Tag: pubmed

Hum Genomics. 2021 Jul 13;15(1):44. doi: 10.1186/s40246-021-00342-3.

ABSTRACT

BACKGROUND: Previous research in autism and other neurodevelopmental disorders (NDDs) has indicated an important contribution of protein-coding (coding) de novo variants (DNVs) within specific genes. The role of de novo noncoding variation has been observable as a general increase in genetic burden but has yet to be resolved to individual functional elements. In this study, we assessed whole-genome sequencing data in 2671 families with autism (discovery cohort of 516 families, replication cohort of 2155 families). We focused on DNVs in enhancers with characterized in vivo activity in the brain and identified an excess of DNVs in an enhancer named hs737.

RESULTS: We adapted the fitDNM statistical model to work in noncoding regions and tested enhancers for excess of DNVs in families with autism. We found only one enhancer (hs737) with nominal significance in the discovery (p = 0.0172), replication (p = 2.5 × 10^-3), and combined dataset (p = 1.1 × 10^-4). Each individual with a DNV in hs737 had shared phenotypes including being male, intact cognitive function, and hypotonia or motor delay. Our in vitro assessment of the DNVs showed they all reduce enhancer activity in a neuronal cell line. By epigenomic analyses, we found that hs737 is brain-specific and targets the transcription factor gene EBF3 in human fetal brain. EBF3 is genome-wide significant for coding DNVs in NDDs (missense p = 8.12 × 10^-35, loss-of-function p = 2.26 × 10^-13) and is widely expressed in the body. Through characterization of promoters bound by EBF3 in neuronal cells, we saw enrichment for binding to NDD genes (p = 7.43 × 10^-6, OR = 1.87) involved in gene regulation. Individuals with coding DNVs have greater phenotypic severity (hypotonia, ataxia, and delayed development syndrome [HADDS]) in comparison to individuals with noncoding DNVs that have autism and hypotonia.

CONCLUSIONS: In this study, we identify DNVs in the hs737 enhancer in individuals with autism. Through multiple approaches, we find hs737 targets the gene EBF3 that is genome-wide significant in NDDs. By assessment of noncoding variation and the genes they affect, we are beginning to understand their impact on gene regulatory networks in NDDs.

PMID:34256850 | DOI:10.1186/s40246-021-00342-3

J Pharm Policy Pract. 2021 Jul 13;14(1):60. doi: 10.1186/s40545-021-00346-3.

ABSTRACT

BACKGROUND: Each year, the French independent bulletin Prescrire publishes a list of medicines, “Drugs to avoid”, that should not be used in clinical practice as their risk-to-benefit ratio is unfavourable. This study assessed the market approval, reimbursement and use of these medicines in Australia.

METHODS: The approval status of the medicines included in 2019 Prescrire “Drugs to avoid” list was assessed by searching the Australian Register of Therapeutic Goods website. Funding status was assessed on the Pharmaceutical Benefits Scheme (PBS) website, the Australian public insurance system. Use levels were determined by examining governmental reports on prescribing rates including the Australian Statistics on Medicines (ASM) reports, drug use reports released by the Drug Utilisation Sub Committee (DUSC) and PBS statistics.

RESULTS: Of the 93 medicines included in the Prescrire 2019 “Drug to avoid” list included, 57 (61%) were approved in Australia in 2019 including 9 (16%) that were sold as over-the-counter medicines, 35 (38%) were listed on the PBS, 22 (24%) were registered but not listed on the PBS. Although most of these medicines were used infrequently, 16 (46%) had substantial use despite serious safety concerns. Dipeptidyl peptidase-4 (DPP-4) inhibitors were used by 22% of patients receiving a treatment for diabetes in 2016. More than 50,000 patients received an anti-dementia medicine in 2014, a 19% increase since 2009. Denosumab became the 8th medicine, in terms of total sales, funded by the Australian Government in 2017-2018.

CONCLUSIONS: Prescrire’s assessments provide a reliable external benchmark to assess the current use of medicines in Australia. Sixteen “drugs to avoid”, judged to be more harmful than beneficial based on systematic, independent evidence reviews, are in substantial use in Australia. These results raise serious concerns about the awareness of Australian clinicians of medicine safety and efficacy. Medicines safety has become an Australian National Health Priority. Regulatory and reimbursement agencies should review the marketing and funding status of medicines which have not been shown to provide an efficacy and safety at least similar to alternative therapeutic options.

PMID:34256874 | DOI:10.1186/s40545-021-00346-3

J Ovarian Res. 2021 Jul 13;14(1):93. doi: 10.1186/s13048-021-00842-9.

ABSTRACT

OBJECTIVE: The aim of this meta-analysis was to assess the effectiveness and safety of secondary cytoreductive surgery plus chemotherapy (SCS + CT) in recurrent ovarian cancer (ROC). Our secondary purpose was to analyze whether patients could benefit from complete resection.

METHODS: We searched EMBASE, MEDLINE, the Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials, from inception to April 2021. We used appropriate scales to assess the risk of bias. Data from included studies that reported median PFS or OS were weighted by individual study sample size, and aggregated for meta-analysis. We calculated the pooled proportion of complications within 30 days after surgery.

RESULTS: We identified 13 articles, including three RCTs and ten retrospective cohort studies. A total of 4572 patients were included, of which 916 patients achieved complete resection, and all patients were comparable at baseline. Compared with chemotherapy alone, SCS + CT significantly improved the PFS (HR = 0.54, 95% CI: 0.43-0.67) and OS (HR = 0.60, 95% CI: 0.44-0.81). Contrary to the results of cohort studies, the meta-analysis of RCTs showed that SCS + CT could not bring OS benefits (HR = 0.93, 95% CI: 0.66-1.3). The subgroup analysis showed the prognostic importance of complete resection. Compared with chemotherapy alone, complete resection was associated with longer PFS (HR = 0.53, 95% CI: 0.45-0.61) and OS (HR = 0.56, 95% CI: 0.39-0.81), while incomplete resection had no survival benefit. Additionally, complete resection could maximize survival benefit compared with incomplete resection (HR = 0.56, 95% CI: 0.46-0.69; HR = 0.61, 95% CI: 0.50-0.75). The pooled proportion for complications at 30 days was 21% (95% CI: 0.12-0.30), and there was no statistical difference in chemotherapy toxicity between the two groups.

CONCLUSION: The review indicated that SCS + CT based regimens was correlated with better clinical prognosis for patients with recurrent ovarian cancer, but the interpretation of OS should be cautious. The meta-analysis emphasizes the importance of complete resection, suggesting that the potential benefits of prolonging survival may outweigh the disadvantages of any short-term complications associated with surgery.

PMID:34256813 | DOI:10.1186/s13048-021-00842-9

Genome Biol. 2021 Jul 13;22(1):208. doi: 10.1186/s13059-021-02418-8.

ABSTRACT

One challenge facing omics association studies is the loss of statistical power when adjusting for confounders and multiple testing. The traditional statistical procedure involves fitting a confounder-adjusted regression model for each omics feature, followed by multiple testing correction. Here we show that the traditional procedure is not optimal and present a new approach, 2dFDR, a two-dimensional false discovery rate control procedure, for powerful confounder adjustment in multiple testing. Through extensive evaluation, we demonstrate that 2dFDR is more powerful than the traditional procedure, and in the presence of strong confounding and weak signals, the power improvement could be more than 100%.

PMID:34256818 | DOI:10.1186/s13059-021-02418-8

Ecol Appl. 2021 Jul 13:e02408. doi: 10.1002/eap.2408. Online ahead of print.

ABSTRACT

Estimating bird and bat fatalities caused by wind-turbine facilities is challenging when carcasses are rare and produce counts that are either exactly or very near zero. The rarity of found carcasses is exacerbated when live members of a particular species are rare and when carcasses degrade quickly, are removed by scavengers, or are not detected by observers. With few observed carcass counts, common statistical methods like logistic, Poisson, or negative binomial regression are unreliable (statistically biased) and often fail to provide answers (i.e., fail to converge). Here, we propose a binomial N-mixture model that estimates fatality rates as well as the total number of carcasses when rates are expanded. Our model extends the ‘evidence of absence’ model (Huso et al., 2015; Dalthorp, Huso, and Dail, 2017) by relating carcass deposition rates to study covariates and by incorporating terms that naturally scale counts from facilities of different sizes. Our model, which we call Evidence of Absence Regression (EoAR), can estimate the total number of birds or bats killed at a single wind energy facility or a fleet of wind energy facilities based on covariate values. Furthermore, with accurate prior distributions the model’s results are extremely robust to sparse data and unobserved combinations of covariate values. In this paper, we describe the model, show its low bias and high precision via computer simulation, and apply it to bat carcass counts observed at 21 wind energy facilities in Iowa.

PMID:34256420 | DOI:10.1002/eap.2408

Phys Med Biol. 2021 Jul 13. doi: 10.1088/1361-6560/ac13fe. Online ahead of print.

ABSTRACT

Conventional PET image reconstruction is achieved by the statistical iterative method. Deep learning provides another opportunity for speeding up the image reconstruction process. However, conventional deep learning-based image reconstruction requires a fully connected network for learning the Radon transform. The use of fully connected networks greatly complicated the network and increased hardware cost. In this study, we proposed a novel deep learning-based image reconstruction method by utilizing the DIRECT data partitioning method. The U-net structure with only convolutional layers was used in our approach. Patch-based model training and testing were used to achieve 3D reconstructions within current hardware limitations. TOF histoimages were first generated from the listmode data to replace conventional sinograms. Different projection angles were used as different channels in the input. A total of 15 patient data were used in this study. For each patient, the dynamic whole-body scanning protocol was used to expand the training dataset and a total of 372 separate scans were included. The leave-one-patient-out validation method was used. Two separate studies were carried out. In the first study, the measured TOF histoimages were directly used for model training and testing, to study the performance of the method in real-world applications. In the second study, TOF histoimages were simulated from already reconstructed images to exclude the scatters, randoms, attenuation activity mismatch effects. This study was used to evaluate the optimal performance when all other corrections are ideal. Volumes of interests (VOI) were placed in the liver and lesion region to study image noise and lesion quantitations. The reconstructed images using the proposed deep learning method showed similar image quality when compared with the conventional EM approach. A minimal difference was observed when the simulated TOF histoimages were used as model input and testing, suggesting the deep learning model can indeed learn the reconstruction process. Some quantitative difference was observed when the measured TOF histoimages were used. The two studies suggested that the major difference is caused by inaccurate corrections performed by the network itself, which indicated that physics-based corrections are still required for better quantitative performance. In conclusion, we have proposed a novel deep learning-based image reconstruction method for TOF PET. With the help of the DIRECT data partitioning method, no fully connected layers were used and 3D image reconstruction can be directly achieved within the limits of the current hardware.

PMID:34256356 | DOI:10.1088/1361-6560/ac13fe

Physiol Meas. 2021 Jul 13. doi: 10.1088/1361-6579/ac13ce. Online ahead of print.

ABSTRACT

OBJECTIVE: There is emerging evidence that analysing the entropy and complexity of biomedical signals can detect underlying changes in physiology which may be reflective of disease pathology. This approach can be used even when only short recordings of biomedical signals are available. This study aimed to determine whether entropy and complexity measures can detect differences between subjects with Parkinson’s disease and healthy controls.

APPROACH: A method based on a diagram of entropy versus complexity, named complexity-entropy plane, was used to re-analyse a dataset of cerebral haemodynamic signals from subjects with Parkinson’s disease and healthy controls obtained under poikilocapnic conditions. A probability distribution for a set of ordinal patterns, designed to capture regularities in a time series, was computed from each signal under analysis. Four types of entropy and ten types of complexity measures were estimated from these distributions. Mean values of entropy and complexity were compared and their classification power was assessed by evaluating the best linear separator on the corresponding complexity-entropy planes.

MAIN RESULTS: Few linear separators obtained significantly better classification, evaluated as the area under the receiver operating characteristic curve, than signal mean values. However, significant differences in both entropy and complexity were detected between the groups of participants.

SIGNIFICANCE: Measures of entropy and complexity were able to detect differences between healthy volunteers and subjects with Parkinson’s disease, in poikilocapnic conditions, even though only short recordings were available for analysis. Further work is needed to refine this promising approach, and to help understand the findings in the context of specific pathophysiological changes.

PMID:34256359 | DOI:10.1088/1361-6579/ac13ce

Early Hum Dev. 2021 Jul 4;160:105421. doi: 10.1016/j.earlhumdev.2021.105421. Online ahead of print.

ABSTRACT

BACKGROUND: Weight gain in the first week of life is indicative of fluid excess in preterm neonates.

AIMS: To determine if morbidity and/or mortality of extremely low birthweight (ELBW) infants was lower in those who did not have excess weight gain in the first week of life, compared with those who did.

STUDY DESIGN: Retrospective cohort study.

SUBJECTS: ELBW infants born from 1st May 2014 – 31st May 2019.

EXCLUSIONS: major congenital abnormalities (including hydrops), died within the first 7 days, no recorded weight on day 6, 7 or 8.

OUTCOME MEASURES: We compared infants whose weight was greater than birthweight by day 7 and infants whose weight remained at, or below, birthweight by day 7.

RESULTS: There were 312 ELBW infants in the study population: 15 (5%) died before discharge from hospital. Holding birthweight and gestational age (GA) constant, the odds of death in neonates with day 7 weight >birthweight was about 3 times the odds of death in neonates with day 7 weight ≤birthweight (adjusted odds ratio 3.18, 95% confidence interval 0.66-15.26, p = 0.15). Neonates with day 7 weight >birthweight were more likely to have had a PDA that required treatment than those with day 7 weight ≤birthweight (65% versus 43% respectively; p <0.001).

CONCLUSIONS: ELBW infants who gain weight in the first week of postnatal life, have a greater risk of PDA requiring treatment and may have a higher risk of mortality than infants who lose weight in the first week of life.

PMID:34256312 | DOI:10.1016/j.earlhumdev.2021.105421

Parkinsonism Relat Disord. 2021 Jul 8;89:90-92. doi: 10.1016/j.parkreldis.2021.07.002. Online ahead of print.

ABSTRACT

BACKGROUND: Parkinson’s disease (PD) patients may be at increased risk of Covid-19 mortality due to the nature of their disease or underlying conditions.

METHOD: The information of 12,909 Covid-19 patients who were hospitalized during the last eleven months were collected from the data depository of two referral university hospitals. Eighty-seven of these patients were diagnosed with PD, and thirty-one of these PD patients died because of Covid-19. 2132 other deaths occurred in these centers, related to Covid-19 of non-PD patients. Fisher exact test, Chi-square test, and Principle component analysis were used for statistical analysis.

RESULTS: The mortality among PD patients and other hospitalized patients was 35.6% and 19.8%, respectively, and the difference between the mortality of these two groups was found to be statistically significant (p-value<0.01). The mean age of PD patients who passed away was 77.06 ± 7.46, and it was not significantly different from that of alive PD patients (p-value>0.05). Alzheimer’s disease as an underlying condition was more frequent in deceased PD patients in comparison to survived PD patients, and this difference was found to be statistically significant (p-value<0.01).

CONCLUSION: PD patients possess a higher rate of Covid-19 mortality in comparison with other patients hospitalized for Covid-19. PD pathophysiology, advanced age, underlying conditions, and health systems’ efficacy may play an essential role in such an outcome.

PMID:34256334 | DOI:10.1016/j.parkreldis.2021.07.002

Epilepsy Behav. 2021 Jul 10;122:108194. doi: 10.1016/j.yebeh.2021.108194. Online ahead of print.

ABSTRACT

BACKGROUND: Epilepsy is associated with a high prevalence of sleep disturbance. However, population-based studies on the burden of sleep disturbance in people with epilepsy are limited. This study assessed sleep duration and sleep quality by epilepsy status in the general U.S. adult population aged ≥ 18 years.

METHODS: We pooled data of cross-sectional National Health Interview Surveys in 2013, 2015, and 2017 to compare the prevalence of sleep duration and quality among those without epilepsy (N = 93,126) with those with any epilepsy (a history of physician-diagnosed epilepsy) (N = 1774), those with active epilepsy (those with a history of physician-diagnosed epilepsy who were currently taking medication to control it, had one or more seizures in the past year, or both) (N = 1101), and those with inactive epilepsy (those with a history of physician-diagnosed epilepsy who were neither taking medication for epilepsy nor had had a seizure in the past year) (N = 673). We also compared these measures between those with active and those with inactive epilepsy. The prevalences were adjusted for sociodemographics, behaviors, and health covariates, with multivariable logistic regression. We used Z-tests to compare prevalences of sleep duration and quality at the statistical significance level of 0.05.

RESULTS: Adults with any epilepsy reported significantly higher adjusted prevalences of short sleep duration (<7 h) (36.0% vs. 31.8%) and long sleep duration (>9 h per day) (6.7% vs. 3.7%) but a lower prevalence of healthy sleep duration (7-9 h per day) (57.4% vs.64.6%) than those without epilepsy. In the past week, adults with any epilepsy reported significantly higher adjusted prevalences than adults without epilepsy of having trouble falling asleep (25.0% vs. 20.3%), staying asleep (34.4% vs. 26.3%), nonrestorative sleep (adults did not wake up feeling well rested) (≥3days) (50.3% vs. 44.3%), and taking medication to help themselves fall asleep or stay asleep (≥1 times) (20.9% vs. 13.5%). However, adults with active epilepsy did not differ from adults with inactive epilepsy with respect to these sleep duration and quality measures.

CONCLUSIONS: Adults with epilepsy reported more short or long sleep duration and worse sleep quality than those without epilepsy. Neither seizure occurrence nor antiepileptic drug use accounted for these differences in sleep duration and quality. Careful screening for sleep complaints as well as identifying and intervening on the modifiable risk factors associated with sleep disturbances among people with epilepsy could improve epilepsy outcomes and quality of life.

PMID:34256341 | DOI:10.1016/j.yebeh.2021.108194