Search

Controversy exists as to whether anxiety and depression increase deep vein thrombosis (DVT) risk, and the mechanisms mediating potential links remain unknown. We aimed to evaluate the association between anxiety and depression and DVT risk and determine whether upregulated stress-related neural activity (SNA), which promotes chronic inflammation, contributes to this link. Our retrospective study included adults (N = 118 871) enrolled in Mass General Brigham Biobank. A subset (N = 1520) underwent clinical 18 F-FDG-PET/CT imaging. SNA was measured as the ratio of amygdalar to cortical activity (AmygA C ). High-sensitivity C-reactive protein (hs-CRP) and heart rate variability (HRV) were also obtained. Median age was 58 [interquartile range (IQR) 42-70] years with 57% female participants. DVT occurred in 1781 participants (1.5%) over median follow-up of 3.6 years [IQR 2.1-5.2]. Both anxiety and depression independently predicted incident DVT risk after robust adjustment (HR [95% CI]: 1.53 [1.38-1.71], p < .001; and 1.48 [1.33-1.65], p < .001, respectively). Additionally, both anxiety and depression associated with increased AmygA C (standardized beta [95% CI]: 0.16 [0.04-0.27], p = .007, and 0.17 [0.05-0.29], p = .006, respectively). Furthermore, AmygA C associated with incident DVT (HR [95% CI]: 1.30 [1.07-1.59], p = .009). Mediation analysis demonstrated that the link between anxiety/depression and DVT was mediated by: (1) higher AmygA C , (2) higher hs-CRP, and (3) lower HRV ( < .05 for each). Anxiety and depression confer an attributable risk of DVT similar to other traditional DVT risk factors. Mechanisms appear to involve increased SNA, autonomic system activity, and inflammation. Future studies are needed to determine whether treatment of anxiety and depression can reduce DVT risk., (© 2024 Wiley Periodicals LLC.)

Context.—: In 2022, 2 distinct guidelines for the diagnosis of myeloid neoplasms became available: the 5th edition of the World Health Organization guideline (WHO2022) solely and the International Consensus Classification (ICC). Despite major overlap, there are important differences that can have important implications., Objective.—: To explore the current opinions and diagnostic practices of hemato-oncologists and hematopathologists across the United States., Design.—: An online anonymous survey was created using REDCap, and a secure link was shared via email to fellowship program leaderships and via posts on social media., Results.—: A total of 310 responses were obtained. Only 33 of 309 respondents (10.7%) reported using solely the 2016 World Health Organization guideline to make diagnoses, whereas 167 of 309 (54%) supplemented it with other guidelines. The rest were either not sure (17; 5.5%), used WHO2022 solely (46; 14.9%), or used ICC solely (6; 1.9%). The choice of guideline was not related to region (P = .15), practice setting (P = .86), or hospital size (P = .22). More than 90% reported it is a source of confusion in clinical diagnosis, management, trial design, and other areas., Conclusions.—: Overall, our study found that having 2 distinct guidelines could be a source of confusion for physicians and calls for a unified diagnostic language., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2024 College of American Pathologists.)

Background: The mechanisms underlying the psychological and cardiovascular disease (CVD) benefits of physical activity (PA) are not fully understood., Objectives: This study tested whether PA: 1) attenuates stress-related neural activity, which is known to potentiate CVD and for its role in anxiety/depression; 2) decreases CVD in part through this neural effect; and 3) has a greater impact on CVD risk among individuals with depression., Methods: Participants from the Mass General Brigham Biobank who completed a PA survey were studied. A subset underwent 18 F-fluorodeoxyglucose positron emission tomography/computed tomographic imaging. Stress-related neural activity was measured as the ratio of resting amygdalar-to-cortical activity (AmygA C ). CVD events were ascertained from electronic health records., Results: A total of 50,359 adults were included (median age 60 years [Q1-Q3: 45-70 years]; 40.1% male). Greater PA was associated with both lower AmygA C (standardized β: -0.245; 95% CI: -0.444 to -0.046; P = 0.016) and CVD events (HR: 0.802; 95% CI: 0.719-0.896; P < 0.001) in multivariable models. AmygA C reductions partially mediated PA's CVD benefit (OR: 0.96; 95% CI: 0.92-0.99; P < 0.05). Moreover, PA's benefit on incident CVD events was greater among those with (vs without) preexisting depression (HR: 0.860; 95% CI: 0.810-0.915; vs HR: 0.929; 95% CI: 0.910-0.949; P interaction = 0.011). Additionally, PA above guideline recommendations further reduced CVD events, but only among those with preexisting depression (P interaction = 0.023)., Conclusions: PA appears to reduce CVD risk in part by acting through the brain's stress-related activity; this may explain the novel observation that PA reduces CVD risk to a greater extent among individuals with depression., Competing Interests: Funding Support and Author Disclosures This study is in part funded by National Institutes of Health (NIH) grants R56AR077187-01 and P01HL131478-05. This study was in part supported by NIH grants 1R01AR077187 (Dr Tawakol), P01HL131478 (Drs Tawakol and Fayad), K23HL151909 (Dr Osborne). Dr Osborne has received consulting fees from WCG Intrinsic Imaging, LLC, for unrelated work. Dr Choi has received support in part by funding from the National Institute of Mental Health (K08MH127413) and a NARSAD Brain and Behavior Foundation Young Investigator Award. Dr Smoller has received support for work outside the submitted research; is a member of the Scientific Advisory Board of Sensorium Therapeutics (with equity); has received an honorarium for an internal seminar at Tempus Labs and Biogen, Inc; and is PI of a study sponsored by 23andMe. Dr Tawakol has received grants from the National Institutes of Health, International Atomic Energy Agency, Osler/Harvard, and Lung Biotechnologies for work outside the submitted research. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

While posttraumatic stress disorder (PTSD) is known to associate with an elevated risk for major adverse cardiovascular events (MACE), few studies have examined mechanisms underlying this link. Recent studies have demonstrated that neuro-immune mechanisms, (manifested by heightened stress-associated neural activity (SNA), autonomic nervous system activity, and inflammation), link common stress syndromes to MACE. However, it is unknown if neuro-immune mechanisms similarly link PTSD to MACE. The current study aimed to test the hypothesis that upregulated neuro-immune mechanisms increase MACE risk among individuals with PTSD. This study included N = 118,827 participants from a large hospital-based biobank. Demographic, diagnostic, and medical history data collected from the biobank. SNA (n = 1,520), heart rate variability (HRV; [n = 11,463]), and high sensitivity C-reactive protein (hs-CRP; [n = 15,164]) were obtained for a subset of participants. PTSD predicted MACE after adjusting for traditional MACE risk factors (hazard ratio (HR) [95 % confidence interval (CI)] = 1.317 [1.098, 1.580], β = 0.276, p = 0.003). The PTSD-to-MACE association was mediated by SNA (CI = 0.005, 0.133, p < 0.05), HRV (CI = 0.024, 0.056, p < 0.05), and hs-CRP (CI = 0.010, 0.040, p < 0.05). This study provides evidence that neuro-immune pathways may play important roles in the mechanisms linking PTSD to MACE. Future studies are needed to determine if these markers are relevant targets for PTSD treatment and if improvements in SNA, HRV, and hs-CRP associate with reduced MACE risk in this patient population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Objectives: Patients with sickle cell disease (SCD) are prone to symptomatic neurologic complications. Previous studies reported accrual of neural injury starting at early age, even without having symptomatic neurologic events. The aim of this study was to assess the prevalence and risk factors of abnormal neurologic findings in patients with SCD with no history of major symptomatic neurologic events., Methods: Our study extracted patients diagnosed with SCD from the Cooperative Study of Sickle Cell Disease. Patients who underwent a neurologic evaluation were included in our analysis. Patients with previous documented major symptomatic neurologic events were excluded. We compared patients with SCD with abnormal neurologic findings with those without in terms of clinical and laboratory parameters using multivariate binary logistic regression., Results: A total of 3,573 patients with SCD were included (median age = 11 [IQR = 19] years, male = 1719 [48.1%]). 519 (14.5%) patients had at least one abnormal neurologic finding. The most common findings in descending order were abnormal reflexes, gait abnormalities, cerebellar dysfunction, language deficits, nystagmus, abnormal muscle tone and strength, Romberg sign, Horner syndrome, and intellectual impairment. History of eye disease (odds ratio [OR] = 2.76, 95% confidence interval [CI] = 1.63-4.68) and history of osteomyelitis (OR = 2.55, 95% CI 1.34-4.84) were the strongest predictors of abnormal neurologic findings, followed by smoking (OR = 1.59, 95% CI 1.08-2.33), aseptic necrosis (OR = 1.57, 95% CI 1.06-2.33), hand-foot syndrome (OR = 1.48, 95% CI 1.04-2.12), and male sex (OR = 1.42, 95% CI 1.01-2.02)., Discussion: Neurologic deficits are relatively common in patients with SCD, even without documented major neurologic insults. They range from peripheral and ophthalmic deficits to central and cognitive disabilities. Patients with SCD should have early regular neurologic evaluations and risk factor modification, particularly actively promoting smoking cessation., Competing Interests: The authors report no relevant disclosures. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp., (© 2023 American Academy of Neurology.)

Background: Chronic stress associates with major adverse cardiovascular events (MACE) via increased stress-related neural network activity (SNA). Light/moderate alcohol consumption (AC l/m ) has been linked to lower MACE risk, but the mechanisms are unclear., Objectives: The purpose of this study was to evaluate whether the association between AC l/m and MACE is mediated by decreased SNA., Methods: Individuals enrolled in the Mass General Brigham Biobank who completed a health behavior survey were studied. A subset underwent 18 F-fluorodeoxyglucose positron emission tomography, enabling assessment of SNA. Alcohol consumption was classified as none/minimal, light/moderate, or high (<1, 1-14, or >14 drinks/week, respectively)., Results: Of 53,064 participants (median age 60 years, 60% women), 23,920 had no/minimal alcohol consumption and 27,053 AC l/m . Over a median follow-up of 3.4 years, 1,914 experienced MACE. AC l/m (vs none/minimal) associated with lower MACE risk (HR: 0.786; 95% CI: 0.717-0.862; P < 0.0001) after adjusting for cardiovascular risk factors. In 713 participants with brain imaging, AC l/m (vs none/minimal) associated with decreased SNA (standardized beta -0.192; 95% CI: -0.338 to -0.046; P = 0.01). Lower SNA partially mediated the beneficial effect of AC l/m on MACE (log OR: -0.040; 95% CI: -0.097 to -0.003; P < 0.05). Further, AC l/m associated with larger decreases in MACE risk among individuals with (vs without) prior anxiety (HR: 0.60 [95% CI: 0.50-0.72] vs 0.78 [95% CI: 0.73-0.80]; P interaction = 0.003)., Conclusions: AC l/m associates with reduced MACE risk, in part, by lowering activity of a stress-related brain network known for its association with cardiovascular disease. Given alcohol's potential health detriments, new interventions with similar effects on SNA are needed., Competing Interests: Funding Support and Author Disclosures This study was in part supported by National Institutes of Health grants 1R01AR077187 (to Dr Tawakol), 5P01HL131478 (to Dr Tawakol), K23HL151909 (to Dr Osborne). Dr Osborne has served as a consultant to WCG Intrinsic Imaging, LLC, unrelated to this work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Air pollution and noise exposures individually associate with major adverse cardiovascular events (MACE) via a mechanism involving arterial inflammation (ArtI); however, their combined impact on ArtI and MACE remains unknown. We tested whether dual (vs. one or neither) exposure associates with greater ArtI and MACE risk and whether MACE risk is mediated via ArtI., Methods: Individuals (N = 474) without active cancer or known cardiovascular disease with clinical 18 F-FDG-PET/CT imaging were followed for 5 years for MACE. ArtI was measured. Average air pollution (particulate matter ≤ 2.5 μm, PM 2.5 ) and transportation noise exposure were determined at individual residences. Higher exposures were defined as noise > 55 dBA (World Health Organization cutoff) and PM 2.5 ≥ sample median., Results: At baseline, 46%, 46%, and 8% were exposed to high levels of neither, one, or both pollutants; 39 experienced MACE over a median 4.1 years. Exposure to an increasing number of pollutants associated with higher ArtI (standardized β [95% CI: .195 [.052, .339], P = .008) and MACE (HR [95% CI]: 2.897 [1.818-4.615], P < .001). In path analysis, ArtI partially mediated the relationship between pollutant exposures and MACE (P < .05)., Conclusion: Air pollution and transportation noise exposures contribute incrementally to ArtI and MACE. The mechanism linking dual exposure to MACE involves ArtI., (© 2022. The Author(s) under exclusive licence to American Society of Nuclear Cardiology.)

A cancer tumor model is an important tool for studying the behavior of various cancer tumors. Recently, many fuzzy time-fractional diffusion equations have been employed to describe cancer tumor models in fuzzy conditions. In this paper, an explicit finite difference method has been developed and applied to solve a fuzzy time-fractional cancer tumor model. The impact of using the fuzzy time-fractional derivative has been examined under the double parametric form of fuzzy numbers rather than using classical time derivatives in fuzzy cancer tumor models. In addition, the stability of the proposed model has been investigated by applying the Fourier method, where the net killing rate of the cancer cells is only time-dependent, and the time-fractional derivative is Caputo's derivative. Moreover, certain numerical experiments are discussed to examine the feasibility of the new approach and to check the related aspects. Over and above, certain needs in studying the fuzzy fractional cancer tumor model are detected to provide a better comprehensive understanding of the behavior of the tumor by utilizing several fuzzy cases on the initial conditions of the proposed model.

Background: Coronavirus disease 2019 (COVID-19) has been shown to associate with increased risk of thromboembolic events. Mechanical thrombectomy (MT) has long been used to effectively manage those with large-vessel occlusive (LVO) stroke and has similarly been implemented in the management of stroke in COVID-19 patients., Review Summary: The COVID-19 pandemic took the health care sector by a storm. Thus, less is known about MT outcomes in this population and evidence suggesting poor outcomes postthrombectomy for COVID-19 patients is accumulating. We provide a narrative on some of the published studies on the outcomes of MT in COVID-19 patients with LVO between March 2020 and February 2021. A description of patient characteristics, risk factors, COVID-19 infection severity, stroke features and thrombectomy success in this population is also presented as data from several studies show that LVO in COVID-19 patients may have some distinguishing characteristics that make management more challenging., Conclusions: The effect of COVID-19 on the long-term prognosis of stroke patients after thrombectomy is yet to be determined. The accumulating evidence from current studies indicates a negative impact of COVID-19 on outcomes in acute ischemic stroke patients who receive MT, irrespective of timely, successful angiographic recanalization. This review may help alert clinicians of some of the COVID-19-specific postthrombectomy challenges., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Owing to specific and compelling gene silencing, RNA interference (RNAi) is expected to become an essential approach in treating a variety of infectious, hemato-oncological, cardiovascular, and neurodegenerative conditions. The mechanism of action of small interfering RNA (siRNA) is based on post-transcriptional gene silencing. siRNA molecules are usually specific and efficient in the knockdown of disease-related genes. However, they are characterized by low cellular uptake and are susceptible to nuclease-mediated degradation. Therefore, siRNAs require a carrier for their protection and efficient delivery into target cells. The current review highlights the siRNA-based mechanism of action, challanges, and recent advances in clinical applications., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Positron emission tomography (PET) imaging can yield unique mechanistic insights into the pathophysiology of atherosclerosis. 18 F-fluorodeoxyglucose ( 18 F-FDG), a radiolabeled glucose analog, is retained by cells in proportion to their glycolytic activity. While 18 F-FDG accumulates within several cell types in the arterial wall, its retention correlates with macrophage content, providing an index of arterial inflammation (ArtI) which predicts subsequent cardiovascular disease (CVD) events. Furthermore, 18 F-FDG-PET imaging allows the simultaneous assessment of metabolic activity in several tissues (e.g., brain, bone marrow) and is performed in conjunction with cross-sectional imaging that enables multi-organ structural assessments. Accordingly, 18 F-FDG-PET/computed tomography (CT) imaging facilitates evaluation of disease pathways that span multiple organ systems. Within this paradigm, 18 F-FDG-PET/CT imaging has been implemented to study the mechanism linking chronic stress to CVD. To evaluate this, stress-associated neural activity can be quantified (as metabolic activity of the amygdala (AmygA)), while leukopoietic activity, ArtI, and coronary plaque burden are assessed concurrently. Such simultaneous quantification of tissue structures and activities enables the evaluation of multi-organ pathways with the aid of mediation analysis. Using this approach, multi-system 18 F-FDG-PET/CT imaging studies have demonstrated that chronically heightened stress-associated neurobiological activity promotes leukopoietic activity and systemic inflammation. This in turn fuels more ArtI and greater non-calcified coronary plaque burden, which result in more CVD events. Subsequent studies have revealed that common stressors, such as chronic noise exposure and income disparities, drive the front end of this pathway to increase CVD risk. Hence, multi-tissue multimodality imaging serves as a powerful tool to uncover complex disease mechanisms.

Aims: Activity in the amygdala, a brain centre involved in the perception of and response to stressors, associates with: (i) heightened sympathetic nervous system and inflammatory output and (ii) risk of cardiovascular disease. We hypothesized that the amygdalar activity (AmygA) ratio is heightened among individuals who develop Takotsubo syndrome (TTS), a heart failure syndrome often triggered by acute stress. We tested the hypotheses that (i) heightened AmygA precedes development of TTS and (ii) those with the highest AmygA develop the syndrome earliest., Methods and Results: Individuals (N=104, median age 67.5 years, 72% female, 86% with malignancy) who underwent clinical 18 F-FDG-PET/CT imaging were retrospectively identified: 41 who subsequently developed TTS and 63 matched controls (median follow-up 2.5 years after imaging). AmygA was measured using validated methods. Individuals with (vs. without) subsequent TTS had higher baseline AmygA (P=0.038) after adjusting for TTS risk factors. Further, AmygA associated with the risk for subsequent TTS after adjustment for risk factors [standardized hazard ratio (95% confidence interval): 1.643 (1.189, 2.270), P=0.003]. Among the subset of individuals who developed TTS, those with the highest AmygA (>mean + 1 SD) developed TTS ∼2 years earlier after imaging vs. those with lower AmygA (P=0.028)., Conclusion: Higher AmygA associates with an increased risk for TTS among a retrospective population with a high rate of malignancy. This heightened neurobiological activity is present years before the onset of TTS and may impact the timing of the syndrome. Accordingly, heightened stress-associated neural activity may represent a therapeutic target to reduce stress-related diseases, including TTS., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background/objective: The absence of receptors in triple-negative breast cancer limits therapeutic choices utilized in clinical management of the disease. Doxorubicin is an important member of therapeutic regimens that is hindered by emergence of resistance. The current work aim to investigate of therapeutic potential of single and combinations of siRNA molecules designed for silencing STAT 3, Notch-1, and β-catenin genes in wild type and doxorubicin resistant MDA-MB-231 triple negative breast cancer cell line., Methods: Doxorubicin resistant MDA-MB-231 cell line was developed and characterized for the expression of multidrug resistance-related genes, CD44/CD24 markers, inflammatory cytokines, and the expression of STAT 3, Notch-1, and β-catenin targeted genes. Further, the effect of single and combinations of siRNA on cell viability and chemosensitivity of both wild type MDA-MB-231 cells (MDA-MB-231/WT) and doxorubicin resistant MDA-MB-231 cells (MDA-MB-231/DR 250 ) were assessed by MTT assay., Results: The IC 50 of doxorubicin was 10-folds higher in MDA-MB-231/DR 250 resistant cells compared to MDA-MB-231/WT control cells, 1.53 ± 0.24 μM compared to 0.16 ± 0.02 μM, respectively. The expression of targeted genes was higher in resistant cells compared to control cells, 3.6 ± 0.16 folds increase in β-catenin, 2.7 ± 0.09 folds increase in Notch-1, and 1.8 ± 0.09 folds increase in STAT-3. Following treatment with siRNAs, there was a variable reduction in mRNA expression of each of the targeted genes compared to scrambled siRNA and a reduction in IC 50 in both cell lines. The effect of a combination of three genes produced the largest reduction in IC 50 in resistant cell line., Conclusion: Our study showed that the silencing of single and multiple genes involved in drug resistance and tumor progression by siRNA can enhance the chemosensitivity of cancer cells to conventional chemotherapy.

Objectives: This study aimed to understand the impact of iron deficiency anemia in female users of a hematology service in a developing country., Design: Retrospective cross-sectional study of adult and adolescent women with iron deficiency anemia who presented to a hospital department of hematology., Setting: A tertiary university hospital inpatient and outpatient hematology service., Participants: All female patients who were ≥13 years of age with confirmed iron deficiency anemia and received hospital hematology services., Results: A total of 208 patients were enrolled and analyzed in the registry. The mean age of the patients was 41.4 years (range, 14-82). A total of 195 patients had anemia that was moderate or severe according to the World Health Organization anemia classification with 13 patients having mild anemia. A total of 108 patients had comorbidities, which were primarily endocrine and cardiovascular. Iron deficiency anemia was associated with very heavy (n = 56, 30%) or heavy menses (n = 84, 45%) in 140 patients and was associated with poor (<200 g/week of red meat) (n = 101, 54%) or very poor (vegan, strict vegetarian) nutrition (n = 34, 18%) in 135 patients. A total of 101 patients had a previous pregnancy history with a mean of six previous pregnancies (range, 1-11 pregnancy episodes per patient). Blood film was performed on all patients; only four had a picture consistent with thalassemia minor., Conclusion: Iron deficiency anemia is caused by multiple factors. Heavy menses and low consumption of red meat were found to be associated with the severity of anemia. Our findings may be useful for healthcare planners and policy makers in increasing efforts to reduce the prevalence and severity of iron deficiency anemia among women in Jordan., Competing Interests: The authors have declared that no competing interests exist.

Multiple Myeloma (MM) is a plasma cell tumor localized to the bone marrow (BM). Despite the fact that current treatment strategies have improved patients' median survival time, MM remains incurable. Epigenetic aberrations are emerging as important players in tumorigenesis making them attractive targets for therapy in cancer including MM. Recently, we suggested the polycomb repressive complex 2 (PRC2) as a common denominator of gene silencing in MM and presented the PRC2 enzymatic subunit enhancer of zeste homolog 2 (EZH2) as a potential therapeutic target in MM. Here we further dissect the anti-myeloma mechanisms mediated by EZH2 inhibition and show that pharmacological inhibition of EZH2 reduces the expression of MM-associated oncogenes; IRF-4, XBP-1, PRDM1/BLIMP-1 and c-MYC. We show that EZH2 inhibition reactivates the expression of microRNAs with tumor suppressor functions predicted to target MM-associated oncogenes; primarily miR-125a-3p and miR-320c. ChIP analysis reveals that miR-125a-3p and miR-320c are targets of EZH2 and H3K27me3 in MM cell lines and primary cells. Our results further highlight that polycomb-mediated silencing in MM includes microRNAs with tumor suppressor activity. This novel role strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.