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Kazemi et al. (SPE Reserv Eng 7(2):219–227, 1992) suggested an empirical matrix-fracture transfer function, verified based on experimental data of Mattax and Kyte (Trans AIME 225(15):177–184, 1962), to model fluid flow in naturally fractured dual porosity petroleum reservoirs using a dual-porosity numerical simulator. Their generalized shape factor should be valid for all possible irregular matrix blocks. The factor is calculated based on the volume of the matrix block, the surface open to flow in all directions and the distances of these surfaces to the centre of the matrix block. The summation is done over all open surfaces of a matrix block. Kazemi et al. (1992) showed that for rectangles and cylinders the formula reduces to the well-known forms of the shape factor. By the time, many authors indicated the validity of the formula, but no theoretical proof was offered for that so far. This study derives the Kazemi et al. (1992) shape factor using control volume finite difference discretization on the fracture-matrix dual continuum. The matrix blocks are handled as Voronoi polyhedra. The derivation is given for both isotropic and tensorial matrix permeability. Based on this derivation the authors conclude that the Kazemi et al. (SPE Reserv Eng 7(2):219–227, 1992) formula is exact under pseudo-steady-state conditions within the dual continuum mathematical concept of natural fractured dual porosity systems.

Kazemi et al. (SPE Reserv Eng 7(2):219–227, 1992) suggested an empirical matrix-fracture transfer function, verified based on experimental data of Mattax and Kyte (Trans AIME 225(15):177–184, 1962), to model fluid flow in naturally fractured dual porosity petroleum reservoirs using a dual-porosity numerical simulator. Their generalized shape factor should be valid for all possible irregular matrix blocks. The factor is calculated based on the volume of the matrix block, the surface open to flow in all directions and the distances of these surfaces to the centre of the matrix block. The summation is done over all open surfaces of a matrix block. Kazemi et al. (1992) showed that for rectangles and cylinders the formula reduces to the well-known forms of the shape factor. By the time, many authors indicated the validity of the formula, but no theoretical proof was offered for that so far. This study derives the Kazemi et al. (1992) shape factor using control volume finite difference discretization on the fracture-matrix dual continuum. The matrix blocks are handled as Voronoi polyhedra. The derivation is given for both isotropic and tensorial matrix permeability. Based on this derivation the authors conclude that the Kazemi et al. (SPE Reserv Eng 7(2):219–227, 1992) formula is exact under pseudo-steady-state conditions within the dual continuum mathematical concept of natural fractured dual porosity systems.

The demand for genetic testing (GT) for prostate cancer (PCa) is expanding, but there is limited knowledge about the genetic counseling (GC) needs of men. A strong-to-moderate inherited genetic predisposition causes approximately 5–20% of prostate cancer (PCa). In men with prostate cancer, germline testing may benefit the patient by informing treatment options, and if a mutation is noticed, it may also guide screening for other cancers and have family implications for cascade genetic testing (testing of close relatives for the same germline mutation). Relatives with the same germline mutations may be eligible for early cancer detection strategies and preventive measures. Cascade family testing can be favorable for family members, but it is currently unutilized, and strategies to overcome obstacles like knowledge deficiency, family communication, lack of access to genetic services, and testing expenses are needed. In this review, we will look at the genetic factors that have been linked to prostate cancer, as well as the role of genetic counseling and testing in the early detection of advanced prostate cancer.

A compact planar antenna is proposed to operate in five millimeter-wave frequency bands at 28, 51, 55, 59, and 63 GHz. The antenna is designed to produce circular polarization at 28 GHz and linear polarization at the other four frequencies. The 28 GHz frequency band is recommended for long range communications, whereas the other four frequencies are recommended for short range communications due to the atmospheric absorption in this range of the millimeter-wave frequencies and to provide more secure communications. The reasons behind the selection of the specific values of the higher frequency bands (51, 55, 59, and 63 GHz) are (i) to provide enough number of multiple bands at such unlicensed frequency range to be used as alternatives for different applications, (ii) to give about 4 GHz separation between the center frequencies of each band and, (iii) finally, to avoid the operation at 60 GHz, in particular, due to the peak atmospheric absorption of millimeter-wave encountered at this frequency. The antenna is constructed as a square patch surrounded by five parasitic elements that are capacitively coupled to the square patch so as to realize the location of the resonant frequencies of the higher frequency bands. The antenna is fabricated and its performance is experimentally evaluated. The proposed antenna is shown to operate efficiently over the five frequency bands 28, 51, 55, 59, and 63 GHz providing impedance matching bandwidths of 2.0, 0.9, 1.2, 1.1, and 1.6 GHz, respectively. The corresponding values of the maximum gain are 7.0, 6.8, 6.0, 6.0, and 8.0 dBi, respectively. Also, the corresponding radiation efficiencies are 90, 90, 91, 78, and 86%, respectively. The 3 dB-axial ratio bandwidth at 28 GHz is about 1.2 GHz.

Fatma M Elsharkawy,1 Maha M Amin,2 Hesham A Shamsel-Din,3 Walaa Ibrahim,3 Ahmed B Ibrahim,3 Sinar Sayed2 1Regulatory Affairs Department, Al Andalous for Pharmaceutical Industries, Giza, Egypt; 2Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt; 3Labeled Compounds Department, Hot Labs Center, Egyptian Atomic Energy Authority, Cairo, 13759, EgyptCorrespondence: Sinar Sayed, Faculty of Pharmacy, Cairo University, Kasr El-Aini, Cairo, 11562, Egypt, Tel +2 01010421543, Email sinar.fouad@pharma.cu.edu.egPurpose: The research objective is to design intranasal brain targeted CLZ loaded lecithin based polymeric micelles (CLZ- LbPM) aiming to improve central systemic CLZ bioavailability.Methods: In our study, intranasal CLZ loaded lecithin based polymeric micelles (CLZ- LbPM) were formulated using soya phosphatidyl choline (SPC) and sodium deoxycholate (SDC) with different CLZ:SPC:SDC ratios via thin film hydration technique aiming to enhance drug solubility, bioavailability and nose to brain targeting efficiency. Optimization of the prepared CLZ-LbPM using Design-Expert® software was achieved showing that M6 which composed of (CLZ:SPC: SDC) in respective ratios of 1:3:10 was selected as the optimized formula. The optimized formula was subjected to further evaluation tests as, Differential Scanning Calorimetry (DSC), TEM, in vitro release profile, ex vivo intranasal permeation and in vivo biodistribution.Results: The optimized formula with the highest desirability exhibiting (0.845), small particle size (12.23± 4.76 nm), Zeta potential of (− 38 mV), percent entrapment efficiency of > 90% and percent drug loading of 6.47%. Ex vivo permeation test showed flux value of 27 μg/cm².h and the enhancement ratio was about 3 when compared to the drug suspension, without any histological alteration. The radioiodinated clozapine ([131I] iodo-CLZ) and radioiodinated optimized formula ([131I] iodo-CLZ-LbPM) were formulated in an excellent radioiodination yield more than 95%. In vivo biodistribution studies of [131I] iodo-CLZ-LbPM showed higher brain uptake (7.8%± 0.1%ID/g) for intranasal administration with rapid onset of action (at 0.25 h) than the intravenous formula. Its pharmacokinetic behavior showed relative bioavailability, direct transport percentage from nose to brain and drug targeting efficiency of 170.59%, 83.42% and 117% respectively.Conclusion: The intranasal self-assembling lecithin based mixed polymeric micelles could be an encouraging way for CLZ brain targeting.Graphical Abstract: Keywords: clozapine, soy lecithin, self-assembling polymeric micelles, intranasal route, brain targeting, radioiodinated clozapine, 131I

Nonalcoholic steatohepatitis (NASH) might soon become the leading cause of end-stage liver disease and indication for liver transplantation worldwide. Fibrosis severity is the only histological predictor of liver-related morbidity and mortality in NASH identified to date. Moreover, fibrosis regression is associated with improved clinical outcomes. However, despite numerous clinical trials of plausible drug candidates, an approved antifibrotic therapy remains elusive. Increased understanding of NASH susceptibility and pathogenesis, emerging human multiomics profiling, integration of electronic health record data and modern pharmacology techniques hold enormous promise in delivering a paradigm shift in antifibrotic drug development in NASH. There is a strong rationale for drug combinations to boost efficacy, and precision medicine strategies targeting key genetic modifiers of NASH are emerging. In this Perspective, we discuss why antifibrotic effects observed in NASH pharmacotherapy trials have been underwhelming and outline potential approaches to improve the likelihood of future clinical success.

Objective This study aimed at exploring the potential role of a panel of serum micro-RNA (miRNA) markers in liver fibrosis and hepatocellular carcinoma (HCC) diagnosis in patients with chronic hepatitis C virus (HCV) infection. Methods The study included 157 chronic HCV patients and 62 HCC patients who presented to the Cairo University Center for Hepatic Fibrosis, Endemic Medicine Department, from 2015 to 2017. Relevant clinical and laboratory data were collected and sera were subjected to miRNA expression profiling. Eleven miRNA markers were studied and receiver operating characteristic curves were constructed to investigate the best cutoff values of the miRNAs that showed altered expression in HCC compared to HCV-associated advanced fibrosis. Results miRNA expression profiling revealed 5 miRNAs (miR-124, miR-141, miR-205, miR-208a, miR-499a) were significantly upregulated and 2 miRNAs were significantly downregulated (miR-103a, miR-15a) in HCC compared to advanced fibrosis patients. No significant difference was observed in miRNA expression between advanced fibrosis and early hepatic fibrosis apart from a significant downregulation of miR-155-5p in advanced fibrosis. Conclusion Serum miRNAs could serve as potential diagnostic tools for the diagnosis of HCC.

Patient retention in care is an essential component of the viral hepatitis care continuum. The aim of this study was to define rates and determinants of retention in care for chronic hepatitis B patients. We used several electronic data sources including patient administrative data, electronic clinical records, laboratory data and electronic prescribing records to examine a multi-ethnic cohort of patients attending a single hepatitis B clinic during a 21-year period. After exclusions, we studied of a cohort of 2,447 patients. Retention in care was 73.2%, 64.1%, 55.6% and 50.3% at 5, 10, 15 and 20 years of follow-up. Asian ethnicity and older age at baseline were associated with lower rates of loss to follow-up. Increasing distance from the patient's current residence to the Liver Clinic was strongly associated with loss to follow-up. Our findings suggest that interventions to maintain retention in care in the United Kingdom should particularly focus on younger patients and on patients with non-Asian ethnicity.

Testing is a tool for measuring the levels of knowledge of individuals, it is a tool of assessing and evaluating the curricula of learners and learners. Therefore, those interested in education are keen to find and develop this important tool at all times. The Arabic Curriculum for Teaching Arabic for Non-Native Speakers (the first version) is one of the most advanced curricula used in some private schools in Pattani, southern Thailand. The Curriculum is divided into three levels (Beginner, intermediate and advanced). The student studies three books in the same order. The second is a test to determine the student's competence and readiness to begin the study of the intermediate level. This test is the field of this study, which the researcher deals with in description and analysis, to find its specifications in terms of honesty and objectivity and his ability to measure various levels of language skills. The researcher reached the following results: The test was characterized by focusing on the lower cognitive levels (memory and perception), and this may be appropriate to the objective for which it is. The test was objective; its questions were specific and short answers, with less effects of self-corrected and personality. The test is relatively honest; it provides a measure of what It put for; reading and writing skills, and I say relatively well, because the authors also set a topic for measuring the level of the student who wants to study the second level, which includes four skills, not just two skills. The test was characterized by the practically; it was placed in the front of the second book in a hundred questions varied between right and wrong questions, multiple choice, complete, match, and arrange.

Background HCV and HIV co-infected patients develop cirrhosis more rapidly than HCV mono-infection. Intestinal injury and microbial translocation are postulated mechanisms for the rapid progression of cirrhosis. Aim Study the effect of HCV treatment with DAAs on serum intestinal fatty acid binding protein (I-FABP) as a marker of intestinal injury in HCV/HIV co-infected patients and its relation to hepatic fibrosis. Comparing the level of I-FABP in HCV mono-infection and HCV/HIV co-infection was a secondary aim. Methods I-FABP levels were measured in 50 non-cirrhotic HCV/HIV co-infected patients pre- and post-HCV treatment (SVR 12) (25 patients were HIV treatment naive, and 25 patients were on HAART) and in 25 chronic HCV patients as a control group. Hepatic fibrosis was assessed by FIB4 score, APRI score, and transient elastography. Results HCV/HIV co-infected patients had significantly higher levels of I-FABP compared to the HCV-mono-infected patients (P = 0.001). After HCV treatment in HCV/HIV co-infected patients, I-FABP level was significantly elevated (P r = 0.283, P-value = 0.047) and (r = 0.340, P-value = 0.016), respectively. Conclusion HCV/HIV co-infection is associated with significantly higher intestinal injury and subsequent hepatic fibrosis than HCV mono-infection. HIV infection is associated with intestinal epithelial injury and microbial translocation and may play a role in the persistence of systemic inflammation after HCV eradication.

Acknowledgements: We thank all our study participants and research study teams for their involvement in providing resources for this research. This article is supported by the members of COST Action “CA17112 - Prospective European Drug-Induced Liver Injury Network” supported by COST (European Cooperation in Science and Technology), www.cost.eu including J.I.G., C.S., M.R.-D., M.I.L., R.J.A., E.A., A.L.G., S.W., H.C.-P., E.S.B., G.S. and G.P.A. We acknowledge support from the members of the PRO-EURO-DILI Network for input on aligning protocols across multiple centers as well as in the case adjudication. We acknowledge Melanie Lingaya, Ryan Criswell, Deborah Hart, James Stejskal, Richard Giovanelli, Kelly Fader, and Heather Llewellyn for their assistance with sample processing. Funding was made available from the Drug Safety Research and Development department within Pfizer’s Worldwide Research Development and Medical. J.I.G., E.A., and G.P.A. are supported by NIHR Nottingham Biomedical Research Centre [BRC-1215-20003]. The views expressed are those of the authors and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health., Funder: Funding was made available from the Drug Safety Research and Development department within Pfizer’s Worldwide Research Development and Medical. JIG, EA and GPA are supported by NIHR Nottingham Biomedical Research Centre [BRC-1215-6 20003]., Diagnosis of drug-induced liver injury (DILI) and its distinction from other liver diseases are significant challenges in drug development and clinical practice. Here, we identify, confirm, and replicate the biomarker performance characteristics of candidate proteins in patients with DILI at onset (DO; n = 133) and follow-up (n = 120), acute non-DILI at onset (NDO; n = 63) and follow-up (n = 42), and healthy volunteers (HV; n = 104). Area under the receiver operating characteristic curve (AUC) for cytoplasmic aconitate hydratase, argininosuccinate synthase, carbamoylphosphate synthase, fumarylacetoacetase, fructose-1,6-bisphosphatase 1 (FBP1) across cohorts achieved near complete separation (range: 0.94-0.99) of DO and HV. In addition, we show that FBP1, alone or in combination with glutathione S-transferase A1 and leukocyte cell-derived chemotaxin 2, could potentially assist in clinical diagnosis by distinguishing NDO from DO (AUC range: 0.65-0.78), but further technical and clinical validation of these candidate biomarkers is needed.

Background: The utility of laboratory values to predict complications in pediatric burn patients is poorly understood. This study assessed the laboratory investigations’ role in morbidities and mortalities prediction after moderate and severe thermal burn in pediatrics. Methods: This prospective cohort study was carried out on 40 children with moderate and major thermal burn. All patients were subjected to clinical evaluation and laboratory investigations such as CBC, c-reactive protein (CRP), serum albumin, serum creatinine and urea. Results: Patients were subdivided into two groups: uncomplicated group (n=25) and complicated group (n=15). CRP, serum albumin, platelet count, serum creatinine and urea can significantly predict sepsis incidence with AUC of 0.922, 0.912, 0.911, 0.807, 0.810, at cut off >12, ≤2, ≤194, >0.7, >23, with sensitivity of 100%, 90.91%, 100 %,100 %, 85.71%, specificity of 86.21 %, 86.21%, 79.31%, 24.24%, 39.39%, PPV of 73.3 %, 71.4%, 64.7%, 21.9% , 23.1% and NPV of 100 %, 96.2 %, 100 %, 100 % , 92.9% respectively. Serum creatinine and urea can significantly predict incidence of acute kidney injury (AKI) with AUC of 0.807, 0.810 At cut off >0.7, >23, with sensitivity of 100.00 %, 85.71%, specificity of 24.24%, 39.39%, PPV of 21.9%, 23.1% and NPV of 100.0%, 92.9% respectively. Percent of burn, total ABSI, CRP, platelet, inhalation injury, albumin, creatinine and urea were dependent predictors for mortality. Sex, inhalation injury, percent of burn, total ABSI, hemoglobin, CRP, platelet, albumin, and creatinine were dependent predictors for sepsis. Sex, inhalation injury, percent of burn, total ABSI, CRP, hemoglobin, platelet, albumin and creatinine were dependent predictors for complication of acute kidney disease. Conclusions: CRP, serum albumin, platelet count, serum creatinine and urea are good predictors of sepsis, AKI and mortalities after moderate to severe burn in pediatrics.

Background Sofosbuvir (SOF) is authorized for hepatitis C virus (HCV) patients. The nephrotoxicity of SOF on HCV mono-infected and HCV–human immunodeficiency virus (HIV) individuals receiving antiretroviral therapy (ART) remains controversial. Methods A prospective study including 159 HCV mono-infected and 124 HCV–HIV individuals (47 were ART naïve and 77 were tenofovir [TDF]-based ART) who presented with an estimated glomerular filtration rate (eGFR) ≥30 ml/min/1.73 m2 at baseline and were treated with SOF–daclatasvir for 12 weeks. The eGFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation over the study period. Results HCV patients had a progressive decline in median levels of eGFR compared with HCV–HIV patients who were ART naïve and those receiving TDF-based ART during and after discontinuing SOF–DAC treatment (96, 109 and 114 at baseline vs 94, 117 and 108 at the end of treatment [EOT]) vs 95, 114 and 115 ml/min/1.73 m2 at 12 weeks after treatment [SVR12], respectively). Moreover, the rate of eGFR stage worsening was more pronounced in HCV mono-infected compared with HCV–HIV individuals who were ART naïve and those receiving TDF-based ART (21.4% vs 8.5% and 14.3% at EOT; 21.4% vs 2.1% and 6.5% at SVR12, respectively). Multivariable regression analysis showed that baseline variables were not independent predictors of eGFR stage worsening either at EOT or SVR12. Conclusions Because the changes in eGFR were minimal and not of clinical significance, and TDF was not associated with an increase in renal dysfunction, SOF-based direct-acting antivirals could be safely used in HCV mono-infected and HCV–HIV individuals, even in those on TDF-based ART.

Alzheimer's disease (AD) is a complex neurodegenerative disease. There is epidemiological evidence that heart failure (HF) patients are at higher risk of developing AD, and the impact of sacubitril/valsartan, the first angiotensin receptor-neprilysin inhibitor (ARNI) approved for HF, on cognitive functions is still controversial. To investigate the effect of sacubitril/valsartan on cognitive functions in colchicine-induced AD rat model. Forty adult male Wistar rats were equally allocated into four groups (each of 10 rats): Group I: normal control, Group II: intracerebroventricular injection of colchicine (15 μg/5 μl/bilaterally), Group III: colchicine (15 μg/5 μl/bilaterally, icv) + oral sacubitril/valsartan (100 mg/kg/day) for 25 days, and Group IV: colchicine (15 μg/5 μl/bilaterally, icv) + oral valsartan (50 mg/kg/day) for 25 days. Behavioral assessment was done using Morris water maze and passive avoidance tasks. Biochemically, β-amyloid (1-40 and 1-42) peptides, oxidative stress (malondialdehyde and superoxide dismutase) and inflammatory (tumor necrosis factor-alpha) parameters were measured in hippocampus and prefrontal cortex. Sacubitril/valsartan exaggerated colchicine-induced cognitive impairment in both Morris water maze and passive avoidance tasks and was associated with significant increase in β-amyloid accumulation, oxidative stress, and inflammation versus valsartan. Sacubitril/valsartan caused deleterious effect on cognitive impairment and biochemical alterations in colchicine-induced AD rat model. Hence, special caution should be taken following long-term intake of ARNI on cognitive functions.

The aim of this study is to investigate the single nucleotide polymorphisms (SNPs) associated with breast cancer in our population of Arab patients. We investigated 26 breast cancer patients and an equal number of healthy age- and sex-matched control volunteers. We examined the exome wide microarray-based biomarkers and screened 243,345 SNPs for their possible significant association with our breast cancer patients. Successfully, we identified the most significant ( p value ≤ 9.14 × 10 − 09 ) four associated SNPs [SNRK and SNRK-AS1-rs202018563G; BRCA2-rs2227943C; ZNF484-rs199826847C; and DCPS-rs1695739G] among persons with breast cancer versus the healthy controls even after Bonferroni corrections ( p value < 2.05 × 10 − 07 ). Although our patients’ numbers were limited, the identified SNPs might shed some light on certain breast cancer-associated functional multigenic variations in Arab patients. We assert on the importance of more extensive large-scale analysis to confirm the candidate biomarkers and possible target genes of breast cancer among Arab ancestries.

Background: Generally ventricular septal defects (VSDs) are repaired with synthetic material: either Dacron (polyethylene terephthalate) or Goretex (expanded polytetrafluoroethylene) depending on surgeons preference. Aim of the work: To compare between the outcome of VSD closure by synthetic patches versus pericardial patches. Patients and methods: This study was conducted on 60 patients with surgical VSD closure. They were divided into 2 groups each included 30 patients. In group I synthetic patch (Dacron or Gortex) was used. In group II pericardial patch (fresh or treated or bovine) was used. The patients were evaluated at 3m and 6m after operation for: residual defects, endocarditis, heart block, AR, TR, LV dimensions and function and any other complications. Results: Ventilation time, was statistically significant shorter in group II (8.53 ± 6.37h) compared with Group I (30.60 ± 20.84h) p value 0.001*. Statistically significant shorter ICU time was found in group II (2.53 ± 0.90d) compared with group I (3.70 ± 1.62d). Twenty (66.7%) patients and 28(93.3%) patients in group I and II respectively had sinus rhythm. While 10 (33.3%) patients and 2 (6.7%) patients in group I and II respectively had temporary heart block.