Multi-omics analysis reveals drivers of loss of ß-cell function after newly diagnosed autoimmune type 1 diabetes: An INNODIA multicenter study.

AIMS: Heterogeneity in the rate of ß-cell loss in newly diagnosed type 1 diabetes patients is poorly understood and creates a barrier to designing and interpreting disease-modifying clinical trials. Integrative analyses of baseline multi-omics data obtained after the diagnosis of type 1 diabetes may provide mechanistic insight into the diverse rates of disease progression after type 1 diabetes diagnosis. METHODS: We collected samples in a pan-European consortium that enabled the concerted analysis of five different omics modalities in data from 97 newly diagnosed patients. In this study, we used Multi-Omics Factor Analysis to identify molecular signatures correlating with post-diagnosis decline in ß-cell mass measured as fasting C-peptide. RESULTS: Two molecular signatures were significantly correlated with fasting C-peptide levels. One signature showed a correlation to neutrophil degranulation, cytokine signalling, lymphoid and non-lymphoid cell interactions and G-protein coupled receptor signalling events that were inversely associated with a rapid decline in ß-cell function. The second signature was related to translation and viral infection was inversely associated with change in ß-cell function. In addition, the immunomics data revealed a Natural Killer cell signature associated with rapid ß-cell decline. CONCLUSIONS: Features that differ between individuals with slow and rapid decline in ß-cell mass could be valuable in staging and prediction of the rate of disease progression and thus enable smarter (shorter and smaller) trial designs for disease modifying therapies as well as offering biomarkers of therapeutic effect.

Autistic adults in China and the Netherlands: Proxy-reported community integration and life satisfaction.

LAY ABSTRACT: Even though there are about 10 million Chinese autistic individuals, we know little about autistic adults in China. This study examined how well young autistic adults in China integrate into their communities (such as having a job, living independently and having friends) and how satisfied they are with their lives as reported by their caregivers. We compared them to autistic adults with similar characteristics (such as high support needs) from the Netherlands. We included 99 autistic adults in China and 109 in the Netherlands (18-30 years). In both countries, autistic adults were reported to have a hard time fitting into their communities. They often had no work, did not live on their own and had few close friends. Also, in both countries, caregivers reported that autistic adults felt low satisfaction with their life. Chinese adults were less satisfied with their life than Dutch adults, as indicated by their caregivers. This could be because of a lack of support for autistic adults in China, higher parental stress in Chinese caregivers, or general cross-country differences in happiness. Only in the Dutch group, younger compared with older adults fitted better into their communities, and adults without additional psychiatric conditions were reported to have higher life satisfaction. Country was a significant predictor of independent living only, with Dutch participants more likely living in care facilities than Chinese participants. In conclusion, our study shows that autistic adults with high support needs generally face similar challenges in both China and the Netherlands.

Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma.

BACKGROUND: Phase 1-2 trials involving patients with resectable, macroscopic stage III melanoma have shown that neoadjuvant immunotherapy is more efficacious than adjuvant immunotherapy. METHODS: In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma, in a 1:1 ratio, to receive two cycles of neoadjuvant ipilimumab plus nivolumab and then undergo surgery or to undergo surgery and then receive 12 cycles of adjuvant nivolumab. Only the patients in the neoadjuvant group who had a partial response or nonresponse received subsequent adjuvant treatment. The primary end point was event-free survival. RESULTS: A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of the patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% among patients in the neoadjuvant group who had a major pathological response, 76.1% among those who had a partial response, and 57.0% among those who had a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of the patients in the neoadjuvant group and in 14.7% in the adjuvant group. CONCLUSIONS: Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.).

The Importance of Practicing at Home During and Following Cognitive Behavioral Therapy for Childhood Anxiety Disorders: A Conceptual Review and New Directions to Enhance Homework Using Mhealth Technology.

Practicing newly acquired skills in different contexts is considered a crucial aspect of Cognitive Behavioral Therapy (CBT) for anxiety disorders (Peris et al. J Am Acad Child Adolesc Psychiatry 56:1043-1052, 2017; Stewart et al. Prof Psychol Res Pract 47:303-311, 2016). Learning to cope with feared stimuli in different situations allows for generalization of learned skills, and experiencing non-occurrence of the feared outcome helps in developing non-catastrophic associations that may enhance treatment outcomes (Bandarian-Balooch et al. J Behav Ther Exp Psychiatry 47:138-144, 2015; Cammin-Nowak et al. J Clin Psychol 69:616-629, 2013; Kendall et al. Cogn Behav Pract 12:136-148, 2005; Tiwari et al. J Clin Child Adolesc Psychol 42:34-43, 2013). To optimize treatment outcome, homework is often integrated into CBT protocols for childhood anxiety disorders during and following treatment. Nevertheless, practicing at home can be challenging, with low motivation, lack of time, and insufficient self-guidance often listed as reasons for low adherence (Tang and Kreindler, JMIR Mental Health 4:e20, 2017). This conceptual review provides an overview of (1) how existing CBT childhood programs incorporate homework, and empirical evidence for the importance of homework practice, (2) evidence-based key elements of practice, and (3) how mHealth apps could potentially enhance practice at home, including an example of the development and application of such an app. This review therefore sets the stage for new directions in developing more effective and engaging CBT-based homework programs for childhood anxiety disorders.

Fear-related associations in children of parents with an anxiety disorder.

BACKGROUND AND OBJECTIVES: Children of parents with an anxiety disorder are at elevated risk for developing an anxiety disorder themselves. According to cognitive theories, a possible risk factor is the development of schema-related associations. This study is the first to investigate whether children of anxious parents display fear-related associations and whether these associations relate to parental anxiety. METHODS: 44 children of parents with panic disorder, 27 children of parents with social anxiety disorder, and 84 children of parents without an anxiety disorder filled out the SCARED-71, and the children performed an Affective Priming Task. RESULTS: We found partial evidence for disorder-specificity: When the primes were related to their parent's disorder and the targets were negative, the children of parents with panic disorder and children of parents with social anxiety disorder showed the lowest error rates related to their parents' disorder, but they did not have faster responses. We did not find any evidence for the expected specificity in the relationship between the parents' or the children's self-reported anxiety and the children's fear-related associations, as measured with the APT. LIMITATIONS: Reliability of the Affective Priming Task was moderate, and power was low for finding small interaction effects. CONCLUSIONS: Whereas clearly more research is needed, our results suggest that negative associations may qualify as a possible vulnerability factor for children of parents with an anxiety disorder.

THE ADDED VALUE OF BLOOD GLUCOSE MONITORING IN HIGH-RISK INDIVIDUALS UNDERGOING PANCREATIC CANCER SURVEILLANCE.

OBJECTIVES: The study aimed to investigate the added value of blood glucose monitoring in high-risk individuals (HRIs) participating in pancreatic cancer surveillance. METHODS: HRIs with a CDKN2A/p16 germline pathogenic variant (PV) participating in pancreatic cancer surveillance were included in this study. Multivariable logistic regression was performed to assess the relationship between new-onset diabetes (NOD) and pancreatic ductal adenocarcinoma (PDAC). To quantify the diagnostic performance of NOD as a marker for PDAC, receiver operating characteristic curve with area under the curve (AUC) was computed. RESULTS: In total, 220 HRIs were included between 2000-2019. Median age was 61 (IQR 53-71) years and 62.7% of participants were female. During the study period, 26 (11.8%) HRIs developed NOD, of whom 5 (19.2%) later developed PDAC. The other 23 (82.1%) PDAC cases remained NOD-free. Multivariable analysis showed no statistically significant relationship between NOD and PDAC (OR 1.21; 95% CI, 0.39-3.78) and four out of five PDAC cases appeared to have NOD within three months before diagnosis. Furthermore, NOD did not differentiate between HRIs with- and without PDAC (AUC 0.54; 95% CI, 0.46-0.61). CONCLUSIONS: In this study we found no added value for longitudinal glucose monitoring in CDKN2A PV carriers participating in an imaging-based pancreatic cancer surveillance program.

Application of Single Cell Gene Expression Technologies to Neurotoxicology.

Neurotoxicological research faces the challenge of linking biological changes resulting from exposures to neuronal function. An additional challenge is understanding cell-type specific differences and selective vulnerabilities of distinct neuronal populations to toxic insults. Single cell RNA-sequencing (scRNA-seq) allows for measurement of the transcriptome of individual cells. This makes it a valuable tool for validating and characterizing cell types present in multicell type samples in complex tissue or cell culture models, but also for understanding how different cell types respond to toxic insults. Pathway analysis of differentially expressed genes can provide in depth insights into underlying cell type-specific mechanisms of neurotoxicity. Toxicological data often has to be translated to outcomes for human health which requires an understanding of inter-species differences. Transcriptomic data aids in understanding these differences, including understanding developmental timelines of different species. We believe that scRNA-seq holds exciting promises for future neurotoxicological research.

Neo-Adjuvant Therapy for Metastatic Melanoma.

Melanoma treatment is leading the neo-adjuvant systemic (NAS) therapy field. It is hypothesized that having the entire tumor in situ, with all of the heterogeneous tumor antigens, allows the patient's immune system to have a broader response to the tumor in all its shapes and forms. This translates into a higher clinical efficacy. Another benefit of NAS therapy potentially includes identifying patients who have a favorable response, which could offer an opportunity for the de-escalation of the extent of surgery and the need for adjuvant radiotherapy and/or adjuvant systemic therapy, as well as tailoring the follow-up in terms of the frequency of visits and cross-sectional imaging. In this paper, we will review the rationale for NAS therapy in resectable metastatic melanoma and the results obtained so far, both for immunotherapy and for BRAF/MEKi therapy, and discuss the response assessment and interpretation, toxicity and surgical considerations. All the trials that have been reported up to now have been investigator-initiated phase I/II trials with either single-agent anti-PD-1, combination anti-CTLA-4 and anti-PD-1 or BRAF/MEK inhibition. The results have been good but are especially encouraging for immunotherapies, showing high durable recurrence-free survival rates. Combination immunotherapy seems superior, with a higher rate of pathologic responses, particularly in patients with a major pathologic response (MPR = pathologic complete response [pCR] + near-pCR [max 10% viable tumor cells]) of 60% vs. 25-30%. The SWOG S1801 trial has recently shown a 23% improvement in event-free survival (EFS) after 2 years for pembrolizumab when giving 3 doses as NAS therapy and 15 as adjuvant versus 18 as adjuvant only. The community is keen to see the first results (expected in 2024) of the phase 3 NADINA trial (NCT04949113), which randomized patients between surgery + adjuvant anti-PD-1 and two NAS therapy courses of a combination of ipilimumab + nivolumab, followed by surgery and a response-driven adjuvant regimen or follow-up. We are on the eve of neo-adjuvant systemic (NAS) therapy, particularly immunotherapy, becoming the novel standard of care for macroscopic stage III melanoma.

Psychiatric assessment prior to and after switch from levetiracetam to brivaracetam.

PURPOSE: Brivaracetam is often used as an alternative to levetiracetam in patients with epilepsy (PWE) encountering efficacy issues or adverse events with levetiracetam. This study evaluated the psychological status of PWE who were switched from levetiracetam to brivaracetam due to psychiatric tolerability concerns in comparison to those who remained on levetiracetam. METHODS: We used various psychological assessments including the Symptom Checklist SCL-90-R, the Beck Depression Inventory-II, and the adverse event profile. Eligible participants completed the questionnaires at baseline and again 8 days later. Psychological changes were assessed using standard statistical methods to show differences between a group that immediately switched from levetiracetam to brivaracetam and another group with unchanged levetiracetam. RESULTS: Between May 2020 and May 2021, 63 patients participated in the study, of whom 34 switched from levetiracetam to brivaracetam. At baseline, participants who switched to brivaracetam had fewer antiseizure medications but experienced more monthly seizures. Baseline scores for anxiety (p = 0.020) and psychoticism (p = 0.046) on SCL-90-R in PWE switched to brivaracetam were higher than in the remaining group. In the subsequent assessment, all psychological scores were reduced and were no longer significantly different between both groups. Using multiple regression, initial treatment with a single antiseizure medication and male gender emerged as predictors of psychological improvement. CONCLUSION: Our study found no increased risk of adverse events or psychiatric symptoms after switching from levetiracetam to brivaracetam. Though statistically non-significant, a trend towards improved psychiatric outcomes in the switch group warrants further investigation in future trials with stronger designs for enhanced statistical power.

Physiological cell bioprinting density in human bone-derived cell-laden scaffolds enhances matrix mineralization rate and stiffness under dynamic loading.

Human organotypic bone models are an emerging technology that replicate bone physiology and mechanobiology for comprehensive in vitro experimentation over prolonged periods of time. Recently, we introduced a mineralized bone model based on 3D bioprinted cell-laden alginate-gelatin-graphene oxide hydrogels cultured under dynamic loading using commercially available human mesenchymal stem cells. In the present study, we created cell-laden scaffolds from primary human osteoblasts isolated from surgical waste material and investigated the effects of a previously reported optimal cell printing density (5 × 106 cells/mL bioink) vs. a higher physiological cell density (10 × 106 cells/mL bioink). We studied mineral formation, scaffold stiffness, and cell morphology over a 10-week period to determine culture conditions for primary human bone cells in this microenvironment. For analysis, the human bone-derived cell-laden scaffolds underwent multiscale assessment at specific timepoints. High cell viability was observed in both groups after bioprinting (>90%) and after 2 weeks of daily mechanical loading (>85%). Bioprinting at a higher cell density resulted in faster mineral formation rates, higher mineral densities and remarkably a 10-fold increase in stiffness compared to a modest 2-fold increase in the lower printing density group. In addition, physiological cell bioprinting densities positively impacted cell spreading and formation of dendritic interconnections. We conclude that our methodology of processing patient-specific human bone cells, subsequent biofabrication and dynamic culturing reliably affords mineralized cell-laden scaffolds. In the future, in vitro systems based on patient-derived cells could be applied to study the individual phenotype of bone disorders such as osteogenesis imperfecta and aid clinical decision making.

Two validation studies of a performance validity test for autistic adults.

In two studies we examined the potential of a simple emotion recognition task, the Morel Emotional Numbing Test (MENT), as a performance validity test (PVT) for autism-related cognitive difficulties in adulthood. The aim of a PVT is to indicate non-credible performance, which can aid the interpretation of psychological assessments. There are currently no validated PVTs for autism-related difficulties in adulthood. In Study 1, non-autistic university students (aged 18-46 years) were instructed to simulate that they were autistic during a psychological assessment (simulation condition; n = 26). These students made more errors on the MENT than those instructed to do their best (control condition; n = 26). In Study 2, we tested how well autistic adults performed on the MENT. We found that clinically diagnosed autistic adults and non-autistic adults (both n = 25; 27-57 years; IQ > 80) performed equally well on the MENT. Moreover, autistic adults made significantly fewer errors than the instructed simulators in Study 1. The MENT reached a specificity of ≥98% (identifying 100% of non-simulators as non-simulator in Study 1 and 98% in Study 2) and a sensitivity of 96% (identifying 96% of simulators as simulator). Together these findings provide the first empirical evidence for the validity of the MENT as a potential PVT for autism-related cognitive difficulties.

Interpretation biases in childhood spider fear: Content-specificity, priming, and avoidance.

BACKGROUND AND OBJECTIVES: The relation between fear and interpretation bias has been widely studied in children. However, much less is known about its content-specificity and how interpretation biases predict variance in avoidance. The current study examined different interpretation bias tasks, the role of priming and the ability of the interpretation bias tasks to predict spider fear-related avoidance behaviour. METHODS: 169 children with varying levels of spider fear performed a behavioural avoidance task, two versions of the Ambiguous Scenarios Task (AST; with and without priming), and a size and distance estimation task. RESULTS: Both versions of the AST and the size-estimation were significantly related to self-reported spider fear and avoidance. These relations were content-specific: children with higher levels of spider fear had a more negative interpretation bias related to spider-related materials than to other materials, and a more negative bias than children with lower levels of spider fear. Furthermore, self-reported spider fear, the AST with priming, and the size-estimation predicted unique variance in avoidance behaviour. LIMITATIONS: Children varied in their level of spider fear, but clinical diagnoses of spider phobia were not assessed. The participants of this study were not randomly selected, they were children of parents with panic disorder or social anxiety disorder or no anxiety disorder and could therefore partly be seen as children at risk. CONCLUSIONS: The results support cognitive models of childhood anxiety and indicate that both controlled and automatic processes play an important role in fear-related behaviour.

The factor structure and measurement invariance of the Autism Spectrum Quotient-28: A cross-cultural comparison between Malaysia and the Netherlands.

LAY ABSTRACT: The AQ-28 is a questionnaire measuring autistic traits, that is, traits that are related to Autism Spectrum Conditions, but its reliability in other cultures has not been thoroughly evaluated. We, therefore, tested whether the properties of the AQ-28 are comparable between two countries with different cultures, Malaysia and the Netherlands. A total of 437 Malaysian and 818 Dutch participants completed the AQ-28 online. We measured whether the AQ-28 measures autistic traits similarly in Malaysia and the Netherlands. The AQ-28 measures autistic traits similarly, and the reliability was acceptable and good in the general population of Malaysia and the Netherlands, respectively. However, Malaysians scored higher than Dutch participants. Moreover, 11 AQ-28 items showed cultural bias, indicating that these items are answered/interpreted differently in Malaysia and the Netherlands. Cross-cultural differences in interpreting, reporting, and/or expressing autistic traits highlighted in this study could potentially explain why some items are culturally biased and why Malaysians score higher on these items. The findings of this work imply that cutoff scores derived from one culture should not be generalised to another culture. Moreover, the findings are informative for future development of culturally neutral or appropriate screening and diagnostic tools for autism.

Intergenerational relations in childhood anxiety: A network approach.

OBJECTIVE: Family factors are assumed to play a central role in the development of childhood anxiety disorders. How child and parental anxiety symptoms are intertwined on a symptom and family level has not yet been examined. Such knowledge may lead to a more detailed understanding of the intergenerational relation in anxiety problems. The current study investigated the relation between anxiety in children and their parents at a symptom level using a network approach. METHOD: Parents of 1,452 clinically referred children in the Netherlands completed questionnaires on anxiety about their children and themselves. We examined relations on a symptom level both within persons and between parents and children. In addition, we also compared the relations between parental and child anxiety symptoms in families with children with an anxiety disorder (n = 350) versus families with children who displayed other psychiatric diagnoses (n = 1,102). RESULTS: Anxiety symptom relations within persons were more intertwined than the symptom relations between family members. Between-person relations were found among similar anxiety symptoms, suggesting specific intergenerational relations. The feeling of being fearful was found to be a central and connecting symptom in all family members (fathers, mothers, and children). The relations between parental and child anxiety symptoms were more specific (i.e., among similar symptoms) in families with children with an anxiety disorder than in families with children with other types of psychopathologies. CONCLUSIONS: This study found that anxiety symptom associations are present within the family on a detailed (symptom) level. This stresses the importance of future studies to examine factors responsible for this family-anxiety transmission.

Sources of stress among domestic and international students: a cross-sectional study of university students in Amsterdam, The Netherlands.

High perceived stress is associated with psychological and academic difficulties among college students. In this study, we aimed to investigate associations of student status (international vs domestic student in the Netherlands) with eight common sources of stress (i.e., financial, health, love life, relationship with family, relationship with people at work/ school, the health of loved ones, other problems of loved ones, and life in general). Participants were 2,196 college students (domestic: n = 1,642, international: n = 554) from two universities in Amsterdam, the Netherlands. Hierarchical linear regression analyses were used to estimate associations of student status with all eight sources of stress. Student status was significantly associated with higher levels of perceived stress in almost all life domains. International student status was significantly associated with higher perceived stress in the domains of financial situation and health of loved ones after adjusting for sociodemographic characteristics, depressive and anxiety symptoms, and other sources of stress. Findings highlight that several differences exist in the magnitude of perceived stress in certain areas between international and domestic students in the Netherlands. Consequently, it is essential to uncover the different needs of college students and develop specific strategies to deliver the most suitable services.

Use of tailoring features and reasons for dropout in a guided internet-based transdiagnostic individually-tailored cognitive behavioral therapy for symptoms of depression and/or anxiety in college students.

Transdiagnostic individually-tailored digital interventions reduce symptoms of depression and anxiety in adults with moderate effects. However, research into these approaches for college students is scarce and contradicting. In addition, the exact reasons for intervention dropout in this target group are not well known, and the use of individually-tailored intervention features, such as optional modules, has not yet been explored. The current study aimed to (1) investigate reasons for dropout from a guided internet-based transdiagnostic individually-tailored intervention for college students assessed in a randomized controlled trial (RCT) and (2) evaluate whether participants used tailoring features intended for their baseline symptoms. A sample of college students with mild to moderate depression and/or anxiety symptoms (n = 48) in the Netherlands (partially) followed a guided internet-based transdiagnostic individually-tailored intervention. We contacted those who did not complete the entire intervention (n = 29) by phone to report the reasons for intervention dropout. Further, we descriptively explored the use of tailoring features (i.e., depression versus anxiety trajectory) and optional modules of the intervention in the whole sample. We identified a range of person- and intervention-related reasons for intervention dropout, most commonly busy schedules, needs for different kinds of help, or absence of personal contact. Furthermore, only less than half of the participants used the individually-tailoring features to address the symptoms they reported as predominant. In conclusion, digital interventions clear about the content and targeted symptoms, tested in user research could prevent dropout and create reasonable expectations of the intervention. Participants would benefit from additional guidance when using tailoring features of digital interventions, as they often do not choose the tailoring features targeting their baseline symptoms.

Psychosocial issues of individuals undergoing surveillance for increased risk of melanoma and pancreatic cancer due to a germline CDKN2A variant: A focus group study.

Individuals with a germline CDKN2A pathogenic variant (PV) are at high risk of developing melanoma and pancreatic cancer and are therefore offered surveillance. The potential advantages and disadvantages associated with genetic testing and surveillance are discussed during medical counseling, although little is known about the associated psychosocial factors that are relevant to this population. This study sought to provide a qualitative exploration of psychosocial factors related to genetic testing and participation in skin and pancreatic surveillance in (potential) carriers of a CDKN2A PV. Fifteen individuals-both at-risk individuals and confirmed variant carriers-participated in one of the three online focus groups. Pre-defined discussion topics, including genetic testing, cancer surveillance, influence on lifestyle and family planning, were discussed. Patients reported that important reasons to engage in genetic testing included the possibility to participate in surveillance to gain control over their cancer risk and to get clarification on the potential carrier status of their children. We observed considerable differences in risk perception and experienced burden of surveillance. Knowledge of the PV has had a positive influence on lifestyle factors and altered attitudes toward life in some. Most participants were not aware of preimplantation genetic testing. This focus group study provided insight into a variety of psychosocial themes related to (potential) carriership of a CDKN2A PV. Future efforts should focus on identifying those who may benefit from additional psychosocial support, development of a centralized source of information, and assessing the knowledge, needs, and timing of counseling for family planning.