Expanded Somatic Mutation Spectrum of MED12 Gene in Uterine Leiomyomas of Saudi Arabian Women

MED12, a subunit of mediator complex genes is known to harbor genetic mutations, (mostly in exon 2), causal to the genesis of uterine leiomyomas among Caucasian, African American, and Asian women. However, the precise relationship between genetic mutations vs. protein or disease phenotype is not well-explained. Therefore, we sought to replicate the MED12 mutation frequency in leiomyomas of Saudi Arabian women, who represents ethnically and culturally distinct population. We performed molecular screening of MED12 gene (in 308 chromosomes belonging to 154 uterine biopsies), analyzed the genotype-disease phenotype correlations and determined the biophysical characteristics of mutated protein through diverse computational approaches. We discovered that >44% (34/77) leiomyomas of Arab women carry a spectrum of MED12 mutations (30 missense, 1 splice site, and 3 indels). In addition to known codon 44, we observed novel somatic mutations in codons 36, 38, and 55. Most genetically mutated tumors (27/30; 90%) demonstrated only one type of genetic change, highlighting that even single allele change in MED12 can have profound impact in transforming the normal uterine myometrium to leiomyomas. An interesting inverse correlation between tumor size and LH is observed when tumor is positive to MED12 mutation (p < 0.05). Our computational investigations suggest that amino acid substitution mutations in exon-2 region of MED12 might contribute to potential alterations in phenotype as well as the stability of MED12 protein. Our study, being the first one from Arab world, confirms the previous findings that somatic MED12 mutations are critical to development and progression of uterine leiomyomas irrespective of the ethnic background. We recommend that mutation screening, particularly codon 44 of MED12 can assist in molecular diagnostics of uterine leiomyomas in majority of the patients

Global prevalence and genotype distribution of hepatitis C virus infection in 2015 : A modelling study

Publisher Copyright: © 2017 Elsevier LtdBackground The 69th World Health Assembly approved the Global Health Sector Strategy to eliminate hepatitis C virus (HCV) infection by 2030, which can become a reality with the recent launch of direct acting antiviral therapies. Reliable disease burden estimates are required for national strategies. This analysis estimates the global prevalence of viraemic HCV at the end of 2015, an update of—and expansion on—the 2014 analysis, which reported 80 million (95% CI 64–103) viraemic infections in 2013. Methods We developed country-level disease burden models following a systematic review of HCV prevalence (number of studies, n=6754) and genotype (n=11 342) studies published after 2013. A Delphi process was used to gain country expert consensus and validate inputs. Published estimates alone were used for countries where expert panel meetings could not be scheduled. Global prevalence was estimated using regional averages for countries without data. Findings Models were built for 100 countries, 59 of which were approved by country experts, with the remaining 41 estimated using published data alone. The remaining countries had insufficient data to create a model. The global prevalence of viraemic HCV is estimated to be 1·0% (95% uncertainty interval 0·8–1·1) in 2015, corresponding to 71·1 million (62·5–79·4) viraemic infections. Genotypes 1 and 3 were the most common cause of infections (44% and 25%, respectively). Interpretation The global estimate of viraemic infections is lower than previous estimates, largely due to more recent (lower) prevalence estimates in Africa. Additionally, increased mortality due to liver-related causes and an ageing population may have contributed to a reduction in infections. Funding John C Martin Foundation.publishersversionPeer reviewe

Infected pancreatic necrosis: outcomes and clinical predictors of mortality. A post hoc analysis of the MANCTRA-1 international study

: The identification of high-risk patients in the early stages of infected pancreatic necrosis (IPN) is critical, because it could help the clinicians to adopt more effective management strategies. We conducted a post hoc analysis of the MANCTRA-1 international study to assess the association between clinical risk factors and mortality among adult patients with IPN. Univariable and multivariable logistic regression models were used to identify prognostic factors of mortality. We identified 247 consecutive patients with IPN hospitalised between January 2019 and December 2020. History of uncontrolled arterial hypertension (p = 0.032; 95% CI 1.135-15.882; aOR 4.245), qSOFA (p = 0.005; 95% CI 1.359-5.879; aOR 2.828), renal failure (p = 0.022; 95% CI 1.138-5.442; aOR 2.489), and haemodynamic failure (p = 0.018; 95% CI 1.184-5.978; aOR 2.661), were identified as independent predictors of mortality in IPN patients. Cholangitis (p = 0.003; 95% CI 1.598-9.930; aOR 3.983), abdominal compartment syndrome (p = 0.032; 95% CI 1.090-6.967; aOR 2.735), and gastrointestinal/intra-abdominal bleeding (p = 0.009; 95% CI 1.286-5.712; aOR 2.710) were independently associated with the risk of mortality. Upfront open surgical necrosectomy was strongly associated with the risk of mortality (p < 0.001; 95% CI 1.912-7.442; aOR 3.772), whereas endoscopic drainage of pancreatic necrosis (p = 0.018; 95% CI 0.138-0.834; aOR 0.339) and enteral nutrition (p = 0.003; 95% CI 0.143-0.716; aOR 0.320) were found as protective factors. Organ failure, acute cholangitis, and upfront open surgical necrosectomy were the most significant predictors of mortality. Our study confirmed that, even in a subgroup of particularly ill patients such as those with IPN, upfront open surgery should be avoided as much as possible. Study protocol registered in ClinicalTrials.Gov (I.D. Number NCT04747990)

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Pattern of abnormal Pap smears in developing countries : A report from a large referral hospital in Saudi Arabia using the revised 2001 Bethesda System

<b>Background: </b> Reports describing the frequency and pattern of abnormal Pap smears in developing countries using the revised Bethesda system for Pap smear are few. We studied the pattern of cervical intraepithelial le--sions and carcinoma detected in Pap smears of Saudi females in the western region of Saudi Arabia using the revised system. <b> Methods: </b> All cervical Pap smears reported in the Department of Pathology of King Abdulaziz Medical City, Jeddah, from 1 January 1998 to 31 August 2005 were reclassified according to the revised system with age ranges identified. <b>RESULTS: </b>Of 5590 sufficient smears, 261 (5&#x0025;) were identified as abnormal and were further classified as atypical squamous cells of undetermined significance (ASC-US) (103 cases, 40&#x0025;), atypical squamous cells of high grade (6 cases, 2&#x0025;), low-grade squamous intraepithelial lesions (LSIL) (56 cases, 22&#x0025;), high-grade squamous intraepithelial lesions (HSIL) (31 cases, 12&#x0025;), glandular cell abnormalities (30 cases, 11&#x0025;) and invasive squa--mous cell carcinoma (21 cases, 9&#x0025;). The ASC-US/SIL ratio was 1.9&#x0025;. Invasive adenocarcinoma accounted for 14 cases (4&#x0025;) with a similar age range as invasive squamous cell carcinoma. <b> Conclusion: </b> Although this study showed a lower incidence and a wider age range of cervical epithelial cell abnormalities than others published internationally, the results emphasize the need for a well-organized cervi--cal screening program supplemented by larger national studies on the pattern of cervical abnormalities in this country. The information provided in this study will encourage use of the Pap smear as a screening method for cervical cancer in developing countries

Histopathological pattern of pediatric renal diseases: A study from a university hospital in western Saudi Arabia

To study the clinical indications and histopathological pattern of renal biopsies and renal resection specimens in the pediatric age group (birth to 17 years) in a large academic center in western Saudi Arabia. A retrospective review of the computerized database of the Pathology Department at King Abdul Aziz University Hospital (KAUH) was carried out on the final patho-logy reports of all children of the age of 17 years and below who either had ultrasound-guided renal biopsies or partial or total renal resections during the period between January 1995 and December 2008. All the specimens were reported by our pathology department. The most common clinical indication in the study group (242) is nephrotic syndrome (117, 48.3%), fol-lowed by systemic lupus erythromatosis for staging (30, 12.4%), nephritic syndrome (27, 11.1%) and renal mass for histological diagnosis (17, 7.0%). The most frequently reported pathological diagnosis was renal glomerulopathies, constituting 183 cases (n = 183, 75.6%) of the total number of pathology reports reviewed. Primary glomerulopathies were more common (n = 155, 88.4%) than the secondary ones (n = 28, 11.6%). The second most common pediatric renal pathology in this study was renal neoplasms (14, 5.7%). Vascular renal diseases and renal glomerulosclerosis ranked as the third pathological diagnosis in order of frequency in this study, with ten cases (10, 4.1%). The most common clinical indication for renal tissue sampling in this study is nephrotic syndrome and the most frequently detected pathology is glomerulonephritis. Larger multicentre studies are needed to further study pediatric nephropathies

Applying Michel Foucault's power theory in Shakespeare's King Lear

Michel Foucault is a French postmodernist philosopher whose theories have impacted different fields of knowledge in the modern era. Foucault is one of the few writers who recognize the nature of power in social relations. Foucault views power as a dynamic relationship between discourses and subjects, produced by discourses dominating specific subjects or governing individuals' demands. Thus, the present paper aims at discovering the power relations in Shakespeare's King Lear in the light of Foucault's theory of power. Like Shakespeare, Foucault is interested in language as a human problem, and hence his dramas can be read as the study of the nature of language. In King Lear, the character's actions and reactions are apparent in words and sentences to reflect the powerful and powerless position. Considered in this way, King Lear seems to dramatize the words and sentences as a total discourse of power relations

Studying pH dependence of the photophysical properties of a blue emitting fluorescent PAMAM dendrimer and evaluation of its sensor potential

The first synthesis of a blue fluorescent PAMAM dendrimer, comprising eight 4-N,N-dimethylaminoethyloxy-1,8-naphthalimide units in the dendrimer periphery has been described. Its functional properties have been investigated in organic solvents of different polarity. The sensor ability of the dendrimer to detect metal (Ag2+, Co2+, Pb2+ Zn2+, Ni2+, Cu2+ and Fe3+) ions has been discussed. The fluorescence intensity of the dendrimer has been investigated as a pH function of the environment. The influence of hydroxyl anions on the dendrimer spectral properties in non-aqueous medium has also been investigated. © 2014 Elsevier Ltd. All rights reserved.Peer Reviewe