bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantifying Free Fibula Flap Growth After Pediatric Mandibular Reconstruction
Authors: Volk Angela S. , Riad Sylvia S.H. , Kania Katarzyna E. , Davies Lesley , Wirthlin John O. , Pederson William C. , Buchanan Edward P.
Published: June 2020

Introduction:

The free fibula flap (FFF) is a preferred option for adult mandibular reconstruction. Due to skeletal immaturity, its routine use in pediatric patients remains in question. Inconsistencies regarding the ability of the FFF to grow in concordance with the patients’ natural growth currently exist in the literature. The purpose of this report is to quantify mandibular growth in a young patient undergoing partial hemi-mandibular reconstruction with a FFF utilizing advanced three-dimensional software.

Methods:

A 2-year old underwent left hemi-mandibular reconstruction with a FFF following resection of a desmoid tumor. The condyle was preserved. Using 3D software, changes in mandibular growth and morphology were evaluated based on preoperative (2.1 years old) and postoperative (2.5 years and 5.2 years old) computed tomography imaging.

Results:

Mandibular growth occurred throughout the mandible in both postoperative evaluations. Greatest growth was seen in the ramus height. Fibula growth was also seen when comparing measurements to the virtual surgical planning guide. A novel parts comparison analysis revealed the greatest growth potential occurred at the condyle.

Conclusion:

Providing an objective evaluation using 3D software, we have demonstrated growth throughout the reconstructed mandible, with greatest growth occurring at the preserved condyle. Despite scientific limitations of our study, the potential for mandibular growth appears to remain after FFF reconstruction, offering successful functional and cosmetic outcomes.
Localization and Topography of the Arteries on the Middle Forehead Region for Eluding Complications Following Forehead Augmentation: Conventional Cadaveric Dissection and Ultrasonography Investigation
Authors: Phumyoo Thirawass , Jiirasutat Nuttapatch , Jitaree Benrita , Rungsawang Chalermquan , Pratoomthai Benjamart , Tansatit Tanvaa
Published: June 2020

Forehead augmentation with filler injection is one of the most dangerous procedures associated with iatrogenic intravascular injection resulting in the severe complications. Nonetheless, few studies have determined the explicit arterial localization and topography related to the facial soft tissues and landmarks. Therefore, this study aimed to determine an arterial distribution and topography on the middle forehead region correlated with facial landmarks to grant an appropriate guideline for enhancing the safety of injection. Nineteen Thai embalmed cadavers were discovered with conventional dissection and 14 Thai healthy volunteers were investigated with ultrasonographic examination on the middle forehead. This study found that at the level of mid-frontal depression point, the transverse distance from the medial canthal vertical line to the superficial and deep branches of supraorbital artery were 9.1 mm and 15.1 mm, respectively. Whereas the depths from the skin of these arteries were 4.1 mm and 4.3 mm, respectively. Furthermore, the frontal branch of superficial temporal artery was detectable in 42.1% as an artery entering the forehead area. At the level of lateral canthal vertical line, the vertical distance of frontal branch was 31.6 mm, and the depth from skin of the artery was 2.7 mm. In conclusion, a proper injection technique could be performed based on an intensive arterial distribution and topography, and ultrasonographic examination before the injection is also suggested in order to restrict the opportunity of severe complications.
Video Virtual Clinical Encounters Versus Office Visits for Postoperative Care After Pelvic Organ Prolapse Surgery: A Randomized Clinical Trial
Authors: Lee Daniel D. , Arya Lily A. , Andy Uduak U. , Harvie Heidi S.
Published: June 2020

Objectives

To determine if patient satisfaction of virtual clinical encounters is noninferior to traditional in-office clinical encounters for postoperative follow-up after reconstructive surgery for pelvic organ prolapse.

Methods

This was a randomized controlled noninferiority trial of women undergoing surgery for pelvic organ prolapse. Women were recruited and randomized during their preoperative counseling visit to virtual clinical encounters via video conference technology or in-office clinical encounters for their 30-day postoperative follow-up visits. The primary outcome was patient satisfaction measured by the validated Patient Satisfaction Questionnaire-18 (score range, 18–90, with higher scores indicating greater satisfaction) administered by telephone following the 30-day visit. Additional information regarding demographics, postoperative health care utilization, and complications was collected via chart review and compared between groups.

Results

A total of 52 women were randomly assigned to virtual clinical encounters via videoconference technology or traditional in-office clinical encounters (26 per group). The mean patient satisfaction score was 80.7 ± 2.6 in the virtual group and 81.2 ± 2.8 in the office group (difference, −0.46 points; 95% confidence interval, −1.95 to 1.03), which was consistent with noninferiority. Postoperative complication rates were 31% in the virtual group and 46% in the office group (P = 0.3). There were no significant between-group differences in secondary measures of unscheduled telephone calls (88% versus 77%, P = 0.5) and office visits (35% versus 38%, P = 0.8), emergency room visits (15% versus 19%, P = 1.0), and hospital readmissions (4% versus 12%, P = 0.6) within 90 days of surgery.

Conclusions

For patients with pelvic organ prolapse undergoing reconstructive surgery, postoperative virtual clinical encounters via video conference technology are noninferior to traditional in-office clinical encounters with high levels of short-term patient satisfaction and no differences in postoperative health care utilization and complications rates.
Patients’ Perceptions on Surgical Care Suspension for Pelvic Floor Disorders During the COVID-19 Pandemic
Authors: Mou Tsung , Brown Oluwateniola , Gillingham Akira , Geynisman-Tan Julia , Collins Sarah , Lewicky-Gaupp Christina , Mueller Margaret G. , Kenton Kimberly , Bretschneider C. Emi
Published: June 2020

Objectives

The primary objective of the study was to evaluate patients’ attitudes toward the postponement of their scheduled procedures for pelvic floor disorders (PFD) because of the COVID-19 pandemic. Secondary objectives were to identify patients who were upset with the postponement of their PFD procedures and to identify factors that are associated with being upset because of the delay in care.

Methods

This was a cross-sectional, survey-based study of women from a single urban, academic practice using a novel questionnaire. The study cohort included women whose PFD surgeries or office procedures were postponed between March 17 and April 30, 2020.

Results

Ninety-eight women had surgeries postponed; 68 (70%) responded to our questionnaire. Nearly half of the respondents (32/68, 47.1%) were upset about their procedures being postponed. Upset patients reported a greater impact of PFD symptoms on their mood than those who were not upset (P=0.002). Those who were upset were also more likely to report feelings of isolation (P=0.006), fear that their PFD would worsen because of delayed care (P < 0.001), and anxiety over surgery postponement (P < 0.001) than those who were not upset about the delays. When controlling for anxiety, social isolation, and impact of PFD symptom, anxiety (adjusted odds ratio = 15.7; 95% confidence interval = 3.7–66.6) and feeling of isolation (adjusted odds ratio = 9.7; 95% confidence interval = 1.5–63.7) remained associated with increased odds of being upset because of procedure delays.

Conclusions

Half of women whose pelvic reconstructive procedures were postponed because of the COVID-19 pandemic were upset because of the delay in care, especially those who are emotionally and socially vulnerable during the COVID-19 pandemic.
Tele–Neuro-Ophthalmology: Vision for 20/20 and Beyond
Authors: Ko Melissa W. , Busis Neil A.
Published: June 2020

Background:

Telehealth provides health care to a patient from a provider at a distant location. Before the COVID-19 pandemic, adoption of telehealth modalities was increasing slowly but steadily. During the public health emergency, rapid widespread telehealth implementation has been encouraged to promote patient and provider safety and preserve access to health care.

Evidence Acquisition:

Evidence was acquired from English language Internet searches of the medical and business literature and following breaking news on the COVID-19 pandemic and responses from health care stakeholders, including policymakers, payers, physicians, health care organizations, and patients. We also had extensive discussions with colleagues who are developing telehealth techniques relevant to neuro-ophthalmology.

Results:

Regulatory, legal, reimbursement, and cultural barriers impeded the widespread adoption of telehealth before the COVID-19 pandemic. With the increased use of telehealth in response to the public health emergency, we are rapidly accumulating experience and an evidence base identifying opportunities and challenges related to the widespread adoption of tele–neuro-ophthalmology. One of the major challenges is the current inability to adequately perform funduscopy remotely.

Conclusions:

Telehealth is an increasingly recognized means of health care delivery. Tele–Neuro-Ophthalmology adoption is necessary for the sake of our patients, the survival of our subspecialty, and the education of our trainees and students. Telehealth does not supplant but supplements and complements in-person neuro-ophthalmologic care. Innovations in digital optical fundus photography, mobile vision testing applications, artificial intelligence, and principles of channel management will facilitate further adoption of tele–neuro-ophthalmology and bring the specialty to the leading edge of health care delivery.
Limited-Montage EEG as a Tool for the Detection of Nonconvulsive Seizures
Authors: Swingle Nicholas , Vuppala Aditya , Datta Proleta , Pedavally Swetha , Swaminathan Arun , Kedar Sachin , Samson Kaeli K. , Wichman Christopher S. , Myers Jacob , Taraschenko Olga
Published: June 2020

Purpose:

Prefabricated arrays with a limited number of electrodes offer an opportunity to hasten the diagnosis of seizures; however, their accuracy to detect seizures is unknown. We examined the utility of two limited-montage EEG setups for the detection of nonconvulsive seizures.

Methods:

Thirty previously interpreted EEG segments with nonconvulsive seizures from 30 patients and 60 segments with background slowing or normal EEG from 60 patients were rendered in a bipolar “double banana” montage, a double distance “neonatal” montage, and a circumferential “hatband” montage. Experts reviewed 60 to 180 seconds long segments to determine whether seizures were present and if the EEG data provided were sufficient to make a decision on escalation of clinical care by ordering an additional EEG or prescribing anticonvulsants. The periodic patterns on the ictal-interictal continuum were specifically excluded for this analysis to keep the focus on definite electrographic seizures.

Results:

The sensitivities for seizure of the neonatal and hatband montages were 0.96 and 0.84, respectively, when compared with full montage EEG, whereas the specificities were 0.94 and 0.98, respectively. Appropriate escalation of care was suggested for 96% and 92% of occurrences of seizure patterns in neonatal and hatband montages, respectively. When compared with clinical EEG, the sensitivities of the neonatal and hatband montages for seizure diagnosis were 0.85 and 0.69, respectively.

Conclusions:

Nonconvulsive seizures were detected with high accuracy using the limited electrode array configuration in the neonatal and hatband montages. The sensitivity of the neonatal montage EEG in detecting seizures was superior to that of a hatband montage. These findings suggest that in some patients with nonconvulsive seizures, limited-montage EEG may allow to differentiate ictal and slow patterns.
Disparities in the analysis of morphological disparity
Authors: Guillerme Thomas , Cooper Natalie , Brusatte Stephen L. , Davis Katie E. , Jackson Andrew L. , Gerber Sylvain , Goswami Anjali , Healy Kevin , Hopkins Melanie J. , Jones Marc E. H. , Lloyd Graeme T. , O'Reilly Joseph E. , Pate Abi , Puttick Mark N. , Rayfield Emily J. , Saupe Erin E. , Sherratt Emma , Slater Graham J. , Weisbecker Vera , Thomas Gavin H. , Donoghue Philip C. J.
Published: June 2020

Analyses of morphological disparity have been used to characterize and investigate the evolution of variation in the anatomy, function and ecology of organisms since the 1980s. While a diversity of methods have been employed, it is unclear whether they provide equivalent insights. Here, we review the most commonly used approaches for characterizing and analysing morphological disparity, all of which have associated limitations that, if ignored, can lead to misinterpretation. We propose best practice guidelines for disparity analyses, while noting that there can be no ‘one-size-fits-all’ approach. The available tools should always be used in the context of a specific biological question that will determine data and method selection at every stage of the analysis.
Signals interpreted as archaic introgression appear to be driven primarily by faster evolution in Africa
Authors: Amos William
Published: June 2020

Non-African humans appear to carry a few per cent archaic DNA due to ancient inter-breeding. This modest legacy and its likely recent timing imply that most introgressed fragments will be rare and hence will occur mainly in the heterozygous state. I tested this prediction by calculating D statistics, a measure of legacy size, for pairs of humans where one of the pair was conditioned always to be either homozygous or heterozygous. Using coalescent simulations, I confirmed that conditioning the non-African to be heterozygous increased D, while conditioning the non-African to be homozygous reduced D to zero. Repeating with real data reveals the exact opposite pattern. In African–non-African comparisons, D is near-zero if the African individual is held homozygous. Conditioning one of two Africans to be either homozygous or heterozygous invariably generates large values of D, even when both individuals are drawn from the same population. Invariably, the African with more heterozygous sites (conditioned heterozygous > unconditioned > conditioned homozygous) appears less related to the archaic. By contrast, the same analysis applied to pairs of non-Africans always yields near-zero D, showing that conditioning does not create large D without an underlying signal to expose. Large D values in humans are therefore driven almost entirely by heterozygous sites in Africans acting to increase divergence from related taxa such as Neanderthals. In comparison with heterozygous Africans, individuals that lack African heterozygous sites, whether non-African or conditioned homozygous African, always appear more similar to archaic outgroups, a signal previously interpreted as evidence for introgression. I hope these analyses will encourage others to consider increased divergence as well as increased similarity to archaics as mechanisms capable of driving asymmetrical base-sharing.
The influence law of eccentric load on the performance of yielding bolt
Authors: Tai Yang , Xia Hongchun , Huang Shaoping , Meng Jie , Li Wei
Published: June 2020

In order to adapt to the high stress and avoid the large deformation in roadways, the pre-stressed yielding bolt has been developed. Prior to the installation of the pre-stressed yielding bolt, boreholes need to be drilled. However, not all boreholes are perpendicular to the surface of the roadway, and the non-perpendicular holes make the pre-stressed yielding bolt exposed to eccentric loads. In order to reveal the influence of the eccentric load on the performance of the pre-stressed yielding bolt, some numerical simulations were carried out in this study. The influence of the eccentric load on the displacement–load relations, utilization rate of the yielding pipe, the plastic strains of the bolt components as well as the evolution of the absorptive capacity of the yielding pipe were analysed. The results are as follows: (i) eccentric loads affected the utilization rate of the yielding pipe, plastic strains of bolt components and the absorptive capacity was quite great when displacement was less than 2 mm, while these impacts could be neglected when displacement is greater than 2 mm; (ii) as the eccentric load increased, the yielding point and its corresponding displacement increased linearly while the yielding magnitude decreased linearly; and (iii) the eccentric load could be adjusted to control the yielding point and magnitude in order to meet the roadway support's requirement for the yielding bolt.
Dopamine-derived nitrogen-doped carboxyl multiwalled carbon nanotube-modified graphite felt with improved electrochemical activity for vanadium redox flow batteries
Authors: Li Qiang , Bai Anyu , Zhang Tianyu , Li Song , Sun Hong
Published: June 2020

Improving the electrochemical activity of electrodes is essential to the development of vanadium redox flow battery (VRFB). In this work, we prepared a novel electrode with the modification of nitrogen-doped carboxyl multiwalled carbon nanotubes using dopamine as an eco-friendly nitrogen source (carboxyl MWCNT@PDAt). Characterization and electrochemical measurements reveal that the synthesized carboxyl MWCNT@PDAt-modified graphite felt electrode (carboxyl MWCNT@PDAt/GF) exhibits excellent electrochemical performance toward VO
2+
/

V

O
2
+

reaction. Superior battery performance was obtained with the energy efficiency of 80.54% at a current density of 80 mA cm
−2
. Excellent durability of the carboxyl MWCNT@PDAt/GF electrode was confirmed by long-term charge/discharge tests. The enhanced reaction kinetics of VO
2+
/

V

O
2
+

is ascribed to the synergetic effect of oxygen and nitrogen containing groups on graphite felt surface and the presence of nitrogen-doped carboxyl multiwalled carbon nanotubes (MWCNT). The facile approach proposed in this paper provides a new route to the fabrication of electrode with excellent performance for VRFB.
An unethical optimization principle
Authors: Beale Nicholas , Battey Heather , Davison Anthony C. , MacKay Robert S.
Published: June 2020

If an artificial intelligence aims to maximize risk-adjusted return, then under mild conditions it is disproportionately likely to pick an unethical strategy unless the objective function allows sufficiently for this risk. Even if the proportionηof available unethical strategies is small, the probabilitypUof picking an unethical strategy can become large; indeed, unless returns are fat-tailedpUtends to unity as the strategy space becomes large. We define an unethical odds ratio,Υ(capital upsilon), that allows us to calculatepUfromη, and we derive a simple formula for the limit ofΥas the strategy space becomes large. We discuss the estimation ofΥandpUin finite cases and how to deal with infinite strategy spaces. We show how the principle can be used to help detect unethical strategies and to estimateη. Finally we sketch some policy implications of this work.
Oncolytic virus therapy benefits from control theory
Authors: Anelone Anet J. N. , Villa-Tamayo María F. , Rivadeneira Pablo S.
Published: June 2020

Oncolytic virus therapy aims to eradicate tumours using viruses which only infect and destroy targeted tumour cells. It is urgent to improve understanding and outcomes of this promising cancer treatment because oncolytic virus therapy could provide sensible solutions for many patients with cancer. Recently, mathematical modelling of oncolytic virus therapy was used to study different treatment protocols for treating breast cancer cells with genetically engineered adenoviruses. Indeed, it is currently challenging to elucidate the number, the schedule, and the dosage of viral injections to achieve tumour regression at a desired level and within a desired time frame. Here, we apply control theory to this model to advance the analysis of oncolytic virus therapy. The control analysis of the model suggests that at least three viral injections are required to control and reduce the tumour from any initial size to a therapeutic target. In addition, we present an impulsive control strategy with an integral action and a state feedback control which achieves tumour regression for different schedule of injections. When oncolytic virus therapy is evaluated
in silico
using this feedback control of the tumour, the controller automatically tunes the dose of viral injections to improve tumour regression and to provide some robustness to uncertainty in biological rates. Feedback control shows the potential to deliver efficient and personalized dose of viral injections to achieve tumour regression better than the ones obtained by former protocols. The control strategy has been evaluated
in silico
with parameters that represent five nude mice from a previous experimental work. Together, our findings suggest theoretical and practical benefits by applying control theory to oncolytic virus therapy.
Sustainable online communities exhibit distinct hierarchical structures across scales of size
Authors: Dover Yaniv , Goldenberg Jacob , Shapira Daniel
Published: June 2020

As humans, we are uniquely competent at incorporating ourselves into groups that scale up from a few members to millions of individuals to engage in joint activities in social circles of varying sizes. Yet, the question of how a group's survival depends on its social structure is not well understood. In an analysis of more than 10 122 real-life online communities (with a total of 134 147 members) hosted by a leading platform over periods of more than a decade, we observe a prominent structural difference between stable and unstable communities, enabling the prediction of sustainability up to a decade ahead. We find that communities that fail to maintain a typical hierarchical social structure that preserves cohesiveness across size scales do not survive, while communities that exhibit such balance prevail. This difference is observable in as early as the first 30 days of a community's lifetime, enabling prediction of community sustainability up to 10 years in the future. We theorize that communities comprising distinct social structures that balance global and local factors across scales of sizes are more likely to maintain sustainability.
The architecture of co-morbidity networks of physical and mental health conditions in military veterans
Authors: Alexander-Bloch Aaron F. , Raznahan Armin , Shinohara Russell T. , Mathias Samuel R. , Bathulapalli Harini , Bhalla Ish P. , Goulet Joseph L. , Satterthwaite Theodore D. , Bassett Danielle S. , Glahn David C. , Brandt Cynthia A.
Published: June 2020

Co-morbidity between medical and psychiatric conditions is commonly considered between individual pairs of conditions. However, an important alternative is to consider all conditions as part of a co-morbidity network, which encompasses all interactions between patients and a healthcare system. Analysis of co-morbidity networks could detect and quantify general tendencies not observed by smaller-scale studies. Here, we investigate the co-morbidity network derived from longitudinal healthcare records from approximately 1 million United States military veterans, a population disproportionately impacted by psychiatric morbidity and psychological trauma. Network analyses revealed marked and heterogenous patterns of co-morbidity, including a multi-scale community structure composed of groups of commonly co-morbid conditions. Psychiatric conditions including posttraumatic stress disorder were strong predictors of future medical morbidity. Neurological conditions and conditions associated with chronic pain were particularly highly co-morbid with psychiatric conditions. Across conditions, the degree of co-morbidity was positively associated with mortality. Co-morbidity was modified by biological sex and could be used to predict future diagnostic status, with out-of-sample prediction accuracy of 90–92%. Understanding complex patterns of disease co-morbidity has the potential to lead to improved designs of systems of care and the development of targeted interventions that consider the broader context of mental and physical health.
Hyponatraemia and mortality in psychiatric patients: protocol for Bayesian causal inference study
Authors: Kaas-Hansen Benjamin Skov , Graudal Niels , Andersen Stig Ejdrup , Thygesen Lau Caspar , Brunak Søren , Jürgens Gesche
Published: June 2020

Introduction

Hyponatriaemia has been associated with mortality in somatic patients, but little is known about the nature of such an association in psychiatric patients. This manuscript details a study to investigate if hyponatraemia be a direct contributor to death in schizophrenic and bipolar patients. It will further gauge the potential role of somatic comorbidity and psychotropic polypharmacy, with emphasis on antipsychotics and antidepressants.

Methods

Density sampled case-control study of schizophrenic and bipolar patients from the Capital Region and Region Zealand in Denmark using prospective data from Danish registries and electronic medical records. Cases deceased between 1 January 2011 and 1 July 2016; controls were found by risk-set sampling, matched by date of birth +/- 180 days. We will use a fully Bayesian, non-linear, conditional logistic regression model to estimate the causal effect of serum sodium level on death, with covariates selected by a causal diagram. Continuous covariates will be modelled with restricted (natural) cubic splines to elicit non-linear relationships. A sample of 10 cases and 50 controls was drawn to ascertain that the proposed study be sound and realistic.

Conclusion

This study will expand the body of evidence on the effect of hyponatriaemia on mortality in schizophrenic and bipolar patients and may guide clinical decision-making in terms of both monitoring intensity and rational use of psychotropics.
The genomic impact of mycoheterotrophy: targeted gene losses but extensive expression reprogramming
Authors: Marcin Jakalski , Julita Minasiewicz , José Caius , May Michał , Marc-André Selosse , Etienne Delannoy
Published: June 2020

Mycoheterotrophic plants have lost the ability to photosynthesize and they parasitize their associated fungus to get the mineral and organic nutrients they need. Despite involving radical changes in life history traits and ecological requirements, the transition from autotrophy to mycoheterotrophy occurred independently in almost all major lineages of land plants, but most often inOrchidaceae. Yet the molecular mechanisms underlying this shift are still poorly understood. The comparison of the transcriptomes ofEpipogium aphyllumandNeottia nidus-avis, two mycoheterotrophic orchids, to other autotrophic and mycoheterotrophic orchids showed massive molecular function losses restricted to photosynthetic activities. In addition to these targeted losses, the analysis of their expression profiles showed that many orthologs had inverted root/shoot ratios compared to autotrophic species. Fatty acid and amino acid biosynthesis as well as primary cell wall metabolism were among the pathways most impacted by this expression reprogramming. Our study suggests that, while associated with function losses rather than metabolic innovations, the shift in nutritional mode from autotrophy to mycoheterotrophy remodeled the architecture of the plant metabolism.
Automatic identification of players in the flavonoid biosynthesis with application on the biomedicinal plantCroton tiglium
Authors: Pucker Boas , Reiher Franziska , Schilbert Hanna Marie
Published: June 2020

The flavonoid biosynthesis is a well characterised model system for specialised metabolism and transcriptional regulation in plants. Flavonoids have numerous biological functions like UV protection and pollinator attraction, but also biotechnological potential. Here, we present Knowledge-based Identification of Pathway Enzymes (KIPEs) as an automatic approach for the identification of players in the flavonoid biosynthesis. KIPEs combines comprehensive sequence similarity analyses with the inspection of functionally relevant amino acid residues and domains in subjected peptide sequences. Comprehensive sequence sets of flavonoid biosynthesis enzymes and knowledge about functionally relevant amino acids were collected. As a proof of concept, KIPEs was applied to investigate the flavonoid biosynthesis of the medicinal plantCroton tigliumbased on a transcriptome assembly. Enzyme candidates for all steps in the biosynthesis network were identified and matched to previous reports of corresponding metabolites inCrotonspecies.
A Time Series Analysis of Trends in Medicare Utilization and Reimbursement for Cancer Immunotherapy Drugs: 2012-2017
Authors: Puri Pranav , Cortese Denis , Baliga Sujith
Published: June 2020

The adoption of immunotherapy has dramatically transformed the landscape of oncology, and improved the prognosis of patients diagnosed with metastatic malignancies. Fee-for-service (FFS) Medicare is the largest payer in the U.S, and pays for physician-administered oncolytics through its medical Part B benefit. However, to the best of our knowledge, trends in Medicare utilization and expenditures for cancer immunotherapy have yet to be described. The aim of this study was to describe trends in Medicare immunotherapy reimbursement. We utilized the public Drugs@FDA database to identify all immunotherapy drugs that were approved by the FDA for solid and hematological cancers in adults as of December 31, 2017. The Medicare Physician Supplier and Other Provider Public Use File (POSPUF) provides reimbursement and utilization data on all services and procedures provided to Medicare fee-for-service beneficiaries. Using the Medicare POSPUF, we aggregated the volume of services, average Medicare reimbursement, and the number of distinct patients receiving each immunotherapy drug from January 2012 to December 2017. The number of Medicare reimbursed cancer immunotherapy drugs increased from 3 in 2012 to 12 in 2017. Over this time period, the number of patients receiving immunotherapy administrations increased 88% from 59,506 to 111,577. Similarly, the number of drug administrations increased by 2,412% from 2,338,691 to 58,752,804. From 2012 to 2017, total Medicare expenditure on cancer immunotherapy drugs increased 154% from $771,434,031 to $1,962,279,164. Medicare expenditure on cancer immunotherapy drugs accounted for 26% of the increase in total Medicare Part B drug expenditures over this time period.
Quantitative occupancy of myriad transcription factors from one DNase experiment enables efficient comparisons across conditions
Authors: Luo Kaixuan , Zhong Jianling , Safi Alexias , Hong Linda K. , Tewari Alok K. , Song Lingyun , Reddy Timothy E. , Ma Li , Crawford Gregory E. , Hartemink Alexander J.
Published: June 2020

Over a thousand different transcription factors (TFs) bind with varying occupancy across the human genome. Chromatin immunoprecipitation (ChIP) can assay occupancy genome-wide, but only one TF at a time, limiting our ability to comprehensively observe the TF occupancy landscape, let alone quantify how it changes across conditions. We developed TOP, a Bayesian hierarchical regression framework, to profile genome-wide quantitative occupancy of numerous TFs using data from a single DNase-seq experiment. TOP is supervised, and its hierarchical structure allows it to predict the occupancy of any sequence-specific TF, even those never assayed with ChIP. We used TOP to profile the quantitative occupancy of nearly 1500 human TF motifs, and examined how their occupancies changed genome-wide in multiple contexts: across 178 cell types, over 12 hours of exposure to different hormones, and across the genetic backgrounds of 70 individuals. TOP enables cost-effective exploration of quantitative changes in the landscape of TF binding.
Post-ictal generalized EEG suppression and seizure-induced mortality are reduced by enhancing dorsal raphe serotonergic neurotransmission
Authors: Petrucci Alexandra N. , Joyal Katelyn G. , Chou Jonathan W. , Li Rui , Vencer Kimberly M. , Buchanan Gordon F.
Published: June 2020

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. A proposed risk marker for SUDEP is the duration of post-ictal generalized EEG suppression (PGES). The mechanisms underlying PGES are unknown. Serotonin (5-HT) has been implicated in SUDEP pathophysiology. Seizures suppress activity of 5-HT neurons in the dorsal raphe nucleus (DRN). We hypothesized that suppression of DRN 5-HT neuron activity contributes to PGES and increasing 5-HT neurotransmission or stimulating the DRN before a seizure would decrease PGES duration. Adult C57BL/6 andPet1-Cremice received EEG/EMG electrodes, a bipolar stimulating/recording electrode in the right basolateral amygdala, and either a microdialysis guide cannula or an injection of adeno-associated virus (AAV) allowing expression of channelrhodopsin2 plus an optic fiber into the DRN. Systemic application of the selective 5-HT reuptake inhibitor citalopram (20 mg/kg) decreased PGES duration from seizures induced during wake (n = 23) and NREM sleep (n = 13) whereas fluoxetine (20 mg/kg) pretreatment decreased PGES duration following seizures induced from wake (n = 11), but not NREM sleep (n = 9). Focal chemical (n = 6) or optogenetic (n = 8) stimulation of the DRN reduced PGES duration following kindled seizures and reduced morality following maximal electroshock seizures (n = 6) induced during wake. During PGES, animals exhibited immobility and suppression of EEG activity that was reduced by citalopram pretreatment. These results indicate that 5-HT and the DRN may regulate PGES and seizure-induced mortality.

Highlights

-

PGES consistently follows seizures induced by amygdala stimulation in amygdala-kindled mice.

-

Seizure-induced dysregulation of 5-HT neurotransmission from the dorsal raphe nucleus may contribute to PGES.

-

Systemic administration of 5-HT enhancing drugs and stimulation of the DRN reduces PGES duration.

-

PGES is associated with post-ictal immobility in kindled mice that can be reduced by pretreatment with citalopram.

-

Recovery of EEG frequencies to baseline occurs in a stepwise manner with the lowest frequencies recovering first.
Whole-Genome Sequences of the Severe Acute Respiratory Syndrome Coronavirus-2 obtained from Romanian patients between March and June of 2020
Authors: Lazar Mihaela , Popovici Odette , Mühlemann Barbara , Durfee Tim , Stan Razvan
Published: June 2020

Impact of mutations on the evolution of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) are needed for ongoing global efforts to track and trace the current pandemic, in order to enact effective prevention and treatment options. SARS-Co-V-2 viral genomes were detected and sequenced from 18 Romanian patients suffering from coronavirus disease-2019. Viral Spike S glycoprotein sequences were used to generate model structures and assess the role of mutations on protein stability. We integrated the phylogenetic tree within the available European SARS-Co-V-2 genomic sequences. We further provide an epidemiological overview of the pre-existing conditions that are lethal in relevant Romanian patients. Non-synonymous mutations in the viral Spike glycoprotein relating to infectivity are constructed in models of protein structures. Continuing search to limit and treat SARS-CoV-2 benefit from our contribution in delineating the viral Spike glycoprotein mutations, as well as from assessment of their role on protein stability or complex formation with human receptor angiotensin-converting enzyme 2. Our results help implement and extend worldwide genomic surveillance of coronavirus disease-2019.
Assembly of 23 Plastid Genomes Provides the Chloroplast View onMiscanthusOrigins
Authors: Evans Dyfed Lloyd
Published: June 2020

Despite its economic importance as a new biofuel resource, little work has been done on the large-scale phylogenetics ofMiscanthus. Twenty-three completeMiscanthuschloroplasts were assembled and annotated. A phylogeny was performed with these assemblies, which shows the relationships between the mainMiscanthusspecies and sub-species. The phylogeny demonstrates that there is no meaningful distinction betweenMiscanthus floridulusandMiscanthus transmorrisonensisas the accessions are not distinct. However, at the crown of the tree there is a clear distinction betweenM. sinensis malepartusandM. sinensis condensatussubspecies. The phylogeny reaveals that the female parent ofMiscanthus xgiganteusisMiscanthus lutarioripariusrather thanMiscanthus sacchariflorus. The phylogeny also shows a novel hybrid betweenMiscanthus oligostachyusandMiscanthus sinensis, a grouping to whichMiscanthus sinensisvar Purpurascens belongs. This hybrid form is namedMiscanthus×oligostachyus.
Nested Stochastic Block Models Applied to the Analysis of Single Cell Data
Authors: Morelli Leonardo , Giansanti Valentina , Cittaro Davide
Published: June 2020

Single cell profiling has been proven to be a powerful tool in molecular biology to understand the complex behaviours of heterogeneous system. The definition of the properties of single cells is the primary endpoint of such analysis, cells are typically clustered to underpin the common determinants that can be used to describe functional properties of the cell mixture under investigation. Several approaches have been proposed to identify cell clusters; while this is matter of active research, one popular approach is based on community detection in neighbourhood graphs by optimisation of modularity. In this paper we propose an alternative and principled solution to this problem, based on Stochastic Block Models. We show that such approach not only is suitable for identification of cell groups, it also provides a solid framework to perform other relevant tasks in single cell analysis, such as label transfer. To encourage the use of Stochastic Block Models, we developed a python library,schist, that is compatible with the popularscanpyframework.
Shotgun scanning glycomutagenesis: a simple and efficient strategy for constructing and characterizing neoglycoproteins
Authors: Li Mingji , Zheng Xiaolu , Shanker Sudhanshu , Jaroentomeechai Thapakorn , Moeller Tyler D. , Hulbert Sophia W. , Koçer Ilkay , Byrne Josef , Cox Emily C. , Fu Qin , Zhang Sheng , Labonte Jason W. , Gray Jeffrey J. , DeLisa Matthew P.
Published: June 2020

As a common protein modification, asparagine-linked (N-linked) glycosylation has the capacity to greatly influence the biological and biophysical properties of proteins. However, the routine use of glycosylation at naïve sites as a strategy for engineering proteins with advantageous properties is currently limited by our inability to construct large collections of glycoproteins for interrogating the structural and functional consequences of glycan installation. To address this challenge, we describe a combinatorial strategy termed shotgun scanning glycomutagenesis (SSGM) in which DNA libraries encoding all possible glycosylation site variants of a given protein are constructed and subsequently expressed in glycosylation-competent bacteria, thereby enabling rapid determination of glycosylatable sites in the protein. Moreover, the resulting neoglycoproteins can be readily subjected to available medium- to high-throughput assays, making it possible to systematically investigate the structural and functional consequences of glycan conjugation along a protein backbone. The utility of this approach was demonstrated with three different acceptor proteins, namely bacterial immunity protein Im7, bovine pancreatic ribonuclease A, and a human anti-HER2 single-chain Fv antibody, all of which were found to tolerateN-glycan attachment at a large number of positions and with relatively high efficiency. The stability and activity of many glycovariants was measurably altered by theN-linked glycan in a manner that critically depended on the precise location of the modification. Importantly, we anticipate that our workflow for creating and characterizing large ensembles of neoglycoproteins should provide access to unexplored regions of glycoprotein structural space and to custom-made glycoproteins with desirable properties.
Feature Frequency Profile-based phylogenies are inaccurate
Authors: Li Yuanning , David Kyle T. , Shen Xing-Xing , Steenwyk Jacob L. , Halanych Kenneth M. , Rokas Antonis
Published: June 2020

Choi and Kim (PNAS, 117: 3678-3686; first published February 4, 2020;https://doi.org/10.1073/pnas.1915766117) used the alignment-free Feature Frequency Profile (FFP) method to reconstruct a broad sketch of the tree of life based on proteome data from 4,023 taxa. The FFP-based reconstruction reports many relationships that strongly contradict the current consensus view of the tree of life and its accuracy has not been tested. Comparison of FFP with current standard approaches, such as concatenation and coalescence, using simulation analyses shows that FFP performs poorly. We conclude that the phylogeny of the tree of life reconstructed by Choi and Kim is suspect based on methodology as well as prior phylogenetic evidence.
Weight and organ specific immune cell profiling of Sleeve Gastrectomy
Authors: Harris David A. , Subramaniam Renuka , Brenner Todd , Tavakkoli Ali , Sheu Eric G.
Published: June 2020

Sleeve gastrectomy (SG) has profound, immediate weight-loss independent effects on obesity related diabetes (T2D). Our prior studies have shown that immunologic remodeling may play a part in this metabolic improvement. However, to date, little is known about how the major immune cell populations change following SG. Using mass cytometry with time of flight analysis (CyTOF) we aimed to broadly explore the organ-specific immune cell repertoire induced by SG. Surgery was performed on obese, insulin resistant and lean mice in order to understand surgery-specific phenotypes. We identified a shift within the splenic B cell compartment with a reduction in follicular and an increase in innate-like B cell subsets in SG animals. There was a concomitant increase in multiple circulating immunoglobulin classes. Further, SG animals had a conserved increase in splenic neutrophils and a tendency toward M2 macrophage polarization. Others have shown that these, weight-loss independent, surgery-specific changes are linked to improved glucose metabolism and thus, may be a major contributor to post SG physiology. Characterizing the complex immune milieu following SG is an important step toward understanding the physiology of SG and the potential therapies therein.
Visualizing active viral infection reveals diverse cell fates in synchronized algal bloom demise
Authors: Vincent Flora , Sheyn Uri , Porat Ziv , Vardi Assaf
Published: June 2020

Marine viruses are considered as major evolutionary and biogeochemical drivers of microbial life, through metabolic reprogramming of their host and cell lysis that modulates nutrient cycling1, primary production and carbon export in the oceans2. Despite the fact that viruses are the most abundant biological entities in the marine environment, we still lack mechanistic and quantitative approaches to assess their impact on the marine food webs. Here, we provide the first quantification of active viral infection, during bloom succession of the cosmopolitan coccolithophoreEmiliania huxleyi, by subcellular visualization of both virus and host transcripts on a single cell resolution across thousands of cells. Using this novel method, that we coined Virocell-FISH, we revealed that distinct transcriptional states co-exist during the infection dynamics, and that viral infection reached only a quarter of theE. huxleyipopulation although the bloom demised in a synchronized manner. Through a detailed laboratory time-course infection ofE. huxleyiby its lytic large virus EhV, we quantitatively show that metabolically active infected cells chronically release viral particles, and that viral-induced lysis is not systematically accompanied by virion increase, thus challenging major assumptions regarding the life cycle of giant lytic viruses. Using Virocell-FISH, we could further assess in a new resolution, the level of viral infection in cell aggregates, a key ecosystem process that can facilitate carbon export to the deep ocean3. We project that our approach can be applied to diverse marine microbial systems, opening a mechanistic dimension to the study of host-pathogen interactions in the ocean.

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Quantifying active viral infection in algal blooms
Distinct genetic architectures underlie divergent thorax, leg, and wing pigmentation betweenDrosophila elegansandD. gunungcola
Authors: Massey Jonathan H. , Li Jun , Stern David L. , Wittkopp Patricia J.
Published: June 2020

Understanding the genetic basis of species differences is a major goal in evolutionary biology. Pigmentation divergence betweenDrosophilaspecies often involves genetic changes in pigmentation candidate genes that pattern the body and wings, but it remains unclear how these changes affect pigmentation evolution in multiple body parts between the same diverging species.Drosophila elegansandD. gunungcolashow pigmentation differences in the thorax, legs, and wings, withD. elegansexhibiting male-specific wing spots andD. gunungcolalacking wing spots with intensely dark thoraces and legs. Here, we performed QTL mapping to identify the genetic architecture of these differences. We find a large effect QTL on the X chromosome for all three body parts. QTL on Muller Element E were found for thorax pigmentation in both backcrosses but were only marginally significant in one backcross for the legs and wings. Consistent with this observation, we isolated the effects of the Muller Element E QTL by introgressingD. gunungcolaalleles into aD. elegansgenetic background and found thatD. gunungcolaalleles linked near the pigmentation candidate geneebonycaused intense darkening of the thorax, minimal darkening of legs, and minimal shrinking of wing spots.D. elegans ebonymutants showed changes in pigmentation consistent with Ebony having different effects on pigmentation in different tissues. Our results suggest that multiple genes have evolved differential effects on pigmentation levels in different body regions.