The Genetics of Adverse Drug Outcomes in Type 2 Diabetes:A Systematic Review

Background: Adverse drug reactions (ADR) are a major clinical problem accounting for significant hospital admission rates, morbidity, mortality, and health care costs. One-third of people with diabetes experience at least one ADR. However, there is notable interindividual heterogeneity resulting in patient harm and unnecessary medical costs. Genomics is at the forefront of research to understand interindividual variability, and there are many genotype-drug response associations in diabetes with inconsistent findings. Here, we conducted a systematic review to comprehensively examine and synthesize the effect of genetic polymorphisms on the incidence of ADRs of oral glucose-lowering drugs in people with type 2 diabetes. Methods: A literature search was made to identify articles that included specific results of research on genetic polymorphism and adverse effects associated with oral glucose-lowering drugs. The electronic search was carried out on 3rd October 2020, through Cochrane Library, PubMed, and Web of Science using keywords and MeSH terms. Result: Eighteen articles consisting of 10, 383 subjects were included in this review. Carriers of reduced-function alleles of organic cation transporter 1 (OCT 1, encoded by SLC22A1) or reduced expression alleles of plasma membrane monoamine transporter (PMAT, encoded by SLC29A4) or serotonin transporter (SERT, encoded by SLC6A4) were associated with increased incidence of metformin-related gastrointestinal (GI) adverse effects. These effects were shown to exacerbate by concomitant treatment with gut transporter inhibiting drugs. The CYP2C9 alleles, (*)2 (rs1799853C>T) and (*)3 (rs1057910A>C) that are predictive of low enzyme activity were more common in subjects who experienced hypoglycemia after treatment with sulfonylureas. However, there was no significant association between sulfonylurea-related hypoglycemia and genetic variants in the ATP-binding cassette transporter sub-family C member 8 (ABCC8)/Potassium Inwardly Rectifying Channel Subfamily J Member 11 (KCNJ11). Compared to the wild type, the low enzyme activity C allele at CYP2C8(*)3 (rs1057910A>C) was associated with less weight gain whereas the C allele at rs6123045 in the NFATC2 gene was significantly associated with edema from rosiglitazone treatment. Conclusion: In spite of limited studies investigating genetics and ADR in diabetes, some convincing results are emerging. Genetic variants in genes encoding drug transporters and metabolizing enzymes are implicated in metformin-related GI adverse effects, and sulfonylurea-induced hypoglycemia, respectively. Further studies to investigate newer antidiabetic drugs such as DPP-4i, GLP-1RA, and SGLT2i are warranted. In addition, pharmacogenetic studies that account for race and ethnic differences are required

Revisiting Epidermal Growth Factor Receptor (EGFR) Amplification as a Target for Anti-EGFR Therapy: Analysis of Cell-Free Circulating Tumor DNA in Patients With Advanced Malignancies.

PurposeTo date, evidence for tissue epidermal growth factor receptor (EGFR) overexpression as a biomarker for anti-EGFR therapies has been weak. We investigated the genomic landscape of EGFR amplification in blood-derived cell-free tumor DNA (cfDNA) across diverse cancers and the role of anti-EGFR therapies in achieving response.MethodsWe assessed EGFR amplification status among 28,584 patients with malignancies evaluated by clinical-grade next-generation sequencing (NGS) of blood-derived cfDNA (54- to 73-gene panel). Furthermore, we curated the clinical characteristics of 1,434 patients at the University of California San Diego who had cfDNA testing by this NGS test.ResultsOverall, EGFR amplification was detected in cfDNA from 8.5% of patients (2,423 of 28,584), most commonly in colorectal (16.3% [458 of 2,807]), non-small-cell lung (9.0% [1,096 of 12,197]), and genitourinary cancers (8.1% [170 of 2,104]). Most patients had genomic coalterations (96.9% [95 of 98]), frequently involving genes affecting other tyrosine kinases (72.4% [71 of 98]), mitogen-activated protein kinase cascades (56.1% [55 of 98]), cell-cycle-associated signals (52.0% [51 of 98]), and the phosphoinositide 3-kinase pathway (35.7% [35 of 98]). EGFR amplification emerged in serial cfDNA after various anticancer therapies (n = 6), including checkpoint inhibitors (n = 4), suggesting a possible role for these amplifications in acquired resistance. Nine evaluable patients with EGFR amplification were treated with anti-EGFR-based regimens; five (55.6%) achieved partial responses, including three patients whose tissue NGS lacked EGFR amplification.ConclusionEGFR amplification was detected in cfDNA among 8.5% of 28,584 diverse cancers. Most patients had coexisting alterations. Responses were observed in five of nine patients who received EGFR inhibitors. Incorporating EGFR inhibitors into the treatment regimens of patients harboring EGFR amplification in cfDNA merits additional study

Engineering properties and microstructure of a sustainable roof tile manufactured with waste rice husk ash and ceramic sludge addition

Clay replacement with waste rice husk ash (RHA) and ceramic sludge (CS), helps to reduce the consumption of natural clay and solves the ecological issues created by waste disposal. In this study, properties of waste RHA and CS added fired clay tile were investigated, focusing on structural, durability, thermal performance as well as the water quality of the harvested run-off from fired clay roof tiles manufactured in an industrial scale plant. Tiles were cast by clay replacement with waste RHA and CS in four mixtures: 10 %RHA and 0 % CS, 10 % RHA and 10 % CS, 10 % RHA and 15 % CS, and 10 % RHA and 20 % CS (by weight). For 10 %RHA and 10 %CS tiles, dry mass was reduced by 4.9 %, compared with conventional roof tiles, promising a light weight roof tile. Roof tiles with 10 % RHA and 10 %CS showed a transverse breaking load of 1519 N, whereas that of 20 %CS tiles showed 1427 N, indicating that a further 6.5 % strength improvement can be achieved with clay replacement with a combination of two waste materials. Clay replacement with 10 % RHA and 10 % CS resulted in water absorption of 15.25 %. When increasing the clay replacement with combined waste from 10% (10 %RHA and 0%CS) to 30 % (10%RHA and 20 %CS), weight gain due to acid and alkaline attacks reduced from 3.5% to 3.0%, and from 2.2 % to 1.6 %, respectively, indicating enhanced durability performance by incorporating combined waste. High porosity, also confirmed by SEM, contributed to enhanced thermal performance: tile with 10 % RHA and 10 % CS achieved 4.4 °C temperature reduction, compared to the conventional tile. pH value and total solid concentration of run-off water were in the range of recommended values of water for agricultural purposes, ensuring that the collected run-off can be utilized as an alternative water source for potable activities.publishedVersio

Results of the alcohol septal ablation in combination with simultaneous endoprosthesis of coronary arteries in treatment of patients, suffering obstructive hypertrophic cardiomyopathy and concurrent ischemic heart disease

Objective. To study the immediate and remote follow-up results of treatment in patients, suffering obstructive hypertrophic cardiomyopathy and concurrent ischemic heart disease, using the alcohol septal ablation in combination with simultaneous endoprosthesis of coronary arteries. Materials and methods. In the investigation were included 129 patients, suffering obstructive hypertrophic cardiomyopathy, to whom the alcohol septal ablation was performed in 2009 - 2018 yrs in M. M. Amosov National Institute of Cardiovascular Surgery. All the patients were distributed into two groups: the first -14 (10.9%) patients with concurrent ischemic heart disease and the second -115 (89.1%) patients without concurrent ischemic heart disease. Results. Reduction of the systolic pressure gradient in the exit tract of the left ventriculus, mitral regurgitation, and the functional class characteristic in accordance to criteria of a New-York Association of Cardiologists in both groups in immediate and late periods of observation have appeared statistically proved. In a remote period of follow-up in 13 (92.9%) patients, suffering the ischemic heart disease, a satisfactory hemodynamical result was registered, and in 1 (7.1%) - poor. Conditionally poor results in this group of patients were absent. The patients without an ischemic heart disease (n=107) in accordance to the above mentioned indices were distributed in a follow manner: 74 (69.2%), 28 (26.2%) and 5 (4.7%), accordingly. Statistically significant difference in accordance to hemodynamical results between two groups of patients was absent in immediate and remote periods of follow-up. Conclusion. Simultaneous conduction of the alcohol septal ablation in combination with endoprosthesis of coronary arteries in patients, suffering obstructive hypertrophic cardiomyopathy and concurrent ischemic heart disease, constitutes a safe proved combined intervention procedure, which owes good immediate results, persisting in the remote period

Prevalence of Plasmodium falciparum infection among pregnant women at first antenatal visit in post-Ebola Monrovia, Liberia

Background: Disruption of malaria control strategies during the West African 2014–2016 Ebola epidemic led to an increase in malaria-attributable mortality. However, recent data on malaria infection in vulnerable groups, such as pregnant women, are lacking in this post-Ebola scenario. This cross-sectional study aimed to assess the prevalence of Plasmodium falciparum infection and of molecular markers of drug resistance among pregnant women attending antenatal care in Monrovia, capital of Liberia. Methods: From October 2016 to June 2017, all pregnant women attending their frst antenatal care visit at the Saint Joseph’s Catholic Hospital, Monrovia, were invited to participate in the study. In addition to their routine antenatal care tests, capillary blood spotted onto flter papers were collected from all consenting participants to determine presence of P. falciparum by real-time quantitative PCR. Molecular markers of anti-malarial drug resistance were assessed through Sanger sequencing and quantitative PCR in specimens positive for P. falciparum analysis. Results: Of the 195 women participants, 24 (12.3%) were P. falciparum-positive by qPCR. Infected women tended to be more commonly primigravidae and younger than uninfected ones. Parasite densities were higher in primigravidae. Fever was more frequently detected among the infected women. No statistically signifcant association between P. falciparum infection and haemoglobin levels or insecticide-treated net use was found. While high prevalence of genetic polymorphisms associated with chloroquine and amodiaquine resistance were detected, no molecular markers of artemisinin resistance were observed. Conclusion: Plasmodium falciparum infections are expected to occur in at least one in every eight women attending frst ANC at private clinics in Monrovia and outside the peak of the rainy season. Young primigravidae are at increased risk of P. falciparum infection. Molecular analyses did not provide evidence of resistance to artemisinins among the P. falciparum isolates tested. Further epidemiological studies involving pregnant women are necessary to describe the risk of malaria in this highly susceptible group outside Monrovia, as well as to closely monitor the emergence of resist‑ ance to anti-malarials, as recommended by the Liberian National Malaria Control Programme