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The fabrication of covalently cross-linked high-surface-area biopolymeric nanogel fibers by nanopore extrusion is reported for the first time. The biopolymer pullulan was functionalized with tert-butyl acetoacetate via a transesterification reaction to synthesize the water-soluble ketone-rich precursor pullulan acetoacetate (PUAA). PUAA and carbonic dihydrazide (CDH) as cross-linker were extruded through anodic aluminum oxide (AAO) nanoporous membranes, which possessed an average pore diameter of 61 ± 2 nm. By changing the concentration of PUAA, the flow rate, and extrusion time, the step polymerization cross-linking reaction was controlled so that the polymer can be extruded gradually during cross-linking through the membrane, avoiding the formation of macroscopic bulk hydrogels and rupture of the AAO membrane. Fibers with diameters on the order of 250 nm were obtained. This approach was also expanded to functionalized PUAA derivatives together with the fluorogenic substrate 4-methylumbelliferyl-β-d-glucuronide MUGlcU in (PUAA-MUGlcU), which exhibited a mean equilibrium swelling ratio of 5.7 and 9.0 in Milli-Q water and in phosphate-buffered saline, respectively. β-Glucuronidase was sensitively detected via fluorescence of 4-methylumbelliferone, which was liberated in the enzymatic hydrolysis reaction of PUAA-MUGlcU. Compared to hydrogel slabs, the rate of the hydrolysis was >20% higher in the nanogel fibers, facilitating the rapid detection of β-glucuronidase-producing Escherichia coli (E. coli Mach1-T1). Nanopore extruded nanogel fibers are therefore considered a viable approach to enhance the functionality of hydrogels in surface-dominated processes.

Background. Early mobilisation of patients in the intensive care unit (ICU) is associated with positive health benefits. Research literature lacks insight into the current status of ICU physical therapy (PT) practice in the Kingdom of Saudi Arabia. Aim. To determine the current standard of ICU PT practice, attitude, and barriers. Methods. A questionnaire was e-mailed to physiotherapists (PTs) working in the hospital. The questions pertained to experience, qualification, barriers, and most frequently encountered case scenarios in the ICU. Results. The response rate was 28.1% (124/442). Frequent cases referred to the PTs were traumatic paraplegia (n = 111, 89%) and stroke (n = 102, 82.3%) as compared to congestive heart failure (n = 20, 16.1%) and pulmonary infections (n = 7, 5.6%). The preferred treatment of choice among PTs was chest physiotherapy (n = 102, 82.2%) and positioning (n = 73, 58.8%), whereas functional electrical stimulation (n = 12, 9.6%) was least preferred irrespective of the condition. Perceived barriers in the ICU PT management were of low confidence in managing cases (n = 89, 71.7%) followed by inadequate training (n = 53, 42.7%), and the least quoted barrier was a communication gap between the critical care team members (n = 8, 6.4%). Conclusion. PTs reported significant variation in the choice of treatment for different clinical cases inside ICU. The main barriers in the ICU setting were low confidence and inadequate training.

HIV-1 encodes a viral protease that is essential for the maturation of infectious viral particles. While protease inhibitors are effective antiretroviral agents, recent studies have shown that prematurely activating, rather than inhibiting, protease function leads to the pyroptotic death of infected cells, with exciting implications for efforts to eradicate viral reservoirs. Despite 40 years of research into the kinetics of protease activation, it remains unclear exactly when protease becomes activated. Recent reports have estimated that protease activation occurs minutes to hours after viral release, suggesting that premature protease activation is challenging to induce efficiently. Here, monitoring viral protease activity with sensitive techniques, including nanoscale flow cytometry and instant structured illumination microscopy, we demonstrate that the viral protease is activated within cells prior to the release of free virions. Using genetic mutants that lock protease into a precursor conformation, we further show that both the precursor and mature protease have rapid activation kinetics and that the activity of the precursor protease is sufficient for viral fusion with target cells. Our finding that HIV-1 protease is activated within producer cells prior to release of free virions helps resolve a long-standing question of when protease is activated and suggests that only a modest acceleration of protease activation kinetics is required to induce potent and specific elimination of HIV-infected cells. IMPORTANCE HIV-1 protease inhibitors have been a mainstay of antiretroviral therapy for more than 2 decades. Although antiretroviral therapy is effective at controlling HIV-1 replication, persistent reservoirs of latently infected cells quickly reestablish replication if therapy is halted. A promising new strategy to eradicate the latent reservoir involves prematurely activating the viral protease, which leads to the pyroptotic killing of infected cells. Here, we use highly sensitive techniques to examine the kinetics of protease activation during and shortly after particle formation. We found that protease is fully activated before virus is released from the cell membrane, which is hours earlier than recent estimates. Our findings help resolve a long-standing debate as to when the viral protease is initially activated during viral assembly and confirm that prematurely activating HIV-1 protease is a viable strategy to eradicate infected cells following latency reversal.

High-utility itemset mining (HUIM), which is the detection of high-utility itemsets (HUIs) in a transactional database, provides the decision maker with greater flexibility to exploit item utilities, such as quantity and profits, to extract remarkable and efficient database patterns. However, most prevailing empirical articles have focused on HUIs. Nevertheless, in many practical situations, low-utility itemsets (LUIs) maintain a high level of significance and usage (e.g., in security systems and the low-utility itemsets represent the security system vulnerabilities that need monitoring). Hence, this paper proposes a new association rule mining (ARM) framework named low-utility itemset mining (LUIM) that extracts LUIs. Enhancing the performance of LUIM, the researchers here propose innovative HUI generators, determining the generators based on the itemset transaction weight utility (TWU) rather than the support values used in HUG-Miner and GHUI-Miner. Moreover, this paper offers two efficient algorithms called LUG-Miner and LUIMA. The LUG-Miner extracts high and low-utility generators while LUIMA extracts low-utility itemsets using low-utility generators (LUGs). The experimental results on both dense and sparse datasets illuminated the recommended framework, and the algorithms are efficiently operational.

Background: Mental stigma represents a critical obstacle for delivering mental health care. Aims: To determine public stigma, knowledge & behaviors of the attendees of outpatient clinics towards People with Mental Illness (PWMI), King Abdulaziz University Hospital (KAUH), Jeddah, Saudi Arabia. Methods: A cross-sectional study was done in 2018. A sample of 600 attendees of outpatient clinics of KAUH were included. A standardized interviewing data collection sheet was used. It included three scales namely: the Community Attitudes towards the Mentally Ill (CAMI), Mental Health Knowledge Schedule (MAKS) & Reported and Intended Behavior Scale (RIBS). Authoritarian, socially restrictiveness, benevolent & Community Mental Health Ideology of CAMI sub-scales were calculated. Descriptive, inferential, and multiple linear regression analyses were applied. Results: About two-thirds of the participants agreed that mental illness causes lacking self-discipline & will power. Gender was significantly associated with all CAMI sub-scales (P < 0.01). An increasing level of knowledge about mental illness was associated with lower stigma towards PWMI (P< 0.001). After controlling confounders in regression analyses, gender and knowledge were significant predictors of all CAMI sub-scales. Concerning MAKS, about half of participants incorrectly identified stress & grief as types of mental illness. Regarding RIBS, living with (30.2%), and having a neighbor (28.8%) with mental illness were the commonest reported experiences. Conclusions: Negative attitudes towards PWMI still prevailed. Mental stigma was higher among males, older people, lower-educators, lower-income & those with poor mental knowledge. Participants had a moderate intention to accept PWMI. Anti-stigma intervention educational programs are required.

One of the major concerns in Evolutionary Algorithms is the premature convergence caused by what is known as the Exploration and Exploitation Balance problem. To maintain this balance, population diversity should be maintained during the initialization/optimization process. Maintaining diversity can be done through different strategies, but they commonly answer one question: when to introduce more diversity to the population? To answer this question there should be diversity metrics upon which a decision can be made to add diversity; consequently, add/reduce exploration/exploitation. There are as many diversity metrics as many problems and representations. That is, diversity metrics are very problem-specific. This work provides diversity metrics for the variable-length chromosome Genetic Algorithm for Shortest Path. The suggested metrics consider the varying lengths of the chromosomes, problem representation, and the search space. To measure chromosome-length diversity, a novel chromosome-length-based metric has been proposed. By exploiting the fact that the possible genes that can form any chromosome are well known in this specific direct-encoded population, a new simple metric that measures the representation of genes in the initial population is proposed and experimentally investigated. The presented metrics put through an extensive simulation and comparatively studied. Relationship between the proposed metrics has been quantified using Principal Component Analysis under varying network/population sizes.

The purpose of this research was to evaluate the efficacy of carsil (CAR) either alone or in combination with α-tocopherol (α-TOCO) and/or turmeric (TUMR) against tetrachloromethane (TCM)-induced cardiomyocyte injury in rats. Administration of CAR either alone or in combination with α-TOCO and/or TUMR post-TCM injection, significantly mitigated the increases in serum troponin T, creatine kinase-MB (CK-MB) as well as interleukin-6 (IL-6), interferon γ (IFN-γ), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP). They also decline the elevation of caspase-3, vascular endothelial growth factor (VEGF) protein expression as well as DNA damage in cardiac tissues induced by TCM. The biochemical results were confirmed by histopathological investigation. Conclusion: The combination of the three antioxidants showed greater cardioprotective potential, compared to individual drugs. Therefore, this combination may be recommended as a complementary therapy to antagonize cardiac injury induced by different insults.

Mercury is the third most hazardous heavy metal and its toxicity causes a severe health risk through unfavorable detrimental pathological and biochemical effects. Mercury is widely found in many ecological and certain occupational settings. Objectives The aim of this study is to elucidate the neuroprotective role of vitamin E (VE) and Lactobacillus plantarum (LTB) either alone or in combination against a toxic sublethal dose of Mercuric chloride (MC). Methods First group served as a normal control group; rats from the second group were intoxicated with(5 mg/kg MC once daily); the third group was treated with VE; the fourth group was treated with LTB; and the fifth group was treated with VE and LTB. All treatments were given daily along with MC for fourteen days. Results The results of the current study confirmed that MC prompted an elevation in serum TNF-α, IL-6 and brain lipid peroxides , protein expression of mitogen-activated protein kinase (MAPK) and mRNA expression of Bax and caspase -3 level as well as DNA degradation. However, Brain-derived neurotrophic factor (BDNF) and cAMP response element-binding (CREB) protein expressions, GSH level and SOD activity were down-regulated. The intake of LTB and /or VE along with MC intoxication significantly mitigated the alteration in all the previous parameters. Moreover, histopathology analysis of brain sections confirmed MC- induced brain injury and that LTB or VE alone or together were capable of ameliorating brain artitechture. Conclusions The combination of LTB and VE was an effective therapy in the management of MC-induced neuroioxicity and this combination can be considered a useful therapeutic candidate against brain injury induced by MC. BDNF, MAPK and CREB protein expressions are implicated in MC -induced brain injury and its treatment..

Epilepsy is a common and serious neurological disorder, with many different constituent conditions characterized by their electro clinical, imaging, and genetic features. MRI has been fundamental in advancing our understanding of brain processes in the epilepsies. Smaller‐scale studies have identified many interesting imaging phenomena, with implications both for understanding pathophysiology and improving clinical care. Through the infrastructure and concepts now well‐established by the ENIGMA Consortium, ENIGMA‐Epilepsy was established to strengthen epilepsy neuroscience by greatly increasing sample sizes, leveraging ideas and methods established in other ENIGMA projects, and generating a body of collaborating scientists and clinicians to drive forward robust research. Here we review published, current, and future projects, that include structural MRI, diffusion tensor imaging (DTI), and resting state functional MRI (rsfMRI), and that employ advanced methods including structural covariance, and event‐based modeling analysis. We explore age of onset‐ and duration‐related features, as well as phenomena‐specific work focusing on particular epilepsy syndromes or phenotypes, multimodal analyses focused on understanding the biology of disease progression, and deep learning approaches. We encourage groups who may be interested in participating to make contact to further grow and develop ENIGMA‐Epilepsy.

The effect of systematically varied mechanical properties and nano- and microscale surface topography on the adhesion and proliferation of human pancreatic cancer cells on fibronectin-functionalized poly(vinyl alcohol) (PVA) hydrogels was studied to understand the impact of these properties of the cell microenvironment on cell attachment and spreading. The mechanical properties of PVA, as assessed by atomic force microscopy (AFM) nanoindentation, were varied by the number of freezing-thawing cycles in the physical cross-linking process used for the generation of the hydrogels. Nano- and micropatterned hydrogel surfaces exposing nanosized PVA pillars and cuboids were fabricated by replicating ordered cylindrical nanopores of anodic aluminum oxide (AAO) and poly(dimethylsiloxane) (PDMS) templates, respectively. Softer PVA hydrogels, functionalized covalently with fibronectin, showed enhanced cell adhesion and proliferation of PaTu 8988t cells in comparison to stiffer hydrogels. In addition, PaTu 8988t cells favored the nanopatterned surfaces over micropatterned and flat hydrogels.

Background: The ABILOCO-Kids is a parent-reported outcome measure that quantifies locomotion ability and has been reported to have satisfactory measurement properties. An Arabic version of the scal...

Background High-grade serous ovarian carcinoma (HGSOC) is the most frequent type of ovarian carcinoma, associated with poor clinical outcome and metastatic disease. Although metastatic processes are becoming more understandable, the genomic landscape and metastatic progression in HGSOC has not been elucidated. Methods Multi-region whole-exome sequencing was performed on HGSOC primary tumours and their metastases (n = 33 tumour regions) from six patients. The resulting somatic variants were analysed to delineate tumour evolution and metastatic dissemination, and to compare the repertoire of events between primary HGSOC and metastasis. Results All cases presented branching evolution patterns in primary HGSOC, with three cases further showing parallel evolution in which different mutations on separate branches of a phylogenetic tree converge on the same gene. Furthermore, linear metastatic progression was observed in 67% of cases with late dissemination, in which the metastatic tumour mostly acquires the same mutational process active in primary tumour, and parallel metastatic progression, with early dissemination in the remaining 33.3% of cases. Metastatic-specific SNVs were further confirmed as late dissemination events. We also found the involvement of metastatic-specific driver events in the Wnt/β-catenin pathway, and identified potential clinically actionable events in individual patients of the metastatic HGSOC cohort. Conclusions This study provides deeper insights into clonal evolution and mutational processes that can pave the way to new therapeutic targets.

The classical Isomap is the most common unsupervised nonlinear manifold method and widely being used in visualizations and dimension reductions. However, when it applied to real-world datasets, it shows shortcomings for the shortest path between all pairs of data points, which are based on the nearest neighborhood $G$ graph via the Dijkstra algorithm, which makes it a very time-consuming step. The other critical problem is the classical Isomap has a lack of topological stability on the nearest neighborhood $G$ graph. In this paper, we propose a novel technique called the FastIsomapVis for the above problems of the classical Isomap. The FastIsomapVis uses hierarchal divide, conquer, and combine approach through two algorithms, which are randomized division tree (KD-tree) and Dijkstra Buckets Double (DKD). The primary aim of the FastIsomapVis is to increase the efficiency and accuracy of the graph. This research paper focuses on transforming the high dimensional datasets into a low dimensional Isomap visualization. The FastIsomapVis makes it easy to construct an accurate $K$ nearest neighborhood $G$ graph and scale high dimensional data points into low dimensional space. Our proposed method is compared to the classical Isomap to verify its effectiveness and provide highly authentic results of the high dimensional datasets. The finding of the current study shows that our proposed method is much fastened than classical Isomap.

Introduction Bevacizumab has demonstrated activity in glioblastoma (GBM), but the true benefits and optimal dose‐schedule are debated. A lower dose‐schedule than standard‐dose bevacizumab (10 mg/kg 2‐weekly) might offer similar benefits with lower costs. At our Institution, patients are randomly assigned at time of primary diagnosis to Neuro‐Oncologists, who have varying practices in terms of bevacizumab dose‐schedule upon progression. Methods In a retrospective analysis we examined overall survival (OS), measured from first administered bevacizumab dose until death, according to dose‐schedule. Patients with de novo WHO Grade IV GBM who received standard‐ or reduced‐dose (5 mg/kg 2‐weekly) bevacizumab were included. MGMT methylation status and time from diagnosis to bevacizumab start were examined as prognostic variables. Clinical benefit and a comparative cost analysis were assessed. Results In total, 1127 bevacizumab doses were administered to 118 patients [Median: 7, Range: 1‐44]. Median OS (mOS) was 5.8 months. 69 (59%) patients received standard‐dose bevacizumab (mOS: 5.97 months) and 49 patients received reduced‐dose (mOS: 5.7 months). No statistically significant difference in OS between dosing schedule was seen (HR: 1.11, P‐value: .584). Patients with MGMT methylated tumors (43%) had improved OS compared to those with unmethylated tumors; 7.03 vs 4.97 months (HR: 0.61, P‐value: .027). If all patients were treated with reduced‐dose bevacizumab, an estimated €2.4M cost reduction would be observed. Conclusions In this retrospective study, reduced‐dose bevacizumab schedule resulted in similar OS to standard‐dose bevacizumab monotherapy with substantial cost savings. MGMT methylation appears to convey a survival benefit in the setting of bevacizumab treatment for progressive GBM., In this analysis, 118 de novo WHO grade IV glioblastoma patients were analysed to assess the impact of standard vs reduced dose bevacizumab on overall survival and a cost analysis was performed to estimate potential cost differences between the dosing schedules. We demonstrated that reducing the dose of bevacizumab would result in a significant cost saving, with no difference in overall survival outcomes, thereby potentially offering better value.

Background: Sleep is a crucial element in human beings' development and sustainment of a healthy lifestyle; any chronic misalignment between the sleep–wake cycles could be associated with numerous physical and mental disturbances. Social jet lag (SJL) is the discrepancy between the midpoints of sleep in workdays and free days. Up to date, there is a scarcity of studies conducted regarding this disorder in the Middle East. Hence, we aimed toward studying the prevalence and predictors of SJL. Methods: This was an observational cross-sectional study. The sample size was 328 participants who are King Saud University employees and their families. Saudi individuals aged 18 years and above were included in the study. Pregnant women were excluded from the study. Data were collected using an interview-administered questionnaire (Munich ChronoType Questionnaire). SJL was calculated as the absolute difference between the midpoints of sleep on free days and workdays. The association between SJL and predictors was assessed using the Chi-square test. Results: A sample of 226 females and 62 males were analyzed. SJL was categorized into three groups, which are 2 h. Our results showed that SJL of >2 h represents approximately half of the participants (49.7%) and appeared to be more among the 18–33 years' age group (56.5%). Participants with >2 h were found to have a significant difference between sleep durations on work and free days (5.9 ± 1.8 vs. 8.67 ± 1.91 h, P < 0.001, respectively). Conclusion: Lower SJL hours are associated with factors such as increased age and similar sleep duration on work and free days, in addition to alarm use on free days. Whereas, younger age, inflexible work schedule, smoking, and soft drinks' consumption are linked with higher SJL hours. Our future aim is to increase the awareness of controlling the factors which lead to higher SJL hours and the importance of having a balanced sleep.

Temporal lobe epilepsy, a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter structural alterations in temporal lobe epilepsy relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry; or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multisite ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 temporal lobe epilepsy patients and 1418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in temporal lobe epilepsy, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity calculated using 207 healthy controls obtained from Human Connectome Project and an independent dataset containing 23 temporal lobe epilepsy patients and 53 healthy controls and examined clinical associations using machine learning. We identified a marked divergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across individual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables. Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of temporal lobe epilepsy-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings refine our notion of the neuropathology of temporal lobe epilepsy and may inform future discovery and validation of complementary MRI biomarkers in temporal lobe epilepsy.

Primary biliary cholangitis (PBC) is a progressive autoimmune cholestatic liver disease that primarily affects females more than males and may lead to end-stage liver disease. We studied baseline characteristics, and the biochemical and clinical response to ursodeoxycholic acid (UDCA), a first-line treatment option for patients with PBC, in a cohort of patients diagnosed with PBC from Saudi Arabia.A total of 30 patients meeting the diagnostic criteria of PBC who were being followed in the King Faisal Specialist Hospital and Research Centre in Riyadh, Saudi Arabia, between January 1, 2008, and December 31, 2017, were enrolled in the study. The patients with autoimmune hepatitis, primary sclerosing cholangitis, and overlap syndromes were excluded. The baseline characteristics of the patients were recorded. The response to UDCA treatment was assessed according to the Barcelona, Paris I, Paris II, and Toronto criteria, and clinical outcomes, and biochemical changes were ascertained.The mean age was 46 years ± 11.7 with a female gender predominance of 93% (n = 28). Pruritus was the predominant symptom reported by 90% (n = 27) of the patients. A total of 23 (77.7%) patients underwent liver biopsy and all of them showed histological features suggestive of PBC. Cirrhosis was documented in 30% (n = 9) of the patients at baseline. Overall, 86.7% (n = 26) of the patients were positive for antimitochondrial antibodies. The biochemical response rates to UDCA based on Paris I, Paris II, Barcelona, and Toronto criteria were 73.3, 40, 56.7, and 53.3%, respectively.Over 10 years, 30 patients with PBC were diagnosed at a large referral center in Saudi Arabia. The response to UDCA treatment was inadequate.