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SummaryBackgroundChronic ulcerative colitis (CUC) and colonic Crohn's disease (CD) increase colorectal neoplasia (CRN) risk. While sessile serrated polyp (SSP) is a known cancer precursor, serrated epithelial changes (SEC) are of uncertain prevalence and neoplastic risk.AimTo assess the serrated lesion detection rates in CUC and CD and documented incidence of subsequent CRN in a retrospective, single‐centre cohort study.MethodsPatients were identified by a central diagnostic index and pathology review confirmed SEC, SSP, CUC and CD diagnoses from 2006–12. Matched controls were identified from among all CUC and CD patients having colonoscopy during the second half of the time period. All were followed for incident CRN, estimated by the Kaplan–Meier method.ResultsBetween 2006 and 2012, 79 SEC and 10 SSP cases were identified. Detection rates were estimated to be 10/1000 and 2/1000 patients, for SEC and SSP respectively, among 4208 unique CUC or CD patients having colonoscopy from 2010–12. With only 10 cases, SSP patients were not further analysed. Cumulative incidence of subsequent CRN at 1 and 3 years was 12% (95% CI, 0–30%) and 30% (3–57%), respectively, in SEC patients compared to 4% (0–12%) and 9% (0–23%), respectively, in CUC or CD controls (P = 0.047, log‐rank). However, this statistical difference was not significant after patients were stratified for history of prior or synchronous dysplasia (P = 0.09).ConclusionsSerrated epithelial changes and sessile serrated polyps are uncommonly detected by colonoscopy in chronic ulcerative colitis and Crohn's disease patients. Histology with changes of serrated epithelium may be associated with risk of subsequent colorectal neoplasia, however further studies are needed to explore this relationship.

Summary Cellular senescence, which is known to halt proliferation of aged and stressed cells, plays a key role against cancer development and is also closely associated with organismal aging. While increased insulin‐like growth factor ( IGF ) signaling induces cell proliferation, survival and cancer progression, disrupted IGF signaling is known to enhance longevity concomitantly with delay in aging processes. The molecular mechanisms involved in the regulation of aging by IGF signaling and whether IGF regulates cellular senescence are still poorly understood. In this study, we demonstrate that IGF ‐1 exerts a dual function in promoting cell proliferation as well as cellular senescence. While acute IGF ‐1 exposure promotes cell proliferation and is opposed by p53, prolonged IGF ‐1 treatment induces premature cellular senescence in a p53‐dependent manner. We show that prolonged IGF ‐1 treatment inhibits SIRT 1 deacetylase activity, resulting in increased p53 acetylation as well as p53 stabilization and activation, thus leading to premature cellular senescence. In addition, either expression of SIRT 1 or inhibition of p53 prevented IGF ‐1‐induced premature cellular senescence. Together, these findings suggest that p53 acts as a molecular switch in monitoring IGF ‐1‐induced proliferation and premature senescence, and suggest a possible molecular connection involving IGF ‐1‐ SIRT 1‐p53 signaling in cellular senescence and aging.

Key PointsCD28 delivers a pro-survival signal to MM cells via regulation of PI3K/Akt, FoxO3a, and Bim. Blockade of CD28:CD80/CD86 in vivo resensitizes MM cells to chemotherapy and significantly reduces tumor burden.

Background and Purpose— The chronological development and natural history of cerebral aneurysms (CAs) remain incompletely understood. We used 14 C birth dating of a main constituent of CAs, that is, collagen type I, as an indicator for biosynthesis and turnover of collagen in CAs in relation to human cerebral arteries to investigate this further. Methods— Forty-six ruptured and unruptured CA samples from 43 patients and 10 cadaveric human cerebral arteries were obtained. The age of collagen, extracted and purified from excised CAs, was estimated using 14 C birth dating and correlated with CA and patient characteristics, including the history of risk factors associated with atherosclerosis and potentially aneurysm growth and rupture. Results— Nearly all CA samples contained collagen type I, which was <5 years old, irrespective of patient age, aneurysm size, morphology, or rupture status. However, CAs from patients with a history of risk factors (smoking or hypertension) contained significantly younger collagen than CAs from patients with no risk factors (mean, 1.6±1.2 versus 3.9±3.3 years, respectively; P =0.012). CAs and cerebral arteries did not share a dominant structural protein, such as collagen type I, which would allow comparison of their collagen turnover. Conclusions— The abundant amount of relatively young collagen type I in CAs suggests that there is an ongoing collagen remodeling in aneurysms, which is significantly more rapid in patients with risk factors. These findings challenge the concept that CAs are present for decades and that they undergo only sporadic episodes of structural change.

Background Prior studies demonstrate reduced cortical thickness and volume in migraineurs. However, the effect of age on cortical thickness has not been assessed in migraineurs. In this study we investigated whether the process of aging on cortical thickness affects migraineurs differently compared to age-matched healthy controls, i.e. whether aging exacerbates cortical thinning in migraineurs. Methods Cortical thickness was estimated using a general linear model vertex-by-vertex approach for 32 healthy controls (mean age = 35.3 years; SD = 11.6) and 27 episodic migraine patients (mean age = 33.6 years; SD = 12.3). Results were modeled using a main effect analysis to estimate the effect of age on cortical thickness for each group separately, and an age-by-group analysis to estimate differences in age-related cortical thinning between migraine patients and normal controls. Results Although migraineurs and normal controls both have expected age-related thinning in many regions along the cortical mantle, migraineurs have age-related thinning of regions that do not thin in healthy controls, including: bilateral postcentral, right fusiform, and right temporal pole areas. Cortical thinning of these regions is more prominent with advancing age. Conclusion Results suggest that migraine is associated with atypical cortical aging, suggesting that the migraine disease process interacts with aging to affect cortical integrity.

Key Points VTE recurrence risk in patients with cancer can be stratified by cancer type, stage, stage progression, and presence of leg paresis. Patients with cancer at high VTE recurrence risk should be considered for secondary prophylaxis.

Context: Molecular markers hold the promise of improved diagnostic yield in thyroid fine-needle biopsy. The Afirma gene expression classifier (GEC), available commercially, reports a negative predictive value of 94% in the diagnosis of benign nodules after indeterminate cytology. However, there are currently no independent studies of the performance of this assay. Objective: The aim was to assess the performance of the Afirma GEC in an academic medical center. Design: Samples for the GEC were collected according to the manufacturer's recommended protocol from patients undergoing thyroid fine-needle aspiration. We requested GEC analysis on nodules reported cytologically as follicular neoplasm or atypia or follicular lesion of undetermined significance from patients willing to defer surgery. Patients: All patients undergoing thyroid fine-needle aspiration during the study period, whose cytology was reported as follicular neoplasm or atypia of undetermined significance/follicular lesion of undetermined significance, were offered access to the test and recruited to this study. Intervention: Patients whose GEC was “benign” were offered ultrasound follow-up in lieu of surgery. Those with a “suspicious” GEC were advised to undergo diagnostic lobectomy. Setting: The study was conducted at a large academic medical center. Main Outcome Measure: We measured the rate of benign and suspicious calls from the Afirma GEC and histological diagnosis after surgery. Results: A total of 72 nucleic acid samples were sent for GEC analysis. In 12 (17%) of these samples, there was insufficient mRNA, leaving 60 Afirma results for analysis. Of these, 16 (27%) were benign, whereas 44 (73%) were suspicious. The rate of confirmed malignancy in GEC-suspicious nodules was only 17%. Conclusion: The Afirma GEC demonstrates a lower than expected rate of benign reports in follicular or Hürthle cell neoplasm and a lower than anticipated malignancy rate within GEC-suspicious nodules. These data suggest that the positive predictive value of the GEC is lower than previously reported and call into question the performance of the test when applied in the context of specialized academic cytopathology.

AbstractRationale, aims and objectivesChecklists have been adopted by various institutions to improve patient outcomes. In particular, readmission prevention checklists may be of potential value to improve patient care and reduce medical costs. As a result, a prior quality improvement study was conducted to create an intensive care unit readmission prevention checklist. The previous pilot demonstrated zero readmissions when the readmission prevention checklist was utilized but yielded low compliance (30%). Thus, a subsequent quality initiative was undertaken to refine the readmission prevention checklist with the primary aim of improved compliance while maintaining a reduced readmission rate that was observed with the original quality improvement study.MethodA single‐centre, cross‐sectional study for assessing baseline data and a prospective observational study to assess the effectiveness of a refined readmission prevention checklist tool in a 20‐bed tertiary medical‐surgical intensive care unit at an academic medical centre in Rochester, MN was conducted. Medical patients admitted through the emergency department, upon direct transfer from outside facility, and post‐operative surgical patients at our institution were included. A refined readmission prevention checklist tool was administered during an 8‐week pilot period for medical and post‐operative surgical patients.ResultsThe refined readmission prevention checklist resulted in an even lower compliance (10.5%) from the initial phase likely resulting from utilization of a paper readmission prevention checklist in an electronic medical environment. Moreover, the refined readmission prevention checklist demonstrated a 22% unplanned readmission rate for patients in which the tool was utilized.ConclusionsIn conclusion, the findings of the current quality improvement study may serve to rethink the process of health care delivery that applies paper tools in an electronic medical environment.

Abstract Rationale Daily azithromycin decreases acute exacerbations of chronic obstructive pulmonary disease (AECOPD), but long-term side effects are unknown. Objectives To identify the types of exacerbations most likely to be reduced and clinical subgroups most likely to benefit from azithromycin, 250 mg daily, added to usual care. Methods Enrollment criteria included irreversible airflow limitation and AECOPD requiring corticosteroids, emergency department visit, or hospitalization in the prior year or use of supplemental oxygen. Recurrent events and cumulative incidence analyses compared treatment received for AECOPD by randomization group, stratified by subgroups of interest. Cox proportional hazards models estimated treatment effects in subgroups adjusted for age, sex, smoking status, FEV1% predicted, concomitant COPD medications, and oxygen use. Measurements and Main Results Azithromycin was most effective in reducing AECOPD requiring both antibiotic and steroid treatment (n = 1,113; cumulative incidence analysis, P = 0.0002; recurrent events analysis, P = 0.002). No difference in treatment response by sex (P = 0.75), presence of chronic bronchitis (P = 0.19), concomitant inhaled therapy (P = 0.29), or supplemental oxygen use (P = 0.23) was observed. Older age and milder Global Initiative for Chronic Obstructive Lung Disease stage were associated with better treatment response (P = 0.02 and 0.04, respectively). A significant interaction between treatment and current smoking was seen (P = 0.03) and azithromycin did not reduce exacerbations in current smokers (hazard ratio, 0.99; 95% confidence interval, 0.71–1.38; P = 0.95). Conclusions Azithromycin is most effective in preventing AECOPD requiring both antibiotic and steroid treatment. Adjusting for confounders, we saw no difference in efficacy by sex, history of chronic bronchitis, oxygen use, or concomitant COPD therapy. Greater efficacy was seen in older patients and milder Global Initiative for Chronic Obstructive Lung Disease stages. We found little evidence of treatment effect among current smokers. Clinical trial registered with www.clinicaltrials.gov (NCT0011986 and NCT00325897).