Angiotensin-Converting Enzyme (ACE) level, but not ACE gene polymorphism, is associated with prognosis of COVID-19 infection: Implications for diabetes and hypertension.

BACKGROUND: The renin-angiotensin-aldosterone system was shown to be activated in severe COVID-19 infection. We aimed to investigate the relationship between angiotensin converting enzyme (ACE) levels, ACE gene polymorphism, type 2 diabetes (T2DM), and hypertension (HT) and the prognosis of COVID-19 infection. METHODS: This cross-sectional study analyzed the clinical features of adult patients with SARS-CoV-2 infection. ACE gene analysis and ACE level measurements were performed. The patients were grouped according to ACE gene polymorphism (DD, ID or II), disease severity (mild, moderate, or severe), and the use of dipeptidyl peptidase-4 enzyme inhibitor (DPP4i), ACE-inhibitor (ACEi) or angiotensin receptor blocker (ARB). Intensive care unit (ICU) admissions and mortality were also recorded. RESULTS: A total of 266 patients were enrolled. Gene analysis detected DD polymorphism in the ACE 1 gene in 32.7% (n = 87), ID in 51.5% (n = 137), and II in 15.8% (n = 42) of the patients. ACE gene polymorphisms were not associated with disease severity, ICU admission, or mortality. ACE levels were higher in patients who died (p = 0.004) or were admitted to the ICU (p<0.001) and in those with severe disease compared to cases with mild (p = 0.023) or moderate (p<0.001) disease. HT, T2DM, and ACEi/ARB or DPP4i use were not associated with mortality or ICU admission. ACE levels were similar in patients with or without HT (p = 0.374) and with HT using or not using ACEi/ARB (p = 0.999). They were also similar in patients with and without T2DM (p = 0.062) and in those with and without DPP4i treatment (p = 0.427). ACE level was a weak predictor of mortality but an important predictor of ICU admission. It predicted ICU admission in total (cutoff value >37.092 ng/mL, AUC: 0.775, p<0.001). CONCLUSION: Our findings suggest that higher ACE levels, but not ACE gene polymorphism, ACEi/ARB or DPP4i use, were associated with the prognosis of COVID-19 infection. The presence of HT and T2DM and ACEi/ARB or DPP4i use were not associated with mortality or ICU admission.

When do we need to suspect maturity onset diabetes of the young in patients with type 2 diabetes mellitus?

ABSTRACT Objetivo: Maturity onset diabetes of the young (MODY) patients have clinical heterogeneity as shown by many studies. Thus, often it is misdiagnosed to type 1 or type 2 diabetes(T2DM). The aim of this study is to evaluate MODY mutations in adult T2DM patients suspicious in terms of MODY, and to show clinical and laboratory differences between these two situations. Subjects and methods: In this study, we analyzed 72 type 2 diabetic patients and their relatives (35F/37M) who had been suspected for MODY and referred to genetic department for mutation analysis. The gene mutations for MODY have been assessed in the laboratory of Marmara University genetics. Totally 67 (32F/35M; median age 36.1) diabetic patients were analyzed for 7 MODY mutations. Twelve patients who have uncertain mutation (VUS) were excluded from study for further evaluation. MODY(+) (n:30) patients and T2DM patients (n:25) were compared for clinical and laboratory parameters. Results: In MODY(+) subjects, mutations in GCK (MODY 2) (n:12; 40%) were the most common followed by HNF4A (MODY 1) (n:4; 13.3%). Diabetes diagnosis age was younger in MODY(+) group but not statistically significant. Sixty-six percent of MODY(+) subjects had diabetes history at 3-consecutive generations in their family compared with 28% of T2DM patients statistically significant (p:0.006). Gender, BMI, C-peptide, HbA1c, lipid parameters, creatinine, GFR, microalbuminuria, vitamin D and calcium were not statistically different between the groups. Conclusion: According to present study results, MODY mutation positivity is most probable in young autoantibody (-) diabetic patients diagnosed before 30 years of age, who have first degree family history of diabetes.

Whole-exome sequencing reveals new potential genes and variants in patients with premature ovarian insufficiency.

PURPOSE: Premature ovarian insufficiency (POI) is a heterogeneous disorder characterized by the cessation of menstrual cycles before the age of 40 years due to the depletion or dysfunction of the ovarian follicles. POI is a highly heterogeneous disease in terms of etiology. The aim of this study is to reveal the genetic etiology in POI patients. METHODS: A total of 35 patients (mean age: 27.2 years) from 28 different families diagnosed with POI were included in the study. Karyotype, FMR1 premutation analysis, single nucleotide polymorphism (SNP) array, and whole-exome sequencing (WES) were conducted to determine the genetic etiology of patients. RESULTS: A total of 35 patients with POI were first evaluated by karyotype analysis, and chromosomal anomaly was detected in three (8.5%) and FMR1 premutation was detected in six patients (17%) from two different families. A total of 29 patients without FMR1 premutation were included in the SNP array analysis, and one patient had a 337-kb deletion in the chromosome 6q26 region including PARK2 gene, which was thought to be associated with POI. Twenty-nine cases included in SNP array analysis were evaluated simultaneously with WES analysis, and genetic variant was detected in 55.1% (16/29). CONCLUSION: In the present study, rare novel variants were identified in genes known to be associated with POI, which contribute to the mutation spectrum. The effects of detected novel genes and variations on different pathways such as gonadal development, meiosis and DNA repair, or metabolism need to be investigated by experimental studies. Molecular etiology allows accurate genetic counseling to the patient and family as well as fertility planning.

When do we need to suspect maturity onset diabetes of the young in patients with type 2 diabetes mellitus?

OBJECTIVE: Maturity onset diabetes of the young (MODY) patients have clinical heterogeneity as shown by many studies. Thus, often it is misdiagnosed to type 1 or type 2 diabetes(T2DM). The aim of this study is to evaluate MODY mutations in adult T2DM patients suspicious in terms of MODY, and to show clinical and laboratory differences between these two situations. METHODS: In this study, we analyzed 72 type 2 diabetic patients and their relatives (35F/37M) who had been suspected for MODY and referred to genetic department for mutation analysis. The gene mutations for MODY have been assessed in the laboratory of Marmara University genetics. Totally 67 (32F/35M; median age 36.1) diabetic patients were analyzed for 7 MODY mutations. Twelve patients who have uncertain mutation (VUS) were excluded from study for further evaluation. MODY(+) (n:30) patients and T2DM patients (n:25) were compared for clinical and laboratory parameters. RESULTS: In MODY(+) subjects, mutations in GCK (MODY 2) (n:12; 40%) were the most common followed by HNF4A (MODY 1) (n:4; 13.3%). Diabetes diagnosis age was younger in MODY(+) group but not statistically significant. Sixty-six percent of MODY(+) subjects had diabetes history at 3-consecutive generations in their family compared with 28% of T2DM patients statistically significant (p:0.006). Gender, BMI, C-peptide, HbA1c, lipid parameters, creatinine, GFR, microalbuminuria, vitamin D and calcium were not statistically different between the groups. CONCLUSION: According to present study results, MODY mutation positivity is most probable in young autoantibody (-) diabetic patients diagnosed before 30 years of age, who have first degree family history of diabetes.

Effects of vitamin D receptor gene polymorphisms on the prognosis of COVID-19.

PURPOSE: Vitamin D deficiency has emerged as another potential risk factor for coronavirus disease (COVID-19) due to the immunomodulatory effects of 25 hydroxyvitamin D [25 (OH)D]. Vitamin D receptor (VDR) gene polymorphisms such as Fok I, Bsm I, Apa I, and Taq I are also associated with different courses of viral infections. This study aimed to evaluate the association between the VDR gene polymorphism at Fok I, Taq I, Bsm I, and Apa I genotypes and the prognosis of COVID-19 in respect to vitamin D deficiency. METHODS: Two-hundred ninety-seven patients with COVID-19 were enrolled. Serum 25 (OH)D levels were measured. Four variant regions of the VDR gene, FokI, BsmI, ApaI, and TaqI were determined. RESULTS: Eighty-three percent of subjects had vitamin D deficiency, and 40.7% of the whole group had severe deficiency. Median 25 (OH)D level was 11.97 ng/ml. Vitamin D levels were not related to inflammatory markers, disease severity, admission to intensive care unit (ICU), and mortality. While disease severity was related to Fok I Ff genotype, it was Taq TT genotype for ICU admission. Moreover, the ApaI aa genotype was common among the patients who were died. None of the deceased subjects had the Fok I FF genotype. CONCLUSION: 25 (OH)D levels were not related to the severity and mortality of COVID-19. VDR gene polymorphisms are independently associated with the severity of COVID-19 and the survival of patients.

Instructors' presence in instructional videos: A systematic review.

The discussion about how to present instructors in instructional videos has become a hot topic in recent years. This systematic review explores how the instructors' presence affects affective, cognitive, and social aspects of learning in different conditions and with different video types. The review analyses 41 empirical studies indexed in Web of Science, ERIC, Scopus, and Education Source research databases from 2014 to 2022. The results indicated that (i) many instructor-present videos were in picture-in-picture format and included direct gaze as a social cue, (ii) learners had positive feelings for instructor-present videos, (iii) the on-screen instructor could not be beneficial for gathering positive learning outcomes, but social and attentional cues provided by the on-screen instructor could foster learning, and (iv) findings regarding the social aspect of learning were inconclusive. This study also emphasizes the need for further studies to clearly explore the role of the instructor in different learning conditions. Supplementary information: The online version contains supplementary material available at 10.1007/s10639-022-11532-4.

Genetic and Clinical Characterization of Patients with Maturity-Onset of Diabetes of the Young (MODY): Identification of Novel Variations.

BACKGROUND: Maturity-onset diabetes of the young (MODY) is a rare monogenic type of diabetes, and accounts for 2-5% of all diabetes cases. An early age of onset, a family history supporting autosomaldominant inheritance, insulin resistance, and the absence of autoimmunity are the major characteristics of MODY. However, genetic testing is crucial for diagnosis. AIMS: To investigate the 7 MODY-related genes and clinical findings of patients with a preliminary clinical diagnosis of MODY. STUDY DESIGN: Retrospective cross-sectional study. METHODS: In this study, 7 genes (KCNJ11, ABCC8, INS, GCK, HNF4A, HNF1A, and HNF1B) related to MODY were screened via targeted sequencing in 182 cases with a confirmed pre-diagnosis of MODY. The clinical characteristics of the patients were evaluated retrospectively. RESULTS: A total of 182 patients, 48% of whom were women, between the ages of 18-62 were included in the study. In 30 cases (16.4%), 28 different pathogenic variations were found, of which 20 were previously reported and 8 were novel variations segregated by disease within the family. Pathogenic variations were detected in the following genes in order of mutation frequency; GCK, HNF1A, ABCC8, HNF4A, HNF1B and KCNJ11. Interestingly, six of the 30 cases (20%) carried a pathogenic variation in the ABCC8 gene. No mutation was detected in the INS gene. A family history of vertically transmitted diabetes and elevated HbA1C at the time of diagnosis were found in 20 (66%) and 16 (52%) cases, respectively. CONCLUSION: In this series, 28 different pathogenic variations are identified, 8 of which are novel. The rate of pathogenic variation in the ABCC8 gene is unexpectedly high. Two-thirds of cases have a family history of vertically transmitted diabetes.

Secondary findings in 622 Turkish clinical exome sequencing data.

CES (Clinical Exome Sequencing) is a method that we use to diagnose rare diseases with nonspesific clinical features. Besides primary indication for testing genetic information may be detected about diseases which have not yet emerged. ACMG guidelines recommend to report pathogenic variations in medically actionable 59 genes. In this study we evaluated CES data of 622 cases which were tested for various indications. According to ACMG recommendations 59 genes were screened for reportable variations. The detected variations were reviewed using distinct databases and ACMG variation classification guidelines. Among 622 cases 13 (2.1%) had reportable variations including oncogenetic, cardiogenetic disorders, and malignant hyperthermia susceptibility-related genes. In 15 cases (2.4%) heterozygous pathogenic and likely pathogenic variations were detected in genes showing autosomal recessive inheritance. Ten novel variations causing truncated protein or splicing defect were reported. We detected 11 variations having conflicting interpretations in databases and 30 novel variations, predicted as likely pathogenic via insilico analysis tools which further evaluations are needed. As to our knowledge this is the first study investigating secondary findings in Turkish population. To extract the information that may lead to prevent severe morbidities and mortalities from big data is a valuable and lifesaving effort. Results of this study will contrbute to existing knowledge about secondary findings in exome sequencing and will be a pioneer for studies in Turkish population.

Thermal properties of rung-disordered two-leg quantum spin ladders: Quantum Monte Carlo study.

A two-leg quenched random bond disordered antiferromagnetic spin-1/2 Heisenberg ladder system is investigated by means of stochastic series expansion quantum Monte Carlo (QMC) method. Thermal properties of the uniform and staggered susceptibilities, the structure factor, the specific heat, and the spin gap are calculated over a large number of random realizations in a wide range of disorder strength. According to our QMC simulation results, the considered system has a special temperature point at which the specific heat takes the same value regardless of the strength of the disorder. Moreover, the uniform susceptibility is shown to display the same character except for a small difference in the location of the special point. Finally, the spin gap values are found to decrease with increasing disorder parameter and the smallest gap value found in this study is well above the weak coupling limit of the clean case.

Dynamic hysteretic features of Ising-type thin films.

In order to elucidate the nature of hysteresis characteristics in a magnetic Ising-type thin film with a certain thickness, such as types of frequency dispersion curves, decay of hysteresis loop area, corresponding coercive field and remanent magnetization values, etc., we investigate the hysteretic response of each layer within effective-field theory. Throughout the analysis, the best appropriate parameter values are chosen since they would allow us to observe the reversed magnetic hysteresis after a certain value of external field frequency. This eccentric phenomenon has prompted us to associate it to the domain nucleation and growth mechanism in the dynamic process. Exotic shapes of the response for different layer indices in two different regimes of modified surface exchange are particularly emphasized.

Dynamic phase transition properties and hysteretic behavior of a ferrimagnetic core-shell nanoparticle in the presence of a time dependent magnetic field.

We have presented dynamic phase transition features and stationary-state behavior of a ferrimagnetic small nanoparticle system with a core-shell structure. By means of detailed Monte Carlo simulations, a complete picture of the phase diagrams and magnetization profiles has been presented and the conditions for the occurrence of a compensation point T(comp) in the system have been investigated. According to Néel nomenclature, the magnetization curves of the particle have been found to obey P-type, N-type and Q-type classification schemes under certain conditions. Much effort has been devoted to investigating the hysteretic response of the particle, and we observed the existence of triple hysteresis loop behavior, which originates from the existence of a weak ferromagnetic core coupling J(c)/J(sh), as well as a strong antiferromagnetic interface exchange interaction J(int)/J(sh). Most of the calculations have been performed for a particle in the presence of oscillating fields of very high frequencies and high amplitudes in comparison with exchange interactions, which resembles a magnetic system under the influence of ultrafast switching fields. Particular attention has also been paid to the influence of the particle size on the thermal and magnetic properties, as well as magnetic features such as coercivity, remanence and the compensation temperature of the particle. We have found that, in the presence of ultrafast switching fields, the particle may exhibit a dynamic phase transition from paramagnetic to a dynamically ordered phase with increasing ferromagnetic shell thickness.

Nonequilibrium phase transitions and stationary-state solutions of a three-dimensional random-field Ising model under a time-dependent periodic external field.

Nonequilibrium behavior and dynamic phase-transition properties of a kinetic Ising model under the influence of periodically oscillating random fields have been analyzed within the framework of effective-field theory based on a decoupling approximation. A dynamic equation of motion has been solved for a simple-cubic lattice (q=6) by utilizing a Glauber-type stochastic process. Amplitude of the sinusoidally oscillating magnetic field is randomly distributed on the lattice sites according to bimodal and trimodal distribution functions. For a bimodal type of amplitude distribution, it is found in the high-frequency regime that the dynamic phase diagrams of the system in the temperature versus field amplitude plane resemble the corresponding phase diagrams of the pure kinetic Ising model. Our numerical results indicate that for a bimodal distribution, both in the low- and high-frequency regimes, the dynamic phase diagrams always exhibit a coexistence region in which the stationary state (ferro or para) of the system is completely dependent on the initial conditions, whereas for a trimodal distribution, the coexistence region disappears depending on the values of the system parameters.

Effective-field-theory analysis of the three-dimensional random-field Ising model on isometric lattices.

An Ising model with quenched random magnetic fields is examined for single-Gaussian, bimodal, and double-Gaussian random-field distributions by introducing an effective-field approximation that takes into account the correlations between different spins that emerge when expanding the identities. Random-field distribution shape dependencies of the phase diagrams and magnetization curves are investigated for simple cubic, body-centered-cubic, and face-centered-cubic lattices. The conditions for the occurrence of reentrant behavior and tricritical points on the system are also discussed in detail.