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IntroductionIn the mitral valve (MV), numerous pathological factors, especially those resulting from changes in external loading, have been shown to affect MV structure and composition. Such changes are driven by the MV interstitial cell (MVIC) population via protein synthesis and enzymatic degradation of extracellular matrix (ECM) components.MethodsWhile cell phenotype, ECM composition and regulation, and tissue level changes in MVIC shape under stress have been studied, a detailed understanding of the three-dimensional (3D) microstructural mechanisms are lacking. As a first step in addressing this challenge, we applied focused ion beam scanning electron microscopy (FIB-SEM) to reveal novel details of the MV microenvironment in 3D.ResultsWe demonstrated that collagen is organized into large fibers consisting of an average of 605 ± 113 fibrils, with a mean diameter of 61.2 ± 9.8 nm. In contrast, elastin was organized into two distinct structural subtypes: (1) sheet-like lamellar elastin, and (2) circumferentially oriented elastin struts, based on both the aspect ratio and transmural tilt. MVICs were observed to have a large cytoplasmic volume, as evidenced by the large mean surface area to volume ratio 3.68 ± 0.35, which increased under physiological loading conditions to 4.98 ± 1.17.ConclusionsOur findings suggest that each MVIC mechanically interacted only with the nearest 3–4 collagen fibers. This key observation suggests that in developing multiscale MV models, each MVIC can be considered a mechanically integral part of the local fiber ensemble and is unlikely to be influenced by more distant structures.

Objectives Papillary thyroid cancer (PTC) is the most frequent subtype of thyroid cancer with overall favorable survival. Currently, little is known about the PTC experience within the United States (U.S.) Armenians. We performed the first study comparing clinicopathologic variables and clinical outcomes of U.S. Armenian PTC patients to a matched control group of non‐Armenians. Methods We performed a single‐center, retrospective, case–control study of adult Armenian PTC patients who received care at COH from 2005 to 2022. Armenian ethnicity was determined by surnames ending in “‐ian” and “‐yan”. We report and compare clinicopathologic presentation and disease outcomes with a gender‐ and age‐matched control non‐Armenian population. Results Fifty‐eight Armenian patients comprised our study cohort. Positive margin status (p = .038), angioinvasion (p = .006), and extrathyroidal extension (p = .014) were more prevalent in the Armenian population. Higher rates of both persistent disease and death due to disease were seen in the Armenians regardless of age groupings. Multivariable analysis revealed significant impact of Armenian status on outcomes. Calculated 5‐ and 10‐ year disease‐specific survival rates in the Armenian cohort were 88% and 73.2%, respectively, compared with 100% and 94.6% in the non‐Armenian group (p < .002). The 5‐ and 10‐ year progression‐free survival was worse in the Armenian group at 61.8% and 50.1%, respectively, compared with 87.5% and 87.5% in the non‐Armenian group (p < .001). Conclusion Armenian PTC patients displayed more aggressive disease than non‐Armenians. In addition, Armenian PTC patients had higher incidence of disease relapse and worse clinical outcomes. Level of Evidence 5 We conducted the first study comparing clinicopathologic variables and clinical outcomes of United States Armenian papillary thyroid cancer patients to a matched control group of non‐Armenians treated at City of Hope Comprehensive Cancer Center.

Solid organ transplantation is a life-saving procedure that has changed the prognosis for infants and children with end-stage organ disease. Cytomegalovirus (CMV) is one of the most common infections that occur after organ transplantation in pediatric patients, yet the standard of care for CMV prevention remains unclear. We review the literature regarding CMV disease effects, risk factors, diagnostics, prevention strategies, and antiviral treatment in pediatric solid organ transplantation. This discussion focuses on the current prevention strategies: prophylaxis, preemptive, and hybrid therapy, as well as novel strategies that may help better prevent the CMV disease in the pediatric solid organ transplant population.

Iodine and particularly its oxidated forms have long been recognized for its effective antiseptic properties. Limited and data suggest that iodine exposure may rapidly inactivate, reduce transmission, and reduce infectivity of SARS-CoV-2. We hypothesized that iodine exposure may be associated with decreased incident COVID-19 infection. A retrospective population-level cohort analysis was performed of the U.S. Veterans Health Administration between 1 March 2020 and 31 December 2020, before the widespread availability of vaccines against SARS-CoV-2. Multivariable logistic regression models estimated the adjusted odds ratios (OR) and 95% confidence intervals (CI) of the associations between iodinated contrast exposure and incident COVID-19 infection, adjusting for age, sex, race/ethnicity, place of residence, socioeconomic status, and insurance status. 530,942 COVID-19 tests from 333,841 Veterans (mean ± SD age, 62.7 ± 15.2 years; 90.2% men; 61.9% non-Hispanic Whites) were analyzed, of whom 9% had received iodinated contrast ≤60 days of a COVID-19 test. Iodine exposure was associated with decreased incident COVID-19 test positivity (OR, 0.75 95% CI, 0.71-0.78). In stratified analyses, the associations between iodinated contrast use and decreased COVID-19 infection risk did not differ by age, sex, and race/ethnicity. Iodine exposure may be protective against incident COVID-19 infection. Weighed against the risks of supraphysiologic iodine intake, dietary, and supplemental iodine nutrition not to exceed its Tolerable Upper Limit may confer an antimicrobial benefit against SARS-CoV-2. A safe but antimicrobial level of iodine supplementation may be considered in susceptible individuals, particularly in geographic regions where effective COVID-19 vaccines are not yet readily available.

Abstract Background Emerging studies demonstrate that some bone-modifying agents (BMAs), such as denosumab (Dmab), can modulate immune responses by increasing tumor-infiltrating T cells and expanding the T-cell repertoire. Female patients with breast cancer in particular often receive concurrent treatment with immune checkpoint inhibitors (ICI) and BMAs. However, the clinical impact of BMAs on immune-related adverse events (irAE) and cancer outcomes in patients treated with ICI remains poorly understood. Materials and methods Female patients with breast cancer treated with pembrolizumab between 2017 and 2024 were included. Patients were categorized according to BMA received: zoledronic acid (ZA), Dmab, or none. BMA therapy was considered received within a dose interval prior to ICI (12 months for ZA; 6 months for Dmab), during ICI therapy, or within 1 month of the last ICI dose. Results In a cohort of 425 female patients with breast cancer treated with pembrolizumab, 55 (12.9%) received Dmab, 31 (7.3%) received ZA, and 339 (80.0%) received no BMA. A total of 255 (60%) patients had early-stage breast cancer, and 170 (40%) had metastatic disease. After a median follow-up of 19.4 months (95% CI, 17.5-20.8), the incidence of severe irAE was higher in patients who received Dmab vs those who received no BMA (21.8% vs 11.5%, P = .04). Patients who received Dmab had higher responses (48.0%) compared to those who received ZA (31.6%) and no BMA (35.0%), although not statistically significant (P = .3). Conclusion This is the first study to suggest an increased rate of severe irAE and potential synergistic anti-tumor effect of Dmab in combination with ICI in female patients with breast cancer.

Abstract Introduction Extended-interval (EI) dosing of pembrolizumab (400 mg IV every 6 weeks) was approved across all solid tumors based on pharmacokinetic modeling and exposure-response analyses. Although EI dosing is more convenient for patients, whether the higher dose and extended dosing interval impacts immune-related adverse events (irAE) and clinical outcomes in patients with breast cancer is unknown. Methods In this retrospective cohort study, patients with breast cancer treated with pembrolizumab between 2017 and 2024 were included. Safety (irAE) and clinical outcomes including event-free survival (EFS), progression-free survival (PFS) and overall survival (OS) were compared between patients who received only standard-interval (SI) dosing (200 mg IV every 3 weeks) pembrolizumab and those who received ≥ 1 cycle of EI dosing. Results Of the 355 patients included, 59 (17%) received ≥ 1 cycle of EI and 296 (83%) received ≥ 1 cycle of only SI. Of those who received ≥ 1 cycle of pembrolizumab EI, 27 (45.8%) started with 200 mg, 7 (11.9%) started with 400 mg, 9 (15.2%) received only 400 mg, and 16 (27.1%) switched between dosing schedules. The majority (71%) of patients had early-stage disease, and 92% had triple-negative breast cancer. In patients with early-stage disease, rates of any-grade irAE were similar (p = 0.3), while grade 3 or higher irAE was lower in EI dosing versus SI (4% vs. 20%; p = 0.01). EFS and OS were similar between the two dosing regimens (p = 0.8 and p = 0.5, respectively). In patients with metastatic disease, any-grade irAE (p = 0.5), grade 3 or higher irAE (p = 0.1), PFS (p = 0.8), and OS (p = 0.5) were similar between the dosing regimens. Conclusion In this real-world study in which patients were often switched to EI dosing after initial SI therapy, safety and efficacy of EI dosing were maintained in patients with breast cancer. As more patients are treated with EI dosing, this data provides new evidence that switching to EI dosing is safe and effective, while improving medication burden for patients.

This dissertation examines the interaction of word prosody with prosodic temporal and tonal events at the phrasal level in Tokyo Japanese and aims to provide a unified account of the coordination relations between them within the framework of Articulatory Phonology. Previous research on phrase-final lengthening and boundary tone coordination in stress languages such as Greek has found that there is some coordination between lexical and phrasal prosodic events, as well as between tonal and temporal phrasal events. Specifically, research on the interaction between word prosody and boundary events in Greek indicates that lexical stress presents similar timing patterns with phrase-final lengthening as with boundary tone initiation, which suggests that these two types of boundary-marking events (i.e., phrase-final lengthening and boundary tones) are timed with respect to each other. This dissertation investigates these relations in a language with lexical pitch accent and proposes an account of the interaction of word prosody with boundary marking within the framework of Articulatory Phonology.In Articulatory Phonology, consonants and vowels are represented as sets of constriction gestures in the vocal tract. Tonal events are also represented as sets of tone gestures which unfold over time and can be coordinated with constriction gestures. Phenomena such as phrase-final lengthening are accounted for by π-gestures, which instantiate prosodic phrase boundaries and have clock-slowing effects on co-active speech gestures. We examine how these types of gestures are coordinated with each other in Japanese by analyzing kinematic and acoustic data of various Japanese words in controlled phrases. These data were collected using EMA (electromagnetic articulography) in experiments designed to test the interaction of lexical pitch accent position with phrase-final lengthening and boundary tone coordination. Three analyses were conducted on (i) the effect of pitch accent on the scope of phrase-final lengthening, (ii) the effect of pitch accent on boundary tone coordination, and (iii) the kinematic correlates of pitch accent per se. Lexical pitch accent position was found to have an effect on the scope of phrase-final lengthening such that the latter was initiated earlier in words with non-final pitch accent. These results imply that the tone gesture for the pitch accent is coordinated with the π-gesture. Similarly, pitch accent position was found to affect the timing of the boundary tone, which was initiated earlier in words with earlier pitch accent. Finally, no robust kinematic correlate of pitch accent was detected. On the basis of these finding, a final account is proposed where the lexical pitch accent gesture is coordinated anti-phase with the boundary tone, which in turn affects πgesture coordination. This account considers tonal and temporal prosodic events together, which may provide a more complete view of intonation and of how word- and phrase-level events are connected.

Background The incidence of intrathyroidal parathyroid adenoma varies from <1% to 6% and can be a diagnostic dilemma. Intrathyroidal parathyroid adenomas can have suspicious sonographic features that prompt fine needle aspiration (FNA) to evaluate for thyroid cancer. Differentiation between thyroid and parathyroid tissue on cytology can be difficult, and these lesions may be diagnosed as indeterminate thyroid nodules. Molecular testing is a useful adjunct that allows for identification of parathyroid adenomas in this setting. Clinical Case A 59-year-old female with osteopenia and a recent history of traumatic vertebral fracture presented for workup of asymptomatic hypercalcemia. Labs showed intact parathyroid hormone (iPTH) 168 pg/mL (reference 11-51 pg/mL), serum total calcium 12.2 mg/dL (reference range 8.6-10.4 mg/dL), albumin 4.7 g/dL (reference 4.1-5.3 g/dL), phosphorus 2.1 mg/dL (reference 2.3-4.4 mg/dL), creatinine 0.7 (reference 0.6-1.3 mg/dL), and 25-OH vitamin of 28 ng/mL (reference 20-50 ng/mL). Cervical ultrasound showed a 2.1 cm hypoechoic left thyroid nodule. Subsequent 99mTc-Sesatmibi scan showed increased tracer retention in the left posterior thyroid lobe. FNA of the left thyroid nodule was performed with cytology showing follicular lesion of undetermined significance (FLUS). Molecular testing with Thyroseq v2 showed parathyroid tissue consistent with intrathyroidal parathyroid adenoma. The patient underwent successful left thyroid lobectomy with removal of an intrathyroidal parathyroid gland, with subsequent decrease of iPTH to 44 pg/mL (reference 11-51 pg/mL) and total serum calcium to 9.5 mg/dL (reference 8.6-10.4 mg/dL). Surgical pathology confirmed parathyroid adenoma. Discussion Due to the ubiquity of thyroid FNAs to rule out malignancy, there has been a rise in the number of incidental parathyroid gland aspirations. Thyroid lesions with diagnosis of FLUS or oncocytic features are prone to misdiagnosis due to similarities in morphologic overlap and anatomic proximity. Molecular testing such as Thyroseq v2 routinely tests for PTH and can identify parathyroid tissue in lesions initially diagnosed as indeterminate thyroid nodules. Newer molecular test versions including ThyroSeq v3 similarly have high analytical accuracy in detecting thyroid cancer and parathyroid lesions. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Disclosure: R. Hilder: None. T. Karen: None. D. Isaacs: None. A. Drakaki: None. M.G. Lechner: None. Introduction: Immune checkpoint inhibitors have revolutionized cancer therapy, producing dramatic tumor shrinkage and durable responses in many advanced malignancies. A limitation of their use is the development of unwanted autoimmunity in healthy tissues, known as Immune Related Adverse Effects (IRAEs), that occur in up to 60% of patients and often affect endocrine organs. For this reason, patients with pre-existing autoimmune diseases, including type 1 diabetes mellitus, have systemically been excluded from clinical trials of ICI therapy. This exclusion has translated to current clinical practice and therefore little is known about the safety and efficacy of ICI in this population. Here we report, for the first time, outcomes in ICI-treated patients with pre-existing T1DM. Methods: This retrospective cohort study included adult patients who received an-FDA approved ICI therapy for solid malignancies from 2015-2021 at two academic medical centers (UCLA Health and City of Hope) and had a diagnosis of T1DM prior to starting ICI. ICD-10 codes E10.9 and E10.65 identified 58 patients with T1DM, screened by manual chart review for inclusion. Patients with prior ICI therapy, bone marrow transplant, or pregnancy were excluded. We collected data on demographic, cancer diagnosis and treatment (stage, ICI therapy, response), Grade 3 or 4 IRAEs [classified by the NIH Common Terminology Criteria for Adverse Events (CTCAE) V5] and diabetes management during ICI therapy, including the incidence of significant hyperglycemia, diabetic ketoacidosis (DKA), and the use of technology. Results: Of 7545 ICI treated cancer patients, we identified five with a pre-existing diagnosis of T1DM. Three were female and mean age was 58 years (range 37-79). All patients were diagnosed with metastatic cancer (cervical, lung and breast) and were treated with anti-PD1/PDL1 monotherapy: Nivolumab, Durvalumab, or Pembrolizumab. Two patients had Grade 3 hepatitis, one of which with concurrent myositis requiring prolonged corticosteroids and IVIG. Both patients recovered with cessation of ICI. Regarding other endocrine IRAEs, one patient had pre-existing hypothyroidism and another developed ICI-thyroiditis during ICI therapy; both were treated with thyroid hormone replacement. Four (80%) utilized insulin pump therapy while on immunotherapy. No patients were hospitalized for DKA or complications of hyperglycemia during ICI therapy. Regarding tumor response to ICI, two patients had complete response, two with partial response, and one was deceased shortly after starting therapy. Discussion: Based on this data, ICI monotherapy can successfully be used in patients with pre-existing T1DM, but patients should be counseled on the risk of IRAEs; in particular hepatitis. Larger, prospective studies of these potentially life-saving ICI therapies that include patients with pre-existing autoimmunity are warranted. Presentation: Thursday, June 15, 2023