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Introduction: Stroke in young people shares traditional modifiable risk factors with older groups, and greatly affects quality of life. However, evidence on the effectiveness of educational interventions in young populations, aiming at spreading stroke knowledge and enhancing prevention, is still scarce. We evaluated baseline knowledge of stroke and possible improvements after an educational intervention among Italian high school students, also considering differences related to sex and type of school. Subjects and methods: Using a mixed educational strategy, a prospective evaluation of stroke knowledge was performed in five humanities and sciences (lyceums) and five vocational high schools of Tuscany (students of the 12th and 13th grade). A baseline assessment with a structured questionnaire (21 questions) was followed by a standardized oral presentation, using audiovisual materials. After 3 months, the same questionnaire was re-administered to evaluate the long-term impact of the educational intervention. Results: Overall, 573 students (50.8% males; age range, 17–19 years) were enrolled; 288 (50.3%) were from lyceums and 285 (49.7%) from vocational schools. Follow-up participation was 97.2%. Baseline performances were comparable between groups for most variables examined. At 3 months, all groups showed a significant improvement from baseline regarding reaction to a stroke event, identification of stroke risk factors, such as smoking (from 62.9% to 83.7%; p Conclusions: Our educational intervention improved stroke awareness in high school students. The effects persisted after 3 months. Improved knowledge in young populations may reduce stroke burden in adult life, increase timely access to therapies, and spread knowledge across families.

G-protein coupled receptor (GPCR) kinase 2 (GRK2) is upregulated in heart failure (HF) patients and mouse models of cardiac disease. GRK2 is a regulator of β-adrenergic receptors (βARs), a GPCR involved in ionotropic and chronotropic responses. We and others have recently reported GRK2 to be localized in the mitochondria, although its function in the mitochondria and/or metabolism remain not clearly defined. We hypothesized that upregulation of GRK2 reduced mitochondrial respiratory function and responses to βAR activation. Utilizing isolated mouse primary adult cardiomyocytes (ACMs), we investigated the role of glucose, palmitate, ketone bodies, and BCAAs in mediating cell survival. Our results showed that myocyte upregulation of GRK2 promotes palmitate-induced cell death. Isotopologue labeling and mass spectrometry showed that the upregulation of GRK2 reduces β-hydroxybutyryl CoA generation. Next, using isoproterenol (ISO), a non-selective βAR-agonist, we determined mitochondrial function in mouse and human primary ACMs. Upregulation of GRK2 impaired ISO-mediated mitochondrial functional responses, which we propose is important for metabolic adaptations in pathological conditions. Increased cardiac levels of GRK2 reduced fatty acid-specific catabolic pathways and impaired ISO-stimulated mitochondrial function. Our data support the notion that GRK2 participates in bioenergetic remodeling and may be an important avenue for the development of novel pharmacological strategies in HF.

BACKGROUND/OBJECTIVES Atrial fibrillation (AF) subtypes may carry different cardiovascular risk profiles, but information on their frequency from population-based studies is lacking. We estimated prevalence of AF subtypes in a representative sample of the Italian older population, projecting figures for Italy and the European Union. DESIGN Cross-sectional study. SETTING Three primary care practices in northern, central, and southern Italy. PARTICIPANTS All individuals aged 65 years or older, for a total sample of 6,016 subjects. Excluding 235 noneligible, participation was 78.3%, which left 4,528 participants. MEASUREMENTS A double systematic and opportunistic screening procedure identified possible AF cases, followed by clinical and electrocardiogram confirmation. Patients were categorized with paroxysmal, persistent, or permanent AF. Prevalence was calculated by sex and 5-year age groups. Prevalence figures were applied to population projections for all 28 European Union states to estimate AF subtypes expected in future decades. RESULTS In the 4,528 participants (mean age = 74.5 ± 6.8 years; 47.2% men), 331 AF cases were identified: 140 (42.3%) paroxysmal, 77 (23.3%) persistent, and 114 (34.4%) permanent. Prevalence was 3.1% (95% confidence interval (CI) = 2.6%-3.6%) for paroxysmal, 1.7% (95% CI = 1.4%-2.1%) for persistent, and 2.5% (95% CI = 2.1%-3.0%) for permanent AF. Italian older persons having AF in 2016 were estimated at approximately 449,000 for paroxysmal, approximately 240,000 for persistent, and approximately 391,000 for permanent AF, projected to increase in 2060 to approximately 785,000, approximately 358,000, and approximately 748,000, respectively. European Union older persons having AF in 2016 were estimated at approximately 3,185,000 for paroxysmal, approximately 1,722,000 for persistent, and approximately 2,710,000 for permanent AF, projected to increase in 2060 to approximately 5,989,000, approximately 2,833,000, and approximately 5,579,000, respectively. CONCLUSION We provided first projections of AF subtypes for Italy and Europe. The worse cardiovascular risk profile of persistent and permanent forms indicates an increased burden in future decades.

Background Current guidelines recommend laparoscopic cholecystectomy be offered for patients with acute cholecystitis except those deemed as high risk. Few studies have examined the impact of frailty on outcomes for patients undergoing laparoscopic cholecystectomy. Therefore, the aim of this study was to determine the association of frailty with postoperative morbidity and mortality in patients undergoing laparoscopic cholecystectomy for acute cholecystitis. Methods Patients undergoing laparoscopic cholecystectomy for acute cholecystectomy were identified from 2005 to 2010 in the American College of Surgeons National Surgical Quality Improvement Project (NSQIP). The Modified Frailty Index (mFI) was used a surrogate for frailty, and patients were stratified as non-frail (mFI 0), low frailty (mFI 1–2), intermediate frailty (mFI 3–4) and high frailty (mFI ≥ 5). Univariable and multivariable analyses were performed. Receiver operator curves (ROC) and an area under the curve (AUC) were generated to determine accuracy of mFI in predicting postoperative morbidity and mortality. Results Of the 6898 patients undergoing laparoscopic cholecystectomy, 3245 (47%) patients were non-frail. There were 2913 (42%) patients with low-frailty, 649 (9%) patients with intermediate frailty, and 91 (2%) with high frailty. Clavien IV complications were higher for intermediate frail patients (OR 1.81, 95% CI 1.00–3.28, p = 0.050) and high-frail patients (OR 4.59, 95% CI 1.98–10.7, p

Introduction: Data on frailty frequency are heterogeneous and mostly based on cross-sectional studies. Little is known about frailty development and progression over time. Our aim was to conduct a systematic analysis of frailty prevalence and incidence in a large cohort of older adults and to evaluate the association with incident disability, in order to tackle the current paucity and fragmentation of longitudinal data on frailty. Methods: As secondary analysis of the Italian Longitudinal Study on Aging (ILSA) population-based cohort (n = 5,632, 65–84), frailty status was operationalized according to Fried criteria (n = 2,457). Weighted prevalence and incidence rates were calculated at each ILSA wave (T0 1992–1993, T1 1995–1996, T2 2000–2001). The association with incident disability in Activities of Daily Living (ADL) or Instrumental Activities of Daily Living (IADL) was investigated through Cox proportional hazard models, controlling for possible confounders. Results: Prevalence of frailty and pre-frailty at baseline (mean age 71.6 years; women 58.9%) were 4.0% (95% confidence interval [CI]: 3.4–4.6) and 44.6% (95% CI: 43.1–46.1), respectively. Incidence rates per 1,000 person-years for the T0–T1 interval were 7.3 (95% CI: 5.2–9.3) for frailty and 83.7 (95% CI: 73.6–93.8) for pre-frailty. Prevalence and incidence of frailty, and to a lesser degree of pre-frailty, were overall higher for women and increased with age, yet no increasing trend with advancing age was detected for pre-frailty incidence. Frailty incidence rates were significantly higher among pre-frail than non-frail individuals at follow-up entry. After full adjustment, being frail markedly increased the risk of incident disability in ADL (hazard ratio [HR] 3.58, 95% CI: 1.97–6.52) and IADL (HR 2.56, 95% CI: 1.58–4.16) over a 4-year period. Discussion/Conclusion: According to our findings, frailty is common among older people and is a strong and independent predictor of disability. Further research on factors and characteristics related to frailty progression, and especially remission, over time is crucial to calibrate effective public health preventive measures.

Benefits of oral anticoagulants (OAC) in atrial fibrillation (AF) patients with moderate-to-high risk of stroke are independent of AF pattern. We evaluated whether AF clinical subtype influenced OAC use in a representative sample of the Italian older population.A cross-sectional examination of all subjects aged 65 + years from three general practices in northern, central, and southern Italy started in 2016. A double-screening procedure was followed by clinical and ECG confirmation. Patients were categorized as having paroxysmal, persistent, or permanent AF. OAC use was evaluated in confirmed AF patients.The sample included 6016 subjects. Excluding 235 non-eligible, participation was 78.3%, which left 4528 participants (mean age 74.5 ± 6.8 years, 47.2% men). Overall, 319 AF cases were identified: 43.0% had paroxysmal, 21.3% persistent, and 35.7% permanent AF. Frequency of OAC therapy was 91.2% in permanent, 85.3% in persistent, and only 43.0% in paroxysmal AF (P 0.001). In multivariate analysis, controlled for baseline variables and risk scales, persistent and permanent AF were associated with a significant increase in the likelihood of receiving OAC compared with paroxysmal AF (P 0.001). This was confirmed for permanent AF also in multivariate analyses considering separately vitamin K antagonists or direct-acting oral anticoagulants (OR, 4.37, 95% CI, 2.43-7.85; and 1.92, 95% CI, 1.07-3.42, respectively) and for persistent AF and direct-acting oral anticoagulants (OR, 4.33, 95% CI, 2.30-8.15).In a population-based survey, AF pattern was an independent predictor of OAC treatment. Paroxysmal AF is still perceived as carrying a lower risk of vascular events.

As the obesity epidemic worsens, the prevalence of fatty liver disease has increased. However, minimal data exist on the impact of combined fatty liver and metabolic syndrome on hepatectomy outcomes. Therefore, the aim of this analysis is to measure the outcomes of patients who do and do not have a fatty liver undergoing hepatectomy in the presence and absence of the metabolic syndrome.Patients with fatty and normal livers undergoing major hepatectomy (≥3 segments) were identified in the 2014 to 2018 American College of Surgeon National Surgical Quality Improvement Program database. Patients undergoing partial hepatectomy and those with missing liver texture data were excluded. Propensity matching was used and adjusted for multiple variables. A subgroup analysis stratified by the metabolic syndrome (body mass index ≥30 kg/mOf 2,927 hepatectomies, 30% of patients (N = 863) had a fatty liver. The median body mass index was 28.6, and the metabolic syndrome was present in 6.3% of patients (N = 184). After propensity matching, 863 patients with fatty and 863 with normal livers were compared. Multiple outcomes were significantly worse in patients with fatty livers (P.05), including serious morbidity (32% vs 24%), postoperative invasive biliary procedures (15% vs 10%), organ space infections (11% vs 7.8%), and pulmonary complications. Patients with fatty livers and the metabolic syndrome had significantly increased postoperative cardiac arrests, pulmonary embolisms, and mortality (P.05).Fatty liver disease is associated with significantly worse outcomes after major hepatectomy. The metabolic syndrome confers an increased risk of postoperative mortality.

After more than 60 years of human activities in outer space, society is highly dependent on space based technologies.

Introduction Liver fibrosis increases progressively with aging and has been associated with poorer cognitive performance in middle‐aged and older adults. We investigated the relationships between a non‐invasive score for advanced liver fibrosis (non‐alcoholic fatty liver disease [NAFLD] fibrosis score [NFS]) and dementia risk. We also assessed physical frailty, a common geriatric condition which is associated to dementia. We tested the joint effects of physical frailty and fibrosis on dementia incidence. Methods A total of 1061 older adults (65 to 84 years), from the Italian Longitudinal Study on Aging, were prospectively evaluated for the risk of dementia in a period between 1992 and 2001. Liver fibrosis was defined according to the NFS. Physical frailty was assessed according to the Fried's criteria. Cox proportional hazards models were used to estimate the short‐ and long‐term risk of overall dementia, associated to the NFS, testing the effect modifier of physical frailty status. Results Older adults with only high NFS (F3‐F4) did not exhibit a significant increased risk of overall dementia. Over 8 years of follow‐up, frail older adults with high NFS had an increased risk of overall dementia (hazard ratio [HR]: 4.23; 95% confidence interval [CI]: 1.22 to 14.70, P = .023). Finally, physically frail older adults with low albumin serum levels (albumin

Purpose The aim of the study was to assess early poststroke prognostic factors in patients admitted for postacute phase rehabilitation. Methods A 1-yr multicenter prospective project was conducted in four Italian regions on 352 patients who were hospitalized after a first stroke and were eligible for postacute rehabilitation. Clinical data were collected in the stroke or acute care units (acute phase), then in rehabilitation units (postacute phase), and, subsequently, after a 6-mo poststroke period (follow-up). Clinical outcome measures were represented using the Barthel Index and the modified Rankin Scale. Univariate and multivariate analyses were performed to identify the most important prognostic index. Results Modified Rankin Scale score, minor neurologic impairment, and early out-of-bed mobilization (within 2 days after the stroke) proved to be important factors related to a better recovery according to Barthel Index (power of prediction = 37%). Similarly, age, premorbid modified Rankin Scale score, and early out-of-bed mobilization were seen to be significant factors in achieving better overall participation and activity according to the modified Rankin Scale (power of prediction = 48%). Barthel Index at admission and certain co-morbidities were also significant prognostic factors correlated with a better outcome. Conclusions According to the Barthel Index and modified Rankin Scale, early mobilization is an early predictor of favorable outcome. To Claim CME Credits Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME Objectives Upon completion of this article, the reader should be able to: (1) Incorporate prognostic factors of good clinical outcomes after stroke in developing treatment plans for patients admitted to rehabilitation; (2) Identify acute phase indicators associated with favorable 6-mo outcome after stroke; and (3) Recognize the cut-off for early mobilization linked to better outcome in stroke survivors admitted to rehabilitation. Level Advanced Accreditation The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

May–Thurner syndrome (MTS) is an anatomic variant where the overlying right common iliac artery compresses and chronically obstructs the left common iliac vein, leading to thrombosis. Interventions for symptomatic MTS include endovascular thrombectomy and stenting. Occluding venous thrombus can be fatal to transplanted allografts. No guidelines exist for patients with MTS after simultaneous kidney-pancreas transplant. A 57-year-old female with ESRD and diabetes mellitus underwent a kidney-pancreas transplant. Post-operative imaging revealed a compressed left CIV with an occlusive thrombus threatening the renal graft. Thrombectomy with stent placement was performed, maintaining patency of both allograft venous outflows. Post-intervention the patient has demonstrated preserved kidney and pancreas allograft function through 1 year of follow-up. Interventions for MTS in patients after transplant are challenging given the complex allograft vascular reconstruction. We present a case which demonstrates that angiographic interventions for MTS can be safely performed after simultaneous kidney-pancreas transplant.

Aims To estimate prevalence of atrial fibrillation (AF) in a representative sample of the Italian elderly population, projecting figures for Italy and the European Union. Methods and results A cross-sectional examination of all subjects aged 65+ years from three general practices in Northern, Central, and Southern Italy started in 2016. Participants were administered a systematic and an opportunistic screening, followed by clinical and electrocardiogram confirmation. The study sample included 6016 subjects. Excluding 235 non-eligible, among the remaining 5781 participation was 78.3%, which left 4528 participants (mean age 74.5 ± 6.8 years, 47.2% men). Prevalence of AF was 7.3% [95% confidence intervals (CI) 6.6–8.1], higher in men and with advancing age (6.6% from systematic plus 0.7% from opportunistic screening). Using prevalence figures, Italian elderly having AF in 2016 were estimated at ∼1 081 000 (95% CI 786 000–1 482 000). Considering stable prevalence, this number will increase by 75% to ∼1 892 000 in 2060 (95% CI 1 378 000–2 579 000). European Union elderly having AF in 2016 were estimated at ∼7 617 000 (95% CI 5 530 000–10 460 000), increasing by 89% to ∼14 401 000 in 2060 (95% CI 10 489 000–19 647 000). In 2016, subjects aged 80+ years represented 53.5% of cases in Italy and 51.2% in the European Union; in 2060, 69.6% and 65.2%, respectively. Conclusions Our findings indicate a high burden of AF in coming decades, especially among the oldest-old, who carry the higher AF-related risk of stroke and medical complications.

Introduction Frailty is a critical intermediate status of the aging process including physical, cognitive, and psychosocial domains/phenotypes. We operationalized a new biopsychosocial frailty (BF) construct, estimating its impact on the risk of incident dementia and its subtypes. Methods In 2171 older individuals from the population-based Italian Longitudinal Study on Aging (ILSA), we identified by latent class procedures the BF construct as the physical frail status plus at least one of the two items of the 30-item Geriatric Depression Scale impaired (items 3/10). Results Over a 3.5-year follow-up, participants with BF showed an increased risk of overall dementia (hazard ratio [HR]: 2.16, 95% confidence interval [CI]:1.07-4.37), particularly vascular dementia (VaD) (HR: 3.21, 95% CI: 1.05-9.75). Similarly, over a 7-year follow-up, an increased risk of overall dementia (HR: 1.84, 95% CI: 1.06-3.20), particularly VaD (HR: 2.53, 95% CI: 1.08-5.91), was also observed. Discussion In a large cohort of Italian older individuals without cognitive impairment at baseline, a BF model was a short- and long-term predictor of overall dementia, particularly VaD.

Stroke is a leading cause of death and disability, with high individual, social and economic costs. Diet has been identified as a modifiable risk factor for cardiovascular diseases and stroke in several large epidemiological studies. The evaluation of foods groups and dietary patterns provides a more realistic representation of actual dietary intake, and gives clues to developing guidelines aimed at general population. We review the role of Mediterranean diet, fruit and vegetables, and olive oil consumption, on the risk of stroke and other vascular outcomes. Findings from major studies indicate that, together with a healthy lifestyle, the traditional Mediterranean way of eating, including social and cultural components, and inscribed on the Representative List of the Intangible Cultural Heritage of Humanity by UNESCO, may be considered a cost-effective intervention to reduce the human, social and economic burden of stroke and cardiovascular disease.

Ischemia reperfusion injury (IRI) during liver transplantation increases morbidity and contributes to allograft dysfunction. There are no therapeutic strategies to mitigate IRI. We examined a novel hypothesis: caspase 1 and caspase 11 serve as danger-associated molecular pattern (DAMPs) sensors in IRI. By performing microarray analysis and using caspase 1/caspase 11 double-knockout (Casp DKO) mice, we show that the canonical and non-canonical inflammasome regulators are upregulated in mouse liver IRI. Ischemic pre (IPC)- and post-conditioning (IPO) induce upregulation of the canonical and non-canonical inflammasome regulators. Trained immunity (TI) regulators are upregulated in IPC and IPO. Furthermore, caspase 1 is activated during liver IRI, and Casp DKO attenuates liver IRI. Casp DKO maintained normal liver histology via decreased DNA damage. Finally, the decreased TUNEL assay-detected DNA damage is the underlying histopathological and molecular mechanisms of attenuated liver pyroptosis and IRI. In summary, liver IRI induces the upregulation of canonical and non-canonical inflammasomes and TI enzyme pathways. Casp DKO attenuate liver IRI. Development of novel therapeutics targeting caspase 1/caspase 11 and TI may help mitigate injury secondary to IRI. Our findings have provided novel insights on the roles of caspase 1, caspase 11, and inflammasome in sensing IRI derived DAMPs and TI-promoted IRI-induced liver injury.

Introduction: Lynch syndrome is caused by germline mutations in one of the mismatch repair genes ( MLH1, MSH2, MSH6, and PMS2) or in the EPCAM gene. Lynch syndrome is defined on the basis of clinical, pathological, and genetic findings. Accordingly, the identification of predisposing genes allows for accurate risk assessment and tailored screening protocols. Case Description: Here, we report a family case with three family members manifesting the Lynch syndrome phenotype, all of which harbor the rare variant c.2635-2A>G affecting the splice site consensus sequence of intron 15 of the MSH2 gene. This mutation was previously described only in one family with Lynch syndrome, in which mismatch repair protein expression in tumor tissues was not assessed. In this study, we report for the first time the molecular characterization of the MSH2 c.2635-2A>G variant through in silico prediction analysis, microsatellite instability, and mismatch repair protein expression experiments on tumor tissues of Lynch syndrome patients. The potential effect of the splice site variant was revealed by three splicing prediction bioinformatics tools, which suggested the generation of a new cryptic splicing site. The potential pathogenic role of this variant was also revealed by the presence of microsatellite instability and the absence of MSH2/MSH6 heterodimer protein expression in the tumor cells of cancer tissues of the affected family members. Conclusions: We provide compelling evidence in favor of the pathogenic role of the MSH2 variant c.2635-2A>G, which could induce an alteration of the canonical splice site and consequently an aberrant form of the protein product (MSH2).

Background: Frailty is a critical intermediate status of the aging process, characterized by an increased risk of negative health-related events, including physical, cognitive, and psychosocial domains/phenotypes. In particular, the psychosocial domain is heterogeneously defined and little explored. We operationalized a new biopsychosocial frailty (BF) construct, easy to implement in clinical and epidemiological settings. Furthermore, we estimated the impact of this new BF construct on the risk of incident dementia and its subtypes. Methods: Out of 5632 older individuals from the Italian Longitudinal Study on Aging, we identified on 1271 subjects specific characteristics mainly based on a Comprehensive Geriatric Assessment for identifying a construct for a BF by a latent class analysis. We obtained a 11-item instrument derived from three items of the Instrumental Activities of Daily Living, six items of the 30-item Geriatric Depression Scale (GDS-30), the cohabitation status of the individuals, and the physical frailty condition. Reliability and scalability of the items involved were estimated. Criterion-related validity of the new BF construct was calculated assessing the independent contribution of baseline BF to incidence of dementia and its subtypes over 3.5 and 7 years. Findings: Three latent classes were identified, one of them highly aggregating (>40%) physical frailty and the items 3 or 10 of the GDS-30. Over a 3.5-year median follow-up, participants with BF showed an increased risk of overall dementia [hazard ratio (HR) 2.16, 95% confidence interval (CI) 1.07-4.37], particularly vascular dementia (VaD) (HR 3.21, 95% CI 1.05-9.75). Similarly, over 7-year of median follow-up, an increased risk of overall dementia (HR 1.84, 95% CI 1.06-3.20), particularly VaD (HR 2.53, 95% CI 1.08-5.91), was also observed. Interpretation: In a large cohort of Italian older individuals without cognitive impairment at baseline, a BF model was a short- and long-term predictor of overall dementia, particularly VaD. Funding Statement: "none declared." Declaration of Interests: "None" Ethics Approval Statement: The study project was approved by the Institutional Review Board of the 8 municipalities of the ILSA.

Background Informing health systems and monitoring hospital performances using administrative data sets, mainly hospital discharge data coded according to International-Classification-Diseases-9edition-Clinical-Modifiers (ICD9-CM), is now commonplace in several countries, but the reliability of diagnostic coding of acute ischemic stroke in the routine practice is uncertain. This study aimed at estimating accuracy of ICD9-CM codes for the identification of acute ischemic stroke and the use of thrombolysis treatment comparing hospital discharge data with medical record review in all the six hospitals of the Florence Area, Italy, through 2015. Methods We reviewed the medical records of all the 3915 potential acute stroke events during 2015 across the six hospitals of the Florence Area, Italy. We then estimated sensitivity and Positive Predictive Value of ICD9-CM code-groups 433*1, 434*1 and thrombolysis code 99.10 against medical record review with clinical adjudication. For each false-positive case we obtained the actual diagnosis. For each false-negative case we obtained the primary and secondary ICD9-CM diagnoses. Results The medical record review identified 1273 acute ischemic stroke events. The hospital discharge records identified 898 among those (true-positive cases),but missed 375 events (false-negative cases), and identified 104 events that were not eventually confirmed as acute ischemic events (false-positive cases). Code-group specific Positive Predictive Value was 85.7% (95%CI,74.6–93.3) for 433*1 and 89.9% (95%CI, 87.8–91.7) for 434*1 codes. Thrombolysis treatment, as identified by ICD9-CM code 99.10, was only documented in 6.0% of acute ischemic stroke events, but was 13.6% in medical record review. Conclusions Hospital discharge data were found to be fairly specific but insensitive in the reporting of acute ischemic stroke and thrombolysis, providing misleading indications about both quantity and quality of acute ischemic stroke hospital care. Efforts to improve coding accuracy should precede the use of hospital discharge data to measure hospital performances in acute ischemic stroke care.

Objectives Cognitive frailty, a condition describing the simultaneous presence of physical frailty and mild cognitive impairment, has been recently defined by an international consensus group. We estimated the predictive role of a “reversible” cognitive frailty model on incident dementia, its subtypes, and all-cause mortality in nondemented older individuals. We verified if vascular risk factors or depressive symptoms could modify this predictive role. Design Longitudinal population-based study with 3.5- and 7-year of median follow-up. Setting Eight Italian municipalities included in the Italian Longitudinal Study on Aging. Participants In 2150 older individuals from the Italian Longitudinal Study on Aging, we operationalized reversible cognitive frailty with the presence of physical frailty and pre-mild cognitive impairment subjective cognitive decline, diagnosed with a self-report measure based on item 14 of the Geriatric Depression Scale. Measurements Incidence of dementia, its subtypes, and all-cause mortality. Results Over a 3.5-year follow-up, participants with reversible cognitive frailty showed an increased risk of overall dementia [hazard ratio (HR) 2.30, 95% confidence interval (CI) 1.02–5.18], particularly vascular dementia (VaD), and all-cause mortality (HR 1.74, 95% CI 1.07–2.83). Over a 7-year follow-up, participants with reversible cognitive frailty showed an increased risk of overall dementia (HR 2.12, 95% CI 1.12–4.03), particularly VaD, and all-cause mortality (HR 1.39, 95% CI 1.03–2.00). Vascular risk factors and depressive symptoms did not have any effect modifier on the relationship between reversible cognitive frailty and incident dementia and all-cause mortality. Conclusions A model of reversible cognitive frailty was a short- and long-term predictor of all-cause mortality and overall dementia, particularly VaD. The absence of vascular risk factors and depressive symptoms did not modify the predictive role of reversible cognitive frailty on these outcomes.

Objective Cognitive frailty is a condition recently defined by operationalized criteria describing the simultaneous presence of physical frailty and mild cognitive impairment (MCI). Two subtypes for this clinical construct have been proposed: "potentially reversible" cognitive frailty (physical frailty plus MCI) and "reversible" cognitive frailty (physical frailty plus pre-MCI subjective cognitive decline). Here the prevalence of a potentially reversible cognitive frailty model was estimated. It was also evaluated if introducing a diagnosis of MCI in older subjects with physical frailty could have an additive role on the risk of dementia, disability, and all-cause mortality in comparison with frailty state or MCI condition alone, with analyses separately performed for inflammatory state. Methods In 2,373 individuals from the population-based Italian Longitudinal Study on Aging with a 3.5-year-follow-up, we operationally categorized older individuals without dementia into four groups: non-frail/non-MCI, non-frail/MCI, frail/non-MCI, and frail/MCI. Results The prevalence of potentially reversible cognitive frailty was 1%, increasing with age and more represented in women than in men, and all groups were associated with significant increased incident rate ratios of dementia, disability, and mortality. A significant difference in rates of disability has been found between the MCI and non-MCI groups (contrasts of adjusted predictions: 0.461; 95% confidence interval: 0.187–0.735) in frail individuals with high inflammatory states (fibrinogen >339 mg/dL). Conclusion In older individuals without dementia and with elevated inflammation, a potentially reversible cognitive frailty model could have a significant additional predictive effect on the risk of disability than the single conditions of frailty or MCI.

Great progress has been made in standardizing 2D medical images, but the standardization of 3D medical models is still lacking. The first Web extra at http://youtu.be/J_h3Pcono7A is a video in which a shoulder muscle is rendered based on a fresh cadaver and then laid out on a computer. The pattern is then applied to a 3D model of a shoulder, with corresponding muscle layers and connections to the bones. The second Web extra at http://youtu.be/u5eVGIuhPUA is a video in which flexion and extension range of motion and movement of the upper arm are applied to a 3D model. The third Web extra http://youtu.be/wS4NPn08NKI is a video rendering showing liquid simulation for realistic virtual surgery and medical communication. The fourth Web extra at http://youtu.be/YZ5PWZyS4E0 is a video rendering showing a colon cancer surgery simulation for realistic virtual surgery and medical communication. The fifth Web extra at http://youtu.be/QN5iJhX8PQ4 is a video rendering showing an arthroscopic surgery simulation for realistic virtual surgery and medical communication.

Multikinase growth inhibitors inhibit their target kinases with varying potency. Patients often require lower doses or therapy breaks due to drug toxicities. To evaluate the effects of drug withdrawal on hepatocellular carcinoma cells after incubation with growth-inhibitory concentrations of regorafenib, cell growth, migration and invasion, and signaling were examined.Cell proliferation, motility, and invasion were analyzed by MTT, wound healing, and invasion assays, respectively, and MAPK pathway protein markers were analyzed by Western blot.After regorafenib removal, cell growth, migration, and invasion recovered. Repeated drug exposure resulted in changes in cell growth patterns. Recovery could be blocked by sub-growth-inhibitory concentrations of either doxorubicin or vitamin K1. Recovery of growth was associated with increased phospho-JNK, phospho-p38, and phospho-STAT3 levels. The recovery of growth, migration, and signaling were blocked by a JNK inhibitor.Removal of regorafenib from growth-inhibited cells resulted in a JNK-dependent recovery of growth and migration.

Background The need for stroke care is escalating with an ageing population, yet methods to estimate the delivery of effective care across countries are not standardised or robust. Associations between quality and intensity of care and stroke outcomes are often assumed but have not been clearly demonstrated. Objective To examine variations in acute care processes across six European populations and investigate associations between the delivery of care and survival. Methods Data were obtained from population-based stroke registers of six centres in France, Lithuania, UK, Spain, Poland and Italy between 2004 and 2006 with follow-up for 1 year. Variations in the delivery of care (stroke unit, multidisciplinary team and acute drug treatments) were analysed adjusting for case mix and sociodemographic factors using logistic regression methods. Unadjusted and adjusted survival probabilities were estimated and stratified by levels of Organised Care Index. Results Of 1918 patients with a first-ever stroke registered, 30.7% spent more than 50% of their hospital stay in a stroke unit (13.9–65.4%) among centres with a stroke unit available. The percentage of patients assessed by a stroke physician varied between 7.1% and 96.6%. There were significant variations after adjustment for confounders, in the organisation of care across populations. Significantly higher probabilities of survival (p

Access to effective acute stroke services is a crucial factor to reduce stroke-related death and disability, but is limited in different parts of Italy. Our study addresses this inequality across the Italian regions by examining the regional legislations issued to adopt and implement the State-Regional Council agreement 03/02/2005 as to the acute stroke management. All decrees and resolutions as to acute stroke were collected from each region and examined by the means of a check list including quantitative and qualitative characteristics, selected in accordance with the recommendations from the State-Regional Council document. Each completed check list was then sent to each regional reference person, who filled in the section on the implementation of the indications and compliance, with the collaboration of stroke specialists if necessary. The study was carried out from November 2009 to September 2010. The documents and information were collected from 19 regions. Our survey revealed disparities both in terms of number of decrees and resolutions and of topics covered by the regional legislations about stroke care. Most legislations lacked practical and economical details. This feedback from national and regional stroke regulations revealed a need of more concrete indications. Involvement of various stakeholders (legislators, consumers, providers) might possibly ensure that policies are actually adopted, implemented and maintained. Although considerable challenges are present to the development of standard and optimal stroke care more widely across Italian regions, the potential gains from such developments are substantial.

This paper points out the main design goals of a novel representation scheme of geometric-topological data, named Linear Algebraic Representation (LAR), characterized by a wide domain, encompassing 2D and 3D meshes, manifold and non-manifold geometric and solid models, and high-resolution 3D images. To demonstrate its simplicity and effectiveness for dealing with huge amounts of geometric data, we apply LAR to the extraction of a clean solid model of the hepatic portal vein subsystem from micro-CT scans of a pig liver.

Background: The use of emergency services with prehospital stroke assessment and early notification to the treatment hospital (stroke code) is a crucial determinant of delay time for acute stroke treatment. We reviewed and summarized the literature on prehospital stroke code system implementation. Methods: Two databases were explored (last update June 20, 2011) with 3 key words (stroke code, stroke prehospital management and stroke prehospital services). Inclusion criteria were: randomized and quasirandomized controlled trials, cohort and case-control studies, and hospital- and emergency-based registers, with no year or language restrictions. We examined the reference lists of all included articles. All potentially relevant reports and abstracts were transcribed into a specifically designed data abstraction form. Results: Only 19 of the 680 studies which were initially retrieved, published from 1999 to 2011, fulfilled our inclusion criteria. One clinical trial was identified. Large differences in stroke code procedures and study designs within and across countries prohibited the pooling of the data. Most studies were carried out in urban areas. Assuming the rate of tissue-plasminogen activator treatment as the performance measure, most studies report a significant increase in the rate of treatment (increase between 3.2 and 16%) with only 1 study not reporting any increase. Conclusions: Despite its limitations, this review suggests that the use of prehospital stroke code is an important intervention to improve the accessibility of the benefits of thrombolysis, especially when implemented together with educational campaigns to optimize the awareness and behavior of patients and bystanders.

Any strategy to reduce stroke burden involves crucial inputs from individuals (risk reduction, rapid recognition and response to symptoms onset) which imply a certain level of stroke knowledge. Health-related applications (apps) have been identified as a novel platform for dissemination of health information to the public. Only few apps about stroke are currently available with scientifically valid information, none of them are available in Italian. We developed the first and only Italian stroke app, ICTUS3R. We also pilot tested ICTUS3R in terms of its usage during the first 12 months following release (October 30, 2014). ICTUS3R was developed in collaboration with communication experts, stroke leaders and web producers. ICTUS3R was pilot tested in terms of number and distribution of downloads. Data about 1 year usage were anonymously collected from ICTUS 3R release on October 30, 2014. ICTUS3R includes a stroke screening tool, information how to react in case of suspected stroke, and information about risk factors including personal stroke risk calculator. ICTUS 3R web site was visited 36,242 times. Mean session duration was over 2 min. The 48 % of downloads were by individuals aged 25–44 years, 12 % by individuals ≥55 years. ICTUS3R downloads were distributed across all the Italian provinces, in varying proportions. The 4.3 % of downloads were done outside Italy. ICTUS3R can be an important contribution to stroke management and prevention, it proved to be well received for dissemination of stroke information among Italians. Its use could contribute to reduce stroke burden in Italy.

Background and Purpose— There are significant differences in the provision of care and outcome after stroke across countries. The European Registers of Stroke study aimed to develop, test, and refine a tool to assess quality of care. Methods— We used a systematic review and grading of evidence for stroke care across the clinical pathway and developed and field-tested a quality tool that was delivered by post and later by site visit at 7 centers. Items were refined by using an algorithm that took into account the level of evidence, measurement properties, and consensus of opinion obtained using, the Delphi techniques. Results— The tool included 251 items across 11 domains, of which 214 items could be categorized by any level of evidence. Overall agreement between postal and site visit modes of delivery was acceptable (κ=0.77), with most items having a κ >0.5. The refinement process resulted in 2 practical versions of the tool (93 items and 22 items). Positive responses to items in the tool indicated implementation of evidence-based stroke care. In field testing, the proportion of positive responses to evidence-based items ranged from 43% to 79% across populations. Proportions of different types of evidence being implemented were similar: high quality 62%, limited quality 72%, and expert opinion 54% across the populations. More than half (4 of 7) of the centers provided stroke unit care and thrombolysis, but availability and access to inpatient rehabilitation varied significantly, with poor access to community follow-up for rehabilitation and medical management. Conclusions— The European Registers of Stroke Quality Assessment Tool has potential to be used as a framework to compare services and promote increased implementation of evidence-based care.

The outcome of stroke patients is complex and multidimensional. We evaluated the impact of acute-phase variables, including clinical state, complications, resource use and interventions, on 6-month survival after first-ever stroke, taking into account baseline conditions exerting a possible effect on outcome. As part of a National Research Program, we performed a prospective observational study of acute stroke patients in four Italian Regions. Consecutive patients admitted for a period of 3 months to the emergency rooms of participating hospitals were included. A total of 1030 patients were enrolled (median age 76.0 years, 52.1% males). At 6 months, 816 (79.2%) were alive, and 164 (15.9%) deceased. Survival status at the 6-month follow-up was missing for 50 (4.9%). Neurological state in the acute phase was significantly worse in patients deceased at 6 months, who showed also higher frequency of acute-phase complications. Cox regression analysis adjusted for demographics, pre-stroke function, baseline diseases and risk factors, indicated as significant predictors of 6-month death altered consciousness (HR, 1.70; 95% CI, 1.14-2.53), total anterior circulation infarct (HR, 2.13; 95% CI, 1.44-3.15), hyperthermia (HR, 1.70; 95% CI, 1.18-2.45), pneumonia (HR, 1.76; 95% CI, 1.18-2.61), heart failure (HR, 2.87; 95% CI, 1.34-6.13) and nasogastric feeding (HR, 2.35; 95% CI, 1.53-3.60), while antiplatelet therapy during acute phase (HR, 0.56; 95% CI, 0.39-0.79), and early mobilisation (HR, 0.55; 95% CI, 0.36-0.84) significantly increased 6-month survival. In a prospective observational study, stroke severity and some acute-phase complications, potentially modifiable, significantly increased the risk of 6-month death, independently of baseline variables. Early mobilisation positively affected survival, highlighting the role of early rehabilitation after stroke.

The authors investigated the relationship of metabolic syndrome (MetS) and its individual components with incident dementia in a prospective population-based study with a 3.5-year follow-up.A total of 2097 participants from a sample of 5632 subjects (65-84 years old) from the Italian Longitudinal Study on Ageing were evaluated. MetS was defined according to the Third Adults Treatment Panel of the National Cholesterol Education Program criteria. Dementia, Alzheimer disease (AD) and vascular dementia (VaD) were classified using current published criteria.MetS subjects (N=918) compared with those without MetS (N=1179) had an increased risk for VaD (1.63% vs 0.85%, adjusted hazard ratio (HR) 3.71, 95% CI 1.40 to 9.83). After excluding 338 subjects with baseline undernutrition, MetS subjects compared with those without MetS had an elevated risk of VaD (adjusted HR, 3.82; 95% CI 1.32 to 11.06). Moreover, those with MetS and high inflammation had a still further higher risk of VaD (multivariate adjusted HR, 9.55; 95% CI 1.17 to 78.17) compared with those without MetS and high inflammation. On the other hand, those with MetS and low inflammation compared with those without MetS and low inflammation did not exhibit a significant increased risk of VaD (adjusted HR, 3.31, 95% CI 0.91 to 12.14). Finally, a synergistic MetS effect versus its individual component effects was verified on the risk of VaD.In our population, MetS subjects had an elevated risk of VaD that increased after excluding patients with baseline undernutrition and selecting MetS subjects with high inflammation.

Background and Purpose— Lacunar infarcts are usually regarded as benign stroke, but population-based studies are required to assess the exact place of this stroke subtype in cerebrovascular pathology. Methods— We evaluated trends in incidence rates, risk factor profiles, and survival rates in symptomatic lacunar stroke from a prospective population-based registry from 1989 to 2006. Results— We recorded 2536 ischemic strokes. Among these, 715 (28%) were lacunar infarcts (354 men and 361 women). From 1989 to 2006, we observed a significant rise in the incidence of lacunar stroke in the 2 sexes considered together (relative risk, 1.02; 95% CI, 1.005 to 1.035; P =0.007), whereas the variation was not significant in either men or women when considered separately. Incidence rates significantly increased in young patients under 65 years old (relative risk, 1.049; 95% CI, 1.0175 to 1.0817; P =0.002). Concerning the distribution of cerebrovascular risk factors, lacunar stroke differed from nonlacunar stroke only with regard to the lower prevalence of a history of atrial fibrillation in the former ( P P Conclusion— Our results suggest a significant increase in the incidence rates of lacunar stroke with a relatively good short-term prognosis in terms of survival. The association among hypertension, diabetes mellitus, and lacunar stroke was no stronger than the association between these 2 risk factors and nonlacunar stroke.

Cognitive decline, particularly when executive functions are compromised, may worsen motor performance (MP) decline in the elderly population. We investigated whether a global test, a memory test, and an attention test predicted MP decline in older community-dwellers with normal baseline MP participating in the Italian Longitudinal Study on Aging (ILSA).One thousand fifty-two ILSA participants (71.2 +/- 4.8 years old, mean +/- standard deviation [SD], 67% men), with normal baseline MP were reassessed after 3 years using the same MP battery. Participants whose MP score reduction from baseline to follow-up was75 percentile were considered to be MP decliners. Global cognition, memory, and attention were assessed using the Mini-Mental State Examination (MMSE), the Babcock Story Recall Test (BSRT), and the Digit Cancellation Test (DCT), respectively. The baseline score on each test was examined as a potential predictor of decline in global MP or in single motor tasks.Baseline scores on the three cognitive tests were worse among the 166 MP decliners, compared with nondecliners. Participants in the lowest quartile of DCT had a2-fold higher adjusted risk of declining than did participants in the highest quartile (odds ratio = 2.47, 95% confidence interval, 1.29-4.74). Conversely, MMSE and BSRT scores no longer predicted MP decline after adjustment. Impaired attention strongly predicted the decline in attention-demanding tasks (tandem walking), but also affected routine tasks (walking).Impairment in a test measuring attention predicts MP decline among older community-dwellers with normal baseline MP. This finding is consistent with the hypothesis that attentional and executive dysfunction is a major determinant of mobility disability in elderly persons.

Kidney transplantation (KT) recipients with donor specific HLA antibodies (DSA) encounter higher rates of acute rejection and inferior allograft survival. We report our single center experience with prospective DSA monitoring and provide details of treatments utilized to overcome the potential impact of DSA in a cohort of predominantly African American adult KT recipients. Seventy-five flow crossmatch negative KT recipients underwent periodic screening for DSA utilizing the single antigen bead assay at 3, 6, 9, and 12 months post-transplant. Allograft biopsies were performed in the presence of DSA and/or evidence of graft dysfunction. The incidence of DSA was 23%, with a predominance of Class II antibodies. The rate of rejection was 6 times higher in DSA positive KT recipients compared to DSA negative patients (41% versus 7%, p = 0.004). In the DSA positive group, rejections occurred exclusively in the presence of de novo DSA and were predominantly antibody-mediated or mixed rejections. Despite a higher incidence of rejection in KT recipients with DSA, there were no significant differences in serum creatinine, graft survival, and patient survival between DSA positive and negative recipients at median follow-up of 18 months. DSA positive patients had significantly higher proteinuria compared to DSA negative recipients at 6 months, 1 year, and 3 years of follow-up. In conclusion, the detrimental effects of DSA on allograft function could be mitigated by serial DSA surveillance, protocol biopsies, and alterations in immunosuppression. With these measures, the improvement in graft survival in DSA positive KT recipients, at least at short-term, is encouraging.

Background Information on determinants and prognosis of ischemic stroke subtypes is scarce. We aimed at evaluating risk factors, pathogenesis, treatment and outcome of different ischemic stroke subtypes. Methods In a European Concerted Action involving seven countries, ischemic stroke subtypes defined according to the Oxfordshire Community Stroke Project (OCSP) were evaluated for demographics, baseline risk factors, resource use, 3-month survival, disability (Barthel Index) and handicap (Rankin Scale). Results During the 12-month study period, cerebral infarction was diagnosed in 2740 patients with first-in-a-lifetime stroke (mean age 70.5 ± 12.4 years, 53.4% males). OCSP classification was achieved in 2472 (90.2%). Of these, 26.7% were total anterior circulation infarctions (TACI), 29.9% partial anterior circulation infarctions (PACI), 16.7% posterior circulation infarctions (POCI) and 26.7% lacunar infarctions (LACI). In multivariate analysis, atrial fibrillation was predictive of TACI (odds ratio [OR], 1.61; 95% CI, 1.28–2.03), hypertension (OR, 1.38; 95% CI, 1.16–1.65) and myocardial infarction (OR, 1.42; 95% CI, 1.08–1.86) predictive of PACI, hypertension (OR, 1.25; 95% CI, 1.04–1.50) predictive of LACI. A negative association was observed between TACI and hypertension (OR, 0.51; 95% CI, 0.42–0.61). Discharge home was 50% less probable in TACI and PACI than in LACI patients. As compared to LACI, TACI significantly increased the risk of 3-month death (OR, 5.73; 95% CI, 3.91–8.41), disability (OR, 3.27; 95% CI, 2.30–4.66) and handicap (OR, 2.71; 95% CI, 1.91–3.85). Conclusions Ischemic stroke subtypes have different risk factors profile, with consequences on pathogenesis and prognosis. Information on determinants of the clinical syndromes may impact on prevention and acute-phase interventions.

OBJECTIVES: To examine risk and predictors of motor-performance (MP) decline targeting subjects performing normally at an initial observation. DESIGN: Cohort study. SETTING: A subsample of the Italian Longitudinal Study on Aging (aged 65-84). PARTICIPANTS: One thousand fifty-two subjects (mean age+/-standard deviation = 71+/-5, 69% men) with normal MP at baseline. MEASUREMENTS: Six tests (standing up from a chair, stepping up, tandem walk, standing on one leg, walking speed, and steps turning 180 degrees ) were used to assess MP at baseline and after 3 years. Baseline characteristics were potential predictors of MP decline. RESULTS: Of the 1,052 subjects performing normally at baseline, 166 (15.8%) had declined in MP at follow-up. Older age, female sex, lower education, symptoms of distal symmetrical neuropathy, cognitive impairment without dementia, parkinsonism, heart failure, anemia, depressive symptoms, worse Mini-Mental State Examination score, and lost activities of daily living and instrumental activities of daily living (IADLs) were significantly associated with MP decline in univariate comparisons. Older age (odds ratio (OR) = 3.84, 95% confidence interval (CI) = 2.14-6.88 comparing age classes > or =80 with 65-69), female sex (OR=1.50, 95% CI = 1.03-2.20), distal symmetric neuropathy (OR = 2.00, 95% CI = 1.03-3.87), depressive symptoms (OR = 1.85, 95% CI = 1.17-2.24), and baseline IADLs (OR = 1.22, 95% CI = 1.08-1.37 for each lost activity) independently predicted MP decline after regression analysis. CONCLUSION: In a population-based cohort of elderly people with normal MP, one-sixth declined in 3 years. Age, sex, distal symmetrical neuropathy, depressive symptoms, and baseline IADLs independently predicted this decline. Distal symmetrical neuropathy is underestimated in the clinical and epidemiological evaluation of motor decline in older people. Language: en

Pancreas transplantation has evolved to offer the most physiologic glucose regulation for patients with diabetes mellitus. This article describes the reported patient benefits of pancreas transplantation and highlights some of the evolving controversies in donor selection, indications for transplantation, surgical options, and updates in immunosuppression.