The favourable alliance between CardioMEMS and levosimendan in patients with advanced heart failure.

AIMS: We report the results of a real-world study based on heart failure (HF) patients' continuous remote monitoring strategy using the CardioMEMS system to assess the impact of this device on healthcare outcomes, costs, and patients' management and quality of life. METHODS AND RESULTS: We enrolled seven patients (69.00 ± 4.88 years; 71.43% men) with HF, implanted with CardioMEMS, and daily remote monitored to optimize both tailored adjustments of home therapy and/or hospital infusions of levosimendan. We recorded clinical, pharmacological, biochemical, and echocardiographic parameters and data on hospitalizations, emergency room access, visits, and costs. Following the implantation of CardioMEMS, we observed a 50% reduction in the total number of hospitalizations and a 68.7% reduction in the number of days in the hospital. Accordingly, improved patient quality of life was recorded with EQ-5D (pre 58.57 ± 10.29 vs. 1 year post 84.29 ± 19.02, P = 0.008). Echocardiographic data show a statistically significant improvement in both systolic pulmonary artery pressure (47.86 ± 8.67 vs. 35.14 ± 9.34, P = 0.022) and E/e' (19.33 ± 5.04 vs. 12.58 ± 3.53, P = 0.023). The Quantikine® HS High-Sensitivity Kit determined elevated interleukin-6 values at enrolment in all patients, with a statistically significant reduction after 6 months (P = 0.0211). From an economic point of view, the net savings, including the cost of CardioMEMS, were on average €1580 per patient during the entire period of observation, while the analysis performed 12 months after the implant vs. 12 months before showed a net saving of €860 per patient. The ad hoc analysis performed on the levosimendan infusions resulted in 315 days of hospital avoidance and a saving of €205 158 for the seven patients enrolled during the observation period. CONCLUSIONS: This innovative strategy prevents unplanned access to the hospital and contributes to the efficient use of healthcare facilities, human resources, and costs.

Use of RNA biomarkers in the antidoping field.

There is growing evidence that various RNA molecules can serve as biomarkers for clinical diagnoses. Over the last decade, the high specificities and sensitivities of RNA biomarkers have led to proposals that they could be used to detect prohibited substances and practices in sports. mRNAs and circulating miRNAs have the potential to improve the detection of doping and expand the performance of the Athlete Biological Passport. This review provides a summary of the use of RNA biomarkers to detect human and equine doping practices, including a discussion of the use of dried blood spots as a stable matrix that supports and improves the general process of RNA biomarker detection. The advantages of RNA biomarkers over protein biomarkers are also discussed.

[Box: see text].

mRNA biomarkers sensitive and specific to micro-dose erythropoietin treatment at sea level and altitude.

Recombinant human erythropoietin (rhEPO) is prohibited by the World Anti-Doping Agency. rhEPO abuse can be indirectly detected via the athlete biological passport (ABP). However, altitude exposure challenges interpretation of the ABP. This study investigated whether 5'-aminolevulinate synthase 2 (ALAS2) and carbonic anhydrase 1 (CA1) in capillary dried blood spots (DBSs) are sensitive and specific markers of rhEPO treatment at altitude. ALAS2 and CA1 expression was monitored in DBS collected weekly before, during, and after a 3-week period at sea level or altitude. Participants were randomly assigned to receive 20 IU kg bw-1 epoetin alpha (rhEPO) or placebo injections every second day for 3 weeks while staying at sea level (rhEPO, n = 25; placebo, n = 9) or altitude (rhEPO, n = 12; placebo, n = 27). ALAS2 and CA1 expression increased up to 300% and 200%, respectively, upon rhEPO treatment at sea-level and altitude (P-values <0.05). When a blinded investigator interpreted the results, ALAS2 and CA1 expression had a sensitivity of 92%. Altitude did not confound the interpretation. Altitude affected ALAS2 and CA1 expression less than actual ABP markers when compared between sea level and altitude results. An individual athlete passport-like approach simulation confirmed the biomarker potential of ALAS2 and CA1. ALAS2 and CA1 were sensitive and specific biomarkers of micro-dose rhEPO treatment at sea level and altitude. Altitude seemed less a confounding factor for these biomarkers, especially when they are combined. Thus, micro-dose rhEPO injections can be detected in a longitudinal blinded setting using mRNA biomarkers in DBS.

Diagnosis of intrahepatic cholangiocarcinoma with CEUS.

Intrahepatic cholangiocarcinoma (ICC) is a rare, heterogeneous, highly lethal tumor of the biliary tract. Due to the lack of effective treatments, an early identification of ICC is essential to achieve the best outcome in terms of therapy and prognosis aiming for a curative intent. ICC may arise on a normal liver or with an underlying liver disease, making the diagnosis more difficult and complex. Contrast-enhancement ultrasound (CEUS) is an accurate procedure able to detect ICC-specific contrast vascular pattern, and thus facilitating the correlation between radiological and histopathological findings with high specificity and sensitivity. CEUS has been shown to have a high diagnostic potential in the diagnosis of ICC thanks to the possibility of studying in real time the intralesional microcirculation and evaluating the precocity of the enhancement of the lesion during the arterial phase. All these features allow to differentiate the ICC from hepatocarcinoma (HCC) with high sensitivity and specificity. Furthermore, CEUS is a rapid, non-invasive, non-nephrotoxic or non-allergenic tool. The only limitations CEUS may have are related to the disease site and patient characteristics (obesity) and compliance, including the operator's experience. A clinical evaluation of the patient, together with tumor markers and biochemical tests assessment, to differentiate ICC from HCC are highly suggested.

Interventions to Address Cardiovascular Risk in Obese Patients: Many Hands Make Light Work.

Obesity is a growing public health epidemic worldwide and is implicated in slowing improved life expectancy and increasing cardiovascular (CV) risk; indeed, several obesity-related mechanisms drive structural, functional, humoral, and hemodynamic heart alterations. On the other hand, obesity may indirectly cause CV disease, mediated through different obesity-associated comorbidities. Diet and physical activity are key points in preventing CV disease and reducing CV risk; however, these strategies alone are not always sufficient, so other approaches, such as pharmacological treatments and bariatric surgery, must support them. Moreover, these strategies are associated with improved CV risk factors and effectively reduce the incidence of death and CV events such as myocardial infarction and stroke; consequently, an individualized care plan with a multidisciplinary approach is recommended. More precisely, this review explores several interventions (diet, physical activity, pharmacological and surgical treatments) to address CV risk in obese patients and emphasizes the importance of adherence to treatments.

Prepectoral Versus Subpectoral Direct-to-Implant Breast Reconstruction: Evaluation of Patient's Quality of Life and Satisfaction with BREAST-Q.

BACKGROUND: Over the years, plastic surgery has acquired a central role in the integrated treatment of breast cancer. Direct-to-implant (DTI) reconstruction using the prepectoral approach has emerged as an alternative to reconstruction using the subpectoral technique to overcome the complications arising from this type of surgery resulting as a consequence of muscle elevation. The satisfaction and quality of life of patients undergoing DTI breast reconstruction were evaluated using the BREAST-Q questionnaire, comparing the prepectoral and the subpectoral technique. METHODS: A single-center cross-sectional study on patients who underwent mastectomy and DTI breast reconstruction at our institution between 2013 and 2021 was conducted. Eighty-one patients were included and mainly divided into two groups based on the surgical procedure: 52 patients undergoing a subpectoral breast reconstruction approach and 29 patients receiving a prepectoral breast reconstruction. In order to assess the quality of life, the postoperative BREAST-Q module was administered electronically to the enrolled patients. RESULTS: Higher scores in BREAST-Q domains were recorded from patients who underwent mastectomy and breast reconstruction with prepectoral technique: psychosocial well-being (P<0.0085), sexual well-being (P<0.0120), physical well-being: lymphoedema (P<0.0001) and satisfaction with information received (P<0.0045). There were further statistically significant differences between the two groups with regard to postoperative complications (p<0.0465) and the need for reoperation (p<0.0275). CONCLUSIONS: Patients who underwent DTI breast reconstruction with prepectoral technique were more satisfied in terms of psychosocial, sexual and also physical well-being. These patients also had statistically lower complications and reoperations compared to patients who received breast reconstruction with the subpectoral technique. LEVEL OF EVIDENCE IV: This journal requires that authors 38 assign a level of evidence to each article. For a full 39 description of these Evidence-Based Medicine ratings, 40 please refer to the Table of Contents or the online 41 Instructions to Authors www.springer.com/00266 .

The effects of iron injection on blood doping biomarkers in dried blood spots.

Iron supplementation is not considered as a doping method; however, it can affect the levels of several biomarkers of the hematologic module of the athlete biological passport (ABP), such as the reticulocyte percentage (%RET) and hemoglobin (HGB) level. Thus, iron injection could be a confounding factor in antidoping analyses. Previous studies have suggested that the HGB level and the expression levels of reticulocyte-related-mRNAs, such as 5'-aminolevulinate synthase 2 (ALAS2) and carbonic anhydrase 1 (CA1), could be promising biomarkers for the ABP and detectable in dried blood spots (DBSs). Therefore, in this study, we examined the impact of iron injection on the levels of these potential biomarkers in DBSs. Reticulocyte-related-mRNAs analyses were performed by RT-qPCR. Ferritin level in DBS was measured with enzyme-linked immunosorbent assay (ELISA) method. Notably, there were no significant effects of iron supplementation on the levels of ALAS2 and CA1 mRNAs but by contrast, the %RET and immature reticulocyte fraction (IRF) measured in whole blood increased significantly following iron injection. As expected, iron supplementation increased the ferritin level significantly in both serum and DBS samples. In conclusion, these findings reinforce the specificity of reticulocyte-related mRNAs in DBSs as biomarkers of blood doping to target in antidoping analyses.

[New insights in the pathophysiology and treatment of renal anemia]. / Nouveautés dans la pathophysiologie et le traitement de l'anémie rénale.

Renal anemia is a frequently encountered complication in patients suffering from advanced chronic kidney disease. This is mainly due to the decreased secretion of erythropoietin by the diseased kidneys. The current treatment of renal anemia is based on iron substitution and administration of recombinant erythropoietin. The discovery of HIF (Hypoxia-Inducible Factor) has led to the development of a new class of molecules that block the activity of prolyl-4-hydroxylases and stabilize HIF (Hypoxia-Inducible Factor), a transcription factor that plays an essential role in numerous cellular pathways, including those linked to erythropoiesis and iron metabolism. In this article, we discuss the current understanding of the pathophysiological mechanisms underlying renal anemia and the potential role of the new HIF-stabilizers in its treatment.

L'anémie rénale est un problème courant chez les patients souffrant d'insuffisance rénale chronique avancée. Elle est due essentiellement à la diminution de la sécrétion d'érythropoïétine par les reins malades. Le traitement actuel de l'anémie rénale repose sur la substitution martiale et l'administration d'érythropoïétine recombinante. Récemment, une nouvelle classe de molécules a été développée, dont l'effet repose sur l'inactivation des prolyl-4-hydroxylases, qui dégradent normalement l'HIF (Hypoxia- Inducible Factor), un facteur de transcription important dans l'expression des gènes liés à l'érythropoïèse et au métabolisme du fer. Dans cet article, nous ferons le point sur les connaissances actuelles de la pathophysiologie de l'anémie rénale et le rôle potentiel des inhibiteurs des prolyl-4-hydroxylases dans son traitement.

Monitoring of hemoglobin and erythropoiesis-related mRNA with dried blood spots in athletes and patients.

Aim: We assessed the feasibility of using hematological parameters (such as hemoglobin and reticulocyte mRNA) in dried blood spot (DBS) samples to test athletes for doping and to improve patient care. Methods: Hemoglobin and erythropoiesis-related mRNAs were measured in venous blood and DBSs from both healthy athletes and hemodialysis patients. Results: We accurately measured hemoglobin changes over time in both venous blood and DBS samples. Combining hemoglobin and mRNA analyses, we detected erythropoietin injection in DBSs more sensitively and with higher efficiency by using the DBS OFF-score than by using the athlete biological passport OFF-score. Conclusion: DBS-based measurements are practical for calculating hemoglobin levels and athlete biological passport OFF-scores. This approach may help detect blood doping and help predict patient response to EPO.

The use of RNA-based 5'-aminolevulinate synthase 2 biomarkers in dried blood spots to detect recombinant human erythropoietin microdoses.

The hematological module of the Athlete Biological Passport (ABP) is used for indirect detection of blood manipulations; however, the use of this method to detect doping, such as with microdoses of recombinant human erythropoietin (rhEPO), is problematic. For this reason, the sensitivity of ABP must be enhanced by implementing novel biomarkers. Here, we show that 5'-aminolevulinate synthase 2 (ALAS2) mRNAs are useful transcriptomic biomarkers to improve the indirect detection of rhEPO microdosing. Moreover, the sensitivity was sufficient to distinguish rhEPO administration from exposure to hypoxic conditions. Levels of mRNAs encoding carbonate anhydrase 1 (CA1) and solute carrier family 4 member 1 (SLC4A1) RNA, as well as the linear (L) and linear + circular (LC) forms of ALAS2 mRNA, were monitored for 16 days after rhEPO microdosing and during exposure to hypoxic conditions. ALAS2 mRNAs increased by 300% compared with the baseline values after rhEPO microdosing. Moreover, ALAS2 mRNAs were not significantly increased under hypoxic conditions. By contrast, CA1 mRNA was increased after both rhEPO microdosing and hypoxia, whereas SLC4A1 mRNA did not significantly increase under either condition. Furthermore, the analyses described here were performed using dried blood spots (DBSs), which provide advantages in terms of the sample collection, transport, and storage logistics. This study demonstrates that ALAS2 mRNA levels are sensitive and specific transcriptomic biomarkers for the detection of rhEPO microdosing using the hematological module of the ABP, and this method is compatible with the use of DBSs for anti-doping analyses.

Automation of RNA-based biomarker extraction from dried blood spots for the detection of blood doping.

Aim: Transcriptomic biomarkers originating from reticulocytes measured in dried blood spots (DBSs) may be reliable indicators of blood doping. Methods/results: Here, we examined changes in the expression levels of the erythropoiesis-related ALAS2, CA1 and SLC4A1 genes in DBS samples from elite athletes and volunteers of clinical study with recombinant erythropoietin dose. Conclusion: By comparing the mean intraday coefficients of variation for ALAS2L, ALASLC, CA1 and SLC4A1 between manual and automated RNA extractions, an average improvement was observed, whereas the assessment of interday variability provided comparable results for both manual and automated approaches. Our results confirmed that RNA biomarkers on DBS support are efficient to detect blood doping.

Clinical and echocardiographic benefit of Sacubitril/Valsartan in a real-world population with HF with reduced ejection fraction.

The aim of this study was to evaluate the effects of Sacubitril/Valsartan (S/V) on clinical, laboratory and echocardiographic parameters and outcomes in a real-world population with heart failure with reduced ejection fraction (HFrEF). This was a prospective observational study enrolling patients with HFrEF undergoing treatment with S/V. The primary outcome was the composite of cardiac death and HF rehospitalization at 12 months follow-up; secondary outcomes were all-cause death, cardiac death and the occurrence of rehospitalization for worsening HF. The clinical outcome was compared with a retrospective cohort of 90 HFrEF patients treated with standard medical therapy. The study included 90 patients (66.1 ± 11.7 years) treated with S/V. The adjusted regression analysis showed a significantly lower risk for the primary outcome (HR:0.31; 95%CI, 0.11-0.83; p = 0.019) and for HF rehospitalization (HR:0.27; 95%CI, 0.08-0.94; p = 0.039) in S/V patients as compared to the control group. A significant improvement in NYHA class, left ventricular ejection fraction, left ventricular end systolic volume and systolic pulmonary arterial pressure was observed up to 6 months. S/V did not affect negatively renal function and was associated with a significantly lower dose of furosemide dose prescribed at 6- and 12-month follow-up. In this study, S/V reduced the risk of HF rehospitalization and cardiac death at 1 year in patients with HFrEF. S/V improved NYHA class, echocardiographic parameters and need of furosemide, and preserved renal function.

Retraction Note to: Contrast-enhanced ultrasound appearances of enhancement patterns of intrahepatic cholangiocarcinoma: correlation with pathological findings.

While Prof. Dott. Di Carlo gave verbal consent to the corresponding author.

What is changing in indications and treatment of hepatic hemangiomas. A review.

Hepatic cavernous hemangioma accounts for 73% of all benign liver tumors with a frequency of 0.4-7.3% at autopsy and is the second most common tumor seen in the liver after metastases. Patients affected by hemangioma usually have their tumor diagnosed by ultrasound abdominal examination for a not well defined pain, but pain persist after treatment of the hemangioma. The causes of pain can be various gastrointestinal pathologies including cholelithiasis and peptic ulcer disease.The malignant trasformation is practically inexistent. Different imaging modalities are used to diagnosis liver hemangioma including ultrasonography, computed tomography (CT), magnetic resonance (MR) imaging, and less frequently scintigraphy, positronemission tomography combined with CT (PET/CT) and angiography. Imaging-guided biopsy of hemangioma is usually not resorted to except in extremely atypical cases. The right indications for surgery remain rupture, intratumoral bleeding, Kasabach-Merritt syndrome and organ or vessels compression (gastric outlet obstruction, Budd-Chiari syndrome, etc.) represents the valid indication for surgery and at the same time they are all complications of the tumor itself. The size of the tumor do not represent a valid indication for treatment. Liver hemangiomas, when indication exist, have to be treated firstly by surgery (hepatic resection or enucleation, open, laproscopic or robotic), but in the recent years other therapies like liver transplantation, radiofrequency ablation, radiotherapy, trans-arterial embolization, and chemotherapy have been applied.

Contrast-enhanced ultrasound appearances of enhancement patterns of intrahepatic cholangiocarcinoma: correlation with pathological findings.

The aim of this study was to investigate the correlation between enhancement patterns of intrahepatic cholangiocarcinoma (ICC) on contrast-enhanced ultrasound (CEUS) and pathological findings. The CEUS enhancement patterns of 40 pathologically proven ICC lesions were retrospectively analysed. Pathologically, the degree of tumour cell and fibrosis distribution in the lesion was semi-quantitatively evaluated. Four enhancement patterns were observed in the arterial phase for 32 mass-forming ICCs: peripheral rim-like hyperenhancement (n = 19); heterogeneous hyperenhancement (n = 6); homogeneous hyperenhancement (n = 3); and heterogeneous hypo-enhancement (n = 4). Among the four enhancement patterns, the differences in tumour cell distribution were statistically significant (p < 0.05). The hyperenhancing area on CEUS corresponded to more tumour cells for mass-forming ICCs. Heterogeneous hyperenhancement (n = 2) and heterogeneous hypo-enhancement (n = 2) were observed in the arterial phase for four periductal-infiltrating ICCs. In this subtype, fibrosis was more commonly found in the lesions. Heterogeneous hyperenhancement (n = 1) and homogeneous hyperenhancement (n = 3) were observed in the arterial phase for four intraductal-growing ICCs. This subtype tended to have abundant tumour cells. The CEUS findings of ICC relate to the degree of carcinoma cell proliferation at pathological examination. Hyperenhancing areas in the tumour always indicated increased density of cancer cells.