Production and separation of positron emitters for hadron therapy at FRS-Cave M.

The FRagment Separator FRS at GSI is a versatile spectrometer and separator for experiments with relativistic in-flight separated short-lived exotic beams. One branch of the FRS is connected to the target hall where the bio-medical cave (Cave M) is located. Recently a joint activity between the experimental groups of the FRS and the biophysics at the GSI and Department of physics at LMU was started to perform biomedical experiments relevant for hadron therapy with positron emitting carbon and oxygen beams. This paper presents the new ion-optical mode and commissioning results of the FRS-Cave M branch where positron emitting 15O-ions were provided to the medical cave for the first time. An overall conversion efficiency of 2.9±0.2×10-4 15O fragments per primary 16O ion accelerated in the synchrotron SIS18 was reached.

Instantaneous wave-free ratio-guided revascularization of nonculprit lesions in STEMI patients with multivessel coronary disease: The WAVE registry.

BACKGROUND: Complete revascularization (CR) of nonculprit lesions (NCL) is strongly recommended in patients with ST-elevation myocardial infarction (STEMI) and multivessel coronary artery disease (MVD), but no definitive evidence is available regarding which diagnostic strategy should be preferred. Instantaneous wave-free ratio (iFR) has never been investigated in this setting. We aimed to describe clinical outcomes of a cohort of patients undergoing iFR-guided CR. METHODS: Following primary percutaneous coronary intervention (PCI), consecutive patients with STEMI and intermediate NCL were enrolled and destinated to an iFR-guided CR. NCL with iFR ≤ 0.89 underwent PCI while NCL with iFR > 0.89 were deferred. The primary endpoint was NC target lesion failure (NC-TLF) and the secondary endpoint was major adverse cardiovascular events (MACE), at 1-year follow-up. RESULTS: Overall, 209 patients were enrolled (ischemic iFR = 83; nonischemic iFR = 126). Patients with ischemic iFR showed a higher prevalence of traditional cardiovascular risk factors and angiographically determined three-vessel disease. In the entire cohort, NC-TLF and MACE occurred in 6.7% and 10.5% of patients, respectively. Compared to the deferred group, patients with ischemic iFR experienced significantly higher rates of both NC-TLF (3.2% vs. 12.1%; p = 0.021) and MACE (7.1% vs. 16.9%; p = 0.041). These results were mostly driven by increased rates of NC-TLF PCI and further revascularizations in this latter group, while no differences were evident in terms of nonfatal myocardial infarction or death. At multivariable analysis, the strongest predictor of MACE was symptom onset to balloon time (HR = 1.17 [95% CI: 1.04-1.31], p = 0.008). CONCLUSIONS: In our study enrolling STEMI patients with MVD, iFR assessment was feasible and safe. PCI-deferring according to iFR evaluation of NCL was associated with low rates of adverse events. Further randomized studies are needed to investigate the effectiveness of iFR-guided revascularization compared to current practice in this setting.

The 'brick diet' and postprandial insulin: a practical method to balance carbohydrates ingested and prandial insulin to prevent hypoglycaemia in hospitalized persons with diabetes.

AIM: Insulin is the preferred treatment for the control of diabetes in hospital, but it raises the risk of hypoglycaemia, often because oral intake of carbohydrates in hospitalized persons is lower than planned. Our aim was to assess the effect on the incidence of hypoglycaemia of giving prandial insulin immediately after a meal depending on the amount of carbohydrate ingested. METHODS: A prospective pre-post intervention study in hospitalized persons with diabetes eating meals with stable doses of carbohydrates present in a few fixed foods. Foods were easily identifiable on the tray and contained fixed doses of carbohydrates that were easily quantifiable by nurses as multiples of 10 g (a 'brick'). Prandial insulin was given immediately after meals in proportion to the amount of carbohydrates eaten. RESULTS: In 83 of the first 100 people treated with the 'brick diet', the oral carbohydrate intake was lower than planned on at least one occasion (median: 3 times; Q1-Q3: 2-6 times) over a median of 5 days. Compared with the last 100 people treated with standard procedures, postprandial insulin given on the basis of ingested carbohydrate significantly reduced the incidence of hypoglycaemic events per day, from 0.11 ± 0.03 to 0.04 ± 0.02 (P < 0.001) with an adjusted incidence rate ratio of 0.70 (95% confidence interval 0.54-0.92; P = 0.011). CONCLUSIONS: In hospitalized persons with diabetes treated with subcutaneous insulin, the 'brick diet' offers a practical method to count the amount of carbohydrates ingested, which is often less than planned. Prandial insulin given immediately after a meal, in doses balanced with actual carbohydrate intake reduces the risk of hypoglycaemia.

Feline Dental Implants: Long-Term Follow-up of Two Cases.

Dental implants have become an option for replacement of lost canine teeth in cats. Although cats appear to manage well after a canine extraction, complications such as lip entrapment can occur after maxillary canine tooth extraction. Even cats with a complicated crown fracture of the maxillary canine tooth that have had root canal therapy can develop lip entrapment. This can lead to painful lip ulcers and potential need for further dental treatment. Canine tooth replacement with a dental implant and prosthodontic crown is, in the authors' experience, a predictable option that can be offered to clients who would like to replace a lost canine tooth. This report will discuss 2 long-term cases of maxillary canines replaced by dental implants/crowns.

Dental Implants and Incisor Bridge Placement in a Dog.

Veterinary dentistry has tended to follow the trends and advancements in the human dental field. As for any procedure performed on a patient, whether human or animal, an informed decision is based on the available evidence regarding treatment options. This is certainly true for the more involved treatments in veterinary dentistry which can include the disciplines of endodontics and dental implantology. A number of published case reports have been accepted by the specialty that endodontic therapy is indeed a predictable and a valuable service that can be offered to pet owners. Oral implantology has become an accepted and predictable procedure in the human dental field and can now be offered to pet owners if performed by suitable trained veterinary clinicians. The success rate for endosseous implant osseointegration is very high in humans. Success rates are also very high in animals used for implantology research. Canine studies have shown good bone-to-implant contact of around 73% in osseointegrated endosseous implants based on histological sections. Radiographic and histological findings demonstrate stable alveolar crestal bone levels after loading endosseous implants for up to 12 months in a dog model. This article discusses use of dental implants in the rostral mandible of a companion dog to replace periodontally diseased incisors, their restoration, to return the animal to full dental function and 3-year follow-up.

The applications of Wearable Cardioverter Defibrillators in Heart Failure and beyond.

Abstract: Wearable cardioverter defibrillator has revealed a crucial device both in patients with a clear indication of ICD implantation but with temporary contraindications or in expectation of a diagnosis, considering that its use should be individualized.

A strange case of Transthyretin Cardiac Amyloidosis in the Elderly: a diagnostic challenge.

Abstract: Transthyretin (TTR)-related cardiac amyloidosis is a progressive infiltrative cardiomyopathy that mimics hypertensive, hypertrophic heart disease and may go undiagnosed. We here report the case of a 83-year-old woman, which has rapresented an unique case of transthyretin-related cardiac amyloidosis, as a patient with an initial diagnosis of hypertensive heart disease later develops an infiltrative cardiomyopathy due to amyloid deposits.

Reel syndrome: a rare presentation of a rare cause of cardiac resynchronization malfunction.

Abstract: Reel syndrome is a rare cause of pacemaker lead displacement. This case report shows a rare presentation of Reel syndrome highlighting the importance of an early diagnosis and discussing the underlying mechanism, management and prevention.

Should temozolomide be used on the basis of O6-methylguanine DNA methyltransferase status in patients with advanced neuroendocrine tumors? A systematic review and meta-analysis.

BACKGROUND: Temozolomide (TEM) is an active treatment in metastatic neuroendocrine tumors (NETs). Patients affected by glioblastoma multiforme or advanced melanoma treated with TEM who have deficiency of O6-methylguanine DNA methyltransferase (MGMT) have a better responses and survival. However, the predictive role of MGMT in patients with NETs treated with TEM is still debated. METHODS: We conducted a systematic review of the literature and meta-analysis, based on PRISMA methodology, searching in the main databases (PubMed, Embase, Scopus, Web of Science, Cochrane Library and clinical trial.gov) and the proceedings of the main international congresses, until April 26, 2021. RESULTS: Twelve out of 616 articles were selected for our analysis, regarding a total of 858 NET patients treated with TEM-based chemotherapy. The status of MGMT had been tested in 513 (60%) patients, using various methods. The pooled overall response rate (ORR) was higher in MGMT-deficient compared with MGMT-proficient NETs, with a risk difference of 0.31 (95% confidence interval, CI: 0.13-0.50; p < 0.001; I2: 73%) and risk ratio of 2.29 (95% CI: 1.34-3.91; p < 0.001; I2: 55%). The pooled progression free survival (PFS) (hazard ratio, HR = 0.56; 95% CI: 0.43-0.74; p < 0.001) and overall survival (OS) (HR = 0.41; 95% CI: 0.20-0.62; p = 0.011) were longer in MGMT-deficient versus MGMT-proficient NETs. CONCLUSIONS: Our meta-analysis suggested that MGMT status may be predictive of TEM efficacy. However, due to the high heterogeneity of the evaluated studies the risk of biases should be considered. On this hypothesis future homogeneous prospective studies are warranted.

Gr-MDSC-linked asset as a potential immune biomarker in pretreated NSCLC receiving nivolumab as second-line therapy.

PURPOSE: Immunotherapy is a new standard first-line treatment for non-small cell lung cancers (NSCLC) with high programmed cell death-ligand 1 (PD-L1) expression (≥ 50%) and second-line treatment regardless of PD-L1 status, though not all patients benefit from this approach. Much effort is ongoing to identify robust prognostic and predictive biomarkers of response to immune checkpoint inhibitors, overcoming PD-L1 that appears limited in its ability to discriminate patient candidates to this new class of anticancer agents. The purpose of this research study is to identify potential new biomarkers for immunotherapy in lung cancer. METHODS: Fifty-three consecutive patients with advanced NSCLC treated with nivolumab were enrolled in the study. All the patients received a blood analysis looking for the relationship between different populations of baseline white blood cells and granulocytic myeloid-derived suppressor cells (Gr-MDSC) detected by flow cytometry, to identify and characterize patients with poor likelihood of benefit from nivolumab in NSCLC second-line setting, regardless of clinical feature and PDL1 expression. RESULTS: Univariate analysis showed that high baseline levels of Gr-MDSC and low baseline CD8/Gr-MDSC ratio are associated with significantly better (P = 0.02) response to immunotherapy treatment. Log-rank tests suggested a significant improvement in OS and PFS with high baseline levels of Gr-MDSC levels (≥ 6 cell/µl), low absolute neutrophil count (< 5840/µl), high eosinophil count (> 90 /µl), and NLR < 3. The multivariate analysis showed a statistically significant improvement for PFS (P = 0.003) and OS (P = 0.05) in favour of the identified good prognostic Gr-MDSC-linked asset group, compared with the poor prognosis group. CONCLUSION: The role of Gr-MDSC appears interesting as a potential biomarker in NSCLC patients receiving immune-checkpoint inhibitors. Further analyses are needed to confirmed and study in deep the role of these particular cells and their role in cancer response and progression during ICI therapy.

Correction to: Gr-MDSC-linked asset as a potential immune biomarker in pretreated NSCLC receiving nivolumab as second-line therapy.

Acknowledgements section was missing.

Effect of exercise training on ventilatory efficiency in patients with heart disease: a review.

The analysis of ventilatory efficiency in cardiopulmonary exercise testing has proven useful for assessing the presence and severity of cardiorespiratory diseases. During exercise, efficient pulmonary gas exchange is characterized by uniform matching of lung ventilation with perfusion. By contrast, mismatching is marked by inefficient pulmonary gas exchange, requiring increased ventilation for a given CO2 production. The etiology of increased and inefficient ventilatory response to exercise in heart disease is multifactorial, involving both peripheral and central mechanisms. Exercise training has been recommended as non-pharmacological treatment for patients with different chronic cardiopulmonary diseases. In this respect, previous studies have reported improvements in ventilatory efficiency after aerobic exercise training in patients with heart disease. Against this background, the primary objective of the present review was to discuss the pathophysiological mechanisms involved in abnormal ventilatory response to exercise, with an emphasis on both patients with heart failure syndrome and coronary artery disease. Secondly, special focus was dedicated to the role of aerobic exercise training in improving indices of ventilatory efficiency among these patients, as well as to the underlying mechanisms involved.

Effects of continuous vs interval exercise training on oxygen uptake efficiency slope in patients with coronary artery disease.

The oxygen uptake efficiency slope (OUES) is a submaximal index incorporating cardiovascular, peripheral, and pulmonary factors that determine the ventilatory response to exercise. The purpose of this study was to evaluate the effects of continuous exercise training and interval exercise training on the OUES in patients with coronary artery disease. Thirty-five patients (59.3±1.8 years old; 28 men, 7 women) with coronary artery disease were randomly divided into two groups: continuous exercise training (n=18) and interval exercise training (n=17). All patients performed graded exercise tests with respiratory gas analysis before and 3 months after the exercise-training program to determine ventilatory anaerobic threshold (VAT), respiratory compensation point, and peak oxygen consumption (peak VO2). The OUES was assessed based on data from the second minute of exercise until exhaustion by calculating the slope of the linear relation between oxygen uptake and the logarithm of total ventilation. After the interventions, both groups showed increased aerobic fitness (P<0.05). In addition, both the continuous exercise and interval exercise training groups demonstrated an increase in OUES (P<0.05). Significant associations were observed in both groups: 1) continuous exercise training (OUES and peak VO2 r=0.57; OUES and VO2 VAT r=0.57); 2) interval exercise training (OUES and peak VO2 r=0.80; OUES and VO2 VAT r=0.67). Continuous and interval exercise training resulted in a similar increase in OUES among patients with coronary artery disease. These findings suggest that improvements in OUES among CAD patients after aerobic exercise training may be dependent on peripheral and central mechanisms.

Right ventricle-sparing heart transplant: promising new technique for recipients with pulmonary hypertension.

BACKGROUND: Right heart failure remains the leading early cause of mortality after heart transplantation, especially with antecedent pulmonary hypertension. Paradoxically, the discarded recipient right heart, acclimated to pulmonary hypertension, is often stronger than its nonconditioned donor replacement. Heterotopic ("piggyback") transplantation is plagued by problems related to the retained, dilated, hypocontractile left ventricle (lung compression, systemic emboli, arrhythmias). Were it possible to retain the recipient's right heart, excising only the left ventricle, this could have important advantages, especially in severe pulmonary hypertension. This report describes such a technique. METHODS AND RESULTS: In four transplantation experiments (dogs), right ventricular-sparing transplantation proved technically feasible and hemodynamically successful. Bleeding after excision of the left ventricle was easily controlled. Back-bleeding from the native aortic valve (now open into the pericardial space) was not problematic. All atrial, aortic, and pulmonary arterial connections proved feasible. The preserved recipient right heart of all animals remained in stable sinus rhythm. All recipients were easily weaned from cardiopulmonary bypass, maintaining mean arterial pressures 60 to 110 mm Hg. CONCLUSIONS: This investigation develops a technique for donor right ventricle sparing in cardiac transplantation, demonstrating technical and hemodynamic feasibility. This method holds promise for the unsolved clinical problem of right heart failure after orthotopic heart transplantation with antecedent pulmonary hypertension.

Comparison of high reloading ROsuvastatin and Atorvastatin pretreatment in patients undergoing elective PCI to reduce the incidence of MyocArdial periprocedural necrosis. The ROMA II trial.

OBJECTIVES: The objective of this study is to compare a reloading dose of Rosuvastatin and Atorvastatin administered within 24 h before coronary angioplasty (PCI) in reducing the rate of periprocedural myonecrosis and major cardiac and cerebrovascular events (MACCE) in patients on chronic statin treatment undergoing elective PCI. BACKGROUND: Elective PCI may be complicated with elevation of cardiac biomarkers. Several studies suggested that pretreatment with statins may be associated with a reduction in periprocedural myocardial necrosis. METHODS: Three hundred and fifty patients with stable angina who underwent elective PCI were randomly assigned to receive a pre-procedural reloading dose of Rosuvastatin (40 mg) (Rosuvastatin Group-RG n=175) or Atorvastatin (80 mg) (Atorvastatin Group-AG n=175) and a control group on chronic statin therapy without reloading (Control-Group-CG). The primary end-point was periprocedural myocardial necrosis and the occurrence of MACCE at 30-day,6-12 month follow-up. Also we evaluate the rise of periprocedural Troponin T serum levels >3× the upper limit of normal. RESULTS: Twelve and 24-hour post-PCI Creatine Kinase Muscle and Brain (CK-MB) elevation >3× occurred more frequently in the CG than in the RG and in the AG (at 24-h: 25.0 vs 7.1; p=0.003 and 25.0 vs 6.1; p=0.001). At 30-day, 6-and 12-month follow-up the incidence of cumulative MACCE was higher in CG than in the RG or AG (at 12-month: 41.0% vs 11.4% vs 12.0%; p=0.001). There was no difference between the RG and AG in terms of myocardial post-procedural necrosis and MACCE occurrence at follow-up. CONCLUSIONS: High-dose statin reloading improves procedural and long term clinical outcomes in stable patients on chronic statin therapy. Both Rosuvastatin and Atorvastatin showed similar beneficial effects on procedural and long-term outcomes.

Effects of continuous vs interval exercise training on oxygen uptake efficiency slope in patients with coronary artery disease

The oxygen uptake efficiency slope (OUES) is a submaximal index incorporating cardiovascular, peripheral, and pulmonary factors that determine the ventilatory response to exercise. The purpose of this study was to evaluate the effects of continuous exercise training and interval exercise training on the OUES in patients with coronary artery disease. Thirty-five patients (59.3±1.8 years old; 28 men, 7 women) with coronary artery disease were randomly divided into two groups: continuous exercise training (n=18) and interval exercise training (n=17). All patients performed graded exercise tests with respiratory gas analysis before and 3 months after the exercise-training program to determine ventilatory anaerobic threshold (VAT), respiratory compensation point, and peak oxygen consumption (peak VO2). The OUES was assessed based on data from the second minute of exercise until exhaustion by calculating the slope of the linear relation between oxygen uptake and the logarithm of total ventilation. After the interventions, both groups showed increased aerobic fitness (P<0.05). In addition, both the continuous exercise and interval exercise training groups demonstrated an increase in OUES (P<0.05). Significant associations were observed in both groups: 1) continuous exercise training (OUES and peak VO2 r=0.57; OUES and VO2 VAT r=0.57); 2) interval exercise training (OUES and peak VO2 r=0.80; OUES and VO2 VAT r=0.67). Continuous and interval exercise training resulted in a similar increase in OUES among patients with coronary artery disease. These findings suggest that improvements in OUES among CAD patients after aerobic exercise training may be dependent on peripheral and central mechanisms.

Effect of exercise training on ventilatory efficiency in patients with heart disease: a review

The analysis of ventilatory efficiency in cardiopulmonary exercise testing has proven useful for assessing the presence and severity of cardiorespiratory diseases. During exercise, efficient pulmonary gas exchange is characterized by uniform matching of lung ventilation with perfusion. By contrast, mismatching is marked by inefficient pulmonary gas exchange, requiring increased ventilation for a given CO2 production. The etiology of increased and inefficient ventilatory response to exercise in heart disease is multifactorial, involving both peripheral and central mechanisms. Exercise training has been recommended as non-pharmacological treatment for patients with different chronic cardiopulmonary diseases. In this respect, previous studies have reported improvements in ventilatory efficiency after aerobic exercise training in patients with heart disease. Against this background, the primary objective of the present review was to discuss the pathophysiological mechanisms involved in abnormal ventilatory response to exercise, with an emphasis on both patients with heart failure syndrome and coronary artery disease. Secondly, special focus was dedicated to the role of aerobic exercise training in improving indices of ventilatory efficiency among these patients, as well as to the underlying mechanisms involved.

A multicenter randomized study to evaluate intracoronary abciximab with the ClearWay catheter to improve outcomes with Lysis (IC ClearLy): trial study design and rationale.

BACKGROUND: Percutaneous coronary intervention (PCI) is a highly effective therapy for acute ST-elevation myocardial infarction. Adjunctive therapy with platelet glycoprotein (GP) IIb/IIIa inhibitor can result in increased vessel patency and improved outcomes in ST-elevation myocardial infarction patients undergoing PCI. The investigation of novel dosing and delivery strategies of this therapy may help to further improve outcomes. METHODS: IC-Clearly is a randomized, open-label, multicenter trial, with the purpose of evaluating the effectiveness of an intracoronary bolus dose of abciximab delivered using the ClearWay RX catheter vs. an intravenous bolus of abciximab for ST-elevation myocardial infarction with angiographically visible thrombus (thrombus grade >or=2). A total of 150 patients will be randomized 1: 1 to treatment of the culprit artery with intracoronary abciximab (75 patients) or intravenous abciximab (75 patients) in addition to a maintenance infusion regimen of abciximab administered intravenously for 12 h after PCI. The number of patients included in this study is based on the estimation of sample size needed to identify a statistically significant difference in the primary endpoints between the two groups. The primary endpoint chosen to evaluate this hypothesis is infarct size assessed by cardiac magnetic resonance. Clinical outcomes will be assessed for each patient through hospital discharge and at 30-day follow-up. CONCLUSION: The purpose of this study is to evaluate whether an intracoronary bolus of abciximab delivered with the ClearWay RX catheter prior to the 12 h post-PCI intravenous infusion regimen of abciximab will result in significant additional clot resolution in vivo and improved myocardial perfusion when compared with an intravenous bolus of abciximab on top of the 12 h post-PCI intravenous infusion regimen of abciximab as per standard practice. The primary endpoint chosen to evaluate this hypothesis is infarct size as assessed by cardiac magnetic resonance.