Systematic analysis of genomic copy number variations in inflammatory bowel diseases

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBD) which are characterized by excessive immune responses to gut microbial flora in genetically susceptible individuals. A comprehensive dissection of the genetic predisposition to IBD needs to assess the contribution of all types of genetic variants including copy number variations (CNVs) to disease risk. In the presented thesis, two related studies were conducted to interrogate the presence of disease-relevant CNVs; In one, SNP-GWAS data-set of a German UC cohort together with four other independent UC case control series were recruited to perform a multi-step genome-wide association analysis. Three CNVs enriched in UC patients were identified; a 15.8 kb deletion upstream of the genes ABCC4 and CLDN10 at 13q32.1, a 119 kb duplication at 7p22.1, overlapping RNF216, ZNF815, OCM and CCZ1 and a 134 kb large duplication upstream of the KCNK9 gene at 8q24.3. Most of these candidate genes have been functionally implicated in inflammatory processes. The probable effects of Del 13q32.1 on expression of the two nearby genes were examined in intestinal biopsies of a UC patient panel. In parallel, genomic DNA from peripheral blood as well as intestinal biopsies from nine monozygotic twin pairs discordant for IBD manifestations (4 CD, 5 UC) were recruited and compared for genome-wide CNVs by means of array-CGH, quantitative PCR and sequencing. Initial CNV calls were also contrasted with expression data of the affected genes in the corresponding twin samples. No consistent copy number differences were however revealed in the genomic DNA of discordant twins. The results implicated the potential contribution of germline structural variants to the risk of UC. Post-zygotic genomic CNVs, however, appear not to be the common cause of IBD-discordance in MZ twin

Pneumatic Tourniquet and Knee Surgery

The pneumatic tourniquet has been used in extremity surgery, especially in knee surgery. Both advantages and disadvantages were reported for using this co-operative instrument. The advantages, such as improving the surgical field and decreasing the blood loss were significant, however, disadvantages—such as increasing risk of deep vein thrombosis (DVT), nerve and muscle injuries—made its use controversial. In this review we evaluated the impact of the tourniquet on knee surgery, briefly focusing on its advantages and disadvantages in order to offer surgeons a more reliable guidelines. In previous studies there were several limitations in methodological design, tourniquet identifications, and post-operative anticoagulant regime, which made the results unreliable. Limitations such as not considering blinding assessors, assessing results with intention to treat principles, justification of sample size on the basis of power calculation and described cohort study were the most common problems in methodological designs. Lack of notification in assessing quality of life in tourniquet-used patients was a major problem which needs to be further evaluated. So we recommended designing a study that would preclude the aforementioned limitations

Replication study of ulcerative colitis risk loci in a Lithuanian-Latvian case control sample

Background: Differences between populations might be reflected in their different genetic risk maps to complex diseases, for example, inflammatory bowel disease. We here investigated the role of known inflammatory bowel disease associated single nucleotide polymorphisms (SNPs) in a subset of patients with ulcerative colitis (UC) from the Northeastern European countries Lithuania and Latvia and evaluated possible epistatic interactions between these genetic variants. Methods: We investigated 77 SNPs derived from 5 previously published genome-wide association studies for Crohn's disease and UC. Our study panel comprised 444 Lithuanian and Latvian patients with UC and 1154 healthy controls. Single marker case control association and SNP-SNP epistasis analyses were performed. Results: We found 14 SNPs tagging 9 loci, including 21q21.1, NKX2-3, MST1, the HLA region, 1p36.13, IL10, JAK2, ORMDL3, and IL23R, to be associated with UC. Interestingly, the association of UC with previously identified variants in the HLA region was not the strongest association in our study (P = 4.34 × 1023, odds ratio [OR] = 1.25), which is in contrast to all previously published studies. No association with any disease subphenotype was found. SNP-SNP interaction analysis showed significant epistasis between SNPs in the PTPN22 (rs2476601) and C13orf31 (rs3764147) genes and increased risk for UC (P = 1.64 × 1026, OR = 2.44). The association has been confirmed in the Danish study group (P = 0.04, OR = 3.25). Conclusions: We confirmed the association of the 9 loci (21q21.1, 1p36.13, NKX2-3, MST1, the HLA region, IL10, JAK2, ORMDL3, and IL23R) with UC in the Lithuanian Latvian population. SNP-SNP interaction analyses showed that the combination of SNPs in the PTPN22 (rs2476601) and C13orf31 (rs3764147) genes increase the risk for UC.publishersversionPeer reviewe

Injury burden in individuals aged 50 years or older in the Eastern Mediterranean region, 1990–2019: a systematic analysis from the Global Burden of Disease Study 2019

Background: Injury poses a major threat to health and longevity in adults aged 50 years or older. The increased life expectancy in the Eastern Mediterranean region warrants a further understanding of the ageing population's inevitable changing health demands and challenges. We aimed to examine injury-related morbidity and mortality among adults aged 50 years or older in 22 Eastern Mediterranean countries. Methods: Drawing on data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we categorised the population into adults aged 50–69 years and adults aged 70 years and older. We examined estimates for transport injuries, self-harm injuries, and unintentional injuries for both age groups, with sex differences reported, and analysed the percentage changes from 1990 to 2019. We reported injury-related mortality rates and disability-adjusted life-years (DALYs). The Socio-demographic Index (SDI) and the Healthcare Access and Quality (HAQ) Index were used to better understand the association of socioeconomic factors and health-care system performance, respectively, with injuries and health status in older people. Healthy life expectancy (HALE) was compared with injury-related deaths and DALYs and to the SDI and HAQ Index to understand the effect of injuries on healthy ageing. Finally, risk factors for injury deaths between 1990 and 2019 were assessed. 95% uncertainty intervals (UIs) are given for all estimates. Findings: Estimated injury mortality rates in the Eastern Mediterranean region exceeded the global rates in 2019, with higher injury mortality rates in males than in females for both age groups. Transport injuries were the leading cause of deaths in adults aged 50–69 years (43·0 [95% UI 31·0–51·8] per 100 000 population) and in adults aged 70 years or older (66·2 [52·5–75·5] per 100 000 population), closely followed by conflict and terrorism for both age groups (10·2 [9·3–11·3] deaths per 100 000 population for 50–69 years and 45·7 [41·5–50·3] deaths per 100 000 population for ≥70 years). The highest annual percentage change in mortality rates due to injury was observed in Afghanistan among people aged 70 years or older (400·4% increase; mortality rate 1109·7 [1017·7–1214·7] per 100 000 population). The leading cause of DALYs was transport injuries for people aged 50–69 years (1798·8 [1394·1–2116·0] per 100 000 population) and unintentional injuries for those aged 70 years or older (2013·2 [1682·2–2408·7] per 100 000 population). The estimates for HALE at 50 years and at 70 years in the Eastern Mediterranean region were lower than global estimates. Eastern Mediterranean countries with the lowest SDIs and HAQ Index values had high prevalence of injury DALYs and ranked the lowest for HALE at 50 years of age and HALE at 70 years. The leading injury mortality risk factors were occupational exposure in people aged 50–69 years and low bone mineral density in those aged 70 years or older. Interpretation: Injuries still pose a real threat to people aged 50 years or older living in the Eastern Mediterranean region, mainly due to transport and violence-related injuries. Dedicated efforts should be implemented to devise injury prevention strategies that are appropriate for older adults and cost-effective injury programmes tailored to the needs and resources of local health-care systems, and to curtail injury-associated risk and promote healthy ageing. Funding: Bill & Melinda Gates Foundation