bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of Total and Unprotonated (Free) Nicotine Content of Nicotine Pouch Products
Authors: Stanfill Stephen , Tran Hang , Tyx Robert , Fernandez Carolina , Zhu Wanzhe , Marynak Kristy , King Brian , Valentín-Blasini Liza , Blount Benjamin C , Watson Clifford
Published: March 2021

Introduction

Nicotine pouch products, oral smokeless products that contain nicotine but no tobacco leaf material, have recently entered the US marketplace. Available data indicate sales of these products in the United States have increased since 2018; however, the extent of use among US youth and adults is uncertain.

Methods

To assay the chemistry of these emerging tobacco products, we analyzed 37 nicotine pouch brands from six total manufacturers. Almost all of the products had flavor descriptors (36 of 37), such as mint, licorice, coffee, cinnamon, and fruit. The amount of free nicotine, the form most easily absorbed, was calculated for each product using total nicotine, product pH, the appropriate pKa, and the Henderson–Hasselbalch equation.

Results

Nicotine pouch products varied in pouch content mass, moisture content (1.12%‒47.2%), alkalinity (pH 6.86‒10.1), and % free nicotine (7.7%‒99.2%). Total nicotine content ranged from 1.29 to 6.11 mg/pouch, whereas free nicotine ranged from 0.166 to 6.07 mg/pouch. These findings indicate that nicotine and pH levels found in some of these nicotine pouches are similar to conventional tobacco products, such as moist snuff and snus, and that most of these pouch products are flavored.

Conclusions

Although these products likely lack many tobacco-related chemicals, each product analyzed contained nicotine, which is both addictive and can harm human health. Given that nicotine pouches may appeal to a spectrum of users, from novice to experienced users, it is important to include these emerging tobacco products in tobacco control research, policy, and practice.

Implications

These “tobacco-free” nicotine pouches have similar pH and nicotine content to conventional tobacco products, such as moist snuff and snus. Although they lack many tobacco-related chemicals, most are highly flavored which could increase experimentation from new users. Given that nicotine pouches may appeal to a spectrum of users, from novice to experienced users, in terms of their flavors and nicotine content, it is important to examine and include these emerging tobacco products as they relate to tobacco control research, policy, and practice.
Voting Age Reform, Political Partisanship and Multi-Level Governance in the UK: The Party Politics of ‘Votes-at-16’
Authors: Tonge Jonathan , Loughran Thomas , Mycock Andrew
Published: March 2021

The UK is now a multi-level polity with asymmetrical minimum ages of enfranchisement. The franchise was first extended to 16- and 17-year-olds in the 2014 Scottish independence referendum. The Scottish and Welsh governments now permit 16- and 17-year-olds to vote in elections to their devolved parliaments and local councils. The Northern Ireland Executive and the devolved authorities in England do not, however, have the power to change the voting age, and across all four nations of the UK, the age of franchise remains 18 for elections to the Westminster Parliament. The previous extension of the age of franchise, from 21 to 18 in 1969, attracted little controversy or political partisanship. But while there has been considerable political consensus regarding voting age reform in Scotland and Wales, debate over ‘Votes-at-16’ for Westminster elections has witnessed growing party-based partisanship. This article draws upon elite interviews with politicians across the political spectrum elected to Westminster and the devolved institutions on their attitudes to voting age reform, conducted as part of a 2-year Leverhulme Trust ‘Lowering the Voting Age in the UK’ project. The article argues that the multi-level party politics of the ‘Votes-at-16’ debate has consolidated rival party opinions on voting age reform at Westminster but not beyond.
Relationship Between Post-Traumatic Stress Disorder Symptoms and Chronic Pain-Related Symptom Domains Among Military Active Duty Service Members
Authors: Li Hongjin , Flynn Diane M , Highland Krista B , Barr Patricia K , Langford Dale J , Doorenbos Ardith Z
Published: March 2021

Objective

This study examined the relationships between symptom domains relevant to post-traumatic stress disorder (PTSD) diagnosis, PTSD screening, and chronic pain-related symptoms (pain intensity, pain interference, physical function, fatigue, depression, anxiety, anger, satisfaction with social roles) experienced by active duty military service members with chronic pain.

Design

ross-sectional study.

Setting

This study was conducted at the Interdisciplinary Pain Management Center (IPMC) at Madigan Army Medical Center between 2014 and 2018.

Subjects

Active duty service members receiving care at IPMC (n = 2745) were included in this study.

Methods

Independent sample t test was conducted to compare pain intensity and pain-related measures of physical, emotional, and social functioning among patients with and without a PTSD diagnosis or PTSD positive screen (≥3 symptoms). Relative weight analysis was used to identify the relative importance of each PTSD symptom cluster (e.g., intrusion, avoidance, hyperarousal, emotional numbness) to pain and related domains.

Results

Approximately 27.9% of the patients had a positive screen for PTSD, and 30.5% of the patients had a PTSD diagnosis. Patients with PTSD diagnosis and positive screening had higher pain interference and lower physical function and social satisfaction scores (P < 0.001) and had increased anger, anxiety, fatigue, and depression scores (P < 0.001). Emotional numbness accounted for the largest proportion of variance in average pain intensity, pain interference, and psychological functioning, and avoidance accounted for the largest proportion of variance in physical function.

Conclusion

To improve treatment effectiveness and overall functioning for active duty military patients, integrated treatment and therapies targeted to reducing chronic pain and PTSD symptoms (focus on emotional numbness and avoidance) are recommended.
Utilization Patterns of Skeletal Muscle Relaxants Among Commercially Insured Adults in the United States from 2006 to 2018
Authors: Li Yan , Delcher Chris , Reisfield Gary M , Wei Yu-Jung , Brown Joshua D , Winterstein Almut G
Published: March 2021

Objective

To examine the prevalence and duration of skeletal muscle relaxant (SMR) treatment among commercially insured adults in the United States.

Methods

We used the MarketScan Research Database to identify a cohort of adults 18 to 64 years who had ≥2-year continuous enrollment between 2005 and 2018. We estimated the prevalence of SMR treatment using a repeated cross-sectional design and derived treatment duration using the Kaplan-Meier method. Analyses were stratified by age group, sex, geographic region, individual SMR agent, and musculoskeletal disorder.

Results

48.7 million individuals were included. Treatment prevalence ranged from 61.5 to 68.3 per 1,000. About one-third of users did not have a preceding musculoskeletal disorder diagnosis. Cyclobenzaprine was the dominant agent accounting for >50% of prescriptions. The considerable growth in the use of baclofen, tizanidine, and methocarbamol paralleled with a decline in carisoprodol and metaxalone use. The prevalence was highest in the South while lowest in the Northeast. The median treatment duration was 14 days with 4.0%, 1.9%, and 1.0% of individuals using SMRs for more than 90, 180, and 365 days, respectively. Compared with cyclobenzaprine, patients initiating baclofen, tizanidine, and carisoprodol had longer treatment duration.

Conclusions

SMRs are widely used in the United States. Their use slightly increased in recent years, but trends varied among individual agents, patient groups, and geographic regions. Despite limited evidence to support efficacy, a sizable number of U.S. adults used SMRs for long-term and off-label conditions. Further study is needed to understand determinants of treatment as well as outcomes associated with such use.
The Role of Intrathecal Morphine for Postoperative Analgesia in Primary Total Joint Arthroplasty under Spinal Anesthesia: A Systematic Review and Meta-Analysis
Authors: Wang Li-Min , Zhang Zhen , Yao Ru-Zhan , Wang Guang-Lin
Published: March 2021

Objective

To assess the efficacy and safety of intrathecal morphine (ITM) for postoperative analgesia in primary total joint arthroplasty (TJA) under spinal anesthesia and to explore the dose-response relationship for analgesic efficacy or risk of side effects.

Methods

We searched MEDLINE, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov for any studies meeting the inclusion criteria. All the data were summarized using the random effects model. Subgroup analyses were performed based on the surgical procedure and dose of ITM. Meta-regression was used to explore the dose-response relationship.

Results

Eighteen randomized controlled trials were included. Compared with the placebo or blank control, ITM reduced the postoperative 24-h morphine consumption by 10.07 mg and prolonged the duration of analgesia. However, ITM significantly increased the risk of pruritus by 2.79 fold, with a tendency to increase the risk of postoperative nausea and/or vomiting (P = 0.08). No difference was observed regarding the length of stay (LOS) and incidence of respiratory depression or urinary retention. Furthermore, meta-regression showed a linear dose-response relationship for the postoperative 24-h morphine consumption but no linear dose-response relationship for the risk of side effects.

Conclusions

Adding morphine to intrathecal anesthetics provides a prolonged and robust analgesic effect without significantly increasing the risk of side effects other than pruritus. Although we found a linear dose-response relationship for the postoperative 24-h morphine consumption, the optimal dose of ITM remains to be further explored in high-quality RCTs with a large sample size.
Assessing sexual function in middle-aged sexually active Spanish women: a community-based study focusing on the intimate partner
Authors: Martínez-Madrid Maria M. , Arnau-Sánchez José , González-Cuello Ana M.
Published: March 2021

Objective:

This study evaluated sexual function, the influence of the relationship with the intimate partner, and the factors related to sexual function in middle-aged Spanish women.

Methods:

The methodology entailed a cross-sectional study of 187 sexually active women aged 40-59 years. The participants were randomly recruited from primary public health care. They completed the 6-item Female Sexual Function Index (FSFI-6), the short-form Woman Abuse Screening Tool (WAST), and a sociodemographic questionnaire. Descriptive and inferential analysis was performed.

Results:

The participants’ median age was 49 years, 90.4% had a steady intimate partner, 54.5% were postmenopausal, 43.3% had chronic diseases, 12.3% reported alcohol abuse, and 35.8% smoked. The prevalence of low sexual function was 33.16% in all the women, and 44.12% in the postmenopausal women (an FSFI-6 total score ≤ 19 reflects low sexual function). WAST screening detected 17.65% cases of intimate partner violence (WAST total score ≤ 1), with low sexual function in 87.9%. Multiple linear regression analysis models revealed that the lowest total FSFI-6 scores (worst sexual function) were negatively associated with intimate partner violence (IPV), depression, hysterectomy, and associated female issues. The scores in the FSFI-6 domains (desire, arousal, lubrication, orgasm, satisfaction, and pain) were linked to IPV (P < 0.001), except for lubrication (P < 0.001 postmenopausal).

Conclusion:

Low sexual function was more common in women who were positively screened for IPV. It was identified as a key factor, which contributes to deteriorating middle-aged women's sexual health.
Obesity among postmenopausal women: what is the best anthropometric index to assess adiposity and success of weight-loss intervention?
Authors: Ghachem Ahmed , Marcotte-Chénard Alexis , Tremblay Dominic , Prud’homme Denis , Rabasa-Lhoret Rémi , Riesco Eléonor , Brochu Martin , Dionne Isabelle J.
Published: March 2021

Objectives:

First, to establish the respective ability of body mass index (BMI), waist circumference (WC), and relative fat mass index (RFM), to estimate body fat (BF%) measured by DXA (DXA-BF%) and correctly identify postmenopausal women living with obesity (BF% > 35). Second, to identify the best indicator of successful weight-loss intervention in postmenopausal women living with obesity.

Methods:

A total of 277 women (age: 59.8 ± 5.3 y; BF%: 43.4 ± 5.3) from five weight-loss studies with complete data for anthropometric measurements [BMI = weight/height (kg/m2); WC (cm)] and BF% were pooled together. Statistical performance indicators were determined to assess ability of RFM [64−(20 × height/waist circumference) + (12 × sex)], BMI and WC to estimate BF% before and after weight-loss intervention and to correctly identify postmenopausal women living with obesity.

Results:

Compared with RFM (r = 0.51; r
2 = 0.27; RMSE = 4.4%; Lin's CCC = 0.46) and WC (r = 0.49; r
2 = 0.25; RMSE = 4.8%; Lin's CCC = 0.41), BMI (r = 0.73; r
2 = 0.52; RMSE = 3.7%; Lin's CCC = 0.71) was the best anthropometric index to estimate DXA-BF% and correctly identify postmenopausal women living with obesity (sensitivity + specificity: BMI = 193; RFM = 152; WC = 158), with lower misclassification error, before weight-loss intervention. After weight-loss, the change in BMI was strongly correlated with change in DXA-BF%, indicating that the BMI is the best indicator of success weight-loss intervention.

Conclusion:

In the absence of more objective measures of adiposity, BMI is a suitable proxy measure for BF% in postmenopausal women, for whom a lifestyle intervention is relevant. Furthermore, BMI can be used as an indicator to assess success of weight-loss intervention in this subpopulation.
Abdominal visceral adipose tissue over the menopause transition and carotid atherosclerosis: the SWAN heart study
Authors: Samargandy Saad , Matthews Karen A. , Brooks Maria M. , Barinas-Mitchell Emma , Magnani Jared W. , Janssen Imke , Kazlauskaite Rasa , El Khoudary Samar R.
Published: March 2021

Objectives:

To characterize abdominal visceral adipose tissue (VAT) trajectory relative to the final menstrual period (FMP), and to test whether menopause-related VAT accumulation is associated with greater average, common carotid artery intima-media thickness (cIMT) and/or internal carotid artery intima-media thickness (ICA-IMT).

Methods:

Participants were 362 women (at baseline: age was (mean ± SD) 51.1 ± 2.8 y; 61% White, 39% Black) with no cardiovascular disease from the Study of Women's Health Across the Nation Heart study. Women had up to two measurements of VAT and cIMT over time. Splines revealed a nonlinear trajectory of VAT with two inflection points demarcating three time segments: segment 1: >2 years before FMP; segment 2: 2 years before FMP to FMP; and segment 3: after FMP. Piecewise-linear random-effects models estimated changes in VAT. Random-effects models tested associations of menopause-related VAT with each cIMT measure separately. Estimates were adjusted for age at FMP, body mass index, and sociodemographic, lifestyle, and cardiovascular disease risk factors.

Results:

VAT increased significantly by 8.2% (95% CI: 4.1%-12.5%) and 5.8% (3.7%-7.9%) per year in segments 2 and 3, respectively, with no significant change in VAT within segment 1. VAT predicted greater ICA-IMT in segment 2, such that a 20% greater VAT was associated with a 2.0% (0.8%-3.1%) greater ICA-IMT. VAT was not an independent predictor of ICA-IMT in the other segments or of the other cIMT measures after adjusting for covariates.

Conclusions:

Women experience an accelerated increase in VAT starting 2 years before menopause. This menopause-related increase in VAT is associated with greater risk of subclinical atherosclerosis in the internal carotid artery.

Video Summary:

http://links.lww.com/MENO/A722.
Contrasting Cases of Complex Lymphatic Anomalies: Case Reports and Review of the Literature
Authors: Ahlers Carolyn G. , Baron Christopher M. , Sarma Asha , Borst Alexandra J.
Published: March 2021

Complex lymphatic anomalies (CLAs) are rare, pediatric developmental lymphatic anomalies that include a spectrum of overlapping clinical presentations, imaging findings, and symptoms. Owing to their rarity, diagnosis and treatment can be challenging. CLAs have significant risk of morbidity and mortality and require multimodal, comprehensive management. New molecular insights into the pathogenesis of CLAs will likely change classification and therapeutic options in the future. We describe herein 2 children with CLAs with distinct presentations and clinical courses but with some overlapping features. These cases highlight the spectrum of disease presentation in CLAs as well as the need for continued use of molecular data to drive diagnosis, classification, and management of these rare disorders.
The Hidden Costs of War: Healthcare Utilization Among Individuals Sustaining Combat-related Trauma (2007–2018)
Authors: Dalton Michael K. , Jarman Molly P. , Manful Adoma , Koehlmoos Tracey P. , Cooper Zara , Weissman Joel S. , Schoenfeld Andrew J.
Published: March 2021

Objective:

We sought to evaluate long-term healthcare requirements of American military servicemembers with combat-related injuries.

Summary of Background Data:

US military conflicts since 2001 have produced the most combat casualties since Vietnam. Long-term consequences on healthcare utilization and associated costs remain unknown.

Methods:

We identified servicemembers who were treated for combat-related injuries between 2007 and 2011. Controls consisted of active-duty servicemembers injured in the civilian sector, without any history of combat-related trauma, matched (1:1) on year of injury, biologic sex injury severity, and age at time of injury. Surveillance was performed through 2018. Total annual healthcare expenditures were evaluated overall and then as expenditures in the first year after injury and for subsequent years. Negative binomial regression was used to identify the adjusted influence of combat injury on healthcare costs.

Results:

The combat-injured cohort consisted of 3981 individuals and we identified 3979 controls. Total healthcare utilization during the follow-up period resulted in median costs of $142,214 (IQR $61,428, $323,060) per combat-injured servicemember as compared to $50,741 (IQR $26,669, $104,134) among controls. Median expenditures, adjusted for duration of follow-up, for the combat-injured were $45,211 (IQR $18,698, $105,437). In adjusted analysis, overall costs were 30% higher (1.30; 95% confidence interval: 1.23, 1.37) for combat-injured personnel.

Conclusion:

This investigation represents the longest continuous observation of healthcare utilization among individuals after combat injury and the first to assess costs. Expenditures were 30% higher for individuals injured as a result of combat-related trauma when compared to those injured in the civilian sector.
Elevation of Lactococcus lactis subsp. cremoris to the species level as Lactococcus cremoris sp. nov. and transfer of Lactococcus lactis subsp. tructae to Lactococcus cremoris as Lactococcus cremoris subsp. tructae comb. nov.
Authors: Li Ting Ting , Tian Wen Li , Gu Chun Tao
Published: March 2021

Currently,

Lactococcus lactis

contains four subspecies:

L. lactis

subsp.

lactis

,

L. lactis

subsp.

hordniae

,

L. lactis

subsp.

cremoris

and

L. lactis

subsp.

tructae

. In the study of Pérez et al., these four subspecies could be clearly divided into two groups based on recA sequence analysis:

L. lactis

subsp.

lactis

and

L. lactis

subsp.

hordniae

;

L. lactis

subsp.

cremoris

and

L. lactis

subsp.

tructae

. The two groups had a relatively low DNA–DNA hybridization value (about 60 %). In the present study, the taxonomic position of

L. lactis

subsp.

cremoris

and

L. lactis

subsp.

tructae

was re-examined based on sequence analyses of 16S rRNA, rpoB, recA and pheS genes, average nucleotide identity (ANI) values and digital DNA–DNA hybridization (dDDH) values. The result of 16S rRNA gene sequence analysis indicated that

L. lactis

subsp.

cremoris

NCDO 607T and

L. lactis

subsp.

tructae

L105T were phylogenetically related to the type strains of

L. lactis

subsp.

hordniae

,

L. lactis

subsp.

lactis

,

Lactococcus taiwanensis

,

Lactococcus kimchii

,

Lactococcus allomyrinae

, Lactococcus protaetiae,

Lactococcus hircilactis

,

Lactococcus fujiensis

and

Lactococcus nasutitermitis

. The 16S rRNA gene, rpoB, recA, pheS and concatenated rpoB, recA and pheS sequence similarities, ANI values, and dDDH values between the type strains of

L. lactis

subsp.

cremoris

,

L. lactis

subsp.

tructae

and phylogenetically related species were 93.5–99.4 %, 83.3–97.6 %, 80.6–92.4 %, 79.7–92.7 %, 83.5–94.3 %, 72.4–86.9 % and 21.4–32.5 %, respectively. Lower than 95–96 % ANI values and lower than 70 % dDDH values confirmed that the type strains of

L. lactis

subsp.

cremoris

and

L. lactis

subsp.

tructae

represent a novel species in the genus

Lactococcus

. Because

L. lactis

subsp.

cremoris

was proposed and validated before

L. lactis

subsp.

tructae

,

L. lactis

subsp.

cremoris

is elevated to the species level as Lactococcus cremoris sp. nov. and

L. lactis

subsp.

tructae

is transferred to L. cremoris as L. cremoris subsp. tructae comb. nov. The type strain of L. cremoris sp. nov. is NCDO 607T (=ATCC 19257T=DSM 20069T=JCM 16167T=LMG 6897T=NBRC 100676T). The type strain of L. cremoris subsp. tructae comb. nov. is L105T (=NBRC 110453T=DSM 21502T=JCM 31125T=LMG 24662T).
Epidemiological health assessment in primary health care in the State of Qatar-2019
Authors: Al-Kuwari Mohamed Ghaith , Al – Abdulla Samya Ahmad , Abdulla Maha Yousef , Bakri Ahmad Haj , Mohammed Azza Mustafa , Kandy Mujeeb Chettiyam , Patterson Amanda
Published: March 2021

Objectives

The Primary Health Care Corporation (PHCC) in Qatar conducted epidemiological health assessment to understand the burden of diseases impacting the PHCC registered population

Design

This is a cross-sectional study design among all PHCC registered population between the 1st of September 2018 and the 31st of August 2019

Setting

Primary Health Care Corporation health centers

Participants

The target population is all persons residing in Qatar aged (0-80) years and registered at the PHCC. Excluding patients with expired Qatar residence permit by the 31st of August

Results

Obesity rates ranged between 37% and 35% among the total population registered with the lowest rate in the central region at 34.7%. Burden of type 2 diabetes, hypertension, and dyslipidemia was the highest among population of the Central region at 13.9%, 15.7% and 11.1%, respectively. Tobacco consumption among males ranged from 25.4 % to 27.8%, with the highest rate in the Northern region. 39.9% of females in the Northern region had BMI above 30 kg/m2. Exclusive breastfeeding at 6 months was significantly lower than that at 4 months across all regions. Children in the Northern region had the highest rate of overweight/obesity based on Z-scores. Western region population had the highest number of communicable diseases notifications especially Chicken pox at 94.6 per 10,000 children

Conclusion

Understanding the patterns of disease in the local population will enable PHCC to provide a clear set of objectives to work towards meeting population health needs
Physical Activity Patterns Among Patients with Intracardiac Remote Monitoring Devices Before, During, and After COVID-19-related Public Health Restrictions
Authors: Lu Yuan , Murugiah Karthik , Jones Paul W , Massey Daisy S , Mahajan Shiwani , Caraballo César , Ahmed Rezwan , Bader Eric M , Krumholz Harlan M
Published: March 2021

Nationwide public health restrictions due to the coronavirus disease 2019 (COVID-19) pandemic have disrupted people’s routine physical activities, yet little objective information is available on the extent to which physical activity has changed among patients with pre-existing cardiac diseases. Using remote monitoring data of 9,924 patients with pacemakers and implantable cardiac defibrillators (ICDs) living in New York City and Minneapolis/Saint Paul, we assessed physical activity patterns among these patients in 2019 and 2020 from January through October. We found marked declines in physical activity among patients with implantable cardiac devices during COVID-19-related restrictions and the reduction was consistent across age and sex subgroups. Moreover, physical activity among these vulnerable patients did not return to pre-restrictions levels several months after COVID-19 restrictions were eased. Our findings highlight the need to consider the unintended consequences of mitigation strategies and develop approaches to encourage safe physical activity during the pandemic.
Mendelian randomization analysis identified genes pleiotropically associated with central corneal thickness
Authors: Yang Zhikun , Yang Jingyun , Liu Di , Yu Weihong
Published: March 2021

Objective

To prioritize genes that were pleiotropically or potentially causally associated with central corneal thickness (CCT).

Methods

We applied the summary data-based Mendelian randomization (SMR) method integrating summarized data of genome-wide association study (GWAS) on CCT and expression quantitative trait loci (eQTL) data to identify genes that were pleiotropically associated with CCT. We performed separate SMR analysis using CAGE eQTL data and GTEx eQTL data. SMR analysis were done for participants of European and East Asian ancestries, separately.

Results

We identified multiple genes showing pleiotropic association with CCT in the participants of European ancestry. CLIC3 (ILMN_1796423; PSMR=4.15×10−12), PTGDS (ILMN_1664464; PSMR=6.88×10−9) and C9orf142 (ILMN_1761138; PSMR=8.09×10−9) were the top three genes using the CAGE eQTL data, and RP11-458F8.4(ENSG00000273142.1; PSMR=5.89×10−9), LCNL1 (ENSG00000214402.6; PSMR=5.67×10−8), and PTGDS (ENSG00000107317.7; PSMR=1.92×10−7) were the top three genes using the GTEx eQTL data. No genes showed significantly pleiotropic association with CCT in the participants of East Asian ancestry after correction for multiple testing.

Conclusion

We identified several genes pleiotropically associated with CCT, some of which represented novel genes influencing CCT. Our findings provided important leads to a better understanding of the genetic factors influencing CCT, and revealed potential therapeutic targets for the treatment of primary open-angle glaucoma and keratoconus.
Negligible impact of SARS-CoV-2 variants on CD4+and CD8+T cell reactivity in COVID-19 exposed donors and vaccinees
Authors: Tarke Alison , Sidney John , Methot Nils , Zhang Yun , Dan Jennifer M. , Goodwin Benjamin , Rubiro Paul , Sutherland Aaron , da Silva Antunes Ricardo , Frazier April , Rawlings Stephen A. , Smith Davey M. , Peters Bjoern , Scheuermann Richard H. , Weiskopf Daniela , Crotty Shane , Grifoni Alba , Sette Alessandro
Published: March 2021

The emergence of SARS-CoV-2 variants highlighted the need to better understand adaptive immune responses to this virus. It is important to address whether also CD4+ and CD8+ T cell responses are affected, because of the role they play in disease resolution and modulation of COVID-19 disease severity. Here we performed a comprehensive analysis of SARS-CoV-2-specific CD4+ and CD8+ T cell responses from COVID-19 convalescent subjects recognizing the ancestral strain, compared to variant lineages B.1.1.7, B.1.351, P.1, and CAL.20C as well as recipients of the Moderna (mRNA-1273) or Pfizer/BioNTech (BNT162b2) COVID-19 vaccines. Similarly, we demonstrate that the sequences of the vast majority of SARS-CoV-2 T cell epitopes are not affected by the mutations found in the variants analyzed. Overall, the results demonstrate that CD4+ and CD8+ T cell responses in convalescent COVID-19 subjects or COVID-19 mRNA vaccinees are not substantially affected by mutations found in the SARS-CoV-2 variants.
Impact of COVID-19 on healthcare workers at a cancer care centre
Authors: Dogra Atika , Parkash Anuj , Mehta Anurag , Bhatia Meenu
Published: March 2021

Background

The services of front-line health care workers (HCWs) have been paramount in the management of novel coronavirus disease 2019 (COVID-19). Health care professionals have been at high occupational risk of getting disease and even dying of the disease, however; they have been the subject of very limited studies in terms of COVID-19. The objectives of this study are to examine the incidence and the impact of COVID-19 infection among HCWs in terms of recovery, productivity, quality of life (QOL) and post-COVID complications.

Materials and Methods

This was a retrospective, questionnaire based study including demographic details, workplace characteristics, symptoms, source/ spread of infection, details of recovery and the consequences of COVID-19 comprising impaired productivity/ QOL, post-COVID-19 complications and others. The data were analyzed by using IBM SPSS software (Version 23, SPSS Inc., Chicago, IL, USA).

Results and Conclusions

Out of a total of 1482 employees, 18.3% (271) were laboratory confirmed to have contracted novel contagion during the study period of 5 months. The median age at diagnosis was 29 (range, 21-62) years. Front-line workers and female workers were the most infected personnel with COVID-19. Flu-like symptoms were the most frequently experienced symptoms. The median time for recovery was 20 (range, 2-150) days. The relationship between pre-existing comorbidities and age was highly significant. The QOL and productivity were associated with pre-existing comorbidities, severity of the disease, time for recovery and post-COVID syndrome. More than a half (51.8%) of all HCWs had suffered from post-COVID complications. There was no fatality reported due to COVID-19. The post-COVID complications were related to pre-existing comorbidities, severity of disease, time for recovery and status of recovery. Further research to explore the consequences of COVID-19 is warranted. The general public needs to be aware of symptoms and management of the post-COVID syndrome.
Modeling COVID-19 Nonpharmaceutical Interventions: Exploring periodic NPI strategies
Authors: Vardavas Raffaele , de Lima Pedro Nascimento , Baker Lawrence
Published: March 2021

We developed a COVID-19 transmission model used as part of RAND’s web-based COVID-19 decision support tool that compares the effects of nonpharmaceutical public health interventions (NPIs) on health and economic outcomes. An interdisciplinary approach informed the selection and use of multiple NPIs, combining quantitative modeling of the health/economic impacts of interventions with qualitative assessments of other important considerations (e.g., cost, ease of implementation, equity). This paper provides further details of our model, describes extensions, presents sensitivity analyses, and analyzes strategies that periodically switch between a base NPI level and a higher NPI level. We find that a periodic strategy, if implemented with perfect compliance, could have produced similar health outcomes as static strategies but might have produced better outcomes when considering other measures of social welfare. Our findings suggest that there are opportunities to shape the tradeoffs between economic and health outcomes by carefully evaluating a more comprehensive range of reopening policies.
Small molecule SWELL1-LRRC8 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes
Authors: Gunasekar Susheel K. , Xie Litao , Chheda Pratik R. , Kang Chen , Kern David M. , My-Ta Chau , Kumar Ashutosh , Maurer Joshua , Gerber Eva E. , Grzesik Wojciech J. , Elliot-Hudson Macaulay , Zhang Yanhui , Kulkarni Chaitanya A. , Samuel Isaac , Smith Jessica K. , Nau Peter , Imai Yumi , Sheldon Ryan D. , Taylor Eric B. , Lerner Daniel J. , Norris Andrew W. , Brohawn Stephen G. , Kerns Robert , Sah Rajan
Published: March 2021

Type 2 diabetes (T2D) is associated with insulin resistance, impaired insulin secretion from the pancreatic β-cell, and nonalcoholic fatty liver disease (NAFLD). SWELL1 (LRRC8a) ablation impairs adipose and skeletal muscle insulin-pAKT2 signaling, β-cell insulin secretion and glycemic control - suggesting that SWELL1-LRRC8 complex dysfunction contributes to T2D pathogenesis. Here, we show that ICl,SWELLand SWELL1 protein are reduced in adipose and β-cells in murine and human T2D. Combining cryo-electron microscopy, molecular docking, medicinal chemistry, and functional studies, we define a structure activity relationship to rationally-designed active derivatives (SN-40X) of a SWELL1 channel inhibitor (DCPIB/SN-401), that bind the SWELL1-LRRC8 hexameric complex, restore SWELL1-LRRC8 protein, plasma membrane trafficking, signaling and islet insulin secretion via SWELL1-dependent mechanisms.In vivo, SN-401 and active SN-40X compounds restore glycemic control and prevents NAFLD by improving insulin-sensitivity and insulin secretion in murine T2D. These findings demonstrate that small molecule SWELL1 modulators restore SWELL1-dependent insulin-sensitivity and insulin secretion in T2D and may represent a first-in-class therapeutic approach for T2D and NAFLD.
Reduced Frontal Cortical Tracking of Conflict between Selfish versus Prosocial Motives in Narcissistic Personality Disorder
Authors: Stolz David S. , Vater Aline , Schott Björn H. , Roepke Stefan , Paulus Frieder M. , Krach Sören
Published: March 2021

Narcissistic Personality Disorder (NPD) entails severe impairments in interpersonal functioning that are likely driven by selfish and exploitative behavior. Here, we investigate the underlying motivational and neural mechanisms of prosocial decision-making by experimentally manipulating motivational conflict between selfish and prosocial incentives. One group of patients diagnosed with NPD and a group of healthy controls (CTL) were scanned using functional magnetic resonance imaging while performing a prosocial decision-making task. In this task, we systematically varied the level of conflict between selfish and prosocial options on each trial. We analyzed choice behavior, response times, and neural activity in regions associated with conflict monitoring to test how motivational conflict drives prosocial choice behavior. Participants in the NPD group behaved less prosocially than the CTL group overall. Varying degrees of motivational conflict between selfish and prosocial options induced response variability in both groups, but more so in the CTL group. The NPD group responded faster than the CTL group, unless choosing prosocially, which slowed response times to a level comparable to the CTL group. Additionally, neural activity tracking motivational conflict in dorsomedial prefrontal cortex was reduced in the NPD group. Collectively, low generosity in NPD appears to arise from reduced consideration of prosocial motives, which obviates motivational conflict with selfish motives and entails reduced activity in neural conflict monitoring systems. Yet, our data also indicate that NPD is not marked by an absolute indifference to others’ needs. This points to potentials for improving interpersonal relationships, effectively supporting the well-being of patients and their peers.
The evaluation of a web‐based tool for measuring the uncorrected visual acuity and refractive error in keratoconus eyes: a prospective open‐label method comparison study
Authors: Muijzer Marc B , Claessens Janneau L J , Cassano Francesco , Godefrooij Daniel A , Prevoo Yves F D M , Wisse Robert P L
Published: March 2021

Purpose

To evaluate the outcome of a web‐based digital assessment of visual acuity and refractive error, compared to a manifest refraction assessment, in keratoconus patients with complex refractive errors.

Material and methods

Keratoconus patients, aged 18 to 40, with a refractive error between ‐6 and +4 diopters were eligible. Each participant subsequently underwent an uncorrected visual acuity and a refractive assessment. Refractive error was assessed with the web‐based tool (index test), an autorefractor, and a manifest refraction (reference test) by an optometrist. Corrected visual acuity was assessed with the web‐based and manifest refractive prescription. Non‐inferiority was defined as the 95% limits‐of‐agreement (95%LoA) of the differences in spherical equivalent between the index and reference test not exceeding +/‐ 0.5 diopters. Agreement was assessed by an intraclass correlation coefficient and Bland‐Altman analyses.

Results

A total of 100 eyes of 50 patients were examined. The overall mean difference of the uncorrected visual acuity measured ‐0.01 LogMAR (95%LoA:‐0.63–0.60). The variability decreased in the high uncorrected visual acuity subgroup (mean difference: 0.15 LogMAR, 95%LoA:‐0.25–0.55). The intraclass correlation coefficient of the three refractive assessments was 0.32. The overall mean difference in spherical equivalent between the index and reference test measured ‐0.58 diopters (95%LoA:‐4.49 – 3.33, P=0.008). The mean differences for myopic and hyperopic subjects were 0.09 diopters (P=0.675) and ‐2.06 diopters (P<0.001), respectively.

Conclusions

Our results show promising results in the ability of the web‐based tool to remotely assess visual acuity in keratoconus patients. The agreement is better in higher visual acuity ranges and could provide physicians with an objective measurement to enhance teleconsultations, especially relevant when access to health care is limited. The assessment of the refractive error using the web‐based tool was found to be inferior to the manifest refraction and deserves further training of the tools algorithm.
A novel splice variant of human TGF-β type II receptor encodes a soluble protein and its Fc-tagged version prevents liver fibrosisin vivo
Authors: Bertolio Marcela Soledad , Colla Anabela La , Carrea Alejandra , Romo Ana , Canziani Gabriela , Echarte Stella Maris , Campisano Sabrina , Barletta German Patricio , Monzon Alexander Miguel , Rodríguez Tania Melina , Chisari Andrea Nancy , Dewey Ricardo Alfredo
Published: March 2021

We describe, for the first time, a new splice variant of the human TGF-β type II receptor (TβRII). The new transcript lacks 149 nucleotides, causing a frameshift with the appearance of an early stop codon, rendering a truncated mature protein of 57 amino acids. The predicted protein, lacking the transmembrane domain and with a distinctive 13 amino acid stretch in the C-terminus, was named TβRII-Soluble Endogenous (TβRII-SE). Binding predictions indicated that the novel 13 amino acid stretch interacts with all three TGF-β cognate ligands and generate a more extensive protein-protein interface than TβRII. TβRII-SE and human IgG1 Fc-domain, were fused in frame in a lentiviral vector (Lv) for further characterization. With this vector, we transduced 293T cells and purified TβRII-SE/Fc by A/G protein chromatography from conditioned medium. Immunoblotting revealed homogeneous bands of approximately 37 kDa (reduced) and 75 kD (non-reduced), indicating that TβRII-SE/Fc is secreted as a disulphide-linked homodimer. Moreover, high affinity binding of TβRII-SE to the three TGF-β isoforms was confirmed by Surface Plasmon Resonance (SPR) analysis. Also, intrahepatic delivery of Lv.TβRII-SE/Fc in a carbon tetrachloride-induced liver fibrosis model revealed amelioration of liver injury and fibrosis. Our results indicate that TβRII-SE is a novel member of the TGF-β signaling pathway with distinctive characteristics. This novel protein offers an alternative for the prevention and treatment of pathologies caused by the overproduction of TGF-β ligands.
Evolutionary Analysis of Transcriptional Regulation Mediated by Cdx2 in Rodents
Authors: Liang Weizheng , Li Guipeng , Cui Huanhuan , Wang Yukai , Wei Wencheng , Sun Siyue , Gan Diwen , Chen Rui , Yi Hongyang , Schaefke Bernhard , Hu Yuhui , Zhou Qi , Li Wei , Chen Wei
Published: March 2021

Differences in gene expression, which can arise from divergence incis-regulatory elements or alterations in transcription factors binding specificity, are one of the most important causes of phenotypic diversity during evolution. By protein sequence analysis, we observed high sequence conservation in the DNA binding domain (DBD) of the transcription factor Cdx2 across many vertebrates, whereas three amino acid changes were exclusively found in mouse Cdx2 (mCdx2), suggesting potential positive selection in the mouse lineage. Multi-omics analyses were then carried out to investigate the effects of these changes. Surprisingly, there were no significant functional differences between mCdx2 and its rat homologue (rCdx2), and none of the three amino acid changes had any impact on its function. Finally, we used rat-mouse allodiploid embryonic stem cells (RMES) to study theciseffects of Cdx2-mediated gene regulation between the two rodents. Interestingly, whereas Cdx2 binding is largely divergent between mouse and rat, the transcriptional effect induced by Cdx2 is conserved to a much larger extent.

Author summary

Our study 1) represented a first systematic analysis of species-specific adaptation in DNA binding pattern of transcription factor. Although the mouse-specific amino acid changes did not manifest functional impact in our system, several explanations may account for it (See Discussion part for the detail); 2) represented a first study of cis-regulation between two reproductively isolated species by using a novel allodiploid system; 3) demonstrated a higher conservation of transcriptional output than that of DNA binding, suggesting the evolvability/plasticity of the latter; 4) finally provided a rich data resource for Cdx2 mediated regulation, including gene expression, chromatin accessibility and DNA binding etc.
Biotransformation of agro-industrial waste to wealth in Africa through mushroom farming
Authors: Ekun Victor S. , Adenipekun Clementina O. , Idowu Olufunmilayo , Etaware Peter M.
Published: March 2021

Discarding Waste in open drainages, water bodies and unauthorized dumpsites is a common practice in Africa that is deleterious to the global ecosystem. Global warming, flooding and land encroachment are direct impact of these actions. Therefore, a proposed eco-friendly solution to efficient waste management in Africa is “Mushroom Farming”. The region between Latitude 6.43–7.95°N and Longitude 2.88–5.24°E (Nigeria) was the research focus. Mushroom samples were collected, identified, coded and geo-tagged in the field, while Laboratory analyses and mushroom cultivation was conducted in NIHORT and University of Ibadan. The result showed that postharvest waste (rice straw) was best for spawning (Ek1-8→23days, LA1-8→21days, OG1-8→20days, and OY1-8→22days), while agro-waste fromGliricidium sepiumfacilitated early pin head emergence (26days) and fruiting (28days). Also, agro-waste fromCedrela odoratafacilitated early maturation (3days after fruiting), and those fromMangifera indica, G. sepiumandC. odorata, improved yield (9.05g), pileus size (4.24g) and dry matter (3.01g), respectively. The Laboratory analyses showed that LA1-8 had the best N2, Na and Ca contents (13.59, 70.49 and 61.90mg/100g, respectively), while fat, fibre and carbohydrate contents were highest in samples from EK1-8 (6.60%), OS1-8 (25.13%) and OG1-8 (54.23%), respectively. Mushroom farming is the key to efficient transformation of waste to wealth in Africa.
The impact of mutations on the structural and functional properties of SARS-CoV-2 proteins: A comprehensive bioinformatics analysis
Authors: Ikram Aqsa , Naz Anam , Awan Faryal Mehwish , Rauff Bisma , Obaid Ayesha , Hakim Mohamad S. , Malik Arif
Published: March 2021

An in-depth analysis of first wave SARS-CoV-2 genome is required to identify various mutations that significantly affect viral fitness. In the present study, we have performed comprehensive in-silico mutational analysis of 3C-like protease (3CLpro), RNA dependent RNA polymerase (RdRp), and spike (S) proteins with the aim of gaining important insights into first wave virus mutations and their functional and structural impact on SARS-CoV-2 proteins. Our integrated analysis gathered 3465 SARS-CoV-2 sequences and identified 92 mutations in S, 37 in RdRp, and 11 in 3CLpro regions. The impact of those mutations was also investigated using various in silico approaches. Among these 32 mutations in S, 15 in RdRp, and 3 in 3CLpro proteins are found to be deleterious in nature and could alter the structural and functional behavior of the encoded proteins. D614G mutation in spike and P323L in RdRp are the globally dominant variants with a high frequency. Most of them have also been found in the binding moiety of the viral proteins which determine their critical involvement in the host-pathogen interactions and drug targets. The findings of the current study may facilitate better understanding of COVID-19 diagnostics, vaccines, and therapeutics.
Modeling gene x environment interactions in PTSD using glucocorticoid-induced transcriptomics in human neurons
Authors: Breen Michael S. , Rusielewicz Tom , Bader Heather N. , Seah Carina , Xu Changxin , Hunter Christopher J. , McCarthy Barry , Chattopadhyay Mitali , Desarnaud Frank , Makotkine Iouri , Flory Janine D. , Bierer Linda M. , Staniskyte Migle ,   NYSCF Global Array Team, Noggle Scott A. , Paull Daniel , Brennand Kristen J. , Yehuda Rachel
Published: March 2021

Post-traumatic stress disorder (PTSD) results from severe trauma exposure, but the extent to which genetic and epigenetic risk factors impact individual clinical outcomes is unknown. We assessed the impact of genomic differences following glucocorticoid administration by examining the transcriptional profile of human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons and live cultured peripheral blood mononuclear cells from combat veterans with PTSD (n=5) and without PTSD (n=5). This parallel examination in baseline and glucocorticoid-treated conditions resolves cell-type specific and diagnosis-dependent elements of stress response, and permits discrimination of gene expression signals associated with PTSD risk from those induced by stress. Computational analyses revealed neuron-specific glucocorticoid-response expression patterns that were enriched for transcriptomic patterns observed in clinical PTSD samples. PTSD-specific signatures, albeit underpowered, accurately stratify veterans with PTSD relative to combat-exposed controls. Overall,in vitroPTSD and glucocorticoid response signatures in blood and brain cells represent exciting new platforms with which to test the genetic and epigenetic mechanisms underlying PTSD, identify biomarkers of PTSD risk and onset, and conduct drug-screening to identify novel therapeutics to prevent or ameliorate clinical phenotypes.
Delineating the complex mechanistic interplay between autophagy and monocyte to macrophage differentiation: a functional perspective
Authors: Bhattacharya Anindita , Ghosh Purnam , Singh Arpana , Ghosh Arnab , Bhowmick Arghya , Sinha Deepak Kumar , Ghosh Abhrajyoti , Sen Prosenjit
Published: March 2021

Autophagy is an extremely essential cellular process aimed to clear redundant and damaged materials. In this study, we demonstrated that mTOR dependent classical autophagy is ubiquitously triggered in differentiating monocytes. Moreover, autophagy plays a decisive role in sustaining the process of monocyte to macrophage differentiation. We have delved deeper into understanding the underlying mechanistic complexities that trigger autophagy during differentiation. We have also shown that autophagy directs monocyte differentiation via protein degradation. Further, we delineated the complex cross-talk between autophagy and cell-cycle arrest in differentiating monocytes. This study also inspects the contribution of adhesion on various steps of autophagy and its ultimate impact on monocyte differentiation. Our study reveals new mechanistic insights into the process of autophagy associated with monocyte differentiation and would undoubtedly help to understand the intricacies of the process better for the effective design of therapeutics as autophagy and autophagy-related processes have enormous importance in human patho-physiology.

Graphical Abstract