bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploratory Assessment of Levosimendan in Infants With Congenital Diaphragmatic Hernia
Authors: Schroeder Lukas , Gries Kristina , Ebach Fabian , Mueller Andreas , Kipfmueller Florian
Published: February 2021

OBJECTIVES:

Infants with congenital diaphragmatic hernia frequently suffer from cardiac dysfunction and pulmonary hypertension during the postnatal course. With the use of the inodilator levosimendan, a therapeutic approach is available in situations with catecholamine-refractory low-cardiac-output failure and severe pulmonary hypertension.

DESIGN:

Retrospective single-center cohort study.

SETTING:

University-based, tertiary-care children’s hospital neonatal ICU.

PATIENTS:

Cohort of 24 infants with congenital diaphragmatic hernia and levosimendan therapy, without underlying major cardiac defect, treated at the University Children´s Hospital Bonn, Germany, between January 2017 and December 2018.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Twenty-four infants with congenital diaphragmatic hernia were treated with levosimendan (41% of hospitalized congenital diaphragmatic hernia infants in the study period). In 88%, the congenital diaphragmatic hernia was left-sided. The median observed-to-expected lung-to-head ratio was 36%. About 60% of the infants were supported with venovenous extracorporeal membrane oxygenation and the mortality was 38% (9/24 infants). Levosimendan administration was associated with improvement of pulmonary hypertension severity (p = 0.013 and p = 0.000) and right ventricular dysfunction (p = 0.011 and p = 0.000) at 24 hours and 7 days after treatment. Similarly, the prevalence of left ventricular dysfunction decreased from 50% at baseline to 10% after 7 days (p = 0.026). A significant reduction in the peak inspiratory pressure was observed after drug application (p = 0.038) and a significant decrease of the Vasoactive-Inotropic Score was apparent (p = 0.022). A relevant arterial hypotension as a drug-related adverse event occurred in one patient.

CONCLUSIONS:

This is the first study exploring clinical and hemodynamic changes after levosimendan treatment in a cohort of infants with congenital diaphragmatic hernia. An association of levosimendan application and an improvement in pulmonary hypertension, right ventricular, and left ventricular dysfunction were observed within 7 days after drug infusion. However, due to the retrospective design of this study, the results should be interpreted carefully.
Point-of-Care Ultrasound Facilitates Management of Ruptured Ectopic Pregnancy
Authors: Moake Matthew M. , Price Amanda B. , Titus M. Olivia , Barnes Ryan M.
Published: February 2021

Abdominal pain in the pregnant adolescent presents a diagnostic dilemma with potential life-threatening etiologies. We present a case where point-of-care ultrasound was used to facilitate diagnosis and expedite lifesaving management of a ruptured ectopic pregnancy. We further review the technique and literature for first-trimester transabdominal point-of-care ultrasound.
Verification of Usefulness of Pediatric Head Trauma Imaging Protocol Combining Computerized Tomography, Observation Unit, and Magnetic Resonance Imaging
Authors: Nozawa Masahiro , Matsuura Jun , Iwata Kentaro , Shiomi Naoto
Published: February 2021

Objective

This study was conducted to investigate computed tomography (CT) scan rate and diagnostic accuracy of our protocol combining CT, observation unit, and magnetic resonance imaging (MRI) and compare them with other clinical decision rules (PECARN, CATCH, and CHALICE).

Methods

This prospective observational study conducted in our hospital between October 2016 and September 2019 included 1946 patients aged 0 to 15 years with head trauma, of whom 1137 were analyzed. Computed tomography scan rate and imaging examination (CT or MRI) rate of our protocol were investigated. Sensitivity and negative predictive value (NPV) were calculated. We also compared our protocol and other clinical decision rules with respect to CT scan rate, sensitivity, and NPV in the same cohort and outcomes.

Results

The CT scan rate of our protocol was 7.9%, and the imaging examination rate, including MRI, was 12.2%. When the outcome was set to intracranial injury, the sensitivity and NPV of our protocol were each 100%. The CT scan rates in each cohort were 14.5% for PECARN (8.1% for our protocol), 34.7% for CATCH (23.2% for ours), and 13.6% for CHALICE (7.9% for ours). The sensitivity and NPV in each cohort were 100% and 100% for PECARN (92.3% and 100% for ours), 64.7% and 92.6% for CATCH (100% and 100% for ours), and 83.9% and 99.5% for CHALICE (100% and 100% for ours), respectively.

Conclusions

The protocol we created by combining CT, observation unit, and MRI was considered to be useful for practice in pediatric head injury cases.
Increasing preexposure prophylaxis use and ‘net prevention coverage’ in behavioural surveillance of Australian gay and bisexual men
Authors: Holt Martin , Broady Timothy R. , Mao Limin , Chan Curtis , Rule John , Ellard Jeanne , O’Donnell Darryl , Grulich Andrew E. , Prestage Garrett , Bavinton Benjamin R.
Published: February 2021

Objective(s):

To assess trends in HIV prevention strategies among Australian gay and bisexual men (GBM) since the introduction of preexposure prophylaxis (PrEP), the level of net prevention coverage (the use of safe strategies), and the characteristics of HIV-negative and untested GBM who remain at risk of HIV.

Design:

Repeated behavioural surveillance of GBM recruited from venues, events and online in seven Australian states and territories.

Methods:

Participants with casual male partners were included. Trends in sexual practices, prevention strategies, net prevention coverage and the characteristics of ‘at risk’ participants were assessed with binary and multivariate logistic regression.

Results:

A total of 32 048 survey responses (2014–2019) were included. The proportion of participants who reported consistent condom use declined (44.6–23.2%). The proportion who reported any condomless anal intercourse with casual partners increased (37.4–62.0%) but net prevention coverage also increased (68.1–74.9%), with higher levels of undetectable viral load among HIV-positive participants and rapidly increasing PrEP use by HIV-negative participants. PrEP became the most commonly reported prevention strategy in 2019 (31.1%). The analysis of ‘at risk’ participants showed that they became more likely to report frequent condomless anal intercourse with casual partners but had fewer partners and more partners with undetectable viral load or on PrEP. ‘At risk’ participants became more likely to identify as bisexual and to be born overseas.

Conclusion:

There has been a rapid, historic shift in HIV prevention among GBM in Australia. Net prevention coverage has increased among GBM and ‘at risk’ GBM have become less at risk of HIV, facilitating reductions in HIV transmission.
Naloxone receipt and overdose prevention care among people with HIV on chronic opioid therapy
Authors: Kimmel Simeon D. , Walley Alexander Y. , Lodi Sara , Forman Leah S. , Liebschutz Jane M. , Lira Marlene C. , Kim Theresa W. , del Rio Carlos , Samet Jeffrey H. , Tsui Judith I.
Published: February 2021

This cross-sectional study describes naloxone rescue kit receipt among people with HIV (PWH) on chronic opioid therapy (COT) and HIV clinician opioid overdose prevention care in two clinics between 2015 and 2017. Naloxone rescue kit receipt was uncommon. History of overdose was associated with receiving naloxone but having a clinician who reported providing overdose prevention care was not. This study suggests that clinicians prescribing COT to PWH should improve overdose prevention care, including naloxone co-prescribing.
Prospective evaluation of blood Epstein–Barr virus DNA load and antibody profile in HIV-related non-Hodgkin lymphomas
Authors: Lupo Julien , Germi Raphaële , Lancar Rémi , Algarte-Genin Michèle , Hendel-Chavez Houria , Taoufik Yassine , Mounier Nicolas , Partisani Marialuisa , Bonnet Fabrice , Meyohas Marie-Caroline , Marchou Bruno , Filippova Anastasiia , Prevot Sophie , Costagliola Dominique , Morand Patrice , Besson Caroline
Published: February 2021

Objectives:

The value of Epstein–Barr virus (EBV) biomarkers on the prognosis of HIV-related non-Hodgkin's lymphoma (NHL) has been poorly explored in the combined antiretroviral therapy (cART) era.

Design:

We evaluated EBV DNA load and EBV antibodies in HIV-NHL patients enrolled in the French ANRS-CO16 Lymphovir Cohort between 2008 and 2015.

Methods:

Whole blood and plasma EBV DNA load and serological profiles were analyzed in 76 HIV-infected patients at diagnosis of NHL and 6 months after the initiation of chemotherapy.

Results:

Prechemotherapy whole blood (WB) and plasma EBV DNA loads were positive for 80 and 45% of HIV-NHL patients, respectively. Pretreatment WB EBV DNA positivity was associated with a positive plasma HIV-1 RNA load (relative risk (RR), 4.42 [1.33; 14.72]) and plasma EBV DNA positivity with EBV in situ detection (RR 10.62 [2.38; 47.49]). Following chemotherapy, the proportions of patients with positive WB or plasma EBV DNA declined from 81 to 23% (P < 0.0001) and from 43 to 8% (P < 0.0001), respectively. Estimated 2-year progression-free survival did not differ according to prechemotherapy WB positivity (82% versus 67%, P = 0.15) or plasma EBV DNA positivity (76% versus 81%, P 
= 0.52).

Conclusions:

The plasma EBV DNA load correlates with in situ EBV detection. The WB EBV DNA load correlates with HIV load. WB and plasma EBV DNA loads at NHL diagnosis do not constitute prognostic markers for HIV-NHL patients in the modern cART era.
Patient-Reported Outcomes: Quality of Care on a Neurosurgical Ward
Authors: Sadrameli Saeed S. , Chan Tiffany M. , Vaziri Sasha , Murad Gregory J. A. , Hooten Kristopher G.
Published: February 2021

Background and Objectives:

Patient experience has become a quality measure in hospitals across the United States. To improve our understanding of our neurosurgical patient populationʼs satisfaction needs, we undertook a detailed survey to identify areas of needed improvement.

Methods:

Upon institutional review board approval, a detailed survey adopted from the Swedish quality-of-care patient questionnaire was distributed to all patients being discharged from the neurosurgical ward over a month period. From June 2014 to July 2014, all patients admitted to the neurosurgery service through the emergency department, clinic, or other facilities were enrolled. There were no specific inclusion criteria except for age older than 18 years, intact cognition to complete the survey, and return of a completed survey. Data were collected in 6 major categories, including information availability, patient accessibility, treatment received, caring perception, hospital environment, and overall satisfaction. Patients were evaluated by age, gender, surgery, and admission type.

Results:

Our analysis demonstrated an improved overall satisfaction in those patients being admitted electively from the clinic as compared with emergency department admissions or hospital transfers. In addition, patients admitted on an emergent basis reported a lower satisfaction pertaining to receiving information, specifically test results.

Conclusions:

Emergent admissions represent a subpopulation that may require additional strategies to improve patient satisfaction survey scores.
Findings and Resolution of Melanoma Perineural Spread Along the Greater Auricular Nerve on FDG PET/CT and MRI
Authors: Nguyen Jennifer , Barber Thomas W. , Cameron Rhoda , Haydon Andrew , Mar Victoria
Published: February 2021

We report an unusual case of a 59-year-old man with recurrent right ear melanoma resulting in perineural spread to the right greater auricular nerve. Direct perineural spread to the greater auricular nerve is not commonly reported in melanoma. Our case demonstrates perineural spread along the greater auricular nerve on 18F-FDG PET/CT and MRI. This finding was supported by intraneural invasion noted at the surgical margin of the wide local excision of the right helix melanoma. Resolution of FDG activity and improved MRI appearances of the right greater auricular nerve were seen after immunotherapy treatment.
Practical Approach to the Tele-Neuro-Ophthalmology and Neuro-Otology Visits: Instructional Videos
Authors: Calix Rachel , Grossman Scott N. , Rasool Nailyn , Small Leslie , Cho Catherine , Galetta Steven L. , Balcer Laura J. , Rucker Janet C.
Published: February 2021

A collection of instructional videos that illustrate a step by step approach to tele-neuro-ophthalmology and neuro-otology visits. These videos provide instruction for patient preparation for their video visit, patient and provider interface with an electronic medical record associated video platform, digital applications to assist with vision testing, and practical advice for detailed remote neuro-ophthalmologic and neuro-otologic examinations.
Early Antibody Responses Associated with Survival in COVID19 Patients
Authors: Zhou Zhao-Hua , Dharmarajan Sai , Lehtimaki Mari , Kirshner Susan L. , Kozlowski Steven
Published: February 2021

Neutralizing antibodies to the SARS CoV-2 spike proteins have been issued Emergency Use Authorizations and are a likely mechanism of vaccines to prevent COVID-19. However, benefit of treatment with monoclonal antibodies has only been observed in clinical trials in outpatients with mild to moderate COVID-19 but not in patients who are hospitalized and/or have advanced disease. To address this observation, we evaluated the timing of anti SARS-CoV-2 antibody production in hospitalized patients with the use of a highly sensitive multiplexed bead-based immunoassay allowing for early detection of antibodies to SARS-CoV-2. We found that significantly lower levels of antibodies to the SARS-CoV-2 spike protein in the first week after symptom onset were associated with patients who expired as compared to patients who were discharged. We also developed a model, based on antibody level trajectory, to predict COVID 19 outcome that is compatible with greater antibody benefit earlier in COVID 19 disease.

Author Summary

We evaluated antibodies to SARS-CoV-2 over time in patients that were hospitalized with COVID 19. Early detection of Anti-SARS-CoV-2 antibodies was associated with survival in patients hospitalized with COVID 19. Early antibody levels predicted outcome in our study. This result is consistent with the benefit of therapeutic antibodies early in the course of COVID 19 disease. With additional study, early antibody levels may be helpful in deciding on appropriate therapies.
Non-pharmaceutical interventions and inoculation rate shape SARS-COV-2 vaccination campaign success
Authors: Galanti Marta , Pei Sen , Yamana Teresa K. , Angulo Frederick J. , Charos Apostolos , Khan Farid , Shea Kimberly M. , Swerdlow David L. , Shaman Jeffrey
Published: February 2021

Nearly one year into the COVID-19 pandemic, the first SARS-COV-2 vaccines received emergency use authorization and vaccination campaigns began. A number of factors can reduce the averted burden of cases and deaths due to vaccination. Here, we use a dynamic model, parametrized with Bayesian inference methods, to assess the effects of non-pharmaceutical interventions, and vaccine administration and uptake rates on infections and deaths averted in the United States. We estimate that high compliance with non-pharmaceutical interventions could avert more than 60% of infections and 70% of deaths during the period of vaccine administration, and that increasing the vaccination rate from 5 to 11 million people per week could increase the averted burden by more than one third. These findings underscore the importance of maintaining non-pharmaceutical interventions and increasing vaccine administration rates.
ExOrthist: a tool to infer exon orthologies at any evolutionary distance
Authors: Márquez Yamile , Mantica Federica , Cozzuto Luca , Burguera Demian , Hermoso-Pulido Antonio , Ponomarenko Julia , Roy Scott W. , Irimia Manuel
Published: February 2021

Several bioinformatic tools have been developed for genome-wide identification of orthologous and paralogous genes among species. However, no existing tool allows the detection of orthologous/paralogous exons. Here, we present ExOrthist, a fully reproducible Nextflow-based software enabling to (i) infer exon homologs and orthogroups, (ii) visualize evolution of exon-intron structures, and (iii) assess conservation of alternative splicing patterns. ExOrthist not only evaluates exon sequence conservation but also considers the surrounding exon-intron context to derive genome-wide multi-species exon homologies at any evolutionary distance. We demonstrate its use in various evolutionary scenarios, from whole genome duplication to convergence of alternative splicing networks.
Can we harness digital technologies and physiology to hasten genetic gain in U.S. maize breeding?
Authors: Diepenbrock C. , Tang T. , Jines M. , Technow F. , Lira S. , Podlich D. , Cooper M. , Messina C.
Published: February 2021

Genetic gain in breeding programs depends on the predictive skill of genotype-to-phenotype algorithms and precision of phenotyping, both integrated with well-defined breeding objectives for a target population of environments (TPE). The integration of physiology and genomics could improve predictive skill by capturing additive and non-additive interaction effects of genotype (G), environment (E), and management (M). Precision phenotyping at managed stress environments (MSEs) can elicit physiological expression of processes that differentiate germplasm for performance in target environments, thus enabling algorithm training. Gap analysis methodology enables design of GxM technologies for target environments by assessing the difference between current and attainable yields within physiological limits. Harnessing digital technologies such as crop growth model-whole genome prediction (CGM-WGP) and gap analysis, and MSEs, can hasten genetic gain by improving predictive skill and definition of breeding goals in the U.S. maize production TPE. A half-diallel maize experiment resulting from crossing 9 elite maize inbreds was conducted at 17 locations in the TPE and 6 locations at MSEs between 2017 and 2019. Analyses over 35 families represented by 2367 hybrids demonstrated that CGM-WGP offered a predictive advantage (y) compared to WGP that increased with occurrence of drought as measured by decreasing whole-season evapotranspiration (ET; log(y) = 0.80(±0.6) − 0.006(±0.001) ×ET;r2= 0.59;df= 21). Predictions of unobserved physiological traits using the CGM, akin to digital phenotyping, were stable. This understanding of germplasm response to ET enables predictive design of opportunities to close productivity gaps. We conclude that enabling physiology through digital methods can hasten genetic gain by improving predictive skill and defining breeding objectives bounded by physiological realities.
Parental attitudes towards mandatory vaccination; a systematic review
Authors: Smith Louise E. , Hodson Ava , Rubin G. James
Published: February 2021

While mandatory vaccination schemes can increase vaccine uptake rates, they can also cause backlash among some parents. We conducted a systematic review investigating parental beliefs about vaccine mandates and factors associated with support for mandatory vaccination schemes. We searched Embase, Ovid MEDLINE, Global Health, APA PsycINFO and Web of Science from inception to 17th September 2020. Seventeen studies (five qualitative, twelve quantitative) were eligible for inclusion. We synthesised results of qualitative and quantitative studies separately. Studies were heterogeneous with regard to schemes investigated and factors investigated. Quantitative studies found little evidence for any factors being consistently associated with support for mandatory vaccination. Qualitative studies found that parents perceived mandatory vaccination schemes as an infringement of their rights and that they preferred universal, compared to targeted, schemes. To optimise engagement with existing child mandatory vaccination legislation, schemes should be designed with parental beliefs in mind.
Heterogeneous Mental Health Development During the COVID-19 Pandemic in the United Kingdom
Authors: Ellwardt Lea , Präg Patrick
Published: February 2021

The COVID-19 pandemic and the mitigation measures by governments have upended the economic and social lives of many, leading to widespread psychological distress. We explore heterogeneity in trajectories of psychological distress during the pandemic in the United Kingdom and relate this heterogeneity to socio-demographic and health factors. We analyze nine waves of longitudinal, nationally representative survey data from the UK Household Longitudinal Study (N=15,914), covering the period from early 2020 to mid-2021. First, latent class mixture modelling (LCCM) is used to identify trajectories of psychological distress. Second, associations of the trajectories with covariates are tested with multinomial logistic regressions. We find four different trajectories of distress: continuously low, temporarily elevated, repeatedly elevated, and continuously elevated distress. Nearly two fifths of the population experienced severely elevated risks of distress during the pandemic. Long-term distress was highest among younger people, women, people living without a partner, those who had no work or lost income, and those with previous health conditions or COVID-19 symptoms. Given the threat of persistent stress on health, policy measures should be sensitized to the unintended yet far-reaching consequences of non-pharmaceutical interventions.
Calcium-Sensing Receptor Polymorphisms at rs1801725 are Associated with Increased Risk of Secondary Malignancies
Authors: Actkins Ky’Era V. , Beasley Heather K. , Faucon Annika B. , Davis Lea K. , Sakwe Amos M.
Published: February 2021

Purpose

Dysregulation of systemic calcium homeostasis during malignancy is common in most patients with high grade tumors. However, it remains unclear whether single nucleotide polymorphisms (SNPs) that alter the sensitivity of the calcium-sensing receptor (CaSR) to circulating calcium are associated with primary and/or secondary neoplasms at specific pathological sites in patients of European and African ancestry.

Methods

Multivariable logistic regression models were used to analyze the association of CASR SNPs with circulating calcium, parathyroid hormone, vitamin D, and primary and secondary neoplasms.

Results

Circulating calcium is associated with an increased risk for breast, prostate, and skin cancers. In patients of European descent, the rs1801725 CASR SNP is associated with bone-related cancer phenotypes, deficiency of humoral immunity, and a higher risk of secondary neoplasms in the lungs and bone. Interestingly, circulating calcium levels are higher in homozygous patients for the inactivating CASR variant at rs1801725 (TT genotype), and this is associated with a higher risk of secondary malignancies.

Conclusions

Breast, prostate, and skin cancer patients with homozygous inactivating variants (TT genotype) at the CASR rs1801725 locus have a higher risk of developing secondary neoplastic lesions in the lungs and bone, due in part, to cancer-induced hypercalcemia and/or tumor immune suppression.
Long COVID neuropsychological deficits after severe, moderate or mild infection
Authors: Voruz P. , Allali G. , Benzakour L. , Nuber-Champier A. , Thomasson M. , Jacot I. , Pierce J. , Lalive P. , Lövblad K-O. , Braillard O. , Coen M. , Serratrice J. , Pugin J. , Ptak R. , Guessous I. , Landis B.N. , Assal F. , Péron J.A.
Published: February 2021

Background

There is growing awareness that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can include long-term neuropsychological deficits, even in its mild or moderate respiratory forms.

Methods

Standardized neuropsychological, psychiatric, neurological and olfactory tests were administered to 45 patients (categorized according to the severity of their respiratory symptoms during the acute phase) 236.51 ± 22.54 days post-discharge following SARS-CoV-2 infection.

Results

Deficits were found in all the domains of cognition and the prevalence of psychiatric symptoms was also high in the three groups. The severe performed more poorly on long-term episodic memory and exhibited greater anosognosia. The moderate had poorer emotion recognition, which was positively correlated with persistent olfactory dysfunction. The mild were more stressed, anxious and depressed.

Conclusion

The data support the hypothesis that the virus targets the central nervous system (and notably the limbic system), and support the notion of different neuropsychological phenotypes.
Using next generation matrices to estimate the proportion of infections that are not detected in an outbreak
Authors: Unwin H Juliette T , Cori Anne , Imai Natsuko , Gaythorpe Katy A. M. , Bhatia Sangeeta , Cattarino Lorenzo , Donnelly Christl A. , Ferguson Neil M. , Baguelin Marc
Published: February 2021

Contact tracing, where exposed individuals are followed up to break ongoing transmission chains, is a key pillar of outbreak response for infectious disease outbreaks. Unfortunately, these systems are not fully effective, and infections can still go undetected as people may not remember all their contacts or contacts may not be traced successfully. A large proportion of undetected infections suggests poor contact tracing and surveillance systems, which could be a potential area of improvement for a disease response. In this paper, we present a method for estimating the proportion of infections that are not detected during an outbreak. Our method uses next generation matrices that are parameterized by linked contact tracing data and case line-lists. We validate the method using simulated data from an individual-based model and then investigate two case studies: the proportion of undetected infections in the SARS-CoV-2 outbreak in New Zealand during 2020 and the Ebola epidemic in Guinea during 2014. We estimate that only 5.26% of SARS-CoV-2 infections were not detected in New Zealand during 2020 (95% credible interval: 0.243 – 16.0%) but depending on assumptions 39.0% or 37.7% of Ebola infections were not detected in Guinea (95% credible intervals: 1.69 – 87.0% or 1.7 – 80.9%).
Plasma Amino Acids Metabolomics’ Profile Important for Glucose Management in Jordanian people with Type 2 Diabetes
Authors: Alqudah Abdelrahim , Wedyan Mohammed , Qnais Esam , Jawarneh Hassan , McClements Lana
Published: February 2021

Background

The disturbances in plasma free amino acid metabolome in diabetes mellitus was studied before but not in Jordanian population. This study aimed to assess the association between type 2 diabetes (T2D) and amino acid metabolome in a representative group of people from Jordan.

Methods

Blood samples from 124 people with T2D and 67 age-, gender- and BMI-matched healthy controls were collected and assayed for glucose and HbA1c. Twenty one amino acids belonging to different categories (essential, non-essential, semi-essential, and metabolic indicators) were evaluated in both groups using amino acids analyser.

Results

Plasma free amino acids concentrations of total amino acids, total essential amino acids, total non-essential amino acids, and total semi-essential amino acids were not different in T2D compared to healthy controls. However, plasma concentrations of four essential amino acids (Leucine, Lysine, Phenylalanine, Tryptophan) were increased in the presence of T2D (Leucine, p<0.01, Lysine, p<0.001, Phenylalanine, p<0.01, Tryptophan, p<0.05). Conversely, amongst the non-essential amino acids, Alanine and Serine were reduced in type 2 diabetes (Alanine, p<0.01, Serine, p<0.001), whereas, Aspartate and Glutamate were increased in T2D compared to healthy control plasma (Aspartate, p<0.001, Glutamate, p<0.01). A semi-essential amino acid, Cystine, was also increased in T2D compared to healthy controls (p<0.01). Citrulline, a metabolic indicator amino acid, demonstrated lower plasma concentration in T2Dcompared to healthy controls (p<0.01).

Conclusion

Several amino acids from different categories are dysregulated in T2D, which could be used as a therapeutic target to improve T2D management and its complications.
Bamlanivimab does not neutralize two SARS-CoV-2 variants carrying E484K in vitro
Authors: Widera Marek , Wilhelm Alexander , Hoehl Sebastian , Pallas Christiane , Kohmer Niko , Wolf Timo , Rabenau Holger F , Corman Victor , Drosten Christian , Vehreschild Maria JGT , Goetsch Udo , Gottschalk Rene , Ciesek Sandra
Published: February 2021

The IgG1 monoclonal antibody (mAb) bamlanivimab (LY-CoV555) prevents viral attachment and entry into human cells by blocking attachment to the ACE2 receptor. However, whether bamlanivimab is equally effective against SARS-CoV-2 emerging variants of concern (VOC) is not fully known. Hence, the aim of this study was to determine whether bamlanivimab is equally effective against SARS-CoV-2 emerging VOC. The ability of bamlanivimab to neutralize five SARS-CoV-2 variants including B.1.1.7 (mutations include N501Y and del69/70), B.1.351 (mutations include E484K and N501Y) and P.2 (mutations include E484K in the absence of a N501Y mutation) was analyzed in infectious cell culture using CaCo2 cells. Additionally, we analyzed vaccine-elicited sera after immunization with BNT162b2, and convalescent sera for its ability to neutralize SARS-CoV-2 variants.

We found that the variant B.1.1.7, as well as two isolates from early 2020 (FFM1 and FFM7) could be efficiently neutralized by bamlanivimab (titer 1/1280, respectively), however, no neutralization effect could be detected against either B.1.135 or P.2, both harboring the E484K substitution. Vaccine-elicited sera showed slightly decreased neutralizing activity against B1.1.7, B.1.135 and P.2

Our in vitro findings indicate that, in contrast to vaccine-elicited sera, bamlanivimab may not provide efficacy against SARS-CoV-2 variants harboring the E484K substitution. Confirmation of the SARS-CoV-2 variant, including screening for E484K, may be needed before initiating mAb treatment with bamlanivimab to ensure both efficacious and efficient use of the antibody product. Hence, variant-specific mAb agents may be required to treat emerging VOC.
SIRT1 regulates sphingolipid metabolism and neural differentiation of mouse embryonic stem cells through c-Myc- SMPDL3B
Authors: Fan Wei , Tang Shuang , Fan Xiaojuan , Fang Yi , Xu Xiaojiang , Li Leping , Xu Jian , Li Jian-Liang , Wang Zefeng , Li Xiaoling
Published: February 2021

Sphingolipids are important structural components of cell membranes and prominent signaling molecules controlling cell growth, differentiation, and apoptosis. Sphingolipids are particularly abundant in the brain, and defects in sphingolipid degradation are associated with several human neurodegenerative diseases. However, molecular mechanisms governing sphingolipid metabolism remain unclear. Here we report that sphingolipid degradation is under transcriptional control of SIRT1, a highly conserved mammalian NAD+-dependent protein deacetylase, in mouse embryonic stem cells (mESCs). Deletion of SIRT1 results in accumulation of sphingomyelin in mESCs, primarily due to reduction of SMPDL3B, a GPI-anchored plasma membrane bound sphingomyelin phosphodiesterase. Mechanistically, SIRT1 regulates transcription ofSmpdl3bthrough c-Myc. Functionally, SIRT1 deficiency-induced accumulation of sphingomyelin increases membrane fluidity and impairs neural differentiationin vitroandin vivo. Our findings discover a key regulatory mechanism for sphingolipid homeostasis and neural differentiation, further imply that pharmacological manipulation of SIRT1-mediated sphingomyelin degradation might be beneficial for treatment of human neurological diseases.
The monocyte-to-lymphocyte ratio: defining a normal range, sex-specific differences in the tuberculosis disease spectrum and diagnostic indices
Authors: Buttle Thomas S. , Hummerstone Claire Y. , Billahalli Thippeswamy , Ward Richard J. B. , Barnes Korina E. , Marshall Natalie J. , Spong Viktoria C. , Bothamley Graham H.
Published: February 2021

Background

The monocyte-to-lymphocyte ratio has been advocated as a biomarker in tuberculosis. Our objective was to evaluate its clinical role in diagnosis, prognosis and treatment outcome.

Methods

Complete blood counts from an unselected population aged 16 to 65 years defined normal values of the ratio and associations with other indices. Blood counts, inflammatory markers and clinical parameters were measured in patients with and those screened for tuberculosis. We examined the ratio for its associations with these variables and for diagnosis, screening, prediction of poor prognosis and response to treatment. Results. In the unselected population, monocyte-to-lymphocyte ratios were higher in males than females and correlated with neutrophil counts (Spearman’s rho=0.48, P<0.00001, n=14,573). In 356 patients notified with tuberculosis, ratios were higher in males (high monocyte counts), especially in smear-positive pulmonary tuberculosis (S+PTB), lung cavitation and raised inflammatory markers. The sensitivities for confirmed tuberculosis were 42% (males) and 32% (females), with specificities of 70% and 71% respectively. Using sex-specific cut-offs in 629 adults screened for tuberculosis and with a positive tuberculin skin test or interferon-gamma release assay, diagnostic sensitivities for active tuberculosis were better in males (25%; all and contacts of a S+PTB index, respectively) than females (14-17%) with specificities of 89-96%. Positive likelihood ratios were better with upper limits alone but were still poor (6.64 when screening for tuberculosis, with an area under the curve of 0.688). Ratios did not predict death or response to treatment. Ratios were especially higher in males than female ratios in the 16-45 years age group.

Conclusions

Severe tuberculosis and male sex associated with high monocyte-to-lymphocyte ratios. The ratio performed poorly as a clinical aid. (269 words)
Polyvalent Guide RNAs for CRISPR Antivirals
Authors: Bagchi Rammyani , Tinker-Kulberg Rachel , Supakar Tinku , Chamberlain Sydney , Ligaba-Osena Ayalew , Josephs Eric A.
Published: February 2021

CRISPR biotechnologies, where CRISPR effectors recognize and degrade specific nucleic acid targets that are complementary to their guide RNA (gRNA) cofactors, have been primarily used as a tool for precision gene editing1but possess an emerging potential for novel antiviral diagnostics, prophylactics, and therapeutics.2–5In gene editing applications, significant efforts are made to limit the natural tolerance of CRISPR effectors for nucleic acids with imperfect complementarity to their gRNAs in order to prevent degradation and mutation at unintended or “off-target” sites; here we exploit those tolerances to engineer gRNAs that are optimized to promote activity at multiple viral target sites, simultaneously, given that multiplexed targeting is a critical tactic for improving viral detection sensitivity,3expanding recognition of clinical strain variants,6and suppressing viral mutagenic escape from CRISPR antivirals.7We demonstratein vitroand in higher plants that single “polyvalent” gRNAs (pgRNAs) in complex with CRISPR effectors Cas9 or Cas13 can effectively degrade pairs of viral targets with significant sequence divergence (up to 40% nucleotide differences) that are prevalent in viral genomes. We find that CRISPR antivirals using pgRNAs can robustly suppress the propagation of plant RNA viruses,in vivo, better than those with a “monovalent” gRNA counterpart. These results represent a powerful new approach to gRNA design for antiviral applications that can be readily incorporated into current viral detection and therapeutic strategies, and highlight the need for specific approaches and tools that can address the differential requirements of precision gene editingvs. CRISPR antiviral applications in order to mature these promising biotechnologies.
Comparison of the pathogenicity and virus shedding of SARS CoV-2 VOC 202012/01 and D614G variant in hamster model
Authors: Mohandas Sreelekshmy , Yadav Pragya D , Nyayanit Dimpal , Deshpande Gururaj , Shete-Aich Anita , Sapkal Gajanan , Kumar Sanjay , Jain Rajlaxmi , Kadam Manoj , Kumar Abhimanyu , Patil Deepak Y , Sarkale Prasad , Gawande Pranita , Abraham Priya
Published: February 2021

The emergence of SARS-CoV-2 variants has posed a serious challenge to public health system and vaccination programs across the globe. We have studied the pathogenicity and virus shedding pattern of the SARS-CoV-2 VOC 202012/01 and compared with D614G variant in Syrian hamsters. VOC 202012/01 could produce disease in hamsters characterized by body weight loss and respiratory tract tropism but mild lung pathology. Further, we also documented that neutralizing antibodies developed against VOC 202012/01 could equally neutralize D614G variant. Higher load of VOC 202012/01 in the nasal wash specimens was observed during the first week of infection outcompeting the D614G variant. The findings suggest increased fitness of VOC 202012/01 to the upper respiratory tract which could lead to higher transmission. Further investigations are needed to understand the transmissibility of new variants.

One-Sentence Summary

SARS-CoV-2 VOC 202012/01 infected hamsters demonstrated high viral RNA shedding through the nasal secretions and significant body weight loss with mild lung pathology compared to the D614G variant.
Experimental increases in temperature mean and variance alter reproductive behaviors in the dung beetlePhanaeus vindex
Authors: Kirkpatrick William H. , Sheldon Kimberly S.
Published: February 2021

Temperature profoundly impacts insect development, but plasticity of reproductive behaviors may mediate the impacts of temperature change on earlier life stages. Few studies have examined the potential for behavioral plasticity of adults to buffer developing offspring from warmer, more variable temperatures associated with climate change. We used a field manipulation to examine whether the dung beetlePhanaeus vindexalters breeding behaviors in response to climate change and whether adult behavioral shifts protect offspring from temperature increases. Dung beetles lay eggs inside brood balls made of dung that are buried underground for the entirety of offspring development. Depth of the brood ball impacts the temperatures offspring experience with consequences for beetle development. We placed females in either control or greenhouse treatments that simultaneously increased temperature mean and variance. We found that females produced smaller brood balls but buried them deeper in the greenhouse treatment, suggesting burial depth may come at a cost to brood ball size, which can impact offspring nutrition. Despite being buried deeper, brood balls from the greenhouse treatment experienced warmer mean temperatures but similar amplitudes of temperature fluctuation relative to the controls. Our findings suggest adult behaviors may buffer offspring from increased temperature variation due to climate change.
ELOF1 is a transcription-coupled DNA repair factor that directs RNA polymerase II ubiquitylation
Authors: van der Weegen Yana , de Lint Klaas , van den Heuvel Diana , Nakazawa Yuka , Narayanan Ishwarya V. , Klaassen Noud H.M. , Wondergem Annelotte P. , Roohollahi Khashayar , van Schie Janne J.M. , Hara Yuichiro , Ljungman Mats , Ogi Tomoo , Wolthuis Rob M.F. , Luijsterburg Martijn S.
Published: February 2021

Cells employ transcription-coupled repair (TCR) to eliminate transcription-blocking DNA lesions. The binding of the TCR-specific repair factor CSB triggers DNA damage-induced ubiquitylation of RNA polymerase II (RNAPII) at a single lysine (K1268) by the CRL4CSAubiquitin ligase. However, how the CRL4CSAligase is specifically directed toward the K1268 site is unknown. Here, we identify ELOF1 as the missing link that facilitates RNAPII ubiquitylation, a key signal for the assembly of downstream repair factors. This function requires its constitutive interaction with RNAPII close to the K1268 site, revealing ELOF1 as a specificity factor that positions CRL4CSAfor optimal RNAPII ubiquitylation. Furthermore, drug-genetic interaction screening reveals an unanticipated compensatory TCR pathway in which ELOF1 together with known factors DOT1L and HIRA protect CSB-deficient cells from collisions between transcription and replication machineries. Our study provides a genetic framework of the transcription stress response and reveals key insights into the molecular mechanism of TCR.
A functional logic for neurotransmitter co-release in the cholinergic forebrain pathway
Authors: Nair Aditya , Graf Martin , Teo Yue Yang , Augustine George J.
Published: February 2021

The forebrain cholinergic system has recently been shown to co-release both acetylcholine and GABA. We have discovered that such co-release by cholinergic inputs to the claustrum differentially affects neurons that project to cortical versus subcortical targets. The resulting changes in neuronal gain toggles network efficiency and discriminability of output between two different projection subcircuits. Our results provide a potential logic for neurotransmitter co-release in cholinergic systems.
Intrinsic Gating Behavior of Voltage-Gated Sodium Channels Predetermines Regulation by Auxiliary β-subunits
Authors: Brake Niklas , Mancino Adamo S , Yan Yuhao , Shimomura Takushi , Silveira Heika , Kubo Yoshihiro , Khadra Anmar , Bowie Derek
Published: February 2021

Voltage-gated sodium (Nav) channels mediate rapid millisecond electrical signaling in excitable cells. Auxiliary subunits, β1-β4, are thought to regulate Nav channel function through covalent and/or polar interactions with the channel’ s voltage-sensing domains. How these interactions translate into the diverse and variable regulatory effects of β-subunits remains unclear. Here, we find that the intrinsic movement order of the voltage-sensing domains during channel gating is unexpectedly variable across Nav channel isoforms. This movement order dictates the channel’ s propensity for closed-state inactivation, which in turn modulates the actions of β1 and β3. We show that the differential regulation of skeletal muscle, cardiac, and neuronal Nav channels is explained by their variable levels of closed-state inactivation. Together, this study provides a unified mechanism for the regulation of all Nav channel isoforms by β1 and β3, which explains how the fixed structural interactions of auxiliary subunits can paradoxically exert variable effects on channel function.
Kasugamycin is a novel chitinase 1 inhibitor with strong antifibrotic effects on pulmonary fibrosis
Authors: Lee Jae-Hyun , Lee Chang-Min , Lee Joyce H. , Kim Mun-Ock , Park Jin Wook , Kamle Suchitra , Akosman Bedia , Herzog Erica L. , Peng Xue Yan , Elias Jack A. , Lee Chun Geun
Published: February 2021

Rationale

Pulmonary fibrosis is a devastating lung disease with few therapeutic options. Chitinase 1 (CHIT1), an 18 glycosyl hydrolase family member, contributes to the pathogenesis of pulmonary fibrosis through regulation of Transforming Growth Factor (TGF)-β signaling and effector function. Therefore, CHIT1 is a potential therapeutic target of pulmonary fibrosis.

Objectives

This study aimed to identify and characterize a druggable CHIT1 inhibitor with strong antifibrotic activity and minimal toxicity for therapeutic application to pulmonary fibrosis.

Methods

Extensive screening of small molecule libraries identified the aminoglycoside antibiotic Kasugamycin as a potent CHIT1 inhibitor.

Measurements and Main Results

Elevated levels of CHIT1 were detected in the lungs of patients with pulmonary fibrosis. In vivo bleomycin- and TGF-β-stimulated murine models of pulmonary fibrosis, Kasugamycin showed impressive anti-fibrotic effects in both preventive and therapeutic conditions. In vitro studies also demonstrated that Kasugamycin inhibits fibrotic macrophage activation, fibroblast proliferation and myofibroblast transformation. Null mutation of transforming growth factor beta associated protein 1 (TGFBRAP1), a recently identified CHIT1 interacting signaling molecule, phenocopied antifibrotic effects of Kasugamycin in in vivo lungs and in vitro fibroblasts responses. Kasugamycin inhibits physical association between CHIT1 and TGFBRAP1, suggesting that antifibrotic effect of Kasugamycin is mediated through regulation of TGFBRAP1, at least in part.

Conclusions

These studies demonstrate that Kasugamycin is a novel CHIT1 inhibitor with strong antifibrotic effect that can be further developed as an effective and safe therapeutic drug for pulmonary fibrosis.
Immunity-longevity tradeoff neurally controlled by GABAergic transcription factor PITX1/UNC-30
Authors: Otarigho Benson , Aballay Alejandro
Published: February 2021

A body of evidence indicates that metazoan immune and aging pathways are largely interconnected, but the mechanisms involved in their homeostatic control remain unclear. In this study, we found that the PITX (paired like homeodomain) transcription factor UNC-30 controls the tradeoff between immunity and longevity from the nervous system inCaenorhabditis elegans. PITX/UNC-30 functional loss enhanced immunity in a GATA/ELT-2- and p38 MAPK/PMK-1-dependent manner and reduced longevity by activating MXD/MDL-1 and the C2H2-type zinc finger transcription factor PQM-1. The immune inhibitory and longevity stimulatory functions of PITX/UNC-30 required the sensory neuron ASG and a neurotransmitter signaling pathway controlled by NPR-1, which is a G protein-coupled receptor related to mammalian neuropeptide Y receptors. Our findings uncovered a suppressive role of GABAergic signaling in the neural control of a biological tradeoff where energy is allocated towards immunity at the expense of longevity.
Regulation of DNA (de)methylation positively impacts seed germination during seed development under heat stress
Authors: Malabarba Jaiana , Windels David , Xu Wenjia , Verdier Jerome
Published: February 2021

Seed development needs the coordination of multiple molecular mechanisms to promote correct tissue development, seed filling and the acquisition of germination capacity, desiccation tolerance, longevity and dormancy. Heat stress can negatively impact these processes and upon the increasing of global mean temperatures, global food security is threatened. Here, we explored the impact of heat stress on seed physiology, morphology, gene expression and methylation on three stages of seed development. Notably, Arabidopsis Col-0 plants under heat stress presented a decrease in germination capacity and also a decrease in longevity. We observed that upon mild stress, gene expression and DNA methylation were moderately affected. Nevertheless, upon severe heat stress during seed development, gene expression was intensively modified, promoting heat stress response mechanisms, including the activation of ABA pathway. By analyzing candidate epigenetic marks using mutants’ physiological assays, we observed that the lack of DNA demethylation byROS1gene impaired seed germination by affecting germination-related genes expression. On the other hand, we also observed that upon severe stress, a large proportion of differentially methylated regions (DMRs) were located in promoters and gene sequences of germination-related genes. To conclude, our results indicate that DNA (de)methylation could be a key regulatory process to ensure proper seed germination of seeds produced under heat stress.

Graphic Abstract