Do maternal demographics and prenatal history impact the efficacy of betamethasone therapy for threatened preterm labor?

Background Betamethasone (BMZ) is used to accelerate fetal lung maturation in women with threatened preterm birth, but its efficacy is variable and limited by the lack of patient individualization in its dosing and administration. To determine sources of variability and potential opportunities for individualization of therapy, the objective of this study was to evaluate maternal factors associated with development of neonatal respiratory distress syndrome (RDS) in a cohort of women who received betamethasone. Methods This study prospectively enrolled women, gestational ages 23–34 weeks, who received betamethasone for threatened preterm birth. Maternal demographics, prenatal history, and neonatal outcomes were abstracted from hospital records. RDS was the primary outcome. Associations between RDS diagnosis and maternal demographics, prenatal history, and betamethasone dosing were evaluated in a case-control analysis and multivariable regression adjusted for gestational age at delivery. Secondary analyses limited the cohort to women who delivered within 1 or 2 weeks of betamethasone dosing. Results Of 209 deliveries, 90 (43 %) resulted in neonatal RDS. Within the overall cohort and controlling for gestational age at birth, RDS was only associated with cesarean births compared to vaginal births (adjusted OR 1.17 [1.06–1.29]). Route of delivery was also the only significant factor related to RDS in the 83 neonates delivered within 7 days of BMZ dosing. However, among 101 deliveries within 14 days of betamethasone dosing and controlling for gestational age at birth, women who experienced preterm premature rupture of membranes (PPROM) had lower RDS rates than those without PPROM (57.9 % vs. 80.2 %, adjusted OR 0.81 [0.67–0.99]). Maternal age, BMI, race, and ethnicity were not associated with RDS in the regression models. Conclusions Of maternal characteristics analyzed, only delivery by cesarean was associated with neonatal RDS after antenatal betamethasone use.

Dexketoprofen Pharmacokinetics is not Significantly Altered by Genetic Polymorphism

Dexketoprofen is the (S)-(+)-enantiomer of racemic ketoprofen, a nonsteroidal anti-inflammatory drug used for the management of different types of pain. To the best of our knowledge, no article was published to date on dexketoprofen pharmacogenetics. Thence, in this work, we aimed to explore the influence of sex, race and several single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (e.g. CYP or UGT) or transporters (e.g., ABC or SLC) in the pharmacokinetics and safety of dexketoprofen to explore whether dosing adjustments based on genetic polymorphism would be beneficial for its prescription. For this regard, 85 healthy volunteers enrolled in three bioequivalence clinical trials were genotyped for 46 SNPs in 14 genes. Women showed lower AUC adjusted by dose/weight (AUC/DW) and higher Vd/F and Cl/F than men (p < 0.05 in univariate and multivariate analysis). CYP1A2*1B allele, CYP2B6 IM/PM and CYP2D6 IM/PM phenotypes were related to drug accumulation (AUC/DW or Cmax/DW) compared to the CYP1A2*1 allele, CYP2B6 NM/RM and CYP2D6 NM/UM phenotypes (p < 0.05 in the univariate analysis). ABCB1 C1236TT, C3435TT and G2677A/TA/T alleles were related to lower Cmax/DW compared to C, C, and G alleles (p < 0.05 in univariate and multivariate analysis). ABCB1 C1236TT allele was also related to lower AUC/DW (p < 0.05 in multivariate analysis). The remaining studied transporter genes (ABCC2, SLC22A1, and SLCO1B1) and metabolizing enzyme genes (CYP3A5, CYP2C19, CYP2C9, CYP2C8, CYP3A4, CYP2A6, and UGT1A1) were unrelated to dexketoprofen pharmacokinetic variability. We conclude that dexketoprofen pharmacokinetics can be influenced by several polymorphisms, although there is not a clear pharmacogenetic predictor that would justify individualization of therapy based on its genotyping. Further studies should be conducted to confirm the role of SNPs in CYP2B6, CYP2D6, CYP1A2 and ABCB1 on the pharmacokinetic variability of dexketoprofen. Current evidence on dexketoprofen pharmacogenetics does not justify its inclusion in pharmacogenetic guidelines.

Do Maternal Demographics and Prenatal History Impact the Efficacy of Betamethasone Therapy for Threatened Preterm Labor?

Background/Objective: Betamethasone is used to accelerate fetal lung maturation in women with threatened preterm labor, but its efficacy is variable and limited by the lack of patient individualization in its dosing and administration. To determine sources of variability and potential opportunities for individualization of therapy, the objective of this study was to evaluate maternal factors associated with development of neonatal respiratory distress syndrome (RDS) in a cohort of women who received betamethasone. Methods: This study prospectively enrolled women, gestational ages 23-34 weeks, who received betamethasone for threatened preterm labor (n=208). Maternal demographics, prenatal history, and neonatal outcomes were abstracted from Epic and Cerner records. RDS was the primary outcome. Associations between RDS diagnosis and factors such as maternal demographics, prenatal history, and betamethasone dosing were evaluated in a multivariable regression adjusted for gestational age at delivery. A secondary analysis limited the cohort to women who delivered within 2 weeks of betamethasone dosing (n=95). Results: Of 208 deliveries, 44.1% resulted in neonatal RDS. Within the overall cohort, the only significant association with RDS was the type of delivery, with 61.3% of cesarean births resulting in RDS versus 28.7% of vaginal births (adjusted OR 1.17 [1.06-1.28]). Among deliveries within 14 days of betamethasone dosing, women who experienced preterm premature rupture of membranes (PPROM) had lower RDS outcome rates than those without PPROM (52.6% vs. 78.9%, adjusted OR 0.80 [0.65-0.98]). Maternal age, BMI, race, and ethnicity were not associated with RDS. Conclusion: Maternal characteristics alone may not be useful biomarkers in predicting neonatal RDS. The association between PPROM and RDS may suggest the importance of the time frame between betamethasone dosing and delivery. The finding of higher risk for RDS among neonates born by cesarean is consistent with other studies and bears further exploration as betamethasone therapy may mediate the association.

Molecular pathogenesis of heart failure in diabetes mellitus – new direction for the therapeutic approach

As it has been proven, cardiovascular diseases are several times more common in diabetic patients than in the general population. Despite many studies and hypotheses, is still not explained why this happens. Considering the frequent coexistence of cardiovascular risk factors with diabetes, the identification of diabetic cardiomyopathy as an independent complication is controversial, and diagnosis in clinical practice is rare. Nevertheless, the presence of diabetes significantly worsens the course and prognosis of cardiovascular diseases, and a better understanding of the diabetic component in the development of heart failure seems essential in the search for an effective therapy. The pathogenetic factors of the development of heart failure in diabetes include: metabolic disorders related to hyperglycaemia, lipotoxicity, insulin resistance, oxidative stress, immune system dysfunction, genetic predisposition and epigenetic disorders. The clinical pictures of diabetic cardiomyopathy vary depending on the type of diabetes, and dysfunction includes not only the cells of the myocardium, as well as stromal cells, endothelial and nervous system cells. The long-term and asymptomatic course of this complication and its progressive nature shortening the lives of diabetic patients prompt the search for new diagnostic and therapeutic methods. A better understanding of the molecular basis of myocardial dysfunction in diabetes appears essential in the search. Stopping the “cascade” of pathways responsible for activation of inflammation, fibrosis or apoptosis in individual organs could effectively prevent the development of diabetic complications. The paper presents existing pathogenetic concepts and their therapeutic implications, which may be used in the prevention of cardiovascular complications in diabetes and allow individualization of therapy.

Biomarkers in Colorectal Cancer: Current Research and Future Prospects

Colorectal cancer (CRC) is a leading cause of death worldwide, despite progress made in detection and management through surgery, chemotherapy, radiotherapy, and immunotherapy. Novel therapeutic agents have improved survival in both the adjuvant and advanced disease settings, albeit with an increased risk of toxicity and cost. However, metastatic disease continues to have a poor long-term prognosis and significant challenges remain due to late stage diagnosis and treatment failure. Biomarkers are a key tool in early detection, prognostication, survival, and predicting treatment response. The past three decades have seen advances in genomics and molecular pathology of cancer biomarkers, allowing for greater individualization of therapy with a positive impact on survival outcomes. Clinically useful predictive biomarkers aid clinical decision making, such as the presence of KRAS gene mutations predicting benefit from epidermal growth factor receptor (EGFR) inhibiting antibodies. However, few biomarkers have been translated into clinical practice highlighting the need for further investigation. We review a range of protein, DNA and RNA-based biomarkers under investigation for diagnostic, predictive, and prognostic properties for CRC. In particular, long non-coding RNAs (lncRNA), have been investigated as biomarkers in a range of cancers including colorectal cancer. Specifically, we evaluate the potential role of lncRNA plasmacytoma variant translocation 1 (PVT1), an oncogene, as a diagnostic, prognostic, and therapeutic biomarker in colorectal cancer.

The development and implementation of stewardship initiatives to optimize the prevention and treatment of cytomegalovirus infection in solid-organ transplant recipients

Classical stewardship efforts have targeted immunocompetent patients; however, appropriate use of antimicrobials in the immunocompromised host has become a target of interest. Cytomegalovirus (CMV) infection is one of the most common and significant complications after solid-organ transplant (SOT). The treatment of CMV requires a dual approach of antiviral drug therapy and reduction of immunosuppression for optimal outcomes. This dual approach to CMV management increases complexity and requires individualization of therapy to balance antiviral efficacy with the risk of allograft rejection. In this review, we focus on the development and implementation of CMV stewardship initiatives, as a component of antimicrobial stewardship in the immunocompromised host, to optimize the management of prevention and treatment of CMV in SOT recipients. These initiatives have the potential not only to improve judicious use of antivirals and prevent resistance but also to improve patient and graft survival given the interconnection between CMV infection and allograft function.

“Liquid biopsy” for brain tumors: state of problem

The possibilities of traditional methods of diagnosis (radiological and morphological) of brain tumors are now almost exhausted. With their availability and visibility, they have a number of drawbacks in the form of risks of subjectivity in the evaluation of images and microscopic pictures, limited capabilities of existing equipment, the need to use invasive techniques to obtain material. In addition, they do not meet the requirements for individualization of treatment methods, which becomes available as knowledge about the molecular genetic characteristics of tumors deepens. Developed in recent years, the method of “liquid biopsy”, based on the definition in the biological fluids of cells or other components of the tumor has shown its informative in a number of malignant tumors of internal organs. With its help, it is possible to identify the genotype of the tumor and on this basis to individualize the treatment process, as well as to evaluate its effectiveness. The process of finding methods and developing techniques for noninvasive diagnosis of refined genotypes of brain tumors is currently under development. By identifying tumorspecific markers in peripheral blood and cerebrospinal fluid, it is already possible to identify the presence and condition of IDH1 and MGMT genes that are critical for gliomas and to start solving the problem of individualization of therapy.