Publications by authors named "Zhi Geng"

123 Publications

Anionic Polysaccharide-Modified Filter Papers for Rapid Isolation of Extracellular Vesicles from Diverse Samples in a Simple Bind-Wash-Elute Manner.

Anal Chem 2021 May 11;93(20):7405-7412. Epub 2021 May 11.

Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, China.

Extracellular vesicles (EVs) play a significant role in the pathophysiological process of many diseases, highlighting their values in medical diagnosis and disease monitoring. However, the current EV isolation methods are time-consuming, inconvenient to operate, and incompatible with downstream analyses. Here, we present a novel isolation method employing anionic polysaccharide-modified filter papers for the isolation of EVs (AppiEV) via electrostatic adsorption. A disc of glass fiber-based filter modified with sodium alginate was assembled into a spin column to function as the solid capture phase. In the acidic condition, EVs were induced to carry more positively charged ions, which enable the capture of EVs by the negatively charged filter paper. After a wash, the EVs were released from the spin column using an alkaline elution buffer, which induces the EVs to carry more negative charges. The EVs isolated by AppiEV from cell culture supernatants, plasma, and urine are similar to or even better than those isolated by ultracentrifugation in terms of EV size distribution, protein distribution, and nucleic acid contents. Due to the interference removal of the EV-free RNA and DNA attributed to the negatively charged capture medium, the eluate of AppiEV could be directly used for genetic analysis, including the stem-loop RT-PCR analysis of miR-21 and the allele-specific PCR analysis of mutation genes of p.L858R and p.T790M. We believe that AppiEV offers a simple and efficient approach for the isolation of high-quality EVs from various liquid specimens.
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http://dx.doi.org/10.1021/acs.analchem.0c02107DOI Listing
May 2021

Advances in the Development of Biomarkers for Poststroke Epilepsy.

Biomed Res Int 2021 17;2021:5567046. Epub 2021 Apr 17.

Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.

Stroke is the main cause of acquired epilepsy in elderly people. Poststroke epilepsy (PSE) not only affects functional recovery after stroke but also brings considerable social consequences. While some factors such as cortical involvement, hemorrhagic transformation, and stroke severity are associated with increased seizure risk, so far that remains controversial. In recent years, there are an increasing number of studies on potential biomarkers of PSE as tools for diagnosing and predicting epileptic seizures. Biomarkers such as interleukin-6 (IL-6), tumor necrosis factor- (TNF-), glutamate, and S100 calcium-binding protein B (S100B) in blood are associated with the occurrence of PSE. This review is aimed at summarizing the progress on potential biomarkers of PSE.
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http://dx.doi.org/10.1155/2021/5567046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075663PMC
May 2021

Causal mediation analysis with sure outcomes of random events model.

Stat Med 2021 Apr 26. Epub 2021 Apr 26.

Beijing International Center for Mathematical Research, Peking University, Beijing, China.

Mediation analysis is a useful tool in randomized trials for understanding how a treatment works, in particular how much of the treatment's effect on an outcome is explained by a mediator variable. The traditional approach to mediation analysis makes sequential ignorability assumption which precludes the existence of unobserved confounders between the mediator and outcome variables. Since the randomized experiment does not randomize the mediator, sequential ignorability may not be plausible. In this article, based on a statistical model termed sure outcomes of random events model, we propose an alternative approach to causal mediation analysis without relying on the sequential ignorability assumption for the case of binary treatment and mediator variables. When the outcome is also binary, we establish the identifiability of the average natural direct and indirect effects in the presence of an unobserved confounder between mediator and outcome variables. More importantly, if the identifiability conditions are violated, we provide new bounds that are narrower than those in the previous studies, and these bound results are extended to the case of an arbitrary bounded outcome. Simulation studies show good performance for the proposed estimators in finite samples. Finally, we use a job training intervention on the mental health study to illustrate our approach.
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http://dx.doi.org/10.1002/sim.9009DOI Listing
April 2021

Staying on Target: Maintaining a Balanced Resuscitation During Damage Control Resuscitation Improves Survival.

J Trauma Acute Care Surg 2021 Apr 24. Epub 2021 Apr 24.

Division of Traumatology, Surgical Critical Care & Emergency Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA Penn Acute Research Collaboration (PARC), Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, PA, USA Center for Translational Injury Research, Division of Acute Care Surgery, Department of Surgery, Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA Arcos, Inc., Missouri City, TX, USA Center for Resuscitation Science, Department of Emergency Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA Division of Trauma, Critical Care, and Burn, Department of Surgery, The Ohio State University, Columbus, OH, USA Department of Nursing, Penn Presbyterian Medical Center, Philadelphia, PA, USA Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.

Background: Damage control resuscitation (DCR) improves survival in severely bleeding patients. However, deviating from balanced transfusion ratios during a resuscitation may limit this benefit. We hypothesize that maintaining a balanced resuscitation during DCR is independently associated with improved survival.

Methods: This was a secondary analysis of the PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study. Patients receiving ≥3 units packed red blood cells (PRBC) in one-hour over the first 6-hours and surviving beyond 30-minutes were included. Linear regression assessed the effect of percent time in a high-ratio range on 24-hour survival. We identified an optimal ratio and percent of time above the target ratio threshold by Youden's index. We compared patients with a 6-hour ratio above the target and above the percent time threshold (On-Target) with all others (Off-Target). Kaplan-Meier analysis assessed the combined effect of blood product ratio and percent time over the target ratio on 24-hour and 30-day survival. Multivariable logistic regression identified factors independently associated with 24-hour and 30-day survival.

Results: Of 1,245 PROMMTT patients, 524 met inclusion criteria. Optimal targets were plasma:PRBC and platelet:PRBC of 0.75 and ≥40% time spent over this threshold. For plasma:PRBC, On-Target (n=213) vs Off-Target (n=311) patients were younger (median 31-years, interquartile range [22, 50] vs 40 [25, 54], p=0.002) with similar injury burdens and presenting physiology. Similar patterns were observed for platelet:PRBC On-Target (n=116) and Off-Target (n=408) patients. After adjusting for differences, On-Target plasma:PRBC patients had significantly improved 24-hour (OR 2.25, 95% CI, 1.20-4.23) and 30-day (OR 1.97, 95% CI 1.14-3.41) survival while On-Target platelet:PRBC patients did not.

Conclusion: Maintaining a high ratio of plasma:PRBC during damage control resuscitation is independently associated with improved survival. Performance improvement efforts and prospective studies should capture time spent in a high-ratio range.

Level Of Evidence: Epidemiologic/prognostic study, Level II.
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http://dx.doi.org/10.1097/TA.0000000000003245DOI Listing
April 2021

SARS-CoV-2-induced Overexpression of miR-4485 Suppresses Osteogenic Differentiation and Impairs Fracture Healing.

Int J Biol Sci 2021 25;17(5):1277-1288. Epub 2021 Mar 25.

Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology Wuhan, Hubei 430022, China.

The angiotensin-converting enzyme 2 (ACE2) receptor has been identified as the cell entry point for SARS-CoV-2. Although ACE2 receptors are present in the bone marrow, the effects of SARS-CoV-2 on the biological activity of bone tissue have not yet been elucidated. In the present study we sought to investigate the impact of SARS-CoV-2 on osteoblastic activity in the context of fracture healing. MicroRNA-4485 (miR-4485), which we found to be upregulated in COVID-19 patients, negatively regulates osteogenic differentiation. We demonstrate this effect both and . Moreover, we identified the toll-like receptor 4 (TLR-4) as the potential target gene of miR-4485, and showed that reduction of TLR-4 induced by miR-4485 suppresses osteoblastic differentiation . Taken together, our findings highlight that up-regulation of miR-4485 is responsible for the suppression of osteogenic differentiation in COVID-19 patients, and TLR-4 is the potential target through which miR-4485 acts, providing a promising target for pro-fracture-healing and anti-osteoporosis therapy in COVID-19 patients.
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http://dx.doi.org/10.7150/ijbs.56657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040480PMC
May 2021

The Pseudomonas aeruginosa PAAR2 cluster encodes a putative VRR-NUC domain-containing effector.

FEBS J 2021 Apr 10. Epub 2021 Apr 10.

Multidiscipline Research Center, Institte of High Energy Physics, Chinese Academy of Sciences, Beijing, China.

The bacterial type VI secretion system (T6SS) secretes many toxic effectors to gain advantage in inter-bacterial competition and for eukaryotic host infection. The cognate immunity proteins of these effectors protect bacteria from the virulence of their own effectors. The T6SS injects its inner-needle Hcp tube, the sharpening tip complex -consisting of VgrG and proline-alanine-alanine-arginine repeats (PAAR) proteins- and toxic effectors into neighboring cells. Its functions are largely determined by the activities of its delivered effectors. Five PAAR proteins were found in the Pseudomonas aeruginosa PAO1 genome with three of them shown to facilitate the delivery of various effectors. Here, we report a putative virus-type replication-repair nuclease domain-containing effector TseV encoded by the least investigated P. aeruginosa PAAR2 cluster. The crystal structure of its putative cognate effector TsiV is presented at 1.6 Å resolution. Through structure and sequence comparisons, we propose TseV-TsiV to be a putative novel effector-immunity (E-I) pair and we discuss the roles of other PAAR2 cluster encoded proteins.
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http://dx.doi.org/10.1111/febs.15870DOI Listing
April 2021

The Heartguard: A Humanitarian Pediatric Cardiac Surgery Program in Rural China.

Thorac Cardiovasc Surg 2021 Feb 18. Epub 2021 Feb 18.

Cardiovascular Center, The 2nd Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.

Background:  Congenital heart disease (CHD) accounts for the most common birth defects in China, pressuring both the physical and mental health in children. The inaccessibility of CHD children in rural China due to financial difficulties is demanding inputs from both the government and society. The Heartguard project is a program developed to improve the delivery of CHD care in rural China.

Methods:  The Heartguard project partners with county hospitals and performs CHD screening to diagnose patients with CHD in rural China. Diagnosed children with CHD who are unable to afford therapy will subsequently receive treatment sponsored by the financial partners. All patients are followed up by the local partner and visiting surgical team members.

Results:  More than 10,000 children across 9 provinces underwent CHD screening. A total of 240 (accounting for an incidence of 2.4%) was treated by the program, of which 226 patients were managed invasively, the other 14 patients conservatively. Open surgery was performed in 162 patients, while endovascular procedures were applied in another 64. No mortality or significant complications occurred during the transfer. There was no perioperative or late death.

Conclusion:  This humanitarian cardiac surgery program is able to promote accessibility of care for CHD children in rural China. The quality of life of these patients can be improved with continuous input from the society.
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http://dx.doi.org/10.1055/s-0041-1723846DOI Listing
February 2021

High-Performance, Free-Standing Symmetric Hybrid Membranes for Osmotic Separation.

ACS Appl Mater Interfaces 2021 Feb 12;13(7):8967-8975. Epub 2021 Feb 12.

College of Environment, Research Centre for Municipal Wastewater Treatment and Water Quality Protection, Northeast Normal University, Changchun 130117, China.

The internal concentration polarization (ICP) of asymmetric osmotic membranes with support layers greatly reduced membrane water permeability, therefore compromising membrane performance. In this study, a series of free-standing symmetric hybrid forward osmosis (FO) membranes without experiencing ICP were fabricated by covalently linking metal-organic framework (MOF) nanofillers with a polymer matrix. Owing to the introduction of MOFs, which allow only water permeation but reject salts by steric hindrance, the prepared hybrid membranes could approach the empirical permeability-selectivity trade-off. The optimized hybrid membrane displayed an outstanding water/NaSO selectivity of ∼1208.4 L mol, compared with that of conventional membranes of ∼375.6 L mol. Additionally, the fabricated hybrid membranes showed excellent mechanical robustness, maintaining structural integrity during the long-term FO separation of high-salinity solution. This work provides an effective methodology to fabricate high-performance, symmetric MOF-based membranes for osmotic separation processes such as seawater desalination and water purification.
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http://dx.doi.org/10.1021/acsami.0c22124DOI Listing
February 2021

Improved Cognitive Promotion through Accelerated Magnetic Stimulation.

eNeuro 2021 Jan-Feb;8(1). Epub 2021 Feb 1.

Department of Neurology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China

Noninvasive brain stimulation to enhance cognition is an area of increasing research interest. Theta burst stimulation (TBS) is a novel accelerated form of stimulation, which more closely mimics the brain's natural firing patterns and may have greater effects on cognitive performance. We report here the comparative assessment of the effect of conventional high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) protocols and TBS protocols on cognition enhancement in healthy controls. Sixty healthy adults (34 males and 26 females) were randomized and counterbalanced and assigned to HF-rTMS ( = 20), TBS ( = 20), or sham ( = 20) groups. The promotion effects of different parameters of prefrontal stimulation on working memory and executive function were compared, as assessed by performance in N-back tasks and the Wisconsin Card Sorting Test (WCST). Both HF-rTMS and intermittent TBS (iTBS) groups displayed a significant improvement in N-back tasks, with an effect size of 0.79 and 1.50, respectively. Furthermore, the iTBS group displayed a significant improvement in the WCST, with an effect size of 0.84. The iTBS group demonstrated higher effect sizes than the HF-rTMS group (=2.68, =0.011), with an effect size of 0.85. However, no improvement in other tasks was observed (>0.05). Intermittent TBS has a stronger cognitive promoting effect than conventional rTMS. In summary, our findings provide direct evidence that iTBS may be a superior protocol for cognitive promotion.
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http://dx.doi.org/10.1523/ENEURO.0392-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901150PMC
February 2021

The vessel density of the superficial retinal capillary plexus as a new biomarker in cerebral small vessel disease: an optical coherence tomography angiography study.

Neurol Sci 2021 Jan 11. Epub 2021 Jan 11.

Department of Neurology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.

Background: Optical coherence tomography angiography (OCTA) is a novel and noninvasive technique for the quantitative assessment of retinal microvascular perfusion. Since the retinal and cerebral small vessels share similar embryological origins, anatomical features, and physiological properties, altered retinal microvasculature might provide a new perspective on the mechanisms of cerebral small vessel disease (CSVD).

Objective: We aimed to evaluate retinal vessel density (VD) in patients with CSVD using OCTA and identify associations with cerebral magnetic resonance imaging (MRI) markers and cognitive function.

Methods: We prospectively recruited 47 CSVD patients and 30 healthy controls (HCs) to participate in the study. All participants underwent OCTA to evaluate retinal microvascular perfusion. The VDs of the macular region in the superficial retinal capillary plexus (SRCP), deep retinal capillary plexus (DRCP), and foveal avascular zone (FAZ) were determined, along with the VD of the optic nerve head (ONH) in the radial peripapillary capillary (RPC) network. Additionally, cerebral MRI and cognitive function tests were performed.

Results: In the macula area, the VD of the CSVD patients was significantly lower than HCs in the temporal quadrant of SRCP. In the ONH area, CSVD patients had lower VD than HCs in the peripapillary RPC network. According to multiple linear regression analysis, decreased VD of the macular SRCP was associated with white matter hyperintensity scores after adjustment for age, hypertension, diabetes, and hyperlipidemia. Furthermore, the VD of the macular SRCP was significantly correlated with CSVD patients' cognitive function, especially global cognition, memory function, attention function, information processing, and executive function.

Conclusion: OCTA revealed a significant decrease in retinal microvascular perfusion in CSVD patients, and retinal hypoperfusion was related to MRI markers and cognitive function, suggesting that these parameters could have potential utility as early disease biomarkers.
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http://dx.doi.org/10.1007/s10072-021-05038-zDOI Listing
January 2021

The Retinal Vessel Density Can Reflect Cognitive Function in Patients with Alzheimer's Disease: Evidence from Optical Coherence Tomography Angiography.

J Alzheimers Dis 2021 ;79(3):1307-1316

Department of Neurology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.

Background: There is increasing evidence that Alzheimer's disease (AD) patients may present decreased cerebral blood perfusion before pathological brain changes. Using the retina as a window to the brain, we can study disorders of the central nervous system through the eyes.

Objective: This study aimed to investigate differences in retinal structure and vessel density (VD) between patients with mild AD and healthy controls (HCs). Furthermore, we explored the relationship between retinal VD and cognitive function.

Methods: We enrolled 37 patients with AD and 29 age-matched HCs who underwent standard ophthalmic optical coherence tomography angiography (OCTA) for evaluation of the retinal layer thickness and VD parameters. Cognitive function was evaluated using a battery of neuropsychological assessments. Finally, the correlations among retinal layer thickness, VD parameters, and cognitive function were evaluated.

Results: The retinal fiber layer thickness and retinal VD of patients with AD were significantly reduced compared with HCs. The retinal VD was significantly correlated with overall cognition, memory, executive, and visual-spatial perception functions. However, there was no significant between-group difference in the macular thickness.

Conclusion: Our findings indicate a positive correlation between retinal VD and some, but not all, cognitive function domains. Most importantly, we demonstrated the role of OCTA in detecting early capillary changes, which could be a noninvasive biomarker for early AD.
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http://dx.doi.org/10.3233/JAD-200971DOI Listing
January 2021

A Quick Route to Multiple Highly Potent SARS-CoV-2 Main Protease Inhibitors*.

ChemMedChem 2021 03 10;16(6):942-948. Epub 2020 Dec 10.

Department of Chemistry, Texas A&M University, College Station, TX 77843-3255, USA.

The COVID-19 pathogen, SARS-CoV-2, requires its main protease (SC2M ) to digest two of its translated long polypeptides to form a number of mature proteins that are essential for viral replication and pathogenesis. Inhibition of this vital proteolytic process is effective in preventing the virus from replicating in infected cells and therefore provides a potential COVID-19 treatment option. Guided by previous medicinal chemistry studies about SARS-CoV-1 main protease (SC1M ), we have designed and synthesized a series of SC2M inhibitors that contain β-(S-2-oxopyrrolidin-3-yl)-alaninal (Opal) for the formation of a reversible covalent bond with the SC2M active-site cysteine C145. All inhibitors display high potency with K values at or below 100 nM. The most potent compound, MPI3, has as a K value of 8.3 nM. Crystallographic analyses of SC2M bound to seven inhibitors indicated both formation of a covalent bond with C145 and structural rearrangement from the apoenzyme to accommodate the inhibitors. Virus inhibition assays revealed that several inhibitors have high potency in inhibiting the SARS-CoV-2-induced cytopathogenic effect in both Vero E6 and A549/ACE2 cells. Two inhibitors, MPI5 and MPI8, completely prevented the SARS-CoV-2-induced cytopathogenic effect in Vero E6 cells at 2.5-5 μM and A549/ACE2 cells at 0.16-0.31 μM. Their virus inhibition potency is much higher than that of some existing molecules that are under preclinical and clinical investigations for the treatment of COVID-19. Our study indicates that there is a large chemical space that needs to be explored for the development of SC2M inhibitors with ultra-high antiviral potency.
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http://dx.doi.org/10.1002/cmdc.202000924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979488PMC
March 2021

Structure and Biochemical Characteristic of the Methyltransferase (MTase) Domain of RNA Capping Enzyme from African Swine Fever Virus.

J Virol 2020 Dec 2. Epub 2020 Dec 2.

Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China

African swine fever virus (ASFV) is a complex nucleocytoplasmic large DNA virus (NCLDV) that causes a devastating swine disease and it is urgently needed to develop effective anti-ASFV vaccines and drugs. The process of mRNA 5'-end capping is a common characteristic in eukaryotes and many viruses, and the cap structure is required for mRNA stability and efficient translation. The ASFV protein pNP868R was found to have guanylyltransferase (GTase) activity involved in mRNA capping. Here we report the crystal structure of pNP868R methyltransferase (MTase) domain (referred as pNP868R) in complex with S-adenosyl-L-methionine (AdoMet). The structure shows the characteristic core fold of the class I MTase family and the AdoMet is bound in a negative-deep groove. Remarkably, the N-terminal extension of pNP868R is ordered and keeps away from the AdoMet-binding site, distinct from the close conformation over the active site of poxvirus RNA capping D1 subunit or the largely disordered conformation in most cellular RNA capping MTases. Structure-based mutagenesis studies based on the pNP868R-cap analog complex model revealed essential residues involved in substrate recognition and binding. Functional studies suggest the N-terminal extension may play an essential role in substrate recognition instead of AdoMet-binding. A positively charged path stretching from the N-terminal extension to the region around the active site was suggested to provide a favorable electrostatic environment for the binding and approaching of substrate RNA into the active site. Our structure and biochemical studies provide novel insights into the methyltransfer process of mRNA cap catalyzed by pNP868R. African swine fever (ASF) is a highly contagious hemorrhagic viral disease in pigs that is caused by African swine fever virus (ASFV). There are no effective drugs or vaccines for protection against ASFV infection till now. The protein pNP868R was predicted to be responsible for process of mRNA 5'-end capping in ASFV, which is essential for mRNA stability and efficient translation. Here, we solved the high-resolution crystal structure of the methyltransferase (MTase) domain of pNP868R. The MTase domain structure shows a canonical class I MTase family fold and the AdoMet binds into a negative pocket. Structure-based mutagenesis studies revealed critical and conserved residues involved in AdoMet-binding and substrate RNA-binding. Notably, both the conformation and the role in MTase activities of the N-terminal extension are distinct from those of previously characterized poxvirus MTase domain. Our structure-function studies provide the basis for potential anti-ASFV inhibitor design targeting the critical enzyme.
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http://dx.doi.org/10.1128/JVI.02029-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092831PMC
December 2020

Oral anticoagulant use in patients with atrial fibrillation and mitral valve repair.

Am Heart J 2021 02 24;232:1-9. Epub 2020 Oct 24.

Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, PA; Penn Cardiovascular Outcomes, Quality, and Evaluative Research Center, Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA; Division of General Internal Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA.

Background: Patients with atrial fibrillation (AF) who have undergone mitral valve repair are at risk for thromboembolic strokes. Prior to 2019, only vitamin K antagonists were recommended for patients with AF who had undergone mitral valve repair despite the introduction of direct oral anticoagulants (DOAC) in 2010.

Objective: To characterize the use of anticoagulants in patients with AF who underwent surgical mitral valve repair (sMVR) or transcatheter mitral valve repair (tMVR).

Methods: We performed a retrospective cohort analysis of patients with AF undergoing sMVR or tMVR between 04/2014 and 12/2018 using Optum's de-identified Clinformatics® Data Mart Database. We identified anticoagulants prescribed within 90 days of discharge from hospitalization.

Results: Overall, 1997 patients with AF underwent valve repair: 1560 underwent sMVR, and 437 underwent tMVR. The mean CHADS-VASc score among all patients was 4.1 (SD 1.9). The overall use of anticoagulation was unchanged between 2014 (72.2%) and 2018 (70.0%) (P = .49). Among patients who underwent sMVR or tMVR between April 2014 and December 2018, the use of VKA therapy decreased from 62.9% to 32.1% (P < .01 for trend) and the use of DOACs increased from 12.4% to 37.3% (P < .01 for trend).

Conclusions: Among patients with AF who underwent sMVR or tMVR between 2014 and 2018, roughly 30% of patients were not treated with any anticoagulant within 90 days of discharge, despite an elevated stroke risk in the cohort. The rate of DOAC use increased steadily over the study period but did not significantly increase the rate of overall anticoagulant use in this high-risk cohort.
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http://dx.doi.org/10.1016/j.ahj.2020.10.056DOI Listing
February 2021

Open resource of clinical data from patients with pneumonia for the prediction of COVID-19 outcomes via deep learning.

Nat Biomed Eng 2020 12 18;4(12):1197-1207. Epub 2020 Nov 18.

Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Data from patients with coronavirus disease 2019 (COVID-19) are essential for guiding clinical decision making, for furthering the understanding of this viral disease, and for diagnostic modelling. Here, we describe an open resource containing data from 1,521 patients with pneumonia (including COVID-19 pneumonia) consisting of chest computed tomography (CT) images, 130 clinical features (from a range of biochemical and cellular analyses of blood and urine samples) and laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clinical status. We show the utility of the database for prediction of COVID-19 morbidity and mortality outcomes using a deep learning algorithm trained with data from 1,170 patients and 19,685 manually labelled CT slices. In an independent validation cohort of 351 patients, the algorithm discriminated between negative, mild and severe cases with areas under the receiver operating characteristic curve of 0.944, 0.860 and 0.884, respectively. The open database may have further uses in the diagnosis and management of patients with COVID-19.
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http://dx.doi.org/10.1038/s41551-020-00633-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723858PMC
December 2020

Acute Kidney Injury in Deceased Organ Donors and Kidney Transplant Outcomes: A National Cohort Study using a Novel Data Source.

Ann Surg 2020 Nov 13. Epub 2020 Nov 13.

Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, PA, USA.

Objective: To determine graft function and survival for kidney transplants from deceased donors with acute kidney injury (AKI) that persists at the time of organ procurement.

Background: Kidneys from donors with AKI are often discarded and may provide an opportunity to selectively expand the donor pool.

Methods: Using OPTN and DonorNet data, we studied adult kidney-only recipients between 5/1/2007-12/31/2016. DonorNet was used to characterize longitudinal creatinine trends and urine output. Donor AKI was defined using KDIGO guidelines and terminal creatinine ≥ 1.5 mg/dL. We compared outcomes between AKI kidneys versus "ideal comparator" kidneys from donors with no or resolved AKI stage 1 plus terminal creatinine < 1.5 mg/dL. We fit proportional hazards models and hierarchical linear regression models for the primary outcomes of all-cause graft failure (ACGF) and 12-month estimated glomerular filtration rate (eGFR), respectively.

Results: We identified 7,660 donors with persistent AKI (33.2% with AKI stage 3) from whom ≥1 kidney was transplanted. Observed rates of ACGF within 3 years were similar between recipient groups (15.5% in AKI vs 15.1% ideal comparator allografts, p = 0.2). After risk adjustment, ACGF was slightly higher among recipients of AKI kidneys (aHR 1.05, 95%CI:1.01-1.09). The mean 12-month eGFR for AKI kidney recipients was lower, but differences were not clinically important (56.6 vs. 57.5 mL/min/1.73m for ideal comparator kidneys; p < 0.001). There were 2,888 kidneys discarded from donors with AKI, age ≤ 65, without hypertension or diabetes, and terminal creatinine ≤ 4 mg/dL.

Conclusions: Kidney allografts from donors with persistent AKI are often discarded, yet those that were transplanted did not have clinically meaningful differences in graft survival and function.
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http://dx.doi.org/10.1097/SLA.0000000000004597DOI Listing
November 2020

Comparing two sample pooling strategies for SARS-CoV-2 RNA detection for efficient screening of COVID-19.

J Med Virol 2021 05 11;93(5):2805-2809. Epub 2021 Mar 11.

Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

The emerging pandemic of coronavirus disease 2019 (COVID-19) has affected over 200 countries and resulted in a shortage of diagnostic resources globally. Rapid diagnosis of COVID-19 is vital to control the spreading of the disease, which, however, is challenged by limited detection capacity and low detection efficiency in many parts of the world. The pooling test may offer an economical and effective approach to increase the virus testing capacity of medical laboratories without requiring more laboratory resources such as laboratory workers, testing reagents, and equipment. In this study, the sample pools of 6 and 10 were detected by a real-time reverse transcription-polymerase chain reaction assay targeting ORF1ab and N genes of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Each pool consisted of five or nine negative SARS-CoV-2 samples and one positive counterpart with varying viral loads. Two different strategies of sample pooling were investigated and the results were compared comprehensively. One approach was to pool the viral transport medium of the samples in the laboratory, and the other was to pool swab samples during the collection process. For swab pooling strategy, qualitative results of SARS-CoV-2 RNA, specific tests of ORF1ab and N genes, remained stable over the different pool sizes. Together, this study demonstrates that the swab pooling strategy may serve as an effective and economical approach for screening SARS-CoV-2 infections in large populations, especially in countries and regions where medical resources are limited during the pandemic and may thus be potential for clinical laboratory applications.
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http://dx.doi.org/10.1002/jmv.26632DOI Listing
May 2021

Author Correction: Automated design of a convolutional neural network with multi-scale filters for cost-efficient seismic data classification.

Nat Commun 2020 Oct 22;11(1):5450. Epub 2020 Oct 22.

Key Laboratory of Petroleum Resources Research, Institute of Geology and Geophysics, Chinese Academy of Sciences, 100029, Beijing, P. R. China.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-020-19282-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582182PMC
October 2020

Detection of SARS-CoV-2 in saliva and characterization of oral symptoms in COVID-19 patients.

Cell Prolif 2020 Dec 19;53(12):e12923. Epub 2020 Oct 19.

Salivary Gland Disease Center and Molecular Laboratory for Gene Therapy and Tooth Regeneration, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China.

Objectives: In order to provide a more comprehensive understanding of the effects of SARS-CoV-2 on oral health and possible saliva transmission, we performed RNA-seq profiles analysis from public databases and also a questionnaire survey on oral-related symptoms of COVID-19 patients.

Materials And Methods: To analyse ACE2 expression in salivary glands, bulk RNA-seq profiles from four public datasets including 31 COVID-19 patients were recruited. Saliva and oropharyngeal swabs were collected. SARS-CoV-2 nucleic acids in saliva were detected by real-time polymerase chain reaction (RT-PCR). Additionally, a questionnaire survey on various oral symptoms such as dry mouth and amblygeustia was also carried out on COVID-19 patients.

Results: ACE2 expression was present at detectable levels in the salivary glands. In addition, of four cases with positive detection of salivary SARS-CoV-2 nucleic acids, three (75%) were critically ill on ventilator support. Furthermore, we observed the two major oral-related symptoms, dry mouth (46.3%) and amblygeustia (47.2%), were manifested by a relatively high proportion of 108 COVID-19 patients who accepted the questionnaire survey.

Conclusions: This study confirms the expression of ACE2 in the salivary glands and demonstrates the possibility of SARS-CoV-2 infection of salivary glands. Saliva may be a new source of diagnostic specimens for critically ill patients, since it can be easily collected without any invasive procedures. In addition, dry mouth and amblygeustia can be considered as initial symptoms of COVID-19 infection.
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http://dx.doi.org/10.1111/cpr.12923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645955PMC
December 2020

Reducing False Negatives in COVID-19 Testing by Using Microneedle-Based Oropharyngeal Swabs.

Matter 2020 Nov 5;3(5):1589-1600. Epub 2020 Oct 5.

Yong Loo Lin School of Medicine and Faculty of Engineering, National University of Singapore, Singapore, 119077, Singapore.

Coronavirus disease 2019 (COVID-19) has become a severe threat to human health worldwide. Early etiological diagnosis plays a critical role in controlling COVID-19 pandemic. However, etiological diagnosis has been largely compromised by high "false-negative" rates of viral nucleic acid testing, resulting from limited sampling efficiency using conventional oropharyngeal swabs. Here, we engineer regular swabs by using a microneedle (MN) patch to significantly improve the quality and quantity of virus collection. The combination of MNs with different crosslinking levels endows the patches with dual capability of mucus penetration and virus extraction. Moreover, the antibody (Ab) against viral spike protein was integrated into the patch, conferring MNs with an active virus capture potential. By taking advantage of the biological and engineered species, we believe that the designed MN/Ab swabs could serve as a promising tool to improve current sampling efficiency with fewer false negatives, contributing to the containment of the COVID-19 pandemic.
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http://dx.doi.org/10.1016/j.matt.2020.09.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7535620PMC
November 2020

A novel path-specific effect statistic for identifying the differential specific paths in systems epidemiology.

BMC Genet 2020 08 8;21(1):85. Epub 2020 Aug 8.

Institute for Medical Dataology, Cheeloo College of Medicine, Shandong University, Jinan, 250000, People's Republic of China.

Background: Biological pathways play an important role in the occurrence, development and recovery of complex diseases, such as cancers, which are multifactorial complex diseases that are generally caused by mutation of multiple genes or dysregulation of pathways.

Results: We propose a path-specific effect statistic (PSE) to detect the differential specific paths under two conditions (e.g. case VS. control groups, exposure Vs. nonexposure groups). In observational studies, the path-specific effect can be obtained by separately calculating the average causal effect of each directed edge through adjusting for the parent nodes of nodes in the specific path and multiplying them under each condition. Theoretical proofs and a series of simulations are conducted to validate the path-specific effect statistic. Applications are also performed to evaluate its practical performances. A series of simulation studies show that the Type I error rates of PSE with Permutation tests are more stable at the nominal level 0.05 and can accurately detect the differential specific paths when comparing with other methods. Specifically, the power reveals an increasing trends with the enlargement of path-specific effects and its effect differences under two conditions. Besides, the power of PSE is robust to the variation of parent or child node of the nodes on specific paths. Application to real data of Glioblastoma Multiforme (GBM), we successfully identified 14 positive specific pathways in mTOR pathway contributing to survival time of patients with GBM. All codes for automatic searching specific paths linking two continuous variables and adjusting set as well as PSE statistic can be found in supplementary materials.  CONCLUSION: The proposed PSE statistic can accurately detect the differential specific pathways contributing to complex disease and thus potentially provides new insights and ways to unlock the black box of disease mechanisms.
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http://dx.doi.org/10.1186/s12863-020-00876-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414699PMC
August 2020

A Speedy Route to Multiple Highly Potent SARS-CoV-2 Main Protease Inhibitors.

bioRxiv 2020 Jul 28. Epub 2020 Jul 28.

The COVID-19 pathogen, SARS-CoV-2, requires its main protease (SC2M ) to digest two of its translated polypeptides to form a number of mature proteins that are essential for viral replication and pathogenesis. Inhibition of this vital proteolytic process is effective in preventing the virus from replication in infected cells and therefore provides a potential COVID-19 treatment option. Guided by previous medicinal chemistry studies about SARS-CoV-1 main protease (SC1M ), we have designed and synthesized a series of SC2M inhibitors that contain β-( -2-oxopyrrolidin-3-yl)-alaninal (Opal) for the formation of a reversible covalent bond with the SC2M active site cysteine C145. All inhibitors display high potency with IC values at or below 100 nM. The most potent compound MPI3 has as an IC value as 8.5 nM. Crystallographic analyses of SC2M bound to 7 inhibitors indicated both formation of a covalent bond with C145 and structural rearrangement from the apoenzyme to accommodate the inhibitors. Virus inhibition assays revealed that several inhibitors have high potency in inhibiting the SARS-CoV-2-induced cytopathogenic effect in both Vero E6 and A549 cells. Two inhibitors MP5 and MPI8 completely prevented the SARS-CoV-2-induced cytopathogenic effect in Vero E6 cells at 2.5-5 μM and A549 cells at 0.16-0.31 μM. Their virus inhibition potency is much higher than some existing molecules that are under preclinical and clinical investigations for the treatment of COVID-19. Our study indicates that there is a large chemical space that needs to be explored for the development of SC2M inhibitors with extreme potency. Due to the urgent matter of the COVID-19 pandemic, MPI5 and MPI8 may be quickly advanced to preclinical and clinical tests for COVID-19.
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http://dx.doi.org/10.1101/2020.07.28.223784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402039PMC
July 2020

Comprehensive analysis of combat casualty outcomes in US service members from the beginning of World War II to the end of Operation Enduring Freedom.

J Trauma Acute Care Surg 2020 08;89(2S Suppl 2):S8-S15

From the Division of Traumatology, Surgical Critical Care & Emergency Surgery, Department of Surgery (J.W.C., D.N.H., C.W.S.), Perelman School of Medicine at the University of Pennsylvania; Leonard Davis Institute of Health Economics (J.W.C., D.N.H., Z.G., Y.H.), University of Pennsylvania, Philadelphia, Pennsylvania; Department of Surgery (J.W.C.), F. Edward Hébert School of Medicine at the Uniformed Services University, Bethesda, Maryland; Clinical Investigation Facility (I.J.S.), David Grant USAF Medical Center, Travis Air Force Base, California; Division of General Internal Medicine, Department of Medicine (Y.H.), Department of Biostatistics, Epidemiology & Informatics, Center for Clinical Epidemiology and Biostatistics (W.Y.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Centre for Blast Injury Studies (E.R.M.), Imperial College London, London, United Kingdom; Department of Surgery, Brooke Army Medical Center (S.C.N.), Ft. Sam Houston, Texas; and US Army Trauma Training Detachment at Ryder Trauma Center (K.R.G.), Miami, Florida.

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http://dx.doi.org/10.1097/TA.0000000000002789DOI Listing
August 2020

A scalable microfluidic chamber array for sample-loss-free and bubble-proof sample compartmentalization by simple pipetting.

Lab Chip 2020 08 22;20(16):2981-2989. Epub 2020 Jul 22.

Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, 100084, China.

Sample compartmentalization is a pivotal technique in many bioanalytical applications, such as multiplex polymerase chain reaction (PCR) and digital PCR (dPCR). In this study, we successfully developed a novel self-compartmentalization device containing an array of microchambers, each of which is connected to a main microchannel with three capillary burst valves (CBVs) for fluid switching and partitioning. As these CBVs can be automatically opened in a predefined sequence, an incoming solution can be spontaneously directed into the chamber and held in place without further mixing. After that, either air or oil can be loaded into the main channel to isolate each chamber completely. By optimizing the relative burst pressures of the CBVs, a 100% sample utilization rate can be achieved even using a manual pipette and air bubbles in the sample cannot interfere with the loading. In addition, the number of the microchambers in an array can be easily scaled from a few to tens of thousands. To verify the feasibility of this self-compartmentalization method, we successfully conducted mock multiplex loop-mediated isothermal amplifications (LAMP) in an array that contains 144 microchambers, proving that our design method will provide a robust and versatile platform for various sample discretization purposes in the future.
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http://dx.doi.org/10.1039/d0lc00348dDOI Listing
August 2020

Asymmetric Differences in the Gray Matter Volume and Functional Connections of the Amygdala Are Associated With Clinical Manifestations of Alzheimer's Disease.

Front Neurosci 2020 26;14:602. Epub 2020 Jun 26.

Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.

Objective: Asymmetry is a subtle but pervasive aspect of the human brain, which may be altered in several neuropsychiatric conditions. Magnetic resonance imaging (MRI) studies have reported that cerebral structural asymmetries are altered in Alzheimer's disease (AD), but most of these studies were conducted at the region-of-interest level. At the functional level, there are few reports of resting-state functional asymmetries based on functional MRI. In this study, we investigated lateral differences in structural volumes and strengths of functional connectivity between individuals with AD and healthy controls (HCs) at the voxel level.

Methods: Forty-eight patients with AD and 32 matched HCs were assessed. An analysis of voxel-based morphometry (VBM) of gray matter volume was performed at the whole-brain level to explore anatomical cerebral asymmetries in AD. We then performed a seed-to-whole-brain functional connectivity (FC) analysis to reveal FC asymmetries in AD. An asymmetry index (AI) was used to measure these changes, and the relationship between the structural and functional AIs and the clinical symptoms of AD was explored.

Results: A VBM analysis revealed a rightward and a leftward lateralization in the amygdala and the thalamus, respectively, in patients with AD. FC between the amygdala and the precuneus showed a rightward lateralization in AD, which was the opposite of the lateralization in the HCs. The asymmetric changes in structure and function were associated with disease severity and functional impairment in AD.

Conclusion: Our study highlights the value of considering asymmetries in the amygdala and the thalamus in clinical evaluations and their relevance to clinical measures.
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http://dx.doi.org/10.3389/fnins.2020.00602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332559PMC
June 2020

Automated design of a convolutional neural network with multi-scale filters for cost-efficient seismic data classification.

Nat Commun 2020 07 3;11(1):3311. Epub 2020 Jul 3.

Key Laboratory of Petroleum Resources Research, Institute of Geology and Geophysics, Chinese Academy of Sciences, 100029, Beijing, P. R. China.

Geoscientists mainly identify subsurface geologic features using exploration-derived seismic data. Classification or segmentation of 2D/3D seismic images commonly relies on conventional deep learning methods for image recognition. However, complex reflections of seismic waves tend to form high-dimensional and multi-scale signals, making traditional convolutional neural networks (CNNs) computationally costly. Here we propose a highly efficient and resource-saving CNN architecture (SeismicPatchNet) with topological modules and multi-scale-feature fusion units for classifying seismic data, which was discovered by an automated data-driven search strategy. The storage volume of the architecture parameters (0.73 M) is only ~2.7 MB, ~0.5% of the well-known VGG-16 architecture. SeismicPatchNet predicts nearly 18 times faster than ResNet-50 and shows an overwhelming advantage in identifying Bottom Simulating Reflection (BSR), an indicator of marine gas-hydrate resources. Saliency mapping demonstrated that our architecture captured key features well. These results suggest the prospect of end-to-end interpretation of multiple seismic datasets at extremely low computational cost.
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http://dx.doi.org/10.1038/s41467-020-17123-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335201PMC
July 2020

Low transmission risk of 9 asymptomatic carriers tested positive for both SARS-CoV-2 nucleic acid and serum IgG.

J Infect 2020 09 18;81(3):452-482. Epub 2020 Jun 18.

Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

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http://dx.doi.org/10.1016/j.jinf.2020.06.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299860PMC
September 2020

Eosinopenia and elevated C-reactive protein facilitate triage of COVID-19 patients in fever clinic: A retrospective case-control study.

EClinicalMedicine 2020 Jun 3;23:100375. Epub 2020 May 3.

Department of Gastrointestinal Surgery, Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.

Background: Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently a pandemic affecting over 200 countries. Many cities have established designated fever clinics to triage suspected COVID-19 patients from other patients with similar symptoms. However, given the limited availability of the nucleic acid test as well as long waiting time for both the test and radiographic examination, the quarantine or therapeutic decisions for a large number of mixed patients were often not made in time. We aimed to identify simple and quickly available laboratory biomarkers to facilitate effective triage at the fever clinics for sorting suspected COVID-19 patients from those with COVID-19-like symptoms.

Methods: We collected clinical, etiological, and laboratory data of 989 patients who visited the Fever Clinic at Wuhan Union Hospital, Wuhan, China, from Jan 31 to Feb 21. Based on polymerase chain reaction (PCR) nucleic acid testing for SARS-CoV-2 infection, they were divided into two groups: SARS-CoV-2-positive patients as cases and SARS-CoV-2-negative patients as controls. We compared the clinical features and laboratory findings of the two groups, and analyzed the diagnostic performance of several laboratory parameters in predicting SARS-CoV-2 infection and made relevant comparisons to the China diagnosis guideline of having a normal or decreased number of leukocytes (≤9·5 10/L) or lymphopenia (<1·1 10/L).

Findings: Normal or decreased number of leukocytes (≤9·5 10/L), lymphopenia (<1·1 10/L), eosinopenia (<0·02 10/L), and elevated hs-CRP (≥4 mg/L) were presented in 95·0%, 52·2%, 74·7% and 86·7% of COVID-19 patients, much higher than 87·2%, 28·8%, 31·3% and 45·2% of the controls, respectively. The eosinopenia produced a sensitivity of 74·7% and specificity of 68·7% for separating the two groups with the area under the curve (AUC) of 0·717. The combination of eosinopenia and elevated hs-CRP yielded a sensitivity of 67·9% and specificity of 78·2% (AUC=0·730). The addition of eosinopenia alone or the combination of eosinopenia and elevated hs-CRP into the guideline-recommended diagnostic parameters for COVID-19 improved the predictive capacity with higher than zero of both net reclassification improvement (NRI) and integrated discrimination improvement (IDI).

Interpretation: The combination of eosinopenia and elevated hs-CRP can effectively triage suspected COVID-19 patients from other patients attending the fever clinic with COVID-19-like initial symptoms. This finding would be particularly useful for designing triage strategies in an epidemic region having a large number of patients with COVID-19 and other respiratory diseases while limited medical resources for nucleic acid tests and radiographic examination.
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http://dx.doi.org/10.1016/j.eclinm.2020.100375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196382PMC
June 2020

Characterization of the Pseudomonas aeruginosa T6SS PldB immunity proteins PA5086, PA5087 and PA5088 explains a novel stockpiling mechanism.

Acta Crystallogr F Struct Biol Commun 2020 May 28;76(Pt 5):222-227. Epub 2020 Apr 28.

Multidiscipline Research Center, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, People's Republic of China.

The bacterial type VI secretion system (T6SS) secretes many toxic effectors to gain advantage in interbacterial competition and for eukaryotic host infection. The cognate immunity proteins of these effectors protect bacteria from their own effectors. PldB is a T6SS trans-kingdom effector in Pseudomonas aeruginosa that can infect both prokaryotic and eukaryotic cells. Three proteins, PA5086, PA5087 and PA5088, are employed to suppress the toxicity of PldB-family proteins. The structures of PA5087 and PA5088 have previously been reported, but the identification of further distinctions between these immunity proteins is needed. Here, the crystal structure of PA5086 is reported at 1.90 Å resolution. A structural comparison of the three PldB immunity proteins showed vast divergences in their electrostatic potential surfaces. This interesting phenomenon provides an explanation of the stockpiling mechanism of T6SS immunity proteins.
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http://dx.doi.org/10.1107/S2053230X2000566XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193511PMC
May 2020

Clinical presentations and outcomes of SARS-CoV-2 infected pneumonia in pregnant women and health status of their neonates.

Sci Bull (Beijing) 2020 Sep 28;65(18):1537-1542. Epub 2020 Apr 28.

Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.

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http://dx.doi.org/10.1016/j.scib.2020.04.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186128PMC
September 2020