bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Frozen and Permanent Section Diagnosis in Ovarian Neoplasms: Analysis of Factors Affecting Accuracy
Authors: Akbarzadeh-Jahromi Mojgan , Aslani Fatemeh Sari , Raeisi Hadi , Momtahan Mozhdeh , Taheri Negar
Published: August 2021

Ovarian cancer is the seventh most common form of cancer among women worldwide. The aim of the study was to determine the accuracy of a frozen section and the factors affecting the accuracy of frozen diagnosis of ovarian neoplasms. This retrospective, cross-sectional study was conducted on 401 patients with ovarian masses with frozen section diagnosis in Shahid Faghihi Hospital affiliated to Shiraz University of Medical Sciences between 2014 and 2018. Each ovarian tumor sample was evaluated for histopathologic diagnosis using frozen and paraffin-embedded sections, which were reviewed by an expert gynecologic pathologist. Accuracy and diagnostic values were estimated by comparing the results of the 2 techniques, using the paraffin section as the gold standard. The overall accuracy of the frozen section was 94.5%. Its sensitivity was 85.3% for malignant, 88.2% for borderline, and 99.6% for benign tumors. Its specificity was also 99.7% for malignant, 98.0% for borderline, and 90.9% for benign tumors. The positive predictive value was 98.9% for malignant, 86.5% for borderline, and 94.6% for benign tumors. Most false negatives occurred in mucinous and borderline tumors. The sensitivity of malignant tumors of germ cell and sex cord-stromal cell types were 64.3% and 95.5%, respectively. The specificity of germ cell and sex-cord stromal tumors were 100% and 93.8%, respectively. Frozen section seems to be a precise technique for histopathologic diagnosis of ovarian tumors. However, borderline and mucinous tumors are the most problematic issues during frozen section diagnosis and malignant germ cell tumors have the lowest sensitivity.
BCOR Internal Tandem Duplication Associated Uterine Sarcoma: Expanding the Clinicopathologic Spectrum
Authors: Thiryayi Sakinah A. , Ettler Helen , Goebel Emily A. , Prefontaine Michel , Paton Tara A. , Wong Andrew , Yee Denise , Agro Evangeline , Mayers Justin , Lerner-Ellis Jordan , Turashvili Gulisa
Published: August 2021

The diagnosis of high-grade endometrial stromal sarcoma has become more refined following molecular characterization of these tumors. Recently BCOR internal tandem duplications (ITD) have been identified in a small number of high-grade endometrial stromal sarcoma. Here we present an additional case of this rare entity in a young woman in her late teens. She presented with menorrhagia and underwent resection of 2 uterine lesions. The tumor was a spindle cell neoplasm composed of long fascicles with low to moderate cellularity, mild to moderate cytologic atypia, and up to 2 mitotic figures per 10 high power fields. Necrosis was not identified. Immunohistochemical stains showed the tumor to be positive for cyclin D1 in >50% of tumor cells, focally positive for CD10, and negative for SMA, desmin, h-caldesmon, and ALK1. BCOR ITD was confirmed by polymerase chain reaction with subsequent Sanger sequencing. Clues to the diagnosis of BCOR ITD uterine sarcoma include young patient age, uniform nuclear features, and diffuse positivity for cyclin D1. These features should prompt further molecular interrogation for definitive diagnosis, which is important for prognostication.
Association between radicular low back pain and constipation: a retrospective cohort study using a real-world national database
Authors: Trager Robert James , Mok Shaffer R.S. , Schlick Kayla J. , Perez Jaime A. , Dusek Jeffery A.
Published: August 2021

Introduction:

Previous observational studies have reported an association between lumbosacral radiculopathy (LSR), a form of low back pain (LBP) with nerve root involvement, and constipation. However, it is unclear whether this association is due to confounding variables such as comorbidities and medications.

Objectives:

This study explores the possible association between LSR and constipation, with the hypothesis that adults with LSR have increased odds of developing constipation compared with those with nonradicular LBP.

Methods:

Adults aged 18 to 49 years with incident LSR and nonradicular LBP were identified from a national 70 million patient electronic health records network (TriNetX). Propensity score matching (PSM) was used to control for covariates and determine the odds ratio (OR) of constipation over a 1-year follow-up. Lumbar stenosis, cauda equina syndrome, and inflammatory bowel diseases were excluded.

Results:

After PSM, 503,062 patients were in each cohort. Before PSM, the likelihood of constipation was identical between cohorts (LSR 10.8% vs 10.9%; OR [confidence interval] = 0.99 [0.98-1.0], P = 0.251). This association was unchanged after PSM (LSR 10.8% vs 11.1%; OR [confidence interval] = 0.98 [0.97-0.99]; P = 0.003).

Conclusions:

The study hypothesis can be refuted given that the OR approximated the null in a large propensity-matched sample. Patients with LSR have equivalent odds of constipation compared with those with nonradicular LBP, suggesting that LSR is not a direct cause of constipation. The similar risk of constipation between cohorts could be explained by factors common to LBP in general, such as pain severity, physical inactivity, and constipating medications.
Examining the Relationship Between the Lean Management System and Quality Improvement Care Management Processes
Authors: Tierney Aaron A. , Shortell Stephen M. , Rundall Thomas G. , Blodgett Janet C. , Reponen Elina
Published: August 2021

Background and Objectives:

The United States has an underperforming health care system on both cost and quality criteria in comparison with other developed countries. One approach to improving system performance on both cost and quality is to use the Lean Management System based on the Shingo principles originally developed by Toyota in Japan. Our objective was to examine the association between hospital use of the Lean Management System and evidence-based or recommended quality improvement care management processes.

Methods:

A cross-sectional analysis of data from 223 hospitals that responded to both the 2017 National Survey of Healthcare Organizations and Systems and the 2017 National Survey of Lean/Transformational Performance Improvement in Hospitals was conducted.

Results:

Controlling for hospital organizational and market characteristics, the number of years using Lean was positively associated with use of electronic health record–based decision support, use of quality-focused information management, use of evidence-based guidelines, and support for care transitions at the P < .05 level. The degree of education and training in Lean methods and processes was also positively associated (P < .05) with greater support for care transitions. The number of years using Lean was marginally associated with screening for clinical conditions at the P < .10 level. There was an unexpected negative association between education and training scores and screening for clinical conditions.

Conclusions:

Greater experience in using the Lean Management System is positively associated with several evidence-based and/or recommended quality improvement care management processes.
Anatomical Study of Ethmoidal Foramina and Optic Canal in Endoscopic Trans-Nasal Approach to Anterior Skull Base
Authors: Cheng Ye , Song Gang , Cao Jun , Bai Jie , Wang Xu , Zhang Lei , Tang Jie , Xiao Xinru
Published: August 2021

Background:

Surgery to anterior skull base is challenging since complex structures are involved. Injury of olfactory fila and optic nerve may result in postoperative complications. In our study, the authors aim to use computer topographic image to provide a comprehensive anatomical information of anterior skull base and set up a new classification of optic canal (OC) in ethmoid sinus by the degree of bony defect, so as to help surgeons in endoscopic transnasal approach to anterior skull base.

Method:

Computer topographic angiography images of 112 individuals were reviewed, the measurement was performed on coronal, sagittal, and axis planes after the multiplanar reformation. Nostril and mid-sagittal lines were used to locate the anterior, middle, and posterior part of ethmoidal foramina and orbital opening of OC. Further, the authors classified OC in ethmoidal sinus into 4 types by the degree of the bony defect.

Result:

Distance between nostril to anterior, middle, and posterior part of ethmoidal foramina and OC are 6.23 ± 0.21, 6.62 ± 0.26, 7.29 ± 0.25, and 7.76 ± 0.41 mm, respectively. Angle between line from nostril to ethmoidal foramina and horizontal plane are 47.50° ± 1.03°, 41.67° ± 1.33°, 37.20° ± 1.34°, respectively. For the 4 types of OC, the percentage is 15.6%, 11.6%, 31.3%, and 41.5%, respectively.

Conclusions:

Our findings provide anatomical information of ethmoidal foramina and OC during endoscopic transnasal approach to anterior skull base, on the basis of some fixed anatomical landmarks. So as to enhance the surgical safety of this procedure and aid in the choice of the appropriate endoscopic equipment for the procedure.
Reporting on Race and Racial Disparities in Breast Cancer
Authors: Loehrer Andrew P. , Cevallos Priscila C. , Jiménez Rafael T. , Wong Sandra L.
Published: August 2021

Objective:

This study reviews the surgical literature on racial disparities in breast cancer mortality, specifically evaluating the inclusion, justification, and discussion of race and ethnicity as a driver of disparities.

Summary of Background Data:

The volume of research on racial disparities has increased over the past 2 decades, but we hypothesize that there is considerable variation in how race is contextualized, defined, and captured in the disparities literature, leading to its questionable validity and relevance as a covariate. Recent guidelines for reporting have been suggested, but not yet applied.

Methods:

A rubric was developed to evaluate the reporting of race and/or ethnicity. A systematic review (2010-2020) was performed to identify studies reporting on racial disparities in breast cancer surgery and mortality. We then evaluated these original articles based on key domains of race and/or ethnicity: justification for inclusion, formal definition, methodology used for classification, and type of racism contributing to disparity.

Results:

Of the 52 studies assessed, none provided a formal definition for race and/or ethnicity. A justification for the inclusion of race and/or ethnicity was provided in 71% of the studies. Although 81% of studies discussed at least 1 potential driver of observed racial disparities, only 1 study explicitly named racism as a driver of racial disparities.

Conclusions:

Significant improvement in the reporting on racial disparities in breast cancer surgical literature is warranted. A more rigorous framework should be applied by both researchers and publishers in reporting on race, racial health disparities, and racism.
High-risk Opioid Prescribing Associated with Postoperative New Persistent Opioid Use in Adolescents and Young Adults
Authors: Vargas Gracia M. , Gunaseelan Vidhya , Upp Lily , Deans Katherine J. , Minneci Peter C. , Gadepalli Samir K. , Englesbe Michael J. , Waljee Jennifer F. , Harbaugh Calista M.
Published: August 2021

Objective:

In this study, we explored which postoperative opioid prescribing practices were associated with persistent opioid use among adolescents and young adults.

Background:

Approximately 5% of adolescents and young adults develop postoperative new persistent opioid use. The impact of physician prescribing practices on persistent use among young patients is unknown.

Methods:

We identified opioid-naïve patients aged 13 to 21 who underwent 1 of 13 procedures (2008–2016) and filled a perioperative opioid prescription using commercial insurance claims (Optum Deidentified Clinformatics Data Mart Database). Persistent use was defined as ≥ 1 opioid prescription fill 91 to 180 days after surgery. High-risk opioid prescribing included overlapping opioid prescriptions, co-prescribed benzodiazepines, high daily prescribed dosage, long-acting formulations, and multiple prescribers. Logistic regression modeled persistent use as a function of exposure to high-risk prescribing, adjusted for patient demographics, procedure, and comorbidities.

Results:

High-risk opioid prescribing practices increased from 34.9% to 43.5% over the study period; the largest increase was in co-prescribed benzodiazepines (24.1%–33.4%). High-risk opioid prescribing was associated with persistent use (aOR 1.235 [1.12,1.36]). Receipt of prescriptions from multiple opioid prescribers was individually associated with persistent use (aOR 1.288 [1.16,1.44]). The majority of opioid prescriptions to patients with persistent use beyond the postoperative period were from nonsurgical prescribers (79.6%).

Conclusions:

High-risk opioid prescribing practices, particularly receiving prescriptions from multiple prescribers across specialties, were associated with a significant increase in adolescent and young adult patients’ risk of persistent opioid use. Prescription drug monitoring programs may help identify young patients at risk of persistent opioid use.
The Trauma Dyad: The Role of Informal Caregivers for Older Adults After Traumatic Injury
Authors: Sokas Claire M. , Bollens-Lund Evan , Husain Mohammed , Ornstein Katherine A. , Kelly Masami T. , Sheu Christina , Kerr Emma , Jarman Molly , Salim Ali , Kelley Amy S. , Cooper Zara
Published: August 2021

Objective:

To investigate the association between higher injury severity and increased informal caregiving received by injured older adults.

Summary of Background Data:

Injured older adults experience high rates of functional decline and disability after hospitalization. Little is known about the scope of caregiving received post-discharge, particularly from informal caregivers such as family.

Methods:

We used the National Health and Aging Trends Study 2011 to 2018 linked to Medicare claims to identify adults ≥65 with hospital admission for traumatic injury and a National Health and Aging Trends Study interview within 12 months pre- and post-trauma. Injury severity was assessed using the injury severity score (ISS, low 0–9; moderate 10–15; severe 16–75). Patients reported the types and hours of formal and informal help received and any unmet care needs. Multi variable logistic regression models examined the association between ISS and increase in informal caregiving hours after discharge.

Results:

We identified 430 trauma patients. Most were female (67.7%), non-Hispanic White (83.4%) and half were frail. The most common mechanism of injury was fall (80.8%) and median injury severity was low (ISS = 9). Those reporting receiving help with any activity increased post-trauma (49.0% to 72.4%, P < 0.01), and unmet needs nearly doubled (22.8% to 43.0%, P < 0.01). Patients had a median of 2 caregivers and most (75.6%) were informal, often family members. Median weekly hours of care received pre- versus post-injury increased from 8 to 14 (P < 0.01). ISS did not independently predict increase in caregiving hours; pre-trauma frailty predicted an increase in hours ≥8 per week.

Conclusions:

Injured older adults reported high baseline care needs which increased significantly after hospital discharge and were mostly met by informal caregivers. Injury was associated with increased need for assistance and unmet needs regardless of injury severity. These results can help set expectations for caregivers and facilitate post-acute care transitions.
Updates in treatment of depression in children and adolescents
Authors: Hazell Philip
Published: August 2021

Purpose of review

To examine recent evidence that informs the treatment of depression in children and adolescents.

Recent findings

There are no new leads in the prevention and early intervention of depression in children and adolescents. For acute treatment of major depressive disorder, talking therapies are moving increasingly to internet-based platforms. Family therapy may have a slight edge over individual psychotherapy in the short-term. Patients with severe depression with endogenous features have a more robust response to pharmacotherapy than do patients with mild-to-moderate depression. Findings in relation to reward sensitivity and changes in brain-derived neurotrophic factor levels contradict research conducted in adults, suggesting developmental differences in the mechanisms underlying depression. Ketamine infusion could have a role for adolescents with treatment refractory depression. There was no new evidence concerning relapse prevention.

Most new findings have been concerned with moderators and mediators of treatment.
Director alignment at the nematic–isotropic interface: elastic anisotropy and active anchoring
Authors: Coelho Rodrigo C. V. , Araújo Nuno A. M. , Telo da Gama Margarida M.
Published: August 2021

Activity in nematics drives interfacial flows that lead to preferential alignment that is tangential or planar for extensile systems (pushers) and perpendicular or homeotropic for contractile ones (pullers). This alignment is known as active anchoring and has been reported for a number of systems and described using active nematic hydrodynamic theories. The latter are based on the one-elastic constant approximation, i.e. they assume elastic isotropy of the underlying passive nematic. Real nematics, however, have different elastic constants, which lead to interfacial anchoring. In this paper, we consider elastic anisotropy in multiphase and multicomponent hydrodynamic models of active nematics and investigate the competition between the interfacial alignment driven by the elastic anisotropy of the passive nematic and the active anchoring. We start by considering systems with translational invariance to analyse the alignment at flat interfaces and, then, consider two-dimensional systems and active nematic droplets. We investigate the competition of the two types of anchoring over a wide range of the other parameters that characterize the system. The results of the simulations reveal that the active anchoring dominates except at very low activities, when the interfaces are static. In addition, we found that the elastic anisotropy does not affect the dynamics but changes the active length that becomes anisotropic.

This article is part of the theme issue ‘Progress in mesoscale methods for fluid dynamics simulation’.
A fast and efficient deep learning procedure for tracking droplet motion in dense microfluidic emulsions
Authors: Durve Mihir , Bonaccorso Fabio , Montessori Andrea , Lauricella Marco , Tiribocchi Adriano , Succi Sauro
Published: August 2021

We present a deep learning-based object detection and object tracking algorithm to study droplet motion in dense microfluidic emulsions. The deep learning procedure is shown to correctly predict the droplets’ shape and track their motion at competitive rates as compared to standard clustering algorithms, even in the presence of significant deformations. The deep learning technique and tool developed in this work could be used for the general study of the dynamics of biological agents in fluid systems, such as moving cells and self-propelled microorganisms in complex biological flows.

This article is part of the theme issue ‘Progress in mesoscale methods for fluid dynamics simulation’.
Prelacteal Feeding and Associated Factors among Mothers of Infants Aged 6 to 12 Months in Chitwan District, Nepal: A Community Based Cross-sectional Study
Authors: Neupane Mani , Dhungana Govinda Prasad , Sharma Bimala , Paudel Dhirendra
Published: August 2021

Background

A Prelacteal feed is any food except mothers’ milk provided to a newborn before breastfeeding is established. Prelacteal feeding is a major barrier to exclusive breastfeeding and is associated with newborn infection. It is a prevalent practice in Nepal. This study aimed to investigate prelacteal feeding practice and associated factors among mothers of infants aged 6 to 12 months in Chitwan district, Nepal.

Methods

A community-based cross-sectional study was conducted. 297 mothers of infants aged 6 to 12 months were selected using a systematic random sampling technique. Descriptive statistics, univariate and binomial logistic regression analysis were done to identify the factors associated with prelacteal feeding practice. Variable with a p-value <0.05 were identified as statistically significant factors.

Result

The prevalence of prelacteal feeding was 40.1% (95% CI: 34.5%-45.7%). Formula milk (n=109), animal milk (n=13), Plain water (n=6) were some of the types of prelacteal feed reported. Respondents in the 25-29 years age group were about 58.2% less likely to practice prelacteal feeding (adjusted odds ratio (AOR)=0.415, 95% confidence interval (CI):0.209-0.837) as compared to the respondents belonging to 35 years or more age group. Economic status was another factor associated with prelacteal feeding practice. Those mothers with poorer economic status were about 57.9 % (AOR= 0.421, CI: 0.179-0.992) less likely to practice prelacteal feeding than the mothers belonging to the richest. Similarly, mothers having poor knowledge on prelacteal feeding were found about three (AOR= 2.661, CI: 1.514-4.674) times more likely to have prelacteal feeding than those mothers who had good knowledge about prelacteal feeding. Home delivery and caesarean section in case of institutional delivery were two major reasons stated for providing prelacteal feeding.

Conclusion

Prelacteal feeding was commonly practiced in the Chitwan district, Nepal. Mother’s age, economic status, mothers’ knowledge of prelacteal feeding practices, and mode of delivery were factors associated with prelacteal feeding practices. Therefore, awareness and knowledge on the risk associated with prelacteal feeding, promotion of institutional delivery, timely initiation of breastfeeding, and avoidance of prelacteal feeding are important measures for preventing prelacteal feeding practices in Chitwan district, Nepal.
Opaganib in COVID-19 pneumonia: Results of a randomized, placebo-controlled Phase 2a trial
Authors: Winthrop Kevin L. , Skolnick Alan W. , Rafiq Adnan M. , Beegle Scott H. , Suszanski Julian , Koehne Guenther , Barnett-Griness Ofra , Bibliowicz Aida , Fathi Reza , Anderson Patricia , Raday Gilead , Eagle Gina , Ben-Yair Vered Katz , Minkowitz Harold S. , Levitt Mark L. , Gordon Michael S.
Published: August 2021

Background

Opaganib, an oral sphingosine kinase-2 inhibitor with antiviral and anti-inflammatory properties, was shown to inhibit SARS-CoV-2 replication in vitro. We thus considered that opaganib could be beneficial for moderate to severe COVID-19 pneumonia. The objective of the study was to evaluate the effect of opaganib on supplemental oxygen requirements, time to hospital discharge and its safety in COVID-19 pneumonia hospitalized patients requiring supplemental oxygen.

Methods

This Phase 2a, randomized, double-blind, placebo-controlled study was conducted between July and December 2020 in eight sites in the USA. Forty-two enrolled patients received opaganib (n=23) or placebo (n=19) added to standard of care for up to 14 days and were followed up for 28 days after their last dose of opaganib/placebo.

Results

The relative decrease in total supplemental oxygen requirement from baseline to Day 14 was 61.6% in the opaganib versus 46.7% in the placebo arms. By Day 14, 50.0% of patients in the opaganib and 22.2% in the placebo group no longer required supplemental oxygen for at least 24 hours, while 86.4% and 55.6%, respectively, were discharged from hospital. The incidence of ≥ Grade 3 treatment-emergent adverse events was 17.4% and 33.3% in the opaganib and placebo groups, respectively. Three deaths occurred in each group.

Conclusions

In this proof-of-concept study, hypoxic, hospitalized patients receiving oral opaganib required less supplementary oxygen and had earlier hospital discharge, with no safety concerns arising. These findings support further evaluation of opaganib in this population.

Upon receiving opaganib, patients with COVID-19 pneumonia who were hospitalized and required supplemental oxygen showed symptomatic clinical improvement compared to placebo, with less supplemental oxygen requirement, resulting in earlier hospital discharge, and no safety concerns arising.
The COVID-19 Pandemic and Mental Health Concerns on Twitter in the United States
Authors: Zhang Senqi , Sun Li , Zhang Daiwei , Li Pin , Liu Yue , Anand Ajay , Xie Zidian , Li Dongmei
Published: August 2021

Background

Mental health illness is a growing problem in recent years. During the COVID-19 pandemic, mental health concerns (such as fear and loneliness) have been actively discussed on social media.

Objective

In this study, we aim to examine mental health discussions on Twitter during the COVID-19 pandemic in the United States and infer the demographic composition of Twitter users who had mental health concerns.

Methods

COVID-19 related tweets from March 5th, 2020 to January 31st, 2021 were collected through Twitter streaming API using COVID-19 related keywords (e.g., “corona”, “covid19”, “covid”). By further filtering using mental health keywords (e.g., “depress”, “failure”, “hopeless”), we extracted mental health-related tweets from the US. Topic modeling using the Latent Dirichlet Allocation model was conducted to monitor users’ discussions surrounding mental health concerns. Demographic inference using deep learning algorithms (including Face++ and Ethnicolr) was performed to infer the demographic composition of Twitter users who had mental health concerns during the COVID-19 pandemic.

Results

We observed a positive correlation between mental health concerns on Twitter and the COVID-19 pandemic in the US. Topic modeling showed that “stay-at-home”, “death poll” and “politics and policy” were the most popular topics in COVID-19 mental health tweets. Among Twitter users who had mental health concerns during the pandemic, Males, White, and 30-49 age group people were more likely to express mental health concerns. In addition, Twitter users from the east and west coast had more mental health concerns.

Conclusions

The COVID-19 pandemic has a significant impact on mental health concerns on Twitter in the US. Certain groups of people (such as Males, White) were more likely to have mental health concerns during the COVID-19 pandemic.
Machine learning-based prediction of motor status in glioma patients using diffusion MRI metrics along the corticospinal tract
Authors: Shams Boshra , Wang Ziqian , Roine Timo , Aydogan Baran , Vajkoczy Peter , Lippert Christoph , Picht Thomas , Fekonja Lucius S.
Published: August 2021

Along tract statistics enables white matter characterization using various diffusion MRI (dMRI) metrics. Here, we applied a machine learning (ML) method to assess the clinical utility of dMRI metrics along corticospinal tracts (CST), investigating whether motor glioma patients can be classified with respect to their motor status. The ML-based analysis included developing models based on support vector machine (SVM) using histogram-based measures of dMRI-based tract profiles (e.g., mean, standard deviation, kurtosis and skewness), following a recursive feature elimination (RFE) method based on SVM (SVM-RFE). Our model achieved high performance (74% sensitivity, 75% specificity, 74% overall accuracy and 77% AUC). Incorporating the patients’ demographics and clinical features such as age, tumor WHO grade, tumor location, gender and resting motor threshold (RMT) into our designed models demonstrated that these features were not as effective as microstructural measures. The results revealed that ADC, FA and RD contributed more than other features to the model.
Common genetic variation associated with Mendelian disease severity revealed through cryptic phenotype analysis
Authors: Blair David R , Hoffmann Thomas J , Shieh Joseph T
Published: August 2021

Clinical heterogeneity is common in Mendelian disease, but small sample sizes make it difficult to identify specific contributing factors. However, if a rare disease represents the severely affected extreme of a spectrum of phenotypic variation, then modifier effects may be apparent within a larger subset of the population. Analyses that take advantage of this full spectrum could have substantially increased power. To test this, we developed cryptic phenotype analysis (CPA), a model-based approach that uses symptom data to infer latent quantitative traits that capture disease-related phenotypic variability. By applying this approach to 50 Mendelian diseases in two large cohorts of patients, we found that these quantitative traits reliably captured disease severity. We then conducted genome-wide association analyses for five of the inferred cryptic phenotypes, uncovering common variation that was predictive of Mendelian disease-related diagnoses and outcomes. Overall, this study highlights the utility of computationally derived phenotypes and biobank-scale cohorts for investigating the complex genetic architecture of Mendelian diseases.
Pathway profiling of a novel SRC inhibitor, AZD0424, in combination with MEK inhibitors
Authors: Dawson John C , Munro Alison , Macleod Kenneth , Muir Morwenna , Timpson Paul , Williams Robert J , Frame Margaret , Brunton Valerie G , Carragher Neil O
Published: August 2021

A more comprehensive understanding of how cells respond to drug intervention, the likely immediate signalling responses and how resistance may develop within different microenvironments allows us anticipate how cells adapt to targeted therapy enabling more informed prediction of rational drug combinations. The non-receptor tyrosine kinase SRC regulates many cellular signalling processes and pharmacological inhibition has long been a target of drug discovery projects for the treatment of cancer. Here we describe thein vitroandin vivocharacterisation of the small molecule SRC inhibitor, AZD0424. We show that AZD0424 potently inhibits the phosphorylation of tyrosine-416 of SRC (IC50 ∼ 100 nM) in many cancer cell lines; however inhibition of cell viability, via a G1 cell cycle arrest, was observed only in a sub-set of cancer cell lines in the low (on target) micromolar range. We profiled the changes in intracellular pathway signalling in cancer cells following exposure to AZD0424 and other targeted therapies using Reverse Phase Protein Array analysis. We demonstrate that SRC is activated in response to MEK inhibitor (trametinib or AZD6244)-treatment of KRAS mutant colorectal cell lines (HCT116 and DLD1) and that AZD0424 abrogates this. Cell lines treated with trametinib or AZD6244 in combination with AZD0424 revealed reduction of EGFR, FAK and SRC compensatory activation, and, synergistically inhibits cell viabilityin vitro. In vivo, trametinib-treatment of mice bearing HCT116 tumours increased phosphorylation of SRC on Tyr416, and when combined with AZD0424, inhibition of tumour growth is greater than trametinib alone. We also demonstrate that drug-induced resistance to trametinib is not re-sensitised by AZD0424 treatmentin vitro, likely as a result of multiple compensatory signalling mechanisms; however inhibition of SRC remains an effective way to block invasion of trametinib resistant tumour cells. These data imply that inhibiting SRC may offer a useful addition to MEK inhibitor combination strategies.
Large-scale differences in functional organization of left- and right-handed individuals using whole-brain, data-driven analysis of connectivity
Authors: Tejavibulya Link , Peterson Hannah , Greene Abigail , Gao Siyuan , Rolison Max , Noble Stephanie , Scheinost Dustin
Published: August 2021

Handedness influences differences in lateralization of language areas as well as dominance of motor and somatosensory cortices. However, differences in whole brain functional organization due to handedness have been relatively understudied beyond pre-specified networks of interest. Functional connectivity offers the ability to unravel differences in the functional organization of the whole brain. Here, we compared connectivity profiles of left- and right-handed individuals using data-driven parcellations of the whole brain. We explored differences in connectivity profiles of previously established regions of interest, and showed functional organization differences between primarily left- and primarily right-handed individuals in the motor, somatosensory, and language areas using functional connectivity. We then proceeded to investigate these differences in the whole brain and found that the functional organization of left- and right-handed individuals are not specific to regions of interest. In particular, we found that connections between and within-hemispheres and the cerebellum show distinct patterns of connectivity. Together these results shed light on regions of the brain beyond those traditionally explored that contribute to differences in the functional organization of left- and right-handed individuals.
dynDeepDRIM: a dynamic deep learning model to infer direct regulatory interactions using single cell time-course gene expression data
Authors: Xu Yu , Chen Jiaxing , Lyu Aiping , Cheung William K , Zhang Lu
Published: August 2021

Time-course single-cell RNA sequencing (scRNA-seq) data have been widely applied to reconstruct the cell-type-specific gene regulatory networks by exploring the dynamic changes of gene expression between transcription factors (TFs) and their target genes. The existing algorithms were commonly designed to analyze bulk gene expression data and could not deal with the dropouts and cell heterogeneity in scRNA-seq data. In this paper, we developed dynDeepDRIM that represents gene pair joint expression as images and considers the neighborhood context to eliminate the transitive interactions. dynDeepDRIM integrated the primary image, neighbor images with time-course into a four-dimensional tensor and trained a convolutional neural network to predict the direct regulatory interactions between TFs and genes. We evaluated the performance of dynDeepDRIM on five time-course gene expression datasets. dynDeepDRIM outperformed the state-of-the-art methods for predicting TF-gene direct interactions and gene functions. We also observed gene functions could be better performed if more neighbor images were involved.
Direct multiplex recombinase polymerase amplification for rapid detection of Staphylococcus aureus and Pseudomonas aeruginosa in food
Authors: Tran Diem Hong , Tran Hau Thi , Pham Trang Nguyen Minh , Phung Huong Thi Thu
Published: August 2021

Foodborne illness undermines human health by causing fever, stomachache and even lethality. Among foodborne bacterial pathogens, Staphylococcus aureus and Pseudomonas aeruginosa are of extraordinary significance which drive reasons of food and beverage poisoning in numerous cases. Today, PCR has been widely used to examine the presence of different foodborne pathogens. However, PCR requires specialized equipment and skillful personnel which limit its application in the field. Recently, there is an emerging of isothermal PCR methods in which the reactions occur at low and constant temperature, allowing their application in restricted-resource settings. In this work, multiplex Recombinase Polymerase Amplification (RPA) was used to simultaneously detect S. aureus and P. aeruginosa with high sensitivity and specificity. The limit detection of multiplex RPA was 10 and 30 fg/reaction of genomic DNAs of S. aureus and P. aeruginosa, respectively. Besides, the reaction time was reduced to only 25 minutes with a low incubation temperature of 39 °C. Markedly, multiplex RPA reactions succeeded to directly detect as low as 1 and 5 CFU/reaction of S. aureus and P. aeruginosa cells, respectively without the requirement of extracting DNA genome. Moreover, the multiplex RPA reliably detected the two foodborne bacteria in milk, fruit juice and bottled water samples. In general, the direct multiplex RPA described in this study is a rapid, simple, sensitive and efficient alternative tool that could be used to detect the presence of S. aureus and P. aeruginosa without the necessity of costly devices and high-trained staff.
Simple Model for Encoding Natural Images by Retinal Ganglion Cells with Nonlinear Spatial Integration
Authors: Liu Jian K. , Karamanlis Dimokratis , Gollisch Tim
Published: August 2021

A central goal in sensory neuroscience is to understand the neuronal signal processing involved in the encoding of natural stimuli. A critical step towards this goal is the development of successful computational encoding models. For ganglion cells in the vertebrate retina, the development of satisfactory models for responses to natural visual scenes is an ongoing challenge. Standard models typically apply linear integration of visual stimuli over space, yet many ganglion cells are known to show nonlinear spatial integration, in particular when stimulated with contrast-reversing gratings. We here study the influence of spatial nonlinearities in the encoding of natural images by ganglion cells, using multielectrode-array recordings from isolated salamander and mouse retinas. We assess how responses to natural images depend on first- and second-order statistics of spatial patterns inside the receptive field. This leads us to a simple extension of current standard ganglion cell models. We show that taking not only the weighted average of light intensity inside the receptive field into account but also its variance over space can partly account for nonlinear integration and substantially improve response predictions of responses to novel images. We find that response predictions for salamander ganglion cell classes with large receptive fields profit most from including spatial contrast information. Finally, we demonstrate how this model framework can be used to assess the spatial scale of nonlinear integration. Our results underscore that nonlinear spatial stimulus integration in the salamander retina translates to stimulation with natural images. Furthermore, the introduced model framework provides a simple, yet powerful extension of standard models and may serve as a benchmark for the development of more detailed models of the nonlinear structure of receptive fields.

Author Summary

For understanding how sensory systems operate in the natural environment, an important goal is to develop models that capture neuronal responses to natural stimuli. For retinal ganglion cells, which connect the eye to the brain, current standard models often fail to capture responses to natural visual scenes. This shortcoming is at least partly rooted in the fact that ganglion cells may combine visual signals over space in a nonlinear fashion. We here show that a simple model, which not only considers the average light intensity inside a cell’s receptive field but also the variance of light intensity over space, can partly account for these nonlinearities and thereby improve current standard models. This provides an easy-to-obtain benchmark for modeling ganglion cell responses to natural images.
Single-embryo phosphoproteomics reveals the importance of intrinsic disorder in cell cycle dynamics
Authors: Valverde Juan M , Dubra Geronimo , van den Toorn Henk , van Mierlo Guido , Vermeulen Michiel , Heck Albert J.R. , Knipscheer Puck , Krasinska Liliana , Fisher Daniel , Altelaar Maarten
Published: August 2021

Switch-like cyclin-dependent kinase (CDK)-1 activation is thought to underlie the abruptness of mitotic onset, but how CDKs can simultaneously phosphorylate many diverse substrates is unknown, and direct evidence for such phosphorylation dynamics in vivo is lacking. Here, we analysed protein phosphorylation states in single Xenopus embryos throughout synchronous cell cycles. Over a thousand phosphosites were dynamic in vivo, and assignment of cell cycle phases using egg extracts revealed hundreds of S-phase phosphorylations. Targeted phosphoproteomics in single embryos showed switch-like mitotic phosphorylation of diverse protein complexes. The majority of cell cycle-regulated phosphosites occurred in CDK consensus motifs, and 72% located to intrinsically disordered regions. Dynamically phosphorylated proteins, and documented substrates of cell cycle kinases, are significantly more disordered than phosphoproteins in general. Furthermore, 30-50% are components of membraneless organelles. Our results suggest that phosphorylation of intrinsically disordered proteins by cell cycle kinases, particularly CDKs, allows switch-like mitotic cellular reorganisation.
Re-polyadenylation occurs predominantly on maternal mRNA degradation intermediates during mammalian oocyte-to-embryo transition
Authors: Liu Yusheng , Zhang Yiwei , Nie Hu , Liu Zhonghua , Wang Jiaqiang , Lu Falong
Published: August 2021

The nascent mRNA transcribed in the nucleus is cleaved and polyadenylated before it is transported to the cytoplasm for translation1. Polyadenylation can also occur in the cytoplasm for post-transcriptional regulation, especially in neurons, oocytes and early embryos1,2. Recently, we revealed transcriptome-wide maternal mRNA cytoplasmic re-polyadenylation during the mammalian oocyte-to-embryo transition (OET)3-6. However, the mechanism of re-polyadenylation during mammalian OET, including the sites to be re-polyadenylated and the enzymes involved, is still poorly understood. Here, by analyzing the PAIso-seq1 and PAIso-seq2 poly(A) inclusive transcriptome data during OET in mice, rats, pigs, and humans, we reveal conserved re-polyadenylation of mRNA degradation intermediates. These re-polyadenylated mRNA degradation intermediates account for over half of the polyadenylated mRNA during OET in all four species. We find that mRNA degradation intermediates for re-polyadenylation are generated through Btg4-mediated deadenylation in both mouse and human. Interestingly, the poly(A) tails on the re-polyadenylated mRNA degradation intermediates are of different lengths and contain different levels of non-A residues compared to regular polyadenylation sites, suggesting specific regulation and function of these poly(A) tails in mammalian OET. Together, our findings reveal the maternal mRNA degradation intermediates as substrates for conserved cytoplasmic dominant re-polyadenylation during mammalian OET, and uncover the mechanism of production of these mRNA degradation intermediates. These findings provide new insights into mRNA post-transcriptional regulation, and a new direction for the study of mammalian OET.
Allosteric regulation of 3CL protease of SARS-CoV-2 and SARS-CoV observed in the crystal structure ensemble
Authors: Kidera Akinori , Moritsugu Kei , Ekimoto Toru , Ikeguchi Mitsunori
Published: August 2021

The 3C-like protease (3CLpro) of SARS-CoV-2 is a potential therapeutic target for COVID-19. Importantly, it has an abundance of structural information solved as a complex with various drug candidate compounds. Collecting these crystal structures (83 Protein Data Bank (PDB) entries) together with those of the highly homologous 3CLpro of SARS-CoV (101 PDB entries), we constructed the crystal structure ensemble of 3CLpro to analyze the dynamic regulation of its catalytic function. The structural dynamics of the 3CLpro dimer observed in the ensemble were characterized by the motions of four separate loops (the C-loop, E-loop, H-loop, and Linker) and the C-terminal domain III on the rigid core of the chymotrypsin fold. Among the four moving loops, the C-loop (also known as the oxyanion binding loop) causes the order (active)–disorder (collapsed) transition, which is regulated cooperatively by five hydrogen bonds made with the surrounding residues. The C-loop, E-loop, and Linker constitute the major ligand binding sites, which consist of a limited variety of binding residues including the substrate binding subsites. Ligand binding causes a ligand size dependent conformational change to the E-loop and Linker, which further stabilize the C-loop via the hydrogen bond between the C-loop and E-loop. The T285A mutation from SARS-CoV 3CLpro to SARS-CoV-2 3CLpro significantly closes the interface of the domain III dimer and allosterically stabilizes the active conformation of the C-loop via hydrogen bonds with Ser1 and Gly2; thus, SARS-CoV-2 3CLpro seems to have increased activity relative to that of SARS-CoV 3CLpro.
ZetaSuite, A Computational Method for Analyzing Multi-dimensional High-throughput Data, Reveals Genes with Opposite Roles in Cancer Dependency
Authors: Hao Yajing , Shao Changwei , Zhao Guofeng , Fu Xiang-Dong
Published: August 2021

The rapid advance of high-throughput technologies has enabled the generation of two-dimensional or even multi-dimensional high-throughput data, e.g., genome-wide siRNA screen (1st dimension) for multiple changes in gene expression (2nd dimension) in many different cell types or tissues or under different experimental conditions (3rd dimension). We show that the simple Z-based statistic and derivatives are no longer suitable for analyzing such data because of the accumulation of experimental noise and/or off-target effects. Here, we introduce ZetaSuite, a statistical package designed to score and rank hits from two-dimensional screens, construct regulatory networks based on response similarities, and eliminate off-targets. Applying this method to two large cancer dependency screen datasets, we identify not only genes critical for cell fitness, but also those required for constraining cell proliferation. Strikingly, most of those cancer constraining genes function in DNA replication/repair checkpoint, suggesting that cancer cells also need to protect their genomes for long-term survival.
Stochastic microbiome assembly depends on context
Authors: Jones Eric W. , Carlson Jean M. , Sivak David A. , Ludington William B.
Published: August 2021

Observational studies reveal substantial variability in microbiome composition across individuals. While some of this variability can be explained by external factors like environmental, dietary, and genetic differences between individuals, in this paper we show that for the model organism Drosophila melanogaster the process of microbiome assembly is inherently stochastic and contributes a baseline level of microbiome variability even among organisms that are identically reared, housed, and fed. In germ-free flies fed known combinations of bacterial species, we find that some species colonize more frequently than others even when fed at the same high concentration. We develop a new ecological technique that infers the presence of interactions between bacterial species based on their colonization odds in different contexts, requiring only presence/absence data from two-species experiments. We use a progressive sequence of probabilistic models, in which the colonization of each bacterial species is treated as an independent stochastic process, to reproduce the empirical distributions of colonization outcomes across experiments. We find that incorporating context-dependent interactions substantially improves the performance of the models. Stochastic, context-dependent microbiome assembly underlies clinical therapies like fecal microbiota transplantation and probiotic administration, and should inform the design of synthetic fecal transplants and dosing regimes.

Significance Statement

Individuals are constantly exposed to microbial organisms that may or may not colonize their gut microbiome, and newborn individuals assemble their microbiomes through a number of these acquisition events. Since microbiome composition has been shown to influence host physiology, a mechanistic understanding of community assembly has potentially therapeutic applications. In this paper we study microbiome acquisition in a highly-controlled setting using germ-free fruit flies inoculated with specific bacterial species at known abundances. Our approach revealed that acquisition events are stochastic, and the colonization odds of different species in different contexts encode ecological information about interactions. These findings have consequences for microbiome-based therapies like fecal microbiota transplantation that attempt to modify a person’s gut microbiome by deliberately introducing foreign microbes.