Genome-Wide Association Study (Gwas) To Uncover Genetic Risk Factors Associated With Low Bone Mineral Density And Osteoporosis In Qatar Population

Osteoporosis is an increasingly prevalent, global health burden characterized by low bone mineral density (BMD) and increased fracture risk. Despite the serious consequences of osteoporosis and the significant impact it can have on human health, the majority of affected individuals are unaware of the disease because of its asymptomatic 'silent' nature. Understanding the genetic basis of the Osteoporosis is crucial to fully elucidate the etiology of the disease. Towards this goal, genome-wide association studies (GWAS) have identified a number of promising genetic variants that are associated with osteoporosis and low BMD. Here, we undertook a genomewide association study (GWAS) in 3000 healthy Qatari individuals from Qatar Biobank to identify risk genetic variants associated with low BMD in the Qatari population. 19 significant single-nucleotide polymorphisms (SNPs) have been identified to be associated with BMD (P<5×10−8). Of these, 6 SNPs were replicated and directionally consistent in UK Biobank, in which 2 of these SNPs were identified and known to be involved in the Wnt signaling pathways which is important in bone formation. The other 13 SNPs weren’t associated to any diseases and thus were regarded as novel. 8 of these variants were intronic variants harbored in 8 gene loci; MALAT1, MRPL39, FASLG, SAG, FAM189A2, RP11-15A1.7, LSAMP, and BMPR1B and 5 were intergenic variants. The finding of our study, which to our knowledge is the first GWAS of any form of bone disease in the Qatari population, provide new insights into the genetic architecture of BMD. Further studies are needed to identify the causal variants and their functional effects to unveil unknown players contributing to BMD variation and fracture susceptibility

Memokath for treating ureteric stricture post cryoablation of renal mass: a case report of rare complication and proposed alternative management

The use of cryoablation in the management of small renal masses is widely acceptable. Although rare but ureteral injury during the procedure with subsequent stricture formation can result in devastating effects on renal function. On the other hand, the management of such strictures requires reconstructive surgery as gold standard. Unfortunately, in some cases the reconstructive surgery might not be feasible, and the treatment usually is ureteral stent insertion that need to be changed regularly. Here we present a case of a 53-year-old gentleman who developed an upper ureteric iatrogenic stricture post cryoablation in which the reconstructive surgery was not feasible due to high procedural risk. We used metallic ureteral stent (Memokath) instead of regular ureteral double J stent. We found that if the reconstructive surgery is not possible the usage of Memokath in treating iatrogenic ureteral strictures is associated with better quality of life, lower costs and a similar functional outcome when compared to ureteral double J stent that needs regular frequent changes

IFN-γ-Inducible Irga6 Mediates Host Resistance against Chlamydia trachomatis via Autophagy

Chlamydial infection of the host cell induces Gamma interferon (IFNγ), a central immunoprotector for humans and mice. The primary defense against Chlamydia infection in the mouse involves the IFNγ-inducible family of IRG proteins; however, the precise mechanisms mediating the pathogen's elimination are unknown. In this study, we identify Irga6 as an important resistance factor against C. trachomatis, but not C. muridarum, infection in IFNγ-stimulated mouse embryonic fibroblasts (MEFs). We show that Irga6, Irgd, Irgm2 and Irgm3 accumulate at bacterial inclusions in MEFs upon stimulation with IFNγ, whereas Irgb6 colocalized in the presence or absence of the cytokine. This accumulation triggers a rerouting of bacterial inclusions to autophagosomes that subsequently fuse to lysosomes for elimination. Autophagy-deficient Atg5−/− MEFs and lysosomal acidification impaired cells surrender to infection. Irgm2, Irgm3 and Irgd still localize to inclusions in IFNγ-induced Atg5−/− cells, but Irga6 localization is disrupted indicating its pivotal role in pathogen resistance. Irga6-deficient (Irga6−/−) MEFs, in which chlamydial growth is enhanced, do not respond to IFNγ even though Irgb6, Irgd, Irgm2 and Irgm3 still localize to inclusions. Taken together, we identify Irga6 as a necessary factor in conferring host resistance by remodelling a classically nonfusogenic intracellular pathogen to stimulate fusion with autophagosomes, thereby rerouting the intruder to the lysosomal compartment for destruction

Management of chronic myeloid leukaemia: current treatment options, challenges, and future strategies.

Small molecule therapy is a critical component of targeted anticancer treatment, with tyrosine kinase inhibitors (TKIs) being the first compounds to treat the clonal Chronic Myelogenous Leukaemia (CML) translocation t (9;22) (q34; q11) effectively since 2001. TKIs, such as imatinib, have improved the 10-year survival rate of CML patients to 80%. They bind the kinase and inhibit downstream signaling pathways. However, therapy failure may be seen in 20-25% of CML patients due to intolerance or inadequacy related to dependent or independent mechanisms. This review aimed to summarize current treatment options involving TKIs, resistance mechanisms and the prospective approaches to overcome TKI resistance. We highlight -dependent mechanisms of TKI resistance by reviewing clinically-documented mutations and their consequences for TKI binding. In addition, we summarize independent pathways, including the relevance of drug efflux, dysregulation of microRNA, and the involvement of alternative signaling pathways. We also discuss future approaches, such as gene-editing techniques in the context of CML, as potential therapeutic strategies

Characteristics of specialists treating hypothyroid patients: the “THESIS” collaborative

Copyright \ua9 2023 Žarković, Attanasio, Nagy, Negro, Papini, Perros, Cohen, Akarsu, Alevizaki, Ayvaz, Bednarczuk, Berta, Bodor, Borissova, Boyanov, Buffet, Burlacu, Ćirić, D\uedez, Dobnig, Fadeyev, Field, Fliers, Fr\uf8lich, F\ufchrer, Galofr\ue9, Hakala, Jiskra, Kopp, Krebs, Kršek, Kužma, Lantz, Laz\ufarov\ue1, Leenhardt, Luchytskiy, McGowan, Melo, Metso, Moran, Morgunova, Mykola, Beleslin, Niculescu, Perić, Planck, Poiana, Puga, Robenshtok, Rosselet, Ruchala, Riis, Shepelkevich, Unuane, Vardarli, Visser, Vrionidou, Younes, Yurenya and Heged\ufcs.Introduction: Thyroid specialists influence how hypothyroid patients are treated, including patients managed in primary care. Given that physician characteristics influence patient care, this study aimed to explore thyroid specialist profiles and associations with geo-economic factors. Methods: Thyroid specialists from 28 countries were invited to respond to a questionnaire, Treatment of Hypothyroidism in Europe by Specialists: an International Survey (THESIS). Geographic regions were defined according to the United Nations Statistics Division. The national economic status was estimated using World Bank data on the gross national income per capita (GNI per capita). Results: 5,695 valid responses were received (response rate 33\ub70%). The mean age was 49 years, and 65\ub70% were female. The proportion of female respondents was lowest in Northern (45\ub76%) and highest in Eastern Europe (77\ub72%) (p &lt;0\ub7001). Respondent work volume, university affiliation and private practice differed significantly between countries (p&lt;0\ub7001). Age and GNI per capita were correlated inversely with the proportion of female respondents (p&lt;0\ub701). GNI per capita was inversely related to the proportion of respondents working exclusively in private practice (p&lt;0\ub7011) and the proportion of respondents who treated &gt;100 patients annually (p&lt;0\ub701). Discussion: THESIS has demonstrated differences in characteristics of thyroid specialists at national and regional levels, strongly associated with GNI per capita. Hypothyroid patients in middle-income countries are more likely to encounter female thyroid specialists working in private practice, with a high workload, compared to high-income countries. Whether these differences influence the quality of care and patient satisfaction is unknown, but merits further study

A Novel Method to Verify Multilevel Computational Models of Biological Systems Using Multiscale Spatio-Temporal Meta Model Checking

Insights gained from multilevel computational models of biological systems can be translated into real-life applications only if the model correctness has been verified first. One of the most frequently employed in silico techniques for computational model verification is model checking. Traditional model checking approaches only consider the evolution of numeric values, such as concentrations, over time and are appropriate for computational models of small scale systems (e.g. intracellular networks). However for gaining a systems level understanding of how biological organisms function it is essential to consider more complex large scale biological systems (e.g. organs). Verifying computational models of such systems requires capturing both how numeric values and properties of (emergent) spatial structures (e.g. area of multicellular population) change over time and across multiple levels of organization, which are not considered by existing model checking approaches. To address this limitation we have developed a novel approximate probabilistic multiscale spatio-temporal meta model checking methodology for verifying multilevel computational models relative to specifications describing the desired/expected system behaviour. The methodology is generic and supports computational models encoded using various high-level modelling formalisms because it is defined relative to time series data and not the models used to generate it. In addition, the methodology can be automatically adapted to case study specific types of spatial structures and properties using the spatio-temporal meta model checking concept. To automate the computational model verification process we have implemented the model checking approach in the software tool Mule (http://mule.modelchecking.org). Its applicability is illustrated against four systems biology computational models previously published in the literature encoding the rat cardiovascular system dynamics, the uterine contractions of labour, the Xenopus laevis cell cycle and the acute inflammation of the gut and lung. Our methodology and software will enable computational biologists to efficiently develop reliable multilevel computational models of biological systems

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p&lt;0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p&lt;0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Anticancer Activity of Guggulsterone in Human Leukemic Cells

Leukemia is a group of blood cancers that is characterized by the uncontrolled proliferation of hematopoietic cells and their progressive accumulation within the bone marrow (BM) and secondary lymphoid tissues. The main cause of leukemia remains unclear, with a combination of genetic and environmental factors involved. Current treatment options have several limitations with major side effects, mainly related to high toxicity. In that respect, alternative forms of treatment are required to effectively manage and treat leukemia patients. Natural products have been shown to effectively treat several types of human cancers. These natural products include plants and other natural substances. Once natural product that has shown promising anti-cancer properties and has been found to possess cancer chemopreventive and therapeutic potential in a number of cancer cell lines is the plant polyphenol Guggulsterone (GS), which is extracted from the gum resin of the commiphora mukul tree. Nevertheless, to date, few studies have investigated the effects of GS in the treatment of leukemia. In this respect, this study focuses on the efficiency of GS in the treatment of leukemia. In this study, we demonstrated that guggulsterone inhibited the viability of human leukemia cells by inducing apoptosis through activation of the intrinsic mitochondrial pathway. Anti-tumour activity of guggusterone has been found to be associated with activation of caspase cascade, upregulation of the proapoptotic proteins (Bax and Bid) and downregulation of the antiapoptotic proteins (Bcl-2, Bcl-xL, xIAP, cIAP-1, cIAP- 2 and survivin). Furthermore, guggulsterone was found to regulate STAT3 signalingpathway. Another specific objective of this study was to exploit the anticancer potential of guggulsterone in combination with the existing chemotherapeutic approved platinum drug cisplatin. Our results revealed that guggulsterone acts synergistically with cisplatin to inhibit the viability of leukemia cells and improved the chemosensitivity of cisplatin. Our results demonstrate that guggulsterone could serve as a potent natural anti-cancer agent that may serve as a promising effective treatment option for leukemia alone or in combination therapies. Our findings serve as a basis for investigating novel regimens to prevent or delay the development of platinum resistance and overall improve the treatment of leukemia

Antibiotics for elevated prostate specific antigen: Where do we stand?

Objective: The empiric use of antibiotics for elevated prostate specific antigen (PSA) is practiced by many urologists worldwide. This study aims to investigate the effect of antibiotics on the degree of PSA change, linking it with histopathology results. Materials and Methods: This is a prospective randomized study. Patients presenting with a high PSA were randomized into two groups. Group 1 received antibiotics for a period of 4 weeks, while Group 2 did not receive any antibiotics. Both groups had repeated samples of PSA measured 6 weeks from their initial presentation. All patients underwent transrectal ultrasound-guided biopsy of the prostate. Results of PSA measurements and the degree of change were correlated with results of histopathology. Results: Eighty-four patients completed the study. Their mean age±standard deviation was 66.8 ± 6.9 years. Group 1 included 44 patients, while Group 2 included 42 patients. Prostate cancer (PCa) was detected in 50% and 35.7% of Group 1 and Group 2 patients, respectively (p = 0.52). No statistically significant difference in the mean change in PSA level (Δ PSA) between both groups was noted (p = 0.54). In Group 1, a more significant lowering of PSA was documented in PCa than in non-PCa patients (p = 0.008). No statistically significant relationship between Δ PSA and Gleason score in both groups was present. Conclusion: The empiric use of antibiotics does not hold any benefit for patients presenting with an elevated PSA. Also, the degree of change in PSA does not correlate with results of transrectal ultrasound-guided biopsy of the prostate