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The adolescent brain undergoes tremendous structural and functional changes throughout puberty. Previous research has demonstrated that pubertal hormones can modulate sexually dimorphic changes in cortical development, as well as age-related maturation of the neural activity underlying cognitive processes. However, the precise impact of pubertal hormones on these functional changes in the developing human brain remains poorly understood. In the current study, we quantified the neural oscillatory activity serving visuospatial processing using magnetoencephalography, and utilized measures of dehydroepiandrosterone (DHEA) as an index of development during the transition from childhood to adolescence (i.e., puberty). Within a sample of typically developing youth (ages 9-15), a novel association between pubertal DHEA and theta oscillatory activity indicated that less mature children exhibited stronger neural responses in higher-order prefrontal cortices during the visuospatial task. Theta coherence between bilateral prefrontal regions also increased with increasing DHEA, such that network-level theta activity became more distributed with more maturity. Additionally, significant DHEA-by-sex interactions in the gamma range were centered on cortical regions relevant for attention processing. These findings suggest that pubertal DHEA may modulate the development of neural oscillatory activity serving visuospatial processing and attention functions during the pubertal period.

Exploring children's awareness of social categories could uncover the foundation of intergroup attitudes and behaviours. Indigenous to Ireland, Travellers are an ethnic minority marked by a tradition of nomadism, only formally recognised as a distinct ethnic group in 2017. This brief report analyses data from 148 children aged 6–12 (55% female) in the Republic of Ireland. A quantitative task was adapted and applied to assess children's awareness of symbols associated with the Traveller community. We found that primary school children could accurately categorise the symbols which relied on perceptually obvious markers of Traveller identity, and that this remained stable across middle childhood. However, children did not correctly categorise symbols related to less observable elements (e.g., language, trade, religion). To the best of our knowledge, these findings are the first to identify specific symbols which are salient in children's awareness about this marginalised group. Implications for school-based interventions are discussed.

Traumatic experiences during childhood can have profound effects on stress sensitive brain structures (e.g., amygdala and hippocampus) and the emergence of psychiatric symptoms. Recent theoretical and empirical work has delineated dimensions of trauma (i.e., threat and deprivation) as having distinct neural and behavioral effects, although there are few longitudinal examinations. A sample of 243 children and adolescents were followed for three time points, with each assessment approximately 1 year apart (ages 9-15 years at Time 1; 120 males). Participants or their caregiver reported on youths' threat exposure, perceived stress (Time 1), underwent a T1-weighted structural high-resolution MRI scan (Time 2), and documented their subsequent psychiatric symptoms later in development (Time 3). The primary findings indicate that left amygdala volume, in particular, mediated the longitudinal association between threat exposure and subsequent internalizing and externalizing symptomatology. Greater threat exposure related to reduced left amygdala volume, which in turn differentially predicted internalizing and externalizing symptoms. Decreased bilateral hippocampal volume was related to subsequently elevated internalizing symptoms. These findings suggest that the left amygdala is highly threat-sensitive and that stress-related alterations may partially explain elevated psychopathology in stress-exposed adolescents. Uncovering potential subclinical and/or preclinical predictive biomarkers is essential to understanding the emergence, progression, and eventual targeted treatment of psychopathology following trauma exposure.

Patient-centered care is the best practice in the care of pregnant and postpartum patients. The COVID-19 pandemic prompted changes in perinatal care policies, which were often reactive, resulting in unintended consequences, many of which made the delivery of patient-centered care more difficult. This study aimed to understand the impact of the COVID-19 pandemic on perinatal health care delivery from the perspective of family physicians in the United States.From October 5 to November 4, 2020, we surveyed mid- to late-career family physicians who provide perinatal care. We conducted descriptive analyses to measure the impact of COVID-19 on prenatal care, labor and delivery, postpartum care, patient experience, and patient volume. An immersion-crystallization approach was used to analyze qualitative data provided as open-text comments.Of the 1518 survey respondents, 1062 (69.8%) stated that they currently attend births; 595 of those elaborated about the impact of COVID-19 on perinatal care in free-text comments. Eight themes emerged related to the impact of COVID-19 on perinatal care: visitation, patient decisions, testing, personal protective equipment, care continuity, changes in care delivery, reassignment, and volume. The greatest perceived impact of COVID-19 was on patient experience.Family physicians who provided perinatal care during the COVID-19 pandemic noted a considerable impact on patient experience, which particularly affected the ability to deliver patient-centered and family-centered care. Continued research is needed to understand the long-term impact of policies affecting the delivery of patient-centered perinatal care and to inform more evidence-based, proactive policies to be implemented in future pandemic or disaster situations.

Semantic processing is the ability to discern and maintain conceptual relationships among words and objects. While the neural circuits serving semantic representation and controlled retrieval are well established, the neuronal dynamics underlying these processes are poorly understood. Herein, we examined 25 healthy young adults who completed a semantic relation word-matching task during magnetoencephalography (MEG). MEG data were examined in the time–frequency domain and significant oscillatory responses were imaged using a beamformer. Whole-brain statistical analyses were conducted to compare semantic-related to length-related neural oscillatory responses. Time series were extracted to visualize the dynamics and were linked to task performance using structural equation modeling. The results indicated that participants had significantly longer reaction times in semantic compared to length trials. Robust MEG responses in the theta (3–6 Hz), alpha (10–16 Hz), and gamma (64–76 Hz and 64–94 Hz) bands were observed in parieto-occipital and frontal cortices. Whole-brain analyses revealed stronger alpha oscillations in a left-lateralized network during semantically related relative to length trials. Importantly, stronger alpha oscillations in the left superior temporal gyrus during semantic trials predicted faster responses. These data reinforce existing literature and add novel temporal evidence supporting the executive role of the semantic control network in behavior.

BACKGROUND: Chronic Kidney Disease of unknown origin (CKDu) excludes known primary renal conditions or systemic disease (such as diabetes mellitus or hypertension). Prominence of CKDu has been noted for some decades in Sri Lanka, especially among men in particular rural areas, prompting many studies directed towards environmental causation. This article critically reviews relevant primary studies. METHODS: Articles for this literature review (n = 86) were found by searching Medline, Embase, Global Health and ProQuest databases over 2000-2020 utilizing a standard algorithm. Articles were critiqued according to criteria for diagnosis of CKDu, aetiological agents investigated, analytic methods employed and findings. RESULTS: Criteria for diagnosis of CKDu varied significantly, including pre-selection by proteinuria, eGFR and biopsy proven interstitial nephritis. Prevalence studies have been largely conducted in the North Central Province, with recent studies demonstrating the presence of CKDu in other regions. Aetiological factors investigated in primary studies included water source, use of agrochemicals, agricultural work, heavy metals, snake bites, ayurvedic medication, heat stress, infectious diseases and usage of tobacco and betel leaf. There is no conclusive evidence for any one aetiological agent despite consistent evidence of distal factors such as male sex, rural residence and farming. CONCLUSIONS: The current body of evidence for any aetiological agent as the cause of CKDu in Sri Lanka is limited. Further research with stronger study designs is necessary to increase knowledge of aetiology of CKDu in Sri Lanka to identify and eliminate exposure to possible causative agent(s) prior to concluding that the disease is multifactorial.

Highlights • One-in-five adolescents reported suicidality or pain. • Pain was associated with an increased risk of suicidality and vice versa (OR=4.00). • Network analysis supported the pain-suicidality association (aOR=1.39). • This cross-sectional association was not moderated by depression. • Pain should be considered as a key risk correlate of suicidality in adolescents., Background Whilst growing research suggests that pain is associated with suicidality in adolescence, it remains unclear whether this relationship is moderated by co-morbid depressive symptoms. The present study aimed to investigate whether the pain-suicidality association is moderated by depressive symptoms. Methods We performed secondary analyses on cross-sectional, pre-intervention data from the ‘My Resilience in Adolescence’ [MYRIAD] trial (ISRCTN ref: 86619085; N=8072, 11-15 years). Using odds ratio tests and (moderated) network analyses, we investigated the relationship between pain and suicidality, after controlling for depression, anxiety, inhibitory control deficits and peer problems. We investigated whether depression moderates this relationship and explored gender differences. Results Overall, 20% of adolescents reported suicidality and 22% reported pain, whilst nine percent of adolescents reported both. The experience of pain was associated with a four-fold increased risk of suicidality and vice versa (OR=4.00, 95%-CI=[3.54;4.51]), with no gender differences. This cross-sectional association remained significant after accounting for depression, anxiety, inhibitory control deficits and peer problems (aOR=1.39). Depression did not moderate the pain-suicidality association. Limitations The item-based, cross-sectional assessment of pain and suicidality precludes any conclusions about the direction of the effects and which aspects of suicidality and pain may drive this association. Conclusions Our findings underscore the need to consider pain as an independent risk correlate of suicidality in adolescents. Longitudinal research should examine how this relationship develops during adolescence. Clinically, our findings emphasise the need to assess and address suicidality in adolescents with pain, even in the absence of depressive symptoms.

Loading of MHC-I molecules with peptide by the catalytic chaperone tapasin in the peptide loading complex plays a critical role in antigen presentation and immune recognition. Mechanistic insight has been hampered by the lack of detailed structural information concerning tapasin–MHC-I. We present here crystal structures of human tapasin complexed with the MHC-I molecule HLA-B*44:05, and with each of two anti-tapasin antibodies. The tapasin-stabilized peptide-receptive state of HLA-B*44:05 is characterized by distortion of the peptide binding groove and destabilization of the β2-microglobulin interaction, leading to release of peptide. Movements of the membrane proximal Ig-like domains of tapasin, HLA-B*44:05, and β2-microglobulin accompany the transition to a peptide-receptive state. Together this ensemble of crystal structures provides insights into a distinct mechanism of tapasin-mediated peptide exchange.

Despite effective antiretroviral therapy, cognitive impairment and other aging-related comorbidities are more prevalent in people with HIV (PWH) than in the general population. Previous research examining DNA methylation has shown PWH exhibit accelerated biological aging. However, it is unclear how accelerated biological aging may affect neural oscillatory activity in virally suppressed PWH, and more broadly how such aberrant neural activity may impact neuropsychological performance.In the present study, participants (n = 134) between the ages of 23 - 72 years underwent a neuropsychological assessment, a blood draw to determine biological age via DNA methylation, and a visuospatial processing task during magnetoencephalography (MEG). Our analyses focused on the relationship between biological age and oscillatory theta (4-8 Hz) and alpha (10 - 16 Hz) activity among PWH (n=65) and seronegative controls (n = 69).PWH had significantly elevated biological age when controlling for chronological age relative to controls. Biological age was differentially associated with theta oscillations in the left posterior cingulate cortex (PCC) and with alpha oscillations in the right medial prefrontal cortex (mPFC) among PWH and seronegative controls. Stronger alpha oscillations in the mPFC were associated with lower CD4 nadir and lower current CD4 counts, suggesting such responses were compensatory. Participants who were on combination antiretroviral therapy for longer had weaker theta oscillations in the PCC.These findings support the concept of interactions between biological aging and HIV status on the neural oscillatory dynamics serving visuospatial processing. Future work should elucidate the long-term trajectory and impact of accelerated aging on neural oscillatory dynamics in PWH.

Somatosensory cortical activity is altered in individuals with cerebral palsy (CP). However, previous studies have focused on the lower extremities in children with CP and have given less attention to structural changes that may contribute to these alterations. We used a multimodal neuroimaging approach to investigate the relationship between somatosensory cortical activity and cortical thickness in 17 adults with CP (age = 32.8 ± 9.3 years) and 18 healthy adult controls (age = 30.7 ± 9.8 years). Participants performed a median nerve paired-pulse stimulation paradigm while undergoing magnetoencephalography (MEG) to investigate somatosensory cortical activity and sensory gating. Participants also underwent magnetic resonance imaging to evaluate cortical thickness within the area of the somatosensory cortex that generated the MEG response. We found that the somatosensory responses were attenuated in the adults with CP (P = 0.004). The adults with CP also hypergated the second stimulation (P = 0.030) and had decreased cortical thickness in the somatosensory cortex (P = 0.015). Finally, the strength of the somatosensory response was significantly correlated with the cortical thickness (P = 0.023). These findings demonstrate that the aberrant somatosensory cortical activity in adults with CP extends to the upper extremities and appears to be related to cortical thickness.

It is well recognized that not all individuals age equivalently, with functional dependence attributable, at least in part, to stress accumulated across the lifespan. Amongst these dependencies are age-related declines in cognitive function, which may be the result of impaired inhibitory processing (e.g., sensory gating). Herein, we examined the unique roles of life and biological stress on somatosensory gating dynamics in 74 adults (22-72 years old). Participants completed a sensory gating paired-pulse electrical stimulation paradigm of the right median nerve during magnetoencephalography (MEG) and data were subjected to advanced oscillatory and time-domain analysis methods. We observed separable mechanisms by which increasing levels of life and biological stress predicted higher oscillatory gating ratios, indicative of age-related impairments in inhibitory function. Specifically, elevations in life stress significantly modulated the neural response to the first stimulation in the pair, while elevations in biological stress significantly modulated the neural response to the second stimulation in the pair. In contrast, neither elevations in life nor biological stress significantly predicted the gating of time-domain neural activity in the somatosensory cortex. Finally, our study is the first to link stress-induced decline in sensory gating to cognitive dysfunction, suggesting that gating paradigms may hold promise for detecting discrepant functional trajectories in age-related pathologies in the future.

Background The telemedicine industry has been experiencing fast growth in recent years. The outbreak of coronavirus disease 2019 (COVID-19) further accelerated the deployment and utilization of telemedicine services. An analysis of the socioeconomic characteristics of telemedicine users to understand potential socioeconomic gaps and disparities is critical for improving the adoption of telemedicine services among patients. Objectives This study aims to measure the correlation of socioeconomic determinants with the use of telemedicine services in Milwaukee metropolitan area. Methods Electronic health record review of patients using telemedicine services compared with those not using telemedicine services within an academic-community health system: patient demographics (e.g., age, gender, race, and ethnicity), insurance status, and socioeconomic determinants obtained through block-level census data in Milwaukee area. The telemedicine users were compared with all other patients using regression analysis. The telemedicine adoption rates were calculated across regional ZIP codes to analyze the geographic patterns of telemedicine adoption. Results A total of 104,139 patients used telemedicine services during the study period. Patients who used video visits were younger (median age 48.12), more likely to be White (odds ratio [OR] 1.34; 95% confidence interval [CI], 1.31–1.37), and have private insurance (OR 1.43; CI, 1.41–1.46); patients who used telephone visits were older (median age 57.58), more likely to be Black (OR 1.31; CI 1.28–1.35), and have public insurance (OR 1.30; CI 1.27–1.32). In general, Latino and Asian populations were less likely to use telemedicine; women used more telemedicine services in general than men. In the multiple regression analysis of social determinant factors across 126 ZIP codes, college education (coefficient 1.41, p = 0.01) had a strong correlation to video telemedicine adoption rate. Conclusion Adoption of telemedicine services was significantly impacted by the social determinant factors of health, such as income, education level, race, and insurance type. The study reveals the potential inequities and disparities in telemedicine adoption.

Purpose During the 2014–2016 Ebola outbreak in West Africa, the Sierra Leone Ministry of Health and Sanitation (MoHS), the US Centers for Disease Control and Prevention, and responding partners under the coordination of the National Ebola Response Center (NERC) and the MoHS's Emergency Operation Center (EOC) systematically recorded information from the 117 Call Center system and district alert phone lines, case investigations, laboratory sample testing, clinical management, and safe and dignified burial records. Since 2017, CDC assisted MoHS in building and managing the Sierra Leone Ebola Database (SLED) to consolidate these major data sources. The primary objectives of the project were helping families to identify the location of graves of their loved ones who died at the time of the Ebola epidemic through the SLED Family Reunification Program and creating a data source for epidemiological research. The objective of this paper is to describe the process of consolidating epidemic records into a useful and accessible data collection and to summarize data characteristics, strength, and limitations of this unique information source for public health research. Methods Because of the unprecedented conditions during the epidemic, most of the records collected from responding organizations required extensive processing before they could be used as a data source for research or the humanitarian purpose of locating burial sites. This process required understanding how the data were collected and used during the outbreak. To manage the complexity of processing the data obtained from various sources, the Sierra Leone Ebola Database (SLED) Team used an organizational strategy that allowed tracking of the data provenance and lifecycle. Results The SLED project brought raw data into one consolidated data collection. It provides researchers with secure and ethical access to the SLED data and serves as a basis for the research capacity building in Sierra Leone. The SLED Family Reunification Program allowed Sierra Leonean families to identify location of the graves of loved ones who died during the Ebola epidemic. Conclusions The SLED project consolidated and utilized epidemic data recorded during the Sierra Leone Ebola Virus Disease outbreak that were collected and contributed to SLED by national and international organizations. This project has provided a foundation for developing a method of ethical and secure SLED data access while preserving the host nation's data ownership. SLED serves as a data source for the SLED Family Reunification Program and for epidemiological research. It presents an opportunity for building research capacity in Sierra Leone and provides a foundation for developing a relational database. Large outbreak data systems such as SLED provide a unique opportunity for researchers to improve responses to epidemics and indicate the need to include data management preparedness in the plans for emergency response.

The ability to allocate neural resources to task-relevant stimuli, while inhibiting distracting information in the surrounding environment (i.e., selective attention) is critical for high-level cognitive function, and declines in this ability have been linked to functional deficits in later life. Studies of age-related declines in selective attention have focused on frontal circuitry, with almost no work evaluating the contribution of motor cortical dynamics to successful task performance. Herein, we examined 69 healthy adults (23–72 years old) who completed a flanker task during magnetoencephalography (MEG). MEG data were imaged in the time-frequency domain using a beamformer to evaluate the contribution of motor cortical dynamics to age-related increases in behavioral interference effects. Our results showed that gamma oscillations in the contralateral motor cortex (M1) were a robust predictor of reaction time, regardless of interference level. Additionally, we observed condition-wise differences in gamma-by-age interactions, such that in younger adults, increases in M1 gamma power were predictive of faster reaction times during incongruent trials, while older adults did not receive this same behavioral benefit. Importantly, these data indicate that M1 gamma oscillations are differentially predictive of behavior in the presence, but not absence of visual interference, resulting in exhausted compensatory strategies with age.

Electrodermal activity (EDA)-a measure of electrical skin conductance reflecting (exclusive) sympathetic control of the eccrine sweat gland-holds promise as an indicator of central sympathetic activation. The aim of this study was to determine whether combat and blast exposure modulate the EDA response to acute exercise stress in specialised military men. Fifty-one men (age M = 36.1, SD = 6.5) participated in this study as part of the Explosive Ordnance Disposal Operational Health Surveillance System. The EDA complex (i.e., tonic + phasic conductance) was continuously measured throughout a maximal effort, graded exercise test. As expected, exercise stress resulted in measurable, stepwise increases in EDA before tapering at higher exercise intensities. Individuals with more substantial combat exposure and those with blast exposure demonstrated blunted EDA patterns in comparison to their low/nonexposed counterparts. This blunted pattern might imply sub-optimal sympathetic nervous system function in the exposed cohorts and enhances our knowledge of factors influencing resilience in these men.

HIV‐infection has been associated with widespread alterations in brain structure and function, although few studies have examined whether such aberrations are co‐localized and the degree to which clinical and cognitive metrics are related. We examine this question in the somatosensory system using high‐resolution structural MRI (sMRI) and magnetoencephalographic (MEG) imaging of neural oscillatory activity. Forty‐four participants with HIV (PWH) and 55 demographically‐matched uninfected controls completed a paired‐pulse somatosensory stimulation paradigm during MEG and underwent 3T sMRI. MEG data were transformed into the time‐frequency domain; significant sensor level responses were imaged using a beamformer. Virtual sensor time series were derived from the peak responses. These data were used to compute response amplitude, sensory gating metrics, and spontaneous cortical activity power. The T1‐weighted sMRI data were processed using morphological methods to derive cortical thickness values across the brain. From these, the cortical thickness of the tissue coinciding with the peak response was estimated. Our findings indicated both PWH and control exhibit somatosensory gating, and that spontaneous cortical activity was significantly stronger in PWH within the left postcentral gyrus. Interestingly, within the same tissue, PWH also had significantly reduced cortical thickness relative to controls. Follow‐up analyses indicated that the reduction in cortical thickness was significantly correlated with CD4 nadir and mediated the relationship between HIV and spontaneous cortical activity within the left postcentral gyrus. These data indicate that PWH have abnormally strong spontaneous cortical activity in the left postcentral gyrus and such elevated activity is driven by locally reduced cortical gray matter thickness., Forty‐four participants with HIV (PWH) and 55 demographically‐matched uninfected controls completed a paired‐pulse somatosensory stimulation paradigm during MEG and underwent 3T sMRI. These data were used to compute response amplitude, sensory gating metrics, and spontaneous cortical activity power. Our findings indicated both PWH and controls exhibit somatosensory gating, and that spontaneous cortical activity was significantly stronger in PWH within the left postcentral gyrus. Interestingly, within the same tissue, PWH also had significantly reduced cortical thickness relative to controls.

The Coronavirus Disease 2019 (COVID-19) pandemic has spread across the world and resulted in over 5 million deaths to date, as well as countless lockdowns, disruptions to daily life, and extended period of social distancing and isolation. The impacts on youth in particular are astounding, with shifts in learning platforms, limited social outlets, and prolonged uncertainty about the future. Surveys have shown that mental health among youth has severely suffered during the pandemic. However, limited research to date has reported on physiological indices of stress surrounding the pandemic, such as cortisol. Cortisol is a stress hormone that typically increases during stressful situations and can have deleterious effects on mental and physical health when chronically heightened. The present study leveraged hair cortisol concentration measurements, which allowed the retrospectiveinvestigation of circulating cortisol prior to- versus after pandemic-related local lockdowns during the first wave of the pandemic. A final sample of 44 youth ages 10- to 18-years-old provided hair samples and reported on their perceived affective well-being and level of concern regarding pandemic-related stressors between May and June of 2020. We found significant levels of concern and decreases in affective well-being following local lockdowns. Moreover, we saw that cortisol robustly increased following local lockdowns, and those increases were predictive of changes in affect. These findings provide critical insights into the underlying neuroendocrinology of stress during the pandemic and support the need for resources to support youths’ mental health and well-being during this globally significant event.

Background Unplanned hospitalizations are common in patients with cardiovascular disease. The “Triage Heart Failure Risk Status” (Triage‐HFRS) algorithm in patients with cardiac implantable electronic devices uses data from up to 9 device‐derived physiological parameters to stratify patients as low/medium/high risk of 30‐day heart failure (HF) hospitalization, but its use to predict all‐cause hospitalization has not been explored. We examined the association between Triage‐HFRS and risk of all‐cause, cardiovascular, or HF hospitalization. Methods and Results A prospective observational study of 435 adults (including patients with and without HF) with a Medtronic Triage‐HFRS–enabled cardiac implantable electronic device (cardiac resynchronization therapy device, implantable cardioverter‐defibrillator, or pacemaker). Cox proportional hazards models explored association between Triage‐HFRS and time to hospitalization; a frailty term at the patient level accounted for repeated measures. A total of 274 of 435 patients (63.0%) transmitted ≥1 high HFRS transmission before or during the study period. The remaining 161 patients never transmitted a high HFRS. A total of 153 (32.9%) patients had ≥1 unplanned hospitalization during the study period, totaling 356 nonelective hospitalizations. A high HFRS conferred a 37.3% sensitivity and an 86.2% specificity for 30‐day all‐cause hospitalization; and for HF hospitalizations, these numbers were 62.5% and 85.6%, respectively. Compared with a low Triage‐HFRS, a high HFRS conferred a 4.2 relative risk of 30‐day all‐cause hospitalization (8.5% versus 2.0%), a 5.0 relative risk of 30‐day cardiovascular hospitalization (3.6% versus 0.7%), and a 7.7 relative risk of 30‐day HF hospitalization (2.0% versus 0.3%). Conclusions In patients with cardiac implantable electronic devices, remotely monitored Triage‐HFRS data discriminated between patients at high and low risk of all‐cause hospitalization (cardiovascular or noncardiovascular) in real time.

Puberty is a period of substantial hormonal fluctuations, and pubertal hormones can modulate structural and functional changes in the developing brain. Many previous studies have characterized the neural oscillatory responses serving movement, which include a beta event-related desynchronization (ERD) preceding movement onset, gamma and theta responses coinciding with movement execution, and a post-movement beta-rebound (PMBR) response following movement offset. While a few studies have investigated the developmental trajectories of these neural oscillations serving motor control, the impact of pubertal hormone levels on the maturation of these dynamics has not yet been examined. Since the timing and tempo of puberty varies greatly between individuals, pubertal hormones may uniquely impact the maturation of motor cortical oscillations distinct from other developmental metrics, such as age. In the current study we quantified these oscillations using magnetoencephalography (MEG) and utilized chronological age and measures of endogenous testosterone as indices of development during the transition from childhood to adolescence in 69 youths. Mediation analyses revealed complex maturation patterns for the beta ERD, in which testosterone predicted both spontaneous baseline and ERD power through direct and indirect effects. Age, but not pubertal hormones, predicted motor-related theta, and no relationships between oscillatory responses and developmental metrics were found for gamma or PMBR responses. These findings provide novel insight into how pubertal hormones affect motor-related oscillations, and highlight the continued development of motor cortical dynamics throughout the pubertal period.

Human visual processing involves the extraction of both global and local information from a visual stimulus. Such processing may be related to cognitive abilities, which is likely going to change over time as we age. We aimed to investigate the impact of healthy aging on the association between visual global vs local processing and intelligence. In this context, we collected behavioral data during a visual search task in 103 adults (50 younger/53 older). We extracted three metrics reflecting global advantage (faster global than local processing), and visual interference in detecting either local or global features (based on interfering visual distractors). We found that older, but not younger, adults with higher levels of fluid and crystallized intelligence showed stronger signs of global advantage and interference effects during local processing, respectively. The present findings also provide promising clues regarding how participants consider and process their visual world in healthy aging.

KEY POINTS Individuals with cerebral palsy (CP) have a reduced somatosensory cortical response Somatosensory cortical response strength decreases from adolescence to early adulthood Somatosensory cortical responses in youth with CP are similar to adult controls Individuals with CP may have aberrant maturation of the somatosensory system ABSTRACT: Numerous studies have documented tactile and proprioceptive deficits in children with cerebral palsy (CP) and linked these with weaker somatosensory cortical activity. However, whether such aberrations in somatosensory processing extend and/or progress into adulthood remains poorly understood. In the current study, we used magnetoencephalography (MEG) to investigate the primary somatosensory responses in a sample of individuals with CP (N = 42; age = 9-28 years) and a cohort of healthy controls (N = 23; age range = 11-23 years). Briefly, transient electrical stimulation was applied to the right tibial nerve, and standardized low-resolution brain electromagnetic tomography (sLORETA) was used to image the dynamic somatosensory cortical response. We found that the strength of somatosensory cortical activity within the 112-252 ms time window was significantly reduced in the individuals with CP compared with the healthy controls (HC = 286.53 ± 30.51, 95% CI [226.74, 346.32]; CP = 208.30 ± 19.66,CI [169.77, 246.83], P = 0.0126). These results corroborate previous findings of aberrant somatosensory cortical activity in individuals with CP. Our results also suggest that the somatosensory cortical activity tends to become weaker with age, with a similar rate of neurophysiological change in individuals with CP and healthy controls (P = 0.8790). Visualization of regression models fitted to the data imply that youth with CP may have somatosensory cortical activity similar to adult controls. These findings suggest that some individuals with CP exhibit an aberrant developmental trajectory of their somatosensory system.

BackgroundThe Cognitive Battery of the National Institutes of Health Toolbox (NIH-TB) is a collection of assessments that have been adapted and normed for administration across the lifespan and is increasingly used in large-scale population-level research. However, despite increasing adoption in longitudinal investigations of neurocognitive development, and growing recommendations that the Toolbox be used in clinical applications, little is known about the long-term temporal stability of the NIH-TB, particularly in youth.MethodsThe present study examined the long-term temporal reliability of the NIH-TB in a large cohort of youth (9–15 years-old) recruited across two data collection sites. Participants were invited to complete testing annually for 3 years.ResultsReliability was generally low-to-moderate, with intraclass correlation coefficients ranging between 0.31 and 0.76 for the full sample. There were multiple significant differences between sites, with one site generally exhibiting stronger temporal stability than the other.ConclusionsReliability of the NIH-TB Cognitive Battery was lower than expected given early work examining shorter test-retest intervals. Moreover, there were very few instances of tests meeting stability requirements for use in research; none of the tests exhibited adequate reliability for use in clinical applications. Reliability is paramount to establishing the validity of the tool, thus the constructs assessed by the NIH-TB may vary over time in youth. We recommend further refinement of the NIH-TB Cognitive Battery and its norming procedures for children before further adoption as a neuropsychological assessment. We also urge researchers who have already employed the NIH-TB in their studies to interpret their results with caution.

Purpose: To determine the acute and chronic effects of exercise on Paraoxonase-1 (PON1) concentration and activity. Methods: A literature search was performed using 16 electronic databases. Effect sizes (ES) were computed and two-tailed α values < .05 and non-overlapping 95% confidence intervals (95% CI) were considered statistically significant. Heterogeneity, inconsistency (I2), and small-study effects using the LFK index were examined. Results: Eighteen studies (n = 377 participants) met the criteria for inclusion. The acute effects of exercise on PON1 concentration were trivial and non-significant (ES = −.03, 95%CI = −.39 to .34, p > .05), heterogeneous (p = .05), moderately inconsistent (I2 = 48%), with minor asymmetry (LFK index = 1.34). The chronic effects of exercise on PON1 concentration were also trivial and non-significant (ES = −.04, 95%CI = −.53 to.45, p > .05), homogenous (p = .65), displayed low inconsistency (I2 = 0%), and minor asymmetry (LFK index = −1.14). The acute effects of exercise on PON1 activity were trivial and non-significant (ES = .11, 95%CI = −.02 to.24, p > .05), homogenous (p = .85), showed low inconsistency (I2 = 0%), and no asymmetry (LFK index = .82). The chronic effects of exercise on PON1 activity were trivial and non-significant (ES = .31, 95%CI = −.03 to.65, p > .05), homogenous (p = .17), moderately inconsistent (I2 = 36%), with no asymmetry (LFK index = .60). Conclusion: Acute and chronic exercise training, overall, exerted a trivial effect on PON1 concentration and activity. UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Sociales::Centro de Investigación en Ciencias del Movimiento Humano (CIMOHU)

Businesses are struggling to re-open as the world continues to deal with the coronavirus 2019 (COVID-19) pandemic. The reopening of businesses will require employers to implement safe return-to-work strategies through evaluation, testing, work modifications, and development of appropriate workplace policies. There will be unique challenges along the way as no one approach will be ideal for all workplaces and industries. This document is intended to provide return-to-work guidance for both employers and the occupational and environmental medicine physicians who will be supporting businesses in implementing safe return-to-work strategies.

Puberty is a period of substantial hormonal fluctuations that induce dramatic physical, neurological, and behavioral changes. Previous research has demonstrated that pubertal hormones modulate cortical development, as well as sex- and age-specific patterns of cognitive development during childhood and adolescence. However, the influence of pubertal hormones on the brain’s functional development, specifically neural oscillatory dynamics, has yet to be fully examined. Thus, in the current study, we used magnetoencephalography to investigate the oscillatory dynamics serving visuospatial perception and attention, and testosterone levels and chronological age as measures of development. Within a sample of typically developing youth, age was associated with changes in alpha, theta, and gamma oscillatory activity. Novel testosterone-by-sex interactions in the gamma range were identified in critical areas of the visual and attention networks. Females had increased gamma activity with increasing testosterone in the right temporal-parietal junction and occipital cortices, while males showed increased gamma activity in the right insula with increasing testosterone. These findings reveal robust developmental alterations in the oscillatory dynamics serving visuospatial processing during childhood and adolescence and provide novel insight into the hormonal basis of sexually dimorphic patterns of functional brain development during the pubertal transition that is at least partially mediated by endogenous testosterone.

ContextTactical athletes commonly experience high levels of physical stress, which may increase their risk of musculoskeletal injury. It is critical to understand psychological predictors of functional movement (FM), which may help prevent musculoskeletal injury in this population.ObjectiveTo determine the associations of combat and trauma exposure with FM characteristics of male tactical athletes. Secondary objectives were to explore confounding influences of age and physical injury history as well as the mediating role of bodily pain.DesignCross-sectional study.SettingResearch laboratory.Patients or Other ParticipantsEighty-two healthy, male, active-duty US Navy Explosive Ordnance Disposal personnel (age = 34.0 ± 6.7 years).Main Outcome Measure(s)Participants completed measures of combat exposure, trauma exposure, physical injury history, and bodily pain. We assessed FM characteristics (ie, Functional Movement Screen [FMS], Y-Balance Test), from which we derived a composite functional status (CFS) measure. Hypotheses were tested using correlational and multiple regression (causal-steps) models.ResultsIn unadjusted models, trauma exposure was inversely associated with the FMS (P = .005) and CFS (P = .009) scores. In adjusted models, these relationships were robust to the confounding influences of age and physical injury history. Trauma exposure and bodily pain were substantive, independent predictors of FMS and CFS in causal-steps models (all P values < .05), implying additive rather than mediated effects (R2adj = 0.18–0.20). Combat exposure did not predict FM characteristics.ConclusionsTo our knowledge, this is the first evidence of the influence of trauma exposure on the FM characteristics of male tactical athletes, independent of age, physical injury, and bodily pain. This program of research may help to advance the prevention and treatment of musculoskeletal injuries in the tactical environment.

Previous studies have assessed the construct validity of individual subtests in the National Institutes of Health (NIH) Toolbox Cognition Battery (NIHTB-CB), though none have examined the construct validity of the cognitive domains. Importantly, the original NIHTB-CB validation studies were administered on a desktop computer, though the NIHTB-CB is now solely administered via an iPad. We examined the construct validity of each cognitive domain assessed in the NIHTB-CB, including a motor dexterity domain using the iPad application compared to a neuropsychological battery in a sample of healthy adults.Eighty-three adults aged 20-66 years (We found theThe NIHTB-CB cognitive domains have poor-to-good construct validity, thus researchers should be aware that some tests representing cognitive constructs may not fully reflect the cognitive domain of interest. Future investigation of the construct validity and reliability of the NIHTB-CB administered using the iPad is recommended. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

More than 420 million children live amid political conflict. In such settings, understanding the development of prosocial behaviours, specifically directed at outgroups, can provide opportunities for peacebuilding. Informed by research on intergroup competition and structural inequality, we focus on outgroup prosocial behaviour targeting conflict rivals. Already from a young age, children are politically socialised and show intergroup biases that dampen helping behaviours towards conflict rivals, which continue into adulthood. We review factors that shape youth's interpersonal helping and broader forms of prosociality, such as civic engagement, across group lines. We conceptualise outgroup prosocial behaviour along a continuum, ranging from interpersonal acts to broader structural and cultural constructive change. We conclude with directions for future research.

Background and Objectives: Racial/ethnic score disparities on standardized tests are well documented. Such differences on the American Board of Family Medicine (ABFM) certification examination have not been previously reported. If such differences exist, it could be due to differences in knowledge at the beginning of residency or due to variations in the rate of knowledge acquisition during residency. Our objective was to examine the residents’ mean initial scores and score trajectories using the In-Training Examination (ITE) and certification examination. Methods: A total of 17,275 certification candidates from 2014 to 2019 were included in this study. Annual ITE scores and certification examination scores are reported on the same scale and serve as the outcome. We conducted multilevel longitudinal regression to determine initial knowledge and growth in knowledge acquisition during residency by race/ethnicity categories. Results: The mean postgraduate year 1 (PGY-1) ITE score was 393.3, with minority residents scoring 16.2 to 36.0 points lower compared to White residents. The mean increase per year in exam performance from PGY-1 ITE to the certification exam was 39.9 points (95% CI, 38.7, 41.1) with additional change among race/ethnicity categories per year of -3.2 to 1.9 points. Conclusions: This study found that there were initial score disparities across race/ethnicity groups in PGY-1, and these disparities continued at the same rate throughout residency training, suggesting equality in acquisition of knowledge during family medicine residency training but with a persistent gap throughout training.

Background Bedside teaching (BST) facilitates medical education and has reduced in practice, often due to patient-related concerns. This study aimed to validate a questionnaire exploring patients attitudes towards BST. Methods International guidelines for questionnaire development were followed. Seven steps were included: literature review, patient interviews, development of clear and understandable items, expert validation, cognitive interviewing and pilot testing. Statistical analyses included exploratory factor analysis, internal consistency, investigation of demographic influences and discriminant validity across subscales. Results Following the literature review, 32 interviews were conducted. Potential items were developed, reviewed and adapted. Experts in medical education and statistics reviewed the draft questionnaire. Fifteen patients consented to cognitive testing and 401 consenting patients completed the final version. The median age of participants was 35 years of age (range: 18 to 70 years). Participants included women attending for antenatal (40%), postnatal (32%) and gynaecology issues (28%). Just under one third (29%) had taken part in medical student teaching previously. Statistical analyses found a two-factor solution, consisting of Educate medical professionals and Conditions for participation subscales with good internal consistency; responses did not vary by age or education. Participants who had opted-in for teaching in the ward and bedside endorsed higher levels of Educate medical professionals, suggesting discriminant validity. A majority of patients (> 92%) reported that they were happy to be involved in BST. Patients believed that they should not be asked to participate in BST should they feel stressed or unwell (68.2%). Conclusion This study shows extensive patient support for BST, independent of age or education. The desire to educate is a strong motivating factor. This strong support by patients for BST is an area that medical schools and universities can potentially develop. Future versions of this questionnaire may include virtual bedside teaching, in the context of social distancing.

There are numerous clinical reports showing that persons with cerebral palsy (CP) have proprioceptive, stereognosis, and tactile discrimination deficits. The current consensus is that these altered perceptions are attributable to aberrant somatosensory cortical activity. It has been inferred from these data that persons with CP do not adequately process ongoing sensory feedback during motor actions, which accentuates the extent of their mobility impairments. However, this hypothesis has yet to be directly tested. We used magnetoencephalographic brain imaging to address this knowledge gap by quantifying the somatosensory dynamics evoked by applying electrical stimulation to the tibial nerve in 22 persons with CP and 25 neurotypical controls at rest and during an ankle plantarflexion isometric force motor task. We also quantified the spatiotemporal gait biomechanics of participants outside the scanner. Consistent with the literature, our results confirmed that the strength of somatosensory cortical activity was weaker in the persons with CP compared to the neurotypical controls. Our results also showed that the strength of the somatosensory cortical responses were significantly weaker during the isometric ankle force task than at rest. Most importantly, our results showed that the strength of somatosensory cortical activity during the ankle plantarflexion force production task mediated the relationship between somatosensory cortical activity at rest and both walking velocity and step length. These results suggest that youth with CP have aberrant somatosensory cortical activity during isometric force generation, which ultimately contributes to the extent of mobility impairments seen in this patient population. KEY POINTS: Persons with cerebral palsy have reduced somatosensory cortical responses at rest and during movement. The somatosensory cortical responses during movement mediate the relationship between the somatosensory cortical responses at rest and mobility. Persons with cerebral palsy may have altered sensorimotor feedback that ultimately contributes to impaired mobility.

Family physicians who report their race as "Other" in a single best option question find the existing categories and forced choice of one category to be problematic. Our analysis of open-text responses in the "Other" race category supports a modification in the way these data are collected to provide more accurate and meaningful ways to understand the workforce and move toward more diverse, equitable, and inclusive policies in family medicine.

Fluid reasoning is the ability to problem solve in the absence of prior knowledge and is commonly conceptualized as "non-verbal" intelligence. Importantly, fluid reasoning abilities rapidly develop throughout childhood and adolescence. Although numerous studies have characterized the neural underpinnings of fluid reasoning in adults, there is a paucity of research detailing the developmental trajectory of this neural processing. Herein, we examine longitudinal changes in the neural oscillatory dynamics underlying fluid intelligence in a sample of typically developing youths. A total of 34 participants age 10 to 16 years-old completed an abstract reasoning task during magnetoencephalography (MEG) on two occasions set one year apart. We found robust longitudinal optimization in theta, beta, and gamma oscillatory activity across years of the study across a distributed network commonly implicated in fluid reasoning abilities. More specifically, activity tended to decrease longitudinally in additional, compensatory areas such as the right lateral prefrontal cortex and increase in areas commonly utilized in mature adult samples (e.g., left frontal and parietal cortices). Importantly, shifts in neural activity were associated with improvements in task performance from one year to the next. Overall, the data suggest a longitudinal shift in performance that is accompanied by a reconfiguration of the functional oscillatory dynamics serving fluid reasoning during this important period of development.

The Coronavirus Disease 2019 (COVID-19) pandemic has caused massive disruptions to daily life in the United States, closing schools and businesses and increasing physical and social isolation, leading to deteriorations in mental health and well-being in people of all ages. Many studies have linked chronic stress with long-term changes in cortisol secretion, which has been implicated in many stress-related physical and mental health problems that commonly emerge in adolescence. However, the physiological consequences of the pandemic in youth remain understudied. Using hair cortisol concentrations (HCC), we quantified average longitudinal changes in cortisol secretion across a four-month period capturing before, during, and after the transition to pandemic-lockdown conditions in a sample of healthy youth (n = 49). Longitudinal changes in HCC were analyzed using linear mixed-effects models. Perceived levels of pandemic-related stress were measured and compared to the physiological changes in HCC. In children and adolescents, cortisol levels significantly increased across the course of the pandemic. These youth reported a multitude of stressors during this time, although changes in HCC were not associated with self-reported levels of COVID-19-related distress. We provide evidence that youth are experiencing significant physiological changes in cortisol activity across the COVID-19 pandemic, yet these biological responses are not associated with perceived stress levels. Youth may be especially vulnerable to the deleterious impacts of chronic cortisol exposure due to their current status in the sensitive periods for development, and the incongruency between biological and psychological stress responses may further complicate these developmental problems.

OBJECTIVE: To evaluate the effects of gaining access to Medicare on key financial outcomes for surgical patients. SUMMARY BACKGROUND DATA: Surgical care poses a significant financial burden, especially among patients with insufficient financial risk protection. Medicare may mitigate the risk of these adverse circumstances, but the impact of Medicare eligibility on surgical patients remains poorly understood. METHODS: Regression discontinuity analysis of national, cross-sectional survey and cost data from the 2008–2018 National Health Interview Survey (NHIS) and Medical Expenditure Panel Survey (MEPS). Patients were between the ages of 57–72 with surgery in the past 12 months. The primary outcomes were the presence of medical debt, delay/deferment of care due to cost, total annual out-of-pocket (OOP) costs, and experiencing catastrophic health expenditures (CHE). RESULTS: Among 45,982,243 NHIS patients, Medicare eligibility was associated with a 6.6 percentage-point decrease (95%CI: −9.0% to −4.3) in being uninsured (>99% relative reduction), 7.6 percentage-point decrease (24% relative reduction) in having medical debt (95%CI: −14.1% to −1.1%), and 4.9 percentage-point decrease (95%CI: −9.4% to −0.4%) in deferrals/delays in medical care due to cost (28% relative reduction). Among 33,084,967 MEPS patients, annual OOP spending decreased by $1,199 per patient (95%CI: −$1,633 to −$765), a 33% relative reduction, and CHE decreased by 7.3 percentage points (95%CI: −13.6% to −0.1%), a 55% relative reduction. CONCLUSIONS: Medicare may reduce the economic burden of healthcare spending and delays in care for older adult surgical patients. These findings have important implications for policy discussions regarding changing insurance eligibility thresholds for the older adult population.

To understand whether perioperative SARS-CoV-2 infection increases risk of pulmonary complications in children.A retrospective cohort study of children who underwent surgery with perioperative SARS-CoV-2 infection at a children's hospital from March 1, 2020, to June 30, 2021. Uninfected, age-matched control patients who underwent the same procedure as infected patients over the past ten years were included in the study in a 3:1 ratio to infected patients. Primary outcomes were 7- and 30-day mortality. Secondary outcomes were development of pulmonary complications, readmission, length of hospital or ICU stay, and oxygen administration in post-anesthesia care unit (PACU).Our study included 73 patients who underwent surgery with perioperative diagnosis of SARS-CoV-2, and 218 control patient undergoing similar procedures. One total mortality event was observed within 7 days in an uninfected control patient, and none occurred in infected patients. Perioperative SARS-CoV-2 infection was associated with increased risk for pulmonary complications in univariate analysis. Infection was not associated with any of our other secondary outcomes. Symptomatic SARS-CoV-2 infection and timing of diagnosis was not associated with development of pulmonary complications among infected patients.Children with perioperative SARS-CoV-2 infection may be at increased risk for development of pulmonary complications. Larger studies should be performed to confirm our results.

To evaluate the effects of gaining access to Medicare on key financial outcomes for surgical patients.Surgical care poses a significant financial burden, especially among patients with insufficient financial risk protection. Medicare may mitigate the risk of these adverse circumstances, but the impact of Medicare eligibility on surgical patients remains poorly understood.Regression discontinuity analysis of national, cross-sectional survey and cost data from the 2008 to 2018 National Health Interview Survey and Medical Expenditure Panel Survey. Patients were between the ages of 57 to 72 with surgery in the past 12 months. The primary outcomes were the presence of medical debt, delay/deferment of care due to cost, total annual out-of-pocket costs, and experiencing catastrophic health expenditures.Among 45,982,243 National Health Interview Survey patients, Medicare eligibility was associated with a 6.6 percentage-point decrease (95% confidence interval [CI]: -9.0% to -4.3) in being uninsured (99% relative reduction), 7.6 percentage-point decrease (24% relative reduction) in having medical debt (95%CI: -14.1% to -1.1%), and 4.9 percentage-point decrease (95%CI: -9.4% to -0.4%) in deferrals/delays in medical care due to cost (28% relative reduction). Among 33,084,967 Medical Expenditure Panel Survey patients, annual out-of-pocket spending decreased by $1199 per patient (95%CI: -$1633 to -$765), a 33% relative reduction, and catastrophic health expenditures decreased by 7.3 percentage points (95%CI: -13.6% to -0.1%), a 55% relative reduction.Medicare may reduce the economic burden of healthcare spending and delays in care for older adult surgical patients. These findings have important implications for policy discussions regarding changing insurance eligibility thresholds for the older adult population.

To evaluate the decision making processes of pediatricians regarding diagnosis and management of developmental dysplasia of the hip (DDH) by conducting a survey of pediatricians in the United States.An electronic survey was sent to multiple American Academy of Pediatrics state chapters and academic pediatrics groups, and responses were received from pediatricians in 10 states. The survey included demographics, guideline use, clinical scenarios, and referrals/imaging practices. The number of responses to each survey question and their relative frequencies were calculated.We received 139 responses and included 126 in our analyses. Only 50% of the responding pediatricians (63 of 126) practiced in an institution that endorses a care pathway for DDH. Only 5.6% of the pediatricians (7 of 125) have referred patients at 12-18 months between diagnosis and management to a specialist for suspected DDH, and 9.5% (12 of 125) have referred patients between 6 and 9 months. Almost one-quarter of the pediatricians (23%; 29 of 126) cited "hip click" as an abnormality that would prompt them to refer a patient to a specialist, and 72.2% (91 of 126) indicated that family history of DDH warrants an ultrasound regardless of the physical examination findings. Moreover, 10.3% of the surveyed pediatricians (13 of 126) reported being only "somewhat" or "moderately" familiar with the Barlow and Ortolani maneuvers.The results of this study indicate that there is an opportunity to better distribute and implement DDH guidelines. The large number of pediatrician respondents who would not refer patients to a specialist or order imaging studies appropriately represents an opportunity for education. The implementation of a care map with standard referral and imaging practices could improve the care of patients with DDH.

Background Doctors, including junior doctors, are vulnerable to greater levels of distress and mental health difficulties than the public. This is exacerbated by their working conditions and cultures. While this vulnerability has been known for many years, little action has been taken to protect and support junior doctors working in the NHS. As such, we present a series of recommendations from the perspective of junior doctors and other relevant stakeholders, designed to improve junior doctors’ working conditions and, thus, their mental health. Methods We interviewed 36 junior doctors, asking them for recommendations for improving their working conditions and culture. Additionally, we held an online stakeholder meeting with a variety of healthcare professionals (including junior doctors), undergraduate medical school leads, postgraduate speciality school leads and NHS policymakers where we asked what could be done to improve junior doctors’ working conditions. We combined interview data with notes from the stakeholder discussions to produce this set of recommendations. Results Junior doctor participants and stakeholders made organisational and interpersonal recommendations. Organisational recommendations include the need for more environmental, staff and educational resources as well as changes to rotas. Interpersonal recommendations include changes to communication and recommendations for better support and teamwork. Conclusion We suggest that NHS policymakers, employers and managers consider and hopefully implement the recommendations set out by the study participants and stakeholders as reported in this paper and that the gold standards of practice which are reported here (such as examples of positive learning environments and supportive supervision) are showcased so that others can learn from them.

The α1-acid glycoprotein (AGP) is an abundant blood plasma protein with important immunomodulatory functions coupled to endogenous and exogenous ligand binding properties. Its affinity for many drug-like structures, however, means AGP can have a significant effect on the pharmokinetics and pharmacodynamics of numerous small molecule therapeutics. Staurosporine, and its hydroxylated forms UCN-01 and UCN-02, are kinase inhibitors that have been investigated at length as anti-tumour compounds. Despite their potency, these compounds display poor pharmokinetics due to binding to both AGP variants, AGP1 and AGP2. Recent renewed interest in UCN-01 as a cytostatic protective agent prompted us to solve the structure of the AGP2/UCN-01 complex by X-ray crystallography, revealing for the first time the precise binding mode of UCN-01. Solution NMR suggests AGP2 undergoes a significant conformational change upon ligand binding, but also that it uses a common set of sidechains with which it captures key groups of UCN-01 and other small molecule ligands. We anticipate that this structure and supporting NMR data will facilitate rational re-design of small molecules that could evade AGP and therefore improve tissue distribution.

Extracorporeal membrane oxygenation (ECMO) is a universally accepted and life-saving therapy for neonates with respiratory or cardiac failure that is refractory to maximal medical management. Early studies found unacceptable risks of mortality and morbidities such as intracranial hemorrhage among premature and low birthweight neonates, leading to widely accepted ECMO inclusion criteria of gestational age ≥34 weeks and birthweight2 kg. Although contemporary data is lacking, the most recent literature demonstrates increased survival and decreased rates of intracranial hemorrhage in premature neonates who are supported with ECMO. As such, it seems like the right time to push the boundaries of ECMO on a case-by-case basis beginning with neonates 32-34 weeks GA in large volume centers with careful neurodevelopmental follow-up to better inform practices changes on this select population.

This study aims to use structural equation modeling (SEM) to investigate the role of error processing in behavioral adaptation in children by testing relationships between error-related and stimulus-related event-related potentials (ERPs) obtained from two sessions of a speeded Eriksen flanker task. First, path models of averaged ERP components and mean response times (N1 → P2 → N2 → P3 → RTs) while controlling for trait effects, age, and sex, on each was examined separately for correct and incorrect trials from each session. While the model demonstrated acceptable fit statistics, the four models yielded diverse results. Next, path models for correct and incorrect trials were tested using latent variables defined by factoring together respective measures of ERP component amplitudes from each session. Comparison of correct and incorrect models revealed significant differences in the relationships between the successive measures of neural processing after controlling for trait effects. Moreover, latent variable models controlling for both trait and session-specific state variables yielded excellent model fit while models without session-specific state variables did not. In the final model, the error-related neural activity (i.e., the ERN and Pe) from incorrect trials was found to significantly relate to the stream of neural processes contributing to trials with the correct behavior. Importantly, the relationship between RT and error detection in the final model signifies a brain-and-behavior feedback loop. These findings provided empirical evidence that supports the adaptive orienting theory of error processing by demonstrating how the neural signals of error processing influence behavioral adaptations that facilitate correct behavioral performance.

A race and gender salary gap has been well-documented throughout the U.S. economy, but little described in primary care. Using self-reported data on the most widely distributed primary care physician specialty, we reveal lower incomes and hourly wages among Black/African American and female family physicians. The clear gradient in family physician compensation by race and gender demands further study and action to better understand and address the underlying sources of these differences.

Our beliefs about aging affect how we interact with others. For example, people know that episodic memory declines with age, and as a result, older adults' memories are less likely to be trusted. However, not all aspects of remembering decline with age; semantic memory (knowledge) increases across adulthood and is relatively unaffected in healthy aging. In the current work, we examined people's awareness of this pattern. Participants estimated the knowledge of hypothetical younger and older adults; in some studies, they also predicted and demonstrated their own knowledge on the same measures. Across studies, both younger and older adults estimated that older adults would perform better on a knowledge test, demonstrating awareness that knowledge is not impaired with aging. Furthermore, people's beliefs about their own knowledge influenced the predictions they made about others' knowledge. We discuss how this work informs theories of metacognition and contributes to positive self-perceptions in older adulthood.

We aimed to explore the trajectory of financial difficulties among breast cancer survivors in the German health system and its association with migration background.In a multicentre prospective study, breast cancer survivors were approached four times (before surgery, before and after adjuvant therapy, five years after surgery) and asked about their migration history and financial difficulties. Migrants were defined as born/resided outside Germany or having citizenship/nationality other than German. Financial difficulties were ascertained with the financial difficulties item of the European Organisation for Research and Treatment of Cancer Core Instrument (EORTC QLQ-C30) at each time-point (cut-off 17). Financial difficulties were classified in trajectories: always (every time-point), never (no time-point), initial (first, not fourth), delayed (only fourth), and acquired (second and/or third, not first). A logistic regression was conducted with the trajectories of financial difficulties as outcome and migration background as exposure. Age, trends in partnership status, and educational level were considered as confounders.Of the 363 participants included, 49% reported financial difficulties at at least one time-point. Financial difficulties were reported always by 7% of the participants, initially by 5%, delayed by 10%, and acquired by 21%. Migrants were almost four times more likely to report delayed (odds ratio [OR] = 3.7; 95% confidence interval [CI] 1.3, 10.5) or acquired (OR = 3.6; 95% CI 1.6, 8.4) financial difficulties compared to non-migrant participants.Survivors with a migration background are more likely to suffer from financial difficulties, especially in later stages of the follow-up. A linguistically/culturally competent active enquiry about financial difficulties and information material regarding supporting services/insurances should be considered.

The emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genetic variants that may alter viral fitness highlights the urgency of widespread next-generation sequencing (NGS) surveillance. To profile genetic variants of the entire SARS-CoV-2 genome, we developed and clinically validated a hybridization capture SARS-CoV-2 NGS assay, integrating novel methods for panel design using double-stranded DNA (dsDNA) biotin-labeled probes, and built accompanying software. This test is the first hybrid capture-based NGS assay given Food and Drug Administration (FDA) emergency use authorization for detection of the SARS-CoV-2 virus. The positive and negative percent agreement (PPA and NPA, respectively) were defined in comparison to the results for an orthogonal real-time reverse transcription polymerase chain reaction (RT-PCR) assay (PPA and NPA, 96.7 and 100%, respectively). The limit of detection was established to be 800 copies/ml with an average fold enrichment of 46,791. Furthermore, utilizing the research-use-only analysis to profile the variants, we identified 55 novel mutations, including 11 in the functionally important spike protein. Finally, we profiled the full nasopharyngeal microbiome using metagenomics and found overrepresentation of 7 taxa and evidence of macrolide resistance in SARS-CoV-2-positive patients. This hybrid capture NGS assay, coupled with optimized software, is a powerful approach to detect and comprehensively map SARS-CoV-2 genetic variants for tracking viral evolution and guiding vaccine updates. IMPORTANCE This is the first FDA emergency-use-authorized hybridization capture-based next-generation sequencing (NGS) assay to detect the SARS-CoV-2 genome. Viral metagenomics and the novel hybrid capture NGS-based assay, along with its research-use-only analysis, can provide important genetic insights into SARS-CoV-2 and other emerging pathogens and improve surveillance and early detection, potentially preventing or mitigating new outbreaks. Better understanding of the continuously evolving SARS-CoV-2 viral genome and the impact of genetic variants may provide individual risk stratification, precision therapeutic options, improved molecular diagnostics, and population-based therapeutic solutions.

Introduction 24-hour movement behaviours (physical activity, sedentary behaviour and sleep) during the early years are associated with health and developmental outcomes, prompting the WHO to develop Global guidelines for physical activity, sedentary behaviour and sleep for children under 5 years of age. Prevalence data on 24-hour movement behaviours is lacking, particularly in low-income and middle-income countries (LMICs). This paper describes the development of the SUNRISE International Study of Movement Behaviours in the Early Years protocol, designed to address this gap. Methods and analysis SUNRISE is the first international cross-sectional study that aims to determine the proportion of 3- and 4-year-old children who meet the WHO Global guidelines. The study will assess if proportions differ by gender, urban/rural location and/or socioeconomic status. Executive function, motor skills and adiposity will be assessed and potential correlates of 24-hour movement behaviours examined. Pilot research from 24 countries (14 LMICs) informed the study design and protocol. Data are collected locally by research staff from partnering institutions who are trained throughout the research process. Piloting of all measures to determine protocol acceptability and feasibility was interrupted by COVID-19 but is nearing completion. At the time of publication 41 countries are participating in the SUNRISE study. Ethics and dissemination The SUNRISE protocol has received ethics approved from the University of Wollongong, Australia, and in each country by the applicable ethics committees. Approval is also sought from any relevant government departments or organisations. The results will inform global efforts to prevent childhood obesity and ensure young children reach their health and developmental potential. Findings on the correlates of movement behaviours can guide future interventions to improve the movement behaviours in culturally specific ways. Study findings will be disseminated via publications, conference presentations and may contribute to the development of local guidelines and public health interventions. Funding Agencies|American Council on Exercise, USA; Beijing Health System High Level Talents Training Project, China [2015-3-88]; Biomedical Research Foundation, Dhaka, Bangladesh [BRF-19-01]; Canadian Institutes of Health Research Frederick Banting and Charles Best Canada Graduate Scholarship (CGS-M)Canadian Institutes of Health Research (CIHR); Canadian Institutes of Health Research Planning and Dissemination GrantCanadian Institutes of Health Research (CIHR) [155265]; Civilian Research Development Foundation (CRDF) Global [OISE-20-66864-1]; Department of National Planning and Monitoring, PNG Government [02704]; Early Start, University of Wollongong, Australia; Faculty of Health Sciences at the University of the Witwatersrand, Johannesburg, South Africa; Fogarty International Center (FIC) of the National Institutes of Health [D43 TW010137]; Geran Universiti Penyelidikan (GUP), Universiti Kebangsaan Malaysia [GUP-2018-142]; Global Challenges Program, University of Wollongong, Australia [888/006/497]; Harry Crossley Foundation, South Africa; National Institute of Education-Ministry of Education, Singapore [OER 04/19 TWP]; Pham Ngoc Thach University of Medicine, Vietnam [1319/QD-TDHYKPNT]; Sasakawa Sports Research Grant, Sasakawa Sports Foundation, Japan [190A2-004]; Stella de Silva Research grant from Sri Lanka College of Paediatricians, Sri Lanka; The DST-NRF Centre for Excellence in Human Development at the University of Witwatersrand, Johannesburg, South Africa; International Society of Behavioral Nutrition and Physical Activity, Pioneers Program (ISBNPA-2021); The University Research Coordination Office of the De La Salle University, Philippines [29 IR S 3TAY192021]; Universidad de La Frontera Research Directorate, Chile [DI20-0093, DFP19-0012, DI20-1002]; WHO European Office for Prevention and Control of Noncommunicable Diseases

Significance Mitochondrial integrity and associated redox profiles have long been revered as key contributors to a host of age- and disease-related pathologies, which eventually lead to neuronal and behavioral dysfunction in the sensorimotor and other systems. However, the precise role of the mitochondrial redox environment in human sensorimotor brain systems and motor behavior remains poorly understood. Herein, we provide evidence for a strong predictive capacity of superoxide and its scavenger, superoxide dismutase, on the neural oscillatory dynamics serving motor planning and execution above and beyond the effects of mitochondrial respiratory capacities alone. Importantly, these data provide insight regarding the impact of the redox environment on the population-level neural oscillations that serve motor function in healthy humans., Motor control requires a coordinated ensemble of spatiotemporally precise neural oscillations across a distributed motor network, particularly in the beta range (15 to 30 Hz) to successfully plan and execute volitional actions. While substantial evidence implicates beta activity as critical to motor control, the molecular processes supporting these microcircuits and their inherent oscillatory dynamics remain poorly understood. Among these processes are mitochondrial integrity and the associated redox environments, although their direct impact on human neurophysiological function is unknown. Herein, 40 healthy adults completed a motor sequence paradigm during magnetoencephalography (MEG). MEG data were imaged in the time–frequency domain using a beamformer to evaluate beta oscillatory profiles during distinct phases of motor control (i.e., planning and execution) and subsequent behavior. To comprehensively quantify features of the mitochondrial redox environment, we used state-of-the-art systems biology approaches including Seahorse Analyzer to assess mitochondrial respiration and electron paramagnetic resonance spectroscopy to measure superoxide levels in whole blood as well as antioxidant activity assays. Using structural equation modeling, we tested the relationship between mitochondrial function and sensorimotor brain-behavior dynamics through alterations in the redox environment (e.g., generation of superoxide and alteration in antioxidant defenses). Our results indicated that superoxide-sensitive but not hydrogen peroxide–sensitive features of the redox environment had direct and mediating effects on the bioenergetic–neural pathways serving motor performance in healthy adults. Importantly, our results suggest that alterations in the redox environment may directly impact behavior above and beyond mitochondrial respiratory capacities alone and further may be effective targets for age- and disease-related declines in cognitive–motor function.