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Sleep debt can accumulate from periods of total or partial nights of sleep loss but is generally conceived of as a build-up of sleep pressure resulting from chronic, partial sleep restriction. Both laboratory and epidemiological studies have been used to characterize the neurobehavioral and physiological consequences of sleep debt. Sleep debt and sleep satiation are intertwined with concepts of sleep need, excess wakefulness, sleep extension, and core and optional sleep. The time course of recovery from sleep debt remains unclear; however, recent studies suggest it may have a relative long time constant.

Background: Admissions for acute myocardial infarction (MI) have declined significantly during the COVID-19 pandemic. The changes in the presentation, management, and outcomes of MI during the pandemic period are not well recognized, and data from low- and middle-income countries are limited. Methods: In this two-timepoint cross-sectional study involving 187 hospitals across India, patients admitted with MI between 15th March to 15th June in 2020 were compared with those admitted during the corresponding period of 2019. We sought to determine the changes in the number of admissions, management practices, and outcomes. Findings: We included 41,832 consecutive adults with MI. Admissions during the pandemic period (n = 16414) decreased by 35·4% as compared to the corresponding period in 2019 (n = 25418). We observed significant heterogeneity in this decline across India with the North zone reporting greater decline (-44·8%) than the South zone (-27·7%). The weekly average decrease in MI admissions in 2020 which peaked around the mid- study period, correlated negatively with the number of COVID cases (r = -0·48; r 2 = 0·2), but strongly correlated with the stringency of lockdown index (r = 0·95; r 2 = 0·90). On a multi-level logistic regression, admissions were lower in 2020 with older age categories, tier 1 cities, and centers with high patient volume, and teaching programs. Adjusted utilization rate of coronary angiography, and percutaneous coronary intervention decreased by 11·3%, and 5·9% respectively. However, the in-hospital mortality rates did not differ. Interpretation: The magnitude of reduction in MI admissions across India was not uniform. The nature, time course, and the patient demographics were different compared to reports from other countries, suggesting a significant impact due to the lockdown. These findings have important implications in managing MI admissions during the pandemic. Funding Statement: The study is funded by cardiological society of India. Declaration of Interests: Nothing to declare for all the authors. Ethics Approval Statement: Individual participating centres either obtained an ethical approval from respective Institutional ethics committees or a no objection certificate from the administration.

Background: The number of implantable cardioverter defibrillator (ICD) infections is increasing due to an increased number of ICD implants, higher-risk patients, and more frequent replacement procedures, which carry a higher risk of infection. Reducing the morbidity, mortality, and cost of ICD-related infections requires an understanding of the current rate of this complication and its predictors. Methods: The Shock Implant Evaluation Trial (SIMPLE) trial randomized 2500 ICD recipients to defibrillation testing or not. Over an average of 3.1 years, patients were seen every 6 months and examined for evidence of ICD infection, which was defined as requiring device removal and/or intravenous antibiotics. Results: Within 24 months, 21 patients (0.8%) developed infection. Fourteen patients (67%) with infection presented within 30 days, 20 patients by 12 months, and only 1 patient beyond 12 months. Univariate analysis demonstrated that patients with primary electrical disorders (3 patients, P = 0.009) and those with a secondary prevention indication (13 patients, P = 0.0009) were more likely to develop infection. Among the 2.2% of patients who developed an ICD wound hematoma, 10.4% developed an infection. Among the 8.3% of patients requiring an ICD reintervention, 1.9% developed an infection. Conclusions: This cohort of ICD recipients at high-volume centres have a low risk of device-related infection. However; strategies to reduce wound hematoma and the need for ICD reintervention could further reduce the rate of infection. Résumé: Contexte: L’incidence des cas d’infection du défibrillateur cardioverteur implantable (DCI) augmente en raison du nombre accru d’implantations, de l’emploi de ces dispositifs chez des patients exposés à un risque très élevé et de l’augmentation de la fréquence des interventions de remplacement, qui sont associées à un plus grand risque d’infections. Pour parvenir à réduire la morbidité, la mortalité et les coûts associés aux infections liées à un DCI, il faut connaître la fréquence de cette complication et les facteurs qui permettent de la prédire. Méthodologie: Lors de l’essai Shock Implant Evaluation Trial (SIMPLE), 2 500 patients ayant reçu un DCI ont été répartis aléatoirement en deux groupes, l’un subissant des tests de défibrillation et l’autre, non. Sur une période de 3,1 ans en moyenne, les patients ont été vus en consultation tous les 6 mois et examinés à la recherche de signes d’infection du DCI, définie comme étant une infection exigeant le retrait du dispositif et/ou l’administration d’antibiotiques par voie intraveineuse. Résultats: Au total, 21 patients (0,8 %) ont présenté une infection dans les 24 mois suivant l’implantation. Quatorze patients (67 %) ont présenté une infection dans les 30 jours suivant l’intervention; à 12 mois, 20 patients avaient présenté une infection. Un seul patient a présenté une infection plus de 12 mois après l’intervention. Les résultats d’une analyse univariée ont démontré qu’une infection était plus probable chez les patients qui présentaient un trouble électrique primaire (3 patients, p = 0,009) et chez ceux qui avaient reçu un dispositif en prévention secondaire (13 patients, p = 0,0009). Parmi les patients qui présentaient un hématome après l’implantation du DCI (2,2 %), 10,4 % ont présenté une infection. Parmi les patients qui ont eu besoin d’une nouvelle intervention relative au DCI (8,3 %), 1,9 % ont présenté une infection. Conclusions: Les patients de cette cohorte ayant reçu un DCI dans des établissements à haut volume étaient exposés à un faible risque d’infection du défibrillateur. Des stratégies visant à réduire les hématomes et la nécessité d’une nouvelle intervention sur les DCI pourraient toutefois contribuer à réduire encore plus la fréquence des infections.

Marine microalgae (MA) has received wide attention as a promising source of omega-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) enrichment in animal products to improve the health status and wellbeing of the consumers. This study evaluated dynamic changes in n-3 LC-PUFA, color, and functional properties as well as atherogenic and thrombogenic health lipid indices of egg yolk from hens fed graded levels (0, 0.5, and 1.0%) of docosahexaenoic acid (DHA)–rich MA (Aurantiochytrium sp.) during a 56-D feeding period. Egg freshness parameters and yolk lipid oxidative stability were also measured after 0, 14, and 28 D of refrigerated storage. The hen performance and egg quality (except for yolk color) were not affected (P > 0.05) by MA supplementation. Docosahexaenoic acid contents in yolk from hens fed 1.0% MA increased quadratically with feeding time with a plateau at about 30 D (P 0.05). Microalgal carotenoids enrichment also helped attenuate fatty acid oxidation of the DHA-enriched yolk and increase their lipid oxidative stability. In conclusion, dietary supplementation with up to 1.0% of MA significantly increased DHA contents with more health-promoting n-6/n-3 ratio and atherogenic and thrombogenic indices, as well as more intense yolk color within consumers' acceptability, and the feeding strategy had a minimal impact on yolk physical and functional properties or oxidative stability during subsequent refrigerated storage.

We report of a 15-year-old patient who initially presented to the specialist children's hospital with neurologic problems including developmental delay, behavioral difficulty and poor cognition. Upon organic acid testing, the patient received a diagnosis of L2-hydroxyglutaric aciduria (L2HGA).Serial MRI scans were performed throughout the patients childhood, demonstrating an evolution of imaging features as the disease progressed.A radiologist's recognition of the key findings associated with L2HGA can help prompt the diagnosis in cases of a nonspecific clinical presentation. This case report highlights the key radiological features associated with L2HGA, whilst illustrating how these changes may evolve and appear over the time course of a patient's journey. Keywords: Neuroradiology, Paediatrics, Imaging, Brain, MRI

Publisher Summary This chapter introduces the basic elements of clinical pharmacology models used in describing the time course of disease progress and changes in progress in response to treatment. The simplest model of disease progress assumes that there is no change in disease status during the period of observation. The linear disease progress model assumes a constant rate of change of a biomarker or clinical outcome that reflects the disease status at any time. The onset of drug effect may be delayed by adding an effect compartment to the drug-action part of the model, which is more realistic, by making active drug concentrations at the effect site. Both an offset effect and a slope effect may be combined to describe the changes in disease status. Phenomena such as a drug concentration–effect delay, tolerance, and rebound to both placebo and active treatments can be made using a linear offset model. The nonzero–asymptote model with all three patterns of disease progress influenced by drug effect is also elaborated in the chapter.

Children are vulnerable to the development of acute, chronic, tardive, and withdrawal emergent drug induced movement disorders (DIMDs). Dopaminergic medications, particularly dopamine receptor blocking agents are common offenders. Certain children, particularly those with autism spectrum disorder, with pre-existing movement disorders, or taking multiple psychotropic medications may be more vulnerable. Chemotherapeutic and immunomodulatory agents can induce changes in white matter in cerebellar and other pathways, resulting in movement disorders. Clinicians need to be aware of spectrum, time course, and treatment strategies for acute and chronic DIMDs in children.

Contemporary single-cell experiments produce vast amounts of data, but the interpretation of these data is far from straightforward. In particular, understanding mechanisms and sources of cell-to-cell variability, given highly complex and nonlinear cellular networks, precludes intuitive interpretation. It requires careful computational and mathematical analysis instead. Here, we discuss different types of single-cell data and computational, model-based methods currently used to analyze them. We argue that mechanistic models incorporating subpopulation or cell-specific parameters can help to identify sources of variation and to understand experimentally observed behaviors. We highlight how data types and qualities, together with the nonlinearity of single-cell dynamics, make it challenging to identify the correct underlying biological mechanisms and we outline avenues to address these challenges., Current Opinion in Systems Biology, 28

Grapheme-colour synaesthesia is a neurodevelopmental condition wherein perception of numbers and letters consistently and involuntarily elicits the concurrent experience of a colour photism. Accumulating evidence suggests that heterogeneity in the visuospatial phenomenology of synaesthesia is attributable to the operation of top-down processes underlying photisms experienced as representations in associator synaesthetes and bottom-up processes subserving photisms experienced as spatially localized in projector synaesthetes. An untested corollary of this hypothesis is that bottom-up mechanisms will actuate earlier photism perception in projector synaesthetes. We tested this prediction in a pre-registered study in which associators and projectors completed adaptive temporal order judgment tasks for graphemes, colours, and photisms. In corroboration of the hypothesis of differential photism access across visuospatial phenomenology subtypes, projectors displayed earlier photism colour thresholds than associators whereas the two subtypes did not significantly differ in veridical colour thresholds. Synesthetes did not differ in grapheme or colour thresholds relative to non-synesthete controls, contrary to previous suggestions of superior colour processing in this condition. These results are consistent with the proposal of differential neural mechanisms underlying photism perception in subtypes of grapheme-colour synaesthesia and warrant renewed attention to heterogeneity in the mechanisms and phenomenology of this condition.

There has been substantial progress in the knowledge of exercise and type 1 diabetes, with the development of guidelines for optimal glucose management. In addition, an increasing number of people living with type 1 diabetes are pushing their physical limits to compete at the highest level of sport. However, the post-exercise recovery routine, particularly with a focus on sporting performance, has received little attention within the scientific literature, with most of the focus being placed on insulin or nutritional adaptations to manage glycaemia before and during the exercise bout. The post-exercise recovery period presents an opportunity for maximising training adaption and recovery, and the clinical management of glycaemia through the rest of the day and overnight. The absence of clear guidance for the post-exercise period means that people with type 1 diabetes should either develop their own recovery strategies on the basis of individual trial and error, or adhere to guidelines that have been developed for people without diabetes. This Review provides an up-to-date consensus on post-exercise recovery and glucose management for individuals living with type 1 diabetes. We aim to: (1) outline the principles and time course of post-exercise recovery, highlighting the implications and challenges for endurance athletes living with type 1 diabetes; (2) provide an overview of potential strategies for post-exercise recovery that could be used by athletes with type 1 diabetes to optimise recovery and adaptation, alongside improved glycaemic monitoring and management; and (3) highlight the potential for technology to ease the burden of managing glycaemia in the post-exercise recovery period.

Pharmacokinetics is the scientific discipline that studies the time course of absorption, distribution, metabolism, and excretion of drugs. Parameters describing a drug’s pharmacokinetics are determined with a number of different methods, including compartmental and noncompartmental methods. Two primary parameters that are determined include clearance and volume of distribution. Clearance is a parameter that measures the elimination of drug from the body, whereas volume of distribution is a proportionality constant that relates the amount of drug in the body with the concentration in plasma. Half-life is a secondary parameter dependent on clearance and volume of distribution that describes is the time required for concentrations to decrease by one-half. Most drugs exhibit linear pharmacokinetics, where drug concentrations change proportionally with dose. For a number of drugs, where this is not the case, their pharmacokinetics are termed nonlinear. Pharmacodynamics is the scientific discipline that studies relationship between the concentration of a drug and the response or effect.

Introduction Dyspareunia has been called the neglected symptom of endometriosis and is underexplored in clinical and research contexts. Understanding the physical experience and patient-important aspects of endometriosis-associated sexual pain can help advance valid measurement of this symptom. Aims The goal of this research was to characterize the physical experience of endometriosis-associated dyspareunia in the words of people affected by this condition. Methods This was a qualitative descriptive study that included participants with current or previous endometriosis-associated dyspareunia recruited from a data registry. Data collection involved semistructured interviews that began with an open-ended question about dyspareunia followed by prompts related to the nature of sexual pain. Main Outcome Measures Interviews transcripts were subjected to qualitative content analysis using a priori (pain site, onset, character, radiation, associations, time course, and exacerbating/relieving factors) and emergent themes. Results A total of 17 participants completed interviews. Mean participant age was 33.3 years and most were identified as white, college-educated, heterosexual, and partnered. Location, onset, and character were important; interrelated features of endometriosis-associated dyspareunia were: (i) introital pain began with initial penetration and had pulling, burning, and stinging qualities and (ii) pelvic pain was experienced with deep penetration or in certain positions and was described as sharp, stabbing, and cramping. Dyspareunia ranged from mild to severe, had a marked psychosocial impact for some participants, and was managed using a variety of treatments and strategies. Conclusion The endometriosis-associated dyspareunia experienced by participants was heterogenous in presentation, severity, and impact. Our findings have implications for the development of valid patient-reported outcome measures of this symptom.

White matter maturation is a nonlinear and heterogeneous phenomenon characterized by axonal packing, increased axon caliber, and a prolonged period of myelination. While current in vivo diffusion MRI (dMRI) methods, like diffusion tensor imaging (DTI), have successfully characterized the gross structure of major white matter tracts, these measures lack the specificity required to unravel the distinct processes that contribute to microstructural development. Neurite orientation dispersion and density imaging (NODDI) is a dMRI approach that probes tissue compartments and provides biologically meaningful measures that quantify neurite density index (NDI) and orientation dispersion index (ODI). The purpose of this study was to characterize the magnitude and timing of major white matter tract maturation with NODDI from infancy through adolescence in a cross-sectional cohort of 104 subjects (0.6-18.8 years). To probe the regional nature of white matter development, we use an along-tract approach that partitions tracts to enable more fine-grained analysis. Major white matter tracts showed exponential age-related changes in NDI with distinct maturational patterns. Overall, analyses revealed callosal fibers developed before association fibers. Our along-tract analyses elucidate spatially varying patterns of maturation with NDI that are distinct from those obtained with DTI. ODI was not significantly associated with age in the majority of tracts. Our results support the conclusion that white matter tract maturation is heterochronous process and, furthermore, we demonstrate regional variability in the developmental timing within major white matter tracts. Together, these results help to disentangle the distinct processes that contribute to and more specifically define the time course of white matter maturation.

In several human biomonitoring surveys, changes in the usage patterns of phthalates have come to light, but their influence on the risks associated with combined exposures is insufficiently understood. Based on the largest study to date, the 27-year survey of urinary phthalate metabolite levels in 24-hour urine samples from the German Environmental Specimen Bank, we present a deep analysis of changing phthalate exposures on mixture risks. This analysis adopts the Hazard Index (HI) approach based on the five phthalates DBP, DIBP, BBP, DEHP and DINP. Calculations of the hazard index for each study participant included updated phthalate reference doses for anti-androgenicity (RfDAAs) that take account of new evidence of phthalates’ developmental toxicity. The Maximum Cumulative Ratio (MCR) approach was used to establish whether a subject’s combined exposure was dominated by one phthalate or was influenced by several phthalates simultaneously. Generally, over the years there was a shift towards lower HIs and higher MCRs, reflecting an increased complexity of the combined exposures. The decade from 1988 to about 1999 was characterised by rather high HIs of between 3 and 7 (95th percentile) which were driven by exposure to DBP and DEHP, often exceeding their single acceptable exposures. Traditional single phthalate risk assessments would have underestimated these risks by up to 50%. From 2006 onwards, no study participant experienced exposures above acceptable levels for a single phthalate, but combined exposures were still in excess of HI = 1. From 2011 onwards most individuals stayed below HI = 1. In interpreting these results, we caution against the use of HI = 1 as an acceptable limit and develop proposals for improved and more realistic mixture risk assessments that take account of co-exposures to other anti-androgenic substances also capable of disrupting the male reproductive system. From this perspective, we regard HIs between 0.1 and 0.2 as more appropriate for evaluating combined phthalate exposures. Assessed against lowered HIs of 0.1 – 0.2, the combined phthalate exposures of most study participants exceeded acceptable levels in all study years, including 2015. Continued monitoring efforts for phthalate combinations are required to provide the basis for appropriate risk management measures. Federal Ministry for the Environment, Nature Conservation, and Nuclear Safety (BMU), Germany; Horizon 2020 research and innovation programme

Evidence from the Full Body Illusion (FBI) has shown that adults can embody full bodies which are not their own when they move synchronously with their own body or are viewed from a first-person perspective. However, there is currently no consensus regarding the time course of the illusion. Here, for the first time, we examined the effect of visuomotor synchrony (synchronous/asynchronous/no movement) on the FBI over time. Surprisingly, we found evidence of embodiment over a virtual body after five seconds in all conditions. Embodiment decreased with increased exposure to asynchronous movement, but remained high in synchronous and no movement conditions. We suggest that embodiment of a body seen from a first-person perspective is felt by default, and that embodiment can then be lost in the face of contradictory cues. These results have significant implications for our understanding of how multisensory cues contribute to embodiment.

In adult bilinguals, a word in one language will activate a related word in the other language, with language dominance modulating the direction of these effects. To determine whether the early bilingual lexicon possesses similar properties to its adult counterpart, two experiments compared translation equivalent priming and cross-linguistic semantic priming in 27-month-old bilingual toddlers learning English and one other language. Priming effects were found in both experiments, irrespective of language dominance and distance between the child’s two languages. The time course of target word recognition revealed a similar pattern for translation equivalent priming and cross-language semantic priming. These results suggest that the early bilingual lexicon possesses properties similar to the adult one in terms of word to concept connections. However, the absence of an advantage of translation equivalent priming over semantic priming, and the lack of dominance and language distance effects, suggest that when two languages are acquired in parallel during infancy, their integration within a single dynamic system is highly robust to input variations.

Summary Severe burn caused hypermetabolism-sustained muscle wasting and other comorbidities. The goal of nutrition support and other care management is to maintain energy homeostasis in burn patients. Due to dramatic changes and other factors that influence over the time course after burn, the plan of nutrition support has to be adjusted continuously with monitoring patient conditions. Inappropriate management of nutrition support adverses patients' status and progress. The current principal of care management has been encouraged in severe burn patients, which includes earlier enteral feeding, 1.5–2 g/kg of protein intake, and others. However, the detail of each territory in nutrition care is still under investigation. Further, nutrition support is more specialized for certain population as the time being.

Over the last decade, an arbovirus surveillance system based on the preservation of nucleic acids (RNA/DNA) has been developed using Flinders Technology Associates (FTAⓇ) cards. Soaked in honey, FTAⓇ cards are applied in the field to detect arboviruses expectorated during mosquito sugar feeding. This technique has been shown to be inexpensive and efficient, and the implementation of this system for detecting parasites could be of international importance. As Leishmania parasites are highly prevalent in developing countries, FTAⓇ cards may offer an alternative inexpensive tool to enhance field surveillance activities for leishmaniasis. The simple approach of applying the cards in programs can substitute the necessary extensive training of personnel. In our hands, Leishmania macropodum DNA was shown to be stable on FTAⓇ cards during a 10-week time course, supporting their suitability for projects where direct access to laboratories is unobtainable and samples require storage prior to processing. This method may benefit programs in remote areas where accessibility to laboratory facilities are limited and samples need to be stored long-term.•This study found that FTA cards could be a valuable tool in the surveillance of leishmaniasis.•The method is based on the long-term preservation and detection of Leishmania DNA expectorated during insect sugar feeding.•The application of FTA cards can preclude the need to screen large samples and analysis of insect populations to provide evidence of disease transmission., Graphical abstract Image, graphical abstract

Synopsis The lateral line of fishes and aquatic amphibians demonstrates robust regenerative capacity. Following selective ablation of sensory hair cells, subsets of surrounding supporting cells proliferate to repopulate the neuromast. This regenerative response restores lateral line mediated behaviors, although the time course of morphological regeneration does not always parallel functional recovery. Aquatic pollutants can negatively impact regeneration, suggesting that fishes in polluted environments may have compromised sensory input. This chapter examines ethological and biomedical studies of lateral line regeneration and highlights unanswered questions in both realms.

The objective of this chapter is to provide an overview of the most common modeling and simulation approaches used in drug discovery and development to understand and predict pharmacokinetic and pharmacodynamic relationship of small molecule and biologic drug candidates. The chapter will first discuss some basic pharmacokinetic modeling concepts to perform absorption, distribution and clearance predictions as well as time course of PK profiles for small molecule and biologics. A few examples of how those models can be applied to predict oral small molecule drug absorption and disposition as well as biologic drug clearance will be discussed. Subsequently, a general overview of pharmacodynamic modeling will be discussed in the context of two specific examples covering CNS and oncology drug development. These examples will highlight the impact of modeling can have on facilitating the preclinical and clinical development of drug candidates.

Multiple visual attention mechanisms are active already in infancy, most notably one supporting orienting towards stimuli and another, maintaining appropriate levels of alertness, when exploring the environment. They are thought to depend on separate brain networks, but their effects are difficult to isolate in existing behavioural paradigms. Better understanding of the contribution of each network to individual differences in visual orienting may help to explain their role in attention development. Here, we tested whether alerting and spatial cues differentially modulate pupil dilation in 8-month-old infants in a visual orienting paradigm. We found differential effects in the time course of these responses depending on the cue type. Moreover, using Principal Component Analysis (PCA) we identified two main components of pupillary response, which may reflect the alerting and orienting network activity. In a regression analysis, these components together explained nearly 40 % of variance in saccadic latencies in the spatial cueing condition of the task. These results likely demonstrate that both networks work together in 8-month-old infants and that their activity can be indexed with pupil dilation combined with PCA, but not with raw changes in pupil diameter.

This data is to document the intraocular pressure (IOP) lowering activity of imidazo[1,2-a]benzimidazole and pyrimido[1,2-a]benzimidazole compounds in ocular normotensive rats. Effects of single drop application of imidazo[1,2-a]benzimidazole and pyrimido[1,2-a]benzimidazole compounds on IOP in ocular normotensive rats are presented at 3 different concentrations (0.1%, 0.2% and 0.4%). Time course of changes in IOP is presented over 6 h period post-instillation. The IOP lowering activities of test compounds were determined by assessing maximum decrease in IOP from baseline and corresponding control, duration of IOP lowering and area under curve (AUC) of time versus response curve. Data shown here may serve as benchmarks for other researchers studying IOP-lowering effect of imidazo[1,2-a]benzimidazole and pyrimido[1,2-a]benzimidazole compounds and would be useful in determining therapeutic potential of these test compounds as IOP lowering agents. Keywords: Drug screening, Intraocular pressure, Intraocular pressure lowering activity, Imidazo[1,2-a]benzimidazoles, Pyrimido[1,2-a]benzimidazoles, Ocular normotensive rats, Rebound tonometry

Objective To predict acidosis in fetus showing deceleration associated with non-reassuring fetal status during delivery, we examined the relationship between duration of the deceleration and umbilical arterial pH. Materials and methods A total of 19,907 deliveries in eight facilities of the Juntendo Perinatal Care Group, 895 cases of vaginal deliveries with level 3 decelerations were selected for the subjects of this study. The cut-off point of time when the umbilical arterial pH fell below 7.20 in all cases of level 3 and for each deceleration type were examined. The explanatory variables were the pH and pO2 of umbilical arterial gas and the time from onset of the level 3 pattern to delivery. From receiver operating characteristic (ROC) analysis using these variables, the critical point indicating low Apgar score was set at an umbilical arterial pH Results The cut-off point of time when the umbilical arterial pH fell below 7.2 was 33.5 min for all cases of level 3, and 604 cases of severe variable decelerations with normal baseline variability and normal baseline heart rates, the cut-off point was 33.5 min as well. For 108 cases of late decelerations, there was no significant cut-off point for either the mild or severe cases. Mild prolonged deceleration showed the cut-off point of 34.5 min. Conclusions We confirmed the time indices for predicting and preventing acidosis in fetuses showing decelerations. To prevent fetal acidosis, the decision related to proper timing for performing assisted delivery by considering the time course is important.

Traumatic brain injury (TBI) is a significant public health concern, and can be especially disruptive in children, derailing on-going neuronal maturation in periods critical for cognitive development. There is considerable heterogeneity in post-injury outcomes, only partially explained by injury severity. Understanding the time course of recovery, and what factors may delay or promote recovery, will aid clinicians in decision-making and provide avenues for future mechanism-based therapeutics. We examined regional changes in brain volume in a pediatric/adolescent moderate-severe TBI (msTBI) cohort, assessed at two time points. Children were first assessed 2–5 months post-injury, and again 12 months later. We used tensor-based morphometry (TBM) to localize longitudinal volume expansion and reduction. We studied 21 msTBI patients (5 F, 8–18 years old) and 26 well-matched healthy control children, also assessed twice over the same interval. In a prior paper, we identified a subgroup of msTBI patients, based on interhemispheric transfer time (IHTT), with significant structural disruption of the white matter (WM) at 2–5 months post injury. We investigated how this subgroup (TBI-slow, N = 11) differed in longitudinal regional volume changes from msTBI patients (TBI-normal, N = 10) with normal WM structure and function. The TBI-slow group had longitudinal decreases in brain volume in several WM clusters, including the corpus callosum and hypothalamus, while the TBI-normal group showed increased volume in WM areas. Our results show prolonged atrophy of the WM over the first 18 months post-injury in the TBI-slow group. The TBI-normal group shows a different pattern that could indicate a return to a healthy trajectory., Highlights • Studied differences in regional volume change longitudinally between TBI and control. • Found decreases in TBI group in white matter, gray matter and subcortical regions • Changes in regional volume were associated with changes in cognitive performance. • Compared subgroups within TBI group based on interhemispheric transfer time (IHTT) • TBI-slow group seems to drive TBI vs. control results, show prolonged degeneration.

The excitability of neuronal membranes is crucially modulated by T-type Ca2+ channels (ICaT) due to their low threshold of activation. ICaT inactivates steeply at potentials close to the resting membrane potential. Therefore, the availability of ICaT following changes in membrane potential depends on the time course of the onset of inactivation as well as on the time course of recovery from inactivation. It was previously shown that the time course of recovery from inactivation depends on the duration of the conditioning pulse in cloned T-type Ca2+ channel subunits (Cav3.1-Cav3.3(Uebachs et al., 2006)). This provides a potential mechanism for an intrinsic form of short term plasticity. Here, we address the question, whether this mechanism results in altered availability of ICaT following physiological changes in membrane potential. We found that the recovery of ICaT during an IPSP depends on the duration of a preceding depolarized period.

The chapter addresses the developmental time course of the perceptual learning underlying spoken language. Many researchers suggest that most of this learning has saturated around the end of the first year of life—during infancy. My own work with young children suggests a different perspective: protracted perceptual learning. I lay out the evidence for perceptual precocity and explain why I think the perceptual precocity story is wrong. Following this, I present my findings on young children's perceptual processing in speech and non-speech contexts (word learning, voice learning, melody learning), using visual fixations and pointing accuracy as response measures. Across all measures, children undershoot adult performance, particularly when perceptual attributes are challenging to tell apart. I then describe alternative, non-perceptual explanations for these findings, as well as ways to address said explanations. Last, I outline possible paths toward a unified picture of auditory perceptual learning across development.

This chapter focuses on the functional and structural adaptations of the skeletal muscle vasculature to exercise training and the impact of these adaptations on muscle blood flow responses to exercise. Repeated exposure to physical exercise of sufficient intensity and duration promotes changes in the local control of microvascular perfusion and elicits growth of arterioles and capillaries within skeletal muscle. Combined, these adaptations alter the magnitude, time course, and distribution of muscle blood flow during exercise and thereby improve blood–myocyte oxygen flux after training. In the first portion of this chapter, we describe the basic features and regulatory mechanisms underlying the exercise hyperemia. We then focus on the characteristics, functional significance, and potential signals that initiate and control the remodeling of the skeletal muscle vasculature induced by physical activity. Particular emphasis is given to animal investigations that employed techniques not possible in humans and which permitted unique mechanistic insights.

Highlights • The cortical dynamics during the mental calculating processes was clarified by using a whole-scalp magnetoencephalography. • The inferior parietal area (IPA) and superior temporal area (STA) of each hemisphere were activated with the strongest activation in the left STA. • The left IPA activated the earliest, and was followed by the activation of the left STA, the right IPA and the right STA., Objective We elucidated active cortical areas and their time courses during simple calculation by using whole-scalp magnetoencephalography. Methods Twelve healthy volunteers were asked to view meaningless figures (figure viewing) or digits (digit viewing) and add single digits (calculation). The magnetic signals of the brain were measured using a helmet-shaped 122-channel neuromagnetometer during the three tasks. Results The occipital, inferior posterior temporal, and middle temporal areas of each hemisphere and the left superior temporal area (STA) were activated during all tasks (approximately 250 ms after the stimulus onset). The calculation-related sources were located in the left inferior parietal area (IPA) in 8 subjects, right IPA in 5, left STA in 3, right STA in 5, right inferior frontal area in 2, and left inferior frontal area in 1. The IPA and STA of the left hemisphere were activated more strongly and significantly earlier than those of the right hemisphere: the left IPA was activated first (mean activation timing: 301 ms), followed by activations of the left STA (369 ms), right IPA (419 ms), and right STA (483 ms). Conclusions Simple digit addition is executed mainly in the left IPA and left STA, followed by the recognition processes of results in the right IPA and right STA. Significance This study clarified the cortical process during simple calculation, with excellent temporal and spatial resolution; the IPA and STA of the left hemisphere were activated more strongly and earlier than the corresponding areas of the right hemisphere.

Hormones, in vacuo, simply do not send out behavioral responses without regard to the stimuli coming in. To understand what hormones really do, it is imperative to undertake methodical thinking, beginning with the stimuli themselves. In a specific set of circumstances, well-defined stimuli will have a quantitatively determined possibility of triggering an assessable response. In the absence of the hormone in question, the number of occurrences, their latency, and their amplitude are recorded. Then the hormone in question is added, using a dose, route of administration, and time course deemed likely to be behaviorally effective. Again the same well-defined stimuli are applied, and the response measures are taken. If the hormone facilitates the behavior of interest, the probability of occurrence goes up, latency goes down, and/or amplitude goes up. If the hormone represses that behavior, the opposite changes are seen.

Anhedonia, broadly defined as the absence of pleasure, is considered a prominent feature of both depression and schizophrenia. However, despite analogous clinical descriptions, differences in symptomatology between the disorders suggest that the term anhedonia in each disorder may capture clinically and neurobiologically distinct phenomena. Particularly, depression seems to be characterized by an episodic deficit in hedonic capacity, while schizophrenia may be characterized by a relatively stable deficit in the retrieval of noncurrent emotional states. In this chapter, we provide an overview of anhedonia, the demonstrated nuances between depression and schizophrenia, and plausible mechanisms including reward sensitivity and emotional reactivity. We describe neurophysiological methodologies utilized to tease apart the time course and intricate nature of these mechanisms, primarily focusing on two neurophysiological components—event-related potentials termed the reward positivity and late positive potential. Reviewing the research, we propose that depression is characterized by experiential deficits in reward consumption and momentary affective experiences, while schizophrenia is distinctly characterized by cognitive deficits rather than deficient experiential capacity in either reward or emotional reactivity.

Pharmacokinetics literally means ‘movement of drugs inside the body’ and is concerned with the fate of drugs administered to an organism. Thus, the study of drug absorption, distribution, metabolism, and excretion involves pharmacokinetics. Apart from understanding the biochemical and physiological processes involved in these steps, emphasis is laid on studying the time course of absorption, distribution, and clearance of drugs. Clinical pharmacokinetics serves as a tool in the hands of the physician to obtain the optimum effects of drugs to benefit and cure patients. This is easily appreciated when a very good correlation exists between drug concentrations and pharmacological or therapeutic responses produced in patients. Pharmacokinetic data revolves around estimation of drug concentration in biological fluids and use of the concentration-time data in mathematical modeling considering drug concentration and receptor sites and maintaining equilibrium with different tissues of the body. The final outcome provides a clear understanding of drug effects to obtain clinical outcomes. Drug interactions occur when one drug affects the pharmacokinetics of another drug or its metabolites. Drug interactions can also be subsequent to the additive or antagonistic action of the pharmacodynamic effect of either drug when taken with the other drug. The main focus of this guidance is pharmacokinetic drug interactions. This guidance reflects the Agency’s view that the pharmacokinetic interactions between an investigational new drug and other drugs should be defined during drug development, as part of an adequate assessment of the drug’s safety and effectiveness. It is important to understand the nature and magnitude of drug–drug interactions (DDI) for several reasons. Concomitant medications, dietary supplements, and some foods—such as grapefruit juice—may alter metabolism and/or drug transport abruptly in individuals who previously had been receiving and tolerating a particular dose of a drug. Such an abrupt alteration in metabolism or transport can change the known safety and efficacy of a drug.

Anterior cruciate ligament (ACL) reconstruction techniques have been improved over the last 10 years, but graft failure is not uncommon. Successful ACL reconstruction requires understanding of several factors: anatomical graft placement, mechanical properties of the selected graft tissue, mechanical behaviour and fixation strength of fixation materials as well as the biological processes that occur during graft remodelling, maturation and incorporation. They influence directly the mechanical properties of the knee joint after ACL reconstruction and, therefore, determine the rehabilitation and time course until normal function of the knee joint can be expected.

Intermittent schedules of reinforcement define the conditions under which learned operant behavior is rewarded. Such schedules offer the opportunity to examine toxicant-induced changes in a variety of behavioral processes, including learning, attention and memory processes, sensory function, motor behavior and motivational states, thus providing critical information about risks arising from toxicant exposure and potential mechanisms of those effects. Such behavior is stable over extended periods of time, allowing for determination of time course of toxicant effects and reversibility. Importantly, schedule-controlled behavior generally shows considerable cross-species generality, facilitating the interpretation of toxicant-induced risks.