Ten Years of Experience Support Pharmacogenetic Testing to Guide Individualized Drug Therapy

Precision medicine utilizing the genetic information of genes involved in the metabolism and disposition of drugs can not only improve drug efficacy but also prevent or minimize adverse events. Polypharmacy is common among multimorbid patients and is associated with increased adverse events. One of the main objectives in health care is safe and efficacious drug therapy, which is directly correlated to the individual response to treatment. Precision medicine can increase drug safety in many scenarios, including polypharmacy. In this report, we share our experience utilizing precision medicine over the past ten years. Based on our experience using pharmacogenetic (PGx)-informed prescribing, we implemented a five-step precision medicine protocol (5SPM) that includes the assessment of the biological–clinical characteristics of the patient, current and past prescription history, and the patient’s PGx test results. To illustrate our approach, we present cases highlighting the clinical relevance of precision medicine with a focus on patients with a complex history and polypharmacy.

Differences in the transient responses of individual glaciers: a case study of the Cascade Mountains of Washington State, USA

Mountain glaciers have response times that govern retreat due to anthropogenic climate change. We use geometric attributes to estimate individual response times for 383 glaciers in the Cascade mountain range of Washington State, USA. Approximately 90% of estimated response times are between 10 and 60 years, with many large glaciers on the short end of this distribution. A simple model of glacier dynamics shows that this range of response times entails consequential differences in recent and ongoing glacier changes: glaciers with decadal response times have nearly kept pace with anthropogenic warming, but those with multi-decadal response times are far from equilibrium, and their additional committed retreat stands well beyond natural variability. These differences have implications for changes in glacier runoff. A simple calculation highlights that transient peaks in area-integrated melt, either at the onset of forcing or due to variations in forcing, depend on the glacier's response time and degree of disequilibrium. We conclude that differences in individual response times should be considered when assessing the state of a population of glaciers and modeling their future response. These differences in response can arise simply from a range of different glacier geometries, and the same basic principles can be expected in other regions as well.

Defence mechanisms as predictors of trust and positive relationships in top management teams

BACKGROUND: Top managers are heavily exposed to strong negative emotions due to the difficult decisive situations that they experience and the persistent pressure of time and uncertainty. At the same time, the relationships they build within TMTs shape their decisions, experiences and reactions at work. The paper refers to defence mechanisms as relatively persistent means of individual response to unwanted emotions and affects. OBJECTIVE: The aim of the paper is to examine the defence mechanisms of TMT members as antecedents of perceived trustworthiness of other team members and positive relationships in the team. METHODS: The empirical study was conducted in a sample of 123 members of top management teams representing furniture industry companies in Poland. RESULTS: The results show that defence mechanisms determine TMT members’ perception of trustworthiness of other team-members and that perceived trustworthiness mediates the relation between the defence mechanisms of TMT members and their evaluation of relationships within a team. CONCLUSIONS: The study explains links between individual characteristics of TMT members and processes within the teams. It contributes to upper echelon theory and literature on trust and positive relationships at work. It also contributes to the line of research introducing unconscious processes and emotions to management studies.

Gut Microbiota–Medication Interaction in Rheumatic Diseases

Besides its contribution to the development of rheumatic diseases, the gut microbiota interact with anti-rheumatic drugs. The intestinal microbiota can directly metabolize many drugs and indirectly change drug metabolism through a complex multi-dimensional interaction with the host, thus affecting individual response to drug therapy and adverse effects. The focus of the current review is to address recent advances and important progress in our understanding of how the gut microbiota interact with anti-rheumatic drugs and provide perspectives on promoting precision treatment, drug discovery, and better therapy for rheumatic diseases.

Metabolite Patterns of Patients With Peripheral Arterial Disease In Response To Exercise

Background: The progression of peripheral arterial disease (PAD) and the metabolome’s response to supervised exercise therapy (SET) has not yet been investigated. Results: When analyzing individual time points during exercise, we found high levels of anandamide (AEA) before any exercise interventions were associated with a shorter, or worse, walking time. We also found increased arachidonic acid (AA) and decreased levels of AA precursors dihomo-γ-linolenic acid and diacylglycerol before any exercise was associated with shorter walking times. Participants who were able to tolerate large increases in AA during acute exercise had longer, or better, walking times both before and after SET. Significance: We identified two pathways of relevance to individual response to SET: AEA synthesis may increase the activity at endocannabinoid receptors, resulting in worse treadmill test performance. SET may help train patients withstand higher levels of AA and inflammatory signaling, resulting in longer walking times.

Preliminary Pharmacogenomic-Based Predictive Models of Tamoxifen Response in Hormone-dependent Chilean Breast Cancer Patients

Tamoxifen (TAM), a selective oestrogen receptor modulator, is one of the most used treatments in oestrogen receptor-positive (ER+) early and metastatic breast cancer (BC) patients. The response to TAM has a high degree of inter-individual variability. This is mainly due to genetic variants in CYP2D6 gene, as well as other genes encoding proteins involved in the TAM pharmacokinetic and/or pharmacodynamic. Therefore, prediction of the TAM response using these genetic factors together with other non-genetic variables may be relevant to improve breast cancer treatment. Thus, in this work, we used genetic polymorphisms and clinical variables for TAM response modelling. One hundred sixty-two ER + BC patients with 2 years of TAM treatment were retrospectively recruited, and the genetic polymorphisms CYP2D6*4, CYP3A4*1B (CYP3A4*1.001), CYP3A5*3, UGT2B7*2, UGT2B15*2, SULT1A1*2, and ESRA V364E were analyzed by PCR-RFLP. Concomitantly, the therapeutic response was obtained from clinical records for association with genotypes using univariate and multivariate biostatistical models. Our results show that UGT2B15*1/*2 genotype protects against relapse (OR = 0.09; p = 0.02), CYP3A5*3/*3 genotype avoids endometrial hyperplasia (OR = 0.07; p = 0.01), SULT1A1*1/*2 genotype avoids vaginal bleeding (OR = 0.09; p = 0.03) and ESRA 364E/364E genotype increases the probability of vaginal bleeding (OR = 5.68; p = 0.02). Logistic regression models, including genomic and non-genomic variables, allowed us to obtain preliminary predictive models to explain relapse (p = 0.010), endometrial hyperplasia (p = 0.002) and vaginal bleeding (p = 0.014). Our results suggest that the response to TAM treatment in ER + BC patients might be associated with the presence of the studied genetic variants in UGT2B15, CYP3A5, SULT1A1 and ESRA genes. After clinical validation protocols, these models might be used to help to predict a percentage of BC relapse and adverse reactions, improving the individual response to TAM-based treatment.

Effect of local somatosensory stimulus on postural sway during sit-to-stand movement in the elderly

Background Sit-to-stand (STS) is a complex movement that requires successful postural control. Aging is a normal part of human life that leads to weakness of sensory capabilities, resulting in diminished postural control. Therefore, STS movement is a challenging task for the elderly. Local tendon vibration (LTV) can be utilized to assist STS of the elderly by improving postural control. Many studies have revealed that the LTV has various physiological positive effect. However, previous studies did not consider subjects’ individual difference for properties of applied LTV. Also, there are almost no studies to assist and to improve elder’s STS movement. Thus, the purpose of this study was to examine the influence of lower limb LTV on postural sway during STS in the elderly, and to examine whether a specific vibration frequency can increase postural control in the elderly. Results The common characteristic differences between the elderly and younger population during STS movement were analyzed. In addition, the effect of vibration on the center of mass (COM) and the center of pressure (COP) variable responses in young adults and the elderly were investigated. As a result, the elderly exhibit larger COP sway area and higher COP mediolateral (ML) displacement than the young adults. In addition, the elderly generally have lower COM velocities in all directions compared to the young adults. It was found that COP and COM related to postural stability are affected when LTV of the 180 Hz, 190 Hz and 250 Hz is applied to the elderly. Particularly, the 190 Hz vibration induced significant reduction in COP sway area and COP ML displacement. Conclusions These results mean that the LTV contributes to stability of elders’ STS movement by reducing postural sway. Furthermore, a reduction of postural sway depends on frequency of the LTV. These findings suggest that individual response to characteristics of vibration must be considered, and imply that the LTV can be used as rehabilitation therapy to improve postural control in the elderly, and utilized in motion assistive devices to deliver apt vibration frequencies. Trial registration CRIS, KCT0005434, Registered 25 September 2020, Retrospectively registered, https://cris.nih.go.kr/cris/index/index.do