Personalized Pain Goals and Responses in Advanced Cancer Patients

To assess the personalized pain intensity goal (PPIG), the achievement of a personalized pain goal response (PPGR), and patients' global impression (PGI) in advanced cancer patients after a comprehensive pain and symptom management

Utrophin Up-Regulation by an Artificial Transcription Factor in Transgenic Mice

Duchenne Muscular Dystrophy (DMD) is a severe muscle degenerative disease, due to absence of dystrophin. There is currently no effective treatment for DMD. Our aim is to up-regulate the expression level of the dystrophin related gene utrophin in DMD, complementing in this way the lack of dystrophin functions. To this end we designed and engineered several synthetic zinc finger based transcription factors. In particular, we have previously shown that the artificial three zinc finger protein named Jazz, fused with the appropriate effector domain, is able to drive the transcription of a test gene from the utrophin promoter “A”. Here we report on the characterization of Vp16-Jazz-transgenic mice that specifically over-express the utrophin gene at the muscular level. A Chromatin Immunoprecipitation assay (ChIP) demonstrated the effective access/binding of the Jazz protein to active chromatin in mouse muscle and Vp16-Jazz was shown to be able to up-regulate endogenous utrophin gene expression by immunohistochemistry, western blot analyses and real-time PCR. To our knowledge, this is the first example of a transgenic mouse expressing an artificial gene coding for a zinc finger based transcription factor. The achievement of Vp16-Jazz transgenic mice validates the strategy of transcriptional targeting of endogenous genes and could represent an exclusive animal model for use in drug discovery and therapeutics

How the First Year of the COVID-19 Pandemic Impacted Patients’ Hospital Admission and Care in the Vascular Surgery Divisions of the Southern Regions of the Italian Peninsula

Background: To investigate the effects of the COVID-19 lockdowns on the vasculopathic population. Methods: The Divisions of Vascular Surgery of the southern Italian peninsula joined this multicenter retrospective study. Each received a 13-point questionnaire investigating the hospitalization rate of vascular patients in the first 11 months of the COVID-19 pandemic and in the preceding 11 months. Results: 27 out of 29 Centers were enrolled. April-December 2020 (7092 patients) vs. 2019 (9161 patients): post-EVAR surveillance, hospitalization for Rutherford category 3 peripheral arterial disease, and asymptomatic carotid stenosis revascularization significantly decreased (1484 (16.2%) vs. 1014 (14.3%), p = 0.0009; 1401 (15.29%) vs. 959 (13.52%), p = 0.0006; and 1558 (17.01%) vs. 934 (13.17%), p < 0.0001, respectively), while admissions for revascularization or major amputations for chronic limb-threatening ischemia and urgent revascularization for symptomatic carotid stenosis significantly increased (1204 (16.98%) vs. 1245 (13.59%), p < 0.0001; 355 (5.01%) vs. 358 (3.91%), p = 0.0007; and 153 (2.16%) vs. 140 (1.53%), p = 0.0009, respectively). Conclusions: The suspension of elective procedures during the COVID-19 pandemic caused a significant reduction in post-EVAR surveillance, and in the hospitalization of asymptomatic carotid stenosis revascularization and Rutherford 3 peripheral arterial disease. Consequentially, we observed a significant increase in admissions for urgent revascularization for symptomatic carotid stenosis, as well as for revascularization or major amputations for chronic limb-threatening ischemia

Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease

BACKGROUND: The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease. METHODS: In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. RESULTS: At 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo. After 1363 of the planned 1670 primary end-point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy. After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91). CONCLUSIONS: Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease. (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998 .)

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Chronotropic and Inotropic Effects of Atrial Peptides On the Isolated Systemic Heart of Octopus-vulgaris

The chronotropic and inotropic effects of four atrial peptides (cardiodilatin 1-16, atrial natriuretic factor 8-33 and atriopeptin I and III) on the isolated systemic heart of Octopus vulgaris were studied. Using a preparation that produces a physiological stroke volume at physiological input pressures, it was found that ANF, atriopeptin I and atriopeptin III exerted both negative chronotropic and inotropic effects. In contrast, cardiodilatin produced a positive inotropic effect. A dose-response curve of ANF is reported, showing a threshold concentration of about 10(-12) M. The pharmacological and physiological implications of these results are discussed in relation to some characteristics of the cephalopod systemic heart

Outcomes of Endovascular Reconstructive Techniques in Trans-Atlantic Inter-Society Consensus II C-D Aortoiliac Lesions

Background: To describe the outcomes of the endovascular reconstruction of TASC C/D lesions involving the infrarenal aorta and aortic bifurcation with different techniques. Methods: This is an observational, retrospective, single-center study. In a 5-year period, we selected all the patients treated with an endovascular procedure for an aorto-iliac TASC C/D lesion involving the infrarenal aorta and/or the aortic bifurcation. Early (<30 days) outcomes were mortality, major amputation, and thrombosis. Late mid-term (1 and 3 years) outcomes were primary, assisted primary and secondary patency, limb salvage rate, and freedom from reintervention. Results: A total of 87 patients were treated during the index period. Kissing covered stent (cKS), covered reconstruction of aortic bifurcation (CERAB), and unimodular bifurcated AFX Unibody stent-graft (Bif-SG) implantation were performed in 35 (40.4%), 26 (29.8%), and 26 (29.8%) cases, respectively. Bif-SG group included 11 (11/26, 42.3%) patients treated for abdominal aortic aneurysm associated with the obstruction of the aortic bifurcation. Technical success was achieved in all cases and no ruptures or conversions to open surgery were recoded. Median follow-up age was 18 months (interquartile range [IQR], 8-34). Overall primary patency rate was 91.2% (95% confidence interval [CI]: 81.3-95.9) at 1 year and 83.5% (95% CI: 69.6-91.4) at 3 years. Assisted primary patency was 96.9% (95% CI: 87.8-99.2) at 1 and 3 years. Secondary patency was 97.8% (95% CI: 85.5-99.6) at 3 years. Limb salvage rate was 98.6% (95% CI: 90.1-99.7) at 1 and 3 years and, freedom from reintervention was 98.4% (95% CI: 88.9-99.7) at 1 year and 87% (95% CI: 66.1-95.4) at 3 years. Univariate analysis did not identify any factor affecting primary patency rate. Conclusions: Endovascular reconstruction in severe aorto-iliac obstructions using advanced techniques offered promising mid-term patency rates and profiles of safety. The variety of reconstructive configurations allows surgeons to customize on patients' anatomies the type of revascularization

Revascularization Outcomes in COVID-19 Patients With Acute Lower Limb Ischemia

Objectives: The outcomes of COVID-19 (coronavirus disease 2019) pa- tients with acute lower limb ischemia (ALI) seem poor compared with those without COVID-19; however, the data are conflicting. Our aim was to evaluate different therapeutic options in the management of ALI in pa- tients with COVID-19. Methods: From January 2020 to January 2022, 27 patients were ur- gently admitted at our department for ALI due to either an embolic/ thrombotic etiology or a thrombosed popliteal artery aneurysm (tPAA). The patients were divided into two groups: 12 patients with COVID-19 infection (C-19) and 15 patients without COVID-19 (control group [CG]). The preoperative data included demographics, Rutherford ALI stage, American Society of Anesthesiologists class, preoperative anticoagulation use, and level of the lesions. The perioperative details were revasculariza- tion type (percutaneous transluminal angioplasty [PTA] with or without stenting, catheter-directed thrombolysis, surgical thrombectomy, throm- bectomy with active aspiration, femoropopliteal bypass), postoperative therapy, and complications. PTA with or without stenting was performed when delayed revascularization (>72 hours) occurred and bypass was performed for tPAA treatment. A primary major amputation was per- formed in two C-19 cases for irreversible ischemia; thus, 25 patients were finally included. Early results were analyzed in terms of 30-day thrombosis, amputation, and death. The follow-up results were analyzed by Kaplan-Meier curves in terms of 12-month primary and secondary patency, freedom from reintervention, amputation-free survival, and over- all survival. Two groups were compared using the log-rank test. P < .05 was considered significant. Results: The mean age was 66 6 14 years (C-19 group, 75 6 12 years; CG, 65 6 14 years). The C-19 group had a more advanced ischemic stage (Rutherford ALI stage IIb or III; C-19 group, 58.3%; CG, 46.5%; P 1⁄4 .12) and poorer clinical condition (American Society of Anesthesiologists class 4; C-19 group, 66.7%; CG, 20%; P 1⁄4 .049), and women were more affected (C-19 group, 41.7%; CG, 0%; P 1⁄4 .006). The lesions were equally distributed in both groups but no tPAAs affected the C-19 group. The C-19 group had undergone PTA with or without stenting more frequently (C-19 group, 41%; CG, 6.7%; P 1⁄4 .071). Thrombolysis was the preferred approach in the CG (C-19 group, 25%; CG, 45%; P 1⁄4 .28). The 30-day outcomes wereas follows: thrombosis rate, 16% (C-19 group, 30%; CG, 6.7%; P 1⁄4 .11); amputation rate, 4% (C-19 group, 10%; CG, 0%; P 1⁄4 .21); and mortality rate, 20% (C-19 group, 40%; CG, 6.7%; P 1⁄4 .041). The median follow-up was 7 months (range, 1-16 months). At follow-up, no patient had died, the overall primary patency was 65% (C-19 group, 40%; CG, 74%; log- rank test, 1.974; P 1⁄4 .16), secondary patency and freedom from reintervention were both 80.5% (C-19 group, 80%; CG, 81%; log-rank test, 0.14; P 1⁄4 .70), and amputation-free survival was 90% (C-19 group, 50%; CG, 100%; log-rank test, 4; P 1⁄4 .046). Conclusions: COVID-19 patients with ALI had worse outcomes in terms of 30-day mortality and amputation-free survival within 1 year after revas- cularization. Patients admitted for COVID-19 and ALI had poorer clinical conditions with a delay between diagnosis and intervention compared with patients with ALI but without COVID-19. These factors could affect therapeutic decisions and outcome