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Mucoadhesive buccal films have found increased popularity in pharmaceutical drug delivery due to the several advantages that they possess. The present study strives to develop and optimize chitosan-based mucoadhesive buccal films by relying on quality-by-design (QbD) principles. Previous knowledge and experience were employed to firstly identify the critical quality attributes (CQAs), followed by a thorough risk assessment, which led to the selection of seven critical material attributes and process parameters, namely, the polymer grade and concentration, the plasticizer type and concentration, the citric acid (CA) concentration, the amount of the casted solution, and the drying condition. Their effects on the breaking hardness and mucoadhesivity, selected as CQAs, were investigated in three steps by three designs of the experiment (DoE). The medium molecular weight of chitosan (CH) was the preferred choice in the optimized formulation, and its concentration was the most important factor affecting the CQAs, thickness, and moisture content of the films. It was found that 0.364 g/cm2 was the suitable amount of the casting solution, and its optimum drying conditions were presented in the form of a design space. Glycerol (Gly) was the best choice as a plasticizer, and a design space representing several combinations of CH and CA concentrations that produce films with the required quality was constructed at a fixed concentration of 35% Gly. A formula from this design space was selected and employed to load with two model drugs to test its drug-carrying properties for drugs with different physicochemical characteristics. Uniform drug distribution with an immediate release profile was achieved in both drugs, although one of the CQAs was outside of the specifications in the case of lidocaine-containing film. To summarize, the obtention of the optimum mucoadhesive buccal film based on CH was efficiently facilitated by the rational application of QbD principles and the DoE approach.

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Endometriosis is described as the implantation of ectopic, viable endometrium. Among the complications associated with this phenomenon, ectopic foci that localizes to the bowel can result in many presentations. An uncommon presentation of such an occurrence is a mass effect on the colon causing an obstruction. This case report describes the progression of endometriosiscausing mass effect in the colon and resulting in perforated hollow viscous. Hence, this demonstrates the importance of maintaining endometriosis as a differential diagnosis in women of childbearing age presenting with bowel obstruction. Although the presence of endometriosis as a cause of bowel obstruction has been reported in the literature, the presentation of large bowel perforation is rare. In this case, an extremely rare presentation of sigmoid obstruction with transverse colonic perforation is observed.

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Triceps tendon avulsion is a rare but debilitating condition and the least frequent of all tendon injuries, but it is receiving increasing attention in the literature. The most common mechanism of injury is resisted extension, which is typically seen in a fall onto an extended hand. Such injuries are easily overlooked and should be considered a differential diagnosis in all patients who describe pain and swelling at the posterior aspect of the elbow following a traumatic event. Non-operative management is the general principle for partial rupture as opposed to a variety of surgical treatments for a complete avulsion. The goal of this meta-analysis is to analyse the current literature on triceps avulsion and provide a detailed overview of the occurrence, diagnosis, treatment options and outcomes, comparison of various repair techniques, and consequences of this injury.

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In this study, we examined the activation of non-canonical nuclear factor Kappa B (NFκB) signalling in U2OS cells, a cellular metastatic bone cancer model. Whilst Lymphotoxin α1ß2 (LTα1ß2) stimulated the expected slow, delayed, sustained activation of serine 866/870 p100 phosphorylation and increased cellular expression of p52 NFκB, we found that canonical agonists, Interleukin-1ß (IL-1ß) and also Tumour necrosis factor-α (TNFα) generated a rapid transient increase in pp100, which was maximal by 15-30 min. This rapid phosphorylation was also observed in other cells types, such as DU145 and HCAECs suggesting the phenomenon is universal. IKKα deletion using CRISPR/Cas9 revealed an IKKα-dependent mechanism for serine 866/870 and additionally serine 872 p100 phosphorylation for both IL-1ß and LTα1ß2. In contrast, knockdown of IKKß using siRNA or pharmacological inhibition of IKKß activity was without effect on p100 phosphorylation. Pre-incubation of cells with the NFκB inducing-kinase (NIK) inhibitor, CW15337, had no effect on IL-1ß induced phosphorylation of p100 however, the response to LTα1ß2 was virtually abolished. Surprisingly IL-1ß also stimulated p52 nuclear translocation as early as 60 min, this response and the concomitant p65 translocation was partially reduced by IKKα deletion. Furthermore, p52 nuclear translocation was unaffected by CW15337. In contrast, the response to LTα1ß2 was essentially abolished by both IKKα deletion and CW15337. Taken together, these finding reveal novel forms of NFκB non-canonical signalling stimulated by ligands that activate the canonical NFκB pathway strongly such as IL-1ß.

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Aim Patients' perspectives on their condition and treatment, their sense of need for healthcare, and their preferences for care and outcomes are all addressed by quality of life metrics. Therefore, it is important to all health professionals and patients involved in orthopedic surgery. This study aimed to evaluate the quality of life after orthopedic procedures and how its results could potentially be used for future improvement. Methods This is a cross-sectional study conducted among patients who underwent orthopedic procedures at Buraydah Central Hospital (BCH) and King Fahad Specialist Hospital (KFSH). A self-administered questionnaire was distributed among the patients using a paper questionnaire. The questionnaire was composed of socio-demographic data (e.g. age, gender, education, etc.) and the 36-Item Short Form Survey (SF-36) to measure patients' quality of life. Results In this study, 215 patients were able to complete the survey (male 82.3% vs female 17.7%). The most common age group was 18 to 30 years old (30.2%) and the most common surgery performed on patients was thigh surgery (19.5%) and hand surgery (13%). The overall mean physical health score after the surgery was 51.1 (SD 11.8) higher than the mental health score (mean 47.7; SD 11.2). Poor quality of life was significantly more common among patients with chronic disease while poor physical functioning and general health subdomains were more associated among patients who underwent hand surgery. Conclusion Patients suffering from chronic diseases tend to exhibit a low quality of life as compared to other patients. The quality of life after the surgery is an important indicator of patient satisfaction which may have a direct impact on the future outlook of a patient. More research is needed to determine the overall quality of life in patients who underwent a surgical procedure in our region.

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In our study, core-shell nanoparticles containing lysozyme were formulated with precipitation and layering self-assembly. Factorial design (DoE) was applied by setting the process parameters during the preparation with Quality by Design (QbD) approach. The factors were the concentration of lysozyme and sodium alginate, and pH. Our aim was to understand the effect of process parameters through the determination of mathematical equations, based on which the optimization parameters can be predicted under different process parameters. The optimization parameters were encapsulation efficiency, particle size, enzyme activity and the amount of α-helix structure. The nanoparticles were analysed with transmission electron microscopy (TEM), Fourier-transform infrared spectroscopy (FTIR) and circular dichroism (CD) spectroscopy. Based on our results, we found that pH was the most important factor and pH 10 was recommended during the formulation. Enzyme activity and α-helix content correlated with each other very well, and particle size and encapsulation efficiency also showed very good correlation with each other. The results of the α-helix content of FTIR and CD measurements were very similar for the precipitated lysozyme due to the solid state of lysozyme. The mixing time had the best influence on the encapsulation efficiency and the particle size, which leads to the conclusion that a mixing time of 1 h is recommended. The novelty in our study is the presentation of a mathematical model with which the secondary structure of the protein and other optimization parameters can be controlled in the future during development of nanoparticle based on the process parameters.

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BRAFV600E mutation is the most frequent genetic alteration in papillary thyroid cancer (PTC). ß-Catenin (Ctnnb1) is a key downstream component of canonical Wnt signaling pathway and is frequently overexpressed in PTC. BRAF V600E-driven tumors have been speculated to rely on Wnt/ß-catenin signaling to sustain its growth, although many details remain to be elucidated. In this study, we investigated the role of ß-catenin in BrafV600E -driven thyroid cancer in a transgenic mouse model. In Braf V600E mice with wild-type (WT) Ctnnb1 (BVE-Ctnnb1WT or BVE), overexpression of ß-catenin was observed in thyroid tumors. In Braf V600E mice with Ctnnb1 knockout (BVE-Ctnnb1null), thyroid tumor growth was slowed with significant reduction in papillary architecture. This was associated with increased expression of genes involved in thyroid hormone synthesis, elevated 124iodine uptake, and serum T4. The survival of BVE-Ctnnb1null mice was increased by more than 50% during 14-month observation. Mechanistically, downregulation of MAPK, PI3K/Akt, and TGFß pathways and loss of epithelial-mesenchymal transition (EMT) were demonstrated in the BVE-Ctnnb1null tumors. Treatment with dual ß-catenin/KDM4A inhibitor PKF118-310 dramatically improved the sensitivity of BVE-Ctnnb1WT tumor cells to BRAFV600E inhibitor PLX4720, resulting in significant growth arrest and apoptosis in vitro, and tumor regression and differentiation in vivo These findings indicate that ß-catenin signaling plays an important role in thyroid cancer growth and resistance to BRAFV600E inhibitors. Simultaneously targeting both Wnt/ß-catenin and MAPK signaling pathways may achieve better therapeutic outcome in BRAFV600E inhibitor-resistant and/or radioiodine-refractory thyroid cancer.

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PURPOSE: Children's Oncology Group (COG) AALL0331 tested whether pegaspargase intensification on a low-intensity chemotherapy backbone would improve the continuous complete remission (CCR) rate in a low-risk subset of children with standard-risk B-acute lymphoblastic leukemia (ALL). METHODS: AALL0331 enrolled 5,377 patients with National Cancer Institute standard-risk B-ALL (age 1-9 years, WBC < 50,000/µL) between 2005 and 2010. Following a common three-drug induction, a cohort of 1,857 eligible patients participated in the low-risk ALL random assignment. Low-risk criteria included no extramedullary disease, < 5% marrow blasts by day 15, end-induction marrow minimal residual disease < 0.1%, and favorable cytogenetics (ETV6-RUNX1 fusion or simultaneous trisomies of chromosomes 4, 10, and 17). Random assignment was to standard COG low-intensity therapy (including two pegaspargase doses, one each during induction and delayed intensification) with or without four additional pegaspargase doses at 3-week intervals during consolidation and interim maintenance. The study was powered to detect a 4% improvement in 6-year CCR rate from 92% to 96%. RESULTS: The 6-year CCR and overall survival (OS) rates for the entire low-risk cohort were 94.7% ± 0.6% and 98.7% ± 0.3%, respectively. The CCR rates were similar between arms (intensified pegaspargase 95.3% ± 0.8% v standard 94.0% ± 0.8%; P = .13) with no difference in OS (98.1% ± 0.5% v 99.2% ± 0.3%; P = .99). Compared to a subset of standard-risk study patients given identical therapy who had the same early response characteristics but did not have favorable or unfavorable cytogenetics, outcomes were significantly superior for low-risk patients (CCR hazard ratio 1.95; P = .0004; OS hazard ratio 5.42; P < .0001). CONCLUSION: Standard COG therapy without intensified pegaspargase, which can easily be given as an outpatient with limited toxicity, cures nearly all children with B-ALL identified as low-risk by clinical, early response, and favorable cytogenetic criteria.

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Purpose: Adolescent and young adult (AYA) patients (15-39 years old) with acute lymphoblastic leukemia (ALL) have less favorable outcomes and higher treatment-related mortality as compared with older children with ALL. Minimal data exist regarding how well AYA patients tolerate the intensity of chemotherapy at doses and regimens designed for children, and the toxicities suffered by this population at children's hospitals have not been thoroughly characterized. Methods: Pediatric Health Information Systems database was queried to analyze health care outcomes in pediatric (ages 10-14) and AYA patients (ages 15-39) with ALL hospitalized between January 1999 and December 2014. We extracted relevant ICD-9 data for each patient related to grades 3 or 4 toxicities as outlined by the NCI. Results: A total of 5345 hospital admissions met inclusion criteria, representing 4046 unique patients. Of these admissions, 2195 (41.1%) were in the AYA age group, and the remainder were in the 10-14-year-old group. AYA patients had a significantly higher incidence of intensive care unit stay but no difference in median hospital stay nor mortality. AYA patients had increased toxicities in almost every organ system as compared with older children. Conclusions: In this large multicenter US database study, we found an overall increased number of toxicities among AYA patients with ALL in children's hospitals. Compared with children between the ages of 10 and 15, AYA patients developed disproportionately higher toxicities from drugs commonly used in pediatric protocols for ALL. Prospective studies are needed to assess whether dose modifications for certain chemotherapeutics may improve the toxicity profile and health care burden of AYA patients with ALL treated in children's hospitals.

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The oral delivery of biopharmaceuticals requires the including of absorption enhancer, protease inhibitor and a suitable carrier system. The aim of the present work was to formulate and characterize chitosan solutions/films incorporating citric acid (CA) as potential excipient in comparison to the well-known acetic acid (AA)-based films as a reference. Films were made by the solvent casting method with/without glycerol (G), propylene glycol (PG) and polyethylene glycol (PEG-400) as plasticizers. The minimum film forming temperature (MFFT) of the prepared solutions, film thickness, hardness/deformation, mucoadhesivity, moisture content, FT-IR spectra and surface free energy (SFE) were investigated. Chitosan has been reported as a safe and effective paracellular absorption enhancer for hydrophilic macromolecules, therefore there would be more rationale for incorporating CA as a solubility enhancer, a permeation enhancer and an enzyme inhibitor. CA shows good cross-linking, an ideal plasticizing property and increases both tensile strength and mucoadhesivity, thus its incorporation simplifies the formulation while improving effectiveness. We concluded that CA (3.5, 4 and 5 w/v %)-based chitosan solution could be used as a novel coating/subcoating polymer for oral macromolecule delivery, or as oral mucoadhesive films.

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OBJECTIVES: The main objective of present review is to explore and evaluate the effectiveness of recently developed methods to improve the bioavailability of orally administered biopharmaceutical drugs. METHODS: A systematic search of sciencedirect, tandfonline and Google Scholar databases based on various sets of keywords was performed. All results were evaluated based on their abstracts, and irrelevant studies were neglected during further evaluation. RESULTS: At present, biopharmaceuticals are used as injectable therapies as they are not absorbed adequately from the different routes of drug administration, particularly the oral one. Their insufficient absorption is attributed to their high molecular weight, degradation by proteolytic enzymes, high hydrophilicity and rigidity of the absorptive tissues. From industrial aspect incorporation of enzyme inhibitors (EIs) and permeation enhancers (PEs) and mucoadhesive polymers into conventional dosage forms may be the easiest way of formulation of orally administered macromolecular drugs, but the effectiveness of protection and absorption enhancement here is the most questionable. Conjugation may be problematic from regulatory aspect. Encapsulation into lipid-based vesicles sufficiently protects the incorporated macromolecule and improves intestinal uptake but have considerable stability issues. In contrast, polymeric nanocarriers may provide good stability but provides lower internalization efficacy in comparison with the lipid-based carriers. CONCLUSION: It can be concluded that the combination of the advantages of mucoadhesive polymeric and lid-based carriers in hybrid lipid/polymer nanoparticles may result in improved absorption and might represent a potential means for the oral administration of therapeutic proteins in the near future. Graphical abstract Delivery systems for oral protein daministration.

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PURPOSE: Children's Oncology Group (COG) AALL0331 tested whether intensified postinduction therapy that improves survival in children with high-risk B-cell acute lymphoblastic leukemia (ALL) would also improve outcomes for those with standard-risk (SR) ALL. PATIENTS AND METHODS: AALL0331 enrolled 5,377 patients between 2005 and 2010. All patients received a 3-drug induction with dexamethasone, vincristine, and pegaspargase (PEG) and were then classified as SR low, SR average, or SR high. Patients with SR-average disease were randomly assigned to receive either standard 4-week consolidation (SC) or 8-week intensified augmented Berlin-Frankfurt-Münster (BFM) consolidation (IC). Those with SR-high disease were nonrandomly assigned to the full COG-augmented BFM regimen, including 2 interim maintenance and delayed intensification phases. RESULTS: The 6-year event-free survival (EFS) rate for all patients enrolled in AALL0331 was 88.96% ± 0.46%, and overall survival (OS) was 95.54% ± 0.31%. For patients with SR-average disease, the 6-year continuous complete remission (CCR) and OS rates for SC versus IC were 87.8% ± 1.3% versus 89.1% ± 1.2% (P = .52) and 95.8% ± 0.8% versus 95.2% ± 0.8% (P = 1.0), respectively. Those with SR-average disease with end-induction minimal residual disease (MRD) of 0.01% to < 0.1% had an inferior outcome compared with those with lower MRD and no improvement with IC (6-year CCR: SC, 77.5% ± 4.8%; IC, 77.1% ± 4.8%; P = .71). At 6 years, the CCR and OS rates among 635 nonrandomly treated patients with SR-high disease were 85.55% ± 1.49% and 92.97% ± 1.08%, respectively. CONCLUSION: The 6-year OS rate for > 5,000 children with SR ALL enrolled in AALL0331 exceeded 95%. The addition of IC to treatment for patients with SR-average disease did not improve CCR or OS, even in patients with higher MRD, in whom it might have been predicted to provide more value. The EFS and OS rates are excellent for this group of patients with SR ALL, with particularly good outcomes for those with SR-high disease.

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The United States is currently experiencing an opioid crisis, with more than 47,000 deaths in 2017 due to opioid overdoses. Current approaches for opioid identification and quantification in body fluids include immunoassays and chromatographic methods (e.g., LC-MS, GC-MS), which require expensive instrumentation and extensive sample preparation. Our aim was to develop a portable point-of-care device that can be used for the instant detection of opioids in body fluids. Here, we reported the development of a morphine-sensitive fluorescence-based sensor chip to sensitively detect morphine in the blood using a homogeneous immunoassay without any washing steps. Morphine-sensitive illuminating peptides were identified using a high throughput one-bead one-compound (OBOC) combinatorial peptide library approach. The OBOC libraries contain a large number of random peptides with a molecular rotor dye, malachite green (MG), that are coupled to the amino group on the side chain of lysine at different positions of the peptides. The OBOC libraries were then screened for fluorescent activation under a confocal microscope, using an anti-morphine monoclonal antibody as the screening probe, in the presence and absence of free morphine. Using this novel three-step fluorescent screening assay, we were able to identify the peptide-beads that fluoresce in the presence of an anti-morphine antibody, but lost fluorescence when the free morphine was present. After the positive beads were decoded using automatic Edman microsequencing, the morphine-sensitive illuminating peptides were then synthesized in soluble form, functionalized with an azido group, and immobilized onto microfabricated PEG-array spots on a glass slide. The sensor chip was then evaluated for the detection of morphine in plasma. We demonstrated that this proof-of-concept platform can be used to develop fluorescence-based sensors against morphine. More importantly, this technology can also be applied to the discovery of other novel illuminating peptidic sensors for the detection of illicit drugs and cancer biomarkers in body fluids.

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INTRODUCTION: De Garengeot hernia was first described in 1731. It is rare type of hernia and there is no established mode of treatment for it to date. This work has been reported in line with the SCARE criteria (Agha et al., 2016). PRESENTATION OF CASE: We present a case of a 72 years old male with a non-reducible right inguinal swelling diagnosed to be a femoral hernia with congested appendix within. There are less than 100 cases like this reported to date in the literature. DISCUSSION: Acute appendicitis within the femoral hernia is not a common problem to cross paths with. Prompt early treatment is recommended and directed at repairing the hernia after appendectomy. The method of treatment is controversial and not well established due to the scarcity of cases but open repair without mesh is the preferred approach. CONCLUSION: De Garengeot hernia is a rare hernia to encounter. Imaging modalities are a major tool in early diagnosis and early prompt surgery is crucial in preventing major complications that may lead to unnecessary morbidity and mortality.

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Achievement of the optimal hydropower generation from operation of water reservoirs, is a complex problems. The purpose of this study was to formulate and improve an approach of a genetic algorithm optimization model (GAOM) in order to increase the maximization of annual hydropower generation for a single reservoir. For this purpose, two simulation algorithms were drafted and applied independently in that GAOM during 20 scenarios (years) for operation of Mosul reservoir, northern Iraq. The first algorithm was based on the traditional simulation of reservoir operation, whilst the second algorithm (Salg) enhanced the GAOM by changing the population values of GA through a new simulation process of reservoir operation. The performances of these two algorithms were evaluated through the comparison of their optimal values of annual hydropower generation during the 20 scenarios of operating. The GAOM achieved an increase in hydropower generation in 17 scenarios using these two algorithms, with the Salg being superior in all scenarios. All of these were done prior adding the evaporation (Ev) and precipitation (Pr) to the water balance equation. Next, the GAOM using the Salg was applied by taking into consideration the volumes of these two parameters. In this case, the optimal values obtained from the GAOM were compared, firstly with their counterpart that found using the same algorithm without taking into consideration of Ev and Pr, secondly with the observed values. The first comparison showed that the optimal values obtained in this case decreased in all scenarios, whilst maintaining the good results compared with the observed in the second comparison. The results proved the effectiveness of the Salg in increasing the hydropower generation through the enhanced approach of the GAOM. In addition, the results indicated to the importance of taking into account the Ev and Pr in the modelling of reservoirs operation.

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BACKGROUND: Obesity is a serious disease, with substantial morbidity and mortality. The endoscopic placement of an intragastric balloon (IGB) in association with a low-calorie diet is an option for the treatment of obesity. IGB complications include dislocation of the balloon causing intestinal obstruction, upper gastro-intestinal bleeding and perforation, especially during balloon insertion or removal. Our work aims at decreasing the morbidity of open laparotomy in the management of such gastric perforations. METHODS: We report three cases of gastric perforation following IGB insertion that needed surgical intervention. Decision was made to treat them with a minimally invasive combined endoscopic and laparoscopic approach to decrease postoperative morbidity. RESULTS: All patients were successfully treated by a minimally invasive approach with less morbidity than the conventional open laparotomy. CONCLUSION: Gastric perforation should be suspected in any patient with IGB who presents with an acute abdomen. This can be managed with a minimal invasive approach.

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Accurate detection of central nervous system (CNS) involvement in children with newly diagnosed acute lymphoblastic leukemia (ALL) could have profound prognostic and therapeutic implications. We examined various cerebrospinal fluid (CSF) preservation methods to yield adequate DNA stability for polymerase chain reaction (PCR) analysis and developed a quantitative real-time PCR assay to detect occult CNS leukemia. Sixty CSF specimens were maintained in several storage conditions for varying amounts of time, and we found that preserving CSF in 1:1 serum-free RPMI tissue culture medium offers the best stability of DNA for PCR analysis. Sixty CSF samples (30 at diagnosis and 30 at the end of induction therapy) from 30 children with ALL were tested for CNS leukemic involvement by real-time PCR using patient-specific antigen receptor gene rearrangement primers. Six of thirty patient diagnosis samples were PCR-positive at levels ranging from 0.5 to 66% leukemic blasts in the CSF. Four of these patients had no clinical or cytomorphological evidence of CNS leukemia involvement at that time. All 30 CSF samples drawn at the end of induction therapy were PCR-negative. The data indicate that real-time PCR analysis of CSF is an excellent tool to assess occult CNS leukemia involvement in patients with ALL and can possibly be used to refine CNS status classification.

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We report a 53 years old Saudi man a known diabetic for more than 15 years. He presented with lower abdominal pain, diarrhea and vomiting. He had symptoms and signs of sepsis. He had pancytopenia, renal failure, and his blood culture grew E.Coli. He remained febrile despite antibiotics administration for one week and developed crepitation over both thighs. Radiologically, plain-x ray, ultrasound and CT scan of the abdomen confirmed the presence of air in the left kidney involving the renal parenchyma and the collecting system and extensive gas in subcutaneous tissue of the thighs with abscesses. Repeated surgical drainage of the renal and the extra renal abscesses helped the antibiotic that was continued for several weeks to control the infection. Emphysematous pyelonephritis is a rare but life threatening condition that can be difficult to treat especially if the gas forming organism extends outside the kidney.