Search

Abstract Background Chronic hepatitis C virus (CHC) infection represents a crucial health problem, especially among children and adolescents. The ledipasvir (LDV)/sofosbuvir (SOF) regimen has been approved to treat adolescents (aged 12 to 17 years old) infected with hepatitis C virus (HCV) genotypes 1, 4, 5, and 6 and then extended to include children above or equal to 3 years old. The current study aims to evaluate the safety and efficacy of SOF/LDV combination in treating CHC-infected 12- to 17-year-old adolescents. Patients and methods This retrospective cohort study was performed on 147 Egyptian adolescents with CHC. The patients were treated with SOF 400 mg/LDV 90 mg combination once daily for 12 weeks. Possible side effects and laboratory data including HCV ribonucleic acid polymerase chain reaction (RNA PCR), complete blood count (CBC), and liver tests were recorded at baseline and week 12 after the end of treatment (EOT). Results Sustained virological response 12 weeks (SVR12) after end of treatment (EOT) was observed in 146 out of 147 patients (99.3%). The treatment regimen was efficiently tolerated with no reported cases of discontinuation caused by intolerability. Moreover, the side effects were minimal; 71.4% of the patients did not report any side effects related to the treatment. However, the rest mentioned fatigue, headache, or both of them. Fatigue was the main side effect reported in 16.3% of the patients. Furthermore, ALT and AST levels were normalized after treatment. FIB-4 and APRI scores were statistically significantly decreased 2 years post-SVR, in comparison to their levels before treatment, from 0.34 and 0.36 to 0.25 and 0.17, respectively. Conclusion The LDV/SOF regimen is one of the safe regimens used to treat adolescent patients with CHC infection.

Abstract: LNPK encodes a conserved membrane protein that stabilizes the junctions of the tubular endoplasmic reticulum network playing crucial roles in diverse biological functions. Recently, homozygous variants in LNPK were shown to cause a neurodevelopmental disorder (OMIM#618090) in four patients displaying developmental delay, epilepsy, and non-specific brain malformations including corpus callosum hypoplasia and variable impairment of cerebellum. We sought to delineate the molecular and phenotypic spectrum of LNPK-related disorder. Exome or genome sequencing was carried out in eleven families. Thorough clinical and neuroradiological evaluation was performed for all the affected individuals, including review of previously reported patients. We identified twelve distinct homozygous loss-of-function variants in sixteen individuals presenting with moderate to profound developmental delay, cognitive impairment, regression, refractory epilepsy and a recognizable neuroimaging pattern consisting of corpus callosum hypoplasia and signal alterations of the forceps minor (“ear-of-the-lynx” sign), variably associated with substantia nigra signal alterations, mild brain atrophy, short midbrain, and cerebellar hypoplasia/atrophy. In summary, we define the core phenotype of LNPK-related disorder and expand the list of neurological disorders presenting with the “ear of the lynx” sign suggesting a possible common underlying mechanism related to endoplasmic reticulum-phagy dysfunction.

This study presents 46 patients from 23 unrelated Egyptian families with ALS2-related disorders without evidence of lower motor neuron involvement. Age at onset ranged from 10 months to 2.5 years, featuring progressive upper motor neuron signs. Detailed clinical phenotypes demonstrated inter- and intrafamilial variability. We identified 16 homozygous disease-causing ALS2 variants; sorted as splice-site, missense, frameshift, nonsense and in-frame in eight, seven, four, three, and one families, respectively. Seven of these variants were novel, expanding the mutational spectrum of the ALS2 gene. As expected, clinical severity was positively correlated with disease onset (p = 0.004). This work provides clinical and molecular profiles of a large single ethnic cohort of patients with ALS2 mutations, and suggests that infantile ascending hereditary spastic paralysis (IAHSP) and juvenile primary lateral sclerosis (JPLS) are belonged to one entity with no phenotype-genotype correlation.

Autosomal-recessive cerebellar hypoplasia and ataxia constitute a group of heterogeneous brain disorders caused by disruption of several fundamental cellular processes. Here, we identified 10 families showing a neurodegenerative condition involving pontocerebellar hypoplasia with microcephaly (PCHM). Patients harbored biallelic mutations in genes encoding the spliceosome components Peptidyl-Prolyl Isomerase Like-1 (PPIL1) or Pre-RNA Processing-17 (PRP17). Mouse knockouts of either gene were lethal in early embryogenesis, whereas PPIL1 patient mutation knockin mice showed neuron-specific apoptosis. Loss of either protein affected splicing integrity, predominantly affecting short and high GC-content introns and genes involved in brain disorders. PPIL1 and PRP17 form an active isomerase-substrate interaction, but we found that isomerase activity is not critical for function. Thus, we establish disrupted splicing integrity and "major spliceosome-opathies" as a new mechanism underlying PCHM and neurodegeneration and uncover a non-enzymatic function of a spliceosomal proline isomerase.

BackgroundThe causes for thousands of individually rare recessive diseases have been discovered since the adoption of next generation sequencing (NGS). Following the molecular diagnosis in older children in a family, parents could use this information to opt for fetal genotyping in subsequent pregnancies, which could inform decisions about elective termination of pregnancy. The use of NGS diagnostic sequencing in families has not been demonstrated to yield benefit in subsequent pregnancies to reduce recurrence. Here we evaluated whether genetic diagnosis in older children in families supports reduction in recurrence of recessive neurogenetic disease.MethodsRetrospective study involving families with a child with a recessive pediatric brain disease (rPBD) that underwent NGS-based molecular diagnosis. Prenatal molecular testing was offered to couples in which a molecular diagnosis was made, to help couples seeking to prevent recurrence. With this information, families made decisions about elective termination. Pregnancies that were carried to term were assessed for the health of child and mother, and compared with historic recurrence risk of recessive disease.ResultsBetween 2010 and 2016, 1172 families presented with a child a likely rPBD, 526 families received a molecular diagnosis, 91 families returned to the clinic with 101 subsequent pregnancies, and 84 opted for fetal genotyping. Sixty tested negative for recurrence for the biallelic mutation in the fetus, and all, except for one spontaneous abortion, carried to term, and were unaffected at follow-up. Of 24 that genotyped positive for the biallelic mutation, 16 were electively terminated, and 8 were carried to term and showed features of disease similar to that of the older affected sibling(s). Among the 101 pregnancies, disease recurrence in living offspring deviated from the expected 25% to the observed 12% ([95% CI 0·04 to 0·20], p = 0·011).ConclusionsMolecular diagnosis in an older child, coupled with prenatal fetal genotyping in subsequent pregnancies and genetic counselling, allows families to make informed decisions to reduce recessive neurogenetic disease recurrence.

Sewage pipelines are considered to be the invaluable asset in municipalities. Inspection process plays a vital role in operation and maintenance (O&M) strategies applied by the concerned municipalities. Fault inspection and regular maintenance of sewage pipelines undoubtedly ensure longer service life; however, it could be a costly process in many cases. The objectives of this study are: indicating the significance of sewer pipelines inspection, defining methods of inspection, discussing the economic factors that affect the selection of appropriate methods of sewer pipelines inspection, and optimizing the most suitable method of sewer pipelines inspection in terms of cost effectiveness. A questionnaire survey including a list of factors of inspection of sewer pipelines in Egypt (from previous researches) was used for information collection (this questionnaire targets civil engineers based on their experience). Then, the collected data was analysed using descriptive statistics, to catch on the factors and methods of inspection of sewer pipelines (first examine the survey response using sample size then graph the results of response). Accordingly, the need for cost optimization solutions for such challenges, which is rapidly increasing, with the purpose of prioritizing the maintenance needs and focusing the municipal engineers’ efforts has emerged. The solution requires a systematic approach to diagnose the fault in the network along with regular customized inspection for performance evaluation. This research presents an optimization model for inspection of deteriorated sewage pipelines. The optimization is focused on the overall cost of the inspection process by reaching the optimum approach to diagnose and maintain the sewage pipelines. In this research, Genetic Optimization Algorithm (GA) is applied to various methods of inspects with the intention of achieving the possible optimal cost. The methods of inspection were selected in line with the outcome of a questionnaire completed by field experts. The research revealed that the acoustic inspection method with the minimum work force is the most cost-friendly method.

Background: Epistaxis is the commonest otorhinolaryngological emergency. Anterior epistaxis usually responds to conservative treatment. But, treatment of posterior epistaxis is challenging.Aim of the work: The current study aimed to compare between transnasal endoscopic sphenopalatine artery ligation [TESPAL] and cauterization for control of posterior epistaxis.Patients and Methods: Fourty patients with posterior epistaxis were included. They were randomly classified into two equal groups. The first [group A] for treatment by transnasal endoscopic sphenopalatine artery ligation. The second [group B] for treatment by transnasal endoscopic sphenopalatine artery cauterization. They were evaluated by history taking, clinical examination and routine laboratory investigations. After surgery, routine follow up consisted of anterior rhinoscopy and endoscopic nasal examination weekly during the first month then monthly up to 6 months. Postoperative complications such as recurrent epistaxis, nasal crustation, synechia, sinusitis and paresthesia in soft palate or nose were recorded.Results: Both groups were comparable regarding patient age, gender [with overall male gender predominance] and associated complications. The majority of epistaxis was from the right side, and only one patient [5%] in each group presented by bilateral epistaxis. The majority were of idiopathic etiology. The majority of operation approached two branches of SPA [60% vs 65% of ligation and cauterization groups respectively]. The duration of surgery was shorter in ligation than cauterization [58.0±14.4 vs 61.5±13.9 minutes respectively]. However, the difference was statistically non-significant. Hospital stay duration also was comparable between both groups. The success rate was 85.0% and 80.0% in ligation and cauterization groups respectively and no significant difference was observed. Nasal crustation was significantly associated with cauterization [30.0%] than ligation [5.0%].Conclusion: Although both ligation and cauterization were comparable as overall results. Ligation is superior in overall success rate and significantly associated with low crustation. This favors SPA ligation than cauterization. However, future studies are warranted.

Abstract Background Tumor-associated macrophages (TAMs), inflammatory cells in tumor microenvironment, are crucial for the tumor occurrence and progression which in turn increase the expression of soluble CD163 (sCD163). Nevertheless, not much has been established regarding sCD163 and its connection to HCC diagnosis and prognosis. This study was conducted to evaluate the diagnostic and prognostic role of sCD163 in patients with HCC on top of HCV-related liver cirrhosis. Forty adult patients with HCV-related liver cirrhosis and HCC (HCC group) were randomly selected and subjected to locoregional therapies, either transarterial chemoembolization (TACE) or radiofrequency ablation (RFA). Four patients were excluded because of portal vein invasion. Another group of 20 patients with liver cirrhosis only served as controls (LC group). Routine laboratory studies and abdominal ultrasound were done for all. Alpha-fetoprotein (AFP) and sCD163 were measured twice, at baseline and 1-month post-intervention, using a commercially available enzyme-linked immunosorbent assay kit. Results At baseline, sCD163 showed an insignificant higher value in HCC group (p > 0.05). The best cutoff value for sCD163 and AFP was 6.2 mg/L and 195 ng/mL, respectively. AFP had a larger area under the curve (0.88 vs. 0.767). An overall significant decline was seen in sCD163 after treatment (6.5±1.5 to 3.1±2.5 mg/L; p < 0.001), while AFP showed an insignificant decrease (p > 0.05). Also, sCD163 decreased significantly in the eradicated cases (6.1±1.4 mg/L before intervention vs. 2.3±1.4 mg/L after intervention, p < 0.01), while there was a significant increase in the recurrent cases (8.4±0.4 mg/L before intervention vs. 10.3±1.6 after intervention; p < 0.05). Moreover, sCD163 showed a significant difference in its pre-intervention and post-intervention values between recurrent and eradicated HCC cases (p < 0.01). Conclusions It is concluded that sCD163 has a minor role as a diagnostic marker for HCC, yet it could be used as a good prognostic marker in predicting the tumor response to locoregional therapies.