bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel remitting leukodystrophy associated with a variant in FBP2
Authors: Gizak Agnieszka , Diegmann Susann , Dreha-Kulaczewski Steffi , Wiśniewski Janusz , Duda Przemysław , Ohlenbusch Andreas , Huppke Brenda , Henneke Marco , Höhne Wolfgang , Altmüller Janine , Thiele Holger , Nürnberg Peter , Rakus Dariusz , Gärtner Jutta , Huppke Peter
Published: March 2021

Leukodystrophies are genetic disorders of cerebral white matter that almost exclusively have a progressive disease course. We became aware of three members of a family with a disorder characterized by a sudden loss of all previously acquired abilities around 1 year of age followed by almost complete recovery within 2 years. Cerebral MRI and myelin sensitive imaging showed a pronounced demyelination that progressed for several months despite signs of clinical improvement and was followed by remyelination. Exome sequencing did not-identify any mutations in known leukodystrophy genes but revealed a heterozygous variant in the FBP2 gene, c.343G>A, p. Val115Met, shared by the affected family members. Cerebral MRI of other family members demonstrated similar white matter abnormalities in all carriers of the variant in FBP2. The FBP2 gene codes for muscle fructose 1,6-bisphosphatase, an enzyme involved in gluconeogenesis that is highly expressed in brain tissue. Biochemical analysis showed that the variant has a dominant negative effect on enzymatic activity, substrate affinity, cooperativity and thermal stability. Moreover, it also affects the non-canonical functions of muscle fructose 1,6-bisphosphatase involved in mitochondrial protection and regulation of several nuclear processes. In patients’ fibroblasts, muscle fructose 1,6-bisphosphatase shows no colocalization with mitochondria and nuclei leading to increased reactive oxygen species production and a disturbed mitochondrial network. In conclusion, the results of this study indicate that the variant in FBP2 disturbs cerebral energy metabolism and is associated with a novel remitting leukodystrophy.
Case report of Takotsubo syndrome following seizures in a patient with pyruvate carboxylase deficiency
Authors: Sahdev Nikhil , Oji Onyedikachi , Babu Aswin , Dutta Roy Smita
Published: March 2021

Background 

Takotsubo syndrome (TS) is defined as transient left ventricular dysfunction, which is often related to an emotional or physically stressful event. We describe a case of TS in a lady with pyruvate carboxylase deficiency (PCD). Pyruvate carboxylase deficiency is rare condition with the majority of those affected demonstrating signs of failure to thrive, recurrent seizures, and metabolic acidosis. To our knowledge, this is the first documented case of TS in an individual with PCD.

Case summary 

This 28-year-old female presented to the emergency department after a tonic-clonic seizure. For 4 days prior to the presentation, she had been suffering from cough and pyrexia. On Day 2, she developed abdominal pain associated with tachycardia and hypotension, and an elevated troponin (791 ng/L). The echocardiogram showed a severely impaired left ventricular systolic function, regional wall motion abnormalities (RWMAs), and a visually estimated left ventricular ejection fraction of 25–30%. Eight days following admission her clinical state significantly improved, with a reduction troponin to 60 ng/L. A repeat echocardiogram on Day 9 showed complete resolution of cardiac function with no RWMAs. Following this, she was discharged from hospital the next day with a diagnosis of TS.

Discussion 

This is the first case report of TS in a patient with PCD. In this case, multiple aetiologies of TS such as emotional and physical stress, seizures, and acute infection were considered. This case also highlights that TS should be an important differential diagnosis in patients presenting with cardiac symptoms.
A case report of a symptomatic right anomalous coronary artery with concomitant atherosclerotic disease: the benefit of a sequential comprehensive non-invasive and invasive diagnostic approach
Authors: Bigler Marius Reto , Huber Adrian Thomas , Räber Lorenz , Gräni Christoph
Published: March 2021

Background 

Anomalous aortic origin of a coronary artery (AAOCA) is a rare congenital disease associated with an increased risk of myocardial ischaemia, ventricular arrhythmias, and heart failure.

Case summary 

A 75-year-old Caucasian man was referred for invasive coronary angiography (ICA) due to atypical chest pain. Invasive coronary angiography demonstrated non-significant atherosclerotic disease of the left coronary artery and an anomalous origin of the right coronary artery (RCA); without selective intubation. Coronary computed tomography angiography (CCTA) revealed a right-AAOCA with interarterial and intramural course, and a soft plaque in the distal RCA. Subsequent physical-stress single-photon emissions computed tomography (SPECT) showed exercise-induced inferoapical myocardial ischaemia, giving a Class IC level of evidence for surgical correction of the AAOCA. Repeated ICA with selective R-AAOCA intubation confirmed an 80% distal atherosclerotic stenosis, which was treated with direct stenting. Subsequent invasive physiologic evaluation under maximal dobutamine-volume challenge (gradually increasing dose of dobutamine max. 40 μg/kg per body weight/min, 3000 mL ringer lactate and 1 mg atropine was given until the patient reached a maximum of 145 b.p.m.), revealed a haemodynamically non-relevant anomalous segment with a fractional flow reserve (FFR) of 0.91. A follow-up SPECT was normal, and the patient was completely symptom-free at 1 month.

Discussion 

We present the sequential diagnostic approach in a symptomatic patient with a right anomalous coronary artery and concomitant atherosclerotic disease. Using this approach, the patient could be deferred from guideline recommended open-heart surgery of the AAOCA, as direct invasive dobutamine/volume FFR revealed haemodynamic non-relevance of the anomalous segment after stenting the concomitant atherosclerotic stenosis in the distal segment within the same coronary artery.
Between Participation and Capture in International Rule-Making: The WHO Framework of Engagement with Non-State Actors
Authors: Berman Ayelet
Published: March 2021

There has been a tremendous rise in the participation of non-state actors – notably business – in international rule-making. While such participation has many benefits, the risk that rule-making gets captured – that is, that rules are made in line with business’ profit-driven interest rather than in the public interest – has increased too. This article, first, explores the growing problem of capture in international rule-making and identifies three modes of capture that have become particularly prevalent in international policy-making: information capture, representational capture and resource capture. The article then explores the World Health Organization’s (WHO) 2016 Framework of Engagement with Non-State Actors (FENSA) and how effectively it manages these risks. FENSA is interesting because it is the first policy by an international organization seeking to comprehensively and systematically regulate non-state actor engagement and to prevent related risks. In assessing FENSA, the article focuses on the WHO’s engagement of two main actors: the Big Food industry and voluntary donors. Finally, the article seeks to draw more general lessons as to the capacity of FENSA-like reforms to prevent capture in international rule-making.
Genetic characterization of aSorghum bicolormultiparent mapping population emphasizing carbon-partitioning dynamics
Authors: Boatwright J Lucas , Brenton Zachary W , Boyles Richard E , Sapkota Sirjan , Myers Matthew T , Jordan Kathleen E , Dale Savanah M , Shakoor Nadia , Cooper Elizabeth A , Morris Geoffrey P , Kresovich Stephen
Published: March 2021

Sorghum bicolor, a photosynthetically efficient C4 grass, represents an important source of grain, forage, fermentable sugars, and cellulosic fibers that can be utilized in myriad applications ranging from bioenergy to bioindustrial feedstocks. Sorghum’s efficient fixation of carbon per unit time per unit area per unit input has led to its classification as a preferred biomass crop highlighted by its designation as an advanced biofuel by the U.S. Department of Energy. Due to its extensive genetic diversity and worldwide colonization, sorghum has considerable diversity for a range of phenotypes influencing productivity, composition, and sink/source dynamics. To dissect the genetic basis of these key traits, we present a sorghum carbon-partitioning nested association mapping (NAM) population generated by crossing 11 diverse founder lines with Grassl as the single recurrent female. By exploiting existing variation among cellulosic, forage, sweet, and grain sorghum carbon partitioning regimes, the sorghum carbon-partitioning NAM population will allow the identification of important biomass-associated traits, elucidate the genetic architecture underlying carbon partitioning and improve our understanding of the genetic determinants affecting unique phenotypes within Poaceae. We contrast this NAM population with an existing grain population generated using Tx430 as the recurrent female. Genotypic data are assessed for quality by examining variant density, nucleotide diversity, linkage decay, and are validated using pericarp and testa phenotypes to map known genes affecting these phenotypes. We release the 11-family NAM population along with corresponding genomic data for use in genetic, genomic, and agronomic studies with a focus on carbon-partitioning regimes.
Desired Characteristics of HIV Testing and Counseling among Diverse Survivors of Intimate Partner Violence Receiving Social Services
Authors: Gonzalez-Guarda Rosa Maria , Williams Jessica , Lorenzo Dalia , Carrington Cherelle
Published: March 2021

Despite recent calls to integrate HIV testing into social services addressing intimate partner violence (IPV), few studies have reported on survivors’ perspectives regarding the desired characteristics of this integration. The purpose of this study was to describe desired characteristics of HIV and sexually transmitted infection (STI) testing services from a survivor’s perspective. A qualitative descriptive approach was taken to describe the perspectives of IPV survivors who may or may not have accessed this service. Four focus groups were conducted with a diverse sample of English and Spanish speakers (N = 25) who sought services through a family justice center and associated shelters. Focus groups were recorded, transcribed, and analyzed using conventional content analysis. Three themes were identified, including (1) peace of mind; (2) interacting stigmas and traumas; and (3) making testing easy, comfortable, and tailored. The findings of this study have the potential to influence survivor-centered practices and policies regarding the integration of culturally informed HIV/STI and IPV services.
The Most Good You Can Do with Your Kidneys: Effective Altruism and the Organ-Shortage Problem
Authors: Tonkens Ryan
Published: March 2021

Effective altruism is a growing philosophical and social movement, whose members design their lives in ways aligned with doing the most good that they can do. The main focus of this paper is to explore what effective altruism has to say about the moral obligations people have to do good with their organs, in the face of an organ-shortage problem. It is argued that an effective altruism framework offers a number of valuable theoretical and practical insights relevant to ongoing debate about how to resolve the organ-shortage problem. Its recommendations constitute a plausible and promising strategy for increasing the supply of, and decreasing the demand for, human organs, in a way that protects (rather than ignores, or preys upon) the global poor. And, many of its recommendations can be implemented into policy without requiring that citizens actually become effective altruists themselves.
Extending modernist stream-of-consciousness aesthetics: Digital variations on William Faulkner’sThe Sound and the Fury
Authors: Wright David Thomas Henry
Published: March 2021

In the development of The Sound and the Fury (1929), William Faulkner proposed using coloured text to help the reader navigate the work’s stream-of-consciousness. Subsequent editors and textual critics have produced colourized versions of Faulkner’s novel. Inspired by these colourized print texts, the born-digital novel Little Emperor Syndrome (2018) was developed. This digital literary work and practice-led research explores the potential of born-digital modes to reimagine modernist stream-of-consciousness through recombinant poetics as defined by Bill Seaman (2001). Little Emperor Syndrome utilizes a stream-of-consciousness style inspired by the first and second (Benjy and Quentin) chapters of The Sound and the Fury. Using recombinant poetics, this digital text also allows the reader to recombine the text (or lexias) in various modes: ‘stream-of-consciousness’ (i.e. similar to Faulkner’s style), ‘cosmos’ (chronological), and ‘chaos’ (random). In Digital Modernism, American media theorist Jessica Pressman (2014) juxtaposes born-digital literature with the modernist period because of substantial points of connections between early 20th-century modernist literature and early 21st-century digital texts. This article does likewise. Through textual criticism, digital scholarship, and practice-led research, this article reimagines Faulkner’s modernist stream-of-consciousness. Following Pressman’s theory of ‘digital modernism,’ this article proposes that the digital recombinant poetics proposed by Seaman and exemplified in Little Emperor Syndrome represents an expression and extension of the high modernist aesthetic utilized by early 20th-century authors such as Faulkner.
Pyomyositis and Infectious Myositis: A Comprehensive, Single-Center Retrospective Study
Authors: Radcliffe Christopher , Gisriel Savanah , Niu Yu Si , Peaper David , Delgado Santiago , Grant Matthew
Published: March 2021

Background

Pyomyositis is a bacterial infection of skeletal muscle that classically leads to abscess formation. A related, but distinct, entity is infectious myositis. The epidemiology of these infections has changed in recent years.

Methods

To better characterize both pyomyositis and infectious myositis, we conducted a retrospective study at our tertiary care institution. We identified 43 cases of pyomyositis and 18 cases of infectious myositis treated between January 2012 and May 2020.

Results

The mean age of patients was 48 years, and 66% were male. Diabetes mellitus affected one third of patients, and 16% had other immunocompromising comorbidities. Staphylococcal species accounted for 46% of all infections, and common symptoms included muscle pain (95%) and subjective fever (49%). Altered mental status was a presenting symptom in 16% of cases. Approximately half of all patients received >1 class of antibiotic, and the median length of antimicrobial therapy was 18 days. Open and percutaneous drainage procedures figured prominently in the management of these infections, with 28% of patients requiring multiple procedures. Pathology specimens were available for 12 of 61 cases. Overall, the treatment success rate was 84%.

Conclusions

Gram-positive bacteria accounted for most infections at our institution, and management commonly involved open or percutaneous drainage procedures. Future studies that prospectively evaluate treatment strategies for pyomyositis and infectious myositis are warranted.
Discontinuation Patterns and Cost Avoidance of a Pharmacist-Driven Methicillin-Resistant Staphylococcus aureus Nasal Polymerase Chain Reaction Testing Protocol for De-escalation of Empiric Vancomycin for Suspected Pneumonia
Authors: Meng L , Pourali S , Hitchcock M M , Ha D R , Mui E , Alegria W , Fox E , Diep C , Swayngim R , Chang A , Banaei N , Deresinski S , Holubar M
Published: March 2021

A pharmacist-driven methicillin-resistant Staphylococcus aureus (MRSA) nasal polymerase chain reaction (PCR)-based testing protocol with a 70% acceptance rate for vancomycin discontinuation within 24 hours of negative results significantly reduced unnecessary vancomycin use with an estimated cost avoidance of $40 per vancomycin course. We found high concordance (141 of 147, 96%) of culture-based versus PCR-based MRSA nasal screening.
Dynastic Precautionary Savings
Authors: Boar Corina
Published: March 2021

This article documents that parents accumulate savings to insure their children against income risk. I refer to this behaviour as dynastic precautionary saving. Using a sample of matched parent–child pairs from the Panel Study of Income Dynamics, I test for dynastic precautionary savings by examining the response of parental consumption to the child’s permanent income uncertainty. I exploit variation in permanent income risk across age and industry–occupation groups to confirm that, all else equal, higher uncertainty in the child’s permanent income depresses parental consumption, indicating a precautionary saving motive across generations.
Ganoderic acid T improves the radiosensitivity of HeLa cells via converting apoptosis to necroptosis
Authors: Shao Chang-Sheng , Feng Na , Zhou Shuai , Zheng Xin-Xin , Wang Peng , Zhang Jing-Song , Huang Qing
Published: March 2021

The use of natural substances derived from traditional Chinese medicine and natural plants as safe radiosensitizing adjuvants is a new trend for cancer radiotherapy. Ganoderma lucidum has been used as a traditional Chinese medicine with a history of more than 2000 years. Ganoderic acid T (GAT) is a typical triterpene of G. lucidum, which has strong cytotoxicity to cancer cells, but whether it has radiation sensitization effect has not been explored. In this work, we treated the HeLa cells with different concentrations of GAT before exposure to gamma-ray radiation and investigated its influence on the radiosensitivity. The cell viability, apoptosis rate, necoptosis rate, intracellular ATP level, cell cycle, the amount of H2AX and 53BP1, reactive oxygen species, and mitochondrial membrane potential were examined. Apoptotic, necroptotic, and autophagic biomarker proteins, including caspase 8, cytochrome c, caspase 3, RIPK, MLKL, P62, and LC3, were analyzed. As a result, we confirmed that with treatment of GAT, the gamma-ray radiation induced both apoptosis and necroptosis in HeLa cells, and with increase of GAT, the percentage ratio of necroptosis was increased. The involved pathways and mechanisms were also explored and discussed.
Synergistic Antimicrobial Effect of Chitosan Polymers and Oligomers
Authors: Attjioui Maha , Gillet Dominique , El Gueddari Nour Eddine , Moerschbacher Bruno M.
Published: March 2021

This study evaluated the efficacy of the combined application of well-characterized chitosan polymer (degree of acetylation = 10%, degree of polymerization [DPn] = 90, and dispersity [ÐDP] = 2.8) and oligomers (partially acetylated chitosan polymers and oligosaccharides [paCOS]) (DP = 2 to 17) on conidia germination and mycelial growth of Fusarium graminearum, the major causal agent of Fusarium head blight in wheat. The polymer alone showed a higher inhibitory effect than the paCOS mixture alone, with half-maximal inhibitory concentrations of less than 50 µg ml−1 and more than 100 µg ml−1, respectively. Using time-lapse microscopy, we also showed that paCOS did not affect conidia germination at 50 µg ml−1, whereas chitosan polymer at the same concentration led to a delay in germination and in elongation of germ tubes. Scanning electron microscopy was used to observe the chitosan-induced changes in hyphal morphology. Surprisingly, the combination of chitosan polymer and paCOS led to strong synergistic effects in inhibiting conidia germination and fungal growth, as quantified by both the Abbot and Wadley equations. To our knowledge, this is the first report on a synergistic effect of a combination of chitosan polymers and oligomers, also highlighting for the first time the importance of ÐDP when studying structure–function relationships of functional biopolymers such as chitosan. The consequences of this finding for the improvement of chitosan-based antimicrobial or plant protective products are discussed. Given the economic importance of F. graminearum, this study suggests that the combination of chitosan polymer and oligomers can be used to support an efficient, sustainable plant protection strategy.

[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY 4.0 International license .
Favorable response to combined androgen blockade for metastatic cutaneous apocrine carcinoma: a case report
Authors: Imajima Takashi , Ito Mamoru , Shinohara Yudai , Tsuchihashi Kenji , Ariyama Hiroshi , Kusaba Hitoshi , Yamamoto Hidetaka , Oda Yoshinao , Akashi Koichi , Baba Eishi
Published: March 2021

Introduction:

Most cases of cutaneous apocrine carcinoma (CAC) express androgen receptor. Androgen signal is thought to have a relationship on the survival and cell growth of the tumor.

Presentation of Case:

A 53-year-old man with a red superficial nodule on the left axilla and a back pain was diagnosed with CAC in the left axilla with multiple bone and bone marrow metastases. After cytotoxic chemotherapy for around 4 years, severe anemia, thrombocytopenia, and disseminated intravascular coagulation progressed. We started combined androgen blockade by bicaltamide and degarelix, and the therapy had successfully maintained stable disease for more than 6 months.

Discussion:

Most cases of CAC express androgen receptor. Androgen signal could have a relationship on the survival and cell growth of the tumor.

Conclusion:

Antiandrogen therapy for androgen-receptor positive CAC is a promising therapeutic option.
Bromhexine Hydrochloride Prophylaxis of COVID-19 for Medical Personnel: A Randomized Open-Label Study
Authors: Mikhaylov Evgeny N , Lyubimtseva Tamara A , Vakhrushev Aleksandr D , Stepanov Dmitry , Lebedev Dmitry S , Vasilieva Elena Yu , Konradi Alexandra O , Shlyakhto Evgeny V
Published: March 2021

Background: Bromhexine hydrochloride has been suggested as a TMPRSS2 protease blocker that precludes the penetration of SARS-CoV-2 into cells. We aimed to assess the preventive potential of regular bromhexine hydrochloride intake for COVID-19 risk reduction in medical staff actively involved in the evaluation and treatment of patients with confirmed or suspected SARS-CoV-2 infection.
Methods: In a single-center randomized open-label study, medical staff managing patients with suspected and confirmed COVID-19 were enrolled and followed up for 8 weeks. The study began at the initiation of COVID-19 management in the clinic. The study was prematurely terminated after the enrollment of 50 participants without a history of SARS-CoV-2 infection: 25 were assigned to bromhexine hydrochloride treatment (8 mg 3 times per day), and 25 were controls. The composite primary endpoint was a positive nasopharyngeal swab polymerase chain reaction (PCR) test for SARS-CoV-2 or signs of clinical infection within 28 days and at week 8. Secondary endpoints included: time from the first contact with a person with COVID-19 to the appearance of respiratory infection symptoms; the number of days before a first positive SARS-CoV-2 test; the number of asymptomatic participants with a positive nasopharyngeal swab test; the number of symptomatic COVID-19 cases; adverse events.
Results: The rate of the combined primary endpoint did not differ significantly between the active treatment group (2/25 [8%]) and control group (7/25 [28%]); P=0.07. A fewer number of participants developed symptomatic COVID-19 in the treatment group compared to controls (0/25 vs 5/25; P = 0.02).
Conclusion: Although the study was underpowered, it showed that Bromhexine hydrochloride prophylaxis was associated with a reduced rate of symptomatic COVID-19. The prophylactic treatment was not associated with a lower combined primary endpoint rate, a positive swab PCR test, or COVID-19. (ClinicalTrials.gov number, NCT04405999)
Risk factor targeting for vaccine prioritization during the COVID-19 pandemic
Authors: Chapman Lloyd A. C. , Shukla Poojan , Rodríguez-Barraquer Isabel , Shete Priya B. , León Tomás M. , Bibbins-Domingo Kirsten , Rutherford George W. , Schechter Robert , Lo Nathan C.
Published: March 2021

A key public health question during any disease outbreak when limited vaccine is available is who should be prioritized for early vaccination. Most vaccine prioritization analyses only consider variation in risk of infection and death by a single risk factor, such as age. We provide a more granular approach with stratification by demographics, risk factors, and location. We use this approach to compare the impact of different COVID-19 vaccine prioritization strategies on COVID-19 cases, deaths and disability-adjusted life years (DALYs) over the first 6 months of vaccine rollout, using California as a case example. We estimate the proportion of cases, deaths and DALYs averted relative to no vaccination for strategies prioritizing vaccination by a single risk factor and by multiple risk factors (e.g. age, location). We find that age-based targeting averts the most deaths (62% for 5 million individuals vaccinated) and DALYs (38%) of strategies targeting by a single risk factor and targeting essential workers averts the least deaths (31%) and DALYs (24%) over the first 6 months of rollout. However, targeting by two or more risk factors simultaneously averts up to 40% more DALYs. Our findings highlight the potential value of multiple-risk-factor targeting of vaccination against COVID-19 and other infectious diseases.
Design of optical cavity for air sanification through ultraviolet germicidal irradiation
Authors: Lombini Matteo , Diolaiti Emiliano , De Rosa Adriano , Lessio Luigi , Pareschi Giovanni , Bianco Andrea , Cortecchia Fausto , Fiorini Mauro , Fiorini Giulia , Malaguti Giuseppe , Zanutta Alessio
Published: March 2021

The transmission of airborne pathogens represents a major issue to worldwide public health. Ultraviolet light irradiation can contribute to the sanification of air to reduce the pathogen transmission. This study concerns the design of a compact filter for airborne pathogen inactivation by means of UV-C LED sources, whose effective irradiance is enhanced thanks to high reflective surfaces. Ray-tracing and computational fluid dynamic simulations are both used to model the device and to maximize the performance inside the filter volume. Simulations foresee the inhibition of SARS-Cov 2 also in the case of high air fluxes. This study demonstrates that current available LED technology is effective for air sanification purposes.
Image- vs. histogram-based considerations in semantic segmentation of pulmonary hyperpolarized gas images
Authors: Tustison Nicholas J. , Altes Talissa A. , Qing Kun , He Mu , Miller G. Wilson , Avants Brian B. , Shim Yun M. , Gee James C. , Mugler John P. , Mata Jaime F.
Published: March 2021

Magnetic resonance imaging (MRI) using hyperpolarized gases has made possible the novel visualization of airspaces in the human lung, which has advanced research into the growth, development, and pathologies of the pulmonary system. In conjunction with the innovations associated with image acquisition, multiple image analysis strategies have been proposed and refined for the quantification of such lung imaging with much research effort devoted to semantic segmentation, or voxelwise classification, into clinically oriented categories based on ventilation levels. Given the functional nature of these images and the consequent sophistication of the segmentation task, many of these algorithmic approaches reduce the complex spatial image information to intensity-only considerations, which can be contextualized in terms of the intensity histogram. Although facilitating computational processing, this simplifying transformation results in the loss of important spatial cues for identifying salient image features, such as ventilation defects (a well-studied correlate of lung pathophysiology), as spatial objects. In this work, we discuss the interrelatedness of the most common approaches for histogram-based optimization of hyperpolarized gas lung imaging segmentation and demonstrate how certain assumptions lead to suboptimal performance, particularly in terms of measurement precision. In contrast, we illustrate how a convolutional neural network is optimized (i.e., trained) directly within the image domain to leverage spatial information. This image-based optimization mitigates the problematic issues associated with histogram-based approaches and suggests a preferred future research direction. Importantly, we provide the entire processing and evaluation framework, including the newly reported deep learning functionality, as open-source through the well-known Advanced Normalization Tools ecosystem.
COVID-19 mRNA vaccine is not detected in human milk
Authors: Golan Yarden , Prahl Mary , Cassidy Arianna , Lin Christine Y. , Ahituv Nadav , Flaherman Valerie J. , Gaw Stephanie L.
Published: March 2021

Several countries have recently approved the use of mRNA vaccines against COVID-19 under an emergency use authorization. However, no pregnant or lactating individuals were included in the Phase 3 clinical trials of these vaccines despite belonging to a group at high risk for severe complications of COVID-19 infection. We show here that the mRNA from anti-COVID BNT162b2 (Pfizer) and mRNA-1273 (Moderna) vaccines is not detected in human breast milk samples collected 4-48 hours post-vaccine. These results strengthen the recommendation of ABM and WHO that lactating individuals who receive the anti-COVID-19 mRNA-based vaccine should continue to breastfeed their infants uninterrupted.
Dynamics of the auditory continuity illusion
Authors: Cao Qianyi , Parks Noah , Goldwyn Joshua H.
Published: March 2021

Illusions give intriguing insights into perceptual and neural dynamics. In the auditory continuity illusion, two brief tones separated by a silent gap may be heard as one continuous tone if a noise burst with appropriate characteristics fills the gap. This illusion probes the conditions under which listeners link related sounds across time and maintain perceptual continuity in the face of sudden changes in sound mixtures. Conceptual explanations of this illusion have been proposed, but its neural basis is still being investigated. In this work we provide a dynamical systems framework, grounded in principles of neural dynamics, to explain the continuity illusion. We construct an idealized firing rate model of a neural population and analyze the conditions under which firing rate responses persist during the interruption between the two tones. First, we show that sustained inputs and hysteresis dynamics (a mismatch between tone levels needed to activate and inactivate the population) can produce continuous responses. Second, we show that transient inputs and bistable dynamics (coexistence of two stable firing rate levels) can also produce continuous responses. Finally, we combine these input types together to obtain neural dynamics consistent with two requirements for the continuity illusion as articulated in a well-known theory of auditory scene analysis: sustained responses occur if noise provides sufficient evidence that the tone continues and if there is no evidence of discontinuities between the tones and noise. By grounding these notions in a quantitative model that incorporates elements of neural circuits (recurrent excitation, and mutual inhibition, specifically), we identify plausible mechanisms for the continuity illusion. Our findings can help guide future studies of neural correlate of this illusion and inform development of more biophysically-based models of the auditory continuity illusion.
Placenta DNA methylation atZNF300is associated with fetal sex and placental morphology
Authors: Ladd-Acosta Christine , Andrews Shan V. , Bakulski Kelly M. , Feinberg Jason I. , Tryggvadottir Rakel , Yao Ruofan , Croen Lisa A. , Hertz-Picciotto Irva , Newschaffer Craig J. , Salafia Carolyn M. , Feinberg Andrew P. , Hansen Kasper D. , Daniele Fallin M.
Published: March 2021

Fetal sex-specific differences in placental morphology and physiology have been associated with sexually dimorphic health outcomes. However, the molecular mechanisms underlying these sex differences are not well understood. We performed whole genome bisulfite sequencing in 133 placenta samples and discovered a significant difference in DNA methylation (DNAm) at theZNF300gene locus between male and female offspring and replicated this result in 6 independent datasets. Additionally, the sex-specific pattern appears to be placenta-specific, is robust to a wide range of gestational ages and adverse health outcomes and is present in sorted placenta villous cytotrophoblast cells. Integration of DNAm, genetic, and placental morphology data from the same individuals revealedZNF300methylation is also associated with placenta area, perimeter, and max diameter, genetic variants on chromosomes 5 and X, and may mediate the effects of genetic variation on placental area.
Procollagen C-Proteinase Enhancer 1 (PCPE-1) is a marker of myocardial fibrosis and impaired cardiac function in a murine model of pressure overload
Authors: Lagoutte Priscillia , Oudot Alexandra , Dussoyer Mélissa , Goncalves Victor , Guillemin Mélanie , Bouchot Olivier , Vandroux David , Bellaye Pierre-Simon , Moali Catherine , Goff Sandrine Vadon-Le
Published: March 2021

(1)

Aims

Procollagen C-proteinase enhancer 1 (PCPE-1) is an extracellular matrix protein and a major regulator of fibrillar collagen biosynthesis. Previous work has shown that its abundance is often increased in the context of tissue repair and fibrosis. The present study was designed to evaluate its potential as a biomarker of myocardial interstitial fibrosis (MIF), a well-established pathogenic pathway leading to heart failure.

(2)

Methods and Results

Cardiac fibrosis was induced in rats using an optimized model of chronic pressure overload triggered by angiotensin II and Nω-nitro-L-arginine methyl ester (L-NAME). All treated animals suffered from heart hypertrophy and the increase in heart collagen volume fraction (CVF), evidenced by histology and68Ga-Collagelin uptake, confirmed the development of cardiac fibrosis. Functional analysis by simultaneous PET-MRI further showed that our model closely reflected the pathological features seen in human MIF, including left ventricle thickening and diastolic dysfunction associated with decreased ejection fraction. PCPE-1 mRNA and protein levels were augmented by factors of 3.4 and 6.1 respectively in the heart tissue of treated rats. Moreover, protein abundance was well-correlated with CVF (r=0.92, p<0.0001) and PCPE-1 immuno-detection mainly localized the protein to fibrotic areas. Finally, PCPE-1 plasma levels measured by ELISA were increased in fibrotic rats compared to controls.

(3)

Conclusion

Together, our findings demonstrate that PCPE-1 levels in the heart and circulation tightly reflect the cardiac fibrosis status and heart function impairment in rats and suggest that it could be a very useful marker to monitor human heart diseases leading to fibrosis.
TCRβrearrangements without D-segment are common, abundant and public
Authors: de Greef Peter C. , de Boer Rob J.
Published: March 2021

T cells play an important role in adaptive immunity. An enormous clonal diversity of T-cells with a different specificity, encoded by the T-cell receptor (TCR), protect the body against infection. Most TCRβchains are generated from a V-, D-, and J-segment during recombination in the thymus. Although complete absence of the D-segment is not easily detectable from sequencing data, we find convincing evidence for a substantial proportion of TCRβrearrangements lacking a D-segment. Additionally, sequences without a D-segment are more likely to be abundant within individuals and/or shared between individuals. We find that such sequences are preferentially generated during fetal development and persist within the elderly. Summarizing, TCRβrearrangements without a D-segment are not uncommon, and tend to allow for TCRβchains with a high abundance in the naive repertoire.
Interleukin-17A causes osteoarthritis-like transcriptional changes in human osteoarthritis-derived chondrocytes and synovial fibroblastsin vitro
Authors: Mimpen Jolet Y. , Baldwin Mathew J. , Cribbs Adam P. , Philpott Martin , Carr Andrew J. , Dakin Stephanie G. , Snelling Sarah J.B.
Published: March 2021

Increased interleukin (IL)-17A has been identified in joints affected by osteoarthritis (OA), but it is unclear how IL-17A, and its family members IL-17AF and IL-17F, can contribute to human OA pathophysiology. Therefore, we aimed to evaluate the gene expression and signalling pathway activation effects of the different IL-17 family members in fibroblasts derived from cartilage and synovium of patients with end-stage knee OA. Immunohistochemistry staining confirmed that IL-17 receptors A (IL-17RA) and IL-17RC are expressed in end-stage OA-derived cartilage and synovium. Chondrocytes and synovial fibroblasts derived from end-stage OA patients were treated with IL-17A, IL-17AF, or IL-17F, and gene expression was assessed with bulk RNA-Seq. Hallmark pathway analysis showed that IL-17 cytokines regulated several OA pathophysiology-related pathways including immune-, angiogenesis-, and complement-pathways in both chondrocytes and synovial fibroblasts derived from end-stage OA patients. While overall IL-17A induced the strongest transcriptional response, followed by IL-17AF and IL-17F, not all genes followed this pattern. Disease-Gene Network analysis revealed that IL-17A-related changes in gene expression in these cells are associated with experimental arthritis, knee arthritis, and musculoskeletal disease gene-sets. Western blot analysis confirmed that IL-17A significantly activates p38 and p65 NF-κB. Incubation of chondrocytes and synovial fibroblasts with IL-17A antibody secukinumab significantly inhibited IL-17A-induced gene expression. In conclusion, the association of IL-17-induced transcriptional changes with arthritic gene-sets supports a role for IL-17A in OA pathophysiology. Therefore, secukinumab could be investigated as a potential therapeutic option in OA patients.
Parallel inference of hierarchical latent dynamics in two-photon calcium imaging of neuronal populations
Authors: Prince Luke Y. , Bakhtiari Shahab , Gillon Colleen J. , Richards Blake A.
Published: March 2021

Dynamic latent variable modelling has provided a powerful tool for understanding how populations of neurons compute. For spiking data, such latent variable modelling can treat the data as a set of point-processes, due to the fact that spiking dynamics occur on a much faster timescale than the computational dynamics being inferred. In contrast, for other experimental techniques, the slow dynamics governing the observed data are similar in timescale to the computational dynamics that researchers want to infer. An example of this is in calcium imaging data, where calcium dynamics can have timescales on the order of hundreds of milliseconds. As such, the successful application of dynamic latent variable modelling to modalities like calcium imaging data will rest on the ability to disentangle the deeper- and shallower-level dynamical systems’ contributions to the data. To-date, no techniques have been developed to directly achieve this. Here we solve this problem by extending recent advances using sequential variational autoencoders for dynamic latent variable modelling of neural data. Our system VaLPACa (Variational Ladders for Parallel Autoencoding of Calcium imaging data) solves the problem of disentangling deeper- and shallower-level dynamics by incorporating a ladder architecture that can infer a hierarchy of dynamical systems. Using some built-in inductive biases for calcium dynamics, we show that we can disentangle calcium flux from the underlying dynamics of neural computation. First, we demonstrate with synthetic calcium data that we can correctly disentangle an underlying Lorenz attractor from calcium dynamics. Next, we show that we can infer appropriate rotational dynamics in spiking data from macaque motor cortex after it has been converted into calcium fluorescence data via a calcium dynamics model. Finally, we show that our method applied to real calcium imaging data from primary visual cortex in mice allows us to infer latent factors that carry salient sensory information about unexpected stimuli. These results demonstrate that variational ladder autoencoders are a promising approach for inferring hierarchical dynamics in experimental settings where the measured variable has its own slow dynamics, such as calcium imaging data. Our new, open-source tool thereby provides the neuroscience community with the ability to apply dynamic latent variable modelling to a wider array of data modalities.
Moral Hazard Heterogeneity: Genes and Health Insurance Influence Smoking after a Health Shock
Authors: Biroli Pietro , Zwyssig Laura
Published: March 2021

Decision-making in the realm of health behaviors, such as smoking or drinking, is influenced both by biological factors, such as genetic predispositions, as well as environmental factors, such as financial liquidity and health insurance status. We show how the choice of smoking after a cardio-vascular health shock is jointly determined by the interaction between these biological and environmental constraints. Individuals who suffer a health shock when uninsured are 25.6 percentage points more likely to reduce smoking, but this is true only for those who have a low index of genetic predisposition to smoking. Individuals with a low index of genetic predisposition are more strategic and flexible in their behavioral response to an external shock. This differential elasticity of response depending on your genetic variants is evidence of individual-level heterogeneity in moral hazard. These results suggest that genetic heterogeneity is a factor that should be considered when evaluating the importance and fairness of health insurance policies.

JEL CODES

I12, I13, D63, D91
A Rapid Method to Evaluate Pre-Travel Programs for COVID-19: A Study in Hawaii
Authors: Hou Amy T. , Pang Genevieve C. , Mills Kristin M. , Bayudan Krizhna L. , Moore Dayna M. , Medina Luz P. , Pang Lorrin W.
Published: March 2021

Background

Pre-travel testing programs are being implemented around the world to curb COVID-19 and its variants from incoming travelers. A common approach is a single pre-travel test, 72 hours before departure, such as in Hawaii; however this raises concerns for those who are incubating or those infected after pre-travel testing or during transit. We need a rapid method to assess the effectiveness of pre-travel testing programs, and we use Hawaii as our case study.

Methods

We invited travelers departing from Kahului main airport at the end of their visit to Maui (major tourist destination among the Hawaiian islands) and performed COVID-19 PCR testing. Eligible participants needed a negative pre-travel test and a Hawaiian stay ≤ 14 days. We designed for anonymous testing at the end of travel so that travel plans would be unaffected, and we aimed for ≥ 70% study participation.

Results

Among consecutive eligible travelers, 282 consented and 111 declined to participate, leading to a 72% (67-76%, 95% confidence interval) participation rate. Among 281 tested participants, two were positive with COVID-19, with an estimated positivity rate of 7 cases per 1,000 travelers. The top states of residence are California (58%) and Washington (21%). The mean length of stay was 7.7 ± 0.2 days. Regarding pre-travel testing, 87% had non-nasopharyngeal tests and 66% had self-administered tests.

Conclusions

This positivity rate leads to an estimated 17-30 infected travelers arriving daily to Maui in November-December 2020, and an estimated 52-70 infected travelers arriving daily to Hawaii during the same period. These counts surpass the Maui District Health Office’s projected ability to accommodate 10 infected visitors daily in Maui; therefore, an additional mitigation layer for travelers is recommended. This rapid field study can be replicated widely in airports to assess effectiveness of pre-travel programs and can be expanded to evaluate COVID-19 importation and its variants.
Robust methylation-based classification of brain tumors using nanopore sequencing
Authors: Kuschel Luis P. , Hench Jürgen , Frank Stephan , Hench Ivana Bratic , Girard Elodie , Blanluet Maud , Masliah-Planchon Julien , Misch Martin , Onken Julia , Czabanka Marcus , Karau Philipp , Ishaque Naveed , Hain Elisabeth G. , Heppner Frank , Idbaih Ahmed , Behr Nikolaus , Harms Christoph , Capper David , Euskirchen Philipp
Published: March 2021

DNA methylation-based classification of cancer provides a comprehensive molecular approach to diagnose tumors. In fact, DNA methylation profiling of human brain tumors already profoundly impacts clinical neuro-oncology. However, current implementations using hybridization microarrays are time-consuming and costly. We recently reported on shallow nanopore whole-genome sequencing for rapid and cost-effective generation of genome-wide 5-methylcytosine profiles as input to supervised classification using random forests complemented by a medium-resolution copy number profile derived from the same raw data. Here, we demonstrate that this approach allows to discriminate a wide spectrum of primary brain tumors using public reference data of 82 distinct tumor entities. We developed a pseudo-probability score as a confidence score for interpretation in a clinical context. Using bootstrap sampling in a discovery cohort of N = 56 cases, we find that a minimum set of 1,000 random CpG features is sufficient for high-confidence classification by ad hoc random forests for most cases and demonstrate robustness across laboratories with matching results in 13/13 cases. When applying the confidence score threshold to an independent validation series (N = 111), the method demonstrated 100% specificity for the remaining 93 cases. In a prospective benchmarking (N = 15), median time to results was 21.1 hours. In conclusion, nanopore sequencing allows robust and rapid methylation-based classification across the full spectrum of brain tumors. The integrated confidence score facilitates possible clinical implementation, while requiring further prospective evaluation.
Estimating the impact of reopening schools on the reproduction number of SARS-CoV-2 in England, using weekly contact survey data
Authors: Munday James D , I Jarvis Christopher , Gimma Amy , Wong Kerry LM , Zandvoort Kevin van ,   CMMID COVID-19 Working Group, Funk Sebastian , Edmunds W. John
Published: March 2021

Background

Schools have been closed in England since the 4th of January 2021 as part of the national restrictions to curb transmission of SARS-CoV-2. The UK Government plans to reopen schools on the 8th of March. Although there is evidence of lower individual-level transmission risk amongst children compared to adults, the combined effects of this with increased contact rates in school settings are not clear.

Methods

We measured social contacts when schools were both open or closed, amongst other restrictions. We combined these data with estimates of the susceptibility and infectiousness of children compared with adults to estimate the impact of reopening schools on the reproduction number.

Results

Our results suggest that reopening all schools could increase R from an assumed baseline of 0.8 to between 1.0 and 1.5, or to between 0.9 and 1.2 reopening primary or secondary schools alone.

Conclusion

Our results suggest that reopening schools is likely to halt the fall in cases observed in recent months and risks returning to rising infections, but these estimates rely heavily on the current estimates or reproduction number and the current validity of the susceptibility and infectiousness profiles we use.