Citations

Summary: Background: Peripheral artery disease (PAD) is a risk factor for adverse limb events (LE) and cardiovascular events (CVE) that coexists with type 1 (T1) and 2 (T2) diabetes mellitus (DM). Little is known about comparative risk of LE and CVE in T1/T2 DM patients with PAD. Patients and methods: We queried our database of 40,144 patients ≥18 years old who underwent ankle brachial index (ABI) measurement from 01/1996-02/2020. We isolated T1/T2 DM patients with PAD diagnosed by ankle brachial index (ABI; low [<1.0] or elevated [>1.4]) and retrieved demographics including glycated hemoglobin (HbA1c). Primary outcomes were LE (critical limb ischemia/vascular amputation) and CVE (myocardial infarction/ischemic stroke). All-cause mortality was a secondary outcome. Multivariable Cox proportional regression yielded hazard ratios (HR) with 95% confidence intervals (CI) after adjusting for pertinent risk factors including age, hypertension, hyperlipidemia, smoking, and HbA1c. Results: Our study found 10,156 patients with PAD and DM (34% T1DM, 66% T2DM) with median follow-up time 34 mo (IQR 85 mo). T1DM patients were younger than T2DM (mean age 67 vs. 70 years), with higher median HbA1c (7.7 [IQR 1.9] vs. 6.7% [IQR 1.6]), and more prevalent hypertension, hyperlipidemia, CAD, and CKD. Antiplatelet and statin use was equivocal. Elevated ABI was more common in T1DM (47 vs. 28%). LE occurred in 23% and CVE in 12% patients. LE risk was higher in T1 than T2 DM patients (HR 1.58 [95% CI 1.44, 1.73], p<0.0001), but CVE and all-cause mortality were equivocal. These observations were preserved across ABI and HbA1c subgroup analyses. Conclusions: PAD patients with T1DM had a higher LE risk than those with T2DM, even after adjustment for glycemic control and pertinent risk factors, but CVE risk and all-cause mortality were equivocal. These data suggest a potential role for more intensive LE risk modification in PAD patients with T1DM, but further investigation is needed.

AbstractMutations leading to colony‐stimulating factor‐1 receptor (CSF‐1R) loss‐of‐function or haploinsufficiency cause CSF1R‐related leukoencephalopathy (CRL), an adult‐onset disease characterized by loss of myelin and neurodegeneration, for which there is no effective therapy. Symptom onset usually occurs in the fourth decade of life and the penetrance of disease in carriers is high. However, familial studies have identified a few carriers of pathogenic CSF1R mutations that remain asymptomatic even in their seventh decade of life, raising the possibility that the development and severity of disease might be influenced by environmental factors. Here we report new cases in which long‐term glucocorticoid treatment is associated with asymptomatic status in elder carriers of pathogenic CSF‐1R mutations. The main objective of the present study was to investigate the link between chronic immunosuppression initiated pre‐symptomatically and resistance to the development of symptomatic CRL, in the Csf1r+/− mouse model. We show that chronic prednisone administration prevents the development of memory, motor coordination and social interaction deficits, as well as the demyelination, neurodegeneration and microgliosis associated with these deficits. These findings are in agreement with the preliminary clinical observations and support the concept that pre‐symptomatic immunosuppression is protective in patients carrying pathogenic CSF1R variants associated with CRL. Proteomic analysis of microglia and oligodendrocytes indicates that prednisone suppresses processes involved in microglial activation and alleviates senescence and improves fitness of oligodendrocytes. This analysis also identifies new potential targets for therapeutic intervention.

AbstractWe performed a cross‐sectional study to determine associations between cognition and MRI‐derived brain outcomes, with obesity, diabetes duration, and metabolic risk factors in 51 Pima American Indians with longstanding type 2 diabetes (T2d) (mean [SD] age: 48.4 [11.3] years, T2d duration: 20.1 [9.1] years). Participants had similar cognition (NIH Toolbox Cognition Battery composite: 45.3 [9.8], p = 0.64, n = 51) compared to normative data. T2d duration, but not other metabolic risk factors, associated with decreased cortical thickness (Point Estimate (PE): −0.0061, 95%CI: −0.0113, −0.0009, n = 45), gray matter volume (PE: −830.39, 95%CI: −1503.14, −157.64, n = 45), and increased white matter hyperintensity volume (PE: 0.0389, 95%CI: 0.0049, 0.0729, n = 45).

AbstractBACKGROUNDDelirium, a common syndrome with heterogeneous etiologies and clinical presentations, is associated with poor long‐term outcomes. Recording and analyzing all delirium equally could be hindering the field's understanding of pathophysiology and identification of targeted treatments. Current delirium subtyping methods reflect clinically evident features but likely do not account for underlying biology.METHODSThe Delirium Subtyping Initiative (DSI) held three sessions with an international panel of 25 experts.RESULTSMeeting participants suggest further characterization of delirium features to complement the existing Diagnostic and Statistical Manual of Mental Disorders Fifth Edition Text Revision diagnostic criteria. These should span the range of delirium‐spectrum syndromes and be measured consistently across studies. Clinical features should be recorded in conjunction with biospecimen collection, where feasible, in a standardized way, to determine temporal associations of biology coincident with clinical fluctuations.DISCUSSIONThe DSI made recommendations spanning the breadth of delirium research including clinical features, study planning, data collection, and data analysis for characterization of candidate delirium subtypes.Highlights Delirium features must be clearly defined, standardized, and operationalized. Large datasets incorporating both clinical and biomarker variables should be analyzed together. Delirium screening should incorporate communication and reasoning.

AbstractGynecological malignancies are a significant cause of morbidity and mortality across the globe. Due to delayed presentation, gynecological cancer patients are often referred late in the disease's course, resulting in poor outcomes. A considerable number of patients ultimately succumb to chemotherapy‐resistant disease, which reoccurs at advanced stages despite treatment interventions. Although efforts have been devoted to developing therapies that demonstrate reduced resistance to chemotherapy and enhanced toxicity profiles, current clinical outcomes remain unsatisfactory due to treatment resistance and unfavorable off‐target effects. Consequently, innovative biological and nanotherapeutic approaches are imperative to strengthen and optimize the therapeutic arsenal for gynecological cancers. Advancements in nanotechnology‐based therapies for gynecological malignancies offer significant advantages, including reduced toxicity, expanded drug circulation, and optimized therapeutic dosing, ultimately leading to enhanced treatment effectiveness. Recent advances in nucleic acid therapeutics using microRNA, small interfering RNA, and messenger RNA provide novel approaches for cancer therapeutics. Effective single‐agent and combinatorial nucleic acid therapeutics for gynecological malignancies have the potential to transform cancer treatment by giving safer, more tailored approaches than conventional therapies. This review highlights current preclinical studies that effectively exploit these approaches for the treatment of gynecological malignant tumors and malignant ascites.

Electrophysiology is the study of the electrical properties of biological tissues, which involves the movement of ions across cell membranes. The analysis of the movement of electrical charges through the body has a wide range of biomedical applications, such as diagnosing and planning treatment in cardiovascular, nervous systems, muscular, and gastrointestinal disorders. The dielectric properties of biological tissues change according to the water content in the tissue and are measured as permittivity and conductivity relative to the frequency of the electrical field. This principle has been applied in diagnostics and therapeutics using microwave energysuch as imaging and ablation, etc. This review article summarizes the potential use of measuring dielectric properties using microwave imaging and how it can augment electrophysiological studies in medicine.

Purpose: To investigate the feasibility of using cone-beam computed tomography (CBCT)-derived synthetic CTs to monitor the daily dose and trigger a plan review for adaptive proton therapy (APT) in head and neck cancer (HNC) patients. Methods: For 84 HNC patients treated with proton pencil-beam scanning (PBS), same-day CBCT and verification CT (vfCT) pairs were retrospectively collected. The ground truth CT (gtCT) was created by deforming the vfCT to the same-day CBCT, and it was then used as a dosimetric baseline and for establishing plan review trigger recommendations. Two different synthetic CT algorithms were tested; the corrected CBCT (corrCBCT) was created using an iterative image correction method and the virtual CT (virtCT) was created by deforming the planning CT to the CBCT, followed by a low-density masking process. Clinical treatment plans were recalculated on the image sets for evaluation. Results: Plan review trigger criteria for adaptive therapy were established after closely reviewing the cohort data. Compared to the vfCT, the corrCBCT and virtCT reliably produced dosimetric data more similar to the gtCT. The average discrepancy in D99 for high-risk clinical target volumes (CTV) was 1.1%, 0.7%, and 0.4% and for standard-risk CTVs was 1.8%, 0.5%, and 0.5% for the vfCT, corrCBCT, and virtCT, respectively. Conclusion: Streamlined APT has been achieved with the proposed plan review criteria and CBCT-based synthetic CT workflow.

Though specific growth rate (SGR) has potential prognostic value for oropharyngeal squamous cell carcinoma (OPSCC), there is sparse literature defining these rates. Our aims were to establish the SGRs of primary tumors (PTs) and lymph nodes (LNs) in OPSCC and to correlate SGR with oncologic outcome. A pilot study was designed with a retrospective analysis examining 54 patients from the University of California, Davis with OPSCC (diagnosed 2012–2019). Radiation oncology software and pretreatment serial CT scans were used to measure PT and LN volumes to calculate SGR and doubling time (DT). The mean PT-SGR was 1.2 ± 2.2%/day and the mean LN-SGR was 1.6 ± 1.9%/day. There was no statistically significant difference between slow-growing and fast-growing cohorts in terms of age, gender, smoking status, tumor subsite, HPV status (as determined with p16 staining), initial volume, or overall stage. SGR had no impact on 2-year overall survival, disease-free survival, or disease-specific survival. We found the average daily growth rates for OPSCC to be 1.2%/day and 1.6%/day. Our findings suggest PT- and LN-SGR are independent factors, not heavily influenced by known biomarkers and patient characteristics, without a statistical impact on prognosis. This information has value in patient counseling regarding tumor growth and in providing patients worried about fast-growing tumors the appropriate reassurance.

Bromodomains (BD) are epigenetic readers of histone acetylation involved in chromatin remodeling and transcriptional regulation of several genes including protooncogene cellular myelocytomatosis (c-Myc). c-Myc is difficult to target directly by agents due to its disordered alpha helical protein structure and predominant nuclear localization. The epigenetic targeting of c-Myc by BD inhibitors is an attractive therapeutic strategy for prostate cancer (PC) associated with increased c-Myc upregulation with advancing disease. MT-1 is a bivalent BD inhibitor that is 100-fold more potent than the first-in-class BD inhibitor JQ1. MT-1 decreased cell viability and causes cell cycle arrest in G0/G1 phase in castration-sensitive and resistant PC cell lines in a dose-dependent fashion. The inhibition of c-Myc function by MT-1 was molecularly corroborated by the de-repression of Protein Kinase D1 (PrKD) and increased phosphorylation of PrKD substrate proteins: threonine 120, serine 11, and serine 216 amino acid residues in β-Catenin, snail, and cell division cycle 25c (CDC25c) proteins, respectively. The treatment of 3D cell cultures derived from three unique clinically annotated heavily pretreated patient-derived PC xenografts (PDX) mice models with increasing doses of MT-1 demonstrated the lowest IC50 in tumors with c-Myc amplification and clinically resistant to Docetaxel, Cabazitaxel, Abiraterone, and Enzalutamide. An intraperitoneal injection of either MT-1 or in combination with 3jc48-3, an inhibitor of obligate heterodimerization with MYC-associated protein X (MAX), in mice implanted with orthotopic PC PDX, decreased tumor growth. This is the first pre-clinical study demonstrating potential utility of MT-1 in the treatment of PC with c-Myc dysregulation.

Introduction: Oral glucose tolerance testing is recommended for all children with CF older than 9 years, yet compliance remains poor across centers. Methods: We performed a small pilot study assessing the glycemic curves and participant satisfaction in seven children and adolescents. Results: We chose a dextrose-based candy (Nerds®) free of any fat, fiber, gelatin, or corn syrup and performed the candy OGTT 1–4 days following the standard oral dextrose solution OGTT. Glucose values at 120 min were similar between the candy and oral dextrose solution (p = 0.8986). Conclusions: Our small pilot suggests that a carefully selected candy alternative may result in similar glycemic OGTT when compared to the standard oral dextrose solution. However, some participants preferred the oral dextrose solution to candy due to having to consume a large volume in a short period of time. This may have significant implications as centers consider candy alternatives to increase OGTT adherence rates.