Galena Biopharma (United States)

Introduction. Adverse drug events (ADEs) are between the third and sixth most common cause of death worldwide. Biosimulation studies performed using real-world data could generate relevant drug safety information without exposing patients to ADEs. Methods. Iclepertin (BI-425809) was virtually added to the actual drug regimens of n = 4,405,063 individuals. Changes in risk level were estimated for drug-induced long QT syndrome and CYP450 drug interactions. The properties used for iclepertin included: dose of 10 mg (oral) once daily; bioavailability (F) = 71%; Cmax of 222 nM; CYP3A4 weak affinity substrate (partial metabolic clearance of ~80%); IC50 for hERG block of 30 μM. Results. A change in total medication risk score (MRS) was observed (6.3 ± 6.6 to 7.2 ± 6.6) following the addition of iclepertin in ~50% (n = 2,138,247) of the studied population. Among individuals with a change in MRS, ~65% had a 2-unit increase (max 11 units). The number of individuals classified in the High/Severe MRS category increased by 0.33%. The addition of iclepertin to individuals receiving CYP3A4 perpetrator drugs produced a greater change in MRS (+1.5) when compared to individuals not exposed to CYP3A4 perpetrators (+0.8). An additional 0.0032% of the population (n = 139) would be at risk of QT prolongation following the intake of iclepertin. Subset analyses performed in individuals with schizophrenia (targeted indication) demonstrated that these individuals had higher MRS values (13.0 ± 10.3) compared to those without schizophrenia (6.2 ± 6.9). However, the addition of iclepertin did not produce a greater increase in MRS in the schizophrenia population vs. the control population. Our pharmacoeconomic model did not account for any beneficial effects of the drug but the model based on MRS changes predicted a USD 91 yearly increase in medical expenditures (emergency department visits and hospitalizations) per individual (USD 3172 to USD 3263) following the addition of iclepertin. A similar increase was observed in the schizophrenia population following iclepertin addition. Conclusions. The increase in MRS associated with the addition of iclepertin to the drug regimen of a large population was minimal and mostly driven by CYP3A4 interactions. Using this model, interactions can be identified a priori, making risk mitigable and preventable without exposing patients to toxicity.

Abstract The National Health and Nutrition Examination Survey (NHANES) provides extensive public data on demographics, health, and nutrition, collected in two-year cycles since 1999. Although invaluable for epidemiological and health-related research, the complexity of NHANES data, involving numerous files and disjoint metadata, makes accessing, managing, and analyzing these datasets challenging. This paper presents a reproducible computational environment built upon Docker containers, PostgreSQL databases, and R/RStudio, designed to streamline NHANES data management, facilitate rigorous quality control, and simplify analyses across multiple survey cycles. We introduce specialized tools, such as the enhanced nhanesA R package and the phonto R package, to provide fast access to data, to help manage metadata, and to handle complexities arising from questionnaire design and cross-cycle data inconsistencies. Furthermore, we describe the Epiconnector platform, established to foster collaborative sharing of code, analytical scripts, and best practices, which taken together can significantly enhance the reproducibility, extensibility, and robustness of scientific research using NHANES data.Database URL:https://epiconnector.github.io

Abstract Familial hypercholesterolemia (FH) is a genetic disorder driven in part by mutations in three genes that encode components of the cholesterol pathway:LDLR,APOB, andPCSK9. However, the majority of FH genetics has been performed in individuals of European descent. Here, we leveraged a cohort of 300 patients from the Mexican FH registry to understand how rare, high liability alleles and common variants might contribute to shaping individual risk. Using a combination of whole exome and of short- and long-read whole genome sequencing, we report three key findings. First, we observed that rare pathogenic point mutations and structural variants in all known FH genes, together with variants inAPOE,CREB3L3, andPLIN1, contribute to a molecular FH diagnosis in 67% of families, including novel gene-disruptive CNVs which arose in a native American background. Second, ancestry-adjusted polygenic risk score analysis identified a significant liability for coronary artery disease, hypertension, LDL, HDL, and Type 2 Diabetes. The polygenic signal for LDL was present in patients with rare, pathogenic FH mutations and was more prominent in individuals bereft of a molecular FH diagnosis. Finally, we report both a whole-gene duplication and common, non-coding variants in a novel locus,PDZK1, which contribute to the genetic burden of FH, a finding we replicated in the UK Biobank (UKB). Together, our analyses illustrate the value of genetic studies in non-European populations and reinforce the notion that individual risk to disease can arise from both rare, large effect alleles (alone or in combination across genes) and common variants that increase the mutational burden of a biological system.

By combining microelectrode array (MEA) and human-induced pluripotent stem cell (hiPSC) technology, this study sought to validate the use of hiPSC-cortical neuron network long-term potentiation (LTP) for drug efficacy and safety studies for Alzheimer’s disease (AD) and anticholinergic cognitive burden (ACB), respectively.

The researcher wrote this scientific paper so that he could set hypotheses that affect each variable to provide benefits for further writing. Through this writing, the researchers obtained the following results: 1) DPK had a positive and significant impact on financing; 2) CAR has a positive and significant impact on financing; 3) NPF has a positive impact and is quite important for financing; 4) Deposits have a positive and significant impact on Profitability; 5) CAR has a positive impact and is quite important to Profitability; 6) NPF has a positive impact and is quite important to Profitability; 7) Financing has a positive and quite important impact on Profitability; 8) DPK has a positive and quite important impact on profitability through financing mediation; 9) CAR has a positive and significant impact on Profitability through financing mediation; 10) NPF has a positive impact and is quite important to profitability mediated by financial lending.

Prodrugs are derivatives with superior properties compared with the parent active pharmaceutical ingredient (API), which undergo biotransformation after administration to generate the API in situ. Although sharing this general characteristic, prodrugs encompass a wide range of different chemical structures, therapeutic indications and properties. Here we provide the first holistic analysis of the current landscape of approved prodrugs using cheminformatics and data science approaches to reveal trends in prodrug development. We highlight rationales that underlie prodrug design, their indications, mechanisms of API release, the chemistry of promoieties added to APIs to form prodrugs and the market impact of prodrugs. On the basis of this analysis, we discuss strengths and limitations of current prodrug approaches and suggest areas for future development.

BackgroundLong COVID provides a new context in which primary health care needs to be re-examined, especially because it has health and social dimensions. Primary care physicians’ experiences and perceptions of caring for patients with long COVID are an underexplored area.AimTo explore the experiences of Slovenian primary care physicians in management and treatment of patients with long COVID.Design & settingA qualitative interview study of physicians in Slovenian primary care.MethodSemi-structured interviews were held with physicians who had treated patients with long COVID until saturation was reached. The interviews were carried out between November 2021 and April 2022. Qualitative content analysis (QCA) was used to analyse the data collected.ResultsSeventeen participants were interviewed. The following five categories were defined based on the coding process: the definition and symptoms of long COVID; social exclusion; sick leave and returning to the work environment; cooperation with rehabilitation centres; and the importance of trust and good communication with the patient.ConclusionThe study showed the experiences of Slovenian primary care physicians in the management and treatment of long COVID. The problems related to long COVID were divided into two groups: health problems and psychosocial problems. Slovenian physicians have the greatest problems with dealing with the patient’s ability to work. It was found that adequate communication and trust between physicians and patients are two important indicators for an integrated model of managing long COVID.

This contribution proposes an interpretation of Girolamo Cardano’s views on witchcraft. To this end, the paper offers a reading of chapter LXXX of Cardano’s De rerum varietate (1557), where he exam-ines the nature of the so-called witches, in light of the broader framework of Cardano’s philosophy, relating it back to the concepts of varietas and subtilitas, as well as his focus on the conjecturales dis-ciplinae. Then, Cardano’s thought is contrasted with two late-medieval authors, namely John Buridan (with the figure of the vetula) and Peter of Abano (with his views on demonic influxes). Against the background of this analysis, it emerges that Cardano views witchcraft as belonging to the natural and human sphere, as a phenomenon that ultimately rests on a series of social and physiological factors, though he does not exclude completely the eventuality of supernatural influxes on worldly affairs: this complex picture cannot thus be reduced to one of the opposing poles of the Renaissance debate on the nature of witchcraft.