Impact of Genetic Variations on Thromboembolic Risk in Saudis with Sickle Cell Disease.

BACKGROUND: Sickle cell disease (SCD) is a Mendelian disease characterized by multigenic phenotypes. Previous reports indicated a higher rate of thromboembolic events (TEEs) in SCD patients. A number of candidate polymorphisms in certain genes (e.g., FVL, PRT, and MTHFR) were previously reported as risk factors for TEEs in different clinical conditions. This study aimed to genotype these genes and other loci predicted to underlie TEEs in SCD patients. METHODOLOGY: A multi-center genome-wide association study (GWAS) involving Saudi SCD adult patients with a history of TEEs (n = 65) and control patients without TEE history (n = 285) was performed. Genotyping used the 10× Affymetrix Axiom array, which includes 683,030 markers. Fisher's exact test was used to generate p-values of TEE associations with each single-nucleotide polymorphism (SNP). The haplotype analysis software tool version 1.05, designed by the University of Göttingen, Germany, was used to identify the common inherited haplotypes. RESULTS: No association was identified between the targeted single-nucleotide polymorphism rs1801133 in MTHFR and TEEs in SCD (p = 0.79). The allele frequency of rs6025 in FVL and rs1799963 in PRT in our cohort was extremely low (<0.01); thus, both variants were excluded from the analysis as no meaningful comparison was possible. In contrast, the GWAS analysis showed novel genome-wide associations (p < 5 × 10-8) with seven signals; five of them were located on Chr 11 (rs35390334, rs331532, rs317777, rs147062602, and rs372091), one SNP on Chr 20 (rs139341092), and another on Chr 9 (rs76076035). The other 34 SNPs located on known genes were also detected at a signal threshold of p < 5 × 10-6. Seven of the identified variants are located in olfactory receptor family 51 genes (OR51B5, OR51V1, OR51A1P, and OR51E2), and five variants were related to family 52 genes (OR52A5, OR52K1, OR52K2, and OR52T1P). The previously reported association between rs5006884-A in OR51B5 and fetal hemoglobin (HbF) levels was confirmed in our study, which showed significantly lower levels of HbF (p = 0.002) and less allele frequency (p = 0.003) in the TEE cases than in the controls. The assessment of the haplotype inheritance pattern involved the top ten significant markers with no LD (rs353988334, rs317777, rs14788626882, rs49188823, rs139349992, rs76076035, rs73395847, rs1368823, rs8888834548, and rs1455957). A haplotype analysis revealed significant associations between two haplotypes (a risk, TT-AA-del-AA-ins-CT-TT-CC-CC-AA, and a reverse protective, CC-GG-ins-GG-del-TT-CC-TT-GG-GG) and TEEs in SCD (p = 0.024, OR = 6.16, CI = 1.34-28.24, and p = 0.019, OR = 0.33, CI = 0.13-0.85, respectively). CONCLUSIONS: Seven markers showed novel genome-wide associations; two of them were exonic variants (rs317777 in OLFM5P and rs147062602 in OR51B5), and less significant associations (p < 5 × 10-6) were identified for 34 other variants in known genes with TEEs in SCD. Moreover, two 10-SNP common haplotypes were determined with contradictory effects. Further replication of these findings is needed.

Impact of telemedicine on glycemic control in type 2 diabetes mellitus during the COVID-19 lockdown period.

Background: The lockdown at the start of coronavirus disease 2019 (COVID-19) pandemic in Saudi Arabia (March 2020 to June 2020) shifted routine in-person care for patients with type 2 diabetes mellitus (T2DM) to telemedicine. The aim of this study was to investigate the impact telemedicine had during this period on glycemic control (HbA1c) in patients with T2DM. Methods: 4,266 patients with T2DM were screened from five Ministry of National Guard Health Affairs hospitals in the Kingdom of Saudi Arabia. Age, gender, body mass index (BMI), HbA1c (before and after the COVID-19 lockdown), duration of T2DM, comorbidities and antidiabetic medications data were obtained. Mean and standard deviation of differences in HbA1c were calculated to assess the impact of telemedicine intervention. Correlations between clinically significant variances (when change in the level is ≥0.5%) in HbA1c with demographics and clinical characteristic data were determined using chi square test. Results: Most of the participants were Saudis (97.7%) with 59.7% female and 56.4% ≥60 years of age. Obesity was 63.8%, dyslipidemia 91%, and hypertension 70%. Mean HbA1c of all patients slightly rose from 8.52% ± 1.5% before lockdown to 8.68% ± 1.6% after lockdown. There were n=1,064 patients (24.9%) whose HbA1c decreased by ≥0.5%, n =1,574 patients whose HbA1c increased by ≥0.5% (36.9%), and n =1,628 patients whose HbA1c changed by <0.5% in either direction (38.2%). More males had significant improvements in glycemia compared to females (28.1% vs 22.8%, p<0.0001), as were individuals below the age of 60 years (28.1% vs 22.5%, p<0.0001). Hypertensive individuals were less likely than non-hypertensive to have glycemic improvement (23.7% vs 27.9%, p=0.015). More patients on sulfonylureas had improvements in HbA1c (42.3% vs 37.9%, p=0.032), whereas patients on insulin had higher HbA1c (62.7% vs 56.2%, p=0.001). HbA1c changes were independent of BMI, duration of disease, hyperlipidemia, heart and kidney diseases. Conclusion: Telemedicine was helpful in delivering care to T2DM patients during COVID-19 lockdown, with 63.1% of patients maintaining HbA1c and improving glycemia. More males than females showed improvements. However, the HbA1c levels in this cohort of patients pre- and post-lockdown were unsatisfactorily high, and may be due to in part lifestyle, age, education, and hypertension.

Pharmacogenes that demonstrate high association evidence according to CPIC, DPWG, and PharmGKB.

Background: Different levels of evidence related to the variable responses of individuals to drug treatment have been reported in various pharmacogenomic (PGx) databases. Identification of gene-drug pairs with strong association evidence can be helpful in prioritizing the implementation of PGx guidelines and focusing on a gene panel. This study aimed to determine the pharmacogenes with the highest evidence-based association and to indicate their involvement in drug-gene interactions. Methodology: The publicly available datasets CPIC, DPWG, and PharmGKB were selected to determine the pharmacogenes with the highest drug outcome associations. The upper two levels of evidence rated by the three scoring methods were specified (levels A-B in CPIC, 3-4 in DPWG, or 1-2 levels in PharmGKB). The identified pharmacogenes were further ranked in this study based on the number of medications they interacted with. Results: Fifty pharmacogenes, with high to moderately high evidence of associations with drug response alterations, with potential influence on the therapeutic and/or toxicity outcomes of 152 drugs were identified. CYP2D6, CYP2C9, CYP2C19, G6PD, HLA-B, SLCO1B1, CACNA1S, RYR1, MT-RNR1, and IFNL4 are the top 10 pharmacogenes, where each is predicted to impact patients' responses to ≥5 drugs. Conclusion: This study identified the most important pharmacogenes based on the highest-ranked association evidence and their frequency of involvement in affecting multiple drugs. The obtained data is useful for customizing a gene panel for PGx testing. Identifying the strength of scientific evidence supporting drug-gene interactions aids drug prescribers in making the best clinical decision.

Elevated plasma level of the glycolysis byproduct methylglyoxal on admission is an independent biomarker of mortality in ICU COVID-19 patients.

Biomarkers to identify ICU COVID-19 patients at high risk for mortality are urgently needed for therapeutic care and management. Here we found plasma levels of the glycolysis byproduct methylglyoxal (MG) were 4.4-fold higher in ICU patients upon admission that later died (n = 33), and 1.7-fold higher in ICU patients that survived (n = 32),compared to uninfected controls (n = 30). The increased MG in patients that died correlated inversely with the levels of the MG-degrading enzyme glyoxalase-1 (r2 = - 0.50), and its co-factor glutathione (r2 = - 0.63), and positively with monocytes (r2 = 0.29). The inflammation markers, SSAO (r2 = 0.52), TNF-α (r2 = 0.41), IL-1ß (r2 = 0.25), CRP (r2 = 0.26) also correlated positively with MG. Logistic regression analysis provides evidence of a significant relationship between the elevated MG upon admission into ICU and death (P < 0.0001), with 42% of the death variability explained. From these data we conclude that elevated plasma MG on admission is a novel independent biomarker that predicts mortality in ICU COVID-19 patients.

Elderly people are inherently sensitive to the pharmacological activity of rivaroxaban: implications for DOAC prescribing.

According to both trial and clinical data on direct oral anticoagulants (DOACs) elderly patients are at greatest risk of bleeding. It is unclear whether age intrinsically affects anticoagulation response. To investigate the age-related sensitivity to DOACs, we compared the pharmacological activity of the direct factor Xa inhibitor, rivaroxaban, between young and elderly subjects ex-vivo. 36 fit elderly and 30 fit young subjects [median (IQR) age: 83(75-87) vs 30(26-38) years] provided a blood sample. Clotting parameters were measured in the resultant plasma samples incubated with rivaroxaban (100-500 ng/ml). Parametric, non-parametric tests and regression lines adjusted for rivaroxaban concentration and baseline values were used to compare data. Rivaroxaban produced a greater prolongation of both Prothrombin Time (PT) and modified Prothrombin Time (mPT) (both p < 0.001) in the elderly compared to young subjects (with difference in mean PT increasing from 1.6 to 6.1s and for mPT from 23.5 to 71.1s at 100 ng/ml and 500 ng/ml plasma rivaroxaban concentration, respectively). Factor X and factor II activity was significantly lower in the elderly in the presence of rivaroxaban (p < 0.001 for both). Rivaroxaban prolonged time-based parameters and suppressed the amount of thrombin generation to a significantly greater extent in the elderly compared to young subjects [%change from baseline for Endogenous Thrombin Potential (ETP): - 35.0 ± 4.4 vs - 29.8 ± 7.4 nM*min; p = 0.002]. The use of validated DOAC assays will be of considerable benefit for monitoring elderly patients who, because of their increased sensitivity to rivaroxaban, may require lower doses of the drug for therapeutic anticoagulation.

The Coronaviruses of Animals and Birds: Their Zoonosis, Vaccines, and Models for SARS-CoV and SARS-CoV2.

The viruses of the family Coronaviridae are ubiquitous in nature due to their existence in a wide spectrum of mammals and avian species. The coronaviruses, as RNA viruses, exist as quasispecies because of their high rate of mutations. This review elaborates on the pathogenesis and the developed vaccines of most of the ubiquitous coronavirus' diseases, mainly bovine, dromedary camel, porcine, feline, canine, and avian coronaviruses. The review emphasizes the significant setbacks in the full exploitation of most of the pathogenesis of the coronavirus' diseases, raising the prospect of effective vaccines for these diseases. The therapeutical trials for the treatment of SARS-CoV2 and the setbacks of these trials are also addressed. The review draws attention to the lessons accumulated from the large number of studies of the pathogenesis of animals and birds' coronaviruses and their vaccines, particularly the bovine, feline, and avian coronaviruses. The lessons drawn from the studies will have an immense influence on how the human coronaviruses pathogenesis and vaccine development will proceed. In addition, the extensive efforts to designate suitable animal models to study the lately emerged human coronaviruses are one of the invaluable contributions carried out by veterinarian scientists. Finally, factors and determinants that contribute to the possibility of emerging new coronavirus zoonotic disease are elaborated on and a call goes out to urge transdisciplinary collaboration in the implementation of the "One Health" concept.

Effect of genetic and patient factors on warfarin pharmacodynamics following warfarin withdrawal: Implications for patients undergoing surgery.

INTRODUCTION: Warfarin therapy is stopped for a fixed period prior to surgery to minimise risk of perioperative bleeding. However, anticoagulation subsides at varying rates among different patients. We evaluated the influence of genetic (CYP2C9 and VKORC1), patient and clinical factors on warfarin clearance and the decline in INR following warfarin withdrawal. MATERIALS AND METHODS: 131 patients completing a course of warfarin provided blood samples over 9 days for initial genotyping, and measurement of INR and plasma warfarin enantiomer concentrations. RESULTS: S-warfarin clearance was significantly lower in patients with either CYP2C9 single (*2 or *3) or double (*2*2 or *2*3) variant alleles compared to those with wild-type genotype (P < 0.001). Regression analysis revealed that patient age (P = 0.037) and CYP2C9 *2*2 & *2*3 genotype (P = 0.005), but not VKORC1 genotype, significantly affected the time taken for the resumption of normal coagulation (INR value declining to ≤1.5). CONCLUSIONS: The inter-individual variability in the time needed for normal coagulation to resume following warfarin withdrawal is influenced, in the main, by variance in S-warfarin clearance, which in turn is affected by CYP2C9 polymorphism and age. Cost-effectiveness of pharmacogenetics-based algorithms incorporating CYP2C9 genotype and patient age could be increased if used not only to guide dosing decisions but also estimation of the correct length of time needed for individual patients to stop taking warfarin prior to surgery.

Individual and monitoring centre influences upon anticoagulation control of AF patients on warfarin: A longitudinal multi-centre UK-based study.

OBJECTIVES: Time within therapeutic INR range (TTR) predicts benefits/risk of warfarin therapy. Identification of individual- and centre-related factors that influence TTR, and addressing them to improve anticoagulation control, are important. This study examined the impact of individual and centre-related factors upon long-term anticoagulation control in atrial fibrillation patients in seven UK-based monitoring services. METHODS: Data between 2000 and 2014 on 25 270 patients (equating to 203 220 patient years) [18 120 (71.7%) in general practice, 2348 (9.3%) in hospital-based clinics and 4802 (19.0%) in domiciliary service] were analysed. RESULTS: TTR increased with increasing age, peaking around 77% at 70-75 years, and then declined, was lower in females than males, and in dependent home-monitored patients than those attending clinic (P < 0.0001). TTR, number of dose changes and INR monitoring events and the probability of TTR ≤ 65%, differed across the centres (P < 0.0001). CONCLUSIONS: Although all the participating centres ostensively followed a standard dosing algorithm, our results indicate that variations in practice do occur between different monitoring sites. We suggest feedback on TTR for individual monitoring sites gauged against the average values reported by others would empower the individual centres to improve quality outcomes of anticoagulation therapy by identifying and adjusting contributory factors within their management system.

Impact of age on long-term anticoagulation and how gender and monitoring setting affect it: implications for decision making and patient management.

AIMS: Stabilization of anticoagulation control is seminal to reducing the risk of adverse effects of vitamin K antagonists. Reliable information on how ageing influences this is lacking. We set out to assess the true age-related changes in anticoagulation control, how gender and patient setting influence this, and the possible implications of these for patient outcomes and management. METHODS: In atrial fibrillation (AF) patients of a unified anticoagulant service monitoring patients in general practice or hospital-based clinics and housebound patients at home, international normalized ratio (INR) and warfarin dose data between 2000 and 2013 were extracted via the DAWN dosing program. Anticoagulation control was assessed by calculating percentage time spent within target INR (TTR). RESULTS: A total of 2094 AF patients [938 (44.8%) in general practice (GP) and 531 (25.4%) in hospital (H)-based clinics and 625 (29.8%) through the domiciliary service (D)] were evaluated. The frequency of warfarin dose changes and INR monitoring events declined until about age 67, then increased as patients got older. The TTR according to age was significantly lower and the probability of having a TTR ≤65% according to age was higher for D than for H and GP, and females had a greater probability of having a TTR ≤65% than age-matched males. CONCLUSION: Identification of factors underlying poorer anticoagulation control in older housebound patients and the introduction of effective modifications to improve the clinical effectiveness of anticoagulation in such patients is needed.

The impact of genetics on the management of patients on warfarin awaiting surgery.

Two older patients with atrial fibrillation, receiving warfarin for thromboembolic prophylaxis, with a target range of 2.0-3.0, were significantly over anticoagulated prior to elective intervention, in spite of having adhered to the standard protocol of 5 days of warfarin interruption. Neither patient had any abnormality of liver function nor was taking any interacting drug known to inhibit warfarin metabolism or affect sensitivity to warfarin. Both had variant cytochrome P2C9 (CYP2C9) alleles which reduce the metabolic capacity of the CYP2C9 enzyme responsible for the metabolism of the S-warfarin enantiomer. Need for preoperative administration of vitamin K or postponement of an operation because of an INR >1.5 could be explained by variant alleles for CYP2C9 and age.

Anticoagulation control and cost of monitoring of older patients on chronic warfarin therapy in three settings in North East England.

BACKGROUND: novel oral anticoagulants may be particularly cost-effective when INR control (TTR) with warfarin is poor or monitoring difficult. SETTING: the Newcastle upon Tyne monitoring service, set in hospital or general practice and a domiciliary-based service for housebound patients. OBJECTIVES: to examine anticoagulation stability and costs of monitoring. SUBJECTS: three hundred and twenty-six atrial fibrillation patients, 75 years and over, with target INR of two to three, accessing hospital (n = 100), general practice (n = 122) and domiciliary (n = 104) service. METHODS: age, co-morbidities, length of warfarin treatment, medications, INR values and dose changes from January to December 2011 were recorded, and costs analysed. RESULTS: home-monitored patients had taken warfarin for longer, mean 5.2 years, than hospital (3.7) or general practice (3.1) patients. Age and total number of drugs prescribed chronically were negatively related to TTR. INR measurements and dose changes were negatively associated with the duration of treatment, positively correlated with co-morbidities. The mean TTR was 78% in hospital, 71% in general practice and 68% in domiciliary monitored patients. INR was monitored more often in hospital and domiciliary groups than in general practice and more dose changes occurred in the domiciliary group than in others. Costs of warfarin and monitoring were £128 per patient per year for hospital, £126 for general practice and £222 for domiciliary patients. CONCLUSIONS: further exploration of the clinical effectiveness of novel anticoagulants in dependent patients is warranted to determine to what extent trial outcomes so far achieved in a fitter elderly population are influenced by the chronic co-morbidities of old age.