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22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1-weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source-based morphometry (SBM) pipeline (SS-Detect) to generate structural brain patterns (SBPs) that capture co-varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV-SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel-based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism.

Abstract Hallucinations can have rather heterogeneous aetiology and presentation. This inspired the concept of different subtypes based on symptom profiles, especially in the field of auditory hallucinations. As many people experience hallucinations in more than one sensory modality, it seems important to investigate potential hallucination subtypes across different sensory modalities. We assessed the content of hallucinations as part of a large survey among the general Dutch population (n = 10,448) using the Questionnaire for Psychotic Experiences. Based on their descriptions, thematic categories were created in a data-driven cluster analysis. 2594 participants who experienced hallucinations over the past week that contained at least 2 different thematic categories were selected. Clustering of their hallucination content was performed with the HDBSCAN method. We identified 4 clusters, i.e., subtypes, which can be typified as 1. hallucinations of foul odors, 2. complex visual scenes, 3. a vast variety of rather common hallucinations possibly related to heightened alertness, and 4. possibly bereavement hallucinations. The bereavement subtype showed an increase in emotional loneliness and the presence of delusions. Our findings suggest that the content of hallucinations can be informative, especially when investigated across sensory modalities. Such subtypes may help to better understand their underlying mechanisms.

Abstract Clinical outcomes after a first-episode of psychosis (FEP) are heterogeneous. Many patient-related factors such as gender and comorbidity have been studied to predict symptomatic outcomes. However, psychiatrist-related factors such as prescription behaviour and gender have received little attention. We assessed the relationship between patients’ psychiatrists, psychosis severity and daily functioning in 201 patients remitted from an FEP for a duration of one year, treated by 18 different psychiatrists. We controlled for baseline severity, dose and type of antipsychotic medication, frequency of visits, and patients’ education. Symptom severity, daily functioning, and antipsychotic drug use were assessed at baseline and at 3, 6, and, 12 months follow-up. We found that psychiatrists accounted for 9.1% of the explained variance in patients’ symptom severity and 10.1% of the explained variance in daily functioning.These effects persisted even when controlling for factors such as baseline severity and the prescribed dose. The effect of prescribed dose on symptom severity and daily functioning differed between psychiatrists. Treatment centre, session frequency, and medication nonadherence were not related to symptom severity. Our results emphasize the importance of individual psychiatrist factors in symptomatic outcomes after an FEP. Further identification of psychiatrist-related factors such as the quality of therapeutic alliances and shared decision-making, may optimize psychiatrists’ training with the goal of improving patient outcomes.

MilestoneTM herbicide contains the active substance propyzamide (500 g/L) and aminopyralid (5.3 g a.e./L) and is formulated as a suspension concentrate (SC). Registration for Milestone for the use in winter oilseed rape was granted in Germany in July 2014. The active substance propyzamide is well known from the product KerbTM FLO (containing 500 g/L propyzamide, suspension concentrate, SC) which is widely used in winter oilseed rape (WITTROCK et al., 2008). Aminopyralid is formulated in the commercial product Runway (clopyralid + picloram + aminopyralid). Milestone is applied with a use rate of 1.5 L/ha as a post-emergence herbicide from growth stage BBCH 14 of the crop at the beginning of November until February. Kerb FLO is applied with a use rate of 1.875 L/ha at the same timing. The efficacy of Milestone and Kerb FLO was tested in randomised and replicated plot trials in Germany, France and the United Kingdom. Milestone and Kerb FLO showed comparable and very high control levels against monocotyledonous species such as Alopecurus myosuroides, Apera spica-venti, Bromus species and volunteer cereals. Milestone shows a broader spectrum of activity vs. Kerb FLO against dicotyledonous weeds such as Matricaria chamomilla, Papaver rhoeas and Centaurea cyanus. The use of Milestone in dense crops (as the situation was in autumn 2014 for many areas in Germany) shows very high efficacy levels as well. The comparison of various application timings between end of October until beginning of December confirms the application date early November for best results. Milestone controls herbicide-resistant weed populations and can be considered an important part of a resistance management program not only in winter oilseed rape but as a component of an integrated weed management strategy in cropping systems.

Abstract Background Engagement and partnership with consumers and communities throughout research processes produces high quality research meeting community needs and promoting translation of research into improved policy and practice. Partnership is critical in research involving Aboriginal and/or Torres Strait Islander people (First Nations Peoples) to ensure cultural safety. We present lessons from the design, implementation and progress of the National Health and Medical Research Council funded INtravenous iron polymaltose for First Nations Australian patients with high FERRitin levels on hemodialysis (INFERR) clinical trial. Main body The trial was designed to understand the benefits and harms of iron therapy in First Nations Australians on haemodialysis with anaemia and hyperferritinaemia. The lack of evidence for treatment was discussed with patients who were potential participants. A key element ensuring safe conduct of the INFERR trial was the establishment of the Indigenous Reference Groups (IRGs) comprising of dialysis patients based in the Top End of Australia and Central Australia. Two IRGs were needed based on advice from First Nations communities and researchers/academics on the project regarding local cultural differences and approaches to trial conduct. The IRGs underpin culturally safe trial conduct by providing input into study materials and translating study findings into effective messages and policies for First Nations dialysis patients. Throughout the trial conduct, the IRGs’ role has developed to provide key mechanisms for advice and guidance regarding research conduct both in this study and more broadly. Support provided to the IRGs by trial First Nations Research Officers and independent First Nations researchers/academics who simplify research concepts is critical. The IRGs have developed feedback documents and processes to participants, stakeholders, and the renal units. They guarantee culturally safe advice for embedding findings from the trial into clinical practice guidelines ensuring evidence-based approaches in managing anaemia in haemodialysis patients with hyperferritinaemia. Conclusion Active consumer and community partnership is critical in research conduct to ensure research impact. Strong partnership with consumers in the INFERR clinical trial has demonstrated that First Nations Consumers will engage in research they understand, that addresses health priorities for them and where they feel respected, listened to, and empowered to achieve change.

Parents of infants and toddlers have expressed concerns that their children's social-emotional development has been affected by the COVID-19 pandemic. The purpose of this intrinsic case study was to gather information about parents' and caregivers' perspectives of experiences in a remote early childhood music class that incorporated explicit social-emotional instruction based on state learning standards. This study is a follow up to a previous intrinsic case study concerning parents' experiences in a remote early childhood music class. Families who chose to participate in synchronous online caregiver-child classes at a local community music school were invited to participate in interviews. Eight adults, representing seven enrolled families, chose to participate. Four themes arose from the interviews: (a) Pandemic and the Upheaval of Family Life, (b) The Experience of the Child in Remote Music Class, (c) The Role of the Parent in Remote Music Class, and (d) The Unpredictable World of Remote Music Class. We share implications for teaching and suggestions for future research.

Background Janus kinase inhibitors are an effective option for achieving sustained remission or low disease activity in patients with rheumatoid arthritis (RA) following inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs. Filgotinib is a Janus kinase 1–preferential inhibitor available in two doses for moderate-to-severe RA. We report the long-term efficacy and safety of filgotinib.Methods In the ongoing long-term extension study FINCH 4 (NCT03025308), patients continue filgotinib 200 mg or 100 mg from FINCH 1, 2 or 3 or receive filgotinib 200 mg or 100 mg de novo. Efficacy assessments up to week 156 include American College of Rheumatology 20% response (ACR20), Disease Activity Score 28 using C-reactive protein of

Abstract Background Autopsy work indicates that the widely-projecting noradrenergic pontine locus coeruleus (LC) is among the earliest regions to accumulate hyperphosphorylated tau, a neuropathological Alzheimer’s disease (AD) hallmark. This early tau deposition is accompanied by a reduced density of LC projections and a reduction of norepinephrine’s neuroprotective effects, potentially compromising the neuronal integrity of LC’s cortical targets. Previous studies suggest that lower magnetic resonance imaging (MRI)-derived LC integrity may signal cortical tissue degeneration in cognitively healthy, older individuals. However, whether these observations are driven by underlying AD pathology remains unknown. To that end, we examined potential effect modifications by cortical beta-amyloid and tau pathology on the association between in vivo LC integrity, as quantified by LC MRI signal intensity, and cortical neurodegeneration, as indexed by cortical thickness. Methods A total of 165 older individuals (74.24 ± 9.72 years, ~ 60% female, 10% cognitively impaired) underwent whole-brain and dedicated LC 3T-MRI, Pittsburgh Compound-B (PiB, beta-amyloid) and Flortaucipir (FTP, tau) positron emission tomography. Linear regression analyses with bootstrapped standard errors (n = 2000) assessed associations between bilateral cortical thickness and i) LC MRI signal intensity and, ii) LC MRI signal intensity interacted with cortical FTP or PiB (i.e., EC FTP, IT FTP, neocortical PiB) in the entire sample and a low beta-amyloid subsample. Results Across the entire sample, we found a direct effect, where lower LC MRI signal intensity was associated with lower mediolateral temporal cortical thickness. Evaluation of potential effect modifications by FTP or PiB revealed that lower LC MRI signal intensity was related to lower cortical thickness, particularly in individuals with elevated (EC, IT) FTP or (neocortical) PiB. The latter result was present starting from subthreshold PiB values. In low PiB individuals, lower LC MRI signal intensity was related to lower EC cortical thickness in the context of elevated EC FTP. Conclusions Our findings suggest that LC-related cortical neurodegeneration patterns in older individuals correspond to regions representing early Braak stages and may reflect a combination of LC projection density loss and emergence of cortical AD pathology. This provides a novel understanding that LC-related cortical neurodegeneration may signal downstream consequences of AD-related pathology, rather than being exclusively a result of aging.

Carlo Mümmler,1 Pontus Mertsch,1 Michaela Barnikel,1 Frank Haubner,2 Ulf Schönermarck,3 Ulrich Grabmaier,4 Hendrik Schulze-Koops,5 Jürgen Behr,1 Nikolaus Kneidinger,1,6 Katrin Milger1 1Department of Medicine V, LMU University Hospital, LMU Munich, Comprehensive Pneumology Center, Member of the German Center of Lung Research (DZL), Munich, Germany; 2Department of Otorhinolaryngology, LMU University Hospital, LMU Munich, Munich, Germany; 3Division of Nephrology, Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany; 4Department of Medicine I, LMU University Hospital, LMU Munich, Munich, Germany; 5Division of Rheumatology and Clinical Immunology, Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany; 6Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, AustriaCorrespondence: Katrin Milger, Department of Medicine V, LMU University Hospital, Marchioninistr, 15, LMU Munich, Munich, 81377, Germany, Tel +49-89-4400-73071, Email Katrin.Milger@med.uni-muenchen.deBackground: Benralizumab reduces exacerbations and long-term oral glucocorticosteroid (OCS) exposure in patients with severe eosinophilic asthma. In patients with eosinophilic granulomatosis with polyangiitis (EGPA), uncontrolled symptoms and exacerbations of asthma and chronic rhinosinusitis (CRS) are important reasons for continued OCS therapies. We aimed to describe outcomes of patients with severe asthma and EGPA treated with benralizumab in real-life.Methods: We retrospectively analyzed adult patients from the Severe Asthma Unit at LMU Munich diagnosed with severe asthma and EGPA treated with benralizumab, differentiating two groups: Group A, patients with a stable daily OCS dose and diagnosis of EGPA > 6 months ago; and Group B, patients treated with high-dose daily OCS due to recent diagnosis of EGPA < 6 months ago. We compared outcome parameters at baseline and 12 months after initiation of benralizumab, including respiratory exacerbations, daily OCS dose, and lung function.Results: Group A included 17 patients, all receiving OCS therapy and additional immunosuppressants; 15 patients (88%) continued benralizumab for more than 12 months, demonstrating a significant reduction in daily OCS dose and exacerbations while FEV1 increased. Group B included 9 patients, all with high-dose daily OCS and some receiving cyclophosphamide pulse therapy for life-threatening disease. Benralizumab addition during induction was well tolerated. A total of 7/9 (78%) continued benralizumab for more than 12 months and preserved EGPA remission at the 12-month timepoint.Conclusion: In this real-life cohort of patients with severe asthma and EGPA, benralizumab initiation during remission maintenance reduced respiratory exacerbations and daily OCS dose. Benralizumab initiation during remission induction was associated with a high rate of clinical EGPA remission.Keywords: EGPA, asthma, CRS, vasculitis, glucocorticoid, OCS, anti-IL5R, biologics, benralizumab

Abstract Characterising how the totality of primate diversity is distributed across the order, and how it evolved, is challenging because diversity in individual traits often show opposing phylogenetic patterns. A species’ combination of traits can be conceptualised as its ‘niche’. Here, we describe and analyse seven-dimensional niche space, comprising 11 traits, for 191 primate species. Multifaceted diversity is distributed unequally among taxonomic groups. Cercopithecoidea and Hominidae occupy the largest areas of niche space, and are the most diverse families; platyrrhine families occupy small areas, and this space overlaps with strepsirrhines. The evolution of species’ locations in niche space is regulated by selection for adaptive optima in trait combinations. Given that niche similarity results in interspecific competition, we quantify two measures of species’ niche locations relative to others. We find that omnivores, frugivores, and species tolerating higher temperatures experience stronger interspecific competition. Hominidae occupation of niche space suggests competitive exclusion from niches by Cercopithecoidea over evolutionary time; but living great apes experience the lowest levels of interspecific competition. Callitrichids experience the highest levels of interspecific competition. Our results provide a standardised measure of primate niches that sheds light on the partitioning and evolution of primate diversity, and how this is driven by interspecific competition.

Abstract Background Holistic housing renovations combine physical housing improvements with social and socioeconomic interventions (e.g. referral to social services, debt counselling, involvement in decision-making, promoting social cohesion). In a deprived neighbourhood in Utrecht, the Netherlands, this paper examined residents’ and professionals’ experiences, ideas, and perceptions regarding holistic housing renovation, its health effects, and underlying mechanisms explaining those effects. Methods Semi-structured in-depth interviews were conducted with 21 social housing residents exposed to holistic housing renovation, and 12 professionals involved in either the physical renovation or social interventions implemented. Residents were interviewed in various renovation stages (before, during, after renovation). Transcripts were deductively and inductively coded using qualitative software. Results Residents experienced and professionals acknowledged renovation stress caused by nuisance from construction work (noise, dust), having to move stuff around, and temporary moving; lack of information and control; and perceived violation of privacy. Involvement in design choices was appreciated, and mental health improvement was expected on the long term due to improved housing quality and visual amenity benefits. Social contact between residents increased as the renovation became topic for small talk. Few comments were made regarding physical health effects. The interviews revealed a certain amount of distrust in and dissatisfaction with the housing corporation, construction company, and other authorities. Conclusions Renovation stress, aggravated by lack of information and poor accessibility of housing corporation and construction company, negatively affects mental health and sense of control. Potential stress relievers are practical help with packing and moving furniture, and increased predictability by good and targeted communication. Social interventions can best be offered after renovation, when residents live in their renovated apartment and the nuisance and stress from the renovation is behind them. Social partners can use the period leading up to the renovation to show their faces, offer practical help to reduce renovation stress, and increase residents’ trust in their organization and authorities in general. This might also contribute to residents’ willingness to accept help with problems in the social domain after renovation.

For correct allergen risk management by industry, retail and food safety authorities, sensitive and reliable fast allergen detection methods are required, even more when precautionary allergen labelling based on reference doses will be implemented in legislation.This study aimed to perform a comparative assessment of three commercially available quantitative or qualitative test kits, for DNA analysis of celery in food products. Five product groups, representing different sectors of the AOAC food-matrix triangle, being (plant-based) meat products, snacks, sauces, dried herbs and spices, and smoothies, were identified to potentially contain celery. From each group, blank and incurred (labelled to contain celery) food products were selected, of which the blank food products were additionally spiked with low protein levels of celery prior to qPCR assessment.Results show that the assessed test kits perform according to their specifications, however, a clear influence of the matrix on the detection ability of celery was observed. In addition, quantification of the amount of celery in the different food products showed to be challenging in all food product groups using the two quantification kits.

Habitat sensitivity is a consideration for decision-making under environmental laws in many jurisdictions. However, habitat sensitivity has been variously defined and there is no consistent approach to its quantification, which limits our understanding of how habitat sensitivity varies among systems and in response to different pressures. We review various definitions offered in the scientific literature and policy documents before suggesting a universal framework for habitat sensitivity as (i) a habitat trait that defines the ecological impacts from a given pressure, (ii) which is composed of three components (habitat resistance, resilience, and recoverability), and (iii) which is quantified by measuring the change and recovery in the state of key habitat attributes in response to pressures. In addition, we provide guidance toward a consistent approach to assessing habitat sensitivity, which includes the use of pressure benchmarks and standardized metrics of change in key habitat attributes to create a common scale for comparison among habitat attributes and pressures. Our framework and recommendations should help to standardize the way in which habitat sensitivity is defined and assessed, and could be integrated into decision-making processes to improve ecosystem management in different jurisdictions.