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PURPOSE We present 5-year results from CheckMate 227 Part 1, in which nivolumab plus ipilimumab improved overall survival (OS) versus chemotherapy in patients with metastatic non–small-cell lung cancer, regardless of tumor programmed death ligand 1 (PD-L1) status. METHODS Adults with stage IV/recurrent non–small-cell lung cancer without EGFR mutations or ALK alterations and with tumor PD-L1 ≥ 1% or < 1% (n = 1739) were randomly assigned. Patients with tumor PD-L1 ≥ 1% were randomly assigned to first-line nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. Patients with tumor PD-L1 < 1% were randomly assigned to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. End points included exploratory 5-year results for efficacy, safety, and quality of life. RESULTS At a minimum follow-up of 61.3 months, 5-year OS rates were 24% versus 14% for nivolumab plus ipilimumab versus chemotherapy (PD-L1 ≥ 1%) and 19% versus 7% (PD-L1 < 1%). The median duration of response was 24.5 versus 6.7 months (PD-L1 ≥ 1%) and 19.4 versus 4.8 months (PD-L1 < 1%). Among patients surviving 5 years, 66% (PD-L1 ≥ 1%) and 64% (PD-L1 < 1%) were off nivolumab plus ipilimumab without initiating subsequent systemic anticancer treatment by the 5-year time point. Survival benefit continued after nivolumab plus ipilimumab discontinuation because of treatment-related adverse events, with a 5-year OS rate of 39% (combined PD-L1 ≥ 1% and < 1% populations). Quality of life in 5-year survivors treated with nivolumab plus ipilimumab was similar to that in the general US population through the 5-year follow-up. No new safety signals were observed. CONCLUSION With all patients off immunotherapy treatment for ≥ 3 years, nivolumab plus ipilimumab increased 5-year survivorship versus chemotherapy, including long-term, durable clinical benefit regardless of tumor PD-L1 expression. These data support nivolumab plus ipilimumab as an effective first-line treatment for patients with metastatic non–small-cell lung cancer. [Media: see text]

Species belonging to the genus are ubiquitous in nature and many of them form the normal microbial flora in human and animal bodies. A wide variety of infections on mucosal surfaces under certain conditions can be caused due to the sp: A total of 40 isolates of Candida, isolated from vaginal swabs among 476 patients with clinically suspected VVC. Antifungal susceptibility testing done using Fluconazole and Voriconazole. Virulence markers Phospholipase activity, Proteinase activity, Biofilm Productionwere detected by standard methods.: Out of 40 isolates, the following species were isolated, (52.5%) was the most common species isolated from vaginal swabs. The species isolated were (27.5%), (15%), (5%).Intense phospholipase activity was observed in 12 (30%) samples, there was no activity in 18 (45%) samples. A moderate phospholipase activity was observed in 6 (15%) isolates, poor activity in 4 (10%) samples.Proteinase activity was strongly positive in 33 isolates which was identified as and. Strong biofilm formation was observed in 9 isolates, moderate in 8, weak in 11 and negative in 12 isolates. All 40 isolates are susceptible to Fluconazole and Voriconazole.From this study it is observed that and are the major species of causing VVC. Virulence marker analysis such as that for phospholipase, proteinase and biofilm formation will help to analyse the pathogenicity and further research required to elucidate the mechanisms involved in these pathways.

We report enantioselective one-carbon ring expansion of aziridines to make azetidines as a new-to-nature activity of engineered “carbene transferase” enzymes. A laboratory-evolved variant of cytochrome P450_(BM3), P411-AzetS, not only exerts unparalleled stereocontrol (99:1 er) over a [1,2]-Stevens rearrangement but also overrides the inherent reactivity of aziridinium ylides, cheletropic extrusion of olefins, to perform a [1,2]-Stevens rearrangement. By controlling the fate of the highly reactive aziridinium ylide intermediates, these evolvable biocatalysts promote a transformation which cannot currently be performed using other catalyst classes.

Objective: Conventional cervical pedicle screw insertion necessitates extensive paraspinal muscle dissection and retraction in order to achieve the lateral to medial angulation needed to achieve the optimal screw trajectory. Minimally invasive transmuscular approach can comfortably achieve this angulation without significant injury to the midline structures and its musculo-ligamentous attachments.Methods: Minimally invasive cervical pedicle screws were inserted in 4 fresh frozen cadaveric specimens. Pre-procedure and post-procedure CT scans were done to assess the pedicle dimensions, suitability for screw insertion and integrity of the screws. The same technique was applied in a clinical cohort of six cases – 3 cases of traumatic subluxation; one case of traumatic vertebral fracture and 2 cases of infective facet destruction (Koch’s); with successful outcomes.Results: Among the 38 screws in the cadaver specimens, a total of 11 screws (28.9%) had breached the pedicle wall (Lateral wall breach–9; Medial wall breach–2). Of the 9 screws (23.6%) that had a lateral breach into the vertebral canal, 4 (10.5%) each had Grade IIa breach and one (2.6%) had Grade III breach. The mean transverse screw angle in the subset of pedicle screws with no breach was 34.1 whereas it was 22.1 in screws that had lateral breach and 43.6 in those with medial breach. Among the 22 screws inserted in the clinical cohort of 6 cases, 4 screws (18.1%) had breached the pedicle wall. All the identified breaches were in the lateral wall (Grade IIa – 3; Grade IIb–1; Grade III–nil). Conclusion: Minimally invasive subaxial pedicle screw insertion can be utilized in cases where a robust posterior fixation is required, either in isolation or as an adjunct to anterior surgery, in cases where a direct posterior decompression is not warranted. It is a safe and effective approach which minimizes injury to the paraspinal structures and midline attachments.

The most prominent challenges in compressive sensing are seeking the domain where an image is represented sparsely and hence be faithfully recovered to obtain high-quality results. This paper introduces an approach for image compression and recovery. The proposed approach involves two phases: the initial step is the compression phase, and the second step is the recovery phase. Initially, the medical image is subjected to the compression module wherein the self-similarity and the 3-dimensional (3D) transform are adapted for compressing the image. Then, in the recovery phase, the compressive sensing recovery is performed based on structural similarity index measure (SSIM)-based collaborative sparsity measure (S-CoSM), and the novel optimization algorithm, named Taylor-based Sunflower optimization (Taylor-SFO) algorithm. An effective S-CoSM measure is designed by modifying the CoSM using the SSIM metric. The proposed Taylor-SFO will be designed by integrating the Taylor series with the sunflower optimization (SFO) algorithm. The performance of the proposed Taylor-SFO approach is evaluated for matrices SSIM of 0.9412 and peak signal to noise ratio of 57.57 dB.

For this study, functional precoalescence (internally crosslinked) and postcoalescence (crosslinkable) conventional latexes were made using seeded semi-continuous emulsion polymerization. Nanosize polymer latexes with or without crosslinkable functional groups were made using a modified microemulsion copolymerization process. Films cast from conventional and nanosize latex were characterized using specific end use tests and fundamental properties using dynamic mechanical analysis, modulated differential scanning calorimetry, and atomic force microscopy. This study compares conventional and nanosize latex with respect to the effect of the type and level of crosslinking, particle size and distribution on latex film formation and morphology, and end use and fundamental properties. Nanosize latex films in general have superior gloss, solvent resistance, and adhesion but inferior water resistance. Stress–strain Young’s modulus showed an increase as a function of increasing crosslinker level in the nanosize latex films.

Drugs are the critical elements in the health care system. They must be manufactured in the high-quality levels. End product testing by itself does not guarantee of the quality of the product. Quality assurance techniques must be used. In pharmaceutical industry, process validation performs this task, by ensuring that the process does what it purports to do. Validation is one of the important steps in achieving and maintaining the quality of the final product. If each step of production process is validated, we can assure that the final product is of the best quality. This study is intended to demonstrate and standardize the data that should be routinely included in the marketing authorization dossier describing evolution and validation of the manufacturing process and distinguish from the validation data which more properly fall under the remit of GMP inspection. During the study of critical process variables of sucralfate oral suspension were validated to demonstrate consistency of manufacturing process to produce the produce the product of desired quality. The validation studies were conducted which were intended for the use of commercial purpose so this validation study is concurrent type. All the in-process variables and finished product characteristics were monitored; the statistical analysis of data was carried out. Further from the results, it is inferred that the manufacturing process of sucralfate oral suspension was validated.

Results of our research on crosslinked latexes and polymer nanoparticles will be reported. Goals of this long-term program have been: comparing precoalescence and post-coalescence crosslinking; synthesizing polymer nanoparticle latexes (~ 20 to 25 nm) from a variety of acrylic monomers, including crosslinking and crosslinkable monomers; and blending nanoparticle latexes with compatible conventional (~ 120 to 130 nm) latexes and understanding their effects on film formation and on fundamental and empirical film properties. As we previously reported, blending conventional and nanolatexes in an 85/15 ratio (w/w of polymer solids) effects substantial changes of fundamental film properties. Best results included reducing minimum filming temperatures (MFT) while increasing Young’s moduli by factors of two to 17. Substantial improvements in empirical film properties such as gloss (up to 97 at 60°), hardness (increased by 2–5 pencils), block resistance, and adhesion to aluminum were also found. The previous report covered only a single blend ratio. Here we report studies of blends with ratios of conventional to nanoparticle latexes ranging from 92.5/7.5 to 30/70 (w/w). As before, the latexes and nanolatexes are BMA/BA copolymers with 0–4 wt.% of 1,3-butylene glycol dimethacrylate (precoalescence crosslinker) and 0–5 wt.% of diacetone acrylamide (for post-coalescence crosslinking with adipic dihydrazide). Films cast from these blends are subjected to everyday empirical coatings tests and are characterized using instrumental tests including dynamic mechanical analysis (DMA) and modulated differential scanning calorimetry (MDSC). Film formation and film morphology are studied using atomic force microscopy (AFM). The results confirm that blending nanoparticles at ratios up to 50/50 (w/w of polymer solids) can substantially improve certain properties of conventional latex films. For many properties, the optimum ratio is around 85/15 conventional/nano; a 92.5/7.5 ratio also affords substantial improvements. As coatings, the blends have near-zero VOC.

Immunotherapeutic manipulation of the antitumor immune response offers an attractive strategy to target genomic instability in cancer. A subset of tumor-specific somatic mutations can be translated into immunogenic and HLA-bound epitopes called neoantigens, which can induce the activation of helper and cytotoxic T lymphocytes. However, cancer immunoediting and immunosuppressive mechanisms often allow tumors to evade immune recognition. Recent evidence also suggests that the tumor neoantigen landscape extends beyond epitopes originating from nonsynonymous single-nucleotide variants in the coding exome. Here we review emerging approaches for identifying, prioritizing, and immunologically targeting personalized neoantigens using polyvalent cancer vaccines and T-cell receptor gene therapy. Significance: Several major challenges currently impede the clinical efficacy of neoantigen-directed immunotherapy, such as the relative infrequency of immunogenic neoantigens, suboptimal potency and priming of de novo tumor-specific T cells, and tumor cell–intrinsic and –extrinsic mechanisms of immune evasion. A deeper understanding of these biological barriers could help facilitate the development of effective and durable immunotherapy for any type of cancer, including immunologically “cold” tumors that are otherwise therapeutically resistant.

Traditional didactic lectures is one of the commonly followed method of teaching learning in most of the medical colleges to teach undergraduate medical students till now. This method is a passive method of learning in which teacher will be talking and students has to listen, this type of teaching is dominating our MBBS curriculum. Students find these lecture classes very boring. Also after the implementation of new competency based medical education (CBME) by Medical council of India, medical education for undegraduates needs lots of recent improvements to provide satisfactory changing demands in medical practice. Physiology lecture classes was restructured with introduction of pre and post-test, knowledge before and after the lecture were obtained by comparing the test scores before and after to evaluate the enhancement of learning after the lectures. Also feedback regarding the introduction of pre & post -test from the students were taken for evaluating the effectiveness of lectures with the introduction of the test before and after the lecture classes. 1. To provide Pre-test & Post-test questions before lecture and after lecture classes on the topic; 2. To evaluate the enhancement of Learning after lecture based on post-test scores; 3. To evaluate the effectiveness of physiology lecture among students in relation to feedback obtained. The present study was conducted on 150 First year M.B.B.S during Physiology lectures, after obtaining Ethical clearance from the Instituitional Ethical Committee, Adichunchanagiri Institute of Medical Sciences, Adichunchanagiri university.I MBBS(150) students after obtaining consent for voluntary participation were asked to take the pre-test question s containing 20 multiple choice questions on topic “Cardiac cycle & Cardiac output” and the same 20 multiple choice questions were provided to the students at the end of the four hour lecture classes on the topic. Performance of the students with the salient concepts on the topic were assessed by the pre-test & post-test scores. Feedback from all students were obtained regarding perception of students on the use of pre and post-test in learning the salient concepts in physiology were obtained by administering a questionnaire.Pre-test score of the students obtained before the start of the lecture was 5.57±1.29 and the Post-test score of the students obtained after the end of four hour lecture classes on the topic was 15.26±9.7 (p < 0.0001) this was highly significant. Feedback obtained from the students was indicative of that most of the students felt that test was very interesting, innovative, they could focus more on the lecture classes, it helped them to learn the salient concepts in physiology, also most of them felt competitive aspect of the test contributed to their effectiveness and most of them wanted it during lectures. From the present study we would like to conclude that introducing pre and post-test in lectures could enhance learning among students. Also we could evaluate the effectiveness of lectures by introducing pre and post – test based on feedback obtained from the students.

Deep operator learning has emerged as a promising tool for reduced-order modelling and PDE model discovery. Leveraging the expressive power of deep neural networks, especially in high dimensions, such methods learn the mapping between functional state variables. While proposed methods have assumed noise only in the dependent variables, experimental and numerical data for operator learning typically exhibit noise in the independent variables as well, since both variables represent signals that are subject to measurement error. In regression on scalar data, failure to account for noisy independent variables can lead to biased parameter estimates. With noisy independent variables, linear models fitted via ordinary least squares (OLS) will show attenuation bias, wherein the slope will be underestimated. In this work, we derive an analogue of attenuation bias for linear operator regression with white noise in both the independent and dependent variables. In the nonlinear setting, we computationally demonstrate underprediction of the action of the Burgers operator in the presence of noise in the independent variable. We propose error-in-variables (EiV) models for two operator regression methods, MOR-Physics and DeepONet, and demonstrate that these new models reduce bias in the presence of noisy independent variables for a variety of operator learning problems. Considering the Burgers operator in 1D and 2D, we demonstrate that EiV operator learning robustly recovers operators in high-noise regimes that defeat OLS operator learning. We also introduce an EiV model for time-evolving PDE discovery and show that OLS and EiV perform similarly in learning the Kuramoto-Sivashinsky evolution operator from corrupted data, suggesting that the effect of bias in OLS operator learning depends on the regularity of the target operator., Comment: 23 pages, 10 figures

Introduction: The emergence and global spread of carbapenem-resistant E. coli is of great concern to the health care facilities due to high rates of morbidity and mortality associated with them. It is necessary to know its epidemiology and the resistant pattern in a geographical area to formulate a antibiotic stewardship policy. Objective: To study the occurrence and mechanisms of carbapenem resistance in Escherichia coli. Materials and Methods: A total of 1172 clinical strains of E. coli obtained from various clinical specimens were screened for carbapenem resistance during the study period. Strains showing reduced susceptibility to imipenem &/or ertapenem &/or meropenem were included in the study. The resistance mechanisms were identified using various phenotypic methods. Results: Total of 53/1172 were found to be carbapenem resistant E. coli (CRE). The most common sample in which CRE were isolated was urine (n=26, 49.1%). A total of 50 isolates were confirmed as Metallobeta- lactamase (MBL) producers using Ezy MICTM strip. One of the three non carbapenemase producing isolate was positive for ESBL with porin loss and the other two isolates were positive for AmpC with porin loss. Conclusion: MBL production being the most common mechanism of carbapenem resistance, the study indicates the importance of regular monitoring of drug resistance in the hospital for an urgent action to be taken for antibiotics stewardship in the institute. Keywords: Escherichia coli, Carbapenem resistance, Super bug, Carba NP, MBL, Carbapenem resistance mechanisms.

In the present investigation the coriander plant volatiles for the tritrophic interactions on the egg parasitoid Trichogramma chilonis Ishii is evaluated. The GCMS profile study of the foliage extract of coriander in both hexane and dichloromethane showed presence of 2-Dodecenal-(E), (E)-Tetradec-2-enal, Octadecane, Nonacosane, Hexadecane, Pentadecane and Heneicosane, which are of biologically active fractions in insects. In laboratory study the maximum parasitization was recorded in hexane extract treated Corcyra card (31.04 eggs/card) compared to 28.16 eggs per card observed in untreated control. The data gathered on number of parasitized eggs hatched into adult indicated that in hexane extract treated Corcyra card had 91.19 per cent while parasitoid emergence was 29.30 eggs per card followed by 87.76 per cent in untreated control 24.90 eggs per card. The GCMS profile study of the foliage extract of coriander in both hexane and dichloromethane showed presence of 2-Dodecenal-(E), (E)-Tetradec-2-enal, Octadecane, Nonacosane, Hexadecane, Pentadecane and Heneicosane, which are of biologically active fractions in insects. The above findings reveal the possible role of such active chemicals in parasitoid compatibility of the intercrop.

The recent developments in wireless communication technologies along with the costs of hardware allow both V2V and V2I communications for information exchange. Such a network is called Vehicular ad Hoc Network (VANET) which is very important for various road safety and non-safety related applications. However, Due to the wireless nature of communication in VANETs, it is also prone to various security attacks which are originally present in wireless networks. Hence to realize the highest potential of VANET, the network should be free from attackers, there by all the information exchanged in the network must be reliable should be originated from authenticated source. The system can be processed by the fuzzy logic method. It does not require any keys for data transmission. The system design is very efficient compared to other techniques. So the users prevent from road accident and traffic jam..

Carbon nanotube (CNT) is prepared by chemical vapor deposition method and their electrochemical behaviors for instance oxygen evolution (OER) and hydrogen evolution (HER) reaction have been successfully studied. In recent times, Pt-free electrocatalysts have been greatly attractive in electrochemical hydrogen evolution reactions for the replacement of fossil fuels and development of sustainable energy carriers. Chemical vapor deposition method was used as an efficient way to synthesize CNTs directly. The as prepared free-standing and multifunctional CNT electrodes are used for overall water splitting applications. In this work, we have designed CNT as electrode material as well as current collector using Ni-foil and Ni-foam substrate and their fundamental characterizations confirm the structural, morphological behaviors of CNTs. Moreover, the well-ordered growth of CNT was obtained in Ni-foam CNTs 1 and 2, whereas in the Ni foil CNTs 1 and 2 less growth of CNT and amorphous carbon sponge was exceeded, which was further confirmed by the SEM images. The achieved electrochemical HER results displayed that the Ni-foam-CNT-2 exhibited lower overpotential, smallest Tafel slope and lower resistance value of 110 mV, 240 mV/dec and 0.24 Ω respectively. Moreover, Ni-foam-CNT-2 revealed excellent stability with 86.6 % retention over 20 h. Hence, it is one of the cost-effective and reliable materials for electrochemical hydrogen evolution reaction. This work was supported by UGC-SAP, DST-FIST, DST-PURSE, MHRD-RUSA grants.

Plant disease is a continuing challenge for smallholder farmers, which has an impact on income and food production. Identifying the disease at starting stage and preventing it from spreading to other parts of the plant is a challenge even for the experts in the field. Experts can identify and diagnose the disease, but the process is time-consuming and a good observation of the infected part is needed. However, these experts are not available readily to smallholder farmers, who are a major part of our country. An adequate method is therefore required to detect plant leaf diseases at starting stage. The recent revolution in smartphone perforation and advancement in computer vision models has provided a way for computer vision applications in the agriculture. Convolutional Neural Networks (CNN) considered as state of the art in classification of images and have the ability to produce a conclusive diagnosis.In this article, a Transfer Learning approach is used, in which a pre trained model is used to train on pictures of different fruit plant leaves from the Plant Village dataset, covering various diseases as well as safe samples.

The aim of this study was to determine the relationship between pilot workload, performance, subjective fatigue, sleep duration, number of sectors and flight duration during short-haul operations. Ninety pilots completed a NASA Task Load Index, Psychomotor Vigilance Task and a Samn-Perelli fatigue scale on top-of-descent of each flight and wore an activity monitor throughout the study. Weak, but significant, correlations were revealed between workload and all factors. Subjective fatigue, number of sectors and lapses were significant predictors of workload. Pilots reported higher workload when fatigue increased, the number of sectors were higher, and objective performance was worse.

Using structure-guided design, several cell based assays, and microdosed positron emission tomography (PET) imaging, we identified a series of highly potent, selective, and brain-penetrant oxazole-4-carboxamide-based inhibitors of glycogen synthase kinase-3 (GSK-3). An isotopologue of our first-generation lead, [(3)H]PF-367, demonstrates selective and specific target engagement in vitro, irrespective of the activation state. We discovered substantial ubiquitous GSK-3-specific radioligand binding in Tg2576 Alzheimer’s disease (AD), suggesting application for these compounds in AD diagnosis and identified [(11)C]OCM-44 as our lead GSK-3 radiotracer, with optimized brain uptake by PET imaging in nonhuman primates. GSK-3β-isozyme selectivity was assessed to reveal OCM-51, the most potent (IC(50) = 0.030 nM) and selective (>10-fold GSK-3β/GSK-3α) GSK-3β inhibitor known to date. Inhibition of CRMP2(T514) and tau phosphorylation, as well as favorable therapeutic window against WNT/β-catenin signaling activation, was observed in cells.

Background The optimal duration of maintenance therapy is controversial in proliferative lupus nephritis (LN). Discordance between clinical parameters of renal remission and histological findings has made repeat biopsy a compulsory tool to confirm the histological remission (HR), but the timing is debatable. Aim of this study was to find the correlation of sustained complete clinical remission (CR) in sever lupus nephritis with histological findings on repeat kidney biopsy and appropriate duration of treatment in maintenance phase after achieving complete clinical remission. Methods Repeated kidney biopsy (biopsy 2) was performed on patients of biopsy proven (biopsy 1) proliferative LN who had been in CR for at least 2-years. The clinical and histologic findings of these groups (biopsy 1 and biopsy 2) were compared. Total 29 patients were included for the final analysis. Group 2 was further divided as per the duration of sustained CR (>48 months & Results Average time taken to achieve CR was 9(range 2–24) months. Average duration of follow up and maintenance therapy was 68 ± 17.8 and 62.5 ± 14.2 months respectively. In the repeat kidney biopsy, HR was observed in 93.1% patients. Immunofluorescence study (IF) was normal in 72% of the patients. Normal light microscopy (LM) findings were observed in 58% patients. Transformation from proliferative to nonproliferative LN was noted in 82% cases. Other than the duration of CR on maintenance therapy and blood pressure, rest of the variables failed to predict HR. In sustained remission for more than 48-months group, 100% patients achieved HR whereas only 84% in 24–48-months group. Conclusion Sustained CR on maintenance immunosuppressive therapy for more than 48-months duration predicts HR in repeat kidney biopsy findings in quiescent proliferative LN. Hence the minimum duration of maintenance therapy in proliferative LN should be at least for another 48 months after achieving CR.

Approximation theorists have established best-in-class optimal approximation rates of deep neural networks by utilizing their ability to simultaneously emulate partitions of unity and monomials. Motivated by this, we propose partition of unity networks (POUnets) which incorporate these elements directly into the architecture. Classification architectures of the type used to learn probability measures are used to build a meshfree partition of space, while polynomial spaces with learnable coefficients are associated to each partition. The resulting hp-element-like approximation allows use of a fast least-squares optimizer, and the resulting architecture size need not scale exponentially with spatial dimension, breaking the curse of dimensionality. An abstract approximation result establishes desirable properties to guide network design. Numerical results for two choices of architecture demonstrate that POUnets yield hp-convergence for smooth functions and consistently outperform MLPs for piecewise polynomial functions with large numbers of discontinuities., Comment: 8 pages, 5 figures

Adapalene-loaded transfersome gel containing vitamin C as a combination therapy for the management of acne vulgaris was developed in the present study. The transfersome was prepared by reverse-phase evaporation, and the effect of various process parameters were investigated by the Design of Experiment (DOE) approach and optimized based on the particle size (PS), polydispersity index (PDI), zeta potential (ZP), and entrapment efficiency (EE). The selected tranfersomes were further evaluated for their thermal behavior and morphology by transmission electron microscopy and turbidity measurements and incorporated into a gel with/without vitamin C. The gel was evaluated and compared with the marketed product (Adiff gel) for various physicochemical parameters, and in vivo studies in testosterone-induced rat models of acne. The prepared transfersomes had PS in the range of 280 to 400 nm, PDI values of 0.416 to 0.8, ZP of − 38 to − 20 mV, and % EE of 32 to 70%. DSC studies confirmed a positive interaction of the components in the transfersome. Surface morphology confirmed that the vesicles were spherical, unilamellar, and discrete. A relative deformability study showed higher elasticity of the transfersomes compared with Adiff aqs gel. Ascorbyl-6-palmitate in adapalene-loaded transfersome gel containing vitamin C (ADVTG) was found to have a good antioxidant free radical–scavenging activity. An in vitro drug release study showed that the sustained release of the transfersomal formulations was attributed to the flexibility of the vesicles by which penetration was increased. ADVTG was found to be promising in treating acne compared with the marketed product.

Studies on indole-3-carboxylic acid derivatives as direct activators of human adenosine monophosphate-activated protein kinase (AMPK) α1β1γ1 isoform have culminated in the identification of PF-06409577 (1), PF-06885249 (2), and PF-06679142 (3) as potential clinical candidates. Compounds 1-3 are primarily cleared in animals and humans via glucuronidation. Herein, we describe the biosynthetic preparation, purification, and structural characterization of the glucuronide conjugates of 1-3. Spectral characterization of the purified glucuronides M1, M2, and M3 indicated that they were acyl glucuronide derivatives. In vitro pharmacological evaluation revealed that all three acyl glucuronides retained selective activation of β1-containing AMPK isoforms. Inhibition of de novo lipogenesis with representative parent carboxylic acids and their respective acyl glucuronide conjugates in human hepatocytes demonstrated their propensity to activate cellular AMPK. Cocrystallization of the AMPK α1β1γ1 isoform with 1-3 and M1-M3 provided molecular insights into the structural basis for AMPK activation by the glucuronide conjugates.

Many diseases are believed to be driven by pathological levels of reactive oxygen species (ROS) and oxidative stress has long been recognized as a driver for inflammatory disorders. Apoptosis signal-regulating kinase 1 (ASK1) has been reported to be activated by intracellular ROS and its inhibition leads to a down regulation of p38-and JNK-dependent signaling. Consequently, ASK1 inhibitors may have the potential to treat clinically important inflammatory pathologies including renal, pulmonary and liver diseases. Analysis of the ASK1 ATP-binding site suggested that Gln756, an amino acid that rarely occurs at the GK+2 position, offered opportunities for achieving kinase selectivity for ASK1 which was applied to the design of a parallel medicinal chemistry library that afforded inhibitors of ASK1 with nanomolar potency and excellent kinome selectivity. A focused optimization strategy utilizing structure-based design resulted in the identification of ASK1 inhibitors with low nanomolar potency in a cellular assay, high selectivity when tested against kinase and broad pharmacology screening panels, and attractive physicochemical properties. The compounds we describe are attractive tool compounds to inform the therapeutic potential of ASK1 inhibition.

Simulations of homogeneously sheared turbulence (HST) are conducted until a universal self-similar state is established at the long non-dimensional time $\unicode[STIX]{x1D6E4}t=20$, where $\unicode[STIX]{x1D6E4}$ is the shear rate. The simulations are enabled by a new robust and discretely conservative algorithm. The method solves the governing equations in physical space using the so-called shear-periodic boundary conditions. Convection by the mean homogeneous shear flow is treated implicitly in a split step approach. An iterative Crank–Nicolson time integrator is chosen for robustness and stability. The numerical strategy captures without distortion the Kelvin modes, rotating waves that are fundamental to homogeneously sheared flows and are at the core of rapid distortion theory. Three direct numerical simulations of HST with the initial Taylor scale Reynolds number $Re_{\unicode[STIX]{x1D706}0}=29$ and shear numbers of $S_{0}^{\ast }=\unicode[STIX]{x1D6E4}q^{2}/\unicode[STIX]{x1D716}=3$, 15 and 27 are performed on a $2048\times 1024\times 1024$ grid. Here, $\unicode[STIX]{x1D716}$ is the dissipation rate and $1/2q^{2}$ is the turbulent kinetic energy. The long integration time considered allows the establishment of a self-similar state observed in experiments but often absent from simulations conducted over shorter times. The asymptotic state appears to be universal with a long time production to dissipation rate ${\mathcal{P}}/\unicode[STIX]{x1D716}\sim 1.5$ and shear number $S^{\ast }\sim 10$ in agreement with experiments. While the small scales exhibit strong anisotropy increasing with initial shear number, the skewness of the transverse velocity derivative decreases with increasing Reynolds number.

We present a verification study of three simulation techniques for fluid–particle flows, including an Euler–Lagrange approach (EL) inspired by Jackson's seminal work on fluidized particles, a quadrature–based moment method based on the anisotropic Gaussian closure (AG), and the traditional two-fluid model. We perform simulations of two problems: particles in frozen homogeneous isotropic turbulence (HIT) and cluster-induced turbulence (CIT). For verification, we evaluate various techniques for extracting statistics from EL and study the convergence properties of the three methods under grid refinement. The convergence is found to depend on the simulation method and on the problem, with CIT simulations posing fewer difficulties than HIT. Specifically, EL converges under refinement for both HIT and CIT, but statistics exhibit dependence on the postprocessing parameters. For CIT, AG produces similar results to EL. For HIT, converging both TFM and AG poses challenges. Overall, extracting converged, parameter-independent Eulerian statistics remains a challenge for all methods. © 2017 American Institute of Chemical Engineers AIChE J, 63: 5396–5412, 2017

Diabetic nephropathy remains an area of high unmet medical need, with current therapies that slow down, but do not prevent, the progression of disease. A reduced phosphorylation state of adenosine monophosphate-activated protein kinase (AMPK) has been correlated with diminished kidney function in both humans and animal models of renal disease. Here, we describe the identification of novel, potent, small molecule activators of AMPK that selectively activate AMPK heterotrimers containing the β1 subunit. After confirming that human and rodent kidney predominately express AMPK β1, we explore the effects of pharmacological activation of AMPK in the ZSF1 rat model of diabetic nephropathy. Chronic administration of these direct activators elevates the phosphorylation of AMPK in the kidney, without impacting blood glucose levels, and reduces the progression of proteinuria to a greater degree than the current standard of care, angiotensin-converting enzyme inhibitor ramipril. Further analyses of urine biomarkers and kidney tissue gene expression reveal AMPK activation leads to the modulation of multiple pathways implicated in kidney injury, including cellular hypertrophy, fibrosis, and oxidative stress. These results support the need for further investigation into the potential beneficial effects of AMPK activation in kidney disease.

Adenosine monophosphate-activated protein kinase (AMPK), a serine/threonine heterotrimeric protein kinase, is a critical regulator of cellular and whole body energy homeostasis. There are twelve known AMPK isoforms that are differentially expressed in tissues and species. Dysregulation of AMPK signaling is associated with a multitude of human pathologies. Hence isoform-selective activators of AMPK are actively being sought for the treatment of cardiovascular and metabolic diseases. The present review summarizes the status of direct AMPK activators from the patent and published literature.

Crystals of phosphorylated JAK1 kinase domain were initially generated in complex with nucleotide (ADP) and magnesium. The tightly bound Mg2+-ADP at the ATP-binding site proved recalcitrant to ligand displacement. Addition of a molar excess of EDTA helped to dislodge the divalent metal ion, promoting the release of ADP and allowing facile exchange with ATP-competitive small-molecule ligands. Many kinases require the presence of a stabilizing ligand in the ATP site for crystallization. This procedure could be useful for developing co-crystallization systems with an exchangeable ligand to enable structure-based drug design of other protein kinases.

Data fields sampled on irregularly spaced points arise in many applications in the sciences and engineering. For regular grids, Convolutional Neural Networks (CNNs) have been successfully used to gaining benefits from weight sharing and invariances. We generalize CNNs by introducing methods for data on unstructured point clouds based on Generalized Moving Least Squares (GMLS). GMLS is a non-parametric technique for estimating linear bounded functionals from scattered data, and has recently been used in the literature for solving partial differential equations. By parameterizing the GMLS estimator, we obtain learning methods for operators with unstructured stencils. In GMLS-Nets the necessary calculations are local, readily parallelizable, and the estimator is supported by a rigorous approximation theory. We show how the framework may be used for unstructured physical data sets to perform functional regression to identify associated differential operators and to regress quantities of interest. The results suggest the architectures to be an attractive foundation for data-driven model development in scientific machine learning applications.

Introduction: Fixed-dose combination (FDC) medicines contain more than one approved active pharmaceutical ingredient (API), are manufactured as a fixed-dose and packed in a single dosage form. FDCs have been drawing attention from the pharmaceutical industries because of the government's ban on 328 irrational FDCs in September 2018. The Drug Technical Advisory Board (DTAB) recommended that 'there is no therapeutic justification' for the active ingredients in the banned FDCs and accordingly these combinations 'may involve a risk to human beings'. Areas covered: The review illustrates the present status of FDCs, its regulatory framework, approvals in India and discusses the substantive cause behind the ban on FDCs in India. Expert opinion: The expert stress to establish a robust regulatory system for the approval of FDCs in India. The pharmaceutical industries should not perceive the ban against irrational FDCs as an impediment; rather, they should view as an opportunity to establish a stronger healthcare system. The current review is an eye-opener for the section of people who consider that the ban on FDCs is irrational. However, the ban on 328 FDCs may prove a landmark decision for the development of stronger healthcare policy in India.

Adapalene-loaded transfersome gel containing vitamin C as a combination therapy for the management of acne vulgaris was developed in the present study. The transfersome was prepared by reverse-phase evaporation, and the effect of various process parameters were investigated by the Design of Experiment (DOE) approach and optimized based on the particle size (PS), polydispersity index (PDI), zeta potential (ZP), and entrapment efficiency (EE). The selected tranfersomes were further evaluated for their thermal behavior and morphology by transmission electron microscopy and turbidity measurements and incorporated into a gel with/without vitamin C. The gel was evaluated and compared with the marketed product (Adiff gel) for various physicochemical parameters, and in vivo studies in testosterone-induced rat models of acne. The prepared transfersomes had PS in the range of 280 to 400 nm, PDI values of 0.416 to 0.8, ZP of - 38 to - 20 mV, and % EE of 32 to 70%. DSC studies confirmed a positive interaction of the components in the transfersome. Surface morphology confirmed that the vesicles were spherical, unilamellar, and discrete. A relative deformability study showed higher elasticity of the transfersomes compared with Adiff aqs gel. Ascorbyl-6-palmitate in adapalene-loaded transfersome gel containing vitamin C (ADVTG) was found to have a good antioxidant free radical-scavenging activity. An in vitro drug release study showed that the sustained release of the transfersomal formulations was attributed to the flexibility of the vesicles by which penetration was increased. ADVTG was found to be promising in treating acne compared with the marketed product. Graphical Abstract.

Vallad, G. E., Bhat, R. G., Koike, S. T., Ryder, E. J., and Subbarao, K. V. 2005. Weedborne reservoirs and seed transmission of Verticillium dahliae in lettuce. Plant Dis. 89:317-324. The seed transmission of Verticillium dahliae was evaluated in lettuce (Lactuca sativa). Seed collected from lettuce plants infected with V. dahliae were plated with or without surface sterilization on Sorenson’s modified NP10 medium. Of the seed plated with or without surface sterilization, 90 and 66%, respectively, yielded colonies of V. dahliae. The incidence of Verticillium wilt ranged from 55 to 80% among lettuce plants grown from seed harvested from infected plants. All evaluated isolates of V. dahliae were capable of seed transmission in lettuce. A V. tricorpus isolate failed to cause significant disease in lettuce or to become seedborne. Storage of contaminated seed at seven temperatures ranging from –20 to 15°C for up to 72 weeks did not reduce the incidence of V. dahliae in seed, whereas storage at room temperature (23 ± 2°C) for 20 to 52 weeks reduced the incidence of V. dahliae without affecting seed viability. Of the 11 weed species collected from fields with a known history of Verticillium wilt of lettuce, four yielded V. dahliae. Pathogenicity tests demonstrated that isolates of V. dahliae from Sonchus oleraceus, Capsella bursa-pastoris, and Solanum sarrachoides were as virulent as or more virulent than an isolate of V. dahliae from lettuce. These results demonstrate the potential of seedborne and weedborne inoculum to disseminate V. dahliae.

Motivated by the gap between theoretical optimal approximation rates of deep neural networks (DNNs) and the accuracy realized in practice, we seek to improve the training of DNNs. The adoption of an adaptive basis viewpoint of DNNs leads to novel initializations and a hybrid least squares/gradient descent optimizer. We provide analysis of these techniques and illustrate via numerical examples dramatic increases in accuracy and convergence rate for benchmarks characterizing scientific applications where DNNs are currently used, including regression problems and physics-informed neural networks for the solution of partial differential equations., Comment: 26 pages

Myocardial fibrosis, identified by late gadolinium enhancement cardiovascular magnetic resonance, predicts outcomes in chronic heart failure (HF). Its prognostic significance in new-onset HF and reduced left ventricular ejection fraction (LVEF) is unclear. We investigated whether the pattern and extent of fibrosis predict survival in new-onset HF and reduced LVEF of initially uncertain pathogenesis.Of 120 consecutive patients with new-onset (6 months) HF and reduced LVEF, 31 (26%) had infarct fibrosis, 25 (21%) had midwall fibrosis, and 64 (53%) had no fibrosis. During median follow-up of 8.9 years, 33 (28%) patients died. Patients with infarct fibrosis (hazard ratios [HR], 3.32; 95% CI, 1.46-7.58; P=0.004) or midwall fibrosis (HR, 2.99; 95% CI, 1.24-7.19; P=0.014) were more likely to die compared with those without fibrosis. On multivariable analysis, the pattern and extent of fibrosis were both associated with all-cause mortality (by fibrosis pattern: infarct: HR, 2.60; 95% CI, 1.08-6.27; P=0.033; midwall: HR, 2.64; 95% CI, 1.08-6.47; P=0.034; by fibrosis extent per 1%: HR, 1.07; 95% CI, 1.03-1.12; P0.001). Fibrosis pattern also predicted composites of cardiovascular mortality or aborted sudden cardiac death (infarct: HR, 3.45; 95% CI, 1.20-9.90; P=0.022; midwall: HR, 6.59; 95% CI, 2.26-19.22; P0.001), and all-cause mortality, HF hospitalization, or aborted sudden cardiac death (infarct: HR, 2.69; 95% CI, 1.26-5.76; P=0.011; midwall fibrosis: HR, 2.97; 95% CI, 1.37-6.45; P=0.006). Addition of fibrosis pattern to LVEF improved risk prediction for all-cause mortality (LVEF versus LVEF+fibrosis C statistic: 0.66 versus 0.71; P=0.033). Importantly, the absence of fibrosis heralded a favorable prognosis with an 85% survival rate over the duration of follow-up.The pattern and extent of myocardial fibrosis predict adverse outcomes in new-onset HF and reduced LVEF. In contrast, the absence of fibrosis portends a durable warranty period with a low incidence of adverse events. These findings support a role for late gadolinium enhancement cardiovascular magnetic resonance in the early risk stratification of patients with HF of uncertain pathogenesis.

Adenosine monophosphate-activated protein kinase (AMPK) is a protein kinase involved in maintaining energy homeostasis within cells. On the basis of human genetic association data, AMPK activators were pursued for the treatment of diabetic nephropathy. Identification of an indazole amide high throughput screening (HTS) hit followed by truncation to its minimal pharmacophore provided an indazole acid lead compound. Optimization of the core and aryl appendage improved oral absorption and culminated in the identification of indole acid, PF-06409577 (7). Compound 7 was advanced to first-in-human trials for the treatment of diabetic nephropathy.

Topical drug delivery system refers to a formulation that carries drug substance into contact with or through the skin for the treatment of cutaneous disorders or the cutaneous manifestation of general diseases. Etodolac is a non-steroidal anti-inflammatory drug used for the treatment of postoperative pain and infections, rheumatoid arthritis and osteoarthritis. SMEDDS of etodolac was developed using oleic acid, tween 80, PEG 400 and evaluated for zeta potential and drug content which were found to be +39mV and 93.33% respectively for F2 formulation. The SMEDDS incorporated etodolac loaded nanosponge were prepared by emulsion solvent evaporation method and optimized using Design Expert® software. The optimized SMEDDS incorporated etodolac loaded nanosponge formulation was found to possess 106.3nm particle size, 0.320 PDI, 87.46% entrapment efficiency and rough, porous surface. Further, all the nanosponge based hydrogel formulations had 6.8 pH and F2 formulation was found to possess 598 cps viscosity, 5.5±0.01cm spreadability and 73.3±0.01% drug content. F4 formulation showed the highest percentage swelling of 93.45% within 24 h. The in vitro drug release and kinetics studies confirmed the sustained release of the drug from the formulation with diffusion controlled drug release mechanism. Hence the nanosponge based hydrogels of etodolac were found to be promising for topical delivery.

Background: Basicervical or cervicotrochanteric fracture of the femur is considered stable variety of fracture pattern. Most common incidence is seen in elderly patient and in young patient with probably high energy trauma. Appropriate Osteosynthesis confers excellent outcome when reduction is optimally achieved.Methods: 86 basitrochanteric fractures had been treated with enders nail or dynamic hip screw (DHS) at our institute by a single surgeon. Implant selection was done purely based on plain radiograph, associated co-morbidities and fracture geometry. Patients had been followed up at 1 month, 3 month and 6 month.Results: In our study there were 86 patients out of which 63 patients (73.25%) were treated with enders nail and 23 patients (26.74%) were treated with DHS. Mean age of patients was 57 years. We noted minimum follow up of 8 months while maximum follow up of 4.5 years where as mean follow up duration is 18 months. We almost noted excellent to fair results in both groups.Conclusions: Most of the implants in basitrochanteric fractures worked on control collapse principle. Both DHS and enders nail with percutaneous cc screw follow this principle and when used with a proper technique, optimal reduction usually fetch the favourable outcomes with minimalistic approach.

The nuclear hormone receptor retinoic acid receptor-related orphan C2 (RORC2, also known as RORγt) is a promising target for the treatment of autoimmune diseases. A small molecule, inverse agonist of the receptor is anticipated to reduce production of IL-17, a key proinflammatory cytokine. Through a high-throughput screening approach, we identified a molecule displaying promising binding affinity for RORC2, inhibition of IL-17 production in Th17 cells, and selectivity against the related RORA and RORB receptor isoforms. Lead optimization to improve the potency and metabolic stability of this hit focused on two key design strategies, namely, iterative optimization driven by increasing lipophilic efficiency and structure-guided conformational restriction to achieve optimal ground state energetics and maximize receptor residence time. This approach successfully identified 3-cyano- N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1 H-pyrrolo[2,3- b]pyridin-5-yl)benzamide as a potent and selective RORC2 inverse agonist, demonstrating good metabolic stability, oral bioavailability, and the ability to reduce IL-17 levels and skin inflammation in a preclinical in vivo animal model upon oral administration.

This study sought to quantify myocardial blood flow (MBF) and myocardial perfusion reserve (MPR) in dilated cardiomyopathy (DCM) and examine the relationship between myocardial perfusion and adverse left ventricular (LV) remodeling.Although regarded as a nonischemic condition, DCM has been associated with microvascular dysfunction, which is postulated to play a role in its pathogenesis. However, the relationship of the resulting perfusion abnormalities to myocardial fibrosis and the degree of LV remodeling is unclear.A total of 65 patients and 35 healthy control subjects underwent adenosine (140 μg/kg/min) stress perfusion cardiovascular magnetic resonance with late gadolinium enhancement imaging. Stress and rest MBF and MPR were derived using a modified Fermi-constrained deconvolution algorithm.Patients had significantly higher global rest MBF compared with control subjects (1.73 ± 0.42 ml/g/min vs. 1.14 ± 0.42 ml/g/min; p 0.001). In contrast, global stress MBF was significantly lower versus control subjects (3.07 ± 1.02 ml/g/min vs. 3.53 ± 0.79 ml/g/min; p = 0.02), resulting in impaired MPR in the DCM group (1.83 ± 0.58 vs. 3.50 ± 1.45; p 0.001). Global stress MBF (2.70 ± 0.89 ml/g/min vs. 3.44 ± 1.03 ml/g/min; p = 0.017) and global MPR (1.67 ± 0.61 vs. 1.99 ± 0.50; p = 0.047) were significantly reduced in patients with DCM with LV ejection fraction ≤35% compared with those with LV ejection fraction35%. Segments with fibrosis had lower rest MBF (mean difference: -0.12 ml/g/min; 95% confidence interval: -0.23 to -0.01 ml/g/min; p = 0.035) and lower stress MBF (mean difference: -0.15 ml/g/min; 95% confidence interval: -0.28 to -0.03 ml/g/min; p = 0.013).Patients with DCM exhibit microvascular dysfunction, the severity of which is associated with the degree of LV impairment. However, rest MBF is elevated rather than reduced in DCM. If microvascular dysfunction contributes to the pathogenesis of DCM, then the underlying mechanism is more likely to involve stress-induced repetitive stunning rather than chronic myocardial hypoperfusion.

Protein-ligand interactions can be evaluated by a number of different biophysical methods. Here we describe some of the experimental methods that we have used to generate AMPK protein reagents and characterize its interactions with direct synthetic activators. Recombinant heterotrimeric AMPK complexes were generated using standard molecular biology methods by expression either in insect cells via infection with three different viruses or more routinely in Escherichia coli with a tricistronic expression vector. Hydrogen/deuterium exchange (HDX) coupled with mass spectrometry was used to probe protein conformational changes and potential binding sites of activators on AMPK. X-ray crystallographic studies were carried out on crystals of AMPK with bound ligands to reveal detailed molecular interactions formed by AMPK activators at near-atomic resolution. In order to gain insights into the mechanism of enzyme activation and to probe the effects of AMPK activators on kinetic parameters such as Michaelis-Menten constant (K

Optimization of the pharmacokinetic (PK) properties of a series of activators of adenosine monophosphate-activated protein kinase (AMPK) is described. Derivatives of the previously described 5-aryl-indole-3-carboxylic acid clinical candidate (1) were examined with the goal of reducing glucuronidation rate and minimizing renal excretion. Compounds 10 (PF-06679142) and 14 (PF-06685249) exhibited robust activation of AMPK in rat kidneys as well as desirable oral absorption, low plasma clearance, and negligible renal clearance in preclinical species. A correlation of in vivo renal clearance in rats with in vitro uptake by human and rat renal organic anion transporters (human OAT/rat Oat) was identified. Variation of polar functional groups was critical to mitigate active renal clearance mediated by the Oat3 transporter. Modification of either the 6-chloroindole core to a 4,6-difluoroindole or the 5-phenyl substituent to a substituted 5-(3-pyridyl) group provided improved metabolic stability while minimizing propensity for active transport by OAT3.