Search results for: management controls
Commenced in January 2007
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Edition: International
Paper Count: 10037

Search results for: management controls

10007 Personality Profiles, Emotional Disturbance and Health-Related Quality of Life in Patients with Epilepsy

Authors: Usha Barahmand, Ruhollah Heydari Sheikh Ahmad, Sara Alaie Khoraem

Abstract:

Introduction: The association of epilepsy with several psychological disorders and reduced quality of life has long been recognized. The present study aimed at comparing the personality profiles, quality of life and symptomatology of anxiety and depression in patients with epilepsy and healthy controls. Materials and Methods: Forty seven patients (29 men and 18 women) with diagnosed epilepsy participated in this study. Forty seven healthy controls who matched the patients in age and gender were also recruited. The participants’ personality and psychological profiles were assessed using the Depression, Anxiety, and Stress Scale (DASS-21), the Short-Form Health Survey (SF-36) and the HEXACO Personality Inventory (HEXACO-PI). Scoring algorithms were applied to the SF-36 produce the physical and mental component scores (PCS and MCS). Results: There were statistically significant differences in the total SF-36 score, anxiety, depression and stress scores of the DASS-21 between patients and controls. Anxiety, stress and depression scores significantly correlated inversely with the PCS and MCS. Data analysis showed that females had higher depression scores than males in both patients and controls, while males in both groups scored higher on stress. Patients’ personality scores were also different from those reported by controls on emotional, agreeableness and extroversion. Patients scored higher on emotionality, and lower on agreeableness and extraversion. Patients also scored lower on indices of quality of life. Regression analysis revealed that emotionality, anxiety, stress and MCS accounted for a significant proportion of the variance in severity of epileptic seizures. Conclusion: Stressful situations and psychological conditions as well as the personality trait of neuroticism were related to the occurrence of recurrent epileptic seizures.

Keywords: anxiety, depression, epilepsy, neuroticism, personality, quality of life, stress

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10006 Half Dose Tissue Plasminogen Activator for Intermediate-Risk Pulmonary Embolism

Authors: Macie Matta, Ahmad Jabri, Stephanie Jackson

Abstract:

Introduction: In the absence of hypotension, pulmonary embolism (PE) causing right ventricular dysfunction or strain, whether confirmed by imaging or cardiac biomarkers, is deemed to be an intermediate-risk category. Urgent treatment of intermediate-risk PE can prevent progression to hemodynamic instability and death. Management options include thrombolysis, thrombectomy, or systemic anticoagulation. We aim to evaluate the short-term outcomes of a half-dose tissue plasminogen activator (tPA) for the management of intermediate-risk PE. Methods: We retrospectively identified adult patients diagnosed with intermediate-risk PE between the years 2000 and 2021. Demographic data, lab values, imaging, treatment choice, and outcomes were all obtained through chart review. Primary outcomes measured include major bleeding events and in-hospital mortality. Patients on standard systemic anticoagulation without receiving thrombolysis or thrombectomy served as controls. Patient data were analyzed using SAS®️ Software (version 9.4; Cary, NC) to compare individuals that received half-dose tPA with controls, and statistical significance was set at a p-value of 0.05. Results: We included 57 patients in our final analysis, with 19 receiving tPA. Patient characteristics and comorbidities were comparable between both groups. There was a significant difference between PE location, presence of acute deep vein thrombosis, and peak troponin level between both groups. The thrombolytic cohort was more likely to demonstrate a 60/60 sign and thrombus in transit finding on echocardiography than controls. The thrombolytic group was more likely to have major bleeding (17% vs 7.9%, p= 0.4) and in-hospital mortality (5.3% vs 0%, p=0.3); however, this was not statistically significant. Patients who received half-dose tPA had non-significantly higher rates of major bleeding and in-hospital mortality. Larger scale, randomized control trials are needed to establish the benefit and safety of thrombolytics in patients with intermediate-risk PE.

Keywords: pulmonary embolism, half dose thrombolysis, tissue plasminogen activator, cardiac biomarkers, echocardiographic findings, major bleeding event

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10005 Corneal Confocal Microscopy As a Surrogate Marker of Neuronal Pathology In Schizophrenia

Authors: Peter W. Woodruff, Georgios Ponirakis, Reem Ibrahim, Amani Ahmed, Hoda Gad, Ioannis N. Petropoulos, Adnan Khan, Ahmed Elsotouhy, Surjith Vattoth, Mahmoud K. M. Alshawwaf, Mohamed Adil Shah Khoodoruth, Marwan Ramadan, Anjushri Bhagat, James Currie, Ziyad Mahfoud, Hanadi Al Hamad, Ahmed Own, Peter Haddad, Majid Alabdulla, Rayaz A. Malik

Abstract:

Introduction:- We aimed to test the hypothesis that, using corneal confocal microscopy (a non-invasive method for assessing corneal nerve fibre integrity), patients with schizophrenia would show neuronal abnormalities compared with healthy participants. Schizophrenia is a neurodevelopmental and progressive neurodegenerative disease, for which there are no validated biomarkers. Corneal confocal microscopy (CCM) is a non-invasive ophthalmic imaging biomarker that can be used to detect neuronal abnormalities in neuropsychiatric syndromes. Methods:- Patients with schizophrenia (DSM-V criteria) without other causes of peripheral neuropathy and healthy controls underwent CCM, vibration perception threshold (VPT) and sudomotor function testing. The diagnostic accuracy of CCM in distinguishing patients from controls was assessed using the area under the curve (AUC) of the Receiver Operating Characterstics (ROC) curve. Findings:- Participants with schizophrenia (n=17) and controls (n=38) with comparable age (35.7±8.5 vs 35.6±12.2, P=0.96) were recruited. Patients with schizophrenia had significantly higher body weight (93.9±25.5 vs 77.1±10.1, P=0.02), lower Low Density Lipoproteins (2.6±1.0 vs 3.4±0.7, P=0.02), but comparable systolic and diastolic blood pressure, HbA1c, total cholesterol, triglycerides and High Density Lipoproteins were comparable with control participants. Patients with schizophrenia had significantly lower corneal nerve fiber density (CNFD, fibers/mm2) (23.5±7.8 vs 35.6±6.5, p<0.0001), branch density (CNBD, branches/mm2) (34.4±26.9 vs 98.1±30.6, p<0.0001), and fiber length (CNFL, mm/mm2) (14.3±4.7 vs 24.2±3.9, p<0.0001) but no difference in VPT (6.1±3.1 vs 4.5±2.8, p=0.12) and electrochemical skin conductance (61.0±24.0 vs 68.9±12.3, p=0.23) compared with controls. The diagnostic accuracy of CNFD, CNBD and CNFL to distinguish patients with schizophrenia from healthy controls were, according to the AUC, (95% CI): 87.0% (76.8-98.2), 93.2% (84.2-102.3), 93.2% (84.4-102.1), respectively. Conclusion:- In conclusion, CCM can be used to help identify neuronal changes and has a high diagnostic accuracy to distinguish subjects with schizophrenia from healthy controls.

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10004 Decision-Making Under Uncertainty in Obsessive-Compulsive Disorder

Authors: Helen Pushkarskaya, David Tolin, Lital Ruderman, Ariel Kirshenbaum, J. MacLaren Kelly, Christopher Pittenger, Ifat Levy

Abstract:

Obsessive-Compulsive Disorder (OCD) produces profound morbidity. Difficulties with decision making and intolerance of uncertainty are prominent clinical features of OCD. The nature and etiology of these deficits are poorly understood. We used a well-validated choice task, grounded in behavioral economic theory, to investigate differences in valuation and value-based choice during decision making under uncertainty in 20 unmedicated participants with OCD and 20 matched healthy controls. Participants’ choices were used to assess individual decision-making characteristics. Compared to controls, individuals with OCD were less consistent in their choices and less able to identify options that were unambiguously preferable. These differences correlated with symptom severity. OCD participants did not differ from controls in how they valued uncertain options when outcome probabilities were known (risk) but were more likely than controls to avoid uncertain options when these probabilities were imprecisely specified (ambiguity). These results suggest that the underlying neural mechanisms of valuation and value-based choices during decision-making are abnormal in OCD. Individuals with OCD show elevated intolerance of uncertainty, but only when outcome probabilities are themselves uncertain. Future research focused on the neural valuation network, which is implicated in value-based computations, may provide new neurocognitive insights into the pathophysiology of OCD. Deficits in decision-making processes may represent a target for therapeutic intervention.

Keywords: obsessive compulsive disorder, decision-making, uncertainty intolerance, risk aversion, ambiguity aversion, valuation

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10003 Evaluating Factors Impacting Functioning Management Control Systems Becoming Dysfunctional Beyond Intra-Organizational Boundaries

Authors: Martin Kartomo

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Though Management Control Systems (MCS) research has evolved beyond intra-organizational boundaries, there is limited understanding of the impact of a functioning MCS being functional beyond intra-organizational boundaries. The purpose of this research is to investigate factors that have an impact on functioning management Control Systems (MCS)becoming (dys-)functional beyond its intra-organizational boundaries. To bridge the theoretical gap, a systematic literature review is conducted to identify inter-and extra-organizational factors that are purposely suggested or unintendingly mentioned by MCS researchers to evaluate functioning MCS becoming (dys-)functional. A conceptual map is rationalized and constructed from five contingent inter-and extra-organizational MCS frameworks illuminating under-investigated MSC research areas and allowing new research avenues based on academically known factors. A multiple case study followed by a co-researcher discussion group with the purpose of identifying academically unknown factors for evaluating MCS (dys-)functionality beyond its intra-organizational boundaries. The study's result will help bridge the gap between what academics know and not know of evaluating MCS being functional beyond intra-organizational boundaries with the opportunity to develop better, more complete theories. Furthermore, it will help organizations to evaluate the impact of their activities beyond intra-organizational boundaries.

Keywords: management control systems, management control systems evaluation, management controls, control system

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10002 Diagnostic Accuracy of the Tuberculin Skin Test for Tuberculosis Diagnosis: Interest of Using ROC Curve and Fagan’s Nomogram

Authors: Nouira Mariem, Ben Rayana Hazem, Ennigrou Samir

Abstract:

Background and aim: During the past decade, the frequency of extrapulmonary forms of tuberculosis has increased. These forms are under-diagnosed using conventional tests. The aim of this study was to evaluate the performance of the Tuberculin Skin Test (TST) for the diagnosis of tuberculosis, using the ROC curve and Fagan’s Nomogram methodology. Methods: This was a case-control, multicenter study in 11 anti-tuberculosis centers in Tunisia, during the period from June to November2014. The cases were adults aged between 18 and 55 years with confirmed tuberculosis. Controls were free from tuberculosis. A data collection sheet was filled out and a TST was performed for each participant. Diagnostic accuracy measures of TST were estimated using ROC curve and Area Under Curve to estimate sensitivity and specificity of a determined cut-off point. Fagan’s nomogram was used to estimate its predictive values. Results: Overall, 1053 patients were enrolled, composed of 339 cases (sex-ratio (M/F)=0.87) and 714 controls (sex-ratio (M/F)=0.99). The mean age was 38.3±11.8 years for cases and 33.6±11 years for controls. The mean diameter of the TST induration was significantly higher among cases than controls (13.7mm vs.6.2mm;p=10-6). Area Under Curve was 0.789 [95% CI: 0.758-0.819; p=0.01], corresponding to a moderate discriminating power for this test. The most discriminative cut-off value of the TST, which were associated with the best sensitivity (73.7%) and specificity (76.6%) couple was about 11 mm with a Youden index of 0.503. Positive and Negative predictive values were 3.11% and 99.52%, respectively. Conclusion: In view of these results, we can conclude that the TST can be used for tuberculosis diagnosis with a good sensitivity and specificity. However, the skin induration measurement and its interpretation is operator dependent and remains difficult and subjective. The combination of the TST with another test such as the Quantiferon test would be a good alternative.

Keywords: tuberculosis, tuberculin skin test, ROC curve, cut-off

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10001 Determinants of Repeated Abortion among Women of Reproductive Age Attending Health Facilities in Northern Ethiopia: A Case-Control Study

Authors: Henok Yebyo Henok, Araya Abrha Araya, Alemayehu Bayray Alemayehu, Gelila Goba Gelila

Abstract:

Background: Every year, an estimated 19–20 million unsafe abortions take place, almost all in developing countries, leading to 68,000 deaths and millions more injured many permanently. Many women throughout the world, experience more than one abortion in their lifetimes. Repeat abortion is an indicator of the larger problem of unintended pregnancy. This study aimed to identify determinants of repeat abortion in Tigray Region, Ethiopia. Methods: Unmatched case-control study was conducted in hospitals in Tigray Region, Northern Ethiopia, from November 2014 to June 2015. The sample included 105 cases and 204 controls, recruited from among women seeking abortion care at public hospitals. Clients having two or more abortions (“repeat abortion”) were taken as cases, and those who had a total of one abortion were taken as controls (“single abortion”). Cases were selected consecutive based on proportional to size allocation while systematic sampling was employed for controls. Data were analyzed using SPSS version 20.0. Binary and multiple variable logistic regression analyses were calculated with 95% CI. Results: Mean age of cases was 24 years (±6.85) and 22 years (±6.25) for controls. 79.0% of cases had their sexual debut in less than 18 years of age compared to 57% of controls. 42.2% of controls and 23.8% of cases cited rape as the reason for having an abortion. Study participants who did not understand their fertility cycle and when they were most likely to conceive after menstruation (adjusted odds ratio [AOR]=2.0, 95% confidence interval [CI]: 1.1-3.7), having a previous abortion using medication(AOR=3.3, CI: 1.83, 6.11), having multiple sexual partners in the preceding 12 months (AOR=4.4, CI: 2.39,8.45), perceiving that the abortion procedure is not painful (AOR=2.3, CI: 1.31,4.26), initiating sexual intercourse before the age of 18 years (AOR=2.7, CI: 1.49, 5.23) and disclosure to a third-party about terminating the pregnancy (AOR=2.1, CI: 1.2,3.83) were independent predictors of repeat abortion. Conclusion: This study identified several factors correlated with women having repeat abortions. It may be helpful for the Government of Ethiopia to encourage women to delay sexual debut and decrease their number of sexual partners, including by promoting discussion within families about sexuality, to decrease the occurrence of repeated abortion.

Keywords: abortion, Ethiopia, repeated abortion, single abortion

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10000 TNF-α, TNF-β and IL-10 Gene Polymorphism and Association with Oral Lichen Planus Risk in Saudi Patients

Authors: Maha Ali Al-Mohaya, Lubna Majed Al-Otaibi, Ebtissam Nassir Al-Bakr, Abdulrahman Al-Asmari

Abstract:

Objectives: Oral lichen planus (OLP) is a chronic inflammatory oral mucosal disease. Cytokines play an important role in the pathogenesis and disease progression of OLP. The purpose of this study was to investigate the association of tumor necrosis factor (TNF)-α, TNF-β and interleukin (IL)-10 gene polymorphisms with the OLP risk. Material and Methods: Forty-two unrelated patients with OLP and 211 healthy volunteers were genotyped for TNF-α (-308 G/A), TNF-β (+252A/G), IL-10 (-1082G/A), IL-10 (-819C/T), and IL-10 (-592C/A) polymorphisms. Results: The frequencies of allele A and genotype GA of TNF-α (-308G/A) were significantly higher while allele G and GG genotypes were lower in OLP patients as compared to the controls (P < 0.001). The frequency of GA genotype of TNF-β (+252A/G) was significantly higher in patients than in controls while the AA genotype was completely absent in OLP patients. These results indicated that allele A and genotype GA of TNF-α (-308G/A) as well as the GA genotype of TNF-β (+252A/G) polymorphisms are associated with OLP risk. The frequencies of alleles and genotypes of -1082G/A, -819C/T and -592C/A polymorphisms in IL-10 gene did not differ significantly between OLP patients and controls (P > 0.05). However, haplotype ATA extracted from 1082G/A, -819C/T, -592C/A polymorphisms of IL-10 were more prevalent in OLP patients when compared to controls indicating its possible association with OLP susceptibility. Conclusion: It is concluded that TNF-α (-308G/A), TNF-β (+252A/G) and IL-10 (-1082G/A, -819C/T and -592C/A) polymorphisms are associated with the susceptibility of OLP, thus giving additional support for the genetic basis of this disease. Further studies are required using a larger sample size to confirm this association and determine the prognostic values of these findings.

Keywords: oral lichen planus, cytokines, polymorphism, genetic

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9999 Gastrointestinal Manifestations and Outcomes in Hospitalized COVID-19 Patients: A Retrospective Study

Authors: Jaylo Abalos, Sophia Zamora

Abstract:

BACKGROUND: Various gastrointestinal (GI) symptoms, including diarrhea, nausea/vomiting and abdominal pain, have been reported in patients with Coronavirus disease 2019 (COVID-19). In this context, the presence of GI symptoms is variably associated with poor clinical outcomes in COVID-19. We aim to determine the outcomes of hospitalized COVID-19 patients with gastrointestinal symptoms. METHODOLOGY: This is a retrospective cohort study that used medical records of admitted COVID-19 patients from March 2020- March 2021 in a tertiary hospital in Pangasinan. Data records were evaluated for the presence of gastrointestinal manifestations, including diarrhea, nausea, vomiting and abdominal pain at the time of admission. Comparison between cases or COVID-19 patients presenting with GI manifestations to controls or COVID-19 patients without GI manifestation was made. RESULTS: Four hundred three patients were included in the study. Of these, 22.3% presented with gastrointestinal symptoms, while 77.7% comprised the study controls. Diarrhea was the most common GI symptom (10.4%). No statistically significant difference was observed in comorbidities and laboratory findings. Mortality was the primary outcome of the study that did not reach statistical significance between cases and controls (13.33% vs. 16.30%, p =0.621). There were also no significant differences observed in the secondary outcomes, mean length of stay, (14 [12-18 days] in cases vs 14 [12- 17.5 days] in controls, p = 0.716) and need for mechanical ventilation (12.22% vs 16.93%, p = 0.329). CONCLUSION: The results of the study revealed no association of the GI symptoms to poor outcomes, including a high rate of mortality, prolonged length of stay and increased need for mechanical ventilation.

Keywords: gastrointestinal symptoms, COVID-19, outcomes, mortality, length of stay

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9998 The Influence of Air Temperature Controls in Estimation of Air Temperature over Homogeneous Terrain

Authors: Fariza Yunus, Jasmee Jaafar, Zamalia Mahmud, Nurul Nisa’ Khairul Azmi, Nursalleh K. Chang, Nursalleh K. Chang

Abstract:

Variation of air temperature from one place to another is cause by air temperature controls. In general, the most important control of air temperature is elevation. Another significant independent variable in estimating air temperature is the location of meteorological stations. Distances to coastline and land use type are also contributed to significant variations in the air temperature. On the other hand, in homogeneous terrain direct interpolation of discrete points of air temperature work well to estimate air temperature values in un-sampled area. In this process the estimation is solely based on discrete points of air temperature. However, this study presents that air temperature controls also play significant roles in estimating air temperature over homogenous terrain of Peninsular Malaysia. An Inverse Distance Weighting (IDW) interpolation technique was adopted to generate continuous data of air temperature. This study compared two different datasets, observed mean monthly data of T, and estimation error of T–T’, where T’ estimated value from a multiple regression model. The multiple regression model considered eight independent variables of elevation, latitude, longitude, coastline, and four land use types of water bodies, forest, agriculture and build up areas, to represent the role of air temperature controls. Cross validation analysis was conducted to review accuracy of the estimation values. Final results show, estimation values of T–T’ produced lower errors for mean monthly mean air temperature over homogeneous terrain in Peninsular Malaysia.

Keywords: air temperature control, interpolation analysis, peninsular Malaysia, regression model, air temperature

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9997 Determinants of Maternal Near-Miss among Women in Public Hospital Maternity Wards in Northern Ethiopia: A Facility Based Case-Control Study

Authors: Dejene Ermias Mekango, Mussie Alemayehu, Gebremedhin Berhe Gebregergs, Araya Abrha Medhanye, Gelila Goba

Abstract:

Background: Maternal near miss (MNM) can be used as a proxy indicator of maternal mortality ratio. There is a huge gap in life time risk between Sub-Saharan Africa and developed countries. In Ethiopia, a significant number of women die each year from complications during pregnancy, childbirth and the post-partum period. Besides, a few studies have been performed on MNM, and little is known regarding determinant factors. This study aims to identify determinants of MNM among women in Tigray region, Northern Ethiopia. Methods: a case-control study in hospital found in Tigray region, Ethiopia was conducted from January 30 - March 30, 2016. The sample included 103 cases and 205 controls recruited from women seeking obstetric care at six public hospitals. Clients having a life-threatening obstetric complication including haemorrhage, hypertensive diseases of pregnancy, dystocia, infections, and anemia or clinical signs of severe anemia in women without haemorrhage were taken as cases and those with normal obstetric outcomes were considered as controls. Cases were selected based on proportional to size allocation while systematic sampling was employed for controls. Data were analyzed using SPSS version 20.0. Binary and multiple variable logistic regression (odds ratio) analyses were calculated with 95% CI. Results: The largest proportion of cases and controls was among the ages of20–29 years, accounting for37.9 %( 39) of cases and 31.7 %( 65) of controls. Roughly 90% of cases and controls were married. About two-thirds of controls and 45.6 %( 47) of cases had gestational age between 37-41 weeks. History of chronic medical conditions was reported in 55.3 %(57) of cases and 33.2%(68) of controls. Women with no formal education [AOR=3.2;95%CI:1.24, 8.12],being less than 16 years old at first pregnancy [AOR=2.5; 95%CI:1.12,5.63],induced labor[AOR=3; 95%CI:1.44, 6.17], history of Cesarean section (C-section) [AOR=4.6; 95%CI: 1.98, 7.61] or chronic medical disorder[AOR=3.5;95%CI:1.78, 6.93], and women who traveled more than 60 minutes before reaching their final place of care[AOR=2.8;95% CI: 1.19,6.35] all had higher odds of experiencing MNM. Conclusions: The Government of Ethiopia should continue its effort to address the lack of road and health facility access as well as education, which will help reduce MNM. Work should also be continued to educate women and providers about common predictors of MNM like the history of C-section, chronic illness, and teenage pregnancy. These efforts should be carried out at the facility, community, and individual levels. The targeted follow-up to women with a history of chronic disease and C-section could also be a practical way to reduce MNM.

Keywords: maternal near miss, severe obstetric hemorrhage, hypertensive disorder, c-section, Tigray, Ethiopia

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9996 Evaluation of Promoter Hypermethylation in Tissue and Blood of Non-Small Cell Lung Cancer Patients and Association with Survival

Authors: Ashraf Ali, Kriti Upadhyay, Puja Sohal, Anant Mohan, Randeep Guleria

Abstract:

Background: Gene silencing by aberrant promoter hypermethylation is common in lung cancer and is an initiating event in its development. Aim: To evaluate the gene promoter hypermethylation frequency in serum and tissue of lung cancer patients. Method: 95 newly diagnosed untreated advance stage lung cancer patients and 50 cancer free matched controls were studied. Bisulfite modification of tissue and serum DNA was done; modified DNA was used as a template for methylation-specific PCR analysis. Survival was assessed for one year. Results: Of 95 patients, 82% were non-small cell lung cancer (34% squamous cell carcinoma, 34% non-small cell lung cancer and 14% adenocarcinoma) and 18% were small cell lung cancer. Biopsy revealed that tissue of 89% and 75% of lung cancer patients and 85% and 52% of controls had promoter hypermethylated for MGMT (p=0.35) and p16(p<0.001) gene, respectively. In serum, 33% and 49% of lung cancer patients and 28% and 43% controls were positive for MGMT and p16 gene. No significant correlation was found between survival and clinico-pathological parameters. Conclusion: High gene promoter methylation frequency of p16 gene in tissue biopsy may be linked with early stages of carcinogenesis. Appropriate follow-up is required for confirmation of this finding.

Keywords: lung cancer, MS- PCR, methylation, molecular biology

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9995 Exact and Approximate Controllability of Nuclear Dynamics Using Bilinear Controls

Authors: Ramdas Sonawane, Mahaveer Gadiya

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The control problem associated with nuclear dynamics is represented by nonlinear integro-differential equation with additive controls. To control chain reaction, certain amount of neutrons is added into (or withdrawn out of) chamber as and when required. It is not realistic. So, we can think of controlling the reactor dynamics by bilinear control, which enters the system as coefficient of state. In this paper, we study the approximate and exact controllability of parabolic integro-differential equation controlled by bilinear control with non-homogeneous boundary conditions in bounded domain. We prove the existence of control and propose an explicit control strategy.

Keywords: approximate control, exact control, bilinear control, nuclear dynamics, integro-differential equations

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9994 Streamlining Cybersecurity Risk Assessment for Industrial Control and Automation Systems: Leveraging the National Institute of Standard and Technology’s Risk Management Framework (RMF) Using Model-Based System Engineering (MBSE)

Authors: Gampel Alexander, Mazzuchi Thomas, Sarkani Shahram

Abstract:

The cybersecurity landscape is constantly evolving, and organizations must adapt to the changing threat environment to protect their assets. The implementation of the NIST Risk Management Framework (RMF) has become critical in ensuring the security and safety of industrial control and automation systems. However, cybersecurity professionals are facing challenges in implementing RMF, leading to systems operating without authorization and being non-compliant with regulations. The current approach to RMF implementation based on business practices is limited and insufficient, leaving organizations vulnerable to cyberattacks resulting in the loss of personal consumer data and critical infrastructure details. To address these challenges, this research proposes a Model-Based Systems Engineering (MBSE) approach to implementing cybersecurity controls and assessing risk through the RMF process. The study emphasizes the need to shift to a modeling approach, which can streamline the RMF process and eliminate bloated structures that make it difficult to receive an Authorization-To-Operate (ATO). The study focuses on the practical application of MBSE in industrial control and automation systems to improve the security and safety of operations. It is concluded that MBSE can be used to solve the implementation challenges of the NIST RMF process and improve the security of industrial control and automation systems. The research suggests that MBSE provides a more effective and efficient method for implementing cybersecurity controls and assessing risk through the RMF process. The future work for this research involves exploring the broader applicability of MBSE in different industries and domains. The study suggests that the MBSE approach can be applied to other domains beyond industrial control and automation systems.

Keywords: authorization-to-operate (ATO), industrial control systems (ICS), model-based system’s engineering (MBSE), risk management framework (RMF)

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9993 Cloud Computing Security for Multi-Cloud Service Providers: Controls and Techniques in Our Modern Threat Landscape

Authors: Sandesh Achar

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Cloud computing security is a broad term that covers a variety of security concerns for organizations that use cloud services. Multi-cloud service providers must consider several factors when addressing security for their customers, including identity and access management, data at rest and in transit, egress and ingress traffic control, vulnerability and threat management, and auditing. This paper explores each of these aspects of cloud security in detail and provides recommendations for best practices for multi-cloud service providers. It also discusses the challenges inherent in securing a multi-cloud environment and offers solutions for overcoming these challenges. By the end of this paper, readers should have a good understanding of the various security concerns associated with multi-cloud environments in the context of today’s modern cyber threats and how to address them.

Keywords: multi-cloud service, system organization control, data loss prevention, identity and access management

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9992 Implementation of Risk Management System to Improve the Quality of Higher Education Institutes

Authors: Muhammad Wasif, Asif Ahmed Shaikh, Sarosh Hashmat Lodi, Muhammad Aslam Bhutto, Riazuddin

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Risk Management System is quite popular in profit- based organizations, health and safety and project management fields since the last few decades. But due to rapidly changing environment and requirement of ISO 9001:2015 standards, public-sector institution, especially higher education institutes are also performing risk assessment to monitor the performance of the institution and aligning it with the latest benchmark. In this context, NED University of Engineering and Technology performed research and developed a Standard Operating Procedure (SOP) for the risk assessment, its monitoring and control. In this research, risks are broken into the four sources, namely; Internal Academics Risks, External Academics Risks, Internal Non-academic Risks, External Non-academic Risks. Risks are identified by the management at all levels. Severity and likelihood of the risks are assigned based on the previous audit results and the customer complains. Risk Ratings are calculated to orderly arrange the risk according to the Risk Rating, and controls for the risks are designed, which are assigned to the responsible person. At the end of the article, result and analysis on the different sources of risk are discussed in details and the conclusion is drawn. Discussion on few sample risks are presented in this article. Hence it is presented in the research that the Risk Management System can be applied in a Higher Education Institute to effectively control the risks which might affect the scope and Quality Management System of an organization.

Keywords: higher education, quality management system, risk assessment, risk management

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9991 Gut Microbiota in Patients with Opioid Use Disorder: A 12-week Follow up Study

Authors: Sheng-Yu Lee

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Aim: Opioid use disorder is often characterized by repetitive drug-seeking and drug-taking behaviors with severe public health consequences. Animal model showed that opioid-induced perturbations in the gut microbiota causally relate to neuroinflammation, deficits in reward responding, and opioid tolerance, possibly due to changes in gut microbiota. Therefore, we propose that the dysbiosis of gut microbiota can be associated with pathogenesis of opioid dependence. In this current study, we explored the differences in gut microbiota between patients and normal controls and in patients before and after initiation of methadone treatment program for 12 weeks. Methods: Patients with opioid use disorder between 20 and 65 years were recruited from the methadone maintenance outpatient clinic in 2 medical centers in the Southern Taiwan. Healthy controls without any family history of major psychiatric disorders (schizophrenia, bipolar disorder and major depressive disorder) were recruited from the community. After initial screening, 15 patients with opioid use disorder joined the study for initial evaluation (Week 0), 12 of them completed the 12-week follow-up while receiving methadone treatment and ceased heroin use (Week 12). Fecal samples were collected from the patients at baseline and the end of 12th week. A one-time fecal sample was collected from the healthy controls. The microbiota of fecal samples were investigated using 16S rRNA V3V4 amplicon sequencing, followed by bioinformatics and statistical analyses. Results: We found no significant differences in species diversity in opioid dependent patients between Week 0 and Week 12, nor compared between patients at both points and controls. For beta diversity, using principal component analysis, we found no significant differences between patients at Week 0 and Week 12, however, both patient groups showed significant differences compared to control (P=0.011). Furthermore, the linear discriminant analysis effect size (LEfSe) analysis was used to identify differentially enriched bacteria between opioid use patients and healthy controls. Compared to controls, the relative abundance of Lactobacillaceae Lactobacillus (L. Lactobacillus), Megasphaera Megasphaerahexanoica (M. Megasphaerahexanoica) and Caecibacter Caecibactermassiliensis (C Caecibactermassiliensis) were increased in patients at Week 0, while Coriobacteriales Atopobiaceae (C. Atopobiaceae), Acidaminococcus Acidaminococcusintestini (A. Acidaminococcusintestini) and Tractidigestivibacter Tractidigestivibacterscatoligenes (T. Tractidigestivibacterscatoligenes) were increased in patients at Week 12. Conclusion: In conclusion, we suggest that the gut microbiome community maybe linked to opioid use disorder, such differences may not be altered even after 12-week of cessation of opioid use.

Keywords: opioid use disorder, gut microbiota, methadone treatment, follow up study

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9990 Association of Vitamin D Levels in Obese and Non-Obese Patients with Polycystic Ovarian Syndrome in East Indian Populations

Authors: Dipanshu Sur, Ratnabali Chakravorty

Abstract:

Introduction: Polycystic ovary syndrome (PCOS) is the most common metabolic abnormality such as changes in lipid profile, diabetes, hypertension and metabolic syndrome occurring in women. Hypovitaminsis D was found to be associated with the development of obesity and insulin resistance in women with PCOS. Aim: To evaluate the association of vitamin D levels in obese and non-obese patients with PCOS in an East Indian populations. Methods: A case control study was conducted. It enrolled 100 cases of PCOS based on Rotterdam criteria and 100 ovulatory normal cases matched for their age and BMI. Vitamin D levels were compared in the obese and non-obese PCOS groups and also with the controls. Results: The mean age of subjects was 29.48 ± 3.29 years in the PCOS group and 26.24 ± 2.56 years in the control group. Hypovitaminosis D was present in 75 out of 100 PCOS women (75.0%) and 25 women (25.0%) showed sufficient 25OHD levels ≥30 ng/ml. Women with PCOS had significantly lower total serum calcium (8.4 ± 0.25 mg/dl versus 9.8 ± 0.17 mg/dl in controls), and 25 OHD (21.2 ± 2.56 ng/ml versus 32.6 ± 2.23 ng/ml in control group) than ovulatory normal women. This difference remained significant for both groups after adjustment for BMI. Obese women in both groups had significantly lower concentration of calcium and 25OHD than normal weight patients in this study. Conclusion: Our study shows majority of the patients and controls had vitamin D deficiency and there was significant difference in the vitamin D levels in PCOS group and controls as well as obese and non-obese groups. This may reflect the vitamin D deficiency status of the community. Vitamin D deficiency should demands immediate attention as it is a severe problem among the East Indian population.

Keywords: vitamin D deficiency, polycystic ovary syndrome, obese, hypovitaminsis D

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9989 Relationship between Strategic Management and Organizational Culture in Sport Organization (Case Study: Selected Sport Federations of Islamic Republic of Iran)

Authors: Mohammad Ali Ghareh, Habib Honari, Alireza Ahmadi

Abstract:

The aim of this study was to investigate the relationship between strategic management and organizational culture in sport federations of Islamic Republic of Iran. Strategic management is a set of decisions and actions which define the long term performance of an organization. Organizational culture can be considered as an identity for every organization and somehow gives an identification to organization members. Organizational culture result in a certain commitments in organization members which is more valuable than individual profits and interests. The method of research was descriptive and correlational, conducted as a field study. The statistical population consisted of the employees of 10 sports federations and 170 persons were selected as sample. For data gathering, Barringer and Bluedorn’s strategic management questionnaire (1999) and Sakyn’s organizational culture questionnaire (2001) were used. The reliability of the questionnaires were 0.82 and 0.80 respectively, and the validity was approved by 8 experienced professors in sport management. To analyze data, KS (Kolmogorov–Smirnov) test and Pearson's coefficient were used. The results have shown that there is a significant meaningful relationship between strategic management and organizational culture (p < 0.05, r= 0.62). Beside this, there is a positive relationship between strategic management variables including scanning intensity, planning flexibility, locus of planning, planning horizon, strategic controls, and organizational culture (p < 0.05). Based on this research result it can be derived that strategic management planning and operation in terms of appropriate organizational culture is more applicable. By agreeing on their values and beliefs, adaptation to changes, caring about the individualities, coordination in tasks, modifying the individual and organizational goals, the federations will be able to achieve their strategic goals.

Keywords: strategic management, organizational culture, sports federations, Islamic Republic of Iran

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9988 Externalised Migration Controls and the Deportation of Minors and Potential Refugees from Mexico

Authors: Vickie Knox

Abstract:

Since the ‘urgent humanitarian crisis’ of the arrival of tens of thousands of Central American minors at the Mexico-US border in early 2014, the USA has increasingly externalised migration controls to Mexico. Although the resulting policy ‘Plan Frontera Sur’ claimed to protect migrants’ human rights, it has manifested as harshly delivered in-country controls and an alarming increase in deportations, particularly of minors. This is of particular concern given the ongoing situation of forced migration caused by criminal violence in Central America because these deportations do not all comply with Mexico’s international obligations and with its own legal framework for international protection that allows inter alia verbal asylum claims and grants minors additional protection against deportation. Notably, the volume of deportations, the speed with which they are carried out and the lack of adequate screening indicate non-compliance with the principle of non-refoulement and the right to claim asylum or other forms of protection. Based on qualitative data gathered in fieldwork in 2015 and quantitative data covering the period 2014-2016, this research details three types of adverse outcome resulting from these externalised controls: human rights violations perpetrated in order to deliver the policy–namely, deportations that may not comply with the principle of non-refoulement or the protection of minors; human rights violations perpetrated in the execution of policy–such as violations by state actors during apprehension and detention; and adverse consequences of the policy – such as increased risk during transit. This research has particular resonance as the Trump era brings tighter enforcement in the region, and has broader relevance for the study of externalisation tools on a global level.

Keywords: deportation, externalisation, forced migration, non-refoulement

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9987 Nature of Body Image Distortion in Eating Disorders

Authors: Katri K. Cornelissen, Lise Gulli Brokjob, Kristofor McCarty, Jiri Gumancik, Martin J. Tovee, Piers L. Cornelissen

Abstract:

Recent research has shown that body size estimation of healthy women is driven by independent attitudinal and perceptual components. The attitudinal component represents psychological concerns about body, coupled to low self-esteem and a tendency towards depressive symptomatology, leading to over-estimation of body size, independent of the Body Mass Index (BMI) someone actually has. The perceptual component is a normal bias known as contraction bias, which, for bodies is dependent on actual BMI. Women with a BMI less than the population norm tend to overestimate their size, while women with a BMI greater than the population norm tend to underestimate their size. Women whose BMI is close to the population mean are most accurate. This is indexed by a regression of estimated BMI on actual BMI with a slope less than one. It is well established that body dissatisfaction, i.e. an attitudinal distortion, leads to body size overestimation in eating disordered individuals. However, debate persists as to whether women with eating disorders may also suffer a perceptual body distortion. Therefore, the current study was set to ask whether women with eating disorders exhibit the normal contraction bias when they estimate their own body size. If they do not, this would suggest differences in the way that women with eating disorders process the perceptual aspects of body shape and size in comparison to healthy controls. 100 healthy controls and 33 women with a history of eating disorders were recruited. Critically, it was ensured that both groups of participants represented comparable and adequate ranges of actual BMI (e.g. ~18 to ~40). Of those with eating disorders, 19 had a history of anorexia nervosa, 6 bulimia nervosa, and 8 OSFED. 87.5% of the women with a history of eating disorders self-reported that they were either recovered or recovering, and 89.7% of them self-reported that they had had one or more instances of relapse. The mean time lapsed since first diagnosis was 5 years and on average participants had experienced two relapses. Participants were asked to fill number of psychometric measures (EDE-Q, BSQ, RSE, BDI) to establish the attitudinal component of their body image as well as their tendency to internalize socio-cultural body ideals. Additionally, participants completed a method of adjustment psychophysical task, using photorealistic avatars calibrated for BMI, in order to provide an estimate of their own body size and shape. The data from the healthy controls replicate previous findings, revealing independent contributions to body size estimation from both attitudinal and perceptual (i.e. contraction bias) body image components, as described above. For the eating disorder group, once the adequacy of their actual BMI ranges was established, a regression of estimated BMI on actual BMI had a slope greater than 1, significantly different to that from controls. This suggests that (some) eating disordered individuals process the perceptual aspects of body image differently from healthy controls. It therefore is necessary to develop interventions which are specific to the perceptual processing of body shape and size for the management of (some) individuals with eating disorders.

Keywords: body image distortion, perception, recovery, relapse, BMI, eating disorders

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9986 Identification of New Familial Breast Cancer Susceptibility Genes: Are We There Yet?

Authors: Ian Campbell, Gillian Mitchell, Paul James, Na Li, Ella Thompson

Abstract:

The genetic cause of the majority of multiple-case breast cancer families remains unresolved. Next generation sequencing has emerged as an efficient strategy for identifying predisposing mutations in individuals with inherited cancer. We are conducting whole exome sequence analysis of germ line DNA from multiple affected relatives from breast cancer families, with the aim of identifying rare protein truncating and non-synonymous variants that are likely to include novel cancer predisposing mutations. Data from more than 200 exomes show that on average each individual carries 30-50 protein truncating mutations and 300-400 rare non-synonymous variants. Heterogeneity among our exome data strongly suggest that numerous moderate penetrance genes remain to be discovered, with each gene individually accounting for only a small fraction of families (~0.5%). This scenario marks validation of candidate breast cancer predisposing genes in large case-control studies as the rate-limiting step in resolving the missing heritability of breast cancer. The aim of this study is to screen genes that are recurrently mutated among our exome data in a larger cohort of cases and controls to assess the prevalence of inactivating mutations that may be associated with breast cancer risk. We are using the Agilent HaloPlex Target Enrichment System to screen the coding regions of 168 genes in 1,000 BRCA1/2 mutation-negative familial breast cancer cases and 1,000 cancer-naive controls. To date, our interim analysis has identified 21 genes which carry an excess of truncating mutations in multiple breast cancer families versus controls. Established breast cancer susceptibility gene PALB2 is the most frequently mutated gene (13/998 cases versus 0/1009 controls), but other interesting candidates include NPSR1, GSN, POLD2, and TOX3. These and other genes are being validated in a second cohort of 1,000 cases and controls. Our experience demonstrates that beyond PALB2, the prevalence of mutations in the remaining breast cancer predisposition genes is likely to be very low making definitive validation exceptionally challenging.

Keywords: predisposition, familial, exome sequencing, breast cancer

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9985 An Investigation of the Effects of Word Length on Amblyopic Eye Movement during Reading

Authors: Yahya Maeni

Abstract:

It is well established that amblyopic patients have a reduced reading performance and oculomotor deficits. Word length has a significant impact on reading performance and eye movement behaviour during reading. As there no previous attempts to assess whether amblyopic eyes would be affected by word length while reading. This study aims to assess the effect of word length on amblyopic eye movement behaviour during reading including fixation duration, number of fixation and gaze duration. 21 adults with amblyopia and 21 age-matched controls participated in the study (age ± SD) (23.80 ± 4.66) for amblyopes and (24.20 ± 3.58) for Controls. Eye movement was recorded during reading binocularly using Eyelink 1000. Study was designed as 2 x 2 (amblyopia vs. control) x 2 lengths (4 letters, and 8 letters). Compared to controls, the amblyopic participants report significant longer duration of fixation, higher number of fixation and longer gaze duration for short words with far higher significant difference for long words. It could be concluded that eye movement in amblyopia during reading might be accounted for by the length of a word within a text and this could possible explanation of reduced reading performance among amblyopes. By understanding the effect of word length on amblyopia will shed light on reading deficits in amblyopia and help to determine the reading needs of amplyopes in educational and clinical settings.

Keywords: amblyopia, eye movement, reading, fixation

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9984 Exploring the Dark Side of IT Security: Delphi Study on Business’ Influencing Factors

Authors: Tizian Matschak, Ilja Nastjuk, Stephan Kühnel, Simon Trang

Abstract:

We argue that besides well-known primary effects of information security controls (ISCs), namely confidentiality, integrity, and availability, ISCs can also have secondary effects. For example, while IT can add business value through impacts on business processes, ISCs can be a barrier and distort the relationship between IT and organizational value through the impact on business processes. By applying the Delphi method with 28 experts, we derived 27 business process influence dimensions of ISCs. Defining and understanding these mechanisms can change the common understanding of the cost-benefit valuation of IT security investments and support managers' effective and efficient decision-making.

Keywords: business process dimensions, dark side of information security, Delphi study, IT security controls

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9983 Analysis of iPSC-Derived Dopaminergic Neuron Susceptibility to Influenza and Excitotoxicity in Non-Affective Psychosis

Authors: Jamileh Ahmed, Helena Hernandez, Gabriel De Erausquin

Abstract:

H1N1 virus susceptibility of iPSC-derived DA neurons from schizophrenia patients and controls will compared. C57/BL-6 fibroblasts were reprogrammed into iPSCs using a lenti-viral vector containing SOKM genes. Pluripotency verification with the AP assay and immunocytochemistry ensured iPSC presence. The experimental outcome of ISPCs from DA neuron differentiation will be discussed in the Results section. Fibroblasts from patients and controls will be reprogrammed into iPSCs using a sendai-virus vector containing SOKM. IPSCs will be characterized using the AP assay, immunocytochemistry and RT-PCR. IPSCs will then be differentiated into DA neurons. Gene methylation will be compared for both groups with custom-designed microarrays.

Keywords: schizophrenia, iPSCs, stem cells, neuroscience

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9982 Evaluation of Nutrition Supplement on Body Composition during Catch-Up Growth, in a Pre-Clinical Model of Growth Restriction

Authors: Bindya Jacob

Abstract:

The aim of the present study was to assess the quality of catchup growth induced by Oral Nutrition Supplement (ONS), in animal model of growth restriction due to under nutrition. Quality of catch-up growth was assessed by proportion of lean body mass (LBM) and fat mass (FM). Young SD rats were food restricted at 70% of normal caloric intake for 4 weeks; and re-fed at 120% of normal caloric intake for 4 weeks. Refeeding diet had 50% calories from animal diet and 50% from ONS formulated for optimal growth. After refeeding, the quantity and quality of catch-up growth were measured including weight, length, LBM and FM. During nutrient restriction, body weight and length of animals was reduced compared to healthy controls. Both LBM and FM were significantly lower than healthy controls (p < 0.001). Refeeding with ONS resulted in increase of weight and length, with significant catch-up growth compared to baseline (p < 0.001). Detailed examination of body composition showed that the catch-up in body weight was due to proportionate increase of LBM and FM, resulting in a final body composition similar to healthy controls. This data supports the use of well-designed ONS for recovery from growth restriction due to under nutrition, and return to normal growth trajectory characterized by normal ratio of lean and fat mass.

Keywords: catch up growth, body composition, nutrient restriction, healthy growth

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9981 Crystalline Silica Exposure in Tunnel Construction: Identifying Barriers to Safe Practices

Authors: Frederick Anlimah, Vinod Gopaldasani, Catherine MacPhail, Brian Davies

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Aim: This study aims to identify the barriers and challenges hindering the implementation of effective controls and the adoption of safe work practices to protect workers from respirable crystalline silica (RCS) exposure. Problem or Situation: Tunnelling is one of many occupations that expose workers to the harmful effects of respirable crystalline silica. Despite various control measures, such as engineering controls and personal protective equipment, exposures remain inadequately controlled, leading to incurable silicosis and other severe illnesses, such as lung cancer. Methods: The research involved surveying tunnel construction workers, conducting interviews, and facilitating focus group discussions. Additionally, site observations and content analysis of work procedures and instructions were performed. Results: Preliminary data analysis reveals notable findings. While there is a commendable level of knowledge and commitment among management and workers concerning RCS exposure in tunnelling, there is a striking lack of prioritization regarding dust control. Moreover, the risks associated with dust exposure are not sufficiently acknowledged. Additionally, the data suggests that engineers and supervisors responsible for implementing dust controls often possess limited knowledge regarding the factors influencing the effectiveness of these measures. These findings emphasise the need for a paradigm shift, including higher prioritisation of dust control, adoption of holistic dust reduction strategies, and enhanced knowledge about effective control measures. Conclusion: This research shed light on tunnel construction workers' barriers and challenges in protecting themselves from RCS exposure. This knowledge will be essential in developing interventions and strategies to enhance dust exposure and prevent the adverse health effects of respirable crystalline silica exposure in tunnelling and similar industries.

Keywords: respirable crystalline silica, dust control, worker practices, exposure prevention, silicosis

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9980 Bone Mineral Density of the Lumbar Spine, Femur in Elite Egyptian Male Swimmers

Authors: Magdy Abouzeid

Abstract:

Introduction: Physical activity has been shown to have a positive effect on bone mineral density (BMD) and bone mineral content (BMC) among children, adolescents, and adults. Sports characterized by little or moderate weight bearing or impact have a low osteogenic effect. However, the action of such sports on bone turnover remains unclear. Swimming, as a non-weight-bearing sport, has been considered to be insignificant in the maintenance of bone mass. Purpose: To examine this issue we measured (BMD) and(BMC) of the lumbar spine, proximal femur via dual energy x-ray absorptiometry in the group of elite male swimmers, and determine the effect of swimming training on bone health and compared the results with matched controls group in age, body weight and height. Materials and Methods: Twenty-five male swimmers (age 20.7+/-0.8 years) training for 12-15 hours/week; and the controls group consisted of 25 non-active male (age 21.3 +/-1.3 years) were studied BMD and BMC of lumbar spine, femur were assessed via (DXA) absorptiometry. Results: There was significant difference between swimmers and control group in BMD and BMC, BMD of Swimmers was significantly greater than controls at all sites. The lumbar spine (1, 08 +/-0.202 vs., 0717+0.57 gxcm (-2), right proximal femur (1, 02 +/-, 044 vs., 771+/-, 027 gxcm (-2), and left proximal femur (1.374+/-0.212 vs. 1.01 +/-0.141 gxcm (-2). Swimmers were significantly taller, and had greater BMC and BMD compared to the controls group (P<0.001). Conclusions: These results suggest that swimming training may be beneficial in the prevention or therapy of OSTEOPENIA, and may lead to increased (BMD) and (BMC) for male swimmers. Swimming may be an effective non-pharmacological intervention for the adults and adolescent. Further research with younger athletes of another type of aquatics sport is warranted to better identify the periods of BMD development during which Aquatics sport has the greatest impact on bone health.

Keywords: bone mineral density, lumbar spine, femur, swimming, DXA absorptiometry

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9979 Mutational Analysis of DNase I Gene in Diabetic Patients

Authors: Hateem Zafar Kayani, Nageen Hussain

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The main aim is to analyze the mutations of DNASE I gene in diabetic patients. A total of 120 diabetes patients and 120 controls were sampled. The total number of male diabetic patients included in the study was 79 (66%) while female patients were 41 (34%) in number. Exon 8 of the DNASE I gene was amplified by using thermo cycler. The possible band of interest was located at 165 base pairs. Two samples showed similar missense mutations at 127th position of exon 8 which replaced amino acid Arginine (Arg) to Glutamine (Gln). All controls showed no mutations. The association of diabetes with different levels of blood pressure and body mass index (BMI) were found to be significant.

Keywords: deoxyribonuclease I, polymerase chain reaction, insulin-dependent diabetes mellitus, non-insulin dependent diabetes mellitus

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9978 Frequent Pattern Mining for Digenic Human Traits

Authors: Atsuko Okazaki, Jurg Ott

Abstract:

Some genetic diseases (‘digenic traits’) are due to the interaction between two DNA variants. For example, certain forms of Retinitis Pigmentosa (a genetic form of blindness) occur in the presence of two mutant variants, one in the ROM1 gene and one in the RDS gene, while the occurrence of only one of these mutant variants leads to a completely normal phenotype. Detecting such digenic traits by genetic methods is difficult. A common approach to finding disease-causing variants is to compare 100,000s of variants between individuals with a trait (cases) and those without the trait (controls). Such genome-wide association studies (GWASs) have been very successful but hinge on genetic effects of single variants, that is, there should be a difference in allele or genotype frequencies between cases and controls at a disease-causing variant. Frequent pattern mining (FPM) methods offer an avenue at detecting digenic traits even in the absence of single-variant effects. The idea is to enumerate pairs of genotypes (genotype patterns) with each of the two genotypes originating from different variants that may be located at very different genomic positions. What is needed is for genotype patterns to be significantly more common in cases than in controls. Let Y = 2 refer to cases and Y = 1 to controls, with X denoting a specific genotype pattern. We are seeking association rules, ‘X → Y’, with high confidence, P(Y = 2|X), significantly higher than the proportion of cases, P(Y = 2) in the study. Clearly, generally available FPM methods are very suitable for detecting disease-associated genotype patterns. We use fpgrowth as the basic FPM algorithm and built a framework around it to enumerate high-frequency digenic genotype patterns and to evaluate their statistical significance by permutation analysis. Application to a published dataset on opioid dependence furnished results that could not be found with classical GWAS methodology. There were 143 cases and 153 healthy controls, each genotyped for 82 variants in eight genes of the opioid system. The aim was to find out whether any of these variants were disease-associated. The single-variant analysis did not lead to significant results. Application of our FPM implementation resulted in one significant (p < 0.01) genotype pattern with both genotypes in the pattern being heterozygous and originating from two variants on different chromosomes. This pattern occurred in 14 cases and none of the controls. Thus, the pattern seems quite specific to this form of substance abuse and is also rather predictive of disease. An algorithm called Multifactor Dimension Reduction (MDR) was developed some 20 years ago and has been in use in human genetics ever since. This and our algorithms share some similar properties, but they are also very different in other respects. The main difference seems to be that our algorithm focuses on patterns of genotypes while the main object of inference in MDR is the 3 × 3 table of genotypes at two variants.

Keywords: digenic traits, DNA variants, epistasis, statistical genetics

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