bluuebunny/crossref_metadata_2025 huggingface dataset:
Acceleration and clustering of cosmic dust in a gravoturbulent gas I. Numerical simulation of the nearly Jeans-unstable case
Authors: Mattsson Lars , Hedvall Robert
Published: November 2021

We investigate the dynamics of interstellar dust particles in moderately high resolution (5123 grid points) simulations of forced compressible transonic turbulence including self-gravity of the gas. Turbulence is induced by stochastic compressive forcing which is delta-correlated in time. By considering the nearly Jeans-unstable case, where the scaling of the simulation is such that a statistical steady state without any irreversible collapses is obtained, we obtain a randomly varying potential, acting as a second stochastic forcing. We show that, in this setting, low-inertia grains follow the gas flow and cluster in much the same way as in a case of statistical steady-state turbulence without self-gravity. Large, high-inertia grains, however, are accelerated to much higher mean velocities in the presence of self-gravity. Grains of intermediate size also show an increased degree of clustering. We conclude that self-gravity effects can play an important role for aggregation/coagulation of dust even in a turbulent system which is not Jeans-unstable. In particular, the collision rate of large grains in the interstellar medium can be much higher than predicted by previous work.
The Emergence of the Spike Furin Cleavage Site in SARS-CoV-2
Authors: Chan Yujia Alina , Zhan Shing Hei
Published: November 2021

Compared with other SARS-related coronaviruses (SARSr-CoVs), SARS-CoV-2 possesses a unique furin cleavage site (FCS) in its spike. This has stimulated discussion pertaining to the origin of SARS-CoV-2 because the FCS has been observed to be under strong selective pressure in humans and confers the enhanced ability to infect some cell types and induce cell–cell fusion. Furthermore, scientists have demonstrated interest in studying novel cleavage sites by introducing them into SARSr-CoVs. We review what is known about the SARS-CoV-2 FCS in the context of its pathogenesis, origin, and how future wildlife coronavirus sampling may alter the interpretation of existing data.
Xpert MTB/RIF Use Is Associated With Earlier Treatment Initiation and Culture Conversion Among Patients With Sputum Smear-Negative Multidrug-Resistant Tuberculosis
Authors: Kipiani Maia , Graciaa Daniel S , Buziashvili Mariana , Darchia Lasha , Avaliani Zaza , Tabagari Nino , Mirtskhulava Veriko , Kempker Russell R
Published: November 2021

Background

Although rapid molecular diagnostic tests for tuberculosis (TB) have decreased detection time of Mycobacterium tuberculosis and drug resistance, whether their use improves clinical care and outcomes is uncertain. To address these knowledge gaps, we evaluated whether use of the Xpert MTB/RIF assay impacts treatment and clinical outcome metrics among patients treated for sputum smear-negative multidrug-resistant (MDR)-TB.

Methods

We conducted a retrospective cohort study of adult patients initiating treatment for sputum smear-negative MDR-TB at the National Center for Tuberculosis and Lung Diseases in Tbilisi, Georgia from 2011 to 2016. The Xpert MTB/RIF was introduced in Georgia in 2010 and implemented into programmatic use in 2014. Exposure was availability of an Xpert result at time of diagnosis. Time to second-line treatment initiation, sputum culture conversion, and end-of-treatment outcomes were determined. Time to event was compared using a Cox proportional hazards model.

Results

Among 151 patients treated for sputum smear-negative MDR-TB (96% culture positive), the Xpert was utilized in the clinical management of 78 (52%) patients and not used in 73 (48%). An adjusted analysis controlling for potential confounders found that patients in the Xpert group had shorter median time to second-line treatment (13 vs 56 days; adjusted hazard ratio [aHR], 10.21; P < .0001) and culture conversion (61 vs 93 days; aHR, 1.93; P < .001). There was no difference in treatment outcomes.

Conclusions

Use of the Xpert in the management of sputum smear-negative MDR-TB decreases time to second-line therapy and sputum culture conversion, providing evidence of its clinical impact and supporting its programmatic utility.
Characterization of Heavily Treatment-Experienced People With HIV and Impact on Health Care Resource Utilization in US Commercial and Medicare Advantage Health Plans
Authors: Priest Julie , Hulbert Erin , Gilliam Bruce L , Burton Tanya
Published: November 2021

Background

This retrospective administrative claims study aimed to describe clinical characteristics, health care resource utilization (HCRU), and costs of people with HIV (PWH) in US commercial and Medicare Advantage health plans by antiretroviral treatment (ART) experience and CD4+ cell count.

Methods

Data from the national Optum Research Database between January 1, 2014, and March 31, 2018, for adult PWH continuously enrolled 6 months before and ≥12 months after the first ART identified (follow-up) were summarized by treatment (heavily treatment-experienced [HTE] with limited remaining ART options, treatment-experienced but not HTE [non-HTE], or treatment-naive starting a first antiretroviral regimen) and index CD4+ cell count (<200, 200–500, or >500 cells/mm3).

Results

Compared with non-HTE (n=7604) and treatment-naive PWH (n=4357), HTE PWH (n=2297) were older (53.5 vs 48.8 and 42.3 years), were more likely to have HIV-related emergency department visits (22.3% vs 12.4% and 18.6%) and inpatient stays (15.8% vs 7.1% and 10.3%), and had a higher mean (SD) daily pill burden (9.7 [7.7] vs 5.1 [5.9] and 3.6 [5.3] pills/d) and a higher mortality rate (5.9% vs 2.9% and 2.3%) during follow-up (all P<.001). More HTE (21.8%) and treatment-naive PWH (27.0%) had <200 CD4+ cells/mm3 vs non-HTE PWH (8.0%; P<.001). All-cause and HIV-related costs were higher among HTE PWH in all CD4+ cell count strata and treatment-naive PWH with CD4+ cell counts <200 cells/mm3 vs non-HTE PWH in all CD4+ cell count strata.

Conclusions

Improved support and clinical monitoring of HTE PWH are needed to prevent worsening outcomes and increased costs.
Coronavirus Disease 2019-Associated Mucormycosis in France: A Rare but Deadly Complication
Authors: Danion François , Letscher-Bru Valérie , Guitard Juliette , Sitbon Karine , Dellière Sarah , Angoulvant Adela , Desoubeaux Guillaume , Botterel Francoise , Bellanger Anne-Pauline , Gargala Gilles , Uhel Fabrice , Bougnoux Marie-Elisabeth , Gerber Victor , Michel Justin , Cornu Marjorie , Bretagne Stéphane , Lanternier Fanny ,   COVID-Mucor study group, Merdji Hamid , Delabranche Xavier , Parrot Antoine , Voiriot Guillaume , Urbina Tomas , Mebazaa Alexandre , Chousterman Benjamin , El Kalioubie Ahmed , Six Sophie , Coulon Pauline , Sendid Boualem , Anguel Nadia , Damoisel Charles , Mussini Charlotte , Villate Alban , Navellou Jean-Christophe , Girault Christophe , Cassagne Carole , Augereau Olivier , Dromer Francoise , Garcia-Hermoso Dea , Lortholary Olivier , Alanio Alexandre
Published: November 2021

We studied COVID-19 associated mucormycosis based on 17 cases reported nationwide and assessed the differences with India. They differed by frequencies of diabetes mellitus (47% in France versus up to 95% in India), hematological malignancies (35% versus 1%), anatomical sites (12% versus >80% rhino-orbito-cerebral) and prognosis (88% mortality versus <50%).
Going Underwater? Flood Risk Belief Heterogeneity and Coastal Home Price Dynamics
Authors: Bakkensen Laura A , Barrage Lint
Published: November 2021

How do climate risk beliefs affect coastal housing markets? This paper provides theoretical and empirical evidence. First, we build a dynamic housing market model and show that belief heterogeneity can reconcile prior mixed evidence on flood risk capitalization. Second, we implement a door-to-door survey in Rhode Island, finding significant flood risk underestimation and sorting based on risk perceptions and amenity values. Third, we estimate that coastal prices exceed fundamentals by 6$\%$-13$\%$ in our benchmark area, with potentially higher overvaluation in other locations. Finally, we quantify both allocative inefficiency and distributional consequences arising from flood risk misperceptions and insurance policy reform.

Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
Tied Staying on the Rise? Declining Migration among Co-Breadwinner Couples in the United States, 1990s to 2010s
Authors: Erickson Matt , Kim ChangHwan
Published: November 2021

This study examines a possible connection between shifting gender and family norms and declining internal migration. Using data from the 1989–1998 and 2009–2018 Annual Social and Economic Supplements of the Current Population Survey, we examine whether co-breadwinner married couples have become less likely to migrate within the US relative to couples with a sole or primary breadwinner. We find a general U-shaped association between wives’ share of a married couple’s income and that couple’s likelihood of moving across state or county lines; in both time periods, couples were least likely to move when their incomes were roughly equal. However, we find this U-shaped pattern grew more pronounced in the 2010s compared with the 1990s: Over time, co-breadwinner couples became increasingly less likely to move relative to other married couples. Given that family migration decision-making has historically been gendered, this suggests dual-career married couples have become less willing to uproot women’s careers for the benefit of men’s. We argue the most likely reason for this change in behavior is a shift in norms governing the gender division of labor—in particular, a shift away from the cultural model of the male breadwinner. Based on a decomposition analysis, we estimate this change explains about one-third of the overall decline in migration among married couples ages 25–39 between the 1990s and 2010s.
Propensity Scored Analysis of Outpatient Anterior Lumbar Interbody Fusion
Authors: Kamalapathy Pramod N. , Bell Joshua , Chen Dennis , Raso Jon , Hassanzadeh Hamid
Published: November 2021

Study Design:

Retrospective cohort study.

Objective:

The aim were to (1) evaluate differences in postoperative outcomes and cost associated with outpatient anterior lumbar interbody fusion (ALIF) compared with inpatient ALIF, and to (2) identify independent factors contributing to complications after outpatient ALIF.

Summary of Background:

While lumbar fusion is traditionally performed inpatient, outpatient spinal surgery is becoming more commonplace as surgical techniques improve.

Methods:

The study population included all patients below 85 years of age who underwent elective ALIF (CPT-22558). Patients were then divided into those who underwent single-level fusion and multilevel fusion using the corresponding additional level fusion codes (CPT-22585). These resulting populations were then split into outpatient and inpatient cohorts by using a service location modifier. To account for selection bias, propensity score matching was performed; the inpatient cohorts were matched with respect to the outpatient cohorts based on age, sex, and Charlson Comorbidity Index. Statistical significance was set at P<0.05 and the Bonferroni correction was used for each multiple comparison (P<0.004).

Results:

Patients undergoing outpatient procedure had decreased rates of medical complications following both single-level and multilevel ALIF. In addition, age above 60, female sex, Charlson Comorbidity Index>3, chronic obstructive pulmonary disease, diabetes mellitus, coronary artery disease, hypertension, and tobacco use were all identified as independent risk factors for increased complications. Finally, the cost of outpatient ALIF was $12,013 while the cost of inpatient ALIF was $27,271 (P<0.001).

Conclusion:

The findings add to the growing body of literature advocating for the utilization of ALIF in the outpatient setting for a properly selected group of patients.

Level of Evidence:

Level IV.
Doravirine: its role in HIV treatment
Authors: Stockdale Alexander J. , Khoo Saye
Published: November 2021

Purpose of review

We reviewed evidence concerning the novel nonnucleoside reverse transcriptase inhibitor doravirine, aiming to identify situations where it may be selected in preference to integrase inhibitors.

Recent findings

Doravirine is licenced for the treatment of HIV-1 in North America and Europe. In two multicentre randomized controlled trials, noninferiority with comparator drugs efavirenz and darunavir/ritonavir was observed at 96 weeks. Doravirine is associated with a lower incidence of neuropsychiatric side effects relative to efavirenz, and favourable lipid changes relative to darunavir over 96 weeks. A lower incidence of weight gain, relative to indirect comparisons with integrase inhibitors, was observed. Doravirine has a high genetic barrier to resistance with retained activity in the presence of single NNRTI mutations K103N, Y181C and G190A. Primary drug resistance is infrequent and may be higher in South Africa relative to European populations. Doravirine may be used in renal or hepatic impairment and has a low potential for drug–drug interactions.

Doravirine is a well tolerated and effective agent in ART-naive patients. Direct comparison with integrase inhibitors, and evidence on the outcomes of treatment with doravirine in the presence of prior NNRTI experience are required to better elucidate which patients will benefit most from doravirine therapy.
Unraveling the Cardiac Effects Induced by Carvacrol in Spontaneously Hypertensive Rats: Involvement of Transient Receptor Potential Melastatin Subfamily 4 and 7 Channels
Authors: Alves Quiara L. , da Silva Santos Paôla V. , Santos William A. , Dantas Damasceno Suiane C. , de Jesus Rafael L. C. , Froes Thamires Q. , Castilho Marcelo S. , Barbosa Andrezza M. , de Moraes Gomes Enéas R. , dos Santos Cruz Jader , Silva Darízy F.
Published: November 2021

Accumulating evidence indicates that transient receptor potential (TRP) channels are involved in the pathophysiological process in the heart, and monoterpenes, such as carvacrol, are able to modulate these channels activity. In this article, our purpose was to evaluate the direct cardiac effect of carvacrol on the contractility of cardiomyocytes and isolated right atria from spontaneously hypertensive and Wistar Kyoto rats. In this way, in vitro experiments were used to evaluate the ventricular cardiomyocytes contractility and the Ca2+ transient measuring, in addition to heart rhythm in the right atria. The role of TRPM channels in carvacrol-mediated cardiac activities was also investigated. The results demonstrated that carvacrol induced a significant reduction in ventricular cell contractility, without changes in transient Ca2+. In addition, carvacrol promoted a significant negative chronotropic response in spontaneously hypertensive and Wistar Kyoto rats' atria. Selective blockage of TRPM channels suggests the involvement of TRP melastatin subfamily 2 (TRPM2), TRPM4, and TRPM7 in the carvacrol-mediated cardiac effects. In silico studies were conducted to further investigate the putative role of TRPM4 in carvacrol-mediated cardiac action. FTMap underscores a conserved pocket in both TRPM4 and TRPM7, revealing a potential carvacrol binding site, and morphological similarity analysis demonstrated that carvacrol shares a more than 85% similarity to 9-phenanthrol. Taken together, these results suggest that carvacrol has direct cardiac actions, leading to reduced cellular contractility and inducing a negative chronotropic effect, which may be related to TRPM7 and TRPM4 modulation.
Rutaecarpine Prevents High Glucose-Induced Endothelial Cell Senescence Through Transient Receptor Potential Vanilloid Subtype 1/ SIRT1 Pathway
Authors: Xiong Yan , Wang Han-Xia , Yan Hang , Zhu Si-Lu , Guo Shu-Wen , Peng Wei-Jie , Luo Dan
Published: November 2021

SIRT1 functions as a longevity factor to counteract vascular aging induced by high glucose. Our previous study revealed that rutaecarpine, the natural agonist of transient receptor potential vanilloid subtype 1 (TRPV1), prevented high glucose-induced endothelial dysfunction. The present study aims to evaluate the effects of rutaecarpine on endothelial cell senescence induced by high glucose, and focus on the regulatory effect on SIRT1 expression. In cultured human umbilical vein endothelial cell (HUVEC), exposure to 33 mM high glucose for 72 hours induced cellular senescence, demonstrated as cell cycle arrest at G0/G1 phase, decreased cell viability, and increased number of senescence-associated β-galactosidase positive senescence cells and ROS production, which were effectively attenuated by treatment with rutaecarpine (0.3, 1, and 3 μM). Furthermore, rutaecarpine upregulated longevity protein SIRT1 expression in HUVECs, accompanied by decreased level of senescence marker p21. In addition, rutaecarpine increased intracellular calcium level in HUVECs, and pretreatment with TRPV1 antagonist capsazepine, intracellular Ca2+ chelator BAPTA-AM or CaM antagonist W-7 abolished the effects of rutaecarpine on SIRT1 expression. In summary, this study shows that rutaecarpine upregulates SIRT1 expression and prevents high glucose-induced endothelial cell senescence, which is related to activation of TRPV1/[Ca2+]i/CaM signal pathway. Our findings provide evidence that rutaecarpine may be a promising candidate with a novel mechanism in prevention vascular aging in diabetes.
Polyherbal Formulation Ameliorates Diabetic Cardiomyopathy Through Attenuation of Cardiac Inflammation and Oxidative Stress Via NF-κB/Nrf-2/HO-1 Pathway in Diabetic Rats
Authors: Uddandrao V. V. Sathibabu , Parim Brahmanaidu , Singaravel Sengottuvelu , Ponnusamy Ponmurugan , Ponnusamy Chandrasekaran , Sasikumar Vadivukkarasi , Saravanan Ganapathy
Published: November 2021

The present study was intended to evaluate the effect of polyherbal formulation (PHF) made with 3 nutraceuticals, such as Piper nigrum, Terminalia paniculata, and Bauhinia purpurea on inflammation and oxidative stress in diabetic cardiomyopathy (DCM), which is induced by streptozotocin and nicotinamide administration in rats. We supplemented DCM rats with PHF (250 and 500 mg/kg/BW) for 45 days and evaluated their effects on oxidative stress markers, proinflammatory cytokines, and messenger RNA expressions of the nuclear factor erythroid 2-related factor-2 (Nrf-2) and its linked genes [heme oxygenase-1 (HO-1), superoxide dismutase, catalase] along with inflammatory genes [tumour necrosis factor α and nuclear factor kappa B (NF-κB)]. Our study demonstrated that PHF successfully attenuated inflammation and oxidative stress via messenger RNA upregulation of Nrf-2, HO-1, superoxide dismutase, and catalase and concomitantly with downregulation of tumour necrosis factor α and NF-κB. Conversely, PHF also protected hyperglycemia-mediated cardiac damage, which was confirmed with histopathological and scanning electron microscopy analysis. In conclusion, our results suggested that PHF successfully ameliorated hyperglycemia-mediated inflammation and oxidative stress via regulation of NF-κB/Nrf-2/HO-1 pathway. Therefore, these results recommend that PHF may be a prospective therapeutic agent for DCM.
Evaluation of the Effectiveness and Safety of Direct Oral Anticoagulants in Elderly Patients With Nonvalvular Atrial Fibrillation Who Are Not Candidates for Warfarin in Real-World Setting
Authors: Lo Catherine T. , Niu Fang , Fredriks Dean A. , Hui Rita L.
Published: November 2021

Limited literature has established the role of direct oral anticoagulants (DOAC) for elderly patients with nonvalvular atrial fibrillation who are unsuited for warfarin. Therefore, the objectives of this study were to assess the effectiveness and safety of DOAC use in this vulnerable patient population. This was a retrospective propensity score matching cohort study. Among all patients aged 75+ years who were not candidates for warfarin, we matched those who initiated DOAC between September 2017 and September 2018 with those who did not receive DOAC or warfarin in a 1:1 ratio. Effectiveness outcome was a composite measure of stroke, transient ischemic attack, and pulmonary embolism. Safety outcome was a composite measure of non–trauma-related intracranial hemorrhage and gastrointestinal bleed. Unless patients died or lost membership, follow-up period for the effectiveness outcome was until the end of 2019, whereas the safety outcome was for a period up to 1 year. Conditional logistic regression was used to analyze both outcomes. We identified 7818 patients who met the inclusion criteria and started DOAC, which matched to 7818 patients who did not receive anticoagulants. The mean age was 82.3 ± 5.1 years, and 51.5% male. The DOAC group had a lower hazard ratio of 0.37 (confidence interval, 0.24–0.57; P < 0.01) for composite effectiveness outcomes, whereas no difference in the composite safety outcome (hazard ratio, 0.91; confidence interval, 0.65–1.25; P = 0.55) when compared with matched control. In conclusion, DOAC was found to be effective in preventing thromboembolic events in patients aged 75+ years with nonvalvular atrial fibrillation who were not eligible for warfarin.
Clinical Presentation, Investigation and Control of an Outbreak of Adenoviral Conjunctivitis in a Neonatal Unit at a Tertiary Hospital
Authors: Thakur Anchal , Goyal Kapil , Chauhan Poonam , Sharma Bhawna , Kant Dhir Shashi , Katoch Deeksha , Biswal Manisha , Talati Shweta , Bhogal Ranjitpal Singh , Mohan Lalit , Sapra Monika , Gupta Amit , Sundaram Venkataseshan , Dutta Sourabh , Kumar Praveen , Singh Mini P.
Published: November 2021

Background:

Nosocomial spread of adenovirus infection has been reported in neonatal, pediatric and adult medical units. This nonenveloped and hardy virus is resistant to numerous disinfectants thus posing a challenge for control and prevention of adenovirus infections in health care settings.

Methods:

An epidemiologic outbreak investigation revealed an adenoviral outbreak in the neonatal nursery as well as in the neonatal screening outpatient department for Retinopathy of Prematurity (ROP). All suspected cases (94 neonates) underwent adenoviral conventional polymerase chain reaction (PCR) and representative samples underwent sequencing by Sanger’s method. The clinical features and disease course were studied. Infected babies were started on tobramycin eye drops. Topical steroid eye drops were added for those who developed pseudomembranes.

Results:

We found 58 cases of laboratory-confirmed neonatal adenovirus conjunctivitis (between July 10 and October 24, 2019). Redness (96%) was the most common presentation followed by discharge (68.9%) and lid edema (51.7%). Pseudomembrane were seen in 77.5% of the infected neonates. Prior ROP examination was carried out in 38 (65.5%) neonates. Respiratory symptoms were present in 7 (12.06%) neonates. Sequencing revealed serotype 8 as the cause of the outbreak. Control measures were strictly implemented. Standard Operating Procedures (SOPs) for ROP screening were revisited, revised and reinforced to prevent future outbreaks.

Conclusions:

We observed ROP screening as a risk factor for the development of adenoviral conjunctivitis in neonatal care units. Neonates present with different clinical manifestations as compared with adults. Prompt control measures were implemented to control the adenoviral outbreak.
Outbreak of SARS-CoV-2 in a Children’s Nursery in the United Kingdom
Authors: Roberts Rebecca Jane , Brooker Annette , Lakshman Rajalakshmi
Published: November 2021

Background:

Early Years’ Settings (EYSs) provide childcare and education for children 0–5 years old. They remained fully open in England during the third National lockdown when other educational settings were only open for selected children. EYSs are generally considered to be low-risk settings for transmission of severe acute respiratory syndrome coronavirus 2 (SARS CoV-2).

Methods:

An observational study describing a large outbreak of SARS CoV-2 within an EYS in Cambridgeshire, United Kingdom.

Results:

Overall 45 cases of SARS-CoV-2 were identified; 24 adults (71% of staff members) and 21 children (25% of nursery attendees). One case was identified as the alpha variant (B.1.1.7 [VOC-20-DEC-01]). One staff member became critically unwell.

Conclusions:

Transmission of SARS-CoV-2 occurred quickly, with a high attack rate; likely a consequence of a variant with enhanced transmissibility and an inability of the setting to adhere to infection control measures.
Population-based Incidence of Myopericarditis After COVID-19 Vaccination in Danish Adolescents
Authors: Nygaard Ulrikka , Holm Mette , Bohnstedt Cathrine , Chai Qing , Schmidt Lisbeth Samsø , Hartling Ulla Birgitte , Petersen Jens Jakob Herrche , Thaarup Jesper , Bjerre Jesper , Vejlstrup Niels Grove , Juul Klaus , Stensballe Lone Graff
Published: November 2021

In this prospective nationwide multicenter study from Denmark, myopericarditis after Pfizer-BioNTech mRNA COVID-19 vaccination was identified in 13 males and 2 females between May 15 and September 15, 2021, among 133,477 vaccinated males and 127,857 vaccinated females 12–17 years of age, equaling 97 males and 16 females per million. In conclusion, the incidence of myopericarditis after COVID-19 vaccination among males appears higher than reports from the United States.
Haemophilus influenzae Serotype a as a Cause of Meningitis in Children in Brazil
Authors: Russo Daniela Otoni , Torres Bruna Ribeiro , Romanelli Roberta Maia Castro , Rocha Fernanda de Souza Vanni , Viegas Eisler Cristiane Carvalho , Diniz Lilian Martins de Oliveira
Published: November 2021

Background:

Since the introduction of Haemophilus influenzae type b vaccines, invasive disease due to Haemophilus influenzae serotype a (Hia) has been reported with increasing frequency.

Methods:

This study is based on hospital-based surveillance for Hia meningitis over a 5-year period.

Results:

Thirty-five patients with H. influenzae meningitis were hospitalized and 12 were serotype a. Hia was detected in blood and cerebrospinal fluid by culture or reverse transcription polymerase chain reaction. Patients’ median age was 10 months, 7 (58%) boys and 5 (41%) girls. Ten (83%) children had received at least 1 vaccine dose against Haemophilus influenzae type b. All patients were treated with ceftriaxone for a median period of 11 days. The main complications described were empyema in 5 (41%) and seizures in 3 (25%) patients. Two (16.6%) patients died due to cerebral damage and shock.

Conclusions:

Invasive disease due to Hia affecting young children accounts for considerable morbidity and mortality.
Is There a Link Between Nailfold Videocapillaroscopy and Pulmonary Function Tests in Systemic Sclerosis Patients?
Authors: Vilela Verônica Silva , Vanhaecke Amber , da Silva Bruno Rangel Antunes , da Costa Cláudia Henrique , Lopes Agnaldo José , Rufino Rogério , Cutolo Maurizio , Smith Vanessa
Published: November 2021

Background/Objective

The aim of this study was to explore the associations between nailfold videocapillaroscopy (NVC) and pulmonary function tests (PFTs) in systemic sclerosis (SSc) patients.

Methods

This was a longitudinal study with follow-up of unselected Brazilian SSc patients. Baseline clinical examination, serological workup, high-resolution chest tomography, and NVC were performed. Pulmonary function test was performed at baseline and after 24 months. Pulmonary function test worsening over time was defined as either a ΔFVC decline ≥10% or a ΔFVC decline ≥5% and <9%, combined with a ΔDLCO decline ≥15%, at 24 months. The NVC parameters were quantitatively (capillary density number, dimension, morphology, and hemorrhages) and qualitatively (NVC pattern) evaluated according to the consented standardized definitions of the EULAR Study Group on Microcirculation in Rheumatic Diseases.

Results

Seventy-nine patients were included. Fifty-nine were rated to have a scleroderma pattern (6 “early”/16 “active”/37 “late”). The mean FVC and DLCO were 76.8% and 67.2% at baseline and 73.8% and 64.3% at 24 months, respectively. After multivariate analysis, we found that a reduced baseline FVC was associated with reduced capillary density (odds ratio [OR], 11; 95% confidence interval [CI], 1.5–90.7; p = 0.03) and a reduced baseline DLCO associated with the late scleroderma pattern (OR, 6.75; 95% CI, 1.09–42; p = 0.03). No association between worsening of PFT over time and NVC was found.

Conclusions

The association between NVC and PFTs might corroborate the link between microangiopathy and interstitial lung disease in patients with SSc. This finding might strengthen the idea of incorporating NVC as a tool to predict progressive interstitial lung disease in these patients in the future.
Risk of Cardiovascular and Venous Thromboembolic Events Associated With Janus Kinase Inhibitors in Rheumatoid Arthritis
Authors: Alves Carlos , Penedones Ana , Mendes Diogo , Marques Francisco Batel
Published: November 2021

Background/Objective

The Janus kinases are cytoplasmic tyrosine kinases associated with membrane cytokine receptors that mediate signaling of multiple cytokines and growth factors, contributing to the pathogenesis of multiple autoimmune disorders. Janus kinase inhibitors (JKIs) are a new class of targeted therapies with proven efficacy in treating rheumatoid arthritis but are associated with an increased risk of infections. This study is aimed at assessing the risk of cardiovascular and venous thromboembolic events associated with JKIs in patients with rheumatoid arthritis.

Methods

PUBMED, EMBASE, Cochrane Library, and clinicaltrials.gov were searched to identify randomized controlled trials evaluating the efficacy and safety of JKIs in patients with rheumatoid arthritis. The outcomes assessed were the risk of major adverse cardiovascular events, venous thromboembolic events, and any cardiovascular event. Sensitivity analysis disaggregated the results according to background therapy, JKI licensed doses, and studies' methodological quality.

Results

Forty-two randomized controlled trials met the inclusion criteria. No statistically significant risk differences were observed between the JKIs for any of the assessed outcomes. Compared with placebo, tofacitinib (odds ratio, 0.32; 95% confidence interval, 0.11–0.89) reduces the risk of venous thromboembolism. The results of the sensitivity analysis are in line with the initial findings.

Conclusions

Current evidence suggests that the risk of cardiovascular and venous thromboembolic events is similar among the JKIs. Postmarketing pharmacovigilance evidence will be of utmost importance in confirming the cardiovascular safety of these drugs.
Serum Myostatin and Follistatin Levels in Patients With Dermatomyositis and Polymyositis
Authors: de Sordi Cintia M. , dos Reis-Neto Edgard T. , Keppeke Gerson D. , Shinjo Samuel K. , Sato Emília Inoue
Published: November 2021

Background

Myostatin is a protein in the TGF-β family that negatively regulates muscle mass, and follistatin is a myostatin antagonist.

Objective

The aim of this study was to measure serum levels of myostatin and follistatin in idiopathic inflammatory myopathy patients and correlate these levels with muscle strength, fatigue, functional capacity, damage, and serum levels of muscle enzymes.

Methods

This was a multicenter cross-sectional study including 50 patients (34 dermatomyositis and 16 polymyositis [PM]) and 52 healthy individuals (control group [CG]). The disease status was evaluated according to the International Myositis Assessment & Clinical Studies. Fatigue was rated according to the Fatigue Severity Scale, and body composition was measured using dual-energy x-ray emission densitometry. Myostatin and follistatin were measured using enzyme-linked immunosorbent assays.

Results

Mean age was 50.9 ± 14.0 years, and mean disease duration was 89.2 ± 80.9 months. There were no differences in levels of myostatin (14.15 ± 9.65 vs. 10.97 ± 6.77 ng/mL; p = 0.131) or follistatin (0.53 ± 0.71 vs. 0.49 ± 0.60 ng/mL; p = 0.968) between patients and the CG. However, myostatin levels were higher in PM than CG (16.9 ± 12.1 vs. 11.0 ± 6.8 ng/mL; p = 0.036). There was no difference in serum myostatin among patients with and without low lean mass. Patients not treated with corticosteroids had higher serum levels of myostatin than the CG. There was a weak negative correlation between follistatin and Manual Muscle Testing and a Subset of Eight Muscles and a weak positive correlation between follistatin and Healthy Assessment Questionnaire.

Conclusions

Serum levels of myostatin and follistatin did not differ between dermatomyositis and PM patients and control subjects. The assessment of serum levels of myostatin and follistatin in idiopathic inflammatory myopathy patients seems not to be helpful in clinical practice.
Predicting Melanoma Staging using Targeted RNA Sequencing data using Machine Learning
Authors: Ahmed Fahad Shabbir , Irfan Furqan Bin
Published: November 2021

The aim of this study is to use machine learning to predict tumor staging and metastasis in melanoma with differentially expressed genes. Machine has been used in different clinical setting to predict different outcomes. However, it has not been used to look at predicting the diagnostic aspect of tumor staging. We used the TCGA RNA-Sequencing data on melanomas to predict tumor staging nodal and/or metastasis using deep neural networks (DNN) and random forest classifier (RF). Results: We were able to predict tumor staging (lower vs higher stage, i.e. Tis / T1 / T2 vs T3 and higher), nodal metastasis and combined nodal or distant metastasis in patients with melanomas with high accuracies. However, we need to further validate these results.
Spread of Xanthomonas vasicola pv. musacearum within banana mats: implications for Xanthomonas wilt management
Authors: Ocimati Walter , Tazuba Anthony Fredrick , Blomme Guy
Published: November 2021

Xanthomonas wilt (XW) of banana caused by Xanthomonas vasicola pv. musacearum (Xvm) does not spread to all plants physically interconnected through the rhizome when one or a few are diseased. However, the factors behind this incomplete systemic spread of Xvm are not fully known yet could inform XW management. This study explored the effect of Xvm inoculum amounts, number and size of suckers, sucker positioning on mother plant corms and other mother plant corm attributes on sucker colonization. A shorter (p <0.05) incubation period (17.9 vs 21.1 days) and higher (p<.001) cumulative number of symptomatic leaves (5.2 vs 1.6 leaves) was observed when all (high inoculum) compared to two leaves (low inoculum) were inoculated. Xvm was recovered in corms at 29 days post inoculation (dpi) in both treatments with no differences (p >0.05) in proportions of corms with Xvm between the treatments. However, Xvm was recovered earlier and at a higher frequency in suckers when all leaves were inoculated. Lower Xvm recoveries occurred in the lower corm sections to which most suckers were attached relative to the middle and upper corm sections. Xvm incidence in corms increased with the number of attached maiden suckers, and the dpi while it declined with increasing mother plant and corm height. Thus, Xvm spread within mats is influenced by the amount of inoculum and the physiological stage (e.g., height) of the plant and attached suckers. The position of suckers, predominantly at the bottom of corms also protects them from infection. Measures that reduce Xvm inoculum build-up in mats are thus crucial for minimizing within mat XW spread.
SARS-CoV-2 infection in free-ranging white-tailed deer (Odocoileus virginianus)
Authors: Hale Vanessa L. , Dennis Patricia M. , McBride Dillon S. , Nolting Jaqueline M. , Madden Christopher , Huey Devra , Ehrlich Margot , Grieser Jennifer , Winston Jenessa , Lombardi Dusty , Gibson Stormy , Saif Linda , Killian Mary L. , Lantz Kristina , Tell Rachel , Torchetti Mia , Robbe-Austerman Suelee , Nelson Martha I. , Faith Seth A. , Bowman Andrew S.
Published: November 2021

Human-to-animal spillover of SARS-CoV-2 virus has occurred in a wide range of animals, but thus far, the establishment of a new natural animal reservoir has not been detected. Here, we detected SARS-CoV-2 virus using rRT-PCR in 129 out of 360 (35.8%) free-ranging white-tailed deer (Odocoileus virginianus) from northeast Ohio (USA) sampled between January-March 2021. Deer in 6 locations were infected with at least 3 lineages of SARS-CoV-2 (B.1.2, B.1.596, B.1.582). The B.1.2 viruses, dominant in Ohio at the time, spilled over multiple times into deer populations in different locations. Deer-to-deer transmission may have occurred in three locations. The establishment of a natural reservoir of SARS-CoV-2 in white-tailed deer could facilitate divergent evolutionary trajectories and future spillback to humans, further complicating long-term COVID-19 control strategies.

One-Sentence Summary

A significant proportion of SARS-CoV-2 infection in free-ranging US white-tailed deer reveals a potential new reservoir.
Validation and invalidation of SARS-CoV-2 papain-like protease inhibitors
Authors: Ma Chunlong , Wang Jun
Published: November 2021

SARS-CoV-2 encodes two viral cysteine proteases, the main protease (Mpro) and the papain-like protease (PLpro), both of which are validated antiviral drug targets. The PLprois involved in the cleavage of viral polyproteins as well as immune modulation through removing ubiquitin and interferon-stimulated gene product 15 (ISG15) from host proteins. Therefore, targeting PLpromight be a two-pronged approach. Several compounds including YM155, cryptotanshinone, tanshinone I, dihydrotanshinone I, tanshinone IIA, SJB2-043, 6-thioguanine, and 6-mercaptopurine were recently identified as SARS-CoV-2 PLproinhibitors through high-throughput screening. In this study, we aim to validate/invalidate the reported PLproinhibitors using a combination of PLprotarget specific assays including enzymatic FRET assay, thermal shift binding assay (TSA), and the cell based FlipGFP assay. Collectively, our results showed that all compounds tested either did not show binding or led to denaturation of the PLproin the TSA binding assay, which might explain their weak enzymatic inhibition in the FRET assay. In addition, none of the compounds showed cellular inhibition of PLproas revealed by the FlipGFP assay. Therefore, more efforts are needed to search for specific and potent SARS-CoV-2 PLproinhibitors.
Brilacidin, a COVID-19 Drug Candidate, demonstrates broad-spectrum antiviral activity against human coronaviruses OC43, 229E and NL63 through targeting both the virus and the host cell
Authors: Hu Yanmei , Jo Hyunil , DeGrado William F. , Wang Jun
Published: November 2021

Brilacidin, a mimetic of host defense peptides (HDPs), is currently in phase 2 clinical trial as an antibiotic drug candidate. A recent study reported that brilacidin has antiviral activity against SARS-CoV-2 by inactivating the virus. In this work, we discovered an additional mechanism of action of brilacidin by targeting heparan sulfate proteoglycans (HSPGs) on host cell surface. Brilacidin, but not acetyl brilacidin, inhibits the entry of SARS-CoV-2 pseudovirus into multiple cell lines, and heparin, a HSPG mimetic, abolishes the inhibitory activity of brilacidin on SARS-CoV-2 pseudovirus cell entry. In addition, we found that brilacidin has broad-spectrum antiviral activity against multiple human coronaviruses (HCoVs) including HCoV-229E, HCoV-OC43, and HCoV-NL63. Mechanistic studies revealed that brilacidin has a dual antiviral mechanism of action including virucidal activity and binding to coronavirus attachment factor HSPGs on host cell surface. Brilacidin partially loses its antiviral activity when heparin was included in the cell cultures, supporting the host-targeting mechanism. Drug combination therapy showed that brilacidin has a strong synergistic effect with remdesivir against HCoV-OC43 in cell culture. Taken together, this study provides appealing findings for the translational potential of brilacidin as a broad-spectrum antiviral for coronaviruses including SARS-CoV-2.
Mutations in CSRP3/MLP, a Z-disc associated gene are functionally associated with dilated cardiomyopathy in Indian population
Authors: Giri Prerna , Dixit Ritu , Kumar Ashok , Mohapatra Bhagyalaxmi
Published: November 2021

CSRP3 is a LIM domain containing protein, known to play an important role in cardiomyocyte development, differentiation and pathology. Mutations in CSRP3 gene are reported in both dilated and hypertrophic cardiomyopathy (DCM and HCM), however, the genotype-phenotype correlation still remains elusive. To investigate the pathogenic potential of CSRP3 variants in our DCM cohort, we have screened 100 DCM cases and 100 controls and identified 3 non-synonymous variations, of which two are missense variants viz., c.233 GGC>GTC, p.G78V; c.420 TGG>TGC, p.W140C, and the third one is a single nucleotide polymorphism (SNP) c.46 ACC>TCC, p.T16S. These variants were absent from 100 control individuals (200 chromosomes). In vitro functional analysis has revealed reduction of CSRP3 protein level in stably-transfected C2C12 cells with p.G78V or p.W140C variants. Immunostaining demonstrates both cytoplasmic and nuclear localization of the wild-type protein, however variants p.G78V and p.W140C cause obvious reduction in the cytoplasmic expression of CSRP3 protein which is more pronounced in case of p.W140C. Disarrayed actin cytoskeleton was also observed in mutants. Besides, the expression of target genes namely Ldb3, Myoz2, Tcap, Tnni3 and Ttn are also downregulated in response to these variants. GST-pulldown assay has also showed a diminished binding of CSRP3 protein with α-Actinin due to both variants p.G78V and p.W140C. Both 2D, 3D-modeling have shown confirmational changes. Most in silico tools predict these variants as deleterious. Taken together, all these results suggest the impaired gene function due to these deleterious variants in CSRP3, implicating its possible disease causing role in DCM.
Distinct profiles of LRRK2 activation and Rab GTPase phosphorylation in clinical samples from different PD cohorts
Authors: Petropoulou-Vathi Lilian , Simitsi Athina , Valkimadi Politymi-Eleni , Kedariti Maria , Dimitrakopoulos Lampros , Koros Christos , Papadimitriou Dimitra , Papadimitriou Alexandros , Stefanis Leonidas , Alcalay Roy N. , Rideout Hardy J.
Published: November 2021

Despite several advances in the field, pharmacodynamic outcome measures reflective of LRRK2 kinase activity in clinical biofluids remain urgently needed. A variety of targets and approaches have been utilized including assessments of LRRK2 itself (levels, phosphorylation), or its substrates (e.g. Rab10 or other Rab GTPases). We have previously shown that intrinsic kinase activity of LRRK2 isolated from PBMCs of G2019S carriers is elevated, irrespective of disease status. In the present study we find that phosphorylation of Rab10 is also elevated in G2019S carriers, but only those with PD. Additionally, phosphorylation of this substrate is also elevated in 2 separate idiopathic PD cohorts, but not in carriers of the A53T mutation in α-synuclein. In contrast, Rab29 phosphorylation was specifically reduced in urinary exosomes from A53T and idiopathic PD patients. Taken together, our findings highlight the need for the assessment of multiple complimentary targets for a more comprehensive picture of the disease.
Affinity sedimentation and magnetic separation with plant-made immunosorbent nanoparticles for therapeutic protein purification
Authors: McNulty Matthew J. , Schwartz Anton , Delzio Jesse , Karuppanan Kalimuthu , Jacobson Aaron , Hart Olivia , Dandekar Abhaya , Giritch Anatoli , Nandi Somen , Gleba Yuri , McDonald Karen A.
Published: November 2021

The virus-based immunosorbent nanoparticle is a nascent technology being developed to serve as a simple and efficacious agent in biosensing and therapeutic antibody purification. There has been particular emphasis on the use of plant virions as immunosorbent nanoparticle chassis for their diverse morphologies and accessible, high yield manufacturing via crop cultivation. To date, studies in this area have focused on proof-of-concept immunosorbent functionality in biosensing and purification contexts. Here we consolidate a previously reported pro-vector system into a singleAgrobacterium tumefaciensvector to investigate and expand the utility of virus-based immunosorbent nanoparticle technology for therapeutic protein purification. We demonstrate the use of this technology for Fc-fusion protein purification, characterize key nanomaterial properties including binding capacity, stability, reusability, and particle integrity, and present an optimized processing scheme with reduced complexity and increased purity. Furthermore, we present a coupling of virus-based immunosorbent nanoparticles with magnetic particles as a strategy to overcome limitations of the immunosorbent nanoparticle sedimentation-based affinity capture methodology. We report magnetic separation results which exceed the binding capacity of current industry standards by an order of magnitude.
Ancient genomes from the last three millennia support multiple human dispersals into Wallacea
Authors: Oliveira Sandra , Nägele Kathrin , Carlhoff Selina , Pugach Irina , Koesbardiati Toetik , Hübner Alexander , Meyer Matthias , Oktaviana Adhi Agus , Takenaka Masami , Katagiri Chiaki , Murti Delta Bayu , Putri Rizky Sugianto , Mahirta  , Higham Thomas , Higham Charles F. W. , O’Connor Sue , Hawkins Stuart , Kinaston Rebecca , Bellwood Peter , Ono Rintaro , Powell Adam , Krause Johannes , Posth Cosimo , Stoneking Mark
Published: November 2021

Previous research indicates that the human genetic diversity found in Wallacea - islands in present-day Eastern Indonesia and Timor-Leste that were never part of the Sunda or Sahul continental shelves - has been shaped by complex interactions between migrating Austronesian farmers and indigenous hunter-gatherer communities. Here, we provide new insights into this region’s demographic history based on genome-wide data from 16 ancient individuals (2600-250 yrs BP) from islands of the North Moluccas, Sulawesi, and East Nusa Tenggara. While the ancestry of individuals from the northern islands fit earlier views of contact between groups related to the Austronesian expansion and the first colonization of Sahul, the ancestry of individuals from the southern islands revealed additional contributions from Mainland Southeast Asia, which seems to predate the Austronesian admixture in the region. Admixture time estimates for the oldest individuals of Wallacea are closer to archaeological estimates for the Austronesian arrival into the region than are admixture time estimates for present-day groups. The decreasing trend in admixture times exhibited by younger individuals supports a scenario of multiple or continuous admixture involving Papuan- and Asian-related groups. Our results clarify previously debated times of admixture and suggest that the Neolithic dispersals into Island Southeast Asia are associated with the spread of multiple genetic ancestries.