Tailoring Surveillance Colonoscopy in Patients With Advanced Adenomas.

BACKGROUND & AIMS: Patients with advanced colorectal adenomas (AAs) are directed to undergo intensive surveillance. However, the benefit derived from surveillance may be outweighed by the risk of death from non-colorectal cancer (CRC) causes, leading to uncertainty on how best to individualize follow-up. The aim of this study was to derive a risk prediction model and risk index that estimate and stratify the risk for non-CRC cancer mortality (NCM) subsequent to diagnosis and removal of AA. METHODS: We conducted a retrospective cohort study of veterans ≥40 years old who had colonoscopy for diagnostic or screening indications at 13 Veterans Affairs Medical Centers between 2002 and 2009 and had 1 or more AAs. The primary outcome was NCM using a fixed follow-up time period of 5 years. Logistic regression using the lasso technique was used to identify factors independently associated with NCM, and an index based on points from regression coefficients was constructed to estimate risk of 5-year NCM. RESULTS: We identified 2943 veterans with AA (mean age [standard deviation] 63 [8.6] years, 98% male, 74% white), with an overall 5-year mortality of 16.7%, which was nearly all due to NCM (16.6%). Age, comorbidity burden, specific comorbid conditions, and hospitalization within the preceding year were independently associated with NCM. The risk prediction model had a goodness of fit (calibration) P value of .41 and c-statistic (discrimination) of 0.74 (95% confidence interval, 0.71-0.76). On the basis of comparable 5-year risks of NCM, the scores comprised 3 risk categories: low (score of 0-1), intermediate (score of 2-4), and high (score of ≥5), in which NCM occurred in 6.5%, 14.1%, and 33.2%, respectively. CONCLUSIONS: We derived a risk prediction model that identifies veterans with advanced adenomas who are at high risk of NCM within 5 years, and who are thus unlikely to benefit from further surveillance.

Prevalence of Advanced Colorectal Neoplasia in Veterans: Effects of Age, Sex, and Race/Ethnicity.

GOAL: We sought to quantify the independent effects of age, sex, and race/ethnicity on risk of colorectal cancer (CRC) and advanced neoplasia (AN) in Veterans. STUDY: We conducted a retrospective, cross-sectional study of Veterans aged 40 to 80 years who had diagnostic or screening colonoscopy between 2002 and 2009 from 1 of 14 Veterans Affairs Medical Centers. Natural language processing identified the most advanced finding and location (proximal, distal). Logistic regression was used to examine the adjusted, independent effects of age, sex, and race, both overall and in screening and diagnostic subgroups. RESULTS: Among 90,598 Veterans [mean (SD) age 61.7 (9.4) y, 5.2% (n=4673) were women], CRC and AN prevalence was 1.3% (n=1171) and 8.9% (n=8081), respectively. Adjusted CRC risk was higher for diagnostic versus screening colonoscopy [odds ratio (OR)=3.79; 95% confidence interval (CI), 3.19-4.50], increased with age, was numerically (but not statistically) higher for men overall (OR=1.53; 95% CI, 0.97-2.39) and in the screening subgroup (OR=2.24; 95% CI, 0.71-7.05), and was higher overall for Blacks and Hispanics, but not in screening. AN prevalence increased with age, and was present in 9.2% of men and 3.9% of women [adjusted OR=1.90; 95% CI, 1.60-2.25]. AN risk was 11% higher in Blacks than in Whites overall (OR=1.11; 95% CI, 1.04-1.20), was no different in screening, and was lower in Hispanics (OR=0.74; 95% CI, 0.55-0.98). Women had more proximal CRC (63% vs. 39% for men; P=0.03), but there was no difference in proximal AN (38.3% for both genders). CONCLUSIONS: Age and race were associated with AN and CRC prevalence. Blacks had a higher overall prevalence of both CRC and AN, but not among screenings. Men had increased risk for AN, while women had a higher proportion of proximal CRC. These findings may be used to tailor when and how Veterans are screened for CRC.

An analysis of osteopathic medical students applying to surgical residencies following transition to a single graduate medical education accreditation system.

CONTEXT: Upon requests from osteopathic medical schools, the National Resident Matching Program (NRMP) Charting Outcomes were redesigned to include osteopathic medical school seniors beginning in 2018 and one joint graduate medical education (GME) accreditation system, the Accreditation Council for Graduate Medical Education (ACGME), formed in 2020. OBJECTIVES: The goal of this study is to analyze the match outcomes and characteristics of osteopathic applicants applying to surgical specialties following the ACGME transition. METHODS: A retrospective analysis of osteopathic senior match outcomes in surgical specialties from the NRMP Main Residency Match data from 2020 to 2022 and the NRMP Charting Outcomes data from 2020 to 2022 was performed. RESULTS: For surgical specialties, results show matching increased as United States Medical Licensing Examination (USMLE) Step 2 CK (clinical knowledge) and Comprehensive Osteopathic Medical Licensing Examination (COMLEX) Level 2 CE (cognitive evaluation) scores increased along with the number of contiguous rankings (p<0.001). The greatest indication for matching looking at scores alone were those who scored greater than 230 on Step 2 CK compared to below (p<0.001) and above 650 on Level 2 CE (p<0.001). However, those who scored 240 (p=0.025) on Step 2 CK were just as likely to match as those who scored 250 (p=0.022) when compared to those who scored below those scores. Increasing research involvement had little to no significance with the likelihood of matching across most surgical subspecialties. CONCLUSIONS: Our study demonstrates that there are unique thresholds for Step 2 CK scores, Level 2 CE scores, and the number of contiguous ranks for each surgical specialty that, when reached, are significantly associated with match success. Although certain board score delineations are linked with higher match success rates, the rates level off after this point for most surgical specialties and do not significantly increase further with higher scores. In addition, thresholds within contiguous ranks for increasing match likelihood exist and vary across surgical specialties. Overall, this study highlights that the quantitative metrics utilized to assess applicants lack the correlation reported historically, and the data presently available need to be more substantiated.

Risk Factors for Early-onset Sporadic Colorectal Cancer in Male Veterans.

Identifying risk factors for early-onset colorectal cancer (EOCRC) could help reverse its rising incidence through risk factor reduction and/or early screening. We sought to identify EOCRC risk factors that could be used for decisions about early screening. Using electronic databases and medical record review, we compared male veterans ages 35 to 49 years diagnosed with sporadic EOCRC (2008-2015) matched 1:4 to clinic and colonoscopy controls without colorectal cancer, excluding those with established inflammatory bowel disease, high-risk polyposis, and nonpolyposis syndromes, prior bowel resection, and high-risk family history. We ascertained sociodemographic and lifestyle factors, family and personal medical history, physical measures, vital signs, medications, and laboratory values 6 to 18 months prior to case diagnosis. In the derivation cohort (75% of the total sample), univariate and multivariate logistic regression models were used to derive a full model and a more parsimonious model. Both models were tested using a validation cohort. Among 600 cases of sporadic EOCRC [mean (SD) age 45.2 (3.5) years; 66% White], 1,200 primary care clinic controls [43.4 (4.2) years; 68% White], and 1,200 colonoscopy controls [44.7 (3.8) years; 63% White], independent risk factors included age, cohabitation and employment status, body mass index (BMI), comorbidity, colorectal cancer, or other visceral cancer in a first- or second-degree relative (FDR or SDR), alcohol use, exercise, hyperlipidemia, use of statins, NSAIDs, and multivitamins. Validation c-statistics were 0.75-0.76 for the full model and 0.74-0.75 for the parsimonious model, respectively. These independent risk factors for EOCRC may identify veterans for whom colorectal cancer screening prior to age 45 or 50 years should be considered. PREVENTION RELEVANCE: Screening 45- to 49-year-olds for colorectal cancer is relatively new with uncertain uptake thus far. Furthermore, half of EOCRC occurs in persons < 45 years old. Using risk factors may help 45- to 49-year-olds accept screening and may identify younger persons for whom earlier screening should be considered. See related Spotlight, p. 479.

Synthetic small molecule furin inhibitors derived from 2,5-dideoxystreptamine.

Furin plays a crucial role in embryogenesis and homeostasis and in diseases such as Alzheimer's disease, cancer, and viral and bacterial infections. Thus, inhibition of furin may provide a feasible and promising approach for therapeutic intervention of furin-mediated disease mechanisms. Here, we report on a class of small molecule furin inhibitors based on 2,5-dideoxystreptamine. Derivatization of 2,5-dideoxystreptamine by the addition of guanidinylated aryl groups yielded a set of furin inhibitors with nanomolar range potency against furin when assayed in a biochemical cleavage assay. Moreover, a subset of these furin inhibitors protected RAW 264.7 macrophage cells from toxicity caused by furin-dependent processing of anthrax protective antigen. These inhibitors were found to behave as competitive inhibitors of furin and to be relatively specific for furin. Molecular modeling revealed that these inhibitors may target the active site of furin as they showed site occupancy similar to the alkylating inhibitor decanoyl-Arg-Val-Lys-Arg-CH(2)Cl. The compounds presented here are bona fide synthetic small molecule furin inhibitors that exhibit potency in the nanomolar range, suggesting that they may serve as valuable tools for studying furin action and potential therapeutics agents for furin-dependent diseases.

Neisseria meningitidis accelerates ferritin degradation in host epithelial cells to yield an essential iron source.

In order to colonize humans and cause disease, pathogenic bacteria must assimilate iron from their host. The vast majority of non-haem iron in humans is localized intracellularly, within the storage molecule ferritin. Despite the vast reserves of iron within ferritin, no pathogen has been demonstrated previously to exploit this molecule as an iron source. Here, we show that the Gram-negative diplococcus Neisseria meningitidis can trigger rapid redistribution and degradation of cytosolic ferritin within infected epithelial cells. Indirect immunofluorescence microscopy revealed that cytosolic ferritin is aggregated and recruited to intracellular meningococci (MC). The half-life of ferritin within cultured epithelial cells was found to decrease from 20.1 to 5.3 h upon infection with MC. Supplementation of infected epithelial cells with ascorbic acid abolished ferritin redistribution and degradation and prevented intracellular MC from replicating. The lysosomal protease inhibitor leupeptin slowed ferritin turnover and also retarded MC replication. Our laboratory has shown recently that MC can interfere with transferrin uptake by infected cells (Bonnah R.A., et al., 2000, Cell Microbiol 2: 207-218) and that, perhaps as a result, the infected cells have a transcriptional profile indicative of iron starvation (Bonnah, R.A., et al., 2004, Cell Microbiol 6: 473-484). In view of these findings, we suggest that accelerated ferritin degradation occurs as a response to an iron starvation state induced by MC infection and that ferritin degradation provides intracellular MC with a critical source of iron.

Replication of Neisseria meningitidis within epithelial cells requires TonB-dependent acquisition of host cell iron.

Neisseria meningitidis (meningococcus [MC]) is able to enter and replicate within epithelial cells. Iron, an essential nutrient for nearly all organisms, is an important determinant in the ability of MC to cause disease; however, its role in MC intracellular replication has not been investigated. We analyzed the growth of MC within the A431 human epithelial cell line and the dependence of this growth on iron uptake. We present evidence here that chelation of iron from infected tissue culture cells with Desferal strongly inhibited intracellular replication of wild-type (wt) MC. We also provide genetic evidence that iron must be acquired by MC from the host cell in order for it to replicate. An hmbR mutant that is unable to use hemoglobin iron and could not grow in tissue culture media without iron supplementation replicated more rapidly within epithelial cells than its wt parent strain. An fbpA mutant that is unable to utilize human transferrin iron or lactoferrin iron replicated normally within cells. In contrast, a tonB mutant could not replicate intracellularly unless infected cultures were supplemented with ferric nitrate. Taken together, these findings strongly suggest that MC intracellular replication requires TonB-dependent uptake of a novel host cell iron source.