Interindividual Variability In Response Research Articles

Effect on emergence from anesthesia following induction with diazepam and its association with CYP2C9, CYP2C19 and CYP3A4 gene polymorphisms

Introduction & Objectives: Benzodiazepines are commonly used as adjuvants to IV anesthetic agents. Diazepam dosage varies widely depending on the desired endpoints. The rationale behind such inter-individual variability in drug responses has been attributed to genetically determined alterations in the enzyme activities. We assessed the emergence time in patients after induction of anesthesia with two different doses of diazepam and evaluated if any correlation exists between the emergence time and genetic polymorphism in drug metabolizers CYP2C19, CYP2C9, and CYP3A4 genes.
 Methodology: The study was conducted on randomly selected adult patients scheduled for elective surgery between 40-60 y of age with predefined inclusion and exclusion criteria. The patients were distributed into 2 groups, with group 1 receiving 0.2 mg/kg and group 2 given 0.3 mg/kg diazepam. Wake-up time after surgery was determined after a standardized verbal command played by a tape-recorder. Three ml blood in Ethylenediaminetetraacetic acid (EDTA) was collected before administering anesthesia.
 Results: Wake-up time between 8-18 min did not vary between the two groups. Comparatively persons having 2C19 2 took longer time to wake-up but this association was not statistically significant. However, CYP2C9 2 and 2 C9 3 and CYP3A4 genotypes had no influence on wake-up time.
 Conclusion: The pilot study suggests the emergence time from diazepam is longer in patients having 2C19 2 which confers slow-metabolizer phenotype. However, this study needs to be replicated in larger sample size to arrive at definitive conclusions before clinical applications.
 Abbreviations: BDZ- benzodiazepine; EDTA- Ethylenediaminetetraacetic acid; GA-General Anesthesia
 Key words: Diazepam; Emergence; Gene Polymorphism; Pharmacogenetics
 Citation: Mittal T, Badhe VK, Badhe DSD, Ahluwalia P, Mitta Bl, Mittal R. Effect on emergence from anesthesia following induction with diazepam and its association with CYP2C9, CYP2C19 and CYP3A4 gene polymorphisms. Anaesth. pain intensive care 2024;28(1):126-138. DOI: 10.35975/apic.v28i1.2380
 Received: July 20, 2023; Reviewed: December 07, 2023; Accepted: December 07, 2023

Integrated Analysis of Genomic and Genome-Wide Association Studies Identified Candidate Genes for Nutrigenetic Studies in Flavonoids and Vascular Health: Path to Precision Nutrition for (Poly)phenols.

Flavonoids exert vasculoprotective effects in humans, but interindividual variability in their action has also been reported. This study aims to identify genes that are associated with vascular health effects of flavonoids and whose polymorphisms could explain interindividual variability in response to their intake. Applying the predetermined literature search criteria, we identified five human intervention studies reporting positive effects of flavonoids on vascular function together with global genomic changes analyzed using microarray methods. Genes involved in vascular dysfunction were identified from genome-wide association studies (GWAS). By extracting data from the eligible human intervention studies, we obtained 5807 differentially expressed genes (DEGs). The number of identified upstream regulators (URs) varied across the studies, from 227 to 1407. The search of the GWAS Catalog revealed 493 genes associated with vascular dysfunction. An integrative analysis of transcriptomic data with GWAS genes identified 106 candidate DEGs and 42 candidate URs, while subsequent functional analyses and a search of the literature identified 20 top priority candidate genes: ALDH2, APOE, CAPZA1, CYP11B2, GNA13, IL6, IRF5, LDLR, LPL, LSP1, MKNK1, MMP3, MTHFR, MYO6, NCR3, PPARG, SARM1, TCF20, TCF7L2, and TNF. In conclusion, this integrated analysis identifies important genes to design future nutrigenetic studies for development of precision nutrition for polyphenols.

Sex-specific heterothermy patterns in wintering captive Microcebus murinus do not translate into differences in energy balance

The physiological mechanisms of responses to stressors are at the core of ecophysiological studies that examine the limits of an organism's flexibility. Interindividual variability in these physiological responses can be particularly important and lead to differences in the stress response among population groups, which can affect population dynamics. Some observations of intersexual differences in heterothermy raise the question of whether there is a difference in energy management between the sexes. In this study, we assessed male and female differences in mouse lemurs (Microcebus murinus), a highly seasonal malagasy primate, by measuring their physiological flexibility in response to caloric restriction and examining the subsequent impact on reproductive success. Using complementary methods aiming to describe large-scale and daily variations in body temperature throughout a 6-month winter-like short-day (SD) period, we monitored 12 males and 12 females, applying chronic 40% caloric restriction (CR) to 6 individuals in each group. We found variations in Tb modulation throughout the SD period and in response to caloric treatment that depended on sex, as females, regardless of food restriction, and CR males, only, entered deep torpor. The use of deeper torpor, however, did not translate into a lower loss of body mass in females and did not affect reproductive success. Captive conditions may have buffered the depth of torpor and minimised the positive effects of torpor on energy savings. However, the significant sex differences in heterothermy we observed may point to physiological benefits other than preservation of energy reserves.

Onchocerca volvulus microfilariae in the anterior chambers of the eye and ocular adverse events after a single dose of 8 mg moxidectin or 150 µg/kg ivermectin: results of a randomized double-blind Phase 3 trial in the Democratic Republic of the Congo, Ghana and Liberia

BackgroundAfter ivermectin became available, diethylcarbamazine (DEC) use was discontinued because of severe adverse reactions, including ocular reactions, in individuals with high Onchocerca volvulus microfilaridermia (microfilariae/mg skin, SmfD). Assuming long-term ivermectin use led to < 5 SmfD with little or no eye involvement, DEC + ivermectin + albendazole treatment a few months after ivermectin was proposed. In 2018, the US FDA approved moxidectin for treatment of O. volvulus infection. The Phase 3 study evaluated SmfD, microfilariae in the anterior chamber (mfAC) and adverse events (AEs) in ivermectin-naïve individuals with ≥ 10 SmfD after 8 mg moxidectin (n = 978) or 150 µg/kg ivermectin (n = 494) treatment.MethodsWe analyzed the data from 1463 participants with both eyes evaluated using six (0, 1–5, 6–10, 11–20, 21–40, > 40) mfAC and three pre-treatment (< 20, 20 to < 50, ≥ 50) and post-treatment (0, > 0–5, > 5) SmfD categories. A linear mixed model evaluated factors and covariates impacting mfAC levels. Ocular AEs were summarized by type and start post-treatment. Logistic models evaluated factors and covariates impacting the risk for ocular AEs.ResultsMoxidectin and ivermectin had the same effect on mfAC levels. These increased from pre-treatment to Day 4 and Month 1 in 20% and 16% of participants, respectively. Six and 12 months post-treatment, mfAC were detected in ≈5% and ≈3% of participants, respectively. Ocular Mazzotti reactions occurred in 12.4% of moxidectin- and 10.2% of ivermectin-treated participants without difference in type or severity. The risk for ≥ 1 ocular Mazzotti reaction increased for women (OR 1.537, 95% CI 1.096–2.157) and with mfAC levels pre- and 4 days post-treatment (OR 0: > 10 mfAC 2.704, 95% CI 1.27–5.749 and 1.619, 95% CI 0.80–3.280, respectively).ConclusionsThe impact of SmfD and mfAC levels before and early after treatment on ocular AEs needs to be better understood before making decisions on the risk-benefit of strategies including DEC. Such decisions should take into account interindividual variability in SmfD, mfAC levels and treatment response and risks to even a small percentage of individuals.Graphical

Delineating immune variation between adult and children COVID-19 cases and associations with disease severity

The SARS-CoV-2 pandemic has emphasized the need to explore how variations in the immune system relate to the severity of the disease. This study aimed to explore inter-individual variation in response to SARS-CoV-2 infection by comparing T cell, B cell, and innate cell immune subsets among primary infected children and adults (i.e., those who had never experienced SARS-CoV-2 infection nor received vaccination previously), with varying disease severity after infection. We also examined immune subset kinetics in convalescent individuals compared to those with persistent infection to identify possible markers of immune dysfunction. Distinct immune subset differences were observed between infected adults and children, as well as among adult cases with mild, moderate, and severe disease. IgM memory B cells were absent in moderate and severe cases whereas frequencies of B cells with a lack of surface immunoglobulin expression were significantly higher in severe cases. Interestingly, these immune subsets remained stable during recovery implying that these subsets could be associated with underlying baseline immune variation. Our results offer insights into the potential immune markers associated with severe COVID-19 and provide a foundation for future research in this area.

Population Pharmacokinetics of Valproate in Children: The Importance of Total Daily Dose, Compliance and Co-Treatment

Abstract Valproate represents one of the most commonly used anticonvulsants worldwide, whose narrow therapeutic range and high potential for drug-drug interactions leads to pronounced intra- and inter-individual variability in plasma concentration and response. The aim of our study was to apply population pharmacokinetics analysis to comprehensively investigate and detect the most important factors affecting pharmacokinetics of valproate in Serbian children with epilepsy. This retrospective observational study was based on demographic and medical data retrieved from the medical records on epileptic patients treated with valproate at the pediatric department of the Clinical Centre, Kragujevac, Serbia. Valproate serum concentrations were obtained as a part of routine medical practice. Population pharmacokinetics analysis was performed by MonolixSuite 2019R1 (Lixoft, Antony, France) software, using one-compartment model with first order absorption and linear elimination. The study included 1642 valproate concentrations obtained from 232 patients, of which 201 (1420 concentrations) were included in the index set used for the modelling, while the other 31 (222 concentrations) were the validation set used for external validation of the final model. Covariate testing based on the whole index set revealed that only total daily valproate dose significanly affected the clearance of valproate: Cl (l/h)= 0.135×1.002DD. When only compliant patients were included, co-treatment with carbamazepine was shown to be of significance as well: Cl(l/h)=0.121×1.002DD×1.2CBZ. Our study demonstrated that valproate clearance correlates with total valproate daily dose. The influence of co-treatment with carbamazepine on valproate pharmacokinetics can be observed and used for clearance estimation only in compliant patients.

Dimensionality and optimal combination of autonomic fear-conditioning measures in humans.

Fear conditioning, also termed threat conditioning, is a commonly used learning model with clinical relevance. Quantification of threat conditioning in humans often relies on conditioned autonomic responses such as skin conductance responses (SCR), pupil size responses (PSR), heart period responses (HPR), or respiration amplitude responses (RAR), which are usually analyzed separately. Here, we investigate whether inter-individual variability in differential conditioned responses, averaged across acquisition, exhibits a multi-dimensional structure, and the extent to which their linear combination could enhance the precision of inference on whether threat conditioning has occurred. In a mega-analytic approach, we re-analyze nine data sets including 256 individuals, acquired by the group of the last author, using standard routines in the framework of psychophysiological modeling (PsPM). Our analysis revealed systematic differences in effect size between measures across datasets, but no evidence for a multidimensional structure across various combinations of measures. We derive the statistically optimal weights for combining the four measures and subsets thereof, and we provide out-of-sample performance metrics for these weights, accompanied by bias-corrected confidence intervals. We show that to achieve the same statistical power, combining measures allows for a relevant reduction in sample size, which in a common scenario amounts to roughly 24%. To summarize, we demonstrate a one-dimensional structure of threat conditioning measures, systematic differences in effect size between measures, and provide weights for their optimal linear combination in terms of maximal retrodictive validity.

The Impact of Human Genome on Interindividual variability in Drug Response

The Impact of Human Genome on Interindividual variability in Drug Response

Anthracyclines induce cardiotoxicity through a shared gene expression response signature.

TOP2 inhibitors (TOP2i) are effective drugs for breast cancer treatment. However, they can cause cardiotoxicity in some women. The most widely used TOP2i include anthracyclines (AC) Doxorubicin (DOX), Daunorubicin (DNR), Epirubicin (EPI), and the anthraquinone Mitoxantrone (MTX). It is unclear whether women would experience the same adverse effects from all drugs in this class, or if specific drugs would be preferable for certain individuals based on their cardiotoxicity risk profile. To investigate this, we studied the effects of treatment of DOX, DNR, EPI, MTX, and an unrelated monoclonal antibody Trastuzumab (TRZ) on iPSC-derived cardiomyocytes (iPSC-CMs) from six healthy females. All TOP2i induce cell death at concentrations observed in cancer patient serum, while TRZ does not. A sub-lethal dose of all TOP2i induces limited cellular stress but affects calcium handling, a function critical for cardiomyocyte contraction. TOP2i induce thousands of gene expression changes over time, giving rise to four distinct gene expression response signatures, denoted as TOP2i early-acute, early-sustained, and late response genes, and non-response genes. There is no drug- or AC-specific signature. TOP2i early response genes are enriched in chromatin regulators, which mediate AC sensitivity across breast cancer patients. However, there is increased transcriptional variability between individuals following AC treatments. To investigate potential genetic effects on response variability, we first identified a reported set of expression quantitative trait loci (eQTLs) uncovered following DOX treatment in iPSC-CMs. Indeed, DOX response eQTLs are enriched in genes that respond to all TOP2i. Next, we identified 38 genes in loci associated with AC toxicity by GWAS or TWAS. Two thirds of the genes that respond to at least one TOP2i, respond to all ACs with the same direction of effect. Our data demonstrate that TOP2i induce thousands of shared gene expression changes in cardiomyocytes, including genes near SNPs associated with inter-individual variation in response to DOX treatment and AC-induced cardiotoxicity.

Use of Genomics to Develop Novel Therapeutics and Personalize Hypertension Therapy.

Hypertension is a prevalent public health problem, contributing to >10 million deaths annually. Though multiple therapeutics exist, many patients suffer from treatment-resistant hypertension or try several medications before achieving blood pressure control. Genomic advances offer mechanistic understanding of blood pressure variability, therapeutic targets, therapeutic response, and promise a stratified approach to treatment of primary hypertension. Cyclic guanosine monophosphate augmentation, aldosterone synthase inhibitors, and angiotensinogen blockade with silencing RNA and antisense therapies are among the promising novel approaches. Pharmacogenomic studies have also been done to explore the genetic bases underpinning interindividual variability in response to existing therapeutics. A polygenic approach using risk scores is likely to be the next frontier in stratifying responses to existing therapeutics.

Precise Therapy Using the Selective Endogenous Encapsidation for Cellular Delivery Vector System.

Interindividual variability in drug response is a major problem in the prescription of pharmacological treatments. The therapeutic effect of drugs can be influenced by human genes. Pharmacogenomic guidelines for individualization of treatment have been validated and used for conventional dosage forms. However, drugs can often target non-specific areas and produce both desired and undesired pharmacological effects. The use of nanoparticles, liposomes, or other available forms for drug formulation could help to overcome the latter problem. Virus-like particles based on retroviruses could be a potential envelope for safe and efficient drug formulations. Human endogenous retroviruses would make it possible to overcome the host immune response and deliver drugs to the desired target. PEG10 is a promising candidate that can bind to mRNA because it is secreted like an enveloped virus-like extracellular vesicle. PEG10 is a retrotransposon-derived gene that has been domesticated. Therefore, formulations with PEG10 may have a lower immunogenicity. The use of existing knowledge can lead to the development of suitable drug formulations for the precise treatment of individual diseases.

Genetic Biomarkers of Sorafenib Response in Patients with Hepatocellular Carcinoma.

The identification of biomarkers for predicting inter-individual sorafenib response variability could allow hepatocellular carcinoma (HCC) patient stratification. SNPs in angiogenesis- and drug absorption, distribution, metabolism, and excretion (ADME)-related genes were evaluated to identify new potential predictive biomarkers of sorafenib response in HCC patients. Five known SNPs in angiogenesis-related genes, including VEGF-A, VEGF-C, HIF-1a, ANGPT2, and NOS3, were investigated in 34 HCC patients (9 sorafenib responders and 25 non-responders). A subgroup of 23 patients was genotyped for SNPs in ADME genes. A machine learning classifier method was used to discover classification rules for our dataset. We found that only the VEGF-A (rs2010963) C allele and CC genotype were significantly associated with sorafenib response. ADME-related gene analysis identified 10 polymorphic variants in ADH1A (rs6811453), ADH6 (rs10008281), SULT1A2/CCDC101 (rs11401), CYP26A1 (rs7905939), DPYD (rs2297595 and rs1801265), FMO2 (rs2020863), and SLC22A14 (rs149738, rs171248, and rs183574) significantly associated with sorafenib response. We have identified a genetic signature of predictive response that could permit non-responder/responder patient stratification. Angiogenesis- and ADME-related genes correlation was confirmed by cumulative genetic risk score and network and pathway enrichment analysis. Our findings provide a proof of concept that needs further validation in follow-up studies for HCC patient stratification for sorafenib prescription.

Of Mice and Men: The Inter-individual Variability of the Brain's Response to Drugs.

Biological variation is ubiquitous in nature. Despite highly standardized breeding and husbandry under controlled environmental conditions, phenotypic diversity exists in laboratory mice and rats just as it does in humans. The resulting inter-individual variability affects various characteristics of animal disease models, including the responsiveness to drugs. Thus, the common practice of averaging data within an experimental group can lead to misinterpretations in neuroscience and other research fields. In this commentary, the impact of inter-individual variation in drug responsiveness is illustrated by examples from the testing of antiseizure medications in rodent temporal lobe epilepsy models. Individual mice and rats rendered epileptic by treatment according to standardized protocols fall into groups that either do or do not respond to antiseizure medications, thus mimicking the clinical situation in patients with epilepsy. Population responses are not normally distributed, and divergent responding is concealed in averages subjected to parametric statistical tests. Genetic, epigenetic, and environmental factors are believed to contribute to inter-individual variation in drug response but the specific molecular and physiological causes are not well understood. Being aware of inter-individual variability in rodents allows an improved interpretation of both behavioral phenotypes and drug effects in a pharmacological experiment.

Effect of insertion/deletion polymorphism of angiotensin-converting enzyme gene on efficacy of antihypertensive therapy with angiotensin II receptor blockers

The efficacy of the antihypertensive therapy may be related to genetic factors that can influence not only the degree of the blood pressure (BP) elevation but also contribute to the interindividual variability of response to the antihypertensive treatment.The aim of the work was to study pharmacodynamic parameters of the therapy efficacy with angiotensin II receptor blockers in the form of monotherapy and as part of combined drugs in patients with the arterial hypertension depending on the genetic features of patients – polymorphism of the gene encoding angiotensin-converting enzyme, or I/D-polymorphism.Materials and methods. The study included 179 patients of the Moscow region with a first-diagnosed arterial hypertension (AH) of 1–2 degree, including 141 (78.8%) women and 38 (21.2%) men aged from 32 to 69 years. By a simple randomization method, the patients were randomly allocated into groups receiving irbesartan and valsartan as mono- or combination therapy with hydrochlorthiazide. After 3 weeks of this pharmacotherapy, the presence of rs4646994 Alu Ins / Del genetic polymorphism of the angiotensin-converting enzyme (ACE) gene and the minimum equilibrium concentration of angiotensin II receptor blockers (ARBs) were determined.Results. The patients treated with irbesartan, the D/D genotype carriers, were significantly less likely to reach the target BP and more likely to require a pharmacotherapy intensification compared to I/D heterozygotes (p=0.042 and p=0.058, respectively) and I/I homozygotes (p=0.011 and p=0.011, respectively). The patients treated with valsartan, the D/D genotype carriers, significantly more often reached the target BP and significantly less often required a pharmacotherapy intensification than the I/D genotype carriers (p=0.05 and p=0.05, respectively). Herewith, at the end of the study, according to the results of the office BP measurements and daily BP monitoring, the target BP achievement was not significantly correlated with the I/D polymorphism of the ACE gene.Conclusion. When personalizing the AH therapy in patients of the Moscow region, the genotype I/I carriers by I/D polymorphism of the ACE gene, can be recommended irbesartan in the form of mono- or bicomponent therapy as a starting therapy of ARBs; the D/D genotype carriers can be recommended valsartan. A more pronounced decrease in the daytime systolic BP (SBP), the daytime diastolic BP (DBP) and the nighttime SBP variabilities in the valsartan group of patients, the D allele carriers may indicate a more persistent effect of the antihypertensive therapy.

Introduction to the Theme "Pharmacological Individuality: New Insights and Strategies for Personalized and Precise Drug Treatment".

The reviews in Volume 64 of the Annual Review of Pharmacology and Toxicology cover diverse topics. A common theme in many of the reviews is the interindividual variability in the clinical response to drugs. Highlighted areas include emerging developments in pharmacogenomics that can predict the personal risk for drug inefficacy and/or adverse drug reactions. Other reviews focus on the use of circulating biomarkers to define drug metabolism phenotypes and the effect of circadian regulation on drug response. Another emerging technology, digital twins that model individual patients, is used to generate computational simulations of drug effects and identify optimal personalized treatments. Another variable that may affect clinical outcomes, the nocebo response (an adverse reaction to a placebo), complicates clinical trials. These reviews further document that pharmacological individuality is an essential component of the concepts of personalized medicine and precision medicine and will likely have an important impact on patient care.

Molecular and genetic predictors of ovarian response in vitro fertilization programs

The most effective method of treating infertility is in vitro fertilization, the key element of which is ovarian stimulation. Ovarian response in IVF protocols has varying variability among patients. The ovarian response depends on many factors, but none of these factors has sufficient prognostic ability, and therefore the question of the individual ovarian response during stimulation in IVF programs still remains open, and the association of the ovarian response with polymorphisms of certain genes is being actively studied. The most effective IVF programs are observed among patients of young reproductive age. A decrease in the effectiveness of IVF programs and the appearance of complications is observed in patients of advanced reproductive age. Several types of ovarian response have been identified: poor (it is possible to obtain 3 oocytes), normal (from 4 to 15 oocytes), suboptimal response (less than 7 oocytes) and hyperergic response (more than 15 oocytes). Also, there is a group of patients of various age groups with a paradoxical ovarian response to stimulation. The response of oocytes to hormones can be regulated depending on the expression of receptor genes. FSH receptor (FSHR) polymorphism may explain interindividual variability in ovarian response to stimulation. Genetic screening is determined once and does not depend on endogenous and exogenous factors, while allowing you to adjust the dose of gonadotropins in ovarian stimulation protocols. This review presents current data on the polymorphism of the main genes that regulate the ovarian response in stimulating superovulation in in vitro fertilization programs.

Pharmacokinetic-pharmacodynamic analysis of drug liking blockade by buprenorphine subcutaneous depot (CAM2038) in participants with opioid use disorder

Buprenorphine is used to treat opioid use disorder (OUD). Weekly and monthly subcutaneous long-acting buprenorphine injections (CAM2038) provide more stable buprenorphine plasma levels and reduce the treatment burden, misuse, and diversion associated with sublingual transmucosal buprenorphine formulations. To characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship, a maximum inhibition (Imax) model was developed relating CAM2038 buprenorphine plasma concentration to drug liking maximum effect (Emax) visual analog scale (VAS; bipolar) score after intramuscular hydromorphone administration. Data included time-matched observations of buprenorphine plasma concentration and drug liking Emax VAS score after hydromorphone 18 mg administration in 47 non-treatment-seeking adults with moderate to severe OUD in a phase 2 study. Analysis used non-‍linear mixed-effects modeling (NONMEM®). The final Imax model adequately described the PK/PD relationship between buprenorphine plasma concentration and drug liking Emax VAS score. Simulations showed drug liking was effectively blocked at low buprenorphine plasma concentrations (0.4 ng/mL) where the upper 95% confidence interval of the drug liking Emax VAS score was below the pre-defined 11-point complete blockade threshold. The buprenorphine plasma concentration required to achieve 90% of the maximal effect (IC90) of drug liking was 0.675 ng/mL. Interindividual variability in responses to buprenorphine was observed; some participants experienced fluctuating responses, and a few did not achieve drug liking blockade even with higher buprenorphine plasma concentrations. This affirms the need to individualize treatment and titrate doses for optimal treatment outcomes. PK/PD models were also developed for desire to use VAS and Clinical Opiate Withdrawal Scale (COWS) scores, with results aligned to those for drug liking.

Polymorphisms and Pharmacogenomics of NQO2: The Past and the Future.

The flavoenzyme N-ribosyldihydronicotinamide (NRH):quinone oxidoreductase 2 (NQO2) catalyzes two-electron reductions of quinones. NQO2 contributes to the metabolism of biogenic and xenobiotic quinones, including a wide range of antitumor drugs, with both toxifying and detoxifying functions. Moreover, NQO2 activity can be inhibited by several compounds, including drugs and phytochemicals such as flavonoids. NQO2 may play important roles that go beyond quinone metabolism and include the regulation of oxidative stress, inflammation, and autophagy, with implications in carcinogenesis and neurodegeneration. NQO2 is a highly polymorphic gene with several allelic variants, including insertions (I), deletions (D) and single-nucleotide (SNP) polymorphisms located mainly in the promoter, but also in other regulatory regions and exons. This is the first systematic review of the literature reporting on NQO2 gene variants as risk factors in degenerative diseases or drug adverse effects. In particular, hypomorphic 29 bp I alleles have been linked to breast and other solid cancer susceptibility as well as to interindividual variability in response to chemotherapy. On the other hand, hypermorphic polymorphisms were associated with Parkinson's and Alzheimer's disease. The I and D promoter variants and other NQO2 polymorphisms may impact cognitive decline, alcoholism and toxicity of several nervous system drugs. Future studies are required to fill several gaps in NQO2 research.

Assessment of inter-individual variability in hamstring muscle recovery after a sport-specific sprint training in women and men.

Background: Hamstring muscles are most affected by multiple sprint-based sports as a result of muscle strain during sprinting, leading to reduced performance and increased risk of injury. Therefore, the purpose of the study was to assess inter-individual variability in hamstrings recovery after a sport-specific repeated-sprint training (RST), through sprint-specific markers of muscle recovery and associated muscle damage biomarkers in women and men. Methods: Healthy females (n = 14) and males (n = 15) underwent 10 repeated 40-m sprints with a 3-min rest pause between each repetition. Force-generating capacity (FGC) by the 90° hip :20° knee test and range of motion Jurdan test, together with serum biomarkers [sarcomeric mitochondrial creatine kinase (sMtCK), oxidative stress, irisin] were tested at baseline and 24-, 48- and 72-h post-exercise through a repeated measures design. Participants were classified according to FGC loss into high responders (HR) and low responders (LR). Results: 21 individuals (10 females, 11 males) were classified as HR (FGC loss >20% and recovery >48h), while 8 individuals (4 females, 4 males) were classified as LR. HR individuals showed unrecovered maximal voluntary isometric contraction (MVIC) torque until 72h post-training (p = 0.003, np 2 = 0.170), whereas only HR males showed decreased range of motion (p = 0.026, np 2 = 0.116). HR individuals also showed increased sMtCK (p = 0.016, np 2 = 0.128), oxidative stress (p = 0.038, np 2 = 0.106) and irisin (p = 0.019, np 2 = 0.123). Conclusion: There is inter-individual variability in the muscular response to a sport-specific RST, identifiable by MVIC torque assessment. The findings support that the 90° hip :20° knee test is a powerful indirect test to screen hamstrings recovery in both women and men, in a cost-effective way. However, the Jurdan test might not be able to monitor hamstrings recovery in sportswomen after RST. Decreases in muscle capacity are linked to damage to muscle sarcolemma and mitochondria until 72h post-exercise. Overall, 72h will not be adequate time to restore hamstrings structure and function after a sport-specific RST in both female and male responders.

The effect of calcaneus and metatarsal head offloading insoles on healthy subjects' gait kinematics, kinetics, asymmetry, and the implications for plantar pressure management: A pilot study.

The global number of people with diabetes is estimated to reach 643 million by 2030 of whom 19-34% will present with diabetic foot ulceration. Insoles which offload high-risk ulcerative regions on the foot, by removing insole material, are the main contemporary conservative treatment to maintain mobility and reduce the likelihood of ulceration. However, their effect on the rest of the foot and relationship with key gait propulsive and balance kinematics and kinetics has not been well researched. The aim of this study is to investigate the effect of offloading insoles on gait kinematics, kinetics, and plantar pressure throughout the gait cycle. 10 healthy subjects were recruited for this experiment to walk in 6 different insole conditions. Subjects walked at three speeds on a treadmill for 10 minutes while both plantar pressure and gait kinematics, kinetics were measured using an in-shoe pressure measurement insole and motion capture system/force plates. Average peak plantar pressure, pressure time integrals, gait kinematics and centre of force were analysed. The average peak plantar pressure and pressure time integrals changed by -30% (-68% to 3%) and -36% (-75% to -1%) at the region of interest when applying offloading insoles, whereas the heel strike and toe-off velocity changed by 15% (-6% to 32%) and 12% (-2% to 19%) whilst walking at three speeds. The study found that offloading insoles reduced plantar pressure in the region of interest with loading transferred to surrounding regions increasing the risk of higher pressure time integrals in these locations. Heel strike and toe-off velocities were increased under certain configurations of offloading insoles which may explain the higher plantar pressures and supporting the potential of integrating kinematic gait variables within a more optimal therapeutic approach. However, there was inter-individual variability in responses for all variables measured supporting individualised prescription.