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New findings What is the topic of this review? We review biological and methodological factors associated with the variable changes in cardiorespiratory fitness in response to endurance training. What advances does it highlight? Several biological and methodological factors exist that each contribute, to a given extent, to response variability. Notably, prescribing exercise intensity relative to physiological thresholds reportedly increases cardiorespiratory fitness response rates compared to when prescribed relative to maximum physiological values. As threshold-based approaches elicit more homogenous acute physiological responses among individuals, when repeated over time, these uniform responses may manifest into more homogenous chronic adaptations thereby reducing response variability. Abstract Changes in cardiorespiratory fitness (CRF) in response to endurance training (ET) exhibit large variations, possibly due to a multitude of biological and methodological factors. It is acknowledged that ∼20% of individuals may not achieve meaningful increases in CRF in response to ET. Genetics, the most potent biological contributor, has been shown to explain ∼50% of response variability, whilst age, sex, and baseline CRF appear to explain a smaller proportion. Methodological factors represent the characteristics of the ET itself including the type, volume, and intensity of exercise, as well as the method used to prescribe and control exercise intensity. Notably, methodological factors are modifiable and, upon manipulation, alter response rates to ET, eliciting increases in CRF regardless of an individual's biological predisposition. Particularly, prescribing exercise intensity relative to a physiological threshold (e.g. ventilatory threshold) is shown to increase CRF response rates compared to when intensity is anchored relative to a maximum physiological value (e.g. maximum heart rate). It is, however, uncertain whether the increased response rates are primarily attributable to reduced response variability, greater mean changes in CRF, or both. Future research is warranted to elucidate whether more homogenous chronic adaptations manifest over time among individuals, as a result of exposure to more homogenous exercise stimuli elicited by threshold-based practices. This article is protected by copyright. All rights reserved.

Acute cannabis intoxication may induce neurocognitive impairment and is a possible cause of human error, injury and psychological distress. One of the major concerns raised about increasing cannabis legalization and the therapeutic use of cannabis is that it will increase cannabis-related harm. However, the impairing effect of cannabis during intoxication varies among individuals and may not occur in all users. There is evidence that the neurocognitive response to acute cannabis exposure is driven by changes in the activity of the mesocorticolimbic and salience networks, can be exacerbated or mitigated by biological and pharmacological factors, varies with product formulations and frequency of use and can differ between recreational and therapeutic use. It is argued that these determinants of the cannabis-induced neurocognitive state should be taken into account when defining and evaluating levels of cannabis impairment in the legal arena, when prescribing cannabis in therapeutic settings and when informing society about the safe and responsible use of cannabis. Acute cannabis exposure modulates numerous aspects of neurocognitive function; however, the effects experienced by individuals are highly variable. Ramaekers and colleagues here review the neural basis of cannabis-induced neurocognitive changes and response variability, and consider the legal, therapeutic and societal implications.

Clinicopathological studies have demonstrated that Alzheimer’s disease dementia (ADD) is often accompanied by clinically undetectable comorbid neurodegenerative and cerebrovascular disease that alter the presence and rate of cognitive decline in aging and ADD. Aside from causing increased variability in clinical response, it is possible that the major ADD comorbidities may not respond to ADD-specific molecular therapeutics. As most reports have focused on comorbidity in the oldest-old, its extent in younger age groups that are more likely to be involved in clinical trials is largely unknown. We conducted a survey of neuropathological comorbidities in sporadic ADD using data from the US National Alzheimer’s Coordinating Center. Subject data was restricted to those with dementia and meeting National Institute on Aging-Alzheimer’s Association (NIA-AA) intermediate or high AD Neuropathological Change (ADNC) levels, excluding those with known autosomal dominant AD-related mutations. Subjects were divided into age-at-death categories for analysis: under 60, 60-69, 70-79, 80-89, 90-99 and 100 or over. Confirmatory of earlier reports, ADD histopathology is less severe with advancing age, effectively increasing the relative contribution of comorbidities, most of which rise in prevalence with age. Highly prevalent ADD comorbidities are not restricted to the oldest-old but are common even in early-onset ADD. The percentage of cases with ADD as the sole major neuropathological diagnosis is highest in the under-60 group, where “pure” ADD cases are still in the minority at 44%. After this AD as a sole major pathology in ADD declines to roughly 20% in the 70s and beyond. Comorbidity rates for some pathologies, especially LBD, are high even in subjects in their 60s and 70s, at nearly 60%, but for most others, their prevalence increases with age. TDP-43 pathology affects more than 35% of ADD subjects 80 and over while microscopic infarcts reach this rate a decade later. Gross infarcts rise more slowly and affect fewer subjects but still involve 15-20% of ADD after age 80. White matter rarefaction may be underestimated in the NACC database but is present in almost 70% of centenarians with ADD. Effective clinical trials depend on accurate estimates of required subject numbers, which are dependent on observed effect size and clinical response variability. Comorbidities are likely to affect both, leading to lower probability of clinical trial success. Stratifying ADD clinical trial analyses by presence and types of accompanying comorbidities might identify subgroups with higher effect sizes and greater clinical response rates, but accurate in-vivo diagnostic methods for most comorbidities are still lacking.

Juvenile hormone (JH) or juvenile hormone analog (JHA) can induce soldier formation in termites. However, different studies have yielded inconsistent results on the effects of JHA on soldier production in Coptotermes formosanus Shiraki. Using filter paper as the testing substrate, the effects of JH III, pyriproxyfen and methoprene on the intact filter paper left, worker mortality and presoldier formation were tested on six colonies. Our results showed that pyriproxyfen and methoprene were more repellent than JH III. No significant difference in toxicity was observed among methoprene, pyriproxyfen and JH III. JH III and pyriproxyfen did not cause workers to differentiate into presoldiers, but methoprene can induce formation of presoldiers. Colony response variability to methoprene was observed. The confirmation of the effects of JH/JHA on C. formosanus establishes the foundation for molecular studies of soldier differentiation in this species.

Background Many studies have attempted to identify the sources of interindividual variability in response to theta-burst stimulation (TBS). However, these studies have been limited by small sample sizes, leading to conflicting results. Objective/Hypothesis This study brought together over 60 TMS researchers to form the ‘Big TMS Data Collaboration’, and create the largest known sample of individual participant TBS data to date. The goal was to enable a more comprehensive evaluation of factors driving TBS response variability. Methods 118 corresponding authors of TMS studies were emailed and asked to provide deidentified individual TMS data. Mixed-effects regression investigated a range of individual and study level variables for their contribution to iTBS and cTBS response variability. Results 430 healthy participants’ TBS data was pooled across 22 studies (mean age = 41.9; range = 17–82; females = 217). Baseline MEP amplitude, age, target muscle, and time of day significantly predicted iTBS-induced plasticity. Baseline MEP amplitude and timepoint after TBS significantly predicted cTBS-induced plasticity. Conclusions This is the largest known study of interindividual variability in TBS. Our findings indicate that a significant portion of variability can be attributed to the methods used to measure the modulatory effects of TBS. We provide specific methodological recommendations in order to control and mitigate these sources of variability.

How can we measure the absence of awareness? Attention research has developed tools for measuring self-caught meta-awareness restoration and behavioral mind-wandering, but we lack a way to dynamically track the loss of meta-awareness. The present pre-registered study sought to bring together three extant paradigms into one tool designed to dynamically measure meta-awareness: the Metronome Counting Task (MCT). The MCT is a continuous performance task wherein participants tap along to a steady beat while counting to 20, indicating the final count by a special button press. This sample (N = 74) provides evidence that participants could self-catch their failures in the task, that a response variability metric measuring mind-wandering depth was successfully recreated in this new tool, and that dynamic performance changes may be useful for detecting meta-awareness loss before participants become internally aware of the loss or are caught by external errors. The MCT was conceived as a tool that will support neuroimaging models of dynamic fluctuations during sustained attention, providing a link between the phenomenology of meta-awareness, the behavior measured by a replicable index of task engagement, and a continuous performance task on time-scales relevant for MRI. We discuss the possibility that meta-awareness may exist on a continuum and that conceptions of mind-wandering as attention failures may plausibly be reconceived as changes in goal priority manifesting as shifting task engagement.

Research examining the efficacy of cognitive behavioral therapy (CBT) in reducing recidivism has paid little attention to treatment factors contributing to response variability. Using an archival sample of 448 participants exposed to a risk-need-responsivity (RNR)-informed CBT program or no treatment, a multigroup latent profile analysis yielded a four-profile solution: a treatment-nonresponsive group and three treatment-responsive groups. Among the treatment-responsive profiles, reduced criminal attitudes were most predictive of desistance from reoffending. Elevated rates of recidivism and negligible gains following treatment were associated with pretreatment elevations in antisocial traits, risk level, and negative attitudes toward treatment. These findings underscore a greater need for individualized assessment of risk and treatment motivation, the importance of altering criminal sentiments to prevent reentry into the system upon release, and challenge the idea that 200 hours of treatment is sufficient for lasting change. Study limitations and further directions are discussed, including the need for correctional treatment outcome research to better isolate individual differences.

A new method of calculating attentional bias from the dot-probe task measures fluctuations in bias towards and away from emotional stimuli over time using trial level bias score metrics. We assessed the stability and reliability of traditional attentional bias scores and trial level bias score measures of attentional bias across time in two five-block dot-probe task experiments in non-clinical samples. In experiments 1 and 2, both traditional attentional bias scores and trial level bias score measures of attentional bias did not habituate/decrease across time. In general, trial level bias score metrics (i.e., attention bias variability as well as the mean biases toward and away from threat) were more reliable than the traditional attention bias measure. This pattern was observed across both experiments. The traditional bias score, however, did improve in reliability in the later blocks of the fearful face dot-probe task. Although trial level bias score measures did not habituate and were more reliable across blocks, these measures did not correlate with state or trait anxiety. On the other hand, trial level bias score measures were strongly correlated with general reaction time variability—and after controlling for this effect no longer superior in reliability in comparison to the traditional attention bias measure. We conclude that general response variability should be removed from trial level bias score measures to ensure that they truly reflect attention bias variability.

Response variability between individuals (interindividual variability) and within individuals (intraindividual variability) is an important issue in the transcranial magnetic stimulation (TMS) literature. This has raised questions of the validity of TMS to assess changes in corticospinal excitability (CSE) in a predictable and reliable manner. Several participant-specific factors contribute to this observed response variability with a current lack of consensus on the degree each factor contributes. This highlights a need for consistency and structure in reporting study designs and methodologies. Currently, there is no summarized review of the participant-specific factors that can be controlled and may contribute to response variability. This systematic review aimed to develop a checklist of methodological measures taken by previously published research to increase the homogeneity of participant selection criteria, preparation of participants before experimental testing, participant scheduling, and the instructions given to participants throughout experimental testing to minimize their effect on response variability. Seven databases were searched in full. Studies were included if CSE was measured via TMS and included methodological measures to increase the homogeneity of the participants. Eighty-four studies were included. Twenty-three included measures to increase participant selection homogeneity, 21 included measures to increase participant preparation homogeneity, while 61 included measures to increase participant scheduling and instructions during experimental testing homogeneity. These methodological measures were summarized into a user-friendly checklist with considerations, suggestions, and rationale/justification for their inclusion. This may provide the framework for further insights into ways to reduce response variability in TMS research.

Transcranial magnetic stimulation (TMS) is used in several FDA-approved treatments and, increasingly, to treat neurological disorders in off-label uses. However, the mechanism by which TMS causes physiological change is unclear, as are the origins of response variability in the general population. Ideally, objective in vivo biomarkers could shed light on these unknowns and eventually inform personalized interventions. Continuous theta burst stimulation (cTBS) is a form of TMS which has been observed to reduce motor evoked potentials (MEPs) for 60 minutes or longer post-stimulation, although the consistency of this effect and its mechanism continue to be under debate. Here, we use glutamate-weighted chemical exchange saturation transfer (gluCEST) magnetic resonance imaging (MRI) at ultra-high magnetic field (7T) to measure changes in glutamate concentration at the site of cTBS. We find that gluCEST signal in the ipsilateral hemisphere of the brain generally decreases in response to cTBS, whereas consistent changes were not detected in the contralateral or in subjects receiving a sham stimulation.One Sentence SummaryWe used glutamate-weighted Chemical Exchange Saturation Transfer (GluCEST) imaging to detect changes in glutamate contrast in the brains of young, healthy adults undergoing transcranial magnetic stimulation (TMS) to the motor cortex.

Metabolomic indicators of asthma treatment responses have yet to be identified. In this study, we aimed to uncover plasma metabolomic profiles associated with asthma exacerbations while on inhaled corticosteroid (ICS) treatment. We determined whether these profiles change with age from adolescence to adulthood. We utilized data from 170 individuals with asthma on ICS from the Mass General Brigham Biobank to identify plasma metabolites associated with asthma exacerbations while on ICS and examined potential effect modification of metabolite-exacerbation associations by age. We used liquid chromatography–high-resolution mass spectrometry-based metabolomic profiling. Sex-stratified analyses were also performed for the significant associations. The age range of the participating individuals was 13–43 years with a mean age of 33.5 years. Of the 783 endogenous metabolites tested, eight demonstrated significant associations with exacerbation after correction for multiple comparisons and adjusting for potential confounders (Bonferroni p value &lt, 6.2 × 10−4). Potential effect modification by sex was detected for fatty acid metabolites, with males showing a greater reduction in their metabolite levels with ICS exacerbation. Thirty-eight metabolites showed suggestive interactions with age on exacerbation (nominal p-value &lt, 0.05). Our findings demonstrate that plasma metabolomic profiles differ for individuals who experience asthma exacerbations while on ICS. The differentiating metabolites may serve as biomarkers of ICS response and may highlight metabolic pathways underlying ICS response variability.

Aim Observed effects of exercise are highly variable between individuals, and subject‐by‐training interaction (i.e., individual response variability) is often not estimated. Here, we measured mitochondrial (citrate synthetase, cytochrome‐c oxidase, succinate dehydrogenase, and mitochondrial copy‐number), performance markers (W peak, lactate threshold [LT], and VO2peak), and fiber type proportions/expression (type I, type IIa, and type IIx) in multiple time points during 12‐week of high‐intensity interval training (HIIT) to investigate effects of exercise at the individual level. Methods Sixteen young (age: 33.1 ± 9.0 years), healthy men (VO2peak 35–60 ml/min/kg and BMI: 26.4 ± 4.2) from the Gene SMART study completed 12‐week of progressive HIIT. Performance markers and muscle biopsies were collected every 4 weeks. We used mixed‐models and bivariate growth models to quantify individual response and to estimate correlations between variables. Results All performance markers exhibited significant (W peak 0.56 ± 0.33 p = 0.003, LT 0.37 ± 0.35 p = 0.007, VO2peak 3.81 ± 6.13 p = 0.02) increases overtime, with subject‐by‐training interaction being present (95% CI: W peak 0.09–0.24, LT 0.06–0.18, VO2peak 0.27–2.32). All other measurements did not exhibit significant changes. Fiber type IIa proportions at baseline was significantly associated with all physiological variables (p, Exercise training leads to whole body and tissue‐specific adaptations. However, the observed effects of exercise are highly variable between individuals, and subject‐by‐training interaction (i.e., individual response variability) is often not estimated. Here, we measured mitochondrial (citrate synthetase, cytochrome‐c oxidase, succinate dehydrogenase and mitochondrial copy‐number), performance markers (W peak, lactate threshold, and VO2peak) and fiber type proportions/expression (type I, type IIa, and type IIx) in multiple time points during 12‐week of high‐intensity interval training to investigate effects of exercise at the individual level, and if measurement changes in different domains covary each other as exercise goes by.

Researchers have demonstrated the efficacy of picture prompts on the acquisition of intraverbals (Coon & Miguel in Journal of Applied Behavior Analysis, 45, 657–666, 2012; Goldsmith, LeBlanc, & Sautter in Research in Autism Spectrum Disorders, 1, 1–13, 2007; Ingvarsson & Hollobaugh in Journal of Applied Behavior Analysis, 44, 659–664, 2011; Ingvarsson & Le in The Analysis of Verbal Behavior, 27, 75–93, 2011; Miguel, Petursdottir, & Carr in The Analysis of Verbal Behavior, 21, 27–41, 2005; Partington & Bailey in The Analysis of Verbal Behavior, 11, 9–18, 1993). However, no one (to our knowledge) has determined the effects of picture prompts on the variability of responding during intraverbal categorization. We evaluated the use of a scenic picture prompt on response variability during the acquisition of intraverbal categorization with 4 children diagnosed with autism. All children mastered the task and initially demonstrated varied responding. However, responding eventually became invariant for all children. These results demonstrate the efficacy of a scenic picture prompt for teaching children with autism intraverbal categorization and for producing initial response variability. Additional research should be conducted to determine teaching procedures that promote continued varied responding for individuals with autism.

Background Statins have shown multiple effects on different renal risk factors such as lowering of total cholesterol (TC) and lowering of urine protein:creatinine ratio (UPCR). We assessed whether these effects of statins vary between individuals, the extent of discordance of treatment effects on both TC and UPCR within an individual, and the association of responses in TC and UPCR with estimated glomerular filtration rate (eGFR) decline. Methods The PLANET I and II (Renal effects of Rosuvastatin and Atorvastatin in Patients Who Have Progressive Renal Disease) trials examined effects of atorvastatin and rosuvastatin on proteinuria and renal function in patients with proteinuria. We post hoc analysed 471 therapy-adherent proteinuric patients from the two trials and assessed the individual variability in UPCR and TC response from 0 to 14 weeks and whether these responses were predictive of eGFR decline during the subsequent 9 months of follow-up. Results UPCR and TC response varied between individuals: mean UPCR response was −1.3% (5th–95th percentile −59.9 to 141.8) and mean TC response was −93.9 mg/dL (−169.1 to −26.9). Out of 471 patients, 123 (26.1%) showed a response in UPCR but not in TC, and 96 (20.4%) showed a response in TC but not in UPCR. eGFR (mL/min/1.73 m2) did not decrease significantly from baseline in both UPCR responders [0.4; 95% confidence interval (CI) −1.6 to 0.9; P = 0.54] and TC responders (0.3; 95% CI −1.8 to 1.1; P = 0.64), whereas UPCR and TC non-responders showed a significant decline in eGFR from baseline (1.8; 95% CI 0.6–3.0; P = 0.004 and 1.7; 95% CI 0.5–2.9; P = 0.007, respectively). A lack of response in both parameters resulted in the fastest rate of eGFR decline (2.1; 95% CI 0.5–3.7; P = 0.01). These findings were not different for rosuvastatin or atorvastatin. Conclusions Statin-induced changes in cholesterol and proteinuria vary between individuals and do not run in parallel within an individual. The initial fall in cholesterol and proteinuria is independently associated with a reduction in eGFR decline. This highlights the importance of monitoring both cholesterol and proteinuria after initiating statin therapy.

Ergonomists measure height loss in relation to loads imposed on the spine. It is difficult to interpret whether height loss responses recorded on different days are accurate due to natural daily fluctuations in height loss and measurement variability. The objective of this research was to investigate whether the variability of height loss in the sitting position is affected by time of day and to analyse day-to-day variability in asymptomatic participants. Fifty asymptomatic participants attended two sessions (morning and afternoon) of stadiometry testing on four separate days. The results showed that a variability of height loss response changes in excess of 0.886 mm in morning and 1.128 mm in afternoon between days indicates that an intervention itself has influenced height loss. Future investigations on height loss in sitting should take theseresults into consideration to confidently state that an intervention has influenced height lossresponse at each time of day. Refereed/Peer-reviewed

Individuals with complex communication needs are likely to experience considerable difficulties and challenges with everyday communication interactions due to limited use and understanding of natural speech. In this editorial, we review the nature of complex communication needs, describe the wide range of individuals who may experience such needs, and provide a brief history of behavioral approaches to addressing these needs. We also highlight the six papers in this special issue that contribute to the further understanding of the use of behavioral intervention approaches for addressing complex communication needs. These papers include one conceptual overview of aided augmentative and alternative communication (AAC) interventions for individuals with complex communication needs, four intervention studies addressing a range of communicative topographies (i.e., vocal speech, AAC, and a social messaging app), and one systematic review examining interventions that promote communicative response variability. These six papers highlight the diversity of complex communication needs and emphasize the importance of examining the efficacy of a wide range of individualized behavioral approaches that are matched to specific needs and goals.

Актуальность. Основанием для проведения данного исследования послужило наличие группы пациентов с бронхиальной астмой (БА), которые предпочитают для купирования приступов удушья использовать короткодействующие антихолинергические препараты (КДХП). Цель. Изучение возможной низкой эффективности длительно действующих Р2-агонистов (ДДБА) у пациентов с БА, не имеющих достаточного ответа на КДБА, а также вероятности уменьшения бронхиальной обструкции с помощью длительно действующих антихолинергических препаратов (ДДХП) у этих пациентов. Материалы и методы. В исследовании приняли участие 12 взрослых некурящих пациентов с БА средней степени тяжести (III-IV ступень по GINA), получавшие в качестве базисной терапии ИГКС в средних или высоких дозах в сочетании с ДДБА, при этом характеризовались отсутствием или неполным контролем над симптомами БА. В первую (n7) группу были определены пациенты с клинически и инструментально подтвержденной эффективностью сальбутамола, которые в то же время имели хороший ответ на ипратропия бромид (КДБАКДХП). Во вторую группу (n5) вошли пациенты с низким ответом на саль-бутамол и положительным тестом с ипратропия бромидом (КДБА-КДХП). Пациентам проводили серию исследований функции внешнего дыхания (ФВД) до и через 5, 10, 15, 30, 60, 120 и 240 мин после ингаляции бронхолитического средства (салметерола 50 мкг, формотерола 12 мкг и тиотропия бромида 18 мкг). Результаты. Было показано, что пациенты с БА и фенотипом КДБА-КДХП имеют низкий ответ на ДДБА: максимальный прирост ОФВгпосле ингаляции сальметерола составил 7,641,67 и 156,0116,03 мл, а после формотерола 9,435,84, 166,71103,14 мл (в сравнении с группой КДБАКДХП, где ответ на сальметерол составил 20,812,42 и 551,4393,94 мл, а на формотерол 30,216,75 и 718,57140,78 мл), и хороший ответ на ДДХП (13,735,78 и 250,0361,61). Заключение. Результаты исследования дают основание к выделению отдельного фенотипа БА с низкой обратимостью бронхиальной обструкции в ответ на КДБА и достаточной обратимостью в ответ на КДХП (КДБА-КДХП). Этой группе пациентов в качестве базисной терапии следует рассматривать сочетание ИГКСДДБА и ДДХП (тиотропия бромида).Background. The aim of this study was to analyse the group of patients with asthma, who prefer to use short-acting anticholinergics (SAMA) for relief of asthma attacks. At the same time, these patients are prescribed inhaled glucocorticosteroids (ICS) in combination with long-acting P2-agonists (LABA) as a basic therapy according to the standards. Tha aim. To study the cause of low efficacy of LABA in patients with asthma who do not have a sufficient response to SABA, as well as the probability of reducing of bronchial obstruction with LAMA. Materials and methods. 12 non-smoking adults with moderate to severe asthma (III-IV stage of GINA), receiving medium or high doses of ICS in combination with LABA as a basic therapy without adequate control over asthma symptoms were included in the study. First group of patients showed the efficacy of salbutamol (FEV1reversibility was more than 12 and more than 200 ml after 400 g of salbutamol) and ipratropium bromide (SABASAMA). Second group included patients with low response to salbutamol and positive test (FEVtreversibility) with ipratropium bromide (SABA-SAMA). Spirometry was performed at baseline point and in 5, 10, 15, 30, 60, 120 and 240 min after inhalation of bronchodilator (salmeterol 50 g, formoterol 12 g and tiotropium bromide 18 g in the different days). Results. It was shown that SABA-SAMA phenotype asthma patients demonstrated low response to LABA: FEV1increased up to 7.641.67, 156.016.0 ml after salmeterol inhalation and up to 9.45.8, 166.7103.1 ml after formoterol inhalation (compared with a group of SABASAMA, where the response to salmeterol was 20.812.42, 551.4393.94 ml and the response to formoterol was 30.216.75, 718.57140.78 ml, p0.05), and a good response to LAMA (13.75.8 and 250.061.6). Conclusion. The results of the study allowed to define asthma phenotype with low bronchial obstruction reversibility to SABA and sufficient reversibility to SAMA (SABA-SAMA). This group of asthma patients need the basic treatment with the combination of ICS and LABA and LAMA (tiotropium bromide).

We aim to investigate the counting response variations of positron emission tomography (PET) scanners with different detector configurations in the presence of solitary pulmonary nodule (SPN). Using experimentally validated Monte Carlo simulations, the counting performance of four different scanner models with varying tumor activity, location, and patient obesity is represented using a noise equivalent count rate (NECR). NECR is a well-established quantitative metric which has positive correlation with clinically perceived image quality. The combined effect of tumor displacement and increased activity shows a linear ascending trend for NECR with slope ranges of (12.5–18.2)*10−3 (kBq/cm3)−1 for three-ring (3R) scanners and (15.3–21.5)*10−3 (kBq/cm3)−1 for four-ring (4R). The trend for the combined effect of tumor displacement and patient obesity is exponential decay with 3R configurations weakly dependent on the patient obesity if the tumor is located at the center of the field of view with exponent’s range of (6.6–33.8)*10−2cm−1. The dependence is stronger for 4R scanners (9.6–38.5)*10−2cm−1. The analysis indicates that quantitative PET data from the same SPN patient possibly examined in different time points (e.g., during staging or for the evaluation of treatment response) are affected by the different detector configurations and need to be normalized with patient weight, activity, and tumor location to reduce unwanted bias of the diagnosis. This paper provides also with a proof of concept for the ability of properly tuned simulations to provide additional insights into the counting response variability especially in tumor types where often borderline decisions have to be made regarding their characterization.

Interventions aimed at increasing communicative response variability hold particular importance for individuals with autism spectrum disorders (ASD). Several procedures have been demonstrated in the applied and translational literature to increase response variability. However, little is known about the relationship between reinforcer magnitude and response variability. In the basic literature, Doughty, Giorno, and Miller evaluated the effects of reinforcer magnitude on behavioral variability by manipulating reinforcer magnitude across alternating relative frequency threshold contingencies, with results suggesting that larger reinforcers induced repetitive responding. The purpose of this study was to translate Doughty et al.’s findings to evaluate the relative effects of different magnitudes of reinforcement on communicative response variability in children with ASD. A Lag 1 schedule of reinforcement was in place during each condition within an alternating treatments design. Magnitudes of reinforcement contingent on variable communicative responding were manipulated across the two conditions. Inconsistent with basic findings, the results showed higher levels of variable communicative responding associated with the larger magnitude of reinforcement. These outcomes may have potential implications for interventions aimed at increasing response variability in individuals with ASD, as well as future research in this area.

Clopidogrel is widely prescribed in patients with cardiovascular disease. Most research has focused on the role of hepatic CYP450 metabolism as the primary source of response variability despite 85-90% of clopidogrel being hydrolyzed by human carboxylesterase-1 (CES1).The purpose of this study is to determine the effects of the known CES1 inhibitor alcohol on clopidogrel metabolism: (1)

Aim To examine the impact of deep brain stimulation (DBS) on gross motor function in children with dystonic movement disorders. Method Prospective audit involving children implanted 2007–2015, followed for up to two years. Outcomes were evaluated across aetiological sub-groups (inherited, acquired, idiopathic) using the GMFM-88 and BFMDRS movement scale (BFM-M). The predictive value of proportion of life lived with dystonia (PLD) and baseline motor capacity were evaluated. Results Data was available for 60 children (median surgery age 10y11mo). Inherited monogenetic dystonias demonstrated a median increase in GMFM-88 scores of 6.9% (p = 0.021) and 14.5% (p = 0.116) at one and two years. Heredodegenerative and idiopathic dystonias showed disparate responses, with non-significant changes seen in GMFM-88 and BFM-M scores, with the exception of improved one-year BFM-M scores in the idiopathic group [median change 5.5, p = 0.021]. Median GMFM-88 and BFM-M change scores were near zero for acquired dystonias, though improvement was noted in 9/18 CP cases with one-year GMFM-88 data. No significant relationship was found between PLD, or baseline GMFM-88, and GMFM-88 change following DBS. Conclusion Gross motor response to DBS is similar in profile to literature reporting results using impairment-based dystonia rating scales. Relatively consistent improvements were seen in inherited monogenetic (“primary”) dystonias, while highly variable, often disappointing, gross motor responses were found in acquired, heredodegenerative, and idiopathic dystonias. In view of such response variability, alternatives to mean group studies, such as single case experimental designs with multiple replications, are needed to determine the efficacy of DBS in childhood-onset dystonias. Ongoing research is needed to identify factors that predict treatment response.

Sensory feedback shapes ongoing behavior and may produce learning and memory. Motor responses to edible or inedible food in a reduced Aplysia preparation were examined to test how sensory feedback affects behavior and memory. Feeding patterns were initiated by applying a cholinomimetic onto the cerebral ganglion. Feedback from buccal muscles increased the response variability and response rate. Repeated application of the cholinomimetic caused decreased responses, expressed in part by lengthening protractions. Swallowing strips of “edible” food, which in intact animals induces learning that enhances ingestion, increased the response rate, and shortened the protraction length, reflecting more swallowing. Testing memory by repeating the procedure prevented the decrease in response rate observed with the cholinomimetic alone, and shortened protractions. Training with “inedible” food that in intact animals produces learning expressed by decreased responses caused lengthened protractions. Testing memory by repeating the procedure did not cause decreased responses or lengthened protractions. After training and testing with edible or inedible food, all preparations were exposed to the cholinomimetic alone. Preparations previously trained with edible food displayed memory expressed as decreased protraction length. Preparations previously trained with inedible food showed decreases in many response parameters. Memory for inedible food may arise in part via a postsynaptic decrease in response to acetylcholine released by afferents sensing food. The lack of change in response number, and in the time that responses are maintained during the two training sessions preceding application of the cholinomimetic alone suggests that memory expression may differ from behavioral changes during training.

There is evidence from human twin and family studies as well as mouse and rat selection experiments that there are considerable interindividual differences in the response of cardiorespiratory fitness (CRF) and other cardiometabolic traits to a given exercise programme dose. We developed this consensus statement on exercise response variability following a symposium dedicated to this topic. There is strong evidence from both animal and human studies that exercise training doses lead to variable responses. A genetic component contributes to exercise training response variability.In this consensus statement, we (1) briefly review the literature on exercise response variability and the various sources of variations in CRF response to an exercise programme, (2) introduce the key research designs and corresponding statistical models with an emphasis on randomised controlled designs with or without multiple pretests and post-tests, crossover designs and repeated measures designs, (3) discuss advantages and disadvantages of multiple methods of categorising exercise response levels—a topic that is of particular interest for personalised exercise medicine and (4) outline approaches that may identify determinants and modifiers of CRF exercise response. We also summarise gaps in knowledge and recommend future research to better understand exercise response variability.

Skill learning is fundamental to the acquisition of many complex behaviors that emerge during development. For example, years of practice give rise to perceptual improvements that contribute to mature speech and language skills. While fully honed learning skills might be thought to offer an advantage during the juvenile period, the ability to learn actually continues to develop through childhood and adolescence, suggesting that the neural mechanisms that support skill learning are slow to mature. To address this issue, we asked whether the rate and magnitude of perceptual learning varies as a function of age as male and female gerbils trained on an auditory task. Adolescents displayed a slower rate of perceptual learning compared with their young and mature counterparts. We recorded auditory cortical neuron activity from a subset of adolescent and adult gerbils as they underwent perceptual training. While training enhanced the sensitivity of most adult units, the sensitivity of many adolescent units remained unchanged, or even declined across training days. Therefore, the average rate of cortical improvement was significantly slower in adolescents compared with adults. Both smaller differences between sound-evoked response magnitudes and greater trial-to-trial response fluctuations contributed to the poorer sensitivity of individual adolescent neurons. Together, these findings suggest that elevated sensory neural variability limits adolescent skill learning.SIGNIFICANCE STATEMENTThe ability to learn new skills emerges gradually as children age. This prolonged development, often lasting well into adolescence, suggests that children, teens, and adults may rely on distinct neural strategies to improve their sensory and motor capabilities. Here, we found that practice-based improvement on a sound detection task is slower in adolescent gerbils than in younger or older animals. Neural recordings made during training revealed that practice enhanced the sound sensitivity of adult cortical neurons, but had a weaker effect in adolescents. This latter finding was partially explained by the fact that adolescent neural responses were more variable than in adults. Our results suggest that one mechanistic basis of adult-like skill learning is a reduction in neural response variability.

A common behavioral marker of optimal attention focus is faster responses or reduced response variability. Our previous study found two dominant brain states during sustained attention, and these states differed in their behavioral accuracy and reaction time (RT) variability. However, RT distributions are often positively skewed with a long tail (i.e., reflecting occasional slow responses). Therefore, a larger RT variance could also be explained by this long tail rather than the variance around an assumed normal distribution (i.e., reflecting pervasive response instability based on both faster and slower responses). Resolving this ambiguity is important for better understanding mechanisms of sustained attention. Here, using a large dataset of over 20,000 participants who performed a sustained attention task, we first demonstrated the utility of the exGuassian distribution that can decompose RTs into a strategy factor, a variance factor, and a long tail factor. We then investigated which factor(s) differed between the two brain states using fMRI. Across two independent datasets, results indicate unambiguously that the variance factor differs between the two dominant brain states. These findings indicate that ‘suboptimal’ is different from ‘slow’ at the behavior and neural level, and have implications for theoretically and methodologically guiding future sustained attention research.

The purpose of the current study was to assess meaningful variability in visual-perceptual skills using a standardized assessment of visual perception, the Test of Visual Perceptual Skills (TVPS), across children with and without autism spectrum disorder (ASD). In addition to assessing overall accuracy across subtests of the TVPS, we also assessed response variability at the item-level, and the linear relationship between quantitative measures of ASD symptoms, task performance, and item-level variance. We report a significant linear relationship between ASD features and performance on the TVPS Figure Ground subtest. Additionally, results of an item-level analysis point to a significant relationship between within-task variability on the Figure Ground subtest and quantitative ASD traits, with a less variable response pattern being associated with increased ASD symptoms. Findings presented here suggest variability in perceptual processing across ASD may be influenced by individual differences in trait distribution.

International audience; Lithium (Li) remains the first line long-term treatment of bipolar disorders notwithstanding a high inter-individual variability of response. Significant research effort has been undertaken to understand the molecular mechanisms underlying Li cellular and clinical effects in order to identify predictive biomarkers of response. Li response has been shown to be partly heritable, however mechanisms that do not rely on DNA variants could also be involved. In recent years, modulation of epigenetic marks in relation with the level of Li response has appeared increasingly plausible. Recent results in this field of research have provided new insights into the molecular processes involved in Li effects. In this review, we examined the literature investigating the involvement of three epigenetic mechanisms (DNA methylation, noncoding RNAs and histone modifications) in Li clinical efficacy in bipolar disorder.

Purpose Transcranial direct current stimulation (tDCS) has mixed effects on walking performance in individuals poststroke. This is likely the result of variations in tDCS electrode montages and individualized responses. The purpose of this study was to quantify the effects of a single session of tDCS using various electrode montages on poststroke walking performance. Methods Individuals with chronic stroke (n = 16) participated in a double-blind, randomized cross-over study with sham stimulation and three tDCS electrode montages. Gait speed, paretic step ratio, and paretic propulsion were assessed prestimulation and poststimulation at self-selected and fastest comfortable speeds. Changes in muscle activation patterns with self-selected walking were quantified by the number of modules derived from nonnegative matrix factorization of EMG signals for hypothesis generation. Results There was no significant effect of active stimulation montages compared with sham. Comparisons between each participant's best response to tDCS and sham show personalized tDCS may have a positive effect on fastest comfortable overground gait speed (P = 0.084), paretic step ratio (P = 0.095) and paretic propulsion (P = 0.090), and self-selected paretic step ratio (P = 0.012). Participants with two or three modules at baseline increased module number in response to the all experimental montages and sham, but responses were highly variable. Conclusions A single session of tDCS may affect clinical and biomechanical walking performance, but effects seem to be dependent on individual response variability to different electrode montages. Findings of this study are consistent with responses to various tDCS electrode montages being the result of underlying neuropathology, and the authors recommend examining how individual factors affect responses to tDCS.

INTRODUCTION: Clopidogrel is the most frequently utilized P2Y(12) inhibitor and is characterized by broad interindividual response variability resulting in impaired platelet inhibition and increased risk of thrombotic complications in a considerable number of patients. The potent P2Y(12) inhibitors, prasugrel and ticagrelor, can overcome this limitation but at the expense of an increased risk of bleeding. Genetic variations of the cytochrome P450 (CYP) 2C19 enzyme, a key determinant in clopidogrel metabolism, have been strongly associated with clopidogrel response profiles prompting investigations of genetic-guided selection of antiplatelet therapy. AREAS COVERED: The present manuscript focuses on the rationale for the use of genetic testing to guide the selection of platelet P2Y(12) inhibitors among patients undergoing percutaneous coronary intervention (PCI). Moreover, a comprehensive appraisal of the available evidence and practical recommendations are provided. EXPERT COMMENTARY: Implementation of genetic testing as a strategy to guide the selection of therapy can result into escalation (i.e., switching to prasugrel or ticagrelor) or de-escalation (i.e., switching to clopidogrel) of P2Y(12) inhibiting therapy. Most recent investigations support the clinical benefit of a genetic guided selection of antiplatelet therapy in patients undergo PCI. Integrating the results of genetic testing with clinical and procedural variables represents a promising strategy for a precision medicine approach for the selection of antiplatelet therapy among patients undergoing PCI.

ObjectiveInterindividual variability of single and paired-pulse TMS data has limited the clinical and experimental applicability of these methods. This study brought together over 60 TMS researchers to create the largest known sample of individual participant single and paired-pulse TMS data to date, enabling a more comprehensive evaluation of factors driving response variability.Methods118 corresponding authors provided deidentified individual TMS data. Mixed-effects regression investigated a range of individual and study level variables for their contribution to variability in response to single and pp TMS data.Results687 healthy participant’s TMS data was pooled across 35 studies. Target muscle, pulse waveform, neuronavigation use, and TMS machine significantly predicted an individual’s single pulse TMS amplitude. Baseline MEP amplitude, M1 hemisphere, and biphasic AMT significantly predicted SICI response. Baseline MEP amplitude, test stimulus intensity, interstimulus interval, monophasic RMT, monophasic AMT, and biphasic RMT significantly predicted ICF response. Age, M1 hemisphere, and TMS machine significantly predicted motor threshold.ConclusionsThis large-scale analysis has identified a number of factors influencing participants’ responses to single and paired pulse TMS. We provide specific recommendations to increase the standardisation of TMS methods within and across laboratories, thereby minimising interindividual variability in single and pp TMS data.Highlights687 healthy participant’s TMS data was pooled across 35 studiesSignificant relationships between age and resting motor thresholdSignificant relationships between baseline MEP amplitude and SICI/ICF

Contains fulltext : 238526.pdf (Publisher’s version ) (Open Access) AIM: To provide insight into outcome and long-term safety and efficacy of deep brain stimulation (DBS), from the perspective of individuals with Lesch-Nyhan disease (LND) and their families. METHOD: We used patient-centered outcome measures to assess long-term outcomes of DBS for 14 individuals (mean [SD] age 10y 10mo [5y 6mo], range 5-23y, all males) with LND, after an average duration of 5y 6mo (range 11mo-10y 5mo) after surgery. We compared these results with a comprehensive review of previously published cases. RESULTS: Patients and their families reported that DBS of the globus pallidus can be effective both for motor and behavioral disturbances in LND. However, outcome measures were often not significantly changed owing to substantial variability among individuals, and were overall less positive than in previous reports based on clinician assessments. In addition, there was an unexpectedly high rate of adverse events, tempering overall enthusiasm for the procedure. INTERPRETATION: Although DBS might be an effective treatment for LND, more research is needed to understand the reasons for response variability and the unusually high rates of adverse events before DBS can be recommended for these patients. What this paper adds Individuals with Lesch-Nyhan disease and their families report variable efficacy of deep brain stimulation. Long-term outcomes are associated with a high adverse event rate.

Using event-related potentials (ERPs), we investigated the effects of passive heat stress and recovery on the human cognitive function with Flanker tasks, involving congruent and incongruent stimuli. We hypothesized that modulation of the peak amplitude and latency of the P300 component in ERP waveforms would differ with task difficulty during passive heat stress and recovery. Subjects performed the Flanker tasks before (Pre), at the end of whole body heating (Heat: internal temperature increase of ~1.2°C from the pre-heat baseline), and after the internal temperature had returned to the pre-heat baseline (Recovery). The internal temperature was regulated by a tube-lined suit by perfusing 50°C water for heat stress and 25°C water for recovery immediately after the heat stress. Regardless of task difficulty, the reaction time (RT) was shortened during Heat rather than Pre and Recovery, and standard deviations of RT (i.e., response variability) were significantly smaller during Heat than Pre. However, the peak amplitudes of the P300 component in ERPs, which involved selective attention, expectancy, and memory updating, were significantly smaller during Heat than during Pre, suggesting the impairment of neural activity in cognitive function. Notably, the peak amplitudes of the P300 component were higher during Recovery than during Heat, indicating that the impaired neural activity had recovered after sufficient whole-body cooling. An indicator of the stimulus classification/evaluation time (peak latency of P300) and the RT were shortened during Heat stress, but such shortening was not noted after whole-body cooling. These results suggest that hyperthermia affects the human cognitive function, reflected by the peak amplitude and latency of the P300 component in ERPs during the Flanker tasks, but sufficient treatment such as whole-body cooling performed in this study can recover those functions.

Why celecoxib exerts chemopreventive activity in only some familial adenomatous polyposis (FAP) patients remains poorly understood. We conducted a phase II clinical study to identify potential predictive biomarkers for celecoxib chemopreventive activity in FAP. Twenty-seven patients with FAP completed a 6-month oral course of 400 mg of celecoxib twice a day; they underwent colonoscopies before and after celecoxib treatment to assess colorectal polyp tumor burden and to obtain normal and polyp colorectal biopsies to measure celecoxib, 13-S-hydroxyoctadecadienoic acid (13-HODE), 15-HETE, 12-HETE, and LTB4 levels by LC/MS-MS. Celecoxib levels in sera from those patients were also measured before treatment and after 2, 4, and 6 months of treatment. Nineteen of the 27 patients experienced a response to celecoxib, with a ≥ 28% reduction of colonic polyp burden on the basis of a reproducible quantitative assessment of colonoscopy results. Celecoxib levels were significantly lower in polyp tissues than in normal colorectal tissues. Celecoxib levels in sera and normal colorectal tissues were correlated in patients who experienced a response to celecoxib but not in those who did not. Among the measured lipoxygenase products, only 13-HODE levels were significantly lower in polyp tissues than in normal tissues. Our findings demonstrate the differential bioavailability of celecoxib between normal and polyp tissues and its potential effects on clinical response in patients with FAP.Prevention Relevance:This study evaluated potential predictive biomarkers for celecoxib chemopreventive activity in patients with FAP. Our findings demonstrated the differential bioavailability of celecoxib between normal and polyp tissues and its potential effects on clinical chemopreventive response in patients with FAP.See related Spotlight, p. 205

Serial dependence is the effect in which the immediately preceding trial influences participants' responses to the current stimulus. But for how long does this bias last in the absence of interference from other stimuli? Here, we had 20 healthy young adult participants (12 women) perform a coincident timing task using different inter-trial intervals to characterize the serial dependence effect as the time between trials increases. Our results show that serial dependence abruptly decreases from 0.1 s to 1 s inter-trial interval, but it remains pronounced after that for up to 8 s. In addition, participants' response variability slightly decreases over longer intervals. We discuss these results in light of recent models suggesting that serial dependence might rely on a short-term memory trace kept through changes in synaptic weights, which might explain its long duration and apparent stability over time.

The aim of the current study was to examine the association between cardiorespiratory fitness and electroencephalogram-based neural oscillations, using midfrontal theta, during an inhibitory control task in children. One-hundred seventy-one school-aged children (mean age = 8.9 ± 0.6 years; 46% girls) were recruited. Cardiorespiratory fitness was assessed by a test of maximal oxygen consumption (VO2peak ) while inhibitory control performance was measured via a modified flanker task with an electroencephalogram. Behavioral findings demonstrated that higher cardiorespiratory fitness was associated with higher response accuracy regardless of task difficulty as well as lower response variability during trials with lower cognitive demand. Neuroelectric outcomes revealed that higher cardiorespiratory fitness was correlated with smaller modulation of theta (4-7 Hz) oscillatory power regardless of task difficulty. Collectively, the current findings indicate that higher cardiorespiratory fitness is associated with better performance on a task that modulates inhibitory control, signified by higher, and more stable, task performance. More importantly, higher childhood cardiorespiratory fitness is associated with better top-down control and cortical communication, as reflected by midfrontal theta. Such findings support the critical role of cardiorespiratory fitness in brain health during childhood.

Background. The aim of this study was to analyse the group of patients with asthma, who prefer to use short-acting anticholinergics (SAMA) for relief of asthma attacks. At the same time, these patients are prescribed inhaled glucocorticosteroids (ICS) in combination with long-acting P2-agonists (LABA) as a basic therapy according to the standards. Tha aim. To study the cause of low efficacy of LABA in patients with asthma who do not have a sufficient response to SABA, as well as the probability of reducing of bronchial obstruction with LAMA. Materials and methods. 12 non-smoking adults with moderate to severe asthma (III-IV stage of GINA), receiving medium or high doses of ICS in combination with LABA as a basic therapy without adequate control over asthma symptoms were included in the study. First group of patients showed the efficacy of salbutamol (FEV1 reversibility was more than 12% and more than 200 ml after 400 ^g of salbutamol) and ipratropium bromide (SABA+SAMA+). Second group included patients with low response to salbutamol and positive test (FEVt reversibility) with ipratropium bromide (SABA-SAMA+). Spirometry was performed at baseline point and in 5, 10, 15, 30, 60, 120 and 240 min after inhalation of bronchodilator (salmeterol 50 ^g, formoterol 12 ^g and tiotropium bromide 18 ^g in the different days). Results. It was shown that SABA-SAMA+ phenotype asthma patients demonstrated low response to LABA: FEV1 increased up to 7.64±1.67%, 156.0±16.0 ml after salmeterol inhalation and up to 9.4±5.8%, 166.7±103.1 ml after formoterol inhalation (compared with a group of SABA+SAMA+, where the response to salmeterol was 20.81±2.42%, 551.43±93.94 ml and the response to formoterol was 30.21±6.75%, 718.57±140.78 ml, p

Members (behaviors) of a response class are equivalent in that they produce the same functional reinforcer. Oftentimes, some members of a response class occur at higher rates than others. This can be problematic when the members that occur at high rates are socially inappropriate (e.g., self-injury, aggression, or disruption). The participant in this study was a 16-year-old female diagnosed with autism spectrum disorder who demonstrated aggression, one-word mands, and mands with autoclitic frames. In a series of contingency reversals, we placed 2 behaviors on extinction (e.g., aggression and one-word mands), which resulted in extinction-induced variability. Capitalizing on extinction-induced variability, we reinforced a different behavior (e.g., mands with autoclitic frames). The results confirmed that (a) the rate of responding for each topography was a function of extinction-induced response variability and differential reinforcement and (b) all response topographies belonged to the same response class. These results provide empirical support for the use of extinction-induced variability to differentially increase the rate of socially appropriate behaviors while decreasing socially inappropriate behaviors that belong to the same response class.

Objective: To evaluate whether a common polymorphism (Val66Met) in the gene for brain-derived neurotrophic factor (BDNF)—a gene thought to influence plasticity—contributes to inter-individual variability in responses to continuous theta-burst stimulation (cTBS), and explore whether variability in stimulation-induced plasticity among Val66Met carriers relates to differences in stimulation intensity (SI) used to probe plasticity.Methods: Motor evoked potentials (MEPs) were collected from 33 healthy individuals (11 Val66Met) prior to cTBS (baseline) and in 10 min intervals immediately following cTBS for a total of 30 min post-cTBS (0 min post-cTBS, 10 min post-cTBS, 20 min post cTBS, and 30 min post-cTBS) of the left primary motor cortex. Analyses assessed changes in cortical excitability as a function of BDNF (Val66Val vs. Val66Met) and SI.Results: For both BDNF groups, MEP-suppression from baseline to post-cTBS time points decreased as a function of increasing SI. However, the effect of SI on MEPs was more pronounced for Val66Met vs. Val66Val carriers, whereby individuals probed with higher vs. lower SIs resulted in paradoxical cTBS aftereffects (MEP-facilitation), which persisted at least 30 min post-cTBS administration.Conclusions: cTBS aftereffects among BDNF Met allele carriers are more variable depending on the SI used to probe cortical excitability when compared to homozygous Val allele carriers, which could, to some extent, account for the inconsistency of previously reported cTBS effects.Significance: These data provide insight into the sources of cTBS response variability, which can inform how best to stratify and optimize its use in investigational and clinical contexts.

Sound localisation is a fundamental attribute of the way that animals perceive their external world. It enables them to locate mates or prey, determine the direction from which a predator is approaching and initiate adaptive behaviours. Evidence from different biological disciplines that has accumulated over the last two decades indicates how small insects with body sizes much smaller than the wavelength of the sound of interest achieve a localisation performance that is similar to that of mammals. This Review starts by describing the distinction between tympanal ears (as in grasshoppers, crickets, cicadas, moths or mantids) and flagellar ears (specifically antennae in mosquitoes and fruit flies). The challenges faced by insects when receiving directional cues differ depending on whether they have tympanal or flagellar years, because the latter respond to the particle velocity component (a vector quantity) of the sound field, whereas the former respond to the pressure component (a scalar quantity). Insects have evolved sophisticated biophysical solutions to meet these challenges, which provide binaural cues for directional hearing. The physiological challenge is to reliably encode these cues in the neuronal activity of the afferent auditory system, a non-trivial problem in particular for those insect systems composed of only few nerve cells which exhibit a considerable amount of intrinsic and extrinsic response variability. To provide an integrative view of directional hearing, I complement the description of these biophysical and physiological solutions by presenting findings on localisation in real-world situations, including evidence for localisation in the vertical plane.

High variability between individuals (i.e. inter-individual variability) in response to transcranial direct current stimulation (tDCS) has become a commonly reported issue in the tDCS literature in recent years. Inherent genetic differences between individuals has been proposed as a contributing factor to observed response variability. This study investigated whether tDCS inter-individual variability was genetically mediated. A large sample-size of sixty-one healthy males received cathodal-tDCS (c-tDCS) and sham-tDCS, of the primary motor cortex at 1mA and 10-minutes via 6×4cm active and 7×5cm return electrodes. Corticospinal excitability (CSE) was assessed via twenty-five single-pulse transcranial magnetic stimulation motor evoked potentials (MEP). Intracortical inhibition (ICI) was assessed via twenty-five 3ms inter-stimulus interval (ISI) paired-pulse MEPs, known as short-interval intracortical inhibition (SICI). Intracortical facilitation (ICF) was assessed via twenty-five 10ms ISI paired-pulse MEPs. Gene variants encoding for excitatory and inhibitory neuroreceptors were determined via saliva samples. Pre-determined thresholds and statistical cluster analyses were used to subgroup individuals. Two distinct subgroups were identified, ‘responders’ reducing CSE following c-tDCS and ‘non-responders’ showing no reduction or even increase in CSE. Differences in CSE between responders and non-responders following c-tDCS were not explained by changes in SICI or ICF. No significant relationships were reported between gene variants and inter-individual variability to c-tDCS suggesting the chosen gene variants did not influence the activity of the neuroreceptors involved in eliciting changes in CSE in responders following c-tDCS. In this largest c-tDCS study of its kind, novel insights were reported into the contribution genetic factors may play in observed inter-individual variability to c-tDCS.

We examined the effect of aging on the integration of position and motion signals, which is essential for tracking visual objects, using the motion-induced position shift (MIPS) phenomenon. We first measured the MIPS and bias in speed perception at three eccentricities. Both young and older adults showed the increasing MIPS and decreasing perceived speed as the eccentricity increased, which is consistent with previous literature. More importantly, we found that the mean MIPS was 2.87 times larger in older adults, and the response variability in position tasks showed a larger difference between age groups compared with the difference in speed tasks. We then measured the MIPS across stimulus durations. Temporal changes in the MIPS showed similar patterns in young and older adults in that the MIPS initially peaked at around 60 ms and approached an asymptote. We further analyzed the changes in response variability across stimulus durations to estimate sensory noise and propagation noise separately and found that only sensory noise was significantly larger in older adults. The overall results suggest that the increased MIPS in older adults is due to the increased dependency on predictive motion signals to compensate for the relatively imprecise position signals, which in turn implies that older adults would depend more on the motion signals to track objects.

The term autologous fecal microbiota transplantation (a-FMT) refers herein to the use of one's feces during a healthy state for later use to restore gut microbial communities after perturbations. Generally, heterologous fecal microbiota transplantation (h-FMT), where feces from a ``healthy” donor is transplanted into a person with illness, has been used to treat infectious diseases such as recurrent Clostridioides difficile infection (CDI), with cure rates of up to 90%. In humans, due to limited response to medicines, h-FMT has become a hallmark intervention to treat CDI. Extrapolating the benefits from CDI, h-FMT has been attempted in various diseases, including inflammatory bowel disease (IBD), but clinical response has been variable and less effective (ranging between 24% and 50%). Differences in h-FMT clinical response could be because CDI is caused by a Clostridial infection, whereas IBD is a complex, microbiome-driven immunological inflammatory disorder that presents predominantly within the gut wall of genetically-susceptible hosts. FMT response variability could also be due to differences in microbiome composition between donors, recipients, and within individuals, which vary with diet, and environments, across regions. While donor selection has emerged as a key factor in FMT success, the use of heterologous donor stool still places the recipient at risk of exposure to infectious/pathogenic microorganisms. As an implementable solution, herein we review the available literature on a-FMT, and list some considerations on the benefits of a-FMT for IBD.

Genetic mediation of cortical plasticity and the role genetic variants play in previously observed response variability to transcranial direct current stimulation (tDCS) have become important issues in the tDCS literature in recent years. This study investigated whether inter-individual variability to tDCS was in-part genetically mediated. In sixty-one healthy males, anodal-tDCS (a-tDCS) and sham-tDCS were administered to the primary motor cortex at 1mA for 10-minutes via 6×4cm active and 7×5cm return electrodes. Twenty-five single-pulse transcranial magnetic stimulation (TMS) motor evoked potentials (MEP) were recorded to represent corticospinal excitability (CSE).Twenty-five paired-pulse MEPs were recorded with 3ms inter-stimulus interval (ISI) to assess intracortical inhibition (ICI) via short-interval intracranial inhibition (SICI) and 10ms ISI for intracortical facilitation (ICF). Saliva samples tested for specific genetic polymorphisms in genes encoding for excitatory and inhibitory neuroreceptors. Individuals were sub-grouped based on a pre-determined threshold and via statistical cluster analysis. Two distinct subgroups were identified, increases in CSE following a-tDCS (i.e. Responders) and no increase or even reductions in CSE (i.e. Non-responders). No changes in ICI or ICF were reported. No relationships were reported between genetic polymorphisms in excitatory receptor genes and a-tDCS responders. An association was reported between a-tDCS responders and GABRA3 gene polymorphisms encoding for GABA-A receptors suggesting potential relationships between GABA-A receptor variations and capacity to undergo tDCS-induced cortical plasticity. In the largest tDCS study of its kind, this study presents an important step forward in determining the contribution genetic factors play in previously observed inter-individual variability to tDCS.

Despite the growing interest in the use of transcranial direct current stimulation (tDCS) for the modulation of human cognitive function, there are contradictory findings regarding the cognitive benefits of this technique. Inter-individual response variability to tDCS may play a significant role. We explored the effects of anodal versus sham tDCS over the left prefrontal cortex (LPFC) on working memory performance, taking into account the inter-individual variability. Twenty-nine healthy volunteers received an ‘offline’ anodal tDCS (1.5 mA, 15 min) to the left prefrontal cortex (F3 electrode site) in an intra-individual, cross-over, sham-controlled experimental design. n-back and Sternberg task performance was assessed before (baseline), immediately after tDCS administration (T1) and 5 min post-T1 (T2). We applied an integrative clustering approach to characterize both the group and individual responses to tDCS, as well as identifying naturally occurring subgroups that may be present within the total sample. Anodal tDCS failed to improve working memory performance in the total sample. Cluster analysis identified a subgroup of ‘responders’ who significantly improved their performance after anodal (vs. sham) stimulation, although not to a greater extent than the best baseline or sham condition. The proportion of ‘responders’ ranged from 15% to 59% across task conditions and behavioral outputs. Our findings show a high inter-individual variability of the tDCS response, suggesting that the use of tCDS may not be an effective tool to improve working memory performance in healthy subjects. We propose that the use of clustering methods is more suitable in identifying ‘responders’ and for evaluating the efficacy of this technique.

Background: In allergic rhinitis, a relevant outcome providing information on the effectiveness of interventions is needed. In MASK-air (Mobile Airways Sentinel Network), a visual analogue scale (VAS) for work is used as a relevant outcome. This study aimed to assess the performance of the work VAS work by comparing VAS work with other VAS measurements and symptom-medication scores obtained concurrently. Methods: All consecutive MASK-air users in 23 countries from 1 June 2016 to 31 October 2018 were included (14 189 users; 205 904 days). Geolocalized users self-assessed daily symptom control using the touchscreen functionality on their smart phone to click on VAS scores (ranging from 0 to 100) for overall symptoms (global), nose, eyes, asthma and work. Two symptom-medication scores were used: the modified EAACI CSMS score and the MASK control score for rhinitis. To assess data quality, the intra-individual response variability (IRV) index was calculated. Results: A strong correlation was observed between VAS work and other VAS. The highest levels for correlation with VAS work and variance explained in VAS work were found with VAS global, followed by VAS nose, eye and asthma. In comparison with VAS global, the mCSMS and MASK control score showed a lower correlation with VAS work. Results are unlikely to be explained by a low quality of data arising from repeated VAS measures. Conclusions: VAS work correlates with other outcomes (VAS global, nose, eye and asthma) but less well with a symptom-medication score. VAS work should be considered as a potentially useful AR outcome in intervention studies. © 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

Skeletal muscle plays a pivotal role in the maintenance of physical and metabolic health and, critically, mobility. Accordingly, strategies focused on increasing the quality and quantity of skeletal muscle are relevant, and resistance exercise is foundational to the process of functional hypertrophy. Much of our current understanding of skeletal muscle hypertrophy can be attributed to the development and utilization of stable isotopically labeled tracers. We know that resistance exercise and sufficient protein intake act synergistically and provide the most effective stimuli to enhance skeletal muscle mass; however, the molecular intricacies that underpin the tremendous response variability to resistance exercise-induced hypertrophy are complex. The purpose of this review is to discuss recent studies with the aim of shedding light on key regulatory mechanisms that dictate hypertrophic gains in skeletal muscle mass. We also aim to provide a brief up-to-date summary of the recent advances in our understanding of skeletal muscle hypertrophy in response to resistance training in humans.

Most models of neural responses are constructed to reproduce the average response to inputs but lack the flexibility to capture observed variability in responses. The origins and structure of this variability have significant implications for how information is encoded and processed in the nervous system, both by limiting information that can be conveyed and by determining processing strategies that are favorable for minimizing its negative effects. Here, we present a new modeling framework that incorporates multiple sources of noise to better capture observed features of neural response variability across stimulus conditions. We apply this model to retinal ganglion cells at two different ambient light levels and demonstrate that it captures the full distribution of responses. Further, the model reveals light level-dependent changes that could not be seen with previous models, showing both large changes in rectification of nonlinear circuit elements and systematic differences in the contributions of different noise sources under different conditions. Significance Statement Current models for neural responses typically focus on accurately estimating a neuron’s average response to a stimulus but often fail to accurately reflect response variability. Such variability is central to the accuracy with which neural responses represent inputs and with which they can guide behavior. We present a new modeling framework that accurately captures observed variability in neural responses and find that multiple stochastic model elements are necessary to capture this variability. We show that model parameters can be accurately estimated using about 8 minutes of data. We then apply the model to retinal ganglion cells, demonstrating light level-dependent changes in both deterministic and stochastic model elements changes that are either obscured or absent using more standard modeling approaches.