Fracture of a Transcatheter Atrial Septal Defect Occluder Device Causing Mitral Valve Perforation

Transcatheter atrial septal defect (ASD) device closure has gained increasing popularity over the past decades due to shorter hospital stay and the absence of skin scars. However, concern about the seriousness of device-related complications is accumulating. We report a case of device fracture in a young asymptomatic woman almost 4 years after percutaneous secundum ASD closure, resulting in mitral valve perforation. Subsequently, elective surgical removal of the device and mitral valve reconstruction was performed. This case demonstrates that complications from transcatheter ASD closure may even occur late after implantation

Improvement in perioperative care in pediatric cardiac surgery by shifting the primary focus of treatment from cardiac output to perfusion pressure: Are beta stimulants still needed?

An important aspect of perioperative care in pediatric cardiac surgery is maintenance of optimal hemodynamic status using vasoactive/inotropic agents. Conventionally, this has focused on maintenance of cardiac output rather than perfusion pressure. However, this approach has been abandoned in our center in favor of one focusing primarily on perfusion pressure, which is presented here and compared to the conventional approach. A retrospective study. Regional center for congenital heart disease. University Hospital of Lausanne, Switzerland. All patients with Aristotle risk score ≥8 that underwent surgery from 1996 to 2012 were included. Patients operated between 1996 and 2005 (Group 1: 206 patients) were treated according to the conventional approach. Patients operated between 2006 and 2012 (Group 2: 217 patients) were treated according to our new approach. All patients had undergone surgery for correction or palliation of congenital cardiac defects. Mortality, duration of ventilation and inotropic treatment, use of ECMO, and complications of poor peripheral perfusion (need for hemofiltration, laparotomy for enterocolitis, amputation). The two groups were similar in age and complexity. Mortality was lower in group 2 (7.3% in group 1 vs 1.4% in group 2, P < .005). Ventilation times (hours) and number of days on inotropic/vasoactive treatment (all agents), expressed as median and interquartile range [Q1-Q3] were shorter in group 2: 69 [24-163] hours in group 1 vs 35 [22-120] hours in group 2 (P < .01) for ventilation, and 9 [3-5] days in group 1 vs 7 [2-5] days in group 2 (P < .05) for inotropic/vasoactive agents. There were no differences in ECMO usage or complications of peripheral perfusion. Results in pediatric cardiac surgery may be improved by shifting the primary focus of perioperative care from cardiac output to perfusion pressure

Anesthetic Management for Concomitant Correction of Congenital Cardiac Defects and Long "O" Ring Tracheal Stenosis: A Role for Heliox?: Report of 2 Cases.

We present 2 infants with the rare association of long congenital tracheal stenosis, ventricular septal defect, and pulmonary hypertension. We describe a step-by-step assessment of the patients and the necessary procedures for a successful concomitant repair of both cardiac and tracheal malformations. The use of a helium-oxygen mixture (heliox) for the induction of anesthesia and pre-cardiopulmonary bypass is discussed

Charge Fluctuations in Quantum Point Contacts and Chaotic Cavities in the Presence of Transport

We analyze the frequency-dependent current fluctuations induced into a gate near a quantum point contact or a quantum chaotic cavity. We use a current and charge conserving, effective scattering approach in which interactions are treated in random phase approximation. The current fluctuations measured at a nearby gate, coupled capacitively to the conductor, are determined by the screened charge fluctuations of the conductor. Both the equilibrium and the non-equilibrium current noise at the gate can be expressed with the help of resistances which are related to the charge dynamics on the conductor. We evaluate these resistances for a point contact and determine their distributions for an ensemble of chaotic cavities. For a quantum point contact these resistances exhibit pronounced oscillations with the opening of new channels. For a chaotic cavity coupled to one channel point contacts the charge relaxation resistance shows a broad distribution between 1/4 and 1/2 of a resistance quantum. The non-equilibrium resistance exhibits a broad distribution between zero and 1/4 of a resistance quantum.Comment: 9 pages, two-column Revtex, 6 figures include

Scattering Theory of Photon-Assisted Electron Transport

The scattering matrix approach to phase-coherent transport is generalized to nonlinear ac-transport. In photon-assisted electron transport it is often only the dc-component of the current that is of experimental interest. But ac-currents at all frequencies exist independently of whether they are measured or not. We present a theory of photon-assisted electron transport which is charge and current conserving for all Fourier components of the current. We find that the photo-current can be considered as an up- and down-conversion of the harmonic potentials associated with the displacement currents. As an example explicit calculations are presented for a resonant double barrier coupled to two reservoirs and capacitively coupled to a gate. Two experimental situations are considered: in the first case the ac-field is applied via a gate, and in the second case one of the contact potentials is modulated. For the first case we show that the relative weight of the conduction sidebands varies with the screening properties of the system. In contrast to the non-interacting case the relative weights are not determined by Bessel functions. Moreover, interactions can give rise to an asymmetry between absorption and emission peaks. In the contact driven case, the theory predicts a zero-bias current proportional to the asymmetry of the double barrier. This is in contrast to the discussion of Tien and Gordon which, in violation of basic symmetry principles, predicts a zero-bias current also for a symmetric double barrier.Comment: 15 pages, 6 figures, REVTE

First-in human, phase 1, dose-escalation pharmacokinetic and pharmacodynamic study of the oral dual PI3K and mTORC1/2 inhibitor PQR309 in patients with advanced solid tumors (SAKK 67/13)

BACKGROUND: PQR309 is an orally bioavailable, balanced pan-phosphatidylinositol-3-kinase (PI3K), mammalian target of rapamycin (mTOR) C1 and mTORC2 inhibitor. PATIENTS AND METHODS: This is an accelerated titration, 3 + 3 dose-escalation, open-label phase I trial of continuous once-daily (OD) PQR309 administration to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics in patients with advanced solid tumours. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). RESULTS: Twenty-eight patients were included in six dosing cohorts and treated at a daily PQR309 dose ranging from 10 to 150 mg. Common adverse events (AEs; ≥30% patients) included fatigue, hyperglycaemia, nausea, diarrhoea, constipation, rash, anorexia and vomiting. Grade (G) 3 or 4 drug-related AEs were seen in 13 (46%) and three (11%) patients, respectively. Dose-limiting toxicity (DLT) was observed in two patients at 100 mg OD (>14-d interruption in PQR309 due to G3 rash, G2 hyperbilirubinaemia, G4 suicide attempt; dose reduction due to G3 fatigue, G2 diarrhoea, G4 transaminitis) and one patient at 80 mg (G3 hyperglycaemia >7 d). PK shows fast absorption (Tmax 1-2 h) and dose proportionality for Cmax and area under the curve. A partial response in a patient with metastatic thymus cancer, 24% disease volume reduction in a patient with sinonasal cancer and stable disease for more than 16 weeks in a patient with clear cell Bartholin's gland cancer were observed. CONCLUSION: The MTD and RP2D of PQR309 is 80 mg of orally OD. PK is dose-proportional. PD shows PI3K pathway phosphoprotein downregulation in paired tumour biopsies. Clinical activity was observed in patients with and without PI3K pathway dysregulation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov # NCT01940133

Efficacy and safety of acoziborole in patients with human African trypanosomiasis caused by Trypanosoma brucei gambiense: a multicentre, open-label, single-arm, phase 2/3 trial

Summary Background Human African trypanosomiasis caused by Trypanosoma brucei gambiense (gambiense HAT) in patients with late-stage disease requires hospital admission to receive nifurtimox-eflornithine combination therapy (NECT). Fexinidazole, the latest treatment that has been recommended by WHO, also requires systematic admission to hospital, which is problematic in areas with few health-care resources. We aim to assess the safety and efficacy of acoziborole in adult and adolescent patients with gambiense HAT. Methods This multicentre, prospective, open-label, single-arm, phase 2/3 study recruited patients aged 15 years or older with confirmed gambiense HAT infection from ten hospitals in the Democratic Republic of the Congo and Guinea. Inclusion criteria included a Karnofsky score less than 50, ability to swallow tablets, a permanent address or traceability, ability to comply with follow-up visits and study requirements, and agreement to hospital admission during treatment. Oral acoziborole was administered as a single 960 mg dose (3 × 320 mg tablets) to fasted patients. Patients were observed in hospital until day 15 after treatment administration then for 18 months as outpatients with visits at 3, 6, 12, and 18 months. The primary efficacy endpoint was the success rate of acoziborole treatment at 18 months in patients with late-stage gambiense HAT (modified intention-to-treat [mITT] population), based on modified WHO criteria. A complementary post-hoc analysis comparing the 18-month success rates for acoziborole and NECT (using historical data) was performed. This study is registered at ClinicalTrials.gov, NCT03087955. Findings Between Oct 11, 2016, and March 25, 2019, 260 patients were screened, of whom 52 were ineligible and 208 were enrolled (167 with late-stage and 41 with early-stage or intermediate-stage gambiense HAT; primary efficacy analysis set). All 41 (100%) patients with early-stage or intermediate-stage and 160 (96%) of 167 with late-stage disease completed the last 18-month follow-up visit. The mean age of participants was 34·0 years (SD 12·4), including 117 (56%) men and 91 (44%) women. Treatment success rate at 18 months was 95·2% (95% CI 91·2-97·7) reached in 159 of 167 patients with late-stage gambiense HAT (mITT population) and 98·1% (95·1-99·5) reached in 159 of 162 patients (evaluable population). Overall, 155 (75%) of 208 patients had 600 treatment-emergent adverse events. A total of 38 drug-related treatment-emergent adverse events occurred in 29 (14%) patients; all were mild or moderate and most common were pyrexia and asthenia. Four deaths occurred during the study; none were considered treatment related. The post-hoc analysis showed similar results to the estimated historical success rate for NECT of 94%. Interpretation Given the high efficacy and favourable safety profile, acoziborole holds promise in the efforts to reach the WHO goal of interrupting HAT transmission by 2030. Funding Bill & Melinda Gates Foundation, UK Aid, Federal Ministry of Education and Research, Swiss Agency for Development and Cooperation, Médecins Sans Frontières, Dutch Ministry of Foreign Affairs, Norwegian Agency for Development Cooperation, Norwegian Ministry of Foreign Affairs, the Stavros Niarchos Foundation, Spanish Agency for International Development Cooperation, and the Banco Bilbao Vizcaya Argentaria Foundation. Translation For the French translation of the abstract see Supplementary Materials section

Current trends in cannulation and neuroprotection during surgery of the aortic arch in Europe†‡

OBJECTIVES To conduct a survey across European cardiac centres to evaluate the methods used for cerebral protection during aortic surgery involving the aortic arch. METHODS All European centres were contacted and surgeons were requested to fill out a short, comprehensive questionnaire on an internet-based platform. One-third of more than 400 contacted centres completed the survey correctly. RESULTS The most preferred site for arterial cannulation is the subclavian-axillary, both in acute and chronic presentation. The femoral artery is still frequently used in the acute condition, while the ascending aorta is a frequent second choice in the case of chronic presentation. Bilateral antegrade brain perfusion is chosen by the majority of centres (2/3 of cases), while retrograde perfusion or circulatory arrest is very seldom used and almost exclusively in acute clinical presentation. The same pumping system of the cardio pulmonary bypass is most of the time used for selective cerebral perfusion, and the perfusate temperature is usually maintained between 22 and 26°C. One-third of the centres use lower temperatures. Perfusate flow and pressure are fairly consistent among centres in the range of 10-15 ml/kg and 60 mmHg, respectively. In 60% of cases, barbiturates are added for cerebral protection, while visceral perfusion still receives little attention. Regarding cerebral monitoring, there is a general tendency to use near-infrared spectroscopy associated with bilateral radial pressure measurement. CONCLUSIONS These data represent a snapshot of the strategies used for cerebral protection during major aortic surgery in current practice, and may serve as a reference for standardization and refinement of different approache