Category: Statistics

Elife. 2023 Oct 26;12:RP87958. doi: 10.7554/eLife.87958.

ABSTRACT

Catalytic signaling outputs of protein kinases are dynamically regulated by an array of structural mechanisms, including allosteric interactions mediated by intrinsically disordered segments flanking the conserved catalytic domain. The doublecortin-like kinases (DCLKs) are a family of microtubule-associated proteins characterized by a flexible C-terminal autoregulatory ‘tail’ segment that varies in length across the various human DCLK isoforms. However, the mechanism whereby these isoform-specific variations contribute to unique modes of autoregulation is not well understood. Here, we employ a combination of statistical sequence analysis, molecular dynamics simulations, and in vitro mutational analysis to define hallmarks of DCLK family evolutionary divergence, including analysis of splice variants within the DCLK1 sub-family, which arise through alternative codon usage and serve to ‘supercharge’ the inhibitory potential of the DCLK1 C-tail. We identify co-conserved motifs that readily distinguish DCLKs from all other calcium calmodulin kinases (CAMKs), and a ‘Swiss Army’ assembly of distinct motifs that tether the C-terminal tail to conserved ATP and substrate-binding regions of the catalytic domain to generate a scaffold for autoregulation through C-tail dynamics. Consistently, deletions and mutations that alter C-terminal tail length or interfere with co-conserved interactions within the catalytic domain alter intrinsic protein stability, nucleotide/inhibitor binding, and catalytic activity, suggesting isoform-specific regulation of activity through alternative splicing. Our studies provide a detailed framework for investigating kinome-wide regulation of catalytic output through cis-regulatory events mediated by intrinsically disordered segments, opening new avenues for the design of mechanistically divergent DCLK1 modulators, stabilizers, or degraders.

PMID:37883155 | DOI:10.7554/eLife.87958

Cryo Letters. 2023 Jul-Aug;44(4):208-218.

ABSTRACT

BACKGROUND: The use of sulfated polysaccharides (PS) in seminal cooling is known to improve seminal quality.

OBJECTIVE: To evaluate the effect of different concentrations of PS, extracted from the macroalgae Gracilaria domigensis as a supplement to the seminal cooling medium of the reophilic fish Prochilodus brevis (common curimatã).

MATERIALS AND METHODS: Five semen pools were diluted in ACP-104 (treatment T1), in BTS® (T2) and in BTS® with different concentrations of PS (0.5 [T3]; 1.0 [T4] and 1.5 [T5]). The samples were cooled for different times (0, 6, 24, 48, 72, 96 and 120 h) and after each hour they were analyzed for: morphology, membrane integrity, DNA integrity and sperm kinetics.

RESULTS: There were no significant differences between the treatments containing different concentrations of sulfated polysaccharides. Regarding the different cooling times, it was possible to observe that after hour 96, there was a reduction in the parameters of sperm kinetics. For DNA integrity there was no significant difference in relation to the treatments nor in relation to the hours. For membrane integrity, a reduction was noted as of hour 96, but there was no influence of polysaccharides. For the sperm morphology, there was no statistical difference between the hours, however the BTS was better than the ACP-104.

CONCLUSION: It is concluded that the use of polysaccharides in seminal cooling has no negative effect on sperm parameters and proves that seminal cooling keeps the material viable for up to 72 hours. Doi: 10.54680/fr23410110512.

PMID:37883138

ACS Appl Mater Interfaces. 2023 Oct 26. doi: 10.1021/acsami.3c12489. Online ahead of print.

ABSTRACT

Viologens are fascinating redox-active organic compounds that have been widely explored in electrochromic devices (ECDs). However, the combination of electrochromic and resistive random-access memory in a single viologen remains unexplored. We report the coexistence of bistate electrochromic and single-resistor (1R) memory functions in a novel viologen. A high-performance electrochromic function is achieved by combining viologen (BzV²⁺2PF₆) with polythiophene (P3HT), enabling a “push-pull” electronic effect due to the efficient intermolecular charge transfer in response to an applied bias. The ECDs show high coloration efficiency (ca. 1150 ± 10 cm² C^-1), subsecond switching time, good cycle stability (>10³ switching cycles), and low-bias operation (±1.5 V). The ECDs require low power for switching the color states (55 μW cm^-2 for magenta and 141 μW cm^-2 for blue color). The random-access memory devices (p⁺²-Si/BzV²⁺2PF₆/Al) exhibit distinct low and high resistive states with an ON/OFF ratio of ∼10³, bipolar and nonvolatile characteristics that manifest good performances, and “Write”-“Read”-“Erase” (WRE) functions. The charge conduction mechanism of the RRAM device is elucidated by the Poole-Frenkel model where SET and RESET states arise at a low transition voltage (V_T = ±1.7 V). Device statistics and performance parameters for both electrochromic and memory devices are compared with the literature data. Our findings on electrochromism and nonvolatile memory originated in the same viologen could boost the development of multifunctional, smart, wearable, flexible, and low-cost optoelectronic devices.

PMID:37883131 | DOI:10.1021/acsami.3c12489

J Clin Ultrasound. 2023 Oct 26. doi: 10.1002/jcu.23593. Online ahead of print.

ABSTRACT

PURPOSE: To determine the effects of gestational diabetes mellitus (GDM) on fetal frontal lobe development.

METHODS: This study was conducted prospectively between May 2023 and August 2023 in Ankara City Hospital perinatology clinic. Maternal age, maternal body mass index (BMI), gestational week (GW), biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), femur length (FL), estimated fetal weight (EFW), frontal antero-posterior diameter (FAPD), occipito-frontal diameter (OFD), FAPD/OFD ratio, and FAPD/HC ratio, were compared between GDM (n = 40) and low risk controls (n = 56).

RESULTS: The mean maternal age was found higher in the GDM group compared to control group (p = 0.002). Maternal BMI was significantly higher in the GDM group than the control group (p = 0.01). Abdominal circumference (AC) was significantly higher in the GDM group compared to control group (p = 0.04). EFW was significantly higher in the GDM group compared to control group (p = 0.04). FAPD/OFD ratio was found to be higher in the GDM group than in the control group (p = 0.001). Among GDM patients, no statistically significant difference was found in the ultrasound measurements between the groups receiving insulin treatment and those without treatment. According to the correlation analysis results a moderate, positive, and statistically significant correlation was present between FAPD/OFD and GDM. In perinatal outcomes, the rate of neonatal intensive care unit admission was significantly higher in the GDM group.

DISCUSSION: Fetal frontal lobe development seems to be affected by GDM.

PMID:37883124 | DOI:10.1002/jcu.23593

PM R. 2023 Oct 26. doi: 10.1002/pmrj.13093. Online ahead of print.

ABSTRACT

INTRODUCTION: Physical medicine and rehabilitation (PM&R) physicians are trained to perform interventional procedures using local anesthetics (LAs) to reduce pain and enhance function and quality of life. Local anesthetic administration is not benign and one potential complication is Local Anesthetic Systemic Toxicity (LAST). Anesthesiologists also perform interventions with LAs, however, training on LAST may differ between medical specialties.

OBJECTIVE: To investigate if a gap exists between physiatry and anesthesiology physicians’ knowledge of LAST.

DESIGN: Prospective cross-sectional survey study.

SETTING AND PARTICIPANTS: All residents, fellows, and attendings of the anesthesiology and PM&R departments at a single academic medical center.

OUTCOME MEASURE: Primary outcome measures include participants’ self-reported exposure to LAST education and comfort with their LAST knowledge as recorded on a Likert scale, as well as percentage of correctly answered knowledge-based questions on the topic.

RESULTS: Fifty-eight physicians including 28 PM&R and 30 anesthesiology physicians (24 attending and 34 trainees) participated. Anesthesiology trainees and attendings exhibited greater overall perceived knowledge of LAST (trainees U=43, p<.001; attendings U=9, p<.001), with greater exposure to LAST education (trainees U=16.5, p<.001; attendings U=12, p<.001). Assessment of responses to knowledge-based questions on LAST revealed a statistically significant knowledge gap between PM&R and Anesthesia trainees (t=6.62, p= <.001) as well as between attending groups (t=3.25, p= <.01).

CONCLUSION: This study reveals a distinction in both the subjective and objective knowledge of LAST between PM&R and anesthesiology physicians at a single academic institution. This suggests there is opportunity for further assessment of the education on LAST amongst physiatrists and residents in training. This article is protected by copyright. All rights reserved.

PMID:37883117 | DOI:10.1002/pmrj.13093

Invest Ophthalmol Vis Sci. 2023 Oct 3;64(13):43. doi: 10.1167/iovs.64.13.43.

ABSTRACT

PURPOSE: This study aimed to establish an image-based classification that can reveal the clinical characteristics of patients with dry eye using unsupervised learning methods.

METHODS: In this study, we analyzed 82,236 meibography images from 20,559 subjects. Using the SimCLR neural network, the images were categorized. Data for each patient were averaged and subjected to mini-batch k-means clustering, and validated through consensus clustering. Statistical metrics determined optimal category numbers. Using a UNet model, images were segmented to identify meibomian gland (MG) areas. Clinical features were assessed, including tear breakup time (BUT), tear meniscus height (TMH), and gland atrophy. A thorough ocular surface evaluation was conducted on 280 cooperative patients.

RESULTS: SimCLR neural network achieved clustering patients with dry eye into six image-based subtypes. Patients in different subtypes harbored significantly different noninvasive BUT, significantly correlated with TMH. Subtypes 1 and 5 had the most severe MG atrophy. Subtype 2 had the highest corneal fluorescent staining (CFS). Subtype 4 had the lowest TMH, whereas subtype 5 had the highest. Subtypes 3 and 6 had the largest MG areas, and the upper MG areas of a person’s bilateral eyes were highly correlated. Image-based subtypes are related to meibum quality, CFS, and morphological characteristics of MG.

CONCLUSIONS: In this study, we developed an unsupervised neural network model to cluster patients with dry eye into image-based subtypes using meibography images. We annotated these subtypes with functional and morphological clinical characteristics.

PMID:37883092 | DOI:10.1167/iovs.64.13.43

JAMA Netw Open. 2023 Oct 2;6(10):e2339934. doi: 10.1001/jamanetworkopen.2023.39934.

ABSTRACT

IMPORTANCE: Targeted therapies directed against ERBB2 are the cornerstone of medical treatment for ERBB2-positive breast cancers but are contraindicated during pregnancy.

OBJECTIVES: To describe the association of exposure to anti-ERBB2 agents during pregnancy with pregnancy and fetal or newborn outcomes, and to compare the risk and types of adverse outcomes reported more frequently in this context than after exposure to other anticancer agents.

DESIGN, SETTING, AND PARTICIPANTS: For this case-control study, All reports with a pregnancy-related condition and an antineoplastic agent (Anatomical Therapeutic Chemical classification group L01) registered in the World Health Organization international pharmacovigilance database VigiBase up to June 26, 2022, were extracted. All reports with a pregnancy, an antineoplastic treatment during pregnancy, and a cancer were retained. Reports with anticancer agents prescribed for nononcologic purposes were not included.

EXPOSURE: The exposure group was defined as reports that mention anti-ERBB2 agents compared with exposure to other anticancer agents.

MAIN OUTCOME AND MEASURES: The main outcome was the reporting odds ratio (ROR) for maternofetal complications in the group exposed to anti-ERBB2 agents compared with other anticancer agents, as determined using a disproportionality analysis.

RESULTS: A total of 3558 reports (anti-ERBB2 agents, 328; other anticancer agents, 3230) were included in the analysis. In the group exposed to anti-ERBB2 agents, most reports were from the US (159 [48.5%]), the mean (SD) age of participants was 30.8 (10.4) years, and 209 patients (97.7%) were treated for breast cancers. The molecules most frequently involved in cases with anti-ERBB2 agents were trastuzumab (n = 302), pertuzumab (n = 55), trastuzumab-emtansine (n = 20), and lapatinib (n = 18). The outcomes overreported in these cases included oligohydramnios (ROR, 17.68 [95% CI, 12.26-25.52]; P < .001), congenital respiratory tract disorders (ROR, 9.98 [95% CI, 2.88-34.67]; P < .001), and neonatal kidney failure (ROR, 9.15 [95% CI, 4.62-18.12]; P < .001). Sensitivity and multivariable analyses found similar results. Toxic effects were also significantly overreported for trastuzumab-emtansine (cardiovascular malformation: ROR, 4.46 [95% CI, 1.02-19.52]) and lapatinib (intrauterine growth restriction: ROR, 7.68 [95% CI, 3.01-19.59]).

CONCLUSIONS AND RELEVANCE: In this case-control study of 328 individuals exposed to anti-ERBB2 agents during pregnancy, exposure was associated with a severe specific adverse pregnancy and fetal or newborn outcomes compared with exposure to other anticancer treatments.

PMID:37883083 | DOI:10.1001/jamanetworkopen.2023.39934

JAMA Ophthalmol. 2023 Oct 26. doi: 10.1001/jamaophthalmol.2023.4716. Online ahead of print.

ABSTRACT

IMPORTANCE: Patients with retinal artery occlusions (RAOs) are recommended to have emergent stroke workup, although the true risk of death and subsequent vascular events post-RAO is not clear.

OBJECTIVE: To determine short-term and long-term rates of stroke, myocardial infarction (MI), and death in patients after RAO compared with a control cohort.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used aggregated electronic health records from January 1, 2003, through April 14, 2023, from TriNetX, a network with data from more than 111 million patients. Patients with RAO and a cataract control group were identified and matched for age, sex, race, and comorbidities, including hypertension, diabetes, hyperlipidemia, and smoking status. Patients were excluded if they had a stroke or MI within 2 years before the diagnosis of RAO or cataract.

EXPOSURE: International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, diagnosis code for RAO or age-related cataract.

MAIN OUTCOMES AND MEASURES: Rate of death, stroke, and MI at 2 weeks, 30 days, 1 year, 5 years, and 10 years after RAO compared with matched controls.

RESULTS: There were a total of 34 874 patients with at least 1 year of follow-up in the RAO cohort. The mean (SD) age at the RAO event was 66 (15.2) years. The rate of death after RAO diagnosis was higher than after cataract diagnosis at 2 weeks (0.14% vs 0.06%; relative risk [RR], 2.45; 95% CI, 1.46-4.12; risk difference [RD], 0.08%; 95% CI, 0.04%-0.13%; P < .001), 30 days (0.29% vs 0.14%; RR, 2.10; 95% CI, 1.49-2.97; RD, 0.15%; 95% CI, 0.08%-0.22%; P < .001), 1 year (3.51% vs 1.99%; RR, 1.78; 95% CI, 1.61-1.94; RD, 1.41%; 95% CI, 1.17%-1.66%; P < .001), 5 years (22.74% vs 17.82%; RR, 1.28; 95% CI, 1.23-1.33; RD, 4.93%; 95% CI, 4.17%-5.68%; P < .001), and 10 years (57.86% vs 55.38%; RR, 1.05; 95% CI, 1.02-1.07; RD, 2.47%; 95% CI, 1.25%-3.69%; P < .001). Risk of stroke after RAO was higher at 2 weeks (1.72% vs 0.08%; RR, 21.43; 95% CI, 14.67-31.29; RD, 1.64%; 95% CI, 1.50%-1.78%; P < .001), 30 days (2.48% vs 0.18%; RR, 14.18; 95% CI, 10.94-18.48; RD, 2.31%; 95% CI, 2.14%-2.47%; P < .001), 1 year (5.89% vs 1.13%; RR, 5.20; 95% CI, 4.67-5.79; RD, 4.64%; 95% CI, 4.37%-4.91%; P < .001), 5 years (10.85% vs 4.86%; RR, 2.24; 95% CI, 2.09-2.40; RD, 6.00%; 95% CI, 5.50%-6.50%; P < .001), and 10 years (14.59% vs 9.18%; RR, 1.59; 95% CI, 1.48-1.70; RD, 5.41%; 95% CI, 4.62%-6.21%; P < .001). Risk of MI after RAO was higher at 2 weeks (0.16% vs 0.06%; RR, 3.00; 95% CI, 1.79-5.04; RD, 0.11%; 95% CI, 0.06%-0.16%; P < .001), 30 days (0.27% vs 0.10%; RR, 2.61; 95% CI, 1.78-3.83; RD, 0.17%; 95% CI, 0.10%-0.23%; P < .001), 1 year (1.66% vs 0.97%; RR, 1.72; 95% CI, 1.51-1.97; RD, 0.59%; 95% CI, 0.42%-0.76%; P < .001), 5 years (6.06% vs 5.00%; RR, 1.21; 95% CI, 1.12-1.31; RD, 1.07%; 95% CI, 0.64%-1.50%; P < .001), and 10 years (10.55% vs 9.43%; RR, 1.12; 95% CI, 1.04-1.21; RD, 1.13%; 95% CI, 0.39%-1.87%; P = .003).

CONCLUSIONS AND RELEVANCE: This study showed an increased risk of death, stroke, and MI in patients with RAO at both short-term and long-term intervals after RAO compared with a matched control population diagnosed with cataract. These findings suggest a potential need for multidisciplinary evaluation and long-term systemic follow-up of patients post-RAO.

PMID:37883068 | DOI:10.1001/jamaophthalmol.2023.4716

J Exp Psychol Learn Mem Cogn. 2023 Oct 26. doi: 10.1037/xlm0001284. Online ahead of print.

ABSTRACT

Evidence for implicit aversive learning effects has been criticized for its lack of experimental rigor and statistical reliability. Here we examine whether attentional emotional responses to aversive conditioned stimuli can occur in the absence of stimulus-outcome contingency awareness, and use a novel Bayesian tool to reliably perform a post hoc categorization of awareness. Across two experiments (n = 40 and 69) participants completed an aversive conditioning task. A novel Bayesian awareness categorization tool was applied to sensitively measure contingency awareness. Finally, attentional and subjective responses toward conditioned stimuli were measured. For participants unaware of contingencies, conditioned stimuli generated attentional avoidance, but only aware participants showed subjective learning effects. For both experiments, awareness scores for unaware participants did not regress above chance level on a subsequent awareness check, revealing a reliable determination of unawareness states. These findings provide evidence for the existence of aversive learning in the absence of contingency awareness, as demonstrated via conditioned attentional responses, and build an analytical framework that can be extrapolated to other implicit paradigms. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

PMID:37883055 | DOI:10.1037/xlm0001284

J Exp Psychol Learn Mem Cogn. 2023 Oct 26. doi: 10.1037/xlm0001275. Online ahead of print.

ABSTRACT

It has been reported that visual statistical learning (VSL) is facilitated in skewed distributions. However, it remains unclear whether enhancement of VSL in Zipfian distributions is due to consciousness of the regularities presented at high frequency. This study addressed this issue. We measured participants’ subjective confidence in regularities and awareness of regularities during familiarization by combining a previously reported procedure for VSL with a postdecision wagering task and posttest questionnaire. The results demonstrated that Zipfian distribution enhanced not only VSL but also metacognitive sensitivity, particularly for high-frequency regularities, as the effects of consciousness on VSL were limited to high-frequency regularities. Moreover, the results indicated that awareness during familiarization mediated VSL enhancement in the Zipfian distribution. These results suggest that VSL for events with high-frequency regularities plays an important role in the cognition of events with low-frequency regularities via awareness. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

PMID:37883051 | DOI:10.1037/xlm0001275