Etiologies underlying subtypes of long-standing type 2 diabetes.

BACKGROUND: Attempts to subtype, type 2 diabetes (T2D) have mostly focused on newly diagnosed European patients. In this study, our aim was to subtype T2D in a non-white Emirati ethnic population with long-standing disease, using unsupervised soft clustering, based on etiological determinants. METHODS: The Auto Cluster model in the IBM SPSS Modeler was used to cluster data from 348 Emirati patients with long-standing T2D. Five predictor variables (fasting blood glucose (FBG), fasting serum insulin (FSI), body mass index (BMI), hemoglobin A1c (HbA1c) and age at diagnosis) were used to determine the appropriate number of clusters and their clinical characteristics. Multinomial logistic regression was used to validate clustering results. RESULTS: Five clusters were identified; the first four matched Ahlqvist et al subgroups: severe insulin-resistant diabetes (SIRD), severe insulin-deficient diabetes (SIDD), mild age-related diabetes (MARD), mild obesity-related diabetes (MOD), and a fifth new subtype of mild early onset diabetes (MEOD). The Modeler algorithm allows for soft assignments, in which a data point can be assigned to multiple clusters with different probabilities. There were 151 patients (43%) with membership in cluster peaks with no overlap. The remaining 197 patients (57%) showed extensive overlap between clusters at the base of distributions. CONCLUSIONS: Despite the complex picture of long-standing T2D with comorbidities and complications, our study demonstrates the feasibility of identifying subtypes and their underlying causes. While clustering provides valuable insights into the architecture of T2D subtypes, its application to individual patient management would remain limited due to overlapping characteristics. Therefore, integrating simplified, personalized metabolic profiles with clustering holds greater promise for guiding clinical decisions than subtyping alone.

Effects of menstrual cycle on hemodynamic and autonomic responses to central hypovolemia.

Background: Estrogen and progesterone levels undergo changes throughout the menstrual cycle. Existing literature regarding the effect of menstrual phases on cardiovascular and autonomic regulation during central hypovolemia is contradictory. Aims and study: This study aims to explore the influence of menstrual phases on cardiovascular and autonomic responses in both resting and during the central hypovolemia induced by lower body negative pressure (LBNP). This is a companion paper, in which data across the menstrual phases from healthy young females, whose results are reported in Shankwar et al. (2023), were further analysed. Methods: The study protocol consisted of three phases: (1) 30 min of supine rest; (2) 16 min of four LBNP levels; and (3) 5 min of supine recovery. Hemodynamic and autonomic responses (assessed via heart rate variability, HRV) were measured before-, during-, and after-LBNP application using Task Force Monitor® (CNSystems, Graz, Austria). Blood was also collected to measure estrogen and progesterone levels. Results: In this companion paper, we have exclusively assessed 14 females from the previous study (Shankwar et al., 2023): 8 in the follicular phase of the menstrual cycle (mean age 23.38 ± 3.58 years, height 166.00 ± 5.78 cm, weight 57.63 ± 5.39 kg and BMI of 20.92 ± 1.96 25 kg/m2) and 6 in the luteal phase (mean age 22.17 ± 1.33 years, height 169.83 ± 5.53 cm, weight 62.00 ± 7.54 kg and BMI of 21.45 ± 2.63 kg/m2). Baseline estrogen levels were significantly different from the follicular phase as compared to the luteal phase: (33.59 pg/ml, 108.02 pg/ml, respectively, p < 0.01). Resting hemodynamic variables showed no difference across the menstrual phases. However, females in the follicular phase showed significantly lower resting values of low-frequency (LF) band power (41.38 ± 11.75 n.u. and 58.47 ± 14.37 n.u., p = 0.01), but higher resting values of high frequency (HF) band power (58.62 ± 11.75 n.u. and 41.53 ± 14.37 n.u., p = 0.01), as compared to females in the luteal phase. During hypovolemia, the LF and HF band powers changed only in the follicular phase F(1, 7) = 77.34, p < 0.0001 and F(1, 7) = 520.06, p < 0.0001, respectively. Conclusions: The menstrual phase had an influence on resting autonomic variables, with higher sympathetic activity being observed during the luteal phase. Central hypovolemia leads to increased cardiovascular and autonomic responses, particularly during the luteal phase of the menstrual cycle, likely due to higher estrogen levels and increased sympathetic activity.

Risk and predictors of severity and mortality in patients with type 2 diabetes and COVID-19 in Dubai.

BACKGROUND: Globally, patients with diabetes suffer from increased disease severity and mortality due to coronavirus disease 2019 (COVID-19). Old age, high body mass index (BMI), comorbidities, and complications of diabetes are recognized as major risk factors for infection severity and mortality. AIM: To investigate the risk and predictors of higher severity and mortality among in-hospital patients with COVID-19 and type 2 diabetes (T2D) during the first wave of the pandemic in Dubai (March-September 2020). METHODS: In this cross-sectional nested case-control study, a total of 1083 patients with COVID-19 were recruited. This study included 890 men and 193 women. Of these, 427 had T2D and 656 were non-diabetic. The clinical, radiographic, and laboratory data of the patients with and without T2D were compared. Independent predictors of mortality in COVID-19 non-survivors were identified in patients with and without T2D. RESULTS: T2D patients with COVID-19 were older and had higher BMI than those without T2D. They had higher rates of comorbidities such as hypertension, ischemic heart disease, heart failure, and more life-threatening complications. All laboratory parameters of disease severity were significantly higher than in those without T2D. Therefore, these patients had a longer hospital stay and a significantly higher mortality rate. They died from COVID-19 at a rate three times higher than patients without. Most laboratory and radiographic severity indices in non-survivors were high in patients with and without T2D. In the univariate analysis of the predictors of mortality among all COVID-19 non-survivors, significant associations were identified with old age, increased white blood cell count, lym-phopenia, and elevated serum troponin levels. In multivariate analysis, only lymphopenia was identified as an independent predictor of mortality among T2D non-survivors. CONCLUSION: Patients with COVID-19 and T2D were older with higher BMI, more comorbidities, higher disease severity indices, more severe proinflammatory state with cardiac involvement, and died from COVID-19 at three times the rate of patients without T2D. The identified mortality predictors will help healthcare workers prioritize the management of patients with COVID-19.

Association of gender with cardiovascular and autonomic responses to central hypovolemia.

Introduction: Lower body negative pressure (LBNP) eliminates the impact of weight-bearing muscles on venous return, as well as the vestibular component of cardiovascular and autonomic responses. We evaluated the hemodynamic and autonomic responses to central hypovolemia, induced by LBNP in both males and females. Methodology: A total of 44 participants recruited in the study. However, 9 participants did not complete the study protocol. Data from the remaining 35 participants were analysed, 18 males (25.28 ± 3.61 years, 181.50 ± 7.43 cm height, 74.22 ± 9.16 kg weight) and 17 females (22.41 ± 2.73 years, 167.41 ± 6.29 cm height, 59.06 ± 6.91 kg weight). During the experimental protocol, participants underwent three phases, which included 30 min of supine rest, four 4 min intervals of stepwise increases in LBNP from -10 mmHg to -40 mmHg, and 5 min of supine recovery. Throughout the protocol, hemodynamic variables such as blood pressure, heart rate, stroke index, cardiac index, and total peripheral resistance index were continuously monitored. Autonomic variables were calculated from heart rate variability measures, using low and high-frequency spectra, as indicators of sympathetic and parasympathetic activity, respectively. Results: At rest, males exhibited higher systolic (118.56 ± 9.59 mmHg and 110.03 ± 10.88 mmHg, p < 0.05) and mean arterial (89.70 ± 6.86 and 82.65 ± 9.78, p < 0.05) blood pressure as compared to females. Different levels of LBNP altered hemodynamic variables in both males and females: heart rate [F(1,16) = 677.46, p < 0.001], [F(1,16) = 550.87, p < 0.001]; systolic blood pressures [F(1,14) = 3,186.77, p < 0.001], [F(1,17) = 1,345.61, p < 0.001]; diastolic blood pressure [F(1,16) = 1,669.458, p < 0.001], [F(1,16) = 1,127.656, p < 0.001]; mean arterial pressures [F(1,16) = 2,330.44, p < 0.001], [F(1,16) = 1,815.68, p < 0.001], respectively. The increment in heart rates during LBNP was significantly different between both males and females (p = 0.025). The low and high-frequency powers were significantly different for males and females (p = 0.002 and p = 0.001, respectively), with the females having a higher increase in low-frequency spectral power. Conclusions and future directions: Cardiovascular activity and autonomic function at rest are influenced by gender. During LBNP application, hemodynamic and autonomic responses differed between genders. These gender-based differences in responses during central hypovolemia could potentially be attributed to the lower sympathetic activity in females. With an increasing number of female crew members in space missions, it is important to understand the role sex-steroid hormones play in the regulation of cardiovascular and autonomic activity, at rest and during LBNP.

Gender-specific Reference Range for Serum Leptin in Omani Population.

Objectives: Leptin is a hormone that contributes to glucose homeostasis and food intake regulation via its action on the hypothalamus. Leptin level increases with obesity and overfeeding and decreases with energy deficiency. Serum leptin levels vary between different ethnic groups with no reports of its reference range in the Arabic population. We sought to determine gender-specific reference ranges for serum leptin in a cohort of the Arabic population and identify the cut-off value for different metabolic derangements. Methods: The study data were obtained from the records of 1198 subjects included in the Oman Family Study. The percentile method was used in the estimation reference range and the receiver operating characteristic to identify cut-off points for multiple metabolic derangements. Results: The reference range of serum leptin was 0.5-90.6 ng/mL, and it was not correlated with the age of the subjects. Higher leptin was observed in females compared to males (p < 0.001), and the reference range for serum leptin in females was 4.9-96.3 ng/mL compared to 0.25-48.8 ng/mL in males. The optimum cut-off value for leptin ranged between 24.1-28.9 ng/mL for metabolic syndrome, obesity, central obesity, and type 2 diabetes. Conclusions: We identified gender-specific reference ranges for serum leptin in a large cohort of Arabs. The optimum cut-off value for serum leptin to determine metabolic derangement with the highest sensitivity and specificity was 24.1-28.9 ng/mL. Future studies are needed to study the relative risk of higher serum leptin using prospective studies.

Estimate of the HOMA-IR Cut-off Value for Identifying Subjects at Risk of Insulin Resistance Using a Machine Learning Approach.

OBJECTIVES: This study describes an unsupervised machine learning approach used to estimate the homeostatic model assessment-insulin resistance (HOMA-IR) cut-off for identifying subjects at risk of IR in a given ethnic group based on the clinical data of a representative sample. METHODS: The approach was applied to analyse the clinical data of individuals with Arab ancestors, which was obtained from a family study conducted in Nizwa, Oman, between January 2000 and December 2004. First, HOMA-IR-correlated variables were identified to which a clustering algorithm was applied. Two clusters having the smallest overlap in their HOMA-IR values were retrieved. These clusters represented the samples of two populations, which are insulin-sensitive subjects and individuals at risk of IR. The cut-off value was estimated from intersections of the Gaussian functions, thereby modelling the HOMA-IR distributions of these populations. RESULTS: A HOMA-IR cut-off value of 1.62 ± 0.06 was identified. The validity of this cut-off was demonstrated by showing the following: 1) that the clinical characteristics of the identified groups matched the published research findings regarding IR; 2) that a strong relationship exists between the segmentations resulting from the proposed cut-off and those resulting from the two-hour glucose cut-off recommended by the World Health Organization for detecting prediabetes. Finally, the method was also able to identify the cut-off values for similar problems (e.g. fasting sugar cut-off for prediabetes). CONCLUSION: The proposed method defines a HOMA-IR cut-off value for detecting individuals at risk of IR. Such methods can identify high-risk individuals at an early stage, which may prevent or delay the onset of chronic diseases such as type 2 diabetes.

Utility of oral glucose tolerance test in predicting type 2 diabetes following gestational diabetes: Towards personalized care.

BACKGROUND: Women with gestational diabetes mellitus (GDM) are at a seven-fold higher risk of developing type 2 diabetes (T2D) within 7-10 years after childbirth, compared with those with normoglycemic pregnancy. Although raised fasting blood glucose (FBG) levels has been said to be the main significant predictor of postpartum progression to T2D, it is difficult to predict who among the women with GDM would develop T2D. Therefore, we conducted a cross-sectional retrospective study to examine the glycemic indices that can predict postnatal T2D in Emirati Arab women with a history of GDM. AIM: To assess how oral glucose tolerance test (OGTT) can identify the distinct GDM pathophysiology and predict possible distinct postnatal T2D subtypes. METHODS: The glycemic status of a cohort of 4603 pregnant Emirati Arab women, who delivered in 2007 at both Latifa Women and Children Hospital and at Dubai Hospital, United Arab Emirates, was assessed retrospectively, using the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. Of the total, 1231 women were followed up and assessed in 2016. The FBG and/or the 2-h blood glucose (2hrBG) levels after a 75-g glucose load were measured to assess the prevalence of GDM and T2D, according to the IADPSG and American Diabetes Association (ADA) criteria, respectively. The receiver operating characteristic curve for the OGTT was plotted and sensitivity, specificity, and predictive values of FBG and 2hrBG for T2D were determined. RESULTS: Considering both FBG and 2hrBG levels, according to the IADPSG criteria, the prevalence of GDM in pregnant Emirati women in 2007 was 1057/4603 (23%), while the prevalence of pre-pregnancy T2D among them, based on ADA criteria, was 230/4603 (5%). In the subset of women (n = 1231) followed up in 2016, the prevalence of GDM in 2007 was 362/1231 (29.6%), while the prevalence of pre-pregnancy T2D was 36/1231 (2.9%). Of the 362 pregnant women with GDM in 2007, 96/362 (26.5%) developed T2D; 142/362 (39.2%) developed impaired fasting glucose; 29/362 (8.0%) developed impaired glucose tolerance, and the remaining 95/362 (26.2%) had normal glycemia in 2016. The prevalence of T2D, based on ADA criteria, stemmed from the prevalence of 36/1231 (2.9%) in 2007 to 141/1231 (11.5%), in 2016. The positive predictive value (PPV) for FBG suggests that if a woman tested positive for GDM in 2007, the probability of developing T2D in 2016 was approximately 24%. The opposite was observed when 2hrBG was used for diagnosis. The PPV value for 2hrBG suggests that if a woman was positive for GDM in 2007 then the probability of developing T2D in 2016 was only 3%. CONCLUSION: FBG and 2hrBG could predict postpartum T2D, following antenatal GDM. However, each test reflects different pathophysiology and possible T2D subtype and could be matched with a relevant T2D prevention program.

Covid-19 infection in pregnant women in Dubai: a case-control study.

BACKGROUND: Whilst the impact of Covid-19 infection in pregnant women has been examined, there is a scarcity of data on pregnant women in the Middle East. Thus, the aim of this study was to examine the impact of Covid-19 infection on pregnant women in the United Arab Emirates population. METHODS: A case-control study was carried out to compare the clinical course and outcome of pregnancy in 79 pregnant women with Covid-19 and 85 non-pregnant women with Covid-19 admitted to Latifa Hospital in Dubai between March and June 2020. RESULTS: Although Pregnant women presented with fewer symptoms such as fever, cough, sore throat, and shortness of breath compared to non-pregnant women; yet they ran a much more severe course of illness. On admission, 12/79 (15.2%) Vs 2/85 (2.4%) had a chest radiograph score [on a scale 1-6] of ≥3 (p-value = 0.0039). On discharge, 6/79 (7.6%) Vs 1/85 (1.2%) had a score ≥3 (p-value = 0.0438). They also had much higher levels of laboratory indicators of severity with values above reference ranges for C-Reactive Protein [(28 (38.3%) Vs 13 (17.6%)] with p < 0.004; and for D-dimer [32 (50.8%) Vs 3(6%)]; with p < 0.001. They required more ICU admissions: 10/79 (12.6%) Vs 1/85 (1.2%) with p=0.0036; and suffered more complications: 9/79 (11.4%) Vs 1/85 (1.2%) with p=0.0066; of Covid-19 infection, particularly in late pregnancy. CONCLUSIONS: Pregnant women presented with fewer Covid-19 symptoms but ran a much more severe course of illness compared to non-pregnant women with the disease. They had worse chest radiograph scores and much higher levels of laboratory indicators of disease severity. They had more ICU admissions and suffered more complications of Covid-19 infection, such as risk for miscarriage and preterm deliveries. Pregnancy with Covid-19 infection, could, therefore, be categorised as high-risk pregnancy and requires management by an obstetric and medical multidisciplinary team.

Heritability and genetic correlations of obesity indices with ambulatory and office beat-to-beat blood pressure in the Oman Family Study.

OBJECTIVE: To more precisely and comprehensively estimate the genetic and environmental correlations between various indices of obesity and BP. METHODS: We estimated heritability and genetic correlations of obesity indices with BP in the Oman family study (n = 1231). Ambulatory and office beat-to-beat BP was measured and mean values for SBP and DBP during daytime, sleep, 24-h and 10 min at rest were calculated. Different indices were used to quantify obesity and fat distribution: BMI, percentage of body fat (%BF), waist circumference and waist-to-height ratio (WHtR). SOLAR software was used to perform univariate and bivariate quantitative genetic analyses adjusting for age, age, sex, age-sex and age--sex interactions. RESULTS: Heritabilities of BP ranged from 30.2 to 38.2% for ambulatory daytime, 16.8--21.4% for sleeping time, 32.1--40.4% for 24-h and 22--24.4% for office beat-to-beat measurements. Heritabilities for obesity indices were 67.8% for BMI, 52.2% for %BF, 37.3% for waist circumference and 37.9% for WHtR. All obesity measures had consistently positive phenotypic correlations with ambulatory and office beat-to-beat SBP and DBP (r-range: 0.14--0.32). Genetic correlations of obesity indices with SBP and DBP were higher than environmental correlations (rG: 0.16--0.50; rE: 0.01--0.31). CONCLUSION: The considerable genetic overlap between a variety of obesity indices and both ambulatory and office beat-to-beat BP highlights the relevance of pleiotropic genes. Future GWAS analyses should discover the specific genes both influencing obesity indices and BP to help unravel their shared genetic background.

Augmenting Flexnerism Via Twitterism: Need for Integrating Social Media Application in Blueprinting Pedagogical Strategies for Undergraduate Medical Education.

BACKGROUND: Flexnerism, or "competency-based medical education," advocates that formal analytic reasoning, the kind of rational thinking fundamental to the basic sciences, especially the natural sciences, should be the foundation of physicians' intellectual training. The complexity of 21st century health care requires rethinking of current (medical) educational paradigms. In this "Millennial Era," promulgation of the tenets of Flexnerism in undergraduate medical education requires a design and blueprint of innovative pedagogical strategies, as the targeted learners are millennials (designated as generation-Y medical students). OBJECTIVE: The aim of this proof-of-concept study was to identify the specific social media app platforms that are selectively preferred by generation-Y medical students in undergraduate medical education. In addition, we aimed to explore if these preferred social media apps can be used to design an effective pedagogical strategy in order to disseminate course learning objectives in the preclinical phase of a spiral curriculum. METHODS: A cross-sectional survey was conducted by distributing a 17-item questionnaire among the first- and second-year medical students in the preclinical phase at the Mohammed Bin Rashid University of Medicine and Health Science. RESULTS: The study identified YouTube and WhatsApp as the social media app platforms preferred by generation-Y medical students in undergraduate medical education. This study also identified the differences between female and male generation-Y medical students in terms of the use of social media apps in medical education, which we believe will assist instructors in designing pedagogical strategies to integrate social media apps. In addition, we determined the perceptions of generation-Y medical students on the implementation of social media apps in medical education. The pedagogical strategy designed using social media apps and implemented in the Biochemistry course was well accepted by generation-Y medical students and can be translated to any course in the preclinical phase of the medical curriculum. Moreover, the identified limitations of this study provide an understanding of the gaps in research in the integration of social media apps in a medical curriculum catering to generation-Y medical students. CONCLUSIONS: 21st century medical education requires effective use of social media app platforms to augment competency-based medical education: Augmentation of Flexnerism in the current scenario is possible only by the adaptation of Twitterism.

Heritability and genetic and environmental correlations of heart rate variability and baroreceptor reflex sensitivity with ambulatory and beat-to-beat blood pressure.

This family study from Oman (n = 1231) explored the heritability and genetic and environmental correlations of heart rate variability (HRV) and baroreceptor reflex sensitivity (BRS) with ambulatory and beat-to-beat blood pressure (BP). Ambulatory BP was measured for 24 hours to calculate mean values for daytime and sleep separately. Time and frequency domain HRV indices, BRS, office beat-to-beat BP, and heart rate (HR) were measured for 10 minutes at rest. SOLAR software was used to perform univariate and bivariate quantitative genetic analyses adjusting for age, age2, sex, their interactions and BMI. Heritability of SBP and DBP ranged from 16.8% to 40.4% for daytime, sleeping, 24-hour and office beat-to-beat measurements. HR and BRS showed a heritability of 31.9% and 20.6%, respectively, and for HRV indices heritability ranged from 11.1% to 20.5%. All HRV measurements and BRS were found to be negatively correlated with BP, but phenotypic correlation coefficients were relatively weak; HR was positively correlated with BP. None of the genetic correlations were statistically significant while environmental factors explained most of the correlations for all HRV indices with BP. Our study found consistent but weak correlations among HRV, HR, BRS and ambulatory/office beat-to-beat BP. However, environmental rather than genetic factors contributed most to those correlations.

A novel 6D-approach to radically transform undergraduate medical education: preliminary reflections from MBRU.

BACKGROUND: Designers of undergraduate medical education (UME) need to address the exponentially expanding volume and variability of scientific knowledge, where by didactic teaching techniques need to be augmented by innovative student-centric pedagogical strategies and implementation of milieus, where information, communication and technology-enabled tools are seamlessly integrated, and lifelong information gathering, assimilation, integration and implementation is the ultimate goal. In UME, the basic sciences provide a solid scaffold allowing students to develop their personal critical decisional framework as well as define the understanding of normal human physiology, pivotal for the identification, categorization and management of pathophysiology. However, most medical schools confine themselves to "stagnant curricula", with the implementation of traditional "teacher centered" pedagogical techniques in the dissemination of the courses pertaining to basic sciences in UME. METHOD: To tackle the above paucity, we present a novel "6D-Approach" for the dissemination of concepts in basic sciences through mentored journal-clubs. The approach is informed by a teaching principle derived from Constructivism. The technique in which the 6D-approach can be implemented in UME, is shown using an example from a first-year course of Molecular Biology and Principles of Genetics at our medical school. A reflection on the impact of 6D-Approach for students as well as instructors is also presented. RESULT: The 6D-approach was positively received by the students and the formal feedback for the course: Molecular Biology and Principles of Genetics, where the approach was repeatedly employed, indicated that students expressed satisfaction with the teaching strategies employed in the course, with ~ 89% of the students in the cohort strongly agreeing with the highest grading score "extremely satisfied". Further, the approach through the use of mentored journal clubs encourages retention of knowledge, critical thinking, metacognition, collaboration and leadership skills in addition to self-evaluation and peer feedback. CONCLUSION: Hence, through the 6D-Approach, our attempt is to initiate, advance and facilitate critical thinking, problem-solving and self-learning in UME, demonstrated by graduating accomplished, competent and safe medical practitioners.

Blending Gagne's Instructional Model with Peyton's Approach to Design an Introductory Bioinformatics Lesson Plan for Medical Students: Proof-of-Concept Study.

BACKGROUND: With the rapid integration of genetics into medicine, it has become evident that practicing physicians as well as medical students and clinical researchers need to be updated on the fundamentals of bioinformatics. To achieve this, the following gaps need to be addressed: a lack of defined learning objectives for "Bioinformatics for Medical Practitioner" courses, an absence of a structured lesson plan to disseminate the learning objectives, and no defined step-by-step strategy to teach the essentials of bioinformatics in the medical curriculum. OBJECTIVE: The objective of this study was to address these gaps to design a streamlined pedagogical strategy for teaching basics of bioinformatics in the undergraduate medical curriculum. METHODS: The established instructional design strategies employed in medical education-Gagne's 9 events of instruction-were followed with further contributions from Peyton's four-step approach to design a structured lesson plan in bioinformatics. RESULTS: First, we defined the specifics of bioinformatics that a medical student or health care professional should be introduced to use this knowledge in a clinical context. Second, we designed a structured lesson plan using a blended approach from both Gagne's and Peyton's instructional models. Lastly, we delineated a step-by-step strategy employing free Web-based bioinformatics module, combining it with a clinical scenario of familial hypercholesterolemia to disseminate the defined specifics of bioinformatics. Implementation of Schon's reflective practice model indicated that the activity was stimulating for the students with favorable outcomes regarding their basic training in bioinformatics. CONCLUSIONS: To the best of our knowledge, the present lesson plan is the first that outlines an effective dissemination strategy for integrating introductory bioinformatics into a medical curriculum. Further, the lesson plan blueprint can be used to develop similar skills in workshops, continuing professional development, or continuing medical education events to introduce bioinformatics to practicing physicians.

Heritability and genetic correlations of heart rate variability at rest and during stress in the Oman Family Study.

INTRODUCTION: Individual differences in heart rate variability (HRV) can be partly attributed to genetic factors that may be more pronounced during stress. Using data from the Oman Family Study (OFS), we aimed to estimate and quantify the relative contribution of genes and environment to the variance of HRV at rest and during stress; calculate the overlap in genetic and environmental influences on HRV at rest and under stress using bivariate analyses of HRV parameters and heart rate (HR). METHODS: Time and frequency domain HRV variables and average HR were measured from beat-to-beat HR obtained from electrocardiogram recordings at rest and during two stress tests [mental: Word Conflict Test (WCT) and physical: Cold Pressor Test (CPT)] in the OFS - a multigenerational pedigree consisting of five large Arab families with a total of 1326 participants. SOLAR software was used to perform quantitative genetic modelling. RESULTS: Heritability estimates for HRV and HR ranged from 0.11 to 0.31 for rest, 0.09-0.43 for WCT, and 0.07-0.36 for CPT. A large part of the genetic influences during rest and stress conditions were shared with genetic correlations ranging between 0.52 and 0.86 for rest-WCT and 0.60-0.92 for rest-CPT. Nonetheless, genetic rest-stress correlations for most traits were significantly smaller than 1 indicating some stress-specific genetic effects. CONCLUSION: Genetic factors significantly influence HRV and HR at rest and under stress. Most of the genetic factors that influence HRV at rest also influence HRV during stress tests, although some unique genetic variance emerges during these challenging conditions.

Erratum: Genetic loci associated with heart rate variability and their effects on cardiac disease risk.

This corrects the article DOI: 10.1038/ncomms15805.

Validity of Prostate Health Index and Percentage of [-2] Pro-Prostate-Specific Antigen as Novel Biomarkers in the Diagnosis of Prostate Cancer: Omani Tertiary Hospitals Experience.

OBJECTIVES: Prostate cancer is the leading cancer in older men. The Ministry of Health Oman Cancer Incidence Registry 2013 lists cancer of the prostate as the first most common cancer in males. Therefore, early detection is important and prostate-specific antigen (PSA) is widely used as an established laboratory test. However, despite its wide use, its value in screening, particularly in asymptomatic males, is controversial when considering the risks and benefits of early detection. METHODS: This prospective, observational study included 136 males (67.0±8.9 years; range 45-90) who were scheduled for a prostate biopsy in two different tertiary care teaching hospitals in Oman: the Royal Hospital and Sultan Qaboos University Hospital. Blood specimens from these patients were collected at the same setting before obtaining a prostatic biopsy. Three PSA markers (total PSA (tPSA), free PSA (fPSA), and [-2]proPSA (p2PSA)) were measured and the Prostate Health Index (phi) calculated. The histopathological report of the prostatic biopsy for each patient was obtained from the histopathology laboratory of the concerned hospital along with clinical and laboratory data through the hospital information system. RESULTS: Phi has the highest validity markers compared with other prostate markers, with a sensitivity of 82.1%, specificity of 80.6%, and area under the curve (AUC) value of 0.81 at a cutoff of 41.9. The other prostatic markers showed sensitivities and specificities of 78.6% and 25.9% for tPSA; 35.7% and 92.6% for %fPSA; and 64.3% and 82.4% for %p2PSA, respectively. The AUCs at the best cutoff values were 0.67 at 10.1 µg/L for tPSA; 0.70 at 11.6% for %fPSA; and 0.55 at 1.4% for %p2PSA. An association between phi values and aggressiveness of prostate malignancy was noted. Of the 28 patients with prostate cancer, 22 patients had tPSA > 4 µg/L. However, no patient had phi in the low-risk category, and five, six, and 17 patients had phi in the moderate-, high-, and very high-risk categories, respectively. CONCLUSIONS: Phi outperforms tPSA and fPSA when used alone or in combination, and appears to be more accurate than both markers in excluding prostate cancer before biopsy. Use of this biomarker helps clinicians to avoid unnecessary biopsies, particularly in patients with gray-zone tPSA level. Phi is the strongest marker that correlates proportionally with Gleason Score; therefore, it is also useful in predicting the aggressiveness of the disease. This is the first reported experience for the use of p2PSA and phi in Oman, the Middle East, and North Africa.

Genetic loci associated with heart rate variability and their effects on cardiac disease risk.

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74

Positive selection of lactase persistence among people of Southern Arabia.

OBJECTIVE: Frequency patterns of the lactase persistence (LP)-associated -13,915 G allele and archaeological records pointing to substantial role played by southern regions in the peopling and domestication processes that involved the Arabian Peninsula suggest that Southern Arabia plausibly represented the center of diffusion of such adaptive variant. Nevertheless, a well-defined scenario for evolution of Arabian LP is still to be elucidated and the burgeoning archaeological picture of complex human migrations occurred through the peninsula is not matched by an equivalent high-resolution description of genetic variation underlying this adaptive trait. To fill this gap, we investigated diversity at a wide genomic interval surrounding the LCT gene in different Southern Arabian populations. METHODS: 40 SNPs were genotyped to characterize LCT profiles of 630 Omani and Yemeni individuals to perform population structure, linkage disequilibrium, population differentiation-based and haplotype-based analyses. RESULTS: Typical Arabian LP-related variation was found in Dhofaris and Yemenis, being characterized by private haplotypes carrying the -13,915 G allele, unusual differentiation with respect to northern groups and conserved homozygous haplotype-blocks, suggesting that the adaptive allele was likely introduced in the Arabian gene pool in southern populations and was then subjected to prolonged selective pressure. CONCLUSION: By pointing to Yemen as one of the best candidate centers of diffusion of the Arabian-specific adaptive variant, obtained results indicate the spread of indigenous groups as the main process underlying dispersal of LP along the Arabian Peninsula, supporting a refugia model for Arabian demic movements occurred during the Terminal Pleistocene and Early Holocene.

Frequencies of the Arg16Gly, Gln27Glu and Thr164Ile Adrenoceptor ß2 Polymorphisms among Omanis.

OBJECTIVES: This study aimed to assess the distribution of missense mutations in the adrenoceptor ß2 (ADRB2) gene in an Omani cohort. METHODS: This study was carried out between May 2014 and March 2015 at the Sultan Qaboos University, Muscat, Oman. Blood samples were taken from 316 unrelated Omani subjects. Genotyping for rs1042713 (c.46A>G, p.Arg16Gly), rs1042714 (c.79C>G, p.Gln27Glu) and rs1800888 (c.491C>T, p.Thr164Ile) polymorphisms was performed by real-time polymerase chain reaction using single nucleotide polymorphism (SNP) genotyping assays. The allelic frequencies of these polymorphisms were estimated on the basis of the observed numbers of specific alleles from the genotype data for male and female subjects. The genotype frequencies for each polymorphism were tested for deviation from the Hardy-Weinberg equilibrium. RESULTS: Gly16 and Glu27 were the most frequent variants found among the cohort (63% and 75%, respectively). The Ile164 variant was not detected in the study population. There was a significant linkage disequilibrium between the rs1042713 and rs1042714 SNPs (r(2) = 0.209; P ≤0.001). The most observed haplotypes were Gly16-Gln27 and Arg16-Gln27 (0.37 and 0.38, respectively). The frequency of Gly16-Glu27 was 0.25, comprising all Glu27 carriers. CONCLUSION: The allelic distribution of variants in this Omani cohort was similar to distributions reported among Caucasian populations.

Epidemiology of Diabetes Mellitus in Oman: Results from two decades of research.

OBJECTIVES: This study aimed to describe the epidemiology of diabetes mellitus over the past two decades in Oman, particularly in terms of its prevalence and incidence. In addition, the study sought to estimate the future incidence of diabetes in Oman. METHODS: Three national and three regional surveys conducted between 1991 and 2010 were analysed to obtain the age-adjusted prevalence and undiagnosed proportion of type 2 diabetes mellitus (T2DM) among Omani subjects aged ≥20 years. Diabetes mellitus registers and published studies were used to determine incidence rates of both type 1 diabetes mellitus (T1DM) and T2DM in Oman. Linear regression was used to determine trends and projections for diabetes in 2050. RESULTS: The age-adjusted prevalence of T2DM in Oman varied from 10.4% to 21.1%, while the highest prevalence of impaired fasting glucose was found in males (35.1%). In comparison to men, higher incidence rates of T2DM were found in women (2.7 cases compared to 2.3 cases per 1,000 person-years, respectively). No significant trends were observed for the prevalence or incidence of T2DM in both genders. Undiagnosed T2DM was more common in men (range: 33-68%) than women (range: 27-53%). The results of this study show that by 2050, there will be an estimated 350,000 people with T2DM living in Oman (a 174% increase compared to estimates for 2015). CONCLUSION: Health authorities need to prioritise diabetes prevention and control in order to prevent or delay long-term complications and avert a potential epidemic of diabetes in Oman.