Skin microdialysis detects distinct immunologic patterns in chronic inflammatory skin diseases.

BACKGROUND: Insight into the pathophysiology of inflammatory skin diseases, especially at the proteomic level, is severely hampered by the lack of adequate in situ data. OBJECTIVE: We characterized lesional and nonlesional skin of inflammatory skin diseases using skin microdialysis. METHODS: Skin microdialysis samples from patients with atopic dermatitis (AD, n = 6), psoriasis vulgaris (PSO, n = 7), or prurigo nodularis (PN, n = 6), as well as healthy controls (n = 7), were subjected to proteomic and multiplex cytokine analysis. Single-cell RNA sequencing of skin biopsy specimens was used to identify the cellular origin of cytokines. RESULTS: Among the top 20 enriched Gene Ontology (GO; geneontology.org) annotations, nicotinamide adenine dinucleotide metabolic process, regulation of secretion by cell, and pyruvate metabolic process were elevated in microdialysates from lesional AD skin compared with both nonlesional skin and controls. The top 20 enriched Kyoto Encyclopedia of Genes and Genomes (KEGG; genome.jp/kegg) pathways in these 3 groups overlapped almost completely. In contrast, nonlesional skin from patients with PSO or PN and control skin showed no overlap with lesional skin in this KEGG pathway analysis. Lesional skin from patients with PSO, but not AD or PN, showed significantly elevated protein levels of MCP-1 compared with nonlesional skin. IL-8 was elevated in lesional versus nonlesional AD and PSO skin, whereas IL-12p40 and IL-22 were higher only in lesional PSO skin. Integrated single-cell RNA sequencing data revealed identical cellular sources of these cytokines in AD, PSO, and PN. CONCLUSION: On the basis of microdialysates, the proteomic data of lesional PSO and PN skin, but not lesional AD skin, differed significantly from those of nonlesional skin. IL-8, IL-22, MCP-1, and IL-12p40 might be suitable markers for minimally invasive molecular profiling.

The Physical Progress of a Professional Scottish Soccer Academy Over a Ten-Year Period.

Background: Increases in high-intensity locomotor activity of match play have been recorded in elite soccer. This places an onus on academy practitioners to develop players for the future demands of the game. At an academy level, locomotor data are not available for analysis over a longitudinal period, and thus changes can only be assessed with physical attribute assessment. The aim of the present study is to establish if changes in physical capacity were observed in a professional Scottish soccer academy over a ten-year period. Methods: A retrospective analysis was completed where linear mixed effect (LME) models were individually fitted to explain variation across each measure of physical capacity. Model selection was undertaken with likelihood ratio tests where the initial complex models were compared to simpler nested models to arrive at the final model by maximum likelihood. Results: The main findings were that most recent players' sprint test data revealed a significant improvement in 5m, 10m and 20m sprint performance, greater increases in CMJ performance in older age groups, and greater increases in YYIR1 performance at U13 and U14. Most physical results showed increased performance with greater relative height and weight. Conclusion: Players recruited more recently to academies are fitter than they were previously. Reference values within clubs that establish first team requirements will contribute to appropriate planning and implementation of training.

SARS-CoV-2 Vaccination and Neuroimmunological Disease: A Review.

Importance: The temporal association between the occurrence of neurological diseases, many autoimmune diseases, and vaccination against SARS-CoV-2 has been topically interesting and remains hotly debated both in the medical literature and the clinic. Given the very low incidences of these events both naturally occurring and in relation to vaccination, it is challenging to determine with certainty whether there is any causative association and most certainly what the pathophysiology of that causation could be. Observations: Data from international cohorts including millions of vaccinated individuals suggest that there is a probable association between the adenovirus-vectored vaccines and Guillain-Barré syndrome (GBS). Further associations between other SARS-CoV-2 vaccines and GBS or Bell palsy have not been clearly demonstrated in large cohort studies, but the possible rare occurrence of Bell palsy following messenger RNA vaccination is a topic of interest. It is also yet to be clearly demonstrated that any other neurological diseases, such as central nervous system demyelinating disease or myasthenia gravis, have any causative association with vaccination against SARS-CoV-2 using any vaccine type, although it is possible that vaccination may rarely trigger a relapse or worsen symptoms or first presentation in already-diagnosed or susceptible individuals. Conclusions and Relevance: The associated risk between SARS-CoV-2 vaccination and GBS, and possibly Bell palsy, is slight, and this should not change the recommendation for individuals to be vaccinated. The same advice should be given to those with preexisting neurological autoimmune disease.

An Evaluation of Item Harmonization Strategies Between Assessment Tools of Psychopathology in Children and Adolescents.

Data aggregation in mental health is complicated by using different questionnaires, and little is known about the impact of item harmonization strategies on measurement precision. Therefore, we aimed to assess the impact of various item harmonization strategies for a target and proxy questionnaire using correlated and bifactor models. Data were obtained from the Brazilian High-Risk Study for Mental Conditions (BHRCS) and the Healthy Brain Network (HBN; N = 6,140, ages 5-22 years, 39.6% females). We tested six item-wise harmonization strategies and compared them based on several indices. The one-by-one (1:1) expert-based semantic item harmonization presented the best strategy as it was the only that resulted in scalar-invariant models for both samples and factor models. The between-questionnaires factor correlation, reliability, and factor score difference in using a proxy instead of a target measure improved little when all other harmonization strategies were compared with a completely at-random strategy. However, for bifactor models, between-questionnaire specific factor correlation increased from 0.05-0.19 (random item harmonization) to 0.43-0.60 (expert-based 1:1 semantic harmonization) in BHRCS and HBN samples, respectively. Therefore, item harmonization strategies are relevant for specific factors from bifactor models and had little impact on p-factors and first-order correlated factors when the child behavior checklist (CBCL) and strengths and difficulties questionnaire (SDQ) were harmonized.

Comparing mental health semi-structured diagnostic interviews and symptom checklists to predict poor life outcomes: an 8-year cohort study from childhood to young adulthood in Brazil.

BACKGROUND: Semi-structured diagnostic interviews and symptom checklists present similar internal reliability. We aim to investigate whether they differ in predicting poor life outcomes in the transition from childhood to young adulthood. METHODS: For this longitudinal study, we used data from the Brazilian High Risk Cohort Study for Childhood Mental Health Conditions. Eligible participants were aged 6-14 years on the day of study enrolment (January to February, 2010) and were enrolled in public schools by a biological parent in Porto Alegre and São Paulo, Brazil. 2511 young people and their caregivers were assessed at baseline in 2010-11, and 1917 were assessed 8 years later (2018-19; 76·3% retention). Clinical thresholds were derived using semi-structured parent-report interview based on the Diagnostic and Statistical Manual of Mental Disorders, according to the Developmental and Well-being Assessment (DAWBA), and clinical scores as defined by the Child Behavior Checklist (CBCL; T-score ≥70 considered positive caseness). At 8 years, participants were assessed for a composite life-threatening outcome (a composite of death, suicide attempts, severe self-harm, psychiatric inpatient admission, or emergency department visits) and a composite poor life chances outcome (a composite of any criminal conviction, substance misuse, or school dropout). We evaluated the accuracy of DAWBA and CBCL to predict these outcomes. Logistic regression models were adjusted for age, sex, race or ethnicity, study site, and socioeconomic class. FINDINGS: DAWBA and CBCL had similar sensitivity, specificity, predictive values, and test accuracy for both composite outcomes and their components. Any mental health problem, as classified by DAWBA and CBCL, was independently associated with the composite life-threatening outcome (DAWBA adjusted odds ratio 1·62, 95% CI 1·20-2·18; CBCL 1·66, 1·19-2·30), but only CBCL independently predicted poor life chances (1·56, 1·19-2·04). Participants classified by both approaches did not have higher odds of the life-threatening outcome when compared with participants classified by DAWBA or CBCL alone, nor for the poor life chances outcome when compared with those classified by CBCL alone. INTERPRETATION: Classifying children and adolescents based on a semi-structured diagnostic interview was not statistically different to symptom checklist in terms of test accuracy and predictive validity for relevant life outcomes. Classification based on symptom checklist might be a valid alternative to costly and time-consuming methods to identify young people at risk for poor life outcomes. FUNDING: Conselho Nacional de Desenvolvimento Científico e Tecnológico; Fundação de Amparo à Pesquisa do Estado de São Paulo; and Medical Research Council, European Research Council. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.

Novel approaches to correlate computerized tomography imaging of bone fracture callus to callus structural mechanics.

Estimating the mechanical properties of bone in vivo without destructive testing would be useful for research and clinical orthopedic applications. Micro-computerized tomography (µCT) imaging can provide quantitative, high-resolution 3D representations of bone morphology and is generally the basis from which bone mechanical properties are non-destructively estimated. The goal of this study was to develop metrics using qualitative and quantitative aspects of bone microarchitecture derived from µCT imaging to estimate the mechanical integrity of bone fracture calluses. Mechanical testing data (peak torque) and µCT image data from 12 rat femur fractures were collected at 4 weeks after fracture. MATLAB was used to analyze the callus µCT imaging data which were then correlated to the empirically determined peak torque of the callus. One metric correlated Z-rays, linear contiguities of voxels running parallel to the neutral axis of the femur and through the fracture callus, to peak torque. Other metrics were based on voxel linkage values (LVs), which is a novel measurement defined by the number of voxels surrounding a given voxel (ranging from 1 to 27) that are all above a specified threshold. Linkage values were utilized to segment the callus and compute healing scores (termed eRUST) based on the modified Radiographic Union Score for Tibial fractures (mRUST). Linkage values were also used to calculate linked bone areas (LBAs). All metrics positively correlated with peak torque, yielding correlations of determination (R2) of 0.863 for eRUST, 0.792 for Z-ray scoring, and 0.764 for a normalized Linked Bone Area metric. These novel metrics appear to be promising approaches for extrapolating fracture callus structural properties from bone microarchitecture using objective analytical methods and without resorting to computationally complex finite element analyses.

Perceived performance of activities of daily living by stroke patients: key in decision to call EMS and outcomes.

Background: Until recently, public education campaigns aimed at improving help-seeking behavior by acute stroke patients have achieved only limited or even no effects. Better understanding of psychological factors determining help-seeking behavior may be relevant in the design of more effective future campaigns. Methods: In this prospective, cross-sectional study, we interviewed 669 acute stroke patients within 72 h after hospital admission. The primary endpoint was the effect of psychological factors on the decision to call emergency medical services (EMS). Secondary endpoints were the effects of such factors on treatment rates and clinical improvement (difference between modified Rankin scale (MRS) scores at admission and at discharge). Results: Only 48.7% of the study population called the EMS. Multivariate logistic and linear regression analyses revealed that perception of unimpaired performance of activities of daily living (ADL) was the only psychological factor that predicted EMS use and outcomes. Thus, patients who perceived only minor impairment in performing ADL were less likely to use EMS (odds ratio, 0.54 [95% confidence interval, 0.38-0.76]; p = 0.001), had lower treatment rates, and had less improvement in MRS scores (b = 0.40, p = 0.004). Additional serial mediation analyses involving ischemic stroke patients showed that perception of low impairment in ADL decreased the likelihood of EMS notification, thereby increasing prehospital delays, leading to reduced thrombolysis rates and, finally, to reduced clinical improvement. Conclusion: Perception of unimpaired performance of ADL is a crucial barrier to appropriate help-seeking behavior after acute stroke, leading to undertreatment and less improvement in clinical symptoms. Thus, beyond improving the public's knowledge of stroke symptoms, future public education campaigns should focus on the need for calling the EMS in case of stroke symptoms even if daily activities do not seem to be severely impaired.

Parent-Perceived Benefits and Harms Associated With Internet Use by Adolescent Offspring.

Importance: Limited systematic information on familial factors and perception of the benefits and harms of internet use by youths is available. Much of the current research has been hampered by small nondiverse samples and limited information on key familial and offspring characteristics. Objective: To characterize parental perceptions and concerns about internet use associated with adolescent development, well-being, safety, family connectedness, and potential for problematic internet use. Design, Setting, and Participants: A 20-minute, English-language survey was developed with expert stakeholders using previously validated questionnaires and was conducted online between June 17 and July 5, 2022. Participants included 1005 parents of children and adolescents aged 9 to 15 years drawn from an online digital survey platform and calibrated for representation with post hoc weightings. Main Outcomes and Measures: Parent survey responses about family characteristics and internet use were used to compute Internet Addiction Test scores for parents and their offspring, Alabama Parenting Questionnaire scores, and an aggregate family connectedness score. Results: The survey cohort of 1005 parents included 568 women (56.5%) and 437 men (43.5%) with a mean age (SD) of 39.5 (6.4) years. In terms of race and ethnicity, the most common categories included Black or African American (95 [9.5%]), Latinx or Hispanic (100 [10.0%]), White (602 [59.9%]), and 2 or more races or ethnicities (122 [12.1%]). Respondents endorsed parental concerns that included exposure to harmful content (646 [64.3%]) and online bullying (533 [53.0%]). Two hundred twenty-five parents (22.4%) had specific concerns about internet addiction in their adolescent offspring, and twice as many parents reported specific concerns about internet addiction than substance addiction. However, parents also indicated that internet use improved family connectedness among immediate families (468 [46.6%]) and extended families (568 [56.5%]). Internet Addiction Test scores in adolescent offspring were correlated with parent scores (ß = 0.62 [SE = 0.02]; P < .001) and Alabama Parenting Questionnaire-Inconsistent Discipline scores (ß = 0.23 [SE = 0.11]; P = .04). Conclusions and Relevance: In this survey study of parent perceptions of internet use among adolescent offspring, parents believed the internet brought families closer yet also expressed concerns. Problematic internet use among youths was correlated with negative parenting styles and parent internet use. This research adds to the literature by suggesting that families, their communities, and industry may have common ground to collaborate on reducing the negative effects of internet use.

Full-body blue light irradiation as treatment for atopic dermatitis: a randomized sham-controlled clinical trial (AD-Blue).

BACKGROUND: Visible blue light (wavelength 400-495 nm) is a promising new treatment option for both psoriasis and atopic dermatitis (AD). Whilst previous clinical trials featured various devices and blue light at a variety of wavelengths, none of these interventions were challenged in objective clinical criteria. PATIENTS AND METHODS: Eighty-seven patients diagnosed with AD were enrolled in AD-Blue, an international, prospective, double-blinded, three-armed (415 nm vs. 450 nm vs. sham control), randomized trial designed to investigate the safety and efficacy of prototype full-body blue light devices. RESULTS: Full-body irradiation with 450 nm blue light but not 415 nm had a significant impact on itch (Itch-VAS, -1.6 ± 2.3; p  =  0.023 vs. sham irradiation). PO-SCORAD values also decreased significantly in response to irradiation at 415 nm (-11.5 ± 18.4; p = 0.028 vs. sham irradiation). None of the other outcome measures (EASI, SCORAD, IGA, DLQI) changed significantly. No safety signals were observed. Evaluation of skin transcriptomes, cytokine levels in serum, and ELISpots from peripheral blood mononuclear cells isolated from a subset of patients revealed moderate decreases in IL-31 in response to irradiation with blue light. CONCLUSIONS: Despite its favorable safety profile and moderate reductions in itch and IL-31 levels, full-body blue light irradiation did not lead to an amelioration of any of the objective measures of AD.

Parental Preferences for Mental Health Screening of Youths From a Multinational Survey.

Importance: Screening youths for mental disorders may assist in prevention, promote early identification, and be associated with reduced related lifetime impairment and distress. Objective: To assess parents' and caregivers' comfort with and preferences for pediatric mental health screening and factors associated with these preferences. Design, Setting, and Participants: This survey study used an online survey available from July 11 to 14, 2021, through Prolific Academic. Analyses were conducted from November 2021 to November 2022. The survey was administered to English-speaking parents and caregivers in the US, UK, Canada, and 16 other countries who were aged 21 years or older and had at least 1 child aged 5 to 21 years living at home. Main Outcomes and Measures: The main outcomes were parental preferences regarding content, implementation, and review of the findings of pediatric mental health screening. Parental comfort with screening topics was reported on a 6-point Likert scale with 6 indicating highest comfort. Mixed-effects logistic regression models were used to evaluate factors associated with parental comfort levels. Results: Of 1200 survey responses requested, data were collected from 1136 participants (94.7%). The final sample meeting the inclusion criteria comprised 972 parents and caregivers aged 21 to 65 years (mean [SD] age, 39.4 [6.9] years; 606 [62.3%] female). A total of 631 participants (64.9%) supported annual mental health screening for their child, and 872 (89.7%) preferred reviewing the screening results with professional staff (eg, physicians). Participants reported significantly decreased comfort with child self-report compared with parent-report screening assessments (b = -0.278; SE = 0.009; P < .001), although they were generally comfortable with both options. Despite slight variations based on country of residence, screening topic, and child's age, participants were generally comfortable discussing all 21 screening topics on the survey. The greatest comfort was with sleep problems (mean [SE] score, 5.30 [0.03]); the least comfort was with firearms (mean [SE] score, 4.71 [0.05]), gender identity (mean [SE] score, 4.68 [0.05]), suicidality (mean [SE] score, 4.62 [0.05]), and substance use or abuse (mean [SE] score, 4.78 [0.05]). Conclusions and Relevance: In this survey study of parents and caregivers, parent-reported and child self-reported mental health screening in primary care settings was supported by the majority of the sample, although comfort levels differed according to various factors (eg, screening topic). Participants preferred to discuss screening results with professional health care staff. In addition to parental need for expert guidance, the study findings highlight the growing awareness of child mental health needs and the importance of addressing mental health concerns early via regular mental health screenings.

PD-1/CTLA-4 Blockade Leads to Expansion of CD8+PD-1int TILs and Results in Tumor Remission in Experimental Liver Cancer.

Background: Checkpoint inhibitors act on exhausted CD8+ T cells and restore their effector function in chronic infections and cancer. The underlying mechanisms of action appear to differ between different types of cancer and are not yet fully understood. Methods: Here, we established a new orthotopic HCC model to study the effects of checkpoint blockade on exhausted CD8+ tumor-infiltrating lymphocytes (TILs). The tumors expressed endogenous levels of HA, which allowed the study of tumor-specific T cells. Results: The induced tumors developed an immune-resistant TME in which few T cells were found. The few recovered CD8+ TILs were mostly terminally exhausted and expressed high levels of PD-1. PD-1/CTLA-4 blockade resulted in a strong increase in the number of CD8+ TILs expressing intermediate amounts of PD-1, also called progenitor-exhausted CD8+ TILs, while terminally exhausted CD8+ TILs were almost absent in the tumors of treated mice. Although transferred naïve tumor-specific T cells did not expand in the tumors of untreated mice, they expanded strongly after treatment and generated progenitor-exhausted but not terminally exhausted CD8+ TILs. Unexpectedly, progenitor-exhausted CD8+ TILs mediated the antitumor response after treatment with minimal changes in their transcriptional profile. Conclusion: In our model, few doses of checkpoint inhibitors during the priming of transferred CD8+ tumor-specific T cells were sufficient to induce tumor remission. Therefore, PD-1/CTLA-4 blockade has an ameliorative effect on the expansion of recently primed CD8+ T cells while preventing their development into terminally exhausted CD8+ TILs in the TME. This finding could have important implications for future T-cell therapies.

Robust Parental Preferences in Mental Health Screening in Youth From a Multinational Online Survey.

Importance: Screening youth for mental disorders may assist in prevention, promote early identification, and reduce related lifetime impairment and distress. Objective: The goal was to survey parents about their comfort and preferences for pediatric mental health screening, as well as factors associated with these preferences. Design: The online survey was available July 11-14, 2021 on Prolific Academic. Analyses were conducted from November 2021 to November 2022. Setting: Online survey. Participants: The survey was administered to English-speaking parents with at least one 5-21-year old child at home. The sample included 972 parents, aged 21 and older, from the United States ( n =265), United Kingdom ( n =282), Canada ( n =171), and Other Countries ( n =254). Exposures: None. Main Outcomes/Measures: Parental preferences regarding the screening content, implementation preferences, and screener reviewing preferences of pediatric mental health screening were assessed in a novel survey. Mixed effects logistic models were employed to evaluate factors that influence parental comfort levels. Results: Parents, aged 21 to 65 ( M =39.4; 62.3% female), supported annual mental health screening for their child and preferred reviewing the screening results with professional staff (e.g., physicians). Parents preferred parent-report over child self-reports, though they were generally comfortable with both options. Despite slight variations based on country of residence, screening topic, and child's age, parents were generally comfortable discussing all 21 topics. The greatest comfort was with sleep problems; the least comfort was with firearms, gender identity, suicidality, and substance use/abuse. Conclusions/Relevance: Our data indicated that parents support annual parent- and child self-report mental health screening in primary care settings, but comfort levels differ according to various factors, such as screening topic. Parents preferred screening to occur in the healthcare office and to discuss screening results with professional staff. In addition to parental need for expert guidance, the growing awareness of child mental health needs highlights the importance of addressing mental health concerns early via regular mental health screenings. KEY POINTS: Question: What are parents' attitudes towards pediatric mental health screening in primary care settings?Findings: The vast majority of parents surveyed online ( N=972) expressed comfort with the screening of children for mental health concerns in the primary care setting. Variations in comfort were noted in relation to age of child and topics included. Parents expressed a preference for parent report over child report, as well as for reviewing screening results with professional medical staff. These findings were robust to the country of residence (e.g., United States, Canada, United Kingdom). Meaning: Our findings document parental preferences that should be incorporated to enhance the feasibility of mental health screening in primary care settings.

Harmonizing bifactor models of psychopathology between distinct assessment instruments: Reliability, measurement invariance, and authenticity.

OBJECTIVES: Model configuration is important for mental health data harmonization. We provide a method to investigate the performance of different bifactor model configurations to harmonize different instruments. METHODS: We used data from six samples from the Reproducible Brain Charts initiative (N = 8,606, ages 5-22 years, 41.0% females). We harmonized items from two psychopathology instruments, Child Behavior Checklist (CBCL) and GOASSESS, based on semantic content. We estimated bifactor models using confirmatory factor analysis, and calculated their model fit, factor reliability, between-instrument invariance, and authenticity (i.e., the correlation and factor score difference between the harmonized and original models). RESULTS: Five out of 12 model configurations presented acceptable fit and were instrument-invariant. Correlations between the harmonized factor scores and the original full-item models were high for the p-factor (>0.89) and small to moderate (0.12-0.81) for the specific factors. 6.3%-50.9% of participants presented factor score differences between harmonized and original models higher than 0.5 z-score. CONCLUSIONS: The CBCL-GOASSESS harmonization indicates that few models provide reliable specific factors and are instrument-invariant. Moreover, authenticity was high for the p-factor and moderate for specific factors. Future studies can use this framework to examine the impact of harmonizing instruments in psychiatric research.

Canine real-time detection of SARS-CoV-2 infections in the context of a mass screening event.

INTRODUCTION: Previous research demonstrated that medical scent detection dogs have the ability to distinguish SARS-CoV-2 positive from negative samples with high diagnostic accuracy. To deploy these dogs as a reliable screening method, it is mandatory to examine if canines maintain their high diagnostic accuracy in real-life screening settings. We conducted a study to evaluate the performance of medical scent detection dogs under real-life circumstances. METHODS: Eight dogs were trained to detect SARS-CoV-2 RT-qPCR-positive samples. Four concerts with a total of 2802 participants were held to evaluate canines' performance in screening individuals for SARS-CoV-2 infection. Sweat samples were taken from all participants and presented in a line-up setting. In addition, every participant had been tested with a SARS-CoV-2 specific rapid antigen test and a RT-qPCR and they provided information regarding age, sex, vaccination status and medical disease history. The participants' infection status was unknown at the time of canine testing. Safety measures such as mask wearing and distance keeping were ensured. RESULTS: The SARS-CoV-2 detection dogs achieved a diagnostic specificity of 99.93% (95% CI 99.74% to 99.99%) and a sensitivity of 81.58% (95% CI 66.58% to 90.78%), respectively. The overall rate of concordant results was 99.68%. The majority of the study population was vaccinated with varying vaccines and vaccination schemes, while several participants had chronic diseases and were under chronic medication. This did not influence dogs' decisions. CONCLUSION: Our results demonstrate that SARS-CoV-2 scent detection dogs achieved high diagnostic accuracy in a real-life scenario. The vaccination status, previous SARS-CoV-2 infection, chronic disease and medication of the participants did not influence the performance of the dogs in detecting the acute infection. This indicates that dogs provide a fast and reliable screening option for public events in which high-throughput screening is required.

Daratumumab-bortezomib-dexamethasone use in relapsed POEMS syndrome.

POEMS syndrome is a rareparaneoplastic disorder driven by an underlying low level plasma cell dyscrasiaand associated with elevated serum vascular endothelial growth factor (VEGF). Dueto its rarity, there are no internationally agreed standards of care, with verylimited data to guide management in the relapse setting. Agents used in myelomaare rational choices and have been employed. Daratumumab has been reported intwo case studies with lenalidomide-dexamethasone, one in the upfront and one inthe relapsed setting. We are the first to report here three cases ofdaratumumab-bortezomib-dexamethasone (DVd) use in relapsed POEMS postautologous stem cell transplant with good VEGF and clinical responses. Our casesadd to the literature on efficacy of daratumumab and are the first to report onits safe use with bortezomib in relapsed POEMS. It should be considered as aclinical option, in patients not responding to conventional first linetherapies.

Status epilepticus during the COVID-19 pandemic in Cologne, Germany: data from a retrospective, multicentre registry.

BACKGROUND: The "coronavirus disease 2019" (COVID-19) pandemic, caused by the "severe-acute-respiratory-syndrome-coronavirus 2" (SARS-CoV-2), challenges healthcare systems worldwide and impacts not only COVID-19 patients but also other emergencies. To date, data are scarce on the extent to which the COVID-19 pandemic impacted status epilepticus (SE) and its treatment. OBJECTIVE: To assess the influence of the COVID-19 pandemic on the incidence, management and outcome of SE patients. STUDY DESIGN: This is a retrospective, multicentre trial, approved by the University of Cologne (21-1443-retro). METHODS: All SE patients from the urban area of Cologne transmitted to all acute neurological departments in Cologne between 03/2019 and 02/2021 were retrospectively analysed and assessed for patient characteristics, SE characteristics, management, and outcome in the first pandemic year compared to the last pre-pandemic year. RESULTS: 157 pre-pandemic (03/2019-02/2020) and 171 pandemic (from 03/2020 to 02/2021) SE patients were included in the analyses. Acute SARS-CoV-2 infections were rarely detected. Patient characteristics, management, and outcome did not reveal significant groupwise differences. In contrast, regarding prehospital management, a prolonged patient transfer to the hospital and variations in SE aetiologies compared to the last pre-pandemic year were observed with less chronic vascular and more cryptogenic and anoxic SE cases. No infections with SARS-CoV-2 occurred during inpatient stays. CONCLUSIONS: SARS-CoV-2 infections did not directly affect SE patients, but the transfer of SE patients to emergency departments was delayed. Interestingly, SE aetiology rates shifted, which warrants further exploration. Fears of contracting an in-hospital SARS-CoV-2-infection were unfounded due to consequent containment measures.

PPP2CA Is a Novel Therapeutic Target in Neuroblastoma Cells That Can Be Activated by the SET Inhibitor OP449.

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood and has a poor prognosis in high-risk cases, requiring novel therapies. Pathways that depend on phospho-signaling maintain the aggressiveness of NB. Protein phosphatase 2 (PP2A) with its catalytic subunit PPP2CA is a major phosphatase in cancer cells, including NB. We show that reduction of PPP2CA by knock-down decreased growth of NB cells and that complete ablation of PPP2CA by knock-out was not tolerated. Thus, NB cells are addicted to PPP2CA, an addiction augmented by MYCN activation. SET, a crucial endogenous inhibitor of PP2A, was overexpressed in poor-prognosis NB. The SET inhibitor OP449 effectively decreased the viability of NB cells, independent of their molecular alterations and in line with a tumor suppressor function of PPP2CA. The contrasting concentration-dependent functions of PPP2CA as an essential survival gene at low expression levels and a tumor suppressor at high levels are reminiscent of other genes showing this so-called Goldilocks phenomenon. PP2A reactivated by OP449 decreased activating phosphorylation of serine/threonine residues in the AKT pathway. Conversely, induced activation of AKT led to partial rescue of OP449-mediated viability inhibition. Dasatinib, a kinase inhibitor used in relapsed/refractory NB, and OP449 synergized, decreasing activating AKT phosphorylations. In summary, concomitantly reactivating phosphatases and inhibiting kinases with a combination of OP449 and dasatinib are promising novel therapeutic approaches to NB.

Reliability and validity of bifactor models of dimensional psychopathology in youth.

Bifactor models are a promising strategy to parse general from specific aspects of psychopathology in youth. Currently, there are multiple configurations of bifactor models originating from different theoretical and empirical perspectives. We aimed to test the reliability, validity, measurement invariance, and the correlation of different bifactor models of psychopathology using the Child Behavior Checklist (CBCL). We used data from the Reproducible Brain Charts (RBC) initiative (N = 7,011, ages 5 to 22 years, 40.2% females). Factor models were tested using the baseline data. To address our aim, we (a) searched for the published item-level bifactor models using the CBCL; (b) tested their global model fit; (c) calculated model-based reliability indices; (d) tested associations with symptoms' impact in everyday life; (e) tested measurement invariance across many characteristics, and (f) analyzed the observed factor correlation across the models. We found 11 bifactor models ranging from 39 to 116 items. Their global model fit was broadly similar. Factor determinacy and H index were acceptable for the p-factors, internalizing, externalizing, and somatic specific factors in most models. However, only the p- and attention factors predicted daily life symptoms' impact in all models. Models were broadly invariant across different characteristics. P-factors were highly correlated across models (r = .88 to .99) and homotypic specific factors were highly correlated. These results suggest that regardless of item selection and strategy to compose CBCL bifactor models, they assess very similar constructs. Taken together, our results support the robustness of the p-factor across distinct bifactor models and studies of distinct characteristics. (PsycInfo Database Record (c) 2022 APA, all rights reserved).