Experience with comprehensive pharmacogenomic multi-gene panel in clinical practice: a retrospective single-center study

AimTo assess the prevalence of actionable pharmacogenetic interventions in patients who underwent pharmacogenetic testing with a multi-gene panel.MethodsWe retrospectively reviewed single-center electronic health records. A total of 319 patients were enrolled who underwent pharmacogenomic testing with the RightMed test panel using TaqMan quantitative real-time PCR method and copy number variation analysis to determine the SNPs in the 27 target genes.ResultsActionable drug-gene pairs were found in 235 (73.7%) patients. Relevant guidelines on genotype-based prescribing were available for 133 (56.7%) patients at the time of testing. Based on the patients’ genotype, 139 (43.6%) patients were using at least one drug with significant pharmacogenetic interactions.ConclusionTwo out of three patients had at least one drug-gene pair in their therapy. Further studies should assess the clinical effectiveness of integrating pharmacogenomic data into patients’ electronic health records.

The field of pharmacogenetics has been booming in the past decades, with research being focused on studying novel genetic variants that impact drug metabolism or pharmacological effect, which ultimately affects the patient’s response to a given dose of medication. Pharmacogenetics examines gene-drug interactions that change pharmacokinetic and/or pharmacodynamic properties of a drug (1). It is impossible to implement any of the principles of personalized medicine without determining the patients'' pharmacogenetic profile before starting a new therapy (2).Several professional organizations, namely, Clinical Pharmacogenetics Implementation Consortium (CPIC) and Dutch Pharmacogenetics Working Group (DPWG), provide comprehensive and understandable guidelines on genotype-based drug prescribing (3,4). Pharmacogenomic prescribing guidelines are growing in number and are available for various drug classes including the cardiovascular drugs, drugs affecting the central nervous system, gastrointestinal drugs, drugs that treat infectious and malignant diseases, immunosuppressives, analgesics, and other (5,6).Several companies specialize in pharmacogenetic panels, making it easily accessible for patients and clinicians of various specialties to obtain the test results in a matter of days or weeks. These commercial tests are developed by industry stakeholders and can be implemented in various settings during the diagnostic or treatment process (7,8). They are comprehensive and include a number of genes that are important for the pharmacologic profile across drug groups, or targeted for a certain category of drugs, ie, psychiatric, analgesics, oncologic drugs, etc. Data on the rate of utilization and clinical utility of such tests are lacking. A recent study found that from 2013 until 2017 only 5712 insured US patients performed pharmacogenetic testing of at least one gene (9). The field of pharmacogenomics is still in its early stages. One of the principal problems is the education of health care providers responsible for ordering and interpreting the test results. In a recent survey, 84.3% of doctors from seven European countries deemed pharmacogenomics relevant for their practice, however 65.7% did not order a pharmacogenomic test in the last year (10). Potential implementation of pharmacogenomics in the clinical practice should be complemented with a clinical decision support tool integrated into the patient’s electronic health record (11,12). In Croatia, pharmacogenomic testing has been available for over a decade, with multiple studies examining population genetics and cost-effectiveness of pharmacogenomic guided therapies (13,14). However, commercial panel-based tests targeting multiple genes known to influence drug response is a new concept that was implemented in 2018 at St. Catherine Hospital in Zagreb (8,15,16).The aim of this retrospective study was to assess the proportion of patients with actionable pharmacogenetic interventions in a single center from 2018 to 2021 who had undergone pharmacogenetic testing of 27 genes by using a commercial gene panel.     

ApoC-III bound to apoB-containing lipoproteins increase with insulin resistance in Cherokee Indian youth

Because Native Americans are predisposed to obesity and type 2 diabetes associated with coronary artery disease, we assessed whether apoC-III bound to apoB-containing (LpB:C-III) and apoA-containing (LpA:C-III) lipoproteins, total apoC-III, apoB, and plasma lipids are associated with insulin resistance, body mass index (BMI), and waist circumference in Cherokee children and adolescents aged 5 to 19 years (n = 975). A cross-sectional analysis was done to determine associations of the lipoproteins with the homeostasis index (HOMA-IR) and BMI. When the data were grouped by quartiles for HOMA-IR and separated by three 5-year age groups (5-9, 10-14, and 15-19 years), the trend for LpB:C-III, triglyceride, and BMI z score to increase was significant for all age groups and both genders (P < .001). The trend to increase LpB:C-III with age was greater in boys (P < .0001) than in girls (P < .05) who tended to plateau after the age of 10 years. In contrast, the ratio of LpA:C-III to LpB:C-III decreased and the decrease was greater in boys (P < .0001) than girls (P < .01). Body mass index z score and waist circumference were correlated with LpB:C-III, triglyceride, apoB, and non-high-density lipoprotein cholesterol within each gender (P < .001). In multiple regression models, LpB:C-III, the dependent variable, was associated with HOMA-IR for both genders. We conclude that increases in LpB:C-III in childhood and adolescence are associated with insulin resistance and obesity supporting the need for prevention programs.     

Bone and Ceramic Interaction in the Bone Union Process

This study applied an experimental rat model and ceramic as an artificial matrix to explore the ultrastructural development of new bone production in tibia defects. By X-ray diffraction control or energy-dispersive X-ray analysis the nature of ceramic was verified and routine histology and TEM investigation were used to demonstrate bone - ceramic interaction. The results show that biphasic ceramic can promote bone growth in an osseous defect and is therefore an alternative to autogenous bone matrix. The porousity and bioactivity of the biphasic ceramic enhanced bone formation and provided a scaffold for new lamellar bone invasion.     

The peridural membrane of the spine has characteristics of synovium

The peridural membrane (PDM) is a well-defined structure between dura mater and the wall of the spinal canal. The spine may be viewed as a multi-segmented joint, with the epidural cavity and neural foramina as joint spaces and PDM as synovial lining. The objective of this investigation was to determine if PDM has histological characteristics of synovium. Samples of the PDM of the thoraco-lumbar spine were taken from 23 human cadavers and analyzed with conventional light microscopy and confocal microscopy. Results were compared to reports on similar analyses of synovium in the literature. Histological distribution of areolar, fibrous, and adipose connective tissue in PDM was similar to synovium. The PDM has an intima and sub-intima. No basement membrane was identified. CD68, a marker for macrophage-like-synoviocytes, and CD55, a marker for fibroblast-like synoviocytes, were seen in the lining and sub-lining of the PDM. Multifunctional hyaluronan receptor CD44 and hyaluronic acid synthetase 2 marker HAS2 were abundantly present throughout the membrane. Marked presence of CD44, CD55, and HAS2 in the well-developed tunica muscularis of blood vessels and in the body of the PDM suggests a role in the maintenance and lubrication of the epidural cavity and neural foramina. Presence of CD68, CD55, and CD44 suggests a scavenging function and a role in the inflammatory response to noxious stimuli. Thus, the human PDM has histological and immunohistochemical characteristics of synovium. This suggests that the PDM may be important for the homeostasis of the flexible spine and the neural structures it contains.     

Plasma apolipoprotein concentrations in familial apolipoprotein A-I and A-II deficiency (Tangier disease)

Familial apolipoprotein A-I and A-II deficiency (Tangier disease) is characterized by cholesterol ester deposition in histiocytes, decreased plasma cholesterol and low density lipoprotein cholesterol (C-LDL), and a striking deficiency of high density lipoproteins (HDL). We measured plasma lipid, lipoprotein cholesterol, and plasma apolipoprotein (apo) A-I, A-II, B, C-I, C-II, C-III, D, and E concentrations in 7 Tangier homozygotes, 2 obligate heterozygotes, and 50 normal subjects. Heterozygotes had modest reductions in high density lipoprotein cholesterol (C-HDL), plasma apoA-I, and apoA-II levels. Mean concentrations (±SD) of plasma C-HDL and apolipoproteins A-I, A-II, B, C-I, C-II, C-III, D, and E in mg% in normals were: 50 ± 14, 134 ± 24, 68 ± 18, 98 ± 20, 7 ± 2, 3.7 ± 2, 13 ± 5, 10 ± 4, and 10 ± 4, respectively; and in homozygotes were: 1 ± 1, 1.3 ± 0.7, 4.8 ± 2.5, 82.6 ± 18, 4.1 ± 1.7, 2.3 ± 0.9, 6.5 ± 3.8, 2.2 ± 0.5, and 5.4 ± 3.1, respectively. Homozygotes had C-HDL, apoA-I and apoA-II levels which were 2%, 1%, and 7% (p < .001) of normal, respectively, and mean levels of apolipoproteins B, C-I, C-II, C-III, D, and E which were 84%, 59%, 62%, 50%, 22%, and 54% of normal, respectively. There was heterogeneity of these latter apolipoprotein concentrations among homozygotes. Mean apoC-I, apoC-III, apoD, and apoE levels were significantly less than normal (pp < .05) in homozygotes. These data indicate that homozygotes have variable but generally decreased apoC and apoE levels, a deficiency of apoD, and a striking reduction in plasma apoA-I and apoA-II concentrations.     

Specifics of Helicobacter pylori infection/NSAID effects in the elderly

The prevalence of Helicobacter pylori (HP) infection increases with age worldwide. Unlike in younger patients, the presentation of peptic disease in the elderly population is subtle and atypical, and thus leads to a delay of diagnosis. Due to comorbidities and advanced age, it results in increased complications, morbidity and mortality. Bleeding and perforation are frequent complications and therefore peptic ulcer in adult patients represents a serious disease. The relationship between the infection caused by HP and the use of non-steroidal anti-inflammatory drugs (NSAID) in the pathogenesis of peptic ulcer disease is still controversial. However these two factors, independently or in synergy, represent the principal cause of peptic ulcer development in the adult population. In patients diagnosed with peptic ulcer caused by HP, more than half take medications containing aminosalicylic acid. Helicobacter pylori infection in elderly NSAID users is associated with an increased ulcer incidence, but not with an increased prevalence of upper digestive tract bleeding. Helicobacter pylori and NSAID consumption are independent and unrelated risk factors for upper gastrointestinal tract bleeding. Eradication of HP is recommended before the initiation of a long-term aspirin administration in elderly patients. Low aspirin dosages are associated with a high risk of ulcer bleeding. The risk of upper gastrointestinal bleeding in elderly patients is significantly higher in the cases of acute abuse of NSAIDs relative to its chronic use. The simultaneous use of NSAID or aspirin and selective serotonin reuptake inhibitors--antidepressants, increases the risk of upper gastrointestinal bleeding. Peptic ulcer disease in the adult population, if combined with old age, presence of serious and/or life- threatening diseases, as well as repeated ulcer bleedings, shows a high mortality rate.     

How to diagnose heart failure with preserved ejection fraction: the HFA–PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC)

Making a firm diagnosis of chronic heart failure with preserved ejection fraction (HFpEF) remains a challenge. We recommend a new stepwise diagnostic process, the ‘HFA–PEFF diagnostic algorithm’. Step 1 (P=Pre‐test assessment) is typically performed in the ambulatory setting and includes assessment for heart failure symptoms and signs, typical clinical demographics (obesity, hypertension, diabetes mellitus, elderly, atrial fibrillation), and diagnostic laboratory tests, electrocardiogram, and echocardiography. In the absence of overt non‐cardiac causes of breathlessness, HFpEF can be suspected if there is a normal left ventricular (LV) ejection fraction, no significant heart valve disease or cardiac ischaemia, and at least one typical risk factor. Elevated natriuretic peptides support, but normal levels do not exclude a diagnosis of HFpEF. The second step (E: Echocardiography and Natriuretic Peptide Score) requires comprehensive echocardiography and is typically performed by a cardiologist. Measures include mitral annular early diastolic velocity (e′), LV filling pressure estimated using E/e′, left atrial volume index, LV mass index, LV relative wall thickness, tricuspid regurgitation velocity, LV global longitudinal systolic strain, and serum natriuretic peptide levels. Major (2 points) and Minor (1 point) criteria were defined from these measures. A score ≥5 points implies definite HFpEF; ≤1 point makes HFpEF unlikely. An intermediate score (2–4 points) implies diagnostic uncertainty, in which case Step 3 (F₁: Functional testing) is recommended with echocardiographic or invasive haemodynamic exercise stress tests. Step 4 (F₂: Final aetiology) is recommended to establish a possible specific cause of HFpEF or alternative explanations. Further research is needed for a better classification of HFpEF.     

The Heart Failure Association Atlas: rationale,objectives, and methods

Heart failure (HF) constitutes the growing cardiovascular burden and the major public health issue, but comprehensive statistics on HF epidemiology and related management in Europe are missing. The Heart Failure Association (HFA) Atlas has been initiated in 2016 in order to close this gap, representing the continuity directly rooted in the European Society of Cardiology (ESC) Atlas of Cardiology. The major aim of the HFA Atlas is to establish a contemporary dataset on HF epidemiology, resources and reimbursement policies for HF management, organization of the National Heart Failure Societies (NHFS) and their major activities, including education and HF awareness. These data are gathered in collaboration with the network of NHFS of the ESC member and ESC affiliated countries. The dataset will be continuously improved and advanced based on the experience and enhanced understanding of data collection in the forthcoming years. This will enable revealing trends, disparities and gaps in knowledge on epidemiology and management of HF. Such data are highly needed by the clinicians of different specialties (aside from cardiologists and cardiac surgeons), researchers, healthcare policy makers, as well as HF patients and their caregivers. It will also allow to map the snapshot of realities in HF care, as well as to provide insights for evidence‐based health care policy in contemporary management of HF. Such data will support the ESC/HFA efforts to improve HF management ant outcomes through stronger recommendations and calls for action. This will likely influence the allocation of funds for the prevention, treatment, education and research in HF.     

Epidemiology,pathophysiology and contemporary management of cardiogenic shock – a position statement from the Heart Failure Association of the European Society of Cardiology

Cardiogenic shock (CS) is a complex multifactorial clinical syndrome with extremely high mortality, developing as a continuum, and progressing from the initial insult (underlying cause) to the subsequent occurrence of organ failure and death. There is a large spectrum of CS presentations resulting from the interaction between an acute cardiac insult and a patient's underlying cardiac and overall medical condition. Phenotyping patients with CS may have clinical impact on management because classification would support initiation of appropriate therapies. CS management should consider appropriate organization of the health care services, and therapies must be given to the appropriately selected patients, in a timely manner, whilst avoiding iatrogenic harm. Although several consensus‐driven algorithms have been proposed, CS management remains challenging and substantial investments in research and development have not yielded proof of efficacy and safety for most of the therapies tested, and outcome in this condition remains poor. Future studies should consider the identification of the new pathophysiological targets, and high‐quality translational research should facilitate incorporation of more targeted interventions in clinical research protocols, aimed to improve individual patient outcomes. Designing outcome clinical trials in CS remains particularly challenging in this critical and very costly scenario in cardiology, but information from these trials is imperiously needed to better inform the guidelines and clinical practice. The goal of this review is to summarize the current knowledge concerning the definition, epidemiology, underlying causes, pathophysiology and management of CS based on important lessons from clinical trials and registries, with a focus on improving in‐hospital management.