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Chronic thromboembolic pulmonary hypertension (CTEPH) is considered a complication of pulmonary embolism (PE). However, signs of CTEPH may exist in patients with a first symptomatic PE.Which radiologic findings on computed tomography pulmonary angiography (CTPA) at the time of acute PE could indicate the presence of a pre-existing CTEPH?We included unselected patients with acute PE who were prospectively followed for 2 years with a structured visit schedule. Two expert radiologists independently assessed patients' baseline CTPAs for pre-existing CTEPH; in case of disagreement, a decision was reached by 2:1 majority with a third expert. In addition, the radiologists checked for predefined individual parameters suggesting chronic PE and pulmonary hypertension. Signs of chronic PE or CTEPH at baseline were identified in 46 (15%) of 303 included patients. Intravascular webs, arterial narrowing or retraction, dilated bronchial arteries and right ventricular hypertrophy were the main drivers of the assessment. Five (1.7%) patients were diagnosed with CTEPH during follow-up. All four patients diagnosed with CTEPH early (83-108 days after acute PE) could be found in enriched subgroups based on the experts' overall assessment or fulfilling a minimum number of the predefined radiologic criteria at baseline. The specificity of pre-existing CTEPH diagnosis and the level of radiologists' agreement improved as the number of required criteria increased.Searching for predefined radiologic parameters suggesting pre-existing CTEPH at the time of acute PE diagnosis may allow for targeted follow-up strategies and risk-adapted CTEPH screening, thus facilitating earlier CTEPH diagnosis.

BACKGROUND AND AIMS Peripheral arterial disease (PAD) is one of the most prevalent cardiovascular diseases with more than 230 million people being affected worldwide. As highlighted by the recent European Society of Cardiology guidelines, data on the epidemiology of PAD is urgently needed. METHODS AND RESULTS We accessed the vital registration data of the Veneto region (Northern Italy, approximately five millions inhabitants) covering the period 2008-2019. We computed annual age-standardized rates for PAD reported as the underlying cause of death (UCOD) or as one of multiple causes of death (MCOD). Age-adjusted odds ratios (OR) served to study the association between PAD and cardiovascular comorbidities. The age-standardized mortality rate for PAD as MCOD slightly declined from 19.6 to 17.8 in men and from 10.8 to 9.1 deaths per 100,000 population-years in women. The age-standardized PAD-specific mortality rate (UCOD) remained stable: 3.1 to 3.7 per 100,000 person-years in women (Average Annual Percent Change 1.3, 95% CI -0.8; 3.4%) and 4.4 to 4.3 per 100,000 person-years (Average Annual Percent Change -0.2, 95% CI -3.6; 3.4%) in men. PAD contributed to 1.6% of all deaths recorded in the region. Ischemic heart disease, diabetes mellitus and neoplasms were the most prevalent UCOD among PAD patients. PAD was associated with diabetes mellitus (OR 3.79, 95%CI 3.55-4.06) and chronic kidney diseases (OR 2.73, 95%CI 2.51-2.97) in men, and with atrial fibrillation (OR 2.26, 95%CI 2.10-2.44) in women. CONCLUSION PAD remains a substantial cause of death in the general population of this high-income region of Western Europe with marked sex-specific differences.

BackgroundIntensive care units (ICU) capacities are one of the most critical determinants in health-care management of the COVID-19 pandemic. Therefore, we aimed to analyze the ICU-admission and case-fatality rate as well as characteristics and outcomes of patient admitted to ICU in order to identify predictors and associated conditions for worsening and case-fatality in this critical ill patient-group.MethodsWe used the German nationwide inpatient sample to analyze all hospitalized patients with confirmed COVID-19 diagnosis in Germany between January and December 2020. All hospitalized patients with confirmed COVID-19 infection during the year 2020 were included in the present study and were stratified according ICU-admission.ResultsOverall, 176,137 hospitalizations of patients with COVID-19-infection (52.3% males; 53.6% aged ≥70 years) were reported in Germany during 2020. Among them, 27,053 (15.4%) were treated in ICU. COVID-19-patients treated on ICU were younger [70.0 (interquartile range (IQR) 59.0–79.0) vs. 72.0 (IQR 55.0–82.0) years, P < 0.001], more often males (66.3 vs. 48.8%, P < 0.001), had more frequently cardiovascular diseases (CVD) and cardiovascular risk-factors with increased in-hospital case-fatality (38.4 vs. 14.2%, P < 0.001). ICU-admission was independently associated with in-hospital death [OR 5.49 (95% CI 5.30–5.68), P < 0.001]. Male sex [OR 1.96 (95% CI 1.90–2.01), P < 0.001], obesity [OR 2.20 (95% CI 2.10–2.31), P < 0.001], diabetes mellitus [OR 1.48 (95% CI 1.44–1.53), P < 0.001], atrial fibrillation/flutter [OR 1.57 (95% CI 1.51–1.62), P < 0.001], and heart failure [OR 1.72 (95% CI 1.66–1.78), P < 0.001] were independently associated with ICU-admission.ConclusionDuring 2020, 15.4% of the hospitalized COVID-19-patients were treated on ICUs with high case-fatality. Male sex, CVD and cardiovascular risk-factors were independent risk-factors for ICU admission.

Background Splanchnic vein thrombosis (SVT) is an uncommon manifestation of venous thromboembolism. Historical epidemiological data on SVT-related mortality rate is not available to date. Methods We investigated time trends in SVT-related mortality, 2008–2019, in Veneto, an Italian high-income region of approximatively 5,000,000 inhabitants. SVT-related deaths were identified by the following ICD-10 codes: I81 (portal vein thrombosis), K75.1 (phlebitis of portal vein), K76.3 (liver infarction), K76.5 (hepatic veno-occlusive disease) or I82.0 (Budd-Chiari syndrome). Results During the study period, a total of 557,932 deaths were recorded. SVT was reported in 823 cases; 776 (94%) consisted of portal vein thrombosis. The age-standardized SVT-related mortality rate varied from 1.47 (year 2008) to 1.52 (year 2019) per 100,000 person-years. An increase in the cause-specific annual mortality rate was observed in women (0.56 in 2008 to 1.04 per 100,000 person-years in 2019; average annual percent change +5.7%, 95%CI +3.1; +8.3%). In men, the cause-specific mortality rate moved from 2.53 in 2008 to 2.03 per 100,000 person-years in 2019 (average annual percent change −1.2%, 95%CI -4.0; +1.6%). After conditioning for age and sex, the odds of having a concomitant liver disease were higher for SVT-related deaths (OR 31.6; 95%CI 17.1–37.0) compared with non-SVT-related deaths. This also applies to gastrointestinal cancers (OR 1.28; 95%CI 1.07–1.55), although to a lesser extent. Conclusions We report first epidemiological estimates of SVT-related mortality in a Western country. These values will serve as a reference to weight novel potential factors associated with SVT-related death, putting them into an epidemiological perspective. Summary box What is already known about this subject? Splanchnic vein thrombosis is a rare manifestation of venous thromboembolism, often related to liver diseases. Currently, there is no available data on its impact on the general population in terms of mortality rates. What are the new findings? Splanchnic vein thrombosis-related mortality rate was higher in men than in women and was strongly associated with the presence of liver diseases. In women, the age-standardized splanchnic vein thrombosis-related mortality rate has been increasing since 2008. How might it impact on clinical practice in the foreseeable future? We report first epidemiological estimates of splanchnic vein thrombosis-related mortality rates in a Western country. These values will serve as a reference to weight novel factors or pathologies potentially associated with splanchnic vein thrombosis and interpret them in an epidemiological perspective.

AIM OF THE STUDY Extracorporeal membrane oxygenation (ECMO) is considered a life-saving treatment option for patients in cardiogenic shock or cardiac arrest undergoing cardiopulmonary resuscitation (CPR) due to acute pulmonary embolism (PE). We sought to analyze use and outcome of ECMO with or without adjunctive treatment strategies in patients with acute PE. METHODS We retrospectively analyzed data on patient characteristics, treatments, and in-hospital outcomes for all PE patients (ICD-code I26) undergoing ECMO in Germany between 2005 and 2018. RESULTS At total of 1,172,354 patients were hospitalized with PE; of those, 2,197 (0.2%) were treated with ECMO support. Cardiac arrest requiring cardiopulmonary resuscitation was present in 77,196 (6.5%) patients. While more than one fourth of those patients were treated with systemic thrombolysis alone (n = 20,839 patients; 27.0%), a minority of patients received thrombolysis and VA-ECMO (n = 165; 0.2%), embolectomy and VA-ECMO (n = 385; 0.5%) or VA-ECMOalone (n = 588; 0.8%). A multivariable logistic regression analysis indicated the lowest risk for in-hospital death in patients who received embolectomy in combination with VA-ECMO (OR, 0.50 [95% CI, 0.41-0.61], p

Tidal Love numbers describe the linear response of a compact object under the presence of external tidal perturbations, and they are found to vanish exactly for black holes within General Relativity. In this paper we investigate the tidal deformability of neutral black holes when non-linearities in the theory are taken into account. As a case in point, we consider scalar tidal perturbations on the black hole background, and find that the tidal Love numbers may be non vanishing depending on the scalar interactions in the bulk theory. Remarkably, for non-linear sigma models, we find that the tidal Love numbers vanish to all orders in perturbation theory., Comment: 30 pages. v2: matching version published in PRD

Septic pulmonary embolism (SPE) is a rare clinical entity that is distinct from the classic and more common non-septic thrombotic pulmonary embolism. SPE should be suspected in patients with a systemic acute inflammatory reaction or sepsis who develop signs and symptoms of pulmonary involvement. The diagnosis of SPE depends on the specific radiologic finding of multiple, peripheral, nodular, possibly cavitated lesions. SPE should prompt an immediate search for the primary source of infection; typically, right-sided infective endocarditis, cardiac implantable electronic devices, and septic thrombophlebitis as a complication of bone, skin, and soft tissue infection including Lemierre's syndrome, indwelling catheters, or direct inoculation via injection drug use. Invasive treatment of the infection source may be necessary; in thrombophlebitis, the efficacy and safety of anticoagulation remain undefined. Blood cultures may be negative, particularly among patients with recent antibiotic exposure, and broad-spectrum antimicrobial therapy should be considered. The in-hospital mortality of SPE ranges up to 20% in published case series. While trends in the incidence of SPE are unknown, the opioid epidemic, the growing use of cardiac implantable electronic devices worldwide, and the reported increase in cases of septic thrombophlebitis may be leading to an escalation in SPE cases. We provide a contemporary profile of SPE and propose a clinical management algorithm in patients with suspected or confirmed SPE.

Background As mortality from pulmonary embolism (PE) decreases, the personal and societal costs among survivors are receiving increasing attention. Detailing this burden would support an efficient public health resource allocation. We aimed to provide estimates for the economic and disease burden of PE also accounting for long‐term health care use and both direct and indirect costs beyond the acute phase. Methods and Results This is a cost‐of‐illness analysis with a bottom‐up approach based on data from the PREFER in VTE registry (Prevention of Thromboembolic Events—European Registry in Venous Thromboembolism). We calculated direct (clinical events and anticoagulation) and indirect costs (loss of productivity) of an acute PE event and its 12‐month follow‐up in 2020 Euros. We estimated a disability weight for the 12‐month post‐PE status and corresponding disability adjusted life years presumably owing to PE. Disease‐specific costs in the first year of follow‐up after an incident PE case ranged between 9135 Euros and 10 620 Euros. The proportion of indirect costs was 42% to 49% of total costs. Costs were lowest in patients with ongoing cancer, mainly because productivity loss was less evident in this already burdened population. The calculated disability weight for survivors who were cancer free 12 months post‐PE was 0.017, and the estimated disability adjusted life years per incident case were 1.17. Conclusions The economic burden imposed by PE to society and affected patients is considerable, and productivity loss is its main driver. The disease burden from PE is remarkable and translates to the loss of roughly 1.2 years of healthy life per incident PE case.

BACKGROUND Few data are available on the long-term course and predictors of quality of life (QoL) following acute pulmonary embolism (PE). RESEARCH QUESTION What are the kinetics and determinants of disease-specific and generic health-related QoL 3 and 12 months following an acute PE? STUDY DESIGN AND METHODS The Follow-up after Acute Pulmonary Embolism (FOCUS) study prospectively followed up consecutive adult patients with objectively diagnosed PE. Patients were considered for study who completed the Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire at predefined visits 3 and 12 months following PE. The course of disease-specific QoL as assessed using the PEmb-QoL and the impact of baseline characteristics using multivariable mixed effects linear regression were studied; also assessed was the course of generic QoL as evaluated by using the EuroQoL Group 5-Dimension 5-Level utility index and the EuroQoL Visual Analog Scale. RESULTS In 620 patients (44% women; median age, 62 years), overall disease-specific QoL improved from 3 to 12 months, with a decrease in the median PEmb-QoL score from 19.4% to 13.0% and a mean individual change of -4.3% (95% CI, -3.2 to -5.5). Female sex, cardiopulmonary disease, and higher BMI were associated with worse QoL at both 3 and 12 months. Over time, the association with BMI became weaker, whereas older age and previous VTE were associated with worsening QoL. Generic QoL also improved: the mean ± SD EuroQoL Group 5-Dimension 5-Level utility index increased from 0.85 ± 0.22 to 0.87 ± 0.20 and the visual analog scale from 72.9 ± 18.8 to 74.4 ± 19.1. INTERPRETATION In a large cohort of survivors of acute PE, the change of QoL was quantified between months 3 and 12 following diagnosis, and factors independently associated with lower QoL and slower recovery of QoL were identified. This information may facilitate the planning and interpretation of clinical trials assessing QoL and help guide patient management. CLINICAL TRIAL REGISTRATION German Clinical Trials Registry (Deutsches Register Klinischer Studien: www.drks.de); No.: DRKS00005939.

Superfluid dark matter, consisting of self-interacting light particles that thermalize and condense to form a superfluid in galaxies, provides a novel theory that matches the success of the standard $\Lambda$CDM model on cosmological scales while simultaneously offering a rich phenomenology on galactic scales. Within galaxies, the dark matter density profile consists of a nearly homogeneous superfluid core surrounded by an isothermal envelope. In this work we compute the density profile of superfluid dark matter around supermassive black holes at the center of galaxies. We show that, depending on the fluid equation of state, the dark matter profile presents distinct power-law behaviors, which can be used to distinguish it from the standard results for collisionless dark matter., Comment: 25 pages, 2 figures. v2: matching version published in JCAP

BackgroundCardiopulmonary exercise testing (CPET) may provide prognostically valuable information during follow-up after pulmonary embolism (PE).ObjectiveTo investigate the association of patterns and degree of exercise limitation, as assessed by CPET, with clinical, echocardiographic, laboratory abnormalities and quality of life (QoL) after PE.MethodsIn a prospective cohort study of unselected consecutive all-comers with PE, survivors of the index acute event underwent 3-month and 12-month follow-up, including CPET. We defined cardiopulmonary limitation as ventilatory inefficiency or insufficient cardiocirculatory reserve. Deconditioning was defined as peak VO2ResultsOverall, 396 patients were included. At 3 months, prevalence of cardiopulmonary limitation and deconditioning was 50.1% (34.7% mild/moderate; 15.4% severe) and 12.1%, respectively; at 12 months, it was 44.8% (29.1% mild/moderate 15.7% severe) and 14.9%. Cardiopulmonary limitation and its severity were associated with age (OR per decade 2.05; 95% CI 1.65–2.55), history of chronic lung disease (OR 2.72; 95% CI 1.06–6.97), smoking (OR 5.87; 2.44–14.15), and intermediate- or high-risk acute PE (OR 4.36; 95% CI 1.92–9.94). Severe cardiopulmonary limitation at 3 months was associated with the prospectively defined, combined clinical-haemodynamic endpoint of “post-PE impairment” (OR 6.40, 95% CI 2.35–18.45) and with poor disease-specific and generic health-related QoL.ConclusionAbnormal exercise capacity of cardiopulmonary origin is frequent after PE, being associated with clinical and hemodynamic impairment as well as long-term QoL reduction. CPET can be considered for selected patients with persisting symptoms after acute PE to identify candidates for closer follow-up and possible therapeutic interventions.

Altered corticospinal excitability in Parkinson’s disease (PD) is related to many of the motor signs. We examined whether the recruitment properties of the corticospinal pathway to hand muscles are changed after 8 weeks of specialized upper limbs exercise in PD. Seven PD subjects were enrolled. Upper limb exercise was achieved by using a specially designed device. The input–output (I–O) curves were obtained by transcranial magnetic stimulation (TMS). The conduction of peripheral axons and H reflex was also recorded. UPDRS scale, part-III motor examination was used to assess the motor symptom. Clinical and neurophysiological data were obtained before and after 2-month exercise training. After 2-month exercise training, the UPDRS score was significantly improved. Threshold, slope, and V50 (i.e., the stimulus intensity required to obtain a response 50% of the maximum) of the I–O curve were unchanged, whereas the plateau value was significantly higher. Exercise training affects the larger motoneurons, that is those activated at higher TMS stimulation intensity. These motoneurones are related to the large, type II motor units. Clinical improvement after exercise may depend upon restoration of the recruitment of the large motor unit, i.e., those necessary to perform rapid and strong movements, known to be deficient in PD.

Performance status (PS) is a reliable prognostic tool for overall survival in patients with cancer-associated pulmonary embolism (PE). However, its association with venous thromboembolism (VTE) recurrence and bleeding remains unclear.The aim of this study was to investigate whether PS at the time of PE diagnosis and its course during follow-up are linked to VTE-related outcomes.In this post hoc analysis of the Hokusai-VTE Cancer study, multivariable survival analysis was used to examine the association of PS with anticoagulation discontinuation and the composite primary outcome of VTE recurrence or major bleeding in patients with cancer-associated PE. PS was assessed using the Eastern Cooperative Oncology Group (ECOG) scale at baseline and at predefined study follow-up visits.Overall, 652 patients with cancer-associated PE were included. During 12-month follow-up, PS worsened in 317 of 642 patients (49.4%) with complete ECOG data at the end of follow-up. Those with worse ECOG values over follow-up were more likely to discontinue anticoagulation for any reason apart from death (adjusted HR: 1.59; 95% CI: 1.31-1.93). The composite primary outcome occurred in 57 of 500 patients with baseline ECOG status 0 or 1 and in 32 of 152 patients with ECOG status 2 (cumulative incidence at 12 months 10.7% [95% CI: 8.2%-13.9%] vs 14.4% [95% CI: 9.7%-21.3%]). Worse ECOG values during follow-up were associated with greater risk for the composite outcome (adjusted HR: 2.13; 95% CI: 1.24-3.67).ECOG PS is a valuable indicator for predicting VTE-related outcomes and may inform decision making regarding anticoagulation during follow-up in patients with cancer-associated PE.

Background Pulmonary embolism (PE) is a potentially fatal disease, but data on the incidence of fatal PE in cancer patients are scant. Objective We sought to estimate the proportion of cancer patients with PE at autopsy. Methods For this retrospective cohort study, all autopsy reports of cancer patients were retrieved from PALGA: Dutch Pathology Registry and used for data extraction. The primary outcome was PE at time of autopsy, defined as any clot obstructing a pulmonary artery. The secondary outcome was venous thromboembolism, defined as the composite of thrombotic PE, deep vein thrombosis, splanchnic vein thrombosis, or internal jugular vein thrombosis. Results A total of 9571 cancer patients were included. In 1191 (12.4%; 95% confidence interval [CI], 11.8‐13.1) patients, one or more PE events were observed at autopsy, of whom 1074 (90.2%) had a thrombotic embolism, 168 (14.1%) a tumor embolism, 9 (0.8%) a septic embolism, 7 (0.6%) a fat tissue embolism, and 3 (0.3%) a bone marrow embolism. Among patients with PE for whom the cause of death was specified in the autopsy report, death was considered PE‐related in 642 patients (66.7%), which was 6.7% of the total study population. Venous thromboembolism was observed in 1223 (12.8%; 95% CI, 12.1‐13.5) patients. Conclusion The proportion of PE in cancer patients at autopsy is substantial. Although the study population is not representative for the total cancer population, it suggests that PE is an important disease complication in cancer patients.

BACKGROUND Pulmonary embolism (PE)-related mortality is decreasing worldwide. AIM Little is known about the burden imposed by pulmonary embolism for Germany, Austria and Switzerland (DACH countries). MATERIALS AND METHODS We aimed to assess pulmonary embolism-related mortality and time trends for the DACH countries based on data from the WHO Mortality Database. Deaths were considered pulmonary embolism-related if the International Classification of Disease-10 code for acute pulmonary embolism or any code for deep or superficial vein thrombosis was listed as the primary cause of death. RESULTS Between 2000 and 2015, age-standardized annual pulmonary embolism-related mortality rates decreased linearly from 15.6 to 7.8 deaths per 1000 population. In the 5‑year period between 2012 and 2016, an average of 9127 pulmonary embolism-related deaths occurred annually in the DACH countries with a population of 98,273,329. Interestingly, pulmonary embolism-related mortality rates were considerably higher among women aged 15-55 years compared to age-matched men. CONCLUSION The observed decreasing trends in pulmonary embolism-related mortality might reflect improved management of the disease including new treatment options as well as advances in imaging technologies. However, pulmonary embolism remains a substantial contributor to total mortality, especially among women aged 15-55 years. For this reason, campaigns to increase physician and public awareness are urgently required to further improve the management and treatment of this preventable thrombotic disorder, which still remains the leading preventable cause of death. Hintergrund Kurzlich veroffentliche Studien zeigen eine steigende Inzidenz fur die Lungenarterienembolie (LE) bei gleichzeitigem Ruckgangs der LE-assoziierten Mortalitat. Ziel der Studie Detaillierte Daten zur Mortalitat der LE in Deutschland, Osterreich und der Schweiz (DACH-Region) sind derzeit nicht vorhanden. Material und Methoden Datensatze wurden aus der Mortalitatsdatenbank der Weltgesundheitsorganisation (WHO) ausgewertet. Hierbei analysierten wir die Haufigkeit sowohl der akuten LE als auch der tiefen/oberflachlichen Venenthrombose als primarer Todesursache. Ergebnisse Demnach sank die jahrliche altersstandardisierte Mortalitat zwischen Januar 2000 und Dezember 2015 von 15,6 auf 7,8 Todesfalle pro 1000 Einwohner. Zwischen Januar 2012 und Dezember 2016 ereigneten sich in der DACH-Region (Bevolkerungsanzahl: 98.273.320 Menschen) durchschnittlich 9127 durch LE verursache Todesfalle pro Jahr. Interessanterweise ist LE–assoziierte Gesamtmortalitat bei Frauen zwischen dem 15. und 55. Lebensjahr deutlich hoher als bei gleichaltrigen Mannern. Schlussfolgerung Der Ruckgang der Mortalitat durch die Erkrankung LE seit dem Jahr 2000 ist vermutlich durch eine verbesserte Patientenversorgung mit Einfuhrung neuer Antikoagulanzien und durch den vermehrten Einsatz und diagnostischen Fortschritt bei den computertomographischen Untersuchungen erklart. Festzuhalten ist, dass die LE eine wichtige Todesursache vor allem im hoheren Alter darstellt. Auserdem ist der Anteil der Frauen im gebarfahigen Alter, die nach einer akuten LE sterben, mit 3,5 % hoch. Daher sind, trotz des medizinischen Fortschritts, weitere Anstrengungen fur eine Verbesserung der Pravention, Diagnostik und Therapie, aber insbesondere auch des Krankheitsbewusstseins notwendig.

We dedicate this thesis to the study of signatures coming from the primordial epochs of the universe. We will focus in particular on Primordial Black Holes (PBHs), which may be formed from perturbations generated during inflation and might comprise a fraction of the dark matter in the universe. In the first part of the thesis, we will address the PBH properties at the time of formation, that are their masses, spins and abundance, and investigate the generation of Gravitational Wave (GW) signals during their production. In the second part, we will describe the PBHs evolution across the cosmic history due to their assemble in binaries, phases of baryonic mass accretion and clustering effects. We will then discuss GW signatures coming from their coalescence, compare these predictions with present GW data detected by the LIGO/Virgo Collaboration (LVC) and assess the role of future GW experiments like 3G detectors and LISA in discovering these objects. Finally, in the third part, we will investigate some aspects of the interplay between black holes and fundamental physics in the early universe, focusing on the role of GWs to shed light on their properties., Comment: 263 pages. PhD thesis

Lemierre Syndrome is a rare form of septic thrombophlebitis of the head and neck veins, most typically of the internal jugular vein, which affects otherwise healthy adolescents and young adults after an oropharyngitis or other local infection. It is characterized by multiple septic embolization. Despite treatment, Lemierre Syndrome displays a high rate of in-hospital complications that include thrombus progression and a new peripheral septic embolization; moreover, it can be fatal or cause disabling sequelae. The mainstay of the treatment is antibiotic therapy; anticoagulation is often used, but its role is controversial. Surgical treatment is often necessary in case of peripheral septic lesions. In the absence of prospective studies, what little guidance exists on its management is based on case series or on analogy with similar conditions, such as other forms of septic thrombophlebitis or non-septic venous thrombosis. Over the last few years, new observational evidence has improved our knowledge of the clinical epidemiology of this condition and highlighted a number of promising management strategies. We provide an overview of the treatment patterns adopted in the contemporary era, and summarize the arguments proposed so far against or in favor of alternative treatments as well as possible decision rules on the use of anticoagulation. Moreover, we outline the priorities of ongoing and future observational and interventional research.

PURPOSE Lemierre syndrome is a life-threatening condition characterized by head/neck bacterial infection, local suppurative thrombophlebitis and septic embolic complications in a range of sites of distant organs. No prior study focused on the course and characteristics of ophthalmic complications of Lemierre syndrome. METHODS We analysed data of 27 patients with ophthalmic complications from a large cohort of 712 cases with Lemierre syndrome reported globally between 2000 and 2017. We focused on initial manifestations, early (in-hospital) course and long-term ophthalmic deficits at the time of hospital discharge or during postdischarge follow-up. The study protocol was registered in the International Prospective Register of Systematic Reviews PROSPERO (CRD42016052572). RESULTS Nine (33%) patients were women; the median age was 20 (Q1-Q3: 15-33) years. Fusobacterium spp. was involved in 56% of cases. The most prevalent initial manifestations were decreased vision (35%) and periocular oedema (38%), followed by impaired eye movements/nerve palsy (28%) and proptosis (28%). Venous involvement, notably cerebral vein thrombosis (70%) and ophthalmic vein thrombosis (55%), explained the symptomatology in most cases. Septic embolism (7%), orbital abscesses (2%) and carotid stenosis (14%) were also present. Ophthalmic sequelae were reported in 9 (33%) patients, often consisting of blindness or reduced visual acuity, and nerve paralysis/paresis. CONCLUSION Ophthalmic complications represent a severe manifestation of Lemierre syndrome, often reflecting an underlying cerebral vein thrombosis. Visual acuity loss and long-term severe complications are frequent. We call for an interdisciplinary approach to the management of patients with Lemierre syndrome and the routine involvement of ophthalmologists.

Background Few data are available on the long-term course and predictors of quality of life (QoL) after acute pulmonary embolism (PE). Aims To evaluate the kinetics and determinants of QoL at 3 and 12 months after acute PE. Methods The Follow-Up after acute pulmonary embolism (FOCUS) study prospectively followed consecutive adult patients with objectively diagnosed PE. For this analysis, we considered patients who completed the Pulmonary Embolism QoL (PEmb-QoL) Questionnaire at two predefined visits 3 and 12 months after PE. PEmb-QoL, studied as total score and in its six dimensions, ranges from 0% (best QoL) to 100% (worst QoL). We studied the course of PEmb-QoL and the impact of baseline characteristics using multivariable linear regression. Results In 617 included patients (44% women, median age 62 years), overall QoL improved from 3 to 12 months, with a decrease of the mean PEmb-QoL score from 25.3% to 21.5% (p-value Conclusions In a large cohort of patients with pulmonary embolism, we quantified the improvement of QoL between 3 and 12 months after diagnosis. We identified factors independently associated with lower QoL and slower recovery of QoL that may reflect special patient needs. These estimates may facilitate the planning and interpretation of clinical trials with QoL as a study outcome. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): University Medical Center of the Johannes Gutenberg University, Mainz, Germany; German Federal Ministry of Education and Research

Background It is unclear to which extent persistence of symptoms and/or residual haemodynamic impairment clinical course of pulmonary embolism are associated with worse quality of life (QoL). Aims To study the correlation between symptoms and haemodynamic impairment with QoL during the first year after acute pulmonary embolism (PE). Methods The Follow-Up after acute pulmonary embolism (FOCUS) study prospectively enrolled and followed consecutive adult patients diagnosed with acute symptomatic objectively diagnosed PE. In the present analysis, we considered patients who completed the Pulmonary Embolism QoL (PEmb-QoL) Questionnaire at predefined visits 3 and 12 months after acute PE. The PEmb-QoL score ranges from 0% (best QoL) to 100% (worst QoL). We evaluated at these two time points the correlation between persisting symptoms (group: symptoms), elevation of natriuretic peptides or residual right ventricular dysfunction (group: RVD), or their combination (group: symptoms + RVD) and QoL. Results A total of 617 patients were included; their median age was 62 years, 44% were women; 8% had active cancer, and 21% previous venous thromboembolism. At 3 months, patients with neither symptoms nor RVD (n=302) had the highest quality of life (median score 18%, 25th–75th percentile: 8%–34%), followed by those without symptoms but with RVD (n=255; median score 19%, 25th–75th percentile: 7%–34%), and by those with symptoms only (n=131; median PEmb-QoL 31%, 25th–75th percentile: 18%–49%). Patients with both symptoms and RVD (n=170) had the worst quality of life (median score 38%, 25th–75th percentile: 19%–53%); Figure 1A. At 12 months, we found an overall improvement of PEmb-QoL score. The degree of this QoL improvement varied across groups, being largest for patients who recovered from having symptoms + RVD at 3 months to normalization of at least one at 12 months. The change in QoL from 3 to 12 months was smaller both in patients who had neither symptoms nor RVD and in patients who had no recovery in either symptoms or RVD; Figure 1B. Conclusions Persistent symptoms after PE, especially in patients with elevated biomarkers or residual echocardiographic dysfunction, were the main drivers of QoL at 3 months as well as of the course of QoL over time. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): University Medical Center of the Johannes Gutenberg University, Mainz, Germany; German Federal Ministry of Education and Research

Lemierre syndrome is a rare but potentially fatal condition characterized by septic thrombophlebitis of the head and neck district, preferentially affecting adolescents and young adults and manifesting as a complication of a local bacterial infection – typically, a pharyngotonsillitis or an abscess. It is historically associated with the Gram-negative anaerobic rod Fusobacterium necrophorum and with thrombophlebitis of the internal jugular vein. However, its definition has never been firmly established, and its spectrum within the continuum of bacteria-associated thrombophlebitis may be larger than what presumed so far. Recent evidence suggests that its prognosis remains serious even one hundred years after its first description, with considerable rates of in-hospital complications, death, and long-term sequelae. There are no specific guidelines on its management other than usual antibiotic stewardship, with ongoing debate on the potential role of therapeutic-dose anticoagulation. We provide an overview of current evidence on the definition, epidemiology, clinical presentation, prognosis and management of this condition and present the background and rationale of the Bacteria-Associated Thrombosis/Thrombophlebitis and LEmierre syndrome (BATTLE) registry: an ambispective, disease-specific, non-population based, multicentre clinical registry of global reach and multidisciplinary scope, specifically designed to address the limitations of current evidence and to provide patients and physicians with clinically viable information to guide management and improve the outcomes of those affected by these conditions.

Septic thrombophlebitis (STP) is a complex, cross-disciplinary clinical condition that combines a localized infection with a neighboring venous thrombosis. STP can occur at several possible anatomic sites, such as dural sinuses, jugular vein (Lemierre syndrome), portal vein (pylephlebitis), and pelvic veins. Its high mortality in the preantibiotic era improved considerably with the introduction of modern antibiotics. However, little evidence exists to date to guide its clinical management. The incidence of STP or its risk factors may be increasing, and its mortality may still be considerable. These trends would have far-reaching implications, especially in the setting of increasing resistance to antimicrobial agents. No clinical assessment tools exist to support patient screening or guide treatment in STP. Few interventional studies exist on the efficacy and safety of anticoagulation. Recommendations on its indications, duration, and the agents of choice are mostly based on evidence derived from small observational studies. While all forms of STP pose similar challenges, future research may benefit from the distinction between bacteria-associated, virus-associated, and mycosis-associated thrombophlebitis. Addressing these gaps in evidence would enhance our ability to diagnose this condition and treat patients effectively.

Data regarding pulmonary embolism (PE)-related mortality in Italy are scarce. We assessed PE-related mortality and its time trend in Italy by using the World Health Organization (WHO) Mortality Database.The vital registration data of Italy from the WHO Mortality Database were analyzed for the period between 2003 and 2015, and compared with time trends in Southern Europe. Death was defined as PE-related when classified with specific codes for PE or limb vein thrombosis listed as the primary cause of death. This coding was based on the International Classification of Diseases, tenth revision.Overall, 28 647 PE-related deaths (10 178 men and 18 469 women) were recorded between 2003 and 2015. The observed age-standardized annual PE-related mortality rates were 2.5 per 100 000 men and 2.8 per 100 000 women. Moreover, PE-related mortality increased with age with a seemingly exponential distribution. Joinpoint regression analysis demonstrated a statistically significant linear decrease in age-standardized PE-related mortality of -0.21 (95% confidence interval -0.27; -0.15) and -0.22 (95% confidence interval -0.28; -0.16) deaths per 100 000 population for men and women, respectively.The Italian age-adjusted mortality rates appeared lower compared to overall Southern Europe, despite a similar decreasing trend over time.

BackgroundThe European Society of Cardiology guidelines for the diagnosis and management of acute pulmonary embolism (PE) developed in collaboration with the European Respiratory Society (ERS) has been updated in 2019. Recommendations were added or updated on all stages of the evaluation and management of pulmonary embolism, encompassing diagnosis, early treatment, and long-term management.Case summaryWe illustrate an exemplary case, assembled for the purposes of this review, of a 70-year-old woman who presented at the emergency department with dyspnoea and thoracic pain. She was diagnosed with intermediate–high-risk acute PE and promptly treated with low molecular weight heparin. After 24 h of stay in intensive care unit, she was transferred to the cardiology department and switched to non-vitamin K-dependent oral anticoagulant apixaban 10 mg b.i.d. for 7 days and then 5 mg b.i.d. After discharge from the hospital 8 days later, she received standard-dose apixaban 5 mg b.i.d. for 6 months; the dose was reduced to 2.5 mg b.i.d. for long-term secondary prevention. During follow-up, investigations for PE sequelae were performed due to persisting dyspnoea.DiscussionThis exemplary case report puts into context the main novel recommendations from the 2019 ESC Guidelines, including the combination of clinical (pre-test) probability and adjusted D-dimer cut-offs for diagnosis of acute PE, the key role of right ventricular dysfunction in risk stratification, the choice and dosage of oral anticoagulant agents in early and extended anticoagulation, and the identification and management of chronic sequelae in the long-term follow-up.

IntroductionEarly discharge of patients with acute low-risk pulmonary embolism requires validation by prospective trials with clinical and quality-of-life outcomes.MethodsThe multinational Home Treatment of Patients with Low-Risk Pulmonary Embolism with the Oral Factor Xa Inhibitor Rivaroxaban (HoT-PE) single-arm management trial investigated early discharge followed by ambulatory treatment with rivaroxaban. The study was stopped for efficacy after the positive results of the predefined interim analysis at 50% of the planned population. The present analysis includes the entire trial population (576 patients). In addition to 3-month recurrence (primary outcome) and 1-year overall mortality, we analysed self-reported disease-specific (Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire) and generic (five-level five-dimension EuroQoL (EQ-5D-5L) scale) quality of life as well as treatment satisfaction (Anti-Clot Treatment Scale (ACTS)) after pulmonary embolism.ResultsThe primary efficacy outcome occurred in three (0.5%, one-sided upper 95% CI 1.3%) patients. The 1-year mortality was 2.4%. The mean±sdPEmb-QoL decreased from 28.9±20.6% at 3 weeks to 19.9±15.4% at 3 months, a mean change (improvement) of −9.1% (pConclusionsOur results further support early discharge and ambulatory oral anticoagulation for selected patients with low-risk pulmonary embolism. Targeted strategies may be necessary to further improve quality of life in specific patient subgroups.

Background Bleeding risk scores in atrial fibrillation (AF) are used to identify risk factors for bleeding but not to determine anticoagulant therapy since high bleeding risk strongly correlates to high risk of stroke. VTE-BLEED is a simple bleeding risk score (Klok FA Eur Respir J 2016) that predicts major bleeding (MB) in patients with venous thromboembolism, but has never been evaluated in AF. Aims To evaluate VTE-BLEED in AF and whether dabigatran dose reduction in VTE-BLEED high-risk patients would result in a lower incidence of MB and the composite endpoint of MB plus stroke/systemic embolism. Methods Assessment of VTE-BLEED in 18040 patients of the RE-LY trial (Connolly SJ NEJM 2009) that compared dabigatran (both 150mg BID and 110mg BID) to warfarin. The score was calibrated to fit the AF population. Hazard ratios (HR) were obtained for the VTE-BLEED high-risk patients randomized to dabigatran. The risk ratios for MB and the composite outcome of MB plus stroke/systemic embolism between dabigatran 150mg and 110mg were calculated for the VTE-BLEED high-risk group. Results The adapted VTE-BLEED score classified 4060 patients (22.5%) as high-risk. A high score indeed predicted MB in patients treated with dabigatran 150mg BID or 110mg BID, for HRs of 2.48 (95% CI 1.96–3.13) and 2.61 (95% CI 2.04–3.33), respectively. In VTE-BLEED high-risk patients, the risk ratio between the two dabigatran doses was 0.53 (95% CI 0.35–0.78) for MB and 0.55 (95% CI 0.38–0.79) for the composite outcome, both in favor of dabigatran 110mg BID (Figure 1). Compared to the current European label of dabigatran, application of VTE-BLEED to determine dabigatran dosing would result in a different dose for 21% of patients. Figure 1 Conclusions VTE-BLEED was validated for AF. Our data suggest that dabigatran dose reduction in VTE-BLEED bleed high-risk patients -in addition to targeting individual modifiable risk factors for bleeding- may lower the risk of MB and improve patient outcome. This finding could have important clinical implications but should be confirmed in future studies.

Background Lemierre syndrome is a potentially life-threatening condition occurring in otherwise healthy children and adolescents with head/neck bacterial infections (usually tonsillitis due to anaerobe bacteria). Peculiar complications are neck vein thromboses contiguous to the site of infection and multiple septic embolization. Arterial thrombosis and cardiac complications have been described as possible clinical manifestations of Lemierre syndrome: however, in light of the rarity of this condition (one case/1,000,000 person-years), no comprehensive analysis has ever been conducted. Purpose To describe the frequency and the patterns of acute cardiac and arterial complications in patients with Lemierre syndrome. Methods We identified 715 cases of Lemierre syndrome (years 2000–2016) and retrieved complete individual patient-level data. Study outcomes assessed on admission or during hospitalization were: i) objectively diagnosed ischemia or arterial infarction/thrombosis, arterial stenosis due to inflammatory process, and septic aneurysms; ii) new objectively diagnosed cardiac complications; iii) all-cause death. Results Of the 715 patients with Lemierre syndrome, 56 (7.6%, 95% confidence interval [CI]: 6.1%–10.0%) experienced cardiac or arterial complications. Median age was 19 (interquartile range [IQR]: 16–25) years and 35 (62.5%) were men. Intracranial ischemia or infarction was found in 23 patients, corresponding to 3.2% of the whole study population. Carotid artery thrombosis, stenosis, or septic aneurysm occurred in 28 (3.9% of total), pericardial disease in 11 (1.5% of total), and infective endocarditis in 5 (0.7% of total) (Figure). A total of 32 (57.1%) patients developed these complications during the course of hospitalization after a median of 6 (IQR: 3–12 days) days from admission. A total of 37 (66.1%) patients received anticoagulation. Fatality rate was 10.7% (95% CI: 5.0%–21.4%; n=6). Cardiac and arterial complications. Conclusions An unexpectedly high proportion of patients with Lemierre syndrome developed acute cardiac or arterial complications. In this group, the fatality rate was substantial. Our observation that most of the cardiovascular events occurred during the course of hospitalization may have implications for the development of diagnostic and management strategies. It remains unclear whether antithrombotic therapies may influence prognosis.

Introduction The interaction between sex and specific provoking risk factors for venous thromboembolism (VTE) may influence initial presentation and prognosis. Purpose We investigated the impact of sex on the risk of recurrence across subgroups of patients with first VTE classified according to baseline risk factors. Methods PREFER in VTE was an international, non-interventional registry (2013–2015) including patients with a first episode of acute symptomatic objectively diagnosed VTE. We studied the risk of recurrence in patients classified according to baseline provoking risk factors for VTE consisted of i) major transient (major surgery/trauma, >5 days in bed), ii) minor transient (pregnancy or puerperium, estroprogestinic therapy, prolonged immobilization, current infection or bone fracture/soft tissue trauma); iii) unprovoked events, iv) active cancer-associated VTE. Results A total of 3,455 patients diagnosed with first acute VTE were identified, of whom 1,623 (47%) were women. The percentage of patients with a major transient risk factor was 22.2% among women and 19.7% among men. Minor transient risk factors were present in 21.3% and 12.4%, unprovoked VTE in 51.6% and 61.6%, cancer-associated VTE in 4.9% of women and 6.3% of men, respectively. The proportions of cases treated with Vitamin-K antagonists (VKAs) and direct oral anticoagulants (DOACs) were similar between sexes. Median length of treatment of VKAs was 181.5 and 182.0 days and of DOACs was 113.0 and 155.0 days in women and men, respectively. At 12-months of follow-up, VTE recurrence was reported in 74 (4.8%) women and 80 (4.5%) men. Table 1 shows the sex-specific proportion of recurrences by VTE risk factor categories. Table 1 Major Transient (n=722) Minor transient (n=573) Cancer-associated (n=195) Unprovoked (1965) Women (361) Men (361) OR (95% CI) Women (346) Men (227) OR (95% CI) Women (79) Men (116) OR (95% CI) Women (837) Men (1128) OR (95% CI) One-year follow-up, n (N%) Recurrent VTE, 21 (6.2) 10 (2.9) 0.46 (0.2; 0.9) 9 (2.7) 12 (5.4) 2.09 (0.9; 5.0) 6 (8.0) 5 (4.5) 0.54 (0.2; 1.9) 38 (4.7) 53 (4.7) 1.03 (0.7; 1.6) Major bleeding, 6 (1.8) 5 (1.5) 0.83 (0.3; 2.7) 5 (1.5) 1 (0.5) 0.30 (0.1; 2.6) 1 (1.3) 3 (2.7) 2.07 (0.2; 20) 10 (1.2) 15 (1.4) 1.11 (0.6; 2.4) All-cause death, 37 (10.2) 31 (8.5) 0.82 (0.5; 1.4) 10 (2.9) 14 (6.2) 2.21 (0.9; 5.1) 26 (32.9) 49 (42.2) 1.49 (0.8; 2.7) 33 (3.9) 30 (2.7) 0.66 (0.4; 1.1) Conclusions The proportion of patients with recurrent VTE events after first acute symptomatic VTE provoked by transient risk factors was not negligible during the first year of follow-up during in both women and men. These results may have implications on the decision whether to consider extended anticoagulant therapy in selected patients with provoked events. Acknowledgement/Funding This study was funded by Daiichi Sankyo.

Standard-dose intravenous recombinant interleukin-2 (rIL-2) is indicated for the treatment of some subtypes of cancer; however, severe adverse events, including venous thromboembolism (VTE), may complicate its administration. Low-dose subcutaneous rIL-2 is being studied for the management of immune-mediated diseases, since it can modulate the immunological response by specifically targeting T regulatory (Treg) cells; importantly, it is supposed to cause fewer or no complications. In this systematic review and meta-analysis of phase II-III randomized controlled trials (RCTs), we investigated the safety of low-dose (

The interesting case of Lemierre syndrome requiring pleural decortication described by A. T. Lanfear and colleagues is of particular clinical interest, as it emphasizes the high intensity of surgic...

Trapezius muscle has a fundamental role in cervico-dorsal pain and posture. Often, in movements involving trapezius, the predominant activity is carried out by the upper trapezius, and many times this may be a risk factor for the integrity of the cervico-dorsal structures. To investigate the effects of physical exercise with the new device called the “Angel’s Wings” on a sample of different professionals. We enrolled 15 volunteers for electromyography (EMG) data, which was collected during the physical performance, 3 volunteers for magnetic resonance imaging (MRI) data, collected before and after a training period, and 73 workers of Ferrari S.p.A. and the Scuderia Ferrari racing team division for a visual analogue scale (VAS) pain score, collected before and after one session of training. EMG shows a decoupling of upper and lower trapezius activity, MRI shows a realignment of cervical-dorsal rachis after one month of training, VAS pain score significantly decreased after the physical exercise with the “Angel’s Wings”. Results show that the use of the “Angel’s Wings” is applicable to counteract and decrease the neck pain by a decontraction of the upper trapezius and correct postural defects of the cervico-dorsal column.

BackgroundChanges in the microcirculation may be used as a surrogate outcome in studies on cardiovascular disease. We assessed the reliability characteristics of the sublingual microcirculation parameters Vascular Density (VD), Red Blood Cell Filling (RBCF), and Perfused Boundary Region (PBR) as obtained by sidestream darkfield imaging.MethodsFor each of the three parameters, the variance components of measurement, the Intraclass Correlation Coefficient (ICC), the Standard Error of Measurement, and the limits of agreement were estimated for the intra-rater setting (N = 50) and the inter-rater setting (N = 48). Subsequently, as a proof of concept, the reliability measures were used for a power analysis to design studies to evaluate the effect of acute stimuli-i.e. having a meal (N = 50) and cigarette smoking (N = 21) on the three parameters.ResultsReproducibility was poor for all three parameters. The intra-rater ICC for 2 measurements was 0.28 (95% CI: 0.04, 0.53) for the VD, 0.51 (95% CI: 0.27, 0.69) for the RBCF, and 0.33 (95% CI: 0.08-0.56) for the PBR. The standard errors of measurement and the limits of agreement for all three parameters were larger than most statistically significant intra-individual or inter-individual differences reported in previous studies. The proofs of concept showed that sample sizes in excess of 600 subjects are necessary to reach statistical significance for the observed effects of having a meal or smoking on VD and PBR.ConclusionsThe reliability of the three sublingual microcirculation parameters in their current form appears to be low and a large sample size is advisable for their use in conditions similar to those we describe.

L’autore cerca di fare un utile raffronto fra la psicologia e psicopatologia di orientamento esistenzialista-fenomenologico e le concezioni della psicologia analitica di Carl Gustav Jung, con lo scopo di mostrarne l’assoluta identita di presupposti e di metodo. Tutto cio al fine di porre la psicologia analitica nell'alveo che le spetta: ossia quello del pensiero scientifico moderno.

Acetaminophen or paracetamol, a commonly used over-the-counter analgesic, is known to elicit severe adverse reactions when taken in overdose, chronically at therapeutic dosage or, sporadically, following single assumptions of a therapeutic dose. Damage patterns including liver damage and, rarely, acute tubular necrosis or a fixed drug exanthema. We present a case of fatal acetaminophen toxicity with postmortem blood concentration 78 μg/mL and unusual clinical features, including a visually striking and massive epidermolysis and rhabdomyolysis, disseminated intravascular coagulation and myocardial ischemia. This case is compared with the most similar previous reports in terms of organ damage, clinical presentation, and cause of death. We conclude that a number of severe patterns of adverse effects to acetaminophen are emerging that were previously greatly underestimated, thus questioning the adequacy of the clinical spectrum traditionally associated with acetaminophen intoxication and leading to the need to review this spectrum and the associated diagnostic criteria.

Purpose: This study aimed to compare technical efficiency of general practice (GP) delivered by the twenty Regions of Italy's decentralized healthcare system and to determine if it was affected by contextual factors. Methods: First, we calculated the Regional efficiency scores by means of Data Envelopment Analysis. Then we carried out a regression analysis to investigate the influence of contextual factors on the efficiency in the provision of GP services. Results: Six Northern Regions were identified as efficient using the best combinations of general practitioners to deliver a given level of GP outcomes. Compared with peer benchmarks, inefficient Regions used more (on-call and regular) general practitioners with important underproductions of outputs (e.g. avoidable hospitalizations). The regression analysis showed a negative relationship between efficiency and the Regional total health care expenditures as percentage of its Gross Domestic Product. Discussion: Improving efficiency of GP services delivery is likely to result in reduced health expenditures. Since there is a general tendency in Europe to decentralize governmental systems of countries and Italy can be seen as an extreme example of this trend, we consider our findings of high relevance for international comparative studies on performance of primary care systems. (C) 2012 Elsevier Ireland Ltd. All rights reserved

The 2005 Report on Social Responsibility and Health of the UNESCO International Bioethics Committee (Ibc) proposes a new approach to implementing the right to healthcare and suggests a number of Courses of Action to be followed in various fields. Based on the latest available data, we intend to present an overview of the current state of European health systems in two of those fields-decision-making procedures and quality assurance in health care-and to attempt a comparison of the situation with the Report's provisions, in order to pave the way for the identification of what still has to be done to bridge international recommendations and the reality of policy and practice in Europe's health care.

Italy is the sixth largest country in Europe and has the second highest average life expectancy, reaching 79.4 years for men and 84.5 years for women in 2011. There are marked regional differences for both men and women in most health indicators, reflecting the economic and social imbalance between the north and south of the country. The main diseases affecting the population are circulatory diseases, malignant tumours and respiratory diseases. Italy's health care system is a regionally based national health service that provides universal coverage largely free of charge at the point of delivery. The main source of financing is national and regional taxes, supplemented by copayments for pharmaceuticals and outpatient care. In 2012, total health expenditure accounted for 9.2 percent of GDP (slightly below the EU average of 9.6 percent). Public sources made up 78.2 percent of total health care spending. While the central government provides a stewardship role, setting the fundamental principles and goals of the health system and determining the core benefit package of health services available to all citizens, the regions are responsible for organizing and delivering primary, secondary and tertiary health care services as well as preventive and health promotion services. Faced with the current economic constraints of having to contain or even reduce health expenditure, the largest challenge facing the health system is to achieve budgetary goals without reducing the provision of health services to patients. This is related to the other key challenge of ensuring equity across regions, where gaps in service provision and health system performance persist. Other issues include ensuring the quality of professionals managing facilities, promoting group practice and other integrated care organizational models in primary care, and ensuring that the concentration of organizational control by regions of health-care providers does not stifle innovation.