Publications

The limb is a commonly used model system for developmental biology. Given the need for precise control of complex signalling pathways to achieve proper patterning, the limb is also becoming a model system for gene regulation studies. Recent developments in genomic technologies have enabled the genome-wide identification of regulatory elements that control limb development, yielding insights into the determination of limb morphology and forelimb versus hindlimb identity. The modulation of regulatory interactions - for example, through the modification of regulatory sequences or chromatin architecture - can lead to morphological evolution, acquired regeneration capacity or limb malformations in diverse species, including humans.

BACKGROUND & AIMS

The most commonly used noninvasive test for colorectal cancer (CRC) screening has been the guaiac fecal occult blood test (gFOBT). The fecal immunochemical test (FIT) detects CRC and colorectal polyps with higher levels of sensitivity than the gFOBT, and may be more acceptable to patients. However, the FIT has not replaced the gFOBT in many clinical settings. We analyzed data from a large healthcare system that replaced the gFOBT with the FIT to determine the effects on CRC screening.

METHODS

We conducted a retrospective observational study of 7898 patients at the Veterans' Administration San Diego Healthcare System, 50-75 years old, who were offered stool-based CRC screening as part of primary care March 2014 through January 2015. Test orders and results were extracted from electronic health records; we performed manual reviews of colonoscopy and pathology reports for Veterans with positive results from the tests. Our primary outcome was test completion within 1 year of order; secondary outcomes were positive results and detection of advanced neoplasia by diagnostic colonoscopy. The primary analysis used an intention-to-screen approach, which included all patients with test orders; as-screened analyses were also performed.

RESULTS

Among 7898 patients, 3236 had gFOBT and 4662 FIT orders. In the intention to screen analysis, a significantly higher proportion of subjects completed a FIT (42.6%) than a gFOBT (33.4%) (P < .001); advanced neoplasia was detected in a significantly higher proportion of subjects offered a FIT (0.79%) than a gFOBT (0.28%) (P = .003). The numbers needed to invite to achieve 1 additional completed test and identify 1 additional patient with advanced neoplasia were 11 and 196, respectively.

CONCLUSIONS

In a retrospective study of patients at a Veterans' administration healthcare system, replacing the gFOBT with the FIT increased the proportion of patients who completed CRC screening. Replacement of the gFOBT with the FIT should be strongly considered by all healthcare systems.

BACKGROUND AND AIMS

Lower GI bleeding (LGIB) is a common cause of morbidity and mortality. Colonoscopy is indicated in all hospitalized patients with LGIB, yet the time frame for performing colonoscopy remains unclear. Prior studies of outcomes in urgent versus elective colonoscopy have yielded conflicting results and were often underpowered. Our study objective was to compare several outcomes between urgent and elective colonoscopy in patients hospitalized for LGIB.

METHODS

Systematic review and meta-analysis were performed on studies that compared urgent and elective colonoscopy in patients with LGIB. Pooled rates were calculated for specific outcomes, and rate ratios were determined for selected comparison groups.

RESULTS

Twelve studies met inclusion criteria, with a total sample size of 10,172 patients in the urgent colonoscopy arm and 14,224 patients in the elective colonoscopy arm. Urgent colonoscopy was associated with increased use of endoscopic therapeutic intervention (RR, 1.70; 95% CI, 1.08-2.67). There were no significant differences in bleeding source localization (RR, 1.08; 95% CI, .92-1.25), adverse event rates (RR, 1.05; 95% CI, .65-1.71), rebleeding rates (RR, 1.14; 95% CI, .74-1.78), transfusion requirement (RR, 1.02; 95% CI, .73-1.41), or mortality (RR, 1.17; 95% CI, .45-3.02).

CONCLUSIONS

Urgent colonoscopy appears to be safe and well tolerated, but there is no clear evidence that it alters important clinical outcomes.

Hepatic steatosis (HS) is common in individuals with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections, but the independent contributions of HCV and HIV to HS are unclear. Magnetic resonance imaging and spectroscopy were used to measure visceral adipose tissue (VAT) and liver fat fraction (LFF) (total lipids/[total lipids + water]) in 356 adults: 57 with HCV monoinfection, 70 with HIV/HCV coinfection, 122 with HIV monoinfection, and 107 with neither infection. Participants who were infected with HCV genotype 3 were excluded because of the genotype's reported steatogenic effects. For prevalence estimates, HS was defined as LFF ≥ 0.05. We estimated the association of HIV and HCV status with LFF using multivariable linear regression, adjusting for demographics, lifestyle, and metabolic factors including the homeostasis model assessment estimate of insulin resistance (HOMA-IR) and liver fibrosis defined using the aspartate aminotransferase-to-platelet ratio index (APRI). The prevalence of HS was highest in the uninfected (33%) and HIV-monoinfected (28%), followed by the HCV-monoinfected (19%) and HIV/HCV-coinfected (11%) (P = 0.003 across groups). Compared with uninfected participants-and after adjusting for demographics, lifestyle, and metabolic factors-HIV monoinfection, HCV monoinfection, and HIV/HCV coinfection were associated with 19% (95% confidence interval [CI], -39% to 6%), 38% (95% CI, -55% to -12%), and 42% (95% CI, -59% to -18%) lower LFF, respectively. HCV monoinfection and HIV/HCV coinfection remained strongly associated with lower LFF after further adjusting for APRI, and results were unchanged after excluding subjects with suspected cirrhosis. Among the entire cohort, Hispanic ethnicity, male sex, VAT, and HOMA-IR were independently associated with greater LFF.

CONCLUSION

Contrary to expectations, HIV/HCV-coinfected and HCV-monoinfected adults had significantly less liver fat than uninfected adults, even after adjusting for demographics, lifestyle, metabolic factors, and hepatic fibrosis. Our findings suggest that non-genotype 3 HCV infection may be protective against HS. The mechanisms by which this occurs and the impact of HCV treatment on HS requires further investigation. (Hepatology 2017;65:853-863).

Lymphocytes integrate Ag and cytokine receptor signals to make cell fate decisions. Using a specific reporter of TCR signaling that is insensitive to cytokine signaling, Nur77-eGFP, we identify a sharp, minimal threshold of cumulative TCR signaling required for proliferation in CD4 and CD8 T cells that is independent of both Ag concentration and affinity. Unexpectedly, IL-2 reduces this threshold in CD8 but not CD4 T cells, suggesting that integration of multiple mitogenic inputs may alter the minimal requirement for TCR signaling in CD8 T cells. Neither naive CD4 nor naive CD8 T cells are responsive to low doses of IL-2. We show that activated CD8 T cells become responsive to low doses of IL-2 more quickly than CD4 T cells, and propose that this relative delay in turn accounts for the differential effects of IL-2 on the minimal TCR signaling threshold for proliferation in these populations. In contrast to Nur77-eGFP, c-Myc protein expression integrates mitogenic signals downstream of both IL-2 and the TCR, yet marks an invariant minimal threshold of cumulative mitogenic stimulation required for cell division. Our work provides a conceptual framework for understanding the regulation of clonal expansion of CD8 T cells by subthreshold TCR signaling in the context of mitogenic IL-2 signals, thereby rendering CD8 T cells exquisitely dependent upon environmental cues. Conversely, CD4 T cell proliferation requires an invariant minimal intensity of TCR signaling that is not modulated by IL-2, thereby restricting responses to low-affinity or low-abundance self-antigens even in the context of an inflammatory milieu.