bluuebunny/crossref_metadata_2025 huggingface dataset:
Sleeping Late Increases the Risk of Myocardial Infarction in the Middle-Aged and Older Populations
Authors: Fan Yajuan , Wu Yanhua , Peng Yuan , Zhao Binbin , Yang Jian , Bai Ling , Ma Xiancang , Yan Bin
Published: September 2021

Objective: Sleep has a significant influence on the incidence of myocardial infarction (MI). The purpose of this study was to investigate the association between sleep timing including bedtime, wake-up time and sleep midpoint, and the incidence of MI.

Methods: A total of 4,576 patients (2,065 men, 2,511 women; age 63.4 ± 11.0 years) were selected from the Sleep Heart Health Study. Sleep timings on weekdays and weekends were recorded or calculated based on the sleep habits questionnaire completed by the participants at baseline. Bedtime was divided into 10:00 PM and before, 10:01 PM−11:00 PM, 11:01 PM−12:00 AM, and later than 12:00 AM. Cox proportional hazards regression analysis was used to examine the relationship between sleep timings and MI.

Results: Participants with a weekday bedtime later than 12:00 AM, between 11:01 PM−12:00 AM, and 10:00 PM or before had a higher incidence of MI than those with a bedtime between 10:01 PM and 11:00 PM (9.2% vs. 7.0% vs. 6.9% vs. 5.1%, respectively; P = 0.008). Multivariable Cox regression analysis showed that sleeping on weekdays later than 12:00 AM was associated with an increased risk of incident MI after adjusting for potential covariates (hazard ratio, 1.628; 95% confidence interval, 1.092–2.427; P = 0.017). However, there was no significant association between late bedtime on weekends and MI. In addition, no significant association of late wake-up time and delayed sleep midpoint on both weekdays and weekends with the incidence of MI was observed.

Conclusion: Sleeping late on weekday (>12:00 AM) independently increased the risk of MI. This finding emphasizes the importance of a proper bedtime for the maintenance of the health of the cardiovascular system.
Predictors of Procedural Success in Patients With Degenerated Surgical Valves Undergoing Transcatheter Aortic Valve-in-Valve Implantation
Authors: Abushouk Abdelrahman I. , Abdelfattah Omar , Saad Anas , Isogai Toshiaki , Farwati Medhat , Yun James , Popovic Zoran , Shekhar Shashank , Puri Rishi , Reed Grant W. , Krishnaswamy Amar , Kapadia Samir R.
Published: September 2021

Background: Valve-in-Valve transcatheter aortic valve implantation (ViV-TAVI) is a growing alternative for redo-surgery in patients with degenerated surgical valves. To our knowledge, data are lacking on the determinants on ViV-TAVI procedural success in patients with degenerated surgical valves.

Methods: All consecutive patients undergoing ViV-TAVI for degenerated surgical valves at the Cleveland Clinic were analyzed. Data were extracted from our patient registry on baseline patient characteristics, echocardiographic parameters, and procedural details. To identify possible predictors of ViV-TAVI procedural success, we employed a multivariate logistic regression model.

Results: A total of 186 patients who underwent ViV-TAVI were analyzed, with procedural success (VARC-2 device success and absence of periprocedural MACCE) reported in 165 (88.7%) patients. Patients with successful ViV-TAVI were significantly younger and had more frequent utilization of the transfemoral access than those with failed procedure. Other baseline and procedural characteristics were comparable between both groups. In terms of echocardiographic parameters, the procedural success group had a significantly lower AV peak pressure gradient (62.1 ± 24.7 vs. 74.1 ± 34.6 mmHg; p = 0.04) and lower incidence of moderate-to-severe aortic regurgitation [AR] (30.4 vs. 55%; p = 0.04). However, no significant differences between both groups were noted in terms of AV mean pressure gradient and left ventricular measurements. In multivariate analysis, lower AV peak pressure gradient (OR = 0.97, 95% CI: 0.95–0.99) and absence of moderate-to-severe AR (OR = 0.65, 95% CI: 0.44–0.95) at baseline emerged as independent predictors of ViV-TAVI procedural success.

Conclusion: Valve-in-Valve TAVI for degenerated surgical valves is a feasible approach with high success rates, especially in those with lower AV peak pressure gradient and absence of moderate-to-severe AR. Studies with larger sample size and longer follow-up are required to further characterize the predictors of ViV-TAVI success and other clinical outcomes.
Prognostic Association Between Perioperative Red Blood Cell Transfusion and Postoperative Cardiac Surgery Outcomes
Authors: Li Yanxiu , Cheang Iokfai , Zhang Zhongwen , Zuo Xiangrong , Cao Quan , Li Jinghang
Published: September 2021

Objective: To investigate the correlation between red blood cell transfusion and clinical outcome in patients after cardiac surgery.

Methods: Demographic, clinical characteristics, treatment with/without transfusion, and outcomes of patients after cardiac surgery from the Medical Information Mart for Intensive Care—III database were collected. Patients were divided into two groups according to perioperative transfusion. A multivariable logistic regression analysis was utilized to adjust for the effect of red blood cell transfusion on outcomes for baseline and covariates and to determine its association with outcomes.

Results: In total, 6,752 patients who underwent cardiac surgery were enrolled for the analysis. Among them, 2,760 (40.9%) patients received a perioperative transfusion. Compared with patients without red blood cell transfusion, transfused patients demonstrated worse outcomes in inhospital mortality, 1-year mortality, and all-cause mortality. Adjusting odds ratios (ORs) for the significant characteristic, patients with perioperative transfusion remained significantly associated with an increased risk of inhospital mortality [OR = 2.8, 95% confidence interval (CI) 1.5–5.1, P = 0.001], 1-year mortality (OR = 2.0, 95% CI 1.4–2.7, P < 0.001), and long-term mortality (OR = 2.2, 95% CI 1.8–2.8, P < 0.001).

Conclusion: Perioperative red blood cell transfusion is associated with a worse prognosis of cardiac surgery patients. Optimal perioperative management and restricted transfusion strategy might be considered in selected patients.
Association of Agriculture Occupational Exposure With Diabetes and Cardiovascular Risk Factors in South Indian Villages: REDSI Study
Authors: Velmurugan Ganesan , Mohanraj Sundaresan , Christy Yacob Jenifer , Keppanan Sundaravadivu , Rekha Balakrishnan , Krishnasamy Anbalagan , Shanmugarajan Suresh , Boopathi Seenivasan , Ayyapparaja Anitha , Ayyapparaja Prabhu Chandhran , RS Tamilselvan , Gopalakrishnan Manigandan , Veerappan Jayaramanathan , Dharmaraj Vithya , Vaithilingam Subramaniyan , Purushothaman Priyadharshini , Chelladurai Sumathi , Pandiyan Jeevan , Selvarajan Vijaya Samoondeeswari , Annathurai Kalidoss , Vengatachalam Sukumaran , Arivuruvone Gorky , Kaliyaperumal Saravanan , G Velsamy , S Kannan , Ramasamy Subbiah , Swaminathan Krishnan
Published: September 2021

There has been a huge increase in diabetes and its associated cardiovascular complications over the last decade, predominantly in the middle- and low-income countries. In these countries, the majority live in rural areas. The Rural Epidemiology of Diabetes in South India (REDSI) study was aimed to analyze the prevalence of diabetes, cardiovascular risk factors, and its complications in rural farming and non-farming villages in Tamil Nadu, South India. A research survey on the prevalence of self-reported diabetes, cardiovascular risk factors (age, sex, obesity, hypertension, hypercholesterolemia, alcohol and tobacco use) and agricultural occupational exposure was executed among 106,111 people from 61 villages in the state of Tamil Nadu, South India, during 2015–2018. Overall, we observed a diabetes prevalence of 11.9% in rural South India. A nearly two-fold higher prevalence of diabetes was observed among the farming community (15.0%) compared to that among the non-farming population (8.7%). Logistic regression analyses revealed a strong association with agrochemical exposure (P < 0.0001) and diabetes prevalence among rural farming people. Our survey indicates a high prevalence of diabetes in rural South India particularly among the farming community. This survey in conjunction with other epidemiological and experimental studies raises the need for understanding the etiology of diabetes and other cardiovascular risk factors in rural communities.
Effects of the Btk-Inhibitors Remibrutinib (LOU064) and Rilzabrutinib (PRN1008) With Varying Btk Selectivity Over Tec on Platelet Aggregation and in vitro Bleeding Time
Authors: Duan Rundan , Goldmann Luise , Brandl Richard , Spannagl Michael , Weber Christian , Siess Wolfgang , von Hundelshausen Philipp
Published: September 2021

Background:Bruton tyrosine kinase inhibitors (BTKi) are used in B-cell malignancies and in development against various autoimmune diseases. Since Btk is also involved in specific pathways of platelet activation, BTKi might be considered to target platelet GPVI/GPIb-mediated atherothrombosis and platelet FcγRIIA-dependent immune disorders. However, BTKi treatment of patients with B-cell malignancies is frequently associated with mild bleeding events caused possibly by off-target inhibition of Tec. Here, we compared the platelet effects of two novel BTKi that exhibit a high (remibrutinib) or low (rilzabrutinib) selectivity for Btk over Tec.

Methods and Results:Remibrutinib and rilzabrutinib were pre-incubated with anticoagulated blood. Platelet aggregation andin vitrobleeding time (closure time) were studied by multiple electrode aggregometry (MEA) and platelet-function analyzer-200 (PFA-200), respectively. Both BTKi inhibited atherosclerotic plaque-stimulated GPVI-mediated platelet aggregation, remibrutinib being more potent (IC50= 0.03 μM) than rilzabrutinib (IC50= 0.16 μM). Concentrations of remibrutinib (0.1 μM) and rilzabrutinib (0.5 μM), >80% inhibitory for plaque-induced aggregation, also significantly suppressed (>90%) the Btk-dependent pathways of platelet aggregation upon GPVI, von Willebrand factor/GPIb and FcγRIIA activation stimulated by low collagen concentrations, ristocetin and antibody cross-linking, respectively. Both BTKi did not inhibit aggregation stimulated by ADP, TRAP-6 or arachidonic acid. Remibrutinib (0.1 μM) only slightly prolonged closure time and significantly less than rilzabrutinib (0.5 μM).

Conclusion:Remibrutinib and rilzabrutinib inhibit Btk-dependent pathways of platelet aggregation upon GPVI, VWF/GPIb, and FcγRIIA activation. Remibrutinib being more potent and showing a better profile of inhibition of Btk-dependent platelet activation vs. hemostatic impairment than rilzabrutinib may be considered for further development as an antiplatelet drug.
Interplay Between Coastal Elevation and Wave Height Controls the Occurrence of Coastal Boulder Deposits in the Aran Islands, Ireland
Authors: Van Blunk Alexis , Kennedy Andrew B. , Cox Rónadh
Published: September 2021

Coastal boulder deposits (CBD) are wave-emplaced supratidal accumulations that record extreme inundation on rocky coasts. They are poorly understood but are of growing importance as we seek to better understand the extremes of wave power on coastlines. The Aran Islands, Ireland, host CBD in varying settings ranging from sheer cliff tops to wide shore platforms, and at elevations to about 40 m above sea level. Deposits are known to be active during strong storm events and provide a unique opportunity to examine relationships between wave energy, setting, and CBD occurrence. We use topographic elevation (Z) and offshore 100-years significant wave height (Hs,100) to calculate a dimensionless elevation Z* = Z/Hs,100 at 25 m intervals all along the Atlantic-facing coasts of the Aran Islands, and record whether CBD were present or absent at each location. The data reveal universal CBD presence at locations with low dimensionless elevations and near-monotonic decreasing frequency of CBD occurrence as Z* increases. On the Aran Islands, CBD are restricted to locations with Z*<3.13. For high elevation deposits it appears that unresolved local factors may be the major determinants in whether CBD will form. This approach can be applied at any CBD-bearing coastline and has the potential to change the way that we think about these deposits. Evaluation of dimensionless elevations at CBD locations around the world will help build broader understanding of the impact local shoreline conditions have on CBD formation. Determining these relationships contributes to the ongoing need to better understand interactions between extreme waves and rocky coasts.
From STEM to STEAM: An Enactive and Ecological Continuum
Authors: Videla Ronnie , Aguayo Claudio , Veloz Tomas
Published: September 2021

STEM and STEAM education promotes the integration between science, technology, engineering, mathematics, and the arts. The latter aims at favoring deep and collaborative learning on students, through curricular integration in K-12 science education. The enactive and ecological psychology approach to education puts attention on the role of the teacher, learning context and socio-cultural environment in shaping lived learning experiences. The approach describes education as a process of embodied cognitive assemblage of guided perception and action. The latter process depends on the interaction of learners with digital and/or analogue learning affordances existing within the socio-technological environment. This article proposes that the scope of an enactive-ecological approach can be extended to the domain of learning science, technology, engineering, arts, and mathematics (STEAM), especially when it comes to understanding deep roots of the learning process. We first present an exhaustive literature review regarding the foundations of both the enactive and the ecological learning theories, along with their differences and key similarities. We then describe the fundamentals and latest research advances of an integrated STEAM pedagogy, followed by the notion of mixed reality (XR) as an emerging educational technology approach, offering an understanding of its current foundations and general disposition on how to understand digital immersion from ecological psychology. Next, we propose a systems theoretical approach to integrate the enactive-ecological approach in STEAM pedagogy, framed in the Santiago school of cognition attending to the interactive dynamics occurring between learners and their interaction with learning affordances existing within their educational medium, establishing that sensorimotor contingencies and attentional anchors are important to restrict sensory variety and stabilize learning concepts. Finally, we consider two empirical studies, one from Chile and the other from New Zealand, in which we demonstrate how the enactive-ecological approach built upon a systems theory perspective can contribute to understanding the roots of STEAM learning and inform its learning design.
The Influence of School Context Factors on the Induction Support as Perceived by Newly Qualified Teachers
Authors: Van der Pers Marieke , Helms-Lorenz Michelle
Published: September 2021

This study explores the relationship between school demographic characteristics and the amount of provided induction activities, as perceived by beginning teachers (BTs), with special attention for Professional Development Schools and non-Professional Development Schools. The aim is to provide information that is useful to improve induction arrangements to particular school contexts. Data were collected in a Dutch national induction program in which qualified BTs are supported in their first 3 years of professional practice. The support monitor measures multiple induction activities with regard to the implementation of workload reduction, school enculturation, professional development plans and lessons support. 1,670 BTs working in 195 schools reported on these activities. Linear regression analyses revealed that less induction activities were associated with schools with multiple locations, more enrolled students and number of BTs employed, and with schools with older male teaching staff. No significant differences were found between the amount of support perceived by BTs in PDSs and non-PDSs. Yet school characteristics revealed stronger predictive values for the amount of support provided in non-PDS settings. These insights are relevant for mapping school differences in induction arrangements in order to enhance the equity of support across schools to assure the development of teaching skills of BTs.
NDUFB6 Polymorphism Is Associated With Physical Activity-Mediated Metabolic Changes in Type 2 Diabetes
Authors: Pesta Dominik , Jelenik Tomas , Zaharia Oana-Patricia , Bobrov Pavel , Görgens Sven , Bódis Kálmán , Karusheva Yanislava , Krako Jakovljevic Nina , Lalic Nebojsa M. , Markgraf Daniel F. , Burkart Volker , Müssig Karsten , Knebel Birgit , Kotzka Jörg , Eckel Jürgen , Strassburger Klaus , Szendroedi Julia , Roden Michael
Published: September 2021

The rs540467 SNP in the NDUFB6 gene, encoding a mitochondrial complex I subunit, has been shown to modulate adaptations to exercise training. Interaction effects with diabetes mellitus remain unclear. We assessed associations of habitual physical activity (PA) levels with metabolic variables and examined a possible modifying effect of the rs540467 SNP. Volunteers with type 2 (n=242), type 1 diabetes (n=250) or normal glucose tolerance (control; n=139) were studied at diagnosis and subgroups with type 1 (n=96) and type 2 diabetes (n=95) after 5 years. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamps, oxygen uptake at the ventilator threshold (VO2AT) by spiroergometry and PA by questionnaires. Translational studies investigated insulin signaling and mitochondrial function in Ndufb6 siRNA-treated C2C12 myotubes, with electronic pulse stimulation (EPS) to simulate exercising. PA levels were 10 and 6%, VO2AT was 31% and 8% lower in type 2 and type 1 diabetes compared to control. Within 5 years, 36% of people with type 2 diabetes did not improve their insulin sensitivity despite increasing PA levels. The NDUFB6 rs540467 SNP modifies PA-mediated changes in insulin sensitivity, body composition and liver fat estimates in type 2 diabetes. Silencing Ndufb6 in myotubes reduced mitochondrial respiration and prevented rescue from palmitate-induced insulin resistance after EPS. A substantial proportion of humans with type 2 diabetes fails to respond to rising PA with increasing insulin sensitivity. This may at least partly relate to a polymorphism of the NDUFB6 gene, which may contribute to modulating mitochondrial function.

Clinical Trial Registration

ClinicalTrials.gov, identifier NCT01055093. The trial was retrospectively registered on 25th of January 2010.
Pilot Data on the Feasibility And Clinical Outcomes of a Nomegestrol Acetate Oral Contraceptive Pill in Women With Premenstrual Dysphoric Disorder
Authors: Robertson Emily , Thew Caroline , Thomas Natalie , Karimi Leila , Kulkarni Jayashri
Published: September 2021

Background

Up to 80% of reproductive-aged women experience premenstrual symptoms. Premenstrual Dysphoric Disorder (PMDD) is a severe form, affecting 2-5% of women. Combined oral contraceptive pills (COCPs) are used in the treatment of PMDD. Clinical practice suggests that a newer COCP containing nomegestrol acetate (2.5mg) and 17-beta estradiol (1.5mg), may be a suitable treatment for mood symptoms in PMDD.

Materials and Methods

This was a clinical follow-up feasibility study of women who had attended the Monash Alfred Psychiatry research centre, Women’s Mental Health Clinic, with a diagnosis of PMDD. 67% of the sample also had concurrent cPTSD, 29% co-morbid anxiety, and 20% depression. They were recommended treatment with nomegestrol acetate/17-beta estradiol. Eligible women were contacted by telephone to answer a questionnaire to assess women’s subjective response to nomegestrol acetate/17-beta estradiol, acceptability and the Depression, Anxiety and Stress Scale-21 (DASS-21) after being recommended nomegestrol acetate/17-beta estradiol. The paired-sample t-test was used to determine if there were any statistically significant differences in the DASS-21 scores over the study observation period (before and after taking nomegestrol acetate/17-beta estradiol).

Results

35 (74.5%) women reported a subjective positive mood response to nomegestrol acetate/17-beta estradiol, 31 (63.3%) adhered to the medication, and only 10 (20.4%) women reported side effects as the main reason for discontinuing nomegestrol acetate/17-beta estradiol. There were statistically significant reductions (p<0.05) in the overall DASS-21 scores from before women commenced nomegestrol acetate/17-beta estradiol and after commencement of treatment.

Conclusions

This preliminary study supports the acceptability and effectiveness of nomegestrol acetate/17-beta estradiol as a treatment for mood symptoms in PMDD. Further research, particularly a randomized controlled trial, is required to elucidate the effect of nomegestrol acetate/17-beta estradiol treatment on mood in PMDD.
The Exploration of Poor Ovarian Response–Related Risk Factors: A Potential Role of Growth Differentiation Factor 8 in Predicting Ovarian Response in IVF-ET Patient
Authors: Bai Long , Pan Huihui , Zhao Yinjun , Chen Qingqing , Xiang Yu , Yang Xiaohang , Zhu Yimin
Published: September 2021

Controlled ovarian hyperstimulation (COH) is the most common therapeutic protocol to obtain a considerable number of oocytes in IVF-ET cycles. To date, the risk factors affecting COH outcomes remain elusive. Growth differentiation factor 8 (GDF-8), a member of transforming growth factor β (TGF-β) superfamily, has been long discerned as a crucial growth factor in folliculogenesis, and the aberrant expression of GDF-8 is closely correlated with the reproductive diseases. However, less is known about the level of GDF-8 in IVF-ET patients with different ovarian response. In the present study, the potential risk factors correlated with ovarian response were explored using logistic regression analysis methods. Meanwhile, the expression changes of GDF-8 and its responsible cellular receptors in various ovarian response patients were determined. Our results showed that several factors were intensely related to poor ovarian response (POR), including aging, obesity, endometriosis, surgery history, and IVF treatment, while irregular menstrual cycles and PCOS contribute to hyperovarian response (HOR). Furthermore, POR patients exhibited a decrease in numbers of MII oocytes and available embryos, thereby manifesting a lower clinical pregnancy rate. The levels of GDF-8, ALK5, and ACVR2B in POR patients were higher compared with those in control groups, whereas the expression level of ACVR2A decreased in poor ovarian response patients. In addition, clinical correlation analysis results showed that the concentration of GDF-8 was negatively correlated with LH and estradiol concentration and antral follicle count. Collectively, our observations provide a novel insight of ovarian response–associated risk factors, highlighting the potential role of GDF-8 levels in ovarian response during COH process.
Comparison of Dydrogesterone and Medroxyprogesterone in the Progestin-Primed Ovarian Stimulation Protocol for Patients With Poor Ovarian Response
Authors: Zhang Junwei , Du Mingze , Li Zhen , Liu Wenxia , Ren Bingnan , Zhang Yuchao , Guan Yichun
Published: September 2021

Objective

To compare the clinical outcomes of dydrogesterone (DYG) and medroxyprogesterone (MPA) in the progestin-primed ovarian stimulation (PPOS) protocol for patients with poor ovarian response (POR).

Patients and Methods

This was a retrospective cohort study. Women with POR who underwent IVF/ICSI at the Reproductive Center of Third Affiliated Hospital of Zhengzhou University between January 2020 and January 2021 were included. The primary outcome measure of our study was the number of oocytes retrieved. The secondary outcome measures in the present study were the number of 2PN, number of available embryos, oocyte retrieval rate, fertilization rate, viable embryo rate per oocyte retrieved, cancellation rate and pregnancy outcomes of the first embryo transfer cycle, including the biochemical pregnancy, clinical pregnancy and miscarriage rates.

Results

In total, 118 women underwent hMG +DYG protocols, and 692 women who underwent hMG +MPA met the Bologna criteria for POR. After baseline characteristics were balanced using the PSM model, 118 hMG +DYG protocols were matched to 118 hMG +MPA protocols, and the baseline characteristics were comparable between the two groups. The numbers of oocytes retrieved, 2PN, and available embryos and the oocyte retrieval rate, fertilization rate, viable embryo rate per oocyte retrieved and cancellation rate of the hMG+DYG and hMG+MPA protocols were comparable. Altogether, 66 women in the hMG+DYG group and 87 women in the hMG+MPA group underwent first embryo transfers. In the hMG+DYG group, 81.8% (54/66) of the patients underwent cleavage embryo transfers; similarly, 79.3% (69/87) of patients in the hMG+MPA group had cleavage embryo transfers (P=0.70).The biochemical pregnancy rate of the hMG+DYG group was 42.4%, and this was comparable to the rate in the hMG+DYG group, at 34.5% (P=0.32). The clinical pregnancy rates were similar between the two groups (36.4% vs. 31.0%, P=0.49), and there was no significant difference in the rate of miscarriage between the two groups (12.5% vs. 29.6%, P=0.14).

Conclusion

For women with POR, the clinical outcome of the hMG + DYG group was similar to that of the hMG + MPA group, indicating that both combinations can be useful options for PPOS protocols.
Recurrence of Primary Aldosteronism 10 Years After Left Adrenalectomy for Aldosterone-Producing Adenoma: A Case Report
Authors: Kong Linghui , Zhang Jin , Dong Lei , Xu Jianzhong , Gao Ping-Jin , Wang Ji-Guang , Zhu Limin
Published: September 2021

A 29-year-old female patient diagnosed with primary aldosteronism (PA) in 2004 underwent complete adrenalectomy for left aldosterone-producing adenoma (APA) confirmed by hematoxylin and eosin (HE) and CYP11B2 staining. Her hypokalemia was corrected, and her blood pressure (BP) normalized and maintained without medication for 10 years. In 2014, her BP became elevated again, and a recurrence of PA with an adenoma on the right adrenal gland was discovered by computed tomography scan. She underwent partial right adrenalectomy in 2018 due to unsatisfactory BP control with medication and gradually enlarging adenoma. The resected adrenal tissue contained a CYP11B2 staining positive APA. Her BP was then controlled by two drugs. Sanger sequencing of DNA extracted from tissue slices revealed that both left and right adenomas carried the same aldosterone-driver KCNJ5 gene mutation, but with different nucleotide changes. We suggest that patients who undergo adrenalectomy for APA should be followed up for life.
Targeted Therapy of Papillary Thyroid Cancer: A Comprehensive Genomic Analysis
Authors: Hescheler Daniel A. , Riemann Burkhard , Hartmann Milan J. M. , Michel Maximilian , Faust Michael , Bruns Christiane J. , Alakus Hakan , Chiapponi Costanza
Published: September 2021

Background

A limited number of targeted therapy options exist for papillary thyroid cancer (PTC) to date. Based on genetic alterations reported by the “The Cancer Genome Atlas (TCGA)”, we explored whether PTC shows alterations that may be targetable by drugs approved by the FDA for other solid cancers.

Methods

Databases of the National Cancer Institute and MyCancerGenome were screened to identify FDA-approved drugs for targeted therapy. Target genes were identified using Drugbank. Genetic alterations were classified into conferring drug sensitivity or resistance using MyCancerGenome, CiViC, TARGET, and OncoKB. Genomic data for PTC were extracted from TCGA and mined for alterations predicting drug response.

Results

A total of 129 FDA-approved drugs with 128 targetable genes were identified. One hundred ninety-six (70%) of 282 classic, 21 (25%) of 84 follicular, and all 30 tall-cell variant PTCs harbored druggable alterations: 259 occurred in 29, 39 in 19, and 31 in 2 targetable genes, respectively. The BRAF V600 mutation was seen in 68% of classic, 16% of follicular variant, and 93% of tall-cell variant PTCs. The RET gene fusion was seen in 8% of classic PTCs, NTRK1 and 3 gene fusions in 3%, and other alterations in <2% of classic variant PTCs. Ninety-nine of 128 (77%) FDA-approved targetable genes did not show any genetic alteration in PTC. Beside selective and non-selective BRAF-inhibitors, no other FDA-approved drug showed any frequent predicted drug sensitivity (<10%).

Conclusion

Treatment strategies need to focus on resistance mechanisms to BRAF inhibition and on genetic alteration–independent alternatives rather than on current targeted drugs.
Ablating Aspiration Needle Tract Prior to Microwave Ablation Can Improve Therapeutic Outcomes for Predominantly Cystic Thyroid Nodules
Authors: Yang Haizhen , Chen Yanwei , Chen Baoding , Zhao Shuangshuang , Zhang Zheng , Wang Keke , Chen Zheming , Feng Huahui , An Maohui
Published: September 2021

Purpose

To investigate whether ablating the aspiration needle tract could improve the safety and efficacy of ultrasound-guided microwave ablation (MWA) for predominantly cystic thyroid nodules.

Materials and Methods

This retrospective study evaluated 41 predominantly cystic thyroid nodules that underwent MWA between June 2017 and August 2019. The nodules were stratified by different procedures into two groups: the aspiration needle tract was ablated before cyst fluid aspiration and MWA when treating 26 nodules in Group A, while the other 15 nodules in Group B underwent MWA directly after cyst fluid aspiration. Baseline characteristics, intervention time, hospital stays, nodules with intraoperative intracystic hemorrhage, and postoperative complications were compared between the two groups. Volume, volume reduction rate (VRR), compressive score (CS), and aesthetic score (AS) were evaluated during follow-up.

Results

Both groups achieved decreases in volume, CS, and AS, as well as an increase in VRR. The volumes and VRRs in Group A at 1, 3, 6, and 12 months were significantly smaller and greater than those in Group B (p < 0.001). The incidence of intraoperative intracystic hemorrhage in Group A was significantly lower than that in Group B (p=0.035). Compared to Group B, hospital stays were much shorter in Group A (p=0.040). There were no significant differences in intervention time, cystic fluid volume or postoperative complications.

Conclusion

Aspiration needle tract ablation dramatically reduces the incidence of intraoperative intracystic hemorrhage and markedly improves the efficacy of MWA for predominantly cystic thyroid nodules.
Optimization Design of SNS Sensor Structural Parameters for Battery Expansion Monitoring
Authors: Xu Shibo , Wang Zhe , Yang Hanrui , Jiao Shengxi , Liu Jien , Shang Zhiyuan
Published: September 2021

In this article, a method to improve refractive index (RI) sensitivity of single‐mode–no core–single‐mode fiber (SNS) sensor structure is addressed by optimization of geometric parameters of no-core fiber (NCF), which could be used to accurately measure the irreversible deformation of the battery expansion state caused by temperature change. From the perspective of temperature changing RI of the electrolyte solution, the impacts of diameter, length, and waveband on the performance of the fiber sensor have been discussed as RI measurement range is 1.340–1.390. After optimization, RI sensitivity can reach approximately 2,252.7 and 2037.3 nm/RIU with the length of 6.55 and 6.75 mm when the RI is from 1.380 to 1.390.
Increasing AZA-Accredited Zoo and Aquarium Engagement in Conservation
Authors: Ripple Kayla J. , Sandhaus Estelle A. , Brown Megan E. , Grow Shelly
Published: September 2021

Conservation should be the higher purpose of any modern zoological facility and has consistently been a required element of accreditation by the Association of Zoos and Aquariums (AZA). Each year, AZA-accredited zoos and aquariums collectively commit considerable resources to conservation around the world, exceeding 150 million USD annually since 2011 and exceeding 231 million USD in 2019. Furthermore, with 195 million people visiting AZA-accredited zoos and aquariums each year, there is enormous opportunity to connect people to nature and engage them as agents of change. As AZA facilities continue to prioritize conservation-driven missions, their participation in field conservation has increased greatly. AZA SAFE: Saving Animals From Extinction (SAFE)®was established in 2014 to encourage greater collaboration of AZA members and their field partners to save species. The SAFE framework is dedicated to species recovery and based on conservation best practices. SAFE species programs develop 3-year action plans that build on established recovery plans, evaluate impact, and combine AZA facilities and visitors to increase resources for research, public engagement, communications, and conservation funding. Here we share preliminary outcomes of the SAFE program as they relate to programmatic measures of success to determine whether the framework 1) is useful for the AZA membership as measured by engagement and participation, and 2) increases conservation activity on behalf of targeted species as measured by the number of facilities supporting a species' conservation and financial investment. In this analysis we utilized data supported by the AZA Annual Report for Conservation and Science (ARCS) to demonstrate benefits of the SAFE framework and provide insights into future strategies to enhance conservation impact.
Redefining the Subsurface Biosphere: Characterization of Fungi Isolated From Energy-Limited Marine Deep Subsurface Sediment
Authors: Kiel Reese Brandi , Sobol Morgan S. , Bowles Marshall Wayne , Hinrichs Kai-Uwe
Published: September 2021

The characterization of metabolically active fungal isolates within the deep marine subsurface will alter current ecosystem models and living biomass estimates that are limited to bacterial and archaeal populations. Although marine fungi have been studied for over fifty years, a detailed description of fungal populations within the deep subsurface is lacking. Fungi possess metabolic pathways capable of utilizing previously considered non-bioavailable energy reserves. Therefore, metabolically active fungi would occupy a unique niche within subsurface ecosystems, with the potential to provide an organic carbon source for heterotrophic prokaryotic populations from the transformation of non-bioavailable energy into substrates, as well as from the fungal necromass itself. These organic carbon sources are not currently being considered in subsurface energy budgets. Sediments from South Pacific Gyre subsurface, one of the most energy-limited environments on Earth, were collected during the Integrated Ocean Drilling Program Expedition 329. Anoxic and oxic sediment slurry enrichments using fresh sediment were used to isolate multiple fungal strains in media types that varied in organic carbon substrates and concentration. Metabolically active and dormant fungal populations were also determined from nucleic acids extracted from in situ cryopreserved South Pacific Gyre sediments. For further characterization of physical growth parameters, two isolates were chosen based on their representation of the whole South Pacific Gyre fungal community. Results from this study show that fungi have adapted to be metabolically active and key community members in South Pacific Gyre sediments and potentially within global biogeochemical cycles.
Systematic Construction and Validation of an RNA-Binding Protein-Associated Prognostic Model for Acute Myeloid Leukemia
Authors: Luo Hongwei , Zhang Yingchun , Hu Nan , He Yancheng , He Chengcheng
Published: September 2021

Background: The abnormal expression of RNA-binding proteins (RBPs) in various malignant tumors is closely related to the occurrence and development of tumors. However, the role of RBPs in acute myeloid leukemia (AML) is unclear.

Methods: We downloaded harmonized RNA-seq count data and clinical data for AML from UCSC Xena, including The Cancer Genome Atlas (TCGA), The Genotype-Tissue Expression (GTEx), and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) cohorts. R package edgeR was used for differential expression analysis of 337 whole-blood data and 173 AML data. The prognostic value of these RBPs was systematically investigated by using univariate Cox regression analysis, least absolute shrinkage and selection operator (LASSO)–Cox regression analysis, and multivariate Cox regression analysis. C-index and calibration diagram were used to judge the accuracy of the model, and decision curve analysis (DCA) was used to judge the net benefit. The biological pathways involved were revealed by gene set enrichment analysis (GSEA). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and the protein–protein interaction (PPI) network performed lateral verification on the selected gene set and LASSO results.

Results: A prognostic model of 12-RBP signature was established. In addition, the net benefit and prediction accuracy of the prognostic model and the mixed model based on it were significantly higher than that of cytogenetics. It is verified in the TARGET cohort and shows good prediction effect. Both the selection of our gene set and the LASSO results have high credibility. Most of these pathways are involved in the development of the disease, and they also accumulate in leukemia and RNA-related pathways.

Conclusion: The prognosis model of the 12-RBP signature found in this study is an optimized biomarker that can effectively stratify the risk of AML patients. Nomogram based on this prognostic model is a reliable method to predict the median survival time of patients. This study expands our current understanding of the role of RBPs in the occurrence of AML and may lay the foundation for future treatment of the disease.
Prenatal Diagnosis in a Fetus With X-Linked Recessive Chondrodysplasia Punctata: Identification and Functional Study of a Novel Missense Mutation in ARSE
Authors: Zhang Li , Hu Haoran , Liang Desheng , Li Zhuo , Wu Lingqian
Published: September 2021

X-Linked recessive chondrodysplasia punctata (CDPX1) is a rare skeletal dysplasia characterized by stippled epiphyses, brachytelephalangy, and nasomaxillary hypoplasia. CDPX1 is caused by function loss of arylsulfatase E (ARSE, also known as ARSL). Pathogenic mutations inARSEare responsible for CDPX1 in newborns or adults; however, studies have not fully explored prenatal cases. In the current study, a novel missense mutation (c.265A > G) inARSEwas identified in a fetus with short limbs using whole-exome sequencing (WES). Bioinformatic analysis showed that the variant was pathogenic, and RT-qPCR, Western blot, and enzymatic assays were performed to further explore pathogenicity of the variant. The findings showed that the variant decreased transcription and protein expression levels and led to loss of enzymatic activity of the protein. The novel mutation c.265A > G inARSEwas thus the genetic cause for the phenotype presented by the fetus. The current study presents a prenatal case in Chinese population using functional analysis ofARSE, which helps the family to predict recurrence risks for future pregnancies and provides more information for understanding this rare condition. The findings show that WES is a feasible method for prenatal diagnosis of fetuses with CDPX1.
Life Expectancy in Marine Mammals Is Unrelated to Telomere Length but Is Associated With Body Size
Authors: Buddhachat Kittisak , Brown Janine L. , Kaewkool Manthanee , Poommouang Anocha , Kaewmong Patcharaporn , Kittiwattanawong Kongkiat , Nganvongpanit Korakot
Published: September 2021

Marine mammals vary greatly in size and lifespan across species. This study determined whether measures of adult body weight, length and relative telomere length were related to lifespan. Skin tissue samples (n = 338) were obtained from 23 marine mammal species, including four Mysticeti, 19 Odontoceti and one dugong species, and the DNA extracted to measure relative telomere length using real-time PCR. Life span, adult body weight, and adult body length of each species were retrieved from existing databases. The phylogenetic signal analysis revealed that body length might be a significant factor for shaping evolutionary processes of cetacean species through time, especially for genus Balaenoptera that have an enormous size. Further, our study found correlations between lifespan and adult body weight (R2 = 0.6465, p < 0.001) and adult body length (R2 = 0.6142, p ≤0.001), but no correlations with relative telomere length (R2 = −0.0476, p = 0.9826). While data support our hypothesis that larger marine mammals live longer, relative telomere length is not a good predictor of species longevity.
Characterization of a Cohort of Patients With LIG4 Deficiency Reveals the Founder Effect of p.R278L, Unique to the Chinese Population
Authors: Luo Xianze , Liu Qing , Jiang Jinqiu , Tang Wenjing , Ding Yuan , Zhou Lina , Yu Jie , Tang Xuemei , An Yunfei , Zhao Xiaodong
Published: September 2021

DNA ligase IV (LIG4) deficiency is an extremely rare autosomal recessive primary immunodeficiency disease caused by mutations in LIG4. Patients suffer from a broad spectrum of clinical problems, including microcephaly, growth retardation, developmental delay, dysmorphic facial features, combined immunodeficiency, and a predisposition to autoimmune diseases and malignancy. In this study, the clinical, molecular, and immunological characteristics of 15 Chinese patients with LIG4 deficiency are summarized in detail. p.R278L (c.833G>T) is a unique mutation site present in the majority of Chinese cases. We conducted pedigree and haplotype analyses to examine the founder effect of this mutation site in China. This suggests that implementation of protocols for genetic diagnosis and for genetic counseling of affected pedigrees is essential. Also, the search might help determine the migration pathways of populations with Asian ancestry.
Lymph Node-Targeted Synthetically Glycosylated Antigen Leads to Antigen-Specific Immunological Tolerance
Authors: Maulloo Chitavi D. , Cao Shijie , Watkins Elyse A. , Raczy Michal M. , Solanki Ani. S. , Nguyen Mindy , Reda Joseph W. , Shim Ha-Na , Wilson D. Scott , Swartz Melody A. , Hubbell Jeffrey A.
Published: September 2021

Inverse vaccines that tolerogenically target antigens to antigen-presenting cells (APCs) offer promise in prevention of immunity to allergens and protein drugs and treatment of autoimmunity. We have previously shown that targeting hepatic APCs through intravenous injection of synthetically glycosylated antigen leads to effective induction of antigen-specific immunological tolerance. Here, we demonstrate that targeting these glycoconjugates to lymph node (LN) APCs under homeostatic conditions leads to local and increased accumulation in the LNs compared to unmodified antigen and induces a tolerogenic state both locally and systemically. Subcutaneous administration directs the polymeric glycoconjugate to the draining LN, where the glycoconjugated antigen generates robust antigen-specific CD4+ and CD8+ T cell tolerance and hypo-responsiveness to antigenic challenge via a number of mechanisms, including clonal deletion, anergy of activated T cells, and expansion of regulatory T cells. Lag-3 up-regulation on CD4+ and CD8+ T cells represents an essential mechanism of suppression. Additionally, presentation of antigen released from the glycoconjugate to naïve T cells is mediated mainly by LN-resident CD8+ and CD11b+ dendritic cells. Thus, here we demonstrate that antigen targeting via synthetic glycosylation to impart affinity for APC scavenger receptors generates tolerance when LN dendritic cells are the cellular target.
Identification of Unique Peptides for SARS-CoV-2 Diagnostics and Vaccine Development by an In Silico Proteomics Approach
Authors: Kesarwani Veerbhan , Gupta Rupal , Vetukuri Ramesh Raju , Kushwaha Sandeep Kumar , Gandhi Sonu
Published: September 2021

Ongoing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus strains is posing new COVID-19 diagnosis and treatment challenges. To help efforts to meet these challenges we examined data acquired from proteomic analyses of human SARS-CoV-2-infected cell lines and samples from COVID-19 patients. Initially, 129 unique peptides were identified, which were rigorously evaluated for repeats, disorders, polymorphisms, antigenicity, immunogenicity, toxicity, allergens, sequence similarity to human proteins, and contributions from other potential cross-reacting pathogenic species or the human saliva microbiome. We also screened SARS-CoV-2-infected NBHE and A549 cell lines for presence of antigenic peptides, and identified paratope peptides from crystal structures of SARS-CoV-2 antigen-antibody complexes. We then selected four antigen peptides for docking with known viral unbound T-cell receptor (TCR), class I and II peptide major histocompatibility complex (pMHC), and identified paratope sequences. We also tested the paratope binding affinity of SARS-CoV T- and B-cell peptides that had been previously experimentally validated. The resultant antigenic peptides have high potential for generating SARS-CoV-2-specific antibodies, and the paratope peptides can be directly used to develop a COVID-19 diagnostics assay. The presented genomics and proteomics-based in-silico approaches have apparent utility for identifying new diagnostic peptides that could be used to fight SARS-CoV-2.
N6-Methyladenosine and Rheumatoid Arthritis: A Comprehensive Review
Authors: Wu Sha , Li Xiao-Feng , Wu Yuan-Yuan , Yin Su-Qin , Huang Cheng , Li Jun
Published: September 2021

Rheumatoid arthritis (RA), one of the most common autoimmune diseases, is characterized by immune cell infiltration, fibroblast-like synovial cell hyperproliferation, and cartilage and bone destruction. To date, numerous studies have demonstrated that immune cells are one of the key targets for the treatment of RA.N6-methyladenosine (m6A) is the most common internal modification to eukaryotic mRNA, which is involved in the splicing, stability, export, and degradation of RNA metabolism. m6A methylated-related genes are divided into writers, erasers, and readers, and they are critical for the regulation of cell life. They play a significant role in various biological processes, such as virus replication and cell differentiation by controlling gene expression. Furthermore, a growing number of studies have indicated that m6A is associated with the occurrence of numerous diseases, such as lung cancer, bladder cancer, gastric cancer, acute myeloid leukemia, and hepatocellular carcinoma. In this review, we summarize the history of m6A research and recent progress on RA research concerning m6A enzymes. The relationship between m6A enzymes, immune cells, and RA suggests that m6A modification offers evidence for the pathogenesis of RA, which will help in the development of new therapies for RA.