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Realizing multiply resonant photonic crystal cavities with large free spectral range is key to achieve integrated devices with highly efficient nonlinear response, such as frequency conversion, four-wave mixing, and parametric oscillation. This task is typically difficult owing to the cavity modes’ sensitivity to fabrication disorder, which makes it hard to reliably achieve a comb-like spectrum of equally spaced modes even when a perfect matching is theoretically predicted. Here we show that a comb-like spectrum of up to eight modes with very high quality factor and diffraction limited volumes can be engineered in the bichromatic-type potential of a two-dimensional photonic crystal cavity fabricated in a thin silicon membrane. To cope with the tight tolerance in terms of frequency spacings and resonance linewidths, we develop a permanent post-processing technique that allows the selective tuning of individual confined modes, thus achieving an almost perfect frequency matching of high Q resonances with record finesse in silicon microresonators. Our experimental results are extremely promising in view of ultra-low power nonlinear photonics in silicon.

Abstract Acute respiratory infections are a major cause of morbidity in children both in developed and developing countries. A wide range of respiratory viruses, including respiratory syncytial virus (RSV), influenza A and B viruses, parainfluenza viruses (PIVs), adenovirus, rhinovirus (HRV), have repeatedly been detected in acute lower respiratory tract infections (LRTI) in children in the past decades. However, in the last ten years thanks to progress in molecular technologies, newly discovered viruses have been identified including human Metapneumovirus (hMPV), coronaviruses NL63 (HcoV-NL63) and HKU1 (HcoV-HKU1), human Bocavirus (HBoV), new enterovirus (HEV), parechovirus (HpeV) and rhinovirus (HRV) strains, polyomaviruses WU (WUPyV) and KI (KIPyV) and the pandemic H1N1v influenza A virus. These discoveries have heavily modified previous knowledge on respiratory infections mainly highlighting that pediatric population is exposed to a variety of viruses with similar seasonal patterns. In this context establishing a causal link between a newly identified virus and the disease as well as an association between mixed infections and an increase in disease severity can be challenging. This review will present an overview of newly recognized as well as the main emerging respiratory viruses and seek to focus on the their contribution to infection and co-infection in LRTIs in childhood.

Abstract Background A novel human enterovirus (HEV) type within the species HEV-C, named EV109, was discovered from cases of respiratory illness in Nicaragua in September 2010. The aim of this study, was to retrospectively examine the presence and the role of EV109 in respiratory samples from two patients populations; infants below the age of 2 years, hospitalized for acute respiratory diseases (ARDs) and adult hematopoietic stem cell transplantation recipients. Results A total of 1149 nasopharingeal aspirates were collected and tested for the presence of EV109 by reverse transcription-PCR (RT-PCR). In positive samples, the presence of the most common respiratory viruses was also assayed and clinical symptoms were evaluated. Samples from 2 of the 974 infants tested positive for EV109 RNA (0.2%) and belonged to patients with lower ARDs; co-infection with other viral pathogens under study was observed in both cases. In transplant recipients, one out of the 175 samples analyzed, from a patients with upper respiratory simptoms tested positive for HEV 109 in the absence of co-infecting viruses. Sequence analysis of amplified EV109 genomic regions, showed only a few nucleotide differences when compared with the Nicaraguan strains. Conclusions Overall these results indicate that HEV109 variants have circulated and differentiated in different lineages worldwide. Although more cases and larger studies are needed, HEV109 infection may be associated to ARDs both in infants and in hematopoietic stem cell transplantation recipients. If these preliminary observations will be confirmed, improved molecular methods with a wider panel of potential pathogens will be useful for monitoring these categories of patients.

Abstract Background Mutations in SCO2 cause cytochrome c oxidase deficiency (COX) and a fatal infantile cardioencephalomyopathy. SCO2 encodes a protein involved in COX copper metabolism; supplementation with copper salts rescues the defect in patients’ cells. Bezafibrate (BZF), an approved hypolipidemic agent, ameliorates the COX deficiency in mice with mutations in COX10, another COX-assembly gene. Methods We have investigated the effect of BZF and copper in cells with SCO2 mutations using spectrophotometric methods to analyse respiratory chain activities and a luciferase assay to measure ATP production.. Results Individual mitochondrial enzymes displayed different responses to BZF. COX activity increased by about 40% above basal levels (both in controls and patients), with SCO2 cells reaching 75-80% COX activity compared to untreated controls. The increase in COX was paralleled by an increase in ATP production. The effect was dose-dependent: it was negligible with 100 μM BZF, and peaked at 400 μM BZF. Higher BZF concentrations were associated with a relative decline of COX activity, indicating that the therapeutic range of this drug is very narrow. Combined treatment with 100 μM CuCl2 and 200 μM BZF (which are only marginally effective when administered individually) achieved complete rescue of COX activity in SCO2 cells. Conclusions These data are crucial to design therapeutic trials for this otherwise fatal disorder. The additive effect of copper and BZF will allow to employ lower doses of each drug and to reduce their potential toxic effects. The exact mechanism of action of BZF remains to be determined.

Abstract Background Kabuki syndrome (Niikawa-Kuroki syndrome) is a rare, multiple congenital anomalies/mental retardation syndrome characterized by a peculiar face, short stature, skeletal, visceral and dermatoglyphic abnormalities, cardiac anomalies, and immunological defects. Recently mutations in the histone methyl transferase MLL2 gene have been identified as its underlying cause. Methods Genomic DNAs were extracted from 62 index patients clinically diagnosed as affected by Kabuki syndrome. Sanger sequencing was performed to analyze the whole coding region of the MLL2 gene including intron-exon junctions. The putative causal and possible functional effect of each nucleotide variant identified was estimated by in silico prediction tools. Results We identified 45 patients with MLL2 nucleotide variants. 38 out of the 42 variants were never described before. Consistently with previous reports, the majority are nonsense or frameshift mutations predicted to generate a truncated polypeptide. We also identified 3 indel, 7 missense and 3 splice site. Conclusions This study emphasizes the relevance of mutational screening of the MLL2 gene among patients diagnosed with Kabuki syndrome. The identification of a large spectrum of MLL2 mutations possibly offers the opportunity to improve the actual knowledge on the clinical basis of this multiple congenital anomalies/mental retardation syndrome, design functional studies to understand the molecular mechanisms underlying this disease, establish genotype-phenotype correlations and improve clinical management.

Abstract Background Hepatitis C virus (HCV) infection is a major public health problem with more than 170 million cases of chronic infections worldwide. There is no protective vaccine currently available for HCV, therefore the development of novel strategy to prevent chronic infection is important. We reported earlier that a recombinant human antibody clone blocks viral NS3 helicase activity and inhibits replication of HCV 1b virus. This study was performed further to explore the mechanism of action of this recombinant antibody and to determine whether or not this antibody inhibits replication and infectivity of a highly efficient JFH1 HCV 2a virus clone. Results The antiviral effect of intracellular expressed antibody against the HCV 2a virus strain was examined using a full-length green fluorescence protein (GFP) labeled infectious cell culture system. For this purpose, a Huh-7.5 cell line stably expressing the NS3 helicase gene specific IgG1 antibody was prepared. Replication of full-length HCV-GFP chimera RNA and negative-strand RNA was strongly inhibited in Huh-7.5 cells stably expressing NS3 antibody but not in the cells expressing an unrelated control antibody. Huh-7.5 cells stably expressing NS3 helicase antibody effectively suppressed infectious virus production after natural infection and the level of HCV in the cell free supernatant remained undetectable after first passage. In contrast, Huh-7.5 cells stably expressing an control antibody against influenza virus had no effect on virus production and high-levels of infectious HCV were detected in culture supernatants over four rounds of infectivity assay. A recombinant adenovirus based expression system was used to demonstrate that Huh-7.5 replicon cell line expressing the intracellular antibody strongly inhibited the replication of HCV-GFP RNA. Conclusion Recombinant human anti-HCV NS3 antibody clone inhibits replication of HCV 2a virus and infectious virus production. Intracellular expression of this recombinant antibody offers a potential antiviral strategy to inhibit intracellular HCV replication and production.

Abstract The characteristics of intra-host human immunodeficiency virus type 1 (HIV-1) env evolution were evaluated in untreated HIV-1-infected subjects with different patterns of disease progression, including 2 normal progressor [NP], and 5 Long term non-progressor [LTNP] patients. High-resolution phylogenetic analysis of the C2-C5 env gene sequences of the replicating HIV-1 was performed in sequential samples collected over a 3–5 year period; overall, 301 HIV-1 genomic RNA sequences were amplified from plasma samples, cloned, sequenced and analyzed. Firstly, the evolutionary rate was calculated separately in the 3 codon positions. In all LTNPs, the 3rd codon mutation rate was equal or even lower than that observed at the 1st and 2nd positions (p = 0.016), thus suggesting strong ongoing positive selection. A Bayesian approach and a maximum-likelihood (ML) method were used to estimate the rate of virus evolution within each subject and to detect positively selected sites respectively. A great number of N-linked glycosylation sites under positive selection were identified in both NP and LTNP subjects. Viral sequences from 4 of the 5 LTNPs showed extensive positive selective pressure on the CD4-binding site (CD4bs). In addition, localized pressure in the area of the IgG-b12 epitope, a broad neutralizing human monoclonal antibody targeting the CD4bs, was documented in one LTNP subject, using a graphic colour grade 3-dimensional visualization. Overall, the data shown here documenting high selective pressure on the HIV-1 CD4bs of a group of LTNP subjects offers important insights for planning novel strategies for the immune control of HIV-1 infection.

Abstract Background Human papillomavirus (HPV) tests are crucial diagnostic tools for the prevention of neoplastic lesions of the uterine cervix. However most commercial methods are designed to detect high-risk (HR) HPV types and a limited selection of low-risk ones, thus missing a fair number of intermediate/low-risk types. As a result, many HPV infections remain undiagnosed, generating distrust in virological diagnosis among gynaecologists, who continue to rely preferentially on cytological and colposcopic findings. Results In this study, we tested 6,335 consecutive clinical samples, most of them from Italian patients with cytological abnormalities. The samples, collected in 2000–2007, were analyzed using PCR amplification of a 173–206 bp (depending on HPV type) conserved region in the L1 open reading frame, restriction endonuclease analysis and, where required, sequence analysis for type determination. Analysis of a smaller male sample and long term follow-up of a few female subjects was also performed. A total of 2,161 samples tested positive for HPV DNA (32.1%); 21.3% of them were mixed infections. Overall, 59 known and 2 unknown HPV types were detected. Their relative prevalence was calculated; notably, types not clearly identifiable using the most common commercial method accounted for 36% of infections. Clinical findings associated with the underdiagnosed types ranged from H-SIL to low-grade abnormalities, although none of these infections resulted in invasive cancer. Conclusion Given the high prevalence of some underdiagnosed HPV types in the population (principally HPV53, HPV66, HPV84, and HPV87) and their frequent association with cytological abnormalities, techniques capable of detecting and typing them would prove extremely useful.

Abstract Background Hyperandrogenic conditions have been associated with a high prevalence of endometrial pathologies related to cell survival. However, the action of androgens on proliferation and apoptosis in endometrial cells is poorly understood. Therefore, the aim of the present study was to evaluate the effect of androstenedione on cell proliferation, cell death and expression of estrogen receptor (ER) isoforms and proteins related to apoptosis in endometrial cells using two in vitro experimental approaches. Methods The endometrial tissue was obtained from 20 eumenorrheic women [28.7 (25 – 35) years] during the early secretory phase. We analyzed cell proliferation (immunohistochemistry of Ki-67 and spectrophotometric assay); apoptosis (DNA fragmentation (TUNEL) and Annexin V-FITC binding); ER-alpha, ER-beta bcl-2 and bax mRNA abundance (RT-PCR) in explants and isolated endometrial epithelial (EEC) and stromal cells (ESC) incubated with androstenedione 1 micro mol/l (A4) or A4 plus hydroxyflutamide 10 micro mol/l (F) for 24 h. Results In explants, A4 induced an increase of cell proliferation and a decrease on apoptosis in the stromal compartment (p < 0.05). In isolated ESC, proliferation augmented with A4 (p < 0.05), whereas, no significant modifications in the expression of ER-alpha, ER-beta bcl-2 and bax nor in the apoptotic index were observed. In EEC, A4 increase the ER-beta mRNA abundance (p < 0.05) and a decrease of the bcl-2/bax ratio (p < 0.05), without an increase in the apoptotic index. Hydroxyflutamide reverted the effect of androstenedione on the parameters described. Conclusions These results indicate that androstenedione may modulate cell survival, expression of ER-beta and proteins related to apoptosis, suggesting a potential mechanism that associates the effect of hyperandrogenemia on the endometrial tissue.

Abstract Background In the rat, the maintenance of gestation is dependent on progesterone production from the corpora lutea (CL), which are under the control of pituitary, decidual and placental hormones. The luteal metabolism of progesterone during gestation has been amply studied. However, the regulation of progesterone synthesis and degradation during pseudopregnancy (PSP), in which the CL are mainly under the control of pituitary prolactin (PRL), is not well known. The objectives of this investigation were: i) to study the luteal metabolism of progesterone during PSP by measuring the activities of the enzymes 3beta-hydroxysteroid dehydrogenase (3betaHSD), involved in progesterone biosynthesis, and that of 20alpha-hydroxysteroid dehydrogenase (20alphaHSD), involved in progesterone catabolism; and ii) to determine the role of decidualization on progesterone metabolism in PSP. Methods PSP was induced mechanically at 10:00 h on the estrus of 4-day cycling Wistar rats, and the stimulus for decidualization was provided by scratching the uterus on day 4 of PSP. 3betaHSD and 20alphaHSD activities were measured in the CL isolated from ovaries of PSP rats using a spectrophotometric method. Serum concentrations of progesterone, PRL, androstenedione, and estradiol were measured by radioimmunoassay (RIA). Results The PSP stage induced mechanically in cycling rats lasted 11.3 ± 0.09 days (n = 14). Serum progesterone concentration was high until day 10 of PSP, and declined thereafter. Serum PRL concentration was high on the first days of PSP but decreased significantly from days 6 to 9, having minimal values on days 10 and 11. Luteal 3betaHSD activities were elevated until day 6 of PSP, after which they progressively declined, reaching minimal values at the end of PSP. Luteal 20alphaHSD activities were very low until day 9, but abruptly increased at the end of PSP. When the deciduoma was induced by scratching the uterus of pseudopregnant animals on day 4 (PSP+D), PSP was extended to 18 ± 2.2 days (n = 8). In PSP + D rats, serum progesterone and PRL levels, and luteal 3betaHSD activities were higher than in pseudopregnant rats on day 11. Decidualization also prevented the increase in luteal 20alphaHSD activities observed on day 11 of PSP. Administration of the dopaminergic agonist CB154 in PSP + D rats on day 10 of PSP induced a decline in both serum PRL and progesterone on day 11 of PSP, values that were not different from that of pseudopregnant controls. Conclusions We have established that during the final period of PSP a decline in progesterone biosynthesis occurs before the increase in progesterone catabolism. We have also shown that decidualization in pseudopregnant rats extends the life of the CL by prolonging the production of pituitary PRL, and by maintaining high 3betaHSD and low 20alphaHSD activities within the CL leading to sustained production of progesterone.

In a largely sleep-deprived society, quantifying the effects of sleep loss on emotion is critical for promoting psychological health. This preregistered systematic review and meta-analysis quantified the effects of various forms of sleep loss on multiple aspects of emotional experiences. Eligible studies used experimental reductions of sleep via total sleep deprivation, partial sleep restriction, or sleep fragmentation in healthy populations to examine effects on positive affect, negative affect, general mood disturbances, emotional reactivity, anxiety symptoms, and/or depressive symptoms. In total, 1,338 effect sizes across 154 studies were included ( N = 5,717; participant age range = 7-79 years). Random effects models were conducted, and all forms of sleep loss resulted in reduced positive affect (standardized mean difference [SMD] = -0.27 to -1.14), increased anxiety symptoms (SMD = 0.57-0.63), and blunted arousal in response to emotional stimuli (SMD = -0.20 to -0.53). Findings for negative affect, reports of emotional valence in response to emotional stimuli, and depressive symptoms were mixed and depended on the type of sleep loss. Nonlinear effects for the amount of sleep loss as well as differences based on the stage of sleep restricted (i.e., rapid eye movement sleep or slow-wave sleep) were also detected. This study represents the most comprehensive quantitative synthesis of experimental sleep and emotion research to date and provides strong evidence that periods of extended wakefulness, shortened sleep duration, and/or nighttime awakenings adversely influence human emotional functioning. Findings provide an integrative foundation for future research on sleep and emotion and elucidate the precise ways that inadequate sleep may impact our daytime emotional lives. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Objective: This observational study aimed to: (i) describe and explore preliminary psychometric properties of a multidimensional sleep health composite score in adolescent females with frequent migraine; and (ii) examine associations between the composite score, headache characteristics, and emotional health., Background: Sleep health is a multidimensional construct comprised of various dimensions of sleep and circadian functioning, including Regularity, Satisfaction, Alertness, Timing, Efficiency, and Duration (Ru-SATED framework). The Ru-SATED sleep health composite score may provide a holistic perspective of sleep among adolescents with frequent migraine in the context of neurobiological and psychosocial impacts on sleep unique to this developmental period., Methods: In all, 60 female adolescents (aged 12-18 years) with high-frequency episodic or chronic migraine completed wrist-worn actigraphy for 10 days and concurrent daily electronic surveys assessing headache, sleep, and emotional health. A sleep health composite score was derived from empirically supported "healthy" versus "unhealthy" ratings on the six Ru-SATED sleep dimensions., Results: Half of participants (27/54 [50%]) had a composite score ≥4 (i.e., at least four of the six dimensions rated as poor). Convergent validity of the composite score was acceptable (rs = 0.30-0.56, all p < 0.05). Internal consistency among the dimensions was low (α = 0.45). Multivariate multiple regression models indicated that worse sleep health was associated with greater headache-related disability (B = 0.71, p = 0.018) and anxiety (B = 0.59, p = 0.010), and trended toward significance for sadness (B = 0.35, p = 0.052). The composite score was not significantly associated with headache frequency or severity., Conclusions: A multidimensional sleep health composite score may provide an alternative, more comprehensive picture of sleep disturbance among adolescent females with frequent migraine. Larger studies are needed to examine psychometric properties more rigorously and further explore the composite score as a potentially unique predictor of headache outcomes., (© 2023 American Headache Society.)

This White Paper addresses the current gaps in knowledge, as well as opportunities for future studies in pediatric sleep. The Sleep Research Society's Pipeline Development Committee assembled a panel of experts tasked to provide information to those interested in learning more about the field of pediatric sleep, including trainees. We cover the scope of pediatric sleep, including epidemiological studies and the development of sleep and circadian rhythms in early childhood and adolescence. Additionally, we discuss current knowledge of insufficient sleep and circadian disruption, addressing the neuropsychological impact (affective functioning) and cardiometabolic consequences. A significant portion of this White Paper explores pediatric sleep disorders (including circadian rhythm disorders, insomnia, restless leg and periodic limb movement disorder, narcolepsy, and sleep apnea), as well as sleep and neurodevelopment disorders (e.g. autism and attention deficit hyperactivity disorder). Finally, we end with a discussion on sleep and public health policy. Although we have made strides in our knowledge of pediatric sleep, it is imperative that we address the gaps to the best of our knowledge and the pitfalls of our methodologies. For example, more work needs to be done to assess pediatric sleep using objective methodologies (i.e. actigraphy and polysomnography), to explore sleep disparities, to improve accessibility to evidence-based treatments, and to identify potential risks and protective markers of disorders in children. Expanding trainee exposure to pediatric sleep and elucidating future directions for study will significantly improve the future of the field., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Adolescent-onset type 2 diabetes (T2D) is a major public health concern of growing proportions. Prevention, therefore, is critical. Unfortunately, standard-of-care treatment for T2D prevention (e.g., exercise training) show insufficient effectiveness and do not address key modifiable barriers (e.g., depression symptoms) to exercise engagement. Depression symptoms are associated with both poorer physical fitness and greater insulin resistance, the key risk factor in adolescent-onset T2D. Thus, a targeted prevention approach that addresses depression symptoms in combination with exercise training may offer a novel approach to mitigating T2D risk., Methods: This manuscript describes the design and study protocol for a multi-site, four-arm randomized controlled trial comparing the efficacy of group cognitive-behavioral therapy, group exercise training, and their combinations for the targeted prevention of worsening insulin resistance in N = 300 adolescent females at-risk for T2D with BMI ≥85th percentile and elevated depression symptoms. All four intervention arms will run in parallel and meet weekly for 1 h per week for 6-week to 6-week segments (12 weeks total). Outcomes are assessed at baseline, 6-week mid-treatment, 12-week follow-up, and 1-year follow-up., Results: The primary outcome is insulin resistance. Key secondary outcomes include insulin sensitivity, cardiorespiratory fitness, physical activity, depression symptoms, and body measurements., Conclusion: Study findings will guide the ideal sequencing of two brief T2D prevention interventions for ameliorating the course of insulin resistance and lessening T2D risk in vulnerable adolescents. These interventions will likely be cost-effective and scalable for dissemination, having the potential for significant public health impact on communities at risk for T2D., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose of Review: Migraine is one of the top reasons for consulting a pediatric neurologist. Although the majority of children and adolescents who receive evidence-based first-line interventions for migraine will improve substantially, a subset of patients develop resistant or refractory migraine., Recent Findings: In this review, we summarize the level of evidence for a variety of acute and preventive treatment options to consider in children and adolescents with resistant or refractory migraine. We describe the level of evidence for interventional procedures (onabotulinumtoxinA injections, greater occipital and other nerve blocks), neuromodulation (single-pulse transcranial magnetic stimulation, external trigeminal nerve stimulation, remote electrical neuromodulation, and non-invasive vagal nerve stimulation), calcitonin gene-related peptide (CGRP) pathway antagonists (anti-CGRP monoclonal antibodies and gepants), psychological therapies, and manual therapies (acupuncture, craniosacral therapy, massage and physical therapy, and spinal manipulation)., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The relationship between sleep disturbances and headaches in the pediatric population is bidirectional. Common underlying molecular mechanisms of sleep and headaches have been speculated to explain the clinical connection. We will summarize various sleep disturbances and their known relationships to headache, focusing on the pediatric population. Careful recognition and assessment of sleep disturbances in patients with headache is critical and may help guide treatment. First line therapies for sleep disturbances consist of behavioral approaches, though surgical and pharmacologic strategies are utilized in particular circumstances., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Conceptual links between perfectionism and chronic pain have been proposed yet minimal empirical data exists. Poor sleep is associated with high levels of perfectionism and is common among youth with chronic pain. This study explores associations between perfectionism and sleep quality in adolescents with chronic pain while considering levels of functional disability., Methods: Adolescents (ages 12-18) with chronic pain (N = 423) completed baseline measures of self-oriented perfectionism (SOP), socially prescribed perfectionism (SPP), sleep quality, and functional disability as part of routine clinical care at an outpatient chronic pain clinic and a pain rehabilitation day treatment program. Multivariate multiple regression assessed associations between perfectionism (SOP and SPP) and sleep (falling asleep/reinitiating sleep, returning to wakefulness, and going to bed). Two moderation models explored how relations between perfectionism (SOP and SPP) and sleep quality (total score) varied depending on level of functional disability. All analyses controlled for clinic setting., Results: Results indicated SPP was associated with more difficulties across all sleep subdomains in adolescents with chronic pain, while SOP was unrelated to sleep quality. Associations between perfectionism and sleep quality were dependent on functional disability; perfectionism was most strongly associated with worse sleep quality for adolescents with less functional disability., Conclusions: This study highlights the relationship between perfectionism and sleep quality in adolescents with chronic pain and suggests that perfectionistic youth with less disability are at the greatest risk for sleep problems. Longitudinal research is needed to understand how perfectionism, sleep, and disability interact over time in youth with chronic pain., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To equip clinicians with recommendations specific to concerns related to the novel coronavirus disease 2019 (COVID-19), which impact the physical, emotional, and social health of youth with headache disorders., Background: COVID-19 has affected societies on a global scale including children and youth with chronic headache disorders. Many concerns are predicted to arise in the 2020-2021 school year, whether classes are conducted in-person or virtually., Methods: Clinical impressions were combined with a review of the literature, although limited due to the recent nature of this issue., Results: We describe recommendations to support caregivers and youth as they face changes expected with the return to school in the fall of 2020., Conclusion: Although there are significant concerns for caregivers and youth with migraine given the context of changes related to the pandemic, there are many recommendations that can help minimize exacerbations of the physical, emotional, and social health of youth with chronic migraine., (© 2020 American Headache Society.)

Sleep-related complaints hold complex reciprocal relationships with anxiety and are a pervasive, distressing feature of childhood generalized anxiety disorders (GAD). Although evidence suggests purely anxiety-focused treatments reduce some sleep problems of anxious children, interventions that directly target both anxiety and sleep might produce superior outcomes in both domains. Targeted Behavioral Therapy (TBT), developed for co-morbid sleep and anxiety problems, demonstrated initial efficacy in a small case series but has not been directly compared to anxiety-focused treatment. The current pilot study used a randomized controlled design to compare TBT to "gold standard" cognitive-behavioral therapy (CBT) for anxiety among n  = 20 children (ages 6-12) with primary GAD. Multi-informant measures of anxiety and sleep (including actigraphy) were obtained at baseline, post-treatment, and 6-month follow-up. Results indicated significant improvements (based on moderate to large effect sizes) in anxiety and subjective sleep in both treatment groups at post-treatment. Improvements were maintained at 6-month follow-up. Objective sleep onset latency also decreased marginally for both groups at post-treatment (based on small effect size). Findings provide preliminary support for the feasibility and potential utility of anxiety-focused interventions for improving some sleep-related problems among anxious youth. Future studies including large samples are needed.

Dialysis treatment has evolved to enable children to live longer and transition to adulthood. Thus, the focus of care shifts to a consideration of pediatric patients' quality of life and psychosocial functioning across childhood, adolescence, and young adulthood. Despite well-documented concerns in various domains (including depression/anxiety, self-esteem and social functioning, behavior problems, and academic and cognitive functioning), limited literature exists regarding psychosocial guidelines for children and adolescents undergoing dialysis. This article aims to address this gap by providing a review of the pediatric literature examining psychosocial functioning in patients treated with dialysis, as well as recommendations for specific psychosocial concerns. Overall recommendations for care include screening for anxiety and depression, referral to pediatric psychologists for evidence-based intervention, utilization of child life specialists, opportunities to promote social functioning, neuropsychological evaluation and school programming, ongoing support in preparing for transition to adult care, and periodic measure of quality of life. Together, these suggestions promote a holistic approach to patient-centered care by supporting both physical and psychosocial well-being.

Pediatric headache patients often experience significant sleep disturbance, which may be a risk factor for poor physical, academic, and emotional functioning, including increased anxiety/fear. The current retrospective cohort study of a clinical sample of youth with persistent headache aimed to examine the impact of sleep on functional outcomes and to explore pain-related fear as a mediator of the association between sleep problems and functioning. A total of 109 youth (aged 7-17 years) with persistent headache presenting to a tertiary pediatric headache center (and their parents) completed measures of sleep problems, fear of pain, functional disability, and school functioning at the time of an initial evaluation and 6 months later. After controlling for age and headache frequency and severity, linear regression analyses indicated that increased sleep problems at baseline were associated with increased functional disability and poorer school functioning at baseline ( β = 0.28, P = .01; β = -0.42, P < .001, respectively). Poor sleep at baseline was associated with poorer school functioning (but not functional disability) at follow-up ( β = -0.25, P = .02). Mediation models demonstrated an indirect mediating effect of pain-related fear on the association between baseline sleep problems and follow-up functional disability ( β = 0.06, 95% confidence interval 0.01, 0.15) and between baseline sleep problems and follow-up school functioning ( β = -0.06, 95% confidence interval -0.13, -0.004). Sleep disturbance in youth with headache may be a risk factor for poor functional outcomes, both concurrently and over time, and may be explained partially through pain-related fear. Given the frequency with which pediatric headache patients experience co-occurring sleep problems, sleep should be thoroughly assessed and considered as a potential early treatment target.

Objectives: Biopsychosocial models emphasize the influence of parent/family factors on pediatric chronic pain. Little is known about how parent factors differ across the acute to chronic pain continuum, or contribute to youths' pain experience in the acute pain period. The purpose of the study was to describe parent factors in youth with acute musculoskeletal pain (n=84) compared with youth with chronic pain (n=60) and youth without pain (n=61). Further, within the acute pain sample, we tested parent factors as predictors of child pain characteristics, as well as the moderating role of child sex on associations., Methods: Participants were 205 youth (age, 10 to 17) and one biological parent per child. Children reported on their own pain and activity limitations. Parents reported on their own chronic pain, somatization, and protective pain responses., Results: Parents of youth with acute pain had higher prevalence of chronic pain and greater somatization than parents of youth without pain. Parents of youth with acute and chronic pain did not differ. Linear regressions within the acute pain sample revealed presence of parent chronic pain and protective behavior were associated with child pain. Moreover, parent somatization was associated with child activity limitations. Within the acute pain sample, associations between parent protectiveness and child pain were moderated by child sex, with relationships stronger for female children., Discussion: Findings highlight the importance of parent factors on pain experiences of youth with acute musculoskeletal pain. Future longitudinal research can elucidate temporal associations that underlie how parent factors may impact transition from acute to chronic pain.

Intolerance of uncertainty (IU) is a dispositional characteristic reflecting negative cognitive, behavioral, and emotional reactivity in response to events or situations that are uncertain. Although closely associated with a generalized anxiety disorder (GAD) diagnosis in adulthood, IU has received little attention in youth. The goal of this study was to examine the construct in children with GAD and nonanxious children, including its incremental validity in predicting GAD severity and worry beyond anxiety. Ninety-eight children 6 to 11 years of age (51% male; 57% Caucasian) were assessed. The sample included 24 with a GAD diagnosis only (i.e., pure GAD), 36 with GAD plus at least one other disorder (i.e., comorbid GAD), and 38 healthy control children. Clinician, parent, and child reports of IU, anxiety, worry, and GAD severity were collected. Significant differences in levels of IU were found across all three groups; the highest levels in children with comorbid GAD, followed by children with pure GAD, and healthy controls. IU significantly contributed to worry but not GAD severity beyond the effects of anxiety. A significantly larger proportion of self-reported IU data were missing for younger (e.g., 6-8 years) as compared to older children, raising question about the validity of the construct in younger children. Overall findings suggest that IU is not specific to a GAD diagnosis in childhood. IU may instead serve as a broad cognitive risk factor for more severe (e.g., comorbid) forms of affective psychopathology. Future directions for research, including developmental considerations, are discussed.

Little is known about the co-sleeping behaviors of school-aged children, particularly among anxious youth who commonly present for the treatment of sleep problems. The current study examined the occurrence of co-sleeping in both healthy and clinically anxious children and its associated sleep patterns. A total of 113 children (ages 6-12), 75 with primary generalized anxiety disorder and 38 healthy controls, participated along with their primary caregiver. Families completed structured diagnostic assessments, and parents reported on their child's co-sleeping behaviors and anxiety severity. Children provided reports of anxiety severity and completed one week of wrist-based actigraphy to assess objective sleep patterns. A significantly greater proportion of anxious youth compared to healthy children co-slept, and greater anxiety severity was related to more frequent co-sleeping. Co-sleeping in anxious youth was associated with a delay in sleep timing and with greater sleep variability (i.e., more variable nightly sleep duration). All analyses controlled for child age, race/ethnicity, family income, and parental marital status. Co-sleeping is highly common in anxious school-aged children, with more than 1 in 3 found to co-sleep at least sometimes (2-4 times a week). Co-sleeping was even more common for youth with greater anxiety severity. Increased dependence on others to initiate and maintain sleep may contribute to poorer sleep in this population via shifted schedules and more variable sleep patterns.

Objective: Identifying factors contributing to high medical utilization and productivity loss is important, given the high cost of pediatric chronic pain. The current study examined chronic pain acceptance as a predictor of medical utilization and school absenteeism in adolescents with chronic pain., Methods: In all, 122 adolescents (aged 12-21 years) with chronic pain and their parents/guardians completed questionnaires assessing medical visits (past 6 months), medication usage, and number of school absences (past month). Homebound school status was also reported. Adolescents completed the Chronic Pain Acceptance Questionnaire and pain intensity ratings, and underwent a diagnostic psychological evaluation., Results: Multivariate generalized linear model analyses indicated lower pain acceptance predicted increased inpatient hospitalizations and higher number of opioid and nonopioid prescription medications, controlling for pain intensity, age, and sex. Pain acceptance was not associated with outpatient consultations or number of nonprescription medications. Exploratory moderation analyses indicated lower pain acceptance significantly predicted increased emergency department visits and inpatient hospitalizations for patients diagnosed with an internalizing psychological disorder. Patients in homebound schooling reported low pain acceptance and for those in school full-time, linear regression indicated lower pain acceptance significantly predicted higher number of school absences., Conclusions: Findings suggest that lower pain acceptance contributes to the use of higher-level medical care (especially for adolescents with internalizing disorders) and increased productivity loss owing to school absences or homebound school status. Clinical implications exist for recommending acceptance-based interventions for pain acceptance promotion and continued development of cost-effective, easily disseminated acceptance-based therapy modules to curb the economic burden of chronic pain.

Attention bias modification (ABM) procedures typically reduce anxiety symptoms, yet little is known about the neural changes associated with this behavioral treatment. Healthy adults with high social anxiety symptoms (n = 53) were randomized to receive either active or placebo ABM. Unlike placebo ABM, active ABM aimed to train individuals' attention away from threat. Using the dot-probe task, threat-related attention bias was measured during magnetic resonance imaging before and after acute and extended training over 4 weeks. A subset of participants completed all procedures (n = 30, 15 per group). Group differences in neural activation were identified using standard analyses. Linear regression tested predictive factors of symptom reduction (i.e., training group, baseline indices of threat bias). The active and placebo groups exhibited different patterns of right and left amygdala activation with training. Across all participants irrespective of group, individuals with greater left amygdala activation in the threat-bias contrast prior to training exhibited greater symptom reduction. After accounting for baseline amygdala activation, greater symptom reduction was associated with assignment to the active training group. Greater left amygdala activation at baseline predicted reductions in social anxiety symptoms following ABM. Further research is needed to clarify brain-behavior mechanisms associated with ABM training., (Published by Oxford University Press 2014. This work is written by US Government employees and is in the public domain in the US.)

This study examined the efficacy of Targeted Behavioral Therapy (TBT), a newly developed intervention targeting features of childhood generalized anxiety disorder (GAD). Using a time-series design, 4 children (7-12 years) with primary GAD were treated with TBT, which includes sleep improvement strategies, systematic desensitization for reducing intolerance of uncertainty, and in vivo exposures for anxiety. Diagnostic interviews and questionnaires were administered at baseline, post-treatment and 3 months follow-up. Anxiety symptoms and sleep characteristics/problems were rated weekly during a 4-week baseline and 14-weeks of treatment. Two children remitted at post-treatment and no child had a GAD diagnosis at follow-up. Child but not parent report revealed improvements in both worry and sleep. Despite improvements from pre- to post-assessment, considerable symptom fluctuation observed during the baseline period preclude conclusion that symptom changes are specifically attributable to the course of treatment. Overall, preliminary support is provided for the efficacy of TBT for childhood GAD., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Attention Bias Modification Treatment (ABMT), an emerging treatment for anxiety disorders, is thought to modify underlying, stable patterns of attention. Therefore, ABMT research should take into account the impact of attention bias stability on attention training response, especially in pediatric populations. ABMT research typically relies on the dot-probe task, where individuals detect a probe following an emotional-neutral stimulus pair. The current research presents two dot-probe experiments relevant to ABMT and attention-bias stability. In Experiment 1, anxious youth receiving 8-weeks of cognitive-behavioral therapy (CBT) were randomly assigned to ABMT that trains attention towards happy faces (n=18) or placebo (n=18). Two additional comparison groups, anxious youth receiving only CBT (n=17) and healthy comparison youth (n=16), were studied. Active attention training towards happy faces did not augment clinician-rated response to CBT; however, individuals receiving training exhibited reductions on self-report measures of anxiety earlier than individuals receiving CBT only. In Experiment 2, healthy youth (n=12) completed a dot-probe task twice while undergoing functional magnetic resonance imaging. Intra-class correlation demonstrated stability of neural activation in response to attention bias in the ventrolateral prefrontal cortex and amygdala. Together, these two studies investigate the ways in which attention-bias stability may impact future work on ABMT., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Mammalian sperm proteins undergo thiol group (SH) oxidation to form disulfides bonds (SS) as they travel through the epididymis during cell maturation. Disulfide bonds are involved in chromatin condensation and tail organelle stabilization. In this work, we used a fluorescent thiol-selective labeling agent, monobromobimane (mBBr), to study the protein thiol status of rat sperm during maturation. Fluorescence signal decrease along the epididymal trip, more evidently in the head, but also in the tail, indicates that both sub cellular regions participate in the thiol changes. The sources of the fluorescence signal are sulfhydryls sperm proteins labeled by mBBr (mBBr-spp). Initial attempts to identify the mBBr-spp labeled were detected in the initial-caput, but not in the distal cauda-segment of the epididymis in sodium dodecyl sulfate (SDS)-PAGE analysis. This phenomenon could be due to protein resistance to solubilization. For this reason, disulfide bond reduction was accomplished by sodium dodecyl sulfate plus dithiothreitol treatment to recover the mBBr signal in SDS-PAGE. Under this protocol, a major 27 kDa protein band displays a strong signal. Protein identification by mass spectrometry and sequence database searching correlated this protein with the outer dense fiber 1 (ODF1). The mBBr specifically bound to N-terminal domain cysteine of ODF1. The mBBr reduces rat sperm motility, quantitatively and qualitatively, and the effects are dose dependent, without significantly increasing the percentage of dead sperm. Thus, we found that ODF1 is highly responsible for mBBr fluorescence detection in the sperm tail, and the motility inhibition by the fluorescence marker indicates that ODF1 N-terminal domain are related to sperm motility. © 2011 Wiley-Liss, Inc., (Copyright © 2011 Wiley-Liss, Inc.)

Hypercholesterolemia represents a high risk factor for frequent diseases and it has also been associated with poor semen quality that may lead to male infertility. The aim of this study was to analyze semen and sperm function in diet-induced hypercholesterolemic rabbits. Twelve adult White New Zealand male rabbits were fed ad libitum a control diet or a diet supplemented with 0.05% cholesterol. Rabbits under cholesterol-enriched diet significantly increased total cholesterol level in the serum. Semen examination revealed a significant reduction in semen volume and sperm motility in hypercholesterolemic rabbits (HCR). Sperm cell morphology was seriously affected, displaying primarily a "folded head"-head fold along the major axe-, and the presence of cytoplasmic droplet on sperm flagellum. Cholesterol was particularly increased in acrosomal region when detected by filipin probe. The rise in cholesterol concentration in sperm cells was determined quantitatively by Gas chromatographic-mass spectrometric analyses. We also found a reduction of protein tyrosine phosphorylation in sperm incubated under capacitating conditions from HCR. Interestingly, the addition of Protein Kinase A pathway activators -dibutyryl-cyclic AMP and iso-butylmethylxanthine- to the medium restored sperm capacitation. Finally, it was also reported a significant decrease in the percentage of reacted sperm in the presence of progesterone. In conclusion, our data showed that diet-induced hypercholesterolemia adversely affects semen quality and sperm motility, capacitation and acrosomal reaction in rabbits; probably due to an increase in cellular cholesterol content that alters membrane related events.

In many mammalian species, sperm associate as a consequence of the epididymal transit. From the classic Rouleaux in guinea pig to the most recent work in mouse and echidna, authors have focused mainly on a detailed morphological description of this phenomenon. Some of these articles have also begun to describe the nature of the material present between sperm heads. Here, we try to better understand the factor/s involved in rat sperm association (Rosette). Based on previous work describing the appearance of Rosettes in the distal segments of the rat epididymis, we consider that sperm during their transit must be in contact with factor/s present in the caudal lumen in order to associate with each other. By an in vitro sperm re-associating assay, we try to determine the in vivo phenomenon observed in the lumen. The assay consists of co-incubating non-associated sperm with several protein fractions obtained from epididymal caudal fluid. After establishing the most active fraction, the proteins were characterized by MALDI-TOF mass spectrometry. Among the proteins we found two members of the serine protease inhibitors family; an alpha-1 antitrypsin and a new protein with an alpha-1 antitrypsin like domain which includes a sequence compatible with the serpins' reactive center loop. These serpins may play a role in the assembly/disassembly process of Rosettes by modulating lumenal protease activity. Finally, a biochemical-morphological model which explains the sperm-proteases interaction was proposed.

Background: In the rat, the maintenance of gestation is dependent on progesterone production from the corpora lutea (CL), which are under the control of pituitary, decidual and placental hormones. The luteal metabolism of progesterone during gestation has been amply studied. However, the regulation of progesterone synthesis and degradation during pseudopregnancy (PSP), in which the CL are mainly under the control of pituitary prolactin (PRL), is not well known. The objectives of this investigation were: i) to study the luteal metabolism of progesterone during PSP by measuring the activities of the enzymes 3beta-hydroxysteroid dehydrogenase (3betaHSD), involved in progesterone biosynthesis, and that of 20alpha-hydroxysteroid dehydrogenase (20alphaHSD), involved in progesterone catabolism; and ii) to determine the role of decidualization on progesterone metabolism in PSP., Methods: PSP was induced mechanically at 10:00 h on the estrus of 4-day cycling Wistar rats, and the stimulus for decidualization was provided by scratching the uterus on day 4 of PSP. 3betaHSD and 20alphaHSD activities were measured in the CL isolated from ovaries of PSP rats using a spectrophotometric method. Serum concentrations of progesterone, PRL, androstenedione, and estradiol were measured by radioimmunoassay (RIA)., Results: The PSP stage induced mechanically in cycling rats lasted 11.3 +/- 0.09 days (n = 14). Serum progesterone concentration was high until day 10 of PSP, and declined thereafter. Serum PRL concentration was high on the first days of PSP but decreased significantly from days 6 to 9, having minimal values on days 10 and 11. Luteal 3betaHSD activities were elevated until day 6 of PSP, after which they progressively declined, reaching minimal values at the end of PSP. Luteal 20alphaHSD activities were very low until day 9, but abruptly increased at the end of PSP. When the deciduoma was induced by scratching the uterus of pseudopregnant animals on day 4 (PSP+D), PSP was extended to 18 +/- 2.2 days (n = 8). In PSP + D rats, serum progesterone and PRL levels, and luteal 3betaHSD activities were higher than in pseudopregnant rats on day 11. Decidualization also prevented the increase in luteal 20alphaHSD activities observed on day 11 of PSP. Administration of the dopaminergic agonist CB154 in PSP + D rats on day 10 of PSP induced a decline in both serum PRL and progesterone on day 11 of PSP, values that were not different from that of pseudopregnant controls., Conclusions: We have established that during the final period of PSP a decline in progesterone biosynthesis occurs before the increase in progesterone catabolism. We have also shown that decidualization in pseudopregnant rats extends the life of the CL by prolonging the production of pituitary PRL, and by maintaining high 3betaHSD and low 20alphaHSD activities within the CL leading to sustained production of progesterone.