How Point-of-Care Ultrasound Led to a Diagnosis of May-Thurner Syndrome.

A 65-year-old man with a history of a left-sided inguinal hernia presented with three days of left-sided groin pain worsened with exertion and fatigue. The patient was afebrile but tachycardic, and physical examination revealed a tender, erythematous immobile bulge in his left groin. Laboratory studies revealed leukocytosis. Lymphadenopathy secondary to infectious or inflammatory etiology was suspected. However, point-of-care ultrasound (POCUS) identified extensive deep vein thrombosis (DVT) of the lower left limb. Follow-up imaging revealed this to be secondary to May-Thurner syndrome, a mechanical compression of an iliocaval vein against the lumbar vertebrae by a common iliac artery. This report demonstrates how POCUS can be used to identify lower extremity DVT, thereby expediting diagnosis and treatment and potentially preventing complications.

Associations of Performance-Based Functional Assessments and Adverse Outcomes in CKD.

Background: The comparative utility of performance-based functional assessments in predicting adverse outcomes in CKD is unknown. To examine their relative utility, we examined three performance-based functional assessments in an observational cohort of patients with CKD. Methods: We recruited 350 participants with stage II-V, predialysis CKD. Participants were administered three performance-based functional assessments: Short Physical Performance Battery (SPPB), Modified Mini-Mental Status Exam (M3SE), and Lawton Instrumental Activities of Daily Living (IADL). Scores were dichotomized on the basis of the median and combined into a summary score. Outcomes included 50% GFR reduction, ESKD, and death. We used Cox proportional hazards to assess the association of performance-based functional assessments with outcomes. Results: Compared with high performers, low SPPB performers had the highest adjusted rate of death, ESKD, or 50% reduction in GFR (HR, 1.96; 95% CI, 1.28 to 2.99). Low SPPB had the strongest association with death when adjusted for multiple covariates (HR, 2.43; 95% CI, 1.36 to 4.34). M3SE performance was not associated with any adverse outcome. None of the performance-based functional assessments were associated with ESKD, but a low IADL score was associated with a lower hazard ratio for ESKD or 50% decline GFR (HR, 0.49; 95% CI, 0.24 to 1.00). Conclusions: Low SPPB score was the strongest predictor of death and all adverse outcomes as a composite. Future trials should determine if outcomes for patients with CKD who have poor physical performance and low SPPB scores are improved by targeted interventions. Clinical Trial registry name and registration number: Safe Kidney Care Cohort Study, NCT01407367.

Vitamin D Deficiency Promotes Liver Tumor Growth in Transforming Growth Factor-ß/Smad3-Deficient Mice Through Wnt and Toll-like Receptor 7 Pathway Modulation.

Disruption of the TGF-ß pathway is associated with liver fibrosis and suppression of liver tumorigenesis, conditions associated with low Vitamin D (VD) levels. However, potential contributions of VD to liver tumor progression in the context of TGF-ß signaling remain unexplored. Our analyses of VD deprivation (VDD) in in vivo models of liver tumor formation revealed striking three-fold increases in tumor burden in Smad3(+/-) mice, with a three-fold increase in TLR7 expression compared to controls. ChIP and transcriptional assays confirm Smad3 binding at two TLR7 promoter SBE sites. Molecular interactions between TGF-ß pathway and VDD were validated clinically, where an absence of VD supplementation was associated with low TGF-ß pathway member expression levels and ß-catenin activation in fibrotic/cirrhotic human liver tissues. Subsequent supplementing VD led to restoration of TGF-ß member expression with lower ß-catenin levels. Bioinformatics analysis provides positive supportive correlation between somatic mutations for VD-related genes and the TGF-ß pathway. We conclude that VDD promotes tumor growth in the context of Smad3 disruption, potentially through regulation of TLR7 expression and ß-catenin activation. VD could therefore be a strong candidate for liver cancer prevention in the context of aberrant Smad3 signaling.

Mutational Profiles Reveal an Aberrant TGF-ß-CEA Regulated Pathway in Colon Adenomas.

Mutational processes and signatures that drive early tumorigenesis are centrally important for early cancer prevention. Yet, to date, biomarkers and risk factors for polyps (adenomas) that inordinately and rapidly develop into colon cancer remain poorly defined. Here, we describe surprisingly high mutational profiles through whole-genome sequence (WGS) analysis in 2 of 4 pairs of benign colorectal adenoma tissue samples. Unsupervised hierarchical clustered transcriptomic analysis of a further 7 pairs of adenomas reveals distinct mutational signatures regardless of adenoma size. Transitional single nucleotide substitutions of C:G>T:A predominate in the adenoma mutational spectrum. Strikingly, we observe mutations in the TGF-ß pathway and CEA-associated genes in 4 out of 11 adenomas, overlapping with the Wnt pathway. Immunohistochemical labeling reveals a nearly 5-fold increase in CEA levels in 23% of adenoma samples with a concomitant loss of TGF-ß signaling. We also define a functional role by which the CEA B3 domain interacts with TGFBR1, potentially inactivating the tumor suppressor function of TGF-ß signaling. Our study uncovers diverse mutational processes underlying the transition from early adenoma to cancer. This has broad implications for biomarker-driven targeting of CEA/TGF-ß in high-risk adenomas and may lead to early detection of aggressive adenoma to CRC progression.