bluuebunny/crossref_metadata_2025 huggingface dataset:
Authenticity:The Ultimate Challenge in the Quest for Lasting Constitutional Legitimacy†
Authors: Kuo Ming-Sung
Published: June 2020

The recent upsurge of populism has prompted a wave of theoretical reflections on constitutional democracy. Echoing Max Weber’s sociology of legitimate authority, Bruce Ackerman’s Revolutionary Constitutions: Charismatic Leadership and the Rule of Law stands out from the crowd by providing an ambitious trichotomy of constitutional legitimacy—revolutionary, establishmentarian and elitist—with a focus on the revolutionary pathway. Engaging with Ackerman’s theoretical modelling of the relationship between constitutionalism and legitimate authority, I argue that the resurgence of popular sovereignty, as embodied in We the People in populist rhetoric indicates the centrality of authenticity in constitutional democracy as constitutional authenticity is underpinned by the ethics of being true to the people’s originality. Yet, with the ethics of authenticity assuming its pathological form, the focus has been shifting from making sense of the constitution to the people’s self-identification with individual politicians. The latest wave of populism crystallises the anti-ethics of authenticity in our quest for lasting constitutional legitimacy.
Prospective Multicenter Evaluation of an Advanced Extracellular Matrix for Wound Management
Authors: Raizman Rose , Hill Rosemary , Woo Kevin
Published: June 2020

OBJECTIVE

To evaluate an advanced extracellular matrix made of ovine forestomach matrix (OFM) for healing a variety of wound types.

METHODS

Participants were enrolled from inpatient, outpatient, and home healthcare settings. The OFM was used to treat all wounds and applied to the wound bed every 3 to 7 days until closure.

RESULTS

Researchers enrolled 29 participants with 33 wounds. Average time to wound closure was 8.2 weeks, the percentage of wounds that reduced in size by 50% or more at 4 weeks was 64%, the average wound area reduction at 4 weeks was 66%, and 73% of wounds had closed at 12 weeks. No adverse effects were observed.

CONCLUSIONS

This represents the first Canadian evaluation of OFM for the treatment of wounds, and the positive healing outcomes observed could support more widespread adoption of this matrix.
Anterior Midline Incision is a Safe and Effective Approach for High-energy Medial Shear Fractures of the Tibial Plateau
Authors: Rodriguez-Buitrago Andres , Cereijo Cesar , Yusi Kurt , Obremskey William T.
Published: June 2020

Objective:

We present a technical trick for surgical treatment of with (Schatzker IV) medial tibial plateau fractures treated with a standardized operative protocol with early radiographic and clinical outcomes.

Methods:

Skeletally mature patients with a medial tibial plateau fracture (Schatzker IV) admitted to an academic level 1 trauma center between 2002 and 2017 were identified by institutional database review. Screening of operative reports selected patients treated with a single anteromedial approach following a standard surgical protocol by a single surgeon. Data relevant to initial injury characteristics, patient comorbidities, operative management, and follow-up were extracted by chart review. Preoperative and postoperative clinical documentation and radiographs were examined to measure specific injury and outcome variables. Radiographic and clinical outcomes were validated by one fellowship-trained orthopedic trauma surgeon and 2 orthopedic trauma fellows.

Results:

Review of 335 patients with tibial plateau fractures during the study period identified a series of 17 high-energy, medial partial articular fractures that met the inclusion criteria. Injury pattern included articular depression in all patients, meniscal injury in 59%, ligamentous injury in 65% and none had compartment syndrome. Immediate radiographic analysis showed restoration of the articular surface, condylar width, and mechanical alignment for all patients. No patient experienced wound healing complications, soft tissue infection or skin necrosis. Median time to radiographic fracture consolidation was 12.9 weeks and ambulation without achieved at 18.9 weeks.

Conclusions:

The use of a standard anteromedial approach to the knee via medial parapatellar arthrotomy with full-thickness medial skin flap for isolated high-energy medial column tibial plateau fractures offers improved visualization and facilitates reduction and fixation of the lateral and anterior articular impaction while enabling immediate repair or reconstruction of associated meniscal and ligamentous (anterior cruciate ligament, posterior cruciate ligament, medial collateral ligament) pathology. Short-term and mid-term follow-up demonstrates good clinical and radiographic patient outcomes. This approach is a safe and reliable option for treatment of this unique and challenging injury pattern.
Medicinal and Recreational Marijuana: Review of the Literature and Recommendations for the Plastic Surgeon
Authors: Edalatpour Armin , Attaluri Pradeep , Larson Jeffrey D.
Published: June 2020

With the shift in public opinion and legalization of cannabis for therapeutic and recreational use, cannabis consumption has become more common. This trend will likely continue as decriminalization and legalization of marijuana and associated cannabinoids expand. Despite this increase in use, our familiarity with this drug and its associated effects remains incomplete. The aim of this review is to describe the physiologic effects of marijuana and its related compounds, review current literature related to therapeutic applications and consequences, discuss potential side effects of marijuana in surgical patients, and provide recommendations for the practicing plastic surgeon. Special attention is given to areas that directly impact plastic surgery patients, including postoperative pain, nausea and vomiting and wound healing. Although the literature demonstrates substantial support for marijuana in areas such as chronic pain and nausea and vomiting associated with chemotherapy, the data supporting its use for common perioperative problems are lacking. Its use for treating perioperative problems, such as pain and nausea, is poorly supported and requires further research.
Radiation Exposure Biomarkers in the Practice of Medical Radiology: Cooperative Research and the Role of the International Atomic Energy Agency (IAEA) Biodosimetry/Radiobiology Laboratory
Authors: Vinnikov Volodymyr A. , Belyakov Oleg
Published: June 2020

The strategy toward personalized medicine in radiation oncology, nuclear medicine, and diagnostic and interventional radiology demands a specific set of assays for individualized estimation of radiation load for safety concerns and prognosis of normal tissue reactions caused by ionizing radiation. Apparently, it seems reasonable to use validated radiation dosimetric biomarkers for these purposes. However, a number of gaps in knowledge and methodological limitations still have to be resolved until dosimetric biomarkers will start to play a valuable role in clinical practice beyond radiation protection and radiation medicine. An extensive international multicenter research is necessary to improve the methodology of clinical applications of biodosimetry. That became a rationale for launching the IAEA Coordinated Research Project E35010 MEDBIODOSE: “Applications of Biological Dosimetry Methods in Radiation Oncology, Nuclear Medicine, and Diagnostic and Interventional Radiology.” At the 2nd Coordination Meeting on MEDBIODOSE (18–22 February 2019, Recife, Brazil), participants reported progress in the usage of biological dosimetry for genotoxicity assessment and/or individualization of radiotherapy treatment plans. Another avenue of research was the prognosis of normal tissue toxicity and cancer risk prediction using biomarkers’ yield measured in vivo or after ex vivo irradiation of patients’ cells. Other important areas are mechanisms of cytogenetic radiation response, validation of new radiation biomarkers, development of innovative techniques, automated and high-throughput assays for biodosimetry, and the overall improvement of biodosimetry service. An important aspect of clinical application of biodosimetry is standardization of techniques and unification of approaches to data interpretation. The new IAEA Biodosimetry/Radiobiology Laboratory, which is being established, will provide support for this activity. The declared lab’s mission includes, among other tasks, a harmonization of the biodosimetry applications with relevant international standards, guidelines on good laboratory practice, and the IAEA EPR-Biodosimetry manual.
Description and Effectiveness of Communication Partner Training in TBI: A Systematic Review
Authors: Behn Nicholas , Francis Jill , Togher Leanne , Hatch Ellie , Moss Becky , Hilari Katerina
Published: June 2020

Objectives:

To evaluate the current evidence on communication partner training and its effectiveness on outcomes for people with traumatic brain injury (TBI) and/or their communication partners.

Methods:

Information sources: Systematic searches of 9 databases (AMED, CINAHL, EMBASE, Medline/EBSCOHOST, PsycINFO, PsycBITE, PsycARTICLES, PubMed, and Scopus) from database inception to February 2019. Eligibility criteria: Empirical studies on interventions for adult communication partners where the primary focus of the program (>50%) was on improving communication skills of people with TBI and/or communication partners. Data: Participants, characteristics of the training, outcome measures, and findings. Risk of bias: Standard checklists were used for methodological quality (PEDro, ROBiN-T) and intervention description (TIDieR). Synthesis: Narrative synthesis and effect sizes (Cohen's d) for group-level studies.

Outcomes:

Ten articles (describing 8 studies) met eligibility criteria: 3 randomized controlled trials, 2 nonrandomized controlled trials, and 3 single-case experimental designs. Studies included a total of 258 people with TBI and 328 communication partners; however, all but one study had fewer than 65 participants. Methodological quality varied and intervention description was poor. Three studies in the final synthesis (n = 41 communication partners, n = 36 people with TBI) reported positive intervention effects. Effect sizes in group studies were d = 0.80 to 1.13 for TBI and d = 1.16 to 2.09 for communication partners.

Conclusions:

The articles provided encouraging, though limited, evidence for training communication partners. Greater methodological rigor, more clearly described interventions, and consistent use of outcome measures and follow-up after treatment are needed. Further research on this topic is warranted.
Total Filling of the Vitreous Cavity With a Cohesive Ophthalmic Viscosurgical Device to Support the Removal of the Intraocular Foreign Body
Authors: Rogaczewska Małgorzata , Stopa Marcin
Published: June 2020

Purpose:

To evaluate the effectiveness of loading the vitreous cavity with a cohesive ophthalmic viscosurgical device in aiding the removal of the posterior segment intraocular foreign body (IOFB).

Methods:

Seven consecutive patients underwent a small-gauge vitrectomy due to eye trauma with the IOFB between January 2019 and December 2019. The IOFB removal was initiated after total filling the vitreous cavity with the ophthalmic viscosurgical device (Eyefill C or Bio-Hyalur Plus) to facilitate maneuvering and slow the descent in cases of the unintendedly released IOFBs. The eye examination was performed at presentation and at 1 day, 7 days, 1 month, and 3 months after surgery. The best-corrected visual acuity and intraocular pressure were evaluated.

Results:

In all eyes, IOFBs were elevated into the center of the vitreous cavity and could be securely gripped while suspended in the ophthalmic viscosurgical device to allow the surgeon for successful and harmless removal. In the 3-month follow-up, the best-corrected visual acuity was 20/20 in 5 patients and 20/25 in 2 patients. In the early postoperative period, the elevation of intraocular pressure did not occur. No patient developed endophthalmitis.

Conclusion:

The authors demonstrated that this uncomplicated technique is an effective surgical option for more reliable removal of posterior segment IOFBs.
Endosonography-guided Radiofrequency Ablation in Pancreatic Diseases
Authors: Vanella Giuseppe , Capurso Gabriele , Arcidiacono Paolo G.
Published: June 2020

Over the past 20 years, endoscopic ultrasound–guided radiofrequency ablation (EUS-RFA) has generated interest as a novel minimally invasive tool in the multimodal treatment of pancreatic malignant and premalignant lesions. However, although optimization of probes and settings has made EUS-RFA relatively safe, questions on the ideal positioning of this treatment in a multimodal strategy remain unanswered. This review will summarize the technical aspects of EUS-RFA and available clinical experiences for each pancreatic indication (pancreatic cancer, neuroendocrine neoplasms, cystic lesions, and celiac ganglia neurolysis). Established indications will be discussed along those requiring additional clinical data or even proof-of-concept studies. A dedicated session will further discuss evidence expected to emerge from ongoing registered trials, together with issues that must be addressed in future research, including the possible combination with immunotherapy, and the personalization of this treatment on the basis of genetic profiling. Despite the great clinical enthusiasm and scientific fervor, while evidence-based answers are produced, EUS-RFA must be centralized in high-volume centers of recognized expertise, where multidisciplinary discussions of indications and actively recruiting research protocols are available.
The Evolving Spectrum of Precursor Lesions of Cervical Adenocarcinomas
Authors: Stolnicu Simona , Talia Karen L. , McCluggage W. Glenn
Published: June 2020

Modern classification schemes divide cervical adenocarcinomas into human papillomavirus (HPV)-associated and HPV-independent types. The precursor lesions of the former are well known and comprise HPV-associated (usual/endocervical) adenocarcinoma in situ (AIS) and the much less common stratified mucin–producing intraepithelial lesion (SMILE). The precursor lesions of HPV-independent cervical adenocarcinomas are much less well known, although postulated precursors of gastric-type adenocarcinoma include atypical lobular endocervical glandular hyperplasia and gastric-type AIS. In this review, we cover HPV-associated and HPV-independent precursor lesions of cervical adenocarcinomas concentrating on diagnostic criteria (morphology and immunophenotype) and differential diagnosis. We propose a uniform terminology and diagnostic criteria for precursor lesions showing intestinal differentiation with goblet cells because this may be a feature of both HPV-associated and HPV-independent AIS.
Efficient differentiation of Nocardia farcinica, Nocardia cyriacigeorgica and Nocardia beijingensis by high-resolution melting analysis using a novel locus
Authors: Xu Shuai , Hou Xuexin , Li Dan , Sun Lina , Li Minghui , Ji Xingzhao , Wang Xuebing , Li Zhenjun
Published: June 2020

Accurate identification of

Nocardia

species remains a challenge due to the complexities of taxonomy and insufficient discriminatory power of traditional techniques. We report the development of a molecular technique that utilizes real-time PCR-based high-resolution melting (HRM) analysis for differentiation of the most common

Nocardia

species. Based on a novel fusA-tuf intergenic region sequence,

Nocardia farcinica

,

Nocardia cyriacigeorgica

and

Nocardia beijingensis

were clearly distinguished from one another by HRM analysis. The limit of detection of the HRM assay for purified

Nocardia

spp. DNA was at least 10 fg. No false positives were observed for specificity testing of 20 non-target clinical samples. In comparison to established matrix-assisted laser desorption/ionization-time of flight MS, the HRM assay improved the identification of

N. beijingensis

. Additionally, all the products of PCR were verified by direct sequencing. In conclusion, the developed molecular assay allows simultaneous detection and differentiation of

N. farcinica

,

N. cyriacigeorgica

and

N. beijingensis

with high sensitivity and specificity.
Pulmonary alveolar regrowth in an adult COVID-19 patient
Authors: Chen Jingyu , Wu Huijuan , Yu Yuanyuan , Tang Nan
Published: June 2020

We detected active alveolar regrowth in the lung of a 58-year-old COVID-19 patient who underwent lung transplantation due to severe lung hemorrhage. Specifically, immunohistological and scanning electronic microscopy analyses revealed that alveolar type II epithelial cells (AT2 cells) accumulate in response to viral pneumonia and that these AT2 cells actively proliferate and differentiate into squamous AT1-like alveolar epithelial cells. Thus, our work establishes that alveolar regrowth does occur in post-COVID-19 injury adult human lungs.
Interictal epileptiform discharges in focal epilepsy are preceded by a gradual increase in low-frequency oscillations
Authors: Westin Karin , Cooray Gerald , Lundqvist Daniel
Published: June 2020

Epilepsy is characterized by recurrent seizures and may also have negative influence on cognitive function. In addition to ictal activity, the epileptic brain also gives rise tointerictal epileptiform discharges(IEDs). These IEDs constitute the diagnostic hallmark of epilepsy, and have been linked to impaired memory formation and negative effects on neurodevelopment. The neurophysiological dynamics underlying IED generation seem to resemble those underlying seizure development. Understanding the neurophysiological characteristics surrounding and preceding IED development would hence provide valuable insights into the pathophysiology of the epileptic brain. In order to improve this understanding, we aimed to characterize the dynamical activity changes that occurs immediately prior to an IED onset. We used magnetoencephalography (MEG) recordings from nine focal epilepsy patients to characterize the oscillatory activity preceding IED onsets. Our results showed a systematic and gradual increase in oscillatory delta and theta band activity (1-4 Hz and 4-8 Hz, respectively) during this pre-IED interval, reaching a maximum power at IED onset. These results indicate that the pre-IED brain state is characterized by a gradual synchronization that culminates in the neuronal hypersynchronization underlying IEDs. We discuss how IED generation might resemble seizure development, where physiological brain activity similarly undergoes a gradual synchronization that terminates in seizure onset.
Estimating excess mortality in people with cancer and multimorbidity in the COVID-19 emergency
Authors: Lai Alvina G , Pasea Laura , Banerjee Amitava , Denaxas Spiros , Katsoulis Michail , Chang Wai Hoong , Williams Bryan , Pillay Deenan , Noursadeghi Mahdad , Linch David , Hughes Derralynn , Forster Martin D , Turnbull Clare , Fitzpatrick Natalie K , Boyd Kathryn , Foster Graham R , Cooper Matt , Jones Monica , Pritchard-Jones Kathy , Sullivan Richard , Hall Geoff , Davie Charlie , Lawler Mark , Hemingway Harry
Published: June 2020

Background:
Cancer and multiple non-cancer conditions are considered by the Centers for Disease Control and Prevention (CDC) as high risk conditions in the COVID-19 emergency. Professional societies have recommended changes in cancer service provision to minimize COVID-19 risks to cancer patients and health care workers. However, we do not know the extent to which cancer patients, in whom multi-morbidity is common, may be at higher overall risk of mortality as a net result of multiple factors including COVID-19 infection, changes in health services, and socioeconomic factors.

Methods:
We report multi-center, weekly cancer diagnostic referrals and chemotherapy treatments until April 2020 in England and Northern Ireland. We analyzed population-based health records from 3,862,012 adults in England to estimate 1-year mortality in 24 cancer sites and 15 non-cancer comorbidity clusters (40 conditions) recognized by CDC as high-risk. We estimated overall (direct and indirect) effects of COVID-19 emergency on mortality under different Relative Impact of the Emergency (RIE) and different Proportions of the population Affected by the Emergency (PAE). We applied the same model to the US, using Surveillance, Epidemiology, and End Results (SEER) program data.

Results:
Weekly data until April 2020 demonstrate significant falls in admissions for chemotherapy (45-66% reduction) and urgent referrals for early cancer diagnosis (70-89% reduction), compared to pre-emergency levels. Under conservative assumptions of the emergency affecting only people with newly diagnosed cancer (incident cases) at COVID-19 PAE of 40%, and an RIE of 1.5, the model estimated 6,270 excess deaths at 1 year in England and 33,890 excess deaths in the US. In England, the proportion of patients with incident cancer with ≥1 comorbidity was 65.2%. The number of comorbidities was strongly associated with cancer mortality risk. Across a range of model assumptions, and across incident and prevalent cancer cases, 78% of excess deaths occur in cancer patients with ≥1 comorbidity.

Conclusion:
We provide the first estimates of potential excess mortality among people with cancer and multimorbidity due to the COVID-19 emergency and demonstrate dramatic changes in cancer services. To better inform prioritization of cancer care and guide policy change, there is an urgent need for weekly data on cause-specific excess mortality, cancer diagnosis and treatment provision and better intelligence on the use of effective treatments for comorbidities.
Influence of interleukin-18 polymorphisms on kidney transplantation outcomes: A meta-analysis
Authors: Einsamtrakoon Thanee , Tharabenjasin Phuntila , Pabalan Noel , Tasanarong Adis
Published: June 2020

Aim: Allograft survival post-kidney transplantation (KT) are in large part attributed to genetics, which render the recipient susceptible or protected from allograft rejection. KT studies involving single nucleotide polymorphisms (SNPs) have reported the association of interleukin-18 (IL-18) with KT and its role in allograft rejection. However, the reported outcomes been inconsistent, prompting a meta-analysis to obtain more precise estimates.
Methods: We posed two hypotheses about the IL-18 SNPs: their association with KT (H1), and increase or decrease in the risks of allograft rejection (H2). Using standard genetic models, we estimated odds ratios [ORs] and 95% confidence intervals by comparing the IL-18 genotypes between two groups: (i) patients and controls for H1 (GD: genotype distribution analysis); (ii) rejectors and non- rejectors for H2 (allograft analysis). Multiple comparisons were corrected with the Holm-Bonferroni (HB) test. Subgrouping was ethnicity-based (Asians and Caucasians). Heterogeneity was outlier-treated and robustness of outcomes was sensitivity-treated. Results: This meta-analysis generated eight significant outcomes, which HB filtered into four core outcomes, found in the dominant/codominant models. Two of the four were in GD, indicating associations of the IL-18 SNPs with KT (ORs 1.34 to 1.39, 95% CIs 1.13-1.70, PHB = .0007-.004). The other two were in allograft analysis indicating reduced risk with HB P-values of .03 for overall (OR 0.74, 95% CI 0.56-0.93) and Asian (OR 0.70, 95% CI 0.53-0.92). In contrast to the protected Asian subgroup, Caucasians showed non-significant increased risk (OR 1.20. 95% CI .82-1.75, Pa = .35). Sensitivity treatment conferred robustness to all the core outcomes. Conclusions: Overall association of IL-18 SNPs with KT was significant (up to 1.4-fold) and Asians KT recipients were protected (up to 30%). Enabled by outlier treatment, these findings were supported by non-heterogeneity and robustness. More studies may confirm or modify our findings.
Pediatric COVID-19 in Southern California: clinical features and viral genetic diversity
Authors: Pandey U , Yee R , Precit M , Bootwalla M , Ryutov A , Shen L , Maglinte DT , Ostrow D , Biegel JA , Judkins AR , Bender JM , Gai X , Bard J Dien
Published: June 2020

As the pandemic enters its fifth month, information regarding COVID-19 in children is rapidly evolving. Here, we explore clinical features and SARS-CoV-2 genetic variation in children presenting with COVID-19. We observed diverse clinical presentations and identified association between disease severity, viral load and age. SARS-CoV-2 genomes from the patients showed limited number of variations and an evolutionary rate comparable to other RNA viruses. We did not identify correlation between disease severity and viral genetic variations. Epidemiological investigation revealed multiple introductions of virus into Southern California.
Development and external validation of a diagnostic model for in-hospital bleeding in patients with acute ST elevation myocardial infarction
Authors: Li Yong
Published: June 2020

Background

Bleeding complications in patients with acute ST segment elevation myocardial infarction (STEMI) are associated with an increased risk of subsequent adverse consequences. We want to develop and externally validate a diagnostic model of in-hospital bleeding in the population of unselected real-world patients with acute STEMI.

Methods

Design: Multivariable logistic regression of a cohort for hospitalized patients with acute STEMI. Setting: Emergency department ward of a university hospital. Participants: Diagnostic model development: Totally 4262 hospitalized patients with acute STEMI from January 2002 to December 2013 in Beijing Anzhen Hospital, Capital Medical University. External validation: Totally 6015 hospitalized patients with acute STEMI from January 2014 to August 2019 in Beijing Anzhen Hospital, Capital Medical University. Outcomes: All-cause in-hospital bleeding not related to coronary artery bypass graft surgery or catheterization.

Results

In-hospital bleeding occurred in 2.6% (112/4262) of patients in the development data set (117/6015) of patients in the validation data set. The strongest predictors of in-hospital bleeding were advanced age and high Killip classification. We developed a diagnostic model of in-hospital bleeding. The area under the receiver operating characteristic ROC curve (AUC) was 0.777±0.021, 95% confidence interval(CI) = 0.73576 ~ 0.81823. We constructed a nomograms using the development database based on age, and Killip classification. The AUC was 0.7234±0.0252,

95% CI = 0.67392 ~ 0.77289 in the validation data set. Discrimination, calibration, and decision curve analysis were satisfactory.

Conclusions

We developed and externally validated a moderate diagnostic model of in-hospital bleeding in patients with acute STEMI.

We registered this study with WHO International Clinical Trials Registry Platform (ICTRP) (registration number: ChiCTR1900027578; registered date: 19 Novmober 2019). http://www.chictr.org.cn/edit.aspx?pid=45926&htm=4.
Adaptive policies for use of physical distancing interventions during the COVID-19 pandemic
Authors: Yaesoubi Reza , Havumaki Joshua , Chitwood Melanie , Menzies Nicolas A , Gonsalves Gregg , Salomon Joshua A , Paltiel A. David , Cohen Ted
Published: June 2020

Policymakers need decision tools to determine when to use physical distancing interventions to maximize the control of COVID-19 while minimizing the economic and social costs of these interventions. We develop a pragmatic decision tool to characterize adaptive policies that combine real-time surveillance data with clear decision rules to guide when to trigger, continue, or stop physical distancing interventions during the current pandemic. In model-based experiments, we find that adaptive policies characterized by our proposed approach prevent more deaths and require a shorter overall duration of physical distancing than alternative physical distancing policies. Our proposed approach can readily be extended to more complex models and interventions.
High heritability of ascending aortic diameter and multi-ethnic prediction of thoracic aortic disease.
Authors: Tcheandjieu Catherine , Xiao Ke , Tejeda Heliodoro , Lynch Julie , Ruotsalainen Sanni , Bellomo Tiffany , Palnati Madhuri , Judy Renae , Kember Rachel , Klarin Derek , Kember Rachel , Verma Shefali ,   Regeneron Genetics Center,   VA Million Veterans Program,   FinnGen Project, Palotie Aarno , Daly Mark , Ritchie Marylyn , Rader Daniel , Rivas Manuel A , Assimes Themosticles , Tsao Philip , Damrauer Scott , Priest James
Published: June 2020

Enlargement of the aorta is an important risk factor for aortic aneurysm and dissection, a leading cause of morbidity in the developed world. While Mendelian genetics account for a portion of thoracic aortic disease, the contribution of common variation is not known. Using standard techniques in computer vision, we performed automated extraction of Ascending Aortic Diameter (AsAoD) from cardiac MRI of 36,021 individuals from the UK Biobank. A multi-ethnic genome wide association study and trans-ethnic meta-analysis identified 99 lead variants across 71 loci including genes related to cardiovascular development (HAND2, TBX20) and Mendelian forms of thoracic aortic disease (ELN, FBN1). A polygenic risk score predicted prevalent risk of thoracic aortic aneurysm within the UK Biobank (OR 1.50 per standard deviation (SD) polygenic risk score (PRS), p=6.30x10-03) which was validated across three additional biobanks including FinnGen, the Penn Medicine Biobank, and the Million Veterans Program (MVP) in individuals of European descent (OR 1.37 [1.31 - 1.43] per SD PRS), individuals of Hispanic descent (OR 1.40 [1.16 - 1.69] per SD PRS, p=5.6x10-04), and individuals of African American descent (OR 1.08 [1.00 - 1.18] per SD PRS, p=0.05). Within individuals of European descent who carried a diagnosis of thoracic aneurysm, the PRS was specifically predictive of the need for surgical intervention (OR 1.57 [1.15 - 2.15] per SD PRS, p=4.45x10-03). Using Mendelian Randomization our data highlight the primary causal role of blood pressure in reducing dilation of the thoracic aorta. Overall our findings link normal anatomic variation to extremes observed in Mendelian syndromes and provide a roadmap for the use of genetic determinants of human anatomy in both understanding cardiovascular development while simultaneously improving prediction and prevention of human disease.
Safety of Breastfeeding in Mothers with SARS-CoV-2 Infection
Authors: Luo Qingqing , Chen Lan , Yao Dujuan , Zhu Jianwen , Zeng Xiangzhi , Xia Lin , Wu Min , Lin Lin , Jin Zhishan , Zhang Qingmiao , Feng Dilu , Yu Shihuan , Song Bo , Zhang Wanlin , Wang Hongbo , Zhang Yanfang , Su Zhengyuan , Luo Minhua , Jiang Xuan , Chen Hui
Published: June 2020

Background: The outbreak of Coronavirus Disease 2019 (COVID-19) is threatening a surging number of populations worldwide, including women in breastfeeding period. Limited evidence is available concerning breastfeeding in women with COVID-19.
Methods: Twenty-three pregnant women and puerperae were enrolled in the study. To evaluate the effect of breastfeeding on SARS-CoV-2 transmission, the presence of SARS-CoV-2, IgG and IgM in breast milk, maternal blood and infant blood were assessed. Feeding patterns were also recorded in follow-up.
Results: No positive detection for SARS-CoV-2 of neonates was found. All breast milk samples were negative for the detection of SARS-CoV-2. The presence of IgM ofSARS-CoV-2 in breast milk was correlated with maternal blood. The results of IgG detection for SARS-CoV-2 were negative in all breast milk samples. All the infants were in healthy condition while six of them were fed with whole or partial breast milk. Eight infants received antibody test for SARS-CoV-2 in one month after birth and the results were all negative.
Conclusion: Findings from this small number of cases suggest that there is currently no evidence for mother-to-child transmission via breast feeding in women with COVID-19 in the third trimester and puerperium.
INGOT-DR: an interpretable classifier for predicting drug resistance in M. tuberculosis
Authors: Zabeti Hooman , Dexter Nick , Safari Amir Hosein , Sedaghat Nafiseh , Libbrecht Maxwell , Chindelevitch Leonid
Published: June 2020

Motivation

Prediction of drug resistance and identification of its mechanisms in bacteria such asMycobacterium tuberculosis, the etiological agent of tuberculosis, is a challenging problem. Solving this problem requires a transparent, accurate, and flexible predictive model. The methods currently used for this purpose rarely satisfy all of these criteria. On the one hand, approaches based on testing strains against a catalogue of previously identified mutations often yield poor predictive performance; on the other hand, machine learning techniques typically have higher predictive accuracy, but often lack interpretability and may learn patterns that produce accurate predictions for the wrong reasons. Current interpretable methods may either exhibit a lower accuracy or lack the flexibility needed to generalize them to previously unseen data.

Contribution

In this paper we propose a novel technique, inspired by the group testing and Boolean compressed sensing, which yields highly accurate predictions, interpretable results, and is flexible enough to be optimized for various evaluation metrics at the same time.

Results

We test the predictive accuracy of our approach on five first-line and seven second-line antibiotics used for treating tuberculosis. We find that it has a higher or comparable accuracy to that of commonly used machine learning models, and is able to identify variants in genes with previously reported association to drug resistance. Our method is intrinsically interpretable, and can be customized for different evaluation metrics. Our implementation is available atgithub.com/hoomanzabeti/INGOT_DRand can be installed via The Python Package Index (Pypi) underingotdr. This package is also compatible with most of the tools in the Scikit-learn machine learning library.
Control of microglial dynamics by Arp2/3 and the autism and schizophrenia-associated protein Cyfip1
Authors: Drew James , Arancibia-Carcamo I. Lorena , Jolivet Renaud , Lopez-Domenech Guillermo , Attwell David , Kittler Josef T.
Published: June 2020

Microglia use a highly complex and dynamic network of processes to sense and respond to their surroundings. Microglial dynamics differ throughout development and in neurological and neuropsychiatric disease, though mechanistic insight into these changes is lacking. Here we identify novel roles for regulators of the actin cytoskeleton in controlling microglial behaviour. We show that the actin branching complex Arp2/3 is critical for maintaining microglial morphology and required for surveillance but not chemotactic motility. Neuropsychiatric disease-associated Cyfip1, a core component of the WAVE regulatory complex that links Rac1 signalling to Arp2/3 activation, is highly expressed in microglia but has unknown function. We report that conditional deletion of Cyfip1 in mouse microglia reduces morphological complexity and surveillance of brain parenchyma, and increases activation state as defined by CD68 expression. Thus, altered actin-dependent microglial dynamics mediated by Cyfip1 and Arp2/3 may contribute to neuropsychiatric disease.
The rise and fall of the ancient northern pike master sex determining gene
Authors: Pan Qiaowei , Feron Romain , Jouanno Elodie , Darras Hugo , Herpin Amaury , Koop Ben , Rondeau Eric , Goetz Frederick W. , Larson Wesley A. , Bernatchez Louis , Tringali Mike , Curran Stephen S. , Saillant Eric , Denys Gael P.J. , von Hippel Frank A. , Chen Songlin , López J. Andrés , Verreycken Hugo , Ocalewicz Konrad , Guyomard Rene , Eche Camille , Lluch Jerome , Roques Celine , Hu Hongxia , Tabor Roger , DeHaan Patrick , Nichols Krista M. , Journot Laurent , Parrinello Hugues , Klopp Christophe , Interesova Elena A. , Trifonov Vladimir , Schartl Manfred , Postlethwait John , Guiguen Yann
Published: June 2020

Sexual reproduction is a ubiquitous basic feature of life and genetic sex determination is thus widespread, at least among eukaryotes. Understanding the remarkable diversity of sex determination mechanisms, however, is limited by the paucity of empirical studies. Here, we traced back the evolution of sex determination in an entire clade of vertebrates and uncovered that the northern pike (Esox lucius) master sex-determining gene initiated from a 65 to 90 million-year-old gene duplication and remained sex-linked on undifferentiated sex chromosomes for at least 56 million years. Contrasting with its ancient origin, we identified several independent species- or population-specific transitions of sex determination mechanisms in this lineage, including an unexpected complete and recent Y-chromosome loss in some North American northern pike populations. These findings highlight the diversity of the evolutionary fates of master sex-determining genes and raise the importance of careful considerations of population demographic history in sex determination studies. Our study also puts forward the hypothesis that occasional sex reversals and genetic bottlenecks provide a non-adaptive explanation for sex determination transitions.
Neurexin1α differentially regulates synaptic efficacy within striatal circuits
Authors: Davatolhagh M. Felicia , Fuccillo Marc V.
Published: June 2020

Mutations in genes essential for shared aspects of synaptic function throughout the CNS, such as the presynaptic adhesion molecule Neurexin1α (Nrxn1α), are strongly implicated in neuropsychiatric pathophysiology. As the input nucleus of the basal ganglia, the striatum integrates diverse excitatory projections governing cognitive and motor control, and its functional impairment underlies neuropsychiatric disorders. While prior work has emphasized Neurexins’ contributions to synaptic transmission in hippocampus and brainstem, their function in striatal circuits remains unstudied. As Nrxn1α is highly expressed at striatal inputs, we employed optogenetic-mediated afferent recruitment of dorsal prefrontal cortex-dorsomedial striatal (DMS) connections, uncovering a decrease in net synaptic strength specifically onto indirect pathway spiny neurons in both Nrxn1α+/-and Nrxn1α-/-mice, driven by reductions in transmitter release probability. In contrast, thalamic excitatory inputs to DMS demonstrated relatively normal excitatory synaptic strength. These findings suggest that dysregulation of Nrxn1α modulates striatal function in an input and target-specific manner.
Identifying digenic disease genes using machine learning in the undiagnosed diseases network
Authors: Mukherjee Souhrid , Cogan Joy D , Newman John H , Phillips John A , Hamid Rizwan ,   Undiagnosed Diseases Network, Meiler Jens , Capra John A.
Published: June 2020

Rare diseases affect hundreds of millions of people worldwide, and diagnosing their genetic causes is challenging. The Undiagnosed Diseases Network (UDN) was formed in 2014 to identify and treat novel rare genetic diseases, and despite many successes, more than half of UDN patients remain undiagnosed. The central hypothesis of this work is that many unsolved rare genetic disorders are caused by multiple variants in more than one gene. However, given the large number of variants in each individual genome, experimentally evaluating even just pairs of variants for potential to cause disease is currently infeasible. To address this challenge, we developed DiGePred, a random forest classifier for identifying candidate digenic disease gene pairs using features derived from biological networks, genomics, evolutionary history, and functional annotations. We trained the DiGePred classifier using DIDA, the largest available database of known digenic disease causing gene pairs, and several sets of non-digenic gene pairs, including variant pairs derived from unaffected relatives of UDN patients. DiGePred achieved high precision and recall in cross-validation and on a held out test set (PR area under the curve >77%), and we further demonstrate its utility using novel digenic pairs from the recent literature. In contrast to other approaches, DiGePred also appropriately controls the number of false positives when applied in realistic clinical settings like the UDN. Finally, to facilitate the rapid screening of variant gene pairs for digenic disease potential, we freely provide the predictions of DiGePred on all human gene pairs. Our work facilitates the discovery of genetic causes for rare non-monogenic diseases by providing a means to rapidly evaluate variant gene pairs for the potential to cause digenic disease.
Mother Brain is Wired for Social Moments
Authors: Shimon-Raz Ortal , Salomon Roy , Bloch Miki , Romano Gabi Aisenberg , Hendler Talma , Yeshurun Yaara , Ulmer-Yaniv Adi , Zagoory-Sharon Orna , Feldman Ruth
Published: June 2020

Reorganization of the maternal brain, primed by oxytocin surge during childbirth, triggers the species-typical maternal social behavior. These brief social moments carry profound effects on the infant’s social brain and likely have a distinct signature in the maternal brain. Utilizing a double-blind, oxytocin/placebo administration crossover design, we imaged mothers twice while observing three naturalistic maternal-infant contexts in the home ecology; “unavailable”, “unresponsive”, and “social”, when mothers engaged in synchronous pick-a-boo play. We found four processes by which mother’s brain registers social moments.Salience- social moments increased activations throughout the maternal brain network;Brain-behavior coupling- caregiving behavior linked with socially-driven neural response;Oxytocin sensitivity– administration impacted neural response mainly to the social context; andTemporal engrams–consistent temporal patterns in insula and TP characterized response to social play. Findings describe how mother’s brain compiles and amplifies these precious social moments to generate dyad-specific brain-behavior patterns that initiate the cross-generational transmission of human sociality.
Functional characterization of a “plant-like” HYL1 homolog in the cnidarianNematostella vectensisindicates a conserved involvement in microRNA biogenesis
Authors: Tripathi Abhinandan Mani , Admoni Yael , Fridrich Arie , Lewandowska Magda , Surm Joachim M. , Aharoni Reuven , Moran Yehu
Published: June 2020

While the biogenesis of microRNAs (miRNAs) in both animals and plants depends on the RNase III Dicer, its partner proteins are considered distinct for each kingdom. Nevertheless, recent discovery of homologs of Hyponastic Leaves1 (HYL1), a “plant-specific” Dicer partner, in the metazoan phylum Cnidaria, challenges the view that miRNAs evolved convergently in animals and plants. Here we show that the HYL1 homolog Hyl1-like a (Hyl1La) is crucial for development and miRNA biogenesis in the cnidarian modelNematostella vectensis. Inhibition of Hyl1La by morpholinos resulted in metamorphosis arrest inNematostellaembryos and a significant reduction in levels of most miRNAs. Further, meta-analysis of morphants of miRNA biogenesis components, like Dicer1, shows clustering of their miRNA profiles with Hyl1La morphants. Strikingly, immunoprecipitation of Hyl1La followed by quantitative PCR revealed that in contrast to the plant HYL1, Hyl1La interacts only with precursor miRNAs and not with primary miRNAs. This was complemented by an in vitro binding assay of Hyl1La to synthetic precursor miRNA. Altogether, these results suggest that the last common ancestor of animals and plants carried a HYL1 homolog that took essential part in miRNA biogenesis and indicate early emergence of the miRNA system before plants and animals separated.

Impact statement

Presence of a functional homolog of HYL1 inNematostellavectensis, a basal animal model, indicates divergent evolution of miRNA biogenesis pathway in plants and animals from an ancestral miRNA system
The Amphibian Antimicrobial Peptide Uperin 3.5 is a Cross-α/Cross-β Chameleon Functional Amyloid
Authors: Salinas Nir , Tayeb-Fligelman Einav , Sammito Massimo , Bloch Daniel , Jelinek Raz , Noy Dror , Uson Isabel , Landau Meytal
Published: June 2020

Antimicrobial activity is being increasingly linked to amyloid fibril formation, suggesting physiological roles for some human amyloids, which have historically been viewed as strictly pathological agents. This work reports on formation of functional cross-α amyloid fibrils of the amphibian antimicrobial peptide uperin 3.5 at atomic-resolution, an architecture initially discovered in the bacterial PSMα3 cytotoxin. The fibrils of uperin 3.5 and PSMα3 were comprised of parallel and anti-parallel helical sheets, respectively, recapitulating properties of β-sheets. Uperin 3.5 helical fibril formation was largely induced by, and formed on, bacterial cells or membrane mimetics, and led to membrane damage and cell death. Uperin 3.5 demonstrated chameleon properties, with a secondary structure switch to cross-β fibrils with reduced antibacterial activity in the absence of lipids or after heat shock. These findings suggest a regulation mechanism, which includes storage of inactive peptides as well as environmentally induced activation of uperin 3.5, via chameleon cross-α/β amyloid fibrils.
Impacts of host phylogeny, feeding styles, and parasite attachment site on isotopic discrimination in helminths infecting coral reef fish hosts
Authors: Riekenberg Philip M. , Briand Marine J. , Moléana Thibaud , Sasal Pierre , van der Meer Marcel , Thieltges David W. , Letourneur Yves
Published: June 2020

Stable isotopes of carbon and nitrogen characterize trophic relationships in predator-prey relationships, with clear differences between consumer and diet (discrimination factor, Δ13C, Δ15N). However, parasite-host isotopic relationships remain unclear, with Δ13C and Δ15N remaining incompletely characterized, especially for helminths. In this study, we used stable isotopes to determine discrimination factors for 13 parasite-host pairings of helminths in coral reef fish. Δ15N differences grouped according to phylogeny and attachment site on the hosts: Δ15N was positive for trematodes and nematodes from the digestive tract and varied for cestodes and nematodes from the general cavity. Δ13C showed more complex patterns with no effect of phylogeny or attachment site. A negative relationship was observed between Δ15N and host δ15N value among different host-parasite pairings as well as within 7 out of the 13 parings, indicating that host metabolic processing affects host-parasite discrimination values. In contrast, no relationships were observed for Δ13C. Our results indicate that host phylogeny, attachment site and host stable isotope value drive Δ15N of helminths in coral reef fish while Δ13C is more idiosyncratic. These results call for use of taxon- or species-specific and scaled framework for bulk stable isotopes in the trophic ecology of parasites.