Rapidly Dissolving Trans-scleral Microneedles for Intraocular Delivery of Cyclosporine A.

Cyclosporine A (CsA) is a cyclic peptide immunosuppressant drug that is beneficial in the treatment of various ocular diseases. However, its ocular bioavailability in the posterior eye is limited due to its poor aqueous solubility. Conventional CsA formulations such as a solution or emulsion permeate poorly across the eye due to various static and dynamic barriers of the eye. Dissolvable microneedle (MN)-based patches can be used to overcome barrier properties and, thus, enhance the ocular bioavailability of CsA in the posterior eye. CsA-loaded dissolvable MN patches were fabricated using polyvinylpyrrolidone (PVP) and characterized for MN uniformity and sharpness using SEM. Further characterization for its failure force, penetration force, and depth of penetration were analyzed using a texture analyzer. Finally, the dissolution time, ex vivo permeation, and ocular distribution of cyclosporine were determined in isolated porcine eyes. PVP MNs were sharp, uniform with good mechanical properties, and dissolved within 5 min. Ocular distribution of CsA in a whole porcine eye perfusion model showed a significant increase of CsA levels in various posterior segment ocular tissues as compared to a topically applied ophthalmic emulsion (Restasis®) (P < 0.001). Dissolving MNs of CsA were prepared, and the MN arrays can deliver CsA to the back of the eye offering potential for treating various inflammatory diseases.

Discovery of Gamma Rays from the Quiescent Sun with HAWC.

We report the first detection of a TeV γ-ray flux from the solar disk (6.3σ), based on 6.1 years of data from the High Altitude Water Cherenkov (HAWC) observatory. The 0.5-2.6 TeV spectrum is well fit by a power law, dN/dE=A(E/1 TeV)^{-γ}, with A=(1.6±0.3)×10^{-12} TeV^{-1} cm^{-2} s^{-1} and γ=3.62±0.14. The flux shows a strong indication of anticorrelation with solar activity. These results extend the bright, hard GeV emission from the disk observed with Fermi-LAT, seemingly due to hadronic Galactic cosmic rays showering on nuclei in the solar atmosphere. However, current theoretical models are unable to explain the details of how solar magnetic fields shape these interactions. HAWC's TeV detection thus deepens the mysteries of the solar-disk emission.

Gentamicin Eluting 3D-Printed Implants for Preventing Post-Surgical Infections in Bone Fractures.

A surgically implantable device is an inevitable treatment option for millions of people worldwide suffering from diseases arising from orthopedic injuries. A global paradigm shift is currently underway to tailor and personalize replacement or reconstructive joints. Additive manufacturing (AM) has provided dynamic outflow to the customized fabrication of orthopedic implants by enabling need-based design and surface modification possibilities. Surgical grade 316L Stainless Steel (316L SS) is promising with its cost, strength, composition, and corrosion resistance to fabricate 3D implants. This work investigates the possibilities of application of the laser powder bed fusion (L-PBF) technique to fabricate 3D-printed (3DP) implants, which are functionalized with a multilayered antimicrobial coating to treat potential complications arising due to postsurgical infections (PSIs). Postsurgical implant-associated infection is a primary reason for implantation failure and is complicated mainly by bacterial colonization and biofilm formation at the installation site. PLGA (poly-d,l-lactide-co-glycolide), a biodegradable polymer, was utilized to impart multiple layers of coating using the airbrush spray technique on 3DP implant surfaces loaded with gentamicin (GEN). Various PLGA-based polymers were tested to optimize the ideal lactic acid: glycolic acid ratio and molecular weight suited for our investigation. 3D-Printed PLGA-GEN substrates sustained the release of gentamicin from the surface for approximately 6 weeks. The 3DP surface modification with PLGA-GEN facilitated cell adhesion and proliferation compared to control surfaces. The cell viability studies showed that the implants were safe for application. The 3DP PLGA-GEN substrates showed good concentration-dependent antibacterial efficacy against the common PSI pathogen Staphylococcus aureus (S. aureus) and Staphylococcus epidermidis (S. epidermidis). The GEN-loaded substrates demonstrated antimicrobial longevity and showed significant biofilm growth inhibition compared to control. The substrates offered great versatility regarding the in vitro release rates, antimicrobial properties, and biocompatibility studies. These results radiate great potential in future human and veterinary clinical applications pertinent to complications arising from PSIs, focusing on personalized sustained antibiotic delivery.

Deep Learning Technique-Enabled Web Application Firewall for the Detection of Web Attacks.

New techniques and tactics are being used to gain unauthorized access to the web that harm, steal, and destroy information. Protecting the system from many threats such as DDoS, SQL injection, cross-site scripting, etc., is always a challenging issue. This research work makes a comparative analysis between normal HTTP traffic and attack traffic that identifies attack-indicating parameters and features. Different features of standard datasets ISCX, CISC, and CICDDoS were analyzed and attack and normal traffic were compared by taking different parameters into consideration. A layered architecture model for DDoS, XSS, and SQL injection attack detection was developed using a dataset collected from the simulation environment. In the long short-term memory (LSTM)-based layered architecture, the first layer was the DDoS detection model designed with an accuracy of 97.57% and the second was the XSS and SQL injection layer with an obtained accuracy of 89.34%. The higher rate of HTTP traffic was investigated first and filtered out, and then passed to the second layer. The web application firewall (WAF) adds an extra layer of security to the web application by providing application-level filtering that cannot be achieved by the traditional network firewall system.

Inclusion Complex of Clomiphene Citrate with Hydroxypropyl-ß-Cyclodextrin for Intravenous Injection: Formulation and Stability Studies.

Clomiphene citrate is the first-line treatment for women with abnormal or failed ovulation. Currently, it is available as oral tablets, and the parenteral formulation does not exist. In this study, we prepared clomiphene citrate-hydroxypropyl-ß-cyclodextrin inclusion complex for its use in intravenous injection. The inclusion complex was characterized in the liquid state (phase solubility) and solid state by differential scanning calorimetry, Fourier transform infrared spectroscopy, and nuclear magnetic resonance spectroscopy analyses. The sterile intravenous injection containing 0.5% clomiphene citrate was prepared and characterized for its physical properties, assay, pH, and osmolality. A stability-indicating high-performance liquid chromatography (HPLC) method for the injection was developed. The HPLC method was validated for the assay, linearity, precision and repeatability, benchtop stability, and forced degradation to elute clomiphene isomers from the degradation products. The injection was packed in sterile 10-ml glass vials with butyl rubber stoppers and stored at 40°C, room temperature, and 4°C. The samples at 0, 0.5, 1, 2, 3, and 6 months were analyzed for clarity, pH, osmolality, and drug assay. The HPLC method was linear (R2 = 0.9999), precise (0.86% relative standard deviation), and stability indicating. The stability data at the accelerated (40°C) storage condition for 6 months showed satisfactory results: the drug assay in the injection was between 90 and 105%, the injection remained clear, pH was between 4.0 and 4.4, and osmolality was between 270 and 350 mOsm. The stability data suggests that the product is stable and meets the given analytical specifications.

Percutaneous absorption and Skin accumulation of Lorazepam-Diphenhydramine- Haloperidol Carbopol gel in Porcine Ear Skin.

This study presents the formulation and evaluation of an ABH Carbopol gel containing lorazepam (Ativan®), diphenhydramine hydrochloride (Benadryl®), and haloperidol (Haldol®) for treating chemotherapy-induced nausea and vomiting (CINV) in hospice patients. ABH PLO gel is widely used for this purpose due to its low cost and presumed efficacy. However, previous studies, including one conducted by the authors, have reported insufficient drug absorption from the ABH PLO gel. Here we hypothesized that the ABH Carbopol gel would provide superior percutaneous absorption of the drugs. ABH Carbopol gel was characterized for pH, viscosity, thermal properties, and infrared spectroscopy. The percutaneous absorption and skin retention of the gel was evaluated across porcine ear skin using Franz diffusion cells, and the drug concentrations were determined by high-performance liquid chromatography. The pH of the ABH Carbopol gel was found to be 6.80 ± 0.33, and the retention time of diphenhydramine, haloperidol, and lorazepam were 4.73, 7.11, and 18.69 minutes, respectively. The thermogram of the ABH Carbopol gel indicates the drugs were present in the dissolved state. Based on the flux data, the estimated steady-state concentration (Css) of diphenhydramine, haloperidol, and lorazepam were found to be 44.64 ng/ml, 2.58 ng/ml, and 20.1 ng/ml, respectively. These values were significantly higher than those obtained from the ABH PLO gel. In conclusion, the ABH Carbopol gel provides a promising alternative to the ABH PLO gel for treating CINV in hospice patients. Further studies are required to validate these findings in clinical settings.

3D-Printed Capsaicin-Loaded Injectable Implants for Targeted Delivery in Obese Patients.

Diet-induced obesity and hyperlipidemia are a growing public health concern leading to various metabolic disorders. Capsaicin, a major bioactive compound obtained from natural chili peppers, has demonstrated its numerous beneficial roles in treating obesity and weight loss. Current treatment involves either administration of antiobesity drugs or surgical procedures such as Roux-en-Y-gastric bypass or sleeve gastrectomy, both of which are associated with serious side effects and poor patient acceptance. Capsaicin, a pungent molecule, has low oral bioavailability. Therefore, there is a need for the development of site-specific drug delivery system for capsaicin. The present study is aimed at preparing and characterizing 3D-printed capsaicin-loaded rod-shaped implants by thermoplastic extrusion-based 3D printing technology. The implants were printed with capsaicin-loaded into a biodegradable polymer, polycaprolactone, at different drug loadings and infill densities. The surface morphology revealed a smooth and uniform external surface without any capsaicin crystals. DSC thermograms showed no significant changes/exothermic events among the blends suggesting no drug polymer interactions. The in vitro release studies showed a biphasic release profile for capsaicin, and the release was sustained for more than three months (~ 85% released) irrespective of drug loading and infill densities. The HPLC method was stability-indicating and showed good resolution for its analogs, dihydrocapsaicin and nordihydrocapsaicin. The implants were stable for three months at accelerated conditions (40°C) without any significant decrease in the assay of capsaicin. Therefore, capsaicin-loaded implants can serve as a long-acting injectable formulation for targeting the adipose tissue region in obese patients.

Reshaping healthcare supply chain using chain-of-things technology and key lessons experienced from COVID-19 pandemic.

The COVID-19 (Corona virus disease 2019) pandemic continues to slash through the entire humanity on the earth causing an international health crisis and financial uncertainty. The pandemic has formed a colossal disruption in supply chain networks. It has caused piling higher mortality in patients with comorbidities and generated a surging demand for critical care equipment, vaccines, pharmaceuticals, and cutting-edge technologies. Personal protective equipment, masks, ventilators, testing kits, and even commodities required for daily care have been scarce as lockdown and social distancing guidelines have kicked in. Amidst COVID-19, implementing and executing key processes of the healthcare supply chain (HSC) in a secured, trusted, effective, universally manageable, and the traceable way is perplexing owing to the fragile nature of the HSC, which is susceptible to redundant efforts and systemic risks that can lead to adverse impacts on consumer health and safety. Though the crisis shone a harsh light on the cracks and weaknesses of the HSC, it brings some significant insights into how HSC can be made more resilient and how healthcare industries figure out solutions to mitigate disruptions. While there are innumerable experiences learned from the disruption of this crisis, in this paper, five important areas to analyze the most vital and immediate HSC enhancements including building a resilient supply chain, thinking localization, implementing reliable reverse logistics, breaking down extant silos to achieve end-to-end visibility, and redesigning HSC using digitalization are emphasized. This work identifies important features related to CoT and HSC. Also, this study links these lessons to a potential solution through Chain of Things (CoT) technology. CoT technology provides a better way to monitor HSC products by integrating the Internet of Things (IoT) with blockchain networks. However, such an integrated solution should not only focus on the required features and aspects but also on the correlation among different features. The major objective of this study is to reveal the influence path of CoT on smart HSC development. Hence, this study exploits (i) fuzzy set theory to eliminate redundant and unrelated features; (ii) the Decision-Making and Experimental Evaluation Laboratory (DEMATEL) method to handle the intricate correlation among different features. This fuzzy-DEMATEL (F-DEMATEL) model attempts to direct CoT technology towards smart HSC by identifying the most influencing factors and investors are recommended to contribute to the development of application systems. This work also demonstrates how CoT can act a vital role in handling the HSC issues triggered by the pandemic now and in the post-COVID-19 world. Also, this work proposes different CoT design patterns for increasing opportunities in the HSC network and applied them as imperative solutions for major challenges related to traditional HSC networks.

A censorious review on the role of natural lignocellulosic fiber waste as a low-cost adsorbent for removal of diverse textile industrial pollutants.

BACKGROUND: Textile industries produce fabricated colored products using toxic dyes and other harsh chemicals. It is the responsibility of the textile industries to treat and eliminate these hazardous pollutants. However, due to the growing population demand, the treatment of these hazardous effluents is ineffective and imposes the treatment cost over the end users. The release of partially treated effluents in the environment may cause a severe threat to the ecology and its biota. The critical objective is to treat textile effluents efficiently using agricultural natural fiber waste. Generation of agricultural lignocellulosic fibrous waste increases every year due to growing population demand. Its use in the modern world is limited due to synthetic products. An alternative has enumerated to avoid wastage of fibrous resources and its clean disposal. OBJECTIVE: The main objective of this review paper discussed the feasibility of lignocellulosic fibers and other lignocellulosic materials as natural low-cost adsorbent. METHODS: The literature study was performed using Web of Science and Scopus indexed journals. The main factors considered to increase the adsorption ability, including the types of lignocellulosic surface modification techniques were searched with utmost importance for quality results. Intending to summarize the literature survey and provide persuasive content, systematic review process was considered for this novel article. RESULTS: Out of 230 valuable publications, 159 published articles were considered for the present study until March 2022. The articles surplus with factors affecting adsorption (pH, adsorption dosage, surface area, temperature, initial concentration, contact time, physical and chemical properties of pollutants) and surface modification techniques (physical, chemical, and biological) were considered for this manuscript. CONCLUSION: Overall, the physical and chemical modification methods are widely used instead of biological methods due to various factors as discussed briefly. Furthermore, the finding of this article supports the fact that the fibrous by-product resources are wasted in various occasions due to the modern lifestyle. Even though there is evidential possibility to implement the low-cost adsorbents, the industries limit their application prospects due to existing technology and financial compromises.

Cardiolipin for Enhanced Cellular Uptake and Cytotoxicity of Thermosensitive Liposome-Encapsulated Daunorubicin toward Breast Cancer Cell Lines.

Daunorubicin (DNR) and cardiolipin (CL) were co-delivered using thermosensitive liposomes (TSLs). 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1-myristoyl-2-stearoyl-sn-glycero-3-phosphocholine (MSPC), cholesterol, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] or DSPE-mPEG (2000) and CL were used in the formulation of liposomes at a molar ratio of 57:40:30:3:20, respectively. CL forms raft-like microdomains that may relocate and change lipid organization of the outer and inner mitochondrial membranes. Such transbilayer lipid movement eventually leads to membrane permeabilization. TSLs were prepared by thin-film hydration (drug:lipid ratio 1:5) where DNR was encapsulated within the aqueous core of the liposomes and CL acted as a component of the lipid bilayer. The liposomes exhibited high drug encapsulation efficiency (>90%), small size (~115 nm), narrow size distribution (polydispersity index ~0.12), and a rapid release profile under the influence of mild hyperthermia. The liposomes also exhibited ~4-fold higher cytotoxicity against MDA-MB-231 cells compared to DNR or liposomes similar to DaunoXome® (p < 0.001). This study provides a basis for developing a co-delivery system of DNR and CL encapsulated in liposomes for treatment of breast cancer.

Hispolon Cyclodextrin Complexes and Their Inclusion in Liposomes for Enhanced Delivery in Melanoma Cell Lines.

Hispolon, a phenolic pigment isolated from the mushroom species Phellinus linteus, has been investigated for anti-inflammatory, antioxidant, and anticancer properties; however, low solubility and poor bioavailability have limited its potential clinical translation. In this study, the inclusion complex of hispolon with Sulfobutylether-ß-cyclodextrin (SBEßCD) was characterized, and the Hispolon-SBEßCD Complex (HSC) was included within the sterically stabilized liposomes (SL) to further investigate its anticancer activity against melanoma cell lines. The HSC-trapped-Liposome (HSC-SL) formulation was investigated for its sustained drug delivery and enhanced cytotoxicity. The inclusion complex in the solid=state was confirmed by a Job's plot analysis, molecular modeling, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), Proton nuclear magnetic resonance (NMR) spectroscopy, and scanning electron microscopy (SEM). The HSC-SL showed no appreciable deviation in size (<150 nm) and polydispersity index (<0.2) and improved drug encapsulation efficiency (>90%) as compared to control hispolon liposomes. Individually incorporated hispolon and SBEßCD in the liposomes (H-CD-SL) was not significant in loading the drug in the liposomes, compared to HSC-SL, as a substantial amount of free drug was separated during dialysis. The HSC-SL formulation showed a sustained release compared to hispolon liposomes (H-SLs) and Hispolon-SBEßCD liposomes (H-CD-SLs). The anticancer activity on melanoma cell lines (B16BL6) of HSC and HSC-SL was higher than in H-CD-SL and hispolon solution. These findings suggest that HSC inclusion in the HSC-SL liposomes stands out as a potential formulation approach for enhancing drug loading, encapsulation, and chemotherapeutic efficiency of hispolon and similar water insoluble drug molecules.

Lysinated Multiwalled Carbon Nanotubes with Carbohydrate Ligands as an Effective Nanocarrier for Targeted Doxorubicin Delivery to Breast Cancer Cells.

Multiwalled carbon nanotubes (MWCNTs) are elongated, hollow cylindrical nanotubes made of sp2 carbon. MWCNTs have attracted significant attention in the area of drug delivery due to their high drug-loading capacity and large surface area. Furthermore, they can be linked to bioactive ligands molecules via covalent and noncovalent bonds that allow for the targeted delivery of anticancer drugs such as doxorubicin. The majority of methodologies reported for the functionalization of MWCNTs for drug delivery are quite complex and use expensive linkers and ligands. In the present study, we report a simple, cost-effective approach for functionalizing MWCNTs with the carbohydrate ligands, galactose (GA), mannose (MA) and lactose (LA), using lysine as a linker. The doxorubicin (Dox)-loaded functionalized MWCNTs were characterized using FT-IR, NMR, Raman, XRD and FE-SEM. The drug-loaded MWCNTs were evaluated for drug loading, drug release and cell toxicity in vitro, in breast cancer cells. The results indicated that the carbohydrate-modified lysinated MWCNTs had greater Dox loading capacity, compared to carboxylated MWCNTs (COOHMWCNTs) and lysinated MWCNTs (LyMWCNTs). In vitro drug release experiments indicated that the carbohydrate functionalized LyMWCNTs had higher Dox release at pH 5.0, compared to the physiological pH of 7.4, over 120 h, indicating that they are suitable candidates for targeting the tumor microenvironment as a result of their sustained release profile of Dox. Doxorubicin-loaded galactosylated MWCNTs (Dox-GAMWCNTs) and doxorubicin loaded mannosylated MWCNTs (Dox-MAMWCNTs) had greater anticancer efficacy and cellular uptake, compared to doxorubicin-loaded lactosylated MWCNTs (Dox-LAMWCNTs) and pure Dox, in MDA-MB231 and MCF7 breast cancer cells. However, neither the ligand conjugated multiwall blank carbon nanotubes (GAMWCNTs, MAMWCNTs and LAMWCNTs) nor the lysinated multiwalled blank carbon nanotubes produced significant toxicity in the normal cells. Our results suggest that sugar-tethered multiwalled carbon nanotubes, especially the galactosylated (Dox-GAMWCNTs) and mannosylated (Dox-MAMWCNTs) formulations, may be used to improve the targeted delivery of anticancer drugs to breast cancer cells.

Niosomal formulation of hydroxytyrosol, a polyphenolic antioxidant, for enhancing transdermal delivery across human cadaver skin.

Hydroxytyrosol (HT), a naturally occurring polyphenol from the olive plant, is a potent antioxidant, cardioprotective, neuroprotective, and anti-inflammatory agent. Upon oral administration, HT undergoes rapid elimination within minutes and thus limiting its therapeutic utility. Due to its hydrophilic nature, percutaneous absorption and transdermal delivery of HT are very low. The aim of this research was to enhance the skin permeation of hydroxytyrosol using a niosome gel formulation. The formulations prepared with Span 60 as surfactant showed uniform particle size and high encapsulation efficiency (>90%). The niosome formulations showed a pseudoplastic behavior for topical application within the lipid/surfactant composition of 45-50%. The formulations showed a controlled release of HT compared to the HT solution. The flux of HT across human skin was increased by 28 and 4.4 fold compared to aqueous and ethanolic HT solutions, respectively (p < 0.001). The presence of lecithin lowered the flux and increased the retention of the formulations compared to HT solutions (p < 0.001). The formulations containing lecithin showed two-fold higher skin retention of hydroxytyrosol (p < 0.05). In conclusion, this study demonstrates niosome gel as a promising alternative to oral delivery of HT, providing sustained delivery and greater efficacy.

Enhanced Topical Co-delivery of Acyclovir and Lidocaine Gel Formulation Across Dermatomed Human Skin.

Acyclovir a widely used drug in the treatment of herpes simplex virus (HSV) infections and lidocaine a local anesthetic were combined in a topical gel formulation. The topical gel with Transcutol P (TP) or N-methyl 2-pyrrolidone (NMP) was prepared and tested for in vitro skin permeation across the intact and microneedle-treated human cadaver skin. The topical gels containing 5% each of acyclovir and lidocaine showed optimal pH, spreadability, and 100% drug release. The transdermal flux and skin retention of the gels were significantly higher compared to Generic 5% acyclovir ointment (Zovirax) (p < 0.001), and 5% lidocaine gel (numb gel) (p < 0.05). As expected, topical gels showed a very high increase in the skin permeation across microporated skin versus intact skin. In viral infections, skin is inflamed, and barrier integrity may be disrupted. The results of the present study are significant because the co-delivery formulation showed a very high increase in the skin permeation across intact and microporated skin (versus respective commercial formulations). The results of this study demonstrate enhanced co-delivery of acyclovir and lidocaine in a topical formulation across skin (intact or barrier compromised) for the treatment of herpes virus infections.

Intelligent Approach to Network Device Migration Planning towards Software-Defined IPv6 Networks.

Internet and telecom service providers worldwide are facing financial sustainability issues in migrating their existing legacy IPv4 networking system due to backward compatibility issues with the latest generation networking paradigms viz. Internet protocol version 6 (IPv6) and software-defined networking (SDN). Bench marking of existing networking devices is required to identify their status whether the existing running devices are upgradable or need replacement to make them operable with SDN and IPv6 networking so that internet and telecom service providers can properly plan their network migration to optimize capital and operational expenditures for future sustainability. In this paper, we implement "adaptive neuro fuzzy inference system (ANFIS)", a well-known intelligent approach for network device status identification to classify whether a network device is upgradable or requires replacement. Similarly, we establish a knowledge base (KB) system to store the information of device internetwork operating system (IoS)/firmware version, its SDN, and IPv6 support with end-of-life and end-of-support. For input to ANFIS, device performance metrics such as average CPU utilization, throughput, and memory capacity are retrieved and mapped with data from KB. We run the experiment with other well-known classification methods, for example, support vector machine (SVM), fine tree, and liner regression to compare performance results with ANFIS. The comparative results show that the ANFIS-based classification approach is more accurate and optimal than other methods. For service providers with a large number of network devices, this approach assists them to properly classify the device and make a decision for the smooth transitioning to SDN-enabled IPv6 networks.

Retrospective analysis of the surgical management of spontaneous supratentorial intracerebral hemorrhage: A single-center study.

BACKGROUND: Intracerebral hemorrhage (ICH) remains a devastating disease with high morbidity and mortality. The mortality rate ranges from 40% at 1 month to 54% at 1 year, and only 12%-39% achieve good outcomes and functional independence. The current management guidelines for spontaneous supratentorial ICH are still controversial. OBJECTIVE: Patients who presented with ICH and underwent craniotomy with hematoma evacuation or minimal procedures from January 2016 to May 2020 were included in the analysis. Several clinical, radiological, and surgical variables were collected to identify the variables most likely related to lower mortality and better functional outcomes. RESULTS: A total of 87 patients presented with HMC with ICH from January 2016 to May 2020. The mean age was 44.7 (42.2-47.2) years. There were 76 male (87.4%)/11 female (12.6%) patients, which reflect the population distribution in Qatar, which is mainly male predominant. Although Qatar is mainly a Middle-Eastern country, the ethnic distribution of patients was mainly of South Asian and Indian (60.9%) and Far-Eastern (20.7%) ethnicities because of diversity. The mean baseline Glasgow coma scale (GCS) was 8.2+/ - 3.7. The mean baseline functional independence measure (FIM) score was 59.4+/ - 36.7. Most hematomas were located in the basal ganglia (79.3%%). Baseline characteristics based on long-term outcomes are summarized in Table 1. The following variables were correlated with poor outcome: low GCS on postoperative day 1 (P = 0.06), low FIM score (P = 0.006), ICH location (P = 0.04), distance of the closest point to the surface (P = 0.009), and presence of uncal herniation (P = 0.04). The baseline characteristics based on mortality are outlined in Table 2. The following variables were correlated with mortality: diabetes mellitus (P = 0.02), baseline GCS (P = 0.04), GCS on postoperative day 1 (P = 0.002), unequal pupils (P = 0.05), and postoperative midline shift (P = 0.001). CONCLUSION: The preoperative clinical neurological status as well as mass effect (uncal herniation and midline shift) can be determinants of functional outcome and mortality. A deeper hematoma may result in poor functional outcome because of more surgical damage in functional brain tissues. Thus, the goal of surgery in spontaneous supratentorial ICH is to reduce mortality, but no evidence support that it can improve functional outcome. Although our findings are interesting, more prospective studies with a larger sample size are needed to confirm our results.

Stability-indicating HPLC method for acyclovir and lidocaine in topical formulations.

A simple, rapid and accurate stability-indicating HPLC assay was developed for the determination of acyclovir and lidocaine in topical formulations. Chromatographic separation of acyclovir and lidocaine was achieved using a reversed-phase C18 column and a gradient mobile phase (20 mm ammonium acetate pH 3.5 in water and acetonitrile). The degradation products of acyclovir and lidocaine in the samples were analyzed by ultra performance liquid chromatography-time of flight mass spectrometry. The HPLC method successfully resolved the analytes from the impurities and degradation products in the topical formulation. Furthermore, the method detected the analytes from the human skin leachables following the extraction of the analytes in the skin homogenate samples. The method showed linearity over wide ranges of 5-500 and 10-200 µg/ml for acyclovir and lidocaine in the topical product, respectively, with a correlation coefficient (r2 ) >0.9995. The relative standard deviations for precision, repeatability, and robustness of the method validation assays were <2%. The skin extraction efficiency for acyclovir and lidocaine was 92.8 ± 0.7% and 91.3 ± 3.2%, respectively, with no interference from the skin leachables. Thus, simultaneous quantification of acyclovir and lidocaine in the topical formulations was achieved.

Co-Delivery of Hispolon and Doxorubicin Liposomes Improves Efficacy Against Melanoma Cells.

Hispolon is a small molecular weight polyphenol that has antioxidant, anti-inflammatory, and anti-proliferative activities. Our recent study has demonstrated hispolon as a potent apoptosis inducer in melanoma cell lines. Doxorubicin is a broad spectrum first-line treatment for various kinds of cancers. In this study, co-delivery of doxorubicin and hispolon using a liposomal system in B16BL6 melanoma cell lines for synergistic cytotoxic effects was investigated. Liposomes were prepared using a lipid film hydration method and loaded with doxorubicin or hispolon. The formulations were characterized for particle size distribution, release profile, and encapsulation efficiency (EE). In addition, in vitro cytotoxicity, in vitro cell apoptosis, and cellular uptake were evaluated. Liposomes exhibited small particle size (mean diameter ~ 100 nm) and narrow size distribution (polydispersity index (< 0.2) and high drug EE% (> 90%). The release from liposomes showed slower release compared to free drug solution as an additional time required for the release of drug from the liposome lipid bilayer. Liposome loaded with doxorubicin or hispolon exhibited significantly higher cytotoxicity against B16BL6 melanoma cells as compared to doxorubicin solution or hispolon solution. Likewise, co-delivery of hispolon and doxorubicin liposomes showed two-fold and three-fold higher cytotoxicity, as compared to hispolon liposomes or doxorubicin liposomes, respectively. In addition, co-delivery of doxorubicin and hispolon in liposomes enhanced apoptosis more than the individual drugs in the liposome formulation. In conclusion, the co-delivery of hispolon and doxorubicin could be a promising therapeutic approach to improve clinical outcomes against melanoma.

The SmoCar Study: A Caribbean-Based Multicenter Study on the Prevalence and Disparities Linked to Smoking and Gingival Health.

The aim of the SmoCar (Smoking in the Caribbean) study was to estimate the prevalence of smoking and the disparities in the smoking practices of three regions in the Caribbean: Jamaica, Dominican Republic, and Puerto Rico. The secondary objective was to assess the prevalence and severity of gingivitis in relation to the smoking practices. The study population comprised 1,847 (weighted N = 1,830) individuals (18 years and older) who were volunteer participants from the capitals of Jamaica, Dominican Republic, and Puerto Rico. A structured interview was used to assess the participants' smoking behaviors. The gingival index was used to determine the extent of gingival inflammation. Polytomous regression was used to estimate the adjusted odds ratios (aORs) for smoking status (current, past, or never), according to risk factors (sex, age-group, education, marital status, tooth-brushing frequency, and city of residence). Logistic regression models were used to assess the associations between different smoking status variables and mild to moderate/severe gingivitis. The majority of the participants were never-smokers, with current smokers being found most commonly in Kingston (33.22%), followed by San Juan (12.76%) and Santo Domingo (8.8%). Both current (aOR = 2.22, 95% confidence interval [1.45, 3.40]) and past (aOR = 1.87, 95% confidence interval [1.19, 2.93]) smoking (vs. never smoking) was strongly associated with severe gingivitis. Smoking was the most prevalent in Jamaicans and the least prevalent in Dominicans. The study population of current smokers was found to have a fourfold increased risk of severe gingivitis and a twofold increased risk of moderate gingivitis.

Protein kinases orchestrate cell cycle regulators in differentiating BeWo choriocarcinoma cells.

Choriocarcinoma, a trophoblastic neoplasia, occurs in women as an incidence of abnormal pregnancy. BeWo choriocarcinoma cells derived from the abnormal placentation are a suitable model system to study the factors associated with differentiation, invasion and other cellular events as an alternative to clinical samples. Many protein kinases orchestrate the complex events of cell cycle and in case of malignancy such regulators are found to be mutated. In the present study, BeWo cells treated with forskolin (Fo) and phorbol 12-myristate 13-acetate (PMA) were used to study the role of PKA (protein kinase A) and PKC (protein kinase C), respectively, on the expression pattern of differentiation-related genes, membrane markers, PKC isoforms and cell cycle regulators. The effect of Fo and PMA on the cell proliferation was assessed. Progressive induction of alkaline phosphatase level and formation of multinucleated differentiated cells were observed in the cells treated with Fo. Exposure of cells to Fo and PMA induced the mRNA transcripts of α-hCG, ß-hCG and endoglin and down-regulates E-cadherin at mRNA and protein levels. Synergistic levels of both up- and down-regulated genes/proteins were observed when cells were treated with the combination of Fo and PMA. The mRNA levels of cyclin D1, cyclin E1, p21, Rb, p53, caspase-3 and caspase-8 decreased gradually during differentiation. Fo significantly inhibited the protein levels of PCNA, Rb, PKC-α and PMA stimulated mRNA expression of PKC-ε and PKC-δ. Further, failure in the activation of essential components of the cell cycle machinery caused G2/M phase arrest in differentiating BeWo cells.