose of this study was to compare clinical and radiological outcomes and complications between the anterior and posterior approaches for four-level cervical spondylotic myelopathy.

Methods:

A total of 19 patients underwent anterior decompression and fusion and 25 patients underwent posterior laminoplasty and instrumentation in this study. Perioperative information, intraoperative blood loss, clinical and radiological outcomes, and complications were recorded. Japanese Orthopedic Association (JOA) score, 36-item short form survey (SF-36) score and cervical alignment were assessed.

Results:

There were no significant differences in JOA scores between the anterior and posterior group preoperatively (11.6 ± 1.6 vs. 12.1 ± 1.5), immediately postoperatively (14.4 ± 1.1 vs. 13.8 ± 1.3), or at the last follow-up (14.6 ± 1.0 vs. 14.2 ± 1.1) (P > 0.05). The JOA scores significantly improved immediately postoperatively and at the last follow-up in both groups compared with their preoperative values. The recovery rate was significantly higher in the anterior group both immediately postoperatively and at the last follow-up. The SF-36 score was significantly higher in the anterior group at the last follow-up compared with the preoperative value (69.4 vs. 61.7). Imaging revealed that there was no significant difference in the Cobb angle at C2–C7 between the two groups preoperatively (−2.0° ± 7.3° vs. −1.4° ± 7.5°). The Cobb angle significantly improved immediately postoperatively (12.3° ± 4.2° vs. 9.2° ± 3.6°) and at the last follow-up (12.4° ± 3.5° vs. 9.0° ± 2.6°) in both groups compared with their preoperative values (P = 0.00). Three patients had temporary dysphagia in the anterior group and four patients had persistent axial symptoms in the posterior group.

Conclusions:

Both the anterior and posterior approaches were effective in treating four-level cervical spondylotic myelopathy in terms of neurological clinical outcomes and radiological features. However, the JOA score recovery rate and SF-36 score in the anterior group were significantly higher. Persistent axial pain could be a major concern when undertaking the posterior approach.
Physical Therapy Student Reports of Blood Pressure Guidelines Learned in the Classroom, and Observed and Practiced in Clinical Experiences
Authors: Marks Ted , Berg Sarah Leah , Granek Batsheva , Rybakov Peter , Taranenko Irina , Yee Dana , Garcia Ralph
Published: October 2020

Purpose:

The purposes of this study were (1) to investigate discrepancies between what physical therapy students report learning in the classroom regarding blood pressure (BP) guidelines and what physical therapy students report observing and practicing in clinical settings and (2) to establish whether students felt discomfort when discrepancies were encountered.

Methods:

This was a prospective descriptive survey study generated using a sample of convenience employing a survey developed by the researchers. Face and content validity were established through expert review. An email was sent to 21 New York State Physical Therapy Programs asking each program to share the survey with students in their programs who had completed clinical experiences. The responses were analyzed descriptively using frequency counts, percentages, and cross tabulations.

Results:

Responses were received from 206 students attending 13 different programs, or 61.9% of the programs contacted. More than half the students (53.4%) reported there were differences between what they learned during classroom instruction regarding BP assessment and what they saw and practiced in the clinic; 24.8% of students expressed discomfort related to discrepancies between what they learned in school and what they saw and practiced in the clinic. Inpatient and outpatient experiences were compared. Statistical differences were found indicating patients had their BP assessed less often in outpatient settings. In addition, students were less likely to discuss BP assessment with their clinical instructors (CIs) in outpatient settings and students were more likely to express increased competence taking BP after inpatient clinical experiences. Across all settings, 20.4% of students reported that neither they nor their CI ever measured BP during their most recent clinical experience.

Conclusions:

Across all settings, the BP assessment practices that students encounter in clinic differ from what students report learning is best practice during their physical therapy education. Students are more likely to encounter discrepancies in outpatient settings. For many students, encountering discrepancies gives rise to feelings of discomfort.
Sutured Custom Foldable Silicone Artificial Iris Implantation Combined With Intraocular Lens Implantation and Penetrating Keratoplasty: Safety and Efficacy Outcomes
Authors: Bonnet Clemence , Vazirnia Parsia , Deng Sophie X. , Aldave Anthony J. , Miller Kevin M.
Published: October 2020

Purpose:

To assess safety and efficacy outcomes of sutured custom silicone artificial iris and intraocular lens implantation combined with penetrating keratoplasty (triple procedure).

Methods:

Prospective consecutive surgical case series of patients who underwent the triple procedure between 2010 and 2019 at Stein Eye Institute, UCLA, followed up for 1 year minimum. Safety outcomes were changes from preoperative to last follow-up in corrected distance visual acuity (CDVA), endothelial cell count, intraocular pressure (IOP), and postoperative complications. Efficacy outcomes included changes in subjective glare (none to severe), cosmetic appearance (worse to very much improved), and visual function as assessed by the Visual Function Questionnaire-25 at 1-year follow-up.

Results:

Among 82 eyes implanted with an artificial iris, 14 eyes (17.1%) underwent the triple procedure. The median follow-up was 18.1 months (range 12.0–54.9 months). The median CDVA improved from 2.0 log of minimum angle of resolution (logMAR) (range 0.9–2.3 logMAR) to 0.7 logMAR (range 0.2–2.6 logMAR) (P = 0.02). Average endothelial cell count decreased 57.6% (P < 0.01). Six eyes (42.9%) experienced IOP elevations, 13 eyes (92.3%) developed iritis, and 11 eyes (78.6%) underwent secondary surgery. Graft rejection or secondary graft failure occurred in 7 eyes each (50.0%). Cosmesis improved in 12 eyes (85.7%; P < 0.01). The Visual Function Questionnaire-25 score improved from 72 to 77 (P < 0.01). Glare symptoms did not change significantly.

Conclusions:

The triple procedure was effective at improving CDVA, cosmesis, and quality of life; however, it was associated with frequent postoperative complications, of which iritis, IOP elevation, and secondary graft failure were the most common.
MIMS Procedure: Concept and Evaluation of Safety, Feasibility, and Efficacy in a Porcine Experimental Model
Authors: Gershoni Assaf , Glovinsky Yoseph , Rotenberg Michael , Barayev Edward , Segal Ori , Geffen Noa
Published: October 2020

Precis:

We present a novel stentless filtration system used to create a permanent sclerocorneal drainage channel that reduces intraocular pressure (IOP) without the need to create a conjunctival incision or a scleral flap.

Purpose:

The purpose of this study was to evaluate the safety, feasibility, and preliminary performance of a novel surgical system, the minimally invasive micro sclerostomy (MIMS), in an in vivo porcine experimental model.

Materials and Methods:

MIMS is an ab externo stentless filtration procedure. An activation system is used to operate a handpiece that includes a 600 µm needle containing an injectable 300 µm triangular blade that spins around its longitudinal axis. The needle is inserted into the subconjunctival space and the blade is injected at the limbal area creating a drainage channel at the sclerocorneal junction, connecting the anterior chamber to the subconjunctival space. The first generation of the MIMS surgical system was assessed in a porcine experimental model, firstly on 6 pigs and thereafter on 10 pigs. All adverse events, IOP measurements, and bleb descriptions were recorded for up to 14 weeks. The shape and location of the scleral tunnel, the subconjunctival bleb, and the healing process were examined by slit-lamp examination, by histopathologic analysis, and by anterior segment optical coherence tomography imaging.

Results:

No device malfunctions were recorded. Scleral tunnels were repeatedly achieved in all models. No significant intraoperative or postoperative complications were recorded. Effective fluid percolation was achieved in all eyes. The mean IOP statistically significantly decreased from 19.0±3.2 mm Hg preoperatively to 11.1±4.9 mm Hg on the first follow-up visit (P=0.0046) in the first leg of the study, and from 18.5±3.8 to 13.3±1.9 mm Hg in the second leg (P=0.0165). In both, IOP gradually returned to preoperative values toward the end of the follow-up period, as expected in a porcine experimental model. Histologic analysis of the analyzed tissue was not associated with significant tissue reaction.

Conclusions:

The MIMS procedure exhibited a consistent and relatively high safety, feasibility, and efficacy profiles. In the future, the MIMS procedure may provide a novel solution for uncontrolled IOP.
Primary Epstein-Barr Virus Infection With Marked Cholestasis, Warm Autoimmune Hemolytic Anemia, and Pancytopenia
Authors: Kazi Aamir S. , Hart Aaron A. , Rajakumar Priya , Janardhan Sujit J. , Dehghan-Paz Irene , Rhee Yoona
Published: October 2020

Primary Epstein-Barr virus (EBV) infection may rarely present with cholestatic hepatitis or hemolytic anemia. We share a case of EBV-associated infectious mononucleosis presenting with a unique triad of findings comprising cholestatic hepatitis with marked hyperbilirubinemia, warm autoimmune hemolytic anemia, and pancytopenia. Early diagnostic challenges included negative Monospot heterophile testing. Additional testing revealed EBV serologies consistent with acute primary infection, EBV viremia and bone marrow biopsy showing EBV-encoded RNA–positive cells. A tapered prednisone course was administered for warm autoimmune hemolytic anemia. Improvement in symptoms and laboratory findings occurred over 3 weeks.
Very Rare Gastrointestinal Anthrax in a Pregnant Woman
Authors: Akrami Alireza , Dolatabad Mostafa Laale , Tashrifi Fatemeh , Gholizadeh Abdolmajid , Moradi Bagher
Published: October 2020

Anthrax is an acute infectious disease caused by Bacillus anthracic. Gastrointestinal anthrax is considered as a rare condition in pregnancy, and there are few reports describing its complication and treatment procedure. Meanwhile, there is no article reporting successful treatment of a pregnant woman; however, we have reported a successful treatment of gastrointestinal anthrax in a pregnant woman. In this study, we reported a 38-years-old pregnant woman who was referred to the hospital with abdominal pain and persistent hemorrhagic diarrhea. Suzerain operation was also used, and laparotomy showed necrotic gangrene in colon. After the first surgery, the patient showed left lower quadrant abdominal pain (left lower quadrant collection), and drainage was performed during the second surgery. Finally, after 20 days, the patient was recovered and discharged from the hospital in a very good condition. Gastrointestinal anthrax during pregnancy is a very rare condition. In this study, we reported a patient with gastrointestinal anthrax who was recovered by a suitable treatment.
Preterm Labor and Birth
Authors: Griggs Kellie M. , Hrelic Debra A. , Williams Nina , McEwen-Campbell Michelle , Cypher Rebecca
Published: October 2020

When caring for women experiencing preterm labor and birth, nurses play a significant role as bedside experts, advocates, patient educators, and key members of the maternity care team. Enhanced expertise on clinical and professional knowledge of preterm labor and birth is crucial in prevention and treatment. As preterm birth rates continue to rise, perinatal nurses as well-informed clinical experts have the opportunity to offer innovative education, holistic assessments, and communication through shared decision-making models. Educating pregnant women about early recognition of preterm labor warning signs and symptoms allows for timely diagnosis, interventions, and treatment. Informed and collaborative nursing practice improves quality of clinical care based on individualized interactions. A clinical review of preterm labor and preterm birth is presented for perinatal nurses.
Infective Uvulitis in a Child
Authors: De Pieri Carlo , Valentini Elena , Pusiol Anna , Passone Eva , Gamalero Lisa , Cogo Paola Elisa
Published: October 2020

Infective uvulitis is a rare condition in children. In this report, we describe the case of a 4-year old-patient who presented a group A Streptococcus pharyngitis with uvulitis. No signs of epiglottitis were detected at nasal fibroscopy. She recovered rapidly with intravenous antibiotic therapy and 2 days of corticosteroid. Uvulitis is usually caused by group A Streptococcus or Haemophilus influentiae, but also other bacteria can be detected. Uvulitis can be isolated, or it can occur with epiglottitis and become an emergency.
Community-based delivery of HIV treatment in Zambia: costs and outcomes
Authors: Nichols Brooke E. , Cele Refiloe , Jamieson Lise , Long Lawrence C. , Siwale Zumbe , Banda Patrick , Moyo Crispin , Rosen Sydney
Published: October 2020

Objective:

The aim is to determine the total annual cost per patient treated and total cost per patient retained on antiretroviral therapy in Zambia in conventional care in facilities and across community-based differentiated service delivery (DSD) models.

Design:

Economic evaluation was conducted using retrospective electronic record review.

Twenty healthcare facilities (13 with DSD models and 7 as comparison sites) in six of Zambia's 10 provinces were considered.

Methods:

All individuals on antiretroviral therapy (ART) >18 years old at the study sites were enrolled in a DSD model or conventional care by site type, respectively, with at least 12 months of follow-up data. Accessing care through DSD models [community adherence groups (CAGs), urban adherence groups (UAGs), home ART delivery and care, and mobile ART services] or facility-based conventional care with 3-monthly visits. Total annual cost per patient treated and the annual cost per patient retained in care 12 months after model enrolment. Retention in care was defined as attending a clinic visit at 12 months ± 3 months.

Results:

The DSD models assessed cost more per patient/year than conventional care. Costs ranged from an annual $116 to $199 for the DSD models, compared with $100 for conventional care. CAGs and UAGs increased retention by 2 and 14%, respectively. All DSD models cost more per patient retained at 12 months than conventional care. The CAG had the lowest cost/patient retained for DSD models ($140–157).

Conclusions:

Although they achieve equal or improved retention in care, out-of-facility models of ART were more expensive than conventional care.
Unexpected interactions between dolutegravir and folate: randomized trial evidence from South Africa
Authors: Chandiwana Nomathemba C. , Chersich Matthew , Venter W.D. François , Akpomiemie Godspower , Hill Andrew , Simmons Bryony , Lockman Shahin , Serenata Celicia M. , Fairlie Lee , Moorhouse Michelle A.
Published: October 2020

Objective:

Dolutegravir exposure at conception was associated with a preliminary signal of increased infant neural tube defect risk. As low maternal folate levels are linked with neural tube defects, we aimed to assess serum folate concentrations in women starting dolutegravir.

Design:

We analysed serum folate concentrations from stored plasma among women enrolled in the South African ADVANCE trial.

Methods:

We compared changes in mean serum folate and occurrence of low serum folate (<14.0 nmol/l) at weeks 0, 12 and 24 across study arms. In ADVANCE, 1053 treatment-naïve participants were randomized to initiate tenofovir–alafenamide/emtricitabine + dolutegravir (TAF/FTC + DTG), tenofovir–disoproxil–fumarate (TDF)/FTC + DTG or TDF/FTC/efavirenz (EFV).

Results:

Analysis includes 406 females, mean age 31.5 years and baseline CD4+ cell count 356 cells/μl. At baseline, folate concentrations were similar across treatment arms. However, serum folate increased over 12 weeks in the TAF/FTC + DTG arm (+4.0 ± 8.1 nmol/l), while folate concentrations decreased slightly in the TDF/FTC + DTG arm (−1.8 ± 8.9 nmol/l) and decreased in the TDF/FTC/EFV arm (−5.9 ± 8.1 nmol/l). Women taking TDF/FTC/EFV had low folate concentrations at both 12 and 24 weeks compared with the other arms (P < 0.001). Of 26 women who became pregnant on study before week 24, folate concentrations increased between baseline and 12 weeks by a mean 2.4 ± 7.1 nmol/l in the TAF/FTC + DTG arm and 2.3 ± 8.4 nmol/l in the TDF/FTC + DTG arm, but decreased by −3.3 ± 8.1 with TDF/FTC/EFV arm.

Conclusion:

Unexpectedly, no declines were noted in the dolutegravir-containing arms, and concentrations were considerably higher than in the EFV arm. The possibility that dolutegravir may block cellular uptake of folate warrants investigation.
The Change of 68Ga–Prostate-Specific Membrane Antigen Uptake in Myeloma After Chemotherapy in a Patient With Multiple Myeloma and Concurrent Prostate Cancer
Authors: Pan Qingqing , Luo Yaping , Ma Yanru , Li Fang
Published: October 2020

A bone lesion in the right calcaneus was found in a 76-year-old man with a history of prostate cancer. 68Ga-PSMA-11 PET/CT showed multiple PSMA-expressing lytic bone lesions in appendicular skeleton. Biopsy of the lesion in the right calcaneus confirmed plasmacytoma. After several cycles of chemotherapy, the patient was in serologically stringent complete remission. The follow-up PET/CT showed a significant reduction of 68Ga-PSMA-11 uptake in the previously PSMA-avid bone lesions without morphological changes on CT. The reduction of PSMA expression in myelomas after chemotherapy is suggested to result from the treatment response.
Concurrent Liver and Mesentery Primary Extraosseous Multiple Myeloma on 18F-FDG PET/CT
Authors: Carnahan Molly B. , Larsen Jeremy T. , Conley Christopher R. , Yang Ming
Published: October 2020

Extramedullary multiple myeloma (EMM) is a subset of multiple myeloma with a poor prognosis. We report a rare case with biopsy-proven concurrent liver and mesentery primary EMM at the time of initial staging after serologic diagnosis of multiple myeloma. 18F-FDG PET/CT is valuable in detection of EMM when the patient has no osseous lesions and a negative bone marrow biopsy.
Evaluating Quality of Life After Facial Reanimation Using the Facial Clinimetric Evaluation Scale in a Series of Pediatric Patients
Authors: Mackay Duncan J.D. , Kimia Rotem , Magee Leanne , Jackson Oksana , Nguyen Phuong D.
Published: October 2020

Background:

Facial palsy can have significant functional and psychological impact. Dynamic facial reanimation methods have provided means of restoration of smile. There remains a dearth of quality of life data in children. The authors aim to assess patient reported outcomes in this underreported population.

Methods:

A retrospective review was performed of pediatric patients with facial palsy who had dynamic facial reanimation from 2009 to 2017 at a single institution. Patients were sent a digital Facial Clinimetric Evaluation (FaCE) questionnaire, a validated tool to assess patient quality of life. FaCE statements are grouped into 6 categories: facial movement, facial comfort, oral function, eye comfort, lacrimal control, and social control.

Results:

Twenty patients met inclusion criteria. Fourteen successfully completed the survey. With normal function being 100, our cohort scored: facial movement 38.7 ± 14.3; facial comfort 67.3 ± 23, oral function 75 ± 22.7, eye comfort 68.75 ± 18.2, lacrimal control 53.6 ± 32.5, social function 64.3 ± 25.6. The overall FaCE score was 61.07 ± 10.85. The facial movement subscores were lower for brow raise 16.1 ± 33.4 relative to smiling 53.6 ± 29.2 and lip pucker, 46.4 ± 23.7. No correlation was found between facial movement scores and total scores (R
2 < 0.01). There was a strong negative correlation between total scores and time since procedure (Spearman's rho R =  –0.45).

Conclusion:

Our pediatric facial reanimation cohort demonstrated excellent social function, in contrast to a relatively lower facial movement score. The low facial movement score was mediated by low score for brow raise and was not correlated to overall FaCE score. Interestingly, overall FaCE score tended to decrease with time from procedure.
Blepharoplasty Combined With Mini-incision and Interrupted Buried Suture Techniques
Authors: Di Wen J. , Liu Bing , Yin Ning B. , Li Si L. , Wang Yong Q.
Published: October 2020

Background:

Blepharoplasty has become one of the most popular plastic surgery techniques for generating double-eyelid folds. The mini-incision blepharoplasty technique results in minimal trauma and the formation of supratarsal folds.

Methods:

In this study, the authors combined mini-incisions with interrupted buried sutures. To perform the blepharoplasty procedure, the authors marked the supratarsal folds and divided them into 5 line segments: 3 cutting lines and 2 noncutting lines. For the cutting lines, the authors used orbicularis-tarsus fixation to form double eyelids and only removed a small strip of muscle under the incision to maintain the physiological structure of the pretarsal tissue. For the noncutting lines, the authors used the interrupted buried suture technique to add 2 fixed points.

Results:

A total of 42 patients (mean age 25.25 years) underwent this minimally invasive blepharoplasty. Among these patients, 42 underwent bilateral surgery. The average follow-up period was 35.91 months (range: 13–47 months). Only one patient underwent a second operation to address a shallow, unilateral supratarsal crease. Nonetheless, all patients were satisfied with their results.

Conclusion:

Our minimally invasive blepharoplasty approach resulted in minimal damage to the pretarsal tissues and robust supratarsal folds and is relatively easy to perform for the novice surgeon.

Evidence Statement:

Level IV
Comprehensive Molecular Characterization of Adenocarcinoma of the Gastroesophageal Junction Between Esophageal and Gastric Adenocarcinomas
Authors: Suh Yun-Suhk , Na Deukchae , Lee Ju-Seog , Chae Jeesoo , Kim EuiHyun , Jang Giyong , Lee Jieun , Min Jimin , Ock Chan-Young , Kong Seong-Ho , George Joshy , Zhang Chengsheng , Lee Hyuk-Joon , Kim Jong-Il , Kim Seong-Jin , Kim Woo Ho , Lee Charles , Yang Han-Kwang
Published: October 2020

Objective:

To investigate the molecular characteristics of AGEJ compared with EAC and gastric adenocarcinoma.

Summary of Background Data:

Classification of AGEJ based on differential molecular characteristics between EAC and gastric adenocarcinoma has been long-standing controversy but rarely conducted due to anatomical ambiguity and epidemiologic difference.

Methods:

The molecular classification model with Bayesian compound covariate predictor was developed based on differential mRNA expression of EAC (N = 78) and GCFB (N = 102) from the Cancer Genome Atlas (TCGA) cohort. AGEJ/cardia (N = 48) in TCGA cohort and AGEJ/upper third GC (N = 46 pairs) in Seoul National University cohort were classified into the EAC-like or GCFB-like groups whose genomic, transcriptomic, and proteomic characteristics were compared.

Results:

AGEJ in both cohorts was similarly classified as EAC-like (31.2%) or GCFB-like (68.8%) based on the 400-gene classifier. The GCFB-like group showed significantly activated phosphoinositide 3-kinase-AKT signaling with decreased expression of ERBB2. The EAC-like group presented significantly different alternative splicing including the skipped exon of RPS24, a significantly higher copy number amplification including ERBB2 amplification, and increased protein expression of ERBB2 and EGFR compared with GCFB-like group. High-throughput 3D drug test using independent cell lines revealed that the EAC-like group showed a significantly better response to lapatinib than the GCFB-like group (P = 0.015).

Conclusions:

AGEJ was the combined entity of the EAC-like and GCFB-like groups with consistently different molecular characteristics in both Seoul National University and TCGA cohorts. The EAC-like group with a high Bayesian compound covariate predictor score could be effectively targeted by dual inhibition of ERBB2 and EGFR.
Implications of Perineural Invasion on Disease Recurrence and Survival After Pancreatectomy for Pancreatic Head Ductal Adenocarcinoma
Authors: Crippa Stefano , Pergolini Ilaria , Javed Ammar A. , Honselmann Kim C. , Weiss Matthew J. , Di Salvo Francesca , Burkhart Richard , Zamboni Giuseppe , Belfiori Giulio , Ferrone Cristina R. , Rubini Corrado , Yu Jun , Gasparini Giulia , Qadan Motaz , He Jin , Lillemoe Keith D. , Castillo Carlos Fernandez-del , Wolfgang Christopher L. , Falconi Massimo
Published: October 2020

Objective:

To describe PNI and to evaluate its impact on disease-free (DFS) and overall survival (OS) in patients with resected pancreatic ductal adenocarcinoma (PDAC).

Summary of Background Data:

Although PNI is a prognostic factor for survival in many GI cancers, there is limited knowledge regarding its impact on tumor recurrence, especially in ‘‘early stage disease’’ (PDAC ≤20 mm, R0/ N0 PDAC).

Methods:

This multicenter retrospective study included patients undergoing PDAC resection between 2009 and 2014. The association of PNI with DFS and OS was analyzed using Cox proportional-hazards models.

Results:

PNI was found in 87% of 778 patients included in the study, with lower rates in PDAC ≤20 mm (78.7%) and in R0/N0 tumors (70.6%). PNI rate did not differ between patients who underwent neoadjuvant therapy and upfront surgery (88% vs 84%, P = 0.08). Although not significant at multivariate analysis (P = 0.07), patients with PNI had worse DFS at univariate analysis (median DFS: 20 vs 15 months, P < 0.01). PNI was the only independent predictor of DFS in R0/N0 tumors (hazard ratio [HR]: 2.2) and in PDAC ≤ 20 mm (HR: 1.8). PNI was an independent predictor of OS in the entire cohort (27 vs 50 months, P = 0.01), together with G3 tumors, pN1 status, carbohydrate antigen (CA) 19.9 >37 and pain.

Conclusions:

PNI represents a major determinant of tumor recurrence and patients’ survival in pancreatic cancer. The role of PNI is particularly relevant in early stages, supporting the hypothesis that invasion of nerves by cancer cells has a driving role in pancreatic cancer progression.
Low Anti-Factor Xa Level Predicts 90-Day Symptomatic Venous Thromboembolism in Surgical Patients Receiving Enoxaparin Prophylaxis
Authors: Pannucci Christopher J. , Fleming Kory I. , Varghese Thomas K. , Stringham John , Huang Lyen C. , Pickron T. Bartley , Prazak Ann Marie , Bertolaccini Corinne , Momeni Arash
Published: October 2020

Objective:

To examine the relationship between enoxaparin dose adequacy, quantified with anti-Factor Xa (aFXa) levels, and 90-day symptomatic venous thromboembolism (VTE) and postoperative bleeding.

Summary Background Data:

Surgical patients often develop “breakthrough” VTE events—those which occur despite receiving chemical anticoagulation. We hypothesize that surgical patients with low aFXa levels will be more likely to develop 90-day VTE, and those with high aFXa will be more likely to bleed.

Methods:

Pooled analysis of eight clinical trials (N = 985) from a single institution over a 4 year period. Patients had peak steady state aFXa levels in response to a known initial enoxaparin dose, and were followed for 90 days. Survival analysis log-rank test examined associations between aFXa level category and 90-day symptomatic VTE and bleeding.

Results:

Among 985 patients, 2.3% (n = 23) had symptomatic 90-day VTE, 4.2% (n = 41) had 90-day clinically relevant bleeding, and 2.1% (n = 21) had major bleeding. Patients with initial low aFXa were significantly more likely to have 90-day VTE than patients with adequate or high aFXa (4.2% vs 1.3%, P = 0.007). In a stratified analysis, this relationship was significant for patients who received twice daily (6.2% vs 1.5%, P = 0.003), but not once daily (3.0% vs 0.7%, P = 0.10) enoxaparin. No association was seen between high aFXa and 90-day clinically relevant bleeding (4.8% vs 2.9%, P = 0.34) or major bleeding (3.6% vs 1.6%, P = 0.18).

Conclusions:

This manuscript establishes inadequate enoxaparin dosing as a plausible mechanism for breakthrough VTE in surgical patients, and identifies anticoagulant dose adequacy as a novel target for process improvement measures.
Virtual Interviews During COVID-19: Perspectives of Female Pelvic Medicine and Reconstructive Surgery Program Directors
Authors: Menhaji Kimia , Gaigbe-Togbe Bertille HA. , Hardart Anne , Bui Anthony H. , Andiman Sarah E. , Ascher-Walsh Charles J. , Dabney Lisa , Do Tran Ann
Published: October 2020

Objective

The aim of the study was to evaluate female pelvic medicine and reconstructive surgery (FPMRS) fellowship program directors’ opinions regarding the effectiveness of virtual interviews for selecting fellows and their future interview mode preferences.

Methods

This was a cross-sectional online survey of all FPMRS program directors in the United States conducted from April 29, 2020, to May 30, 2020. At the time of this study, there were 73 program directors and 69 obstetrics and gynecology and urology–accredited FPMRS programs nationwide. The primary outcome was to subjectively assess the effectiveness of virtual interviews as compared with in-person interviews for evaluating applicants.

Results

Fifty seven (82.6%) of the program directors completed the survey. A total of 80.7% (46/57) of the respondents had participated in interviews for the active match cycle. Of the programs that participated in the interview process, almost all conducted interviews using virtual platforms (97.8%, 45/46). Program directors who conducted interviews virtually found them effective in evaluating applicants (88.9%, 40/45) and were satisfied with the virtual interview process (86.7%, 39/45). A total of 31.1% of respondents (14/45) preferred a virtual platform to an in-person setting for future interviews, and 60% (27/45) reported that they will likely perform future interviews virtually.

Conclusions

Although the pandemic resulted in a sudden reformatting of FPMRS fellowship interviews, most program directors nationally were satisfied with the process and found virtual interviews effective for assessing applicants. More than 50% of FPMRS program directors are likely to consider the virtual format for future interviews.
Management of anxiety disorders in children with attention-deficit hyperactivity disorder: a narrative review
Authors: Golubchik Pavel , Weizman Abraham
Published: October 2020

Anxiety disorders are common comorbidities of attention deficit/hyperactivity disorder (ADHD) and conversely, ADHD is prevalent among anxious youths. A variety of treatments, both psychopharmacological and nonpsychopharmacological, are used to manage combined ADHD/anxiety disorder. This article aims to review the literature on the treatment of ADHD with comorbid anxiety disorders, and make evidence-based recommendations for clinical practice. In most cases, when ADHD is the primary condition, stimulants are the first-line of treatment, frequently resulting not only in improvement in ADHD symptoms but also alleviating the symptoms of the comorbid anxiety disorder. Stimulant treatment is relatively safe and well-tolerated in ADHD with comorbid anxiety disorder. When the stimulant administration does not attenuate the severity of the comorbid anxiety disorder, a treatment that targets specifically the anxiety disorder should be added. This recommendation, however, might be challenged by the impressive efficacy of atomoxetine for both the ADHD and anxiety disorder symptoms. Adjunctive cognitive-behavior therapy for anxiety disorder symptoms is strongly recommended and is considered superior to medication alone. Other options include adding pharmacological treatment for the anxiety symptoms. In moderate and severe cases of comorbid Ads, selective serotonin reuptake inhibitors can be added to the stimulants, with the required caution.
Evaluation of long-acting injectable antipsychotics with the corresponding oral formulation in a cohort of patients with schizophrenia: a real-world study in Spain
Authors: García-Carmona Juan Antonio , Simal-Aguado Jorge , Campos-Navarro María Pilar , Valdivia-Muñoz Francisco , Galindo-Tovar Alejandro
Published: October 2020

To date, only a few studies compared some long-acting injectables (LAIs) antipsychotics showing similar symptom improvement, relapse rates and adherence to treatment. We evaluated the use of LAIs antipsychotics [aripiprazole-1-month (A1M); paliperidone-1-month and 3-month (PP1M and PP3M) and biweekly (2w)-LAIs] and their corresponding oral formulations through (1) the number of hospital re-admissions, (2) the number of documented suicidal behaviour/attempts and (3) the use of concomitant benzodiazepines, oral antipsychotics and biperiden. A total of 277 patients, ≥18 years old, were included if were treated with the corresponding oral or LAI antipsychotic during at least 12 months and were previously diagnosed with schizophrenia. Our results showed that LAIs associated significantly lower suicidal behaviour, reduced the number of hospital admissions, lower diazepam and haloperidol equivalents and mean daily dose of biperiden intake versus oral antipsychotics. Furthermore, significant differences were found between LAIs. Specifically, PP3M was associated to lower hospital admissions versus A1M; PP1M and PP3M lower doses of diazepam equivalents versus 2w-LAIs and finally, PP1M lower antipsychotic intake versus 2w-LAIs. In conclusion, LAIs improved clinical outcomes by reducing the need for concomitant treatments and hospital admissions over oral antipsychotics. PP1M and PP3M showed better outcomes versus A1M and biweekly LAIs.
Multi-model and network inference based on ensemble estimates: avoiding the madness of crowds
Authors: Stumpf Michael P. H.
Published: October 2020

Recent progress in theoretical systems biology, applied mathematics and computational statistics allows us to compare the performance of different candidate models at describing a particular biological system quantitatively. Model selection has been applied with great success to problems where a small number—typically less than 10—of models are compared, but recent studies have started to consider thousands and even millions of candidate models. Often, however, we are left with sets of models that are compatible with the data, and then we can use ensembles of models to make predictions. These ensembles can have very desirable characteristics, but as I show here are not guaranteed to improve on individual estimators or predictors. I will show in the cases of model selection and network inference when we can trust ensembles, and when we should be cautious. The analyses suggest that the careful construction of an ensemble—choosing good predictors—is of paramount importance, more than had perhaps been realized before: merely adding different methods does not suffice. The success of ensemble network inference methods is also shown to rest on their ability to suppress false-positive results. A Jupyter notebook which allows carrying out an assessment of ensemble estimators is provided.
Cyclic epidemics and extreme outbreaks induced by hydro-climatic variability and memory
Authors: Hooshyar Milad , Wagner Caroline E. , Baker Rachel E. , Metcalf C. Jessica E. , Grenfell Bryan T. , Porporato Amilcare
Published: October 2020

A minimalist model of ecohydrologic dynamics is coupled to the well-known susceptible–infected–recovered epidemiological model to explore hydro-climatic controls on infection dynamics and extreme outbreaks. The resulting HYSIR model reveals the existence of a noise-induced bifurcation producing oscillations in infection dynamics. Linearization of the governing equations allows for an analytic expression for the periodicity of infections in terms of both epidemiological (e.g. transmission and recovery rate) and hydrologic (i.e. soil moisture decay rate or memory) parameters. Numerical simulations of the full stochastic, nonlinear system show extreme outbreaks in response to particular combinations of hydro-climatic conditions, neither of which is extreme
per se
, rather than a single major climatic event. These combinations depend on the assumed functional relationship between the hydrologic variables and the transmission rate. Our results emphasize the importance of hydro-climatic history and system memory in evaluating the risk of severe outbreaks.
Layered assemblers for scalable parallel integration
Authors: Hiller Jonathan , Mici Joni , Lipson Hod
Published: October 2020

Many complex natural and artificial systems are composed of large numbers of elementary building blocks, such as organisms made of many biological cells or processors made of many electronic transistors. This modular substrate is essential to the evolution of biological and technological complexity, but has been difficult to replicate for mechanical systems. This study seeks to answer if layered assembly can engender exponential gains in the speed and efficacy of block or cell-based manufacturing processes. A key challenge is how to deterministically assemble large numbers of small building blocks in a scalable manner. Here, we describe two new layered assembly principles that allow assembly faster than linear time, integrating
n
modules in O(

n
2/3

) and O(

n
1/3

) time: one process uses a novel opto-capillary effect to selectively deposit entire layers of building blocks at a time, and a second process jets building block rows in rapid succession. We demonstrate the fabrication of multi-component structures out of up to 20 000 millimetre scale spherical building blocks in 3 h. While these building blocks and structures are still simple, we suggest that scalable layered assembly approaches, combined with a growing repertoire of standardized passive and active building blocks could help bridge the meso-scale assembly gap, and open the door to the fabrication of increasingly complex, adaptive and recyclable systems.
Neutral components show a hierarchical community structure in the genotype–phenotype map of RNA secondary structure
Authors: Weiß Marcel , Ahnert Sebastian E.
Published: October 2020

Genotype–phenotype (GP) maps describe the relationship between biological sequences and structural or functional outcomes. They can be represented as networks in which genotypes are the nodes, and one-point mutations between them are the edges. The genotypes that map to the same phenotype form subnetworks consisting of one or multiple disjoint connected components–so-called neutral components (NCs). For the GP map of RNA secondary structure, the NCs have been found to exhibit distinctive network features that can affect the dynamical processes taking place on them. Here, we focus on the community structure of RNA secondary structure NCs. Building on previous findings, we introduce a method to reveal the hierarchical community structure solely from the sequence constraints and composition of the genotypes that form a given NC. Thereby, we obtain modularity values similar to common community detection algorithms, which are much more complex. From this knowledge, we endorse a sampling method that allows a fast exploration of the different communities of a given NC. Furthermore, we introduce a way to estimate the community structure from genotype samples, which is useful when an exhaustive analysis of the NC is not feasible, as is the case for longer sequence lengths.
The role of Wnt signalling in development of coronary artery disease and its risk factors
Authors: Liu Ya , Neogi Arpita , Mani Arya
Published: October 2020

The Wnt signalling pathways are composed of a highly conserved cascade of events that govern cell differentiation, apoptosis and cell orientation. Three major and distinct Wnt signalling pathways have been characterized: the canonical Wnt pathway (or Wnt/β-catenin pathway), the non-canonical planar cell polarity pathway and the non-canonical Wnt/Ca
2+
pathway. Altered Wnt signalling pathway has been associated with diverse diseases such as disorders of bone density, different malignancies, cardiac malformations and heart failure. Coronary artery disease is the most common type of heart disease in the United States. Atherosclerosis is a multi-step pathological process, which starts with lipid deposition and endothelial cell dysfunction, triggering inflammatory reactions, followed by recruitment and aggregation of monocytes. Subsequently, monocytes differentiate into tissue-resident macrophages and transform into foam cells by the uptake of modified low-density lipoprotein. Meanwhile, further accumulations of lipids, infiltration and proliferation of vascular smooth muscle cells, and deposition of the extracellular matrix occur under the intima. An atheromatous plaque or hyperplasia of the intima and media is eventually formed, resulting in luminal narrowing and reduced blood flow to the myocardium, leading to chest pain, angina and even myocardial infarction. The Wnt pathway participates in all different stages of this process, from endothelial dysfunction to lipid deposit, and from initial inflammation to plaque formation. Here, we focus on the role of Wnt cascade in pathophysiological mechanisms that take part in coronary artery disease from both clinical and experimental perspectives.
PGE
2
upregulates gene expression of dual oxidase in a lepidopteran insect midgut via cAMP signalling pathway
Authors: Sajjadian Seyedeh Minoo , Kim Yonggyun
Published: October 2020

In insect midgut, prostaglandins (PGs) play a crucial role in defending bacterial and malarial pathogens. However, little is known about the PG signalling pathway in the midgut. A dual oxidase (
Se-Duox
) with presumed function of catalysing reactive oxygen species (ROS) production in the midgut was identified in beet armyworm,
Spodoptera exigua
.
Se-Duox
was expressed in all developmental stages, exhibiting relatively high expression levels in the midgut of late larval instars.
Se-Duox
expression was upregulated upon bacterial challenge. RNA interference (RNAi) of
Se-Duox
expression significantly suppressed ROS levels in the midgut lumen. The suppression of ROS levels increased insecticidal activity of
Serratia marcescens
after oral infection. Interestingly, treatment with a PLA
2
inhibitor prevented the induction of
Se-Duox
expression in response to bacterial challenge. On the other hand, addition of its catalytic product rescued the induction of
Se-Duox
expression. Especially, PG synthesis inhibitor significantly suppressed
Se-Duox
expression, while the addition of PGE
2
or PGD
2
rescued the inhibition. Subsequent PG signals involved cAMP and downstream components because specific inhibitors of cAMP signal components such as adenylate cyclase (AC) and protein kinase A (PKA) significantly inhibited
Se-Duox
expression. Indeed, addition of a cAMP analogue stimulated
Se-Duox
expression in the midgut. Furthermore, individual RNAi specific to PGE
2
receptor (a trimeric G-protein subunit), AC, PKA or cAMP-responsive element-binding protein resulted in suppression of
Se-Duox
expression. These results suggest that PGs can activate midgut immunity via cAMP signalling pathway by inducing
Se-Duox
expression along with increased ROS levels.
Human intestinal models to study interactions between intestine and microbes
Authors: Aguilar-Rojas Arturo , Olivo-Marin Jean-Christophe , Guillen Nancy
Published: October 2020

Implementations of suitablein vitrocell culture systems of the human intestine have been essential tools in the study of the interaction among organs, commensal microbiota, pathogens and parasites. Due to the great complexity exhibited by the intestinal tissue, researchers have been developingin vitro/ex vivosystems to diminish the gap between conventional cell culture models and the human intestine. These models are able to reproduce different structures and functional aspects of the tissue. In the present review, information is recapitulated on the most used models, such as cell culture, intestinal organoids, scaffold-based three-dimensional models, and organ-on-a-chip and their use in studying the interaction between human intestine and microbes, and their advantages and limitations are also discussed.