bluuebunny/crossref_metadata_2025 huggingface dataset:
FDG PET/CT in a Patient With Mantle Cell Lymphoma and COVID-19
Authors: Playe Margot , Siavellis Justine , Braun Thorsten , Soussan Michaël
Published: May 2020

A 52-year-old woman with no medical history was admitted on March 18, 2020, presenting since 3 days asthenia, abdominal pain, and dry cough but no fever. Adenomegalies, splenomegaly, leukocytosis, and elevated LDH suggested mature lymphoproliferation. Considering the current health context, an RT-PCR testing for COVID-19 (coronavirus disease 2019) was performed and found to be positive. Early chest CT showed no sign of pulmonary infection but multiple adenomegalies. An 18F-FDG PET/CT performed 5 days later to assess the extent of the hemopathy revealed the apparition of FDG-avid bilateral ground glass and subpleural curvilinear opacities suggesting COVID-19–associated pneumopathy.
Solitary Breast Metastasis From Thyroid Papillary Carcinoma Revealed on Whole-Body Radioactive 131I Scan
Authors: Kharroubi Dris , Richa Carine , Saie Clotilde , Chami Linda , Lussey-Lepoutre Charlotte
Published: May 2020

Breast metastasis from thyroid papillary carcinoma is an exceptional situation. Here, we present the diagnostic approach and the management of a 19-year-old woman with single breast metastasis from thyroid carcinoma. There was no extra thyroidal extension, neoplastic emboli, or lymph node invasion. The metastasis was revealed by whole-body radioactive 131I scan, explored by a fine-needle aspiration, and confirmed by elevated thyroglobulin in situ.
Four-dimensional Flow Magnetic Resonance Imaging Quantification of Blood Flow in Bicuspid Aortic Valve
Authors: Gordon Daniel Z. , Abbasi Muhannad A. , Lee Jeesoo , Sarnari Roberto , Sojoudi Alireza , Wei Qiao , Scott Michael B. , Collins Jeremy D. , Allen Bradley D. , Blaisdell Julie A. , Carr James C. , Markl Michael
Published: May 2020

Background:

Four-dimensional (D) flow magnetic resonance imaging (MRI) is limited by time-consuming and nonstandardized data analysis. We aimed to test the efficiency and interobserver reproducibility of a dedicated 4D flow MRI analysis workflow.

Materials and Methods:

Thirty retrospectively identified patients with bicuspid aortic valve (BAV, age=47.8±11.8 y, 9 male) and 30 healthy controls (age=48.8±12.5 y, 21 male) underwent Aortic 4D flow MRI using 1.5 and 3 T MRI systems. Two independent readers performed 4D flow analysis on a dedicated workstation including preprocessing, aorta segmentation, and placement of four 2D planes throughout the aorta for quantification of net flow, peak velocity, and regurgitant fraction. 3D flow visualization using streamlines was used to grade aortic valve outflow jets and extent of helical flow.

Results:

4D flow analysis workflow time for both observers: 5.0±1.4 minutes per case (range=3 to 10 min). Valve outflow jets and flow derangement was visible in all 30 BAV patients (both observers). Net flow, peak velocity, and regurgitant fraction was significantly elevated in BAV patients compared with controls except for regurgitant fraction in plane 4 (91.1±29.7 vs. 62.6±19.6 mL/s, 37.1% difference; 121.7±49.7 vs. 90.9±26.4 cm/s, 28.9% difference; 9.3±10.1% vs. 2.0±3.4%, 128.0% difference, respectively; P<0.001). Excellent intraclass correlation coefficient agreement for net flow: 0.979, peak velocity: 0.931, and regurgitant fraction: 0.928.

Conclusion:

Our study demonstrates the potential of an efficient data analysis workflow to perform standardized 4D flow MRI processing in under 10 minutes and with good-to-excellent reproducibility for flow and velocity quantification in the thoracic aorta.
Efficacy of Sedation by Midazolam in Association With Meperidine or Fentanyl and Role of Patient Distress During Elective Colonoscopy
Authors: Pontone Stefano , Palma Rossella , Donato Giuseppe , Borghini Raffaele , Frattaroli Stefano , Raniolo Marilena , Panetta Cristina , Lauriola Marco
Published: May 2020

Meperidine and fentanyl are opioids currently used in addition to midazolam for sedation and analgesia during colonoscopy in Italy. The aim of the study was to assess the impact of patients' psychological state before elective colonoscopy on the efficacy of the sedation regimens. Eighty outpatients who underwent an elective colonoscopy were included in our study. The Hospital Anxiety and Depression Scale questionnaire was self-administered to evaluate basal anxiety and depression state. The rate of baseline discomfort was evaluated by a standard 100-mm visual analog scale. Sedation was obtained alternatively with a midazolam–meperidine or midazolam–fentanyl combination. There were no statistically significant differences between the fentanyl and meperidine groups on body mass index, age, and gender composition. Patients in the meperidine group reported less pain during colonoscopy than patients in the fentanyl group. There were statistically significant positive correlations in the meperidine group with the distress, anxiety, and depression. Our study has pointed out greater effectiveness of the midazolam plus meperidine regimen, equal recovery times, and no significant differences in the duration of the endoscopic examinations. The evaluation of patients' psychological status seems to predict the efficacy of sedation when the nociceptive component of pain is well controlled.
Brown Adipose Tissue: A Potential Site for Islet Transplantation
Authors: Xu Kang , Xie Raoying , Lin Xiaolin , Jia Junshuang , Zeng Nan , Li Wangen , Xiao Dong , Du Tao
Published: May 2020

Background.

Islet transplantation is a promising treatment in patients with complicated diabetes. The ideal transplant site that can extend islet graft survival and reduce the required number of engrafted islets remains to be established.

Methods.

Donor islets were isolated from red fluorescent protein (RFP+) mice and transplanted into interscapular brown adipose tissue (BAT) or unilateral inguinal white adipose tissue of age-matched diabetic RFP− mice. Blood glucose and body weight of the mice were monitored, and vitality and function of ectopic RFP+ islets were detected by fluorescence imaging, histological examination, and intraperitoneal glucose tolerance test (GTT).

Results.

BAT enabled the marginal number of grafted islets (80 islets) to restore blood glucose, insulin level, and GTT to normal values in all diabetic recipient mice in the short term after graft, and maintained these values for 1 year at the end of the experiment. Importantly, in the short term after transplantation, abundant extra- and intraislet neovasculatures were observed in BAT, but not in white adipose tissue, which allowed the ectopic islets to retain typical architecture and morphology and contributed to the normal GTT. Moreover, the islet-engrafted BAT displayed normal structure and morphology without significant immunocyte infiltration, and the recipient mice also showed normal lipid levels in the blood.

Conclusions.

BAT remarkably enhances the viability and biological function of the transplanted ectopic islets. Moreover, the anatomical location of BAT lends itself to biopsy, removal, and islet retransplantation, which strongly suggests the BAT as a potential desirable site for islet transplantation in basic and clinical research.
Waggle needling wields preferable neuroprotective and anti-spastic effects on post-stroke spasticity rats by attenuating γ-aminobutyric acid transaminase and enhancing γ-aminobutyric acid.
Authors: Wang Jun-Xiang , Mu Jie-Dan , Ma Liang-Xiao , Sun Tian-Yi , Qian Xu , Yu Wen-Yan , Tian Yuan , Song Yue , Gan Ying-Ying , Guo Meng-Wei , Ren Xiao-Xuan , Li Jia-Lin
Published: May 2020

Waggle needling, a classical anti-spastic needling technique characterized by combination of acupuncture with joint movement, has gained increasing popularity of spasticity treatment in China. This study was designed to compare the anti-spastic effect of waggle needling to the routine needling and to explore its underlying mechanism. We established post-stroke spasticity model based on ischemia stroke operation (middle cerebral artery occlusion). Rats were divided into six groups: normal control group, sham-operated control group, ischemia stroke model group, waggle needling group, routine needling group and baclofen group. Neurological function and muscle tone were assessed by the Zea Longa score and modified Ashworth scale, respectively. Indirect muscle tone was testified with electrophysiological recording. Cerebral infarction was measured by 2,3,5-triphenyltetrazolium chloride staining. The concentrations and expressions of γ-aminobutyric acid transaminase (GABAT) and γ-aminobutyric acid (GABA) were detected by enzyme-linked immunosorbent assay and western blot assay. Waggle needling markedly alleviated neurological deficits, decreased cerebral infarction and eased muscle tone; simultaneously, attenuated GABAT and enhanced GABA expression in the cortical infarct regions in comparison with the routine needling (P < 0.01), yet showed similar therapeutic effect to the baclofen group (P > 0.05). These results preliminary supported that waggle needling as a potential promising non-pharmacological intervention for the treatment of cerebral ischemia and spasticity.
The preattentive change detection in preschool children with attention deficit hyperactivity disorder: a mismatch negativity study.
Authors: Zhang Jinsong , Qiu Meihui , Pan Jingxue , Zhao Lun
Published: May 2020

To investigate the preattentive change detection in preschool children with attention deficit hyperactivity disorder (ADHD), we compared the mismatch negativity (MMN) and P3a of event-related potentials (ERPs) between preschool ADHD and normal children using three-stimulus oddball paradigm. Analyzing MMN and P3a components, we found that MMN elicited by deviants and P3a elicited by novelty were significantly reduced in patients than in controls. In addition, the P3a amplitude was positive correlated to IQ and negatively correlated to hyperactivity, antagonistic defiance and conduct problems in Swanson, Nolan, and Pelham IV Rating Scale, parent version. These data provided new neurophysiological evidence for the dysfunction of preattentive change detection and attentional shift in ADHD children.
Kratom (Mitragyna speciosa): worldwide issues
Authors: Ramanathan Surash , McCurdy Christopher R.
Published: May 2020

Purpose of review

To inform readers about the increasingly popular Western dietary supplement, kratom (Mitragyna speciosa) and how the products are available in the Western world compared with traditional Southeast Asian use. Kratom has been traditionally used for increasing stamina of outdoor laborers (farmers), mood enhancement, pain, and opium addiction. Interestingly, kratom has been reported to have a paradoxical effect in that stimulant feelings, and sedative feelings can be obtained depending on the amount utilized. There are several biologically active alkaloids present in kratom.

Recent findings

Recent studies have been focused on the interactions of mitragynine, the most abundant alkaloid, and opioid-like effects. This has been driven by the harm that kratom products have produced in the Western world, in stark contrast to the lack of harm in Southeast Asian traditional use over centuries. Many users in the Western world ingest kratom for mood enhancement and/or to ween themselves from prescription or illicit opioids. Highly concentrated products and recreational use and misuse have resulted in individuals pushing doses to levels that have not been imagined or ever studied in animal, let alone humans.

Kratom, as a preparation and how it is utilized is different around the world.
Condition dependence of phenotypic integration and the evolvability of genitalic traits in a neriid fly
Authors: Wylde Zachariah , Bonduriansky Russell
Published: May 2020

The spectacular diversity of insect male genitalia, and their relative insensitivity to the environment, have long puzzled evolutionary biologists and taxonomists. We asked whether the unusual evolvability of male genitalia could be associated with low morphological integration of genitalic traits, by comparison with male somatic traits and female traits. We also asked whether this pattern was robust to variation in resource availability during development, which affects adult condition. To address these questions, we manipulated larval diet quality in a split-brood design and compared levels of integration of male and female genitalic and somatic traits in the neriid fly,Telostylinus angusticollis. We found that male genitalic traits were substantially less integrated than male somatic traits, and less integrated than female genitalic traits. Female genitalic traits were also less integrated than female somatic traits, but the difference was less pronounced than in males. However, integration of male genitalic traits was negatively condition-dependent, with high-condition males exhibiting lower trait integration than low-condition males. Finally, genitalic traits exhibited lower larval diet × family interactions than somatic traits. These results could help explain the unusually high evolvability of male genitalic traits in insects.
Chimpanzee lip-smacks confirm primate continuity for speech-rhythm evolution
Authors: Pereira André S. , Kavanagh Eithne , Hobaiter Catherine , Slocombe Katie E. , Lameira Adriano R.
Published: May 2020

Speech is a human hallmark, but its evolutionary origins continue to defy scientific explanation. Recently, the open–close mouth rhythm of 2–7 Hz (cycles/second) characteristic of all spoken languages has been identified in the orofacial signals of several nonhuman primate genera, including orangutans, but evidence from any of the African apes remained missing. Evolutionary continuity for the emergence of speech is, thus, still inconclusive. To address this empirical gap, we investigated the rhythm of chimpanzee lip-smacks across four populations (two captive and two wild). We found that lip-smacks exhibit a speech-like rhythm at approximately 4 Hz, closing a gap in the evidence for the evolution of speech-rhythm within the primate order. We observed sizeable rhythmic variation within and between chimpanzee populations, with differences of over 2 Hz at each level. This variation did not result, however, in systematic group differences within our sample. To further explore the phylogenetic and evolutionary perspective on this variability, inter-individual and inter-population analyses will be necessary across primate species producing mouth signals at speech-like rhythm. Our findings support the hypothesis that speech recruited ancient primate rhythmic signals and suggest that multi-site studies may still reveal new windows of understanding about these signals' use and production along the evolutionary timeline of speech.
The interplay of spatial organization and biochemistry in building blocks of cellular signalling pathways
Authors: Krishnan J. , Lu Lingjun , Alam Nazki Aiman
Published: May 2020

Biochemical pathways and networks are central to cellular information processing. While a broad range of studies have dissected multiple aspects of information processing in biochemical pathways, the effect of spatial organization remains much less understood. It is clear that space is central to intracellular organization, plays important roles in cellular information processing and has been exploited in evolution; additionally, it is being increasingly exploited in synthetic biology through the development of artificial compartments, in a variety of ways. In this paper, we dissect different aspects of the interplay between spatial organization and biochemical pathways, by focusing on basic building blocks of these pathways: covalent modification cycles and two-component systems, with enzymes which may be monofunctional or bifunctional. Our analysis of spatial organization is performed by examining a range of ‘spatial designs’: patterns of localization or non-localization of enzymes/substrates, theoretically and computationally. Using these well-characterizedin silicosystems, we analyse the following. (i) The effect of different types of spatial organization on the overall kinetics of modification, and the role of distinct modification mechanisms therein. (ii) How different information processing characteristics seen experimentally and studied from the viewpoint of kinetics are perturbed, or generated. (iii) How the activity of enzymes (bifunctional enzymes in particular) may be spatially manipulated, and the relationship between localization and activity. (iv) How transitions in spatial organization (encountered either through evolution or through the lifetime of cells, as seen in multiple model organisms) impacts the kinetic module (and pathway) behaviour, and how transitions in chemistry may be impacted by prior spatial organization. The basic insights which emerge are central to understanding the role of spatial organization in biochemical pathways in both bacteria and eukaryotes, and are of direct relevance to engineering spatial organization of pathways in bottom-up synthetic biology in cellular and cell-free systems.
George Keith Batchelor's Interaction with Chinese Fluid Dynamicists and Inspirational Influence: a historical perspective
Authors: Shi John Z.
Published: May 2020

George Keith Batchelor (1920–2000, FRS 1957) was a towering figure in the twentieth century international fluid mechanics community. Much has been written about him since his death. This article presents an account of Batchelor's early interactions and relationships with Chinese fluid dynamicists and his continuing inspirational influence on them, which have not yet been documented in English. The theory of homogeneous turbulence, to which Batchelor contributed greatly, has had both indirect and direct inspirational influence on generations of Chinese fluid dynamicists, as they have sought to make their own contributions. Batchelor made visits to China in 1980 and 1983. His first ice-breaking trip to China in April 1980 is of special importance to Sino-British fluid mechanics and to China, even though Batchelor did not speak about turbulence but instead about his more recent research interest, microhydrodynamics. Batchelor's philosophical view of applied mathematics (fluid mechanics)—that ‘You have got to inject some physical thinking as well as mathematical thinking’—has had great inspirational influence on generations of fluid dynamicists in the UK, in China, and around the world. Batchelor's generosity of spirit and frugality of habit is warmly remembered by his students and Chinese friends. The author presents details of Batchelor's interaction with Chinese fluid dynamicists in the 1980s within the general context of the scientific relationship between China and the UK.
Explanation of the onset of bouncing cycles in isotropic rotor dynamics; a grazing bifurcation analysis
Authors: Mora Karin , Champneys Alan R. , Shaw Alexander D. , Friswell Michael I.
Published: May 2020

The dynamics associated with bouncing-type partial contact cycles are considered for a 2 degree-of-freedom unbalanced rotor in the rigid-stator limit. Specifically, analytical explanation is provided for a previously proposed criterion for the onset upon increasing the rotor speed
Ω
of single-bounce-per-period periodic motion, namely internal resonance between forward and backward whirling modes. Focusing on the cases of 2 : 1 and 3 : 2 resonances, detailed numerical results for small rotor damping reveal that stable bouncing periodic orbits, which coexist with non-contacting motion, arise just beyond the resonance speed
Ω

p
:
q

. The theory of discontinuity maps is used to analyse the problem as a codimension-two degenerate grazing bifurcation in the limit of zero rotor damping and
Ω
 = 
Ω

p
:
q

. An analytic unfolding of the map explains all the features of the bouncing orbits locally. In particular, for non-zero damping
ζ
, stable bouncing motion bifurcates in the direction of increasing
Ω
speed in a smooth fold bifurcation point that is at rotor speed

O

(
ζ
)

beyond
Ω

p
:
q

. The results provide the first analytic explanation of partial-contact bouncing orbits and has implications for prediction and avoidance of unwanted machine vibrations in a number of different industrial settings.
Collective communication and behaviour in response to uncertain ‘Danger’ in network experiments
Authors: Shirado Hirokazu , Crawford Forrest W. , Christakis Nicholas A.
Published: May 2020

In emergencies, social coordination is especially challenging. People connected with each other may respond better or worse to an uncertain danger than isolated individuals. We performed experiments involving a novel scenario simulating an unpredictable situation faced by a group in which 2480 subjects in 108 groups had to both communicate information and decide whether to ‘evacuate’. We manipulated the permissible sorts of interpersonal communication and varied group topology and size. Compared to groups of isolated individuals, we find that communication networks suppress necessary evacuations because of the spontaneous and diffuse emergence of false reassurance; yet, communication networks also restrain unnecessary evacuations in situations without disasters. At the individual level, subjects have thresholds for responding to social information that are sensitive to the negativity, but not the actual accuracy, of the signals being transmitted. Social networks can function poorly as pathways for inconvenient truths that people would rather ignore.
A refined dynamic finite-strain shell theory for incompressible hyperelastic materials: equations and two-dimensional shell virtual work principle
Authors: Yu Xiang , Fu Yibin , Dai Hui-Hui
Published: May 2020

Based on previous work for the static problem, in this paper, we first derive one form of dynamic finite-strain shell equations for incompressible hyperelastic materials that involve three shell constitutive relations. In order to single out the bending effect as well as to reduce the number of shell constitutive relations, a further refinement is performed, which leads to a refined dynamic finite-strain shell theory with only two shell constitutive relations (deducible from the given three-dimensional (3D) strain energy function) and some new insights are also deduced. By using the weak formulation of the shell equations and the variation of the 3D Lagrange functional, boundary conditions and the two-dimensional shell virtual work principle are derived. As a benchmark problem, we consider the extension and inflation of an arterial segment. The good agreement between the asymptotic solution based on the shell equations and that from the 3D exact one gives verification of the former. The refined shell theory is also applied to study the plane-strain vibrations of a pressurized artery, and the effects of the axial pre-stretch, pressure and fibre angle on the vibration frequencies are investigated in detail.
Evolution of contribution timing in public goods games
Authors: Morsky Bryce , Smolla Marco , Akçay Erol
Published: May 2020

Life-history strategies are a crucial aspect of life, which are complicated in group-living species, where pay-offs additionally depend on others’ behaviours. Previous theoretical models of public goods games have generally focused on the amounts individuals contribute to the public good. Yet a much less-studied strategic aspect of public goods games, the timing of contributions, can also have dramatic consequences for individual and collective performance. Here, we develop two stage game theoretical models to explore how the timing of contributions evolves. In the first stage, individuals contribute to a threshold public good based on a performance schedule. The second stage begins once the threshold is met, and the individuals then compete as a function of their performance. We show how contributing rapidly is not necessarily optimal, because delayers can act as ‘cheats,’ avoiding contributing while reaping the benefits of the public good. However, delaying too long can put the delayers at a disadvantage as they may be ill-equipped to compete. These effects lead to bistability in a single group, and spatial diversity among multiple interacting groups.
Forecasting COVID-19 cases and deaths in epidemic-mitigating European countries by Richards function-based regression analyses
Authors: FU XINMIAO
Published: May 2020

The COVID-19 pandemic has hit many countries, and in some European countries it has been mitigated since April. Here we applied Richards function to simulate and forecast the course of COVID-19 epidemics in Italy, Spain, France, Germany, Turkey, Belgium, Ireland, Netherlands, Portugal and Switzerland. Potential total COVID-19 confirmed cases in these countries were estimated to be 240400±1300, 294100±4000, 178500±800, 176900±700, 155400±1000, 57900±400, 24000±200, 46200±300, 30000±300 and 30700±100 respectively. Most of these countries are predicted to approach ending stage between late May and early June such that daily new cases will become minimal, which may guide societal and economic restorations. In addition, total COVID-19 deaths were estimated to be 33500±300, 28200±200, 27800±200, 8740±80, 4500±30, 9250±70, 1530±20, 6240±50, 1380±10 and 1960±8, respectively. To our best knowledge, this is the first study forecasting the COVID-19 epidemic by applying the Richard function-based regression analysis.
The assembly effect: the connectedness between populations is a double-edged sword for public health interventions
Authors: Tun Sai Thein Than , Parker Daniel M. , Aguas Ricardo , White Lisa J.
Published: May 2020

Many public health interventions lead to disruption or decrease of transmission, providing a beneficial effect for people in the population regardless of whether or not they individually participate in the intervention. This protective benefit has been referred to as a herd or community effect and is dependent on sufficient population participation. In practice, public health interventions are implemented at different spatial scales (i.e. at the village, district, or provincial level). Populations, however defined, are frequently connected to other populations and this connectedness can influence potential herd effects. In this research we model the impact of a public health intervention (mass drug administration for malaria), given different levels of connectedness between similar populations and between populations of varying epidemiology (i.e. baseline transmission levels and intervention coverage). We show that the way such intervention units are connected to each other may influence the impact of the focal interventions deployed in both positive (adding value to the intervention) and negative (reducing the impact of the intervention) ways. We term this phenomenon the "assembly effect" which is a meta-population version of the more commonly understood "herd effect". We conclude that public health interventions should consider the connectedness of intervention units or populations in order to achieve success.
SARS-CoV-2 infection, clinical features and outcome of COVID-19 in United Kingdom nursing homes
Authors: Graham NSN , Junghans C , Downes R , Sendall C , Lai H , McKirdy A , Elliott P , Howard R , Wingfield D , Priestman M , Ciechonska M , Cameron L , Storch M , Crone MA , Freemont PS , Randell P , McLaren R , Lang N , Ladhani S , Sanderson F , Sharp DJ
Published: May 2020

Objectives

To understand SARS-Co-V-2 infection and transmission in UK nursing homes in order to develop preventive strategies for protecting the frail elderly residents.

Design

An outbreak investigation.

Setting

4 nursing homes affected by COVID-19 outbreaks in central London.

Participants

394 residents and 70 staff in nursing homes.

Interventions

Two point-prevalence surveys one week apart where residents underwent SARS-CoV-2 testing and had relevant symptoms documented. Asymptomatic staff from three of the four homes were also offered SARS-CoV-2 testing.

Main outcome measures

All-cause mortality, and mortality attributed to COVID-19 on death certificates. Prevalence of SARS-CoV-2 infection and symptoms in residents and staff.

Results

Overall, 26% (95% confidence interval 22 to 31) of residents died over the two-month period. All-cause mortality increased by 203% (95% CI 70 to 336). Systematic testing identified 40% (95% CI 35 to 46) of residents, of whom 43% (95% CI 34 to 52) were asymptomatic and 18% (95% CI 11 to 24) had atypical symptoms, as well as 4% (95% CI -1 to 9) of asymptomatic staff who tested positive for SARS-CoV-2.

Conclusions

The SARS-CoV-2 outbreak was associated with a very high mortality rate in residents of nursing homes. Systematic testing of all residents and a representative sample of staff identified high rates of SARS-CoV-2 positivity across the four nursing homes, highlighting a potential for regular screening to prevent future outbreaks.
European lockdowns and the consequences of relaxation during the COVID-19 pandemic
Authors: Glass David H.
Published: May 2020

This paper investigates the lockdowns introduced in France, Germany, Italy, Spain, and the UK and also explores the potential consequences of different degrees of relaxation. The analysis employs a two-stage SEIR model with different reproductive numbers pre-and post-lockdown. These parameters are estimated from data on the daily number of confirmed cases in a process that automatically detects the time at which the lockdown became effective. The model is evaluated by considering its predictive accuracy on current data and it is then deployed to explore partial relaxations. The results indicate that the different countries have been successful in reducing the reproductive number to values ranging from 0.67 (95% CI: 0.64 - 0.70) to 0.92 (95% CI: 0.89 - 0.95). Results also suggest that a relaxation of 25% could halt the decline incases in all five countries, while a 50% relaxation could lead to second peaks that are higher and last longer than the earlier peaks in each country. Even though the relaxations so far may have preserved the success of the lockdowns, vigilance is still needed. A relaxation of around 10-15% is recommended if COVID-19 is to continue to decline in all five countries.
Automated Identification of Patients with Immune-related Adverse Events from Clinical Notes using Word embedding and Machine Learning
Authors: Gupta Samir , Belouali Anas , Shah Neil J , Atkins Michael B , Madhavan Subha
Published: May 2020

Immune Checkpoint Inhibitors (ICIs) have substantially improved survival in patients with advanced malignancies. However, ICIs are associated with a unique spectrum of side effects termed Immune-Related Adverse Events (irAEs). To ensure treatment safety, research efforts are needed to comprehensively detect and understand irAEs from real world data (RWD). The goal of this work is to evaluate a Machine Learning-based phenotyping approach that can identify patients with irAEs from a large volume of retrospective clinical notes representing RWD. Evaluation shows promising results with an average F1-score=0.75 and AUC-ROC=0.78. While the extraction of any available irAEs in charts achieves high accuracy, individual irAEs extraction has room for further improvement.
Study Data Element Mapping: Feasibility of Defining Common Data Elements Across COVID-19 Studies
Authors: Mathewson Priscilla , Gordon Ben , Snowley Kay , Fennessy Clara , Denniston Alastair , Sebire Neil
Published: May 2020

Background: Numerous clinical studies are now underway investigating aspects of COVID-19. The aim of this study was to identify a selection of national and/or multicentre clinical COVID-19 studies in the United Kingdom to examine the feasibility and outcomes of documenting the most frequent data elements common across studies to rapidly inform future study design and demonstrate proof-of-concept for further subject-specific study data element mapping to improve research data management.
Methods: 25 COVID-19 studies were included. For each, information regarding the specific data elements being collected was recorded. Data elements collated were arbitrarily divided into categories for ease of visualisation. Elements which were most frequently and consistently recorded across studies are presented in relation to their relative commonality.
Results: Across the 25 studies, 261 data elements were recorded in total. The most frequently recorded 100 data elements were identified across all studies and are presented with relative frequencies. Categories with the largest numbers of common elements included demographics, admission criteria, medical history and investigations. Mortality and need for specific respiratory support were the most common outcome measures, but with specific studies including a range of other outcome measures.
Conclusion: The findings of this study have demonstrated that it is feasible to collate specific data elements recorded across a range of studies investigating a specific clinical condition in order to identify those elements which are most common among studies. These data may be of value for those establishing new studies and to allow researchers to rapidly identify studies collecting data of potential use hence minimising duplication and increasing data re-use and interoperability
Investigation on the interaction between nifedipine and ritonavir containing antivirus regimens: a physiologically-based pharmacokinetic/pharmacodynamic analysis
Authors: Niu Wan-jie , Li Si-ze , Jin Sha-sha , Lin Xi-ying , Zhang Meng-wan , Cai Wei-min , Zhong Ming-kang , Xiang Xiao-qiang , Jiao Zheng
Published: May 2020

Background and Objective

Hypertension is a common comorbidity of patients with COVID-19, SARS or HIV infection. Those patients are often treated with commonly used antiviral and antihypertensive agents concomitantly, such as ritonavir-containing regimens and nifedipine. Since ritonavir is a strong inhibitor of CYP3A, when nifedipine is combined with ritonavir-containing antiviral drugs, there is a potential risk of drug-drug interaction. This study aimed to provide guidance on nifedipine treatment during and after co-administration with ritonavir-containing regimens using a physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) analysis.

Methods

A PBPK/PD model was developed for nifedipine by the software of Simcyp®, and the model was verified using published data. The effects of ritonavir on nifedipine exposures and systolic blood pressure were assessed for instant-release, sustained-release and controlled-release formulations. Moreover, various nifedipine regimens were investigated when co-administrated with and withdrawing ritonavir.

Results

PBPK/PD models for three formulations of nifedipine were successfully established. The model predicted pharmacokinetic profiles of nifedipine were comparable to the published data. Ratios of predicted versus observed AUCDDI/AUCNifedipineof nifedipine were within 0.70- to 1.83-fold. Model simulations showed that the inhibitory effect of ritonavir on CYP3A4 increased the Cmaxof nifedipine by 9.82-34.35 times and the AUC24hby 44.94-50.77 times at steady state. Moreover, nifedipine dose reduced to 1/16 of the regular dose during ritonavir co-administration could lead to severe hypotension.

Conclusions

Ritonavir had a pronounced influence on the pharmacokinetics and antihypertensive effect of nifedipine. It is not recommended for patients to take nifedipine and ritonavir-containing regimens simultaneously.
Hypertension and renin-angiotensin system blockers are not associated with expression of Angiotensin Converting Enzyme 2 (ACE2) in the kidney
Authors: Jiang Xiao , Eales James M. , Scannali David , Nazgiewicz Alicja , Prestes Priscilla , Maier Michelle , Denniff Matthew J. , Xu Xiaoguang , Saluja Sushant , Cano-Gamez Eddie , Wystrychowski Wojciech , Szulinska Monika , Antczak Andrzej , Byars Sean , Glyda Maciej , Krol Robert , Zywiec Joanna , Zukowska-Szczechowska Ewa , Burrell Louise M. , Woolf Adrian S. , Greenstein Adam , Bogdanski Pawel , Keavney Bernard , Morris Andrew P. , Heagerty Anthony , Williams Bryan , Harrap Stephen B. , Trynka Gosia , Samani Nilesh J. , Guzik Tomasz J. , Charchar Fadi J. , Tomaszewski Maciej
Published: May 2020

Angiotensin converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2) - the cause of COVID-19 disease. It has been hypothesized that use of renin-angiotensin system (RAS) inhibiting medications in patients with hypertension, increases the expression of ACE2 and thereby increases the risk of COVID-19 infection and severe outcomes or death. However, the effect of RAS-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported.
We examined how hypertension, its major metabolic co-phenotypes and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterised by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model.
Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis.
Collectively, our data indicate that neither hypertension nor antihypertensive treatment are likely to alter individual risk of SARS-CoV-2 infection or influence clinical outcomes in COVID-19 through changes of ACE2 expression. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection.
Currently prescribed drugs in the UK that could up or downregulate ACE2 in COVID-19 disease: A systematic review
Authors: Dambha-Miller Hajira , Albasri Ali , Hodgson Sam , Wilcox Christopher R , Khan Shareen , Nazrul Islam Nazrul , Little Paul , Griffin Simon J
Published: May 2020

Objective: To review evidence on routinely prescribed drugs in the UK that could up or downregulate Angiotensin Converting Enzyme 2 (ACE2) and potentially affect COVID-19 disease

Design: Systematic review

Data source: MEDLINE, EMBASE, CINAHL, the Cochrane Library and Web of Science
Study selection: Any design with animal or human models examining a currently prescribed UK drug compared to a control, placebo or sham group, and reporting an effect on ACE2 level, activity or gene expression.

Data extraction and synthesis: MEDLINE, EMBASE, CINAHL, the Cochrane Library, Web of Science and OpenGrey from inception to 1st April 2020. Methodological quality was assessed using the SYRCLE's risk of bias tool for animal studies and Cochrane risk of bias tool for human studies.

Results: We screened 3,360 titles and included 112 studies with 21 different drug classes identified as influencing ACE2 activity. Ten studies were in humans and 102 were in animal models None examined ACE2 in human lungs. The most frequently examined drugs were Angiotensin Receptor Blockers (ARBs) (n= 55) and Angiotensin-Converting Enzyme- Inhibitors (ACE-I) (n= 22). More studies reported upregulation than downregulation with ACE-I (n=22), ARBs (n=55), insulin (n=8), thiazolidinedione (n=7) aldosterone agonists (n=3), statins (n=5), oestrogens (n=5) calcium channel-blockers (n=3) GLP-1 agonists (n=2) and NSAIDs (n=2).

Conclusions: There is an abundance of academic literature and media reports on the potential of drugs that could attenuate or exacerbate COVID-19 disease. This is leading to trials of repurposed drugs and uncertainty amongst patients and clinicians concerning continuation or cessation of prescribed medications. Our review indicates that the impact of currently prescribed drugs on ACE2 has been poorly studied in-vivo, particularly in human lungs where the SARS-CoV-2 virus appears to enact its pathogenic effects. We found no convincing evidence to justify starting or stopping currently prescribed drugs to influence outcomes of COVID-19 disease.
Strict Physical Distancing May Be More Efficient: A Mathematical Argument for Making Lockdowns Count
Authors: Sheffield Scott R , York Anna , Swartwood Nicole A , Bilinski Alyssa , Williamson Anne , Fitzpatrick Meagan C
Published: May 2020

COVID-19 created a global public health and economic emergency. Policymakers acted quickly and decisively to contain the spread of disease through physical distancing measures. However, these measures also impact physical, mental and economic well-being, creating difficult trade-offs. Here we use a simple mathematical model to explore the balance between public health measures and their associated social and economic costs. Across a range of cost-functions and model structures, commitment to intermittent and strict social distancing measures leads to better overall outcomes than temporally consistent implementation of moderate physical distancing measures. With regard to the trade-offs that policymakers may soon face, our results emphasize that economic and health outcomes do not exist in full competition. Compared to consistent moderation, intermittently strict policies can better mitigate the impact of the pandemic on both of these priorities for a range of plausible utility functions.
COVID-19: A Chronological Review of the Neurological Repercussions - What do We Know by May, 2020?
Authors: Mei Paulo Afonso , Loeb Laura
Published: May 2020

Abstract

Introduction: Despite the new SARS-CoV-2 (COVID-19) be the seventh of the coronavirus family viruses known to cause human disease, little is known about potential symptoms and syndromes secondary to the compromise of the central and peripheral nervous systems. We reviewed neurological manifestations due to the new coronavirus, thus far published in the literature, as well as guidelines issued by sub-specialties in Neurology, to tackle the disease.

Methods: we searched medical databases, such as PubMed, PubMed Central, LILACS and Google scholar for papers (case reports, short letters, case series, etc) describing neurological symptoms in patients with confirmed or suspect COVID-19 diagnosis and also searched webpages of associations and organizations that deal with neurological disorders.

Results: we describe briefly each article considered for this review. Forty-one papers were found associating neurological conditions and COVID-19. Cases are divided by disease groups and, within each disease group, results are listed in chronological order or publication date. We also discuss briefly recommendations for neurological patients, according to disease group.

Conclusion: Although there is evidence of neurological manifestations with previous coronaviruses, COVID-19 is assuring a volume of published papers not seen before for other coronavirus infections. Most neurological cases are not life-threatening, but 10 to 20% of cases will require hospitalization and are in risk for sequelae and death. Although a lot of data coming from these papers is amassing, researchers must bear in mind that many papers currently published are not yet peer-reviewed, and thus are prone to further corrections.
Computational simulation to assess patient safety of uncompensated COVID-19 two-patient ventilator sharing using the Pulse Physiology Engine
Authors: Webb Jeffrey B. , Bray Aaron , Asare Philip K. , Clipp Rachel B. , Mehta Yatin B. , Penupolu Sudheer , Patel Aalpen A. , Poler S. Mark
Published: May 2020

Background

The COVID-19 pandemic is stretching medical resources internationally, sometimes creating ventilator shortages that complicate clinical and ethical situations. The possibility of needing to ventilate multiple patients with a single ventilator raises patient health and safety concerns in addition to clinical conditions needing treatment.

Wherever ventilators are employed, additional tubing and splitting adaptors may be available. Adjustable flow-compensating resistance for differences in lung compliance on individual limbs may not be readily implementable.

By exploring a number and range of possible contributing factors using computational simulation without risk of patient harm, this paper attempts to define useful bounds for ventilation parameters when compensatory resistance in limbs of a shared breathing circuit is not possible. This desperate approach to shared ventilation support would be a last resort when alternatives have been exhausted.

Methods

A whole-body computational physiology model (using lumped parameters) was used to simulate each patient being ventilated. The primary model of a single patient with a dedicated ventilator was augmented to model two patients sharing a single ventilator. In addition to lung mechanics or estimation of CO2 and pH expected for set ventilation parameters (considerations of lung physiology alone), full physiological simulation provides estimates of additional values for oxyhemoglobin saturation, arterial oxygen tension, and other patient parameters. A range of ventilator settings and patient characteristics were simulated for paired patients.

Findings

To be useful for clinicians, attention has been directed to clinically available parameters. These simulations show patient outcome during multi-patient ventilation is most closely correlated to lung compliance, oxygenation index, oxygen saturation index, and end-tidal carbon dioxide of individual patients. The simulated patient outcome metrics were satisfactory when the lung compliance difference between two patients was less than 12 mL/cmH2O, and the oxygen saturation index difference was less than 2 mmHg.

Interpretation

In resource-limited regions of the world, the COVID-19 pandemic will result in equipment shortages. While single-patient ventilation is preferable, if that option is unavailable and ventilator sharing using limbs without flow resistance compensation is the only available alternative, these simulations provide a conceptual framework and guidelines for clinical patient selection.
Time-varying reproduction numbers of COVID-19 in Georgia, USA, March 2-June 14, 2020
Authors: Muniz-Rodriguez Kamalich , Chowell Gerardo , Schwind Jessica S. , Ford Randall , Ofori Sylvia K. , Ogwara Chigozie A. , Davies Margaret R. , Jacobs Terrence , Cheung Chi-Hin , Cowan Logan T. , Hansen Andrew R. , Fung Isaac Chun-Hai
Published: May 2020

In 2020, SARS-CoV-2 impacted Georgia, USA. Georgia announced state-wide shelter-in-place on April 2 and partially lifted restrictions on April 27. We analyzed daily incidence of confirmed COVID-19 cases by reporting date, March 2-June 14, in Georgia, Metro Atlanta, and Dougherty County and estimate the time-varying reproduction number, Rt, using R package EpiEstim. The median Rt estimate in Georgia dropped from between 2 and 4 in mid-March, to <2 in late March, and around 1 from mid-April to mid-June. Regarding Metro Atlanta, Rt fluctuated above 1.5 in March and around 1 since April. In Dougherty County, the median Rt declined from around 2 in late March to 0.32 on April 26. In Spring 2020, SARS-CoV-2 transmission in Georgia declined likely because of social distancing measures. However, as restrictions were relaxed in late April, community transmission continued with Rt fluctuating around 1 across Georgia, Metro Atlanta, and Dougherty County as of mid-June.