Category: Statistics

Hum Reprod. 2021 Apr 23:deab078. doi: 10.1093/humrep/deab078. Online ahead of print.

ABSTRACT

STUDY QUESTION: Do the epigenome-wide DNA methylation profiles of adolescents born from ART differ from the epigenome of naturally conceived counterparts?

SUMMARY ANSWER: No significant differences in the DNA methylation profiles of adolescents born from ART [IVF or ICSI] were observed when compared to their naturally conceived, similar aged counterparts.

WHAT IS KNOWN ALREADY: Short-term and longer-term studies have investigated the general health outcomes of children born from IVF treatment, albeit without common agreement as to the cause and underlying mechanisms of these adverse health findings. Growing evidence suggests that the reported adverse health outcomes in IVF-born offspring might have underlying epigenetic mechanisms.

STUDY DESIGN, SIZE, DURATION: The Growing Up Healthy Study (GUHS) is a prospective study that recruited 303 adolescents and young adults, conceived through ART, to compare various long-term health outcomes and DNA methylation profiles with similar aged counterparts from Generation 2 from the Raine Study. GUHS assessments were conducted between 2013 and 2017. The effect of ART on DNA methylation levels of 231 adolescents mean age 15.96 ± 1.59 years (52.8% male) was compared to 1188 naturally conceived counterparts, 17.25 ± 0.58 years (50.9% male) from the Raine Study.

PARTICIPANTS/MATERIALS, SETTING, METHODS: DNA methylation profiles from a subset of 231 adolescents (13-19.9 years) from the GUHS, generated using the Infinium Methylation Epic Bead Chip (EPIC) array were compared to 1188 profiles from the Raine Study previously measured using the Illumina 450K array. We conducted epigenome-wide association approach (EWAS) and tested for an association between the cohorts applying Firth’s bias reduced logistic regression against the outcome of ART versus naturally conceived offspring. Additionally, within the GUHS cohort, we investigated differences in methylation status in fresh versus frozen embryo transfers, cause of infertility as well as IVF versus ICSI conceived offspring. Following the EWAS analysis we investigated nominally significant probes using Gene Set Enrichment Analysis (GSEA) to identify enriched biological pathways. Finally, within GUHS we compared four estimates (Horvath, Hanuum, PhenoAge [Levine], and skin Horvath) of epigenetic age and their correlation with chronological age.

MAIN RESULTS AND THE ROLE OF CHANCE: Between the two cohorts, we did not identify any DNA methylation probes that reached a Bonferroni corrected P-value < 1.24E-0.7. When comparing IVF versus ICSI conceived adolescents within the GUHS cohort, after adjustment for participant age, sex, maternal smoking, multiple births, and batch effect, three methylation probes (cg15016734, cg26744878 and cg20233073) reached a Bonferroni correction of 6.31E-08. After correcting for cell count heterogeneity, two of the aforementioned probes remained significant and an additional two probes (cg 0331628 and cg 20235051) were identified. A general trend towards hypomethylation in the ICSI offspring was observed. All four measures of epigenetic age were highly correlated with chronological age and showed no evidence of accelerated epigenetic aging within their whole blood.

LIMITATIONS, REASONS FOR CAUTION: The small sample size coupled with the use of whole blood, where epigenetic differences may occur in other tissue. This was corrected by the utilized statistical method that accounts for imbalanced sample size between groups and adjusting for cell count heterogeneity. Only a small portion of the methylome was analysed and rare individual differences may be missed.

WIDER IMPLICATIONS OF THE FINDINGS: Our findings provide further reassurance that the effects of the ART manipulations occurring during early embryogenesis, existing in the neonatal period are indeed of a transient nature and do not persist into adolescence. However, we have not excluded that alternative epigenetic mechanisms may be at play.

STUDY FUNDING/COMPETING INTEREST(S): This project was supported by NHMRC project Grant no. 1042269 and R.J.H. received funding support from Ferring Pharmaceuticals Pty Ltd. R.J.H. is the Medical Director of Fertility Specialists of Western Australia and a shareholder in Western IVF. He has received educational sponsorship from Merck Sharp & Dohme Corp.- Australia, Merck-Serono Australia Pty Ltd and Ferring Pharmaceuticals Pty Ltd. P.B. is the Scientific Director of Concept Fertility Centre, Subiaco, Western Australia. J.L.Y. is the Medical Director of PIVET Medical Centre, Perth, Western Australia. The remaining authors have no conflicts of interest.

PMID:33890633 | DOI:10.1093/humrep/deab078

J Biomol Struct Dyn. 2021 Apr 23:1-20. doi: 10.1080/07391102.2021.1913231. Online ahead of print.

ABSTRACT

The dysregulation of cyclin-CDK6 interactions has been implicated in human breast cancer, providing a rationale for more therapeutic options. Recently, ATP-competitive inhibitors have been employed for managing breast cancer. These molecules, like most natural CDKs inhibitors, potently bind in the ATP-binding site of CDK6 to regulate trans-activation. Nonetheless, only a few numbers of these molecules are approved to mitigate breast cancer, thus, ensuring that the search for more selective inhibitors continues. In this study, we attempted to establish the selective predictive models for identifying potent CDK6 inhibitors against a human breast cancer cell-line using a dataset of fifty-two 1,3,4-thiadiazole derivatives. The significant eight descriptor hybrid QSAR models generated exhibited encouraging statistical attributes including R2> 0.70, Q²_LOO > 0.70, Q²_LMO > 0.60, Qfn2 > 0.6. Furthermore, the study designed new compounds based on the activity and structural basis for selectivity of compounds for CDK6. While demonstrating good potency and modest selectivity, the compound C16, which showed significantly high activity of 5.5607 µM and binding energy value of -9.0 Kcal/mol, was used as template for compounds design to generate 10 novel series of 1,3,4-thiadiazole analogues containing benzisoselenazolone scaffolds, with significant pharmacological activity and better selectivity for CDK6. By our rationale, four of the designed compounds (C16b, C16h, C16i, and C16j) with activity values of 6.2584 µM, 6.7812 µM, 6.4717 µM, and 6.2666 µM respectively, and binding affinities of -10.0 kcal/mol, -9.9 kcal/mol, -9.9 kcal/mol, and -9.9 kcal/mol respectively, may emerge as therapeutic options for breast cancer treatment after extensive in vitro and in vivo studies.Communicated by Ramaswamy H. Sarma.

PMID:33890551 | DOI:10.1080/07391102.2021.1913231

Zygote. 2021 Apr 23:1-10. doi: 10.1017/S0967199420000933. Online ahead of print.

ABSTRACT

Dynamic changes in microRNAs in oocyte and cumulus cells before and after maturation may explain the spatiotemporal post-transcriptional gene regulation within bovine follicular cells during the oocyte maturation process. miR-20a has been previously shown to regulate proliferation and differentiation as well as progesterone levels in cultured bovine granulosa cells. In the present study, we aimed to demonstrate the function of miR-20a during the bovine oocyte maturation process. Maturation of cumulus-oocyte complexes (COCs) was performed at 39°C in an humidified atmosphere with 5% CO2 in air. The expression of miR-20a was investigated in the cumulus cells and oocytes at 22 h post culture. The functional role of miR-20a was examined by modulating the expression of miR-20a in COCs during in vitro maturation (IVM). We found that the miR-20a expression was increased in cumulus cells but decreased in oocytes after IVM. Overexpression of miR-20a increased the oocyte maturation rate. Even though not statistically significant, miR-20a overexpression during IVM increased progesterone levels in the spent medium. This was further supported by the expression of STAR and CYP11A1 genes in cumulus cells. The phenotypes observed due to overexpression of miR-20a were validated by BMP15 supplementation during IVM and subsequent transfection of BMP15-treated COCs using miR-20a mimic or BMPR2 siRNA. We found that miR-20a mimic or BMPR2 siRNA transfection rescued BMP15-reduced oocyte maturation and progesterone levels. We concluded that miR-20a regulates oocyte maturation by increasing cumulus cell progesterone synthesis by simultaneous suppression of BMPR2 expression.

PMID:33890561 | DOI:10.1017/S0967199420000933

Mayo Clin Proc. 2020 Oct 21:S0025-6196(20)31119-8. doi: 10.1016/j.mayocp.2020.08.051. Online ahead of print.

ABSTRACT

OBJECTIVE: To assess the presence of clinically actionable results and other genetic findings in an otherwise healthy population of adults seen in a medical practice setting and offered “predictive” genomic testing.

PATIENTS AND METHODS: In 2014, a predictive genomics clinic for generally healthy adults was launched through the Mayo Clinic Executive Health Program. Self-identified interested patients met with a genomic nurse and genetic counselor for pretest advice and education. Two genome sequencing platforms and one gene panel-based health screen were offered. Posttest genetic counseling was available for patients who elected testing. From March 1, 2014, through June 1, 2019, 1281 patients were seen and 301 (23.5%) chose testing. Uptake rates increased to 36.3% [70 of 193]) in 2019 from 11.8% [2 of 17] in 2014. Clinically actionable results and genetic findings were analyzed using descriptive statistics.

RESULTS: Clinically actionable results were detected in 11.6% of patients (35 of 301), and of those, 51.7% (15 of 29) with a cancer or cardiovascular result = did not have a personal or family history concerning for a hereditary disorder. The most common actionable results were in the BCHE, BRCA2, CHEK2, LDLR, MUTYH, and MYH7 genes. A carrier of at least one recessive condition was found in 53.8% of patients (162 of 301). At least one variant associated with multifactorial disease was found in 44.5% (134 of 301) (eg, 25 patients were heterozygous for the F5 factor V Leiden variant associated with thrombophilia risk).

CONCLUSION: Our predictive screening revealed that 11.6% of individuals will test positive for a clinically actionable, likely pathogenic/pathogenic variant. This finding suggests that wider knowledge and adoption of predictive genomic services could be beneficial in medical practice, although additional studies are needed.

PMID:33890576 | DOI:10.1016/j.mayocp.2020.08.051

Curr Med Res Opin. 2021 Apr 23:1. doi: 10.1080/03007995.2021.1920899. Online ahead of print.

ABSTRACT

OBJECTIVES: This study examined the incidence and predictors of antimuscarinic medication use including non-selective antimuscarinics among older adults with dementia and overactive bladder (OAB).

METHODS: The study used a new-user cohort design involving older adults (≥65 years) with dementia and OAB based on 2013-2015 Medicare Data. Antimuscarinics included non-selective (oxybutynin, tolterodine, trospium, fesoterodine) and selective (solifenacin, darifenacin) medications. Descriptive statistics and multivariable logistic regression models were used to determine the incidence and predictors of new antimuscarinic use including non-selective antimuscarinics, respectively.

RESULTS: Of the 3.38 million Medicare beneficiaries with dementia, over one million (1.05) had OAB (31.03%). Of those, 287,612 (27.39%) were reported as prevalent antimuscarinics users. After applying continuous eligibility criteria, 21,848 (10.34%) incident antimuscarinic users were identified [77.6% non-selective; 22.4% selective]. Most frequently reported antimuscarinics were oxybutynin (56.3%) and solifenacin (21.4%). Multivariable analysis revealed that patients ≥75 years, of black race, and those with schizophrenia, epilepsy, delirium, and Elixhauser’s score were less likely to initiate antimuscarinics. Women, those with abnormal involuntary moments, bipolar disorder, gastroesophageal reflux disease, insomnia, irritable bowel syndrome, muscle spasm/low back pain, neuropathic pain, benign prostatic hyperplasia, falls/fractures, myasthenia gravis, narrow-angle glaucoma, Parkinson’s disease, syncope, urinary tract infection and vulvovaginitis were more likely to initiate antimuscarinics. Further, patients with muscle spasms/low back pain, benign prostatic hyperplasia and those taking higher anticholinergics had lower odds of receiving non-selective antimuscarinics, whereas white patients, black patients and those with schizophrenia and delirium were more likely to receive them.

CONCLUSIONS: Nearly one-third of dementia patients had OAB and over one-fourth of them used antimuscarinics. Majority of the incident users were prescribed non-selective antimuscarinics with several demographic and clinical factors contributing to their prescribing. Given the high prevalence of OAB among dementia patients, there is a need to optimize their antimuscarinics use, considering their vulnerability for anticholinergic adverse effects.

PMID:33890538 | DOI:10.1080/03007995.2021.1920899

Curr Med Res Opin. 2021 Apr 23:1. doi: 10.1080/03007995.2021.1920900. Online ahead of print.

ABSTRACT

INTRODUCTION: Favipiravir is a repurposed drug to treat coronavirus 2019 (COVID-19). Due to a lack of available real-world data, we assessed its effectiveness and safety in moderately to critically ill COVID-19 patients.

METHODS: This retrospective study was conducted in two public/specialty hospitals in Saudi Arabia. We included patients (≥ 18 years) admitted April-August 2020 with confirmed SARS-CoV-2 diagnosed by real-time polymerase chain reaction (RT-PCR) from nasopharyngeal swab. Patients received either favipiravir (1800 mg or 1600 mg BID loading dose, followed by 800 mg or 600 mg QD) or supportive-care treatment. Patients were excluded if they were outside the study period, classified as having a mild form of the disease per WHO criteria, or had an incomplete patient file. Kaplan-Meier (KM) models were used to estimate median time to discharge. Discharge ratios, progression to mechanical ventilation, and mortality outcomes were estimated across the severity spectrum using Cox proportional-hazards models. As a sensitivity analysis, we performed propensity score-matching (PSM) analysis.

RESULTS: Overall, median time to discharge was 10 days (95%CI =9-10) in the favipiravir arm versus 15 days (95%CI =14-16) in the supportive-care arm. The accelerated discharge benefit was seen across the COVID-19 spectrum of severity. The adjusted discharge ratio was 1.96 (95%CI =1.56-2.46). Progression to mechanical ventilation was slower with favipiravir (HR_adj=0.10, 95%CI =0.04-0.29). There was no significant effect on mortality (HR_adj=1.56, 95%CI =0.73-3.36). There was a statistically non-significant trend toward worse outcomes in the critical category (HR_adj=2.80, 95%CI =0.99-7.89). Age was an independent risk factor for mortality in mechanically ventilated patients. PSM analyses confirmed these findings.

CONCLUSION: Favipiravir was associated with clinical benefits, including accelerated discharge rate and less progression to mechanical ventilation; however, no overall mortality benefits were seen across the severity spectrum.

PMID:33890544 | DOI:10.1080/03007995.2021.1920900

J Appl Anim Welf Sci. 2021 Apr 23:1-29. doi: 10.1080/10888705.2021.1902811. Online ahead of print.

ABSTRACT

This research focused on different aspects of play behavior including ethogram, ontogeny, and individual differences, in one male and one female captive bottlenose dolphin calves (Tursiops truncatus) from November 2003 to June 2004. We presented the first peer-reviewed description of a play ethogram in bottlenose dolphin calves whose behaviors were grouped into three hierarchical levels: two categories: solitary and social play; four subcategories: locomotor, object, bubble play, and in the presence of humans, and 35 entries. It was conducted in two phases: the descriptive phase – from 3 to 5 months old – with 29 entries and the quantitative phase – from 6 to 10 months old -with six entries. All social and solitary locomotor behaviors appeared when animals were 3 months old meanwhile more complex behaviors concerning playing with objects, bubbles, and in the presence of humans were observed for 6 months old. There were no statistically significant intra-individual and inter-individual differences in the play behavioral diversity, in the time invested in play and in the Shannon’s evenness index. However, we observed statistically significant inter-individual but not intra-individual differences for the Shannon’s diversity index.

PMID:33890533 | DOI:10.1080/10888705.2021.1902811

Strabismus. 2021 Apr 23:1-7. doi: 10.1080/09273972.2021.1914677. Online ahead of print.

ABSTRACT

To evaluate the effect of monocular blur induced by Bangerter filters (BF) on visual acuity (VA) and stereoacuity. Monocular blur was induced by a range of Trusetal BF strengths (0.1, 0.2, 0.4, 0.6) to 23 visually normal adult volunteers (aged 18-25, mean age 20.33 ± 1.79 years). The right monocular and binocular logMAR VA and distance stereoacuity using the FD2 were measured at 6 m with no filter (baseline) and with each filter strength. The order of testing the filters was randomized. Results were analyzed using one factor repeated measures ANOVAs, t-tests using Bonferroni correction and Pearson’s product moment correlation. All filters degraded right monocular distance VA from baseline, but less significantly between the 0.4 and 0.6 filters than the other filters (p < .05 and p < .001, respectively). Degradation was in concordance with the labeled filter density, excluding filter strength 0.4. For all filter strengths, binocular VA was significantly but not clinically reduced from baseline (p < .05). Filters statistically and clinically significantly degraded distance stereoacuity from baseline (p < .001). A significant negative correlation existed between the mean degraded right monocular VA and stereoacuity (r = -0.998, p < .02). Trusetal BF significantly reduced monocular VA and stereoacuity but binocular VA remained within normal levels. The impact on VA and stereoacuity in a normal population can be of clinical relevance when applied to the use of BF for management of amblyopia and intractable diplopia. It is advised that clinicians ensure the desired level of degradation has been achieved in clinic before prescribing a particular filter strength.

PMID:33890535 | DOI:10.1080/09273972.2021.1914677

Strabismus. 2021 Apr 23:1-8. doi: 10.1080/09273972.2021.1914685. Online ahead of print.

ABSTRACT

INTRODUCTION: Alcohol Dependence Syndrome (ADS) is defined as excessive alcohol consumption accompanied by psychological, physical, social, and economic disorders. Alcohol consumption affects motor and proprioceptive functions, decreasing motor and cognitive functions and causing attention deficits. We aim to evaluate visual function and attention, and psychological profiles in consumer and abstainer ADS patients.

METHODS: This quantitative, descriptive, cross-sectional and correlational study evaluates visual function in a sample of ADS patients. The Portuguese version of the Brief Symptom Inventory was used to assess patients’ psychological status. The orthoptic examination protocol for visual function consisted of 11 standardized tests: VA for distance and near, ocular movements, near convergence and accommodation point, cover and prismatic cover tests, fusional vergence for distance and near, near stereoacuity, chromatic vision, contrast sensitivity and visual attention.

RESULTS: The sample included 176 patients. 121 were consumers and 55 were abstainers, aged between 31 and 72. The most affected parameters of visual function were visual acuity (80.39%), contrast sensitivity (67.50%), convergence at distance (66.44%) and near stereopsis (62.75%). Visual function was impacted in both groups. Regarding psychological status, consumers had higher averages for the Depression subscale, followed by Paranoid Ideation and Obsession. Abstainers had the highest averages in the Obsession subscale, followed by Paranoid Ideation and Depression. Statistically significant differences existed between the groups in the subscales for depression (p=.046) and paranoid ideation (p =.042).

CONCLUSION: Changes in visual function and attention, as well as psychopathological function, should be considered in the rehabilitation of ADS patients.

PMID:33890536 | DOI:10.1080/09273972.2021.1914685

Phys Act Nutr. 2021 Mar;25(1):30-34. doi: 10.20463/pan.2021.0005. Epub 2021 Mar 31.

ABSTRACT

PURPOSE: Many studies have observed a high prevalence of erectile dysfunction among individuals performing physical activity in less leisure-time. However, this relationship in patients with type 2 diabetic patients is not well studied. In exposure outcome studies with ordinal outcome variables, investigators often try to make the outcome variable dichotomous and lose information by collapsing categories. Several statistical models have been developed to make full use of all information in ordinal response data, but they have not been widely used in public health research. In this paper, we discuss the application of two statistical models to determine the association of physical inactivity with erectile dysfunction among patients with type 2 diabetes.

METHODS: A total of 204 married men aged 20-60 years with a diagnosis of type 2 diabetes at the outpatient unit of the Department of Endocrinology at PSG hospitals during the months of May and June 2019 were studied. We examined the association between physical inactivity and erectile dysfunction using proportional odds ordinal logistic regression models and continuation ratio models.

RESULTS: The proportional odds model revealed that patients with diabetes who perform leisure time physical activity for over 40 minutes per day have reduced odds of erectile dysfunction (odds ratio=0.38) across the severity categories of erectile dysfunction after adjusting for age and duration of diabetes.

CONCLUSION: The present study suggests that physical inactivity has a negative impact on erectile function. We observed that the simple logistic regression model had only 75% efficiency compared to the proportional odds model used here; hence, more valid estimates were obtained here.

PMID:33887826 | DOI:10.20463/pan.2021.0005