Towards global neural network abstractions with locally-exact reconstruction.

Neural networks are a powerful class of non-linear functions. However, their black-box nature makes it difficult to explain their behaviour and certify their safety. Abstraction techniques address this challenge by transforming the neural network into a simpler, over-approximated function. Unfortunately, existing abstraction techniques are slack, which limits their applicability to small local regions of the input domain. In this paper, we propose Global Interval Neural Network Abstractions with Center-Exact Reconstruction (GINNACER). Our novel abstraction technique produces sound over-approximation bounds over the whole input domain while guaranteeing exact reconstructions for any given local input. Our experiments show that GINNACER is several orders of magnitude tighter than state-of-the-art global abstraction techniques, while being competitive with local ones.

Formal synthesis of non-fragile state-feedback digital controllers considering performance requirements for step response.

This work describes an approach for synthesizing state-feedback controllers for discrete-time systems, taking into account performance aspects. The proposed methodology is based on counterexample-guided inductive synthesis (CEGIS), producing safe controllers based on step response performance requirements, such as settling time and maximum-overshoot. Controller candidates are generated through constrained optimization based on genetic algorithms. Each iteration that does not satisfy the initial system requirements is learned as a failed result and then used in another attempt. During the verification phase, it is considered the controller fragility to ensure deployable implementations. Such an approach assists the discrete-time control system design since weaknesses occur during implementation on digital platforms, where systems that meet design requirements are employed. The proposed method is implemented in DSVerifier, a tool that uses bounded (and unbounded) model checking based on satisfiability modulo theories. Experimental results showed that our approach is practical and sound regarding the synthesis of discrete state-feedback control systems that present performance requirements. It considers finite word-length effects, unlike other methods that routinely ignore them.

Efficacy, safety, and immunogenicity of a biosimilar recombinant human follicle-stimulating hormone (Folitime®) vs. Gonal-f® in women undergoing ovarian stimulation for IVF: A randomized, multicenter, evaluator-blinded, non-inferiority study.

OBJECTIVE: We compared the efficacy, safety, and immunogenicity of a biosimilar recombinant human follicle-stimulating hormone (Folitime®) with Gonal-f® in women undergoing ovarian stimulation for in-vitro fertilization. METHODS: This randomized (1:1), multicenter, assessor-blinded, non-inferiority, parallel-group, controlled study conducted at four infertility clinics in Argentina included infertile normogonadotropic women with ages below 39 years, with menstrual cycles of 25/35 days and a body mass index of 18-32 kg/m2 undergoing assisted reproductive technology therapy. During a 5-day fixed-dose phase, the women received 225 IU/day of Folitime® (n=49) or Gonal-f® (n=44), followed by a dose-adaptation phase up to a maximum of 450 IU/day. The non-inferiority margin for oocyte retrieval was estimated at -4 oocytes (one-sided test). Immunogenicity was investigated on days 9 and 84, following the start of treatment. RESULTS: The mean number of oocytes retrieved was 12.6 (SD 7.4) in the Folitime® group and 13.4 (SD 6.9) in the Gonal-f® group (per protocol analysis, 95% confidence interval = -3.82; 2.33), within the non-inferiority margin. Pregnancy rate at week 10 was 24.4% among subjects treated with Folitime® and 19.5% for subjects treated with Gonal-f®. One serious adverse drug reaction-late mild ovarian hyper stimulation syndrome and deep venous thrombosis in the left deep jugular vein-occurred in a subject treated with Folitime®. None of the subjects developed antibodies against the study drugs. There were no unexpected safety findings. CONCLUSIONS: Folitime® is non-inferior to Gonal-f®, with no differences in the safety profile and has been approved as a biosimilar in Argentina.

Co-exposure to nTiO2 impairs arsenic metabolism and affects antioxidant capacity in the marine shrimp Litopenaeus vannamei.

Aquatic animals are vulnerable to arsenic (As) toxicity. However, rarely does a contaminant occur alone in the aquatic environment. For this reason, this study was conducted to evaluate whether titanium dioxide nanoparticles (nTiO2) can interfere with the effects induced by As in Litopenaeus vannamei. Arsenic accumulation and metabolic capacity; expression and enzymatic activity of GSTΩ (glutathione-S-transferase omega isoform); antioxidant responses such as GSH, GR, and GST (reduced glutathione levels, glutathione reductase, and glutathione-S-transferase activity, respectively); and lipid peroxidation in the gills and hepatopancreas of shrimp were evaluated. The results are summarized as follows: (1) higher accumulation of As occurred in both tissues after exposure to As alone; (2) co-exposure to nTiO2 affected the capacity to metabolize As; (3) GSTΩ gene expression was not modified, but its activity was decreased by co-exposure to both contaminants; (4) As alone increased the GSH levels in the hepatopancreas, and co-exposure to nTiO2 reduced these levels in both tissues; (5) a decrease in the GST activity in the gills occurred with all treatments; (6) in the gills, GR activity was increased by As, and nTiO2 reversed this increase, whereas in the hepatopancreas co-exposure inhibited enzyme activity; (7) only in the hepatopancreas lipid damage was observed when animals were exposed to As or nTiO2 but not in co-exposure. The results showed that the As induces toxic effects in both tissues of shrimp and that co-exposure to nTiO2 can potentiate these effects and decrease the capacity to metabolize As, favoring the accumulation of more toxic compounds.

Efficacy, Safety, and Immunogenicity of Biosimilar Etanercept (Enerceptan) Versus Its Original Form in Combination With Methotrexate in Patients With Rheumatoid Arthritis: A Randomized, Multicenter, Evaluator-Blinded, Noninferiority Study.

BACKGROUND: Enerceptan (EtaBS) has been developed as a proposed biosimilar of etanercept. METHODS: This randomized, multicenter, evaluator-blinded, noninferiority study conducted in Argentina included adults with active, moderate, and severe rheumatoid arthritis with inadequate response to methotrexate. Subjects were randomly assigned to 32 weeks treatment with EtaBS (n = 99) or etanercept (n = 51) at a weekly 50-mg dose administered subcutaneously. Patients were categorized according to prior use of biologic disease-modifying antirheumatic drugs and concomitant use of steroids. The primary efficacy endpoint was ACR20 response rate at week 32. Safety, immunogenicity, and steady-state concentration of both drugs were evaluated. The noninferiority margin for ACR20 was estimated at 12%. RESULTS: In the per-protocol population, 85 subjects (92.4%) treated with EtaBS and 44 subjects (93.6%) treated with etanercept achieved ACR20 (difference, -1.2%; 95% confidence interval, -10.1% to 7.6%). Frequent adverse drug reactions occurred in 34.3% and 38% of subjects treated with EtaBS and etanercept, respectively. The most common reaction was upper respiratory tract infection. Six and 3 serious adverse events occurred in 4 and 3 subjects treated with EtaBS and etanercept, respectively. Injection site reactions occurred in 67.7% and 66.0% of subjects treated with EtaBS and etanercept, respectively. Two subjects treated with EtaBS and 1 subject treated with etanercept developed antibodies by week 32. CONCLUSIONS: Efficacy outcomes for EtaBS were noninferior to original etanercept in patients with moderate-to-severe rheumatoid arthritis with inadequate response to methotrexate. Safety and immunogenicity results were comparable between the two. This study is a major step toward improving access to biologics in Latin America.

Automated formal synthesis of provably safe digital controllers for continuous plants.

We present a sound and automated approach to synthesizing safe, digital controllers for physical plants represented as time-invariant models. Models are linear differential equations with inputs, evolving over a continuous state space. The synthesis precisely accounts for the effects of finite-precision arithmetic introduced by the controller. The approach uses counterexample-guided inductive synthesis: an inductive generalization phase produces a controller that is known to stabilize the model but that may not be safe for all initial conditions of the model. Safety is then verified via bounded model checking: if the verification step fails, a counterexample is provided to the inductive generalization, and the process further iterates until a safe controller is obtained. We demonstrate the practical value of this approach by automatically synthesizing safe controllers for physical plant models from the digital control literature.

Evaluation of coexposure to inorganic arsenic and titanium dioxide nanoparticles in the marine shrimp Litopenaeus vannamei.

The acute toxicity of titanium dioxide nanoparticles (nTiO2) that occur concomitantly in the aquatic environment with other contaminants such as arsenic (As) is little known in crustaceans. The objective of the present study is to evaluate whether coexposure to nTiO2 can influence the accumulation, metabolism, and oxidative stress parameters induced by arsenic exposure in the gills and hepatopancreas of the shrimp Litopenaeus vannamei. Organisms were exposed by dissolving chemicals in seawater (salinity = 30) at nominal concentrations of 10 µg/L nTiO2 or As(III), dosed alone and in combination. Results showed that there was not a significant accumulation of As in either tissue type, but the coexposure altered the pattern of the metabolism. In the hepatopancreas, no changes were observed in the biochemical response, while in the gills, an increase in the glutamate-cysteine-ligase (GCL) activity was observed upon exposure to As or nTiO2 alone, an increase in the reduced glutathione (GSH) levels was observed upon exposure to As alone, and an increase in the total antioxidant capacity was observed upon exposure to nTiO2 or nTiO2 + As. However, these modulations were not sufficient enough to prevent the lipid damage induced by nTiO2 exposure. Our results suggest that coexposure to nTiO2 and As does not alter the toxicity of this metalloid in the gills and hepatopancreas of L. vannamei but does alter its metabolism, favoring its accumulation of organic As species considered moderately toxic.

Toxicity of fullerene and nanosilver nanomaterials against bacteria associated to the body surface of the estuarine worm Laeonereis acuta (Polychaeta, Nereididae).

This study analyzed the growth and biochemical responses of six bacterial colonies isolated from the mucus of the estuarine polychaeta Laeonereis acuta (Nereididae) after exposure to a water suspension of fullerene (nC60) and nanosilver (nAg) separately (0.01; 0.10; and 1.00 mg/L) and together (0.01; 0.10; and 1.00 mg/L of nanosilver and 1.00 mg/L of fullerene added to each nAg concentration). Exposures were performed in darkness during 24 h and then samples were taken from the worms and inoculated on agar during 24 h to analyze colonies growth. After this the material was analyzed biochemically. Colonies growth (tested by wet biomass weight) was inhibited at 0.01 and 0.10 mg/L of nAg and 0.01 and 0.10 mg/L nAg + constant 1.00 mg/L of nC60 (p < 0.05). Lipid peroxidation damage was significant from the control for the concentrations of 0.01 and 0.10 mg/L of nC60 and glutathione-S-transferase (GST) activity was significantly higher for the concentration of 1.00 mg/L mg/L nAg + constant 1.00 mg/L of nC60 (p < 0.05). Although nC60 did not induced growth inhibition, it triggered lipid peroxidation alone and increased GST activity together with nAg.60 Contrary to nC60, nanosilver inhibited bacterial growth, although the biochemical measurements indicate that this response is not due to reactive oxygen species generation.

Toxicological effects induced by the nanomaterials fullerene and nanosilver in the polychaeta Laeonereis acuta (Nereididae) and in the bacteria communities living at their surface.

Fullerene (nC60) and nanosilver (nAg) are nanomaterials with bactericide properties. The increments in their use raise questions about their potential environmental impacts, including estuarine ones. The polychaete Laeonereis acuta (Nereididae) secretes mucus that is colonized by bacteria communities. We analyzed the antioxidant and oxidative damage responses of anterior, middle and posterior region of L. acuta and bacteria communities after nC60 or nAg exposure during 24 h. Molecular analysis showed a prevalence of Vibrio genera in the communities. Bacteria biomass was lowered in worms exposed to 1.0 mg/L of nAg. nC60 reduced total antioxidant capacity of bacteria from worms exposed to 0.1 mg/L. Worms anterior region presented lower antioxidant capacity after exposure to 1.0 mg nC60/L, and the same was observed in the posterior region of worms exposed to 1.0 mg nAg/L. Lipid peroxidation was reduced in the anterior region of worms exposed to nC60 and the opposite was observed in the posterior region.