Citations

Abstract Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. Significance: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.

Abstract Objective Our objectives were to examine cross‐sectional correlations of headache disability with measures of resilience, anxiety, and depression, and to determine if resilience modified the association between headache severity/frequency and disability. Background Resilience is associated with quality of life and functioning among patients with chronic conditions. We investigated whether resilience strongly mitigates headache‐related disability as measured by the Migraine Disability Assessment (MIDAS). Methods We prospectively recruited 160 patients with primary headache disorders seen in a tertiary headache medicine program between February 20, 2018 and August 2, 2019. Each participant completed the MIDAS, Conner Davidson Resilience Scale (CDRS‐25), Patient Health Questionnaire‐9 (PHQ‐9), Generalized Anxiety Disorder‐7 (GAD‐7), and WHO‐5 Well‐Being Index. Results The CDRS‐25 score was negatively correlated with the total MIDAS ( r = −0.21, p = 0.009), GAD‐7 ( r = −0.56, p < 0.001), and PHQ‐9 scores ( r = −0.34, p < 0.001). Well‐being inversely correlated with disability ( r = −0.37, p < 0.001). Increases in anxiety and depression increased the odds of disability. A 1 point increase in the CDRS‐25 score decreased the odds of being severely disabled by 4% (OR = 0.96, 95% CI: 0.94 to 0.99, p = 0.001). However, the CDRS‐25 score did not significantly moderate the association between headache days and disability. Conclusion Traits associated with resilience decreased the odds of severe disability from headaches, whereas anxiety, depression, and headache frequency were strongly associated with higher disability from headache.

The objective of this study was to examine the effect of pulling angle on time-zero mechanical properties of intact infraspinatus tendon or infraspinatus tendon repaired with the modified Mason-Allen technique in a canine model in vitro. Thirty-six canine shoulder samples were used. Twenty intact samples were randomly allocated into functional pull (135°) and anatomic pull (70°) groups (n = 10 per group). The remaining sixteen infraspinatus tendons were transected from the insertion and repaired using the modified Mason-Allen technique before being randomly allocated into functional pull or anatomic pull groups (n = 8 per group). Load to failure testing was performed on all specimens. The ultimate failure load and ultimate stress of the functional pulled intact tendons were significantly lower compared with anatomic pulled tendons (1310.2 ± 167.6 N vs. 1687.4 ± 228.2 N, p = 0.0005: 55.6 ± 8.4 MPa vs. 67.1 ± 13.3 MPa, p = 0.0334). For the tendons repaired with the modified Mason-Allen technique, no significant differences were observed in ultimate failure load, ultimate stress or stiffness between functional pull and anatomic pull groups. The variance of pulling angle had a significant influence on the biomechanical properties of the rotator cuff tendon in a canine shoulder model in vitro. Load to failure of the intact infraspinatus tendon was lower at the functional pulling position compared to the anatomic pulling position. This result indicates that uneven load distribution across tendon fibers under functional pull may predispose the tendon to tear. However, this mechanical character is not presented after rotator cuff repair using the modified Mason-Allen technique.

Background Intra-procedural characterization of stroke thromboemboli might guide mechanical thrombectomy (MT) device choice to improve recanalization rates. Electrochemical impedance spectroscopy (EIS) has been used to characterize various biological tissues in real time but has not been used in thrombus. Objective To perform a feasibility study of EIS analysis of thrombi retrieved by MT to evaluate: (1) the ability of EIS and machine learning to predict red blood cell (RBC) percentage content of thrombi and (2) to classify the thrombi as “RBC-rich” or “RBC-poor” based on a range of cutoff values of RBC. Methods ClotbasePilot was a multicentric, international, prospective feasibility study. Retrieved thrombi underwent histological analysis to identify proportions of RBC and other components. EIS results were analyzed with machine learning. Linear regression was used to evaluate the correlation between the histology and EIS. Sensitivity and specificity of the model to classify the thrombus as RBC-rich or RBC-poor were also evaluated. Results Among 514 MT,179 thrombi were included for EIS and histological analysis. The mean composition in RBC of the thrombi was 36% ± 24. Good correlation between the impedance-based prediction and histology was achieved (slope of 0.9, R 2 = 0.53, Pearson coefficient = 0.72). Depending on the chosen cutoff, ranging from 20 to 60% of RBC, the calculated sensitivity for classification of thrombi ranged from 77 to 85% and the specificity from 72 to 88%. Conclusion Combination of EIS and machine learning can reliably predict the RBC composition of retrieved ex vivo AIS thrombi and then classify them into groups according to their RBC composition with good sensitivity and specificity.

Abstract The objective of this study was to determine the prevalence, incidence, and clinical diagnostic accuracy for neuropathologically diagnosed progressive supranuclear palsy (PSP) with data from a longitudinal clinicopathological study using Rainwater criteria to define neuropathological PSP. Of 954 autopsy cases, 101 met Rainwater criteria for the neuropathologic diagnosis of PSP. Of these, 87 were termed clinicopathological PSP as they also had either dementia or parkinsonism or both. The prevalence of clinicopathologically defined PSP subjects in the entire autopsy dataset was 9.1%, while the incidence rate was estimated at 780 per 100 000 persons per year, roughly 50-fold greater than most previous clinically determined PSP incidence estimates. A clinical diagnosis of PSP was 99.6% specific but only 9.2% sensitive based on first examination, and 99.3% specific and 20.7% sensitive based on the final clinical exam. Of the clinicopathologically defined PSP cases, 35/87 (∼40%) had no form of parkinsonism at first assessment, while this decreased to 18/83 (21.7%) at final assessment. Our study confirms a high specificity but low sensitivity for the clinical diagnosis of PSP. The low clinical sensitivity for PSP is likely primarily responsible for previous underestimates of the PSP population incidence rate.

In cancer cells, endogenous or therapy-induced DNA damage leads to the abnormal presence of DNA in the cytoplasm, which triggers the activation of cGAS (cyclic GMP–AMP synthase) and STING (stimulator of interferon genes). STAT2 suppresses the cGAMP-induced expression of IRF3-dependent genes by binding to STING, blocking its intracellular trafficking, which is essential for the full response to STING activation. STAT2 reshapes STING signaling by inhibiting the induction of IRF3-dependent, but not NF-κB–dependent genes. This noncanonical activity of STAT2 is regulated independently of its tyrosine phosphorylation but does depend on the phosphorylation of threonine 404, which promotes the formation of a STAT2:STING complex that keeps STING bound to the endoplasmic reticulum (ER) and increases resistance to DNA damage. We conclude that STAT2 is a key negative intracellular regulator of STING, a function that is quite distinct from its function as a transcription factor.

Background: Essential tremor (ET) is a common movement disorder in which cerebellar microscopic and volume alterations have been repeatedly reported although with disagreement between studies. However, pronounced heterogeneity was found with regard to cerebellar volume alterations. Objective: This study aimed to assess postmortem cerebellar volume in subjects with or without ET, as compared with subjects with multiple system atrophy (MSA), a well-established cerebellar neurodegeneration. Methods: Cases with ET ( n = 29), MSA ( n = 7), and non-demented control cases without any movement disorder ( n = 22) were selected from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), a longitudinal clinicopathological study with annual research-dedicated clinical assessments by neuropsychologists, subspecialist movement disorders, and cognitive/behavioral neurologists, with comprehensive neuropathological examinations after death. Group comparisons were controlled for common age-related neurodegenerative and cerebrovascular pathologies. Cerebellar volumes were calculated using digital images of slices taken at the time of autopsy, immediately after brain removal and before fixation. Results: Cerebellar volume was not reduced in ET subjects compared to controls. The two groups did not differ in terms of incidental cerebrovascular and Alzheimer’s disease neuropathology. In contrast, cerebellar volume was significantly reduced in subjects with MSA when compared to ET and control subjects. Conclusion: In a well-characterized cohort, postmortem cerebellar volume measurements suggest that there are no volume alterations in ET when compared to controls, in contrast to significant cerebellar atrophy in subjects with MSA.