Citations

During contrast-enhanced ultrasound (CEUS) imaging of tumor microvascular perfusion, nearby arteriole enhancement can be a dominant feature of the wash-in kinetics that obscures the perfusion characteristics of the capillary bed. This presentation demonstrates that statistical wash-in curves generated using our compound CEUS speckle model1 exhibit two distinct phases corresponding to “fast-flow” and “slow-flow” enhancement that can be detected by fitting a linear combination of two monoexponential functions with different time constants. CEUS cine loops were acquired from a patient-derived xenograft model of renal cell carcinoma, where fresh tumor fragments were engrafted into the chicken embryo chorioallantoic membrane. Subharmonic CEUS images were acquired at 18 MHz using a destruction-replenishment protocol. Enhancement of manually segmented tumor cross-sections was analyzed offline in MATLAB. The CEUS cine loops from this xenograft model frequently exhibited in-plane arteriole enhancement. The two-phase fit discriminated a slow-flow component in 26.6% of time-intensity wash-in curves and 62.9% of the statistical wash-in curves, leading to a decrease in estimated tumor blood volume by 22.1% and 24.7%, respectively, compared to a simple monoexponential fit. These results suggest that conventional CEUS processing may frequently overestimate capillary blood volume. 1M.R. Lowerison et al., Med. Phys. 44, 99-111 (2017).

Background For many patients with kidney failure, the cause and underlying defect remain unknown. Here, we describe a novel mechanism of a genetic order characterized by renal Fanconi syndrome and kidney failure. Methods We clinically and genetically characterized members of five families with autosomal dominant renal Fanconi syndrome and kidney failure. We performed genome-wide linkage analysis, sequencing, and expression studies in kidney biopsy specimens and renal cells along with knockout mouse studies and evaluations of mitochondrial morphology and function. Structural studies examined the effects of recognized mutations. Results The renal disease in these patients resulted from monoallelic mutations in the gene encoding glycine amidinotransferase (GATM), a renal proximal tubular enzyme in the creatine biosynthetic pathway that is otherwise associated with a recessive disorder of creatine deficiency. In silico analysis showed that the particular GATM mutations, identified in 28 members of the five families, create an additional interaction interface within the GATM protein and likely cause the linear aggregation of GATM observed in patient biopsy specimens and cultured proximal tubule cells. GATM aggregates-containing mitochondria were elongated and associated with increased ROS production, activation of the NLRP3 inflammasome, enhanced expression of the profibrotic cytokine IL-18, and increased cell death. Conclusions In this novel genetic disorder, fully penetrant heterozygous missense mutations in GATM trigger intramitochondrial fibrillary deposition of GATM and lead to elongated and abnormal mitochondria. We speculate that this renal proximal tubular mitochondrial pathology initiates a response from the inflammasome, with subsequent development of kidney fibrosis.

AbstractThe objective of this study was to assess the recommended DVH parameter (e.g., D2 cc) addition method used for combining EBRT and HDR plans, against a reference dataset generated from an EQD2‐based DVH addition method. A revised DVH parameter addition method using EBRT DVH parameters derived from each patient's plan was proposed and also compared with the reference dataset. Thirty‐one biopsy‐proven cervical cancer patients who received EBRT and HDR brachytherapy were retrospectively analyzed. A parametrial and/or paraaortic EBRT boost were clinically performed on 13 patients. Ten IMRT and 21 3DCRT plans were determined. Two different HDR techniques for each HDR plan were analyzed. Overall D2 cc and D0.1 cc OAR doses in EQD2 were statistically analyzed for three different DVH parameter addition methods: a currently recommended method, a proposed revised method, and a reference DVH addition method. The overall D2 ccEQD2 values for all rectum, bladder, and sigmoid for a conformal, volume optimization HDR plan generated using the current DVH parameter addition method were significantly underestimated on average −5 to −8% when compared to the values obtained from the reference DVH addition technique (P < 0.01). The revised DVH parameter addition method did not present statistical differences with the reference technique (P > 0.099). When PM boosts were considered, there was an even greater average underestimation of −8~−10% for overall OAR doses of conformal HDR plans when using the current DVH parameter addition technique as compared to the revised DVH parameter addition. No statistically significant differences were found between the 3DCRT and IMRT techniques (P > 0.3148). It is recommended that the overall D2 cc EBRT doses are obtained from each patient's EBRT plan.

Background: A shorter sleep duration has been identified as a risk factor for cardiovascular diseases and increased mortality. It has been hypothesized that a short sleep duration may be linked to changes in ghrelin and leptin production, leading to an alteration of stress hormone production. Here, we conducted a systematic review and meta-analysis to investigate the potential relationship between a sleep duration and cardiovascular disease mortality. Methods: We conducted a comprehensive search of Ovid Medline In-Process and other non-indexed citations, Ovid MEDLINE, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, and Scopus from database inception to March 2017. Observational studies were included if the studies reported hazard ratios or odds ratios of the associations between sleep durations (short and long) and cardiovascular disease mortality. Data were extracted by a reviewer and then reviewed by two separate reviewers. Conflicts were resolved through consensus. Using the DerSimonian and Laird random effects models, we calculated pooled hazard ratios and pooled odds ratios with 95% confidence intervals (CI). Subgroup analyses were performed to explore potential sources of heterogeneity. The quality of the included studies and publication bias were assessed. Results: In total, our meta-analysis included 19 studies (31 cohorts) with a total of 816,995 individuals with 42,870 cardiovascular disease mortality cases. In pooled analyses, both short (risk ratio 1.19; 95% CI 1.13 to 1.26, P<0.001, I2=30.7, Pheterogeneity=0.034), and long (risk ratio 1.37; 95% CI 1.23 to 1.52, P<0.001, I2=79.75, Pheterogeneity<0.001) sleep durations were associated with a greater risk of cardiovascular disease mortality. Conclusions: Both short (<7 hours) and long sleep durations (>9 hours) can increase the risk of overall cardiovascular disease mortality, particularly in Asian populations and elderly individuals. Future epidemiological studies would ideally include objective sleep measurements, rather than self-report measures, and all potential confounders, such as genetic variants.

Purpose To identify common and overlapping themes among the interpersonal and communication skills (ICS), practice-based learning and improvement (PBLI), professionalism (PROF), and systems-based practice (SBP) milestones of the transitional year and 26 specialties. Method In May 2017, milestones were accessed from the Accreditation Council for Graduate Medical Education specialties website. A thematic analysis of the ICS, PBLI, PROF, and SBP milestones was performed to determine unique and common themes across these competencies and across specialties. Keywords from the common program requirements were initially applied as codes to the milestones. Codes were then grouped into common themes. Results Twenty-two themes were identified: 15 (68%) were unique to a given competency (3 related to ICS, 4 related to PBLI, 5 related to PROF, and 3 related to SBP), and 7 (32%) appeared in the milestones of more than one core competency. Eleven themes (50%) were used by 20 or more specialties, and 6 themes (27%) by 10 or fewer specialties. No theme was present across all specialties. Conclusions The ICS, PBLI, PROF, and SBP milestones contain multiple themes with areas of overlap among these four competencies and substantial variability across specialties. This variability may create differential expectations of residents across specialties, complicate faculty development, and make sharing assessment tools difficult. The thematic analysis provides important insights into how individual specialties interpret and operationalize the ICS, PBLI, PROF, and SBP competency domains and can inform future revisions of milestones to enable harmonization and shared understanding of these competencies across specialties where appropriate.