bluuebunny/crossref_metadata_2025 huggingface dataset:
Tranexamic acid is associated with reduced complement activation in trauma patients with hemorrhagic shock and hyperfibrinolysis on thromboelastography
Authors: Barrett Christopher D. , Vigneshwar Navin , Moore Hunter B. , Ghasabyan Arsen , Chandler James , Moore Ernest E. , Yaffe Michael B.
Published: July 2020

Trauma with hemorrhagic shock causes massive tissue plasminogen activator release, plasmin generation, and hyperfibrinolysis. Tranexamic acid (TXA) has recently been used to treat bleeding in trauma by preventing plasmin generation to limit fibrinolysis. Trauma patients also have increased complement activation that correlates with mortality and organ failure, but the source of activation is not clear, and plasmin has recently been shown to efficiently cleave C3 and C5 to their activated fragments. We hypothesized that trauma patients in hemorrhagic shock with hyperfibrinolysis on thromboelastography (TEG) LY30 would have increased complement activation at early time points, as measured by soluble C5b-9 complex, and TXA would prevent this. Plasma samples were obtained from an unrelated, previously performed IRB-approved prospective randomized study of trauma patients. Three groups were studied with n = 5 patients in each group: patients without hyperfibrinolysis (TEG LY30 < 3%) (who therefore did not get TXA), patients with hyperfibrinolysis (TEG LY30 > 3%) who did not get TXA, and patients with hyperfibrinolysis who were then treated with TXA. We found that patients who did not receive TXA, regardless of fibrinolytic phenotype, had elevated soluble C5b-9 levels at 6 h relative to emergency department levels. In contrast, all five patients with initial TEG LY30 more than 3% and were then treated with TXA had reduced soluble C5b-9 levels at 6 h relative to emergency department levels. There were no differences in PF1 + 2, Bb, or C4d levels between groups, suggesting that coagulation and complement activation pathways may not be primarily responsible for the observed differences.
Best techniques for endoscopic ampullectomy
Authors: Klair Jagpal S. , Irani Shayan , Kozarek Richard
Published: July 2020

Purpose of review

Endoscopic ampullectomy has proven its safety and efficacy in multiple studies, making it the favorable option for the management of endoscopic ampullectomy. In this review, we plan to review the basic steps every endoscopist should be familiar with before undertaking endoscopic ampullectomy.

Recent findings

In this review, we plan to discuss the indications, preresection evaluation process including endoscopic ultrasound, endoscopic ampullectomy techniques with side-viewing endoscope and endoscopist experience/comfort with the management of the endoscopic ampullectomy complications.

Things of utmost interest include reviewing all the ampullary biopsy specimens by an expert gastrointestinal pathologist, careful preresection staging, en bloc resection, familiarity with tools and techniques of endoscopic ampullectomy, postresection adverse events & management and postprocedure surveillance.
Breath testing for the diagnosis of pancreatic disease
Authors: Dominguez-Muñoz J. Enrique
Published: July 2020

Purpose of review

Pancreatic function tests are mainly used for the diagnosis of exocrine pancreatic insufficiency (EPI) in patients with pancreatic diseases or after pancreatic or gastric surgery. Breath tests evaluate not just pancreatic secretion but the digestion capacity of the pancreas. These tests are good candidates for the diagnosis of EPI as they are noninvasive, accurate and easy to apply to clinical practice.

Recent findings

The 13C-labelled mixed triglyceride (MTG) breath test has been optimized and validated against adequate reference methods for the diagnosis of EPI in patients with chronic pancreatitis and for the evaluation of the efficacy of pancreatic enzyme replacement therapy (PERT). In addition, reported 13C-MTG breath test results in patients with other pancreatic diseases and after pancreatic and gastric surgery support the accuracy and clinical applicability of this test. The evidence of pancreatic function breath tests with other 13C-labelled substrates is limited.

Increasing evidence supports the accuracy and clinical usefulness of the 13C-MTG breath test for the diagnosis of EPI and the evaluation of the efficacy of PERT in different clinical conditions. Commercial availability of this test is required for a wide clinical use. The use of optimized and validated breath test protocols is mandatory.
Precision medicine for pancreatic diseases
Authors: Shelton Celeste A. , Whitcomb David C.
Published: July 2020

Purpose of review

We describe and contrast the strengths of precision medicine with Western medicine, and complex trait genetics with Mendelian genetics. Classic genetics focuses on highly penetrant pathogenic variants in a single gene believed to cause or confer a high risk for well-defined phenotypes. However, a minority of disorders have a single gene cause. Further, even individuals with identical Mendelian disease-associated genotypes may exhibit substantial phenotypic variability indicative of genetic and environmental modifiers. Still, most diseases are considered complex traits (or complex diseases).

Recent findings

New insights into the genetic underpinnings of complex traits provide opportunities for advances in diagnosis and management. Precision medicine provides the framework for integrating complex trait knowledge into clinical care through a sophisticated analysis pipeline. Multidimensional modeling of acquired diseases includes multiple genetic risks scattered over many genes and gene regulators that must be interpreted on the basis of functional evidence (e.g., genomics, transcriptomics) with structured models and expert systems; strengthened with machine learning and artificial intelligence. The choice of genotyping approaches (shotgun sequencing, single nucleotide polymorphism chips, targeted panels) is discussed.

The result of a good precision medicine tool is clinical-decision support and guidance to tackle complex disorders such as pancreatitis, diabetes, and pancreatic cancer oncogenesis.
Robotics in flexible endoscopy: current status and future prospects
Authors: Seeliger Barbara , Swanström Lee L.
Published: July 2020

Purpose of review

Advanced endoscopy procedures are technically challenging and require extensive training. Recent technological advances made in computer science and robotics have the potential to enhance the performance of complex intraluminal and transluminal interventions and potentially optimize precision and safety. This review covers the different technologies used for robot-assisted interventions in the gastrointestinal tract, organized according to their clinical availability, and focusing on flexible endoscopy-based systems.

Recent findings

In the curvilinear gastrointestinal anatomy, robotic technology can enhance flexible endoscopes to augment effectiveness, safety, and therapeutic capabilities, particularly for complex intraluminal and transluminal interventions. Increased visual angles, increased degrees of freedom of instrumentation, optimized navigation, and locomotion, which may lead to a reduced physician learning curve and workload, are promising achievements with the promise to ultimately replace conventional endoscopy techniques for screening and therapeutic endoscopy.

The majority of these devices are not commercially available yet. The best clinical applications are also currently being researched. Nonetheless, robotic assistance may encourage surgeons to use flexible endoscopes to administer surgical therapies and increase interest among gastroenterologists in advanced therapies. Robotics may be a means to overcome the technical obstacles of incisionless natural orifice procedures and favor an increased adoption of complex endoscopic procedures such as third-space therapies.
Clinical impact of PET imaging in prostate cancer management
Authors: Emmett Louise , Hruby George
Published: July 2020

Purpose of review

Imaging of prostate cancer has been a rapidly evolving field in recent years with the introduction of multiple new PET tracer agents. Introduction of novel imaging techniques into clinical practice requires careful evaluation, with the ultimate aims of improved patient outcomes, better sequencing of treatments, and cost effectiveness. The increased sensitivity and specificity of these new PET agents present both challenges and opportunities. We know they frequently change management, but are these effective management changes, and is it always in the best interests of the patients?

Recent findings

This review will focus on recent publications that provide high-level evidence for the use of PET in prostate cancer. It will discuss studies that have evaluated the clinical impact of PET imaging in prostate cancer and will review a number of trials that demonstrate the potential of PET to change current standard of care, from diagnosis, to prognostic capabilities in men with metastatic prostate cancer.

Evidence for the use of PET in prostate cancer is building with studies evaluating diagnostic accuracy of PET at all stages of prostate cancer. We review the evidence available, focusing on prospective trials that are measuring the impact of new technology on patient outcomes.
mpMRI-targeted biopsy versus systematic biopsy for clinically significant prostate cancer diagnosis: a systematic review and metaanalysis
Authors: Baccaglini Willy , Glina Felipe P.A. , Pazeto Cristiano L. , Bernardo Wanderley M. , Sanchez-Salas Rafael
Published: July 2020

Purpose of review

We aimed to compare the accuracy of clinically significant prostate cancer (csPCa) diagnosis by magnetic resonance imaging-targeted biopsy (MRI-TB) versus systematic biopsy (SB) in men suspected of having prostate cancer (PCa).

Recent findings

In biopsy-naïve patients, MRI-TB was more accurate to identify csPCa than SB. However, when comparing specifically MRI-TB versus transperineal (SB), we did not find any difference. Furthermore, in a repeat biopsy scenario, MRI-TB found more csPCa than SB as well. Finally, postanalysis comparing combined biopsy (SB plus MRI-TB) suggests that the later alone may play a role in both scenarios for identifying csPCa.

MRI-TB found more csPCa than SB in patients with suspected PCa in both scenarios, naïve and repeat biopsies, but more studies comparing those methods are warranted before any recommendation on this topic.
Genomic analysis of 21 patients with corneal neuralgia after refractive surgery
Authors: Yuan Jun-Hui , Schulman Betsy R. , Effraim Philip R. , Sulayman Dib-Hajj , Jacobs Deborah S. , Waxman Stephen G.
Published: July 2020

Background:

Refractive surgery, specifically laser-assisted in situ keratomileusis and photorefractive keratectomy, are widely applied procedures to treat myopia, hyperopia, and astigmatism. After surgery, a subgroup of cases suffers from persistent and intractable pain of obscure etiology, thought to be neuropathic. We aimed to investigate the contribution of genomic factors in the pathogenesis of these patients with corneal neuralgia.

Methods:

We enrolled 21 cases (6 males and 15 females) from 20 unrelated families, who reported persistent pain (>3 months), after refractive surgery (20 laser-assisted in situ keratomileusis and 1 photorefractive keratectomy patients). Whole-exome sequencing and gene-based association test were performed.

Results:

Whole-exome sequencing demonstrated low-frequency variants (allele frequency < 0.05) in electrogenisome-related ion channels and cornea-expressed collagens, most frequently in SCN10A (5 cases), SCN9A (4 cases), TRPV1 (4 cases), CACNA1H and CACNA2D2 (5 cases each), COL5A1 (6 cases), COL6A3 (5 cases), and COL4A2 (4 cases). Two variants, p.K655R of SCN9A and p.Q85R of TRPV1, were previously characterized as gain-of-function. Gene-based association test assessing “damaging” missense variants against gnomAD exome database (non-Finnish European or global), identified a gene, SLC9A3R1, with statistically significant effect (odds ratio = 17.09 or 17.04; Bonferroni-corrected P-value < 0.05).

Conclusion:

These findings in a small patient cohort did not identify a common gene/variant among most of these cases, as found in other disorders, for example small-fiber neuropathy. Further studies of these candidate genes/variants might enhance understanding of the role of genetic factors in the pathogenesis of corneal neuralgia.
The association between daily physical exercise and pain among women with fibromyalgia: the moderating role of pain catastrophizing
Authors: Lazaridou Asimina , Paschali Myrella , Schreiber Kristin , Galenkamp Laura , Berry Michael , Paschalis Theodoros , Napadow Vitaly , Edwards Robert R.
Published: July 2020

Introduction:

Fibromyalgia (FM) is a condition marked by widespread chronic pain and an array of somatic and psychological symptoms. The primary objective of this study was to explore daily associations between physical activity and pain intensity among a sample of women with FM and the potential moderation of this association by pain catastrophizing.

Methods:

Women with FM (N = 107) completed questionnaires assessing pain, FM symptoms, and psychological measures and were then asked to report their levels of daily pain catastrophizing, physical activity, and pain intensity once per day for a period of 1 week using daily electronic diary-based tracking. In addition, objective measures of physical activity were collected using an activity tracker (Fitbit Flex), which measured step counts. Daily self-report physical activity was used as the independent variable and pain intensity (Brief Pain Inventory) was the outcome, whereas daily pain catastrophizing was tested in the model as the potential moderator.

Results:

Moderation analyses demonstrated associations between physical activity and pain intensity, which were moderated by patient's level of catastrophizing (B = 0.003, SE = 0.001, P < 0.05), with patients scoring higher in daily catastrophizing showing a relatively stronger link between higher day-to-day physical activity and increased daily FM pain. Significant associations were observed between pain catastrophizing, pain intensity, and Fitbit Flex step count (P < 0.05).

Conclusions:

Our findings suggest that increases in daily physical activity is associated with more self-reported pain intensity in women with FM pain, particularly among those with higher levels of pain catastrophizing.
A novel cortical biomarker signature for predicting pain sensitivity: protocol for the PREDICT longitudinal analytical validation study
Authors: Seminowicz David A. , Bilska Katarzyna , Chowdhury Nahian S. , Skippen Patrick , Millard Samantha K. , Chiang Alan K.I. , Chen Shuo , Furman Andrew J. , Schabrun Siobhan M.
Published: July 2020

Introduction:

Temporomandibular disorder is a common musculoskeletal pain condition with development of chronic symptoms in 49% of patients. Although a number of biological factors have shown an association with chronic temporomandibular disorder in cross-sectional and case control studies, there are currently no biomarkers that can predict the development of chronic symptoms. The PREDICT study aims to undertake analytical validation of a novel peak alpha frequency (PAF) and corticomotor excitability (CME) biomarker signature using a human model of the transition to sustained myofascial temporomandibular pain (masseter intramuscular injection of nerve growth factor [NGF]). This article describes, a priori, the methods and analysis plan.

Methods:

This study uses a multisite longitudinal, experimental study to follow individuals for a period of 30 days as they progressively develop and experience complete resolution of NGF-induced muscle pain. One hundred fifty healthy participants will be recruited. Participants will complete twice daily electronic pain diaries from day 0 to day 30 and undergo assessment of pressure pain thresholds, and recording of PAF and CME on days 0, 2, and 5. Intramuscular injection of NGF will be given into the right masseter muscle on days 0 and 2. The primary outcome is pain sensitivity.

Perspective:

PREDICT is the first study to undertake analytical validation of a PAF and CME biomarker signature. The study will determine the sensitivity, specificity, and accuracy of the biomarker signature to predict an individual's sensitivity to pain.

Registration details:

ClinicalTrials.gov: NCT04241562 (prospective).
Neurotization of the Nipple-Areola Complex during Implant-Based Reconstruction: Evaluation of Early Sensation Recovery
Authors: Djohan Risal , Scomacao Isis , Knackstedt Rebecca , Cakmakoglu Cagri , Grobmyer Stephen R.
Published: July 2020

The concept of sensate autologous breast reconstruction is not novel, and prior literature has focused mainly on sensate abdominally based breast reconstruction. The goal of this article is to present the authors’ results with a novel technique performing sensate implant-based reconstruction. A database was prospectively maintained for patients who underwent implant-based sensate breast reconstruction. The anterior branch of the lateral fourth intercostal is identified and preserved during the mastectomy by the breast surgeon. A processed nerve allograft is used as an interpositional graft connecting the donor nerve to the targeted nipple-areola complex. The sensory recovery process was objectively monitored using a pressure-specified sensory device. Thirteen patients underwent the proposed technique. Eight patients with 15 breasts were monitored for sensory recovery. For sensory measurement, the nipple had a mean threshold of 67.33 ± 34.48 g/nm2. The upper inner (29 ± 26.75 g/nm2) and upper outer (46.82 ± 32.72 g/nm2) nipple-areola complex quadrants demonstrated better scores during the moving test compared with the static test. Mean time between the test and surgery was 4.18 ± 2.3 months, and mean time between the second test and surgery was 10.59 ± 3.57 months. Threshold improvements were documented after the second test for all nipple-areola complex areas evaluated. This is the first study to report on early results obtained after performing sensate implant-based breast reconstruction. More studies are required to determine the long-term outcomes and impact on quality of life and to assess whether patient or breast characteristics impact the success of this procedure.
Genetic Risk of Trigger Finger: Results of a Genomewide Association Study
Authors: Sood Ravi F. , Westenberg Ritsaart F. , Winograd Jonathan M. , Eberlin Kyle R. , Chen Neal C.
Published: July 2020

Background:

Trigger finger, or stenosing tenosynovitis, is one of the most common conditions affecting the hand, yet its pathophysiology remains poorly understood, and genetic association studies of trigger finger are lacking. The purpose of this study was to identify single-nucleotide polymorphisms associated with trigger finger through a genomewide approach.

Methods:

The authors performed a case-control genomewide association study in the Partners HealthCare Biobank. Single-nucleotide polymorphism– and gene-based association analyses were carried out after quality control, imputation, and filtering.

Results:

Among 942 trigger finger cases and 24,472 controls, the authors tested 7,846,471 single-nucleotide polymorphisms for association with trigger finger. In the single-nucleotide polymorphism–based analysis, a single locus on chromosome 13 corresponding to KLHL1 met the genomewide significance threshold (lead single-nucleotide polymorphism rs59988404; OR, 1.74; 95 percent CI, 1.47 to 2.07; p = 1.99 × 10−10). After mapping, gene-based analysis demonstrated a significant association with POLE2 (p = 7.53 × 10−7) on chromosome 14. Among trigger finger cases, rs59988404 genotype was significantly associated with the total number of trigger finger procedures performed (p = 0.026).

Conclusions:

In the first reported genomewide association study of trigger finger, the authors report significant associations of KLHL1 and POLE2 with risk of trigger finger. The authors’ results may help to elucidate the pathophysiology of trigger finger and facilitate an individualized, precision-medicine treatment approach.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Risk, III.
Management of Congenital Auricular Anomalies
Authors: Joukhadar Nadim , McKee Daniel , Caouette-Laberge Louise , Bezuhly Michael
Published: July 2020

Learning Objectives:

After studying this article, the participant should be able to: 1. Describe normal ear anatomy and development, and evaluate the patient’s ears for differences in shape, size, prominence, and symmetry. 2. Identify common congenital ear deformities, including prominent ear, macrotia, Stahl ear, cryptotia, constricted ear, and lobule anomalies. 3. Describe both early nonoperative management and operative techniques for correction of these ear deformities. 4. Be aware of advantages and disadvantages of common and emerging techniques for correction of pediatric ear deformities.

Whereas severe ear malformations such as microtia/anotia are rare, other ear deformities, such as prominent ear, Stahl ear, and cryptotia, are common. Although these ear deformities result in minimal physiologic morbidity, their psychological and cosmetic impact can be significant. Identifying these common deformities and understanding how they differ from normal ear anatomy is critical to their management. In cases where a deformity is identified in neonatal life, ear molding may obviate the need for surgery. Although various surgical techniques have been described for correction of common ear deformities, the surgeon should follow a careful stepwise approach to address the auricular deformity or deformities present. By using such an approach, complications may be minimized and predictable aesthetic outcomes achieved.
#PlasticSurgery: A Comparative Deep Dive Analysis into Social Media and Plastic Surgery
Authors: Mullens Cody Lendon , Hardy Kristen M. , Hernandez J. Andres , McCulloch Ian L. , Henderson Joshua T. , Gabbay Joubin , Ueno Cristiane M.
Published: July 2020

Background:

As social media have become pervasive in contemporary society, plastic surgery content has become commonplace. Two of the most engaging and popular platforms are Instagram and Twitter, and much research has been performed with respect to Twitter. Currently, there are no studies comparing and contrasting the two platforms. The aim of this study was to robustly sample plastic surgery posts on Twitter and Instagram to quantitatively and qualitatively evaluate platform content differences.

Methods:

The hashtag #PlasticSurgery was systematically queried twice per day, for 30 consecutive days, on Twitter and Instagram. Account type, specific media content, possible patient-identifying information, content analysis, and post engagement were assessed. Post volume and engagement between Instagram and Twitter posts were compared. Post characteristics garnering high engagement from each platform were also evaluated.

Results:

A total of 3867 Twitter posts and 5098 Instagram posts were included in this analysis. Daily total post volume for the 1-month duration of the study was significantly higher on Instagram compared with Twitter. Overall post engagement was significantly higher on Instagram compared with Twitter. Plastic surgeons and plastic surgery clinics represented the majority of accounts posting on both platforms with #PlasticSurgery. Identifiable patient features were much more prevalent on Instagram. The majority of Instagram posts were promotional in nature, outcome-based, or unrelated to plastic surgery. Alternatively, tweets were predominantly educational in nature.

Conclusions:

For physicians to harness the power of social media in plastic surgery, we need to understand how these media are currently being used and how different platforms compare to one another. This study has highlighted the inherent similarities and differences between these two highly popular platforms.
Training Future Speech–Language Pathologists for Work in End-of-Life and Palliative Care
Authors: Stead Amanda , Dirks Kyla , Fryer Melissa , Wong Sami
Published: July 2020

Speech–language pathologists often lack preparation for palliative care practice and this lack of training can lead to poor outcomes for patients. Lack of training can additionally lead to burnout and compassion fatigue in clinicians. Careful implementation of training is necessary to increase the knowledge base for palliative practice and careful attention must also be paid to the emotional component of end-of-life care. The history and current practice of palliative care education across health care disciplines are examined. Finally, a pilot study evaluating a course module on palliative and end-of-life care for speech–language pathologist graduate students is presented. Results from the pilot indicate that students improved both their knowledge and comfort related to issues of end-of-life care topics. In addition, students responded positively to the opportunity to learn about the topic and the instructional strategies used within the course module.
Microbial material cycling, energetic constraints and ecosystem expansion in subsurface ecosystems
Authors: Seto Mayumi , Iwasa Yoh
Published: July 2020

To harvest energy from chemical reactions, microbes engage in diverse catabolic interactions that drive material cycles in the environment. Here, we consider a simple mathematical model for cycling reactions between alternative forms of an element (A and A
e
), where reaction 1 converts A to A
e
and reaction 2 converts A
e
to A. There are two types of microbes: type 1 microbes harness reaction 1, and type 2 microbes harness reaction 2. Each type receives its own catabolic resources from the other type and provides the other type with the by-products as the catabolic resources. Analyses of the model show that each type increases its steady-state abundance in the presence of the other type. The flux of material flow becomes faster in the presence of microbes. By coupling two catabolic reactions, types 1 and 2 can also expand their realized niches through the abundant resource premium, the effect of relative quantities of products and reactants on the available chemical energy, which is especially important for microbes under strong energetic limitations. The plausibility of mutually beneficial interactions is controlled by the available chemical energy (Gibbs energy) of the system. We conclude that mutualistic catabolic interactions can be an important factor that enables microbes in subsurface ecosystems to increase ecosystem productivity and expand the ecosystem.
Microbe Profile: Komagataella phaffii: a methanol devouring biotech yeast formerly known as Pichia pastoris
Authors: Heistinger Lina , Gasser Brigitte , Mattanovich Diethard
Published: July 2020

Methylotrophic yeasts of the genus Komagataella are abundantly found in tree exudates. Their ability to utilize methanol as carbon and energy source relies on an assimilation pathway localized in largely expanded peroxisomes, and a cytosolic methanol dissimilation pathway. Other substrates like glucose or glycerol are readily utilized as well. Komagataella yeasts usually grow as haploid cells and are secondary homothallic as they can switch mating type. Upon mating diploid cells sporulate readily, forming asci with four haploid spores. Their ability to secrete high amounts of heterologous proteins made them interesting for biotechnology, which expands today also to other products of primary and secondary metabolism.
Mononeuritis multiplex: an unexpectedly common feature of severe COVID-19
Authors: Needham Edward , Newcombe Virginia , Michell Andrew , Thornton Rachel , Grainger Andrew , Anwar Fahim , Warburton Elizabeth , Menon David , Trivedi Monica , Sawcer Stephen
Published: July 2020

The prolonged mechanical ventilation required by patients with severe COVID-19 is expected to result in significant Intensive Care Unit – Acquired Weakness (ICUAW) in many of the survivors. However, in our post-COVID-19 follow up clinic we have found that, as well as the anticipated global weakness related to loss of muscle mass, a significant proportion of these patients also have disabling focal neurological deficits relating to an axonal mononeuritis multiplex. Amongst the 69 patients with severe COVID-19 that have been discharged from the intensive care units in our hospital, we have seen 11 individuals (16%) with such neuropathies. In many instances, the multi-focal nature of the weakness in these patients was initially unrecognised as symptoms were wrongly assumed to simply relate to “critical illness neuropathy”. While mononeuropathy is well recognised as an occasional complication of intensive care, our experience suggests that such deficits are common and frequently disabling in patients recovering from COVID-19.
A High-throughput Anti-SARS-CoV-2 IgG Testing Platform for COVID-19
Authors: Du Jinwei , Chu Eric , Zhang Dayu , Lu Chuanyi M. , Zhang Aiguo , Sha Michael Y.
Published: July 2020

Background

Serology tests for detecting the antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can identify previous infection and help to confirm the presence of current infection.

Objective

The aim of this study was to evaluate the performances of a newly developed high throughput immunoassay for anti-SARS-CoV-2 IgG antibody detection.

Results

Clinical agreement studies were performed in 77 COVID-19 patient serum samples and 226 negative donor serum/plasma samples. Positive percent agreement (PPA) was 42.86% (95% CI: 9.90% to 81.59%), 55.56% (95% CI: 21.20% to 86.30%), and 96.72% (95% CI: 88.65% to 99.60%) for samples collected on 0-7 days, 8-14 days, and ≥15 days from symptom onset, respectively. Negative Percent Agreement (NPA) was 98.23% (95% CI: 95.53% to 99.52%). No cross-reactivity was observed to patient samples positive for IgG antibodies against the following pathogens: HIV, HAV, HBV, RSV, CMV, EBV, Rubella, Influenza A, and Influenza B. Hemoglobin (200 mg/dL), bilirubin (2 mg/dL) and EDTA (10 mM) showed no significant interfering effect on this assay.

Conclusion

An anti-SARS-CoV-2 IgG antibody assay with high sensitivity and specificity has been developed. With the high throughput, this assay will speed up the anti-SARS-CoV-2 IgG testing.
Genetic diversity and phylogeographic analysis of human herpesvirus type 8 (HHV-8) in two distant regions of Argentina: association with the genetic ancestry of the population
Authors: Hulaniuk María Laura , Mojsiejczuk Laura , Jauk Federico , Remondegui Carlos , Mammana Lilia , Bouzas María Belén , Zapiola Inés , Ferro María Verónica , Ajalla Claudia , Blejer Jorgelina , Alter Adriana , Acevedo María Elina , Rodríguez Eulalia , Fernández Roberto , Bartoli Sonia , Volonteri Victoria , Kohan Dana , Elsner Boris , Bürgesser María Virginia , Reynaud Ana Laura , Sánchez Marisa , González Carlos , Rivello Hernán García , Corach Daniel , Caputo Mariela , Trinks Julieta
Published: July 2020

Background

The genetic diversity of persistent infectious agents, such as HHV-8, correlates closely with the migration of modern humans out of East Africa which makes them useful to trace human migrations. However, there is scarce data about the evolutionary history of HHV-8 particularly in multiethnic Latin American populations.

Objectives

The aim of this study was to characterize the genetic diversity and the phylogeography of HHV-8 in two distant geographic regions of Argentina and to establish potential associations with the genetic ancestry of the population.

Study design

A total of 605 HIV-1 infected subjects, Kaposi’s Sarcoma (KS) patients and blood donors were recruited in the metropolitan (MET) and north-western regions of Argentina (NWA). After HHV-8 DNA detection, ORF-26 and ORF-K1 were analyzed for subtype assignment. Uniparental and biparental ancestry markers were evaluated in samples in which subtypes could be assigned. Phylogeographic analysis was performed in the ORF-K1 sequences from this study combined with 388 GenBank sequences.

Results

HHV-8 was detected in 24.8% of samples. ORF-K1 phylogenetic analyses showed that subtypes A (A1-A5), B1, C (C1-C3) and F were present in 46.9%, 6.25%, 43.75% and 3.1% of cases, respectively. Analyses of ORF-26 fragment revealed that 81.95% of strains were subtypes A/C followed by J, B2, R, and K. Among KS patients, subtype A/C was more commonly detected in MET whereas subtype J was the most frequent in NWA. Subtypes A/C was significantly associated with Native American maternal haplogroups (p=0.004), whereas subtype J was related to non-Native American haplogroups (p<0.0001). Sub-Saharan Africa, Europe and Latin America were the most probable locations from where HHV-8 was introduced to Argentina.

Conclusions

These results give evidence of the geographic circulation of HHV-8 in Argentina, provide new insights about its relationship with ancient and modern human migrations and identify the possible origins of this virus in Argentina.
Public Reactions towards the COVID-19 Pandemic on Twitter in the United Kingdom and the United States
Authors: Zou Canruo , Wang Xueting , Xie Zidian , Li Dongmei
Published: July 2020

Background

The coronavirus disease 2019 (COVID-19) has spread globally since December 2019. Twitter is a popular social media platform with active discussions about the COVID-19 pandemic. The public reactions on Twitter about the COVID-19 pandemic in different countries have not been studied. This study aims to compare the public reactions towards the COVID-19 pandemic between the United Kingdom and the United States from March 6, 2020 to April 2, 2020.

Data

The numbers of confirmed COVID-19 cases in the United Kingdom and the United States were obtained from the 1Point3Acres website. Twitter data were collected using COVID-19 related keywords from March 6, 2020 to April 2, 2020.

Methods

Temporal analyses were performed on COVID-19 related Twitter posts (tweets) during the study period to show daily trends and hourly trends. The sentiment scores of the tweets on COVID-19 were analyzed and associated with the policy announcements and the number of confirmed COVID-19 cases. Topic modeling was conducted to identify related topics discussed with COVID-19 in the United Kingdom and the United States.

Results

The number of daily new confirmed COVID-19 cases in the United Kingdom was significantly lower than that in the United States during our study period. There were 3,556,442 COVID-19 tweets in the United Kingdom and 16,280,065 tweets in the United States during the study period. The number of COVID-19 tweets per 10,000 Twitter users in the United Kingdom was lower than that in the United States. The sentiment scores of COVID-19 tweets in the United Kingdom were less negative than those in the United States. The topics discussed in COVID-19 tweets in the United Kingdom were mostly about the gratitude to government and health workers, while the topics in the United States were mostly about the global COVID-19 pandemic situation.

Conclusion

Our study showed correlations between the public reactions towards the COVID-19 pandemic on Twitter and the confirmed COVID-19 cases as well as the policies related to the COVID-19 pandemic in the United Kingdom and the United States.
Effectiveness and Safety of Chloroquine or Hydroxychloroquine as a mono-therapy or in combination with Azithromycin in the treatment of COVID-19 patients: Systematic Review and Meta-Analysis
Authors: Ghazy Ramy Mohamed , Elmaghraby Abdallah , Shaaban Ramy , Kamal Ahmed , Beshir Hatem , Moursi Amr , Ramadan Ahmed , Taha Sarah Hamed N.
Published: July 2020

Many recent studies have investigated the role of either Chloroquine (CQ) alone, Hydroxychloroquine (HCQ) alone, or CQ/HCQ in combination with azithromycin (AZM) in management of the emerging coronavirus. This systematic review and meta-analysis of either published or preprint observational or interventional studies were conducted to assess the cure rate, duration of hospital stay, radiological progression, clinical worsening, need for mechanical ventilation, the occurrence of side effects, and mortality. A search of the online database through June 2020 was performed and examined the reference lists of pertinent articles for in-vivo studies only. Pooled relative risks (RRs), standard mean, of 95 % confidence intervals (CIs) were calculated with the random-effects model.

Results

The duration of hospital stay was shorter in the standard care in comparison with HCQ group, the standard mean of hospital stay was 0.57, 95% CI, and 0.20-0.94. Overall virological cure, or more specifically at day 4, 10, and 14 among patients exposed to HCQ did not differ significantly from the standard care [(RR=0.92, 95% CI 0.78-1.15), (RR=1.11, 95% CI 0.74-1.65), (RR=1.21, 95%CI 0.70-2.01), and (RR=0.98, 95% CI, 0.76-1.27)] respectively. Radiological improvement or clinical worsening was not statistically different between HCQ and standard care [(RR=1.11, 95% CI 0.64-1.65) and (RR=1.28, 95% CI 0.33-4.99)]. The need for mechanical ventilation (MV) was not significant between the HCQ group and the standard care (RR= 1.5, 95%CI 0.78-2.89). Side effects were more reported in the HCQ group than the standard care (RR=3.14, 95% CI 1.58-6.24). Mortality among HCQ was not affected by receiving HCQ (RR=3.14, 95% CI 1.58-6.24), meta-regression analysis revealed that country is a strong predictor of mortality. The duration of hospital stay among the HCQ and AZM didn’t differ significantly from the standard care (standard mean= 0.77, 95% CI 0.46-1.08). Despite virological cure and need for MV did not differ significantly [(RR= 3.23, 95% CI 0.70-14.97) and (RR=1.27, 95%CI 0.7-2.13)] respectively. Mortality among the HCQ+AZM was more significantly higher than among the standard care (RR= 1.8, 95% CI 1.19-2.27).

Conclusion

Despite the scarcity of published data of good quality, the effectiveness and safety of either HCQ alone or in combination with AZM in treating the pandemic of COVID-19 can’t be assured. Future randomized control trials need to be carried out to verify this conclusion.

Registration

PROSPERO registration number: CRD42020192084
Comprehensive phenotyping of 3q29 deletion syndrome: recommendations for clinical care
Authors: Russo Rossana Sanchez , Gambello Michael J. , Murphy Melissa M. , Aberizk Katrina , Black Emily , Burrell T. Lindsey , Carlock Grace , Cubells Joseph F. , Epstein Michael T. , Espana Roberto , Goines Katrina , Guest Ryan , Klaiman Cheryl , Koh Sookyong , Leslie Elizabeth , Li Longchuan , Novacek Derek , Saulnier Celine A. , Sefik Esra , Schultz Sarah , Walker Elaine , White Stormi ,   The Emory 3q29 Project, Mulle Jennifer Gladys
Published: July 2020

Purpose

To understand the consequences of the 3q29 deletion on medical, neurodevelopmental, psychiatric, and neurological sequalae by systematic evaluation of affected individuals. To develop evidence-based recommendations using these data for effective clinical care.

Methods

32 Individuals with the 3q29 deletion were evaluated using a defined phenotyping protocol and standardized data collection instruments.

Results

Medical manifestations were varied and reported across nearly every bodily system, with congenital heart defects (25%) the most severe and heterogeneous gastrointestinal symptoms (81%) the most common. Physical exam revealed a high proportion of musculoskeletal findings (81%). Neurodevelopmental phenotypes represent a significant burden and include intellectual disability (34%), autism spectrum disorder (38%), executive function deficits (46%), and graphomotor weakness (78%). Psychiatric illness manifests across the lifespan with schizophrenia prodrome (15%), psychosis (20%), anxiety disorders (40%) and ADHD (63%). On neurological exam study subjects displayed only mild or moderate motor difficulties.

Conclusions

By direct evaluation of 3q29 deletion study subjects, we document common features of the syndrome, including a high burden of neurodevelopmental and neuropsychiatric phenotypes. Evidence-based recommendations for evaluation, referral, and management are provided to help guide clinicians in the care of 3q29 deletion patients.
Development of a small molecule that corrects misfolding and increases secretion of Z α1-antitrypsin
Authors: Lomas David A. , Irving James A. , Arico-Muendel Christopher , Belyanskaya Svetlana , Brewster Andrew , Brown Murray , Chung Chun-wa , Dave Hitesh , Denis Alexis , Dodic Nerina , Dossang Anthony , Eddershaw Peter , Klimaszewska Diana , Haq Imran , Holmes Duncan S. , Hutchinson Jonathan P. , Jagger Alistair , Jakhria Toral , Jigorel Emilie , Liddle John , Lind Ken , Marciniak Stefan J. , Messer Jeff , Neu Margaret , Olszewski Allison , Ordonez Adriana , Ronzoni Riccardo , Rowedder James , Rüdiger Martin , Skinner Steve , Smith Kathrine J. , Terry Rebecca , Trottet Lionel , Uings Iain , Wilson Steve , Zhu Zhengrong , Pearce Andrew C.
Published: July 2020

Severe α1-antitrypsin deficiency results from the Z allele (Glu342Lys) that causes the accumulation of homopolymers of mutant α1-antitrypsin within the endoplasmic reticulum of hepatocytes in association with liver disease. We have used a DNA-encoded chemical library to undertake a high throughput screen to identify small molecules that bind to, and stabilise Z α1-antitrypsin. The lead compound blocks Z α1-antitrypsin polymerisationin vitro, reduces intracellular polymerisation and increases the secretion of Z α1-antitrypsin three-fold in mammalian cells including an iPSC model of disease. Crystallographic and biophysical analyses demonstrate that GSK716 and related molecules bind to a cryptic binding pocket, negate the local effects of the Z mutation and stabilise the bound state against progression along the polymerization pathway. Oral dosing of transgenic mice at 100 mg/kg three times a day for 20 days increased the secretion of Z α1-antitrypsin into the plasma by 7-fold. There was no observable clearance of hepatic inclusions with respect to controls. This study provides proof-of-principle that ‘mutation ameliorating’ small molecules are a viable approach to treat protein conformational diseases.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Membrane (M) Protein Inhibits Type I and III Interferon Production by Targeting RIG-I/MDA-5 Signaling
Authors: Zheng Yi , Zhuang Meng-Wei , Han Lulu , Zhang Jing , Nan Mei-Ling , Gao Chengjiang , Wang Pei-Hui
Published: July 2020

The coronavirus disease 2019 (COVID-19) caused by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has quickly spread worldwide and has infected more than ten million individuals. One of the typical features of COVID-19 is that both type I and III interferon (IFN)-mediated antiviral immunity are suppressed. However, the molecular mechanism by which SARS-CoV-2 evades this antiviral immunity remains elusive. Here, we report that the SARS-CoV-2 membrane (M) protein inhibits the production of type I and III IFNs induced by the cytosolic dsRNA-sensing pathway of RIG-I/MDA-5-MAVS signaling. The SARS-CoV2 M protein also dampens type I and III IFN induction stimulated by Sendai virus infection or poly (I:C) transfection. Mechanistically, the SARS-CoV-2 M protein interacts with RIG-I, MAVS, and TBK1 and prevents the formation of a multi-protein complex containing RIG-I, MAVS, TRAF3, and TBK1, thus impeding IRF3 phosphorylation, nuclear translocation, and activation. Consequently, the ectopic expression of the SARS-CoV2 M protein facilitates the replication of vesicular stomatitis virus (VSV). Taken together, the SARS-CoV-2 M protein antagonizes type I and III IFN production by targeting RIG-I/MDA-5 signaling, which subsequently attenuates antiviral immunity and enhances viral replication. This study provides insight into the interpretation of the SARS-CoV-2-induced antiviral immune suppression and sheds light on the pathogenic mechanism of COVID-19.
Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing
Authors: Sahakijpijarn Sawittree , Moon Chaeho , Koleng John J. , Christensen Dale J. , Williams Robert O.
Published: July 2020

Remdesivir exhibits in vitro activity against SARS-CoV-2 and was granted approval for Emergency Use. To maximize delivery to the lungs, we formulated remdesivir as a dry powder for inhalation using thin film freezing (TFF). TFF produces brittle matrix nanostructured aggregates that are sheared into respirable low-density microparticles upon aerosolization from a passive dry powder inhaler. In vitro aerodynamic testing demonstrated that drug loading and excipient type affected the aerosol performance of remdesivir. Remdesivir combined with optimal excipients exhibited desirable aerosol performance (up to 93.0% FPF; 0.82μm MMAD). Remdesivir was amorphous after the TFF process, which benefitted drug dissolution in simulated lung fluid. TFF remdesivir formulations are stable after one-month storage at 25 °C/60%RH. In vivo pharmacokinetic evaluation showed that TFF-remdesivir-leucine was poorly absorbed into systemic circulation while TFF-remdesivir-Captisol® demonstrated increased systemic uptake compared to leucine. Remdesivir was hydrolyzed to the nucleoside analog GS-441524 in lung, and levels of GS-441524 were greater in lung with the leucine formulation compared to Captisol®. In conclusion, TFF technology produces high potency remdesivir dry powder formulations for inhalation suitable to treat patients with COVID-19 on an outpatient basis and earlier in the disease course where effective antiviral therapy can reduce related morbidity and mortality.
Levels of the TNF related cytokine, LIGHT increase in hospitalized COVID-19 patients with Cytokine Release Syndrome and ARDS
Authors: Perlin David S. , Zafir-Lavie Inbal , Roadcap Lori , Raines Shane , Ware Carl F. , Neil Garry A.
Published: July 2020

Many COVID-19 patients demonstrate lethal respiratory complications caused by cytokine release syndrome (CRS). Multiple cytokines have been implicated in CRS, but TNFSF14 (LIGHT) has not been previously measured in this setting. In this study, we observed significantly elevated serum LIGHT levels in hospitalized COVID-19 patients as compared to healthy age and gender matched control patients. The assay detected bioavailable LIGHT unbound to the inhibitor Decoy receptor-3 (DcR3). Bioavailable LIGHT levels were elevated in patients both on and off ventilatory support, with a trend toward higher levels in patients requiring mechanical ventilation. In hospitalized patients over the age of 60, who exhibited a mortality rate of 82%, LIGHT levels were significantly higher (p=0.0209) in those who died compared to survivors. As previously reported, interleukin 6 (IL-6) levels were also elevated in these patients with significantly (p=0.0076) higher levels observed in patients who died vs. survivors, paralleling the LIGHT levels. Although attempts to block IL-6 binding to its receptor have shown limited effect in COVID-19 CRS, neutralization of LIGHT may prove to be more effective owing to its more central role in regulating antiviral immune responses.