bluuebunny/crossref_metadata_2025 huggingface dataset:
A curious case of ovarian cysts
Authors: Hodges Rebecca , Watkins Elyse
Published: November 2022

Benign mature cystic teratomas are a form of ovarian germ cell tumor that originates from primordial germ cells in the ovaries. Of the three types of teratoma neoplasms, benign mature cystic teratomas (also called dermoid cysts) are the most common. Patients may present with intermittent abdominal or pelvic pain, abdominal enlargement, dysmenorrhea, dyspareunia, or may be asymptomatic. Clinicians should have a high suspicion for benign mature cystic teratomas, which account for more than 20% of all ovarian neoplasms. This article focuses on the clinical symptoms, ovarian growth characteristics, pathophysiology, potential complications, management options, and recurrence of benign mature cystic teratomas.
Utility of the Global Appraisal of Individual Needs Recommendation and Referral Report for Substance Use Diagnosis, Treatment Planning, and Placement
Authors: Welsh Justine W. , Sitar Siara I. , Dennis Michael L.
Published: November 2022

Objectives

This study aims to evaluate the utility of the Global Appraisal of Individual Needs Recommendation and Referral Report (GRRS) as guided by American Psychiatric Association diagnosis criteria and American Society of Addiction Medicine guidelines for treatment planning and placement.

Methods

Global Appraisal of Individual Needs data were gathered between March 2018 and June 2020 from a total of 82 agencies and 245 clinicians as part of a program evaluation of agencies receiving public funding through the Mid-State Health Network under contract with the Michigan Department of Health and Human Services and the Office of Recovery Oriented Systems of Care. Of the 1395 patients 18 years or older, 1027 GRRS reports were produced by clinical staff. κ And ρ analyses were used to measure rates of clinician agreement with the recommendations produced by the GRRS report based on patient interviews.

Results

Clinicians agreed with the GRRS preliminary diagnostic recommendations 88% to 100% of the time, with κ scores indicating excellent agreement by ranging from 0.6 to 0.9. For an average patient, 41 of 46 treatment planning statements generated by the GRRS were used by clinicians, with moderate to high correlation indicated by ρ scores ranging from 0.62 to 0.82. The percent agreement for all American Society of Addiction Medicine dimension ratings was greater than 99%, with κ scores of 0.98 and higher.

Conclusions

This study demonstrates the utility and efficiency of the GRRS as a clinical decision support system to support diagnosis, treatment, and placement in routine practice.
Thomas Dent Mütter, M.D. (1811 to 1859): Exemplar of Expertise
Authors: Schwartz Alan Jay , Coleman Melissa L. , Moon Jane S.
Published: November 2022

Thomas Dent Mütter, a Philadelphia plastic surgeon in the 1840s, boldly championed anesthesia when few physicians were convinced of its virtues. He was an early advocate of handwashing and hygienic wound care and helped pioneer the concept of postoperative recovery units. A leader in education, Mütter used a highly interactive style of teaching and restructured medical school classes to raise the caliber of clinical training. He supplemented his lectures with a myriad of specimens that he amassed over 24 yr. In 1863, this vast collection would serve as the basis for the Mütter Museum, which remains active today. Mütter exemplified expertise by tirelessly pursuing new knowledge and methods for the benefit of his patients and students.
Perioperative Supplemental Oxygen and Postoperative Nausea and Vomiting: Subanalysis of a Trial, Systematic Review, and Meta-analysis
Authors: Markwei Metabel T. , Babatunde Ifeoluwa O. , Kutlu-Yalcin Esra , Essber Hani A. , Mascha Edward J. , Liu Liu , Kurz Andrea M. , Sessler Daniel I.
Published: November 2022

Background

Intraoperative supplemental oxygen may reduce postoperative nausea and vomiting by mitigating hypoxic stress on the gastrointestinal tract. The authors therefore tested the hypothesis that supplemental oxygen reduces nausea and vomiting in adults recovering from colorectal surgery at the Cleveland Clinic between January 28, 2013, and March 11, 2016.

Methods

Initially, the authors conducted an unplanned subanalysis of a previous trial that evaluated the effect of 80% versus 30% intraoperative inspired oxygen on surgical site infection. Specifically, they assessed the effect of 80% versus 30% oxygen concentration on the incidence of postoperative nausea and/or vomiting. Thereafter, the authors conducted a systematic review and meta-analysis of the effect of supplemental oxygen on postoperative nausea and vomiting.

Results

The authors’ underlying analysis included 5,057 colorectal surgeries on 4,001 patients. For 2,554 surgeries, assignment was to 80% oxygen, and in 2,503 surgeries, to 30%. Postoperative nausea and vomiting was 852 of 2,554 (33%) in 80% oxygen and 814 of 2,503 (33%) in 30% oxygen. The estimated relative risk (95% CI) of 80% versus 30% oxygen on postoperative nausea and vomiting was 1.04 (0.96 to 1.12) in a generalized estimating equation model adjusting for within-patient correlation for patients with multiple surgeries, P = 0.355. Furthermore, supplemental oxygen did not reduce antiemetic use (P = 0.911) or the severity of nausea and vomiting (P = 0.924). The authors’ meta-analysis included 10 qualifying trials (6,749 patients) and did not find a difference in postoperative nausea and vomiting: relative risk, 0.97 [95% CI, 0.86 to 1.08], P = 0.55, I2 = 52%.

Conclusions

The incidence of postoperative nausea and vomiting did not differ in patients assigned to 80% or 30% inspired oxygen. A meta-analysis of available trials similarly indicated that supplemental intraoperative oxygen does not reduce postoperative nausea and vomiting. Therefore, supplemental oxygen should not be given in the expectation that it will reduce nausea and vomiting.

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New
Preoperative Computed Tomography Radiomics Analysis for Predicting Receptors Status and Ki-67 Levels in Breast Cancer
Authors: Fan Yuan , Pan Xuelin , Yang Fan , Liu Siyun , Wang Zhu , Sun Jiayu , Chen Jie
Published: November 2022

Background:

To assess the prediction performance of preoperative chest computed tomography (CT) based radiomics features for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER2+), and Ki-67 status of breast cancer.

Materials and Methods:

This study enrolled 108 breast cancer patients who received preoperative chest CT examinations in our institution from July 2018 to January 2020. Radiomics features were separately extracted from nonenhanced, arterial, and portal-venous phases CT images. The least absolute shrinkage and selection operator logistic regression was used for feature selection. Then the radiomics signatures for each phase and a combined model of 3 phases were built. Finally, the receiver operating characteristic curves and calibration curves were used to confirm the performance of the radiomics signatures and combined model. In addition, the decision curves were performed to estimate the clinical usefulness of the combined model.

Results:

The 20 most predictive features were finally selected to build radiomics signatures for each phase. The combined model achieved the overall best performance than using either of the nonenhanced, arterial and portal-venous phases alone, achieving an area under the receiver operating characteristic curve of 0.870 for ER+ versus ER−, 0.797 for PR+ versus PR−, 0.881 for HER2+ versus HER2−, and 0.726 for Ki-67. The decision curve demonstrated that the CT-based radiomics features were clinically useful.

Conclusion:

This study indicated preopreative chest CT radiomics analysis might be able to assess ER, PR, HER2+, and Ki-67 status of breast cancer. The findings need further to be verified in future larger studies.
Predicting Factors for a Favorable Pathologic Response to Neoadjuvant Therapy in Esophageal Cancer
Authors: Wiesel Ory , Zlotnik Oran , Morgenstern Sarah , Tsur Maya , Menasherov Nikolai , Feferman Yael , Ben-Aharon Irit , Kashtan Hanoch
Published: November 2022

Background:

Favorable pathologic response(FPR) is a significant predictor for improved survival following Neoadjuvant therapy(NAT) in esophageal and gastroesophageal cancer(GEJ). Preoperative prediction of FPR could modify treatment plans. No reliable method for predicting FPR exists. We sought to identify preoperative predicting factors for FPR.

Materials and Methods:

Retrospective analysis of patients with esophageal and GEJ cancer who underwent esophagectomy following (NAT). Univariate and multivariate analysis was used to identify preoperative predicting factors for FPR. A comparison of Tumor Regression Grade(TRG) was used to assess treatment response on overall survival(OS).

Results:

Out of 121 patients, 82(67.8%) had neoadjuvant chemoradiation. FPR was observed in 60(49.6%). Female sex, Radiation therapy(RT), squamous cell carcinoma(SCC), lack of signet ring feature, and FDG avidity posttreatment were associated with FPR on univariate analysis. RT and SCC were associated with FPR (OR=3.9 and 4.0, respectively) on multivariate analysis. OS was lower among patients who did not achieve FPR to NAT(P=0.027).

Conclusions:

FPR is a predictor of improved OS. SCC and radiation therapy-based protocol were identified as major prediction factors of FPR in patients with esophageal and GEJ cancers.
Use of the Toxicity Index in Evaluating Adverse Events in Anal Cancer Trials
Authors: Kharofa Jordan R. , Yothers Greg , Kachnic Lisa A. , Ajani Jaffer , Meyer Joshua E. , Augspurger Mark E. , Okawara Gordon S. , Garg Madhur K. , Schefter Tracey E. , Swanson Todd A. , Doncals Desiree E. , Kim Hyun , Zaki Bassem I. , Narayan Samir , Lee R. Jeffery , Mamon Harvey J. , Schwartz Michael A. , Moughan Jennifer , Crane Christopher H.
Published: November 2022

Novel toxicity metrics that account for all adverse event (AE) grades and the frequency of may enhance toxicity reporting in clinical trials. The Toxicity Index (TI) accounts for all AE grades and frequencies for categories of interest. We evaluate the feasibility of using the TI methodology in 2 prospective anal cancer trials and to evaluate whether more conformal radiation (using Intensity Modulated Radiation Therapy) results in improved toxicity as measured by the TI. Patients enrolled on NRG/RTOG 0529 or nonconformal RT enrolled on the 5-Fluorouracil/Mitomycin arm of NRG/RTOG 9811 were compared using the TI. Patients treated on NRG/RTOG 0529 had lower median TI compared with patients treated with nonconformal RT on NRG/RTOG 9811 for combined GI/GU/Heme/Derm events (3.935 vs 3.996, P=0.014). The TI methodology is a feasible method to assess all AEs of interest and may be useful as a composite metric for future efforts aimed at treatment de-escalation or escalation
Communicating With Unconscious Patients
Authors: Lawrence Madelaine M. , Ramirez Rebecca P. , Bauer Paul J.
Published: November 2022

Background

Nurses are told to speak to their unconscious patients because hearing is said to be the last sense to depart. There was little reliable evidence before the 1990s that patients in an unconscious state could hear and understand what was being said. That led to reluctance on the part of health professionals to communicate with these unresponsive patients.

Objective

This historical overview aims to present researched evidence from the 1990s to the present detailing awareness that occurs in unconscious patients, when that awareness increases, and how to detect that awareness. It also includes research about the benefits of communicating with unconscious patients and descriptions of how registered nurses and other health care professionals, from a postsurvey after a continuing education course on experiences of unconscious patients, plan to communicate with unconscious patients.

Methods

A literature search was conducted, which included more than 150 articles and books about experiences of unconscious patients in several electronic databases, including PubMed, CINAHL, and the British Nursing Index. In addition, an analysis of 105 postcourse responses by registered nurses (89%) and other health professionals (11%), licensed practical nurses, emergency medical technicians, and cardiac technicians after taking a continuing education course on experiences of previously unconscious patients were analyzed.

Results

The Glasgow Coma Scale and the Full Outline of Unresponsiveness scale are helpful behavioral tools to identify levels of coma but miss detecting awareness in patients who can hear and understand but cannot move. The estimates are that 25% to 40% (J Trauma. 1975;15:94-98; J Neurosci Nurs. 1988;20:223-228; J Neurosci Nurs. 1990;22(1):52-53; Am J Crit Care. 1995;3:227-232) of patients diagnosed with a disorder of consciousness can hear and understand what is being said in their environment. Substantial evidence supports that isolation and loneliness, such as experienced by some patients perceived to be unaware, can be physically and psychologically harmful.

Conclusions

Strong evidence shows that some patients diagnosed as being in a vegetative state can hear and understand what is being said in their environment. Interviews with previously unconscious patients and electrophysiological methods show that awareness can be detected in patients perceived to be unconscious. There is documented evidence that patients experience awareness when going into unconsciousness, even when they appear unaware and when moved. To our knowledge, these times have not been researched using electrophysiological devices but established from interviews.
Nurse-Led Motor Function Rehabilitation Program for Acute Ischemic Stroke: A Randomized Pilot Study
Authors: WANG Jianmiao , ZHANG Yuping , CHEN Yuanyuan , LI Mei , JIN Jingfen
Published: November 2022

Background

Rehabilitation care for patients with stroke in the acute stage must be strengthened. However, the evidence on how to strengthen this care is insufficient.

Purpose

This article was designed to evaluate the feasibility and effectiveness of implementing a nurse-led motor function rehabilitation program on patients with acute ischemic stroke.

Methods

From January to October 2018, patients with initial acute ischemic stroke were assigned to one of two groups using a pilot randomized controlled trial design, with one group receiving a nurse-led motor function intervention program developed based on Orem's theory (7 consecutive days, twice daily for 30 minutes, experimental group) and the other receiving usual care (control group). The effectiveness measures included changes in the Motor Assessment Scale, the modified Barthel Index, and the National Institutes of Health Stroke Scale. The feasibility measures included patient retention rate, incidence of adverse events, and acceptance of nurses and patients.

Results

We assigned 104 patients (male: 55.7%; age: 62.8 ± 13.2 years) to receive either a nurse-led motor function rehabilitation program or usual care. Eighty-eight patients were evaluated after 7 days (87% retention rate), including 43 (83% retention rate) in the experimental group. Patients accepted the intervention well, and no severe adverse events were reported. Nurses had good fidelity and showed high acceptance. The experimental group showed significantly higher postintervention Motor Assessment Scale and modified Barthel Index scores than the control group (p < .001), whereas postintervention National Institutes of Health Stroke Scale scores did not differ significantly between the two groups.

Conclusions/Implications for Practice

The nurse-led rehabilitation program used in this study was shown to be feasible and effective in improving motor function in patients with acute ischemic stroke. Further study is recommended to determine related clinical recommendations.
Acute Left Ventricular Assist Device Failure From Outflow Graft Dissection Flap Successfully Treated With Stent Placement
Authors: Hernandez Gabriel A. , Talha Khawaja M. , Lennep Brandon , Winscott John G.
Published: November 2022

Outflow graft obstruction (OGO) is a potentially fatal complication of left ventricular assist device (LVAD) implantation. Common causes include graft kinking, luminal stenosis, and graft thrombosis. We describe a case of a 51-year-old female who presented with acute LVAD failure and cardiogenic shock. Initial imaging revealed OGO without luminal stenosis following which she was she was empirically treated for graft thrombosis with anticoagulation and catheter-based thrombolytic therapy with no success. Further imaging in the catheterization laboratory revealed a potential neointimal flap dissection acting as a one-way valve. A stent was successfully placed across the outflow graft with immediate resolution of cardiogenic shock. The case emphasizes the importance of including neointimal flap as a differential for OGO in acute LVAD failure, especially in cases where thrombolytic therapy fails to correct hemodynamic compromise.
Update of surgical treatment of polydactyly
Authors: Tawfeeq Yaser , Hendry J. Michael , Wood Kristi Sue
Published: November 2022

Purpose of review

Polydactyly presents with variable extent of duplication and may involve preaxial/radial (hand)/medial (foot), postaxial/ulnar (hand)/lateral (foot) or central duplication. This review will summarize recent advancements in the surgical management of this common entity.

Recent findings

Modifications to classification systems aim to help guide surgical management of polydactyly. Attempts have been made at quantifying preoperative angulation of the duplicated digits to minimize the chance of residual or recurrent deformity after surgical reconstruction. As a result, consideration should be given to the need for soft tissue correction vs. osteotomy to optimize the clinical outcome. On-top plasty is an option that may be beneficial in ‘unequal’ preaxial polydactyly, where neither duplicate is preferred on its own.

Polydactyly is one of the most common congenital anomalies in the hands and feet. Determination of surgical intervention often begins with classification systems that exist, which primarily separate these into preaxial, postaxial, and central. Referral for surgical consideration is indicated, given the management is often surgical.
Gabapentin for Pain Management in Total Joint Arthroplasty
Authors: Schultz Jeanette R.
Published: November 2022

Gabapentin is routinely used in preoperative multimodal anesthesia to reduce pain following total joint arthroplasty (TJA) surgery. Evolving evidence has shown it is ineffective in reducing postoperative pain and should be used cautiously in this patient population due to its adverse effects. The purpose of this work was to implement an evidence-based practice (EBP) change in a small preadmission testing center. Utilizing the Melnyk EBP model, implementation occurred over 30 days. Pharmacy reports were used to determine the number of doses of gabapentin 300 mg dispensed from the ASU Phase II Omnicell 30 days before implementation and 30 days following implementation. During implementation, there was 23.8% reduction in gabapentin administration preoperatively. Advanced practice registered nurses (APRNs) removed gabapentin from the preoperative order set, resulting in a decrease in gabapentin use. This work demonstrates the role APRNs have in driving EBP changes.
Decoding Single-cell Landscape and Intercellular Crosstalk in the Transplanted Liver
Authors: Huang Haitao , Chen Ruihan , Lin Yimou , Jiang Jingyu , Feng Shi , Zhang Xueyou , Zhang Cheng , Ji Qinghua , Chen Hui , Xie Haiyang , Zheng Shusen , Ling Qi
Published: November 2022

Background.

Liver transplantation (LT) is the most effective treatment for various end-stage liver diseases. However, the cellular complexity and intercellular crosstalk of the transplanted liver have constrained analyses of graft reconstruction after LT.

Methods.

We established an immune-tolerated orthotopic LT mouse model to understand the physiological process of graft recovery and intercellular crosstalk. We employed single-cell RNA sequencing and cytometry by time-of-flight to comprehensively reveal the cellular landscape.

Results.

We identified an acute and stable phase during perioperative graft recovery. Using single-cell technology, we made detailed annotations of the cellular landscape of the transplanted liver and determined dynamic modifications of these cells during LT. We found that 96% of graft-derived immune cells were replaced by recipient-derived cells from the preoperative to the stable phase. However, CD206+MerTK+ macrophages and CD49a+CD49b- natural killer cells were composed of both graft and recipient sources even in the stable phase. Intriguingly, the transcriptional profiles of these populations exhibited tissue-resident characteristics, suggesting that recipient-derived macrophages and natural killer cells have the potential to differentiate into ‘tissue-resident cells’ after LT. Furthermore, we described the transcriptional characteristics of these populations and implicated their role in regulating the metabolic and immune remodeling of the transplanted liver.

Conclusions.

In summary, this study delineated a cell atlas (type-proportion-source-time) of the transplanted liver and shed light on the physiological process of graft reconstruction and graft-recipient crosstalk.
Structural analysis of Toxoplasma gondiisortilin
Authors: Honfozo Ariane , Ghouil Rania , Alayi Tchilabalo Dilezitoko , Ouldali Malika , Arteni Ana-Andreea , Atindehou Cynthia Menonve , Fanou Lucie Ayi , Hathout Yetrib , Zinn-Justin Sophie , Tomavo Stanislas
Published: November 2022

Rhoptries and micronemes are essential for host cell invasion and survival of all apicomplexan parasites, which are composed of numerous obligate intracellular protozoan pathogens includingPlasmodium falciparum(malaria) andToxoplasma gondii(toxoplasmosis) that infect humans and animals causing severe diseases. We identifiedToxoplasma gondiiTgSORT as an essential cargo receptor, which drives the transport of rhoptry (ROP) and microneme (MIC) proteins to ensure the biogenesis of these secretory organelles. The luminal ectodomain of 752 amino acid long situated at the N-terminus end of TgSORT has been described to bind to MIC and ROP proteins. Here, we present an optimized protocol for expression of the entire luminal ectodomain of TgSORT (Tg-NSORT) in the yeastPichia pastoris.Optimization of its coding sequence, cloning and transformation of the yeastP. pastorisallowed the secretion of Tg-NSORT. The protein was purified and further analyzed by negative staining electron microscopy. In addition, molecular modeling using AlphaFold identified key differences between human andT gondiisortilin. The structural features that are only present inT. gondiiand other apicomplexan parasites were highlighted. Elucidating the roles of these specific structural features may be useful for designing new therapeutic agents against apicomplexan parasites
Maximum Classifier Discrepancy Generative Adversarial Network for Jointly Harmonizing Scanner Effects and Improving Reproducibility of Downstream Tasks
Authors: Yan Weizheng , Fu Zening , Jiang Rongtao , Sui Jing , Calhoun Vince D.
Published: November 2022

Objective

Multi-site collaboration is essential for overcoming small-sample problems when exploring reproducible biomarkers in MRI studies. However, various scanner-specific factors dramatically reduce the cross-scanner replicability. Moreover, existing harmony methods mostly could not guarantee the improved performance of downstream tasks.

Methods

we proposed a new multi-scanner harmony framework, called ‘maximum classifier discrepancy generative adversarial network’, or MCD-GAN, for removing scanner effects in the original feature space while preserving substantial biological information for downstream tasks. Specifically, the adversarial generative network was utilized for persisting the structural layout of each sample, and the maximum classifier discrepancy module was introduced for regulating GAN generators by incorporating the downstream tasks.

Results

We compared the MCD-GAN with other state-of-the-art data harmony approaches (e.g., ComBat, CycleGAN) on simulated data and the Adolescent Brain Cognitive Development (ABCD) dataset. Results demonstrate that MCD-GAN outperformed other approaches in improving cross-scanner classification performance while preserving the anatomical layout of the original images.

Significance

To the best of our knowledge, the proposed MCD-GAN is the first generative model which incorporates downstream tasks while harmonizing, and is a promising solution for facilitating cross-site reproducibility in various tasks such as classification and regression. The codes of the MCD-GAN are available athttps://github.com/trendscenter/MCD-GAN.
SUMO –In SilicoSequence Assessment Using Multiple Optimization Parameters
Authors: Evers Andreas , Malhotra Shipra , Bolick Wolf-Guido , Najafian Ahmad , Borisovska Maria , Warszawski Shira , Nanfack Yves Fomekong , Kuhn Daniel , Rippmann Friedrich , Crespo Alejandro , Sood Vanita
Published: November 2022

To select the most promising screening hits from antibody and VHH display campaigns for subsequent in-depth profiling and optimization, it is highly desirable to assess and select sequences on properties beyond only their binding signals from the sorting process. In addition, developability risk criteria, sequence diversity and the anticipated complexity for sequence optimization are relevant attributes for hit selection and optimization. Here, we describe an approach for thein silicodevelopability assessment of antibody and VHH sequences. This method not only allows for ranking and filtering multiple sequences with regard to their predicted developability properties and diversity, but also visualizes relevant sequence and structural features of potentially problematic regions and thereby provides rationales and starting points for multi-parameter sequence optimization.
Use of whole genome sequencing to identify low-frequency mutations in COVID-19 patients treated with remdesivir
Authors: Nirmalarajah Kuganya , Maguire Finlay , Yim Winfield , Aftanas Patryk , Li Angel X. , Shigayeva Altynay , Yip Lily , Zhong Xi Zoe , McGeer Allison J. , Muberka Samira , Kozak Robert
Published: November 2022

Background

We investigate the effects of remdesivir (RDV) treatment on intra-host SARS-CoV-2 diversity and low-frequency mutations in moderately ill hospitalized COVID-19 patients and compare them to patients without RDV treatment.

Methods

Sequential collections of nasopharyngeal and mid-turbinate swabs were obtained from 16 patients with and 31 patients without RDV treatment. A total of 113 samples were sequenced and mutation analyses were performed.

Results

We did not identify any drug resistant mutations during RDV therapy. In genes encoding and associated with the replication complex, low-frequency minority variants that do not reach fixation within the sampling period were detected in 6/16 (37.5%) and 14/31 (45%) patients with and without RDV treatment respectively. We did not detect significant differences in within-host diversity and positive selection between the RDV-treated and untreated groups.

Conclusions

Minimal intra-host variability and stochastic low-frequency variants detected in moderately ill patients suggests little selective pressure in patients receiving short courses of RDV. Patients undergoing short regimens of RDV therapy should continue to be monitored.
The interaction of polygenic risk for depression and age on white blood cell count
Authors: Tio Earvin , Felsky Daniel
Published: November 2022

Recent epidemiological studies suggest that polygenic risk for depression is associated with elevated white blood cell count, indicating shared genetic mechanisms between depression as a psychiatric disorder and the pro-inflammatory states often observed in clinical depression. However, the effects of aging on depressive symptoms and inflammation are not often fully appreciated in these studies, despite known variation across the human lifespan. To investigate the interaction of polygenic risk for depression and age on white blood cell count, we calculated depression polygenic risk scores (PRS) in 324,098 individuals from the UK Biobank (UKB) and 22,758 individuals from the Canadian Longitudinal Study on Aging (CLSA). Linear regression models of white blood cell count were fit to each sample, including interaction effects between age and the depression PRS. Significant age by PRS interaction effects were found in both samples (UKB interaction term: t=-2.9,p=3.7×10−3; CLSA interaction term: t=-2.6,p=9.0×10−3). While the previously reported main positive association between PRS and increasing white blood cell count was observed, we show in this study that the strength of the association diminishes with increasing age. Considering this potential age-dependency, these findings should encourage efforts to uncover genome-wide markers of late-life depression, which are needed to fully understand these age-related interaction effects.
Computational Pipeline to Identify Gene signatures that Define Cancer Subtypes
Authors: Mittal Ekansh , Parikh Vatsal , Kirchgaessner Raphael
Published: November 2022

Motivation

The heterogeneous nature of cancers with multiple subtypes makes them challenging to treat. However, multi-omics data can be used to identify new therapeutic targets and we established a computational strategy to improve data mining.

Results

Using our approach we identified genes and pathways specific to cancer subtypes that can serve as biomarkers and therapeutic targets. Using a TCGA breast cancer dataset we applied the ExtraTreesClassifier dimensionality reduction along with logistic regression to select a subset of genes for model training. Applying hyperparameter tuning, increased the model accuracy up to 92%. Finally, we identified 20 significant genes using differential expression. These targetable genes are associated with various cellular processes that impact cancer progression. We then applied our approach to a glioma dataset and again identified subtype specific targetable genes.

Conclusion

Our research indicates a broader applicability of our strategy to identify specific cancer subtypes and targetable pathways for various cancers.
Mapping splice QTLs reveals distinct transcriptional and post-transcriptional regulatory variation of gene expression in pigs
Authors: Zhang Fei , Velez-Irizarry Deborah , Ernst Catherine W , Huang Wen
Published: November 2022

Background

Alternative splicing is an important step in gene expression, generating multiple isoforms for the same genes and greatly expanding the diversity of proteomes. Genetic variation in alternative splicing contributes to phenotypic diversity in natural populations. However, the genetic basis of variation in alternative splicing in livestock animals including pigs remains poorly understood.

Results

In this study, using a Duroc x Pietrain F2 pig population, we performed genome-wide analysis of alternative splicing estimated from stranded RNA-Seq data in skeletal muscle. We characterized the genetic architecture of alternative splicing and compared its basic features with overall gene expression. We detected a large number of novel alternative splicing events that were not previously annotated. We found heritability of quantitative alternative splicing scores (percent spliced in or PSI) to be lower than that of overall gene expression. In addition, heritabilities showed little correlation between alternative splicing and overall gene expression. Finally, we mapped expression QTLs (eQTLs) and splice QTLs (sQTLs) and found them to be largely non-overlapping.

Conclusions

Our results suggest that regulatory variation exists at multiple levels and that their genetic controls are distinct, offering opportunities for genetic improvement.
scFormer: A Universal Representation Learning Approach for Single-Cell Data Using Transformers
Authors: Cui Haotian , Wang Chloe , Maan Hassaan , Duan Nan , Wang Bo
Published: November 2022

Abstract

Single-cell sequencing has emerged as a promising technique to decode cellular heterogeneity and analyze gene functions. With the high throughput of modern techniques and resulting large-scale sequencing data, deep learning has been used extensively to learn representations of individual cells for downstream tasks. However, most existing methods rely on fully connected networks and are unable to model complex relationships between both cell and gene representations. We hereby propose scFormer, a novel transformer-based deep learning framework to jointly optimize cell and gene embeddings for single-cell biology in an unsupervised manner. By drawing parallels between natural language processing and genomics, scFormer applies self-attention to learn salient gene and cell embeddings through masked gene modelling. scFormer provides a unified framework to readily address a variety of downstream tasks such as data integration, analysis of gene function, and perturbation response prediction. Extensive experiments using scFormer show state-of-the-art performance on seven datasets across the relevant tasks. The scFormer model implementation is available athttps://github.com/bowang-lab/scFormer.
Subacute changes in brain functional network connectivity after nocturnal sodium oxybate intake are associated with anterior cingulate GABA/glutamate balance
Authors: Bavato Francesco , Esposito Fabrizio , Dornbierer Dario A. , Zölch Niklaus , Quednow Boris B. , Staempfli Philipp , Landolt Hans-Peter , Seifritz Erich , Bosch Oliver G.
Published: November 2022

Sodium oxybate (γ-hydroxybutyrate, GHB) is an endogenous GHB/GABABreceptor agonist, clinically used to promote slow-wave sleep and reduce next-day sleepiness in disorders such as narcolepsy and fibromyalgia. The neurobiological signature of these unique therapeutic effects remains elusive. Promising current neuropsychopharmacological approaches to understand the neural underpinnings of specific drug effects address cerebral resting-state functional connectivity (rsFC) patterns and neurometabolic alterations. Hence, we performed a placebo-controlled, double-blind, randomized, cross-over pharmacological magnetic resonance imaging study with a nocturnal administration of GHB, combined with magnetic resonance spectroscopy of GABA and glutamate (Glu) in the anterior cingulate cortex (ACC). Sixteen healthy male volunteers received 50mg/kg GHB p.o. or placebo at 02:30am to maximize deep sleep enhancement and multi-modal brain imaging was performed at 09:00am of the following morning. Independent component analysis of whole-brain rsFC revealed a significant increase of rsFC between the salience network (SN) and the right central executive network (rCEN) after GHB intake compared to placebo. This SN-rCEN coupling was significantly associated with changes in GABA and GABA/Glu levels in the ACC (pall<0.05). The proposed framework allows to identify a neural pattern of pharmacological modulation of the SN, which may serve as a neurobiological signature of the wake-promoting effects of GHB.
Transcription bodies regulate gene expression by sequestering CDK9
Authors: Ugolini Martino , Kuznetsova Ksenia , Oda Haruka , Kimura Hiroshi , Vastenhouw Nadine L.
Published: November 2022

The localization of transcriptional activity in specialized transcription bodies is a hallmark of gene expression in eukaryotic cells. It remains unclear, however, if and how they affect gene expression. Here, we disrupted the formation of two prominent endogenous transcription bodies that mark the onset of zygotic transcription in zebrafish embryos and analysed the effect on gene expression using enriched SLAM-Seq and live-cell imaging. We find that the disruption of transcription bodies results in downregulation of hundreds of genes, providing experimental support for a model in which transcription bodies increase the efficiency of transcription. We also find that a significant number of genes are upregulated, counter to the suggested stimulatory effect of transcription bodies. These upregulated genes have accessible chromatin and are poised to be transcribed in the presence of the two transcription bodies, but they do not go into elongation. Live-cell imaging shows that the disruption of the two large transcription bodies enables these poised genes to be transcribed in ectopic transcription bodies, suggesting that the large transcription bodies sequester a pause release factor. Supporting this hypothesis, we find that CDK9, the kinase that releases paused polymerase II, is highly enriched in the two large transcription bodies. Importantly, overexpression of CDK9 in wild type embryos results in the formation of ectopic transcription bodies and thus phenocopies the removal of the two large transcription bodies. Taken together, our results show that transcription bodies regulate transcription genome-wide: the accumulation of transcriptional machinery creates a favourable environment for transcription locally, while depriving genes elsewhere in the nucleus from the same machinery.
An updated evolutionary history and taxonomy ofMycobacterium tuberculosislineage 5, also calledM. africanum
Authors: Sahal Muhammed Rabiu , Senelle Gaetan , La Kevin , Molina-Moya Barbara , Dominguez Jose , Panda Tukur , Cambau Emmanuelle , Refregier Guislaine , Sola Christophe , Guyeux Christophe
Published: November 2022

Contrarily to other lineages such as L2 and L4, there are still scarce whole-genome-sequence data on L5-L6 MTBC clinical isolates in public genomes repositories. Recent results suggest a high complexity of L5 history in Africa. It is of importance for an adequate assessment of TB infection in Africa, that is still related to the presence of L5-L6 MTBC strains. This study reports a significant improvement of our knowledge of L5 diversity, phylogeographical history, and global population structure ofMycobacterium africanumL5. To achieve this aim, we sequenced new clinical isolates from Northern Nigeria and from proprietary collections, and used a new powerful bioinformatical pipeline,TB-Annotatorthat explores not only the shared SNPs but also shared missing genes, identical IS6110insertion sites and shared regions of deletion. This study using both newly sequenced genomes and available public genomes allows to describe new L5 sublineages. We report that the MTBC L5 tree is made-up of at least 12 sublineages from which 6 are new descriptions. We confront our new classification to the most recent published one and suggest new naming for the discovered sublineages. Finally, we discuss the phylogeographical specificity of sublineages 5.1 and sublineage 5.2 and suggest a new hypothesis of L5-L6 emergence in Africa.

Impact statement

Recent studies onMycobacterium africanum(L5-L6-L9 of MTBC) genomic diversity and its evolution in Africa discovered three new lineages of theMycobacterium tuberculosiscomplex (MTBC) in the last ten years (L7, L8, L9). These discoveries are symptomatic of the delay in characterizing the diversity of the MTBC on the African continent. Another understudied part of MTBC diversity is the intra-lineage diversity of L5 and L6. This study unravels an hidden diversity of L5 in Africa and provides a more exhaustive description of specific genetic features of each sublineage by using a proprietary “TB-Annotator” pipeline. Furthermore, we identify different phylogeographical localization trends between L5.1 and L5.2, suggesting different histories. Our results suggest that a better understanding of the spatiotemporal dynamics of MTBC in Africa absolutely requires a large sampling effort and powerful tools to dig into the retrieved diversity.

Data summary

[A section describing all supporting external data, software or code, including the DOI(s) and/or accession numbers(s), and the associated URL. If no data was generated or reused in the research, please state this.]

The search was done in the TB-Annotator 15901 genomes version which is available at: http://(to be added). The new sequenced genomes are available via NCBI Bioproject accession number: (to be added). The authors confirm all supporting data, code and protocols have been provided within the article or through supplementary data files.
Learning Fast and Slow: Increased cortical plasticity leads to memory interference and enhanced hippocampal-cortical interactions
Authors: Navarro-Lobato Irene , Aleman-Zapata Adrian , Samanta Anumita , Bogers Milan , Narayanan Shekhar , Rayan Abdelrahman , Alonso Alejandra , van der Meij Jacqueline , Khamassi Mehdi , Khan Zafar , Genzel Lisa
Published: November 2022

Our brain is continuously challenged by daily experiences. Thus, how to avoid systematic erasing of previously encoded memories? While it has been proposed that a dual-learning system with “slow” learning in the cortex and “fast” learning in the hippocampus could protect previous knowledge from interference, this has never been observed in the living organism. Here, we report that increasing plasticity via the viral-induced overexpression of RGS14414 in the prelimbic cortex leads to better one-trial memory, but that this comes at the price of increased interference in semantic-like memory. Indeed, electrophysiological recordings showed that this manipulation also resulted in shorter NonREM-sleep bouts, smaller delta-waves and decreased neuronal firing rates. In contrast, hippocampal-cortical interactions in form of theta coherence during wake and REM-sleep as well as oscillatory coupling during NonREM-sleep were enhanced. Thus, we provide the first experimental evidence for the long-standing and unproven fundamental idea that high thresholds for plasticity in the cortex protects preexisting memories and modulating these thresholds affects both memory encoding and consolidation mechanisms.
Defects in the HIV immature lattice support essential lattice remodeling within budded virions
Authors: Guo Sikao , Saha Ipsita , Saffarian Saveez , Johnson Margaret E
Published: November 2022

For HIV virions to become infectious, the immature lattice of Gag polyproteins attached to the virion membrane must be cleaved. Cleavage cannot initiate without the protease formed by the homo-dimerization of domains linked to Gag. However, only 5% of the Gag polyproteins, termed Gag-Pol, carry this protease domain, and they are embedded within the structured lattice. The mechanism of Gag-Pol dimerization is unknown. Here, we use reaction-diffusion simulations of the immature Gag lattice as derived from experimental structures, showing that dynamics of the lattice on the membrane is unavoidable due to the missing 1/3 of the spherical protein coat. These dynamics allow for Gag-Pol molecules carrying the protease domains to detach and reattach at new places within the lattice. Surprisingly, dimerization timescales of minutes or less are achievable for realistic binding energies and rates despite retaining most of the large-scale lattice structure. We derive a formula allowing extrapolation of timescales as a function of interaction free energy and binding rate, thus predicting how additional stabilization of the lattice would impact dimerization times. We further show that during assembly, dimerization of Gag-Pol occurs stochastically and therefore must be actively suppressed to prevent early activation. By direct comparison to recent biochemical measurements within budded virions, we find that only moderately stable hexamer contacts (−12kBT<ΔG<-8kBT) retain both the dynamics and lattice structures that are consistent with experiment. These dynamics are likely essential for proper maturation, and our models quantify and predict lattice dynamics and protease dimerization timescales that define a key step in understanding formation of infectious viruses.

Statement of Significance

For retroviruses such as HIV-1, the Gag polyprotein assembles an immature lattice that ensures successful budding from the cell plasma membrane. The first step in the subsequent maturation requires a pair of protease domains embedded within the lattice to form a homodimer. We show here that this homo-dimerization can proceed within minutes despite involving a small subset of Gag monomers, due to the incompleteness of the immature lattice. Using reaction-diffusion simulations, we quantify timescales of first dimerization events between the protease domains and define a formula to extrapolate across a range of energies and rates. Our models illustrate how protein contacts can be weakened to disrupt lattice assembly or stabilized to slow the remodeling essential for viral infectivity.
Risk Factors for 30-day Postoperative Surgical Site Hematoma Requiring Evacuation After Resection of Brain Metastases
Authors: Zheng Yilong , Teo Kejia , Nga Vincent Diong Weng , Yeo Tseng Tsai , Lim Mervyn Jun Rui
Published: November 2022

Objective

To identify the risk factors for a 30-day postoperative surgical site hematoma requiring evacuation (POH) after surgical resection of brain metastases.

Methods

Patients who underwent surgical resection of brain metastases between 2011 and 2019 at our institution were included. Risk factors for a 30-day POH were identified using a multivariate logistic regression model.

Results

A total of 158 patients were included in the analysis. The mean (SD) age of the study population was 59.3 (12.0) years, and 82 (53.2%) patients were female. The incidence of a 30-day POH was 8.2% (13 patients). There was no statistically significant association between the occurrence of a 30-day POH and overall mortality (p=0.100). On multivariate analysis, there was a statistically significant association between a 30-day POH and younger age (OR=0.91; 95% CI=0.83, 0.99; p=0.035), higher BMI (OR=1.61; 95% CI=1.16, 2.46; p=0.010), and blood type AB (OR=21.7; 95% CI=1.66, 522; p=0.031). On receiver operating characteristic analysis, a threshold BMI of 25.1 kg/m2and threshold age of 57 gave the optimum balance of sensitivity and specificity in predicting the occurrence of a 30-day POH.

Conclusions

Patients below 57 years old, who have a BMI of above 25, and/or have blood type AB were at higher risk of developing a 30-day POH after surgical resection of brain metastases. Additional care in intraoperative hemostasis and postoperative monitoring may be indicated among patients who have these risk factors.
A compact von Hámos spectrometer for parallel X-ray Raman scattering and X-ray emission spectroscopy at ID20 of the European Synchrotron Radiation Facility
Authors: Sahle Ch. J. , Gerbon F. , Henriquet C. , Verbeni R. , Detlefs B. , Longo A. , Mirone A. , Lagier M.-C. , Otte F. , Spiekermann G. , Petitgirard S.
Published: November 2022

A compact spectrometer for medium-resolution resonant and non-resonant X-ray emission spectroscopy in von Hámos geometry is described. The main motivation for the design and construction of the spectrometer is to allow for acquisition of non-resonant X-ray emission spectra while measuring non-resonant X-ray Raman scattering spectra at beamline ID20 of the European Synchrotron Radiation Facility. Technical details are provided and the performance and possible use of the spectrometer are demonstrated by presenting results of several X-ray spectroscopic methods on various compounds.