Citations

Abstract Alzheimer's disease (AD) is neuropathologically defined by amyloid‐beta (Aβ) plaques and tau neurofibrillary tangles. However, co‐pathologies and other pathobiological processes are involved in the pathogenesis of AD, contributing to neurodegeneration and clinical symptoms. The most common co‐pathologies in people with AD are alpha‐synucleinopathy, vascular brain injury and transactive response DNA‐binding protein of 43 kDa‐related pathology. Neuroinflammation, iron accumulation, cholinergic dysfunction and cellular senescence are recognized pathobiological processes beyond Aβ‐ and tau‐related pathology. However, the exact mechanisms by which these co‐pathologies and pathobiological processes contribute to the neurodegeneration and clinical symptoms in people with AD remain unclear. The individual combination of these co‐pathologies and pathobiological processes increases phenotypical heterogeneity in people with AD. This highlights the unmet need to advance their current understanding, and the field strives to develop accurate biomarkers for personalized assessment and investigation. Elucidating this biologic‐clinical complexity and heterogeneity is crucial for increasing our current understanding of AD, with implications for diagnosis, prognosis and therapeutics.

Abstract Background Estimating effective dose (E) for CT is often done with dose‐length product (DLP) and effective dose conversion factors, a.k.a. k ‐factors. Previous studies have primarily focused on k ‐factor values derived from certain fixed‐sized phantoms but have not extensively explored all the contributing factors and associated variations in E. Purpose In this study, we investigated the contributing factors and variations of E using k ‐factors as surrogates in adult and pediatric CT exams and provided empirical formula to estimate a comprehensive new set of k ‐factors. Methods Effective dose was estimated using NCICT (National Cancer Institute, USA), including organ and effective dose conversion coefficient library estimated by Monte‐Carlo radiation transport techniques. The k ‐factors were derived as a surrogate of DLP‐normalized E, via E/DLP (unit: mSv/mGy·cm). We examined the variations of effective dose estimates for different phantom and scan parameters represented by the calculations of k ‐factors. This included variations in patient sex, weight, height, kVp, and scan length across typical adult and pediatric CT examinations of anatomical regions such as the head, neck, chest, abdomen, and pelvis. Multivariable regression analyses with/without standardization were conducted to evaluate the significance of the dependency of k ‐factors on the studied parameters. Tube current modulation (TCM) parameters, modeled as a function of patient attenuation using variable modulation strengths, were also incorporated to reflect realistic clinical CT dose variations. Results The variations of DLP‐normalized E were substantially affected by multiple factors, exceeding 100% for adults (weight for adult pelvis) and more than 200% for pediatrics (height for pediatric head). The analysis of standardized regression coefficients revealed that patient weight is the most critical factor, except for head scans in adults, where scan length and patient height are the main determinants. In pediatric CT, both patient weight and height had critical impact. Similarly, for pediatric head CT scans, patient height and scan length are the dominant factors, as observed in adults. Consequently, the k ‐factors have a wide range, from 0.0099 to 0.0357 mSv/mGy·cm for adult chest and from 0.0085 to 0.0363 mSv/mGy·cm for adult abdomen. Empirical formulas to estimate k ‐factors were obtained based on multi‐variable regression with adjusted R square ranging from 0.71 to 0.93. Based on NCICT's TCM model, the use of TCM resulted in an additional average variation of 110% in the k ‐factor compared to non‐TCM results. Conclusions Our study demonstrated the large variations of DLP‐normalized effective dose. Standardized coefficients revealed that patient weight, height and/or scan length were the most crucial determinants. Depending on the specific TCM model used, even greater variations may be observed. This work also provided a practical framework for estimating CT effective dose using the traditional k ‐factor method with updated new conversion factors.

Background/Objectives: While doxorubicin (DOX) and trastuzumab (TRZ) improve overall survival in women with breast cancer, these two anti-cancer drugs increase the risk of developing heart failure. As a novel and largely unexplored approach, our aim was to evaluate whether the prophylactic use of the sodium-glucose co-transporter 2 inhibitor empagliflozin (EMPA), with and without the angiotensin converting enzyme inhibitor perindopril (PER), is cardioprotective in preventing DOX + TRZ-mediated cardiotoxicity. Methods: In a chronic in vivo murine model, female mice received prophylactic treatment with PER (3 mg/kg), EMPA (10 mg/kg), or EMPA + PER via oral gavage for a total of 3 weeks as a run-in period prior to weekly administration of DOX + TRZ (8 mg/kg and 3 mg/kg, respectively) intraperitoneally for an additional 3 weeks (total of 6 weeks). Results: In mice treated with DOX + TRZ, the left ventricular ejection fraction (LVEF) decreased from 75 ± 2% at baseline to 40 ± 4% at week 6. Prophylactic treatment with either PER, EMPA, or EMPA+PER improved LVEF to 58 ± 3%, 66 ± 3%, and 67 ± 4% at week 6, respectively (p < 0.05). Histological analyses confirmed significant disruption of myofibrils, vacuolization, and loss of sarcomere integrity in the DOX + TRZ-treated mice. Prophylactic administration with PER, EMPA, or EMPA + PER, however, improved myofibril integrity at week 6 in mice receiving DOX + TRZ. Finally, although the Bax/Bcl-xL ratio was significantly elevated by 1.5-fold in mice treated with DOX + TRZ, this marker of apoptosis was attenuated by prophylactic treatment with either PER, EMPA, or EMPA + PER. Conclusions: Prophylactic administration of EMPA mitigated adverse cardiovascular remodeling in a chronic in vivo model of DOX + TRZ-mediated cardiotoxicity.

The tumor microenvironment (TME) plays a crucial role in tumor progression and therapeutic response. Monocytes and macrophages, depending on their phenotype, can either enhance anti-tumor immunity or promote tumor growth by regulating cytokines such as IL-6. Multiple myeloma (MM), a hematologic malignancy, expresses the IL-6 receptor CD126 on its surface. Chimeric antigen receptor (CAR)-T cells targeting CD126 have been developed and shown to effectively eliminate CD126-positive tumor cells. However, interactions between macrophages, myeloma cells, and CAR-T cells require further investigation to optimize treatment strategies and minimize adverse effects. In this study, THP-1-derived macrophages, CD126 CAR-T cells, and MM cells, especially RPMI 8226 cells, were used to explore these interactions. A reduced cell population and an increased apoptosis of RPMI 8226 cells were observed in the presence of M1 macrophages. Metformin, known to influence IL-6 production, reduced the viability of RPMI 8226 cells with decreased CD126 expression. However, the killing activity of CD126 CAR-T cells against RPMI 8226 cells decreased after co-culture with macrophages, likely due to interactions between the CAR-T cells and the macrophages. These findings highlight the significant role of macrophages and inflammatory responses in MM progression and in modulating the efficacy of CAR-T cell therapy, providing valuable insights for the optimization of immunotherapeutic strategies.

ABSTRACT Chronic lymphocytic leukemia is not uniformly low risk for tumor lysis syndrome. This case shows that first‐cycle bendamustine–rituximab in patients with high disease burden can precipitate severe TLS with acute kidney injury and multiorgan failure. Individualized prophylaxis, patient education, and close monitoring during early therapy are essential.

ABSTRACT Background Street Medicine, where healthcare is provided in non‐traditional settings, provides care to people experiencing homelessness (PEH). Street medicine has been shown to improve patients' health and decrease Emergency Department visits, making it a cost effective way to provide medical care to PEH. Methods This paper is based on the SAEM25 didactic session as conducted in Philadelphia, where a panel of providers who are directly involved in street medicine clinics shared their experiences and perspectives on the various designs in practice. These topics included key logistical challenges and solutions, barriers to care and trust building, strategies for fostering sustainable partnerships with community organizations, and options for medical student or resident involvement. Results The design and unique approach of four different universities across the country was compared and contrasted by a panel of experts, all with experiences working directly with PEH. There are similarly identified barriers to providing care to PEH including location and transportation, financial and food insecurity, and trust between the community and the healthcare system. Conclusion There are multiple options that exist to provide a framework to create a clinic to support populations of PEH.

Abstract Variants of the shoulder are commonly encountered and may occasionally be confused with pathological conditions. Our goal is to provide an overview of common normal variants of the shoulder’s anatomical structures as well as any associated clinical or surgical relevance. Following a literature search of common variants of the shoulder and supporting structures, this review provides a summary of variants related to the scapular body, acromion, glenoid, coracoid, labrum, long head biceps tendon, glenohumeral ligamentous complex, and rotator cuff. The shoulder is composed of the glenohumeral, acromioclavicular, sternoclavicular, and scapulothoracic joints and their associated osseous, ligamentous, cartilaginous, and musculotendinous stabilizers. Anatomic variants about the shoulder, especially in the adolescent and young adult populations, are frequently encountered. An awareness of associated pathological conditions and an understanding of when variants might be clinically significant is important in interpreting radiological exams.

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