Aberrant crypt foci in colorectal carcinogenesis. Cell and crypt dynamics

Aberrant crypt foci (ACF) have been identified on the colonic mucosal surface of rodents treated with colon carcinogens and of humans after methylene-blue staining and observation under a light microscope. Several lines of evidence strongly suggest that ACF with certain morphological, histological, cell kinetics, and genetic features are precursor lesions of colon cancer both in rodents and in humans. Thus, ACF represent the earliest step in colorectal carcinogenesis. This paper has the main purpose of reviewing the evidence supporting this view, with particular emphasis on cell and crypt dynamics in ACF. ACF have been used as intermediate biomarkers of cancer development in animal studies aimed at the identification of colon carcinogens and chemopreventive agents. Recently, evidence has also shown that ACF can be effectively employed in chemopreventive studies also in humans

Measuring empathy in pediatrics: validation of the Visual CARE measure

Background: Empathy is a key element of “Patient and Family Centered Care”, a clinical approach recommended by the American Academy of Pediatrics. However, there is a lack of validated tools to evaluate paediatrician empathy. This study aimed to validate the Visual CARE Measure, a patient rated questionnaire measuring physician empathy, in the setting of a Pediatric Emergency Department (ED). Methods: The empathy of physicians working in the Pediatric ED of the University Hospital of Udine, Italy, was assessed using an Italian translation of the Visual Care Measure. This test has three versions suited to different age groups: the 5Q questionnaire was administered to children aged 7–11, the 10Q version to those older than 11, and the 10Q–Parent questionnaire to parents of children younger than 7. The internal reliability, homogeneity and construct validity of the 5Q and 10Q/10Q–Parent versions of the Visual Care Measure, were separately assessed. The influence of family background on the rating of physician empathy and satisfaction with the clinical encounter was also evaluated. Results: Seven physicians and 416 children and their parents were included in the study. Internal consistency measured by Cronbach’s alpha was 0.95 for the 10Q/10Q–Parent versions and 0.88 for the 5Q version. The item-total correlation was > 0.75 for each item. An exploratory factor analysis showed that all the items load onto the first factor. Physicians’ empathy scores correlated with patients’ satisfaction for both the 10Q and 10Q–Parent questionnaires (Spearman’s rho = 0.7189; p < 0.001) and for the 5Q questionnaire (Spearman’s rho = 0.5968; p < 0,001). Trust in the consulting physician was lower among immigrant parents (OR 0.43. 95% CI 0.20–0.93). Conclusions: The Visual Care Measure is a reliable second-person test of physician empathy in the setting of a Pediatric Emergency Room. More studies are needed to evaluate the reliability of this instrument in other pediatric settings distinct from the Emergency Room and to further evaluate its utility in measuring the impact of communication and empathy training programmes for healthcare professionals working in pediatrics

Increased risk of cognitive and functional decline in patients with atrial fibrillation: results of the ontarget and transcend studies

Background: The role of atrial fibrillation in cognitive impairment and dementia, independent of stroke, is uncertain. We sought to determine the association of atrial fibrillation with cognitive and physical impairment in a large group of patients at high cardiovascular risk. Methods: We conducted a post-hoc analysis of two randomized controlled trials involving 31 546 patients, the aims of which were to evaluate the efficacy of treatment with ramipril plus telmisartan (ONTARGET) or telmisartan alone (TRANSCEND) in reducing cardiovascular disease. We evaluated the cognitive function of participants at baseline and after two and five years using the Mini-Mental State Examination (MMSE). In addition, we recorded incident dementia, loss of independence in activities of daily living and admission to long-term care facilities. We used a Cox regression model adjusting for main confounders to determine the association between atrial fibrillation and our primary outcomes: a decrease of three or more points in MMSE score, incident dementia, loss of independence in performing activities of daily living and admission to long-term care. Results: We enrolled 31 506 participants for whom complete information on atrial fibrillation was available, 70.4% of whom were men. The mean age of participants was 66.5 years, and the mean baseline MMSE score was 27.7 (standard deviation 2.9) points. At baseline, 1016 participants (3.3%) had atrial fibrillation, with the condition developing in an additional 2052 participants (6.5%) during a median follow-up of 56 months. Atrial fibrillation was associated with an increased risk of cognitive decline (hazard ratio [HR] 1.14, 95% confidence interval [CI] 1.03-1.26), new dementia (HR 1.30, 95% CI 1.14-1.49), loss of independence in performing activities of daily living (HR 1.35, 95% CI 1.19-1.54) and admission to long-term care facilities (HR 1.53, 95% CI 1.31-1.79). Results were consistent among participants with and without stroke or receiving antihypertensive drugs. Interpretation: Cognitive and functional decline are important consequences of atrial fibrillation, even in the absence of overt stroke

Increased risk of cognitive and functional decline in patients with atrial fibrillation: results of the ontarget and transcend studies

Background: The role of atrial fibrillation in cognitive impairment and dementia, independent of stroke, is uncertain. We sought to determine the association of atrial fibrillation with cognitive and physical impairment in a large group of patients at high cardiovascular risk. Methods: We conducted a post-hoc analysis of two randomized controlled trials involving 31 546 patients, the aims of which were to evaluate the efficacy of treatment with ramipril plus telmisartan (ONTARGET) or telmisartan alone (TRANSCEND) in reducing cardiovascular disease. We evaluated the cognitive function of participants at baseline and after two and five years using the Mini-Mental State Examination (MMSE). In addition, we recorded incident dementia, loss of independence in activities of daily living and admission to long-term care facilities. We used a Cox regression model adjusting for main confounders to determine the association between atrial fibrillation and our primary outcomes: a decrease of three or more points in MMSE score, incident dementia, loss of independence in performing activities of daily living and admission to long-term care. Results: We enrolled 31 506 participants for whom complete information on atrial fibrillation was available, 70.4% of whom were men. The mean age of participants was 66.5 years, and the mean baseline MMSE score was 27.7 (standard deviation 2.9) points. At baseline, 1016 participants (3.3%) had atrial fibrillation, with the condition developing in an additional 2052 participants (6.5%) during a median follow-up of 56 months. Atrial fibrillation was associated with an increased risk of cognitive decline (hazard ratio [HR] 1.14, 95% confidence interval [CI] 1.03-1.26), new dementia (HR 1.30, 95% CI 1.14-1.49), loss of independence in performing activities of daily living (HR 1.35, 95% CI 1.19-1.54) and admission to long-term care facilities (HR 1.53, 95% CI 1.31-1.79). Results were consistent among participants with and without stroke or receiving antihypertensive drugs. Interpretation: Cognitive and functional decline are important consequences of atrial fibrillation, even in the absence of overt stroke

Impact of Liver Disease on Oral Anticoagulant Prescription and Major Adverse Events in Patients with Atrial Fibrillation

Aims\u2003 Data on the impact of liver disease (LD) in patients with atrial fibrillation (AF) and the role of oral anticoagulant (OAC) drugs for stroke prevention are limited. Methods and results\u2003 A retrospective observational population-based cohort study on the administrative health databases of Lombardy region Italy. All AF patients 6540\u2009years admitted to hospital from 2000 to 2018 were considered. Atrial fibrillation and LD diagnosis were established using ICD9-CM codes. Use of OAC was determined with Anatomical Therapeutic Chemical codes. Primary study outcomes were stroke, major bleeding, and all-cause death. Among 393\u2009507 AF patients, 16\u2009168 (4.1%) had concomitant LD. Liver disease AF patients were significantly less treated with OAC. Concomitant LD was associated with an increased risk in all the study outcomes [hazard ratio (HR): 1.18, 95% confidence interval (CI): 1.11\u20131.25 for stroke; HR: 1.57, 95% CI: 1.47\u20131.66 for major bleeding; HR: 1.41, 95% CI: 1.39\u20131.44 for all-cause death]. Use of OAC in patients with AF and LD resulted in a reduction in stroke (HR: 0.80, 95% CI: 0.70\u20130.92), major bleeding (HR: 0.86, 95% CI: 0.74\u20130.99), and all-cause death (HR: 0.77, 95% CI: 0.73\u20130.80), with similar results according to subgroups. A net clinical benefit (NCB) analysis suggested a positive benefit/risk ratio in using OAC in AF patients with LD (NCB: 0.408, 95% CI: 0.375\u20130.472). Conclusion In AF patients, concomitant LD carries a significantly higher risk for all clinical outcomes. Use of OAC in AF patients with LD was associated with a significant favourable benefit/risk ratio, even in high-risk patient subgroups

Sex-related differences in prevalence, treatment and outcomes in patients with atrial fibrillation

To analyze sex-related differences about AF prevalence, use of OAC and outcomes focusing on the older age classes. We used administrative data of the Lombardy Region, describing period prevalence, use of OAC and outcomes from 2002 to 2014 for all patients diagnosed with AF. AF prevalence over the 2002\u20132014 period was higher in males than in females (2.7% vs. 2.1%, p < 0.001), increasing with age. From 2003 to 2014, not treated AF patients decreased mostly in males (from 40.3 to 33.7% with respect to 43.7\u201339.8% in females). Age-stratified adjusted logistic regression analysis found that females were more likely treated with OAC when < 65 years in 2003 (OR 1.51, 95% CI 1.35\u20131.69) and in 2014 (OR 1.32, 95% CI 1.13\u20131.53); contrariwise, were less likely treated with OAC when age 65 75 years, in 2003 (OR 0.92, 95% CI 0.86\u20130.98) and in 2014 (OR 0.77, 95% CI 0.72\u20130.81).Adjusted Cox regression analysis confirmed that female AF patients had a higher risk of stroke (HR 1.18, 95% CI 1.14\u20131.21) and a lower risk of major bleeding (HR 0.83, 95% CI 0.80\u20130.86), while, had a lower risk for all-cause death (HR 0.82, 95% CI 0.80\u20130.83). AF prevalence was higher in male than in female patients, while thromboembolic risk was higher in female. Older female patients were under-treated with OAC particularly in recent years. Over long-term follow-up, female had a higher risk of stroke and a lower risk of major bleeding and all-cause death

Cellularizing hydrogel-based scaffolds to repair bone tissue: How to create a physiologically relevant micro-environment?

Tissue engineering is a promising alternative to autografts or allografts for the regeneration of large bone defects. Cell-free biomaterials with different degrees of sophistication can be used for several therapeutic indications, to stimulate bone repair by the host tissue. However, when osteoprogenitors are not available in the damaged tissue, exogenous cells with an osteoblast differentiation potential must be provided. These cells should have the capacity to colonize the defect and to participate in the building of new bone tissue. To achieve this goal, cells must survive, remain in the defect site, eventually proliferate, and differentiate into mature osteoblasts. A critical issue for these engrafted cells is to be fed by oxygen and nutrients: the transient absence of a vascular network upon implantation is a major challenge for cells to survive in the site of implantation, and different strategies can be followed to promote cell survival under poor oxygen and nutrient supply and to promote rapid vascularization of the defect area. These strategies involve the use of scaffolds designed to create the appropriate micro-environment for cells to survive, proliferate, and differentiate in vitro and in vivo. Hydrogels are an eclectic class of materials that can be easily cellularized and provide effective, minimally invasive approaches to fill bone defects and favor bone tissue regeneration. Furthermore, by playing on their composition and processing, it is possible to obtain biocompatible systems with adequate chemical, biological, and mechanical properties. However, only a good combination of scaffold and cells, possibly with the aid of incorporated growth factors, can lead to successful results in bone regeneration. This review presents the strategies used to design cellularized hydrogel-based systems for bone regeneration, identifying the key parameters of the many different micro-environments created within hydrogels