Tag: nevin manimala

J Mol Evol. 2022 Jun 2. doi: 10.1007/s00239-022-10058-0. Online ahead of print.

ABSTRACT

We draw attention to an under-appreciated simulation method for generating artificial data in a phylogenetic context. The approach, which we refer to as jump-chain simulation, can invoke rich models of molecular evolution having intractable likelihood functions. As an example, we simulate data under a context-dependent model allowing for CpG hypermutability and show how such a feature can mislead common codon models used for detecting positive selection. We discuss more generally how this method can serve to elucidate the ways by which currently used models for inference are susceptible to violations of their underlying assumptions. Finally, we show how the method could serve as an inference engine in the Approximate Bayesian Computation framework.

PMID:35652926 | DOI:10.1007/s00239-022-10058-0

Acta Obstet Gynecol Scand. 2022 Jun 2. doi: 10.1111/aogs.14386. Online ahead of print.

ABSTRACT

INTRODUCTION: Glucocorticoid (GC) -induced fetal programming of the activity of the hypothalamus-pituitary-adrenal axis (HPAA) and its associated cognitive and behavioral consequences in later life have been well characterized in several animal species. However, information on humans is scarce. In this study, we examined HPAA activity markers and associated outcomes at 8 to 9 years of age among children prenatally exposed to GC for suspected preterm birth. Our hypothesis was that antenatal exposure to the betamethasone (BM) is associated with exacerbation of HPAA activity in childhood.

MATERIAL AND METHODS: Prospective observational study in 31 children whose mothers received single (n = 19) or multiple (n = 12) courses of BM for threatened preterm birth but born with normal weight appropriate for the gestational age (median 37+⁶ weeks of gestation) compared with 38 non-exposed, age-matched children. Primary end point was the activity of the HPAA in response to the Trier Social Stress Test. Secondary end points were changes in autonomic nervous system (ANS) activity, cognitive performance (IQ), attention-deficit/hyperactivity disorder (ADHD) symptoms, and electrocortical activity (EEG).

RESULTS: There was no statistically significant difference in HPAA activity markers between antenatal BM exposed and unexposed groups. ANS activity in BM-exposed children shifted towards a higher parasympathetic tone reflected by a higher overall high-frequency band power of heart rate variability. IQ scores were within normal limits for both groups; however, BM-exposed children had lower IQ scores than the unexposed group. BM-exposed group had marginally more ADHD core symptoms and increased electrocortical activity in the occipital brain region compared with controls. A monotonic dose-response relationship between BM exposure and activity of the ANS and IQ was estimated in post-hoc analyses.

CONCLUSIONS: Antenatal exposure to BM in the context of threatened preterm birth was not associated with changes in HPAA activity in childhood. However, BM exposure may be associated with changes in ANS activity. Antenatal GC prophylaxis is a valuable and often life-saving therapy, but its prescription may warrant a well-balanced risk-benefit assessment.

PMID:35652410 | DOI:10.1111/aogs.14386

Anticancer Agents Med Chem. 2022 Jun 1. doi: 10.2174/1871520622666220601115458. Online ahead of print.

ABSTRACT

Purpose To investigate the safety and efficacy of lobaplatin-TACE in the treatment of primary hepatocellular carcinoma. Method The data of 536 patients who underwent TACE in the interventional department from January 2016 to January 2020 were collected. Patients were divided into two groups according to the chemotherapeutic drugs used in TACE.: epirubicin-TACE group(N = 260), lobaplatin-TACE group(N = 276). Primary study endpoint: (1) The tumor response after TACE; (2)The survival rates ; Secondary study endpoints:(1)Changes of liver function and blood routine before and after TACE;(2)Occurrence of post-embolization syndrome and infection after TACE. Results The ORR was 35.0% in epirubicin-TACE group and 51.1% in lobaplatin-TACE group(P=0.001). The DCR was 73.1% in epirubicin-TACE group and 82.2% in lobaplatin-TACE group(P=0.011). The 6-month, 9-month, 12-month, and 15-month survival rates were higher in the lobaplatin-TACE group than in the epirubicin-TACE group(P=0.029,P=0.001,P=0.005,P=0.002). mOS: Epirubicin-TACE group,14.8 months; Lobaplatin-TACE group,18.6 months (P =0.007). mPFS: Epirubicin-TACE group,9.5 months; Lobaplatin-TACE group,12.8 months (P =0.000). There was no statistical difference in ALT, AST, total bilirubin and Leucocyte after TACE between the two groups (P=0.343,P=0.368,P=0.288,P=0.359). The platelet decrease after TACE was more significant in the lobaplatin-TACE group than in the epirubicin-TACE group (P=0.046). There was no statistical difference in the incidence rate of abdominal pain, fever and infection after TACE between the two groups (P=0.502,P=0.602,P=0.726).The incidence of vomiting after TACE in the lobaplatin-TACE group was higher than that in the epirubicin-TACE group (P=0.003). Conclusion Lobaplatin-TACE has higher tumor response rate and survival rate.Lobaplatin-TACE is a safe and effective treatment strategy,it is worthy of clinical application.

PMID:35652401 | DOI:10.2174/1871520622666220601115458

Inquiry. 2022 Jan-Dec;59:469580221098755. doi: 10.1177/00469580221098755.

ABSTRACT

Courses on basic life support (BLS) and automated external defibrillator (AED) in schools lead to increase in knowledge but its retention is less well explored. We aimed to explore the long-term retention of knowledge and practical skills among schoolchildren after a BLS and AED course to be able to tailor future courses accordingly. Study was conducted in 3 parts and included 823 seventh and ninth graders from different elementary schools in Maribor, Slovenia. In Study 1 (n=611) we assessed students’ baseline knowledge and immediate knowledge gain after our BLS and AED course with a validated questionnaire; in Study 2 (n=116) we assessed retention of gained knowledge and skills after 5 months with a modified Cardiff test and Little Anne QCPR manikin; in Study 3 (n=96) we assessed retention of knowledge 2 years after the course. Mean differences in knowledge before and after the course in Study 1 and between studies were analyzed using paired t-tests and independent t-tests. Differences between individual question scores at different time points were compared using Mann – Whitney U test. A two-sided P<0,05 was considered significant. Practical skills retention was presented with descriptive statistics. Knowledge gain was significant immediately after the course with 83% correct answers compared to 60% at baseline. Scores dropped significantly after 5 months (73%) and after 2 years (75%), but remained significantly better than at baseline (P<0.001). Practical skills perfomance score as per Cardiff test after 5 months was 63%. Overall BLS performance score as per QCPR app was 59%, with an overall cardio score of 77% (average compression rate: 124/min and depth: 52 mm) and ventilation score of 44%. This study showed that long term retention of theoretical knowledge was satisfying whereas poor practical skills performance after 5 months calls for a more intense practical training on repeat courses.

PMID:35652386 | DOI:10.1177/00469580221098755

Anticancer Agents Med Chem. 2022 Jun 1. doi: 10.2174/1871520622666220601093452. Online ahead of print.

ABSTRACT

Background C-KIT is a receptor tyrosine kinase with oncogenic properties overexpressed in PCa cases. Through the use of an alternative promoter, a truncated c-KIT protein (tr-KIT) of 30-50 kDa is generated, lacking the extracellular and transmembrane domain. Tr-KIT promotes the formation of a multi-molecular complex composed by Fyn, Plcγ1 and Sam68. Imatinib blocks the activity of full-length c-KIT but has no effect on tr-KIT. LNCaP is the human PCa cell line that shows tr-KIT overexpression and PC3 does not show tr-KIT overexpression. miR-128/193a-5p/494 are miRNAs targeting FYN, PLCγ1 and SAM68 combinatorily. The question of the study is that: can miR-128/193a-5p/494 be related with imatinib resistance in PCa? Method LNCaP and PC3 cells were treated with imatinib in IC50 doses. Before and after imatinib administration, RNA was isolated and cDNA conversion was performed. By qPCR analysis, expression changes of tr-KIT specific pathway elements and miR-128/193a-5p/494 analyzed before and after imatinib administration. Results After imatinib administration, miR-128/193a-5p/494 were overexpressed statistically significantly in LNCaP cells while they were downregulated statistically significantly in PC3 cells (p<0.05). Also, FYN was upregulated in LNCaP cells (p<0.05) but there was no change in PC3 after imatinib administration. Conclusion Especially upregulation of FYN may sponge miR128/193a-5p/494 and downregulate their transcriptional activity in LNCaP cells having tr-KIT acitivity. So, miR-128/193a-5p/494 may have critical role in imatinib resistance via tr-KIT pathway.

PMID:35652400 | DOI:10.2174/1871520622666220601093452

Stroke. 2022 Jun 2:101161STROKEAHA121038035. doi: 10.1161/STROKEAHA.121.038035. Online ahead of print.

ABSTRACT

BACKGROUND: The risk of aneurysmal subarachnoid hemorrhage (aSAH) is increased in postmenopausal women compared with men of similar age, suggesting a role for sex hormones. We aimed to explore whether sex hormones, and age at menarche/menopause have a causal effect on aSAH risk by conducting a 2-sample MR study (Mendelian randomization).

METHODS: We obtained sex-specific genetic instruments for serum estradiol, bioavailable testosterone (BioT), SHBG (sex hormone-binding globulin), and age at menarche/menopause from genome-wide association studies. The associated sex-specific aSAH risk was estimated with inverse-variance weighted MR analyses with various statistical sensitivity analyses. Multivariable and cluster MR analyses were performed for BioT and SHBG to account for a genetic and phenotypic correlation between the 2 exposures. The clusters represented (1) single-nucleotide polymorphisms primarily increasing SHBG, with secondary decreasing effects on BioT, and (2) single-nucleotide polymorphisms affecting BioT without affecting SHBG.

RESULTS: Univariable MR analyses showed an 18% increased aSAH risk among women per 1-SD increase in genetically determined SHBG levels (odds ratio, 1.18 [95% CI, 1.05-1.34]; P=0.007). Suggestive evidence was identified for a 27% decreased risk of aSAH among women per 1-SD increase in BioT (odds ratio, 0.73 [95% CI, 0.55-0.95]; P=0.02). The latter association disappeared in cluster analysis when only using SHBG-independent variants. MR analyses with variants from the cluster with primary SHBG effects and secondary (opposite) BioT-effects yielded a statistically significant association (odds ratio, 1.21 [95% CI, 1.05-1.40]; P=0.008). No other causal associations were identified.

CONCLUSIONS: Genetic predisposition to elevated serum levels of SHBG, with secondary lower serum BioT levels, is associated with an increased aSAH risk among women, suggesting that SHBG and BioT causally elevate aSAH risk. Further studies are required to elucidate the underlying mechanisms and their potential as an interventional target to lower aSAH incidence.

PMID:35652345 | DOI:10.1161/STROKEAHA.121.038035

Circulation. 2022 Jun 2:101161CIRCULATIONAHA121055484. doi: 10.1161/CIRCULATIONAHA.121.055484. Online ahead of print.

ABSTRACT

BACKGROUND: Cardiovascular health (CVH) from young adulthood is strongly associated with an individual’s future risk of cardiovascular disease (CVD) and total mortality. Defining epigenomic biomarkers of lifelong CVH exposure and understanding their roles in CVD development may help develop preventive and therapeutic strategies for CVD.

METHODS: In 1085 CARDIA study (Coronary Artery Risk Development in Young Adults) participants, we defined a clinical cumulative CVH score that combines body mass index, blood pressure, total cholesterol, and fasting glucose measured longitudinally from young adulthood through middle age over 20 years (mean age, 25-45). Blood DNA methylation at >840 000 methylation markers was measured twice over 5 years (mean age, 40 and 45). Epigenome-wide association analyses on the cumulative CVH score were performed in CARDIA and compared in the FHS (Framingham Heart Study). We used penalized regression to build a methylation-based risk score to evaluate the risk of incident coronary artery calcification and clinical CVD events.

RESULTS: We identified 45 methylation markers associated with cumulative CVH at false discovery rate <0.01 (P=4.7E-7-5.8E-17) in CARDIA and replicated in FHS. These associations were more pronounced with methylation measured at an older age. CPT1A, ABCG1, and SREBF1 appeared as the most prominent genes. The 45 methylation markers were mostly located in transcriptionally active chromatin and involved lipid metabolism, insulin secretion, and cytokine production pathways. Three methylation markers located in genes SARS1, SOCS3, and LINC-PINT statistically mediated 20.4% of the total effect between CVH and risk of incident coronary artery calcification. The methylation risk score added information and significantly (P=0.004) improved the discrimination capacity of coronary artery calcification status versus CVH score alone and showed association with risk of incident coronary artery calcification 5 to 10 years later independent of cumulative CVH score (odds ratio, 1.87; P=9.66E-09). The methylation risk score was also associated with incident clinical CVD in FHS (hazard ratio, 1.28; P=1.22E-05).

CONCLUSIONS: Cumulative CVH from young adulthood contributes to midlife epigenetic programming over time. Our findings demonstrate the role of epigenetic markers in response to CVH changes and highlight the potential of epigenomic markers for precision CVD prevention, and earlier detection of subclinical CVD, as well.

PMID:35652342 | DOI:10.1161/CIRCULATIONAHA.121.055484

Int J Soc Psychiatry. 2022 Jun 2:207640221099416. doi: 10.1177/00207640221099416. Online ahead of print.

ABSTRACT

BACKGROUND: Although technologies (including information, e-learning, and communication) have been daily employed by University students in the last years, the COVID-19 pandemic has led to a considerable increase in their use. Technostress is a modern term referring to levels of stress caused by the prolonged exposure to technology.

AIM: The aim of this study is to assess the technostress and related anxiety and depression among Paraguayan University students, describing their sociodemographic characteristics and relevant associations.

METHODS: A cross-sectional and descriptive study has been conducted. Participants were recruited through an Internet-based survey. Technostress, anxiety, and depression have been assessed with the Technostress Questionnaire (TechQ), the Generalized Anxiety Disorder-7 (GAD-7) questionnaire, and the Patient Health Questionnaire-2 (PHQ-2), respectively.

RESULTS: A total of 378 participants were included, 74.1% of whom were women. According to the TechQ scores, 47.4% of the participants reported a low/moderate level of technostress whereas 5.2% showed severe scores. About 58.5% of participants reported a GAD-7 score ⩾10, meeting diagnostic criteria for generalized anxiety. About 60.3% scored ⩾3 at the PHQ-2 reporting significant levels of depression. Technostress has been significantly associated with levels of anxiety (p < .001) as well as depression (p < .001).

CONCLUSION: Our results suggest further research regarding the implications of technostress on the well-being of University students. Specific measures aimed to improve students’ coping with the challenges of technology and technostress should be promoted.

PMID:35652309 | DOI:10.1177/00207640221099416

Adv Clin Exp Med. 2022 Jun 2. doi: 10.17219/acem/149988. Online ahead of print.

ABSTRACT

BACKGROUND: Air pollution has a negative influence on neurological and psychiatric disorders. However, findings concerning the impact of air pollution on depression remain inconclusive. A deeper insight into these associations is warranted.

OBJECTIVES: To evaluate the impact of long-term exposure to air pollution on the incidence of depression among residents of 13 counties in the Lower Silesia region of Poland.

MATERIAL AND METHODS: We used data on cases of depression from the National Health Fund (Narodowy Fundusz Zdrowia – NFZ) from 13 counties of Lower Silesia between January 1, 2010, and December 31, 2015. Patients with a confirmed diagnosis of depression were included. Data on air pollution levels were extracted from the Chief Inspectorate of Environmental Protection (Główny Inspektorat Ochrony Środowiska – GIOŚ), and demographic data were extracted from Statistics Poland (Główny Urząd Statystyczny – GUS).

RESULTS: The percentage of people diagnosed with depression over the 6-year study period depended on the group of counties homogeneous in terms of air pollution exposure (p < 0.001). We showed statistically significant correlations between different depression diagnoses and exposure to air pollutants. Elevated concentration of airborne fine particles with a diameter less than 2.5 μm (PM2.5) and carbon monoxide (CO), and low benzo(a)pyrene (BaP), sulfur dioxide (SO2) and cadmium (Cd) levels were independent risk factors for major depressive episodes with psychotic symptoms (F32.3). There was a significant negative correlation between ozone (O3) levels and depression incidence.

CONCLUSIONS: Regions with heavy air pollution had a higher incidence of depression. There is a significant association between the exposure to air pollutants and different depression diagnoses.

PMID:35652299 | DOI:10.17219/acem/149988

Turk Neurosurg. 2022 Mar 25. doi: 10.5137/1019-5149.JTN.38252-22.3. Online ahead of print.

ABSTRACT

AIM: The present study aimed to evaluate the effects of favipiravir (FVP) on cell viability and cytotoxicity in human degenerated primary intervertebral disc (IVD) tissue cell cultures treated with FVP. Furthermore, the protein expressions of hypoxia-inducible factor 1 alpha (HIF-1α), nuclear factor-kappa-b (NF-κB), and interleukin-1 beta (IL-1β) were also examined.

MATERIAL AND METHODS: Untreated cell cultures served as the control group, named group 1. Cell cultures treated with FVP served as the study group, named group 2. Pharmacomolecular analyses were performed in all groups at 0, 24, 48, and 72 hours (h). Obtained data were evaluated statistically.

RESULTS: Cell proliferation was suppressed in the FVP-treated samples compared to the control group samples at 24 and 72 h, and this was statistically significant (P 0.05). Decreased or increased protein expression levels of HIF-1 NF-κB, and IL-1β in FVP-treated samples may be an indication of suppression in anabolic events as well as proliferation in IVD cultures. FVP administration showed that AF/NP cells in a culture medium may induce a strong inflammatory response to FVP. This strong inflammatory response is likely to cause slowed proliferation. It may also be a trigger for many catabolic events. NF-B expression increased within the first 24 h and then decreased rapidly. Based on the data obtained, it may be suggested that the rapidly increasing NF-kB may have stimulated the expression of many antiproliferative genes.

CONCLUSION: The suppression of IL-1β and NF-kB protein expressions in IVD cells treated with FVP is important in the treatment of IVD degeneration (IDD). If the protein expression of HIF-1α could be increased along with the suppression of IL-1β and NF-kB, FVP would perhaps be a promising pharmacological agent in the treatment of IDD.

PMID:35652184 | DOI:10.5137/1019-5149.JTN.38252-22.3