Publications

BACKGROUND

A simple endoscopic classification to accurately predict deep submucosal invasive (SM-d) carcinoma would be clinically useful.

OBJECTIVE

To develop and assess the validity of the NBI international colorectal endoscopic (NICE) classification for the characterization of SM-d carcinoma.

DESIGN

The study was conducted in 4 phases: (1) evaluation of endoscopic differentiation by NBI-experienced colonoscopists; (2) extension of the NICE classification to incorporate SM-d (type 3) by using a modified Delphi method; (3) prospective validation of the individual criteria by inexperienced participants, by using high-definition still images without magnification of known histology; and (4) prospective validation of the individual criteria and overall classification by inexperienced participants after training.

SETTING

Japanese academic unit.

MAIN OUTCOME MEASUREMENTS

Performance characteristics of the NICE criteria (phase 3) and overall classification (phase 4) for SM-d carcinoma; sensitivity, specificity, predictive values, and accuracy.

RESULTS

We expanded the NICE classification for the endoscopic diagnosis of SM-d carcinoma (type 3) and established the predictive validity of its individual components. The negative predictive values of the individual criteria for diagnosis of SM-d carcinoma were 76.2% (color), 88.5% (vessels), and 79.1% (surface pattern). When any 1 of the 3 SM-d criteria was present, the sensitivity was 94.9%, and the negative predictive value was 95.9%. The overall sensitivity and negative predictive value of a global, high-confidence prediction of SM-d carcinoma was 92%. Interobserver agreement for an overall SM-d carcinoma prediction was substantial (kappa 0.70).

LIMITATIONS

Single Japanese center, use of still images without prospective clinical evaluation.

CONCLUSION

The NICE classification is a valid tool for predicting SM-d carcinomas in colorectal tumors.

BACKGROUND

Few studies have examined the relationship of human immunodeficiency virus (HIV) monoinfection and its associated perturbations with liver fibrosis.

METHODS

USING multivariable linear regression, we examined the demographic, behavioral, metabolic and viral factors associated with transient elastography-measured liver stiffness in 314 participants (165 HIV positive/hepatitis C virus [HCV] negative, 78 HIV positive/HCV positive, 14 HIV negative/HCV positive, 57 HIV negative/HCV negative) in the Women's Interagency HIV Study.

RESULTS

Compared with HIV negative/HCV negative women, HIV positive/HCV positive women had higher median liver stiffness values (7.1 vs 4.4 kPa; P < .001); HIV positive/HCV negative and HIV negative/HCV negative women had similar liver stiffness values (both 4.4 kPa; P = .94). HIV/HCV coinfection remained associated with higher liver stiffness values (74% higher; 95% confidence interval [CI], 49-104) even after multivariable adjustment. Among HCV positive women, waist circumference (per 10-cm increase) was associated with 18% (95% CI, 7.5%-30%) higher liver stiffness values after multivariable adjustment; waist circumference showed little association among HIV positive/HCV negative or HIV negative/HCV negative women. Among HIV positive/HCV negative women, history of AIDS (13%; 95% CI, 4% -27%) and HIV RNA (7.3%; 95% CI, 1.59%-13.3%, per 10-fold increase) were associated with greater liver stiffness.

CONCLUSIONS

HCV infection but not HIV infection is associated with greater liver stiffness when infected women are compared with those with neither infection. Our finding that waist circumference, a marker of central obesity, is associated with greater liver stiffness in HIV/HCV-coinfected but not HIV-monoinfected or women with neither infection suggests that in the absence of HCV-associated liver injury the adverse effects of obesity are lessened.

BACKGROUND

In Africa, human immunodeficiency virus (HIV)-infected patients who present to care with CD4 levels >350 cells/µL (ie, current antiretroviral treatment thresholds) are often thought to be poorly retained in care, but most estimates do not account for outcomes among patients lost to follow-up.

METHODS

We evaluated HIV-infected adults who had made a visit in the last 2.5 years in a program in Uganda. We identified a random sample of patients lost to follow-up (9 months without a visit). Ascertainers sought patients in the community in this sample and outcomes were incorporated into revised survival estimates of mortality and retention for the clinic population using a probability weight.

RESULTS

Of 6473 patients, (29% male, median age 29 years, median CD4 count 550 cells/µL), 1294 (20%) became lost to follow-up over 2.5 years. Two hundred seven (16%) randomly selected lost patients were sought, and in 175 (85%) vital status was ascertained. In 19 of 175 (11%), the patient had died. Of the 156 (89%) alive, 74 (47%) were interviewed in person, and 38 of 74 (51%) reported HIV care elsewhere, whereas 36 of 74 (49%) were not in care. Application of weights derived from sampling found that at 2.5 years, retention among patients who enrolled with CD4 levels >350 cells/µL was 88.2% and mortality was 2.5%. Lower income, unemployment, and rural residence were associated with failure to be retained.

CONCLUSIONS

Retention in patients entering care with high CD4 counts under routine program conditions in Africa is high in a Ugandan care program and may be systematically underestimated in many other settings.

Among ∼5,000,000 fungal species, C. albicans is exceptional in its lifelong association with humans, either within the gastrointestinal microbiome or as an invasive pathogen. Opportunistic infections are generally ascribed to defective host immunity but may require specific microbial programs. Here we report that exposure of C. albicans to the mammalian gut triggers a developmental switch, driven by the Wor1 transcription factor, to a commensal cell type. Wor1 expression was previously observed only in rare genetic backgrounds, where it controls a white-opaque switch in mating. We show that passage of wild-type cells through the mouse gastrointestinal tract triggers WOR1 expression and a novel phenotypic switch. The resulting GUT (gastrointestinally induced transition) cells differ morphologically and functionally from previously defined cell types, including opaque cells, and express a transcriptome that is optimized for the digestive tract. The white-GUT switch illuminates how a microorganism can use distinct genetic programs to transition between commensalism and invasive pathogenesis.

Despite continual progress in the cataloging of vertebrate regulatory elements, little is known about their organization and regulatory architecture. Here we describe a massively parallel experiment to systematically test the impact of copy number, spacing, combination and order of transcription factor binding sites on gene expression. A complex library of ∼5,000 synthetic regulatory elements containing patterns from 12 liver-specific transcription factor binding sites was assayed in mice and in HepG2 cells. We find that certain transcription factors act as direct drivers of gene expression in homotypic clusters of binding sites, independent of spacing between sites, whereas others function only synergistically. Heterotypic enhancers are stronger than their homotypic analogs and favor specific transcription factor binding site combinations, mimicking putative native enhancers. Exhaustive testing of binding site permutations suggests that there is flexibility in binding site order. Our findings provide quantitative support for a flexible model of regulatory element activity and suggest a framework for the design of synthetic tissue-specific enhancers.