bluuebunny/crossref_metadata_2025 huggingface dataset:
An Education Intervention to Improve Knowledge of Post-Traumatic Stress Disorder Symptoms and Treatments Among U.S. Women Service Members and Veterans
Authors: Proctor Denise M , Emmons Kevin R , Scannell-Desch Elizabeth
Published: December 2021

Introduction

Due to decades of prolonged combat operations, post-traumatic stress disorder (PTSD) is widely discussed and generally well conceptualized. The objective of this study was to determine if an educational program on the signs and symptoms of PTSD and an explanation of the current treatments utilized by the Veterans Administration is effective in increasing the knowledge levels of women service members and veterans, leading to seeking treatment.

Materials and Methods

The design of this study was a quantitative pretest/posttest interventional study. The educational program was conducted at a Senior Citizen Center. The population was a purposive sample of 44 women service members and veterans from a military base in New Jersey. A 25-item PTSD Knowledge Questionnaire developed for the earlier Web-Based Post-traumatic Stress Disorder Education for Military Family Members (2012) study was used as the pretest and posttest.

Results

The knowledge level of PTSD among women service members and veterans who participated in this study was significantly higher after completing the educational program with 43% indicating that they would seek mental health care.

Conclusions

Women service members and veterans were ill-informed on the signs, symptoms, and treatment options of PTSD. If the results of this survey are an indicator of the knowledge level of women service members in broader populations, there is a need to restructure how those who are at risk of developing PTSD are educated. Through better educational programs, women and men could seek care with increasingly favorable long-term outcomes.
Faraday depolarization and induced circular polarization by multipath propagation with application to FRBs
Authors: Beniamini Paz , Kumar Pawan , Narayan Ramesh
Published: December 2021

We describe how the observed polarization properties of an astronomical object are related to its intrinsic polarization properties and the finite temporal and spectral resolutions of the observing device. Moreover, we discuss the effect that a scattering screen, with non-zero magnetic field, between the source and observer has on the observed polarization properties. We show that the polarization properties are determined by the ratio of observing bandwidth and coherence bandwidth of the scattering screen and the ratio of temporal resolution of the instrument and the variability time of screen, as long as the length over which the Faraday rotation induced by the screen changes by ∼π is smaller than the size of the screen visible to the observer. We describe the conditions under which a source that is 100 per cent linearly polarized intrinsically might be observed as partially depolarized, and how the source’s temporal variability can be distinguished from the temporal variability induced by the scattering screen. In general, linearly polarized waves passing through a magnetized scattering screen can develop a significant circular polarization. We apply the work to the observed polarization properties of a few fast radio bursts (FRBs), and outline potential applications to pulsars.
miRetrieve—an R package and web application for miRNA text mining
Authors: Friedrich Julian , Hammes Hans-Peter , Krenning Guido
Published: December 2021

microRNAs (miRNAs) regulate gene expression and thereby influence biological processes in health and disease. As a consequence, miRNAs are intensely studied and literature on miRNAs has been constantly growing. While this growing body of literature reflects the interest in miRNAs, it generates a challenge to maintain an overview, and the comparison of miRNAs that may function across diverse disease fields is complex due to this large number of relevant publications. To address these challenges, we designed miRetrieve, an R package and web application that provides an overview on miRNAs. By text mining, miRetrieve can characterize and compare miRNAs within specific disease fields and across disease areas. This overview provides focus and facilitates the generation of new hypotheses. Here, we explain how miRetrieve works and how it is used. Furthermore, we demonstrate its applicability in an exemplary case study and discuss its advantages and disadvantages.
Extent of MGMT promoter methylation modifies the effect of temozolomide on overall survival in patients with glioblastoma: a regional cohort study
Authors: Poon Michael T C , Keni Shivank , Vimalan Vineeth , Ip Chak , Smith Colin , Erridge Sara , Weir Christopher J , Brennan Paul M
Published: December 2021

Background

MGMT methylation in glioblastoma predicts response to temozolomide but dichotomizing methylation status may mask the true prognostic value of quantitative MGMT methylation. This study evaluated whether extent of MGMT methylation interacts with the effect of temozolomide on overall survival.

Methods

We included consecutive glioblastoma patients aged ≥16 years diagnosed (April 2012–May 2020) at a neuro-oncology center. All patients had quantitative MGMT methylation measured using pyrosequencing. Those with MGMT methylated tumors were stratified into high and low methylation groups based on a cut-off using Youden index on 2-year survival. Our accelerated failure time survival models included extent of MGMT methylation, age, postoperative Karnofsky performance score, extent of resection, temozolomide regimen, and radiotherapy.

Results

There were 414 patients. Optimal cut-off point using Youden index was 25.9% MGMT methylation. The number of patients in the unmethylated, low and high methylation groups was 223 (53.9%), 81 (19.6%), and 110 (26.6%), respectively. In the adjusted model, high (hazard ratio [HR] 0.60, 95% confidence intervals [CI] 0.46–0.79, P = 0.005) and low (HR 0.67, 95% CI 0.50–0.89, P < 0.001) methylation groups had better survival compared to unmethylated group. There was no evidence for interaction between MGMT methylation and completed temozolomide regimen (interaction term for low methylation P = 0.097; high methylation P = 0.071). This suggests no strong effect of MGMT status on survival in patients completing temozolomide regimen. In patients not completing the temozolomide regimen, higher MGMT methylation predicted better survival (interaction terms P < 0.001).

Conclusions

Quantitative MGMT methylation may provide additional prognostic value. This is important when assessing clinical and research therapies.
Increased Moxifloxacin Dosing Among Patients With Multidrug-Resistant Tuberculosis With Low-Level Resistance to Moxifloxacin Did Not Improve Treatment Outcomes in a Tertiary Care Center in Mumbai, India
Authors: Tornheim Jeffrey A , Udwadia Zarir F , Arora Prerna R , Gajjar Ishita , Sharma Samridhi , Karane Megha , Sawant Namrata , Kharat Nisha , Blum Alexander J , Shivakumar Shri Vijay Bala Yogendra , Gupte Akshay N , Gupte Nikhil , Mullerpattan Jai B , Pinto Lancelot M , Ashavaid Tester F , Gupta Amita , Rodrigues Camilla
Published: December 2021

Background

Mycobacterium tuberculosis (Mtb) strains resistant to isoniazid and rifampin (multidrug-resistant tuberculosis [MDR-TB]) are increasingly reported worldwide, requiring renewed focus on the nuances of drug resistance. Patients with low-level moxifloxacin resistance may benefit from higher doses, but limited clinical data on this strategy are available.

Methods

We conducted a 5-year observational cohort study of MDR-TB patients at a tertiary care center in India. Participants with Mtb isolates resistant to isoniazid, rifampin, and moxifloxacin (at the 0.5 µg/mL threshold) were analyzed according to receipt of high-dose moxifloxacin (600 mg daily) as part of a susceptibility-guided treatment regimen. Univariable and multivariable Cox proportional hazard models assessed the relationship between high-dose moxifloxacin and unfavorable treatment outcomes.

Results

Of 354 participants with MDR-TB resistant to moxifloxacin, 291 (82.2%) received high-dose moxifloxacin. The majority experienced good treatment outcomes (200 [56.5%]), which was similar between groups (56.7% vs 54.0%, P = .74). Unfavorable outcomes were associated with greater extent of radiographic disease, lower initial body mass index, and concurrent treatment with fewer drugs with confirmed phenotypic susceptibility. Treatment with high-dose moxifloxacin was not associated with improved outcomes in either unadjusted (hazard ratio [HR], 1.2 [95% confidence interval {CI}, .6–2.4]) or adjusted (HR, 0.8 [95% CI, .5–1.4]) models but was associated with joint pain (HR, 3.2 [95% CI, 1.2–8.8]).

Conclusions

In a large observational cohort, adding high-dose (600 mg) moxifloxacin to a drug susceptibility test–based treatment regimen for MDR-TB was associated with increased treatment-associated side effects without improving overall outcomes and should be avoided for empiric treatment of moxifloxacin-resistant MDR-TB.
Contemporary Clinical and Molecular Epidemiology of Vancomycin-Resistant Enterococcal Bacteremia: A Prospective Multicenter Cohort Study (VENOUS I)
Authors: Contreras German A , Munita Jose M , Simar Shelby , Luterbach Courtney , Dinh An Q , Rydell Kirsten , Sahasrabhojane Pranoti V , Rios Rafael , Diaz Lorena , Reyes Katherine , Zervos Marcus , Misikir Helina M , Sanchez-Petitto Gabriela , Liu Catherine , Doi Yohei , Abbo Lilian M , Shimose Luis , Seifert Harald , Gudiol Carlota , Barberis Fernanda , Pedroza Claudia , Aitken Samuel L , Shelburne Samuel A , van Duin David , Tran Truc T , Hanson Blake M , Arias Cesar A
Published: December 2021

Background

Vancomycin-resistant enterococci (VRE) are major therapeutic challenges. Prospective contemporary data characterizing the clinical and molecular epidemiology of VRE bloodstream infections (BSIs) are lacking.

Methods

The Vancomycin-Resistant Enterococcal BSI Outcomes Study (VENOUS I) is a prospective observational cohort of adult patients with enterococcal BSI in 11 US hospitals. We included patients with Enterococcus faecalis or Enterococcus faecium BSI with ≥1 follow-up blood culture(s) within 7 days and availability of isolate(s) for further characterization. The primary study outcome was in-hospital mortality. Secondary outcomes were mortality at days 4, 7, 10, 12, and 15 after index blood culture. A desirability of outcome ranking was constructed to assess the association of vancomycin resistance with outcomes. All index isolates were subjected to whole genome sequencing.

Results

Forty-two of 232 (18%) patients died in hospital and 39 (17%) exhibited microbiological failure (lack of clearance in the first 4 days). Neutropenia (hazard ratio [HR], 3.13), microbiological failure (HR, 2.4), VRE BSI (HR, 2.13), use of urinary catheter (HR, 1.85), and Pitt BSI score ≥2 (HR, 1.83) were significant predictors of in-hospital mortality. Microbiological failure was the strongest predictor of in-hospital mortality in patients with E faecium bacteremia (HR, 5.03). The impact of vancomycin resistance on mortality in our cohort changed throughout the course of hospitalization. Enterococcus faecalis sequence type 6 was a predominant multidrug-resistant lineage, whereas a heterogeneous genomic population of E faecium was identified.

Conclusions

Failure of early eradication of VRE from the bloodstream is a major factor associated with poor outcomes.
Ultrathin metal–organic framework nanosheets and devices
Authors: Meiyazhagan AshokKumar
Published: December 2021

A few recent findings on ultrathin two-dimensional (2D) metal–organic frameworks (MOFs) were discussed in this spotlight review. MOFs are a class of materials with intriguing properties for possible applications in several fields ranging from catalysis to sensors and functional devices. To date, several synthesis strategies have been explored to derive crystalline 2D MOF structures. However, most synthetic strategies to obtain such materials remain underexplored. This highlighted review evaluated select synthesis strategies focused on deriving micron-sized 2D MOF crystals, emphasizing their rich chemistries. More importantly, the possibility of integrating the synthesized ultrathin 2D crystalline MOFs into the functional device and their electrical conductivity measurements is reviewed. Overall, this review provides the most recent outcomes in the ultrathin 2D MOF community and its influence on electronic devices.
Thin-film growth of MAX phases as functional materials
Authors: Biswas Abhijit , Natu Varun , Puthirath Anand B
Published: December 2021

Layered nanolaminate ternary carbides, nitrides and carbonitrides with general formula Mn+1AXn or MAX (n = 1, 2, or 3, M is an early transition metal, A is mostly group 13 or 14 element and X is C and/or N) has revolutionized the world of nanomaterials, due to the coexistence of both ceramic and metallic nature, giving rise to exceptional mechanical, thermal, electrical, chemical properties and wide range of applications. Although several solid-state bulk synthesis methods have been developed to produce a variety of MAX phases, however, for certain applications, the growth of MAX phases, especially in its high-quality epitaxial thin-films form is of increasing interest. Here, we summarize the progress made thus far in epitaxial growth and property evaluation of MAX phase thin films grown by various deposition techniques. We also address the important future research directions to be made in terms of thin-film growth. Overall, in the future, high-quality single-phase epitaxial thin-film growth and engineering of chemically diverse MAX phases may open up interesting new avenues for next-generation technology.
Temporal and Spatial Variations of Enriched Source Components in Linzizong Volcanic Succession, Tibet, and Implications for the India–Asia Collision
Authors: Liu An-Lin , Wang Qing , Zhu Di-Cheng , Cawood Peter A , Xia Ying , Li Shi-Min , Liu Sheng-Ao , Huang Fang , Liu Li , Zhao Zhi-Dan , Mo Xuan-Xue
Published: December 2021

The temporal and spatial distribution of enriched source components at sites of continent–continent collision provides critical insights into mantle dynamic processes associated with subduction- and collision-related events. However, determining the origin of such enriched components remains a significant challenge. We report a comprehensive dataset of the Linzizong volcanic succession (LVS) from four locations with varying distance across-strike to the Indus–Yarlung suture in southern Tibet, which marks the exposed surface expression of the India–Asia collision zone. The LVS rocks in this study can be divided into two groups: a calc-alkaline Group 1 (69–55 Ma), mainly including basaltic–andesitic varieties, and a shoshonitic Group 2 (52–50 Ma), consisting predominantly of silicic rocks with minor mafic compositions. Group 1 samples are likely derived from the fractional crystallization of primitive basaltic melts as a result of the partial melting of a metasomatized mantle wedge. These samples are decoupled in Nd–Hf isotopic compositions, suggesting an incorporation of subducting sediment-derived melts into the mantle wedge. The influence of sediment-derived melt on the mantle source increases away from the suture zone toward Asia (i.e., from the south to the north) as indicated by the more enriched Sr, Nd, Pb, and Hf isotopic compositions, as well as elevated Th/La and La/Sm ratios. The heavy δ26Mg values, and high Ba/Th and Sr/Th ratios of samples close to the suture coincide with the dehydration of the subducting Neo-Tethyan slab. Group 2 mafic samples have depleted and coupled εNd–εHf isotopic compositions and are characterized by elevated (La/Yb)N and Dy/Yb ratios as well as low Zr/Nb ratios, indicating an origin of enriched garnet-bearing lithospheric mantle with contributions from asthenosphere-derived materials. Group 2 silicic samples are isotopically enriched both near and far away from the suture, which can be attributed to the involvement of ancient lower crust-derived melt from Tethyan Himalaya and central Lhasa subterrane basement, respectively. Our results show that the LVS are the magmatic response to late subduction (Group 1), and to initial India–Asia collision and slab breakoff (Group 2). Negative trends in the whole-rock Nd and zircon Hf isotopic compositions at ~51 Ma should be treated with caution for geodynamic interpretations, depending on the distance between the samples and the India–Asia suture.
Pandemic Ethics and Status Quo Risk
Authors: Chappell Richard Yetter
Published: December 2021

Conservative assumptions in medical ethics risk immense harms during a pandemic. Public health institutions and public discourse alike have repeatedly privileged inaction over aggressive medical interventions to address the pandemic, perversely increasing population-wide risks while claiming to be guided by ‘caution’. This puzzling disconnect between rhetoric and reality is suggestive of an underlying philosophical confusion. In this paper, I argue that we have been misled by status quo bias—exaggerating the moral significance of the risks inherent in medical interventions, while systematically neglecting the (objectively greater) risks inherent in the status quo prospect of an out-of-control pandemic. By coming to appreciate the possibility and significance of status quo risk, we will be better prepared to respond appropriately when the next pandemic strikes.
Improvement of base editors and prime editors advances precision genome engineering in plants
Authors: Hua Kai , Han Peijin , Zhu Jian-Kang
Published: December 2021

Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein (Cas)-mediated gene disruption has revolutionized biomedical research as well as plant and animal breeding. However, most disease-causing mutations and agronomically important genetic variations are single base polymorphisms (single-nucleotide polymorphisms) that require precision genome editing tools for correction of the sequences. Although homology-directed repair of double-stranded breaks (DSBs) can introduce precise changes, such repairs are inefficient in differentiated animal and plant cells. Base editing and prime editing are two recently developed genome engineering approaches that can efficiently introduce precise edits into target sites without requirement of DSB formation or donor DNA templates. They have been applied in several plant species with promising results. Here, we review the extensive literature on improving the efficiency, target scope, and specificity of base editors and prime editors in plants. We also highlight recent progress on base editing in plant organellar genomes and discuss how these precision genome editing tools are advancing basic plant research and crop breeding.
Deficiency in flavonoid biosynthesis genesCHS,CHI, andCHILalters rice flavonoid and lignin profiles
Authors: Lam Pui Ying , Wang Lanxiang , Lui Andy C W , Liu Hongjia , Takeda-Kimura Yuri , Chen Mo-Xian , Zhu Fu-Yuan , Zhang Jianhua , Umezawa Toshiaki , Tobimatsu Yuki , Lo Clive
Published: December 2021

Lignin is a complex phenylpropanoid polymer deposited in the secondary cell walls of vascular plants. Unlike most gymnosperm and eudicot lignins that are generated via the polymerization of monolignols, grass lignins additionally incorporate the flavonoid tricin as a natural lignin monomer. The biosynthesis and functions of tricin-integrated lignin (tricin-lignin) in grass cell walls and its effects on the utility of grass biomass remain largely unknown. We herein report a comparative analysis of rice (Oryza sativa) mutants deficient in the early flavonoid biosynthetic genes encoding CHALCONE SYNTHASE (CHS), CHALCONE ISOMERASE (CHI), and CHI-LIKE (CHIL), with an emphasis on the analyses of disrupted tricin-lignin formation and the concurrent changes in lignin profiles and cell wall digestibility. All examined CHS-, CHI-, and CHIL-deficient rice mutants were largely depleted of extractable flavones, including tricin, and nearly devoid of tricin-lignin in the cell walls, supporting the crucial roles of CHS and CHI as committed enzymes and CHIL as a noncatalytic enhancer in the conserved biosynthetic pathway leading to flavone and tricin-lignin formation. In-depth cell wall structural analyses further indicated that lignin content and composition, including the monolignol-derived units, were differentially altered in the mutants. However, regardless of the extent of the lignin alterations, cell wall saccharification efficiencies of all tested rice mutants were similar to that of the wild-type controls. Together with earlier studies on other tricin-depleted grass mutant and transgenic plants, our results reflect the complexity in the metabolic consequences of tricin pathway perturbations and the relationships between lignin profiles and cell wall properties.
Injectable self-healing ceria-based nanocomposite hydrogel with ROS-scavenging activity for skin wound repair
Authors: Gong Xueyun , Luo Meng , Wang Min , Niu Wen , Wang Yidan , Lei Bo
Published: December 2021

Excessive reactive oxygen species (ROS) in the injured skin may impede the wound repair and skin regeneration. Herein, we develop an injectable self-healing ceria-based nanocomposite hydrogel with ROS-scavenging activity to accelerate wound healing. The nanocomposite hydrogels were successfully prepared by coating cerium oxide nanorods with polyethylenimine and crosslinked with benzaldehyde-terminated F127 (F127-CHO) through the dynamic Schiff-base reaction (FVEC hydrogel). The results showed that the FVEC hydrogel possessed the good thermosensitivity, injectability, self-healing ability and ROS scavenging activity. The subcutaneous implantation experiments in mice confirmed that FVEC hydrogels are biocompatible and biodegradable in vivo. The full-thickness skin wound studies showed that FVEC hydrogel could significantly enhance the wound healing and epithelium regeneration with the formation of hair follicle and adipocyte tissue. This work provides a new strategy for the development of multifunctional Ce-based nanocomposite hydrogel for full-thickness skin wound healing and regeneration.
Tick-Borne Disease–Associated Thrombocytopenia
Authors: Papamanoli Aikaterini , Kaplun Olga , Lobo Zeena , LeMaitre Beth , Romano Christopher L. , Campbell Scott R. , Psevdos George
Published: December 2021

Background

North America, and especially Suffolk County, Long Island, New York, is a recognized region for tick-borne diseases. Thrombocytopenia is a common manifestation of certain tick-borne diseases. Our objective was to review cases of thrombocytopenia attributed to tick-borne diseases and to also report local tick surveillance data.

Methods

A retrospective chart review was conducted from 2000 to 2018 analyzing confirmed cases of anaplasmosis, ehrlichiosis, and babesiosis seen in our facility. The Suffolk County tick-borne disease pathogen surveillance program reports data annually. We report surveillance data on ticks and the pathogens they harbored.

Results

A total of 35 veterans were identified with the following tick-borne diseases: babesiosis, 23; ehrlichiosis, 7; and anaplasmosis, 5. The median temperature on presentation was 102.0°F. The median platelet count for the whole cohort was 95,000/μL, with no statistical difference between the 3 diseases, P = 0.169. Rising incidence is noted on all tick-borne diseases, including coinfections in ticks analyzed in Suffolk County.

Conclusions

Based on current epidemiologic trends, and local tick surveillance data, coinfections with tick-borne diseases need to be considered.
Condomless Sex With Partners and Clients Among Female Sex Workers in Iran: A Systematic Review and Meta-Analysis
Authors: Khezri Mehrdad , Tavakoli Fatemeh , Bazrafshan Azam , Sharifi Hamid , Shokoohi Mostafa
Published: December 2021

Condomless sex is the most proximal risk for HIV acquisition among female sex workers (FSWs). We performed a systematic review and meta-analysis to summarize the evidence for the prevalence of condomless sex among FSWs in Iran. A random-effect meta-analysis model was used to pool the prevalence estimates and their 95% confidence intervals (CIs). The pooled prevalence of condomless sex at last sex with a paying client and a nonpaying partner was 34.23% (95% CI: 27.83–40.93) and 48.34 (95% CI: 38.43–58.32), respectively. Last-month inconsistent condom use was 49.01% (95% CI: 21.64–76.71) with paying clients and 60.21% (95% CI: 31.27–85.73) with nonpaying partners. The pooled prevalence of lifetime condom nonuse with any partners/clients was 15.26% (95% CI: 10.68–20.49). These findings indicate that a substantial proportion of FSWs engage in high-risk sexual practices. Community-led programs should be stimulated to improve consistent condom use among FSWs.
Analysis of Fibrotic Plaques in Angiographic Manifest Cardiac Allograft Vasculopathy in Long-term Heart Transplanted Patients Using Optical Coherence Tomography
Authors: Orban Madeleine , Dischl Dominic , Müller Christoph , Ulrich Sarah , Petzold Tobias , Rizas Konstantinos , Orban Martin W. , Braun Daniel , Hausleiter Jörg , Hagl Christian , Mehilli Julinda , Massberg Steffen
Published: December 2021

Background.

The development and progression of cardiac allograft vasculopathy documented by coronary angiography (CAVangio) after heart transplantation (HTx) has prognostic relevance. Yet there are limited data regarding the role of concomitant intracoronary imaging in the presence CAVangio. In particular, atherosclerotic plaques might represent a potential target for prevention, but their impact on stenosis is understudied.

Methods.

We used high-resolution intracoronary optical coherence tomography (OCT) to quantify and compare findings of intimal hyperplasia (IH) and plaque morphologies in HTx patients (fibrotic plaque, lipid plaque, and calcified plaque). OCT findings were related to the presence of CAVangio as well as to the severity of stenosis.

Results.

We included 65 consecutive patients into analysis (66% with CAVangio, posttransplant interval 9.9 ± 7.6 y). Fibrotic, lipid, and calcified plaques were present in 41 (63.1%), 39 (60%), and 18 (27.7%) patients, respectively. In addition to IH, the presence of fibrotic, lipid, and calcified plaques was found to be associated with CAVangio. The prevalence of lipid plaque and quantitative measurements of fibrotic plaque increased with stenosis severity (lipid plaque, P < 0.001, maximal and mean fibrotic arc, P = 0.05 and P = 0.001, respectively). Receiver operating characteristic analysis showed that area under the curve of the fibrotic plaque parameter mean fibrotic arc (0.87, 95% confidence interval [0.76-0.99]; P = 0.002) was superior to area under the curve of intima parameters regarding CAVangio. The effect of mean fibrotic arc (r = 0.52, P < 0.001) was relevant regarding stenosis severity.

Conclusions.

After a longer posttransplant interval, CAV findings in OCT included a combination of IH and atherosclerotic plaques. In addition to IH, the presence of fibrotic, lipid, and calcified plaques is associated with CAVangio. Further studies are warranted to evaluate if the in vivo screening for plaque progress, particularly of fibrotic plaque, could improve individual secondary prevention and outcome in HTx patients.
Development of full-length cell-culture infectious clone and subgenomic replicon for a genotype 3a isolate of hepatitis C virus
Authors: Chen Mingxiao , Xu Yi , Li Ni , Yin Ping , Zhou Qing , Feng Shengjun , Wu Tiantian , Wei Lai , Wang Haihe , Fu Yongshui , Li Yi-Ping
Published: December 2021

Hepatitis C virus (HCV) genotype 3 is widely distributed, and genotype 3-infected patients achieve a lower cure rate in direct-acting antiviral (DAA) therapy and are associated with a higher risk of hepatic steatosis than patients with other genotypes. Thus, the study of the virology and pathogenesis of genotype 3 HCV is increasingly relevant. Here, we developed a full-length infectious clone and a subgenomic replicon for the genotype 3a isolate, CH3a. From an infected serum, we constructed a full-length CH3a clone, however, it was nonviable in Huh7.5.1 cells. Next, we systematically adapted several intergenotypic recombinants containing Core-NS2 and 5′UTR-NS5A from CH3a, and other sequences from a replication-competent genotype 2 a clone JFH1. Adaptive mutations were identified, of which several combinations facilitated the replication of CH3a-JFH1 recombinants; however, they failed to adapt to the full-length CH3a and the recombinants containing CH3a NS5B. Thus, we attempted to separately adapt CH3a NS5B-3′UTR by constructing an intragenotypic recombinant using 5′UTR-NS5A from an infectious genotype 3a clone, DBN3acc, from which L3004P/M in NS5B and a deletion of 11 nucleotides (Δ11nt) downstream of the polyU/UC tract of the 3′UTR were identified and demonstrated to efficiently improve virus production. Finally, we combined functional 5′UTR-NS5A and NS5B-3′UTR sequences that carried the selected mutations to generate full-length CH3a with 26 or 27 substitutions (CH3acc), and both revealed efficient replication and virus spread in transfected and infected cells, releasing HCV of 104.2 f.f.u. ml−1. CH3acc was inhibited by DAAs targeting NS3/4A, NS5A and NS5B in a dose-dependent manner. The selected mutations permitted the development of subgenomic replicon CH3a-SGRep, by which L3004P, L3004M and Δ11nt were proven, together with a single-cycle virus production assay, to facilitate virus assembly, release, and RNA replication. CH3acc clones and CH3a-SGRep replicon provide new tools for the study of HCV genotype 3.
COVID-19: Salient Aspects of Coronavirus Infection, Vaccines and Vaccination Testing and their Implications
Authors: Pasricha Pradeep K. , Upadhayaya Arun K.
Published: December 2021

In the present study, three basic aspects related to COVID-19 are presented.

The occurrence of coronavirus infection is analyzed statistically as number of coronaviruses infected alveolar cells compared to normal alveolar cells in human lungs. The mole concept is used to estimate the number of normal alveolar cells per human lung. The number of coronavirus infections in infected alveolar cells is estimated from the published Lower Respiratory Tract (LRT) load data. The Poisson probability distribution is aptly applied to imply the incubation period of the coronavirus infection to be within day-3 to day-7, with the cumulative probability of 75%. The incubation period within day-0 to day-10 has a cumulative probability of 98%. It implies a 10-day quarantine to isolate an uninfected individual as a precautionary measure.

Three vaccines to combat COVID-19, which adopt distinct paradigms while preparing them, are analyzed. These are Moderna’s mRNA-1273, Oxford-AstraZeneca’s ChAdOx1 nCoV-19 and Bharat BioTech’s COVAXIN. The mole concept is used to estimate the antigen mass density per dose of each of these vaccines as 10 g cm-3, 0.1 g cm-3 and 1 g cm-3, respectively. The vaccines are deemed to be compatible to neutralize the infection.

A statistical analysis is performed of the Moderna’s mRNA-1273 vaccine efficacy of 94.1% and Oxford’s ChAdOx1 nCoV-19 vaccine efficacy of 62.1% in terms of groups of volunteers testing negative to vaccine by chance. In the Moderna vaccination testing scenario, since the probability of negative response of vaccine is small, the Poisson probability distribution for 95% cumulative probability is used to describe the vaccination testing in 300 samples of 47 volunteers each. Thus, 87% of samples have average group of 3 volunteers testing negative to vaccine. About 6% of samples have all volunteers testing positive to vaccine. In the Oxford vaccination testing scenario, since the probability of negative response of vaccine is finite, the Gaussian probability distribution for 95% probability is used to describe the vaccination testing in 75 samples of 120 volunteers each. Thus, 68% of samples have average group of 45 volunteers testing negative to vaccine. No sample has all volunteers testing positive to vaccine. A vaccine, irrespective of its efficacy being high or low, is necessary for mass immunization.
Broad and Long-lasting Immune Response against SARS-CoV-2 Omicron and Other Variants by PIKA-Adjuvanted Recombinant SARS-CoV-2 Spike (S) Protein Subunit Vaccine (YS-SC2-010)
Authors: Liu Yuan , Zhang Nan , Wang Bin , Zhang Yi
Published: December 2021

Recently SARS-CoV-2 Omicron (B.1.1.529) variant was identified in South Africa with numerous mutations in spike protein, and numerous community infections have been reported and raised grave concern around the world. Some studies found that the neutralization effects of several licensed vaccines against Omicron were dramatically reduced, which significantly affected antibody mediated protection, especially for individuals whose immunization were completed after extended period. In this regard, we studied the persistence and neutralization activity toward mutant strains in animal serum immunized with PIKA-adjuvanted recombinant SARS-CoV-2 spike protein subunit vaccine (YS-SC2-010). Here we are reporting that animal serum collected at 596 days after immunization with YS-SC2-010 still retains high and persistent neutralizing activity against all the Variant of Concern (VOC) variants, including Omicron variant. Although it is a blessed event to achieve 20 months long neutralization against Omicron variant after immunization with YS-SC2-010, it was also founded that the neutralization effect of immune serum on Omicron decreased by 6.29 folds as compared to D614G, more significantly when compared with other mutant strains.
Waning immune responses against SARS-CoV-2 among vaccinees in Hong Kong
Authors: Peng Qiaoli , Zhou Runhong , Wang Yuewen , Zhao Meiqing , Liu Na , Li Shuang , Huang Haode , Yang Dawei , Au Ka-Kit , Wang Hui , Man Kwan , Yuen Kwok-Yung , Chen Zhiwei
Published: December 2021

Background

Nearly 4 billion doses of the BioNTech-mRNA and Sinovac-inactivated vaccines have been administrated globally, yet different vaccine-induced immunity against SARS-CoV-2 variants of concern (VOCs) remain incompletely investigated.

Methods

We compare the immunogenicity and durability of these two vaccines among fully vaccinated Hong Kong people.

Findings

Standard BioNTech and Sinovac vaccinations were tolerated and induced neutralizing antibody (NAb) (100% and 85.7%) and spike-specific CD4 T cell responses (96.7% and 82.1%), respectively. The geometric mean NAb IC50 and median frequencies of reactive CD4 subsets were consistently lower among Sinovac-vaccinees than BioNTech-vaccinees. Against VOCs, NAb response rate and geometric mean IC50 against B1.351 and B.1.617.2 were significantly lower for Sinovac (14.3%, 15 and 50%, 23.2) than BioNTech (79.4%, 107 and 94.1%, 131). Three months after vaccinations, NAbs to VOCs dropped near to detection limit, along with waning memory T cell responses, mainly among Sinovac-vaccinees.

Interpretation

Our results indicate that Sinovac-vaccinees may face higher risk to pandemic VOCs breakthrough infection.

Funding

This study was supported by the Hong Kong Research Grants Council Collaborative Research Fund (C7156-20GF to Z.C and C1134-20GF); the National Program on Key Research Project of China (Grant 2020YFC0860600, 2020YFA0707500 and 2020YFA0707504); Shenzhen Science and Technology Program (JSGG20200225151410198 and JCYJ20210324131610027); HKU Development Fund and LKS Faculty of Medicine Matching Fund to AIDS Institute; Hong Kong Innovation and Technology Fund, Innovation and Technology Commission and generous donation from the Friends of Hope Education Fund. Z.C.’s team was also partly supported by the Theme-Based Research Scheme (T11-706/18-N).
Increased Long-Term Mortality in Patients Admitted to the Intensive Care Unit with Health-Care Associated Pneumonia
Authors: Wise Kristin R. , Kempker Jordan A. , Neamu Radu F. , Kobaidze Ketino
Published: December 2021

Background

Pneumonia is a leading cause of death in the United States. Guidelines for its diagnosis and management are periodically updated, but long-term mortality in critically ill patients has not been well studied.

Objective

To determine differences in one-year mortality between patients with community-acquired pneumonia (CAP) and healthcare-associated pneumonia or hospital-acquired pneumonia (HCAP/HAP).

Methods

A retrospective multivariate analysis of a prospective cohort study that included all patients admitted to a single-center medical intensive care unit (ICU) from October 1, 2007, through September 30, 2008, with a diagnosis of pneumonia.

Results

There were 181 patients admitted to the medical ICU with a diagnosis of pneumonia, 58.0% with HCAP/HAP and 42.0% with CAP. Those with HCAP/HAP had an older age distribution and higher proportions of cardiovascular (79.1% vs. 63.2%, P=0.02) and neurological (36.2% vs. 18.4%, P=0.01) comorbidities. The HCAP/HAP patients demonstrated an increased risk of death within one a year in the unadjusted analysis (HR 1.6, 95% CI 1.1-2.2, P=0.01) that did not remain significant in the multivariate analysis (HR 1.3, 95% CI 0.80-2.10. P=0.29) when adjusting for simplified acute physiology score (SAPS) II score, age category, source of admission and a history of diabetes mellitus, neurological disease or malignancy.

Conclusion

Compared to patients admitted to a medical ICU with CAP, those with HCAP/HAP had a higher one-year mortality that is accounted for by the increased co-morbidities associated with a HCAP/HAP diagnosis.

Summary of Key Points

The American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) developed and periodically update guidelines for the diagnosis and management of community-acquired and nosocomial pneumonia based on the patient-care setting in which pneumonia evolved. ATS/IDSA provides guidelines for empiric antibiotic choices based on the category of pneumonia that is diagnosed.

Pneumonia is a significant cause of mortality in the United States and when combined with influenza ranks as the eighth leading cause of death nationwide yet little is known about the mortality of critically ill patients with pneumonia that require admission to a medical intensive care unit (ICU).

Our findings suggest that older age, higher severity of illness at ICU admission, and chronic comorbid illnesses are the main contributors to long-term mortality from pneumonia requiring ICU admission.

In this cohort, we found an independent association between increased mortality and admission from the general hospital ward rather than directly from the emergency department.

Our study did not demonstrate that initial guideline-based antibiotic therapy was associated with a reduction in short-term mortality; however, it did demonstrate a high prevalence of resistant pathogens in HCAP/HAP patients, which reflects ATS/IDSA guideline expectations.
Surveillance and correlation of SARS-CoV-2 viral RNA, antigen, virus isolation, and self-reported symptoms in a longitudinal study with daily sampling
Authors: Bonenfant Gaston , Deyoe Jessica , Wong Terianne , Grijalva Carlos G. , Cui Dan , Talbot H. Keipp , Hassell Norman , Halasa Natasha , Chappell James , Thornburg Natalie J. , Rolfes Melissa A. , Wentworth David , Zhou Bin
Published: December 2021

The novel coronavirus pandemic incited unprecedented demand for assays that detect viral nucleic acids, viral proteins, and corresponding antibodies. The 320 molecular diagnostics in receipt of FDA emergency use authorization mainly focus on viral detection; however, no currently approved test can be used to infer infectiousness, i.e., the presence of replicable virus. As the number of tests conducted increased, persistent SARS-CoV-2 RNA positivity by RT-PCR in some individuals led to concerns over quarantine guidelines. To this end, we attempted to design an assay that reduces the frequency of positive test results from individuals who do not shed culturable virus. We describe multiplex quantitative RT-PCR (qRT-PCR) assays that detect genomic RNA (gRNA) and subgenomic RNA (sgRNA) species of SARS-CoV-2, including spike (S), nucleocapsid (N), membrane (M), envelope (E), and ORF8. The absolute copy number of each RNA target was determined in longitudinal specimens from a household transmission study. Calculated viral RNA levels over the 14-day follow up period were compared with antigen testing and self-reported symptoms to characterize the clinical and molecular dynamics of infection and infer predictive values of these qRT-PCR assays relative to culture isolation. When detection of sgS RNA was added to the CDC 2019-Novel Coronavirus Real-Time RT-PCR Diagnostic Panel, we found a qRT-PCR positive result was 98% predictive of a positive culture (negative predictive value was 94%). Our findings suggest sgRNA presence correlates with active infection, may help identify individuals shedding culturable virus, and that similar multiplex assays can be adapted to current and future variants.
Single cell RNA-seq identifies developing corneal cell fates in the human cornea organoid
Authors: Maiti George , de Barros Maithe Rocha Monteiro , Hu Nan , Roshan Mona , Wahlin Karl J , Chakravarti Shukti
Published: December 2021

The cornea is a protective and refractive barrier in the eye crucial for vision. Understanding the human cornea in health, disease and cell-based treatments can be greatly advanced with cornea organoids developed in culture from induced pluripotent stem cells. While a limited number of studies have investigated the single-cell transcriptomic composition of the human cornea, its organoids have not been examined similarly. Here we elucidated the transcriptomic cell fate map of 4 month-old human cornea organoids and the central cornea from three donors. The organoids harbor cell clusters representing corneal epithelium, stroma and endothelium with sub populations that capture signatures of early developmental states. Unlike the adult cornea where the largest cell population is stromal, the organoids develop almost equal proportion of the three major cell types. These corneal organoids offer a three-dimensional platform to model corneal diseases and integrated responses of the different cell types to treatments.

Teaser

Transcriptomic Map of Cornea Organoid and Human Cornea
Learning enhances encoding of time and temporal surprise in primary sensory cortex
Authors: Rabinovich Rebecca J. , Kato Daniel D. , Bruno Randy M.
Published: December 2021

Primary sensory cortex has long been believed to play a straightforward role in the initial processing of sensory information. Yet, the superficial layers of cortex overall are sparsely active, even during sensory stimulation; moreover, cortical activity is influenced by other modalities, task context, reward, and behavioral state. Our study demonstrates that reinforcement learning dramatically alters representations among longitudinally imaged neurons in superficial layers of mouse primary somatosensory cortex. Learning an object detection task recruits previously unresponsive neurons, enlarging the neuronal population sensitive to touch and behavioral choice. In contrast, cortical responses decrease upon repeated exposure to unrewarded stimuli. Moreover, training improved population encoding of the passage of time, and unexpected deviations in trial timing elicited even stronger responses than touch did. In conclusion, the superficial layers of sensory cortex exhibit a high degree of learning-dependent plasticity and are strongly modulated by non-sensory but behaviorally-relevant features, such as timing and surprise.
Two distinct binding modes provide the RNA binding protein RbFox with extraordinary sequence specificity
Authors: Ye Xuan , Yang Wen , Yi Soon , Zhao Yanan , Yang Fan , Varani Gabriele , Jankowsky Eckhard
Published: December 2021

The specificity of RNA-binding proteins for their target sequences varies considerably. Yet, it is not understood how certain proteins achieve markedly higher sequence specificity than most others. Here we show that the RNA Recognition Motif of RbFox accomplishes extraordinary sequence specificity by employing functionally and structurally distinct binding modes. Affinity measurements of RbFox for all binding site variants reveal the existence of two different binding modes. The first exclusively binds the cognate and a closely related RNA variant with high affinity. The second mode accommodates all other RNAs with greatly reduced affinity, thereby imposing large thermodynamic penalties on even near-cognate sequences. NMR studies indicate marked structural differences between the two binding modes, including large conformational rearrangements distant from the RNA binding site. Distinct binding modes by a single RNA binding module explain extraordinary sequence selectivity and reveal an unknown layer of functional diversity, cross talk and regulation for RNA-protein interactions.
Metabolic regulation by prostaglandin E2 impairs lung group 2 innate lymphoid cell responses
Authors: Robb Calum T. , Zhou You , Felton Jennifer M. , Zhang Birong , Goepp Marie , Jheeta Privjyot , Smyth Danielle J. , Breyer Richard M. , Narumiya Shuh , McSorley Henry J. , Maizels Rick M. , Schwarze Jürgen K.J. , Rossi Adriano G. , Yao Chengcan
Published: December 2021

Group 2 innate lymphoid cells (ILC2s) play a critical role in asthma pathogenesis. Non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) is associated with reduced signaling via EP2, a receptor for prostaglandin E2 (PGE2). However, the respective roles for the PGE2 receptors EP2 and EP4 (both share same downstream signaling) in the regulation of lung ILC2 responses has yet been deciphered. Here, we find that deficiency of EP2 rather than EP4 augments IL-33-induced lung ILC2 responses and eosinophilic inflammation in vivo. In contrast, exogenous agonism of EP4 but not EP2 markedly restricts IL-33- and Alternaria alternata-induced lung ILC2 responses and eosinophilic inflammation. Mechanistically, PGE2 directly suppresses IL-33-dependent ILC2 activation through the EP2/EP4-cAMP pathway, which downregulates STAT5 and MYC pathway gene expression and ILC2 energy metabolism. Blocking glycolysis diminishes IL-33-dependent ILC2 responses in mice lacking endogenous PG synthesis but not in PG-competent mice. Together, we have defined a mechanism for optimal suppression of lung ILC2 responses by endogenous PGE2-EP2 signaling which underpins the clinical findings of defective EP2 signaling in patients with NERD. Our findings also indicate that exogenously targeting the PGE2-EP4-cAMP and energy metabolic pathways may provide novel opportunities for treating ILC2-initiated lung inflammation in asthma and NERD.

Graphical abstract

Schematic of potential roles for activation of EP2 and EP4 by endogenous versus exogenous ligands in regulation of lung ILC2 immune responses. Endogenous PGE2 in the lung preferentially activates EP2 rather than EP4 to inhibit ILC2 responses and eosinophilic inflammation, and ablation of EP2 enhances lung ILC2 responses. Conversely, lung ILC2 responses are not altered by EP4 deficiency. However, they are markedly inhibited by EP4 agonism but not EP2 agonism. Mechanistically, PGE2-EP2/EP4 signaling activates the cAMP pathway which inhibits ILC2 energy metabolism, possibly through interruption of NF-κB (reported in Nagashima H, et al. Immunity 2019;51:682-695) and STAT5 signaling, leading to decline of ILC2 survival, proliferation and type 2 cytokine production.