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Purpose: Sleep impairment is associated with many chronic pain disorders. While there is an association between chronic pain and sleep disturbances, little is known about the influence of pharmacotherapy for chronic pain conditions, particularly chronic opioid therapy, on sleep. This study aimed to 1) compare the sleep quality (SQ) in patients with two different pain conditions-chronic body pain and chronic orofacial pain; 2) assess the correlation of SQ and pain intensity; and 3) evaluate the association between pharmacotherapy and SQ. Patients and Methods: The Pittsburgh Sleep Quality Index (PSQI) was used to measure the SQ in subjects with 1) chronic body pain (n = 100) and 2) chronic orofacial pain (n = 100). The visual analogue scale was applied for pain intensity rating. All subjects were adults recruited at Massachusetts General Hospital, United States. The subjects' demographic data, pain intensity, diagnosis and concurrent use of medications were extracted from their electronic medical records (EMR). Statistical analyses were performed using 7-test and Pearson correlation coefficient. Results: Among 200 subjects (mean age 51.01 [+ or -] 15.52 years), 141 (70.5%) were females. PSQI and pain intensity were statistically significantly different between the two groups (p < 0.05 and p < 0.0001, respectively) and higher in subjects with chronic body pain. There was a positive correlation between PSQI and pain intensity (chronic orofacial pain r = 0.3535, p = 0.0004; chronic body pain: r = 0.2247, p < 0.026). PSQI was higher in chronic orofacial pain subjects utilizing opioids and benzodiazepines (PSQI = 15.25). Conclusion: Chronic pain impairs SQ, which is noticeably worse in subjects with body pain conditions. In addition, pain intensity was correlated with poorer SQ, which in turn was linked to the concomitant use of opioid and benzodiazepine therapy in chronic orofacial pain. Keywords: sleep quality, chronic pain, pain intensity, pharmacotherapy, opioids, benzodiazepines

Alpha oscillations (7–14Hz) are modulated in response to visual temporal and spatial cues. However, the neural response to alerting cues is less explored, as is how this response is affected by healthy aging. Using scalp EEG, we examined how visual cortical alpha activity relates to working memory performance. Younger (20–30 years) and older (60–70 years) participants were presented with a visual alerting cue uninformative of the position or size of a lateralized working memory array. Older adults showed longer response times overall and reduced accuracy when memory load was high. Older adults had less consistent cue-evoked alpha phase resetting than younger adults, which predicted worse performance. Alpha phase prior to memory array presentation predicted response time, but the relationship between phase and response time was weaker in older adults. These results suggest that changes in alpha phase dynamics, especially prior to presentation of task-relevant stimuli, potentially contribute to age-related cognitive decline. •Older adults had worse accuracy and longer response times on a working memory task.•Older adults had less consistent alpha phase response to a pretarget alerting cue.•Consistency of phase response to the alerting cue predicted accuracy.•Pretarget alpha phase predicted response times on a trial-by-trial basis.•The relationship between alpha phase and response time was weaker in older adults.

Alpha oscillations are modulated in response to visual temporal and spatial cues, However, the neural response to alerting cues is less explored, as is how this response is affected by healthy aging. Using scalp EEG, we examined how visual cortical alpha activity relates to working memory performance. Younger (20-30 years) and older (60-70 years) participants were presented with a visual alerting cue uninformative of the position or size of a lateralized working memory array. Older adults showed longer response times overall, and reduced accuracy when memory load was high. Older adults had less consistent cue-evoked phase resetting than younger adults, which predicted worse performance. Alpha phase prior to memory array presentation predicted response time, but the relationship between phase and response time was weaker in older adults. These results suggest that changes in alpha phase dynamics, especially prior to presentation of task-relevant stimuli, potentially contribute to age-related cognitive decline.

Food insecurity, limited access to adequate food, in adulthood is associated with poor health outcomes that suggest a pattern of accelerated aging. However, little is known about factors that impact food insecurity in midlife which in turn could help to identify potential pathways of accelerated aging. Low-income adults (n = 17,866; 2014 National Health Interview Survey), ages 18 to 84, completed a 10-item food security module and answered questions regarding health challenges (chronic conditions and functional limitations) and financial worry. We used multinomial logistic regression for complex samples to assess the association of health challenges and financial worry with food insecurity status and determine whether these associations differed by age group, while adjusting for poverty, sex, race/ethnicity, education, family structure, social security, and food assistance. Food insecurity rates were highest in late- (37.5%) and early- (36.0%) midlife, relative to younger (33.7%) and older (20.2%) age groups and, furthermore, age moderated the relationship between food insecurity and both risk factors (interaction p-values < .05, for both). The effects of poor health were stronger in midlife relative to younger and older ages. Unlike younger and older adults, however, adults in midlife showed high levels of food insecurity regardless of financial worry.

Effective therapies are urgently needed for the SARS-CoV-2/COVID-19 pandemic. We identified panels of fully human monoclonal antibodies (mAbs) from large phage-displayed Fab, scFv, and VH libraries by panning against the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) glycoprotein. A high-affinity Fab was selected from one of the libraries and converted to a full-size antibody, IgG1 ab1, which competed with human ACE2 for binding to RBD. It potently neutralized replication-competent SARS-CoV-2 but not SARS-CoV, as measured by two different tissue culture assays, as well as a replication-competent mouse ACE2-adapted SARS-CoV-2 in BALB/c mice and native virus in hACE2-expressing transgenic mice showing activity at the lowest tested dose of 2 mg/kg. IgG1 ab1 also exhibited high prophylactic and therapeutic efficacy in a hamster model of SARS-CoV-2 infection. The mechanism of neutralization is by competition with ACE2 but could involve antibody-dependent cellular cytotoxicity (ADCC) as IgG1 ab1 had ADCC activity in vitro. The ab1 sequence has a relatively low number of somatic mutations, indicating that ab1-like antibodies could be quickly elicited during natural SARS-CoV-2 infection or by RBD-based vaccines. IgG1 ab1 did not aggregate, did not exhibit other developability liabilities, and did not bind to any of the 5,300 human membrane-associated proteins tested. These results suggest that IgG1 ab1 has potential for therapy and prophylaxis of SARS-CoV-2 infections. The rapid identification (within 6 d of availability of antigen for panning) of potent mAbs shows the value of large antibody libraries for response to public health threats from emerging microbes.

Background Selective BRAF inhibitors, vemurafenib and dabrafenib, and the MEK inhibitor, trametinib, have been approved for treatment of metastatic melanomas with a BRAF p.V600E mutation. The clinical significance of non-codon 600 mutations remains unclear, in part, due to variation of kinase activity for different mutants. Methods In this study, we categorized BRAF mutations according to the reported mutant kinase activity. A total of 1027 lung cancer, colorectal cancer or melanoma specimens were submitted for clinical mutation detection by next generation sequencing. Results Non-codon 600 mutations were observed in 37 % of BRAF -mutated tumors. Of all BRAF mutants, 75 % were kinase-activated, 15 % kinase-impaired and 10 % kinase-unknown. The most common kinase-impaired mutant involves codon 594, specifically, p.D594G (c.1781A > G) and p.D594N (c.1780G > A). Lung cancers showed significantly higher incidences of kinase-impaired or kinase-unknown mutants. Kinase-impaired BRAF mutants showed a significant association with concomitant activating KRAS or NRAS mutations, but not PIK3CA mutations, supporting the reported interaction of these mutations. Conclusions BRAF mutants with impaired or unknown kinase activity as well as concomitant kinase-impaired BRAF mutations and RAS mutations were detected in lung cancers, colorectal cancers and melanomas. Different therapeutic strategies based on the BRAF mutant kinase activity and the concomitant mutations may be worthwhile.

Background Irritability, an increased proneness to anger, is a primary reason youth present for psychiatric care. While initial evidence supports the efficacy of exposure-based cognitive behavioral therapy (CBT) for youth with clinically impairing irritability, treatment mechanisms remain unclear. Here, we propose to measure peripheral psychophysiological indicators of arousal—heart rate (HR)/electrodermal activity (EDA)—and regulation—heart rate variability (HRV)—during exposures to anger-inducing stimuli as potential predictors of treatment efficacy. The objective of this study is to evaluate whether in-situ biosensing data provides peripheral physiological indicators of in-session response to exposures. Methods Blood volume pulse (BVP; from which HR and HRV canl be derived) and EDA will be collected ambulatorily using the Empatica EmbracePlus from 40 youth (all genders; ages 8-17) undergoing six in-person exposure treatment sessions, as part of a multiple-baseline trial of exposure-based CBT for clinically impairing irritability. Clinical ratings of irritability will be conducted at baseline, weekly throughout treatment, and at 3-month and 6-month follow-ups via the Clinical Global Impressions Scale (CGI) and the Affective Reactivity Index (ARI; clinician-, parent-, and child-report). Multilevel modeling will be used to assess within- and between-person changes in physiological arousal and regulation throughout exposure-based CBT and to determine whether individual differences are predictive of treatment response. Discussion This study protocol leverages a wearable biosensor (Empatica) to continuously record HR/HRV (derived from BVP) and EDA during in-person exposure sessions for youth with clinically impairing irritability. Here, the goal is to identify changes in physiological arousal (EDA, HR) and regulation (HRV) over the course of treatment in tandem with changes in clinical symptoms. Trial registration The participants in this study come from an overarching clinical trial (trial registration numbers: NCT02531893 first registered on 8/25/2015; last updated on 8/25/2023). The research project and all related materials were submitted and approved by the appropriate Institutional Review Board of the National Institute of Mental Health (NIMH).

Cold stimulation induces the synthesis and release of the lipid species 12,13-diHOME from brown adipose tissue. This ‘lipokine’ then acts on brown adipocytes to promote the uptake of fatty acids to fuel this cell type's heat production. Brown adipose tissue (BAT) and beige adipose tissue combust fuels for heat production in adult humans, and so constitute an appealing target for the treatment of metabolic disorders such as obesity, diabetes and hyperlipidemia 1 , 2 . Cold exposure can enhance energy expenditure by activating BAT, and it has been shown to improve nutrient metabolism 3 , 4 , 5 . These therapies, however, are time consuming and uncomfortable, demonstrating the need for pharmacological interventions. Recently, lipids have been identified that are released from tissues and act locally or systemically to promote insulin sensitivity and glucose tolerance; as a class, these lipids are referred to as 'lipokines' 6 , 7 , 8 . Because BAT is a specialized metabolic tissue that takes up and burns lipids and is linked to systemic metabolic homeostasis, we hypothesized that there might be thermogenic lipokines that activate BAT in response to cold. Here we show that the lipid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) is a stimulator of BAT activity, and that its levels are negatively correlated with body-mass index and insulin resistance. Using a global lipidomic analysis, we found that 12,13-diHOME was increased in the circulation of humans and mice exposed to cold. Furthermore, we found that the enzymes that produce 12,13-diHOME were uniquely induced in BAT by cold stimulation. The injection of 12,13-diHOME acutely activated BAT fuel uptake and enhanced cold tolerance, which resulted in decreased levels of serum triglycerides. Mechanistically, 12,13-diHOME increased fatty acid (FA) uptake into brown adipocytes by promoting the translocation of the FA transporters FATP1 and CD36 to the cell membrane. These data suggest that 12,13-diHOME, or a functional analog, could be developed as a treatment for metabolic disorders.

This article discusses influences of historical time and place on the development of children and youth of Asian descent in the U.S. Chinese, Indian, Hmong, and Filipino American experiences illustrate how history has defined race and racial stereotypes, determined cultural and community contexts, established pre-/post-migration circumstances, and influenced oppression and discrimination. Cross-cutting issues as applied to other ethnicities are discussed. By recognizing history's reach on child development, this article intends to inspire others to acknowledge and consider historical influences in their work. It also lays a foundation for the two ensuing articles within this Special Section, which present a novel conceptual framework (Mistry et al., this volume) and methodological recommendations (Yoshikawa, Mistry, & Wang, this volume) for research.