Structural Motifs at the Telomeres and Their Role in Regulatory Pathways.

Telomeres are specialized structures, found at the ends of linear chromosomes in eukaryotic cells, that play a crucial role in maintaining the stability and integrity of genomes. They are composed of repetitive DNA sequences, ssDNA overhangs, and several associated proteins. The length of telomeres is linked to cellular aging in humans, and deficiencies in their maintenance are associated with various diseases. Key structural motifs at the telomeres serve to protect vulnerable chromosomal ends. Telomeric DNA also has the ability to form diverse complex DNA higher-order structures, including T-loops, D-loops, R-loops, G-loops, G-quadruplexes, and i-motifs, in the complementary C-rich strand. While many essential proteins at telomeres have been identified, the intricacies of their interactions and structural details are still not fully understood. This Perspective highlights recent advancements in comprehending the structures associated with human telomeres. It emphasizes the significance of telomeres, explores various telomeric structural motifs, and delves into the structural biology surrounding telomeres and telomerase. Furthermore, telomeric loops, their topologies, and the associated proteins that contribute to the safeguarding of telomeres are discussed.

Identification and Characterization of Novel Mutations in Chronic Kidney Disease (CKD) and Autosomal Dominant Polycystic Kidney Disease (ADPKD) in Saudi Subjects by Whole-Exome Sequencing.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a condition usually caused by a single gene mutation and manifested by both renal and extrarenal features, eventually leading to end-stage renal disease (ESRD) by the median age of 60 years worldwide. Approximately 89% of ADPKD patients had either PKD1 or PKD2 gene mutations. The majority (85%) of the mutations are in the PKD1 gene, especially in the context of family history. Objectives: This study investigated the genetic basis and the undiscovered genes that are involved in ADPKD development among the Saudi population. Materials and Methods: In this study, 11 patients with chronic kidney disease were enrolled. The diagnosis of ADPKD was based on history and diagnostic images: CT images include enlargement of renal outlines, renal echogenicity, and presence of multiple renal cysts with dilated collecting ducts, loss of corticomedullary differentiation, and changes in GFR and serum creatinine levels. Next-generation whole-exome sequencing was conducted using the Ion Torrent PGM platform. Results: Of the 11 Saudi patients diagnosed with chronic kidney disease (CKD) and ADPKD, the most common heterozygote nonsynonymous variant in the PKD1 gene was exon15: (c.4264G > A). Two missense mutations were identified with a PKD1 (c.1758A > C and c.9774T > G), and one patient had a PKD2 mutation (c.1445T > G). Three detected variants were novel, identified at PKD1 (c.1758A > C), PKD2L2 (c.1364A > T), and TSC2 (deletion of a'a at the 3'UTR, R1680C) genes. Other variants in PKD1L1 (c.3813_381 4delinsTG) and PKD1L2 (c.404C > T) were also detected. The median age of end-stage renal disease for ADPK patients in Saudi Arabia was 30 years. Conclusion: This study reported a common variant in the PKD1 gene in Saudi patients with typical ADPKD. We also reported (to our knowledge) for the first time two novel missense variants in PKD1 and PKD2L2 genes and one indel mutation at the 3'UTR of the TSC2 gene. This study establishes that the reported mutations in the affected genes resulted in ADPKD development in the Saudi population by a median age of 30. Nevertheless, future protein−protein interaction studies to investigate the influence of these mutations on PKD1 and PKD2 functions are required. Furthermore, large-scale population-based studies to verify these findings are recommended.

Hospital admission trends due to respiratory diseases in England and Wales between 1999 and 2019: an ecologic study.

BACKGROUND: Identifying trends of hospital admissions for respiratory diseases is crucial for public health and research to guide future clinical improvements for better outcomes. This study aims to define the trends of respiratory disease-related hospital admissions (RRHA) in England and Wales between 1999 and 2019. METHODS: An ecological study was conducted using hospital admission data taken from the Hospital Episode Statistics database in England and the Patient Episode Database for Wales. Hospital admissions data for respiratory diseases were extracted for the period between April 1999 and March 2019. The trend in hospital admissions was assessed using a Poisson model. RESULTS: Hospital admission rate increased by 104.7% [from 1535.05 (95% CI 1531.71-1538.38) in 1999 to 3142.83 (95% CI 3138.39-3147.26) in 2019 per 100,000 persons, trend test, p < 0.01]. The most common causes were influenza and pneumonia, chronic lower respiratory diseases, other acute lower respiratory infections, which accounted for 26.6%, 26.4%, and 14.9%, respectively. The age group 75 years and above accounted for 34.1% of the total number of hospital admissions. Males contributed to 50.5% of the total number of hospital admissions. Hospital admission rate in females increased by 119.8% [from 1442.18 (95% CI 1437.66-1446.70) in 1999 to 3169.38 (95% CI 3163.11-3175.64) in 2019 per 100,000 persons, trend test, p < 0.001]. Hospital admission rate increased by 92.9% in males [from 1633.25 (95% CI 1628.32-1638.17) in 1999 to 3149.78 (95% CI 3143.46-3156.09) in 2019 per 100,000 persons, trend test, p < 0.001]. CONCLUSION: During the study period, hospital admissions rate due to respiratory diseases increased sharply. The rates of hospital admissions were higher among males for the vast majority of respiratory diseases. Further observational studies are warranted to identify risk factors for these hospital admissions and to offer relevant interventions to mitigate the risk.

Trends of Hospital Admissions Due to Congenital Anomalies in England and Wales between 1999 and 2019: An Ecological Study.

Objectives: To investigate the trends in congenital anomalies-related hospital admissions in England and Wales. Methods: This was an ecological study that was conducted using hospital admission data taken from the Hospital Episode Statistics database in England and the Patient Episode Database for Wales. Congenital malformations, deformations and chromosomal abnormalities hospital admissions data were extracted for the period between April 1999 and March 2019. Results: Hospital admission rate increased by 4.9% [from 198.74 (95% CI 197.53-199.94) in 1999 to 208.55 (95% CI 207.39-209.71) in 2019 per 100,000 persons, trend test, p < 0.01]. The most common hospital admissions causes were congenital malformations of the circulatory system, the musculoskeletal system, genital organs, and the digestive system. The most notable increase in hospital admissions rate was observed in congenital malformations of the respiratory system (1.01-fold). The age group below 15 years accounted for 75.1% of the total number of hospital admissions. Males contributed to 57.5% of the whole number of hospital admission. Hospital admission rate between females was increased by 6.4% [from 162.63 (95% CI 161.10-164.16) in 1999 to 173.05 (95% CI 171.57-174.54) in 2019 per 100,000 persons]. Hospital admission rate between males was increased by 3.4% [from 236.61 (95% CI 234.72-238.50) in 1999 to 244.70 (95% CI 242.92-246.49) in 2019 per 100,000 persons]. Conclusions: Males had a higher percentage of hospitalisation compared to females. Further studies to investigate the factors associated with higher hospitalisation rate among males are needed.

Prevalence of Chronic Kidney Diseases in Patients with Diabetes Mellitus in the Middle East: A Systematic Review and Meta-Analysis.

AIMS: The prevalence of CKD in patients with diabetes mellitus in the Middle East region is unknown. Therefore, we aimed to understand the pooled prevalence of CKD in patients with diabetes mellitus in the Middle East region. METHODS: PubMed, Embase, and Cochrane databases were searched for relevant studies up to October 2020. The search strategy was conducted using both keywords and MeSH terms. Randomised controlled trials (RCTs) and observational studies that included patients from all age groups and any study design that reported on the prevalence of CKD in patients with diabetes mellitus were included. The pooled estimate for the prevalence of CKD in patients with diabetes was calculated using random-effect models with 95% confidence intervals (CIs). RESULTS: A total of 489 citations were identified, of which only nine studies matched our inclusion criteria and were included in the meta-analysis. All of the studies used an observational study design covering a total of 59,395 patients with type 2 diabetes mellitus. The pooled estimate of the prevalence of CKD in patients with diabetes mellitus was 28.96% (95% CI: 19.80-38.11). CONCLUSIONS: A high prevalence of CKD in patients with diabetes mellitus in the Middle East region was found. Further epidemiological studies are warranted in this area to have a better estimate of the prevalence of CKD among DM in the Middle East region.

Hospital Admissions Due to Ischemic Heart Diseases and Prescriptions of Cardiovascular Diseases Medications in England and Wales in the Past Two Decades.

OBJECTIVES: The aim of this study was to explore the trend of ischemic heart disease (IHD) admission and the prescriptions of IHD medications in England and Wales. METHODS: A secular trends study was conducted during the period of 1999 to 2019. We extracted hospital admission data for patients from all age groups from the Hospital Episode Statistics database in England and the Patient Episode Database for Wales. Prescriptions of IHD medications were extracted from the Prescription Cost Analysis database from 2004 to 2019. The chi-squared test was used to assess the difference between the admission rates and the difference between IHD medication prescription rates. The trends in IHD-related hospital admission and IHD-related medication prescription were assessed using a Poisson model. The correlation between hospital admissions for IHD and its IHD medication-related prescriptions was assessed using the Pearson correlation coefficient. RESULTS: Our study detected a significant increase in the rate of cardiovascular disease (CVD) medication prescriptions in England and Wales, representing a rise in the CVD medications prescription rate of 41.8% (from 539,334.95 (95% CI = 539,286.30-539,383.59) in 2004 to 764,584.55 (95% CI = 764,545.55-764,623.56) in 2019 prescriptions per 100,000 persons), with a mean increase of 2.8% per year during the past 15 years. This increase was connected with a reduction in the IHD hospital admission rate by 15.4% (from 838.50 (95% CI = 836.05-840.94) in 2004 to 709.78 (95% CI = 707.65-711.92) in 2019 per 100,000 persons, trend test, p < 0.01), with a mean decrease of 1.02% per year during the past 15 years and by 5% (from 747.43 (95% CI = 745.09-749.77) in 1999 to 709.78 (95% CI = 707.65-711.92) in 2019 per 100,000 persons, trend test, p < 0.01) with a mean decrease of 0.25% per year during the past two decades in England and Wales. CONCLUSION: The rate of hospitalisation due to IHD has decreased in England and Wales during the past two decades. Hospitalisation due to IHD was strongly and negatively correlated with the increase in the rates of dispensing of IHD-related medications. Other factors contributing to this decline could be the increase in controlling IHD risk factors during the past few years. Future studies exploring other risk factors that are associated with IHD hospitalisation are warranted.