Application of a reconfigurable all-optical activation unit based on optical injection into a bistable Fabry-Perot laser in multilayer perceptron neural networks.

In this Letter, we theoretically investigate the application of a bistable Fabry-Perot semiconductor laser under optical injection as an all-optical activation unit for multilayer perceptron optical neural networks. The proposed device is programmed to provide reconfigurable sigmoid-like activation functions with adjustable thresholds and saturation points and benchmarked on machine learning image recognition problems. Due to the reconfigurability of the activation unit, the accuracy can be increased by up to 2% simply by adjusting the control parameter of the activation unit to suit the specific problem. For a simple two-layer perceptron neural network, we achieve inference accuracies of up to 95% and 85%, for the MNIST and Fashion-MNIST datasets, respectively.

Cranial suture lineage and contributions to repair of the mouse skull.

The cranial sutures are proposed to be a stem cell niche, harbouring skeletal stem cells that are directly involved in development, homeostasis and healing. Like the craniofacial bones, the sutures are formed from both mesoderm and neural crest. During cranial bone repair, neural crest cells have been proposed to be key players; however, neural crest contributions to adult sutures are not well defined, and the relative importance of suture proximity is unclear. Here, we use genetic approaches to re-examine the neural crest-mesoderm boundaries in the adult mouse skull. These are combined with calvarial wounding experiments suggesting that suture proximity improves the efficiency of cranial repair. Furthermore, we demonstrate that Gli1+ and Axin2+ skeletal stem cells are present in all calvarial sutures examined. We propose that the position of the defect determines the availability of neural crest-derived progenitors, which appear to be a key element in the repair of calvarial defects.

Carob Extract (Ceratonia siliqua L.): Effects on Dyslipidemia and Obesity in a High-Fat Diet-Fed Rat Model.

Dyslipidemia and obesity are recognized as two of the major global health issues and main risk factors for coronary heart disease and cerebrovascular disease. In recent years, carob has shown certain antioxidant and anti-dyslipidemic potential. In this study, Wistar rats were fed with a standard and cholesterol-enriched diet and treated orally with carob extract and simvastatin for four weeks. After sacrifice, blood samples were collected for biochemical analysis, and liver tissue was taken for histological and immunohistochemical assessment. Weight gain was significantly higher in groups fed with cholesterol-fortified granules; total cholesterol was found to be significantly lower in the hypercholesterolemic groups treated with simvastatin and simvastatin/carob combined regimens compared with hypercholesterolemic animals treated with saline (p < 0.05). The same was true for low-density lipoprotein cholesterol and the LDL/HDL ratio (p < 0.05). Adiponectin was remarkably higher in animals treated with simvastatin compared to all other groups (p < 0.05). Leptin was significantly lower in groups treated with carob and simvastatin compared to the hypercholesterolemic group treated with saline (p < 0.05). Carob/simvastatin co-administration reduced hepatocyte damage and improved liver morphology. A study confirmed the anti-dyslipidemic, anti-obesity, and hepatoprotective potential of carob pulp alone or in combination with simvastatin in the treatment of high-fat diet-fed rats.

Reconfigurable all-optical bistability/tristability in dual injection-locked Fabry-Perot laser diodes.

In this Letter, we present a detailed theoretical and experimental investigation of optical bistability and tristability in dual injection-locked Fabry-Perot laser diodes. The proposed device can be reconfigured between the bistable and tristable regimes, simply by adjusting the power level of the injected control optical signal. The tristability presented in the experiment is achieved for relatively low optical input powers between 1.03 and 1.25 mW, with the output signal ratio of up to 7 dB between stable states. Such a device is a potential candidate for designing trits, a bit analogy in ternary computational logic.

Isolation of Garlic Bioactives by Pressurized Liquid and Subcritical Water Extraction.

Garlic (Allium sativum L.) is widely used in various food products and traditional medicine. Besides unique taste and flavour, it is well known for its chemical profile and bioactive potential. The aim of this study was to apply subcritical water extraction (SWE) and pressurized liquid extraction (PLE) for the extraction of bioactive compounds from the Ranco genotype of garlic. Moreover, PLE process was optimized using response surface methodology (RSM) in order to determine effects and optimize ethanol concentration (45-75%), number of cycles (1-3), extraction time (1-3 min) and temperature (70-110 °C) for maximized total phenols content (TP) and antioxidant activity evaluated by various in vitro assays. Furthermore, temperature effect in SWE process on all responses was evaluated, while allicin content (AC), as a major organosulphur compound, was determined in all samples. Results indicated that PLE provided tremendous advantage over SWE in terms of improved yield and antioxidant activity of garlic extracts. Therefore, high-pressure processes could be used as clean and green procedures for the isolation of garlic bioactives.

Current Expertise, Opinions, and Attitude toward TNF-⍺ Antagonist Biosimilars among Physicians: A Self-Administered Online Survey in Western Switzerland.

Tumor necrosis factor-alpha (TNF-⍺) antagonists are biological drugs with multiple authorized biosimilars. Biosimilars are becoming critical to the financial sustainability of health systems. Recent studies emphasize that physicians' knowledge regarding biosimilars has not yet progressed sufficiently to overcome their concerns regarding biosimilars' safety and efficacy. To assess the current knowledge, opinions, and attitudes toward TNF-⍺ antagonist biosimilars among postgraduate physicians and specialists, an anonymous, self-administered survey was implemented on SurveyMonkey between February and May 2022. The survey was validated through think-aloud interviews with senior and postgraduate physicians in rheumatology, gastroenterology, and immunoallergology, and a senior epidemiologist. Participant recruitment was conducted with the help of the physicians' professional societies and departmental head physicians of two university hospitals in Western Switzerland. Most physicians felt more comfortable initiating a TNF-⍺ antagonist biosimilar in biologic-naive patients (BNPs) than switching patients stabilized on the original biologic (originator). However, most participants agreed that BNPs should start treatment with the biosimilar rather than the originator when available. Postgraduate physicians and specialists in rheumatology, gastroenterology, and immunoallergology who participated in this survey were familiar with TNF-⍺ antagonist biosimilars and were confident in prescribing them. Yet, they still preferred to avoid switching a patient already on the originator.

Exploring the Reasons Behind the Substantial Discontinuation Rate Among Patients Taking CT-P13 in a Large Tertiary Hospital in Western Switzerland: A Retrospective Cohort Study Using Routinely Collected Medical Data.

BACKGROUND: CT-P13 is an infliximab biosimilar that was granted market authorization in Switzerland in 2016. Despite the growing literature supporting the equivalence of CT-P13 compared with originator infliximab regarding the efficacy, safety, and immunogenicity and the undeniable cost-saving opportunities, CT-P13 remains widely underused in Switzerland. OBJECTIVE: Leaving aside the phenomenon of a low initiation rate, this study aimed to explore the reasons behind the high discontinuation rate observed among the patients taking CT-P13 in a large tertiary hospital in Western Switzerland. METHODS: We performed a retrospective cohort study using routinely collected data. Patients were eligible if they received originator infliximab or CT-P13 between September 2017 and December 2020. They were included if they had received at least two CT-P13 infusions during the same period. Patients were excluded if the follow-up was incomplete prior to or 6 months after their first CT-P13 infusion and if they had an oncological main diagnosis. Primary outcomes were the reasons for treatment discontinuation. RESULTS: One hundred and fifty-six patients were included and classified into two groups: switchers who were treated with originator infliximab and were switched to CT-P13 (n = 85, 54%) and initiators who did not receive originator infliximab prior to CT-P13 treatment (n = 71, 46%). Included patients belonged to three different groups of diagnosis: gastroenterological (67, 43%), rheumatological (61, 39%), and immunological (28, 18%). Twenty-three (27%) switchers and 35 (49%) initiators discontinued CT-P13 after 12 months. Main reasons for CT-P13 discontinuation were lack of efficacy (n = 21, 36%) and secondary loss of response (n = 16, 28%); however, objective assessments were not available. Initiators' probability to discontinue CT-P13 at 12 months was significantly higher than switchers' (p < 0.01). CONCLUSIONS: Lack of efficacy and secondary loss of response were the main reasons for the high CT-P13 discontinuation rate observed in a large tertiary hospital in Western Switzerland. Lack of active training and coordination among healthcare professionals and little education in patients may have exacerbated patients' subjective complaints and increased the CT-P13 discontinuation rate.

Long-term stability of clopidogrel solid dispersions-Importance of in vitro dissolution test.

Formulation of solid dispersions (SDs), in which the drug substance is dissolved or dispersed inside a polymer matrix, is one of the modern approaches to increase the solubility and dissolution rate of poorly soluble active pharmaceutical ingredients (APIs), such as clopidogrel. In the form of a free base, clopidogrel is unstable under increased both high moisture and temperature, so it is most often used as its salt form, clopidogrel hydrogen sulfate (CHS).The aim of this study was the formulation, characterization, and long-term stability investigation of CHS solid dispersions, prepared with four different hydrophilic polymers (poloxamer 407, macrogol 6000, povidone, copovidone) in five API/polymer ratios (1:1, 1:2, 1:3, 1:5, 1:9). SDs were prepared by the solvent evaporation method, employing ethanol (96% v/v) as a solvent. Initial results of the in vitro dissolution test showed an increase in the amount of dissolved CHS from all prepared SD samples compared to pure CHS, corresponding physical mixtures (PMs), and commercial tablets. SDs, prepared with poloxamer 407, macrogol 6000, and copovidone, at CHS/polymer ratios 1:5 and 1:9, notably increased the amount of dissolved CHS (> 80%, after 60 min), thus they were selected for further characterization. To assess the SDs long-term stability, in vitro dissolution studies, clopidogrel content determination, differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FT-IR) were performed initially and after 12 months of long-term stability studies under controlled conditions (25°C, 60% RH) meeting the ICH guideline Q1A (R2) requirements. The clopidogrel content in the selected samples was very similar at the beginning (96.13% to 99.93%) and at the end (95.98% to 99.86%) of the conducted test. DSC curves and FT-IR spectra of all SD samples after 12 months of stability study, showed the absence of CHS crystallization, which is an indication of good stability. However, the in vitro dissolution test showed a considerable reduction in CHS released from SDs with macrogol 6000. The amount of dissolved CHS from SDs with macrogol 6000 was initially 94.02% and 92.01%, and after 12 months of stability study, only 65.13% and 49.62%. In contrast, the amount of dissolved CHS from SDs prepared with poloxamer 407 and copovidone was very similar after 12 months of the stability study compared to the initial values. Results obtained indicated the great importance of the in vitro dissolution test in determining the long-term stability and quality of SDs.

Optimization of frequency combs spectral-flatness using evolutionary algorithm.

We demonstrate the use of meta-heuristics algorithms for flatness optimization of optical frequency combs (OFCs). Without any additional component for flatness compensation, the laser alone is explored when driven by optimized bias current and radio frequency (RF) driving signals composed by multiple harmonics. The bias current amplitude and RF harmonic amplitudes and relative phases are optimized using particle swarm optimization (PSO) and differential evolution (DE) algorithms. The numerical results lead to a 9 lines-GS-laser-based OFC spectrum with 2.9 dB flatness. An online experimental optimization using the DE algorithm results in a 7-line-GS-laser-based OFC with 2 dB flatness.

Generation of a dual optical frequency comb by large signal modulation of a semiconductor laser.

In this paper, we present and theoretically investigate a simple and power efficient scheme for dual optical frequency comb generation residing on a single directly modulated semiconductor laser driven by two superimposed current waveforms. Our detailed model estimates dual combs comprising teeth pairs within 20 dB margin spanning up to 116 GHz with power per teeth pair up to 8.8 µW. In addition, we report dual combs with 40 GHz span comprising ultraflat teeth pairs, with flatness of the order of 1 dB.

Adaptive sigmoid-like and PReLU activation functions for all-optical perceptron.

We present an approach for the generation of an adaptive sigmoid-like and PReLU nonlinear activation function of an all-optical perceptron, exploiting the bistability of an injection-locked Fabry-Perot semiconductor laser. The profile of the activation function can be tailored by adjusting the injection-locked side-mode order, frequency detuning of the input optical signal, Henry factor, or bias current. The universal fitting function for both families of the activation functions is presented.

Pharmacists' considerations on non-medical switching at the hospital: a systematic review of the economic outcomes of cost-saving therapeutic drug classes.

OBJECTIVES: Non-medical switching (NMS) strategies have the capacity to reduce overall costs in hospitals while maintaining a high level of care. However, the most appropriate diseases and/or medicines for NMS strategies are still vague. The aim of this review was to give a state-of-the-art summary regarding the economic outcomes resulting from the use of NMS strategies and to discuss whether they would be implementable in a hospital inpatient setting. METHODS: A systematic literature search was conducted in Medline, Embase, and ScienceDirect. Studies published between 1988 and 2018 were included if they evaluated the economic impact of NMS strategies or if they performed an economic evaluation between two drugs. Studies regarding antineoplastic agents, endocrine therapies, and immunostimulants, or immunosuppressants, and biosimilars were excluded. RESULTS: Fifty (69%) studies assessing an NMS strategy and 22 (31%) studies comparing two medicines were allocated to four categories: prospective studies (n=8, 11%); retrospective chart reviews (n=29, 40%); retrospective claims analysis (n=13, 18%); and retrospective data analysis (n=22, 31%). Hypercholesterolemia, peptic ulcer, and gastro-oesophageal reflux diseases, diabetes mellitus, and venous thromboembolism were the most prevalent diseases in studies evaluating an NMS strategy. Sixty-eight per cent of the included papers reported a reduction in costs with no significant changes in health outcomes and 8 per cent reported a deterioration in health outcomes and/or increased costs. CONCLUSION: Regardless of the exclusion of studies regarding biologics or medicines used in oncology, the review highlights that NMS strategies with medicines whose management do not require a thorough clinical assessment were associated with reduced costs and no significant changes in patients' health outcomes, in the inpatient setting. NMS strategies targeting medicines that require an extensive clinical assessment should be evaluated using hospital-specific effectiveness and/or utility data prior to their implementation.

Binary polymeric amorphous carvedilol solid dispersions: In vitro and in vivo characterization.

Binary polymeric amorphous carvedilol solid dispersions were prepared using solvent method by varying solvent type, polymer type and carvedilol to polymer ratio in order to assess the influence of these factors and maximize carvedilol dissolution rate. Low and high molecular weight polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer were used as polymeric carriers in carvedilol to polymer ratios 1:1, 1:2 or 1:4, while absolute ethanol or acetone were used as solvents. Hard gelatin capsules were prepared with carvedilol solid dispersion and lactose monohydrate, mannitol or microcrystalline cellulose. FTIR and PXRD were used to detect carvedilol crystallinity and identify carvedilol-polymer interactions and carvedilol polymorphs. These techniques confirmed carvedilol transition to amorphous state and suggested that hydrogen bonds were formed between carvedilol and polymer molecules. Carvedilol dissolution rate was significantly higher from solid dispersions with higher carvedilol to polymer ratio and solid dispersions prepared using the solvent in which the polymer was more soluble. Solid dispersion with polyvinylpyrrolidone-vinyl acetate copolymer in 1:4 ratio in absolute ethanol displayed the highest carvedilol dissolution rate with 91.78% carvedilol dissolved in the first 30 min. Capsules prepared with the selected solid dispersion and microcrystalline cellulose as diluent displayed the highest carvedilol dissolution rate, with 93.43% carvedilol dissolved within the first 30 min. Carvedilol bioavailability was significantly increased by formulating solid dispersions, while the analysis of serum biochemical parameters excluded damage on liver and kidney function and the lipid profile of animals exposed to investigated drug delivery system.

Power efficient optical frequency comb generation using laser gain switching and dual-drive Mach-Zehnder modulator.

We propose and experimentally demonstrate a power efficient dual-stage optical frequency comb using laser gain switching followed by a dual-drive Mach-Zehnder modulator (DD-MZM). The laser is initially gain switched at ∼ 9.5 GHz and the resultant comb is then expanded using a dual-drive Mach-Zehnder modulator driven at ∼ 19 GHz with signal amplitudes below 1.5 V. The setup generates an optical frequency comb, with 12 lines within 3 dB flatness, in a power efficient manner. Theoretical analysis is presented and verified through simulation and experimental results.

Development of ternary solid dispersions with hydrophilic polymer and surface adsorbent for improving dissolution rate of carbamazepine.

In this study solid dispersions of carbamazepine in the hydrophilic Kollidon® VA64 polymer, adsorbed onto Neusilin® UFL2 adsorption carrier have been employed to improve carbamazepine dissolution rate. In order to evaluate effects of changing in the proportions of all solid dispersion components on carbamazepine dissolution rate, D-optimal mixture experimental design was used in the formulation development. From all prepared solid dispersion formulations, significantly faster carbamazepine dissolution was observed compared to pure drug. Ternary solid dispersions containing carbamazepine, Kollidon® VA64 and Neusilin® UFL2 showed superior dissolution performances over binary ones, containing only carbamazepine and Neusilin® UFL2. Proportion of Kollidon® VA64 showed the most profound effect on the amount of carbamazepine dissolved after 10 and 30 min, whereby these parameters increase upon increasing in Kollidon® VA64 concentrations up to the middle values in the studied range of Kollidon® VA64 concentrations. Physicochemical characterization of the selected samples using differential scanning calorimetry, FT-IR spectroscopy, powder X-ray diffraction and polarizing light microscopy showed polymorphic transition of carbamazepine from more thermodynamically stable monoclinic form (form III) to less thermodynamically stable triclinic form (form I) in the case of ternary, but not of binary solid dispersion formulations. This polymorphic transition can be one of the factors responsible for improving of carbamazepine dissolution rate from studied solid dispersions. Ternary solid dispersions prepared with Kollidon® VA64 hydrophilic polymer and Neusilin® UFL2 adsorption carrier resulted in significantly improvement of carbamazepine dissolution rate, but formation of metastable polymorphic form of carbamazepine requires particular care to be taken in ensuring product long term stability.

Analytical Approaches to the Characterization of Solid Drug Delivery Systems with Porous Adsorbent Carriers.

A large variety of analytical techniques are available to meet the needs of characterization of solid samples. But, when solid drug delivery systems are concerned we are faced with demanding methodologies which have to compile capabilities of analytical techniques in regard to large diversity of structures and surface functionality of analyzed adsorbent carriers. In this review, the most commonly used analytical techniques are presented with their basic principles, advantages and disadvantages in applications of interest. Adsorbent carriers are widely used today as ingredients in the formulation of pharmaceutical forms, for increasing the dissolution rate of the drug and hence the bioavailability. They are also used in the formulation of substances with modified or target drug release into a specific tissue. Methods of thermal analysis (Thermogravimetry - TGA, Differential Scanning Calorimetry - DSC and Thermal microscopy - TM), spectroscopic methods (Infrared Spectroscopy - IR, especially Fourier Transform Infrared Spectroscopy - FTIR and Raman spectroscopy), crystallographic methods (Powder X-Ray Diffraction - PXRD) and finally Scanning Electron Microscopy (SEM) are the most powerful in the characterization of modern therapeutic systems with porous adsorbents. The problem-solving power of each particular analytical method is often enhanced by using simultaneous methods rather than a single technique.

Formulation and characterization of nanofibers and films with carvedilol prepared by electrospinning and solution casting method.

The preparation and characterization of films and nanofibers with carvedilol as a poorly water-soluble drug in poly (ethylene oxide) (PEO) polymer were investigated. Films are prepared by solution casting method, and nanofibers by electrospinning from a polymer solution. Water and mixture of ethanol and water were used as solvents. FT-IR analysis of the samples showed that there was no interaction between the polymer and the drug substance. DSC analysis revealed that carvedilol was dissolved in the polymer and influenced the degree of crystallinity of PEO. Carvedilol release rate for all of the formulations was increased in comparison with pure carvedilol. Significant differences in the rate of release of carvedilol from the films and nanofibers were observed. Field Emission Scanning Electron Microscope (FESEM) images of the obtained fiber was revealed the dependence of the fiber diameter of formulation and electrospinning process parameters, and consequently influence the amount and distribution of carvedilol in the encapsulated fibers.

Influence of Solid Drug Delivery System Formulation on Poorly Water-Soluble Drug Dissolution and Permeability.

The majority of drugs have a low dissolution rate, which is a limiting step for their absorption. In this manuscript, solid dispersions (SD), solid self-microemulsifying drug delivery systems (S-SMEDDS) and solid self-nanoemulsifying drug delivery systems (S-SNEDDS) were evaluated as potential formulation strategies to increase the dissolution rate of carbamazepine. Influence of increased dissolution rate on permeability of carbamazepine was evaluated using PAMPA test. In S-SMEDDS and S-SNEDDS formulations, the ratio of liquid SMEDDS/SNEDDS and solid carrier (Neusilin(®) UFL2) was varied, and carbamazepine content was constant. In SD formulations, the ratio of carbamazepine and Neusilin(®) UFL2, was varied. Formulations that showed the best dissolution rate of carbamazepine (SD_1:6, SMEDDS_1:1, SNEDDS_1:6) were mutually compared, characterization of these formulations was performed by DSC, PXRD and FT-IR analyses, and a PAMPA test was done. All formulations have shown a significant increase in dissolution rate compared to pure carbamazepine and immediate-release carbamazepine tablets. Formulation S-SMEDDS_1:1 showed the fastest release rate and permeability of carbamazepine. DSC, PXRD and FT-IR analyses confirmed that in S-SMEDDS and S-SNEDDS carbamazepine remained in polymorph form III, and that it was converted to an amorphous state in SD formulations. All formulations showed increased permeability of carbamazepine, compared to pure carbamazepine.

Application of quality by design concepts in the development of fluidized bed granulation and tableting processes.

This study illustrates the application of experimental design and multivariate data analysis in defining design space for granulation and tableting processes. According to the quality by design concepts, critical quality attributes (CQAs) of granules and tablets, as well as critical parameters of granulation and tableting processes, were identified and evaluated. Acetaminophen was used as the model drug, and one of the study aims was to investigate the possibility of the development of immediate- or extended-release acetaminophen tablets. Granulation experiments were performed in the fluid bed processor using polyethylene oxide polymer as a binder in the direct granulation method. Tablets were compressed in the laboratory excenter tablet press. The first set of experiments was organized according to Plackett-Burman design, followed by the full factorial experimental design. Principal component analysis and partial least squares regression were applied as the multivariate analysis techniques. By using these different methods, CQAs and process parameters were identified and quantified. Furthermore, an in-line method was developed to monitor the temperature during the fluidized bed granulation process, to foresee possible defects in granules CQAs. Various control strategies that are based on the process understanding and assure desired quality attributes of the product are proposed.

Design space approach in optimization of fluid bed granulation and tablets compression process.

The aim of this study was to optimize fluid bed granulation and tablets compression processes using design space approach. Type of diluent, binder concentration, temperature during mixing, granulation and drying, spray rate, and atomization pressure were recognized as critical formulation and process parameters. They were varied in the first set of experiments in order to estimate their influences on critical quality attributes, that is, granules characteristics (size distribution, flowability, bulk density, tapped density, Carr's index, Hausner's ratio, and moisture content) using Plackett-Burman experimental design. Type of diluent and atomization pressure were selected as the most important parameters. In the second set of experiments, design space for process parameters (atomization pressure and compression force) and its influence on tablets characteristics was developed. Percent of paracetamol released and tablets hardness were determined as critical quality attributes. Artificial neural networks (ANNs) were applied in order to determine design space. ANNs models showed that atomization pressure influences mostly on the dissolution profile, whereas compression force affects mainly the tablets hardness. Based on the obtained ANNs models, it is possible to predict tablet hardness and paracetamol release profile for any combination of analyzed factors.