bluuebunny/crossref_metadata_2025 huggingface dataset:
Nebulized Poractant Alfa Reduces the Risk of Respiratory Failure at 72 Hours in Spontaneously Breathing Surfactant-Deficient Newborn Piglets
Authors: Rey-Santano Carmen , Mielgo Victoria E. , Gomez-Solaetxe Miguel Angel , Bianco Federico , Salomone Fabrizio , Loureiro Begoña
Published: April 2020

Objectives:

We have setup for the first time a long-term (72 hr) respiratory distress syndrome model in spontaneously breathing surfactant-deficient newborn piglets to investigate the continuous positive airway pressure failure rate with nebulized poractant alfa compared with that with the intubation surfactant extubation technique or continuous positive airway pressure only.

Design:

Prospective randomized animal study.

Setting:

Biocruces-Bizkaia Health Research Institute Animal Facility.

Subjects-Interventions:

Eighteen newborn piglets (n = 6/group) with surfactant-deficient respiratory distress syndrome were randomized to three continuous positive airway pressure–ventilated groups: 1) nebulized surfactant (poractant alfa 400 mg/kg) via a customized investigational eFlow-Neos vibrating membrane nebulizer system, 2) bolus administration using the Intubation Surfactant Extubation method (200 mg/kg), or 3) continuous positive airway pressure alone.

Measurements and Main Results:

Pulmonary and hemodynamic variables were assessed at 6-hour intervals for 72 hours. Lung and brain histological analyses were performed. After bronchoalveolar lavages, piglets developed respiratory distress syndrome. Over the follow-up, both surfactant-treated groups had significantly better pulmonary outcomes than the continuous positive airway pressure alone group. Furthermore, unlike in the continuous positive airway pressure group, there were no cases of respiratory failure in either of the surfactant-treated groups.

Conclusions:

In newborn piglets with respiratory distress syndrome, the nebulization of 400 mg/kg of poractant alfa using a customized investigational eFlow-Neos nebulizer was found to be safe and effective in reducing the risk of respiratory failure in the 72 hours after treatment.
Association between plasma prostaglandin E2 level and colorectal cancer
Authors: Wang Fan , Wang Maoqing , Yin Huihui , Long Zhiping , Zhu Lin , Yu Huan , Sun Hongru , Bi Haoran , Li Shuying , Zhao Yashuang , Dong Xinshu , Zhou Junde
Published: April 2020

Evidences for the personalized use of nonsteroidal anti-inflammatory drugs (NSAIDs) in colorectal cancer (CRC) prevention and treatment that include consideration of prostaglandin E2 levels are necessary. This study was designed as a case-control study including 60 CRC patients and 120 cancer-free controls. A sensitive empirical method, precolumn derivatization HPLC, was used to determine plasma PGE2 levels. The TaqMan SNP Genotyping Assay was used for the genotyping of prostaglandin-endoperoxide synthase 2 (PTGS2) polymorphisms. Multivariate logistic regression analysis suggested that 1 log10(PGE2) increase would result in a 3.64-fold increase in the risk of CRC. Moreover, subjects with log10(PGE2) level in the 75th percentile had a significantly higher risk of CRC than those with log10(PGE2) levels in the 25th percentile [odds ratio (OR), 3.50; 95% confidence interval (CI), 1.35−9.05]. This association was more evident after adjustment for history of NSAIDs use (OR, 3.85; 95% CI, 1.46−10.16). Preliminarily, 260.02 and 414.95 pg/ml might be proposed as the preventive and warning cutoff values of plasma PGE2 for CRC. The preferred NSAIDs dose for patients with the AG+GG (rs689466) and CC+CT (rs5275) genotypes should be higher than that of patients carrying AA or TT genotypes, despite the presence of equal plasma PGE2 levels. We show for the first time that the plasma PGE2 level is associated with the risk of CRC. We provide a preliminary suggestion for NSAIDs doses adjustment according to PTGS2 genotypes after consideration of plasma PGE2 levels.
Knowledge, awareness, and practices of cervical cancer, its risk factors, screening, and prevention among women in Karachi, Pakistan
Authors: Hirani Samina , Khan Sarah , Akram Sidra , Virji Safna Naozer , Shaikh Preet Ayoub , Naeem Ehsun , Chaudhry Rayaan Asad , Khalid Ahmed Bilal , Khan Jalal Ud Din , Qasim Muhammad Suhaib , Jehan Imtiaz
Published: April 2020

Background

Cervical cancer has a high mortality rate worldwide; in Pakistan it kills more than 7000 women every year. Prevention is possible through vaccination against human papilloma virus, the causative agent of cervical cancer, or by screening for premalignant lesions through routine Pap smear tests. We have studied the knowledge and practices regarding cervical cancer, its risk factors, screening and prevention and the role of human papilloma virus vaccination and Pap smear testing, among young women of Karachi.

Methods

Information was gathered using a modified version of Cervical Cancer Awareness Measure Toolkit version 2.1 from 384 women aged 15 to 50 with no medical background attending outpatient clinics of AKUH, Karachi. Data entry was done through EpiData and analysis was done using SPSS version 22.0.

Results

Our respondents’ mean age was 30 (±7.6) years. Out of the 61.2% of women who had heard about cervical cancer, 47.0% had heard about Pap smear test and among them, 73% had gotten a Pap test. A total of 25.5% of women out of the 61.2%, knew that a vaccine existed for prevention and out of them only 9.8% had vaccinated against human papilloma virus.

Conclusion

Majority of women in our study belonged to a higher socioeconomic class and were mostly educated but their knowledge and practices regarding prevention and screening of cervical cancer were poor. This reflects that the knowledge levels as a whole would be considerably lower in the city’s general population.
Association between dietary sodium intake and blood pressure variability in Chinese patients with hypertension
Authors: Wang Chi , Liu Tong-Bo , Mu Lei , Wang Miao , Li Yao , Yao Si-Yu , Zhao Mao-Xiang , Xue Hao
Published: April 2020

Background

The association between dietary sodium intake and blood pressure variability (BPV) in hypertensive patients remains unclear. The objective of this study was to demonstrate whether dietary sodium intake is a predictor of elevated BPV in Chinese patients with hypertension.

Methods

A total of 235 patients with essential hypertension were enrolled in the Department of Cardiology, Chinese People's Liberation Army (PLA) General Hospital in 2018 to 2019, all of whom underwent 24-h ambulatory blood pressure monitoring. BPV was calculated as the standard deviation (SD), coefficient of variation (CV), variation independent of mean (VIM) of blood pressure measurements, respectively, and divided into diurnal systolic BPV (SBPV), diurnal diastolic BPV (DBPV), nocturnal SBPV, and nocturnal DBPV. 24-h urine samples were collected to measure 24-h urine sodium excretion, which represents dietary sodium intake. The relationship between dietary sodium intake and BPV was analyzed by using Spearman correlations and multiple linear regression analysis.

Results

Nocturnal SBPV-SD, CV, VIM, and nocturnal DBPV-SD in the high urine sodium excretion group were significantly higher than those in the medium and low urine sodium excretion groups, whereas diurnal SBPV-SD, CV, VIM, diurnal DBPV-SD, CV, VIM, and nocturnal DBPV-CV, VIM were not. Using the Spearman correlation analysis, we found a linear correlation between 24-h urine sodium excretion and nocturnal SBPV-SD, CV, VIM (SD, r = 0.22, P = 0.001; CV, r = 0.17, P = 0.009; VIM, r = 0.16, P = 0.020), nocturnal DBPV-SD (r = 0.21, P = 0.001), respectively. After further adjusting for confounding factors by multiple linear regression, the positive correlations remained between 24-h urine sodium excretion and nocturnal SBPV-SD, CV, VIM (SD, β = 0.224, P < 0.001; CV, β = 0.211, P = 0.001; VIM, β = 0.213, P = 0.001), nocturnal DBPV (SD, β = 0.215, P = 0.001), respectively.

Conclusions

Dietary sodium intake is associated with nocturnal SBPV in Chinese patients with hypertension.
Effect of High Homocysteine Level on the Severity of Coronary Heart Disease and Prognosis After Stent Implantation
Authors: Li Shanshan , Sun Liping , Qi Liqun , Jia Yongsheng , Cui Zhuo , Wang Zhongsuo , Li Fengshuai , Zhao Xiaofeng
Published: April 2020

Objectives:

To determine the effect of high homocysteine (HCY) levels on the severity of coronary artery disease and prognosis after stent implantation.

Methods:

A prospective study was conducted on 667 patients with coronary heart disease who underwent drug-eluting stent implantation for the first time at the Department of Cardiology, Huludao Central Hospital, from January 2015 to December 2017. The patients were divided into the control and hyperhomocysteinemia (H-HCY) groups based on the serum HCY levels. The demographic and clinical characteristics of both groups were compared. In addition, the patients were followed up for 1 year to compare the incidence of major adverse cardiovascular and cerebrovascular events (MACCE). Multivariate logistic regression was used to determine the correlation between serum HCY levels and MACCE.

Results:

Compared with the control group, the stenosis degree was significantly higher among patients in the H-Hcy group, as indicated by more coronary artery lesions (P < 0.001) and higher SYNTAX scores (P < 0.001). After 1 year of follow-up, the incidence of MACCE was also significantly higher in the H-HCY versus control group (9.5% vs. 15.1%; P = 0.042). Furthermore, age, history of diabetes, discontinuation of antiplatelet aggregation drugs, and HCY levels were independent predictors of MACCE.

Conclusions:

High HCY level is associated with severe coronary artery disease in patients with coronary heart disease and is an independent predictor of MACCE after stent implantation.
Cardiovascular Pharmacology in the Time of COVID-19: A Focus on Angiotensin-Converting Enzyme 2
Authors: Buckley Leo F. , Cheng Judy W. M. , Desai Akshay
Published: April 2020

Coronavirus disease-2019 (COVID-19) has emerged as a pandemic affecting millions of adults. Severe acute respiratory syndrome coronavirus-2019 (SARS-CoV-2), the causative virus of COVID-19, infects host cells through angiotensin-converting enzyme 2 (ACE2). Preclinical models suggest that ACE2 upregulation confers protective effects in acute lung injury. In addition, renin–angiotensin aldosterone system inhibitors reduce adverse atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease outcomes, but may increase ACE2 levels. We review current knowledge of the role of ACE2 in cardiovascular physiology and SARS-CoV-2 virology, as well as clinical data to inform the management of patients with or at risk for COVID-19 who require renin–angiotensin–aldosterone system inhibitor therapy.
Activation of sphingosine-1-phosphate receptor subtype 1 in the central nervous system contributes to morphine-induced hyperalgesia and antinociceptive tolerance in rodents
Authors: Doyle Timothy M. , Janes Kali , Chen Zhoumou , Grace Peter M. , Esposito Emanuela , Cuzzocrea Salvatore , Largent-Milnes Tally M. , Neumann William L. , Watkins Linda R. , Spiegel Sarah , Vanderah Todd W. , Salvemini Daniela
Published: April 2020

Morphine-induced alterations in sphingolipid metabolism in the spinal cord and increased formation of the bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P) have been implicated in the development of morphine-induced hyperalgesia (OIH; increased pain sensitivity) and antinociceptive tolerance. These adverse effects hamper opioid use for treating chronic pain and contribute to dependence and abuse. S1P produces distinct effects through 5 G-protein-coupled receptors (S1PR1-5) and several intracellular targets. How S1P exerts its effects in response to morphine remains unknown. Here, we report that S1P contributes to the development of morphine-induced hyperalgesia and tolerance through S1P receptor subtype 1 (S1PR1) signaling in uninjured male and female rodents, which can be blocked by targeting S1PR1 with S1PR1 antagonists or RNA silencing. In mouse neuropathic pain models, S1PR1 antagonists blocked the development of tolerance to the antiallodynic effects of morphine without altering morphine pharmacokinetics and prevented prolonged morphine-induced neuropathic pain. Targeting S1PR1 reduced morphine-induced neuroinflammatory events in the dorsal horn of the spinal cord: increased glial marker expression, mitogen-activated protein kinase p38 and nuclear factor κB activation, and increased inflammatory cytokine expression, such as interleukin-1β, a cytokine central in the modulation of opioid-induced neural plasticity. Our results identify S1PR1 as a critical path for S1P signaling in response to sustained morphine and reveal downstream neuroinflammatory pathways impacted by S1PR1 activation. Our data support investigating S1PR1 antagonists as a clinical approach to mitigate opioid-induced adverse effects and repurposing the functional S1PR1 antagonist FTY720, which is FDA-approved for multiple sclerosis, as an opioid adjunct.
Improving Communication in Outpatient Consultations in People With Cirrhosis
Authors: Low Joseph T.S. , Davis Sarah , Greenslade Lynda , Carroll Cathy , Craig Rachel , Wilson Jo , Clancy Jennifer-Louise , Marshall Aileen , Thorburn Douglas , Stone Patrick
Published: April 2020

Background and Aims:

Liver health professionals have difficulty discussing liver cirrhosis and its prognosis with patients and families. Question Prompt Lists (QPLs), which are evidence-based lists of “recommended questions,” may improve communication but need to be designed specifically for the target population. This study aimed to develop and pilot a QPL for patients with cirrhosis.

Methods:

A mixed-methods design in 3 phases. In phase 1 (item generation), potential questions for inclusion in the QPL were identified from 3 sources—a scoping literature review; an online survey; and interviews with patients, family members, and health professionals. In phase 2 (QPL construction), a multidisciplinary expert panel finalized the selection of questions and the format of the QPL. In phase 3 (pilot study), the QPL was assessed for acceptability and feasibility in a hepatology outpatient clinic population.

Results:

From 258 topics initially identified, 30 questions were included in the first draft of the QPL. After review by a multidisciplinary expert panel including patients, the QPL was reduced to 22 questions. In the pilot study, 133/215 eligible patients consented to participate, although only 67/133 used the QPL in their clinic appointment. Among those who used the QPL, all questions were asked at least once. The most commonly asked question related to life expectancy. Most participants expressed support for the content of the QPL.

Conclusions:

A QPL, suitable for use in patients with liver cirrhosis attending hepatology outpatient clinics, has been developed and piloted. The QPL seems to be feasible to use and acceptable to patients and clinicians. Further work is needed to evaluate its effectiveness and to determine optimum delivery in clinical practice.
Nonbiopsy Approach for Celiac Disease Is Accurate When Using Exact Duodenal Histomorphometry
Authors: Popp Alina , Arvola Taina , Taavela Juha , Kivelä Laura , Ene Adina , Laurila Kaija , Saavalainen Päivi , Mäki Markku , Kurppa Kalle
Published: April 2020

Goals:

To test the accuracy of serology-based criteria for diagnosing celiac disease utilizing quantitative histomorphometry.

Background:

The revised European pediatric guidelines allow noninvasive celiac disease diagnosis for a subgroup of children. However, in some of the studies on this issue, the positive predictive value (PPV) of serology has remained suboptimal, possibly because of challenges of histopathology as the reference standard.

Study:

Prospectively enrolled children with transglutaminase 2 antibodies (TGA) above the upper limit of normal (ULN) underwent blood sampling and duodenal biopsy in Finland and Romania. Those with TGA ≥10× ULN, positive endomysium antibodies (EmA), and disease-associated genetics were considered to fulfill triple criteria for celiac disease. Initial histopathologic analysis was conducted using grouped classification, whereupon centralized morphometry was performed.

Results:

Altogether 88 (54%) children were triple positive. In local evaluation, 99% of triple-positive children and 73% of children with TGA <10× ULN had celiac disease. These figures increased to 100% and 85% after more precise morphometric analysis. Triple-positive children had more anemia and higher median EmA and liver enzyme values than those with TGA<10× ULN; the groups were comparable in other clinical features and laboratory parameters.

Conclusions:

When applied as recommended, the nonbiopsy strategy had already yielded excellent PPV regardless of the site of diagnosis or clinical presentation in the local analysis. PPV further increased to 100% with standardized duodenal morphometry.
Psychological Distress During Pregnancy
Authors: Spedding Maxine F. , Sorsdahl Katherine , Parry Charles D.H. , Mathews Catherine , Stein Dan J. , Williams Petal Petersen
Published: April 2020

The prevalence and risk factors associated with peripartum psychological distress—a unifying factor among common mental disorders (CMDs)—are not widely understood in underresourced settings. Cross-sectional data were collected from 664 pregnant women who reported for antenatal care at any of one of the 11 midwife and obstetrics units in Cape Town, South Africa. The prevalence of prepartum psychological distress was 38.6%. Associated factors included low socioeconomic status as measured by asset ownership (odds ratio [OR], 1.45; 95% CI, 1.24–1.68), recent physical abuse and/or rape (OR, 1.94; 95% CI, 1.57–2.40), complications during a previous birth (OR, 1.18; 95% CI, 1.01–1.38), and having given birth before (OR, 1.61; 95% CI, 1.21–2.14). The high prevalence of psychological distress is consistent with those found in other South African studies of peripartum CMDs. If effective context-specific interventions are to be appropriately designed, closer investigation of a broader symptomology associated with peripartum CMDs in these settings is warranted.
Evaluation of Intrinsic Hand Musculature Reinnervation following Supercharge End-to-Side Anterior Interosseous–to–Ulnar Motor Nerve Transfer
Authors: Head Linden K. , Zhang Zach Z. , Hicks Katie , Wolff Gerald , Boyd Kirsty U.
Published: April 2020

Supercharge end-to-side anterior interosseous–to–ulnar motor nerve transfer is commonly performed in the authors’ institution to augment intrinsic hand function. Following observations of recovery patterns, the authors hypothesized that despite its more distal innervation, the first dorsal interosseous muscle recovers to a greater extent than the abductor digiti minimi muscle. The objective of this work was to evaluate the clinical and electrodiagnostic pattern of reinnervation of intrinsic hand musculature following supercharge end-to-side anterior interosseous–to–ulnar motor nerve transfer. A retrospective cohort of prospectively collected data included all patients who underwent a supercharge end-to-side anterior interosseous–to–ulnar motor nerve transfer. Two independent reviewers performed data collection. Reinnervation was assessed with two primary outcome measures: (1) clinically, with serial Medical Research Council strength assessments; and (2) electrodiagnostically, with serial motor amplitude measurements. Statistical analysis was performed using nonparametric statistics. Seventeen patients (65 percent male; mean age, 56.9 ± 13.3 years) were included with a mean follow-up of 16.7 ± 8.5 months. Preoperatively, all patients demonstrated clinically significant weakness and electrodiagnostic evidence of denervation. Postoperatively, strength and motor amplitude increased significantly for both the first dorsal interosseous muscle (p = 0.002 and p = 0.016) and the abductor digiti minimi muscle (p = 0.044 and p = 0.015). Despite comparable preoperative strength (p = 0.098), postoperatively, the first dorsal interosseous muscle achieved significantly greater strength when compared to the abductor digiti minimi muscle (p = 0.023). Following supercharge end-to-side anterior interosseous–to–ulnar motor nerve transfer, recovery of intrinsic muscle function differs between the abductor digiti minimi and the first dorsal interosseous muscles, with better recovery observed in the more distally innervated first dorsal interosseous muscle. Further work to elucidate the underlying physiologic and anatomical basis for this discrepancy is indicated.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Observable Variations in Human Sex Ratio at Birth
Authors: Long Yanan , Chen Qi , Larsson Henrik , Rzhetsky Andrey
Published: April 2020

The human sex ratio at birth (SRB), defined as the ratio between the number of newborn boys to the total number of newborns, is typically slightly greater than 1/2 (more boys than girls) and tends to vary across different geographical regions and time periods. In this large-scale study, we sought to validate previously-reported associations and test new hypotheses using statistical analysis of two very large datasets incorporating electronic medical records (EMRs). One of the datasets represents over half (∼150 million) of the US population for over 8 years (IBM Watson Health MarketScan insurance claims) while another covers the entire Swedish population (∼9 million) for over 30 years (the Swedish National Patient Register). After testing more than 100 hypotheses, we showed that neither dataset supported models in which the SRB changed seasonally or in response to variations in ambient temperature. However, increased levels of a diverse array of air and water pollutants, were associated with lower SRBs, including increased levels of industrial and agricultural activity, which served as proxies for water pollution. Moreover, some exogenous factors generally considered to be environmental toxins turned out to induce higher SRBs. Finally, we identified new factors with signals for either higher or lower SRBs. In all cases, the effect sizes were modest but highly statistically significant owing to the large sizes of the two datasets. We suggest that while it was unlikely that the associations have arisen from sex-specific selection mechanisms, they are still useful for the purpose of public health surveillance if they can be corroborated by empirical evidences.

Author Summary

The human sex ratio at birth (SRB), usually slightly greater than 1/2, have been reported to vary in response to a wide array of exogenous factors. In the literature, many such factors have been posited to be associated with higher or lower SRBs, but the studies conducted so far have focused on no more than a few factors at a time and used far smaller datasets, thus prone to generating spurious correlations. We performed a series of statistical tests on 2 large, country-wide health datasets representing the United States and Sweden to investigate associations between putative exogenous factors and the SRB, and were able to validate a set of previously-reported associations while also discovering new signals. We propose to interpret these results simply as public health indicators awaiting further empirical confirmation rather than as implicated in (adaptive) sexual selection mechanisms.
When Resources Are Scarce - Feasibility of Emergency Ventilation of Two Patients With One Ventilator
Authors: Reinacher Peter C. , Schlaepfer Thomas E. , Schick Martin A. , Beck Jürgen , Bürkle Hartmut , Schumann Stefan
Published: April 2020

A potential shortage of intensive care ventilators has led to the idea to ventilate more than one patient with a single ventilator. Besides other problems, this is associated with the lack of knowledge concerning distribution of tidal volume and the patients’ individual respiratory system mechanics.

In this study we used two simple hand-manufactured adaptors to connect physical models of two adult respiratory systems to one ventilator. The artificial lungs were ventilated in the pressure-controlled mode and we investigated if disconnecting one lung from the ventilation circuit for several breaths would allow to determine reliably the other lung’s tidal volume and compliance.

Compliances and volumes were measured both with the ventilator and external sensors corresponded well. However, tidal volumes measured via the ventilator were smaller compared to the tidal volumes measured via the external sensors with an absolute error of 5.3 ± 2.5%. The tidal volumes of the individual artificial lungs were distributed in proportion to the compliances and did not differ relevantly when both artificial lungs were connected to when one was disconnected.

We conclude that in case of emergency, ventilation of two patients with one ventilator requires two simple hand-crafted tubes as adaptors and available standard breathing circuit components. In such a setting, respiratory system mechanics and tidal volume of each individual patient can be reliably measured during short term clamping of the tracheal tube of the respective other patient.
Household Secondary Attack Rate of COVID-19 and Associated Determinants
Authors: Jing Qin-Long , Liu Ming-Jin , Yuan Jun , Zhang Zhou-Bin , Zhang An-Ran , Dean Natalie E. , Luo Lei , Ma Mengmeng , Longini Ira , Kenah Eben , Lu Ying , Ma Yu , Jalali Neda , Fang Li-Qun , Yang Zhi-Cong , Yang Yang
Published: April 2020

Background

As of April 2, 2020, the global reported number of COVID-19 cases has crossed over 1 million with more than 55,000 deaths. The household transmissibility of SARS-CoV-2, the causative pathogen, remains elusive.

Methods

Based on a comprehensive contact-tracing dataset from Guangzhou, we estimated both the population-level effective reproductive number and individual-level secondary attack rate (SAR) in the household setting. We assessed age effects on transmissibility and the infectivity of COVID-19 cases during their incubation period.

Results

A total of 195 unrelated clusters with 212 primary cases, 137 nonprimary (secondary or tertiary) cases and 1938 uninfected close contacts were traced. We estimated the household SAR to be 13.8% (95% CI: 11.1-17.0%) if household contacts are defined as all close relatives and 19.3% (95% CI: 15.5-23.9%) if household contacts only include those at the same residential address as the cases, assuming a mean incubation period of 4 days and a maximum infectious period of 13 days. The odds of infection among children (<20 years old) was only 0.26 (95% CI: 0.13-0.54) times of that among the elderly (≥60 years old). There was no gender difference in the risk of infection. COVID-19 cases were at least as infectious during their incubation period as during their illness. On average, a COVID-19 case infected 0.48 (95% CI: 0.39-0.58) close contacts. Had isolation not been implemented, this number increases to 0.62 (95% CI: 0.51-0.75). The effective reproductive number in Guangzhou dropped from above 1 to below 0.5 in about 1 week.

Conclusion

SARS-CoV-2 is more transmissible in households than SARS-CoV and MERS-CoV, and the elderly ≥60 years old are the most vulnerable to household transmission. Case finding and isolation alone may be inadequate to contain the pandemic and need to be used in conjunction with heightened restriction of human movement as implemented in Guangzhou.
Assessment of N95 respirator decontamination and re-use for SARS-CoV-2
Authors: Fischer Robert J. , Morris Dylan H. , van Doremalen Neeltje , Sarchette Shanda , Matson M. Jeremiah , Bushmaker Trenton , Yinda Claude Kwe , Seifert Stephanie N. , Gamble Amandine , Williamson Brandi N. , Judson Seth D. , de Wit Emmie , Lloyd-Smith James O. , Munster Vincent J.
Published: April 2020

The unprecedented pandemic of SARS-CoV-2 has created worldwide shortages of personal protective equipment, in particular respiratory protection such as N95 respirators. SARS-CoV-2 transmission is frequently occurring in hospital settings, with numerous reported cases of nosocomial transmission highlighting the vulnerability of healthcare workers. In general, N95 respirators are designed for single use prior to disposal. Here, we have analyzed four readily available and often used decontamination methods: UV, 70% ethanol, 70C heat and vaporized hydrogen peroxide for inactivation of SARS-CoV-2 on N95 respirators. Equally important we assessed the function of the N95 respirators after multiple wear and decontamination sessions.
Detection of spreader nodes and ranking of interacting edges in Human-SARS-CoV protein interaction network
Authors: Saha Sovan , Chatterjee Piyali , Basu Subhadip , Nasipuri Mita
Published: April 2020

The entire world has recently witnessed the commencement of coronavirus disease 19 (COVID-19) pandemic. It is caused by a novel coronavirus (n-CoV) generally distinguished as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). It has exploited human vulnerabilities to coronavirus outbreak. SARS-CoV-2 promotes fatal chronic respiratory disease followed by multiple organ failure which ultimately puts an end to human life. No proven vaccine for n-CoV is available till date in spite of significant research efforts worldwide. International Committee on Taxonomy of Viruses (ICTV) has reached to a consensus that the virus SARS-CoV-2 is highly genetically similar to Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) outbreak of 2003. It has been reported that SARS-CoV has ∼89% genetic similarities with n-CoV. With this hypothesis, the current work focuses on the identification of spreader nodes in SARS-CoV protein interaction network. Various network characteristics like edge ratio, neighborhood density and node weight have been explored for defining a new feature spreadability index by virtue of which spreader nodes and edges are identified. The selected top spreader nodes having high spreadability index have been also validated by Susceptible-Infected-Susceptible (SIS) disease model. Initially, the proposed method is applied on a synthetic protein interaction network followed by SARS-CoV-human protein interaction network. Hence, key spreader nodes and edges (ranked edges) are unmasked in SARS-CoV proteins and its connected level 1 and level 2 human proteins. The new network attribute spreadability index along with generated SIS values of selected top spreader nodes when compared with the other network centrality based methodologies like Degree centrality (DC), Closeness centrality (CC), Local average centrality (LAC) and Betweeness centrality (BC) is found to perform relatively better than theexisting-state-of-art.
Challenges in control of COVID-19: short doubling times and long delay to effect of interventions
Authors: Pellis Lorenzo , Scarabel Francesca , Stage Helena B. , Overton Christopher E. , Chappell Lauren H. K. , Lythgoe Katrina A. , Fearon Elizabeth , Bennett Emma , Curran-Sebastian Jacob , Das Rajenki , Fyles Martyn , Lewkowicz Hugo , Pang Xiaoxi , Vekaria Bindu , Webb Luke , House Thomas A. , Hall Ian
Published: April 2020

The unconstrained growth rate of COVID-19 is crucial for measuring the impact of interventions, assessing worst-case scenarios, and calibrating mathematical models for policy planning. However, robust estimates are limited, with scientific focus on the time-insensitive basic reproduction number R0. Using multiple countries, data streams and methods, we consistently estimate that European COVID-19 cases doubled every three days when unconstrained, with the impact of physical distancing interventions typically seen about nine days after implementation, during which time cases grew eight-fold. The combination of fast growth and long detection delays explains the struggle in countries’ response better than large values of R0 alone, and warns against relaxing physical distancing measures too quickly. Testing and tracing are fundamental in shortening such delays, thus preventing cases from escalating unnoticed.
Incidence, clinical outcomes, and transmission dynamics of hospitalized 2019 coronavirus disease among 9,596,321 individuals residing in California and Washington, United States: a prospective cohort study
Authors: Lewnard Joseph A. , Liu Vincent X. , Jackson Michael L. , Schmidt Mark A. , Jewell Britta L. , Flores Jean P. , Jentz Chris , Northrup Graham R. , Mahmud Ayesha , Reingold Arthur L. , Petersen Maya , Jewell Nicholas P. , Young Scott , Bellows Jim
Published: April 2020

Background

The United States is now the country reporting the highest number of 2019 coronavirus disease (COVID-19) cases and deaths. However, little is known about the epidemiology and burden of severe COVID-19 to inform planning within healthcare systems and modeling of intervention impact.

Methods

We assessed incidence, duration of hospitalization, and clinical outcomes of acute COVID-19 inpatient admissions in a prospectively-followed cohort of 9,596,321 individuals enrolled in comprehensive, integrated healthcare delivery plans from Kaiser Permanente in California and Washington state. We also estimated the effective reproductive number (RE) describing transmission in the study populations.

Results

Data covered 1277 hospitalized patients with laboratory- or clinically-confirmed COVID-19 diagnosis by April 9, 2020. Cumulative incidence of first COVID-19 acute inpatient admission was 10.6-12.4 per 100,000 cohort members across the study regions. Mean censoring-adjusted duration of hospitalization was 10.7 days (2.5-97.5%iles: 0.8-30.1) among survivors and 13.7 days (2.5-97.5%iles: 1.7-34.6) among non-survivors. Among all hospitalized confirmed cases, censoring-adjusted probabilities of ICU admission and mortality were 41.9% (95% confidence interval: 34.1-51.4%) and 17.8% (14.3-22.2%), respectively, and higher among men than women. We estimated RE was 1.43 (1.17-1.73), 2.09 (1.63-2.69), and 1.47 (0.07-2.59) in Northern California, Southern California, and Washington, respectively, for infections acquired March 1, 2020. RE declined to 0.98 (0.76-1.27), 0.89 (0.74-1.06), and 0.92 (0.05-1.55) respectively, for infections acquired March 20, 2020.

Conclusions

We identify high probability of ICU admission, long durations of stay, and considerable mortality risk among hospitalized COVID-19 cases in the western United States. Reductions in RE have occurred in conjunction with implementation of non-pharmaceutical interventions.
Improving COVID-19 Testing Efficiency using Guided Agglomerative Sampling
Authors: Minhas Fayyaz , Grammatopoulos Dimitris , Young Lawrence , Amin Imran , Snead David , Anderson Neil , Ben-Hur Asa , Rajpoot Nasir
Published: April 2020

One of the challenges in the current COVID-19 crisis is the time and cost of performing tests especially for large-scale population surveillance. Since, the probability of testing positive in large population studies is expected to be small (<15%), therefore, most of the test outcomes will be negative. Here, we propose the use of agglomerative sampling which can prune out multiple negative cases in a single test by intelligently combining samples from different individuals. The proposed scheme builds on the assumption that samples from the population may not be independent of each other. Our simulation results show that the proposed sampling strategy can significantly increase testing capacity under resource constraints: on average, a saving of ~40% tests can be expected assuming a positive test probability of 10% across the given samples. The proposed scheme can also be used in conjunction with heuristic or Machine Learning guided clustering for improving the efficiency of large-scale testing further. The code for generating the simulation results for this work is available here:https://github.com/foxtrotmike/AS.
Synaptic learning rules for sequence learning
Authors: Reifenstein Eric T. , Kempter Richard
Published: April 2020

Remembering the temporal order of a sequence of events is a task easily performed by humans in everyday life, but the underlying neuronal mechanisms are unclear. This problem is particularly intriguing as human behavior often proceeds on a time scale of seconds, which is in stark contrast to the much faster millisecond time-scale of neuronal processing in our brains. One long-held hypothesis in sequence learning suggests that a particular temporal fine-structure of neuronal activity — termed “phase precession” — enables the compression of slow behavioral sequences down to the fast time scale of the induction of synaptic plasticity. Using mathematical analysis and computer simulations, we find that — for short enough synaptic learning windows — phase precession can improve temporal-order learning tremendously and that the asymmetric part of the synaptic learning window is essential for temporal-order learning. To test these predictions, we suggest experiments that selectively alter phase precession or the learning window and evaluate memory of temporal order.
Ancestry-Specific Predisposing Germline Variants in Cancer
Authors: Oak Ninad , Cherniack Andrew D. , Mashl R. Jay ,   TCGA Analysis Network, Hirsch Fred R. , Ding Li , Beroukhim Rameen , Gümüş Zeynep H. , Plon Sharon E. , Huang Kuan-lin
Published: April 2020

Background

Cancer risk differs across ancestries and these differences may result from differing prevalence of inherited genetic predisposition. Yet, most germline genomic studies performed to date have focused on individuals of European ancestry. Ancestry-specific analyses of germline genomes are required to inform cancer genetic risk and prognosis for each ancestral group. Here, we investigate potentially germline pathogenic variants in cancer predisposition genes (CPG) and their somatic effects in patients across diverse ancestral backgrounds.

Methods

We performed a retrospective analysis of germline genomic data of 9,899 patients from 33 cancer types generated by The Cancer Genome Atlas (TCGA) project along with matching somatic genomic and transcriptomic data. By collapsing pathogenic and likely pathogenic variants to the gene level, we analyzed the association between variants in CPGs and cancer types within each ancestry. We also identified ancestry- specific predisposing variants and their associated somatic two-hit events and gene expression levels.

Results

Recent genetic ancestry analysis classified the cohort of 9,899 cancer cases into individuals of primarily European, (N = 8,184, 82.7%), African (N = 966, 9.8%), East Asian (N = 649, 6.6%), South Asian (N=48, 0.5%), Native/Latin American (N=41, 0.4%), and admixed (N=11, 0.1%) ancestries. In the African ancestry, we discovered a potentially novel association ofBRCA2in lung squamous cell carcinoma (OR = 41.4 [95% CI, 6.1-275.6]; FDR = 0.002) along with the previously identified association ofBRCA2in ovarian serous cystadenocarcinoma (OR=8.5 [95% CI, 1.5-47.4]; FDR=0.045). Similarly, in the East Asian ancestry, we discovered one previously known association ofBRIP1in stomach adenocarcinoma (OR=12.8 [95% CI, 1.8-90.84]; FDR=0.038). Rare variant burden analysis further identified 7 suggestive associations for cancer-gene pairs in African ancestry individuals previously well described in European ancestry includingSDHBin pheochromocytoma and paraganglioma,ATMin prostate adenocarcinoma,VHLin kidney renal clear cell carcinoma,FHin kidney renal papillary cell carcinoma, andPTENin uterine corpus endometrial carcinoma. Loss of heterozygosity was identified for 7 out of the 15 African ancestry carriers of predisposing variants. Further, tumors from theSDHBorBRCA2carriers showed simultaneous allelic specific expression and low gene expression of their respective affected genes; andFHsplice-site variant carriers showed mis-splicing ofFH.

Conclusion

While several predisposing genes are shared across patients, many pathogenic variants are found to be ancestry-specific and trigger somatic effects. Analysis of larger diverse ancestries genomic cohorts are required to pinpoint ancestry- specific genetic predisposition to inform personalized diagnosis and screening strategies.
Multidrug treatment with nelfinavir and cepharanthine against COVID-19
Authors: Ohashi Hirofumi , Watashi Koichi , Saso Wakana , Shionoya Kaho , Iwanami Shoya , Hirokawa Takatsugu , Shirai Tsuyoshi , Kanaya Shigehiko , Ito Yusuke , Kim Kwang Su , Nishioka Kazane , Ando Shuji , Ejima Keisuke , Koizumi Yoshiki , Tanaka Tomohiro , Aoki Shin , Kuramochi Kouji , Suzuki Tadaki , Maenaka Katsumi , Matano Tetsuro , Muramatsu Masamichi , Saijo Masayuki , Aihara Kazuyuki , Iwami Shingo , Takeda Makoto , McKeating Jane A. , Wakita Takaji
Published: April 2020

Antiviral treatments targeting the emerging coronavirus disease 2019 (COVID-19) are urgently required. We screened a panel of already-approved drugs in a cell culture model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and identified two new antiviral agents: the HIV protease inhibitor Nelfinavir and the anti-inflammatory drug Cepharanthine.In silicomodeling shows Nelfinavir binds the SARS-CoV-2 main protease consistent with its inhibition of viral replication, whilst Cepharanthine inhibits viral attachment and entry into cells. Consistent with their different modes of action,in vitroassays highlight a synergistic effect of this combined treatment to limit SARS-CoV-2 proliferation. Mathematical modeling in vitro antiviral activity coupled with the known pharmacokinetics for these drugs predicts that Nelfinavir will facilitate viral clearance. Combining Nelfinavir/Cepharanthine enhanced their predicted efficacy to control viral proliferation, to ameliorate both the progression of disease and risk of transmission. In summary, this study identifies a new multidrug combination treatment for COVID-19.
The relative densities of cell cytoplasm, nucleoplasm, and nucleoli are robustly conserved during cell cycle and drug perturbations
Authors: Kim Kyoohyun , Guck Jochen
Published: April 2020

The cell nucleus is a compartment in which essential processes such as gene transcription and DNA replication occur. While the large amount of chromatin confined in the finite nuclear space could install the picture of a particularly dense organelle surrounded by less dense cytoplasm, recent studies have begun to report the opposite. However, the generality of this newly emerging, opposite picture has so far not been tested. Here, we used combined optical diffraction tomography (ODT) and epi-fluorescence microscopy to systematically quantify the mass densities of cytoplasm, nucleoplasm, and nucleoli of human cell lines, challenged by various perturbations. We found that the nucleoplasm maintains a lower mass density than cytoplasm during cell cycle progression by scaling its volume to match the increase of dry mass during cell growth. At the same time, nucleoli exhibited a significantly higher mass density than the cytoplasm. Moreover, actin and microtubule depolymerization and changing chromatin condensation altered volume, shape, and dry mass of those compartments, while the relative distribution of mass densities was generally unchanged. Our findings suggest that the relative mass densities across membrane-bound and membraneless compartments are robustly conserved, likely by different as of yet unknown mechanisms, which hints at an underlying functional relevance. This surprising robustness of mass densities contributes to an increasing recognition of the importance of physico-chemical properties in determining cellular characteristics and compartments.
Sleep Induction by Mechanosensory Stimulation inDrosophila
Authors: Öztürk-Çolak Arzu , McClanahan Patrick D. , Buchler Joseph R. , Inami Sho , Cruz Andri , Fang-Yen Christopher , Koh Kyunghee
Published: April 2020

People tend to fall asleep when gently rocked or vibrated. Experimental studies have shown rocking promotes sleep in humans and mice. The prevailing “synchronization” model proposes synchronization of brain activity to mechanosensory stimuli mediates the phenomenon. The alternative “habituation” model proposes habituation, a form of non-associative learning, mediates sleep induction by monotonous stimulation. Here we show that gentle vibration promotes sleep inDrosophilain part through habituation. Vibration-induced sleep (VIS) leads to the accrual of homeostatic sleep credit, is associated with reduced arousability, and can be suppressed by heightened arousal. Sleep induction improves over successive blocks of vibration and exhibits stimulus specificity, supporting the habituation model. Multiple mechanosensory organs mediate VIS, and the magnitude of sleep gain depends on the vibration frequency and genetic background. Our findings suggest habituation is a major contributor to VIS, but synchronization of brain activity may play a role under certain stimulus conditions.
The capacity of the ovarian cancer tumor microenvironment to integrate inflammation signaling conveys a shorter disease-free interval
Authors: Jordan Kimberly R. , Sikora Matthew J. , Slansky Jill E. , Minic Angela , Richer Jennifer K , Moroney Marisa R. , Costello James C. , Clauset Aaron , Behbakht Kian , Kumar T. Rajendra , Bitler Benjamin G.
Published: April 2020

Ovarian cancer has one of the highest deaths to incidence ratios across all cancers. Initial chemotherapy is typically effective, but most patients will develop chemo-resistant disease. Mechanisms driving clinical chemo-response and -resistance in ovarian cancer are not well understood. However, achieving optimal surgical cytoreduction improves survival, and cytoreduction is improved by neoadjuvant platinum/taxane-based chemotherapy (NACT). NACT offers a window to profile pre-versus post-therapy tumor specimens, which we used to identify chemotherapy-induced changes to the tumor microenvironment. We hypothesized changes in the immune microenvironment correlate with tumor chemo-response and disease progression. We obtained matched pre- and post-NACT archival tumor tissues from patients with high-grade serous ovarian cancer (patient n=6). We measured mRNA levels of 770 genes (NanoString), and performed reverse phase protein array (RPPA) on a subset of matched tumors. We examined cytokine levels in additional pre-NACT ascites samples (n=39) by multiplex ELISA. A tissue microarray with 128 annotated ovarian tumors expanded the transcriptional, RPPA, and cytokine data by multi-spectral immunohistochemistry. In NanoString analyses, transcriptional profiles segregated based on pre- and post-NACT status. The most upregulated gene post-NACT wasIL6(17.1-fold, adjusted p = 0.045). RPPA data were highly concordant with mRNA, consistent with elevated immune infiltration. Elevated IL-6 in pre-NACT ascites specimens correlated with a shorter time to recurrence. Integrating NanoString, RPPA, and cytokine studies identified an activated inflammatory signaling network and inducedIL6andIER3(Immediate Early Response 3) post-NACT, associated with poor chemo-response and decreased time to recurrence. Taken together, multi-omic profiling of ovarian tumor samples before and after NACT provides unique insight into chemo-induced changes to the tumor and microenvironment. We integrated transcriptional, proteomic, and cytokine data and identified a novel IL-6/IER3 signaling axis through increased inflammatory signaling which may drive ovarian cancer chemo-resistance.