bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical identification of malignant pleural effusions
Authors: Jia Jianlong , Marazioti Antonia , Voulgaridis Apostolos , Psallidas Ioannis , Lamort Anne-Sophie , Iliopoulou Marianthi , Krontira Anthi C. , Lilis Ioannis , Asciak Rachelle , Kanellakis Nikolaos I. , Rahman Najib M. , Karkoulias Kyriakos , Spiropoulos Konstantinos , Liu Ruonan , Kaiser Jan-Christian , Stathopoulos Georgios T.
Published: June 2020

Importance

Pleural effusions frequently signal disseminated cancer. Diagnostic markers of pleural malignancy at presentation that would assess cancer risk and would streamline diagnostic decisions remain unidentified.

Objective

The present study aimed at identifying and validating predictors of malignant pleural effusion at patient presentation.

DESIGN, SETTING, AND PARTICIPANTS

A consecutive cohort of 323 patients with pleural effusion (PE) from different etiologies were recruited between 2013-2017 and was retrospectively analyzed. Data included history, chest X-ray, and blood/pleural fluid cell counts and biochemistry. Group comparison, receiver-operator characteristics, unsupervised hierarchical clustering, binary logistic regression, and random forests were used to develop the malignant pleural effusion detection (MAPED) score. MAPED was validated in an independent retrospective UK cohort (n= 238).

Main Outcomes and Measures

The outcome was diagnostic of pleural effusion in patients, and the clinical and laboratory indicators available of the patient were measured.

Results

Five variables showed significant diagnostic power and were incorporated into the 5-point MAPED score. Age > 55 years, effusion size > 50% of the most affected lung field, pleural neutrophil count < 2,500/mm3, effusion protein > 3.5 g/dL, and effusion lactate dehydrogenase > 250 U/L, each scoring one point, predicted underlying cancer with the area under curve(AUC) = 0.819 (sensitivity=82%, specificity=74%,P< 10-15) in the derivation cohort. The AUC and net reclassification improvement (NRI) of MAPED score and cytology were not significantly different. However, the integrated discrimination improvement (IDI) of The MAPED score displayed a slight increment(P<0.001). The calibration curves of the cytology model were slightly better than The MAPED score. Decision curve analysis (DCA) indicated that The MAPED score generated net clinical benefit. In the validation dataset, the results were generally consistent with the above findings, with an AUC of 0.723 (sensitivity=76%, specificity=62%, P =3*10-9) for The MAPED score. Interestingly, MAPED correctly identified 33/42(79%) of cytology-negative patients that indeed had cancer. The MAPED score is used to create nomogram so clinicians can predict the probability of malignant pleural effusions.

Conclusions

The MAPED score identifies malignant pleural effusions with satisfactory accuracy and can be used complementary to cytology to streamline diagnostic procedures.
Covid-19 and Population Age Structure
Authors: Haridas Ajit , Prathap Gangan
Published: June 2020

Epidemiological studies suggest that age distribution of a population has a non-trivial effect on how morbidity rates, mortality rates and case fatality rates (CFR) vary when there is an epidemic or pandemic. We look at the empirical evidence from a large cohort of countries to see the sensitivity of Covid-19 data to their respective median ages. The insights that emerge could be used to control for age structure effects while investigating other factors like cross-protection, comorbidities, etc.
A Projection Model of COVID-19 Pandemic for Belgium
Authors: Ruzhansky Michael , Tokmagambetov Niyaz , Torebek Berikbol T.
Published: June 2020

We consider a simple model for the COVID-19 pandemic to analyse the relative effectiveness of several stages of the lockdown in Belgium, as well as of several phases of its relaxation. We also make a future projection of different types of measures relative to different stages of the already experienced lockdown.
Model Based Covid-19 Case Studies in the UK, the USA and India
Authors: Basu Santanu
Published: June 2020

Time dependent spread of Covid-19 among the population of the UK, the USA and India is analyzed using a recently developed mathematical model [1-3]. Results of model predictions of case growth in these countries during the next six weeks are also presented. The model is applicable to case studies and near term predictions for other countries and regions.
Roadmap to Help Develop Personalized Targeted Treatments for Autism as a Disorder of the Nervous Systems
Authors: Torres Elizabeth B
Published: June 2020

There is a disconnect between the clinical behavioral definition of autism and the genomic science that this definition largely informs and steers. But the digital sensor revolution paired with open access to genomics data has the potential to bridge the gap between these two layers of knowledge. Here we use the SFARI genes module and interrogate the human genome upon removing those genes. We then compare the remaining genes’ expression on tissues responsible for brain, heart and organs function to its counterpart in well-known neurological disorders of genetic origins. Despite clinical criteria emphasizing a behavioral definition of Autism, over a neurological one, here we find convergence between Autism and the neurological disorders. Tissues involved in motor control, emotions and memory are the most affected by the removal of the SFARI Autism genes. Congruent with this picture, the Ataxias, Parkinson’s disease and Fragile X share 76.9% of the most affected tissues, including those related to motor control and autonomic function, while mitochondria disorder share 61.5% with autism. Together, these results offer a new roadmap to help diagnosis and personalized targeted treatments of autism. They underscore Autism as an objectively quantifiable disorder of the nervous systems.
Inhibition of Angiotensin II Dependent AT1a Receptor Stimulation Attenuates Thoracic Aortic Pathology in Fibrillin-1C1041G/+Mice
Authors: Chen Jeff Z. , Sawada Hisashi , Moorleghen Jessica J. , Franklin Michael K. , Howatt Deborah A. , Sheppard Mary B. , Mullick Adam E. , Lu Hong S. , Daugherty Alan
Published: June 2020

Graphic Abstract

Objective

A cardinal feature of Marfan syndrome is thoracic aortic aneurysm (TAA). The contribution of ligand-dependent stimulation of angiotensin II receptor type 1a (AT1aR) to TAA progression remains controversial because the beneficial effects of angiotensin receptor blockers have been ascribed to off-target effects. This study used genetic and pharmacologic modes of attenuating angiotensin receptor and ligand, respectively, to determine their roles on TAA in mice with fibrillin-1 haploinsufficiency (Fbn1C1041G/+).

Approach and Results

TAA in Fbn1C1041G/+mice were determined in both sexes and found to be strikingly sexual dimorphic. Males displayed progressive dilation over 12 months while ascending aortic dilation in Fbn1C1041G/+females did not differ significantly from wild type mice. To determine the role of AT1aR, Fbn1C1041G/+mice that were either +/+ or −/− for AT1aR were generated. AT1aR deletion reduced progressive expansion of ascending aorta and aortic root diameter from 1 to 12 months of age in males. Medial thickening and elastin fragmentation were attenuated. An antisense oligonucleotide against angiotensinogen (AGT-ASO) was administered to male Fbn1C1041G/+mice to determine the effects of angiotensin II depletion. AGT-ASO administration, at doses that markedly reduced plasma AGT concentrations, attenuated progressive dilation of the ascending aorta and aortic root. AGT-ASO also reduced medial thickening and elastin fragmentation.

Conclusions

Genetic approaches to delete AT1aR and deplete AngII production exerted similar effects in attenuating pathology in the proximal thoracic aorta of male Fbn1C1041G/+mice. These data are consistent with ligand (AngII) dependent stimulation of AT1aR being responsible for aortic disease progression.

Highlights

Profound sexual dimorphism of aortic disease occurs in Fbn1C1041G/+mice, with female mice being more resistant and male mice being more susceptible.

Inhibition of the AngII-AT1aR axis attenuates aortic pathology in male Fbn1C1041G/+mice.

Antisense oligonucleotides targeting angiotensinogen deplete plasma angiotensinogen and attenuate thoracic aortic aneurysms.
“Estimating abundance and phenology from transect count data with GLMs”
Authors: Edwards Collin , Crone Elizabeth E.
Published: June 2020

Estimating population abundance is central to population ecology. With increasing concern over declining insect populations, estimating trends in abundance has become even more urgent. At the same time, there is an emerging in interest in quantifying phenological patterns, in part because phenological shifts are one of the most conspicuous signs of climate change. Existing techniques to fit activity curves (and thus both abundance and phenology) to repeated transect counts of insects (a common form of data for these taxa) frequently fail for sparse data, and often require advanced knowledge of statistical computing. These limitations prevent us from understanding both population trends and phenological shifts, especially in the at-risk species for which this understanding is most vital. Here we present a method to fit repeated transect count data with Gaussian curves using linear models, and show how robust abundance and phenological metrics can be obtained using standard regression tools. We then apply this method to eight years of Baltimore checkerspot data using generalized linear models (GLMs). This case study illustrates the ability of our method to fit even years with only a few non-zero survey counts, and identifies a significant negative relationship between population size and annual variation in thermal environment (in growing degree days). We believe our new method provides a key tool to unlock previously-unusable sparse data sets, and may provide a useful middle ground between ad hoc metrics of abundance and phenology and custom-coded mechanistic models.
Prefrontal and Parietal Attractor Networks Mediate Working Memory Judgments
Authors: Li Sihai , Constantinidis Christos , Qi Xue-Lian
Published: June 2020

The dorsolateral prefrontal cortex plays a critical role in spatial working memory and its activity predicts behavioral responses in delayed response tasks. Here we addressed whether this predictive ability extends to categorical judgments based on information retained in working memory, and is present in other brain areas. We trained monkeys in a novel, Match-Stay, Nonmatch-Go task, which required them to observe two stimuli presented in sequence with an intervening delay period between them. If the two stimuli were different, the monkeys had to saccade to the location of the second stimulus; if they were the same, they held fixation. Neurophysiological recordings were performed in areas 8a and 46 of the dlPFC and 7a and lateral intraparietal cortex (LIP) of the PPC. We hypothesized that random drifts causing the peak activity of the network to move away from the first stimulus location and towards the location of the second stimulus would result in categorical errors. Indeed, for both areas, when the first stimulus appeared in a neuron’s preferred location, the neuron showed significantly higher firing rates in correct than in error trials. When the first stimulus appeared at a nonpreferred location and the second stimulus at a preferred, activity in error trials was higher than in correct. The results indicate that the activity of both dlPFC and PPC neurons is predictive of categorical judgments of information maintained in working memory, and the magnitude of neuronal firing rate deviations is revealing of the contents of working memory as it determines performance.

SIGNIFICANCE STATEMENT

The neural basis of working memory and the areas mediating this function is a topic of controversy. Persistent activity in the prefrontal cortex has traditionally been thought to be the neural correlate of working memory, however recent studies have proposed alternative mechanisms and brain areas. Here we show that persistent activity in both the dorsolateral prefrontal cortex and posterior parietal cortex predicts behavior in a working memory task that requires a categorical judgement. Our results offer support to the idea that a network of neurons in both areas act as an attractor network that maintains information in working memory, which informs behavior.
Physiological noise modeling in fMRI based on the pulsatile component of photoplethysmograph
Authors: Kassinopoulos Michalis , Mitsis Georgios D.
Published: June 2020

The blood oxygenation level-dependent (BOLD) contrast mechanism allows the noninvasive monitoring of changes in deoxyhemoglobin content. As such, it is commonly used in functional magnetic resonance imaging (fMRI) to study brain activity since levels of deoxyhemoglobin are indirectly related to local neuronal activity through neurovascular coupling mechanisms. However, the BOLD signal is severely affected by physiological processes as well as motion. Due to this, several noise correction techniques have been developed to correct for the associated confounds. The present study focuses on cardiac pulsatility fMRI confounds, aiming to refine model-based techniques that utilize the photoplethysmograph (PPG) signal. Specifically, we propose a new technique based on convolution filtering, termed cardiac pulsatility model (CPM) and compare its performance with the cardiac-related RETROICOR (Card-RETROICOR), which is a technique commonly used to model fMRI fluctuations due to cardiac pulsatility. Further, we investigate whether variations in the amplitude of the PPG pulses (PPG-Amp) covary with variations in amplitude of pulse-related fMRI fluctuations, as well as with the systemic low frequency oscillations (SLFOs) component of the fMRI global signal (GS – defined as the mean signal across all gray matter voxels). Capitalizing on 3T fMRI data from the Human Connectome Project, CPM was found to explain a significantly larger fraction of the fMRI signal variance compared to Card-RETROICOR, particularly for subjects with larger heart rate variability during the scan. The amplitude of the fMRI pulse-related fluctuations did not covary with PPG-Amp; however, PPG-Amp explained significant variance in the GS that was not attributed to variations in heart rate or breathing patterns. Our results suggest that the proposed approach can model high-frequency fluctuations due to pulsation as well as low-frequency physiological fluctuations more accurately compared to model-based techniques commonly employed in fMRI studies.
TeamTree analysis: a new approach to evaluate scientific production
Authors: Pfrieger Frank W.
Published: June 2020

Advances in science and technology depend on the work of research teams and the publication of results through peer-reviewed articles representing a growing socio-economic resource. Current methods to mine the scientific literature regarding a field of interest focus on content, but the workforce credited by authorship remains largely unexplored, and appropriate measures of scientific production are debated. Here, a new bibliometric approach named TeamTree analysis is introduced that visualizes the development and composition of the workforce driving a field. A new citation-independent measure that scales with the H index estimates impact based on publication record, genealogical ties and collaborative connections. This author-centered approach complements existing tools to mine the scientific literature and to evaluate research across disciplines.
Relatedness and genetic structure of big brown bat (Eptesicus fuscus) maternity colonies in an urban-wildland interface provides insight into rabies transmission dynamics
Authors: Walker Faith M. , Sobek Colin J. , Platts-McPharlin Camille E. , Chambers Carol L.
Published: June 2020

Big brown bats (Eptesicus fuscus) are the bat species most frequently found to be rabid in North America and are a key source of sylvatic rabies in wildlife. Females can form summer maternity colonies in urban areas, often using access holes in the exterior of buildings to roost in relatively large numbers. In Flagstaff, Arizona, these roosts are commonly found in houses adjacent to golf courses, where habitat quality (food, water, shelter) is high for bats and for mesocarnivores such as striped skunks (Mephitis mephitis) and gray foxes (Urocyon cinereoargenteus). Periodic rabies outbreaks in Flagstaff involving all three of these mammals are primarily caused by anE. fuscusvariant of the disease. However, little is known aboutE. fuscussocial behavior during the summer months and how it may drive space use and hence disease exposure to conspecifics and mesocarnivores. To address this knowledge gap, we collected 88 unique genetic samples via buccal swabs fromE. fuscuscaptured at four maternity roosts surrounding a golf course during summer of 2013. We used 7 microsatellite loci to estimate genetic relatedness among individuals and genetic structure within and among colonies in order to infer whether females selected roosts based on kinship, and used genetics and radio telemetry to determine the frequency of roost switching. We found roost switching through genetics (two mother and adult daughter pairs at the same and different roosts) and telemetry, and no evidence of elevated genetic relatedness within colonies or genetic structure between colonies. These results have important implications for disease transmission dynamics in that social cohesion based on relatedness does not act to constrain the virus to a particular roost area. Instead, geographic mobility may increase disease exposure to neighboring areas. We discuss mitigating actions for bat conservation and public health.
Morphological colour adaptation during development: Involvement of Growth Hormone Receptor 1
Authors: Delgadin Tomás Horacio , Castañeda-Cortés Diana Carolina , Sacks Clara , Breccia Andrés , Fernandino Juan Ignacio , Vissio Paula Gabriela
Published: June 2020

Morphological background adaptation is both an endocrine and a nervous response, involving changes in the amount and shape of chromatophores. However, if this adaptation takes place at early developmental stages is largely unknown. Somatolactin (SL) is a pituitary hormone present in fish, which has been associated to skin pigmentation. Moreover, growth hormone receptor type 1 (ghr1) has been suggested to be the SL receptor and was associated to background adaptation in adults. In this context, the aim of this work was to evaluate the ontogeny of morphological adaptation to background and the participation ofghr1in this process. We found in larval stages ofCichlasoma dimerusthat the number of head melanophores and ir-SL pituitary cells were increased in individuals reared in black backgrounds compared to fish grown in white tanks. In medaka (Oryzias latipes)larval stages a similar response was observed that is altered by aghr1biallelic mutations using CRISPR/cas9.Interestingly, melanophore and leucophore numbers are highly associated. Furthermore, we found that somatic growth is reduced inghr1biallelic mutant medaka, establishing the dual function of this growth hormone receptor. Taken together, these results show that morphological background adaptation is present at early stages during development and that is dependent uponghr1unless during this period.
Identification of polyketide biosynthetic gene clusters that harbor self-resistance target genes
Authors: Vandova Gergana A , Nivina Aleksandra , Khosla Chaitan , Davis Ronald W , Fisher Curt R , Hillenmeyer Maureen E
Published: June 2020

Background

Polyketide secondary metabolites have been a rich source of antibiotic discovery for decades. Thousands of novel polyketide synthase (PKS) gene clusters have been identified in recent years with advances in DNA sequencing. However, experimental characterization of novel and useful PKS activities remains complicated. As a result, computational tools to analyze sequence data are essential to identify and prioritize potentially novel PKS activities. Here we exploit the concept of genetically-encoded self-resistance to identify and rank biosynthetic gene clusters for their potential to encode novel antibiotics.

Results

To identify PKS genes that are likely to produce an antibacterial compound, we developed an automated method to identify and catalog clusters that harbor potential self-resistance genes. We manually curated a list of known self-resistance genes and searched all NCBI genome databases for homologs of these self-resistance genes in biosynthetic gene clusters. The algorithm takes into account (1) the distance of the potential self-resistance gene to a core enzyme in the biosynthetic gene cluster; (2) the presence of a duplicated housekeeping copy of the self-resistance gene; (3) the presence of close homologs of the biosynthetic gene cluster in diverse species also harboring the putative self-resistance gene; (4) evidence for coevolution of the self-resistance gene and core biosynthetic gene; and (5) self-resistance gene ubiquity. We generated a catalog of 190 unique PKS clusters whose products likely target known enzymes of antibacterial importance. We also present an expanded set of putative self-resistance genes that may be useful in identifying small molecules active against novel microbial targets.

Conclusions

We developed a bioinformatic approach to identify and rank biosynthetic gene clusters that likely harbor self-resistance genes and may produce compounds with antibacterial properties. We compiled a list of putative self-resistance genes for novel antibacterial targets, and of orphan PKS clusters harboring these targets. These catalogues are a resource for discovery of novel antibiotics.
Spike-frequency dependent inhibition and excitation of neural activity by high-frequency ultrasound
Authors: Prieto Martin Loynaz , Firouzi Kamyar , Khuri-Yakub Butrus T. , Madison Daniel V. , Maduke Merritt
Published: June 2020

Ultrasound can modulate action-potential firingin vivoandin vitro, but the mechanistic basis of this phenomenon is not well understood. To address this problem, we used patch-clamp recording to quantify the effects of focused, high-frequency (43 MHz) ultrasound on evoked action potential firing in CA1 pyramidal neurons in acute rodent hippocampal brain slices. We find that ultrasound can either inhibit or potentiate firing in a spike-frequency-dependent manner: at low (near-threshold) input currents and low firing frequencies, ultrasound inhibits firing, while at higher input currents and higher firing frequencies, ultrasound potentiates firing. The net result of these two competing effects is that ultrasound increases the threshold current for action potential firing, the slope of frequency-input curves, and the maximum firing frequency. In addition, ultrasound slightly hyperpolarizes the resting membrane potential, decreases action potential width, and increases the depth of the afterhyperpolarization. All of these results can be explained by the hypothesis that ultrasound activates a sustained potassium conductance. According to this hypothesis, increased outward potassium currents hyperpolarize the resting membrane potential and inhibit firing at near-threshold input currents, but potentiate firing in response to higher input currents by limiting inactivation of voltage-dependent sodium channels during the action potential. This latter effect is a consequence of faster action-potential repolarization, which limits inactivation of voltage-dependent sodium channels, and deeper (more negative) afterhyperpolarization, which increases the rate of recovery from inactivation. Based on these results we propose that ultrasound activates thermosensitive and mechanosensitive two-pore-domain potassium (K2P) channels, through heating or mechanical effects of acoustic radiation force. Finite-element modelling of the effects of ultrasound on brain tissue suggests that the effects of ultrasound on firing frequency are caused by a small (less than 2°C) increase in temperature, with possible additional contributions from mechanical effects

Prieto et al. describe how ultrasound can either inhibit or potentiate action potential firing in hippocampal pyramidal neurons and demonstrate that these effects can be explained by increased potassium conductance.
Spatial modelling improves genetic evaluation in smallholder breeding programs
Authors: Selle Maria L. , Steinsland Ingelin , Powell Owen , Hickey John M. , Gorjanc Gregor
Published: June 2020

Breeders and geneticists use statistical models for genetic evaluation of animals to separate genetic and environmental effects on phenotype. A common way to separate these effects is to model a descriptor of an environment, a contemporary group or herd, and account for genetic relationship between animals across the environments. However, separating the genetic and environmental effects in smallholder systems is challenging due to small herd sizes and weak genetic connectedness across herds. Our hypothesis was that accounting for spatial relationships between nearby herds can improve genetic evaluation in smallholder systems. Further, geographically referenced environmental covariates are increasingly available and could be used to model underlying sources of the spatial relationships. The objective of this study was therefore to evaluate the potential of spatial modelling to improve genetic evaluation in smallholder systems. We focus solely on dairy cattle smallholder systems.

We performed simulations and real dairy cattle data analysis to test our hypothesis. We used a range of models to account for environmental variation by estimating herd and spatial effects. We compared these models using pedigree or genomic data.

The results show that in smallholder systems (i) standard models are not able to separate genetic and environmental effects, (ii) spatial modelling increases accuracy of genetic evaluation for phenotyped and non-phenotyped animals, (iii) environmental covariates do not substantially improve accuracy of genetic evaluation beyond simple distance-driven spatial relationships between herds, (iv) the benefit of spatial modelling was the largest when the genetic and environmental effects were hard to separate and (v) spatial modelling was beneficial when using either pedigree or genomic data.

We have demonstrated the potential of spatial modelling to improve genetic evaluation in smallholder systems. This improvement is driven by establishing environmental connectedness between herds that enhances separation of the genetic and environmental effects. We suggest routine spatial modelling in genetic evaluations, particularly for smallholder systems. Spatial modelling could also have major impact in studies of human and wild populations.
Concordance of “rapid” serological tests and IgG and IgM chemiluminescence for SARS-COV-2
Authors: Sáenz-Flor K , y Sanatafé L
Published: June 2020

Abstarct

Background

The COVID-19 serological tests for IgG and IgM have been developed with several methodologies: Immunoenzymatic Assay (ELISA), Chemiluminescence, Electro Chemiluminescence, Fluorescent Lateral Flow Immunoassays and Immunochromatography. None of these tests should be used for the diagnosis or population screening of the disease, considering that the antibodies appear only on the 8th – 14th day of the disease onset. The present study evaluates a sample of immunofluorescent and immunochromatographic rapid tests to show their agreement in relation to Chemiluminescence.

Methods

A diagnostic test evaluation assay was performed to establish the performance of five “rapid” tests (4 immunochromatographic and 1 immunofluorescent tests) for IgG and IgM serology for SARS-CoV-2 using a panel of 30 serum samples from patients received in the laboratory analysis routine. For the evaluation of clinical performance, the qualitative results of the “rapid” tests were compared against those obtained by chemiluminescence, dichotomized as positives (≥ 10 AU / mL) or negative (<10 UA / mL).

Findings

The best agreement is seen in the immunofluorescent assay, for the IgG contrast, with a particularly good kappa index (0.85), without positive disagreements and a negative disagreement of about 15%. In the immunochromatographic methods Kappa index was 0.61 at best, with disagreements in negative findings of ≈35% and in positive cases of up to ≈70%.

The IgM concordance behavior, on the other hand, reflects a weak to moderate Kappa concordance value (Kappa 0.2 to 0.6), with negative disagreements reaching up to 55% and positives of up to 84%, without any evaluated test reaching Kappa performance equal to or greater than 0.8.

Interpretation

Serological studies should be used in the clinical and epidemiological context and of other diagnostic tests. Given the high demand and supply in the market of “rapid serological tests”, its evaluation against panels of serologically positive or negative samples established by Chemiluminescence or Electro chemiluminescence is essential to authorize its extensive use in populations

Funding

None
Is death from Covid-19 a multistep process?
Authors: Pearce Neil , Moirano Giovenale , Maule Milena , Kogevinas Manolis , Rodo Xavier , Lawlor Deborah A , Vandenbroucke Jan , Vandenbroucke-Grauls Christina , Polack Fernando P , Custovic Adnan
Published: June 2020

Covid-19 death has a different relationship with age than is the case for other severe respiratory pathogens. The Covid-19 death rate increases exponentially with age, and the main risk factors are age itself, as well as having underlying conditions such as hypertension, diabetes, cardiovascular disease, severe chronic respiratory disease and cancer. Furthermore, the almost complete lack of deaths in children suggests that infection alone is not sufficient to cause death; rather, one must have gone through a number of changes, either as a result of undefined aspects of aging, or as a result of chronic disease. These characteristics of Covid-19 death are consistent with the multistep model of disease, a model which has primarily been used for cancer, and more recently for amyotrophic lateral sclerosis (ALS). We applied the multi-step model to data on Covid-19 case fatality rates (CFRs) from China, South Korea, Italy, Spain and Japan. In all countries we found that a plot of ln (CFR) against ln (age) was approximately linear with a slope of about 5. As a comparison, we also conducted similar analyses for selected other respiratory diseases. SARS showed a similar log-log age-pattern to that of Covid-19, albeit with a lower slope, whereas seasonal and pandemic influenza showed quite different age-patterns. Thus, death from Covid-19 and SARS appears to follow a distinct age-pattern, consistent with a multistep model of disease that in the case of Covid-19 is probably defined by comorbidities and age producing immune-related susceptibility. Identification of these steps would be potentially important for prevention and therapy for SARS-COV-2 infection.
Continuous positive airway pressure face-mask ventilation to manage massive influx of patients requiring respiratory support during the SARS-CoV-2 outbreak
Authors: Alviset S. , Riller Q. , Aboab J. , Dilworth K. , Billy PA. , Lombardi Y. , Azzi M. , Ferreira Vargas L. , Laine L. , Lermuzeaux M. , Memain N. , Silva D. , Tchoubou T. , Ushmorova D. , Dabbagh H. , Escoda S. , Lefrançois R. , Nardi A. , Ngima A. , Ioos V.
Published: June 2020

Background

Since December 2019, a global outbreak of coronavirus disease (COVID-19) is responsible for massive influx of patients with acute respiratory failure in hospitals. We describe the characteristics, clinical course, and outcomes of COVID-19 patients treated with continuous positive airway pressure (CPAP) in a large public hospital in France.

Method

It is a single centre retrospective observational cohort. From 27th March to 23rd April, consecutive patients who had signs of respiratory failure or were unable to maintain an SpO2 > 90%, despite receiving 10 to 15 l/min of oxygen with a non-rebreather mask, were treated by CPAP with a face-mask unless the ICU physician judged that immediate intubation was indicated. The main outcomes under study were reasons for CPAP discontinuation and mortality.

Results

A total of 585 patients were admitted in Delafontaine hospital for severe COVID-19. ICU was quickly overwhelmed. Fifty-nine out of 159 (37%) patients requiring ICU care had to be referred to other hospitals. CPAP therapy was initiated in 49 patients and performed out of ICU in 41 (84%). SARS-CoV2 pneumonia was confirmed by PCR from respiratory tract in 39 (79%) patients and by thoracic CT scan in the remaining patients. CPAP was performed out of ICU in 41 (84%) cases. Median age was 65 years (IQR=54-71). Median duration of CPAP treatment was 3 days (IQR=1-5). Reasons for discontinuation of CPAP were intubation for invasive ventilation in 25 (51%) patients, improvement in 16 (33%), poor tolerance in 6 (12%) and death in 2 (4%). A decision not to intubate had been taken for the 2 patients who died while on CPAP.

Conclusions

Treatment with CPAP is feasible and safe in a non-ICU environment in the context of a massive influx of patients. One third of these patients with high oxygen requirements did not eventually need invasive ventilation.

Key messages

What is the key question?

What is the best respiratory support strategy to manage a massive influx of patients with hypoxemic respiratory failure despite high-flow oxygen delivered with a non-rebreather mask?

What is the bottom line?

Continuous positive airway pressure face mask ventilation delivered in non-ICU wards to patients who do not require immediate intubation is feasible and safe.

Why read on?

Face mask ventilation with CPAP should be considered as an option of respiratory support in the context of the on-going COVID-19 pandemic and limited availability of ICU beds.
Evaluation of Confocal Laser Endomicroscopy for Detection of Occult Gastric Carcinoma in CDH1 Variant Carriers
Authors: Schueler Samuel A. , Gamble Lauren A. , Curtin Bryan F. , Ruff Samantha M. , Connolly Maureen , Hannah Cathleen , Quezado Martha , Miettinen Markku , George Maureen , Blakely Andrew M. , Hernandez Jonathan M. , Heller Theo , Koh Christopher , Davis Jeremy L.
Published: June 2020

Background & Aims

Hereditary diffuse gastric cancer, attributed to inactivating germline CDH1 variants, is characterized by signet ring cell (SRC) morphology. We sought to evaluate the occult cancer detection rate using probe-based confocal laser endomicroscopy (pCLE) during endoscopic surveillance.

Methods

A prospective, single-institution study was conducted in asymptomatic adults with pathogenic or likely pathogenic (P/LP) CDH1 variants. Subjects received endoscopic gastric surveillance using pCLE in conjunction with the consensus Cambridge method (CM) of non-targeted mucosal biopsies. Systematic examination was performed with white light endoscopy (WLE) and pCLE. Abnormalities visualized by pCLE were biopsied, followed by non-targeted mucosal biopsies according to the CM. Pathologists were blinded to clinical and endomicroscopic findings. Primary endpoint was to determine pCLE sensitivity for detection of occult SRC carcinoma compared to CM.

Results

Thirty-six patients with P/LP CDH1 variants underwent endoscopy using pCLE and CM. Majority were female (75%) with median age 47 years. Median procedure time was 52.5 minutes, without serious adverse events. Targeted biopsies of focal abnormalities on WLE were negative for carcinoma. Overall, 19.4% (7/36) patients had SRC detected on ≥1 biopsy. Non-targeted CM biopsies revealed SRC in 11.1% (4/36), whereas pCLE revealed SRC in 16.7% (6/36). Fifteen patients, 5 of whom had SRC at endoscopy, underwent total gastrectomy; all 15 explants contained occult carcinoma. In those 15 patients, the false-negative SRC detection rates for pCLE and CM were 67% and 87%, respectively.

Conclusions

Confocal endomicroscopy alone has low sensitivity for occult cancer detection in CDH1 variant carriers. Reliable endoscopic surveillance is lacking as an alternative to prophylactic surgery in this high-risk population. (http://ClinicalTrials.gov, Number: NCT03648879).
The COVID-19 Pandemic in Africa: Predictions using the SIR Model
Authors: Sinkala Musalula , Nkhoma Panji , Zulu Mildred , Kafita Doris , Tembo Rabecca , Daka Victor
Published: June 2020

Since the earliest reports of the Coronavirus disease - 2019 (COVID-19) in Wuhan, China in December 2019, the disease has rapidly spread worldwide, attaining pandemic levels in early March 2020. However, the spread of COVID-19 has differed in the African setting compared to countries on other continents. To predict the spread of COVID-19 in Africa and within each country on the continent, we applied a Susceptible-Infectious-Recovered mathematical model. Here, our results show that, overall, Africa is currently (July 24, 2020) at the peak of the COVID-19 pandemic, after which we predict the number of cases would begin to fall in August 2020. Furthermore, we predict that the ending phase of the pandemic would be in Late-November 2020 and that decreasing cases of COVID-19 infections would be detected until around August 2021 and September 2021. Our results also reveal that of the 51 countries with reported COVID-19 cases, only eight, including Algeria, Morocco and Zambia, are likely to report higher monthly COVID-19 cases in the coming months of 2020 than those reported in the previous months. Overall, at the end of this pandemic, we predict that approximately 2,201,849 (about 1,451,567 future cases) individuals in Africa would have been infected with the COVID-19 virus. Here, our predictions are data-driven and based on the previously observed trends in the spread of the COVID-19 pandemic. Shifts in the population dynamics and/or changes in the infectiousness of the COVID-19 virus may require new forecasts of the disease spread.
Who do not wash their hands during the Covid-19 pandemic? Social media use as a potential predictor
Authors: Zhang Stephen X. , Graf-Vlachy Lorenz , Su Rui , Li Jizhen , Looi Kim Hoe
Published: June 2020

This study predicts handwashing behavior during the Covid-19 pandemic. An analysis of 674 adults in Malaysia identifies their time spent on social media per day as a key predictor of handwashing. The association between time spent on social media and handwashing substantially depends on gender and the number of children in the same household. Additional predictors include age and health condition. This study helps identify specific target groups for health communication on hand hygiene via people’s use of social media, which can be a key channel for health communication campaigns during a pandemic.
ANGPTL4 from adipose, but not liver, is responsible for regulating plasma triglyceride partitioning
Authors: Spitler Kathryn M. , Shetty Shwetha K. , Cushing Emily M. , Sylvers-Davie Kelli L. , Davies Brandon S.J.
Published: June 2020

Elevated plasma triglyceride levels are associated with metabolic disease. Angiopoietin-like protein 4 (ANGPTL4) regulates plasma triglyceride levels by inhibiting lipoprotein lipase (LPL). Our aim was to investigate the role of tissue-specific ANGPTL4 expression in the setting of high fat diet. Adipocyte- and hepatocyte-specific ANGPTL4 deficient mice were fed a high fat diet (60% kCal from fat) for either 12 weeks or 6 months. We performed plasma metabolic measurements, triglyceride clearance and uptake assays, LPL activity assays, and assessed glucose homeostasis. Mice lacking adipocyte ANGPTL4 recapitulated the triglyceride phenotypes of whole-body ANGPTL4 deficiency, whereas mice lacking hepatocyte ANGPTL4 had few triglyceride phenotypes. When fed a high fat diet (HFD), mice deficient in adipocyte ANGPTL4 gained more weight, had enhanced adipose LPL activity, and initially had improved glucose and insulin sensitivity. However, this improvement was largely lost after 6 months on HFD. Conversely, mice deficient in hepatocyte ANGPTL4 initially displayed no differences in glucose homeostasis, but began to manifest improved glucose tolerance after 6 months on HFD. We conclude that it is primarily adipocyte-derived ANGPTL4 that is responsible for regulating plasma triglyceride levels. Deficiency in adipocyte- or hepatocyte-derived ANGPTL4 may confer some protections against high fat diet induced dysregulation of glucose homeostasis.
Extended Application of Genomic Selection to Screen Multi-Omics Data for Prognostic Signatures of Prostate Cancer
Authors: Li Ruidong , Wang Shibo , Cui Yanru , Qu Han , Chater John M. , Zhang Le , Wei Julong , Wang Meiyue , Xu Yang , Yu Lei , Lu Jianming , Feng Yuanfa , Zhou Rui , Huang Yuhan , Ma Renyuan , Zhu Jianguo , Zhong Weide , Jia Zhenyu
Published: June 2020

Prognostic tests using expression profiles of several dozen genes help provide treatment choices for prostate cancer (PCa). However, these tests require improvement to meet the clinical need for resolving overtreatment which continues to be a pervasive problem in PCa management. Genomic selection (GS) methodology, which utilizes whole-genome markers to predict agronomic traits, was adopted in this study for PCa prognosis. We leveraged The Cancer Genome Atlas (TCGA) database to evaluate the prediction performance of six GS methods and seven omics data combinations, which showed that the Best Linear Unbiased Prediction (BLUP) model outperformed the other methods regarding predictability and computational efficiency. Leveraging the BLUP-HAT method, an accelerated version of BLUP, we demonstrated that using expression data of a large number of disease-relevant genes and with an integration of other omics data (i.e., miRNAs) significantly increased outcome predictability when compared with panels consisting of small numbers of genes. Finally, we developed a novel stepwise forward selection BLUP-HAT method to facilitate searching multi-omics data for predictor variables with prognostic potential. The new method was applied to the TCGA data to derive mRNA and miRNA expression signatures for predicting relapse-free survival of PCa, which were validated in six independent cohorts. This is a transdisciplinary adoption of the highly efficient BLUP-HAT method and its derived algorithms to analyze multi-omics data for PCa prognosis. The results demonstrated the efficacy and robustness of the new methodology in developing prognostic models in PCa, suggesting a potential utility in managing other types of cancer.
Diploid chromosome-scale assembly of theMuscadinia rotundifoliagenome supports chromosome fusion and disease resistance gene expansion duringVitisandMuscadiniadivergence
Authors: Cochetel Noé , Minio Andrea , Massonnet Mélanie , Vondras Amanda M. , Figueroa-Balderas Rosa , Cantu Dario
Published: June 2020

Muscadinia rotundifolia, the muscadine grape, has been cultivated for centuries in the southeastern United States.M. rotundifoliais resistant to many of the pathogens that detrimentally affectVitis vinifera, the grape species commonly used for winemaking. For this reason,M. rotundifoliais a valuable genetic resource for breeding. Single-molecule real-time reads were combined with optical maps to reconstruct the two haplotypes of each of the 20M. rotundifoliacv. Trayshed chromosomes. The completeness and accuracy of the assembly were confirmed using a high-density linkage map ofM. rotundifolia.Protein-coding genes were annotated using an integrated and comprehensive approach. This included using Full-length cDNA sequencing (Iso-Seq) to improve gene structure and hypothetical spliced variant predictions. Our data strongly support thatMuscadiniachromosomes 7 and 20 are fused inVitisand pinpoint the location of the fusion in Cabernet Sauvignon and PN40024 chromosome 7. Disease-related gene numbers in Trayshed and Cabernet Sauvignon were similar, but their clustering locations were different. A dramatic expansion of the Toll/Interleukin-1 Receptor-like Nucleotide-Binding Site Leucine-Rich Repeat (TIR-NBS-LRR) class was detected on Trayshed chromosome 12 at theResistance to Uncinula necator 1(RUN1)/Resistance to Plasmopara viticola 1(RPV1) locus, which confers strong dominant resistance to powdery and downy mildews. A genome browser for Trayshed, its annotation, and an associated Blast tool are available atwww.grapegenomics.com.
A computational method for immune repertoire mining that identifies novel binders from different clonotypes, demonstrated by identifying anti-Pertussis toxoid antibodies
Authors: Richardson Eve , Galson Jacob D. , Kellam Paul , Kelly Dominic F. , Smith Sarah E. , Palser Anne , Watson Simon , Deane Charlotte M.
Published: June 2020

Due to their shared genetic history, antibodies from the same clonotype often bind to the same epitope. This knowledge is used in immune repertoire mining, where known binders are used to search bulk sequencing repertoires to identify new binders. However current computational methods cannot identify epitope convergence between antibodies from different clonotypes, limiting the sequence diversity of antigen-specific antibodies which can be identified. We describe how the antibody binding site, the paratope, can be used to cluster antibodies with common antigen reactivity from different clonotypes. Our method, paratyping, uses the predicted paratope to identify these novel cross clonotype matches. We experimentally validated our predictions on a Pertussis toxoid dataset. Our results show that even the simplest abstraction of the antibody binding site, using only the length of the loops involved and predicted binding residues, is sufficient to group antigen-specific antibodies and provide additional information to conventional clonotype analysis.
Optogenetic currents in myofibroblasts acutely alter electrophysiology and conduction of co-cultured cardiomyocytes
Authors: Kostecki Geran , Shi Yu , Chen Christopher , Reich Daniel H. , Entcheva Emilia , Tung Leslie
Published: June 2020

Interactions between cardiac myofibroblasts and myocytes may slow conduction after cardiac injury, increasing the chance of life-threatening arrhythmia. While co-culture studies have shown that myofibroblasts can affect cardiomyocyte electrophysiologyin vitro, the mechanism(s) remain debatable. In this study, primary neonatal rat cardiac myofibroblasts were transduced with the light-activated ion channel Channelrhodopsin-2, which allowed acute and selective modulation of myofibroblast currents in co-cultures with cardiomyocytes. Optical mapping revealed that myofibroblast-specific optogenetically induced inward currents decreased conduction velocity in the co-cultures by 27±6% (baseline = 17.7±5.3 cm/s), and shortened the cardiac action potential duration by 14±7% (baseline = 161±11 ms) when 0.017 mW/mm2light was applied. When light irradiance was increased to 0.057 mW/mm2, the myofibroblast currents led to spontaneous beating in 6/7 co-cultures. Experiments showed that optogenetic perturbation did not lead to changes in myofibroblast strain and force generation, suggesting purely electrical effects in this model.In silicomodeling of optogenetically modified myofibroblast-cardiomyocyte co-cultures largely reproduced these results and enabled a comprehensive study of relevant parameters. These results clearly demonstrate that myofibroblasts are sufficiently electrically connected to cardiomyocytes to effectively alter macroscopic electrophysiological properties in this model of cardiac tissue.