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Ribosomes are macromolecular machines that are globally required for the translation of all proteins in all cells. Ribosome biogenesis, which is essential for cell growth, proliferation and survival, commences with transcription of a variety of RNAs by RNA Polymerases I and III. RNA Polymerase I (Pol I) transcribes ribosomal RNA (rRNA), while RNA Polymerase III (Pol III) transcribes 5S ribosomal RNA and transfer RNAs (tRNA) in addition to a wide variety of small non-coding RNAs. Interestingly, despite their global importance, disruptions in Pol I and Pol III function result in tissue-specific developmental disorders, with craniofacial anomalies and leukodystrophy/neurodegenerative disease being among the most prevalent. Furthermore, pathogenic variants in genes encoding subunits shared between Pol I and Pol III give rise to distinct syndromes depending on whether Pol I or Pol III function is disrupted. In this review, we discuss the global roles of Pol I and III transcription, the consequences of disruptions in Pol I and III transcription, disorders arising from pathogenic variants in Pol I and Pol III subunits, and mechanisms underpinning their tissue-specific phenotypes.

The connection between vascular and brain metrics is well-studied in older adults, but neglected in youth and in psychiatric populations at increased cardiovascular risk. We therefore examined the association of retinal vascular caliber with cerebral blood flow (CBF) in adolescents with and without bipolar disorder (BD).Ninety-four adolescents (n = 48 BD, n = 46 controls) completed retinal fundus imaging, yielding estimates of arteriolar and venular diameter. Arterial spin labelling MRI was performed to measure CBF. We tested for associations between retinal vascular caliber and CBF in regions of interest; anterior cingulate cortex (ACC), middle frontal gyrus, and hippocampus in BD and controls separately. Complementary voxel-wise analyses were also performed.In the BD group, higher arteriovenous ratio (AVR) was associated with greater ACC CBF (β = 0.34, pLimited sample size; young, medically healthy sample limits signal detection; cross-sectional design.This study reveals that higher AVR is associated with higher regional CBF in adolescents with BD. Present findings advance understanding of potential neurofunctional mechanisms linking retinal vascular caliber with psychiatric diagnoses. This proof-of-concept study was designed to generate initial insights to guide future studies focusing on the vascular-brain connection in youth and in psychiatry.

MRI‐derived brain measures offer a link between genes, the environment and behavior and have been widely studied in bipolar disorder (BD). However, many neuroimaging studies of BD have been underpowered, leading to varied results and uncertainty regarding effects. The Enhancing Neuro Imaging Genetics through Meta‐Analysis (ENIGMA) Bipolar Disorder Working Group was formed in 2012 to empower discoveries, generate consensus findings and inform future hypothesis‐driven studies of BD. Through this effort, over 150 researchers from 20 countries and 55 institutions pool data and resources to produce the largest neuroimaging studies of BD ever conducted. The ENIGMA Bipolar Disorder Working Group applies standardized processing and analysis techniques to empower large‐scale meta‐ and mega‐analyses of multimodal brain MRI and improve the replicability of studies relating brain variation to clinical and genetic data. Initial BD Working Group studies reveal widespread patterns of lower cortical thickness, subcortical volume and disrupted white matter integrity associated with BD. Findings also include mapping brain alterations of common medications like lithium, symptom patterns and clinical risk profiles and have provided further insights into the pathophysiological mechanisms of BD. Here we discuss key findings from the BD working group, its ongoing projects and future directions for large‐scale, collaborative studies of mental illness., This review discusses the major challenges facing neuroimaging research of bipolar disorder and highlights the major accomplishments, ongoing challenges and future goals of the ENIGMA Bipolar Disorder Working Group.

Rapid antigen screening can be effective in identifying infectious individuals in occupational settings to reduce transmission and outbreaks. We report results from a pilot project at the Greater Toronto Airports Authority (GTAA) and describe the operationalization. Toronto Pearson is a large international airport encompassing over 400 employers and, pre-pandemic, with approximately 50,000 employees.An employee screening program was piloted between March 8 and May 28, 2021, to implement rapid antigen testing for asymptomatic employees. Recruitment targeted enrolment of 400 employees and yielded participation of 717 from 58 companies. Employees were recommended to book three times per week for nasal swabs on site, and were tested on the Abbot PanbioA total of 5117 tests were performed on 717 individuals over 12 weeks; 5091 tests were negative (99.5%), and 22 individuals tested positive (3.1% positivity rate). One hundred twenty-four (17%) completed the post-participation survey. All respondents reported that testing did not change their behaviour at work with respect to public health recommendations, and only 1 (1%) reported behaviour change outside of work (socializing with family) as a result of the program.This pilot program identified 22 (3.1%) potentially infectious employees. Onsite testing was feasible and highly accepted by this group of employees who completed the survey. Education resulted in reasonable uptake and no substantial change in behaviour, although the survey response rate may limit generalizability. Home-based testing may facilitate larger recruitment.RéSUMé: LIEU: Le dépistage antigénique rapide peut être efficace pour repérer les personnes infectieuses en milieu de travail afin de réduire la transmission et les éclosions. Nous rendons compte des résultats d’un projet pilote mené par l’Autorité aéroportuaire du Grand Toronto (GTAA) et nous en décrivons l’opérationnalisation. L’aéroport Toronto Pearson est un vaste aéroport international qui compte plus de 400 employeurs et, avant la pandémie, environ 50 000 employés. INTERVENTION: Un programme de dépistage au travail a fait l’objet d’un projet pilote entre le 8 mars et le 28 mai 2021 pour mettre en œuvre le dépistage antigénique rapide chez les employés asymptomatiques. Le recrutement visait l’inscription de 400 employés et a donné lieu à une participation de 717 personnes dans 58 entreprises. Il était recommandé aux employés de s’inscrire à un prélèvement nasal sur place trois fois par semaine; le test antigénique rapide d’Abbot Panbio

This is the first of three articles exploring the aspects of clinical care for children with rare neurological disorders including uncertainties old and new. The disruptive technologies of genomic sequencing and advanced therapeutics such as gene-based therapies offer parents of children with severe but rare neurological conditions for the first-time unprecedented opportunities for 'precision medicine'. At the same time, the realities of limited genomic diagnostic yields and not infrequent detection of variants of uncertain significance, lack of natural history study data and management guidelines for individually rare neurogenetic conditions, means that high pre-genomic test expectations are all too often replaced by an accumulation of new uncertainties. This can add to the chronic traumatic stress experienced by many families but may also have under-recognised impacts for their clinicians, contributing to 'burn-out' and attendant negative psychosocial impacts. This first article aims to address how clinicians might manage the accumulation of uncertainties to be more helpful to patients and their families. Moreover, it seeks to address how clinicians can move forward providing compassionate care to their patients and a little more consideration for themselves.

Most invasive lobular breast cancers (ILC) are of the luminal A subtype and are strongly hormone receptor–positive. Yet, ILC is relatively resistant to tamoxifen and associated with inferior long-term outcomes compared with invasive ductal cancers (IDC). In this study, we sought to gain mechanistic insights into these clinical findings that are not explained by the genetic landscape of ILC and to identify strategies to improve patient outcomes. A comprehensive analysis of the epigenome of ILC in preclinical models and clinical samples showed that, compared with IDC, ILC harbored a distinct chromatin state linked to gained recruitment of FOXA1, a lineage-defining pioneer transcription factor. This resulted in an ILC-unique FOXA1–estrogen receptor (ER) axis that promoted the transcription of genes associated with tumor progression and poor outcomes. The ILC-unique FOXA1–ER axis led to retained ER chromatin binding after tamoxifen treatment, which facilitated tamoxifen resistance while remaining strongly dependent on ER signaling. Mechanistically, gained FOXA1 binding was associated with the autoinduction of FOXA1 in ILC through an ILC-unique FOXA1 binding site. Targeted silencing of this regulatory site resulted in the disruption of the feed-forward loop and growth inhibition in ILC. In summary, ILC is characterized by a unique chromatin state and FOXA1–ER axis that is associated with tumor progression, offering a novel mechanism of tamoxifen resistance. These results underscore the importance of conducting clinical trials dedicated to patients with ILC in order to optimize treatments in this breast cancer subtype. Significance: A unique FOXA1–ER axis in invasive lobular breast cancer promotes disease progression and tamoxifen resistance, highlighting a potential therapeutic avenue for clinical investigations dedicated to this disease. See related commentary by Blawski and Toska, p. 3668

Clinical Practice Guidelines (CPGs) have been shown to improve healthcare services and clinical outcomes. However, they are useful resources only to the degree that they are developed according to the most rigorous standards. Multiple studies have demonstrated significant variability between CPGs with regard to specific indicators of quality. The Ordre des psychologues du Québec (OPQ), the College of psychologists of Quebec, has published several CPGs that are intended to provide empirically supported guidance for psychologists in the areas of assessment, diagnosis, general functioning, treatment and other decision-making support. The aim of this study was to evaluate the quality of these CPGs.The Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument was used to assess the quality of the CPGs.Our results show that although there have been some modest improvements in quality of the CPGs over time, there are important methodological inadequacies in all CPGs evaluated.The findings of this study demonstrate the need for more methodological rigour in CPGs development as such, recommendations to improve CPG quality are discussed.

White matter hyperintensities (WMHs) are emblematic of cerebral small vessel disease, yet effects on the brain have not been well characterized at midlife. Here, we investigated whether WMH volume is associated with brain network alterations in midlife adults. Two hundred and fifty-four participants from the Coronary Artery Risk Development in Young Adults study were selected and stratified by WMH burden into Lo-WMH (mean age = 50 ± 3.5 years) and Hi-WMH (mean age = 51 ± 3.7 years) groups of equal size. We constructed group-level covariance networks based on cerebral blood flow (CBF) and gray matter volume (GMV) maps across 74 gray matter regions. Through consensus clustering, we found that both CBF and GMV covariance networks partitioned into modules that were largely consistent between groups. Next, CBF and GMV covariance network topologies were compared between Lo- and Hi-WMH groups at global (clustering coefficient, characteristic path length, global efficiency) and regional (degree, betweenness centrality, local efficiency) levels. At the global level, there were no between-group differences in either CBF or GMV covariance networks. In contrast, we found between-group differences in the regional degree, betweenness centrality, and local efficiency of several brain regions in both CBF and GMV covariance networks. Overall, CBF and GMV covariance analyses provide evidence that WMH-related network alterations are present at midlife.

Topical glycopyrronium tosylate (GT) is an anticholinergic medication for treatment of axillary hyperhidrosis. Pharmacologic mydriasis and anisocoria from topical GT has been reported and may be underrecognized. This study aims to clinically characterize patients presenting with pharmacologic mydriasis from exposure to this medication.This study is a retrospective observational case series. A multicenter chart review of 16 patients diagnosed with pharmacologic mydriasis secondary to topical GT was performed.Eight patients (50.0%) were age 18 years and younger, and 14 patients (87.5%) were female. Unilateral mydriasis (anisocoria) occurred in 14 patients (87.5%). Fourteen patients (87.5%) did not initially volunteer topical GT as a "medication," and the history of topical GT exposure needed to be elicited with further questioning. Hand hygiene details were known for 12 patients, and all reported that they did not wash their hands after GT application. Six patients (37.5%) were soft contact lens users. One patient had possible exposure through a family member's use of the medication. Ocular symptoms were common (blurry vision [11 patients, 68.8%] and eye dryness [7 patients, 43.8%]), but systemic anticholinergic symptoms were uncommon (such as constipation [1 patient, 6.3%] and urinary symptoms [3 patients, 18.8%]).Mydriasis associated with topical GT seems to be a consequence of local exposure rather than systemic toxicity. Because patients may not volunteer topical GT as a medication, eliciting a history of exposure often requires further specific questioning. Soft contact lens wear and poor postapplication hand hygiene seem to be associated with mydriasis in GT use.

The energetics of cycling represents a well-studied area of exercise science, yet there are still many questions that remain. Efficiency, broadly defined as the ratio of energy output to energy input, is one key metric that, despite its importance from both a scientific as well as performance perspective, is commonly misunderstood. There are many factors that may affect cycling efficiency, both intrinsic (e.g., muscle fiber type composition) and extrinsic (e.g., cycling cadence, prior exercise, and training), creating a complex interplay of many components. Due to its relative simplicity, the measurement of oxygen uptake continues to be the most common means of measuring the energy cost of exercise (and thus efficiency); however, it is limited to only a small proportion of the range of outputs humans are capable of, further limiting our understanding of the energetics of high-intensity exercise and any mechanistic bases therein. This review presents evidence that delta efficiency does not represent muscular efficiency and challenges the notion that the slow component of oxygen uptake represents decreasing efficiency. It is noted that gross efficiency increases as intensity of exercise increases in spite of the fact that fast-twitch fibers are recruited to achieve this high power output. Understanding the energetics of high-intensity exercise will require critical evaluation of the available data.

Background Bipolar disorder (BD) is associated with elevated body mass index (BMI) and increased rates of obesity. Obesity among individuals with BD is associated with more severe course of illness. Motivated by previous research on BD and BMI in youth as well as brain findings in the reward circuit, the current study investigates differences in cerebral blood flow (CBF) in youth BD with and without comorbid overweight/obesity (OW/OB). Methods Participants consisted of youth, ages 13–20 years, including BD with OW/OB (BDOW/OB; n = 25), BD with normal weight (BDNW; n = 55), and normal-weight healthy controls (HC; n = 61). High-resolution T1-weighted and pseudo-continuous arterial spin labeling images were acquired using 3 Tesla magnetic resonance imaging. CBF differences were assessed using both region of interest and whole-brain voxel-wise approaches. Results Voxel-wise analysis revealed significantly higher CBF in reward-associated regions in the BDNW group relative to the HC and BDOW/OB groups. CBF did not differ between the HC and BDOW/OB groups. There were no significant region of interest findings. Conclusions The current study identified distinct CBF levels relating to BMI in BD in the reward circuit, which may relate to underlying differences in cerebral metabolism, compensatory effects, and/or BD severity. Future neuroimaging studies are warranted to examine for changes in the CBF-OW/OB link over time and in relation to treatment.

The endolysosomal system not only is an integral part of the cellular catabolic machinery that processes and recycles nutrients for synthesis of biomaterials, but also acts as signaling hub to sense and coordinate the energy state of cells with growth and differentiation. Lysosomal dysfunction adversely influences vesicular transport-dependent macromolecular degradation and thus causes serious problems for human health. In mammalian cells, loss of the lysosome associated membrane proteins LAMP1 and LAMP2 strongly affects autophagy and cholesterol trafficking. Here we show that the previously uncharacterized Drosophila Lamp1 is a bona fide ortholog of vertebrate LAMP1 and LAMP2. Surprisingly and in contrast to lamp1 lamp2 double-mutant mice, Drosophila Lamp1 is not required for viability or autophagy, suggesting that fly and vertebrate LAMP proteins acquired distinct functions, or that autophagy defects in lamp1 lamp2 mutants may have indirect causes. However, Lamp1 deficiency results in an increase in the number of acidic organelles in flies. Furthermore, we find that Lamp1 mutant larvae have defects in lipid metabolism as they show elevated levels of sterols and diacylglycerols (DAGs). Because DAGs are the main lipid species used for transport through the hemolymph (blood) in insects, our results indicate broader functions of Lamp1 in lipid transport. Our findings make Drosophila an ideal model to study the role of LAMP proteins in lipid assimilation without the confounding effects of their storage and without interfering with autophagic processes. Abbreviations: aa: amino acid; AL: autolysosome; AP: autophagosome; APGL: autophagolysosome; AV: autophagic vacuole (i.e. AP and APGL/AL); AVi: early/initial autophagic vacuoles; AVd: late/degradative autophagic vacuoles; Atg: autophagy-related; CMA: chaperone-mediated autophagy; Cnx99A: Calnexin 99A; DAG: diacylglycerol; eMI: endosomal microautophagy; ESCRT: endosomal sorting complexes required for transport; FB: fat body; HDL: high-density lipoprotein; Hrs: Hepatocyte growth factor regulated tyrosine kinase substrate; LAMP: lysosomal associated membrane protein; LD: lipid droplet; LDL: low-density lipoprotein; Lpp: lipophorin; LTP: Lipid transfer particle; LTR: LysoTracker Red; MA: macroautophagy; MCC: Manders colocalization coefficient; MEF: mouse embryonic fibroblast MTORC: mechanistic target of rapamycin kinase complex; PV: parasitophorous vacuole; SNARE: soluble N-ethylmaleimide sensitive factor attachment protein receptor; Snap: Synaptosomal-associated protein; st: starved; TAG: triacylglycerol; TEM: transmission electron microscopy; TFEB/Mitf: transcription factor EB; TM: transmembrane domain; tub: tubulin; UTR: untranslated region.

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a “shift” of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Item does not contain fulltext Cerebral small vessel disease (SVD) is common during ageing and can present as stroke, cognitive decline, neurobehavioural symptoms, or functional impairment. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive and other symptoms and affect activities of daily living. Standards for Reporting Vascular Changes on Neuroimaging 1 (STRIVE-1) categorised and standardised the diverse features of SVD that are visible on structural MRI. Since then, new information on these established SVD markers and novel MRI sequences and imaging features have emerged. As the effect of combined SVD imaging features becomes clearer, a key role for quantitative imaging biomarkers to determine sub-visible tissue damage, subtle abnormalities visible at high-field strength MRI, and lesion-symptom patterns, is also apparent. Together with rapidly emerging machine learning methods, these metrics can more comprehensively capture the effect of SVD on the brain than the structural MRI features alone and serve as intermediary outcomes in clinical trials and future routine practice. Using a similar approach to that adopted in STRIVE-1, we updated the guidance on neuroimaging of vascular changes in studies of ageing and neurodegeneration to create STRIVE-2. 01 juli 2023

Background: Associations between body mass index (BMI) and psychological distress (PD) have been reported; however, few longitudinal studies have accounted for likely life-course differences in BMI and PD stability, consistency, and their interplay across time. Methods: Via random intercepts cross-lagged panel models, we assessed the predictive effects (from BMI to PD or vice-versa) across the last two centuries in the Coronary Artery Risk Development in Young Adults [CARDIA, beginning in 1985-6] study using the Center for Epidemiological Studies-Depression Scale [CES-D], and in the National Child Development Study [NCDS, beginning in 1958] and British Cohort Study [BCS, beginning in 1970] using the Malaise Inventory [MI]), assessed at least 4 times in adult life. Findings: In CARDIA (n = 4724), NCDS58 (n = 7149) and BCS70 (n = 5967), autoregressive effects were stronger for BMI than for PD, meaning that carry-over effects from one occasion to the next were larger for BMI than for PD. Small interindividual correlations between traits of higher BMI and higher PD were identified among females (rfemale

Objective Heightened inflammation, dysregulated immunity, and thrombotic events are characteristic of hospitalized COVID‐19 patients. Given that platelets are key regulators of thrombosis, inflammation, and immunity they represent prime candidates as mediators of COVID‐19‐associated pathogenesis. The objective of this study was to understand the contribution of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) to the platelet phenotype via phenotypic (activation, aggregation) and transcriptomic characterization. Approach and Results In a cohort of 3915 hospitalized COVID‐19 patients, we analyzed blood platelet indices collected at hospital admission. Following adjustment for demographics, clinical risk factors, medication, and biomarkers of inflammation and thrombosis, we find platelet count, size, and immaturity are associated with increased critical illness and all‐cause mortality. Bone marrow, lung tissue, and blood from COVID‐19 patients revealed the presence of SARS‐CoV‐2 virions in megakaryocytes and platelets. Characterization of COVID‐19 platelets found them to be hyperreactive (increased aggregation, and expression of P‐selectin and CD40) and to have a distinct transcriptomic profile characteristic of prothrombotic large and immature platelets. In vitro mechanistic studies highlight that the interaction of SARS‐CoV‐2 with megakaryocytes alters the platelet transcriptome, and its effects are distinct from the coronavirus responsible for the common cold (CoV‐OC43). Conclusions Platelet count, size, and maturity associate with increased critical illness and all‐cause mortality among hospitalized COVID‐19 patients. Profiling tissues and blood from COVID‐19 patients revealed that SARS‐CoV‐2 virions enter megakaryocytes and platelets and associate with alterations to the platelet transcriptome and activation profile.

Background: The detailed extent of neuroinvasion or deleterious brain changes resulting from COVID-19 and their time courses remain to be determined in relation to “long-haul” COVID-19 symptoms. Our objective is to determine whether there are alterations in functional brain imaging measures among people with COVID-19 after hospital discharge or self-isolation. Methods: This paper describes a protocol for NeuroCOVID-19, a longitudinal observational study of adults aged 20–75 years at Sunnybrook Health Sciences Centre in Toronto, Ontario, that began in April 2020. We aim to recruit 240 adults, 60 per group: people who contracted COVID-19 and were admitted to hospital (group 1), people who contracted COVID-19 and self-isolated (group 2), people who experienced influenza-like symptoms at acute presentation but tested negative for COVID-19 and self-isolated (group 3, control) and healthy people (group 4, control). Participants are excluded based on premorbid neurologic or severe psychiatric illness, unstable cardiovascular disease, and magnetic resonance imaging (MRI) contraindications. Initial and 3-month follow-up assessments include multiparametric brain MRI and electroencephalography. Sensation and cognition are assessed alongside neuropsychiatric assessments and symptom self-reports. We will test the data from the initial and follow-up assessments for group differences based on 3 outcome measures: MRI cerebral blood flow, MRI resting state fractional amplitude of low-frequency fluctuation and electroencephalography spectral power. Interpretation: If neurophysiologic alterations are detected in the COVID-19 groups in our NeuroCOVID-19 study, this information could inform future research regarding interventions for long-haul COVID-19. The study results will be disseminated to scientists, clinicians and COVID-19 survivors, as well as the public and private sectors to provide context on how brain measures relate to lingering symptoms.

Purpose Phosphatidylinositol Glycan Anchor Biosynthesis, class G (PIGG) is an ethanolamine phosphate transferase catalyzing the modification of glycosylphosphatidylinositol (GPI). GPI serves as an anchor on the cell membrane for surface proteins called GPI-anchored proteins (GPI-APs). Pathogenic variants in genes involved in the biosynthesis of GPI cause inherited GPI deficiency (IGD), which still needs to be further characterized. Methods We describe 22 individuals from 19 unrelated families with biallelic variants in PIGG. We analyzed GPI-AP surface levels on granulocytes and fibroblasts for three and two individuals, respectively. We demonstrated enzymatic activity defects for PIGG variants in vitro in a PIGG/PIGO double knockout system. Results Phenotypic analysis of reported individuals reveals shared PIGG deficiency–associated features. All tested GPI-APs were unchanged on granulocytes whereas CD73 level in fibroblasts was decreased. In addition to classic IGD symptoms such as hypotonia, intellectual disability/developmental delay (ID/DD), and seizures, individuals with PIGG variants of null or severely decreased activity showed cerebellar atrophy, various neurological manifestations, and mitochondrial dysfunction, a feature increasingly recognized in IGDs. Individuals with mildly decreased activity showed autism spectrum disorder. Conclusion This in vitro system is a useful method to validate the pathogenicity of variants in PIGG and to study PIGG physiological functions. Unlabelled Image

Background Adolescents with bipolar disorder have high rates of cannabis use, and cannabis use is associated with increased symptom severity and treatment resistance in bipolar disorder. Studies have identified anomalous resting-state functional connectivity among reward networks in bipolar disorder and cannabis use independently, but have yet to examine their convergence. Methods Participants included 134 adolescents, aged 13 to 20 years: 40 with bipolar disorder and lifetime cannabis use, 31 with bipolar disorder and no history of cannabis use, and 63 healthy controls without lifetime cannabis use. We used a seed-to-voxel analysis to assess the restingstate functional connectivity of the amygdala, the nucleus accumbens and the orbitofrontal cortex, regions implicated in bipolar disorder and cannabis use. We used a generalized linear model to explore bivariate correlations for each seed, controlling for age and sex. Results We found 3 significant clusters. Resting-state functional connectivity between the left nucleus accumbens seed and the left superior parietal lobe was negative in adolescents with bipolar disorder and no history of cannabis use, and positive in healthy controls. Resting-state functional connectivity between the right orbitofrontal cortex seed and the right lateral occipital cortex was positive in adolescents with bipolar disorder and lifetime cannabis use, and negative in healthy controls and adolescents with bipolar disorder and no history of cannabis use. Resting-state functional connectivity between the right orbitofrontal cortex seed and right occipital pole was positive in adolescents with bipolar disorder and lifetime cannabis use, and negative in adolescents with bipolar disorder and no history of cannabis use. Limitations The study did not include a cannabis-using control group. Conclusion This study provides preliminary evidence of cannabis-related differences in functional reward circuits in adolescents with bipolar disorder. Further studies are necessary to evaluate whether the present findings reflect consequences of or predisposition to cannabis use.

BACKGROUND Critical care nurses (CCNs) frequently provide end of life (EOL) care in intensive care units (ICUs). Obstacles to EOL care in ICUs exist and have been previously published along with reports from CCNs. Further data exploring obstacles faced during ICU EOL care may increase awareness of common EOL obstacles. Research focusing on obstacles related to physician behaviors and nursing issues (and others) may provide improvement of care. OBJECTIVE The aim of this study was to gather first-hand data from CCNs regarding obstacles related to EOL care. METHODS A random, geographically dispersed sample of 2000 members of the American Association of Critical-Care Nurses was surveyed. Responses from an item asking CCNs to tell us of the obstacles they experience providing EOL care to dying patients were analyzed. RESULTS There were 104 participants who provided 146 responses to this item reflecting EOL obstacles. These obstacles were divided into 11 themes; 6 physician-related obstacles and 5 nursing- and other related obstacles. Major EOL ICU barrier themes were inadequate physician communication, physicians giving false hope, poor nurse staffing, and inadequate EOL care education for nurses. DISCUSSION AND CONCLUSION Poor physician communication was the main obstacle noted by CCNs during ICU EOL care, followed by physicians giving false hope. Heavy patient workloads with inadequate staffing were also a major barrier in CCNs providing EOL care.

Background Bipolar disorder (BD) is among the most heritable psychiatric disorders, particularly in early-onset cases, owing to multiple genes of small effect. Here we examine a multi-gene risk score (MGRS), to address the gap in multi-gene research in early-onset BD. Methods MGRS was derived from 34 genetic variants relevant to neuropsychiatric diseases and related systemic processes. Multiple MGRS were calculated across a spectrum of inclusion p-value thresholds, based on allelic associations with BD. Youth participants (123 BD, 103 healthy control [HC]) of European descent were included, of which 101 participants (58 BD, 43 HC) underwent MRI T1-weighted structural neuroimaging. Hierarchical regressions examined for main effects and MGRS-by-diagnosis interaction effects on 6 regions-of-interest (ROIs). Vertex-wise analysis also examined MGRS-by-diagnosis interactions. Results MGRS based on allelic association p≤0.60 was most robust, explaining 6.8% of variance (t(226)=3.46, p=.001). There was an MGRS-by-diagnosis interaction effect on ventrolateral prefrontal cortex surface area (vlPFC; β=.21, p=.0007). Higher MGRS was associated with larger vlPFC surface area in BD vs. HC. There were 8 significant clusters in vertex-wise analyses, primarily in fronto-temporal regions, including vlPFC. Limitations Cross-sectional design, modest sample size. Conclusions There was a diagnosis-by-MGRS interaction effect on vlPFC surface area, a region involved in emotional processing, emotional regulation, and reward response. Vertex-wise analysis also identified several clusters overlapping this region. This preliminary study provides an example of an approach to imaging-genetics that is intermediate between candidate gene and genome-wide association studies, enriched for genetic variants with established relevance to neuropsychiatric diseases.

Purpose: The objective of this study was to evaluate a plyometric conditioning activity (3 sets of 5 countermovement jumps, [CA]) for twitch properties and voluntary knee extension. Methods: After a familiarization session, fourteen highly trained sprint athletes, 12 men (23.25 ± 7.17 years) and 2 women (23.0 ± 2.8 years) performed 2 experiments, each in a randomized order (crossover design). In one experiment, the time-course of twitch contractile properties was evaluated with and without the previous CA at 2, min intervals to 10 min of recovery. In the second session, maximal voluntary knee extension was evaluated at the same recovery intervals, for control and experimental condition in random order. Results: Mixed-model ANOVA with Bonferroni post-hoc revealed significant differences between pre-test and 2 min (p 0.05). No significant difference was observed for voluntary RTD following CA. Conclusion: The plyometric CA increased twitch peak torque and RTD consistent with PAP; however, there was no effect of CA on voluntary RTD of knee extension at any time after the plyometric CA. Even with PAP confirmed, we observed that the CA fails to improve isometric RTD of quadriceps femoris muscles. HighlightsA plyometric CA significantly increased twitch peak torque (at 2 and 4 min) and twitch rate of torque development (at 2 min) of quadriceps femoris muscles, indicating postactivation potentiation (PAP).No effect was observed for twitch contraction time and ½ relaxation time after the CA.No improvement was observed on voluntary rate of torque development evaluated at the same time intervals.

This manuscript provides an introduction to the special issue: Where are we now? A consolidation of the research on long-term impact of child sexual abuse. Over the past thirty years, there has been an explosion of research about the long-term impacts of childhood sexual abuse (CSA) on adult functioning and wellbeing. However, the consolidation of this vast literature has not kept up with the creation of new research despite the complexity and sophistication of these newer investigations. We have compiled a special issue of the Journal of Child Sexual Abuse to summarize and analyze this vast literature into a cohesive, consolidated whole. The goal of this issue was to consolidate recent research about the effects of CSA on alcohol and substance use in survivors, revictimization, sexual risk and sexual well-being and couple and parenting functioning.

Objective:Peripheral artery disease (PAD) is an atherothrombotic disease of the lower limbs with substantial morbidity and mortality. We used next-generation sequencing to identify genome-wide expression signatures associated with prevalent PAD and its outcomes.Approach and Results:We performed whole blood RNA sequencing among patients with severe symptomatic PAD undergoing lower extremity revascularization and controls. Dysregulated pathways and blood transcriptional modules were identified by comparing patients with PAD (n=42) to age- and sex-matched controls (N=29). The identified signature was compared in patients with PAD before LER with or without incident major adverse cardiac or limb events (MACLE). A novel microRNA associated with prevalent PAD and incident MACLE was then evaluated in a mouse hindlimb ischemia model. One hundred twenty-seven transcripts were differentially expressed (77 upregulated and 50 downregulated; adjustedP0.5) and analyzed using weighted gene co-expression network analysis. Weighted gene co-expression network analysis revealed blood modules enriched for immune activation, secretory granules, and coagulation in patients with PAD. Of these 127 differentially expressed transcripts, 40 were significantly associated with MACLE (log-rank false discovery rate Conclusions:A whole blood transcript signature identified patients with symptomatic PAD and PAD patients at increased risk of MACLE. A previously uncharacterized transcript microRNA-4477b was overexpressed in prevalent PAD, incident MACLE, and in a mouse hindlimb ischemia model. Our novel transcriptomic signature provides insight into potential mechanisms of patients with severe symptomatic PAD.

Background Critical access hospitals were created to bring health care to rural populations. These hospitals lack equipment and resources, but the nurses who work there still provide end-of-life care to critically ill and dying patients. Objective To determine how nurses in critical access hospitals perceive the size of obstacles and helpful behaviors for the provision of end-of-life care. Methods Questionnaires were sent to a cross-sectional, nationally representative sample of nurses working in 39 critical access hospitals. The nurses were asked to score obstacle and helpful behavior items on a scale of from 0 (not an obstacle or not a help, respectively) to 5 (extremely large obstacle or extremely large help, respectively). The items were then ranked from highest to lowest according to their mean scores. Results Seven of the top 10 obstacles were directly related to family behaviors and attitudes, such as families not understanding what lifesaving measures entail and internal family disagreements about life support. Helpful behaviors ranked in the top 10 included interventions that were controlled by nurses and items that affected the nurses’ having adequate time to deliver end-of-life care. Obstacles and helpful behavior items unique to critical access hospitals, such as a lack of resources and the nurse knowing the patient or the patient’s family, ranked below the top 10 items. Conclusion Obstacles and helpful behaviors for providing end-of-life care remain consistent. Nurses in critical access hospitals are accustomed to working without the typical resources found in urban hospitals and thus did not perceive resource deficits to be among the greatest obstacles to providing end-of-life care. Family behaviors and attitudes remain the most dominant obstacle noted by nurses.

Long noncoding RNAs (lncRNAs) have emerged as critical regulators of gene expression, yet their contribution to immune regulation in humans remains poorly understood. Here, we report that the primate-specific lncRNA

This is the second of a three-part series that explores different aspects of uncertainty, certainty and hope in the context of providing clinical care for children with rare and life-limiting neurological disorders. When caring for families impacted by an overwhelming complex disorder in a child, complicated by threatening uncertainties and potentially more threatening certainties, clinicians utilise skills drawn from differing fields to make the load of information, and the emotional impact more manageable. The first article in this series addressed how clinicians might manage the 'accumulation of uncertainties' and to provide compassionate care not only to their patients, and their families, but also to themselves. This second paper delves into the less helpful aspects of 'certainty', including the associated losses and griefs endured by parents responding to threatening fears associated with their child's condition. In the extreme, disconnection and psychological isolation borne by parents can lead to a sense of hopelessness and desperation. Facing unwelcome certainties - clinicians and parents together - forms the basis of future trust and hope. Clinicians who share the field of trust with families and show commitment to helping parents, even when cure remains elusive, build a sense of hope. This is the sort of hopefulness that clinicians need to have and to offer as they share the journey with families. In this series, we seek to harness a shared approach to face unwelcome certainties and to kindle a sense of hope that is both credible and meaningful to the parents, family and clinician.

This is the third article of a three-part series and addresses how clinicians provide hopefulness meaningfully to families coping with life-limiting and quality of life impairing neurological conditions. The first two articles addressed the enormous challenges faced by carers and also explored the struggles of clinicians trying to provide relief and comfort. Can these families, and those helping clinically, legitimately hope? It is expectation that consolidates desire into a substantial hope that may motivate finding a way forward. Hope must be realistic and directed to something in particular and in someone in particular. Hope and despair are not monolithic but often travel together for both children, families and clinicians. Hope is not denial but a belief that there are positive possibilities. Finding what can be helpfully hoped for and what must be realistically despaired of, is the discerning struggle. Clinicians aim to change what we can and accept what we cannot. Acceptance and grief are arrived at slowly for carers and families. Similarly, clinicians struggle with the hopes of bringing meaningful solace and are supported by trusted colleagues who have shared the same experience. Clinicians strive to respond appropriately and effectively in a dynamic process based on trust, providing presence and compassion when cure is not possible. Clinicians help find the small doable things that foster hope and lessen isolation and abandonment, mindful of the limits of their medical expertise. Surprisingly these modest hopes and faltering acceptances often provide a different form of strength and comfort to sustain a family.

Objective Abnormal blood lipid levels are common in bipolar disorder (BD) and correlate with mood symptoms and neurocognition. However, studies have not examined the lipid-brain structure association in BD or youth. Methods This study examined low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C), triglycerides, and total cholesterol (TC) levels in relation to brain structure utilizing T1-weighted images, among participants ages 13-20 with BD (n = 55) and healthy controls (HC; n = 47). General linear models investigated group differences in the association of lipids with anterior cingulate cortex (ACC), hippocampus, and inferior parietal lobe structure, controlling for age, sex, body mass index, and intracranial volume. For significant associations, post hoc within-group analyses were undertaken. Exploratory vertex-wise analyses further investigated group differences in the lipid-brain structure association. Results There were significant group differences in the association of LDL-C (β = -0.29 p = 0.001), and TC (β = -0.21 p = 0.016), with hippocampal volume, and triglycerides with ACC volume (β = -0.25 p = 0.01) and area (β = -0.26 p = 0.004). Elevated lipids were associated with smaller brain structure to a significantly greater extent in BD vs HC. Post hoc analyses revealed that elevated LDL-C (β = -0.27 p = 0.007) and reduced HDL-C (β = 0.24 p = 0.01) were associated with smaller hippocampal volume in the BD group. Exclusion of BD second-generation antipsychotic users did not alter these results. Vertex-wise analyses further showed that elevated lipids were associated with smaller brain structure to a significantly greater extent in BD vs HC, across the cortex. Conclusion Elevated lipids are associated with smaller brain structure in BD. Research evaluating lipid-brain structure associations prospectively and whether lipid optimization has salutary effects on brain structure is necessary.

Following effective treatment with systemic antifungal therapy, eyelid lesions from blastomycosis infection may be replaced by disfiguring fibrosis and scarring, which may be surgically challenging to correct. A 68-year-old man with biopsy-proven eyelid blastomycosis was treated with 6 months of oral voriconazole, but resolution of the lesion was complicated by cicatricial changes causing complete lower eyelid defect, epicanthal web, cicatricial mechanical ptosis, and skin plaques. Although repair adhered to the fundamentals of eyelid reconstruction, cicatricial changes associated with blastomycosis infection necessitated a modified approach and attachment sites. A tarsoconjunctival flap (Hughes flap) with modified flap connections utilizing cicatrix and remaining viable tissue was employed to reconstruct the lower eyelid defect and combined with tissue advancement using a Mustardé four-flap epicanthoplasty and post-auricular full-thickness skin graft. Satisfactory cosmetic outcome was achieved at last follow-up of 3.5 months postoperatively. This case demonstrates a feasible technique for reconstruction of significant eyelid defects following robust cicatricial changes such as those after blastomycosis. This report also presents the first description of reconstruction of lower eyelid defect and of posterior lamellar loss after blastomycosis infection.

ObjectiveTo assess the benefits and limitations of whole genome sequencing (WGS) compared to exome sequencing (ES) or multigene panel (MGP) in the molecular diagnosis of developmental and epileptic encephalopathies (DEE).MethodsWe performed WGS of 30 comprehensively phenotyped DEE patient trios that were undiagnosed after first-tier testing, including chromosomal microarray and either research ES (n = 15) or diagnostic MGP (n = 15).ResultsEight diagnoses were made in the 15 individuals who received prior ES (53%): 3 individuals had complex structural variants; 5 had ES-detectable variants, which now had additional evidence for pathogenicity. Eleven diagnoses were made in the 15 MGP-negative individuals (68%); the majority (n = 10) involved genes not included in the panel, particularly in individuals with postneonatal onset of seizures and those with more complex presentations including movement disorders, dysmorphic features, or multiorgan involvement. A total of 42% of diagnoses were autosomal recessive or X-chromosome linked.ConclusionWGS was able to improve diagnostic yield over ES primarily through the detection of complex structural variants (n = 3). The higher diagnostic yield was otherwise better attributed to the power of re-analysis rather than inherent advantages of the WGS platform. Additional research is required to assist in the assessment of pathogenicity of novel noncoding and complex structural variants and further improve diagnostic yield for patients with DEE and other neurogenetic disorders.

This study determined the interindividual variation in the cardiometabolic response to 6 months of moderate or vigorous intensity exercise training (ET) among youth at risk for type 2 diabetes mellitus. Youth were randomized to moderate intensity ET (45–55% heart rate reserve; n = 31), vigorous intensity ET (70–85% heart rate reserve; n = 37), or control (n = 36). Only those attending ≥70% of ET sessions were included. Cardiometabolic measures included insulin sensitivity, hepatic triglyceride content, visceral adipose area, and cardiorespiratory fitness. The contribution of ET to interindividual variation was determined using the standard deviation of individual responses (SDIR) and considered meaningful if the SDIR surpassed the smallest worthwhile difference (SWD), calculated as 0.2 × the standard deviation of the control group baseline values. ET meaningfully contributed to the interindividual variation among changes in peak oxygen uptake following moderate (SDIR: 2.04) and vigorous (SDIR: 3.43) ET (SWD: 1.17 mL·kg fat free mass−1·min−1), body fat percentage and hepatic triglyceride content following moderate-intensity ET (SDIR: 1.64, SWD: 1.05%; SDIR: 10.08, SWD: 1.06%, respectively), and visceral fat mass following vigorous ET (SDIR: 11.06, SWD: 7.13 cm2). Variation in the changes in insulin sensitivity were not influenced by ET. The contribution of ET to interindividual variation appears to be influenced by the desired outcome and prescribed intensity. Trial registration at ClinicalTrials.gov (identifier no.: NCT00755547). Novelty: The contribution of exercise to interindividual variation following training depends on the outcome and exercise intensity. Increasing exercise intensity does not systematically reduce non-response among youth at risk for type 2 diabetes.

Childhood sexual abuse (CSA) is a global problem with serious repercussions for survivors in various domains of adult interpersonal functioning, including sexual risk behavior. This review aimed to summarize findings from the recent literature on the connections between CSA and later adult sexual risk behaviors (e.g., unprotected intercourse, sexually transmitted infection [STSI] diagnosis). The sexual risk behaviors consistently associated with CSA were having sex under the influence of alcohol/substances and reports of concurrent sexual partners/infidelity. Notably, studies investigating the links between CSA and history of STI diagnosis and CSA and reports of unprotected sex (with the exception of samples comprised men who have sex with men) produced inconsistent findings. The methodological limitations of existing studies are considered and suggestions for future research are offered.

Consistent cerebral blood flow (CBF) is fundamental to brain function. Cerebral autoregulation ensures CBF stability. Chronic hypertension can lead to disrupted cerebral autoregulation in older people, potentially leading to blood pressure levels interfering with CBF. This study tested whether low BP and AHD use are associated with contemporaneous low CBF, and whether longitudinal change in BP is associated with change in CBF, using arterial spin labelling (ASL) MRI, in a prospective longitudinal cohort of 186 community-dwelling older individuals with hypertension (77 ± 3 years, 53% female), 125 (67%) of whom with 3-year follow-up. Diastolic blood pressure, systolic blood pressure, mean arterial pressure, and pulse pressure were assessed as blood pressure parameters. As additional cerebrovascular marker, we evaluated the ASL signal spatial coefficient of variation (ASL SCoV), a measure of ASL signal heterogeneity that may reflect cerebrovascular health. We found no associations between any of the blood pressure measures and concurrent CBF nor between changes in blood pressure measures and CBF over three-year follow-up. Antihypertensive use was associated with lower grey matter CBF (−5.49 ml/100 g/min, 95%CI = −10.7|−0.27, p = 0.04) and higher ASL SCoV (0.32 SD, 95%CI = 0.12|0.52, p = 0.002). These results warrant future research on the potential relations between antihypertensive use and cerebral perfusion.