Global longitudinal strain for prediction of mortality in ST-segment elevation myocardial infarction and aortic stenosis patients: two sides of the same coin.

OBJECTIVE: Global longitudinal strain (GLS) predicts major adverse events in ST-segment elevation myocardial infarction (STEMI) and aortic stenosis (AS). Different cut-off values and different end-points have been proposed for prognostic stratification. We aimed to verify whether a single GLS cut-off value can be used to identify increased risk of all-cause death in STEMI and AS. PATIENTS AND METHODS: One-hundred- seventeen successfully treated first STEMI (age 63.8±12.5 yrs, 70% men) and 64 AS (age 80.3±6.9 yrs, 44% men) patients, undergoing echocardiography before discharge and before AS treatment, respectively, were retrospectively analyzed. GLS was analyzed, together with pulmonary artery systolic pressure (PASP), Killip class and Genereux stage. End-point was all-cause death at 6-month follow-up. RESULTS: All-cause death occurred in 4 (3.4%) STEMI and 5 (7.8%) AS patients (p=ns). AS patients who died had GLS similar to died STEMI patients (9.7±2.1 vs. 11.3±1.7, p=ns). GLS cut-off ≤12% predicted death with 89% sensitivity and 70% specificity (AUC 0.84, p=0.001): STEMI and AS patients with GLS ≤12% had worse survival than STEMI and AS patients with GLS >12% (log-rank p=0.001). At multivariate Cox regression analysis, lower GLS values independently predicted death (HR 0.667, 95% CI 0.451-0.986, p=0.042), and the prediction model was improved when GLS was added to old age, significant comorbidities, PASP and Killip/Genereux stage (χ2 6.691 vs. 1.364, p=0.010). CONCLUSIONS: Died patients with STEMI and AS show similar values of GLS. A unique cut-off value of GLS can reliably be used to stratify the risk of all-cause death at 6-month follow-up in both two clinical settings.

Laparoscopic and robotic pyeloplasty as minimally invasive alternatives to the open approach for the treatment of uretero-pelvic junction obstruction in infants: a multi-institutional comparison of outcomes and learning curves.

BACKGROUND: Since the development of minimally invasive surgery (MIS), laparoscopic and robotic approaches have been widely adopted. However, little has been published detailing the learning curve of MIS, especially in infants. OBJECTIVE: To quantify the learning curve of laparoscopic (LP) and robot-assisted laparoscopic pyeloplasty (RAL-P) for treatment of uretero-pelvic junction obstruction (UPJO) in infants evidenced by number of cases, operative time, success and complications. PATIENTS AND METHODS: Between 2009 and 2017, we retrospectively reviewed pyeloplasty cases for treatment of UPJO in infants at three academic institutions. The primary outcome was success. Secondary outcomes were UPJO recurrence, complications, and operative time as a surrogate of skill acquisition. Continuous variables were analyzed by t test, Welch-test, and one-way ANOVA. Non-continuous variables were analyzed by Chi-squared test or Fisher's exact test. Learning curves (LC) were studied by r-to-z transformation and CUSUM. RESULTS: Thirty-nine OP, 26 LP, and 39 RAL-P had mean operative times (OT) of 106, 121, and 151 min, respectively. LCs showed plateau in OT after 18 and 13 cases for LP and RAL-P, respectively. RAL-P showed a second phase of further improvements after 37 cases. At 16 months follow-up, there were similar rates of success and complications between the three groups. CONCLUSIONS: Despite different duration of learning phases, proficiency was achieved in both LP and RAL-P as evidenced by stabilization of operative time and similar success rates and complications to OP. Before and after achievement of proficiency, LP and RAL-P can be safely learned and implemented for treatment of UPJO in infants.

The Monte Carlo method to build up models of the hydrolysis half-lives of organic compounds.

The hydrolysis of organic chemicals such as pesticides, pollutants, or drugs can affect the fate and behaviour of environmental contaminants, so it is of interest to evaluate the stability of substances in water for various purposes. For the registration of organic compounds in Europe, information on hydrolysis must be presented. However, the experimental measurements of all chemicals would require enormous resources, and computational models may become attractive. Applying the CORAL software (http://www.insilico.eu/coral) quantitative structure-property relationships (QSPRs) were built up to model hydrolysis. The 2D-optimal descriptor is calculated with so-called correlation weights for attributes of simplified molecular input-line entry systems (SMILES). The correlation weights are obtained as results of the special Monte Carlo optimization. The nature of (five- and six-member) rings is an important component of this approach. Another important component is the atom pair proportions for nitrogen, oxygen, and sulphur. The statistical quality of the best model is: n = 44, r2 = 0.74 (training set); n = 14, r2 = 0.75 (calibration set); and n = 12, r2 = 0.80 (validation set).

Pediatric robotic-assisted laparoscopic ureterocalycostomy: Salient tips and technical modifications for optimal repair.

Introduction: Ureterocalycostomy is a necessary option for renal salvage in cases where conventional reconstructions have failed or as a primary option in anatomic situations such as intrarenal pelvis, malrotated, or horseshoe kidney. The primary principle of this procedure is to allow for dependent drainage. Ureterocalycostomy is often difficult due to extensive scar tissue and may be complicated by bleeding in the setting of a normal functioning lower pole cortex, compared to thin renal cortex and poor renal function as seen in end-spectrum of the obstruction. Identification of a dependent calyx and hemostasis can be difficult when there is a normal cortical thickness. Though the vascular control of hilum is an option, we suggest some simple tips to avoid this step and optimize surgical results. We present our experience and salient technical tips with pediatric robotic-assisted laparoscopic ureterocalycostomy and provide a step-by-step video. Methods: Four patients underwent robotic-assisted laparoscopic ureterocalycostomy between the years 2012 and 2016 by a single surgeon. Perioperative outcomes measured included operative time, hospital stay, pain relief, degree of hydronephrosis on postoperative ultrasound at 3 months, and renal scintigraphy as needed. We describe the operative procedure and provide tips on identifying a dependent lower pole calyx with flexible nephroscopy and needle puncture, the use of harmonic scalpel for incision of the lower pole cortex, and anastomosis by pre-placement of interrupted sutures as the urothelium of the renal calyces is thin and friable. Results: Patients ranged in age between 11 months and 14 years old. Three of four patients had one prior pyeloplasty, and one patient had two prior pyeloplasties. Mean operative time (incision to closure) was 208 minutes. No Clavien-Dindo 30-day complications were encountered and no patients required blood transfusion. Anatomic success was reported in all patients with a mean follow-up of 4.46 years; however, one patient ultimately required nephrectomy despite patent anastomosis, which would not drain due to a capacious pelvis. Conclusions: Robotic-assisted laparoscopic ureterocalycostomy is feasible in re-operative cases with extensive scaring and in patients with normal lower pole renal cortex. We offer tips to allow for safe and proficient performance of this procedure.

Choice architecture-based prescribing tool for TB preventive therapy: a pilot study in South Africa.

BACKGROUND: All people with HIV who screen negative for active tuberculosis (TB) should receive isoniazid preventive therapy (IPT). IPT implementation remains substantially below the 90% WHO target. This study sought to further understanding of IPT prescription by piloting a simplified prescribing approach. SETTING: Primary care clinics in Matlosana, South Africa. DESIGN: This was a mixed-methods implementation study. METHODS: Nine providers were recruited and underwent training on 2018 WHO guidelines. A simplified prescribing tool containing antiretroviral therapy (ART) and IPT prescriptions was introduced into the workflow for 2 weeks. Prescription data were collected from file review. Interviews were conducted with prescribers. RESULTS: During the study period, 41 patients were evaluated for ART initiation; 34 (83%) files used the simplified prescribing tool. Thirty-seven (90%) patients were eligible for same-day ART and IPT initiation, of whom 36 (97%) received IPT prescription. Qualitative interviews identified the following barriers to IPT prescription: cognitive burden, extensive documentation, limited management support, paucity of training, stock-outs, and patient-related factors. Provider acceptability of the tool was favorable, with unanimous recommendation to colleagues on the basis of streamlining documentation and reminding to prescribe. CONCLUSIONS: This simplified prescribing device for IPT was feasible to implement. Streamlining documentation and reminding providers to prescribe can reduce work-flow barriers to IPT provision.

Duchenne muscular dystrophy: preliminary experience with sacubitril-valsartan in patients with asymptomatic left ventricular dysfunction.

OBJECTIVE: Duchenne muscular dystrophy (DMD) is an inherited X-linked recessive neuromuscular disease caused by mutations of the dystrophin gene, leading to early and progressive muscle deterioration and dilated cardiomyopathy. The aim of this investigation was to assess whether treatment with sacubitril/valsartan (S/V) is well tolerated and may have beneficial effects in DMD patients with left ventricle (LV) dysfunction. PATIENTS AND METHODS: We administered S/V to 3 DMD patients (19-29 yeard old) with LV ejection fraction <35% at echocardiography but no symptoms of heart failure. All patients were on optimal medical therapy. S/V was initiated at a very low dose of 12/13 mg/die, after withdrawal of angiotensin-converting enzyme inhibitor therapy, and slowly titrated to the dose of 49/51 mg twice daily or the maximally tolerated dose. Clinical and echocardiographic follow-up was performed after 3, 6 and 12 months. RESULTS: At baseline, the LV ejection fraction was 32±1%. A significant improvement of LV ejection fraction was observed at 3 months (44.0±6.0%; p<0.05), which was maintained at 6 (45.7±5.0%) and 12 (43.3±3.2%) months (p<0.05 for both). No relevant side effects were reported throughout the period of the study. CONCLUSIONS: Our preliminary data suggest that, in DMD patients with reduced LV ejection fraction, S/V is safe and may improve LV function.

Localized Nanoresonator Mode in Plasmonic Microcavities.

Submicron-thick hexagonal boron nitride crystals embedded in noble metals form planar Fabry-Perot half-microcavities. Depositing Au nanoparticles on top of these microcavities forms previously unidentified angle- and polarization-sensitive nanoresonator modes that are tightly laterally confined by the nanoparticle. Comparing dark-field scattering with reflection spectroscopies shows plasmonic and Fabry-Perot-like enhancements magnify subtle interference contributions, which lead to unexpected redshifts in the dark-field spectra, explained by the presence of these new modes.

QSAR models for biocides: The example of the prediction of Daphnia magna acute toxicity.

Biocides are multi-component products used to control undesired and harmful organisms able to affect human or animal health or to damage natural and manufactured products. Because of their widespread use, aquatic and terrestrial ecosystems could be contaminated by biocides. The environmental impact of biocides is evaluated through eco-toxicological studies with model organisms of terrestrial and aquatic ecosystems. We focused on the development of in silico models for the evaluation of the acute toxicity (EC50) of a set of biocides collected from different sources on the freshwater crustacean Daphnia magna, one of the most widely used model organisms in aquatic toxicology. Toxicological data specific for biocides are limited, so we developed three models for daphnid toxicity using different strategies (linear regression, random forest, Monte Carlo (CORAL)) to overcome this limitation. All models gave satisfactory results in our datasets: the random forest model showed the best results with a determination coefficient r2 = 0.97 and 0.89, respectively, for the training (TS) and the validation sets (VS) while linear regression model and the CORAL model had similar but lower performance (r2 = 0.83 and 0.75, respectively, for TS and VS in the linear regression model and r2 = 0.74 and 0.75 for the CORAL model).

TRPML1 links lysosomal calcium to autophagosome biogenesis through the activation of the CaMKKß/VPS34 pathway.

The lysosomal calcium channel TRPML1, whose mutations cause the lysosomal storage disorder (LSD) mucolipidosis type IV (MLIV), contributes to upregulate autophagic genes by inducing the nuclear translocation of the transcription factor EB (TFEB). Here we show that TRPML1 activation also induces autophagic vesicle (AV) biogenesis through the generation of phosphatidylinositol 3-phosphate (PI3P) and the recruitment of essential PI3P-binding proteins to the nascent phagophore in a TFEB-independent manner. Thus, TRPML1 activation of phagophore formation requires the calcium-dependent kinase CaMKKß and AMPK, which increase the activation of ULK1 and VPS34 autophagic protein complexes. Consistently, cells from MLIV patients show a reduced recruitment of PI3P-binding proteins to the phagophore during autophagy induction, suggesting that altered AV biogenesis is part of the pathological features of this disease. Together, we show that TRPML1 is a multistep regulator of autophagy that may be targeted for therapeutic purposes to treat LSDs and other autophagic disorders.

Clinical applications of Bioactive glass S53P4 in bone infections: a systematic review.

OBJECTIVE: Treatment of osteomyelitis, in of itself, is challenging but is further complicated by attendant bone infections. The management of bone infection, and bone rebuilding may be assisted by the use of bioactive glasses (BAGs) which have antimicrobial and osteo-stimulative proprieties. However, this clinical application and potential complications associated with BAGs (e.g., BAG S53P4), are poorly defined. The aim of this study is to review the results of clinical research using BAG S53P4 in the treatment of human bone infections. MATERIALS AND METHODS: This review was conducted in accordance with the PRISMA statement. The following databases were searched: PubMed, Cochrane Library, EMBASE, and Scopus. We examined electronic databases from 1965 to 2018 using different combinations of the following keywords: "S53P4", "BonAlive", "infection" and "osteomyelitis". RESULTS: Eight studies were considered which included a total of 276 cases (mean age of 49.3 years). The most frequent pathogen isolated was Staphylococcus aureus. A one-step surgical procedure was performed in 89.85% of cases. Good clinical and radiological outcomes were reported with a mean follow-up of 21.5 months. Twenty-three complications (8.3% of total cases) were described with the recurrence of bone infection as the most common complication (6.15% of total cases). CONCLUSIONS: BAG-S53P4 seems to be a useful bone filler in orthopaedic surgery for osteomyelitis treatment. The attendant clinical results and associated rate of complications associated with BAG S53P4 use are comparable with those of other techniques in the short term. However, long-term follow-up studies are required in order to confirm the longevity of this treatment.

Diagnostic role of echocardiography in patients admitted to the emergency room with suspect no-ST-segment elevation acute myocardial infarction.

OBJECTIVE: We investigated whether echocardiography may help identify, among patients admitted with a suspect of non-ST-segment elevation acute myocardial infarction (NSTEMI), those with athero-thrombotic coronary artery disease (CAD). PATIENTS AND METHODS: We studied consecutive patients admitted with a clinical suspect of first NSTEMI. Echocardiography was assessed within 24 hours from admission. Patients were divided into two groups, according to the results of coronary angiography: 1) patients with obstructive stenosis (≥ 50%) and/or images of thrombosis in one or more coronary arteries (CAD group); 2) patients with no evidence of obstructive coronary arteries (NOCAD group). RESULTS: Of 101 patients enrolled in the study, 53 (52.5%) showed obstructive CAD and 48 (47.5%) NOCAD. At echocardiographic examination, regional wall motion abnormalities were found in 52.8% of patients in the CAD group and 43.7% in the NOCAD group (p=0.43). Left ventricle ejection fraction was 56.4±6.8 vs. 54.7±9.8% (p=0.30) and wall motion score index was 1.16±0.26 vs. 1.21±0.32 (p=0.39) in the two groups, respectively. A multivariable logistic regression independent predictors of obstructive CAD included age, male gender, typical angina, diabetes and hypertension. CONCLUSIONS: Our data showed that, in patients with acute chest pain and increased serum troponin T concentration, routine standard echocardiography does not significantly improve the diagnostic accuracy for the presence of obstructive CAD.

Cleaning interfaces in layered materials heterostructures.

Heterostructures formed by stacking layered materials require atomically clean interfaces. However, contaminants are usually trapped between the layers, aggregating into randomly located blisters, incompatible with scalable fabrication processes. Here we report a process to remove blisters from fully formed heterostructures. Our method is over an order of magnitude faster than those previously reported and allows multiple interfaces to be cleaned simultaneously. We fabricate blister-free regions of graphene encapsulated in hexagonal boron nitride with an area ~ 5000 µm2, achieving mobilities up to 180,000 cm2 V-1 s-1 at room temperature, and 1.8 × 106 cm2 V-1 s-1 at 9 K. We also assemble heterostructures using graphene intentionally exposed to polymers and solvents. After cleaning, these samples reach similar mobilities. This demonstrates that exposure of graphene to process-related contaminants is compatible with the realization of high mobility samples, paving the way to the development of wafer-scale processes for the integration of layered materials in (opto)electronic devices.

Long Spin Diffusion Length in Few-Layer Graphene Flakes.

We report a spin valve with a few-layer graphene flake bridging highly spin-polarized La_{0.67}Sr_{0.33}MnO_{3} electrodes, whose surfaces are kept clean during lithographic definition. Sharp magnetic switching is verified using photoemission electron microscopy with x-ray magnetic circular dichroism contrast. A naturally occurring high interfacial resistance ∼12 MΩ facilitates spin injection, and a large resistive switching (0.8 MΩ at 10 K) implies a 70-130 µm spin diffusion length that exceeds previous values obtained with sharp-switching electrodes.

Assessment of in silico models for acute aquatic toxicity towards fish under REACH regulation.

We evaluated the performance of eight QSAR in silico modelling packages (ACD/ToxSuite™, ADMET Predictor™, DEMETRA, ECOSAR, TerraQSAR™, Toxicity Estimation Software Tool, TOPKAT™ and VEGA) for acute aquatic toxicity towards two species of fish: Fathead Minnow and Rainbow Trout. For the Fathead Minnow, we compared model predictions for 567 substances with the corresponding experimental values for 96-h median lethal concentrations (LC50). Some models gave good results, with r2 up to 0.85. We also classified the predictions of all the models into four toxicity classes defined by CLP. This permitted us to assess other parameters, such as the percentage of correct predictions for each class. Then we used a set of 351 substances with toxicity data towards Rainbow Trout (96-h LC50). In this case the predictability was unacceptable for all the in silico models. The calculated r2 gave poor correlations (≤0.53). Another analysis was performed according to chemical classes and for mode of action. In the first case, all the classes show a high percentage of correct predictions, in the second case only narcotics and polar narcotics were predicted with good confidence. The results indicate the possibility of using in silico methods to estimate aquatic toxicity within REACH regulation, after careful evaluation.

Anomalous low-temperature Coulomb drag in graphene-GaAs heterostructures.

Vertical heterostructures combining different layered materials offer novel opportunities for applications and fundamental studies. Here we report a new class of heterostructures comprising a single-layer (or bilayer) graphene in close proximity to a quantum well created in GaAs and supporting a high-mobility two-dimensional electron gas. In our devices, graphene is naturally hole-doped, thereby allowing for the investigation of electron-hole interactions. We focus on the Coulomb drag transport measurements, which are sensitive to many-body effects, and find that the Coulomb drag resistivity significantly increases for temperatures <5-10 K. The low-temperature data follow a logarithmic law, therefore displaying a notable departure from the ordinary quadratic temperature dependence expected in a weakly correlated Fermi-liquid. This anomalous behaviour is consistent with the onset of strong interlayer correlations. Our heterostructures represent a new platform for the creation of coherent circuits and topologically protected quantum bits.

Comparison of in silico models for prediction of Daphnia magna acute toxicity.

Eight in silico modelling packages were evaluated and compared for the prediction of Daphnia magna acute toxicity from the viewpoint of the European legislation on chemicals, REACH. We tested the following models: Discovery Studio (DS) TOPKAT, ACD/Tox Suite, ADMET Predictor, ECOSAR (Ecological Structure Activity Relationships), TerraQSAR, T.E.S.T. (Toxicity Estimation Software Tool) and two models implemented in VEGA on 480 industrial compounds for 48-h median lethal concentrations (LC50) to D. magna, matching them with experimental values. The quality of the estimates was compared using a standard statistical review and an additional classification approach in which the hazard predictions were grouped using well-defined regulatory criteria. The regression parameters, correlation coefficient being the most influential, showed that four models (ADMET Predictor, DS TOPKAT, TerraQSAR and VEGA DEMETRA) had similar reliability. These performed better than the others, but the coefficient of determination was still low (r2 around 0.6), considering that at least half the predicted compounds were inside the training sets. Additionally, we grouped the results in four defined toxicity classes. TerraQSAR™ gave 60% of correct classifications, followed by DS TOPKAT, ADMET Predictor™ and VEGA DEMETRA, with 56%, 54% and 48%, respectively. These results highlight the challenges associated with developing reliable and easily applied acceptability criteria for the regulatory use of QSAR models to D. magna acute toxicity.

Ultrafast collinear scattering and carrier multiplication in graphene.

Graphene is emerging as a viable alternative to conventional optoelectronic, plasmonic and nanophotonic materials. The interaction of light with charge carriers creates an out-of-equilibrium distribution, which relaxes on an ultrafast timescale to a hot Fermi-Dirac distribution, that subsequently cools emitting phonons. Although the slower relaxation mechanisms have been extensively investigated, the initial stages still pose a challenge. Experimentally, they defy the resolution of most pump-probe setups, due to the extremely fast sub-100 fs carrier dynamics. Theoretically, massless Dirac fermions represent a novel many-body problem, fundamentally different from Schrödinger fermions. Here we combine pump-probe spectroscopy with a microscopic theory to investigate electron-electron interactions during the early stages of relaxation. We identify the mechanisms controlling the ultrafast dynamics, in particular the role of collinear scattering. This gives rise to Auger processes, including charge multiplication, which is key in photovoltage generation and photodetectors.

Measurement of filling-factor-dependent magnetophonon resonances in graphene using Raman spectroscopy.

We perform polarization-resolved Raman spectroscopy on graphene in magnetic fields up to 45 T. This reveals a filling-factor-dependent, multicomponent anticrossing structure of the Raman G peak, resulting from magnetophonon resonances between magnetoexcitons and E(2g) phonons. This is explained with a model of Raman scattering taking into account the effects of spatially inhomogeneous carrier densities and strain. Random fluctuations of strain-induced pseudomagnetic fields lead to increased scattering intensity inside the anticrossing gap, consistent with the experiments.

Electroluminescence in single layer MoS2.

We detect electroluminescence in single layer molybdenum disulfide (MoS2) field-effect transistors built on transparent glass substrates. By comparing the absorption, photoluminescence, and electroluminescence of the same MoS2 layer, we find that they all involve the same excited state at 1.8 eV. The electroluminescence has pronounced threshold behavior and is localized at the contacts. The results show that single layer MoS2, a direct band gap semiconductor, could be promising for novel optoelectronic devices, such as two-dimensional light detectors and emitters.

Graphene field-effect transistors as room-temperature terahertz detectors.

The unique optoelectronic properties of graphene make it an ideal platform for a variety of photonic applications, including fast photodetectors, transparent electrodes in displays and photovoltaic modules, optical modulators, plasmonic devices, microcavities, and ultra-fast lasers. Owing to its high carrier mobility, gapless spectrum and frequency-independent absorption, graphene is a very promising material for the development of detectors and modulators operating in the terahertz region of the electromagnetic spectrum (wavelengths in the hundreds of micrometres), still severely lacking in terms of solid-state devices. Here we demonstrate terahertz detectors based on antenna-coupled graphene field-effect transistors. These exploit the nonlinear response to the oscillating radiation field at the gate electrode, with contributions of thermoelectric and photoconductive origin. We demonstrate room temperature operation at 0.3 THz, showing that our devices can already be used in realistic settings, enabling large-area, fast imaging of macroscopic samples.