Potential of resistance inducers for citrus huanglongbing management via soil application and assessment of induction of pathogenesis-related protein genes.

Huanglongbing (HLB) or citrus greening currently is the most devastating citrus disease worldwide. Unfortunately, no practical cure has been available up to now. This makes the control of HLB as early as possible very important to be conducted. The objective of this study was to investigate the efficacy of the application of salicylic acid (SA) and Phenylacetic acid (PAA) on one-year-old seedlings of different citrus species (Citrus reticulata, C. sinensis, C. aurantifolii) growing on C. volkameriana and C. aurantium by soil drench methods. Factorial analysis of variance showed the percent change in "Candidatus Liberibacter asiaticus" titer and disease severity on a different combination of citrus species growing on the two rootstocks treated with inducers and Oxytetracycline (OTC) were significantly different compared to the untreated plants. SA alone or in combination with OTC provided excellent (P-value < 0.05) control of HLB based on all parameters. The interaction between both factors (Rootstocks x Citrus species) significantly influenced the Ct value (P-value = 0.0001). "Candidatus Liberibacter asiaticus" titer in plants treated with OTC was reduced significantly with a range of -18.75 up to -78.42. Overall, the highest reduction was observed in the application of OTC on sweet orange growing on C. volkameriana (-78.42), while the lowest reduction was observed in the same cultivar which was treated with a combination of SA and OTC (-3.36). Induction of pathogenesis-related (PR) genes, i.e., PR1, PR2, and PR15, biosynthesis of Jasmonic acid and ethylene which are also important pathways to defense activity were also significantly increased in treated plants compared to untreated plants. This study suggests that the application of inducer alone is acceptable for HLB management. We proposed the application of SA and PAA as a soil drench on the citrus seedlings as promising, easy, and environmentally safe for HLB disease control on citrus seedlings.

Using the LeiCNS-PK3.0 Physiologically-Based Pharmacokinetic Model to Predict Brain Extracellular Fluid Pharmacokinetics in Mice.

INTRODUCTION: The unbound brain extracelullar fluid (brainECF) to plasma steady state partition coefficient, Kp,uu,BBB, values provide steady-state information on the extent of blood-brain barrier (BBB) transport equilibration, but not on pharmacokinetic (PK) profiles seen by the brain targets. Mouse models are frequently used to study brain PK, but this information cannot directly be used to inform on human brain PK, given the different CNS physiology of mouse and human. Physiologically based PK (PBPK) models are useful to translate PK information across species. AIM: Use the LeiCNS-PK3.0 PBPK model, to predict brain extracellular fluid PK in mice. METHODS: Information on mouse brain physiology was collected from literature. All available connected data on unbound plasma, brainECF PK of 10 drugs (cyclophosphamide, quinidine, erlotonib, phenobarbital, colchicine, ribociclib, topotecan, cefradroxil, prexasertib, and methotrexate) from different mouse strains were used. Dosing regimen dependent plasma PK was modelled, and Kpuu,BBB values were estimated, and provided as input into the LeiCNS-PK3.0 model to result in prediction of PK profiles in brainECF. RESULTS: Overall, the model gave an adequate prediction of the brainECF PK profile for 7 out of the 10 drugs. For 7 drugs, the predicted versus observed brainECF data was within two-fold error limit and the other 2 drugs were within five-fold error limit. CONCLUSION: The current version of the mouse LeiCNS-PK3.0 model seems to reasonably predict available information on brainECF from healthy mice for most drugs. This brings the translation between mouse and human brain PK one step further.

The PBPK LeiCNS-PK3.0 framework predicts Nirmatrelvir (but not Remdesivir or Molnupiravir) to achieve effective concentrations against SARS-CoV-2 in human brain cells.

SARS-CoV-2 was shown to infect and persist in the human brain cells for up to 230 days, highlighting the need to treat the brain viral load. The CNS disposition of the antiCOVID-19 drugs: Remdesivir, Molnupiravir, and Nirmatrelvir, remains, however, unexplored. Here, we assessed the human brain pharmacokinetic profile (PK) against the EC90 values of the antiCOVID-19 drugs to predict drugs with favorable brain PK against the delta and the omicron variants. We also evaluated the intracellular PK of GS443902 and EIDD2061, the active metabolites of Remdesivir and Molnupiravir, respectively. Towards this, we applied LeiCNS-PK3.0, the physiologically based pharmacokinetic framework with demonstrated adequate predictions of human CNS PK. Under the recommended dosing regimens, the predicted brain extracellular fluid PK of only Nirmatrelvir was above the variants' EC90. The intracellular levels of GS443902 and EIDD2061 were below the intracellular EC90. Summarizing, our model recommends Nirmatrelvir as the promising candidate for (pre)clinical studies investigating the CNS efficacy of antiCOVID-19 drugs.

Physiologically Based Modelling Framework for Prediction of Pulmonary Pharmacokinetics of Antimicrobial Target Site Concentrations.

BACKGROUND AND OBJECTIVES: Prediction of antimicrobial target-site pharmacokinetics is of relevance to optimize treatment with antimicrobial agents. A physiologically based pharmacokinetic (PBPK) model framework was developed for prediction of pulmonary pharmacokinetics, including key pulmonary infection sites (i.e. the alveolar macrophages and the epithelial lining fluid). METHODS: The modelling framework incorporated three lung PBPK models: a general passive permeability-limited model, a drug-specific permeability-limited model and a quantitative structure-property relationship (QSPR)-informed perfusion-limited model. We applied the modelling framework to three fluoroquinolone antibiotics. Incorporation of experimental drug-specific permeability data was found essential for accurate prediction. RESULTS: In the absence of drug-specific transport data, our QSPR-based model has generic applicability. Furthermore, we evaluated the impact of drug properties and pathophysiologically related changes on pulmonary pharmacokinetics. Pulmonary pharmacokinetics were highly affected by physiological changes, causing a shift in the main route of diffusion (i.e. paracellular or transcellular). Finally, we show that lysosomal trapping can cause an overestimation of cytosolic concentrations for basic compounds when measuring drug concentrations in cell homogenate. CONCLUSION: The developed lung PBPK model framework constitutes a promising tool for characterization of pulmonary exposure of systemically administrated antimicrobials.

A Multicenter Study Evaluating the Discontinuation of Eculizumab Therapy in Children with Atypical Hemolytic Uremic Syndrome.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening thrombotic microangiopathy (TMA), which has been treated successfully with eculizumab. The optimal duration of eculizumab in treating patients with aHUS remains poorly defined. METHODS: We conducted a multicenter retrospective study in the Arabian Gulf region for children of less than 18 years of age who were diagnosed with aHUS and who discontinued eculizumab between June 2013 and June 2021 to assess the rate and risk factors of aHUS recurrence. RESULTS: We analyzed 28 patients with a clinical diagnosis of aHUS who had discontinued eculizumab. The most common reason for the discontinuation of eculizumab was renal and hematological remission (71.4%), followed by negative genetic testing (28.6%). During a median follow-up period of 24 months after discontinuation, 8 patients (28.5%) experienced HUS relapse. The risk factors of recurrence were positive genetic mutations (p = 0.020). On the other hand, there was no significant relationship between the relapse and age of presentation, the need for acute dialysis, the duration of eculizumab therapy before discontinuation, or the timing of eculizumab after the presentation. Regarding the renal outcomes after discontinuation, 23 patients were in remission with normal renal function, while 4 patients had chronic kidney disease (CKD) (three of them had pre-existing chronic kidney disease (CKD) before discontinuation, and one case developed a new CKD after discontinuation) and one patient underwent transplantation. CONCLUSIONS: The discontinuation of eculizumab in patients with aHUS is not without risk; it can result in HUS recurrence. Eculizumab discontinuation can be performed with close monitoring of the patients. It is essential to assess risk the factors for relapse before eculizumab discontinuation, in particular in children with a positive complement variant and any degree of residual CKD, as HUS relapse may lead to additional loss of kidney function. Resuming eculizumab promptly after relapse is effective in most patients.

Enhancing the sensing behavior of a reduced graphene magnetite-based plasmonic optical fiber sensor.

The D-shaped optical fiber is a base for the magnetite-based graphene nanocomposite (rGO/Fe3O4) for a Pb heavy metal sensing layer. The designed sensor was studied under the effects of rapid annealing, water circulation, and plasmonic tuning. Various annealing temperatures (100°C, 200°C, 300°C, and 400°C) were investigated. The effect of rapid thermal annealing (RTA) temperature on the transmission results were found at a short wavelength of 300 nm and a minimum point of ∼380nm. The bandgap energy was verified between 2.3 and 3.17 eV for 100°C and 400°C, respectively. The sensor results show modification toward a short wavelength by increasing the rapid annealing temperature. Compared with furnace methods, the transmittance shift of the plasmonic effect showed the best performance under the influence of RTA. RTA at 300°C and 400°C offered an acceptable degree of stability at the beginning (1-50 min). The best performance of the proposed sensor was improved by introducing a circulating liquid chamber into the initial design. The resonance shifts due to Pb ion concentration (5, 10, and 15 ppm) were studied for transmission and wavelength shifts. The sensor shift was enhanced by using a free space polarizer controller attached to the second design. The results give detection and sensing potential in the visible range at a possible remarkable response time. The figure of merit was 62.5 a.u., and the maximum sensitivity was 1 a.u./ppm by using a polarizer controller. This article presents the optical characterizations of plasmonic sensor-based rGO/Fe3O4 for detecting Pb ions and enhancing the resonance shift. RTA for composite material and water circulation associated with D-shaped optical fiber enhances response time and stability designed using a polarizer controller.

Characterization of the Asian Citrus Psyllid-'Candidatus Liberibacter Asiaticus' Pathosystem in Saudi Arabia Reveals Two Predominant CLas Lineages and One Asian Citrus Psyllid Vector Haplotype.

In Saudi Arabia (SA), the citrus greening disease is caused by 'Candidatus Liberibacter asiaticus' (CLas) transmitted by the Asian citrus psyllid (ACP) Diaphorina citri. The origin and route(s) of the ACP-CLas pathosystem invasion in SA have not been studied. Adult ACP were collected from citrus trees in SA and differentiated by analysis of the mitochondrial cytochrome oxidase I (mtCOI) and nuclear copper transporting protein (atox1) genes. A phylogenetic analysis of the Wolbachia spp. surface protein (wsp) gene was used to identify the ACP-associated Wolbachia spp. A phylogenetic analysis of the atox1 and mtCOI gene sequences revealed one predominant ACP haplotype most closely related to the Indian subcontinent founder populations. The detection and identification of CLas in citrus trees were carried out by polymerase chain reaction (PCR) amplification and sequencing of the 16S rDNA gene. The CLas-integrated prophage genomes were sequenced, annotated, and used to differentiate CLas populations. The ML and ASTRAL trees reconstructed with prophages type 1 and 2 genome sequences, separately and concatenated, resolved two major lineages, CLas-1 and -2. The CLas-1 clade, reported here for the first time, consisted of isolates from SA isolates and Pakistan. The CLas-2 sequences formed two groups, CLas-2-1 and -2-2, previously the 'Asiatic' and 'Floridian' strains, respectively. Members of CLas-2-1 originated from Southeast Asia, the USA, and other worldwide locations, while CLas-2-2 was identified only in Florida. This study provides the first snapshot into the status of the ACP-CLas pathosystem in SA. In addition, the results provide new insights into the pathosystem coevolution and global invasion histories of two ACP-CLas lineages with a predicted center of origin in South and Southeast Asia, respectively.

Enhancing performance of WDM-RoFSO communication system utilizing dual channel technique for 5G applications.

In this work, the performance of wavelength division multiplexing based radio over free space optics (WDM-RoFSO) communication system is investigated utilizing OptiSystem 0.7 software. Four weather conditions are adopted in this paper, namely, clear, haze, rain and fog with attenuation losses of 0.2 dB/km, 2.3 dB/km, 4.3 dB/km and 8 dB/km, respectively In addition, a high radio frequency of 30 GHz with high bit rate of 160 Gbps is modulated and carried on optical signal for fifth generation (5G) applications. The dual channel technique is employed in order to enhance the performance parameters of proposed WDM-RoFSO communication system. The enhancement in the link range is about; 46.1%, 35%, 29.4% and 25.9% for clear, haze, rain and fog, respectively.

Drug Distribution in Brain and Cerebrospinal Fluids in Relation to IC50 Values in Aging and Alzheimer's Disease, Using the Physiologically Based LeiCNS-PK3.0 Model.

BACKGROUND: Very little knowledge exists on the impact of Alzheimer's disease on the CNS target site pharmacokinetics (PK). AIM: To predict the CNS PK of cognitively healthy young and elderly and of Alzheimer's patients using the physiologically based LeiCNS-PK3.0 model. METHODS: LeiCNS-PK3.0 was used to predict the PK profiles in brain extracellular (brainECF) and intracellular (brainICF) fluids and cerebrospinal fluid of the subarachnoid space (CSFSAS) of donepezil, galantamine, memantine, rivastigmine, and semagacestat in young, elderly, and Alzheimer's patients. The physiological parameters of LeiCNS-PK3.0 were adapted for aging and Alzheimer's based on an extensive literature search. The CNS PK profiles at plateau for clinical dose regimens were related to in vitro IC50 values of acetylcholinesterase, butyrylcholinesterase, N-methyl-D-aspartate, or gamma-secretase. RESULTS: The PK profiles of all drugs differed between the CNS compartments regarding plateau levels and fluctuation. BrainECF, brainICF and CSFSAS PK profile relationships were different between the drugs. Aging and Alzheimer's had little to no impact on CNS PK. Rivastigmine acetylcholinesterase IC50 values were not reached. Semagacestat brain PK plateau levels were below the IC50 of gamma-secretase for half of the interdose interval, unlike CSFSAS PK profiles that were consistently above IC50. CONCLUSION: This study provides insights into the relations between CNS compartments PK profiles, including target sites. CSFSAS PK appears to be an unreliable predictor of brain PK. Also, despite extensive changes in blood-brain barrier and brain properties in Alzheimer's, this study shows that the impact of aging and Alzheimer's pathology on CNS distribution of the five drugs is insignificant.

The Extension of the LeiCNS-PK3.0 Model in Combination with the "Handshake" Approach to Understand Brain Tumor Pathophysiology.

Micrometastatic brain tumor cells, which cause recurrence of malignant brain tumors, are often protected by the intact blood-brain barrier (BBB). Therefore, it is essential to deliver effective drugs across not only the disrupted blood-tumor barrier (BTB) but also the intact BBB to effectively treat malignant brain tumors. Our aim is to predict pharmacokinetic (PK) profiles in brain tumor regions with the disrupted BTB and the intact BBB to support the successful drug development for malignant brain tumors. LeiCNS-PK3.0, a comprehensive central nervous system (CNS) physiologically based pharmacokinetic (PBPK) model, was extended to incorporate brain tumor compartments. Most pathophysiological parameters of brain tumors were obtained from literature and two missing parameters of the BTB, paracellular pore size and expression level of active transporters, were estimated by fitting existing data, like a "handshake". Simultaneous predictions were made for PK profiles in extracellular fluids (ECF) of brain tumors and normal-appearing brain and validated on existing data for six small molecule anticancer drugs. The LeiCNS-tumor model predicted ECF PK profiles in brain tumor as well as normal-appearing brain in rat brain tumor models and high-grade glioma patients within twofold error for most data points, in combination with estimated paracellular pore size of the BTB and active efflux clearance at the BTB. Our model demonstrated a potential to predict PK profiles of small molecule drugs in brain tumors, for which quantitative information on pathophysiological alterations is available, and contribute to the efficient and successful drug development for malignant brain tumors.

Identification and molecular characterization of cotton leaf curl Gezira betasatellite and two distinct begomoviruses infecting papaya trees in the Kingdom of Saudi Arabia.

Begomovirus is the largest genus in the family Geminiviridae and constitutes more than 445 virus species. Begomoviruses are characterized by single-stranded circular genomes with monopartite or bipartite components and transmitted by whitefly (Bemisia tabaci). Begomoviruses cause severe diseases in many economically important crops throughout the world. Typical symptoms of a begomovirus infection including severe leaf curling, vein thickening, vein darkening and reduced leaf size were observed in papaya plants in the Dammam district of the Eastern Province of Saudi Arabia during the growing season in 2022. A total of 10 samples were collected, and total genomic DNA was isolated from naturally infected papaya tree samples and subjected to PCR amplification using universal diagnostic primers for begomoviruses and associated satellites. Three PCR-amplified genomic components of begomoviruses and betasatellite namely P61Begomo (645 bp), P62Begomo (341 bp) and P62Beta (563 bp) were sent for Sanger DNA sequencing to Macrogen Inc. These partial viral genome sequences were submitted to Genbank database and accession numbers ON206051, ON206052 and ON206050 were assigned to P61Begomo, P62Begomo and P62Beta respectively. Phylogenetic analysis and pairwise nucleotide sequence identity studies identified P61Begomo was identified as Tomato yellow leaf curl virus, P62Begomo as DNA A component of a bipartite begomovirus Watermelon chlorotic stunt virus and P62Beta as begomovirus associated betasatellite; Cotton leaf curl Gezira betasatellite. To the best of our knowledge, this is the first report of a begomovirus complex infecting papaya (Carica papaya) in the Kingdom of Saudi Arabia.

Lumbar cerebrospinal fluid-to-brain extracellular fluid surrogacy is context-specific: insights from LeiCNS-PK3.0 simulations.

Predicting brain pharmacokinetics is critical for central nervous system (CNS) drug development yet difficult due to ethical restrictions of human brain sampling. CNS pharmacokinetic (PK) profiles are often altered in CNS diseases due to disease-specific pathophysiology. We previously published a comprehensive CNS physiologically-based PK (PBPK) model that predicted the PK profiles of small drugs at brain and cerebrospinal fluid compartments. Here, we improved this model with brain non-specific binding and pH effect on drug ionization and passive transport. We refer to this improved model as Leiden CNS PBPK predictor V3.0 (LeiCNS-PK3.0). LeiCNS-PK3.0 predicted the unbound drug concentrations of brain ECF and CSF compartments in rats and humans with less than two-fold error. We then applied LeiCNS-PK3.0 to study the effect of altered cerebrospinal fluid (CSF) dynamics, CSF volume and flow, on brain extracellular fluid (ECF) pharmacokinetics. The effect of altered CSF dynamics was simulated using LeiCNS-PK3.0 for six drugs and the resulting drug exposure at brain ECF and lumbar CSF were compared. Simulation results showed that altered CSF dynamics changed the CSF PK profiles, but not the brain ECF profiles, irrespective of the drug's physicochemical properties. Our analysis supports the notion that lumbar CSF drug concentration is not an accurate surrogate of brain ECF, particularly in CNS diseases. Systems approaches account for multiple levels of CNS complexity and are better suited to predict brain PK.

The Leukodystrophy Spectrum in Saudi Arabia: Epidemiological, Clinical, Radiological, and Genetic Data.

Background: Leukodystrophies (LDs) are inherited heterogeneous conditions that affect the central nervous system with or without peripheral nerve involvement. They are individually rare, but collectively, they are common. Thirty disorders were included by the Global Leukodystrophy Initiative Consortium (GLIA) as LDs. Methods: We conducted a retrospective chart review of a consecutive series of patients diagnosed with different types of LD from four large tertiary referral centers in Riyadh, Saudi Arabia. Only those 30 disorders defined by GLIA as LDs were included. Results: In total, 83 children from 61 families were identified and recruited for this study. The male-to-female ratio was 1.5:1, and a consanguinity rate of 58.5% was observed. An estimated prevalence of 1:48,780 or 2.05/100,000 was observed based on the clinical cohort, whereas a minimum of 1:32,857 or 3.04/100,000 was observed based on the local genetic database. The central region of the country exhibited the highest prevalence of LDs (48.5%). The most common LD was metachromatic leukodystrophy (MLD), and it accounted for 25.3%. The most common disorder based on carrier frequency was AGS. Novel variants were discovered in 51% of the cases, but 49% possessed previously reported variants. Missense variants were high in number and accounted for 73% of all cases. Compared with other disorders, MLD due to saposin b deficiency was more common than expected, Pelizaeus-Merzbacher-like disease was more prevalent than Pelizaeus-Merzbacher disease, and X-linked adrenoleukodystrophy was less common than expected. The mortality rate among our patients with LD was 24%. Conclusion: To the best of our knowledge, this is the largest cohort of patients with LD from Saudi Arabia. We present epidemiological, clinical, radiological, and genetic data. Furthermore, we report 18 variants that have not been reported previously. These findings are of great clinical and molecular utility for diagnosing and managing patients with LD.

The genotypic and phenotypic spectrum of pycnodysostosis in Saudi Arabia: Novel variants and clinical findings.

Pycnodysostosis is characterized by short stature, osteosclerosis, acro-osteolysis, increased tendency of fractures, and distinctive dysmorphic features. It is a rare autosomal recessive disease caused by biallelic CTSK mutations. The clinical details of 18 patients from Saudi Arabia were reviewed. Short stature, osteopetrosis, acro-osteolysis, and distinctive facial dysmorphism were documented in all cases. Our results highlight the significant complications associated with this disease. The large anterior fontanelle is one of the cardinal signs of this disease; however, half of our patients had small fontanelles and a quarter had craniosynostosis, which caused optic nerve compression. Sleep apnea was of the major complications in three patients. Bone fracture can be a presenting symptom, and in our patients it mainly occurred after the age of 3 years. Bone marrow suppression was seen in a single patient of our cohort who was misdiagnosed initially with malignant osteopetrosis. In this study, we also describe two novel (c.5G > A [p.Trp2Ter], c.538G > A [p.Gly180Ser]) and two reported (c.244-29 A > G, c.830C > T [p.Ala277Val]) CTSK mutations. Our results indicate that the recurrent intronic variant, c.244-29 A > G is likely to be a founder mutation, as it was found in 78% (14/18 patients) of our cohort belonging to the same tribe.

Generation and Characterization of Nanobodies Against Tomato Leaf Curl Sudan Virus.

Begomoviruses infect food, fiber, and vegetable crop plants, including tomato, potato, bean, cotton, cucumber, and pumpkin, and damage many economically important crop plants worldwide. Tomato leaf curl Sudan virus (ToLCSDV) is the most widespread tomato-infecting begomovirus in Saudi Arabia. Using phage display technology, this study isolated two camel-derived nanobodies against purified ToLCSDV virions from a library of antigen-binding fragments (VHH or nanobody) of heavy-chain antibodies built from an immunized camel. The isolated nanobodies also cross-reacted with purified tomato yellow leaf curl virus virions and showed significant enzyme-linked immunosorbent assay reactivity with extracts from plants with typical begomovirus infection symptoms. The results can pave the way to developing diagnostics for begomovirus detection, design, and characterization of novel nanomaterials based on virus-like particles, in addition to nanobody-mediated begomovirus resistance in economically important crops, such as tomato, potato, and cucumber.

Biomarker-Guided Individualization of Antibiotic Therapy.

Treatment failure of antibiotic therapy due to insufficient efficacy or occurrence of toxicity is a major clinical challenge, and is expected to become even more urgent with the global rise of antibiotic resistance. Strategies to optimize treatment in individual patients are therefore of crucial importance. Currently, therapeutic drug monitoring plays an important role in optimizing antibiotic exposure to reduce treatment failure and toxicity. Biomarker-based strategies may be a powerful tool to further quantify and monitor antibiotic treatment response, and reduce variation in treatment response between patients. Host response biomarkers, such as CRP, procalcitonin, IL-6, and presepsin, could potentially carry significant information to be utilized for treatment individualization. To achieve this, the complex interactions among immune system, pathogen, drug, and biomarker need to be better understood and characterized. The purpose of this tutorial is to discuss the use and evidence of currently available biomarker-based approaches to inform antibiotic treatment. To this end, we also included a discussion on how treatment response biomarker data from preclinical, healthy volunteer, and patient-based studies can be further characterized using pharmacometric and system pharmacology based modeling approaches. As an illustrative example of how such modeling strategies can be used, we describe a case study in which we quantitatively characterize procalcitonin dynamics in relation to antibiotic treatments in patients with sepsis.

Impact of CNS Diseases on Drug Delivery to Brain Extracellular and Intracellular Target Sites in Human: A "WHAT-IF" Simulation Study.

The blood-brain barrier (BBB) is equipped with unique physical and functional processes that control central nervous system (CNS) drug transport and the resulting concentration-time profiles (PK). In CNS diseases, the altered BBB and CNS pathophysiology may affect the CNS PK at the drug target sites in the brain extracellular fluid (brainECF) and intracellular fluid (brainICF) that may result in changes in CNS drug effects. Here, we used our human CNS physiologically-based PK model (LeiCNS-PK3.0) to investigate the impact of altered cerebral blood flow (CBF), tight junction paracellular pore radius (pararadius), brainECF volume, and pH of brainECF (pHECF) and of brainICF (pHICF) on brainECF and brainICF PK for 46 small drugs with distinct physicochemical properties. LeiCNS-PK3.0 simulations showed a drug-dependent effect of the pathophysiological changes on the rate and extent of BBB transport and on brainECF and brainICF PK. Altered pararadius, pHECF, and pHICF affected both the rate and extent of BBB drug transport, whereas changes in CBF and brainECF volume modestly affected the rate of BBB drug transport. While the focus is often on BBB paracellular and active transport processes, this study indicates that also changes in pH should be considered for their important implications on brainECF and brainICF target site PK.

Robot applications for autism: a comprehensive review.

PURPOSE: Technological advances in robotics have brought about exciting developments in different areas such as education, training, and therapy. Recent research has suggested that the robot can be even more effective in rehabilitation, therapy, and education for individuals with Autism Spectrum Disorder (ASD). In this paper, a comprehensive review of robotic technology for children with ASD is presented wherein a large number of journals and conference proceedings in science and engineering search engines' databases were implicated. MATERIALS AND METHODS: A search for related literature was conducted in three search engines' databases, Web of Science, Scopus, and IEEE Xplore. Thematic keywords were used to identify articles in the recent ten years in titles, keywords, and abstracts. The retrieved articles were filtered, analysed, and evaluated based on specific inclusion and exclusion criteria. RESULTS: A total of 208 studies were retrieved, while 166 met the inclusion criteria. The selected studies were reviewed according to the type of robot, the participants, objectives, and methods. 68 robots were used in all studies, NAO robot was used in 30.5% of those studies. The total number of participants in all studies was 1671. The highest percentage of the studies reviewed were dedicated to augmenting the learning skills. CONCLUSIONS: Robots and the associated schemes were used to determine their feasibility and validity for augmenting the learning skills of autistic children. Most of the studies reviewed were focused on improving the social communication skills of autistic children and measuring the extent of robot mitigation of stereotyped autistic behaviours.Implications for rehabilitationSocial robots are not considered as promising tools to be utilized for rehabilitation of autistic children only, but also has been used for children and young people with severe intellectual disability.Rehabilitation for individuals with ASD using robots can augment their cognitive and social skills, but further studies should be conducted to clarify its effectiveness based on other factors such as sex, age and IQ of the participates.Robotic-based rehabilitation is not limited to the physical robots only, but virtual robots have been used also, whereas each of which can be used individually or simultaneously. However, further study is required to assess the extent of its efficiency and effectiveness for both cases.

Predicting Unacceptable Pain in Cardiac Surgery Patients Receiving Morphine Maintenance and Rescue Doses: A Model-Based Pharmacokinetic-Pharmacodynamic Analysis.

BACKGROUND: Optimal analgesic treatment following cardiac surgery is crucial for both patient comfort and successful postoperative recovery. While knowledge of both the pharmacokinetics and pharmacodynamics of analgesics is required to predict optimal drug dosing, models quantifying the pharmacodynamics are scarce. Here, we quantify the pharmacodynamics of morphine by modeling the need for rescue morphine to treat unacceptable pain in 118 patients after cardiac surgery. METHODS: The rescue morphine event data were analyzed with repeated time-to-event (RTTE) modeling using NONMEM. Postoperative pain titration protocol consisted of continuous morphine infusions (median duration 20.5 hours) with paracetamol 4 times daily and rescue morphine in case of unacceptable pain (numerical rating scale ≥4). RESULTS: Patients had a median age of 73 years (interquartile range [IQR]: 63-77) and median bodyweight of 80 kg (IQR: 72-90 kg). Most patients (55%) required at least 1 rescue morphine dose. The hazard for rescue morphine following cardiac surgery was found to be significantly influenced by time after surgery, a day/night cycle with a peak at 23:00 (95% confidence interval [CI], 19:35-02:03) each day, and an effect of morphine concentration with 50% hazard reduction at 9.3 ng·mL-1 (95% CI, 6.7-16). CONCLUSIONS: The pharmacodynamics of morphine after cardiac surgery was successfully quantified using RTTE modeling. Future studies can be used to expand the model to better predict morphine's pharmacodynamics on the individual level and to include the pharmacodynamics of other analgesics so that improved postoperative pain treatment protocols can be developed.

6-Pyruvoyltetrahydropterin Synthase Deficiency: Review and Report of 28 Arab Subjects.

BACKGROUND: Tetrahydrobiopterin is an essential cofactor for the hydroxylation of aromatic amino acids phenylalanine, tyrosine, and tryptophan. Therefore, tetrahydrobiopterin deficiency results in hyperphenylalaninemia as well as dopamine and serotonin depletion in the central nervous system. The enzyme 6-pyruvoyltetrahydropterin synthase catalyzes the second step of de novo synthesis of tetrahydrobiopterin, and its deficiency is the most frequent cause of tetrahydrobiopterin metabolism disorders. METHOD: We conducted a retrospective chart review of 28 subjects from 24 families with molecularly confirmed 6-pyruvoyltetrahydropterin synthase deficiency from six centers in three Arab countries. We reviewed clinical, biochemical, and molecular data. We also reviewed previously published cohorts of subjects with 6-pyruvoyltetrahydropterin synthase deficiency. RESULTS: Similar to previous observations, we show that early treatment (less than two months) is associated with better outcome. We identify eight PTS variants in 24 independent families. The most common variant is (c.238A>G; p.M80V) with an allele count of 33%. We also identify one novel variant (c.2T>G; p.?). CONCLUSION: The deficiency of 6-pyruvoyltetrahydropterin synthase is relatively common in the Arab population and should be considered in individuals with hyperphenylalaninemia. More natural history studies with comprehensive biochemical and molecular genetics data are needed for a robust base for the development of future therapy.