Pumping stations play an important role in flood mitigation in metropolitan areas. The existing sewerage systems, however, are facing a great challenge of fast rising peak flow resulting from ...urbanization and climate change. It is imperative to construct an efficient and accurate operating prediction model for pumping stations to simulate the drainage mechanism for discharging the rainwater in advance. In this study, we propose two rule-based fuzzy neural networks, adaptive neuro-fuzzy inference system (ANFIS) and counterpropagation fuzzy neural network for on-line predicting of the number of open and closed pumps of a pivotal pumping station in Taipei city up to a lead time of 20 min. The performance of ANFIS outperforms that of CFNN in terms of model efficiency, accuracy, and correctness. Furthermore, the results not only show the predictive water levels do contribute to the successfully operating pumping stations but also demonstrate the applicability and reliability of ANFIS in automatically controlling the urban sewerage systems.
Elevated body mass index (BMI) is heritable and associated with many health conditions that impact morbidity and mortality. The study of the genetic association of BMI across a broad range of common ...disease conditions offers the opportunity to extend current knowledge regarding the breadth and depth of adiposity-related diseases. We identify 906 (364 novel) and 41 (6 novel) genome-wide significant loci for BMI among participants of European (N~1.1 million) and African (N~100,000) ancestry, respectively. Using a BMI genetic risk score including 2446 variants, 316 diagnoses are associated in the Million Veteran Program, with 96.5% showing increased risk. A co-morbidity network analysis reveals seven disease communities containing multiple interconnected diseases associated with BMI as well as extensive connections across communities. Mendelian randomization analysis confirms numerous phenotypes across a breadth of organ systems, including conditions of the circulatory (heart failure, ischemic heart disease, atrial fibrillation), genitourinary (chronic renal failure), respiratory (respiratory failure, asthma), musculoskeletal and dermatologic systems that are deeply interconnected within and across the disease communities. This work shows that the complex genetic architecture of BMI associates with a broad range of major health conditions, supporting the need for comprehensive approaches to prevent and treat obesity.
Though immensely successful, the standard model of particle physics does not offer any explanation as to why our Universe contains so much more matter than antimatter. A key to a dynamically ...generated matter-antimatter asymmetry is the existence of processes that violate the combined charge conjugation and parity (CP) symmetry
. As such, precision tests of CP symmetry may be used to search for physics beyond the standard model. However, hadrons decay through an interplay of strong and weak processes, quantified in terms of relative phases between the amplitudes. Although previous experiments constructed CP observables that depend on both strong and weak phases, we present an approach where sequential two-body decays of entangled multi-strange baryon-antibaryon pairs provide a separation between these phases. Our method, exploiting spin entanglement between the double-strange Ξ
baryon and its antiparticle
Formula: see text, has enabled a direct determination of the weak-phase difference, (ξ
- ξ
) = (1.2 ± 3.4 ± 0.8) × 10
rad. Furthermore, three independent CP observables can be constructed from our measured parameters. The precision in the estimated parameters for a given data sample size is several orders of magnitude greater than achieved with previous methods
. Finally, we provide an independent measurement of the recently debated Λ decay parameter α
(refs.
). The Formula: see text asymmetry is in agreement with and compatible in precision to the most precise previous measurement
.
Rearranged during transfection (RET) gene fusions are a validated target in non-small-cell lung cancer (NSCLC). RET-selective inhibitors selpercatinib (LOXO-292) and pralsetinib (BLU-667) recently ...demonstrated favorable antitumor activity and safety profiles in advanced RET fusion-positive NSCLC, and both have received approval by the US Food and Drug Administration for this indication. Insights into mechanisms of resistance to selective RET inhibitors remain limited.
This study was performed at five institutions. Tissue and/or cell-free DNA was obtained from patients with RET fusion-positive NSCLC after treatment with selpercatinib or pralsetinib and assessed by next-generation sequencing (NGS) or MET FISH.
We analyzed a total of 23 post-treatment tissue and/or plasma biopsies from 18 RET fusion-positive patients who received an RET-selective inhibitor (selpercatinib, n = 10; pralsetinib, n = 7; pralsetinib followed by selpercatinib, n = 1, with biopsy after each inhibitor). Three cases had paired tissue and plasma samples, of which one also had two serial resistant tissue specimens. The median progression-free survival on RET inhibitors was 6.3 months 95% confidence interval 3.6–10.8 months. Acquired RET mutations were identified in two cases (10%), both affecting the RET G810 residue in the kinase solvent front. Three resistant cases (15%) harbored acquired MET amplification without concurrent RET resistance mutations, and one specimen had acquired KRAS amplification. No other canonical driver alterations were identified by NGS. Among 16 resistant tumor specimens, none had evidence of squamous or small-cell histologic transformation.
RET solvent front mutations are a recurrent mechanism of RET inhibitor resistance, although they occurred at a relatively low frequency. The majority of resistance to selective RET inhibition may be driven by RET-independent resistance such as acquired MET or KRAS amplification. Next-generation RET inhibitors with potency against RET resistance mutations and combination strategies are needed to effectively overcome resistance in these patients.
•Resistance is a major challenge in RET fusion-positive lung cancer treated with RET tyrosine kinase inhibitors (TKIs).•RET mutations involving the solvent front residue G810 are a recurrent yet infrequent mechanism of resistance to RET TKIs.•The majority of resistance to selective RET inhibition is driven by RET-independent resistance, such as MET amplification.•RET TKIs with potency against RET solvent front mutations and combination strategies are needed to overcome resistance.
Abstract Objective To test in a prospective randomized study the hypothesis that use of thromboelastography (TEG) decreases blood transfusion during major surgery. Material and Methods Twenty-eight ...patients undergoing orthotopic liver transplantation were recruited over 2 years. Patients were randomized into 2 groups: those monitored during surgery using point-of-care TEG analysis, and those monitored using standard laboratory measures of blood coagulation. Specific trigger points for transfusion were established in each group. Results In patients monitored via TEG, significantly less fresh-frozen plasma was used (mean SD, 12.8 7.0 units vs 21.5 12.7 units). There was a trend toward less blood loss in the TEG-monitored patients; however, the difference was not significant. There were no differences in total fluid administration and 3-year survival. Conclusion Thromboelastography-guided transfusion decreases transfusion of fresh- frozen plasma in patients undergoing orthotopic liver transplantation, but does not affect 3-year survival.
We have fabricated graphene-silicon Schottky diodes by depositing mechanically exfoliated graphene on top of silicon substrates. The resulting current–voltage characteristics exhibit rectifying diode ...behavior with a barrier energy of 0.41 eV on n-type silicon and 0.45 eV on p-type silicon at the room temperature. The I–V characteristics measured at 100, 300, and 400 K indicate that temperature strongly influences the ideality factor of graphene–silicon Schottky diodes. The ideality factor, however, does not depend strongly on the number of graphene layers. The optical transparency of the thin graphene layer allows the underlying silicon substrate to absorb incident laser light and generate a photocurrent. Spatially resolved photocurrent measurements reveal the importance of inhomogeneity and series resistance in the devices.
We present X-ray timing results of the new black hole candidate MAXI J1535−571 during its 2017 outburst from Hard X-ray Modulation Telescope (Insight-HXMT) observations taken from 2017 September 6 to ...23. Following the definitions given by Belloni, we find that the source exhibits transitions from the low/hard state to the hard intermediate state, and eventually to the soft intermediate state. Quasi-periodic oscillations (QPOs) are found in the intermediate states, which suggest different types of QPOs. With the large effective area of Insight-HXMT at high energies, we are able to present the energy dependence of the QPO amplitude and centroid frequency up to 100 keV, which has rarely been explored by previous satellites. We also find that the phase lag at the type-C QPOs centroid frequency is negative (soft lag) and strongly correlated with the centroid frequency. Assuming a geometrical origin of type-C QPOs, the source is consistent with being a high-inclination system.
Metastatic basal cell carcinoma (mBCC) is a rare condition with no effective second-line treatment options. Cemiplimab is an immune checkpoint inhibitor that blocks the binding of programmed cell ...death-1 (PD-1) to its ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). Here, we present the final analysis of cemiplimab in patients with mBCC after first-line hedgehog pathway inhibitor (HHI) treatment (NCT03132636).
In this open-label, single-arm, phase II study, adults with mBCC and Eastern Cooperative Oncology Group performance status ≤1, post-HHI treatment, received cemiplimab 350 mg intravenously every 3 weeks for ≤93 weeks or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by independent central review (ICR). Duration of response (DOR) was a key secondary endpoint. Other secondary endpoints were ORR per investigator assessment, progression-free survival (PFS), overall survival (OS), complete response rate, safety, and tolerability.
Fifty-four patients were enrolled: 70% were male and the median age of patients was 64 interquartile range (IQR) 57.0-73.0 years. The median duration of follow-up was 8 months (IQR 4-21 months). The ORR per ICR was 22% 95% confidence interval (CI) 12% to 36%, with 2 complete responses and 10 partial responses. Among responders, the median time to response per ICR was 3 months (IQR 2-7 months). The estimated median DOR per ICR was not reached 95% CI 10 months–not evaluable (NE). The disease control rate was 63% (95% CI 49% to 76%) per ICR and 70% (95% CI 56% to 82%) per investigator assessment. The median PFS per ICR was 10 months (95% CI 4-16 months); the median OS was 50 months (95% CI 28 months-NE). The most common treatment-emergent adverse events were fatigue 23 (43%) and diarrhoea 20 (37%). There were no treatment-related deaths.
Cemiplimab demonstrated clinically meaningful antitumour activity, including durable responses, and an acceptable safety profile in patients with mBCC who had disease progression on or intolerance to HHI therapy.
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•There is no standard second-line treatment for patients with mBCC who progress on or are intolerant to HHIs.•In this phase II study (NCT03132636), cemiplimab showed an ORR of 22% and acceptable safety in patients with mBCC.•This is the first study to show activity of a systemic therapy in mBCC after HHI use.•The results support the use of cemiplimab in patients with mBCC who progress on or are intolerant to HHIs.•Cemiplimab addresses an unmet need by providing a treatment option for patients with mBCC following first-line HHI therapy.
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