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Current systemic treatments for children younger than 6 years with moderate-to-severe atopic dermatitis that is uncontrolled with topical therapies might have suboptimal efficacy and safety. Dupilumab is approved for older children and adults with atopic dermatitis and for other type 2 inflammatory conditions. We aimed to evaluate efficacy and safety of dupilumab with concomitant low-potency topical corticosteroids in children aged 6 months to younger than 6 years with moderate-to-severe atopic dermatitis.This randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial was conducted in 31 hospitals, clinics, and academic institutions in Europe and North America. Eligible patients were aged 6 months to younger than 6 years, with moderate-to-severe atopic dermatitis (Investigator's Global Assessment [IGA] score 3-4) diagnosed according to consensus criteria of the American Academy of Dermatology, and an inadequate response to topical corticosteroids. Patients were randomly assigned (1:1) to subcutaneous placebo or dupilumab (bodyweight ≥5 kg to15 kg: 200 mg; bodyweight ≥15 kg to30 kg: 300 mg) every 4 weeks plus low-potency topical corticosteroids (hydrocortisone acetate 1% cream) for 16 weeks. Randomisation was stratified by age, baseline bodyweight, and region. Patient allocation was done via a central interactive web response system, and treatment allocation was masked. The primary endpoint at week 16 was the proportion of patients with IGA score 0-1 (clear or almost clear skin). The key secondary endpoint (coprimary endpoint for the EU and EU reference market) at week 16 was the proportion of patients with at least a 75% improvement from baseline in Eczema Area and Severity Index (EASI-75). Primary analyses were done in the full analysis set (ie, all randomly assigned patients, as randomly assigned) and safety analyses were done in all patients who received any study drug. This study was registered with ClinicalTrials.gov, NCT03346434.Between June 30, 2020, and Feb 12, 2021, 197 patients were screened for eligibility, 162 of whom were randomly assigned to receive dupilumab (n=83) or placebo (n=79) plus topical corticosteroids. At week 16, significantly more patients in the dupilumab group than in the placebo group had IGA 0-1 (23 [28%] vs three [4%], difference 24% [95% CI 13-34]; p0·0001) and EASI-75 (44 [53%] vs eight [11%], difference 42% [95% CI 29-55]; p0·0001). Overall prevalence of adverse events was similar in the dupilumab group (53 [64%] of 83 patients) and placebo group (58 [74%] of 78 patients). Conjunctivitis incidence was higher in the dupilumab group (four [5%]) than the placebo group (none). No dupilumab-related adverse events were serious or led to treatment discontinuation.Dupilumab significantly improved atopic dermatitis signs and symptoms versus placebo in children younger than 6 years. Dupilumab was well tolerated and showed an acceptable safety profile, similar to results in older children and adults.Sanofi and Regeneron Pharmaceuticals.

To evaluate improvement during the (a) cognitive and (b) exposure therapy phases of cognitive-behavioral therapy (CBT) for autistic youth with anxiety disorders.Participants were 148 autistic youth (aged 7-13; 77% male; 64% White) with clinically significant anxiety who were randomized to standard or adapted CBT. Clinician-rated anxiety severity was recorded at each appointment. Trajectories of change during (a) the cognitive phase and (b) the exposure phase of treatment were analyzed using piecewise multilevel modeling.Compared to the psychoeducation and cognitive therapy phases, the exposure phase corresponded with significantly more rapid symptom reduction, b = -.11, 95% CI [-.13, -.071]. This finding was true for standard CBT, which included nine sessions prior to exposure initiation (on average), as well as for CBT personalized for autistic youth, which introduced exposure following the fifth session (on average). In contrast, compared with improvements during initial psychoeducation sessions, the introduction of cognitive skills corresponded with significantly slower symptom reduction, b = .066, 95% CI [.020, .11]. This finding was also true for both adapted and standard CBT.Results underscore the central role of exposure in the treatment of anxiety among autistic youth and question the utility of cognitive strategies without subsequent practice of these skills during exposure. Assuming a working relationship, therapists should consider moving through the preexposure coping phase of CBT quickly. Future research should evaluate the extent to which exposure can maintain its potency while minimizing coping skill preparation. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

To establish the clinical relevance of porcine model of traumatic brain injury (TBI) using the plasma biomarkers of injury with diffusion tensor imaging (DTI) over 30 days, we performed a randomized, blinded, pre-clinical trial using Yorkshire pigs weighing 7-10 kg. Twelve pigs were subjected to Sham injury (n = 5) by skin incision or TBI (n = 7) by controlled cortical impact. Blood samples were collected before the injury, then at approximately 5-day intervals until 30 days. Both groups also had DTI at 24 h and at 30 days after injury. Plasma samples were isolated and single molecule array (Simoa) was performed for glial fibrillary acidic protein (GFAP) and neurofilament light (NFL) levels. Afterwards, brain tissue samples were stained for β-APP. DTI showed fractional anisotropy (FA) decrease in the right corona radiata (ipsilateral to injury), contralateral corona radiata, and anterior corpus callosum at 1 day. At 30 days, ipsilateral corona radiata showed decreased FA. Pigs with TBI also had increase in GFAP and NFL at 1-5 days after injury. Significant difference between Sham and TBI animals continued up to 20 days. Linear regression showed significant negative correlation between ipsilateral corona radiata FA and both NFL and GFAP levels at 1 day. To further validate the degree of axonal injury found in DTI, β-APP immunohistochemistry was performed on a perilesional tissue as well as corona radiata bilaterally. Variable degree of staining was found in ipsilateral corona radiata. Porcine model of TBI replicates the acute increase in plasma biomarkers seen in clinical TBI. Further, long term white matter injury is confirmed in the areas such as the splenium and corona radiata. However, future study stratifying severe and mild TBI, as well as comparison with other subtypes of TBI such as diffuse axonal injury, may be warranted.

Traumatic brain injury (TBI) results in the generation of tau. As hyperphosphorylated tau (p-tau) is one of the major consequences of TBI, targeting p-tau in TBI may lead to the development of new therapy. Twenty-five pigs underwent a controlled cortical impact. One hour after TBI, pigs were administered either vehicle (n = 13) or PNT001 (n = 12), a monoclonal antibody for the cis conformer of tau phosphorylated at threonine 231. Plasma biomarkers of neural injury were assessed for 14 days. Diffusion tensor imaging was performed at day 1 and 14 after injury, and these were compared to historical control animals (n = 4). The fractional anisotropy data showed significant white matter injury for groups at 1 day after injury in the corona radiata. At 14 days, the vehicle-treated pigs, but not the PNT001-treated animals, exhibited significant white matter injury compared to sham pigs in the ipsilateral corona radiata. The PNT001-treated pigs had significantly lower levels of plasma glial fibrillary acidic protein (GFAP) at day 2 and day 4. These findings demonstrate a subtle reduction in the areas of white matter injury and biomarkers of neurological injury after treatment with PNT001 following TBI. These findings support additional studies for PNT001 as well as the potential use of this agent in clinical trials in the near future.

This study examines how individuals understand spiritual calling to work. We draw on theoretic insights from Max Weber and Karl Marx to analyze 186 in-depth interviews with religious individuals in the United States. We argue that these classical frameworks can help us to better understand contemporary religious interpretations of calling in relationship to work. We propose a framework for categorizing ways of viewing work as a calling that consists of intrinsic/extrinsic meanings in work and goals that are proximal/distal to the workplace. While focusing primarily on Christian respondents, we note that some respondents from Jewish and Muslim traditions did not resonate directly with the term “calling” but had alternate ways of viewing their work that closely aligned with Christian conceptions of calling. We ultimately argue for the theoretical benefit of a Weberian conception of calling for contemporary understandings of how meaning is attached to work, but also highlight that seeing work as calling may be a double-edged sword because doing so may provide benefits to workers while simultaneously obscuring their own oppression.

This study examined the reliability and validity of the Patient Reported Outcomes Measurement System (PROMIS)-25, a profile instrument consisting of 4-item fixed short forms for six health domains, in children living with burn injury. Data were provided by children participating in a multi-center longitudinal study of outcomes after burn injury. Floor and ceiling effects, unidimensionality, internal consistency, reliability, and differential item functioning (DIF) of the PROMIS-25 Profile v.2.0 were examined. Correlations with other established measures were calculated to assess concurrent validity. Children (n=256) between the ages of 8-18 years with moderate to severe injury provided responses on PROMIS-25 domains. All PROMIS-25 domains showed high internal consistency. Substantial portions of the sample reported no symptoms (anxiety [58.2%], depressive symptoms [54.6%], fatigue [50.8%], pain [60.1%]). There was a large ceiling effect on peer relationships (46.8%) and physical function mobility (57.5%). One-factor confirmatory factor analyses supported unidimensionality for all domains. Reliability was sufficient for group mean comparisons (>0.8) across at least some trait levels for most domains except fatigue and anxiety. No DIF with respect to burn status was detected when comparing the burn sample to the PROMIS pediatric general US population testing sample. These results provide evidence of reliability and validity of PROMIS-25 scores among children living with burn injury. Reliability of domains was low to moderate and would likely be improved, and ceiling effects reduced for some domains, by administering the PROMIS-37, which includes six items per domain.

This cross-sectional study estimates trends in stroke prevalence representative of the noninstitutionalized civilian population of US adults 20 years and older using data from the 1999 to 2018 National Health and Nutrition Examination Surveys.

By the work of P. Lévy, the sample paths of the Brownian motion are known to satisfy a certain Hölder regularity condition almost surely. This was later improved by Ciesielski, who studied the regularity of these paths in Besov and Besov-Orlicz spaces. We review these results and propose new function spaces of Besov type, strictly smaller than those of Ciesielski and Lévy, in which the sample paths of the Brownian motion almost surely lie. In the same spirit, we review and extend the work of Kamont, who investigated the same question for the multivariate Brownian sheet and function spaces of dominating mixed smoothness.

Understanding the factors shaping patterns of ecological resilience is critical for mitigating the loss of global biodiversity. Throughout aquatic environments, highly mobile predators are thought to serve as important vectors of energy between ecosystems thereby promoting stability and resilience. However, the role these predators play in connecting food webs and promoting energy flow remains poorly understood in most contexts. Using carbon and nitrogen isotopes, we quantified the use of several prey resource pools (small oceanic forage, large oceanics, coral reef, and seagrass) by 17 species of elasmobranch fishes ( n = 351 individuals) in The Bahamas to determine their functional diversity and roles as ecosystem links. We observed remarkable functional diversity across species and identified four major groups responsible for connecting discrete regions of the seascape. Elasmobranchs were responsible for promoting energetic connectivity between neritic, oceanic and deep-sea ecosystems. Our findings illustrate how mobile predators promote ecosystem connectivity, underscoring their functional significance and role in supporting ecological resilience. More broadly, strong predator conservation efforts in developing island nations, such as The Bahamas, are likely to yield ecological benefits that enhance the resilience of marine ecosystems to combat imminent threats such as habitat degradation and climate change.

Disparities in socioeconomic status and minority status affect the risk of burn injury and the severity of that injury, thus affecting the subsequent cost of care. We aimed to characterize the demographic details surrounding receipt of financial assistance due to burn injury and its relationship with health-related quality of life scores. Participants ≥18 from Burn Model System National Longitudinal Database (BMS) with complete demographic data were included (n = 4330). Nonresponders to financial assistance questions were analyzed separately. The remaining sample (n = 1255) was divided into participants who received financial assistance because of burn injury, those who received no financial assistance, and those who received financial assistance before injury and as a result of injury. A demographic and injury-characteristic comparison was conducted. Health-related quality of life metrics (Satisfaction with Life, Short Form-12/Veterans RAND 12-Item Health Survey, Community Integration Questionnaire Social Component, and the Post-Traumatic Growth Inventory) were analyzed preinjury, then 6-months, 1-year, and 2-years postinjury. A matched cohort analysis compared these scores. When compared to their no financial assistance counterparts, participants receiving financial assistance due to burns were more likely to be minorities (19% vs 14%), have more severe injuries (%TBSA burn 21% vs 10%), and receive workers’ compensation (24% vs 9%). They also had lower health-related quality of life scores on all metrics except the post-traumatic growth inventory. Financial assistance may aid in combating disparities in posttraumatic growth scores for participants at the greatest risk of financial toxicity but does not improve other health-related quality of life metrics.

BackgroundNeuroprotective treatment strategies aiming at interfering with either inflammation or cell death indicate the importance of these mechanisms in the development of brain injury after subarachnoid hemorrhage (SAH). This study was undertaken to evaluate the influence of minocycline on microglia/macrophage cell activity and its neuroprotective and anti-inflammatory impact 14 days after aneurismal SAH in mice.MethodsEndovascular filament perforation was used to induce SAH in mice. SAH + vehicle-operated mice were used as controls for SAH vehicle-treated mice and SAH + minocycline-treated mice. The drug administration started 4 h after SAH induction and was daily repeated until day 7 post SAH and continued until day 14 every second day. Brain cryosections were immunolabeled for Iba1 to detect microglia/macrophages and NeuN to visualize neurons. Phagocytosis assay was performed to determine the microglia/macrophage activity status. Apoptotic cells were stained using terminal deoxyuridine triphosphate nick end labeling. Real-time quantitative polymerase chain reaction was used to estimate cytokine gene expression.ResultsWe observed a significantly reduced phagocytic activity of microglia/macrophages accompanied by a lowered spatial interaction with neurons and reduced neuronal apoptosis achieved by minocycline administration after SAH. Moreover, the SAH-induced overexpression of pro-inflammatory cytokines and neuronal cell death was markedly attenuated by the compound.ConclusionsMinocycline treatment may be implicated as a therapeutic approach with long-term benefits in the management of secondary brain injury after SAH in a clinically relevant time window.

We describe the perceptions of mental health clinicians practicing in the United States about the effects of the COVID-19 pandemic on the presentation and treatment course of active clients with anxiety. Clinician participants reported on client symptomology at the beginning of treatment, just before (prior to March 2020), and at a mid-pandemic timepoint (December 2020/January 2021). An initial sample of 70 clinicians responded to a survey assessing their clients’ overall anxiety severity, anxiety sensitivity, pathological uncertainty, family accommodation, and avoidance levels. Of these, 54 clinician responses were included in study analyses, providing detailed clinical information on 81 clients. Findings suggest that the COVID-19 pandemic was associated with increases in anxiety severity in the majority of clients; overall, clinicians reported that 53% of clients had symptoms worsen due to COVID-19 and that only 16% experienced improvement of symptoms during treatment. Those who had lower levels of avoidance pre-pandemic and those who increased their frequency of treatment were more likely to experience increases in anxiety severity by the mid-pandemic timepoint. Further research is needed to understand the extended effects of the COVID-19 pandemic on anxiety symptomology and treatment.

Objective To describe differences in traumatic brain injury patient characteristics and outcomes by inpatient rehabilitation facility profit status. Design Retrospective database review utilizing the Uniform Data System for Medical Rehabilitation® (UDSMR). Setting Inpatient rehabilitation facilities. Participants Individual discharges (n = 53,630) from 877 distinct rehabilitation facilities for calendar years 2016 through 2018. Intervention NA Main Outcome Measures Patient demographic data (age, race, primary payer source), admission and discharge Functional Independence Measure® (FIM®), FIM® gain, length of stay efficiency, acute hospital readmission from for-profit and not-for-profit IRFs within 30 days, and community discharges by facility profit status. Results Patients at for-profit facilities were significantly older (69.69 vs. 64.12 years), with lower admission FIM® scores (52 vs. 57), shorter lengths of stay (13 vs. 15 days), and higher discharge FIM® scores (88 vs. 86); for-profit facilities had higher rates of community discharges (76.8% vs. 74.6%), but also had higher rates of readmission (10.3% vs. 9.9%). Conclusions The finding that for-profit facilities admit older patients who are reportedly less functional on admission and more functional on discharge, with higher rates of community discharge but higher readmission rates than not-for-profit facilities is an unexpected and potentially anomalous finding. In general, older, less functional patients who stay for shorter periods of time would not necessarily be expected to make greater functional gains. These differences should be further studied, to determine if differences in patient selection, coding/billing, or other unreported factors underlie these differences.

PurposeDespite best intentions, mergers and acquisitions often do not live up to the expectations for performance. This study examined how the salience of multiple identities creates dynamics in postmerger integration processes and how these dynamics influence the acquisition of the target's capabilities.Design/methodology/approachThe authors conducted an in-depth case study of a large American consumer goods multinational corporation's acquisition of a family-owned German beauty business and examined responses to decisions and events during the postmerger integration process.FindingsThe results show how and why efforts to acquire unique target capabilities might not deliver the hoped-for results. The authors discovered multiple identities that became salient during the postmerger integration process which subsequently influenced interpretations and reactions to decisions and events and which created intergroup dynamics. The authors also noted the role of language in making these identities salient. Such dynamics pose challenges to managing the postmerger integration process and to acquiring sought after capabilities.Originality/valueThis study reveals how different identities become salient in the interpretation of particular events and decisions, resulting in emotional and behavioral reactions and intergroup dynamics. Furthermore, it uncovers the role of language in making identities salient. This study offers further insight into identity dynamics when the capability of the target firm is the motive of the acquisition.