Frequency of <i>KLK3 </i>gene deletions in the general population

Background One of the kallikrein genes ( KLK3) encodes prostate-specific antigen, a key biomarker for prostate cancer. A number of factors, both genetic and non-genetic, determine variation of serum prostate-specific antigen concentrations in the population. We have recently found three KLK3 deletions in individuals with very low prostate-specific antigen concentrations, suggesting a link between abnormally reduced KLK3 expression and deletions of KLK3. Here, we aim to determine the frequency of kallikrein gene 3 deletions in the general population. Methods The frequency of KLK3 deletions in the general population was estimated from the 1958 Birth Cohort sample ( n = 3815) using amplification ratiometry control system. In silico analyses using PennCNV were carried out in the same cohort and in NBS-WTCCC2 in order to provide an independent estimation of the frequency of KLK3 deletions in the general population. Results Amplification ratiometry control system results from the 1958 cohort indicated a frequency of KLK3 deletions of 0.81% (3.98% following a less stringent calling criterion). From in silico analyses, we found that potential deletions harbouring the KLK3 gene occurred at rates of 2.13% (1958 Cohort, n = 2867) and 0.99% (NBS-WTCCC2, n = 2737), respectively. These results are in good agreement with our in vitro experiments. All deletions found were in heterozygosis. Conclusions We conclude that a number of individuals from the general population present KLK3 deletions in heterozygosis. Further studies are required in order to know if interpretation of low serum prostate-specific antigen concentrations in individuals with KLK3 deletions may offer false-negative assurances with consequences for prostate cancer screening, diagnosis and monitoring. </jats:sec

Influence of Adiposity-Related Genetic Markers in a Population of Saudi Arabians Where Other Variables Influencing Obesity May Be Reduced

Large scale studies in Europeans have clearly identified common polymorphism affecting BMI and obesity. We undertook a genotype study to examine the impact of variants, known to influence obesity, in a sample from the Saudi Arabian population, notable for its profound combination of low mean physical activity indices and high energy intake. Anthropometry measures and genotypes were obtained for 367 Saudis, taken from King Saud University and Biomarker Screening Project in Riyadh (Riyadh Cohort). We observed large effect sizes with obesity for rs10767664 (BDNF) (OR = 1.923, P=0.00072) and rs3751812 (FTO) (OR = 1.523, P=0.016) in our sample and, using weighted genetic risk scores, we found strong evidence of a cumulative effect using 11 SNPs taken predominantly from loci principally affecting appetite (OR = 2.57, P=0.00092). We used conditional analyses to discern which of our three highly correlated FTO SNPs were responsible for the observed signal, although we were unable to determine with confidence which best marked the causal site. Our analysis indicates that markers located in loci known to influence fat mass through increased appetite affect obesity in Saudi Arabians to an extent possibly greater than in Europeans. Larger scale studies will be necessary to obtain a precise comparison

Genome-Wide Analysis of the Emerging Infection with Mycobacterium avium Subspecies paratuberculosis in the Arabian Camels (Camelus dromedarius)

Mycobacterium avium subspecies paratuberculosis (M. ap) is the causative agent of paratuberculosis or Johne's disease (JD) in herbivores with potential involvement in cases of Crohn's disease in humans. JD is spread worldwide and is economically important for both beef and dairy industries. Generally, pathogenic ovine strains (M. ap-S) are mainly found in sheep while bovine strains (M. ap-C) infect other ruminants (e.g. cattle, goat, deer), as well as sheep. In an effort to characterize this emerging infection in dromedary/Arabian camels, we successfully cultured M. ap from several samples collected from infected camels suffering from chronic, intermittent diarrhea suggestive of JD. Gene-based typing of isolates indicated that all isolates belong to sheep lineage of strains of M. ap (M. ap-S), suggesting a putative transmission from infected sheep herds. Screening sheep and goat herds associated with camels identified the circulation of this type in sheep but not goats. The current genome-wide analysis recognizes these camel isolates as a sub-lineage of the sheep strain with a significant number of single nucleotide polymorphisms (SNPs) between sheep and camel isolates (∼1000 SNPs). Such polymorphism could represent geographical differences among isolates or host adaptation of M. ap during camel infection. To our knowledge, this is the first attempt to examine the genomic basis of this emerging infection in camels with implications on the evolution of this important pathogen. The sequenced genomes of M. ap isolates from camels will further assist our efforts to understand JD pathogenesis and the dynamic of disease transmission across animal species

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10&nbsp;years; 78.2% included were male with a median age of 37&nbsp;years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020

Direct and indirect effects of leadership styles on employee commitment and performance in Saudi Airlines

The Path-Goal Theory is strongly referred to as one of the main organisational subjects of leadership styles in human resources literature. The theory proposes four leadership behaviors that are directive, supportive, participative, and achievement-oriented. In addition, the primary premise of the theory is to predict leadership effectiveness in maximizing employee attitude and performance in different situations. Nevertheless, several deficiencies have been identified in the literature which require further development such as understanding the underlying mechanisms and the boundary conditions of leadership effects. Building on the Path-Goal Theory and the Social Identity Theory, the general objective of this study is to examine the effects of leadership styles on employee affective commitment and performance directly and through the mediating effect of organisational identification, as well as the moderating effect of job security in the context of Saudi Airlines in Saudi Arabia. This is motivated by the fact that Saudi Airlines faces an ongoing internal organisational and external environmental changes, and therefore, the role of organisational identification and job security is relevant. This quantitative study utilized a stratified random sampling technique and used a sample of 353 respondents from the company headquarter, as well as the four international airports of Saudi Arabia (Jeddah, Riyadh, Dammam, and Medina). In addition, the collected data were analyzed using the partial least squares technique to achieve the study findings. In general, these findings revealed that the behaviors of leaders at Saudi Airlines were major determinants of the Path-Goal Theory’s role on subordinates’ attitudes and behavior. It was confirmed that there are significant relationships between leadership styles and the studied outcomes, as well as significant mediating and moderating effects of organisational identification and job security respectively. In specific, the results showed that affective commitment is influenced by participative leadership, achievement-oriented leadership, and organisational identification. Job performance is influenced by supportive leadership, organisational identification, and affective commitment. Organisational identification is influenced by directive, supportive and achievement-oriented leadership. In addition, organisational identification mediates the effect of directive, supportive, and achievement-oriented leadership on affective commitment and job performance. On the other hand, job security had a significant moderating effect on the influence of achievement-oriented leadership style on organisational identification. This study has identified the leadership determinants of organisational identification, affective commitment, and job performance, yet it demonstrates that leadership styles, according to the Path-Goal Theory, are good indicators for employee attitude and performance in the study context

Development and application of approaches to population mutation scanning

This study develops a new approach to population scanning  for unknown rare variants with high throughout and cost-effectiveness.  Melt-MADGE combines the properties of microplate array diagonal gel electrophoresis (MADGE) with a reconfiguration of denaturing gradient gel electrophoresis (DGGE) (using a thermal ramp rather than a urea gradient).  It may be the most powerful method yet devised, enabling over 4,000 DNA samples to be scanned by a single investigator per day (4x10x96-well gels) in two 2 litre tanks. I have developed 9 assay amplicons representing MC4R and examined a population sample of 1,100 subjects.  Two paucimorphisms were identified (V1031 in 28 subjects and -178A&gt;C in 22 subjects).  Anthropometric studies of these variants have the power to detect, for example, BMI effects as little as 0.5 units.  Two rare variants were also identified, one previously described (T112M) and one unknown (A87D).  BMI of 31.5 in the latter, might point to mild functional effects.  In LDLR, which has 18 exons, hotspot exons were scanned in both case collections and unselected population samples.  Assays of LDLR exons 3, 4 and 8 were validated in 460 familial hypercholesterolemia cases with known mutations.  I then applied the exon 3 assay in several DNA banks representing 9,000 subjects with known cholesterol values and applied 3 exons assays in one DNA bank (n=3,600).  In exon 3, I have identified one known mutation, P84S (n=1), also associated with moderate hypercholesterolemia in this subject; and an unknown severe hypercholesterolemia splice mutation 313+1G&gt;A (n=2).  In exon 4, only one frameshift mutation was detected by the melt-MADGE method.  Around exon 8, I have identified a paucimorphism (n=35) at splice site 1061-8T&gt;C (I found it to be in complete linkage disequilibrium with T7051), and an unknown mutation 1186+11G&gt;A (n=1) and D335N G&lt;A (n=1).</p

Development and application of approaches to population mutation scanning

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Command and prohibition forms and its implication according to usuliyyun: An applied study toward fatawa of Jama'ah al-Takfir Wa al-Hijrah / Khalid Hindi K Alharbi

This thesis studies the command and prohibition forms and its implication According to usuliyyun (Scholars of the principles of jurisprudence) an applied study toward fatwa of jama’ah Al-takfir wa Al-hijra "Excommunication and Exodus” group) through an examination and analysis of the implications and phrasing mentioned in the verses of the Qur’an and hadith, related to this matter. To that purpose is utilized: a review of the books of the principles of jurisprudence, scrutiny of the views of scholars on the mentioned wordings and their implications and a discussion on them by means of stating examples from the Qur’an and Sunnah. Later, an exposé of the danger of the mix-up of these wordings and implications on the individual and society in these texts is addressed. The study aims at finding the implicit wordings in the Islamic legal text so as to exploit them in the interpretation of the wordings of the injunctive discourse, stated in the Islamic legal text. Other objectives would be to constrain farfetched understanding of the Islamic legal texts, which could lead to religious fanaticism, and prevent misinterpretation of the Shariah’s texts through undermining the legal rulings and permitting the prohibited, under the pretext that The Legislator (Allah Almighty) has not obligated averting that prohibited in His Book. The study also aims to analyse the approach of the Takfir wal-Hijra (Excommunication and Exodus) group, through the wordings and implications of the explicit injunctions and prohibitions as well as the implicit ones, as mentioned in the Islamic legal text; the purpose is to comprehend and refute scholastically, away from extremism, the confusion into which this group has fallen when releasing its fatwas. Two approaches were adopted in this study: the method of collecting the material through the library, and the process of data analysis, by which the scholastic substance is applied to the fatwas of the group of Takfir wal-Hijra (Excommunication and Exodus). The Quranic verses and ahadith on which the group relies and misinterprets are also exposed with the right interpretation, and the group’s false deductions are addressed. The study was concluded with some of the findings; they hold that the scholars of the principles of jurisprudence did not articulate the implicit wordings, indicating injunction or prohibition, by single expressions as was the case with the explicit ones; the researcher mentioned the reason. Furthermore, ignorance of the wordings and their meanings generates extremist thought or radical jurisprudence in the rulings of religion and Islamic legal texts and their objectives. The consequences lead to labeling people with transgression, innovation, and infidelity of designated individuals; all of that, on account of the misinterpretation of the wordings of injunction and prohibition and their implications in the Qur’an and Sunnah. In addition, the study concluded that the main causes of the emergence of this group and it deviant ideology are: first, the oppression and persecution faced by those who affiliated themselves to Islam; second, the ignorance of the wording and meaning of the legal Islamic text; third, the ethical chaos and divergence in the schools of thought