Interindividual Differences In Response Research Articles

Exercise Response Variation: Avoiding Hysteron Proteron

ABSTRACT Precision exercise medicine is currently one of the most important topics in the clinical exercise physiology field, including exercise-based cardiac rehabilitation (EBCR). A critical component of precision exercise medicine is an appropriate examination for true exercise-associated interindividual response differences (IIRDs) because of EBCR, something that has historically not occurred. As a result, misguided efforts aimed at determining potential moderators and mediators, including genetic interactions and unethical follow-up studies, can occur given that random- and within-subject variation is not accounted for. In this article, a description is provided on how to properly test for true exercise-associated IIRDs in original randomized controlled trials (RCTs) using the standard deviation of individual response (SDIR) approach before deciding on whether an additional examination and/or follow-up studies addressing potential moderators and mediators, including genetic interactions, are necessary. To provide greater readability for a wider audience, we intentionally minimized the use of statistical formulas. It is the hope that the guidance provided in this article will lead to wider adoption of the SDIR approach for examining true IIRDs in original RCTs of EBCR studies as well as spur continued research on this topic. Adherence to the proposed methods will help avoid false conclusions regarding potential moderators and mediators, including genetic interactions, as well as unneeded follow-up studies.

Transcriptomic and epigenomic signatures distinguish high- and low-risk endotypes for liver tumor development.

The epigenome is a target for environmental exposures and a potential determinant of inter-individual differences in response. In genetically identical C57Bl/6 mice exposed from gestation to weaning to the endocrine-disrupting chemical (EDC) tributyltin (TBT), hepatic tumor development later in life varied across multiple cohorts over time and depending on sex and diet. In one cohort where approximately half of TBT-exposed male mice developed liver tumors at 10 months (Katz et al. Hepatic tumor formation in adult mice developmentally exposed to organotin, Environmental Health Perspectives, 128 (1), 17010, 2020), transcriptomic (RNA-seq) and epigenomic (ChIP-seq) profiling was performed on blood and liver tissue from mice that developed tumors (i.e., "high-risk") and equivalently exposed mice did not (i.e., "low-risk"). Blood transcriptomic signatures separated TBT-exposed from vehicle controls but did not discriminate between animals that developed tumors versus those that did not. However, uninvolved liver tissue of mice with tumors exhibited transcriptomic and epigenomic signatures distinct from liver tissue of mice without tumors and had many features in common with tumors. These high-risk transcriptomic and epigenomic features were also found in 10/26 TBT-exposed mice at 5 months, indicating that this risk signature preceded tumor development. Thus, while early life exposure to TBT exhibits variable penetrance for hepatic tumor development, indicating TBT exposure is not sufficient for liver tumorigenesis, increased risk for hepatic tumor development is linked to epigenomic and transcriptomic reprogramming of the liver induced by this EDC.

Heart Rate Variability as a Potential Predictor of Response to Intranasal Esketamine in Patients with Treatment-Resistant Depression: A Preliminary Report.

Background: Esketamine has received approval as a nasal spray (ESK-NS) for treatment-resistant depression (TRD) and evidence from real-world investigations has confirmed the effectiveness of ESK-NS, albeit with interindividual differences in response. Heart rate variability (HRV), defined as the fluctuation in time interval between consecutive heartbeats, can be used to measure autonomic dysfunction in psychiatric disorders and its role has been investigated in diagnosis and prognosis of depression. Methods: This preliminary report aims to evaluate HRV parameters and their association with treatment outcome in 18 patients (55.6% males, 55.6 ± 9.39 years old) with TRD treated with a target dose of ESK-NS for one month (mean dose: 80.9 ± 9.05 mg). The Beck Depression Inventory (BDI) and a 3 min resting electrocardiogram were used to assess changes in depressive symptoms and HRV measurements before and after treatment. Results: Responders (n = 8, 44.5%; based on ≥30% BDI scores reduction) displayed lower HRV values than non-responders at baseline (p = 0.019), which increased at one month (p = 0.038). Receiver-Operating Characteristic (ROC) curves obtained from a logistic regression displayed a discriminative potential for baseline HRV in our sample (AUC = 0.844). Conclusions: These preliminary observations suggest a mutual interaction between esketamine and HRV, especially in relation to treatment response. Further studies are required to investigate electrophysiological profiles among predictors of response to ESK-NS and allow for personalized intervention strategies in TRD that still represent a public health concern.

Individualized Technique Feedback for Instant Technique Improvements and Knee Abduction Moment Reductions - A New Approach for 'Sidestepping' ACL Injuries?

Sidestep cutting technique is highly individual and has been shown to influence knee joint loading. However, studies assessing whether individualized technique feedback improves technique and ACL injury-relevant knee joint loads instantly in a sport-specific task are lacking. To determine the instant effects of individualized augmented technique feedback and instructions on technique and the peak external knee abduction moment (pKAM) in a handball-specific sidestep cut. Additionally, to determine the effects of technique modifications on the resultant ground reaction force and its frontal plane moment arm to the knee joint center. Controlled laboratory cohort study. Three-dimensional biomechanics of 48 adolescent female handball players were recorded during a handball-specific sidestep cut. Following baseline cuts to each side, leg-specific visual and verbal technique feedback on foot strike angle, knee valgus motion, or vertical impact velocity using a hierarchically organized structure accounting for the variables' association with performance was provided. Subsequently, sidestep cuts were performed again while verbal instructions were provided to guide technique modifications. Combined effects of feedback and instructions on technique and pKAM as well as on the resultant ground reaction force and its frontal plane moment arm to the knee joint center were assessed. On average, each targeted technique variable improved following feedback and instructions, leading to instant reductions in pKAM of 13.4% to 17.1%. High inter-individual differences in response to feedback-instruction combinations were observed. These differences were evident in both the adherence to instructions and the impact on pKAM and its components. Most players were able to instantly adapt their technique and decrease ACL injury-relevant knee joint loads through individualized augmented technique feedback, thereby potentially reducing the risk of injury. More research is needed to assess the retention of these adaptations and move towards on-field technique assessments using low-cost equipment. Level 3.

Recovery management in sport: Overview and outcomes of a nine-year multicenter research program

The nine-year multicenter research project, titled REGman—Optimization of Training and Competition: Management of Regeneration in Elite Sports—aimed to advance the understanding of recovery management in sports and generate practical recommendations. In this article, we outline the overarching research program that links the specific research strands and outputs during the two federal funding cycles (2012–2021) and summarize the main project findings. The two-stage conceptual framework involved investigating monitoring measures for short-term fatigue and recovery, as well as assessing the efficacy of various recovery interventions. These interventions encompassed psychological relaxation and recovery strategies, sleep, cooling techniques like precooling, percooling, cold water immersion, or whole-body cryotherapy, compression garments, active recovery, stretching, heating interventions such as sauna or contrast water therapy, massage, and foam rolling. The findings revealed inconclusive or marginal effects of recovery interventions at the group level, while indicating possible interindividual differences in responses. Additionally, the findings highlighted the effectiveness of diverse monitoring measures, showing satisfactory sensitivity in tracking performance changes related to fatigue and recovery. The use of individualized reference ranges significantly improved classification accuracy compared to group-based reference ranges. Athletes and coaches are encouraged to prioritize fundamental aspects of training and recovery: meticulous training planning and execution, effective sleep management, and proper nutrition. Furthermore, monitoring and analyzing individual responses, even though it demands suitable methodologies and presents challenges in high-performance sports environments, can yield valuable insights for personalized recovery management. If these aspects are comprehensively addressed, and resources allow, additional recovery strategies might be explored.

Resistance training and inter-interindividual response differences on cardiorespiratory fitness in older adults: An ancillary meta-analysis of randomized controlled trials.

Examine true inter-individual response differences (IIRD) as a result of resistance training on cardiorespiratory fitness in older adults. Data from a recent meta-analysis of 22 randomized controlled trials representing 552 men and women (292 resistance training, 260 control) ≥ 60 years of age were included. The primary outcome was cardiorespiratory fitness (VO2max) in ml.kg-1.min-1. Using the inverse variance heterogeneity (IVhet) model, statistically significant treatment effect (resistance training minus control) increases in VO2max in ml.kg-1.min-1 were found (mean, 1.8, 95% CI, 0.4 to 3.3 ml.kg-1.min-1, p = 0.01; Q = 82.8, p < 0.001; I2 = 74.6%, 95% CI, 61.6 to 83.3%; =1.1). The 95% prediction interval (PI) was -0.8 to 4.5 ml.kg-1.min-1. However, no statistically significant IIRD was observed (mean, 0.6, 95% CI, -1.1 to 1.4 ml.kg-1.min-1; =1.5). The 95% PI was -1.8 to 2.0 ml.kg-1.min-1. In conclusion, while progressive resistance training may increase VO2max in ml.kg-1.min-1, a lack of true resistance-training-associated IIRD exist.

Pharmacogenomic and pharmacometabolomic biomarkers of the efficacy and safety of antidepressants: focus on selective serotonin reuptake inhibitors

The efficacy and safety of psychopharmacotherapy with antidepressants is of great medical importance. The search for clinical and biological predictors for choosing the optimal psychopharmacotherapy with antidepressants is actively underway all over the world. Research is mainly devoted to searching for associations of polymorphic gene variants with the efficacy and safety of therapy. However, information about a patient's genetic polymorphism is often insufficient to predict the efficacy and safety of a drug. Modern research on the personalization of pharmacotherapy should include, in addition to genetic, phenotypic biomarkers. This is important because genotyping, for example, cannot accurately predict the actual metabolic activity of an isoenzyme. To personalize therapy, a combination of methods is required to obtain the most complete profile of the efficacy and safety of the drug. Successful treatment of depression remains a challenge, and inter-individual differences in response to antidepressants are common. About half of patients with depressive disorders do not respond to the first attempt at antidepressant therapy. Serious side-effects of antidepressant pharmacotherapy and discontinuation of treatment due to their intolerance are associated with ineffective therapy. This review presents the results of the latest studies of «omics» biomarkers of the efficacy and safety of antidepressants.

The expanding role of gene-based prescribing for phase II drug-metabolizing enzymes

Clinical pharmacogenomics has expanded rapidly with the ability to translate evidence from basic science findings into actionable decisions guiding pharmacotherapy in – various disease states. Most findings with potential clinical relevance have been in drug-metabolizing enzymes where variation could cause interindividual differences in response and efficacy. Conventionally, these metabolizing enzymes are classified as Phase I and Phase II enzymes. Although Phase II enzymes are responsible for the metabolism of many drugs, research has focused more on variation in Phase I enzymes. Our aim in this review was to discuss from a historical to present context, the research on key variants in major Phase II enzymes and to summarize clinical pharmacogenetic association studies that could help guide future translation into practice. We evaluated pivotal articles in PubMed (1980–2022) on human pharmacogenomic studies (preclinical and clinical) of N-acetyltransferases (NATs), methyltransferases, glutathione transferases, sulfotransferases, and glucuronosyltransferases for the evidence of clinical applicability and utility. Of the 5 Phase II enzyme superfamilies reviewed, there is presently evidence to support clinical utility for gene-based prescribing for two of them. A third family (NATs) is evaluated as having strong likelihood for future utility in the pharmacological treatment of acquired immunodeficiency syndrome-associated opportunistic infections, tuberculosis, and endemic diseases.

The microbial metabolite desaminotyrosine enhances T-cell priming and cancer immunotherapy with immune checkpoint inhibitors

Inter-individual differences in response to immune checkpoint inhibitors (ICI) remain a major challenge in cancer treatment. The composition of the gut microbiome has been associated with differential ICI outcome, but the underlying molecular mechanisms remain unclear, and therapeutic modulation challenging. We established an invivo model to treat C57Bl/6j mice with the type-I interferon (IFN-I)-modulating, bacterial-derived metabolite desaminotyrosine (DAT) to improve ICI therapy. Broad spectrum antibiotics were used to mimic gut microbial dysbiosis and associated ICI resistance. We utilized genetic mouse models to address the role of host IFN-I in DAT-modulated antitumour immunity. Changes in gut microbiota were assessed using 16S-rRNA sequencing analyses. We found that oral supplementation of mice with the microbial metabolite DAT delays tumour growth and promotes ICI immunotherapy with anti-CTLA-4 or anti-PD-1. DAT-enhanced antitumour immunity was associated with more activated T cells and natural killer cells in the tumour microenvironment and was dependent on host IFN-I signalling. Consistent with this, DAT potently enhanced expansion of antigen-specific T cells following vaccination with an IFN-I-inducing adjuvant. DAT supplementation in mice compensated for the negative effects of broad-spectrum antibiotic-induced dysbiosis on anti-CTLA-4-mediated antitumour immunity. Oral administration of DAT altered the gut microbial composition in mice with increased abundance of bacterial taxa that are associated with beneficial response to ICI immunotherapy. We introduce the therapeutic use of an IFN-I-modulating bacterial-derived metabolite to overcome resistance to ICI. This approach is a promising strategy particularly for patients with a history of broad-spectrum antibiotic use and associated loss of gut microbial diversity. Melanoma Research Alliance, Deutsche Forschungsgemeinschaft, German Cancer Aid, Wilhelm Sander Foundation, Novartis Foundation.

Influence of pharmacogenetics on the diversity of response to statins associated with adverse drug reactions.

Statins are one of the most prescribed medications in developed countries as the treatment of choice for reducing cholesterol and preventing cardiovascular diseases. However, a large proportion of patients experience adverse drug reactions, especially myotoxicity. Among the factors that influence the diversity of response, pharmacogenetics emerges as a relevant factor of influence in inter-individual differences in response to statins and can be useful in the prevention of adverse drug effects. A systematic review was performed of current knowledge of the influence of pharmacogenetics on the occurrence and prevention of statin-associated adverse reactions and clinical benefits of preemptive pharmacogenetics testing. Genetic variants SLCO1B1 (rs4149056) for all statins; ABCG2 (rs2231142) for rosuvastatin; or CYP2C9 (rs1799853 and rs1057910) for fluvastatin are associated with an increase in muscle-related adverse effects and poor treatment adherence. Besides, various inhibitors of these transporters and biotransformation enzymes increase the systemic exposure of statins, thereby favoring the occurrence of adverse drug reactions. The clinical preemptive testing of this pharmacogenetic panel would largely prevent the incidence of adverse drug reactions. Standardized methods should be used for the identification of adverse effects and the performance and interpretation of genotyping test results. Standardization would allow to obtain more conclusive results about the association between SLCO1B1, ABCG and CYP2C9 variants and the occurrence of adverse drug reactions. As a result, more personalized recommendations could be established for each statin.

Poor inhibitory control predicts sex-specific vulnerability to nicotine rewarding properties in mice.

The risk of becoming addicted to tobacco varies greatly from individual to individual, raising the possibility of behavioural biomarkers capable of predicting sensitivity to nicotine reward, a crucial step in the development of nicotine addiction. Amongst all of nicotine's pharmacological properties, one of central importance is theenhancement of cognitive performances, which depend on the balance between attentional processes and inhibitory control. However, whether the cognitive enhancement effects of nicotine are predictive of sensitivity to its rewarding properties is still unknown. Using male and female mice, we investigated whether the effects of nicotine on cognitive performances are predictive of sensitivity to the rewarding properties of nicotine and, if so, whether this relationship is sex dependent. Naïve male and female mice were first assessed for their performances in both baseline conditions and following nicotine injection (0.15 and 0.30mg/kg) in a cued-Fixed Consecutive Number task (FCNcue) measuring both optimal (attention) and premature (inhibitory control) responding. Next, all mice underwent nicotine-induced conditioned place preference (CPP) in order to evaluate inter-individual differences in response to nicotine reward (0.30mg/kg). Results showed that males and females benefited from the effect of nicotine as a cognitive enhancer in the FCNcue task. However, only those males displaying poor inhibitory control, namely high-impulsive animals, subsequently displayed sensitivity to nicotine reward. In females, sensitivity to nicotine reward was independent of FCNcue performances, in both basal and nicotine conditions. Thus, our study suggests that poor inhibitory control and its modulation by nicotine may be a behavioural biomarker for sensitivity to nicotine reward and consequent vulnerability to nicotine addiction in males but not females.

Resilience, aging, and response to radiation exposure (RARRE) in nonhuman primates: a resource review.

The Wake Forest nonhuman primate (NHP) Radiation Late Effects Cohort (RLEC) is a unique and irreplaceable population of aging NHP radiation survivors which serves the nation's need to understand the late effects of radiation exposure. Over the past 16years, Wake Forest has evaluated > 250 previously irradiated rhesus macaques (Macaca mulatta) that were exposed to single total body irradiation (IR) doses of 1.14-8.5Gy or to partial body exposures of up to 10Gy (5% bone marrow sparing) or 10.75Gy (whole thorax). Though primarily used to examine IR effects on disease-specific processes or to develop radiation countermeasures, this resource provides insights on resilience across physiologic systems and its relationship with biological aging. Exposure to IR has well documented deleterious effects on health, but the late effects of IR are highly variable. Some animals exhibit multimorbidity and accumulated health deficits, whereas others remain relatively resilient years after exposure to total body IR. This provides an opportunity to evaluate biological aging at the nexus of resilient/vulnerable responses to a stressor. Consideration of inter-individual differences in response to this stressor can inform individualized strategies to manage late effects of radiation exposure, and provide insight into mechanisms underlying systemic resilience and aging. The utility of this cohort for age-related research questions was summarized at the 2022 Trans-NIH Geroscience Interest Group's Workshop on Animal Models for Geroscience. We present a brief review of radiation injury and its relationship to aging and resilience in NHPs with a focus on the RLEC.

Effects of resistance training on body weight and body composition in older adults: An inter-individual response difference meta-analysis of randomized controlled trials.

Whether true inter-individual response differences (IIRD) occur as a result of resistance training on body weight and body composition in older adults with overweight and obesity is not known. To address this gap, data from a previous meta-analysis representing 587 men and women (333 resistance training, 254 control) ≥ 60 years of age nested in 15 randomized controlled trials of resistance training ≥ 8 weeks were included. Resistance training and control group change outcome standard deviations treated as point estimates for body weight and body composition (percent body fat, fat mass, body mass index in kg.m2, and lean body mass) were used to calculate true IIRD from each study. True IIRD as well as traditional pairwise comparisons were pooled using the inverse-variance (IVhet) model. Both 95% confidence intervals (CI) and prediction intervals (PI) were calculated. While statistically significant improvements were found for body weight and all body composition outcomes (p < 0.05 for all), no statistically significant IIRD was observed for any of the outcomes (p > 0.05 for all) and all 95% PIs overlapped. Conclusions: While resistance training is associated with improvements in body weight and body composition in older adults, the lack of true IIRD suggests that factors other than training response variation (random variation, physiological responses associated with behavioral changes that are not the result of resistance training) are responsible for the observed variation in body weight and body composition.

“Sport knowledge creates value” Old age on the move: physical activity to promote physical and cognitive health in old age

Against the background of demographic change, health in old age is an important topic. This applies not solely to healthy older adults living independently but also to residents of nursing homes. Physical activity and exercise are essential determinants of maintaining health throughout the entire life span. In this regard, physical activity and exercise are central to physical as well as cognitive health. However, not all exercise programs are universally effective. There are differential effects on different bodily systems and interindividual differences in responses to physical activity or exercise. Therefore, tailored exercise programs that meet the individual needs of older adults are increasingly in focus.&#x0D; This talk will review research on physical activity in older adults concerning various dependent variables, such as physical fitness, motor function, cognition, and dual-tasking. Additionally, findings for different target groups will be presented, from healthy older adults to the very old and multimorbid in long-term care settings. The aim is to highlight how physical activity and exercise can contribute to physical and cognitive health in old age. Particular emphasis will be placed on individualization and studies conducted in scenarios close to everyday life.

Increasing Shoe Longitudinal Bending Stiffness Is Not Beneficial to Reduce Energy Cost During Graded Running

Carbon plates have been used to increase running shoes' longitudinal bending stiffness (LBS), leading to reductions in the energy cost of level running (Cr). However, whether or not this is true during uphill (UH) running remains unknown. The aim of our study was to identify the effect of LBS on Cr during UH running. Twenty well-trained male runners participated in this study. Cr was determined using gas exchange during nine 4-minute bouts performed using 3 different LBS shoe conditions at 2.22 and 4.44m/s on level and 2.22m/s UH (gradient: + 15%) running. All variables were compared using 2-way analyses of variance (LBS × speed/grade effects). There was no significant effect of LBS (F = 2.04; P = .14, ηp2=.11) and no significant LBS × grade interaction (F = 0.31; P = .87, ηp2=.02). Results were characterized by a very large interindividual variability in response to LBS changes. The current study contributes to a growing body of literature reporting no effect of LBS on Cr during level and UH running. Yet, the very large interindividual differences in response to changes in LBS suggest that increasing shoe LBS may be beneficial for some runners.

CYP2D in the brain impacts oral hydrocodone analgesia in vivo

Cytochrome P450 2D (CYP2D) metabolises many centrally-acting substrates including opioids. Hydrocodone, an opioid and CYP2D substrate, is metabolised to hydromorphone, an active metabolite. CYP2D in the brain is active in vivo and can alter drug response however, it is unknown whether metabolism by CYP2D in the brain alters oral hydrocodone induced analgesia. Propranolol, a selective CYP2D mechanism-based inhibitor, or vehicle, was administered into the right cerebral ventricle of male rats, (HAN Wistars, Envigo), 24 h before testing for analgesia from oral hydrocodone (or hydromorphone, a non-CYP2D substrate). Hydrocodone and its CYP2D-mediated metabolites were simultaneously quantified using a novel LC-MS/MS assay. After propranolol vs vehicle pretreatment, there was significantly higher analgesia from oral hydrocodone, and a significantly lower brain CYP2D metabolic ratio (an in vivo phenotype of brain CYP2D activity that was derived from the molar sum of hydromorphone and its metabolites divided by hydrocodone). The brain CYP2D metabolic ratio correlated significantly with analgesia. There was no pretreatment effect on plasma hydrocodone concentrations, elimination rates, or metabolic ratio (an in vivo phenotype for hepatic CYP2D activity). The liver CYP2D metabolic ratio did not correlate with analgesia. Propranolol pretreatment had no impact on analgesia from oral hydromorphone. These data suggest that inhibited CYP2D activity in brain, causing reduced metabolism of brain hydrocodone, resulted in higher analgesia from oral hydrocodone, despite hydrocodone having a lower μ-opioid receptor affinity than hydromorphone. Thus, variation in CYP2D in the brain may be an important source of interindividual differences in response to CYP2D substrates, including oral hydrocodone.

Mechanistic Understanding of the Olfactory Neuroepithelium Involvement Leading to Short-Term Anosmia in COVID-19 Using the Adverse Outcome Pathway Framework.

Loss of the sense of smell (anosmia) has been included as a COVID-19 symptom by the World Health Organization. The majority of patients recover the sense of smell within a few weeks postinfection (short-term anosmia), while others report persistent anosmia. Several studies have investigated the mechanisms leading to anosmia in COVID-19; however, the evidence is scattered, and the mechanisms remain poorly understood. Based on a comprehensive review of the literature, we aim here to evaluate the current knowledge and uncertainties regarding the mechanisms leading to short-term anosmia following SARS-CoV-2 infection. We applied an adverse outcome pathway (AOP) framework, well established in toxicology, to propose a sequence of measurable key events (KEs) leading to short-term anosmia in COVID-19. Those KEs are (1) SARS-CoV-2 Spike proteins binding to ACE-2 expressed by the sustentacular (SUS) cells in the olfactory epithelium (OE); (2) viral entry into SUS cells; (3) viral replication in the SUS cells; (4) SUS cell death; (5) damage to the olfactory sensory neurons and the olfactory epithelium (OE). This AOP-aligned approach allows for the identification of gaps where more research should be conducted and where therapeutic intervention could act. Finally, this AOP gives a frame to explain several disease features and can be linked to specific factors that lead to interindividual differences in response to SARS-CoV-2 infection.

Genetic Variation among Pharmacogenes in the Sardinian Population.

Pharmacogenetics (PGx) aims to identify the genetic factors that determine inter-individual differences in response to drug treatment maximizing efficacy while decreasing the risk of adverse events. Estimating the prevalence of PGx variants involved in drug response, is a critical preparatory step for large-scale implementation of a personalized medicine program in a target population. Here, we profiled pharmacogenetic variation in fourteen clinically relevant genes in a representative sample set of 1577 unrelated sequenced Sardinians, an ancient island population that accounts for genetic variation in Europe as a whole, and, at the same time is enriched in genetic variants that are very rare elsewhere. To this end, we used PGxPOP, a PGx allele caller based on the guidelines created by the Clinical Pharmacogenetics Implementation Consortium (CPIC), to identify the main phenotypes associated with the PGx alleles most represented in Sardinians. We estimated that 99.43% of Sardinian individuals might potentially respond atypically to at least one drug, that on average each individual is expected to have an abnormal response to about 17 drugs, and that for 27 drugs the fraction of the population at risk of atypical responses to therapy is more than 40%. Finally, we identified 174 pharmacogenetic variants for which the minor allele frequency was at least 10% higher among Sardinians as compared to other European populations, a fact that may contribute to substantial interpopulation variability in drug response phenotypes. This study provides baseline information for further large-scale pharmacogenomic investigations in the Sardinian population and underlines the importance of PGx characterization of diverse European populations, such as Sardinians.

Inter-individual Differences In Anxiety As A Result Of Aerobic Exercise In Adults With Fibromyalgia: Meta-analysis

It is unknown whether true inter-individual response differences (IIRD) exist with respect to changes in anxiety as a result of aerobic exercise training in adults with fibromyalgia (FM). PURPOSE: Determine whether true IIRD exist with respect to changes in anxiety as a result of aerobic exercise training in adults with FM. METHODS: Data from a previous as well as updated meta-analytic database of randomized controlled trials of exercise in adults with arthritis and other rheumatic diseases were sourced. Randomized controlled trials limited to aerobic exercise training on anxiety in adults >18 years of age with FM were included. Change outcome standard deviations treated as point estimates for anxiety were used to calculate true IIRD from each study. In addition, treatment effect data were extracted. The inverse variance heterogeneity (IVhet) model was used to pool all results. RESULTS: For the five studies and 321 participants in which results were pooled, statistically significant treatment effect reductions in anxiety were observed (Mean, -0.77 points, 95% CI, -1.25 to -0.77). However, no significant IIRD were found (Mean, 0.6 points, 95% confidence interval, -1.2 to 1.5). The 95% prediction interval for true IIRD in a future study was -1.7 to 0.8. The percent chance, i.e., probability, of a clinically meaningful difference in variability, i.e., IIRD, was 61.5% (only possibly clinically important). CONCLUSION: While aerobic exercise is associated with reductions in anxiety among adults with fibromyalgia, there is currently a lack of convincing evidence to support the notion that true IIRD exist. Therefore, a search for potential mediators and moderators associated with aerobic exercise and changes in anxiety among adults with FM may not be warranted. However, additional research is needed before any true level of certainty can be established. This includes (1) the assessment of IIRD in future randomized controlled trials, (2) randomized controlled trials of longer duration, and (3) an increase in the proportion of men included in randomized controlled trials.

Desmopressin testing in von Willebrand disease: Lowering the burden

BackgroundIndividuals with von Willebrand disease (VWD) require desmopressin testing because of interindividual response differences. However, testing is burdensome, while not all patients may need extensive testing. ObjectivesTo provide von Willebrand factor (VWF) cutoffs that predict desmopressin nonresponse and thereby identify individuals who do not need extensive testing in a retrospective cohort. We validated these cutoffs in a prospective cohort. Patients and MethodsWe included 376 patients (Type 1 VWD with VWF activity [VWF:Act] <0.30 IU/ml: n = 112; with VWF:Act 0.30–0.50 IU/ml: n = 206; Type 2 VWD: n = 58; ages, 5–76 years) from January 2000 to July 2020. We collected VWF:Act and factor VIII activity (FVIII:C) at baseline and several time points after desmopressin (T1–T6). We defined response as VWF:Act and FVIII:C 0.50 IU/ml or greater at T1 and T4. We compared VWF:Act and FVIII:C distribution (historically lowest level, baseline, and T1) between responders and nonresponders and determined cutoffs discriminating between these groups. Results were validated in a group of 30 individuals. ResultsAll individuals with Type 1 VWD and Type 2 VWD, respectively, with baseline VWF:Act 0.34 IU/ml or greater or 0.28 IU/ml or greater were responders. In individuals with T1 VWF:Act ≥0.89 IU/ml (Type 1 VWD) or T1 VWF:Act 1.10 IU/ml or greater (Type 2 VWD), response remained at T4. ConclusionDesmopressin testing is not needed when lowest historical VWF:Act is 0.30 IU/ml or greater. In patients with Type 1 VWD who require testing, measurements after T1 are often not needed. In patients with Type 2 VWD who require testing, we advise performing T1 and T4 measurements.