Severe Combined Immunodeficiency from a Homozygous DNA Ligase 1 Mutant with Reduced Catalytic Activity but Increased Ligation Fidelity.

A cell's ability to survive and to evade cancer is contingent on its ability to retain genomic integrity, which can be seriously compromised when nucleic acid phosphodiester bonds are disrupted. DNA Ligase 1 (LIG1) plays a key role in genome maintenance by sealing single-stranded nicks that are produced during DNA replication and repair. Autosomal recessive mutations in a limited number of individuals have been previously described for this gene. Here we report a homozygous LIG1 mutation (p.A624T), affecting a universally conserved residue, in a patient presenting with leukopenia, neutropenia, lymphopenia, pan-hypogammaglobulinemia, and diminished in vitro response to mitogen stimulation. Patient fibroblasts expressed normal levels of LIG1 protein but exhibited impaired growth, poor viability, high baseline levels of gamma-H2AX foci, and an enhanced susceptibility to DNA-damaging agents. The mutation reduced LIG1 activity by lowering its affinity for magnesium 2.5-fold. Remarkably, it also increased LIG1 fidelity > 50-fold against 3' end 8-Oxoguanine mismatches, exhibiting a marked reduction in its ability to process such nicks. This is expected to yield increased ss- and dsDNA breaks. Molecular dynamic simulations, and Residue Interaction Network studies, predicted an allosteric effect for this mutation on the protein loops associated with the LIG1 high-fidelity magnesium, as well as on DNA binding within the adenylation domain. These dual alterations of suppressed activity and enhanced fidelity, arising from a single mutation, underscore the mechanistic picture of how a LIG1 defect can lead to severe immunological disease.

Public Perception in Saudi Arabia Toward Herpes Zoster and Its Vaccination: A Cross-Sectional Study.

Background Herpes zoster (HZ) or shingles, arises from the reactivation of the varicella zoster virus (VZV), mainly affecting older and immunocompromised individuals. Despite the efficacy of vaccines, vaccination rates in Saudi Arabia are low. Thus, this study aimed to assess the knowledge, attitude, and practice of the Saudi Arabian population toward HZ and its vaccination. Methods An observational cross-sectional study was carried out to evaluate the public perception in Saudi Arabia toward HZ and its vaccination, during the period from January to March 2024. Participants were selected using a non-probability, convenience sampling method, with recruitment facilitated through WhatsApp, a messaging app. Data has been analyzed using the statistical software Statistical Package for Social Sciences (SPSS), version 26.0 (IBM Corp., Armonk, NY). A p-value of <0.05 has been used to report the statistical significance. Results The study's demographic profile included 1237 participants, predominantly younger than 30 years (65.5%), with a female majority (65.7%). Public knowledge about HZ was limited, only 29.6% of participants recognized the risk of HZ post-chickenpox. More than half of the participants were not aware that the vaccine is provided by the Saudi Ministry of Health (MOH) for certain groups. However, over 75% are willing to receive the HZ vaccine upon physician recommendation. Conclusion This study shows a general lack of awareness about HZ and its vaccination in Saudi Arabia, including misconceptions about vaccination availability, recommendations, and the disease's complications. Gender differences in attitude and interest highlight the potential for tailored educational campaigns. Addressing these issues is essential for improving vaccination rates and mitigating HZ's impact.

Parents' Awareness and Perception of Children's Eye Diseases in Madinah, Saudi Arabia: A Cross-Sectional Study.

Background The visual system becomes more susceptible to conditions causing abnormal binocular interaction or blurred visual input as it matures during the first six years of life. Therefore, detection and treatment of visual impairment at a young age can lower the burden of the condition in adulthood. According to estimates, there are 19 million children worldwide with visual impairment, and 1.4 million children suffer from blindness. One of the strategies to address blinding eye conditions and visual impairment is through health promotion. For children, the efficient way of intervention is through parents and their school environment. Therefore, the establishment of an effective health promotion model for addressing childhood blindness requires awareness building of parents and health care practices. Few studies were undertaken in Saudi Arabia to focus on the awareness of parents about childhood eye diseases and visual impairment. The aim of this study is to assess parents' awareness and perception of children's eye diseases in Madinah, Saudi Arabia. Methods This cross-sectional study was conducted in Madinah, Saudi Arabia, from January to December 2021. A self-administered questionnaire was randomly distributed to parents of children aged 15 and younger via WhatsApp. The survey consisted of four main sections: socio-demographic data, knowledge about eye care, knowledge about eye diseases, and eye care practice. Results The knowledge about eye diseases in children was of excellent grade in 20 parents (3.6%), good in 101 (18.2%), and poor in 434 (78.2%). Knowledge was good in 287 parents (51.7%) for amblyopia, 65 (11.7%) for childhood cataract, and 69 (12.4%) for childhood glaucoma. The attitude regarding children wearing spectacles and undergoing ophthalmic surgery when needed was positive in 427 (76.9%) and 474 (85.4%) parents, respectively. Over half of the participants (58.6%) had visited an ophthalmology clinic for the examination of their children. Doctors, campaigns, and social media were the preferred modes of receiving knowledge. Participants aged 51 years or over (p = 0.022), with a higher income level (p = 0.004), of Saudi origin (p = 0.036), and those with a child with an eye disease (p = 0.001) had significantly higher knowledge scores about childhood eye diseases. Conclusion The levels of knowledge, practice, and attitude among parents regarding pediatric eye diseases were unsatisfactory. Health promotion through utilizing parents' preferred modes of media could improve the eye care of children in the study area.

Frictional Pressure Drop and Cost Savings for Graphene Nanoplatelets Nanofluids in Turbulent Flow Environments.

Covalent-functionalized graphene nanoplatelets (CF-GNPs) inside a circular heated-pipe and the subsequent pressure decrease loss within a fully developed turbulent flow were discussed in this research. Four samples of nanofluids were prepared and investigated in the ranges of 0.025 wt.%, 0.05 wt.%, 0.075 wt.%, and 0.1 wt.%. Different tools such as field emission scanning electron microscopy (FE-SEM), ultraviolet-visible-spectrophotometer (UV-visible), energy-dispersive X-ray spectroscopy (EDX), zeta potential, and nanoparticle sizing were used for the data preparation. The thermophysical properties of the working fluids were experimentally determined using the testing conditions established via computational fluid dynamic (CFD) simulations that had been designed to solve governing equations involving distilled water (DW) and nanofluidic flows. The average error between the numerical solution and the Blasius formula was ~4.85%. Relative to the DW, the pressure dropped by 27.80% for 0.025 wt.%, 35.69% for 0.05 wt.%, 41.61% for 0.075 wt.%, and 47.04% for 0.1 wt.%. Meanwhile, the pumping power increased by 3.8% for 0.025 wt.%, 5.3% for 0.05 wt.%, 6.6% for 0.075%, and 7.8% for 0.1 wt.%. The research findings on the cost analysis demonstrated that the daily electric costs were USD 214, 350, 416, 482, and 558 for DW of 0.025 wt.%, 0.05 wt.%, 0.075 wt.%, and 0.1 wt.%, respectively.

The use of nocturnal home hemodialysis as salvage therapy for patients experiencing peritoneal dialysis failure.

BACKGROUND: Failure of peritoneal dialysis (PD) results in poor quality of life and worsening morbidity in patients with end-stage renal disease (ESRD). Traditionally, hospital-based conventional hemodialysis has been the only option for this patient population. We hypothesized that nocturnal home hemodialysis (NHD), 3-6 sessions per week, 6-8 hours per session, is a suitable alternative salvage therapy for this vulnerable patient group. METHODS: This is a descriptive cohort study of all consecutive ESRD patients failing PD that were converted to NHD at the University Health Network and Humber River Regional Hospital from 2003 to 2005. Our primary objective was to describe the changes in clinical and biochemical indices before and after conversion from PD to NHD. RESULTS: 69 patients required transfer from PD to another form of renal replacement therapy during the period of interest. Our pilot cohort included 8 ESRD patients (5 males, 3 females; age 53 +/- 7 years). Mean duration on PD was 4.8 +/- 4.6 years. NHD delivered a higher dose of dialysis, as reflected by lower plasma creatinine concentration 1 year after beginning NHD (from 1107 +/- 312 micromol/L with PD to 649 +/- 309 micromol/L, p = 0.01) and a rise in standardized Kt/V (from 2.21 +/- 0.73 with PD to 4.49 +/- 1.92 after 6 months of NHD, to 4.51 +/- 1.77 after 1 year of NHD; p < 0.001). There was a progressive and sustained rise in plasma albumin after conversion to NHD (from 31 +/- 4 g/L with PD to 36 +/- 4 g/L after 6 months of NHD, to 39 +/- 2 g/L after 1 year of NHD; p = 0.001). Hemoglobin concentrations increased (from 102 +/- 13 to 125 +/- 7 g/L, p = 0.03), while erythropoietin requirement tended to fall (from 17500 +/- 8669 to 9197 +/- 7573 U/week). Plasma phosphate fell (from 2.1 +/- 0.6 to 1.1 +/- 0.3 mmol/L, p = 0.01) despite a decrease in phosphate binder requirement. Blood pressure profile also tended to improve after conversion to NHD. CONCLUSION: Nocturnal HD represents a promising, viable, alternative renal replacement therapy for patients experiencing PD failure. The clinical impact of transferring ESRD patients failing PD to NHD deserves further investigation.