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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.

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.

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.

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

Being able to track objects that surround us is key for planning actions in dynamic environments. However, rigorous cognitive models for tracking of one or more objects are currently lacking. In this study, we asked human subjects to judge the time to contact (TTC) a finish line for one or two objects that became invisible shortly after moving. We showed that the pattern of subject responses had an error variance best explained by an inverse Gaussian distribution and consistent with the output of a biased drift-diffusion model. Furthermore, we demonstrated that the pattern of errors made when tracking two objects showed a level of dependence that was consistent with subjects using a single decision variable for reporting the TTC for two objects. This finding reveals a serious limitation in the capacity for tracking multiple objects resulting in error propagation between objects. Apart from explaining our own data, our approach helps interpret previous findings such as asymmetric interference when tracking multiple objects.

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.

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.

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.

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.

Can experimental studies on the behavioural impacts of ocean acidification be trusted? That question was raised in early 2020 when a high-profile paper failed to corroborate previously observed responses of coral reef fish to high CO2. New information on the methodologies used in the “replicated” studies now provides a plausible explanation: the experimental conditions were substantially different. High sensitivity to test conditions is characteristic of ocean acidification research; such response variability shows that effects are complex, interacting with many other factors. Open-minded assessment of all research results, both negative and positive, remains the best way to develop process-based understanding. As in other fields, replication studies in ocean acidification are most likely to contribute to scientific advancement when carried out in a spirit of collaboration rather than confrontation.

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

Nowadays analytical models of seismic isolators can fairly reproduce the force response of such devices, when implemented in a large variety of structural systems, such as buildings and bridges. Consequently, realistic hysteretic rules are available for the definition of the dynamic system for Non-Linear Time History Analyses, and earthquake simulations of the considered isolated structural systems can be computed. Such models are generally defined, according to mean values of mechanical properties of isolation devices, even though a certain variability has been experimentally assessed: precisely, statistical analyses of the outcomes of test database have outlined that the main response parameters of isolators should be considered as random variables, rather than as deterministic values. On the other hand, in the common practice both design and assessment procedures are mainly based on deterministic approaches, and bound analyses are ruled in just few standard codes. The present endeavor presents a wide parametric study on a case study structure, in order to assess the variability of the main response parameters, by accounting for random mechanical properties of isolation devices. Precisely, a combination of Lead Rubber Bearings and Flat Slider devices have been considered, and the spatial layout of isolators has been defined, according to a given performance point. The structural response of the case study building has been computed through Non-Linear Time History Analyses, by extracting 10'000 individual values of mechanical properties of devices. Presented results are related to the mean response of a spectrum-compatible set of natural records, in terms of displacement and force of both superstructure and isolation system.

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.

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

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

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.

Most current sequential sampling models have random between-trial variability in their parameters. These sources of variability make the models more complex in order to fit response time data, do not provide any further explanation to how the data were generated, and have recently been criticised for allowing infinite flexibility in the models. To explore and test the need of between-trial variability parameters we develop a simple sequential sampling model of N-choice speeded decision making: the racing diffusion model. The model makes speeded decisions from a race of evidence accumulators that integrate information in a noisy fashion within a trial. The racing diffusion does not assume that any evidence accumulation process varies between trial, and so, the model provides alternative explanations of key response time phenomena, such as fast and slow error response times relative to correct response times. Overall, our paper gives good reason to rethink including between-trial variability parameters in sequential sampling models.

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.

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.

Objective Single-pulse electrical stimulation (SPES) of intracranial electrodes evokes responses that may help identify the seizure onset zone (SOZ); however, lack of automation and response variability has limited clinical adoption of this technique. We evaluated whether automated delivery of low-current SPES could evoke delayed high-frequency suppression (DHFS) of ongoing electrocorticography (ECoG) signals that, when combined with objective analytic techniques, may provide a reliable marker of this zone. Methods Low-current SPES (1-ms, 3.5-mA biphasic pulses) was delivered to 652 electrodes across 10 patients undergoing ECoG for seizure focus localization. DHFS was measured by calculating the normalized trial-averaged time-frequency power (70–250 Hz) 0.4–1 sec post-stimulation. Electrodes that evoked suppression when stimulated or recorded suppression when stimulation was nearby were used to estimate the SOZ. Results The estimated SOZ significantly identified the clinical SOZ in 6 of 10 patients (5 of 7 temporal foci) with a false-positive rate of 0–0.06. Stimulation required Conclusions We show that DHFS provides accurate estimates of the clinical SOZ in patients with refractory epilepsy. Significance This approach may increase the safety, speed, and reproducibility of SOZ identification while reducing cost, subjectivity, and patient discomfort.

Aim: The present study aimed to investigate whether the response variability of infants to modified constraint-induced movement therapy and bimanual therapy are associated with different types of brain lesions. Method: Infants with unilateral cerebral palsy (N = 22) ages 8-15 months (mean = 10.95, standard deviation = 2.15 months) were grouped according to having either a periventricular brain lesion or a middle cerebral artery infarct lesion. Improvement in hand function was analyzed based on the mini–Assistive Hand Assessment results. Results: Infants with periventricular brain lesion displayed greater positive response to upper limb treatment compared to those with middle cerebral artery infarct ( P = .02). A significant difference in improvement according to type of treatment was found in the middle cerebral artery infarct group but not in the periventricular brain lesion. Conclusion: The present study showed an association between the type of brain lesion and the efficacy of upper limb treatment in infants. Infants with periventricular brain lesions displayed greater positive responses than those with middle cerebral artery infarct.

Background Few trauma guidelines evaluate and recommend anesthesiology practices and there are no trauma anesthesia-specific guidelines. There is no information on how anesthesiologists perceive clinical practice patterns. Our objective was to understand the perceptions of anesthesiologists regarding trauma anesthesia practices. Methods A survey assessing anesthesia management of trauma patients was distributed to 21,491 anesthesiologists. A subset of 10 of these questions was subsequently reviewed by a trauma anesthesiology focus group through a 3-round web-based Delphi process. A question was deemed to have respondent consensus if the response with the highest percentage of agreement was unchanged between rounds 1 and 2. Results A total of 2360 anesthesiologists (11% response rate) responded to the survey. Results demonstrated that the practitioners' answers conflicted with existing surgical trauma society recommendations (ie, when to transfuse component therapy), and several areas that lacked any guidelines, resulted in response variability among anesthesiologists where not 1 answer achieved >75% agreement (ie, intubation technique of choice for patients with uncleared cervical spine). Thirteen trauma anesthesiologists participated in round 1 (response rate 100%), and 12 responded in rounds 2 and 3 (response rate 92%) of the Delphi process. None of the questions received 100% agreement. Consensus was achieved on 9 of 10 statements pertaining to trauma anesthesia care. Consensus was not reached on the intubating technique in a hemodynamically unstable patient with an uncleared cervical spine with deficits. Delphi participant opinion conflicted with existing guidelines on 2 statements: the use of cricoid pressure, and when to begin blood component therapy. Conclusions There are several important areas of trauma anesthesia practice where guidelines do not exist and several where existing guidelines are not endorsed by the majority of practitioners who completed our survey. The lack of consensus on trauma anesthesia management and the variation in survey responses demonstrate a need to develop evidence-based trauma anesthesia guidelines.

Measurements of stature change have been used to compare spinal loading in the sitting posture. However, it is difficult to interpret whether the stature change response recorded is truly due to an intervention or to the natural fluctuation of stature change response between the days. The aim of this study was to investigate the effect of time of day (morning and afternoon) on the variability of stature change in participants with chronic low back pain (CLBP) on 2 consecutive days. Forty-four participants with CLBP attended 2 sessions (morning and afternoon) of stature change testing on 4 separate days. A stature change response of more than 0.985 mm in the morning and 1.149 mm in the afternoon on 2 consecutive days indicates that an intervention itself has influenced stature change measurement in CLBP participants. The magnitude of stature change response on different days and times of day established specific levels of natural variation meaning changes above these levels can be attributed to intervention effects in participants with CLBP. HIGHLIGHTS The findings suggest that it is important to control the time at which stature change investigations are conducted Seated stadiometry measurement, changes above 0.985 mm (morning) and 1.149 mm (afternoon) can be attributed to intervention effects between consecutive 2 days The results of the current study presented no significant difference in magnitude of stature change response in the morning versus the afternoon in chronic low back pain participants GRAPHICAL ABSTRACT

The objective of this paper is to examine the reliability of cold-formed steel framed shear walls with a particular emphasis on walls sheathed with wood structural panels. A sheathed cold-formed steel framed shear wall is a system consisting of studs, tracks, and sheathing often with bridging and/or blocking, connected with steel-to-steel and sheathing-to-steel fasteners. The shear walls may be integrally connected to foundations, floors, or other shear walls through a variety of means including hold downs, straps, diaphragm chords and collectors. Shear wall lateral resistance in cold-formed steel framed buildings varies because of the randomness in the components and connections that comprise the wall. The interaction between fasteners and sheathing is particularly important because (1) sheathing-to-steel fastener response is the main source of shear wall nonlinearity (2) there is high variability in this fastener response. Although the nominal strengths for different shear wall configurations are stated in current design specifications (e.g., AISI S400), variability of shear walls has not been explicitly considered. Existing resistance factors are extrapolations from steel diaphragm testing. To explore the impact of fastener response variability on shear wall reliability, Monte Carlo simulation of typical cold-formed steel framed wood sheathed shear walls with random fastener input was conducted. Variability in fasteners was determined based on existing physical fastener tests. Statistical properties of shear wall strength, demand capacity ratio of key fasteners, as well as relations between fastener strength and shear wall strength are all explored. Reliability evaluation is provided for four different design methods. The results indicate that shear wall strength benefits from a system effect whereby variability in fastener response is reduced through redistribution resulting in reduced variability in overall shear wall strength. Concomitant with this is a slight decrease, approximately 3%, in the mean system strength that also must be considered.

System identification is a data-driven input-output modeling approach more and more used in biology and biomedicine. In this application context, several assays are repeated to estimate the response variability and reproducibility. The inference of the modeling conclusions to the whole population requires to account for the inter-individual variability within the modeling procedure. One solution consists of using mixed effects models but up to now no similar approach exists in the system identification literature. In this article, we propose a first solution based on an ARX (Auto Regressive model with eXternal inputs) structure using the EM (Expectation-Maximisation) algorithm for the estimation of the model parameters. Using the Fisher information matrix, the parameter standard errors are estimated; this allows for group comparison tests. Simulations show the relevance of this solution compared with a classical procedure of system identification repeated on each subject. Taking into account all the information available in the population allows to gather the parameters between individuals.

Regular physical activity is strongly recommended to prevent chronic respiratory diseases, including asthma. On the other hand, vigorous physical training may trigger airway symptoms and bronchoconstriction. The transient airway narrowing occurring because of exercise is named exercise-induced bronchoconstriction (EIB). Despite management according to guidelines, a significant proportion of patients experiences uncontrolled EIB, which thus represents a relevant unmet medical need. In particular, although prevention and treatment of EIB are effectively based on the use of beta-2 bronchodilator drugs, high heterogeneity in individual responses has been reported. Furthermore, even though beta-2 adrenergic drugs remain the mainstay of EIB management, occurrence of tolerance and side effects, as well as doping concerns have been reported with their use. In regard to this, inhaled antimuscarinics could represent an alternative or additional effective and safe bronchodilator therapeutic option for achieving optimal EIB control and minimize adverse events. The present systematic review aims to collect and provide the most updated and evidence-based literature findings on the efficacy and safety of short- and long-acting inhaled anti-muscarinic drugs for the preventive treatment of EIB in both children and adults. Take-Home Message: Anti-muscarinic drugs are effective and safe in preventing EIB, despite response variability is reported. Further studies should focus on long-acting molecules, chronic administration and phenotype-driven effects.

Major depressive disorder (MDD) is a global problem for which current pharmacotherapies are not completely effective. Hypothalamic–pituitary–adrenal (HPA) axis dysfunction has long been associated with MDD; however, the value of assessing cortisol as a biological benchmark of the pathophysiology or treatment of MDD is still debated. In this review, we critically evaluate the relationship between HPA axis dysfunction and cortisol level in relation to MDD subtype, stress, gender and treatment regime, as well as in rodent models. We find that an elevated cortisol response to stress is associated with acute and severe, but not mild or atypical, forms of MDD. Furthermore, the increased incidence of MDD in females is associated with greater cortisol response variability rather than higher baseline levels of cortisol. Despite almost all current MDD treatments influencing cortisol levels, we could find no convincing relationship between cortisol level and therapeutic response in either a clinical or preclinical setting. Thus, we argue that the absolute level of cortisol is unreliable for predicting the efficacy of antidepressant treatment. We propose that future preclinical models should reliably produce exaggerated HPA axis responses to acute or chronic stress a priori, which may, or may not, alter baseline cortisol levels, while also modelling the core symptoms of MDD that can be targeted for reversal. Combining genetic and environmental risk factors in such a model, together with the interrogation of the resultant molecular, cellular, and behavioral changes, promises a new mechanistic understanding of MDD and focused therapeutic strategies.

We appreciate the comment by Dr. Sethi and fully agree that a diagnosis of brain death is—and should continue to be—a clinical diagnosis, with the use of ancillary testing only in situations where the clinical examination cannot be fully completed.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that is very complex and heterogeneous. If not adequately treated, RA patients are likely to manifest excess of morbidity and disability with an important impact on the quality of life. Pharmacological treatment is based on the administration of the disease-modifying antirheumatic drugs (DMARDs), subdivided into conventional synthetic (csDMARDs), targeted synthetic (tsDMARDs), and biological (bDMARDs). bDMARDs are now frequently administered in patients, both as alternative treatment and together with csDMARDs. Unfortunately, there is a therapeutic response variability both to old and new drugs. Therefore, to identify pre-therapeutic and on-treatment predictors of response is a priority. This review aims to summarize recent advances in understanding the causes of the variability in treatment response in RA, with particular attention to predictive potential of autoantibodies and DMARD pharmacogenetics. In recent years, several biomarkers have been proposed to personalize the therapy. Unfortunately, a magic bullet does not exist, as many factors concur to disease susceptibility and treatment outcomes, acting around the patient’s congenital background. Models integrating demographic, clinical, biochemical, and genetic data are needed to enhance the predictive capacity of specific factors singularly considered to optimize RA treatment in light of multidisciplinary patient management.

Objective. Direct electrical stimulation of the brain through intracranial electrodes is currently used to probe the epileptic brain as part of pre-surgical evaluation, and it is also being considered for therapeutic treatments through neuromodulation. In order to effectively modulate neural activity, a given neuromodulation design must elicit similar responses throughout the course of treatment. However, it is unknown whether intracranial electrical stimulation responses are consistent across sessions. The objective of this study was to investigate the within-subject, cross-session consistency of the electrophysiological effect of electrical stimulation delivered through intracranial electroencephalography (iEEG). Approach. We analysed data from 79 epilepsy patients implanted with iEEG who underwent brain stimulation as part of a memory experiment. We quantified the effect of stimulation in terms of band power modulation and compared this effect from session to session. As a reference, we made the same measurements during baseline periods. Main results. In most sessions, the effect of stimulation on band power could not be distinguished from baseline fluctuations of band power. Stimulation effect was consistent in a third of the session pairs, while the rest had a consistency measure not exceeding the baseline standards. Cross-session consistency was highly correlated with the degree of band power increase, and it also tended to be higher when the baseline conditions were more similar between sessions. Significance. These findings can inform our practices for designing neuromodulation with greater efficacy when using direct electrical brain stimulation as a therapeutic treatment.

Objectives\ud To assess the prevalence of high on-clopidogrel platelet reactivity (HCPR) in patients with ischaemic stroke or transient ischaemic attack (IS/TIA), their outcome and genetic basis of on-treatment response variability in IS/TIA patients.\ud \ud Methods\ud We conducted a comprehensive search of PubMed and EMBASE from their inceptions to March 9, 2019. Studies that reported absolute numbers/percentages of HCRP at any time point after IS/TIA onset evaluated with any type of platelet function tests, clinical outcomes and genotyping data were included.\ud \ud Results\ud Among 21 studies of 4312 IS/TIA patients treated with clopidogrel, the pooled prevalence of HCPR was 28% (95%CI: 24–32%; high heterogeneity: I2 = 88.2%, p < 0.001). Heterogeneity degree diminished across groups defined by the HCPR testing method. Clopidogrel non-responder IS/TIA patients had poorer outcome compared to responders (RR = 2.09, 95%CI: 1.61–2.70; p = 0.036; low heterogeneity across studies: I2 = 27.4%, p = 0.210). IS/TIA carriers of CYP2C19*2 or CYP2C19*3 loss of function alleles had a higher risk of HCPR compared to wild type (RR = 1.69, 95%CI: 1.47–1.95; p < 0.001; I2 = 0.01%, p = 0.475).\ud \ud Conclusions\ud This systematic review shows a high prevalence of clopidogrel resistance in IS/TIA and poor outcome in these patients. CYP2C19 polymorphisms may potentially influence clopidogrel resistance.

Background Reduction or differences in facial expression are a core diagnostic feature of autism spectrum disorder (ASD), yet evidence regarding the extent of this discrepancy is limited and inconsistent. Use of automated facial expression detection technology enables accurate and efficient tracking of facial expressions that has potential to identify individual response differences. Methods Children and adults with ASD (N = 124) and typically developing (TD, N = 41) were shown short clips of “funny videos.” Using automated facial analysis software, we investigated differences between ASD and TD groups and within the ASD group in evidence of facial action unit (AU) activation related to the expression of positive facial expression, in particular, a smile. Results Individuals with ASD on average showed less evidence of facial AUs (AU12, AU6) relating to positive facial expression, compared to the TD group (p < .05, r = − 0.17). Using Gaussian mixture model for clustering, we identified two distinct distributions within the ASD group, which were then compared to the TD group. One subgroup (n = 35), termed “over-responsive,” expressed more intense positive facial expressions in response to the videos than the TD group (p < .001, r = 0.31). The second subgroup (n = 89), (“under-responsive”), displayed fewer, less intense positive facial expressions in response to videos than the TD group (p < .001; r = − 0.36). The over-responsive subgroup differed from the under-responsive subgroup in age and caregiver-reported impulsivity (p < .05, r = 0.21). Reduced expression in the under-responsive, but not the over-responsive group, was related to caregiver-reported social withdrawal (p < .01, r = − 0.3). Limitations This exploratory study does not account for multiple comparisons, and future work will have to ascertain the strength and reproducibility of all results. Reduced displays of positive facial expressions do not mean individuals with ASD do not experience positive emotions. Conclusions Individuals with ASD differed from the TD group in their facial expressions of positive emotion in response to “funny videos.” Identification of subgroups based on response may help in parsing heterogeneity in ASD and enable targeting of treatment based on subtypes. Trial registration ClinicalTrials.gov, NCT02299700. Registration date: November 24, 2014

To make informed decisions in natural environments that change over time, humans must update their beliefs as new observations are gathered. Studies exploring human inference as a dynamical process that unfolds in time have focused on situations in which the statistics of observations are history-independent. Yet temporal structure is everywhere in nature, and yields history-dependent observations. Do humans modify their inference processes depending on the latent temporal statistics of their observations? We investigate this question experimentally and theoretically using a change-point inference task. We show that humans adapt their inference process to fine aspects of the temporal structure in the statistics of stimuli. As such, humans behave qualitatively in a Bayesian fashion, but, quantitatively, deviate away from optimality. Perhaps more importantly, humans behave suboptimally in that their responses are not deterministic, but variable. We show that this variability itself is modulated by the temporal statistics of stimuli. To elucidate the cognitive algorithm that yields this behavior, we investigate a broad array of existing and new models that characterize different sources of suboptimal deviations away from Bayesian inference. While models with 'output noise' that corrupts the response-selection process are natural candidates, human behavior is best described by sampling-based inference models, in which the main ingredient is a compressed approximation of the posterior, represented through a modest set of random samples and updated over time. This result comes to complement a growing literature on sample-based representation and learning in humans., Comment: 59 pages, 21 figures, and 6 tables

Bayesian theories of cognition assume that people can integrate probabilities rationally. However, several empirical findings contradict this proposition: human probabilistic inferences are prone to systematic deviations from optimality. Puzzlingly, these deviations sometimes go in opposite directions. Whereas some studies suggest that people under-react to prior probabilities (base rate neglect), other studies find that people under-react to the likelihood of the data (conservatism). We argue that these deviations arise because the human brain does not rely solely on a general-purpose mechanism for approximating Bayesian inference that is invariant across queries. Instead, the brain is equipped with a recognition model that maps queries to probability distributions. The parameters of this recognition model are optimized to get the output as close as possible, on average, to the true posterior. Because of our limited computational resources, the recognition model will allocate its resources so as to be more accurate for high probability queries than for low probability queries. By adapting to the query distribution, the recognition model “learns to infer.” We show that this theory can explain why and when people under-react to the data or the prior, and a new experiment demonstrates that these two forms of under-reaction can be systematically controlled by manipulating the query distribution. The theory also explains a range of related phenomena: memory effects, belief bias, and the structure of response variability in probabilistic reasoning. We also discuss how the theory can be integrated with prior sampling-based accounts of approximate inference.

Life and reliability analysis of hot section components like high pressure turbine (HPT) discs plays an important role for ensuring the engine structural integrity. HPT disc operates under high temperatures to withstand complex loadings, its basic parameters, including the applied loads, material properties and working environments, have shown multi-source uncertainties. The influence of these uncertainties on the structural response of the turbine disc cannot be ignored. According to this, the variations of applied loads and material properties are quantified for fatigue reliability analysis of turbine disc. In particular, material response variability is modeled by using the Chaboche model and Fatemi-Socie damage criterion. Moreover, the inhomogeneity of its constituent material is also considered through combining FE simulation with Latin hypercube sampling. Finally, fatigue reliability analysis of a HPT disc under multi-source uncertainties is conducted for different flight missions.

The detection of a sensory stimulus arises from a significant change in neural activity, but a sensory neuron's response is rarely identical to successive presentations of the same stimulus. Large trial-to-trial variability would limit the central nervous system's ability to reliably detect a stimulus, presumably affecting perceptual performance. However, if response variability were to decrease while firing rate remained constant, then neural sensitivity could improve. Here, we asked whether engagement in an auditory detection task can modulate response variability, thereby increasing neural sensitivity. We recorded telemetrically from the core auditory cortex of gerbils, both while they engaged in an amplitude-modulation detection task and while they sat quietly listening to the identical stimuli. Using a signal detection theory framework, we found that neural sensitivity was improved during task performance, and this improvement was closely associated with a decrease in response variability. Moreover, units with the greatest change in response variability had absolute neural thresholds most closely aligned with simultaneously measured perceptual thresholds. Our findings suggest that the limitations imposed by response variability diminish during task performance, thereby improving the sensitivity of neural encoding and potentially leading to better perceptual sensitivity.SIGNIFICANCE STATEMENTThe detection of a sensory stimulus arises from a significant change in neural activity. However, trial-to-trial variability of the neural response may limit perceptual performance. If the neural response to a stimulus is quite variable, then the response on a given trial could be confused with the pattern of neural activity generated when the stimulus is absent. Therefore, a neural mechanism that served to reduce response variability would allow for better stimulus detection. By recording from the cortex of freely moving animals engaged in an auditory detection task, we found that variability of the neural response becomes smaller during task performance, thereby improving neural detection thresholds.