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Background Chronic Thromboembolic Pulmonary Hypertension (CTEPH) is the most serious long-term complication of acute pulmonary embolism (PE) though it is the only potentially reversible form of Pulmonary Hypertension (PH). Its incidence is mainly limited to the first 2 years following the embolic event, however it is often underdiagnosed or misdiagnosed. Methods This is a multicenter observational cross-sectional and prospective study. Patients with a prior diagnosis of PE will be enrolled and undergo baseline evaluation for prevalent PH detection through a clinical examination and an echocardiogram as first screening exam. All cases of intermediate-high echocardiographic probability of PH will be confirmed by right heart catheterization and then identified as CTEPH through appropriate imaging and functional examinations in order to exclude other causes of PH. A CTEPH Risk Score will be created using retrospective data from this prevalent cohort of patients and will be then validated on an incident cohort of patients with acute PE. Results 1000 retrospective and 218 prospective patients are expected to be enrolled and the study is expected to be completed by the end of 2021. Up to now 841 patients (620 retrospective and 221 prospective) have been enrolled. Conclusions This study is the first large prospective study for the prediction of CTEPH development in patients with PE. It aims to create a comprehensive scoring tool that includes echocardiographic data which may allow early detection of CTEPH and the application of targeted follow up screening programs in patients with PE.

The so-called "smoking paradox", conditioning lower mortality in smokers among STEMI patients, has seldom been addressed in the settings of modern primary PCI protocols. The ISACS-STEMI COVID-19 is a large-scale retrospective multicenter registry addressing in-hospital mortality, reperfusion, and 30-day mortality among primary PCI patients in the era of the COVID-19 pandemic. Among the 16,083 STEMI patients, 6819 (42.3%) patients were active smokers, 2099 (13.1%) previous smokers, and 7165 (44.6%) non-smokers. Despite the impaired preprocedural recanalization (p < 0.001), active smokers had a significantly better postprocedural TIMI flow compared with non-smokers (p < 0.001); this was confirmed after adjustment for all baseline and procedural confounders, and the propensity score. Active smokers had a significantly lower in-hospital (p < 0.001) and 30-day (p < 0.001) mortality compared with non-smokers and previous smokers; this was confirmed after adjustment for all baseline and procedural confounders, and the propensity score. In conclusion, in our population, active smoking was significantly associated with improved epicardial recanalization and lower in-hospital and 30-day mortality compared with previous and non-smoking history.

ObjectiveThe initial data of the International Study on Acute Coronary Syndromes - ST Elevation Myocardial Infarction COVID-19 showed in Europe a remarkable reduction in primary percutaneous coronary intervention procedures and higher in-hospital mortality during the initial phase of the pandemic as compared with the prepandemic period. The aim of the current study was to provide the final results of the registry, subsequently extended outside Europe with a larger inclusion period (up to June 2020) and longer follow-up (up to 30 days).MethodsThis is a retrospective multicentre registry in 109 high-volume primary percutaneous coronary intervention (PPCI) centres from Europe, Latin America, South-East Asia and North Africa, enrolling 16 674 patients with ST segment elevation myocardial infarction (STEMI) undergoing PPPCI in March/June 2019 and 2020. The main study outcomes were the incidence of PPCI, delayed treatment (ischaemia time >12 hours and door-to-balloon >30 min), in-hospital and 30-day mortality.ResultsIn 2020, during the pandemic, there was a significant reduction in PPCI as compared with 2019 (incidence rate ratio 0.843, 95% CI 0.825 to 0.861, p75 years) (p=0.015), and was not related to the peak of cases or deaths due to COVID-19. The heterogeneity among centres was high (pConclusionPercutaneous revascularisation for STEMI was significantly affected by the COVID-19 pandemic, with a 16% reduction in PPCI procedures, especially among older patients (about 20%), and longer delays to treatment, which may have contributed to the increased in-hospital and 30-day mortality during the pandemic.Trial registration numberNCT04412655.

Purpose Wire-based coronary physiology pullback performed before percutaneous coronary intervention (PCI) discriminates coronary artery disease (CAD) distribution and extent, and is able to predict functional PCI result. No research investigated if quantitative flow ratio (QFR)–based physiology assessment is able to provide similar information. Methods In 111 patients (120 vessels) treated with PCI, QFR was measured both before and after PCI. Pre-PCI QFR trace was used to discriminate functional patterns of CAD (focal, serial lesions, diffuse disease, combination). Functional CAD patterns were identified analyzing changes in the QFR virtual pullback trace (qualitative method) or after computation of the QFR virtual pullback index (QVPindex) (quantitative method). QVPindex calculation was based on the maximal QFR drop over 20 mm and the length of epicardial coronary segment with QFR most relevant drop. Then, the ability of the different functional patterns of CAD to predict post-PCI QFR value was tested. Results By qualitative method, 51 (43%), 20 (17%), 15 (12%), and 34 (28%) vessels were classified as focal, serial focal lesions, diffuse disease, and combination, respectively. QVPindex values >0.71 and ≤0.51 predicted focal and diffuse patterns, respectively. Suboptimal PCI result (post-PCI QFR value ≤0.89) was present in 22 (18%) vessels. Its occurrence differed across functional patterns of CAD (focal 8% vs. serial lesions 15% vs. diffuse disease 33% vs. combination 29%, p=0.03). Similarly, QVPindex was correlated with post-PCI QFR value (r=0.62, 95% CI 0.50–0.72). Conclusion Our results suggest that functional patterns of CAD based on pre-PCI QFR trace can predict the functional outcome after PCI. Clinical Trial Registration ClinicalTrials.gov, number NCT02811796. Date of registration: June 23, 2016.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has spread worldwide determining dramatic impacts on healthcare systems. Early identification of high-risk parameters is required in order to provide the best therapeutic approach. Coronary, thoracic aorta and aortic valve calcium can be measured from a non-gated chest computer tomography (CT) and are validated predictors of cardiovascular events and all-cause mortality. However, their prognostic role in acute systemic inflammatory diseases, such as COVID-19, has not been investigated. OBJECTIVES: The aim was to evaluate the association of coronary artery calcium and total thoracic calcium on in-hospital mortality in COVID-19 patients. METHODS: 1093 consecutive patients from 16 Italian hospitals with a positive swab for COVID-19 and an admission chest CT for pneumonia severity assessment were included. At CT, coronary, aortic valve and thoracic aorta calcium were qualitatively and quantitatively evaluated separately and combined together (total thoracic calcium) by a central Core-lab blinded to patients' outcomes. RESULTS: Non-survivors compared to survivors had higher coronary artery [Agatston (467.76 ​± ​570.92 vs 206.80 ​± ​424.13 ​mm2, p ​

Background and aims The potential impact of coronary atherosclerosis, as detected by coronary artery calcium, on clinical outcomes in COVID-19 patients remains unsettled. We aimed to evaluate the prognostic impact of clinical and subclinical coronary artery disease (CAD), as assessed by coronary artery calcium score (CAC), in a large, unselected population of hospitalized COVID-19 patients undergoing non-gated chest computed tomography (CT) for clinical practice. Methods SARS-CoV 2 positive patients from the multicenter (16 Italian hospitals), retrospective observational SCORE COVID-19 (calcium score for COVID-19 Risk Evaluation) registry were stratified in three groups: (a) “clinical CAD” (prior revascularization history), (b) “subclinical CAD” (CAC >0), (c) “No CAD” (CAC=0). Primary endpoint was in-hospital mortality and the secondary endpoint was a composite of myocardial infarction and cerebrovascular accident (MI/CVA). Results Amongst 1625 patients (male 67.2%, median age 69 [interquartile range 58-77] years), 31%, 57.8% and 11.1% had no, subclinical and clinical CAD, respectively. Increasing rates of in-hospital mortality (11.3% vs. 27.3% vs. 39.8%, p400, respectively, p, Graphical abstract Image 1

Background It has been suggested the COVID pandemic may have indirectly affected the treatment and outcome of STEMI patients, by avoidance or significant delays in contacting the emergency system. No data have been reported on the impact of diabetes on treatment and outcome of STEMI patients, that was therefore the aim of the current subanalysis conducted in patients included in the International Study on Acute Coronary Syndromes–ST Elevation Myocardial Infarction (ISACS-STEMI) COVID-19. Methods The ISACS-STEMI COVID-19 is a retrospective registry performed in European centers with an annual volume of > 120 primary percutaneous coronary intervention (PCI) and assessed STEMI patients, treated with primary PCI during the same periods of the years 2019 versus 2020 (March and April). Main outcomes are the incidences of primary PCI, delayed treatment, and in-hospital mortality. Results A total of 6609 patients underwent primary PCI in 77 centers, located in 18 countries. Diabetes was observed in a total of 1356 patients (20.5%), with similar proportion between 2019 and 2020. During the pandemic, there was a significant reduction in primary PCI as compared to 2019, similar in both patients with (Incidence rate ratio (IRR) 0.79 (95% CI: 0.73–0.85, p p p Furthermore, the pandemic was independently associated with a significant increase in door-to-balloon and total ischemia times only among patients without diabetes, which may have contributed to the higher mortality, during the pandemic, observed in this group of patients. Conclusions The COVID-19 pandemic had a significant impact on the treatment of patients with STEMI, with a similar reduction in primary PCI procedures in both patients with and without diabetes. Hypertension had a significant impact on PCI reduction only among patients without diabetes. We observed a significant increase in ischemia time and door-to-balloon time mainly in absence of diabetes, that contributed to explain the increased mortality observed in this group of patients during the pandemic. Trial registration number: NCT 04412655.

Background: During the coronavirus disease 2019 (COVID-19) pandemic, concerns have been arisen on the use of renin-angiotensin system inhibitors (RASI) due to the potentially increased expression of Angiotensin-converting-enzyme (ACE)2 and patient's susceptibility to SARS-CoV2 infection. Diabetes mellitus have been recognized favoring the coronavirus infection with consequent increase mortality in COVID-19. No data have been so far reported in diabetic patients suffering from ST-elevation myocardial infarction (STEMI), a very high-risk population deserving of RASI treatment.Methods: The ISACS-STEMI COVID-19 registry retrospectively assessed STEMI patients treated with primary percutaneous coronary intervention (PPCI) in March/June 2019 and 2020 in 109 European high-volume primary PCI centers. This subanalysis assessed the prognostic impact of chronic RASI therapy at admission on mortality and SARS-CoV2 infection among diabetic patients.Results: Our population is represented by 3812 diabetic STEMI patients undergoing mechanical reperfusion, 2038 in 2019 and 1774 in 2020. Among 3761 patients with available data on chronic RASI therapy, between those ones with and without treatment there were several differences in baseline characteristics, (similar in both periods) but no difference in the prevalence of SARS-CoV2 infection (1.6% vs 1.3%, respectively, p = 0.786). Considering in-hospital medication, RASI therapy was overall associated with a significantly lower in-hospital mortality (3.3% vs 15.8%, p < 0.0001), consistently both in 2019 and in 2010.Conclusions: This is first study to investigate the impact of RASI therapy on prognosis and SARS-CoV2 infection of diabetic patients experiencing STEMI and undergoing PPCI during the COVID-19 pandemic. Both pre-admission chronic RASI therapy and in-hospital RASI did not negatively affected patients' survival during the hospitalization, neither increased the risk of SARS-CoV2 infection.Trial registration number: NCT04412655.

Background and aims SARS-Cov-2 predisposes patients to thrombotic complications, due to excessive inflammation, endothelial dysfunction, platelet activation, and coagulation/fibrinolysis disturbances. The aim of the present study was to evaluate clinical characteristics and prognostic impact of SARS-CoV-2 positivity among STEMI patients undergoing primary percutaneous coronary intervention (PPCI). Methods We selected SARS-CoV-2 positive patients included in the ISACS-STEMI COVID-19, a retrospective multicenter European registry including 6609 STEMI patients treated with PPCI from March 1st until April 30th, in 2019 and 2020. As a reference group, we randomly sampled 5 SARS-Cov-2 negative patients per each SARS-CoV-2 positive patient, individually matched for age, sex, and hospital/geographic area. Study endpoints were in-hospital mortality, definite stent thrombosis, heart failure. Results Our population is represented by 62 positive SARS-CoV-2 positive patients who were compared with a matched population of 310 STEMI patients. No significant difference was observed in baseline characteristics or the modality of access to the PCI center. In the SARS-CoV-2 positive patients, the culprit lesion was more often located in the RCA (p, Graphical abstract Image 1

Objectives The purpose of this study was to explore speckle tracking echocardiographic right ventricular (RV) post-systolic strain patterns and their clinical relevance in idiopathic pulmonary arterial hypertension (PAH). Background The imaging of RV diastolic function in PAH remains incompletely understood. Methods Speckle tracking echocardiography of RV post-systolic strain recordings were examined in 108 consecutive idiopathic patients with PAH. Each of them underwent baseline clinical, hemodynamic, and complete echocardiographic evaluation and follow-up. Results In total, 3 post-systolic strain patterns derived from the mid-basal RV free wall segments were identified. Pattern 1 was characterized by prompt return of strain-time curves to baseline after peak systolic negativity, like in normal control subjects. Pattern 2 was characterized by persisting negativity of strain-time curves well into diastole, before an end-diastolic returning to baseline. Pattern 3 was characterized by a slow return of strain-time curves to baseline during diastole. The 3 patterns corresponded respectively to mild PH, more advanced PH but with still preserved RV function, and PH with obvious end-stage right heart failure. Patterns were characterized by optimal reproducibility when complementary to quantitative measurement of right ventricular longitudinal early diastolic strain rate (RVLSR-E), and right ventricular longitudinal late diastolic strain rate (RVLSR-A) (Cohen's κ = 0.88; p = 0.0001). Multivariable models for clinical worsening prediction demonstrated that the addition of RV post-systolic patterns to clinical and hemodynamic variables significantly increased their prognostic power (0.78 vs. 0.66; p Conclusions Speckle tracking echocardiography allows for the identification of 3 phenotypically distinct, reproducible, and clinically meaningful RV strain-derived post-systolic patterns.

Objectives To investigate the correlation between quantitative flow ratio (QFR), Pd/Pa, diastolic hyperemia-free ratio (DFR) and fractional flow reserve (FFR, gold standard) in non-culprit lesion (NCL) of patients with non ST-segment elevation myocardial infarction (NSTEMI). Background The non-hyperemic pressure ratio (NHPR) and the angiography-based indexes have been developed to overcome the limitation of the use of the FFR. Methods Between January and December 2019, 184 NCL from 116 NSTEMI patients underwent physiologic assessment and were included in the study. NCLs were investigated with QFR, Pd/Pa, DFR, and FFR. Mean values of QFR, Pd/Pa, DFR and FFR were 0.85 ± 0.10, 0.92 ± 0.07, 0.93 ± 0.05 and 0.84 ± 0.07, respectively. Results DFR and FFR showed a good correlation (r = 0.76). Bland and Altman plot showed a mean difference of 0.080. DFR Diagnostic accuracy was 88%. The area under the ROC curve (AUC) for DFR was 0.946 (95%CI 0.90-0.97, p = .0001). Similar findings were reported for Pd/Pa (r = 0.73; mean difference 0.095, diagnostic accuracy 84%, AUC 0.909 [95%CI 0.85-0.94, p = .0001]) and QFR (r = 0.68; mean difference 0.01; diagnostic accuracy 88%, AUC 0.964 [95% CI 0.91-0.98, p = .0001]). FFR, QFR, Pd/Pa and DFR identified 31%, 32%, 30% and 32% potentially flow-limiting lesions, respectively. Conclusions In NSTEMI patients, QFR, Pd/Pa and DFR showed equivalence as compared to gold standard FFR in the discrimination of non-culprit lesions requiring revascularization.

Background The prognostic role of diabetes mellitus (DM) in heart failure (HF) patients is undefined, since DM is outweighed by several DM-related variables when confounders are considered. We determined the prognostic role of DM, treatment, and glycemic control in a real-life HF population. Methods 3927 HF patients included in the Metabolic Exercise Cardiac Kidney Index (MECKI) score database were evaluated with a median follow-up of 3.66 years (IQR 1.70–6.67). Data analysis considered survival between DM (n = 897) vs. non-DM (n = 3030) patients, and, in diabetics, between insulin (n = 304), oral antidiabetics (n = 479), and dietary only (n = 88) treatments. The role of glycemic control was evaluated grouping DM patients according to glycated hemoglobin (HbA1c): 8% (n = 149). All analyses were performed also adjusting for ejection fraction, renal function, hemoglobin, sodium, exercise peak oxygen uptake, and ventilation/carbon dioxide relationship slope. Study primary endpoint was the composite of cardiovascular death, urgent heart transplantation, or left ventricular assist device implantation. Secondary endpoints were cardiovascular and all causes death. Results For all endpoints, upon adjustment for confounders, DM status and insulin treatment or dietary regimen were not significantly associated with adverse long-term prognosis compared to non-DM and oral antidiabetic treated patients, respectively. A worse prognosis was observed in HbA1c >8% patients (Log-Rank p Conclusion In HF patients, DM, insulin treatment and dietary regimen are not adverse outcome predictors. The only condition related to long-term prognosis, considering potential confounders, is poor glycemic control.

Recent clinical and demographical studies on COVID-19 patients have demonstrated that men experience worse outcomes than women. However, in most cases, the data were not stratified according to gender, limiting the understanding of the real impact of gender on outcomes. This study aimed to evaluate the disaggregated in-hospital outcomes and explore the possible interactions between gender and cardiovascular calcifications. Data was derived from the sCORE-COVID-19 registry, an Italian multicentre registry that enrolled COVID-19 patients who had undergone a chest computer tomography scan on admission. A total of 1683 hospitalized patients (mean age 67±14 years) were included. Men had a higher prevalence of cardiovascular comorbidities, a higher pneumonia extension, more coronary calcifications (63% vs.50.9%, p3, pp=0.001), but the death event tended to occur earlier in women (15±7 vs. 8±7 days, p= 0.07). Non-survivors had a higher coronary, thoracic aorta, and aortic valve calcium score. Female sex, a known independent predictor of a favorable outcome in SARS-CoV2 infection, was not protective in women with a coronary calcification volume greater than 100 mm3. There were significant differences in cardiovascular comorbidities and vascular calcifications between men and women with SARS-CoV2 pneumonia. The differences in outcomes can be at least partially explained by the different cardiovascular profiles. However, women with poor outcomes had the same coronary calcific burden as men. The presumed favorable female sex bias in COVID-19 must therefore be reviewed in the context of comorbidities, especially cardiovascular ones.

The authors regret that the Author Dr. Bussotti Maurizio appears with the following affiliation: Unità Operativa Cardiologia Riabilitativa, Multimedica IRCCS, Milano, Italy. But that was a mistake, the right affiliation of Dr. Bussotti Maurizio is instead: Department of Cardiology, Istituti Clinici Scientifici Maugeri IRCCS, Milano, Italy. The authors kindly ask you to correct this affiliation also with all abstracting partners as PubMed. The authors would like to apologise for any inconvenience caused. DOI of original article: .

Background Coronary, thoracic aorta and aortic valve calcium can be measured from a non-gated chest computer tomography (CT) and are validated predictors of cardiovascular events and all-cause mortality. However, their prognostic role in acute systemic inflammatory diseases, such as COVID-19, has not been investigated. Purpose The principal aim was to evaluate the association of coronary artery calcium (CAC) and total thoracic calcium on in-hospital mortality in COVID-19 patients. Then, to evaluate the prognostic impact of clinical and subclinical coronary artery disease (CAD), as assessed by CAC. Methods 1093 consecutive patients from 16 Italian hospitals with a positive swab for COVID-19 and an admission chest CT for pneumonia severity assessment were included in the SCORE COVID-19 registry (calcium score for COVID-19 Risk Evaluation). At CT, coronary, aortic valve and thoracic aorta calcium were qualitatively and quantitatively evaluated separately and combined together (total thoracic calcium) by a central Core-lab blinded to patients' outcomes. A specific sub analysis on CAC was performed stratifying the patients in three groups: (a) “clinical CAD” (prior revascularization history), (b) “subclinical CAD” (CAC >0), (c) “No CAD” (CAC=0). In-hospital mortality was the primary endpoint, while a composite of myocardial infarction and cerebrovascular accident (MI/CVA) was the secondary one. Results Non-survivors compared to survivors had higher coronary artery [(487.7±565.3 vs 207.7±406.8, p400, respectively, p Conclusion Coronary, aortic valve and thoracic aortic calcium assessment on admission non-gated CT permits to stratify the COVID-19 patients in-hospital mortality risk. Cardiovascular calcifications may represent a bystander of an impaired vascular reserve, both microvascular and endothelial, but also a sign of vascular senescence. Therefore, it can be considered an index of biological frailty, likely more accurate than age and other risk factors. Funding Acknowledgement Type of funding sources: None. Figure 1Figure 2

Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe and under-recognized complication of acute pulmonary embolism (PE). Forty consecutive patients with acute PE (Group 1), predominantly female (22, 55%) with a mean age of 69 ± 15 years, were matched for demographic data with 40 healthy subjects (Group 2), 40 systemic hypertension patients (Group 3) and 45 prevalent idiopathic pulmonary arterial hypertension (IPAH) patients (Group 4). The baseline evaluation included physical examination, NYHA/WHO functional class, right heart catheterization (RHC) limited to IPAH patients, echocardiographic assessment and systemic arterial stiffness measurement by cardio-ankle vascular index (CAVI). Patients with PE underwent an echocardiographic evaluation within 1 month from hospital discharge (median 27 days, IQR 21–30) to assess the echo-derived probability of PH. The CAVI values were significantly higher in the PE and IPAH groups compared with the others (Group 1 vs. Group 2, p &lt, 0.001, Group 1 vs. Group 3, p &lt, Group 1 vs. Group 4, p = ns, Group 4 vs. Group 2, p &lt, Group 4 vs. Group 3, p &lt, Group 2 vs. Group 3, p = ns). The predicted probability of echocardiography-derived high-risk criteria of PH increases for any unit increase of CAVI (OR 9.0, C.I.3.9–20.5, p = 0.0001). The PE patients with CAVI ≥ 9.0 at the time of hospital discharge presented an increased probability of PH. This study highlights a possible positive predictive role of CAVI as an early marker for the development of CTEPH.

Background: Concerns have been raised on a potential interaction between renin-angiotensin system inhibitors (RASI) and the susceptibility to coronavirus disease 2019 (COVID-19). No data have been so far reported on the prognostic impact of RASI in patients suffering from ST-elevation myocardial infarction (STEMI) during COVID-19 pandemic, which was the aim of the present study. Methods: STEMI patients treated with primary percutaneous coronary intervention (PPCI) and enrolled in the ISACS-STEMI COVID-19 registry were included in the present sub-analysis and divided according to RASI therapy at admission. Results: Our population is represented by 6095 patients, of whom 3654 admitted in 2019 and 2441 in 2020. No difference in the prevalence of SARSCoV2 infection was observed according to RASI therapy at admission (2.5% vs 2.1%, p = 0.5), which was associated with a significantly lower mortality (adjusted OR [95% CI]=0.68 [0.51 & ndash;0.90], P = 0.006), confirmed in the analysis restricted to 2020 (adjusted OR [95% CI]=0.5[0.33 & ndash;0.74], P = 0.001). Among the 5388 patients in whom data on in-hospital medication were available, in-hospital RASI therapy was associated with a significantly lower mortality (2.1% vs 16.7%, OR [95% CI]=0.11 [0.084 & ndash;0.14], p < 0.0001), confirmed after adjustment in both periods. Among the 62 SARSCoV-2 positive patients, RASI therapy, both at admission or in-hospital, showed no prognostic effect. Conclusions: This is the first study to investigate the impact of RASI therapy on the prognosis and SARSCoV2 infection of STEMI patients undergoing PPCI during the COVID-19 pandemic. Both pre-admission and in-hospital RASI were associated with lower mortality. Among SARSCoV2-positive patients, both chronic and in-hospital RASI therapy showed no impact on survival.

Aims The prognostic implication of periprocedural myocardial infarction (MI) in older patients has been less investigated. The aim of this study is to assess the relationship between large periprocedural MI and long-term mortality in older patients with non-ST-segment elevation acute coronary syndrome (NSTEACS) undergoing percutaneous coronary intervention (PCI). Methods This is a pooled analysis of older NSTEACS patients who were included in the FRASER and HULK studies. Periprocedural MI was defined in agreement with the Society for Cardiovascular Angiography and Interventions definition. The primary outcome was all-cause mortality. The secondary outcome was cardiovascular mortality. The predictors of periprocedural MI and the relationship with scales of physical performance, namely Short Physical Performance Battery and grip strength, were also investigated. Results The study included 586 patients. Overall, periprocedural MI occurred in 24 (4.1%) patients. After a median follow-up of 1023 (740-1446) days, the primary endpoint occurred in 94 (16%) patients. After multivariable analysis, periprocedural MI emerged as an independent predictor of all-cause mortality (hazard risk 4.30, 95% confidence interval 2.27-8.12). This finding was consistent for cardiovascular mortality (hazard risk 7.45, 95% confidence interval 3.56-15.67). SYNTAX score, multivessel PCI and total stent length were independent predictors of large periprocedural MI. At hospital discharge, patients suffering from periprocedural MI showed poor values of Short Physical Performance Battery and grip strength as compared with others. Conclusion In a cohort of older NSTEACS patients undergoing PCI, large periprocedural MI occurred in around 4% of patients and was associated with long-term occurrence of all-cause and cardiovascular mortality. Clinical trial registration ClinicalTrials.gov: NCT02324660 and NCT03021044.

BACKGROUND COPD patients have higher recurrence of adverse events and worse prognosis after acute coronary syndrome (ACS). The underlying pathophysiological mechanism is not fully elucidated. METHODS In screening for COPD in ACS (SCAP) trial (NCT02324660), ACS patients with smoking habit underwent a predischarge screening procedure to detect undiagnosed chronic obstructive pulmonary disease (UCOPD) confirmed with spirometry at 60 days. Patients were then categorized as UCOPD or no-COPD. In 65 NSTE-ACS patients, we performed near infrared spectroscopy (NIRS) in the culprit and at least one non-culprit vessel (151 vessels overall), and we calculated the SYNTAX I score. Primary endpoint was max lipid core burden index (LCBI) 4 mm. Secondary endpoints were SYNTAX score I and vessel LCBI. RESULTS Max LCBI 4 mm and vessel LCBI were significantly higher in the UCOPD compared to the no-COPD group (UCOPD 388±122, no-COPD 264±131, p

Pulmonary arterial hypertension (PAH) is a rare, progressive disease with a poor prognosis. The pathophysiologic model is mainly characterized by an afterload mismatch in which an increased right ventricle afterload, driven by increased pulmonary vascular resistance (PVR), leads to right heart failure. International guidelines recommend optimization of treatment based on regular risk assessments to achieve or maintain a low-risk status. Current risk scores are based on a multi-modality approach, including demographic, clinical, functional, exercise, laboratory, and hemodynamic parameters, which lack significant echocardiographic parameters. The originality of echocardiography relies on the opportunity to assess in a non-invasive way a physiologically meaningful combination of easy to measure variables tightly related to right ventricle adaptation/maladaptation to increased afterload, the main determinant of a patient’s prognosis. Echo-derived morphological and functional parameters have been investigated in PAH, proving to have prognostic relevance. Different therapeutic strategies proved to have different effects in reducing PVR. An upfront combination of drugs, including a parenteral prostacyclin, has shown to be associated with right heart reverse remodeling in a greater proportion of patients than other treatment strategies as a function of PVR reduction. Adding echocardiographic data to current risk scores would allow better identification of right ventricle (RV) adaptation in PAH patients’ follow-up. This additional information would allow better stratification of the patient, leading to optimized and personalized therapeutic management.

Context The role of growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) on aromatase regulation is poorly understood in humans. Objective Determine GDF9 and BMP15 effects on FSH stimulation of estradiol production in primary human cumulus granulosa cells (GCs). We hypothesized that the combination of GDF9 and BMP15 potentiates FSH-induced aromatase expression. Design Primary human cumulus GCs in culture. Setting University infertility center. Patients or Other Participants GCs of 60 women undergoing in vitro fertilization were collected. Interventions Cells were treated with GDF9 and/or BMP15 (GB) in the presence or absence of FSH, dibutyryl cAMP, or SMAD inhibitors. Main Outcome Measures Promoter activity, mRNA, protein, and estradiol levels were quantified. Results FSH and GB treatment increased CYP19A1 promoter activity, mRNA, and protein levels as well as estradiol when compared with cells treated with FSH only. GB treatment potentiated cAMP stimulation of aromatase and IGF2 stimulation by FSH. GB effects were inhibited by SMAD3 inhibitors and IGF1 receptor inhibitors. GB, but not FSH, stimulates SMAD3 phosphorylation. Conclusion The combination of GDF9 and BMP15 potently stimulates the effect of FSH and cAMP on CYP19a1 promoter activity and mRNA/protein levels. These effects translate into an increase in estradiol production. This potentiation seems to occur through activation of the SMAD2/3 and SMAD3 signaling pathway and involves, at least in part, the effect of the IGF system.

Background Recent advances in wearable technology make continuous cardiorespiratory monitoring possible, with potential applications in assessment of cardiopulmonary patients, healthy subjects and athletes. The aim of the present study was to qualitatively and quantitatively evaluate a new wearable device (Learn Inspire Free Entertain = L.I.F.E.) by embedding in a compression shirt a 12‑lead ECG system and 5 respiratory sensors. Methods Thirty cardiorespiratory patients and ten healthy subjects were studied for 24 h during their usual life activities. In 8 healthy subjects, simultaneous measurements of the device and of an ergo-spirometer were performed during different levels of ventilation in five different body positions. The quality of ECG signals in terms of measurability of heart rate, P wave, QRS complex and ST segment, was analyzed by four expert cardiologists/respiratory physiologists using an arbitrary 1–5 scale. The sum of the respiratory signals was used to calculate the respiratory rate, inspiratory time and relative changes of tidal volume. These parameters were compared to ergo-spirometer measurements. Results Median quality value was >3 for heart rate, QRS complex, ST segment and P wave (except in L3, aVL, aVF, V1 and V2 leads). Median quality of respiratory traces was >4 in patients and between 3 and 4 in healthy subjects. The respiratory monitoring of respiratory rate and inspiratory time was accurate in all body positions. Tidal volumes were underestimated due to a high level of ventilation. Conclusions The L.I.F.E. device provides an accurate continuous monitoring of cardiorespiratory signals during the 24 h both in normal subjects and cardiorespiratory patients.

BACKGROUND >Despite advances in drug development, life expectancy in idiopathic pulmonary arterial hypertension (IPAH) remains unacceptable. Contemporary IPAH characterization is based on criteria that may not adequately capture disease heterogeneity and may be proposed as a possible explanation for why patient outcome is still unfavorable. The aim of this study was to apply cluster analysis to improve phenotyping of patients with IPAH and analyze long-term clinical outcome of derived clusters. METHODS Patients with IPAH from 2 referral centers (n = 252) were evaluated with clinical, hemodynamic, and echocardiographic assessment and cardiopulmonary exercise test. Patients were classified according to cluster analysis and followed for clinical worsening occurrence. RESULTS The cluster analysis identified 4 IPAH phenotypes. Cluster 1 was characterized by young patients, mild pulmonary hypertension (PH), mild right ventricular (RV) dilation and high oxygen (O2) pulse; Cluster 2 by severe PH and RV dilation and high O2 pulse; and Cluster 3 by male patients, severe PH and RV dilation, and low O2 pulse. Cluster 4 patients were older and overweight, with mild PH and RV dilation and low O2 pulse. After a mean follow-up of 995 ± 623 days, 123 (48.8%) patients had clinical worsening. Cluster 1 patients presented the best prognosis, whereas Cluster 3 had the highest rates of clinical worsening. Compared with Cluster 1, risk of clinical worsening ranged from 4.12 (confidence interval [CI] 1.43–11.92; p = 0.009) for Cluster 4 to 7.38 (CI 2.80–19.40) for Cluster 2 and 13.8 (CI 5.60–34.0; p = 0.0001) for Cluster 3. CONCLUSIONS Cluster analysis of clinical variables identified 4 distinct phenotypes of IPAH. Our findings underscore the high degree of disease heterogeneity that exists within patients with IPAH and the need for advanced clinical testing to define phenotypes to improve treatment strategy decision-making. CONDENSED ABSTRACT Idiopathic pulmonary arterial hypertension (IPAH) characterization is based on criteria that may not adequately capture disease heterogeneity. The aim of this study was to apply cluster analysis to improve phenotyping of IPAH. Patients with IPAH (n = 252) were evaluated with clinical, hemodynamic, and echocardiographic assessment and cardiopulmonary exercise test. Within the umbrella category of IPAH, it was the combination of mean pulmonary arterial pressure, right ventricular size, and oxygen pulse that further stratified patients into novel IPAH phenotypes that significantly associate with clinical worsening. These findings underscore the need for novel multidimensional IPAH phenotyping for improved patient care and trial quality.

Context Human granulosa cells (hGCs) produce and respond to insulin-like growth factor 2 (IGF2) but whether the oocyte participates in IGF2 regulation in humans is unknown. Objective To determine the role of oocyte-secreted factors (OSFs) such as growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) in IGF2 production by hGCs. Design Primary human cumulus GCs in culture. Setting University infertility center. Patients or Other Participants GCs of women undergoing in vitro fertilization. Intervention(s) Cells treated with GDF9 and BMP15 in the presence of vehicle, follicle-stimulating hormone (FSH), dibutyryl cyclic-AMP (dbcAMP), or mothers against decapentaplegic homolog (SMAD) inhibitors. Main Outcome Measure(s) Quantification of mRNA, protein, promoter activity, and DNA methylation. Results FSH stimulation of IGF2 (protein and mRNA) was significantly potentiated by the GDF9 and BMP15 (G+B) combination (P < 0.0001) in a concentration-dependent manner showing a maximal effect at 5 ng/mL each. However, GDF9 or BMP15 alone or in combination (G+B) have no effect on IGF2 in the absence of FSH. FSH stimulated IGF2 promoter 3 activity, but G+B had no effect on promoter activity. G+B potentiated IGF2 stimulation by cAMP. SMAD3 inhibitors inhibited G+B enhancement of IGF2 stimulation by FSH (P < 0.05) but had no effect on FSH induction. Moreover, inhibition of insulin-like growth factor receptor partially blocked G+B potentiation of FSH actions (P < 0.009). Conclusions For the first time, we show that the oocyte actively participates in the regulation of IGF2 expression in hGCs, an effect that is mediated by the specific combination of G+B via SMAD2/3, which in turn target mechanisms downstream of the FSH receptor.

Lipofilling (LF) is a largely employed technique in reconstructive and esthetic breast surgery. Over the years, it has demonstrated to be extremely useful for treatment of soft tissue defects after demolitive or conservative breast cancer surgery and different procedures have been developed to improve the survival of transplanted fat graft. The regenerative potential of LF is attributed to the multipotent stem cells found in large quantity in adipose tissue. However, a growing body of pre-clinical evidence shows that adipocytes and adipose-derived stromal cells may have pro-tumorigenic potential. Despite no clear indication from clinical studies has demonstrated an increased risk of cancer recurrence upon LF, these observations challenge the oncologic safety of the procedure. This review aims to provide an updated overview of both the clinical and the pre-clinical indications to the suitability and safety of LF in breast oncological surgery. Cellular and molecular players in the crosstalk between adipose tissue and cancer are described, and heterogeneous contradictory results are discussed, highlighting that important issues still remain to be solved to get a clear understanding of LF safety in breast cancer patients.

The goal of an antimicrobial stewardship program (ASP) is to prevent the emergence of antimicrobial drug resistance and reduce adverse drug events, optimizing the selection, dosing, and duration of therapy in individual patients.This retrospective study evaluated changes in antimicrobial agent use associated with implementation of an ASP in a general and emergency unit. The pre-intervention and post-intervention periods were defined as July 1, 2013, to December 31, 2013 (pre-intervention) and January 1, 2014, to June 30, 2014 (post-intervention).The mean total monthly antimicrobial use decreased by 18.8%, from 1,074.9 defined daily doses (DDD) per 1,000 patient-days to 873.0 DDD per 1,000 patient-days after the intervention. There was a significant reduction in the use of piperacillin-tazobactam, by 33.7% (p 0.05), in imipenem/cilastatin, by 63.9% (p 0.05), in meropenem by 68.0% (p 0.05), and in levofloxacin by 45.0% (p 0.05) without any negative effect on patient susceptibility to infections. Indeed, patient outcomes, including deaths, length of stay in the hospital, and re-admission within 30 days were not affected.The implementation of an education-based ASP achieved a significant improvement in all antimicrobial agent prescriptions in the surgical unit and a reduction in antimicrobial drug consumption, even when no restrictive measures were implemented.

Introduction Autologous fat transfer (AFT) is widely adopted for breast reconstruction, but its long-term oncologic safety is still not clearly established. The aim of the present study was to compare the 10-year loco-regional recurrence (LRR)-free and distant metastases (DM)-free survival probabilities in AFT vs. control patients, also evaluating the impact of AFT in different intrinsic molecular subtypes of breast cancer. Materials and methods 464 AFT patients were exactly matched with a cohort of 3100 control patients treated between 2007 and 2017. A multivariate survival analysis was performed accounting for all variables related to LRR and DM, including adjuvant/neoadjuvant treatments. End-points were analyzed both overall and in each molecular subtype. Results LRR occurred in 6.4% of AFT and in 5.0% of control patients (p = 0.42), while DM were observed respectively in 7.7% and 5.4% of cases (p = 0.20). AFT showed no effect on the 10-year LRR-free survival probability (adjusted HR 0.87, 95%CI 0.43–1.76, p = 0.69) or the 10-year DM-free survival probability (adjusted HR 0.82, 95%CI 0.43–1.57, p = 0.55). Luminal A patients treated by AFT showed a decreased LRR-free survival probability (HR 2.38, 95%CI 0.91–6.17, Log-Rank p = 0.07), which was significantly lower than controls after 80 months (Log-Rank p = 0.02). No differences in the 10-year event-free survival probability were found in Luminal B, HER2-positive or triple-negative patients. Conclusion AFT does not increase breast cancer recurrence, with the possible exception of late LRRs for Luminal A patients, but further clinical and preclinical data are required to better clarify this data. The use of AFT should not be discouraged.

Obtaining a tailored breast resection is challenging in microcalcifications detected on screening mammography, and an accurate localization is required. The aim of this study was to compare the efficacy of radio-guided localization (ROLL) versus ultrasound localization of a titanium clip with collagen (TCC) in terms of clear margins, re-intervention rates, excess of resected breast tissue, and operative times in pure malignant microcalcifications detected on screening mammography. Two hundred and twenty-one consecutive patients with malignant microcalcifications detected on screening mammography from a tertiary breast unit were reviewed: 177 patients were localized by TCC and 44 patients by stereotactic ROLL. A propensity score-matched analysis was performed, followed by a logistic regression model, to avoid selection bias. Adequacy of resection was expressed as the calculated resection ratio considering lesion size. No differences were found in clear margins with ROLL versus TCC (77.3% vs 81.8%, adjusted OR 2, P = 0.27). Re-operation rates were similar, being 11.3% with ROLL and 7.4% with TCC (P = 0.627). Mean resection volume was 46.2 cm3 with ROLL versus 54.2 cm3 with TCC (P = 0.222). Adjusted mean calculated resection ratio was 1.8 with ROLL and 2.1 with TCC (P = 0.38). Surgery time was longer with TCC compared to ROLL (69.6 vs 52.7 minutes, P < 0.0001). ROLL and TCC are equally effective to excise malignant microcalcifications with clear margins, providing similar re-intervention rates and resection volumes.

IGF-2 is highly expressed in the granulosa cells of human dominant ovarian follicles; however, little is known about the regulation of the IGF-2 gene or the interaction of IGF-2 and FSH during follicle development.To examine the mechanisms involved in the regulation of the IGF-2 gene by FSH and the interplay between FSH and IGF-2 during granulosa cell differentiation. Design, Setting, Patients, and Interventions: Cumulus granulosa cells were separated from cumulus-oocyte complexes isolated from the follicular aspirates of in vitro fertilization patients and cultured for in vitro studies.Protein and mRNA levels of IGF-2 and CYP19A1 (aromatase) were quantified using Western blot and quantitative real-time PCR. IGF-2 promoter-specific activation was determined by the amplification of alternative exons by PCR. Cell proliferation was assessed after treatment with FSH and/or IGF-2.FSH significantly enhanced IGF-2 expression after 8 hours of treatment and at low doses (1 ng/mL). Reciprocally, IGF-2 synergized with FSH to increase cell proliferation and the expression of CYP19A1. When IGF-2 activity was blocked, FSH was no longer able to stimulate CYP19A1 expression. Determination of IGF-2 promoter usage in human cumulus cells showed that the IGF-2 gene is driven by promoters P3 and P4. However, FSH exclusively increased P3 promoter-derived transcripts. Moreover, the FSH-induced stimulation of P3-driven IGF-2 transcripts was blocked by cotreatment with inhibitors of AKT or IGF-1 receptor (IGF-1R). The inhibitory effect of the IGF-1R inhibitor on FSH-induced IGF-2 mRNA accumulation was reversed by overexpression of a constitutively active AKT construct.FSH is a potent enhancer of IGF-2 expression in human granulosa cells. In return, IGF-2 activation of the IGF-1R and AKT is required for FSH to stimulate CYP19A1 expression and proliferation of granulosa cells. These findings suggest a positive loop interaction between FSH and IGF-2 that is critical for human granulosa cell proliferation and differentiation.

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is associated with early organ damage such as left ventricular hypertrophy and higher cardiovascular risk when compared to essential hypertension (EH). Epicardial adipose tissue (EAT) is a new cardiovascular risk factor, but its role and correlation with left ventricular mass (LVM) in ADPKD is unknown. Aims: we sought to investigate whether EAT is higher and related to LVM indexed by body surface area (LVMi) in hypertensive patients with ADPKD compared to those with EH. Methods: We performed ultrasound measurement of EAT thickness, LVM, LVMi, and left atrium size (left atrial volume indexed for body surface, LAVI) in 41 consecutive hypertensive patients with ADPKD, compared to 89 EH patients. Results: EAT was significantly higher in the ADPKD group in comparison to EH subjects (9.2 ± 2.9 mm vs. 7.8 ± 1.6 mm, p < 0.001), and significantly correlated with LVM, LVMi, and LAVI in the ADPKD group (r = 0.56, p = 0.005; r = 0.424, p = 0.022; and r = 0.48, p = < 0.001, respectively). Comparing EAT against body mass index, systolic blood pressure, and age, we found that EAT was the strongest predictor of LVMi (β = 0.42, p = 0.007). Conclusion: Our data showed that EAT was higher in ADPKD patients than in EH subjects and independently correlated with LVMi. EAT measurement can be a useful marker for the cardiovascular risk stratification in ADPKD.

FSH is routinely administered to in vitro fertilization patients to induce follicle maturation. During this process, granulosa cells differentiate and acquire specific functional characteristics that are required to coordinate ovulation and oocyte maturation.The objective of the study was to gain insight into the molecular mechanisms regulating human granulosa cell differentiation. Design, Setting, Patients, and Interventions: Cumulus and mural granulosa cells were isolated from the follicular aspirates of in vitro fertilization patients and analyzed immediately or cultured in serum-free media in the presence of FSH, IGFs, or an inhibitor of type I IGF receptor (IGF1R) activity.We quantified the mRNA and protein levels of steroidogenic enzymes, components of the IGF system, and gonadotropin receptors; measured 17β-estradiol levels; and examined the activation of intracellular signaling pathways to assess the granulosa cell differentiation as well as the FSH and IGF actions in both cumulus and mural cells.In freshly isolated cells, LH receptor (Lhr) and steroidogenic acute regulator (Star) were expressed at lower levels in cumulus than mural cells, whereas FSH receptor (Fshr) and anti-Müllerian hormone (Amh) were expressed at higher levels in cumulus than mural cells. In vitro, the expression of Igf2, the differentiation markers Lhr, Star, and Cyp19a1 (aromatase) as well as 17β-estradiol production remained low in untreated cumulus cells but increased significantly after FSH treatment. Strikingly, this stimulatory effect of FSH was abolished by the inhibition of IGF1R activity. FSH-induced activation of v-akt murine thymoma viral oncogene homolog 3 (AKT) required IGF1R activity, and overexpression of constitutively active AKT rescued the induction of differentiation markers and 17β-estradiol production by FSH in the presence of the IGF1R inhibitor.The cumulus cell response to FSH resembles the differentiation of preantral to preovulatory granulosa cells. This differentiation program requires IGF1R activity and subsequent AKT activation.

Study question Is the genome-wide response of human cumulus cells to FSH and insulin-like growth factors (IGFs) comparable to the response observed in undifferentiated granulosa cells (GCs)? Summary answer FSH actions in human cumulus cells mimic those observed in preantral undifferentiated GCs from laboratory animals, and approximately half of the regulated genes are dependent on the simultaneous activation of the IGF1 receptor (IGF1R). What is known already Animal studies have shown that FSH and the IGFs system are required for follicle growth and maturation. In humans, IGF levels in the follicular fluid correlate with patients' responses to IVF protocols. The main targets of FSH and IGFs in the ovary are the GCs; however, the genomic mechanisms involved in the response of GCs to these hormones are unknown. Study design, size, duration Human cumulus cells isolated from IVF patients were cultured for 48 h in serum-free media in the presence of vehicle, FSH, IGF1R inhibitor or their combination. Participants/materials, setting, methods Discarded cumulus cells were donated to research by reproductive-aged women undergoing IVF due to non-ovarian etiologies of infertility at a university-affiliated clinic. The effect of FSH and/or IGF1R inhibition on cumulus cell function was evaluated using Affymetrix microarrays, quantitative PCR, western blot, promoter assays and hormone level measurements. Main results and the role of chance The findings demonstrate that human cumulus cells from IVF patients respond to FSH with the expression of genes known to be markers of the preantral to preovulatory differentiation of GCs. These results also demonstrate that ~50% of FSH-regulated genes require IGF1R activity and suggest that several aspects of follicle growth are coordinately regulated by FSH and IGFs in humans. This novel approach will allow for future mechanistic and molecular studies on the regulation of human follicle maturation. Large scale data Data set can be accessed at Gene Expression Omnibus number GSE86427. Limitations, reasons for caution Experiments were performed using primary human cumulus cells. This may not represent the response of intact follicles. Wider implications of the findings Understanding the mechanisms involved in the regulation of GC differentiation by FSH and IGF in humans will contribute to improving treatments for infertility. Study funding/competing interest(s) The project was financed by the National Instituted of Health grant number R56HD086054 and R01HD057110 (C.S.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We have no competing interests to declare.

Summary Objective Adverse changes in lipoprotein particle number and size are common with insulin resistance and are associated with increased cardiovascular risk. Comprehensive information regarding lipoprotein particle number and size, and how these parameters relate to body weight, insulin resistance and hyperandrogenemia is lacking in polycystic ovary syndrome (PCOS). We tested the hypothesis that PCOS is associated with atherogenic changes in lipoprotein profile independent of body weight and examined the role of insulin resistance and androgens in these atherogenic changes. Design Case–control study performed at Clinical Research Center at an Academic Medical Center in the United States. Patients and measurements Fasting blood was obtained from 25 PCOS and 25 control women of similar age and body mass index (BMI). Lipoprotein particle number and size was determined by nuclear magnetic resonance and compared between the groups. Results The mean BMI for both groups was

Objective To review and critique the literature regarding ovulation induction and cancer risk. Design Identification of relevant clinical and epidemiological literature through PubMed and other sources. Conclusion(s) Ovulation and associated hormonal changes have been linked with selected cancers, raising concerns regarding ovulation-inducing agents. Clinical studies have suggested potential links, but more definitive analytic investigations have been difficult to interpret given the small numbers, short follow-up, and imprecise information on drugs or indications for usage. Prospective studies have been limited by inabilities to control for other cancer predictors (including parity), while selective recall has been a concern for retrospective studies. Reports of large increases in ovarian cancer risk associated with fertility medications have not been replicated by more recent investigations. Some findings, based on small numbers, suggest slight increases in risk associated with fertility drugs among nulligravid women or after extended follow-up or for certain tumor subtypes, but further replication is needed. Fewer studies have assessed relationships with other hormonally related cancers, but limited findings support the need for further monitoring of long-term effects for breast and endometrial cancers. Findings regarding other cancers are extremely limited but should be pursued for cancers showing evidence of hormonal influences, including colon cancers and melanomas.

Background Despite the recognized role of hormones in the aetiology of breast cancer, there has been little evaluation of hormonal preparations used to treat infertility. Methods A retrospective cohort study of 12,193 women evaluated for infertility between 1965 and 1988 at five clinical sites identified 292 in situ and invasive breast cancers in follow-up through 1999. Standardized incidence ratios (SIRs) compared breast cancer risks with those of the general population. Analyses within the cohort estimated rate ratios (RRs) associated with medications after adjustment for other breast cancer predictors. Results Infertile patients had a significantly higher breast cancer risk than the general population [SIR = 1.29, 95% confidence interval (CI) 1.1-1.4]. Analyses within the cohort showed adjusted RRs of 1.02 for clomiphene citrate and 1.07 for gonadotrophins, and no substantial relationships to dosage or cycles of use. Slight and non-significant elevations in risk were seen for both drugs after > or = 20 years of follow-up (RRs = 1.39 for clomiphene and 1.54 for gonadotrophins). However, the risk associated with clomiphene for invasive breast cancers was statistically significant (RR = 1.60, 95% CI 1.0-2.5). Conclusions Although there was no overall increase in breast cancer risk associated with use of ovulation-stimulating drugs, long-term effects should continue to be monitored.

Equine infectious anemia (EIA) is an infectious and potentially fatal viral disease of equids. EIA virus is usually transmitted from horse to horse by large biting insects, such as horseflies. The aim of this study was to evaluate the results of a national surveillance plan from 2007 to 2009 and evaluate the potential risk factors of EIA in horse populations in central Italy. In 2007, 18 of 6,773; in 2008, 30 of 7,940; and in 2009, 21 of 11,666 equines tested were seropositive for EIA. No statistical association was found between location or sex and the diagnosis of EIA. The seroprevalence rate (2007-2008-2009) was higher among older equids (older than 6 years) than among young (3 months to 5 years old) ( P P

Background Serum protein electrophoresis (SPE) provides useful information in ruminants, but reference intervals (RI) are different from other species. There have been no reports of SPE RI for dairy sheep using agarose gel electrophoresis (AGE). Objective The purpose of the study was to evaluate the serum concentration of total protein (TP) and protein fractions determined by AGE in mid-lactating dairy ewes, to establish RI, and to assess potential differences between Lacaune (L) and Sarda (S) sheep breeds. Methods Blood samples were collected from healthy, mid-lactating ewes. SPE was assessed using a semi-automated AGE system. Reference intervals (90% confidence intervals) for TP and each protein fraction were determined using the nonparametric method for combined data, and the robust method for data from the single breeds. Data from S and L sheep were compared using the Mann–Whitney U test. Results The 172 sheep included 116 L and 56 S ewes, 2–6 years old. There were significant differences between S and L breeds, and RI were calculated for TP, albumin, α1-globulin, α2-globulin, β1-globulin, β2-globulin, γ1-globulin, and γ2-globulin concentrations, and for the Albumin/Globulin ratio. Group S showed higher concentrations of TP, α2-, β1-, β2-, and γ1-globulins, whereas L was higher for albumin and γ2-globulin concentrations, and A/G ratio (P < .05). Conclusions The resolution with AGE was excellent, allowing standardization of 7 protein fractions, detection of differences between S and L ewes, and determination of RI for French (Lacaune) and Italian (Sarda) dairy sheep.

Are certain ethnic groups with polycystic ovary syndrome (PCOS) at increased risk of metabolic disorders?Obese Hispanic women with PCOS are at increased risk of metabolic disorders compared with age- and BMI-matched obese non-Hispanic white women with PCOS in the USA.Ethnic differences in body composition and metabolic risk are well established. PCOS is a common disorder in women of reproductive age and is associated with high rates of insulin resistance, glucose intolerance and dyslipidemia.A cross-sectional observational study was performed at an Academic Medical Center on 60 women of reproductive age with PCOS.Blood was obtained after fasting from 17 Hispanic, 22 non-Hispanic black and 21 non-Hispanic white women with PCOS who were similar in age and BMI. Anthropometric parameters, insulin, lipid and lipoprotein levels (measured by nuclear magnetic resonance) were compared between the three groups.Age and BMI did not differ between the groups. Hispanic women with PCOS had higher waist-to-hip ratio (WHR) (P = 0.02), homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.03) and a more atherogenic lipid and lipoprotein profile consisting of lower high-density lipoprotein (HDL) (P = 0.02), higher low-density lipoprotein (LDL) particle number (P = 0.02), higher very low-density lipoprotein particle (VLDL) size (P = 0.03) and lower LDL (P = 0.03) and HDL particle size (P = 0.005) compared with non-Hispanic white women. The differences in HDL, HOMA-IR, VLDL and LDL size did not persist after adjustment for WHR while differences in LDL particle number (P = 0.04) and HDL size (P = 0.01) persisted.The sample size for the three groups was small but the findings were still significant. The women were mostly obese so the ethnic differences in metabolic disorders may not apply to non-obese women with PCOS.Independent of BMI, obese, reproductive age, Hispanic women with PCOS in the USA had a greater degree of abdominal obesity, insulin resistance and dyslipidemia. Hispanic women with PCOS may benefit from more focused management of metabolic parameters.This project was supported by the following National Institutes of Health grants: K23 DK080988-01A1 to S.S. and UL1RR029879 to CTSA at University of Illinois. None of the authors report any conflict of interests.

Ovarian cancer is the second most common malignancy of the female reproductive tract. Approximately 50% of ovarian cancers have elevated levels of epidermal growth factor receptor (EGFR). This overexpression is correlated with a poor prognosis for patient survival. Ovarian cancers also express a number of sex steroid receptors. The androgen receptor (AR) is the predominant sex steroid receptor and is expressed in over 80% of ovarian cancers. We investigated whether a relationship exists between EGFR and AR in ovarian cancer. Sixty serous cystadenocarcinomas were analyzed for their relative levels of EGFR and AR by Western blot analysis. Data were analyzed by Student's t test and linear regression analysis for statistical significance. More than 98% of the tumors expressed detectable levels of EGFR, while 65% of the tumors expressed detectable levels of AR. The levels of EGFR (mean +/- SEM) were found to be significantly (P0.01) higher in AR+ (516 +/- 15) than in AR- (304 +/- 57) tumors. EGFR levels significantly correlated to AR levels (r = 0.49, P0.001). These results demonstrate an association between EGFR and AR levels in ovarian cancer. Whether this association represents a causal or a casual relationship remains to be determined.

Postmenopausal hormone replacement therapy (HRT) relieves menopausal symptoms and may decrease mortality in recently postmenopausal women, but increases breast cancer risk. Low-dose tamoxifen has shown retained activity in phase-II studies.We conducted a phase-III trial in 1884 recently postmenopausal women on HRT who were randomly assigned to either tamoxifen, 5 mg/day, or placebo for 5 years. The primary end point was breast cancer incidence.After 6.2 ± 1.9 years mean follow-up, there were 24 breast cancers on placebo and 19 on tamoxifen (risk ratio, RR, 0.80; 95% CI 0.44-1.46). Tamoxifen showed favorable trends in luminal-A tumors (RR, 0.32; 95% CI 0.12-0.86), in HRT users5 years (RR, 0.35; 95% CI 0.15-0.82) and in women completing at least 12 months of treatment (RR, 0.49; 95% CI 0.23-1.02). Serious adverse events did not differ between placebo and tamoxifen, including, respectively, coronary heart syndrome (6 versus 4), cerebrovascular events (2 versus 5), VTE (2 versus 5) and uterine cancers (3 versus 1). Vasomotor symptoms were 50% more frequent on tamoxifen.The addition of low-dose tamoxifen to HRT did not significantly reduce breast cancer risk and increased climacteric symptoms in recently postmenopausal women. However, we noted beneficial trends in some subgroups which may deserve a larger study.

Background Relapsing remitting multiple sclerosis (RRMS) has an increasing incidence in young adults and a high social-economic impact. Treatment delays progression and does not cure the disease, but new oral drugs’ innovative pharmacodynamics profiles can improve the therapeutic approach. Therapy review could prompt a better understanding of RRMS care’s effectiveness. Purpose To investigate the economic impact of RRMS therapy on the pharmacy of Macerata’s General Hospital from January 2011 to December 2014. To analyse patient demographics and clinical characteristics (ie, failures and adherence). Material and methods This review was conducted in collaboration with RecordData srl (prescription data regional provider) and neurologists and nurses for analysis of failure reasons. Teamwork produced a database of patients’ therapeutic histories. We analysed prescriptions of: first generation disease modifying therapies (DMT) (interferon β-1a and β-1b, glatiramer); second generation DMT (fingolimod, natalizumab); and relapsing therapy (methylprednisolone). Dosage and administration frequency were compared with data from the Summary of Product Characteristics (SPC). Results During the studied period, in a population of 118 patients treated (73 females; 45 males) with an average age of 39.8 years (range 16 to 63) and a mode of 32 years for both genders, 49 450 doses were prescribed (4086 packages: 21.9% in 2011; 24.72% in 2012; 25.48% in 2013; 27.9% in 2014) and 5 109 761.97€ spent (21.62% in 2011; 23.21% in 2012; 26.88% in 2013; 28.29% in 2014). Natalizumab, although only 1.62% of the provided doses (806/49 450), was the most expensive drug: 2 160 963.38€ (42.29%). Interferons represented 32.86% of costs with 38 154 doses (77.16%; -1.543 from 2011 to 2014) for 308 patients. From 2012, fingolimod was prescribed to 37 patients (10 304 doses; 20.84%) consisting of 12.48% of expenditure. Relapsing therapy concerned 83.1% of patients with 186 doses (0.37%) of methylprednisolone. Number of administrations was consistent with SPC data. Failures included 51 patients (43.22%): 17.65% interruptions (2 cases of adverse drug reactions); 42 (82.35%) switches (40.48% interferon-glatiramer; 28.57% interferon-fingolimod; 14.28% interferon-natalizumab). Conclusion The review showed DMT high costs and complexity for RRMS management (interruptions/switches/relapsing). Teamwork is a priceless resource for patient healthcare. Monitoring is being extended through 2015, including teriflunomide, dimethyl-fumarate and alemtuzumab prescriptions. References and/or Acknowledgements Summary of Product Characteristics. No conflict of interest.

The evaluation of cancer risk among patients treated for infertility is complex, given the need to consider indications for use, treatment details, and the effects of other factors (including parity status) that independently affect cancer risk. Many studies have had methodologic limitations. Recent studies that have overcome some of these limitations have not confirmed a link between drug use and invasive ovarian cancers, although there is still a lingering question as to whether borderline tumors might be increased. It is unclear whether this merely reflects increased surveillance. Investigations regarding breast cancer risk have produced inconsistent results. In contrast, an increasing number of studies suggest that fertility drugs may have a special predisposition for the development of uterine cancers, of interest given that these tumors are recognized as particularly hormonally responsive. Additional studies are needed to clarify the effects on cancer risk of fertility drugs, especially those used in conjunction with in vitro fertilization. Because many women who have received such treatments are still relatively young, further monitoring should be pursued in large well-designed studies that enable assessment of effects within a variety of subgroups defined by both patient and disease characteristics.

Objective To study the risk for obstructive sleep apnea (OSA) in a group of nonobese and obese polycystic ovary syndrome (PCOS) and control women. Design Prospective study. Setting Academic tertiary care medical center. Patient(s) Forty-four women with PCOS and 34 control women. Intervention(s) All of the women completed the Berlin questionnaire for assessment of OSA risk. Main Outcome Measure(s) All of the women underwent fasting determination of androgens, glucose, and insulin. Result(s) Women with PCOS were more obese compared with control women. However, there were no differences in BMI once subjects were divided into nonobese (PCOS: n=17; control: n=26) and obese (PCOS: n=27; control: n=8) groups. Women with PCOS had higher prevalence of high-risk OSA compared with control women (47% vs. 15%). However, none of the nonobese PCOS and control women screened positively for high-risk OSA. Among the obese group, the risk did not differ between groups (77% vs. 63%). Conclusion(s) Our findings indicate that even though the risk for OSA in PCOS is high, it is related to the high prevalence of severe obesity. The risk for OSA among nonobese women with PCOS is very low. However, our findings are limited by lack of polysomnographic confirmation of OSA.

To assess the long-term effects of ovulation-stimulating drugs on the risk of ovarian cancer.A retrospective cohort study of 12,193 eligible study subjects (median age 30 years) who were evaluated for infertility during the period of 1965-1988 at 5 clinical sites identified 45 subsequent ovarian cancers in follow-up through 1999. Standardized incidence ratios compared the risk of cancer among the infertile patients to the general population, whereas analyses within the cohort allowed the derivation of rate ratios for drug usage compared with no usage after adjustment for other ovarian cancer predictors.The infertility patients had a significantly elevated ovarian cancer risk compared with the general population (standardized incidence ratio 1.98, 95% confidence intervals [CI] 1.4, 2.6). When patient characteristics were taken into account and risks assessed within the infertile women, the rate ratios associated with ever usage were 0.82 (95% CI 0.4, 1.5) for clomiphene and 1.09 (95% CI 0.4, 2.8) for gonadotropins. There were higher, albeit nonsignificant, risks with follow-up time, with the rate ratios after 15 or more years being 1.48 (95% CI 0.7, 3.2) for exposure to clomiphene (5 exposed cancer patients) and 2.46 (95% CI 0.7, 8.3) for gonadotropins (3 exposed cancer patients). Although drug effects did not vary by causes of infertility, there was a slightly higher risk associated with clomiphene use among women who remained nulligravid, based on 6 exposed patients (rate ratio 1.75; 95% CI 0.5, 5.7).The results of this study generally were reassuring in not confirming a strong link between ovulation-stimulating drugs and ovarian cancer. Slight but nonsignificant elevations in risk associated with drug usage among certain subgroups of users, however, support the need for continued monitoring of long-term risks.II-2

To test our hypothesis that the hormonal phenotype of mild 3beta-hydroxysteroid dehydrogenase (HSD3B) deficiency in hyperandrogenic females (HF) is related to insulin-resistant polycystic ovary syndrome (PCOS), we compared insulin sensitivity and gonadotropin secretion in HF with compromised ( downward arrow ) adrenal HSD3B phenotype despite normal HSD3B2 genes (n = 6) to those in HF with classic PCOS (n = 9) of similar ages (14-36 yr). The same was examined in premature pubarche (PP) girls with (n = 4) and without the descending HSD3B phenotype (n = 5). The descending HSD3B phenotype was defined by ACTH-stimulated Delta(5)-precursor steroid levels and Delta(5)-precursors to Delta(4)-product steroid ratios higher than those in normal females (n = 30 for adult, n = 12 for pubertal). Classic PCOS HF had elevated testosterone levels and normal ACTH-stimulated hormonal profiles. The insulin sensitivity index determined by the frequently sampled iv glucose-tolbutamide test (FSIVGTT) in all HF with descending HSD3B phenotype and in all HF with classic PCOS, regardless of body mass index (BMI), was lower than in all eight normal BMI and five high BMI normal females. Integrated incremental insulin determined by FSIVGTT, the area under the curve for insulin, and fasting and 2 h glucose load insulin levels determined by an oral glucose tolerance test in both HF groups were higher (P0.01-0.0001) than those in normal females with normal or high BMI. LHRH-stimulated LH levels and LH/FSH ratios in both HF groups were higher (P0.01) than those in normal females. No statistical differences were found in the insulin sensitivity and gonadotropin parameter between the two PP girl groups. The insulin sensitivity index in each half of PP girls with the descending HSD3B phenotype was lower than or similar to that in control PP girls with a similar weight length index. The fasting glucose to insulin ratio in three of four PP girls with the descending HSD3B phenotype was lower than that in control PP girls, but one of four with the descending HSD3B phenotype had a higher fasting glucose to insulin ratio than the control PP girls. The findings of insulin sensitivity and gonadotropin data in both HF with the descending HSD3B phenotype and classic PCOS indicate significant insulin resistance and LH hypersecretion in both. These suggest that the descending HSD3B phenotype in HF is associated with a variant of insulin-resistant PCOS. The variable insulin sensitivity parameter in the small number of PP girls with the descending HSD3B phenotype warrants a further large scale study to examine this phenotype association with childhood insulin resistance.