bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel continuum-based framework for translating behavioral health integration to primary care settings
Authors: Goldman Matthew L , Smali Ekaterina , Richkin Talia , Pincus Harold A , Chung Henry
Published: August 2020

Although evidence-based behavioral health integration models have been demonstrated to work well when implemented properly, primary care practices need practical guidance on the steps they can take to build behavioral health integration capacities. This is especially true for practice settings with fewer resources. This study is a pilot field test of a framework continuum composed of core components of behavioral health integration that can be used to translate the implementation of behavioral health into diverse clinical settings guided by a practice's priorities and available resources. This framework, in combination with technical assistance by the study team, was piloted in 11 small primary care sites (defined as ≤5 primary care providers) throughout New York State. Surveys were collected at baseline, 6 months, and 12 months. Informal check-in calls and site visits using qualitative semistructured individual and group interviews were conducted with 10 of the 11 sites. A mixed-methods approach was used to incorporate the survey data and qualitative thematic analysis. All practices advanced at least one level of behavioral health integration along various components of the framework. These advances included implementing depression screening, standardizing workflows for positive screens, integrating patient tracking tools for follow-up behavioral health visits, incorporating warm hand-offs to on-site or off-site behavioral health providers, and formalized external referrals using collaborative agreements. Practices reported they had overall positive experiences using the framework and offered feedback for how to improve future iterations. The framework continuum, in combination with technical assistance, was shown to be useful for primary care practices to advance integrated behavioral health care based on their priorities and resource availability. The results combined with feedback from the practices have yielded a revised “Framework 2.0” that includes a new organization as well as the addition of a “Sustainability” domain.
Defining and measuring core processes and structures in integrated behavioral health in primary care: a cross-model framework
Authors: Stephens Kari A , van Eeghen Constance , Mollis Brenda , Au Margaret , Brennhofer Stephanie A , Martin Matthew , Clifton Jessica , Witwer Elizabeth , Hansen Audrey , Monkman Jeyn , Buchanan Gretchen , Kessler Rodger
Published: August 2020

A movement towards integrated behavioral health (IBH) in primary care continues to grow, among an accumulating evidence base for its effectiveness for improving care. However, healthcare organizations struggle to navigate where to target their limited resources for improving integration. We evaluated a cross-model framework of IBH core processes and structures. We used a mixed-methods approach for evaluation of the framework, which included (a) an evaluation survey of national experts and stakeholders, (b) crosswalks with common IBH measures, and (c) a real-world usability test. Five core IBH principles, mapping to 25 processes, and nine clinic structures were defined. Survey responses from 29 IBH domain and policy experts and stakeholders resulted in uniformly high ratings of importance and variable levels of feasibility for measurement, particularly with respect to electronic health record (EHR) systems. A real-world usability test resulted in good uptake and use of the framework across a state-wide effort. An IBH Cross-Model Framework of core principles, processes, and structures generated good acceptability and showed good real-world utility in a state-wide effort to improve IBH across disparate levels of integration in diverse primary care settings. Findings identify feasible areas of measurement, particularly with EHR systems. Next steps include testing the relationship between the individual framework components and patient outcomes to help guide clinics towards prioritizing efforts focused on improving integration.
The Emergence and Spread of Practice-Based Medical Education Research Networks
Authors: Schwartz Alan , King Beth , Mink Richard , Hicks Patricia J.
Published: August 2020

Educational research networks leverage shared goals and common infrastructure to overcome traditional barriers to medical education research, including small sample sizes, lack of generalizability, need for expertise in statistical analysis, and limitations on data sharing. The diversity of extant network models today is exciting and provides a set of common options and challenges that newly emerging networks can expect. These include decisions about network focus, organization of data, sampling strategies, funding, and governance. Common challenges include managing authorship, human subjects protection rules, data use agreements, and statistical disclosure control. Medical education research networks both advance the field and develop the researchers who participate in them. The authors repeat the call that they and others have made for the development of networks to promulgate best practices and coordinate multinetwork (multinational, multispecialty, and cross-curriculum) studies.
Congenital Unilesional Cutaneous Langerhans Cell Histiocytosis: A Case Report
Authors: Ungari Marco , Caresana Gioachino , Tanzi Giulia , Drera Bruno , Frittoli Marta Claudia , Gusolfino Marino Daniel , Ferrero Giuseppina , Varotti Elena , Manotti Laura , Trombatore Monica , Bertoni Ramona
Published: August 2020

Langerhans cell histiocytosis (LCH) is a clonal proliferation of bone-marrow-derived cells, which normally reside as epidermal and mucosal dendritic cells involved in antigen presentation. It is a rare disease more common in children than adults, that is believed to be neoplastic in most cases. The diagnosis is based on clinical and radiological findings in combination with histopathologic, immunophenotypic, or ultrastructural analyses. LCH have a broad spectrum of clinical manifestations, ranging from benign cutaneous lesions to malignant multisystem disease. Based on the extent of involvement at diagnosis, LCH can be divided in single-system LCH when only one organ or system is involved, usually with multiple lesions, and multisystem LCH, when 2 or more organs or systems are involved at diagnosis. One variant of LCH is characterized by congenital isolated cutaneous involvement. It typically manifests at birth or in the postnatal period with a widespread eruption of red-to-brown papulo-nodules or, more uncommonly, a solitary lesion. The overall prognosis for single lesion skin limited LCH is excellent and most lesions spontaneously resolve within 4–18 weeks. Systemic involvement is rare. Skin findings cannot predict systemic disease and obtaining an oncology consultation is recommended for further evaluation. Herein, we present an additional case in a full-term, well-appearing, female infant with an isolated, asymptomatic, ulcerated, papule of the left arm, that was noted at birth.
The Use of Dermal Substitutes for Donor Site Closure After Radial Forearm Free Flap Harvesting
Authors: Abbate Vincenzo , Iaconetta Giorgio , Sani Lorenzo , Bonavolontà Paola , Di Lauro Alessandro E. , Masone Stefania , Califano Luigi , Orabona Giovanni D.A.
Published: August 2020

Objective:

The aim of our study was to analyze the aesthetic and functional outcome in the radial forearm free flap donor site using a simple split thickness skin grafting (STSG) closure compared with the use of dermal scaffold supporting the STSG closure.

Methods:

The study analyzed 18 patients, divided in 2 groups based on the donor site closure modality. In STSG group, a simple STSG was used to cover the defect. In the DS + STSG group, the defect was covered by the use of dermal substitute (MatriDerm) supporting the STSG. Groups were compared on the following outcome variable: scar status; hand function; circumferences at most proximal and most distal point of the graft. All patients were followed up 1, 6, and 12 months post-operative.

Results:

Nine patients from STSG group showed a difference in circumference between the operated and contralateral limbs respectively of 2.9 mm proximal and 1.2 mm distal; in the 9 patients of DS + STGS group the difference was respectively of 1.2 mm proximal and 1.3 mm distal. Welch unequal variances t-test demonstrated statistical significance of the values with P < 0.004 (P < 0.5). The average VSS was 1.82 ± 0.2 for STSG group and 1.75 ± 0.2 for DS + STGS group. The DASH score was 21.8% in STSG group and 19.4% in DS + STGS group.

Conclusion:

Our study shows that patients treated with Matriderm + STSG obtained a better result both in esthetic and functional outcomes.
Endoscopic Lateral Osteotomy in Rhinoplasty
Authors: Altunay Zeynep Onerci , Onerci Metin
Published: August 2020

Objectives:

The purpose of this study was to investigate the advantages of endoscopic lateral osteotomy, to evaluate the effects of the periosteal elevation on ecchymosis and to search the reasons for the ecchymosis and the intranasal mucosal tears.

Methods:

On a randomly chosen side a subperiosteal tunnel was elevated, on the other side a subperiosteal tunnel was not elevated. Bilateral lateral osteotomies were performed. Internal nasal packing was not used. The post-operative care was similar for all patients. The patients were evaluated on the third post-operative day. The intranasal mucosal tears, the lateral osteotomy cut on the periosteal elevation side were examined using endoscopes. The degree of ecchymosis was determined by 2 other surgeons, who were unaware of the elevated side, using the grading system adapted from Hoffman et al.

Results:

The intranasal mucosal injury was seen in 16 of non-elevated side whereas it was 14 on the periosteal elevated side. Endoscopy showed the perforating arteries and elevation of the periosteum caused rupture and oozing from these arteries which might be a cause for ecchymosis. Ecchymosis was more severe on the side with subperiosteal tunnel in 6 patients; whereas only in 2 patients it was more severe on the side with no subperiosteal tunnel elevation while in 12 patients the degree of ecchymosis was the same on both sides.

Conclusion:

Endoscopy gives a great opportunity to visualize the lateral osteotomy site. Besides the lateral osteotomy cut, the arteries and the intranasal mucosal injury can be visualized. Periost elevation increases the severity of ecchymosis due to the rupture of the perforating arteries, not due to the trauma of the angular artery. Intramucosal tears do not increase the severity of the ecchymosis.
Orthognatic Quality of Life: What Are We Measuring?
Authors: Vidakovic Renata , Zigante Martina , Perkovic Vjera , Zibar Belasic Tihana , Uhac Mia , Spalj Stjepan
Published: August 2020

Objective:

To assess properties of Orthognathic Quality of Life Questionnaire in Croatian cultural context by analyzing: how dentofacial deformity influences quality of life (QoL), what aspects of QoL are patients’ primary motives to undergo orthognathic surgery, what changes after surgery and how personality traits influence QoL.

Materials and Methods:

A total of 472 subjects (65% females) aged 12 to 45 years (median 20) were included. Orthognathic Quality of Life Questionnaire, Oral Health Impact Profile, Psychosocial Impact of Dental Aesthetics Questionnaire, Orofacial Aesthetics Scale, Self-Esteem Scale, Multidimensional Perfectionism Scale, and Big Five Inventory were used. The subjects’ dentofacial deformity and malocclusion severity was assessed by Index of Complexity, Outcome and Need, and Index of Orthodontic Treatment Need.

Results:

Social aspect is mostly influenced by dentofacial deformity (P < 0.05). Impaired oral function was the primary motive to undergo orthognathic surgery (P < 0.001). Social aspect and aesthetic concern mostly decreased after the surgery (P < 0.001). Self-esteem was the strongest predictor of the orthognathic QoL, the increase of self-esteem decreases the QoL impairment. Neuroticism and extraversion were in the background of problems in social interactions and facial aesthetic concerns, while perfectionism affected social contacts (r = 0.284–0.410; P < 0.001). Only awareness of deformity did not correlate to any of the other instruments.

Conclusion:

Impaired oral function seems to be the most powerful motive for orthognathic surgery, but social aspects and facial aesthetic concern are more accurate indicators of conditions and changes. Self-esteem is the strongest personality trait influencing orthognathic QoL.
Surgical Planning for Cleft Lip and/or Palate-Induced Moderate-to-Severe Midfacial Hypoplasia
Authors: Zhai Junya , Lv Yang , Zheng Yilue , Wang Binqing , Tong Haizhou , Yin Ningbei , Song Tao
Published: August 2020

Background:

Distraction osteogenesis and conventional bimaxillary orthognathic surgery have been performed for the treatment of midfacial hypoplasia for a long time. However, the effect of these 2 techniques on the maxilla, mandible, and whole-facial profile is significantly different. In this study, we aimed to measure the pre- to post-treatment changes in maxillary prominence, mandible size, and facial length and compare them between these 2 techniques to inform selection of the best technique.

Methods:

This single-center, retrospective study included 35 patients with a cleft lip and/or palate-induced midfacial hypoplasia; 25 were treated using rigid external distraction osteogenesis and 10 using bimaxillary orthognathic surgery. Three-dimensional measures of changes in facial structure were obtained from reconstructed computed tomography images and used to compare the effects of the 2 techniques.

Results:

Satisfactory appearance and occlusion were achieved in all patients. Three-dimensional reconstruction of the craniofacial skeleton revealed significant maxillary advancement (P < 0.001), mandibular (clockwise) rotation (P < 0.001), and increased facial length (P < 0.001) after rigid external distraction osteogenesis and obvious shortening of the mandibular body (P < 0.001) after bimaxillary orthognathic surgery.

Conclusion:

Distraction osteogenesis can be selected as the first choice of treatment for cleft lip and/or palate-induced midfacial hypoplasia. A mandibular setback procedure can be performed as a second-stage surgery when severe temporomandibular joint complications develop with distraction osteogenesis. Bimaxillary orthognathic surgery results in an obvious shortening of the mandibular body, which is not a natural change in facial morphology.

Level of Evidence:

Therapeutic III
Rules governing genetic exchanges among viral types from different Enterovirus A clusters
Authors: Wang Min , Zhu Liuyao , Fan Jun , Yan Jingjing , Dun Ying , Yu Rui , Liu Lizhen , Zhang Shuye
Published: August 2020

The species Enterovirus A (EV-A) consists of two conventional clusters and one unconventional cluster. At present, sequence analysis shows no evidence of recombination between conventional and unconventional EV-A types. However, the factors underlying this genetic barrier are unclear. Here, we systematically dissected the genome components linked to these peculiar phenomena, using the viral reverse genetic tools. We reported that viral capsids of the unconventional EV-A types expressed poorly in human cells. The trans-encapsidation outputs across conventional and unconventional EV-A types were also with low efficiency. However, replicons of conventional types bearing exchanged 5′-untranslated region (UTR) or non-structural regions from the unconventional types were replication-competent. Furthermore, we created a viable recombinant EVA71 (conventional type) with its P3 region replaced by that from EVA89 (unconventional type). Thus, our data for the first time reveal the potential for fertile genetic exchanges between conventional and unconventional EV-A types. It also discloses that the mysterious recombination barriers may lie in uncoordinated capsid expression and particle assembly by different EV-A clusters.
Clinical and intestinal histopathological findings in SARS-CoV-2/COVID-19 patients with hematochezia
Authors: Cho Margaret , Liu Weiguo , Balzora Sophie , Suarez Yvelisse , Hoskoppal Deepthi , Theise Neil , Cao Wenqing , Sarkar Suparna A.
Published: August 2020

Gastrointestinal (GI) symptoms of SARS-CoV2/COVID-19 in the form of anorexia, nausea, vomiting, abdominal pain and diarrhea are usually preceeded by respiratory manifestations and are associated with a poor prognosis. Hematochezia is an uncommon clinical presentation of COVID-19 disease and we hypothesize that older patients with significant comorbidites (obesity and cardiovascular) and prolonged hospitalization are suspectible to ischemic injury to the bowel.

We reviewed the clinical course, key laboratory data including acute phase reactants, drug/medication history in two elderly male patients admitted for COVID-19 respiratory failure. Both patients had a complicated clinical course and suffered from hematochezia and acute blood loss anemia requiring blood transfusion around day 40 of their hospitalization. Colonoscopic impressions were correlated with the histopathological findings in the colonic biopies and changes compatible with ischemia to nonspecific acute inflammation, edema and increased eosinophils in the lamina propria were noted. Both patients were on anticoagulants, multiple antibiotics and antifungal agents due to respiratory infections at the time of lower GI bleeding. Hematochezia resolved spontaneously with supportive care. Both patients eventually recovered and were discharged.

Elderly patients with significant comorbid conditions are uniquely at risk for ischemic injury to the bowel. Hypoxic conditions due to COVID-19 pneumonia and respiratory failure, compounded by preexisting cardiovascular complications, and/or cytokine storm orchestrated by the viral infection leading to alteration in coagulation profile and/or drug/medication injury can be difficult to distinguish in these critically ill patients. Presentation of hematochezia may further increase the mortality and morbidity of COVID-19 patients, and prompt consultation and management by gastroenterology is therefore warranted.
Safety and cardiovascular effects of multiple-dose administration of aripiprazole and olanzapine in a randomised clinical trial
Authors: Koller Dora , Almenara Susana , Mejía Gina , Saiz-Rodríguez Miriam , Zubiaur Pablo , Román Manuel , Ochoa Dolores , Wojnicz Aneta , Martín Samuel , Romero-Palacián Daniel , Navares-Gómez Marcos , Abad-Santos Francisco
Published: August 2020

Objective

To assess adverse events and safety of aripiprazole and olanzapine treatment.

Methods

Twenty-four healthy volunteers receiving 5 daily oral doses of 10 mg aripiprazole and 5 mg olanzapine in a crossover clinical trial were genotyped for 46 polymorphisms in 14 genes by qPCR. Drug plasma concentrations were measured by HPLC-MS/MS. Blood pressure and 12-lead ECG were measured in supine position. Adverse events were also recorded.

Results

Aripiprazole decreased diastolic blood pressure on the first day and decreased QTc on the third and fifth day. Olanzapine had a systolic and diastolic blood pressure, heart rate and QTc lowering effect on the first day. Polymorphisms in ADRA2A, COMT, DRD3 and HTR2A genes were significantly associated to these changes. The most frequent adverse drug reactions to aripiprazole were somnolence, headache, insomnia, dizziness, restlessness, palpitations, akathisia and nausea while were somnolence, dizziness, asthenia, constipation, dry mouth, headache and nausea to olanzapine. Additionally, HTR2A, HTR2C, DRD2, DRD3, OPRM1, UGT1A1 and CYP1A2 polymorphisms had a role in the development of adverse drug reactions.

Conclusions

Olanzapine induced more cardiovascular changes; however, more adverse drug reactions were registered to aripiprazole. In addition, some polymorphisms may explain the difference in the incidence of these effects among subjects.
How to handle the deceased body of COVID-19: an insight from Indonesian muslim burial handlers’ knowledge, perception, and practice
Authors: Purnama Tri Bayu , Khodijah Siti , Sadri Idris
Published: August 2020

ABSTRAK

Introduction

Handling the remained body affected by COVID-19 in Indonesia is still an issue as it is done by community.

Aim

This study aims to explore the handler’s knowledge, perception, and practice in handling the remains.

Method

This study elaborates qualitative design in exploring the handler’s knowledge, perception, and practice in handling the remains dealing with universal precaution during the handling of the deceased body of COVID-19. The data is obtained through in-depth interview with guides.

Result

The majority of participants were acknowledged that the universal precaution is a precautionary conduct which remains general and nontechnical. Technicality on the universal precaution such as personal protective equipment and safety standards for infectious substance on the dead body are still incomprehensive. The perception of each handler of the body is still obscure. It was showed by cautious/apprehensive sense predominated the handlers in handling the dead body.

Conclusion

Improving the knowledge and strengthening the network of the handlers among the community play an important role in interrupting the chain of transmission of COVID-19 in the community.
Aerosol Generation from Different Wind Instruments
Authors: He Ruichen , Gao Linyue , Trifonov Maximilian , Hong Jiarong
Published: August 2020

The potential airborne transmission of COVID-19 has raised significant concerns regarding the safety of musical activities involving wind instruments. However, currently, there is a lack of systematic study and quantitative information of the aerosol generation during these instruments, which is crucial for offering risk assessment and the corresponding mitigation strategies for the reopening of these activities. Collaborating with 15 musicians from the Minnesota Orchestra, we conduct a systematic study of the aerosol generation from a large variety of wind instruments under different music dynamic levels and articulation patterns. We find that the aerosol concentration from different brass and woodwinds exhibits two orders of magnitude variation. Accordingly, we categorize the instruments into low (tuba), intermediate (bassoon, piccolo, flute, bass clarinet, French horn, and clarinet) and high risk (trumpet, bass trombone, and oboe) levels based on a comparison of their aerosol generation with those from normal breathing and speaking. In addition, we observe that the aerosol generation can be affected by the changing dynamic level, articulation pattern, the normal respiratory behaviors of individuals, and even the usage of some special techniques during the instrument play. However, such effects vary substantially for different types of instrument, depending on specific breathing techniques as well as the tube structure and inlet design of the instrument. Overall, our findings can bring insights into the risk assessment of airborne decrease transmission and the corresponding mitigation strategies for various musical activities involving wind instrument plays, including orchestras, community and worship bands, music classes, etc.
Predicted Cellular Immunity Population Coverage Gaps for SARS-CoV-2 Subunit Vaccines and their Augmentation by Compact Peptide Sets
Authors: Liu Ge , Carter Brandon , Gifford David K.
Published: August 2020

Subunit vaccines induce immunity to a pathogen by presenting a component of the pathogen and thus inherently limit the representation of pathogen peptides for cellular immunity based memory. We find that SARS-CoV-2 subunit peptides may not be robustly displayed by the Major Histocompatibility Complex (MHC) molecules in certain individuals. We introduce an augmentation strategy for subunit vaccines that adds a small number of SARS-CoV-2 peptides to a vaccine to improve the population coverage of pathogen peptide display. Our population coverage estimates integrate clinical data on peptide immunogenicity in convalescent COVID-19 patients and machine learning predictions. We evaluate the population coverage of 9 different subunits of SARS-CoV-2, including 5 functional domains and 4 full proteins, and augment each of them to fill a predicted coverage gap.
A Long-Lasting Sanitizing Skin Protectant based on CAGE, a Choline and Geranic Acid Eutectic
Authors: Shevachman Marina , Mandal Abhirup , Mitragotri Samir , Joshi Nitin
Published: August 2020

The recent outbreak and rapid spread of coronavirus disease 2019 (COVID-19) is a global pandemic and a massive public health crisis. COVID-19 has also had a severe impact on the quality of life and mental health. While different health authorities such as WHO and CDC are encouraging adoption of strategies including hand washing and use of facemasks to reduce the spread of the pathogens and infections, adoption of these approaches requires substantial commitment. Current hand sanitizers based on ethanol provide immediate protection, however, the protection rendered by such sanitizers is very short-lived due to their rapid evaporation. A long-lasting sanitizing skin protectant that can effectively inactivate SARS-CoV-2 and provide persistent efficacy over several hours will provide people the freedom to carry on with their activities without constant concerns about the cleanliness of their hands. Herein, we describe a novel skin sanitizer, IonLAST™, based on an ionic liquid/deep eutectic solvent, formed by GRAS materials, choline and geranic acid (CAGE, CG-101), that provides protection for at least 4h after a single application. IonLAST™ was formulated as a gel that facilitates easy application on the skin. Tolerance of CG-101 was substantiated through a study in human volunteers. In vitro studies confirmed that IonLAST™ effectively inactivates a human coronavirus hCoV229E. A second human clinical study established that a single application of IonLAST™ imparts protection against microbes that lasts up to several hours.
High-throughput siRNA screening reveals functional interactions and redundancies of human processive exoribonucleases
Authors: Hojka-Osinska Anna , Chlebowski Aleksander , Owczarek Ewelina P. , Afek Kamila , Kłosowska Kamila , Szczesny Roman J. , Dziembowski Andrzej
Published: August 2020

Processive exoribonucleases, the executors of RNA decay, participate in multiple physical and functional interactions. Unlike physical ones, functional relationships have not been investigated in human cells. Here we have screened cells deficient in DIS3, XRN2, EXOSC10, DIS3L, and DIS3L2 with a custom siRNA library and determined their functional interactions with diverse pathways of RNA metabolism. We uncover a complex network of positive interactions that buffer alterations in RNA degradation. We reveal important reciprocal actions between RNA decay and transcription and explore alleviating interactions between RNA splicing and DIS3 mediated degradation. We also use a large scale library of genes associated with RNA metabolism to determine genetic interactions of nuclear DIS3 and cytoplasmic DIS3L, revealing their unique functions in RNA degradation and uncovering cooperation between the cytoplasmic degradation and nuclear processing of RNA. Finally, genome-wide siRNA screening of DIS3 reveals processes such as microtubule organization and regulation of telomerase activity that are also functionally associated with nuclear exosome-mediated RNA degradation.
Functional drug susceptibility testing based on biophysical measurements predicts patient outcome in glioblastoma patient-derived neurosphere models
Authors: Stockslager Max A. , Malinowski Seth , Touat Mehdi , Yoon Jennifer C. , Geduldig Jack , Mirza Mahnoor , Kim Annette S. , Wen Patrick Y. , Chow Kin-Hoe , Ligon Keith L. , Manalis Scott R.
Published: August 2020

Functional precision medicine aims to match each cancer patient to the most effective treatment by performingex vivodrug susceptibility testing on the patient’s tumor cells. Despite promising feasibility studies, functional drug susceptibility testing is not yet used in clinical oncology practice to make treatment decisions. Often, functional testing approaches have measuredex vivodrug response using metabolic assays such as CellTiter-Glo, which measures ATP as a proxy for numbers of viable cells. As a complement to these existing metabolic drug response assays, we evaluated whether biophysical assays based on cell mass (the suspended microchannel resonator mass assay) or size as measured by microscopy (the IncuCyte assay) could be used as a readout forex vivodrug response. Using these biophysical assays, we profiled theex vivotemozolomide responses of a retrospective cohort of 70 glioblastoma patient-derived neurosphere models with matched clinical outcomes and found that both biophysical assays predicted patients’ overall survival with similar power to MGMT promoter methylation, the clinical gold standard biomarker for predicting temozolomide response in glioblastoma. These findings suggest that biophysical assays could be a useful complement to existing metabolic approaches as “universal biomarkers” to measure sensitivity or resistance to anti-cancer drugs with a wide variety of cytostatic or cytotoxic mechanisms.

One-sentence summary

By using biophysical assays to performex vivodrug susceptibility testing on 70 glioblastoma patient-derived neurosphere models, we find that functional testing predicts the duration that patients survive when treated with temozolomide, the standard of care chemotherapy.
FertilityOnline, a straight pipeline for functional gene annotation and disease mutation discovery, identifies novel infertility causative mutations inSYCE1andSTAG3
Authors: Gao Jianing , Zhang Huan , Jiang Xiaohua , Ali Asim , Zhao Daren , Bao Jianqiang , Jiang Long , Iqbal Furhan , Shi Qinghua , Zhang Yuanwei
Published: August 2020

Exploring the genetic basis of human infertility is currently under intensive investigation. However, only a handful of genes are validated in animal models as disease-causing genes in infertile men. Thus, to better understand the genetic basis of spermatogenesis in human and to bridge the knowledge gap between human and other animal species, we have constructed FertilityOnline database, which is a resource that integrates the functional genes reported in literature related to spermatogenesis into an existing spermatogenic database, SpermatogenesisOnline 1.0. Additional features like functional annotation and statistical analysis of genetic variants of human genes, are also incorporated into FertilityOnline. By searching this database, users can focus on the top candidate genes associated with infertility and can perform enrichment analysis to instantly refine the number of candidates in a user-friendly web interface. Clinical validation of this database is established by the identification of novel causative mutations inSYCE1andSTAG3in azoospermia men. In conclusion, FertilityOnline is not only an integrated resource for analysis of spermatogenic genes, but also a useful tool that facilitates to study underlying genetic basis of male infertility.

Availability

FertilityOnline can be freely accessed athttp://mcg.ustc.edu.cn/bsc/spermgenes2.0/index.html.
Identification of pituitary thyrotrope signature genes and regulatory elements
Authors: Daly Alexandre Z. , Dudley Lindsey A. , Peel Michael T. , Liebhaber Stephen A. , Parker Stephen C. J. , Camper Sally A.
Published: August 2020

Pituitary thyrotropes are specialized cells that produce thyroid stimulating hormone (TSH), a critical factor for growth and maintenance of metabolism. The transcription factors POU1F1 and GATA2 have been implicated in thyrotrope fate and transcriptional regulation of the beta subunit of TSH,Tshb, but no transcriptomic or epigenomic analyses of these cells has been undertaken. The goal of this work was to discover key transcriptional regulatory elements that drive thyrotrope fate. We identified the transcription factors and epigenomic changes in chromatin that are associated with differentiation of POU1F1-expressing progenitors into thyrotropes, a process modeled by two cell lines: one that represents an early, undifferentiatedPou1f1lineage progenitor (GHF-T1) and one that is a committed thyrotrope that produces TSH (TαT1). We generated and compared RNA-seq, ATAC-seq, histone modification (including H3K27Ac, H3K4Me1, and H3K27Me3), and transcription factor (POU1F1) binding in these two cell lines to identify regulatory elements and candidate transcriptional regulators. We identified POU1F1 binding sites that were unique to each cell line. POU1F1 binding sites are commonly associated with bZIP transcription factor consensus binding sites in GHF-T1 cells and Helix-Turn-Helix (HTH) or basic Helix-Loop-Helix (bHLH) factors in TαT1 cells, suggesting that these classes of transcription factors may recruit or cooperate with POU1F1 binding to unique sites. We validated enhancer function of novel elements we mapped nearCga, Pitx1, Gata2,andTshbby transfection in TαT1 cells. Finally, we confirmed that an enhancer element nearTshbcan drive expression in thyrotropes of transgenic mice, and we demonstrate that GATA2 enhancesTshbexpression through this element. These results extend the ENCODE multi-omic profiling approach to an organ that is critical for growth and metabolism, which should be valuable for understanding pituitary development and disease pathogenesis.
Evaluating Methods for Differential Gene Expression And Alternative Splicing Using Internal Synthetic Controls
Authors: Mehrotra Sudeep , Bronstein Revital , Navarro-Gomez Daniel , Segrè Ayellet V. , Pierce Eric A.
Published: August 2020

High-throughput transcriptome sequencing has become a powerful tool in the study of human diseases. Identification of causal mechanisms may entail analysis of differential gene expression (DGE), differential transcript/isoform expression (DTE) and identification, classification and quantification of alternative splicing (AS) and/or detection of novel AS events. For such a global transcriptome profiling execution of multi-level data analysis methodologies is required. Each level presents its own unique challenges and the questions about their performance remains. In this work we present results from systematic and consistent assessing and comparing a number of widely used methods for detecting DGE, DTE and AS using internal control “spike-in” sequences (Sequins) in RNA-seq data. We demonstrated that inclusion of internal controls in RNA-seq experiments allows accurate determination of lower bounds detection levels, and better assessment of DGE, DTE and AS accuracy and sensitivity. Tools for RNA-seq read alignment and detection of DGE performed reasonably. More efforts are needed to improve specificity and sensitivity of DTE and AS detection. Low expression of isoforms accompanied with sequencing depth does impact sensitivity and specificity of DTE and AS tools.
Reprogramming of stromal fibroblasts by chemotherapy-induced secretion of IFNβ1 drives re-growth of breast cancer cells after treatment
Authors: Maia Ana , Gu Zuguang , Koch André , Will Rainer , Schlesner Matthias , Wiemann Stefan
Published: August 2020

Chemotherapy is still the standard of care for a large number of aggressive tumours including breast cancer. In breast cancer, chemotherapeutic regimens are administered in intervaled cycles of the maximum tolerated dose, allowing cancer cells to re-grow or adapt during the resting periods between cycles. However, how stromal fibroblasts impact the fate of cancer cells after chemotherapy treatment remains poorly understood. We show that cancer cells utilize paracrine signalling with stromal fibroblasts to drive their recovery after treatment withdrawal. Secretion of IFNβ1 by cancer cells after treatment with high doses of chemotherapy instigates the acquisition of an anti-viral state in stromal fibroblasts associated with the expression of several interferon stimulated genes (ISGs), including numerous pro-inflammatory cytokines. This crosstalk is an important driver of the expansion of breast cancer cells after chemotherapy and blocking of IFNβ1 in tumour cells abrogated their increased recovery potential. Analysis of human breast carcinomas supports the proposed role of IFNβ1 since its expression is inversely correlated with recurrence free survival (RFS). Moreover, expression of the interferon signature identified in stromal fibroblasts is equally associated with higher recurrence rates and a worse outcome in breast cancer patients. Our study unravels a novel paracrine communication between cancer cells and fibroblasts that ultimately results in the escape of malignant cells to treatment. Targeting of this axis could potentially improve the outcome of breast cancer patients to chemotherapy treatment.
Explaining decisions of Graph Convolutional Neural Networks: patient-specific molecular subnetworks responsible for metastasis prediction in breast cancer
Authors: Chereda Hryhorii , Bleckmann Annalen , Menck Kerstin , Perera-Bel Júlia , Stegmaier Philip , Auer Florian , Kramer Frank , Leha Andreas , Beißbarth Tim
Published: August 2020

Motivation

Contemporary deep learning approaches show cutting-edge performance in a variety of complex prediction tasks. Nonetheless, the application of deep learning in healthcare remains limited since deep learning methods are often considered as non-interpretable black-box models. Layer-wise Relevance Propagation (LRP) is a technique to explain decisions of deep learning methods. It is widely used to interpret Convolutional Neural Networks (CNNs) applied on image data. Recently, CNNs started to extend towards non-euclidean domains like graphs. Molecular networks are commonly represented as graphs detailing interactions between molecules. Gene expression data can be assigned to the vertices of these graphs. In other words, gene expression data can be structured by utilizing molecular network information as prior knowledge. Graph-CNNs can be applied to structured gene expression data, for example, to predict metastatic events in breast cancer. Therefore, there is a need for explanations showing which part of a molecular network is relevant for predicting an event, e.g. distant metastasis in cancer, for each individual patient.

Results

We extended the procedure of LRP to make it available for Graph-CNN and tested its applicability on a large breast cancer dataset. We present Graph Layer-wise Relevance Propagation (GLRP) as a new method to explain the decisions made by Graph-CNNs. We demonstrate a sanity check of the developed GLRP on a hand-written digits dataset, and then applied the method on gene expression data. We show that GLRP provides patient-specific molecular subnetworks that largely agree with clinical knowledge and identify common as well as novel, and potentially druggable, drivers of tumor progression. As a result this method could be potentially highly useful on interpreting classification results on the individual patient level, as for example in precision medicine approaches or a molecular tumor board.

Availability

https://gitlab.gwdg.de/UKEBpublic/graph-lrphttps://frankkramer-lab.github.io/MetaRelSubNetVis/

Contact

tim.beissbarth@bioinf.med.uni-goettingen.de
Kinetics of Plasma cfDNA Predicts Clinical Response in Non-Small Cell Lung Cancer Patients
Authors: Zhou Xiaorong , Li Chenchen , Zhang Zhao , Li Daniel Y. , Du Jinwei , Li Ronglei , Ho Effie , Zhang Aiguo , Okunieff Paul , Lu Jianwei , Sha Michael Y.
Published: August 2020

Background

Tyrosine Kinases Inhibitors (TKIs), VEGF/VEGF receptor inhibitors (VEGFIs, bevacizumab) and immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced cancer including non-small-cell lung cancer (NSCLC). Cell-free DNA (cfDNA) has been adapted as a convenient liquid biopsy that reflects characteristics of the status of both the primary and metastatic tumors, assisting in personalized medicine. This study aims to evaluate the utility of cfDNA as a prognostic biomarker and efficacy predictor of chemotherapy with or without these precision therapies in NSCLC patients.

Methods

Peripheral cfDNA levels were quantified in 154 patients with NSCLC before (baseline) and after (post-chemotherapy) the first target cycle of chemotherapy. These patients were divided into four subgroups receiving chemotherapy only, chemotherapy plus TKIs, chemotherapy plus VEGFIs, and chemotherapy plus immune checkpoint inhibitors (ICIs), respectively. The correlations of cfDNA with tumor burden, clinical characteristics, progression-free survival (PFS), objective response ratio (ORR), and therapy regimens were analyzed.

Results

Baseline cfDNA, but not post-chemotherapy, positively correlates with tumor burden. cfDNA Ratio (post-chemotherapy/baseline) well distinguished responsive individuals (CR/PR) from non-responsive patients (PD/SD). Additionally, cfDNA Ratio was found to be negatively correlated with PFS in lung adenocarcinoma (LUAD), but not in lung squamous-cell carcinoma (LUSC). LUAD patients with low cfDNA Ratio benefit significantly including prolonged PFS and improved ORR, compared with those with high cfDNA Ratio. When stratified by therapy regimen, the predictive value of cfDNA Ratio is significant in patients with chemotherapy plus VEGFIs.

Conclusion

The kinetics of plasma cfDNA during the chemotherapy may function as a prognostic biomarker and efficacy predictor for NSCLC patients.
Occurrence of Drosophilids in the Pernambuco’s coastal region (years 2000-2001) and the Frequency of chromosomal inversions found inDrosophila malerkotliana
Authors: Félix Pierre Teodósio , dos Santos José Ferreira
Published: August 2020

Drosophilids were collected in thecampusof UFPE (Recife), Rio Doce (Olinda), Vila Velha (Itamaracá), Parque de dois Irmãos (Recife) and Charles Darwin Ecological Refuge (Igarassu), in the years 2000 and 2001, seeking to establish the frequency of occurrence of the various species of the genus Drosophila. In these collections,D. malerkotlianaoccurred in an average frequency of 64%, followed byD. melanogaster, with an average frequency of 23%. The frequency ofD. malerkotlianawas higher than that ofD. melanogasterin localities with high and medium degree of urbanization. Despite the great distance from the distribution center of the species (Africa),D. malerkotlianapresented high polymorphism of chromosomal inversions. In the locality of Rio Doce, inversions In(IIL)24B-39A and In(IIL)21-25, occurred with frequencies of 18.5% and 100%, respectively, while inversion In(IIIR)84-88B occurred with a frequency of 100%. In the population ofcampusUFPE (Recife), also with high urbanization, two inversions were found, In(IIIR)93C-94A and In(IIIL)64A-72A with frequencies of 37.1 and 60%, respectively. In the population of The Parque de Dois Irmãos (Recife), with medium urbanization, four inversions were visualized: In(IIIL)70C-73B (66%); In(IIIR)93C-94A (52%); In(IIL)24B-39A (33%); and In(IIR)50B-51A (33%). In the population of the Charles Darwin Ecological Refuge (Igarassu), of low urbanization, only the inversion In(IIIR)100A-98B(?) was found. −88(?), with 100% frequency. These data suggest that the polymorphism of inversions is higher in localities with greater urbanization, possibly due to the longer colonization time, which allowed the accumulation of genetic variations.
Continuous psychophysics shows millisecond-scale visual processing delays are faithfully preserved in movement dynamics
Authors: Burge Johannes , Cormack Lawrence K.
Published: August 2020

Image differences between the eyes can cause interocular discrepancies in the speed of visual processing. Millisecond-scale differences in visual processing speed can cause dramatic misperceptions of the depth and 3D direction of moving objects. Here, we develop a monocular and binocular continuous target-tracking psychophysics paradigm that can quantify such tiny differences in visual processing speed. Human observers continuously tracked a target undergoing Brownian motion with a range of luminance levels in each eye. Suitable analyses recover the time-course of the visuomotor response in each condition, the dependence of visual processing speed on luminance level, and the temporal evolution of processing differences between the eyes. Importantly, using a direct within-observer comparison, we show that continuous target-tracking and traditional forced-choice psychophysical methods provide estimates of interocular delays that agree on average to within a fraction of a millisecond. Thus, visual processing delays are preserved in the movement dynamics of the hand. Finally, we show analytically, and partially confirm experimentally, that differences between the temporal impulse response functions in the two eyes predicts how lateral target motion causes misperceptions of motion-in-depth and associated tracking responses. Because continuous target-tracking can accurately recover millisecond-scale differences in visual processing speed and has multiple advantages over traditional psychophysics, it should facilitate the study of temporal processing in the future.
Songbirds can learn flexible contextual control over syllable sequencing
Authors: Veit Lena , Tian Lucas Y , Hernandez Christian J Monroy , Brainard Michael S
Published: August 2020

The flexible control of sequential behavior is a fundamental aspect of speech, enabling endless reordering of a limited set of learned vocal elements (syllables or words). Songbirds are phylogenetically distant from humans but share both the capacity for vocal learning and neural circuitry for vocal control that includes direct pallial-brainstem projections. Based on these similarities, we hypothesized that songbirds might likewise be able to learn flexible, moment by-moment control over vocalizations. Here, we demonstrate that Bengalese finches (Lonchura striata domestica), which sing variable syllable sequences, can learn to rapidly modify the probability of specific sequences (e.g. ‘ab-c’ versus ‘ab-d’) in response to arbitrary visual cues. Moreover, once learned, this modulation of sequencing occurs immediately following changes in contextual cues and persists without external reinforcement. Our findings reveal a capacity in songbirds for learned contextual control over syllable sequencing that parallels human cognitive control over syllable sequencing in speech.