bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Hasner valvulotomy outcomes in pediatric and adult patients: does age matter?
Authors: Sun Hua , Ding Jing-Wen , Li Dong-Mei , Wang Ning-Li
Published: September 2020

Background

Hasner valve incision has been recently introduced as a new treatment for ophthalmic patients with epiphora symptoms. The aim of this study was to examine whether surgical outcomes of Hasner valve incision for inferior nasolacrimal duct obstruction were different between pediatric and adult patients.

Methods

A total of 53 eyes of 52 patients who underwent Hasner valve incision in the Beijing Tongren Hospital from October 2016 to November 2019 were retrospectively observed. Patients were divided into two groups, including pediatric group (23 eyes of 22 patients, <18 years old) and adult group (30 eyes of 30 patients, ≥18 years old). Success rate of surgery was determined by both subjective measure (complete resolution of epiphora) and objective measure (lacrimal passage irrigation and tear meniscus height). Fisher exact test was conducted.

Results

By conducting Fisher exact test and comparing complete resolution of epiphora (P = 0.627), lacrimal passage irrigation (P = 0.663), measurement of Tear Meniscus Height (P = 0.561), and appearance of complication (P = 0.339), there was no statistically significant difference of surgical outcomes between pediatric and adult patients (P > 0.05).

Conclusion

Hasner valve incision was effective for both adult and children with inferior nasolacrimal duct obstruction, with no difference in surgical outcomes between the two groups.
Impact of Therapeutic Drug Monitoring on Once-Daily Regimen of Amikacin in Patients With Urinary Tract Infection: A Prospective Observational Study
Authors: Jayakumar Ilanthamizhan , Mathaiyan Jayanthi , Mandal Jharna , Deepanjali Surendran , Sreenivasan Sreerag K.
Published: September 2020

Background:

Amikacin is a semisynthetic antibiotic used in the treatment of gram-negative bacterial infections and has a narrow therapeutic index. Although therapeutic drug monitoring is recommended for amikacin, it is not routinely performed because of the use of a less toxic once-daily regimen. Only few studies have evaluated the role of therapeutic drug monitoring in patients treated with amikacin. The objective of our study was to find an association between the pharmacokinetic parameters of amikacin and the time required for a clinical cure, creatinine clearance, and frequency of ototoxicity in patients with urinary tract infection treated for 7 or more days.

Methods:

A prospective study was conducted on patients with urinary tract infections who were administered amikacin for 7 or more days. Blood samples were obtained from the patients to measure the maximum drug concentration (Cmax) and trough concentration (Ctrough). Minimum inhibitory concentration (MIC) values were determined for patients with positive urine cultures. Serum creatinine levels were estimated every 3 days. The auditory assessment was performed using pure tone audiometry at baseline and weekly until the patients were discharged. Levels of amikacin were analyzed using a validated liquid chromatography-tandem mass spectrometry method.

Results:

Of 125 patients analyzed, the median time required for a clinical cure was less in the group of patients who achieved a Cmax/MIC ratio ≥8 than it was in those who did not achieve this level [7 versus 8 days (P = 0.02)]. The Ctrough of amikacin was associated with the change in serum creatinine level (P = 0.01) and the incidence of nephrotoxicity (P = 0.004).

Conclusions:

In patients receiving short-term amikacin therapy, Cmax/MIC value can be used to predict the time required for a clinical cure. Ctrough can be used to predict the occurrence of nephrotoxicity in patients receiving amikacin therapy.
Comparison of the Long-term Impact and Clinical Outcomes of Fewer Doses and Standard Doses of Human Papillomavirus Vaccine in the United States: A Database Study
Authors: Rodriguez Ana M. , Zeybek Burak , Vaughn Micah , Westra Jordan , Kaul Sapna , Montealegre Jane R. , Lin Yu-Li , Kuo Yong-Fang
Published: September 2020

(Abstracted from Cancer 2020;126:1656–1667)

Human papillomavirus (HPV) is the most common sexually transmitted disease in the United States, and persistent infection with 1 of the 12 high-risk genotypes has been causally linked with development of cervical cancer. Several vaccines targeting high-risk genotypes have been developed and implemented.
Hepatitis B Virus Infection in Pregnancy: An Update on Evidence-Based Management
Authors: Sirilert Sirinart , Tongsong Theera
Published: September 2020

Importance

Vertical hepatitis B virus (HBV) transmission is the important route of chronic HBV infection. Although infant immunoprophylaxis is effective, a significant number of infants still become infected, most are associated with intrauterine infection. New evidences support intrauterine treatment in cases of high risk.

Objective

The aim of this study was to review the current evidences and recommendations for management of HBV infection in pregnancy.

Evidence Acquisition

Original research articles, review articles, and guidelines were reviewed.

Results

The management can be summarized as follows: (1) all pregnant women should be screened for hepatitis B surface antigen (HBsAg) and antibody to HBsAg. High-risk HBsAg-negative pregnant women without immunity should be vaccinated during pregnancy. (2) HBsAg-positive pregnant women should undergo further workup for liver status and indicative factors for immunoprophylaxis failure. (3) Pregnant women should be treated with HBV DNA levels greater than 200,000 IU/mL or 6 log copies/mL. (4) Antiviral drug should be started around 28 to 32 weeks. The first-line drug is tenofovir disoproxil fumarate. (5) Delivery route should be chosen based only on obstetric indications. (6) Breastfeeding is not contraindicated because it does not increase the risk of transmission in neonates with HBV vaccine and immunoglobulin administration. (7) Neonates born to HBsAg-positive mothers should receive HBV vaccine and immunoglobulin after birth as soon as possible. (8) Follow-up of the mothers and neonates is important. Beware of hepatitis flare after birth and after antiretroviral drug discontinuation; alanine transaminase assessment every 1 to 3 months until 6 months is suggested. Also, the schedule of infant vaccination and follow-up of serologic testing at 9 to 12 months old is needed.

Target Audience

Obstetricians and gynecologists, family physicians

Learning Objectives

After the completion of this review, the learners should be better able to summarize updated knowledge of infant immunoprophylaxis failure; outline how to manage pregnancy with HBV infection, both antepartum and postpartum period; and describe advantages and disadvantages of the commonly used antiviral drugs.
Are Simulation Learning Objectives Educationally Sound? A Single-Center Cross-Sectional Study
Authors: Hui Madeleine , Mansoor Muqtasid , Sibbald Matthew
Published: September 2020

Introduction

Accreditation standards of simulation stress the importance of educationally sound learning objectives. We aimed to assess whether learning objectives adhered to theoretical frameworks outlined by accreditation standards, lending themselves to maximal learning outcomes.

Methods

A retrospective study was conducted at the Centre for Simulation-Based Learning at McMaster University. Raters coded 848 faculty-designed learning objectives from 722 sessions based on Bloom's Taxonomy, SMART (Specific, Measurable, Attainable, Realistic, and Timely) criteria, and the presence of inappropriate verbs. Learning objective categorization was compared with student evaluations.

Results

Using Bloom's Taxonomy, learning objectives were mostly focused on application 53%, followed by smaller percentages focused on knowledge 21.4% and comprehension 12.2%. Few learning objectives focused on higher levels of analysis 7.2%, synthesis 2.3%, and evaluation 3.7%. By SMART criteria, learning objectives were 49.6% specific, 60.8% measurable, 88.8% attainable, 85.0% realistic, and 9.1% timely. Approximately 1 in 5 objectives used inappropriate verbs. No correlations were observed between categorization by Bloom's Taxonomy or inappropriate verbs to student ratings. However, those containing attainable and timely goals were associated with lower levels of perceived achievement by students.

Conclusions

There was a disconnect between simulation accreditation standards and current practices at McMaster University's simulation center. Most objectives were classified at lower stages of Bloom's Taxonomy. The majority followed SMART guidelines, with the exception of specificity and mention of time frames. A minority of learning objectives contained inappropriate verbs. Given the costs associated with simulation-based education, educators should focus simulation learning objectives on higher levels of Bloom's Taxonomy and include references to time frames.
Medical Device–Related Pressure Injuries in Infants and Children
Authors: Stellar Judith J. , Hasbani Natalie R. , Kulik Lindyce A. , Shelley Stacey S. , Quigley Sandy , Wypij David , Curley Martha A. Q.
Published: September 2020

PURPOSE:

The purpose of this study was to describe medical device–related pressure injuries (MDRPIs) in hospitalized pediatric patients.

DESIGN:

A prospective, descriptive study.

SAMPLE/SUBJECTS AND SETTING:

The sample comprised 625 patients cared for in 8 US pediatric hospitals. Participants were aged preterm to 21 years, on bed rest for at least 24 hours, and had a medical device in place.

METHODS:

Two nursing teams, blinded to the other's assessments, worked in tandem to assess pressure injury risk, type of medical devices in use, and preventive interventions for each medical device. They also identified the presence, location, and stage of MDRPI. Subjects were observed up to 8 times over 4 weeks, or until discharge, whichever occurred first.

RESULTS:

Of 625 enrolled patients, 42 (7%) developed 1 or more MDRPIs. Two-thirds of patients with MDRPIs were younger than 8 years. Patients experiencing MDRPIs had higher acuity scores on hospital admission, were more frequently cognitively and/or functionally impaired, or were extreme in body mass index. Respiratory devices caused the most injuries (6.19/1000 device-days), followed by immobilizers (2.40/1000 device-days), gastric tubes (2.24/1000 device-days), and external monitoring devices (1.77/1000 device-days). Of the 6336 devices in place, 36% did not have an MDRPI preventive intervention in place. Clinical variables contributing to MDRPI development included intensive care unit care (odds ratio [OR] 8.9, 95% confidence interval [CI] 1.9-43.6), use of neuromuscular blockade (OR 3.7, 95% CI 1.7-7.8), and inotropic/vasopressor medications (OR 2.7, 95% CI 1.7-4.3). Multivariable analysis indicated that Braden QD scores alone predicted MDRPI development.

CONCLUSION:

Medical devices are common in hospitalized infants and children and these medical devices place patients at risk for MDRPI.
Wait and snap: eastern snapping turtles (Chelydra serpentina) prey on migratory fish at road-stream crossing culverts
Authors: Alcott Derrick , Long Michael , Castro-Santos Theodore
Published: September 2020

There is growing evidence that culverts at road-stream crossings can increase fish density by reducing stream width and fish movement rates, making these passageways ideal predator ambush locations. In this study, we used a combination of videography and δ13C stable isotope analyses to investigate predator–prey interactions at a road-stream crossing culvert. Eastern snapping turtles (Chelydra serpentina) were found to regularly reside within the culvert to ambush migratory river herring (Alosaspp.). Resident fish species displayed avoidance of the snapping turtles, resulting in zero attempted attacks on these fish. In contrast, river herring did not display avoidance and were attacked by a snapping turtle on 79% of approaches with a 15% capture rate. Stable isotope analyses identified an apparent shift in turtle diet to consumption of river herring in turtles from culvert sites that was not observed in individuals from non-culvert sites. These findings suggest that anthropogenic barriers like culverts that are designed to allow passage may create predation opportunities by serving as a bottleneck to resident and migrant fish movement.
Heliconiini butterflies can learn time-dependent reward associations
Authors: Toure M. Wyatt , Young Fletcher J. , McMillan W. Owen , Montgomery Stephen H.
Published: September 2020

For many pollinators, flowers provide predictable temporal schedules of resource availability, meaning an ability to learn time-dependent information could be widely beneficial. However, this ability has only been demonstrated in a handful of species. Observations ofHeliconiusbutterflies suggest that they may have an ability to form time-dependent foraging preferences.Heliconiusare unique among butterflies in actively collecting pollen, a dietary behaviour linked to spatio-temporally faithful ‘trap-line' foraging. Time dependency of foraging preferences is hypothesized to allowHeliconiusto exploit temporal predictability in alternative pollen resources. Here, we provide the first experimental evidence in support of this hypothesis, demonstrating thatHeliconius hecalecan learn opposing colour preferences in two time periods. This shift in preference is robust to the order of presentation, suggesting that preference is tied to the time of day and not due to ordinal or interval learning. However, this ability is not limited toHeliconius, as previously hypothesized, but also present in a related genus of non-pollen feeding butterflies. This demonstrates time learning likely pre-dates the origin of pollen feeding and may be prevalent across butterflies with less specialized foraging behaviours.
A little damping goes a long way: a simulation study of how damping influences task-level stability in running
Authors: Heim Steve , Millard Matthew , Le Mouel Charlotte , Badri-Spröwitz Alexander
Published: September 2020

It is currently unclear if damping plays a functional role in legged locomotion, and simple models often do not include damping terms. We present a new model with a damping term that is isolated from other parameters: that is, the damping term can be adjusted without retuning other model parameters for nominal motion. We systematically compare how increased damping affects stability in the face of unexpected ground-height perturbations. Unlike most studies, we focus on task-level stability: instead of observing whether trajectories converge towards a nominal limit-cycle, we quantify the ability to avoid falls using a recently developed mathematical measure. This measure allows trajectories to be compared quantitatively instead of only being separated into a binary classification of ‘stable' or ‘unstable'. Our simulation study shows that increased damping contributes significantly to task-level stability; however, this benefit quickly plateaus after only a small amount of damping. These results suggest that the low intrinsic damping values observed experimentally may have stability benefits and are not simply minimized for energetic reasons. All Python code and data needed to generate our results are available open source.
Prader-Willi syndrome: reflections on seminal studies and future therapies
Authors: Chung Michael S. , Langouët Maéva , Chamberlain Stormy J. , Carmichael Gordon G.
Published: September 2020

Prader-Willi syndrome (PWS) is caused by the loss of function of the paternally inherited 15q11-q13 locus. This region is governed by genomic imprinting, a phenomenon in which genes are expressed exclusively from one parental allele. The genomic imprinting of the 15q11-q13 locus is established in the germline and is largely controlled by a bipartite imprinting centre. One part, termed the Prader-Willi syndrome imprinting center (PWS-IC), comprises a CpG island that is unmethylated on the paternal allele and methylated on the maternal allele. The second part, termed the Angelman syndrome imprinting centre, is required to silence the PWS_IC in the maternal germline. The loss of the paternal contribution of the imprinted 15q11-q13 locus most frequently occurs owing to a large deletion of the entire imprinted region but can also occur through maternal uniparental disomy or an imprinting defect. While PWS is considered a contiguous gene syndrome based on large-deletion and uniparental disomy patients, the lack of expression of only non-coding RNA transcripts from theSNURF-SNRPN/SNHG14may be the primary cause of PWS. Patients with small atypical deletions of the paternalSNORD116cluster alone appear to have most of the PWS related clinical phenotypes. The loss of the maternal contribution of the 15q11-q13 locus causes a separate and distinct condition called Angelman syndrome. Importantly, while much has been learned about the regulation and expression of genes and transcripts deriving from the 15q11-q13 locus, there remains much to be learned about how these genes and transcripts contribute at the molecular level to the clinical traits and developmental aspects of PWS that have been observed.
Gender-Related Variables for Health Research
Authors: Nielsen Mathias W. , Stefanick Marcia L. , Peragine Diana , Neilands Torsten B. , Ioannidis John P. A. , Pilote Louise , Prochaska Judith J. , Cullen Mark R. , Einstein Gillian , Klinge Ineke , LeBlanc Hannah , Paik Hee Y. , Schiebinger Londa
Published: September 2020

This study develops a gender assessment tool—the Stanford Gender-Related Variables for Health Research—for use in clinical and population research, including large-scale health surveys involving diverse Western populations. While analyzing sex as a biological variable is widely mandated, gender as a sociocultural variable is not, largely because the field lacks quantitative tools for analyzing the influence of gender on health outcomes. We conducted a comprehensive review of English-language measures of gender from 1975 to 2015 to identify variables across three domains: gender norms, gender-related traits, and gender relations. This yielded 11 variables tested with 44 items in three US cross-sectional survey populations: two internet-based (N= 2,051; N= 2,135) and a patient-research registry (N= 489), conducted between May 2017 and January 2018. Exploratory and confirmatory factor analyses distilled 11 constructs to 7 gender-related variables: caregiver strain, work strain, independence, risk-taking, emotional intelligence, social support, and discrimination. Regression analyses, adjusted for age, ethnicity, income, education, sex assigned at birth, and self-reported gender identity, identified associations between these gender-related variables and self-rated general health, physical and mental health, and health-risk behaviors. Our new instrument can be used to develop health interventions based on a fuller understanding of gender associations with health.
The Causal Effects of Blood Iron and Copper on Lipid Metabolism Disease: Evidence from Phenome-wide Mendelian Randomization Study
Authors: Zhou Jingqi , Liu Chang , Francis Michael , Sun Yitang , Ryu Moon-Suhn , Grider Arthur , Ye Kaixiong
Published: September 2020

Background

Blood levels of iron and copper, even within their normal ranges, have been associated with a wide range of clinical outcomes. Available epidemiological evidence on blood iron and copper association with potential clinical effects, such as lipid metabolism disorder, is inconsistent and scarce. This study aims to examine and disentangle the causal clinical effects of iron and copper.

Methods

Genetic instruments for the blood level of iron and copper were curated from existing genome-wide association studies. Candidate clinical outcomes were identified based on a phenome-wide association study (PheWAS) between these genetic instruments and multiple phenotypes in 310,999 unrelated individuals of European ancestry from the UK Biobank. All signals passing stringent correction for multiple testing were followed by Mendelian randomization (MR) analyses, with replication in independent data sources where possible.

Results

Genetically predicted higher blood levels of iron and copper are both associated with lower risks of iron deficiency anemia (OR = 0.75, 95% CI:0.67-0.85,p=1.90×10−06for iron; OR= 0.88, 95% CI: 0.78-0.98,p=0.03 for cooper), lipid metabolism disorders and its two subcategories, hyperlipidemia (OR = 0.90, 95% CI:0.85-0.96,p=6.44×10−04for iron; OR = 0.92, 95% CI:0.87-0.98,p= 5.51×10−03for cooper) and hypercholesterolemia (OR = 0.90, 95% CI:0.84-0.95,p= 5.34×10−04for iron; OR = 0.93, 95% CI:0.89–0.99,p=0.02 for cooper). Consistently, they are also associated with lower blood levels of total cholesterol and low-density lipoprotein cholesterol. Multiple sensitivity tests were applied to assess the pleiotropy and stability of the estimation, and consistent evidence across different approaches was obtained. Additionally, unique clinical effects of each blood mineral were also pinpointed, and sex-stratified MR analysis further revealed the clinical implication of iron and copper exhibits some degree of sex differences.

Conclusions

Our comparative PheWAS-MR study of iron and copper comprehensively characterized their shared and unique clinical effects, highlighting their novel causal roles in hyperlipidemia and hypercholesterolemia. Given the modifiable and variable nature of blood mineral status, these findings warrant further investigation.
Multiple measures of depression to enhance validity of Major Depressive Disorder in the UK Biobank
Authors: Glanville Kylie P , Coleman Jonathan R I , Howard David M , Pain Oliver , Hanscombe Ken B , Jermy Bradley , Arathimos Ryan , Hübel Christopher , Breen Gerome , O’Reilly Paul F , Lewis Cathryn M
Published: September 2020

Background

The UK Biobank (UKB) contains data with varying degrees of reliability and completeness for assessing depression. A third of participants completed a Mental Health Questionnaire (MHQ) containing the gold-standard Composite International Diagnostic Interview (CIDI) criteria for assessing mental health disorders.

Aims

To investigate whether multiple observations of depression from sources other than the MHQ can enhance the validity of Major Depressive Disorder.

Methods

In participants who did not complete the MHQ (n = 325k), we calculated the number of other depression measures endorsed, e.g. from hospital episode statistics and interview data. We compared the strength of the genetic contribution in cases defined this way, to CIDI-defined cases. We compared the variance explained by polygenic risk scores (PRS), area under the curve attributable to PRS, SNP-based heritability, and genetic correlations with summary statistics from the Psychiatric Genomics Consortium Major Depressive Disorder (PGC MDD) GWAS.

Results

The strength of the genetic contribution increased with the number of measures endorsed. For example, SNP-based heritability increased from 7% with one measure of depression to 21% with four or five. The strength of the genetic contribution to cases defined by at least two measures approximated that for CIDI-defined cases. Most genetic correlations between UKB and PGC MDD exceeded 0.7, but there was variability between pairwise comparisons.

Conclusions

Multiple measures of depression can serve as a reliable approximation for case-status where the CIDI measure is not available, with the implication that sample size can be optimised using the full suite of UKB data.
Cancer Diagnosis, Polygenic Risk, and Longevity-Associated Variants
Authors: Goetz Laura H. , Don Janith , Schork Andrew J. , Duggan David , Price Nathan D. , Evans Daniel S. , Cummings Steve , Perls Thomas , Sebastiani Paola , Schork Nicholas J.
Published: September 2020

Background

Polygenic risk scores (PRS) have been developed to predict individual cancer risk and their potential clinical utility is receiving a great deal of attention. However, the degree to which the predictive utility of individual cancer-specific PRS may be augmented or refined by the incorporation of other cancer PRS, non-cancer disease PRS, or the protective effects of health and longevity-associated variants, is largely unexplored.

Methods

We constructed PRS for different cancers from public domain data as well as genetic scores for longevity (‘Polygenic Longevity Scores’ or ‘PLS’) for individuals in the UK Biobank. We then explored the relationships of these multiple PRS and PLS among those with and without various cancers.

Results

We found statistically significant associations between some PLS and individual cancers, even after accounting for cancer-specific PRS. None of the PLS in their current form had an effect pronounced enough to motivate clinical cancer risk stratification based on its combined use with cancer PRS. A few variants at loci used in the PLS had known associations with Alzheimer’s disease and other diseases.

Conclusion

Underlying heterogeneity behind cancer susceptibility in the population at large is not captured by PRS derived from analytical models that only consider marginal associations of individual variants with cancer diagnoses. Our results have implications for the derivation and calculation of PRS and their use in clinical and biomedical research settings.

Impact

Extensions of analyses like ours could result in a more refined understanding of cancer biology and how to construct PRS for cancer.
Reporting quality of trend analyses in leading medicine and oncology journals
Authors: Yuan Xiaoling , Lin Yong , Wang Yating , Zhang Lanjing
Published: September 2020

Trend analyses are critical for assessing changes and predicting future of epidemiological parameters. Recent trend-analysis guidelines recommended reporting slopes or beta/coefficient if possible. American Statistical Association and others recommended reporting effect-size. However, reporting of these statistics in trend analyses was largely unclear. We searched the Pubmed for the articles published during Jan. 1, 2008 to Dec. 31, 2018, whose titles included “trend” or “trends” among the following medicine and oncology journals:Ann Intern Med, Ann Oncol, BMJ, J Clin Oncol, J Natl Cancer Inst, JAMA Oncol, JAMA, Lancet, Lancet OncolandN Engl J Med. We examined proportions of the trend analyses in leading medicine and oncology journals, that reported p-value, effect-size or beta/coefficient/Annual percent change (APC), and identified associated factors. Among the 398 identified reports of trend analysis published during 2008-2018, there were 297 qualified reports, including 38 (12.8%) analyses using non-parametric model, 226 (76.1%) analyses using (piece-wise) linear model, 32 (10.8%) analyses using non-linear parametric model and 1 (0.3%) analyses using semi-parametric model (Cox regression). In these analyses, 193 (66.0%) and 216 (72,7%) analyses reportedP-value and effect-size, respectively. Among the 226 trend analyses using linear model, 169 (74.8%) reported p-value, 183 (81.0%) reported effect-size, 94 (41.6%) reported APC and 34 (15.0%) reported Beta/coefficient. Only 13 (5.8%) analyses reported neither p-value/effect size nor beta/coefficient/APC. In multivariable regression models, author affiliation with epidemiology department or statistics department was associated with reporting effect-size, and U.S. senior-authors (versus non-U.S.) more likely reported p-value. No factors were linked to reporting APC. In summary, reporting quality of the included trend analyses was overall good. However, reporting p-value or effect-size did not change with publication years, and reporting APC or Beta/coefficient was uncommon. Additional works and training appear warranted to improve reporting quality of trend analyses.
Estimation and Interactive Visualization of the Time-Varying Reproduction NumberRtand the Time-Delay from Infection to Estimation
Authors: Valka Fabian , Schuler Carla
Published: September 2020

Abstract

Rtplays a key role in the development of the COVID-19 pandemic. The methods used for building an interactive website for the visualization of the time-varying reproduction numberRtand a novel way to visualize the time delay from infection to estimation overlayed with theRtestimate are described and analyzed with regards to the influence of parameters chosen and compared to published estimates for Austria. Visualizing the time delays enables the interactive exploration of suspected changes in transmission and their effect on theRtestimate.
Detection of oncometabolites 1-methylnicotinamide, nicotine imine and N-Methylnicotinium in nails of oral cancer patients and prediction of them as modulators of DNMT1
Authors: Dutta Anwesha Deep , Kumar Ajay , Lokhande Kiran , Mitruka Manmohan , Pal Jayanta K. , Sarode Sachin C. , Sharma Nilesh Kumar
Published: September 2020

Background

The prominent among various existing views on the role of nicotine and nicotine-metabolized products in Oral squamous cell carcinoma (OSSC) is metabolic adaptation that allows the use of methyl-donor S-adenosylmethionine (SAM) for non-epigenetic purpose including the methylation of nicotinamide and nicotine. In fact, channeling of SAM for generation of 1-methylnicotinamide (1-MNA) and methylated nicotine products is seen as a key event in cancer cells that allows favorable epigenetic states by forcing DNA hypomethylation. A better perception of such events can be appreciated by analyzing samples like nail, which represents a perfect biological material for studying long-term metabolic reflections of the body.

Methods

Potential nicotine-metabolized products and 1-MNA in nails of OSCC patients were analyzed by using a novel approach of Vertical tube gel electrophoresis (VTGE)- assisted purification followed by their identification by LC-HRMS. Further, these identified nicotine metabolized products and 1-MNA were evaluated for their molecular interactions with known methyltransferases including cytosolic nicotinamide methyltransferase (NNMT), DNA methyltransferase (DNMT)1 and histone methyltransferases by molecular docking and molecular dynamics simulation (MDS) analyses.

Results

Our data suggests the presence of N-methylnicotinium ion and nicotine imine in the nail samples of OSCC patients. Further, 1-MNA is also detected in the nails as a major enzymatic product of a known detoxifying enzyme NNMT. Molecular docking of all nicotine and nicotine metabolized products with DNMT1revealed a specific binding affinity of nicotine imine only with a -6.2 Kcal/Mol docking energy. Importantly, binding of nicotine imine is within the CXCC regulatory domain of DNMT1 and it displays molecular interactions with the key amino acid residues, namely ARG690, PRO574, VAL658, PRO692 and ALA695. Furthermore, MDS data corroborated well with the specific binding affinity of nicotine imine to DNMT1 obtained by docking analysis.

Conclusion

Identification of N-methylnicotinium ion, nicotine imine and 1-MNA in nail samples indicates their potential as predictive and detectable biomarkers for OSCC. Molecular docking and MDS data lead us to propose a role of nicotine imine in modulating the activity of DNMT1. These data further suggest a novel understanding on the role of nicotine metabolized products in modulating DNA methylation that may contribute to tumorigenicity in oral cancer patients.
Comparative analysis reveals the species-specific genetic determinants of ACE2 required for SARS-CoV-2 entry
Authors: Ren Wenlin , Hu Gaowei , Zhao Xiaomin , Wang Yuyan , Shi Hongyang , Lan Jun , Zhu Yunkai , Wu Jianping , Kenney Devin J. , Florian Douam , Tong Yimin , Zhong Jin , Xie Youhua , Wang Xinquan , Yuan Zhenghong , Zhou Dongming , Zhang Rong , Ding Qiang
Published: September 2020

Coronavirus interaction with its viral receptor is a primary genetic determinant of host range and tissue tropism. SARS-CoV-2 utilizes ACE2 as the receptor to enter host cell in a species-specific manner. We and others have previously shown that ACE2 orthologs from New World monkey, koala and mouse cannot interact with SARS-CoV-2 to mediate viral entry, and this defect can be restored by humanization of the restrictive residues in New World monkey ACE2. To better understand the genetic determinants behind the ability of ACE2 orthologs to support viral entry, we compared koala and mouse ACE2 sequences with that of human and identified the key residues in koala and mouse ACE2 that restrict viral receptor activity. Humanization of these critical residues rendered both koala and mouse ACE2 capable of binding the spike protein and facilitating viral entry. The single mutation that allowed for mouse ACE2 to serve as a viral receptor provides a potential avenue for the development of SARS-CoV-2 mouse model.
Default Mode and Salience Network Alterations in Suicidal and Non-Suicidal Self-Injurious Thoughts and Behaviors in Adolescents with Depression
Authors: Ho Tiffany C. , Walker Johanna C. , Teresi Giana I. , Kulla Artenisa , Kirshenbaum Jaclyn S. , Gifuni Anthony J. , Singh Manpreet K. , Gotlib Ian H.
Published: September 2020

Suicidal ideation (SI) and non-suicidal self-injury (NSSI) are two distinct yet often co-occurring risk factors for suicide in adolescents. Elucidating the neurobiological patterns that specifically characterize SI and NSSI in adolescents is needed to inform the use of these markers in intervention studies and to develop brain-based treatment targets. Here, we clinically assessed 70 adolescents—49 adolescents with depression and 21 healthy controls—to determine SI and NSSI history. Twenty-eight of the depressed adolescents had a history of SI and 29 had a history of NSSI (20 overlapping). All participants underwent a resting-state fMRI scan. We compared groups in network coherence of subdivisions of the central executive network (CEN), default mode network (DMN), and salience network (SN). We also examined group differences in between-network connectivity and explored brain-behavior correlations. Depressed adolescents with SI and with NSSI had lower coherence in the ventral DMN compared to those without SI or NSSI, respectively, and healthy controls (allps<0.043). Depressed adolescents with NSSI had lower coherence in the anterior DMN and in insula-SN (allps<0.030), and higher CEN–DMN connectivity compared to those without NSSI and healthy controls (allps<0.030). Lower network coherence in all DMN subnetworks and insula-SN were associated with higher SI and NSSI (allps<0.001). Thus, SI and NSSI are related to brain networks associated with difficulties in self-referential processing and future planning, while NSSI specifically is related to brain networks associated with disruptions in interoceptive awareness. Intrinsic network patterns may be reliable biomarkers of SI and NSSI in adolescents.
A Multi-center Cross-platform Single-cell RNA Sequencing Reference Dataset
Authors: Chen Xin , Yang Zhaowei , Chen Wanqiu , Zhao Yongmei , Farmer Andrew , Tran Bao , Furtak Vyacheslav , Moos Malcolm , Xiao Wenming , Wang Charles
Published: September 2020

Single-cell RNA sequencing (scRNA-seq) is developing rapidly, and investigators seeking to use this technology are left with a variety of options for both experimental platform and bioinformatics methods. There is an urgent need for scRNA-seq reference datasets for benchmarking of different scRNA-seq platforms and bioinformatics methods. To be broadly applicable, these should be generated from renewable, well characterized reference samples and processed in multiple centers across different platforms. Here we present a benchmarking scRNA-seq dataset that includes 20 scRNA-seq datasets acquired either as a mixtures or as individual samples from two biologically distinct cell lines for which a large amount of multi-platform whole genome sequencing data are also available. These scRNA-seq datasets were generated from multiple popular platforms across four sequencing centers. Our benchmark datasets provide a resource that we believe will have great value for the single-cell community by serving as a reference dataset for evaluating various bioinformatics methods for scRNA-seq analyses, including but not limited to data preprocessing, imputation, normalization, clustering, batch correction, and differential analysis.
The Dynamic Influence of Linker Histone Saturation within the Poly-Nucleosome Array
Authors: Woods Dustin C. , Rodríguez-Ropero Francisco , Wereszczynski Jeff
Published: September 2020

Linker histones bind to nucleosomes and modify chromatin structure and dynamics as a means of epigenetic regulation. Biophysical studies have shown that chromatin fibers can adopt a plethora of conformations with varying levels of compaction. Linker histone condensation, and its specific binding disposition, has been associated with directly tuning this ensemble of states. However, the atomistic dynamics and quantification of this mechanism remains poorly understood. Here, we present molecular dynamics simulations of octa-nucleosome arrays, based on a cryo-EM structure of the 30-nm chromatin fiber, with and without the globular domains of the H1 linker histone to determine how they influence fiber structures and dynamics. Results show that when bound, linker histones inhibit DNA flexibility and stabilize repeating tetra-nucleosomal units, giving rise to increased chromatin compaction. Furthermore, upon the removal of H1, there is a significant destabilization of this compact structure as the fiber adopts less strained and untwisted states. Interestingly, linker DNA sampling in the octa-nucleosome is exaggerated compared to its mono-nucleosome counterparts, suggesting that chromatin architecture plays a significant role in DNA strain even in the absence of linker histones. Moreover, H1-bound states are shown to have increased stiffness within tetra-nucleosomes, but not between them. This increased stiffness leads to stronger long-range correlations within the fiber, which may result in the propagation of epigenetic signals over longer spatial ranges. These simulations highlight the effects of linker histone binding on the internal dynamics and global structure of poly-nucleosome arrays, while providing physical insight into a mechanism of chromatin compaction.

Significance

Linker histones dynamically bind to DNA in chromatin fibers and serve as epigentic regulators. However, the extent to which they influence the gamut of chromatin architecture is still not well understood. Using molecular dynamics simulations, we studied compact octa-nucleosome arrays with and without the H1 linker histone to better understand the mechanisms dictating the structure of the chromatin fiber. Inclusion of H1 results in stabilization of the compact chromatin structure, while its removal results in a major conformational change towards an untwisted ladder-like state. The increased rigidity and correlations within the H1-bound array suggests that H1-saturated chromatin fibers are better suited to transferring long-range epigentic information.
Resistance to different antibiotics in clinical isolates ofEnterococcus faecalisobtained from urine cultures of patients with urinary tract infection
Authors: Rodríguez Mariana Islas , Esquivel José Carlos Valencia , Peña Silvia Patricia Rodríguez , de Freitas Elisangela Oliveira , Villegas Jorge Angel Almeida
Published: September 2020

Objective

To identify patterns of resistance against various antibiotics inEnterococcus faecalisin urinary tract infections in a population of the Toluca valley, Mexico

Methods

155 samples were collected from patients with suspected urinary tract infection without exclusion criteria such as age or gender. Automated equipment was used for the identification of the etiological agent and sensitivity tests.

Results

80 positive cultures were obtained, of which 20 strains belong to Enterococcus faecalis, which show 100% sensitivity for penicillins, linezolid, vancomycin, bacitracin, a high pattern of sensitivity for quinolones, and a high pattern of resistance to rifampicin, erythromycin and 100% resistance in tetracycline

Conclusion

It shows 100% sensitivity to penicillins, vancomycin and linezolid, first-line treatments and for cases of infection complicated by Enterococci. And 100% resistance for tetracycline and high resistance patterns for erythromycin and rifampin.
Epidemiology of COVID-19 vs. Influenza: Differential Failure of COVID-19 Mitigation among Hispanics
Authors: Trick William E. , Badri Sheila , Doshi Kruti , Zhang Huiyuan , Rezai Katayoun , Hoffman Michael J. , Weinstein Robert A.
Published: September 2020

BACKGROUND

During the early phases of the COVID-19 pandemic, predominantly African-American or Hispanic communities were disproportionately impacted. We sought to better understand the epidemiology of COVID-19 among hospitalized Hispanic patients by comparing individual and census-tract level characteristics of patients diagnosed with COVID-19 to those diagnosed with influenza, another viral infection with respiratory transmission. We evaluated the temporal changes in epidemiology across race-ethnicity related to a shelter-in-place mandate.

METHODS

We evaluated patients hospitalized at Cook County Health, the safety-net health system for the Chicago metropolitan area. Among self-identified hospitalized Hispanic patients, we compared those with influenza (2019-2020 influenza season) to COVID-19 infection during March 16, 2020 through May 11, 2020. We used multivariable analysis to identify differences in individual and census-tract level characteristics between the two groups.

RESULTS

Relative to non-Hispanic blacks and whites, COVID-19 rapidly increased among Hispanics during promotion of social-distancing policies. Whereas non-Hispanic blacks were more likely to be hospitalized for influenza, Hispanic patients predominated among COVID-19 infections (40% relative increase compared to influenza). In the comparative analysis of influenza and COVID-19, Hispanic patients with COVID-19 were more likely to reside in census tracts with higher proportions of residents with the following characteristics: Hispanic; no high school diploma; non-US citizen; limited English speaking ability; employed in manufacturing or construction; and, overcrowding. By multivariable analysis, Hispanic patients hospitalized with COVID-19 compared to those with influenza were more likely to be male (adjusted OR=1.8; 95% CI 1.1 to 2.9) or obese (aOR=2.5; 95% CI 1.5 to 4.2), and to reside in a census tract with ≥40% of residents without a high-school diploma (aOR=2.5; 95% CI 1.3 to 4.8).

CONCLUSIONS

The rapid and disproportionate increase in COVID-19 hospitalizations among Hispanics after the shelter-in-place mandate indicates that public health strategies were inadequate in protecting this population. In particular, those residing in neighborhoods with lower levels of educational attainment.
A natural mutation between SARS-CoV-2 and SARS-CoV determines neutralization by a cross-reactive antibody
Authors: Wu Nicholas C. , Yuan Meng , Bangaru Sandhya , Huang Deli , Zhu Xueyong , Lee Chang-Chun D. , Turner Hannah L. , Peng Linghang , Yang Linlin , Nemazee David , Ward Andrew B. , Wilson Ian A.
Published: September 2020

Epitopes that are conserved among SARS-like coronaviruses are attractive targets for design of cross-reactive vaccines and therapeutics. CR3022 is a SARS-CoV neutralizing antibody to a highly conserved epitope on the receptor binding domain (RBD) on the spike protein that can cross-react with SARS-CoV-2, but with lower affinity. Using x-ray crystallography, mutagenesis, and binding experiments, we illustrate that of four amino acid differences in the CR3022 epitope between SARS-CoV-2 and SARS-CoV, a single mutation P384A fully determines the affinity difference. CR3022 does not neutralize SARS-CoV-2, but the increased affinity to SARS-CoV-2 P384A mutant now enables neutralization with a similar potency to SARS-CoV. We further investigated CR3022 interaction with the SARS-CoV spike protein by negative-stain EM and cryo-EM. Three CR3022 Fabs bind per trimer with the RBD observed in different up-conformations due to considerable flexibility of the RBD. In one of these conformations, quaternary interactions are made by CR3022 to the N-terminal domain (NTD) of an adjacent subunit. Overall, this study provides insights into antigenic variation and potential for cross-neutralizing epitopes on SARS-like viruses.
Antimetabolic cooperativity with the clinically approved kidrolase and tyrosine kinase inhibitors to eradicate cml stem cells
Authors: Trinh Anne , Khamari Raeeka , Fovez Quentin , Mahon François-Xavier , Turcq Béatrice , Bouscary Didier , Maboudou Patrice , Joncquel Marie , Coiteux Valérie , Germain Nicolas , Laine William , Dekiouk Salim , Ghesquiere Bart , Idziorek Thierry , Quesnel Bruno , Kluza Jerome , Marchetti Philippe
Published: September 2020

Long-term treatment with tyrosine kinase inhibitors (TKI) represents an effective treatment for chronic myeloid leukemia (CML) and discontinuation of TKI therapy is now proposed to patient with deep molecular responses. However, evidence demonstrating that TKI are unable to fully eradicate dormant leukemic stem cells indicate that new therapeutic strategies are needed to prevent molecular relapses. We investigated the metabolic pathways responsible for CML surviving to Imatinib exposure and its potential therapeutic utility to improve the efficiency of TKI against CML stem cells. Using complementary cell-based techniques, we demonstrated that TKI suppressed glycolysis in a large panel of BCR-ABL1 + cell lines as well as in primary CD34+ stem-like cells from CML patients. However, compensatory glutamine-dependent mitochondrial oxidation supported ATP synthesis and CML cell survival. Glutamine metabolism was inhibited by L-asparaginases such as Kidrolase without inducing predominant CML cell death. Clinically relevant concentrations of TKI render CML progenitors and stem cells susceptible to Kidrolase. The combination of TKI with L-asparaginase reactivated the intinsic apoptotic pathway leading to efficient CML cell death. Thus, targeting glutamine metabolism with the clinically-approved drug Kidrolase, in combination with TKI that suppress glycolysis represents an effective and widely applicable therapeutic strategy for eradicating CML stem cells.