bluuebunny/crossref_metadata_2025 huggingface dataset:
A Seven-year Study on the Effects of Intravenous Antibiotic Therapy on Infection of Ventriculoperitoneal Shunts in Children
Authors: Mostafavi Sayed Nasser , Khedmati Majid , Kelishadi Roya
Published: April 2020

Background:

Infection is one of the most common complications of ventriculoperitoneal (VP) shunts. Its optimal management is controversial. We aimed to report current practice within a large pediatric neurosurgical center.

Methods:

We retrospectively studied a cohort of children <15 years with VP shunt infection, who underwent treatment from March 2011 to March 2018 in the main referral children hospital in Isfahan, Iran. Patients with distal shunt infection or associated wound infection were not included. The initial protocol was empiric intravenous antibiotic therapy and repeated evaluation of cerebrospinal fluid (CSF) analysis and culture. After obtaining the culture results, antibiotic regimen was adjusted according to the sensitivity results. Response to protocol was defined as negative culture results after 72 hours of appropriate antibiotic, which persisted at least for 1 month after discontinuation of therapy. In patients who failed to respond to protocol, the shunts were replaced.

Results:

Totally, 148 cases with mean (SD) age of 21.2 (30.1) months included to the study. Of which, 56.1% were boys and 68.2% had responded to the protocol. This response was significantly prominent in patients who infected with Gram-negative bacteria (82.9%), especially with Acinetobacter spp. (100%) and Pseudomonas aeruginosa (100%). The response was significantly higher in patients with CSF glucose of greater than 40 mg/dl (83% versus 58.1%, respectively, P = 0.004).

Conclusion:

We found that using only intravenous antibiotics is sufficiently enough for treating many children with VP shunt infections, especially in those infected by Gram-negative organisms and CSF glucose level of greater than 40 mg/dl.
Opioid-Prescribing Metrics in Washington State: Trends and Challenges
Authors: Fulton-Kehoe Deborah , Lofy Kathryn H. , Le Vi , Sterling Ryan , Sears Jeanne M. , Franklin Gary
Published: April 2020

Context:

Analyses of prescribing trends using prescription drug monitoring programs (PDMP) are impacted by changes in reporting requirements and in the scheduling of medications by the Drug Enforcement Administration. In 2014, the Drug Enforcement Administration changed the status of tramadol from an unscheduled to a scheduled medication. The addition of tramadol to the PDMP may affect the prevalence of opioid-prescribing metrics and the interpretation of prescribing trends.

Objective:

The objectives were to (1) examine trends in opioid prescribing in Washington State between 2012 and 2017, (2) assess the potential impact of adding tramadol to PDMP on these trends, and (3) describe challenges in defining and implementing opioid-prescribing metrics.

Design:

Analysis of quarterly summary statistics of opioid prescribing.

Setting:

Washington State.

Participants:

Washington State residents.

Main Outcome Measures:

The metrics include measures of opioid prescribing overall and by age group, chronic opioid prescribing, high-dose prescribing among those on chronic opioid therapy, prescribing of concurrent opioids and sedatives, days' supply of new opioid prescriptions, and transition from short-term to long-term use of opioids.

Results:

In Washington, the prevalence of any opioid prescribing, chronic opioid prescribing, high-dose opioid prescribing, and prescribing of concurrent opioids and sedatives declined between 2012 and 2017. The prevalence of opioid prescribing was higher in older than in younger age groups. The addition of tramadol to the Washington PDMP in 2014 affected the observed prevalence of all opioid metrics and of all opioid-prescribing trends. Conclusions about trends in opioid prescribing differ substantially depending on whether tramadol is included or not, particularly in 2014 and 2015.

Conclusions:

The development of opioid-prescribing metrics is relatively new. There is likely much benefit of standard definitions of opioid metrics at the state and national levels to track important trends and compare progress from state to state.
Brief Report: Integrase Strand Transfer Inhibitors Are Associated With Lower Risk of Incident Cardiovascular Disease in People Living With HIV
Authors: O'Halloran Jane A. , Sahrmann John , Butler Anne M. , Olsen Margaret A. , Powderly William G.
Published: April 2020

Background:

Several antiretroviral therapy (ART) classes have been associated with increased myocardial infarction (MI) risk. Cardiovascular disease in people living with HIV (PLWH) on integrase strand transfer inhibitors (INSTI) has not been examined. Here we aim to examine this.

Setting:

Retrospective cohort design study.

Methods:

We used the IBMMarketScan databases for U.S. commercially insured and Medicaid covered adults to identify PLWH newly initiated on ART between January 1, 2008 and December 30, 2015. Major adverse cardiac event (MACE), a composite of acute MI, ischemic stroke, coronary artery bypass grafting, and percutaneous coronary intervention was the primary outcome. We used calendar time-specific probability-weighted Cox proportional hazards models to estimate hazard ratios and 95% confidence intervals for the association between INSTI use and MACE. We used propensity score weighting methods to account for potential confounding.

Results:

Twenty thousand two hundred forty-two new ART initiators were identified. 5069 (25%) PLWH initiated INSTI-based regimens. 203 MACE events occurred; acute MI 16 (0.32%) vs 66 (0.43%), stroke 24 (0.47%) vs 54 (0.36), coronary artery bypass grafting 2 (0.04%) vs 9 (0.06%), percutaneous coronary intervention 7 (0.14%) vs 25 (0.16%) of INSTI users vs non-users. INSTI-based ART was associated with significantly lower risk of MACE events (hazard ratios 0.79; 95% confidence intervals: 0.64 to 0.96) compared with non–INSTI-based regimens.

Conclusion:

In this cohort, INSTI-based regimens were associated with a 21% decreased risk of incident cardiovascular disease. These finding require validation in other cohorts and with longer follow-up.
Effect of HIV and Interpersonal Trauma on Cortical Thickness, Cognition, and Daily Functioning
Authors: Kapetanovic Suad , Norato Gina , Nair Govind , Julnes Peter Siyahhan , Traino Katherine A. , Geannopoulos Katrina , Smith Bryan R. , Snow Joseph , Nath Avindra
Published: April 2020

Background:

Interpersonal trauma (IPT) is highly prevalent among HIV-positive (HIV+) individuals, but its relationship with brain morphology and function is poorly understood.

Setting:

This cross-sectional analysis evaluated the associations of IPT with cognitive task performance, daily functioning, magnetic resonance imaging (MRI) brain cortical thickness, and bilateral volumes of 4 selected basal ganglia regions in a US-based cohort of aviremic HIV+ individuals, with (HIV+ IPT+) and without IPT exposure (HIV+ IPT−), and sociodemographically matched HIV-negative controls with (HIV− IPT+) and without IPT exposure (HIV− IPT−).

Methods:

Enrollees completed brain MRI scans, a semistructured psychiatric interview, a neurocognitive battery, and 3 measures of daily functioning. Demographic and clinical characteristics of the 4 groups were described, and pairwise between-group comparisons performed using χ2 tests, analysis of variance, or t-tests. Linear or Poisson regressions evaluated relationships between group status and the outcomes of interest, in 6 pairwise comparisons, using Bonferroni correction for statistical significance.

Results:

Among 187 participants (mean age 50.0 years, 63% male, 64% non-white), 102 were HIV+ IPT+, 35 were HIV+ IPT−, 26 were HIV− IPT−, and 24 were HIV− IPT+. Compared with the remaining 3 groups, the HIV+ IPT+ group had more activities of daily living declines, higher number of impaired Patient's Assessment of Own Functioning Inventory scores, and lower cortical thickness in multiple cerebral regions. Attention/working memory test performances were significantly better in HIV− IPT− compared with the HIV+ IPT+ and HIV+ IPT− groups. Basal ganglia MRI volumes were not significantly different in any between-group comparisons.

Conclusion:

IPT exposure and HIV infection have a synergistic effect on daily functioning and cortical thickness in aviremic HIV+ individuals.
Artificial Intelligence-based Fully Automated Per Lobe Segmentation and Emphysema-quantification Based on Chest Computed Tomography Compared With Global Initiative for Chronic Obstructive Lung Disease Severity of Smokers
Authors: Fischer Andreas M. , Varga-Szemes Akos , Martin Simon S. , Sperl Jonathan I. , Sahbaee Pooyan , Neumann Dominik , Gawlitza Joshua , Henzler Thomas , Johnson Colin M. , Nance John W. , Schoenberg Stefan O. , Schoepf U. Joseph
Published: April 2020

Objectives:

The objective of this study was to evaluate an artificial intelligence (AI)-based prototype algorithm for the fully automated per lobe segmentation and emphysema quantification (EQ) on chest-computed tomography as it compares to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) severity classification of chronic obstructive pulmonary disease (COPD) patients.

Methods:

Patients (n=137) who underwent chest-computed tomography acquisition and spirometry within 6 months were retrospectively included in this Institutional Review Board-approved and Health Insurance Portability and Accountability Act-compliant study. Patient-specific spirometry data, which included forced expiratory volume in 1 second, forced vital capacity, and the forced expiratory volume in 1 second/forced vital capacity ratio (Tiffeneau-Index), were used to assign patients to their respective GOLD stage I to IV. Lung lobe segmentation was carried out using AI-RAD Companion software prototype (Siemens Healthineers), a deep convolution image-to-image network and emphysema was quantified in each lung lobe to detect the low attenuation volume.

Results:

A strong correlation between the whole-lung-EQ and the GOLD stages was found (ρ=0.88, P<0.0001). The most significant correlation was noted in the left upper lobe (ρ=0.85, P<0.0001), and the weakest in the left lower lobe (ρ=0.72, P<0.0001) and right middle lobe (ρ=0.72, P<0.0001).

Conclusions:

AI-based per lobe segmentation and its EQ demonstrate a very strong correlation with the GOLD severity stages of COPD patients. Furthermore, the low attenuation volume of the left upper lobe not only showed the strongest correlation to GOLD severity but was also able to most clearly distinguish mild and moderate forms of COPD. This is particularly relevant due to the fact that early disease processes often elude conventional pulmonary function diagnostics. Earlier detection of COPD is a crucial element for positively altering the course of disease progression through various therapeutic options.
A Comparative Study of Chest Computed Tomography Features in Young and Older Adults With Corona Virus Disease (COVID-19)
Authors: Zhu Tingting , Wang Yujin , Zhou Shuchang , Zhang Na , Xia Liming
Published: April 2020

Objective:

To analyze the most common computed tomography (CT) findings of pneumonia caused by new coronavirus in younger patients (60 and younger) and older adults (older than 60).

Materials and Methods:

The chest CT images of 72 symptomatic patients with corona virus disease (COVID-19) were analyzed retrospectively, including 44 younger patients (47.5±8.7 y old) and 28 older patients (68.4±6.0 y old). CT findings including density (pure ground-glass opacities, ground-glass opacities with consolidation, consolidation), the number of lobes involved, lesion distribution, and the main accompanying signs were analyzed and compared.

Results:

Characteristic CT findings included the lobes of bilateral lung extensively involved, ground-glass opacity and ground-glass opacity with consolidation in the peripheral area, sometimes accompanied by interlobular septal thickening, and subpleural line and pleural thickening. Compared with the younger group, the proportion of extensive involvement of lung lobes was higher in the elderly group (71.4% vs. 36.4%, P=0.009), and subpleural line and pleural thickening were more likely to occur (50.0% vs. 25.0%, and 71.4% vs. 40.9%, P=0.030 and 0.011, respectively).

Conclusion:

Elderly and younger patients with corona virus disease have some common CT features, but older patients are more likely to have extensive lung lobe involvement, and subpleural line and pleural thickening. These differentiated characteristics may be related to the progress and prognosis of the disease.
Impact of Donor Age on the Outcome of Living-donor Liver Transplantation: Special Consideration to the Feasibility of Using Elderly Donors
Authors: Kadohisa Masashi , Inomata Yukihiro , Uto Keiichi , Hayashida Shintaro , Ohya Yuki , Yamamoto Hidekazu , Sugawara Yasuhiko , Hibi Taizo
Published: April 2020

Background.

The use of elderly donors (≥60 y) in living-donor liver transplantation (LDLT) remains controversial. In this study, we aimed to determine the safety of surgery for elderly donors and the impact of donor age on LDLT outcomes.

Methods.

We, retrospectively, reviewed 470 cases of LDLT at Kumamoto University Hospital from December 1998 to March 2017.

Results.

Donors were divided into 5 groups according to age: 20–29 (n = 109), 30–39 (n = 157), 40–49 (n = 87), 50–59 (n = 81), and ≥60 (n = 36). At our institution, elderly donor candidates required additional preoperative work-up. There were no significant differences in the incidence of postoperative complications and duration of postoperative hospital stay among the 5 donor groups. Regardless of graft type, elderly donors were comparable to younger donor groups (<30 y) in postoperative recovery of liver function. Risk-adjusted overall survival rates of recipients among donor groups were not significantly different. Additionally, donor age was not significantly associated with 6-month graft survival of adult and pediatric recipients.

Conclusions.

Elderly candidates ≥60 years of age can safely be selected as LDLT donors after meticulous preoperative work-up.
CD38 Antibody Daratumumab for the Treatment of Chronic Active Antibody-mediated Kidney Allograft Rejection
Authors: Doberer Konstantin , Kläger Johannes , Gualdoni Guido A. , Mayer Katharina A. , Eskandary Farsad , Farkash Evan A. , Agis Hermine , Reiter Thomas , Reindl-Schwaighofer Roman , Wahrmann Markus , Cohen Gerald , Haslacher Helmuth , Bond Gregor , Simonitsch-Klupp Ingrid , Halloran Philip F. , Böhmig Georg A.
Published: April 2020

Background.

Late antibody-mediated rejection (AMR) is a major cause of transplant failure. Potential therapeutic targets are plasma cells and natural killer (NK) cells, both expressing high levels of CD38.

Methods.

Here, we report the use of CD38 monoclonal antibody daratumumab (9-mo course) in a kidney allograft recipient diagnosed with smoldering myeloma and anti-HLA class II donor-specific antibody-positive chronic active AMR 13 years after transplantation. Patient monitoring included serial HLA single-antigen testing, peripheral blood immune cell phenotyping, as well as follow-up allograft and bone marrow biopsies at 3 and 9 months, including analyses of rejection-related gene expression patterns.

Results.

Daratumumab led to persistent CD138+ cell depletion in the bone marrow and blood and substantially decreased NK cells counts in blood and graft tissue. At the same time, donor-specific antibody in serum disappeared, and in vitro alloantibody production by CD138+ cells enriched from bone marrow aspirates was abrogated. A 3-month follow-up biopsy revealed a complete resolution of microcirculation inflammation (g+ptc: 3 to 0) and molecular AMR activity (AMR score: 0.79 to <0.2). The same biopsy showed (subclinical) tubulointerstitial inflammation, which prompted steroid treatment. Over an observation period of 12 months, graft function stabilized.

Conclusions.

Targeting CD38 for plasma cell and NK cell depletion may be an effective strategy to counteract AMR. Our results may encourage the design of future trials to clarify the role of this innovative treatment concept in organ transplantation.
Multimodal Imaging in a Case of Peripapillary Choroidal Neovascular Membrane Associated With Idiopathic Intracranial Hypertension
Authors: Igwe Chinedu N. , Nderitu Paul , Eframidis Stefanos , Eleftheriadis Haralabos , O'Sullivan Eoin
Published: April 2020

Optical coherence tomography angiography is one of the latest noninvasive imaging modalities for visualizing the vasculature of retina and choroid. We describe its application in the diagnosis, treatment, and monitoring of a patient with peripapillary choroidal neovascular membrane in the setting of idiopathic intracranial hypertension, who responded well to a course of ranibizumab intravitreal injections.
James Petiver's apothecary practice and the consumption of American drugs in early modern London
Authors: Maydom Katrina Elizabeth
Published: April 2020

In the late seventeenth century, there was a boom in English imports of drugs from the Americas, such as sassafras, guaiacum and sarsaparilla. This was a result of a wider increase in colonial trade, the English acquisition of new drug-producing territories, such as Jamaica, and a broader trend towards greater medical consumption of drugs. How were these American drugs received in early modern English medicine? James Petiver (1665–1718), an apothecary in London, incorporated these drugs in his retail trade and institutional care. Analysis of Petiver's medical receipt books, daily prescription journals and administrative records demonstrates that American drugs, such as Virginia snakeroot, guaiacum and jalap, were readily accessible and dispensed to patients of all social classes in London by the turn of the eighteenth century. One-third of Petiver's private patients and one-fifth of his institutional patients were treated with American drugs. While men, women and children were all routinely prescribed American drugs, a greater variety of these drugs were available to his retail clients.
Structural analysis of SARS-CoV-2 genome and predictions of the human interactome
Authors: Vandelli Andrea , Monti Michele , Milanetti Edoardo , Armaos Alexandros , Rupert Jakob , Zacco Elsa , Bechara Elias , Ponti Riccardo Delli , Tartaglia Gian Gaetano
Published: April 2020

Specific elements of viral genomes regulate interactions within host cells. Here, we calculated the secondary structure content of >2000 coronaviruses and computed >100000 human protein interactions with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The genomic regions display different degrees of conservation. SARS-CoV-2 domain encompassing nucleotides 22500 – 23000 is conserved both at the sequence and structural level. The regions upstream and downstream, however, vary significantly. This part codes for the Spike S protein that interacts with the human receptor angiotensin-converting enzyme 2 (ACE2). Thus, variability of Spike S may be connected to different levels of viral entry in human cells within the population.

Our predictions indicate that the 5’ end of SARS-CoV-2 is highly structured and interacts with several human proteins. The binding proteins are involved in viral RNA processing such as double-stranded RNA specific editases and ATP-dependent RNA-helicases and have strong propensity to form stress granules and phase-separated complexes. We propose that these proteins, also implicated in viral infections such as HIV, are selectively recruited by SARS-CoV-2 genome to alter transcriptional and post-transcriptional regulation of host cells and to promote viral replication.
The Covid-19 infection in Italy: a statistical study of an abnormally severe disease
Authors: De Natale Giuseppe , Ricciardi Valerio , De Luca Gabriele , De Natale Dario , Di Meglio Giovanni , Ferragamo Antonio , Marchitelli Vito , Piccolo Andrea , Scala Antonio , Somma Renato , Spina Emanuele , Troise Claudia
Published: April 2020

We statistically investigate the Coronavirus Disease 19 (hereinafter Covid-19) epidemics, which is particularly invasive in Italy. We show that the high apparent mortality (or Case Fatality Ratio, CFR) observed in Italy, as compared with other countries, is likely biased by a strong underestimation of infected cases. To give a more realistic estimate of the mortality of Covid-19, we use the most recent estimates of the IFR (Infection Fatality Ratio) of epidemic, based on the minimum observed CFR, and furthermore analyse data obtained from the ship Diamond Princess, a good representation of a ‘laboratory’ case-study from an isolated system in which all the people have been tested. From such analyses we derive more realistic estimates of the real extension of the infection, as well as more accurate indicators of how fast the infection propagates. We then point out from the various explanations proposed, the dominant factors causing such an abnormal seriousness of the disease in Italy. Finally, we use the deceased data, the only ones estimated to be reliable enough, to predict the total number of infected people and the interval of time when the infection in Italy could stop.
Sequence variation among SARS-CoV-2 isolates in Taiwan
Authors: Gong Yu-Nong , Tsao Kuo-Chien , Hsiao Mei-Jen , Huang Chung-Guei , Huang Peng-Nien , Huang Po-Wei , Lee Kuo-Ming , Liu Yi-Chun , Yang Shu-Li , Kuo Rei-Lin , Liu Ming-Tsan , Yang Ji-Rong , Chiu Cheng-Hsun , Yang Cheng-Ta , Shih Shin-Ru , Chen Guang-Wu
Published: April 2020

Taiwan experienced two waves of imported cases of coronavirus disease 2019 (COVID-19), first from China in January to late February, followed by those from other countries starting in early March. Additionally, several cases could not be traced to any imported cases and were suspected as sporadic local transmission. Twelve full viral genomes were determined in this study by Illumina sequencing either from virus isolates or directly from specimens, among which 5 originated from clustered infections. Phylogenetic tree analysis revealed that these sequences were in different clades, indicating that no major strain has been circulating in Taiwan. A deletion in open reading frame 8 was found in one isolate. Only a 4-nucleotide difference was observed among the 5 genomes from clustered infections.
Computational Prediction of the Comprehensive SARS-CoV-2 vs. Human Interactome to Guide the Design of Therapeutics
Authors: Dick Kevin , Biggar Kyle K. , Green James R.
Published: April 2020

Abstract

Understanding the disease pathogenesis of the novel coronavirus, denoted SARS-CoV-2, is critical to the development of anti-SARS-CoV-2 therapeutics. The global propagation of the viral disease, denoted COVID-19 (“coronavirus disease 2019”), has unified the scientific community in searching for possible inhibitory small molecules or polypeptides. Given the known interaction between the human ACE2 (“Angiotensin-converting enzyme 2”) protein and the SARS-CoV virus (responsible for the coronavirus outbreakcirca. 2003), considerable focus has been directed towards the putative interaction between the SARS-CoV-2 Spike protein and ACE2. However, a more holistic understanding of the SARS-CoV-2 vs. human inter-species interactome promises additional putative protein-protein interactions (PPI) that may be considered targets for the development of inhibitory therapeutics.

To that end, we leverage two state-of-the-art, sequence-based PPI predictors (PIPE4 & SPRINT) capable of generating the comprehensive SARS-CoV-2 vs. human interactome, comprising approximately 285,000 pairwise predictions. Of these, we identify the high-scoring subset of human proteins predicted to interact with each of the 14 SARS-CoV-2 proteins by both methods, comprising 279 high-confidence putative interactions involving 225 human proteins. Notably, the Spike-ACE2 interaction was the highest ranked for both the PIPE4 and SPRINT predictors, corroborating existing evidence for this PPI. Furthermore, the PIPE-Sites algorithm was used to predict the putative subsequence that might mediate each interaction and thereby inform the design of inhibitory polypeptides intended to disrupt the corresponding host-pathogen interactions.

We hereby publicly release the comprehensive set of PPI predictions and their corresponding PIPE-Sites landscapes in the following DataVerse repository: 10.5683/SP2/JZ77XA. All data and metadata are released under a CC-BY 4.0 licence. The information provided represents theoretical modeling only and caution should be exercised in its use. It is intended as a resource for the scientific community at large in furthering our understanding of SARS-CoV-2.
A phased lift of control: a practical strategy to achieve herd immunity against Covid-19 at the country level
Authors: de Vlas Sake J. , Coffeng Luc E.
Published: April 2020

Most countries are affected by the Covid-19 pandemic and experience rapidly increasing numbers of cases and deaths. Many have implemented nationwide stringent control to avoid overburdening the health care system. This paralyzes economic and social activities until the availability of a vaccine, which may take years. We propose an alternative exit strategy to develop herd immunity in a predictable and controllable way: a phased lift of control. This means that successive parts of the country (e.g. provinces) stop stringent control, and Covid-19-related IC admissions are distributed over the country as the whole. Importantly, vulnerable individuals need to be shielded until herd immunity has developed in their area. We explore the characteristics and duration of this strategy using a novel individual-based model for geographically stratified transmission of Covid-19 in a country. The model predicts that individuals will have to experience stringent control for about 14 months on average, but this duration may be significantly shortened by future developments (more IC beds, better drugs). Clearly, the strategy will have a profound impact on individuals and society, and should therefore be considered carefully by various other disciplines (e.g. health systems, ethics, economics) before actual implementation.
Early surveillance and public health emergency disposal measures between novel coronavirus disease 2019 and avian influenza in China: a case-comparison study
Authors: Zhang Tiantian , Shi Wenming , Wang Ying , Bai Ge , Dai Ruiming , Wang Qian , Luo Li
Published: April 2020

Background

The novel coronavirus disease 2019 (COVID-19) outbreak is spreading rapidly throughout China and the world. Hence, early surveillance and public health emergency disposal are considered crucial to curb this emerging infectious disease. However, studies that investigated the early surveillance and public health emergency disposal for the prevention and control of the COVID-19 outbreak in China are relatively few. We aimed to compare the strengths and weaknesses of early surveillance and public health emergency disposal for prevention and control between COVID-19 and H7N9 avian influenza, which was commended by the international community, in China.

Methods

A case-comparison study was conducted using a set of six key time nodes to form a reference framework for evaluating early surveillance and public health emergency disposal between H7N9 avian influenza (2013) in Shanghai, China and COVID-19 in Wuhan, China.

Findings

A report to the local Center for Disease Control and Prevention, China, for the first hospitalized patient was sent after 6 and 20 days for H7N9 avian influenza and COVID-19, respectively. In contrast, the pathogen was identified faster in the case of COVID-19 than in the case of H7N9 avian influenza (12 days vs. 31 days). The government response regarding COVID-19 was 10 days later than that regarding avian influenza. The entire process of early surveillance and public health emergency disposal lasted 5 days longer in COVID-19 than in H7N9 avian influenza (46 days vs. 41 days).

Conclusions

The identification of the unknown pathogen improved in China between the outbreaks of avian influenza and COVID-19. The longer emergency disposal period in the case of COVID-19 could be attributed to the government’s slower response to the epidemic. Improving public health emergency management could lessen the adverse social effects of emerging infectious diseases and public health crisis in the future.
THE EMOTIONAL IMPACT OF THE ASRM GUIDELINES ON FERTILITY PATIENTS DURING THE COVID-19 PANDEMIC
Authors: Turocy Jenna , Robles Alex , Hercz Daniel , D’Alton Mary , Forman Eric J. , Williams Zev
Published: April 2020

Objective

To survey fertility patients’ agreement with ASRM recommendations during the COVID-19 pandemic and the emotional impact on them.

Design

An online survey was sent to current fertility patients

Setting

New York City academic fertility practice at the epicenter of the COVID-19 pandemic

Patient(s)

Fertility patients seen within the last year

Intervention(s)

None

Main Outcome Measures(s)

Patient agreement with the ASRM recommendations during the COVID-19 pandemic and the emotional impact rated on a Likert scale.

Result(s)

A total of 518 patients completed the survey for a response rate of 17%. Fifty percent of respondents had a cycle canceled due to the COVID-19 pandemic. Of those who had a cycle cancelled, 85% of respondents found it to be moderately to extremely upsetting with 22% rating it to be equivalent to the loss of a child. There was no difference on the emotional impact based on the type of cycle cancelled. Fifty-five percent of patients agreed that diagnostic procedures such as hysterosalpingograms should be cancelled while 36% of patients agreed all fertility cycles should be cancelled. Patients were slightly more likely to agree with the ASRM guidelines if they have an upcoming cycle cancelled (p = 0.041). Of all respondents 82% would have preferred to have the option to start a treatment cycle in consultation with their doctor.

Conclusion(s)

Given the severity of the COVID-19 pandemic, the physical, financial and emotional impact of this unprecedented threat cannot be underestimated in our fertility patients.
Short-term outcomes associated with temozolomide vs. PCV chemotherapy for 1p/19q-codeleted WHO grade III anaplastic oligodendrogliomas: a national evaluation
Authors: Lamba Nayan , McAvoy Malia , Kavouridis Vasileios K. , Smith Timothy R. , Touat Mehdi , Reardon David A. , Iorgulescu J. Bryan
Published: April 2020

PURPOSE

The optimal chemotherapy regimen between temozolomide (TMZ) and procarbazine, lomustine, and vincristine (PCV) remains uncertain for newly-diagnosed anaplastic oligodendroglioma (AO). We therefore addressed this question using a national database.

METHODS

Patients newly-diagnosed with 1p/19q-codeleted W.H.O. grade III AO between 2010-2016 were identified from the National Cancer Database. Predictors of receiving first-line single-agent TMZ vs. multi-agent PCV were assessed by multivariable logistic regression. Overall survival (OS) was estimated by Kaplan-Meier techniques and evaluated by multivariable Cox regression.

RESULTS

1,360 AO patients were identified: 74.5% (n=1,013) treated with TMZ, 9.6% (n=131) with PCV, and 15.9% (n=216) with no chemotherapy in the first-line setting. In multivariable logistic analysis, PCV utilization increased from 2010 to 2016 (OR=1.38/year, 95%CI: 1.22-1.56, p<0.001) and was less commonly utilized in privately insured patients (OR=0.38 vs. uninsured, 95%CI: 0.15-0.97, p=0.04). In survival analyses (33.1% reached endpoint), there was no difference in unadjusted OS between TMZ (5yr-OS 60.1%, 95%CI: 55.9-64.1) and PCV (5yr-OS 61.1%, 95%CI: 45.6-73.5; p=0.42). There remained no OS difference between TMZ and PCV in the 75.9% (n=1,032) of AO patients that also received radiotherapy (p=0.51), in the Cox regression analysis adjusted by age, extent of resection, and radiotherapy (TMZ vs. PCV HR=1.31, 95%CI: 0.83-2.08, p=0.24), and in subgroup analyses that incorporate KPS or MGMT status.

CONCLUSIONS

In a national database of AOs managed in the ‘real-world’ setting, there is no difference in the short-term mortality between first-line TMZ and PCV chemotherapy. These findings provide preliminary data while we await the long-term results from the CODEL trial.
Transmission Dynamics of COVID-19 and Impact on Public Health Policy
Authors: Shayak B , Sharma Mohit , Rand Richard H , Singh Awadhesh Kumar , Misra Anoop
Published: April 2020

In this work we construct a mathematical model for the transmission and spread of coronavirus disease 2019 or COVID-19. Our model features delay terms to account for (a) the time lapse or latency period between contracting the disease and displaying symptoms, and (b) the time lag in testing patients for the virus due to the limited numbers of testing facilities currently available. We find that the delay introduces a significant disparity between the actual and reported time-trajectories of cases in a particular region. Specifically, the reported case histories lag the actual histories by a few days. Hence, to minimize the spread of the disease, lockdowns and similarly drastic social isolation measures need to be imposed some time before the reported figures are approaching their peak values. We then account for the social reality that lockdowns can only be of a limited duration in view of practical considerations. We find that the most effective interval for imposing such a limited-time lockdown is one where the midpoint of the lockdown period coincides with the actual peak of the spread of the disease in the absence of the lockdown. We further show that the true effectivity of imposing a lockdown may be misrepresented and grossly underestimated by the reported case trajectories in the days following the action.
Sickness behaviour reduces network centrality in wild vampire bats
Authors: Ripperger Simon P. , Stockmaier Sebastian , Carter Gerald G.
Published: April 2020

Sickness behaviours, like lethargy, can slow the spread of pathogens across a social network. We conducted a field experiment to investigate how sickness behaviour reduces individual connectedness in a high-resolution dynamic social network. We captured adult female vampire bats (Desmodus rotundus) from a wild roost. To create ‘sick’ bats, we injected a random half of the bats (n=16) with the immune-challenging substance, lipopolysaccharide, and injected control bats with saline (n=15). Over the next three days, we used proximity sensors to continuously track their associations under natural conditions. The ‘sick’ bats showed a clear decrease in social connectedness (degree, strength, and eigenvector centrality). Bats in the control group encountered fewer ‘sick’ bats and also spent less time near them. These effects varied by time of day and declined over 48 hours. High-resolution proximity data allow researchers to define network connections based on how a pathogen spreads (e.g. the minimum contact time or distance for transmission). We therefore show how the estimate of the sickness effect changes as network ties are defined using varying distances and durations of association. Tracking the effects of sickness behaviour on high-resolution dynamic social networks can help create more sophisticated simulations of pathogen transmission through structured populations.
Recombination and purifying selection preserves covariant movements of mosaic SARS-CoV-2 protein S
Authors: Tagliamonte Massimiliano S. , Abid Nabil , Ostrov David A. , Chillemi Giovanni , Pond Sergei L. Kosakovsky , Salemi Marco , Mavian Carla
Published: April 2020

In depth evolutionary and structural analyses of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) isolated from bats, pangolins, and humans are necessary to assess the role of natural selection and recombination in the emergence of the current pandemic strain. The SARS-CoV-2 S glycoprotein unique features have been associated with efficient viral spread in the human population. Phylogeny-based and genetic algorithm methods clearly show that recombination events between viral progenitors infecting animal hosts led to a mosaic structure in the S gene. We identified recombination coldspots in the S glycoprotein and strong purifying selection. Moreover, although there is little evidence of diversifying positive selection during host-switching, structural analysis suggests that some of the residues emerged along the ancestral lineage of current pandemic strains may contribute to enhanced ability to infect human cells. Interestingly, recombination did not affect the long-range covariant movements of SARS-CoV-2 S glycoprotein monomer in pre-fusion conformation but, on the contrary, could contribute to the observed overall viral efficiency. Our dynamic simulations revealed that the movements between the host cell receptor binding domain (RBD) and the novel furin-like cleavage site are correlated. We identified threonine 333 (under purifying selection), at the beginning of the RBD, as the hinge of the opening/closing mechanism of the SARS-CoV-2 S glycoprotein monomer functional to hACE2 binding. Our findings support a scenario where ancestral recombination and fixation of amino acid residues in the RBD of the S glycoprotein generated a virus with unique features, capable of extremely efficient infection of the human host.
New Soluble Angiopoietin Analog of C4BP-ANG1 Prevents Pathological Vascular Leakage
Authors: Liu Pan , Ryczko Michael , Xie Xinfang , Taiyab Aftab , Sheardown Heather , Quaggin Susan E. , Jin Jing
Published: April 2020

Vascular leak is a key driver of organ injury in diseases such as Acute Respiratory Distress Syndrome caused by viruses, including COVID-19. Strategies that reduce enhanced permeability and vascular inflammation are promising therapeutic targets. Activation of the Angiopoietin-1 (Angpt1)-Tie2 tyrosine kinase signaling pathway is an important regulator of vascular quiescence. Here we describe the design and construction of a new soluble ANGPT1 mimetic that is a potent activator of endothelial Tie2 in vitro and in vivo. Using a chimeric fusion strategy, we replaced the extracellular matrix (ECM) binding and oligomerization domain of ANGPT1 with a heptameric scaffold derived from the C-terminus of serum complement protein C4-binding protein α (C4BP). We refer to this new fusion protein biologic as C4BP-ANG1, which forms a stable heptamer and induces TIE2 phosphorylation in cultured cells, and in the lung followingi.v.injection of mice. Injection of C4BP-ANG1 ameliorates VEGF- and lipopolysaccharide-induced vascular leakage, in keeping with the known functions of Angpt1-Tie2 in maintaining quiescent vascular stability, and therefore is a promising candidate treatment for inflammatory endothelial dysfunction.
Using a fragment-based approach to identify novel chemical scaffolds targeting the dihydrofolate reductase (DHFR) fromMycobacterium tuberculosis
Authors: Ribeiro João Augusto , Hammer Alexander , Libreros Zúñiga Gerardo Andrés , Chavez-Pacheco Sair Maximo , Tyrakis Petros , de Oliveira Gabriel Stephani , Kirkman Timothy , Bakali Jamal El , Rocco Silvana Aparecida , Sforça Mauricio Luís , Parise-Filho Roberto , Coyne Anthony G. , Blundell Tom L , Abell Chris , Bertacine Dias Marcio Vinicius
Published: April 2020

Dihydrofolate reductase (DHFR), a key enzyme involved in folate metabolism, is a widely explored target in the treatment of cancer, immune diseases, bacteria and protozoa infections. Although several antifolates have proved successful in the treatment of infectious diseases, none have been developed to combat tuberculosis, despite the essentiality ofM. tuberculosisDHFR (MtDHFR). Herein, we describe an integrated fragment-based drug discovery approach to target MtDHFR that has identified hits with scaffolds not yet explored in any previous drug design campaign for this enzyme. The application of a SAR by catalog strategy of an in house library for one of the identified fragments has led to a series of molecules that bind MtDHFR with low micromolar affinities. Crystal structures of MtDHFR in complex with compounds of this series demonstrated a novel binding mode that differs from other DHFR antifolates, thus opening perspectives for the development of novel and relevant MtDHFR inhibitors.
Integrative Frontal-Parietal Dynamics Supporting Cognitive Control
Authors: Nee Derek Evan
Published: April 2020

Coordinating among the demands of the external environment and internal plans requires cognitive control supported by a fronto-parietal control network (FPCN). Evidence suggests that multiple control systems span the FPCN whose operations are poorly understood. Previously (Nee and D’Esposito, 2016; 2017), we detailed frontal dynamics that support control processing, but left open their role in broader cortical function. Here, I show that the FPCN consists of an external/present-oriented to internal/future-oriented cortical gradient extending outwardly from sensory-motor cortices. Areas at the ends of this gradient act in a segregative manner, exciting areas at the same level, but suppressing areas at different levels. By contrast, areas in the middle of the gradient excite areas at all levels, promoting integration of control processing. Individual differences in integrative dynamics predict higher-level cognitive ability and amenability to neuromodulation. These data suggest that an intermediary zone within the FPCN underlies integrative processing that supports cognitive control.

Impact Statement

This study shows that intermediary areas within the FPCN are critical for integrating control processing, cognitive ability, and amenability to neuromodulation.
PhyDOSE: Design of Follow-up Single-cell Sequencing Experiments of Tumors
Authors: Weber Leah , Aguse Nuraini , Chia Nicholas , El-Kebir Mohammed
Published: April 2020

The combination of bulk and single-cell DNA sequencing data of the same tumor enables the inference of high-fidelity phylogenies that form the input to many important downstream analyses in cancer genomics. While many studies simultaneously perform bulk and single-cell sequencing, some studies have analyzed initial bulk data to identify which mutations to target in a follow-up single-cell sequencing experiment, thereby decreasing cost. Bulk data provide an additional untapped source of valuable information, composed of candidate phylogenies and associated clonal prevalence. Here, we introduce PhyDOSE, a method that uses this information to strategically optimize the design of follow-up single cell experiments. Underpinning our method is the observation that only a small number of clones uniquely distinguish one candidate tree from all other trees. We incorporate distinguishing features into a probabilistic model that infers the number of cells to sequence so as to confidently reconstruct the phylogeny of the tumor. We validate PhyDOSE using simulations and a retrospective analysis of a leukemia patient, concluding that PhyDOSE’s computed number of cells resolves tree ambiguity even in the presence of typical single-cell sequencing errors. We also conduct a retrospective analysis on an acute myeloid leukemia cohort, demonstrating the potential to achieve similar results with a significant reduction in the number of cells sequenced. In a prospective analysis, we demonstrate that only a small number of cells suffice to disambiguate the solution space of trees in a recent lung cancer cohort. In summary, PhyDOSE proposes cost-efficient single-cell sequencing experiments that yield high-fidelity phylogenies, which will improve downstream analyses aimed at deepening our understanding of cancer biology.

Author summary

Cancer development in a patient can be explained using a phylogeny — a tree that describes the evolutionary history of a tumor and has therapeutic implications. A tumor phylogeny is constructed from sequencing data, commonly obtained using either bulk or single-cell DNA sequencing technology. The accuracy of tumor phylogeny inference increases when both types of data are used, but single-cell sequencing may become prohibitively costly with increasing number of cells. Here, we propose a method that uses bulk sequencing data to guide the design of a follow-up single-cell sequencing experiment. Our results suggest that PhyDOSE provides a significant decrease in the number of cells to sequence compared to the number of cells sequenced in existing studies. The ability to make informed decisions based on prior data can help reduce the cost of follow-up single cell sequencing experiments of tumors, improving accuracy of tumor phylogeny inference and ultimately getting us closer to understanding and treating cancer.
Directed manipulation of membrane proteins by fluorescent magnetic nanoparticles
Authors: Li Jia Hui , Santos-Otte Paula , Au Braedyn , Rentsch Jakob , Block Stephan , Ewers Helge
Published: April 2020

The plasma membrane is the interface through which cells interact with their environment. Membrane proteins are embedded in the lipid bilayer of the plasma membrane and their function in this context is often linked to their specific location and dynamics within the membrane. However, few methods are available for nanoscale manipulation of membrane protein location at the single molecule level. Here, we report the use of fluorescent magnetic nanoparticles (FMNPs) to track membrane molecules and to manipulate their movement. FMNPs allow single-particle tracking (SPT) at 10 nm spatial and 5 ms temporal resolution, and using a magnetic needle, we pull membrane components laterally through the membrane with femtonewton-range forces. In this way, we successfully dragged lipid-anchored and transmembrane proteins over the surface of living cells. Doing so, we detected submembrane barriers and in combination with super-resolution microscopy could localize these barriers to the actin cytoskeleton. We present here a versatile approach to probe membrane processes in live cells via the magnetic control of membrane protein motion.
The target landscape of N4-hydroxycytidine based on its chemical neighborhood
Authors: Mestres Jordi
Published: April 2020

N4-hydroxycytidine (NHC) has been recently reported to have promising antiviral activity against SARS-CoV-2. To join worldwide efforts in identifying potential drug targets against this pandemic, the target landscape of NHC was defined by extracting all known targets of its chemical neighborhood, including drugs, analogues, and metabolites, and by performing target predictions from two independent platforms, following the recent Public Health Assessment via Structural Evaluation (PHASE) protocol. The analysis provides a list of over 30 protein targets that could be useful in future design activities of new COVID-19 antivirals. The relevance for existing drugs within the same chemical space, such as remdesivir, is also discussed.