Tag: pubmed

Neurotoxicol Teratol. 2021 Feb 21:106963. doi: 10.1016/j.ntt.2021.106963. Online ahead of print.

ABSTRACT

Methylmercury (MeHg) is a persistent environmental neurotoxicant that may cause adverse neurodevelopmental effects. Previous studies showed that developmental MeHg exposure caused damage to brain functions that were unmasked after a silent period of years or decades. However, the underlying mechanisms of the latent neurotoxicity associated with MeHg exposure from earlier developmental stages have yet to be fully understood. Herein, we established a Caenorhabditis elegans (C. elegans) model of developmental MeHg latent toxicity. Synchronized L1 stage worms were exposed to MeHg (0, 0.05, 0.5 and 5 μM) for 48 h. Swimming moving speeds at adulthood were analyzed in worms exposed to MeHg exposure at early larvae stages. Worms developmentally exposed to MeHg had a significant decline in swimming moving speed on day 10 adult stage, but not on day 1 or 5 adult stage, even though the mercury level in the worms exposed to 0.05 or 0.5 μM MeHg were below the quantification limit on day 10 adult. Day 10 adult worms treated with MeHg showed a significant decrease in bending angle and bending frequency during swimming. Furthermore, their reduced moving speeds tended to increase during the 300-s swimming experiment. Dopamine signaling is known to be involved in the regulation of worms’ moving speed. Accordingly, the moving speed of worms with cat-2 (mammalian tyrosine hydroxylase homolog) mutation or dat-1 deletion were assayed on day 10 adult. The cat-2 mutant worms did not show a decline in moving speeds, body bends or bending angles during swimming on day 10 adult stage. Analyses of moving speeds of worms with dat-1 deletion showed that the moving speeds were further reduced after MeHg exposure. However, the effects of MeHg and dat-1 deletion were not synergistic, as the interaction between these parameters did not attain statistical significance. Altogether, our results suggest that developmental MeHg exposure reduced moving speed, and this latent toxicity was less pronounced in the context of deficient production of dopamine synthesis. Tyrosine hydroxylase plays an important role in regulating dopamine-mediated modulation of neurobehavioral functions. These findings uncovered a pivotal role of dopamine and its metabolism in the latent neurotoxic effects of MeHg.

PMID:33626374 | DOI:10.1016/j.ntt.2021.106963

Ann Oncol. 2021 Jan 21:S0923-7534(21)00014-4. doi: 10.1016/j.annonc.2021.01.006. Online ahead of print.

ABSTRACT

BACKGROUND: We predicted cancer mortality statistics for 2021 for the European Union (EU) and its five most populous countries plus the UK. We also focused on pancreatic cancer and female lung cancer.

MATERIALS AND METHODS: We obtained cancer death certifications and population data from the World Health Organization and Eurostat databases for 1970-2015. We predicted numbers of deaths and age-standardized (world population) rates for 2021 for total cancers and 10 major cancer sites, using a joinpoint regression model. We calculated the number of avoided deaths over the period 1989-2021.

RESULTS: We predicted 1,267,000 cancer deaths for 2021 in the EU, corresponding to age-standardized rates of 130.4/100,000 men (-6.6% since 2015) and 81.0 for women (-4.5%). We estimated further falls in male lung cancer rates, but still trending upward in women by +6.5%, reaching 14.5/100,000 in 2021. Breast cancer predicted rate in the EU was 13.3 (-7.8%). Rates for stomach and leukaemias in both sexes and for bladder in males are predicted to fall by over 10%; trends for other cancer sites were also favourable, except for pancreas, which showed stable patterns in both sexes, with predicted rates of 8.1/100,000 men and 5.6 for women. Rates for pancreas in EU men aged 25-49 and 50-64 declined, respectively, by 10% and 1.8%, while for those aged 65+ increased by 1.3%. Rates fell for young women only (-3.4%). Over 1989-2021, about 5 million cancer deaths were avoided in the EU27 compared with peak rates in 1988.

CONCLUSION: Overall cancer mortality continues to fall in both sexes. However, specific focus is needed on pancreatic cancer, which shows some hint of decline for young men only. Tobacco control remains a priority for the prevention of pancreatic and other tobacco-related cancers, which account for a third of the total EU cancer deaths, especially in women, who showed less favourable trends.

PMID:33626377 | DOI:10.1016/j.annonc.2021.01.006

JAMIA Open. 2020 Dec 14;3(4):557-566. doi: 10.1093/jamiaopen/ooaa060. eCollection 2020 Dec.

ABSTRACT

BACKGROUND: Synthetic data may provide a solution to researchers who wish to generate and share data in support of precision healthcare. Recent advances in data synthesis enable the creation and analysis of synthetic derivatives as if they were the original data; this process has significant advantages over data deidentification.

OBJECTIVES: To assess a big-data platform with data-synthesizing capabilities (MDClone Ltd., Beer Sheva, Israel) for its ability to produce data that can be used for research purposes while obviating privacy and confidentiality concerns.

METHODS: We explored three use cases and tested the robustness of synthetic data by comparing the results of analyses using synthetic derivatives to analyses using the original data using traditional statistics, machine learning approaches, and spatial representations of the data. We designed these use cases with the purpose of conducting analyses at the observation level (Use Case 1), patient cohorts (Use Case 2), and population-level data (Use Case 3).

RESULTS: For each use case, the results of the analyses were sufficiently statistically similar (P > 0.05) between the synthetic derivative and the real data to draw the same conclusions.

DISCUSSION AND CONCLUSION: This article presents the results of each use case and outlines key considerations for the use of synthetic data, examining their role in clinical research for faster insights and improved data sharing in support of precision healthcare.

PMID:33623891 | PMC:PMC7886551 | DOI:10.1093/jamiaopen/ooaa060

JAMIA Open. 2020 Dec 31;3(4):602-610. doi: 10.1093/jamiaopen/ooaa058. eCollection 2020 Dec.

ABSTRACT

OBJECTIVE: Patient information can be retrieved more efficiently in electronic medical record (EMR) systems by using machine learning models that predict which information a physician will seek in a clinical context. However, information-seeking behavior varies across EMR users. To explicitly account for this variability, we derived hierarchical models and compared their performance to nonhierarchical models in identifying relevant patient information in intensive care unit (ICU) cases.

MATERIALS AND METHODS: Critical care physicians reviewed ICU patient cases and selected data items relevant for presenting at morning rounds. Using patient EMR data as predictors, we derived hierarchical logistic regression (HLR) and standard logistic regression (LR) models to predict their relevance.

RESULTS: In 73 pairs of HLR and LR models, the HLR models achieved an area under the receiver operating characteristic curve of 0.81, 95% confidence interval (CI) [0.80-0.82], which was statistically significantly higher than that of LR models (0.75, 95% CI [0.74-0.76]). Further, the HLR models achieved statistically significantly lower expected calibration error (0.07, 95% CI [0.06-0.08]) than LR models (0.16, 95% CI [0.14-0.17]).

DISCUSSION: The physician reviewers demonstrated variability in selecting relevant data. Our results show that HLR models perform significantly better than LR models with respect to both discrimination and calibration. This is likely due to explicitly modeling physician-related variability.

CONCLUSION: Hierarchical models can yield better performance when there is physician-related variability as in the case of identifying relevant information in the EMR.

PMID:33623894 | PMC:PMC7886572 | DOI:10.1093/jamiaopen/ooaa058

Transp Res Interdiscip Perspect. 2021 Feb 18:100327. doi: 10.1016/j.trip.2021.100327. Online ahead of print.

ABSTRACT

During the COVID-19 period and particularly during lockdown, deviations from nominal operations have shown to become more frequent. To confirm this observation this paper proposes to evaluate the impact of COVID-19, and more generally of crises that lead to a sharp drop in traffic, on the pilot/controller system, especially during the critical approach and landing phases. To study the influence of this type of crisis on flight operations at Charles De Gaulle airport, an existing energy atypicality metric is applied on a reference period before COVID-19 and compared to the COVID-19 period. Whereas the traffic at Charles De Gaulle airport has decreased by around 90% on April 2020, the obtained statistics underlined an increase in the atypical flight ratio of around 50%. This trend can be explained in part by the appearance of glide interceptions from above as a result of trajectory shortenings, and an increase in the proportion of high speed approaches.

PMID:33623897 | PMC:PMC7891053 | DOI:10.1016/j.trip.2021.100327

North Clin Istanb. 2020 Nov 23;8(1):1-7. doi: 10.14744/nci.2020.10586. eCollection 2021.

ABSTRACT

OBJECTIVE: Obstructive sleep apnea syndrome (OSAS) is a health problem that has increasing importance in society. In the literature, many studies about an audition in patients with OSAS are present. In this study, the effects of hypoxia on an audition that develop during the apnea attacks in OSAS were investigated experimentally.

METHODS: This study was conducted in Inonu University Audiology Laboratory after the approval of Inonu University Faculty of Medicine Experimental Animal Research Ethics Committee (Protocol Number: 2011/A-102). In this study, 15 Wistar albino rats with a weight of 250-300 g were used. Anesthesia was performed by 40 mg/kg Ketamine and 5 mg/kg Xylazine through intramuscular administration. The processes were applied in the silence. This study involved 15 rats with normal auditory functions. Only tracheotomy was performed in the control group. Auditory assays were administered with otoacoustic emission (DP gram) before and after the process. In hypoxia group, hypoxia was created by making apnea attacks that lasted at least 10 seconds after the tracheotomy process. Auditory assays using DP gram were performed before tracheotomy and during hypoxia in the hypoxia group.

RESULTS: In the control group, statistically significant values were not found. In the hypoxia group, statistically significant differences were detected in high frequencies.

CONCLUSION: In conclusion, cochlear reply decreased in high frequencies during hypoxia that was created by apnea attacks.

PMID:33623866 | PMC:PMC7881432 | DOI:10.14744/nci.2020.10586

North Clin Istanb. 2020 Nov 24;8(1):57-62. doi: 10.14744/nci.2020.00533. eCollection 2021.

ABSTRACT

OBJECTIVE: Urinary incontinence remains one of the main problems affecting the quality of life after radical prostatectomy. Along with the improved understanding of the precise anatomy of the prostate, urethra and their surrounding structures, minimally invasive surgical techniques have been refined and described, aiming to improve functional outcomes without oncological compromise. This study aimed to investigate the impacts of anterior urethral fixation (AUF) and bladder neck sparing (BNS) on the early continence success after Robot-assisted Radical Prostatectomy (RALP).

METHODS: This retrospective study included 120 patients who underwent RALP between January 2018 and June 2019. Patients were allocated to one of two groups; group 1 (n=60) underwent RALP with BNS, group 2 (n=60) underwent RALP with both AUF and BNS. The patient continence status was measured at baseline on day 7 and in the 1^st, 3^rd, and 6^th months postoperatively.

RESULTS: Concerning Incontinence Impact Questionnaire-7 form, statistically significant better results in group 2 were recorded in all visits, but the last (month 6) (p=0.023). Following catheter removal, postmicturition symptoms, including incomplete emptying and post-micturition dribble rate, were significantly higher in group 1 after catheter removal and in the 1^st month (13.3% vs. 0 p=0.006). This difference was not recorded at the next visits (months 3 and 6).

CONCLUSION: Our findings showed that the combination of AUF and BNS significantly increases early continence rates and decreases post-mictional symptoms after RALP without hampering oncologic outcomes.

PMID:33623874 | PMC:PMC7881433 | DOI:10.14744/nci.2020.00533

JAMIA Open. 2020 Dec 31;3(4):536-544. doi: 10.1093/jamiaopen/ooaa048. eCollection 2020 Dec.

ABSTRACT

OBJECTIVE: Observational medical databases, such as electronic health records and insurance claims, track the healthcare trajectory of millions of individuals. These databases provide real-world longitudinal information on large cohorts of patients and their medication prescription history. We present an easy-to-customize framework that systematically analyzes such databases to identify new indications for on-market prescription drugs.

MATERIALS AND METHODS: Our framework provides an interface for defining study design parameters and extracting patient cohorts, disease-related outcomes, and potential confounders in observational databases. It then applies causal inference methodology to emulate hundreds of randomized controlled trials (RCTs) for prescribed drugs, while adjusting for confounding and selection biases. After correcting for multiple testing, it outputs the estimated effects and their statistical significance in each database.

RESULTS: We demonstrate the utility of the framework in a case study of Parkinson’s disease (PD) and evaluate the effect of 259 drugs on various PD progression measures in two observational medical databases, covering more than 150 million patients. The results of these emulated trials reveal remarkable agreement between the two databases for the most promising candidates.

DISCUSSION: Estimating drug effects from observational data is challenging due to data biases and noise. To tackle this challenge, we integrate causal inference methodology with domain knowledge and compare the estimated effects in two separate databases.

CONCLUSION: Our framework enables systematic search for drug repurposing candidates by emulating RCTs using observational data. The high level of agreement between separate databases strongly supports the identified effects.

PMID:33623890 | PMC:PMC7886555 | DOI:10.1093/jamiaopen/ooaa048

Gene Rep. 2021 Feb 19:101044. doi: 10.1016/j.genrep.2021.101044. Online ahead of print.

ABSTRACT

SARS-CoV-2 is mutating and creating divergent variants by altering the composition of essential constituent proteins. Pharmacologically, it is crucial to understand the diverse mechanism of mutations for stable vaccine or anti-viral drug design. Our current study concentrates on all the constituent proteins of 469 SARS-CoV-2 genome samples, derived from Indian patients. However, the study may easily be extended to the samples across the globe. We perform clustering analysis towards identifying unique variants in each of the SARS-CoV-2 proteins. A total of 536 mutated positions within the coding regions of SARS-CoV-2 proteins are detected among the identified variants from Indian isolates. We quantify mutations by focusing on the unique variants of each SARS-CoV-2 protein. We report the average number of mutation per variant, percentage of mutated positions, synonymous and non-synonymous mutations, mutations occurring in three codon positions and so on. Our study reveals the most susceptible six (06) proteins, which are ORF1ab, Spike (S), Nucleocapsid (N), ORF3a, ORF7a, and ORF8. Several non-synonymous substitutions are observed to be unique in different SARS-CoV-2 proteins. A total of 57 possible deleterious amino acid substitutions are predicted, which may impact on the protein functions. Several mutations show a large decrease in protein stability and are observed in putative functional domains of the proteins that might have some role in disease pathogenesis. We observe a good number of physicochemical property change during above deleterious substitutions.

PMID:33623833 | PMC:PMC7893251 | DOI:10.1016/j.genrep.2021.101044

Chronic Stress (Thousand Oaks). 2021 Feb 9;5:2470547020979780. doi: 10.1177/2470547020979780. eCollection 2021 Jan-Dec.

ABSTRACT

BACKGROUND: The α₁-adrenoreceptor antagonist prazosin has in many but not all studies been found to be effective for PTSD associated nightmares, hyperarousal symptoms, and total symptom severity. The particular efficacy of prazosin for nightmares and hyperarousal symptoms suggests there may be a subset of PTSD symptoms that are more tightly associated with an α₁-adrenoreceptor mediated noradrenergic mechanism, but cross traditional diagnostic symptom clusters. However, the efficacy of prazosin for individual symptoms other than nightmares and sleep disruption has not previously been examined.

METHODS: In a post hoc reanalysis of a previously published, randomized controlled trial of twice daily prazosin for PTSD, we examined the relative effect of prazosin on individual items of the CAPS for DSM-IV, and tested whether prazosin responsiveness predicted the partial correlation of the changes in symptom intensity at the level of individual subjects. Results were not adjusted for multiple comparisons.

RESULTS: Prazosin showed the largest effect for distressing dreams, anhedonia, difficulty falling or staying asleep, difficulty concentrating, and hypervigilance. These items were also (a) of higher baseline severity in the underlying population, and (b) more related in how they fluctuated at the level of individual subjects. Covariance analysis did not support a clear cutoff between highly prazosin responsive items and those showing a smaller, not statistically significant response.

CONCLUSIONS: In this data set, twice daily prazosin substantially reduced not only nightmares and sleep disruption, but the majority of hyperarousal symptoms, with some evidence of efficacy for avoidance symptoms. The relationship of baseline symptom distribution to which symptoms showed significant response to prazosin reinforces the possibility that differences in a clinical trial’s participant populations may significantly influence trial outcome. The pattern of symptom endorsement at the level of individual subjects was consistent with prazosin-responsive items sharing a common pathophysiologic mechanism.

PMID:33623856 | PMC:PMC7876758 | DOI:10.1177/2470547020979780