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Coronary Calcification: Types, Morphology and Distribution
No full textThe development and progression of coronary calcification is of growing interest with the emergence of new imaging modalities and calcium modifying technologies that can facilitate optimal results during complex percutaneous coronary intervention (PCI). Coronary atherosclerotic disease typically begins within the intima with pathological intimal thickening and microcalcifications (>0.5 μm and <15 μm). These microcalcifications can coalesce into larger areas of calcification, including sheet calcium, which is typically seen in fibrocalcific plaque, nodular calcification and calcified nodules. Calcified nodules typically protrude into the vessel lumen. Erosive calcified nodules lack the coverage of protective anti-aggregatory endothelium and frequently show adherence of intraluminal thrombus. Greater calcification within coronary plaque does not correlate with an increased risk of acute coronary syndrome, however, coronary calcium can lead to challenges with stent delivery and full stent expansion during PCI. An understanding of plaque morphology, distribution of calcium, degree of calcification and underlying shape will enable interventional cardiologists to appropriately interpret intravascular ultrasound and optical coherence tomography imaging findings and optimise results during complex PCI
Heterogeneous clinical phenotypes of sporadic early-onset Alzheimer's disease: a neuropsychological data-driven approach
No full textBackground: The clinical presentations of early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease are distinct, with EOAD having a more aggressive disease course with greater heterogeneity. Recent publications from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) described EOAD as predominantly amnestic, though this phenotypic description was based solely on clinical judgment. To better understand the phenotypic range of EOAD presentation, we applied a neuropsychological data-driven method to subtype the LEADS cohort.
Methods: Neuropsychological test performance from 169 amyloid-positive EOAD participants were analyzed. Education-corrected normative comparisons were made using a sample of 98 cognitively normal participants. Comparing the relative levels of impairment between each cognitive domain, we applied a cut-off of 1 SD below all other domain scores to indicate a phenotype of "predominant" impairment in a given cognitive domain. Individuals were otherwise considered to have multidomain impairment. Whole-cortex general linear modeling of cortical atrophy was applied as an MRI-based validation of these distinct clinical phenotypes.
Results: We identified 6 phenotypic subtypes of EOAD: Dysexecutive Predominant (22% of sample), Amnestic Predominant (11%), Language Predominant (11%), Visuospatial Predominant (15%), Mixed Amnestic/Dysexecutive Predominant (11%), and Multidomain (30%). These phenotypes did not differ by age, sex, or years of education. The APOE ɛ4 genotype was enriched in the Amnestic Predominant group, who were also rated as least impaired. Cortical thickness analysis validated these clinical phenotypes with dissociations in atrophy patterns observed between the Dysexecutive and Amnestic Predominant groups. In contrast to the heterogeneity observed from our neuropsychological data-driven approach, diagnostic classifications for this same sample based solely on clinical judgment indicated that 82% of individuals were amnestic-predominant, 9% were non-amnestic, 4% met criteria for Posterior Cortical Atrophy, and 5% met criteria for Primary Progressive Aphasia.
Conclusion: A neuropsychological data-driven method to phenotype EOAD individuals uncovered a more detailed understanding of the presenting heterogeneity in this atypical AD sample compared to clinical judgment alone. Clinicians and patients may over-report memory dysfunction at the expense of non-memory symptoms. These findings have important implications for diagnostic accuracy and treatment considerations
Pregnant maternal brain dorsal anterior cingulate cortex choline/creatine ratios on 1H-MR spectroscopy in opioid exposure
No full textThere is growing interest in understanding the effects of opioid use on the brain, yet the effects of opioid use on the pregnant maternal brain are still relatively unknown. Pregnant women with opioid exposure during pregnancy are at high risk for adverse neurological and neuropsychiatric outcomes. Much of what is currently known about the impact of opioids on the maternal brain is mainly derived from studies in animal models; however, species-specific opioid pathways and other socio-environmental factors complicate the interpretation of results. A few studies in non-pregnant adults have shown the utility of magnetic resonance spectroscopy (MRS) in risk prediction in substance exposure. We know that pregnancy alters the pharmacodynamics and pharmacokinetics of opioid metabolism, and the impact of opioids on synapses may differ during pregnancy compared to the non-pregnant state. We, therefore, aimed to understand the neurometabolic alterations in pregnant women on medications for opioid use disorder (MOUD). In our multicenter study, we utilized 1H MRS to analyze metabolic alterations in the dorsal anterior cingulate cortex (dACC) in pregnant women on MOUD (12 subjects) vs. pregnant control women (21 subjects) without substance exposure. Using multivariable linear regression, we identified a positive association between opioid exposure and choline-to-creatine (Cho/Cr) ratios after correcting for gestational age and scanner site. We also identified a significant elevation in the Cho/Cr ratio in pregnant women on MOUD and concomitant polysubstance exposure when compared to pregnant women on MOUD without exposure to other substances and control pregnant women. These altered metabolite concentrations that we identified in the dACC may provide a mechanistic understanding of the neurobiology of MOUD and insights for better management and outcomes
Amyloidogenesis promotes HSF1 activity enhancing cell survival during breast cancer metastatic colonization
No full textBreast cancer is the most commonly diagnosed cancer among women and the second leading cause of cancer deaths in women. A majority of these breast cancer deaths are due to metastasis, which occurs when primary tumor cells invade into the blood stream to travel and colonize at distant organ sites. Metastatic colonization is the rate-limiting step of metastasis. Heat shock factor 1 (HSF1) is a transcription factor that has been shown to be involved in promoting malignancy with a function in metastatic dissemination due to its contribution to promoting epithelial-to-mesenchymal transition. The role of HSF1 in colonization is unclear. In this study, we observed that HSF1 was essential for metastatic colonization. Consistent with these findings, we also observed that HSF1 was more active in human metastatic tumors compared to primary tumors. HSF1 was also seen to be activated during in vitro colony formation, which was accompanied by increases in amyloid beta (Aβ) fibrils, which was also observed in human metastatic tumors. Aβ fibrils led to HSF1 activation and depletion or inhibition of HSF1 led to increases in Aβ fibrils. HSF1 inhibition with small molecule inhibitors suppressed in vitro colony formation and mammosphere growth of metastatic breast cancer cells. These results suggest that colonization increases Aβ fibril formation that subsequently activates HSF1 as a cell survival mechanism that is essential for metastatic initiation and outgrowth
Associations Between the Built Environment in GPS-Derived Activity Spaces and Sedentary Behavior, Light Physical Activity, and Moderate-to-Vigorous Physical Activity
No full textBuilt environment and physical activity (PA) studies have predominantly used fixed or home-centric approaches to identify environmental exposures. In this study, GPS-derived daily activity spaces were used to examine the relationships between the built environment and sedentary behavior (SB), light PA (LPA), and moderate-to-vigorous PA (MVPA). Thirty-one adults were assessed with activity monitors and GPS units. Three types of activity spaces were created: 50 m buffered GPS tracks, minimum convex hulls (MCHs), and standard deviational ellipses (SDEs). The environmental variables included land use mix, greenness, and intersection, multi-use trail, bike infrastructure, and bike station densities. Repeated measures regression was used to test the associations for 141 person-days, controlling for age, gender, income, body mass index, crime, precipitation, and temperature. Greenness within MCH activity spaces was positively associated with LPA (p = 0.02). The bike infrastructure density within SDE spaces had a significant positive association with MVPA (p = 0.04). Multi-use trail, bike infrastructure, and bike station densities had significant negative associations with LPA (p ≤ 0.05). There were no significant adjusted associations with SB. The few significant associations in this study varied by outcome and type of activity space. Further studies are needed to determine optimal, yet flexible methods for activity spaces in built environment and PA research
Relationship Between Health Care Team Segregation and Receipt of Care by a Cardiologist According to Patient Race in a Midwestern State
No full textBackground: Segregation index (SI) has been associated with worsened health. However, the relationship between SI within health care teams (degree of heterogeneity between teams caring for Black compared with White patients) and cardiovascular care is unclear among adequately insured populations. We sought to assess the relationship between health care team SI, patient race, receipt of care by a cardiologist, 1-year survival, and 30-day readmission rates for Black compared with White patients admitted with heart failure, ischemic heart disease, or valvular heart disease.
Methods: Using Optum's de-identified Clinformatics Data Mart Database (CDM) from 2009 to 2020, generalized linear mixed-effects were used to analyze effects of patient race and SI on receipt of care by a cardiologist, and care by a cardiologist on 1-year survival and 30-day readmission.
Results: Among 6572 patients (17.1% Black), the odds of receiving care by a cardiologist were 31.3% less for Black than White patients (adjusted odds ratio 0.687 [95% CI, 0.545-0.872]; P=0.001). However, there was no statistically significant association of SI on receipt of care by a cardiologist (P=0.14). For those seen by a cardiologist, the adjusted odds ratio (Black-to-White) of 1-year survival increased with increasing SI (P=0.02). SI had no statistically significant effect on 30-day readmission (P=0.86).
Conclusions: Among patients hospitalized for heart failure, ischemic heart disease, or valvular heart disease, segregation of health care teams was not associated with receipt of care by cardiologists in Indiana hospitals. When cardiologists were included, the odds of 1-year survival increased for Black versus White patients with increasing segregation of clinicians, and segregation was not associated with 30-day readmission
Electrical Stimulation Generates Induced Tumor-Suppressing Cells, Offering a Potential Option for Combatting Breast Cancer and Bone Metastasis
No full textTreating advanced metastatic cancer, particularly with bone metastasis, remains a significant challenge. In previous studies, induced tumor-suppressing (iTS) cells were successfully generated through genetic, chemical, and mechanical interventions. This study investigates the potential of electrical stimulation to generate iTS cells. Using a custom electrical stimulator with platinum electrodes, mesenchymal stem cells (MSCs) and Jurkat T cells were stimulated under optimized conditions (50 mV/cm, 10-100 Hz, 1 h). Conditioned medium (CM) from electrically stimulated cells demonstrated tumor-suppressing capabilities, inhibiting tumor cell migration, 3D spheroid growth, and cancer tissue fragment viability. Additionally, the CM reduced osteoclast maturation while promoting osteoblast differentiation. Proteomic analysis revealed enrichment of tumor-suppressing proteins, including histone H4, in the CM. Functional studies identified Piezo1 as a key mediator, as its knockdown significantly impaired the tumor-suppressive effects. Mechanistically, the process was distinct from other methods, such as mechanical vibration, with SUN1 inhibition showing no effect on iTS cell generation by electrical stimulation. These findings demonstrate the efficacy of electrical stimulation in enhancing the antitumor capabilities of MSCs and T cells, offering a novel approach to cancer therapy. Further exploration of this strategy could provide valuable insights into developing new treatments for metastatic cancer
