Objectives: Pseudarthrosis after mandibular reconstruction leads to chronic overload of the osteosynthesis and impedes dental rehabilitation. This study evaluates the impact of gap site on osseous union in mandible reconstruction using a new volumetric analysis method with repeated cone-beam computed tomography (CBCT).

Methods: The degree of bone regeneration was evaluated in 16 patients after mandible reconstruction with a fibula free flap and patient-specific reconstruction plates. Percentual bone volume and width changes in intersegmental gaps were retrospectively analyzed using a baseline CBCT in comparison to a follow-up CBCT. Patients’ characteristics, plate-related complications, and gap sites (anterior/posterior) were analyzed. Detailed assessments of both gap sites (buccal/lingual/superior/inferior) were additionally performed.

Results: Intersegmental gap width (p = 0.002) and site (p < 0.001) significantly influence bone volume change over two consecutive CBCTs. An initial larger gap width resulted in a lower bone volume change. In addition, anterior gaps showed significantly less bone volume changes. Initial gap width was larger at posterior segmental gaps (2.97 vs 1.65 mm, p = 0.017).

Conclusions: A methodology framework has been developed that allows to quantify pseuarthrosis in reconstructed mandibles using CBCT imaging. The study identifies the anterior segmental gap as a further risk factor for pseudarthrosis in reconstructions with CAD/CAM reconstruction plates. Future research should evaluate whether this outcome is related to the biomechanics induced at this site.

Objective Specialized literature has identified a need for evidence-based, low-threshold, short-term, and intracultural psychological interventions that can be made available to migrants, including refugees, who suffer from psychological symptoms in host countries. The objective of the present study is to measure the efficacy of value-based counselling (VBC) as such an intervention.

Method We conducted a pragmatic, rater-blinded randomized controlled trial employing a pre-post control group design to assess the efficacy of VBC based on a study sample of 103 migrants, including refugees, who resided in Germany at the time. A set of instruments was used to evaluate primary outcome measures of depression, posttraumatic stress disorder (PTSD) symptoms, perceived stress, generalized anxiety, and somatic complaints.

Results Per protocol analysis included 42 participants in the VBC group, and 43 in the waiting list. Compared with participants in the waiting-list group, the VBC group, following an average of four counselling sessions, experienced a clinically meaningful reduction of depression (adjusted difference 7.06, 95% CI [4.86, 9.26], effect size 0.68, p < .001), PTSD (adjusted difference 17.15, 95% CI [10.49, 23.81], effect size 0.76, p < .001), perceived stress (adjusted difference 9.25, 95% CI [6.23, 12.27], effect size 0.75, p < .001), anxiety (adjusted difference 5.34, 95% CI [3.47, 7.20], effect size 0.70, p < .001), and somatic complaints (adjusted difference 5.52, 95% CI [3.30, 7.74], effect size 0.72, p < .001). The positive outcomes were maintained at 3-month follow-up. Utilization of mental health services was significantly reduced at the 3-month follow-up conducted with participants of the VBC group.

Conclusions VBC, a culturally sensitive and strength-based mental health service, is an effective short-term intervention which meets the specific mental health needs of migrants, including refugees.

Objective This systematic review evaluated the effectiveness of soft tissue augmentation procedures for complete coverage and mean coverage of buccal soft tissue dehiscence (BSTD) in patients with implant-supported restorations.

Methods Three databases were surveyed for randomized (RCTs), non-randomized controlled clinical trials (CCTs), cohort studies, case–control studies, and case series with a minimum of five patients per control or test group. Studies dealing with soft tissue augmentation procedures to cover BSTD—occurring during implant function and not due to the result of peri-implantitis—were included. Risk of bias was evaluated with RoB 2 or the National Institutes of Health's Quality Assessment. Whenever possible, exploratory meta-analyses were performed to evaluate weighted mean effects (WME) for the different outcomes. The primary outcomes were the percentage of complete coverage and mean coverage of BSTD.

Results Seven articles were included. Only one study was a RCT, with a high risk of bias. Meta-analyses showed that after 1 year (2 studies, n = 36 patients; WME = 70; 95% confidence interval [CI] = 50; 90; p = .23) as well as after 5 years (3 studies, n = 54 patients; WME = 70; 95%; CI = 60; 80; p = .44), complete coverage of BSTD could be achieved in 70% of the cases.

Conclusion Based on limited evidence, it can be concluded that BSTD can be substantially reduced with the use of soft tissue augmentation procedures. Further research with comparative trials using larger samples and longer follow-up periods is needed to study the stability of soft tissues in the long term.

Known hereditary human diseases featuring impaired copper trafficking across cellular membranes involve ATP7A (Menkes disease, occipital horn disease, X-linked spinal muscular atrophy type 3) and ATP7B (Wilson disease). Herein, we report a newborn infant of consanguineous parents with a homozygous pathogenic variant in a highly conserved sequence of SLC31A1, coding for the copper influx transporter 1, CTR1. This missense variant, c.236T > C, was detected by whole exome sequencing. The infant was born with pulmonary hypoplasia and suffered from severe respiratory distress immediately after birth, necessitating aggressive mechanical ventilation. At 2 weeks of age, multifocal brain hemorrhages were diagnosed by cerebral ultrasound and magnetic resonance imaging, together with increased tortuosity of cerebral arteries. Ensuing seizures were only partly controlled by antiepileptic drugs, and the infant became progressively comatose. Laboratory investigations revealed very low serum concentrations of copper and ceruloplasmin. No hair shaft abnormalities were detected by dermatoscopy or light microscopic analyses of embedded hair shafts obtained at 4 weeks of life. The infant died after redirection of care and elective cessation of invasive mechanical ventilation at 1 month of age. This case adds SLC31A1 to the genes implicated in severe hereditary disorders of copper transport in humans.

Background Patients with atopic dermatitis (AD) frequently use acupuncture (ACU) and osteopathic medicine (OM), although their therapeutic benefits are unclear.

Aim To investigate the effectiveness of ACU and OM in patients with AD.

Methods In a three‐armed, single‐centre, randomized controlled open explorative clinical trial, adult patients with AD received ACU, OM or no study intervention (control group; CG) plus routine care. Outcomes included disease severity (SCORing Atopic Dermatitis; SCORAD), itching intensity (visual analogue scale; VAS), frequency of topical corticosteroid (TCS) use over 7 days and cost‐effectiveness. Endpoints were analysed by analysis of covariance adjusted for the respective baseline value and TCS use.

Results Overall, 121 patients (92 women, 29 men) with a mean ± SD age of 31.4 ± 10.5 years were randomized. After 12 weeks, the adjusted means (95% CI) for ACU, OM and control were, respectively, 22.3 (18.3–26.3), 26.4 (22.6–30.2) and 23.7 (19.9–27.5) for SCORAD (P = 0.32); 27.9 (19.5–36.4), 35.0 (26.9–43.0) and 42.3 (34.7–50.0) for VAS itching (P < 0.05); and 2.3 (0.8–3.9), 1.9 (0.4–3.5) and 4.3 (2.6–6.0), for TCS use (P = 0.10). ACU and OM were not cost‐effective compared with the CG.

Conclusion Although no differences in disease severity were found, our findings indicate that ACU might reduce itching in patients with AD. Furthermore, ACU and OM showed a trend towards reducing TCS use.

The impact on health-related quality of life (HRQL) plays a key role for patients suffering from allergies and anaphylaxis. In this narrative review we review the HRQL in allergic patients suffering from food and venom allergy, both being the most frequent elicitors of severe allergic, potential life-threatening reactions and provide an overview on the current knowledge and identified gaps.

The data show that for food and venom allergy standardized assessment tools to measure HRQL are available and have been successfully applied. Our analysis shows that multiple factors can modulate HRQL in these patient groups. These include sociodemographic data like patients' age and sex, fear of accidental reactions but also external factors like the social environment and the appreciation of the seriousness of the condition by others. External factors may have a significant impact on HRQL and should be considered in patient-related outcome assessments to avoid biased measurements possibly affecting the results. The assessment of the quality of life in the context of specific immunotherapy should consider lifestyle factors and ideally, the individual change in HRQL should be measured.

Although there are many data indicating a negative impact on HRQL in food allergic children and their caregivers, limited data are existing from adults with food allergy and venom allergic patients from all age groups. Also, the use of standardized questionnaires should be extended to allow for a better comparability of results between studies. Therefore, translation to additional languages is necessary.

Taken together, the eliciting allergen, the severity of the allergic disease but moreover multiple external factors impact the outcome in HRQL and should be considered in HRQL assessment.

In patients with hereditary angioedema (HAE), bradykinin causes swelling episodes by activating bradykinin B-2 receptors. Icatibant, a selective bradykinin B-2 receptor antagonist, is approved for on-demand treatment of HAE attacks. The Icatibant Outcome Survey (IOS; NCT01034969) is an ongoing observational registry initiated in 2009 to monitor the effectiveness/safety of icatibant in routine clinical practice. As of March 2019, 549 patients with HAE type 1 or 2 from the IOS registry had been treated of 5995 total attacks. This article reviews data published from IOS over time which have demonstrated that the effectiveness of icatibant in a real-world setting is comparable to efficacy in clinical trials; one dose is effective for the majority of attacks; early treatment (facilitated by self-administration) leads to faster resolution and shorter attack duration; effectiveness/safety of icatibant has been shown across a broad range of patient subgroups, including children/adolescents and patients with HAE with normal C1 inhibitor levels; and tolerability has been demonstrated in patients aged >= 65 years. Additionally, this review highlights how IOS data have provided valuable insights into patients' diagnostic journeys and treatment behaviours across individual countries. Such findings have helped to inform clinical strategies and guidelines to optimise HAE management and limit disease burden.

Background Food allergy is a growing health concern with a prevalence of 2%–3% in the adult population in Europe. Non-immune-mediated food hypersensitivities, which include reactions after ingestion of food additives, affect 1% of adults and may resemble IgE-induced allergic reactions without identifiable immunologic sensitization. A double-blind placebo-controlled food challenge (DBPCFC) is the gold standard for the diagnosis of any food hypersensitivity.

Objective We analysed a large group of adult patients with suspected food hypersensitivity, who had undergone DBPCFC, to better understand IgE-mediated food allergy and non-immune-dependent food hypersensitivity to food additives in adults regarding elicitors, symptoms and positivity rates of oral challenges.

Methods Data from 541 patients with suspected food hypersensitivity were analysed, who underwent an oral food challenge between 2010 and 2019.

Results IgE-dependent food allergy was confirmed in 114 of 329 adult patients (34.6%). The confirmation rate was lower in the group of patients with suspected non-immune-mediated reactions to food additives (65 of 286, 22.7%). Urticaria and angioedema appeared more frequently in patients with IgE-mediated food allergies. By contrast, flush and diarrhoea were the most frequent symptoms after a challenge in the group with the non-immune-mediated reactions to food additives. Wheat and celery were the most frequently identified food allergens in adults, whereas colourings and preservatives were the most frequent elicitors of non-immune-mediated food hypersensitivity.

Conclusion The importance of oral food challenges for the diagnosis of food hypersensitivity is confirmed. IgE-dependent food allergy is more frequently proven, reaching a positivity rate of one-third and only about 20% for non-immune-mediated hypersensitivity. Future studies should elaborate on the mechanisms of non-immune-mediated food hypersensitivity and the clinical impact of cofactors in this setting.

Background Only a small number of apps addressing allergic rhinitis (AR) patients have been evaluated. This makes their selection difficult. We aimed to introduce a new approach to market research for AR apps, based on the automatic screening of Apple App and Google Play stores.

Methods A JavaScript programme was devised for automatic app screening, and applied in a market assessment of AR self-management apps. We searched the Google Play and Apple App stores of three countries (USA, UK and Australia) with the following search terms: "hay fever", "hayfever", "asthma", "rhinitis", "allergic rhinitis". Apps were eligible if symptoms were evaluated. Results obtained with the automatic programme were compared to those of a blinded manual search. As an example, we used the search to assess apps that can be used to design a combined medication score for AR.

Results The automatic search programme identified 39 potentially eligible apps out of a total of 1593 retrieved apps. Each of the 39 apps was individually checked, with 20 being classified as relevant. The manual search identified 19 relevant apps (out of 6750 screened apps). Combining both methods, a total of 21 relevant apps were identified, pointing to a sensitivity of 95% and a specificity of 99% for the automatic method. Among these 21 apps, only two could be used for the combined symptom-medication score for AR.

Conclusions The programmed algorithm presented herein is able to continuously retrieve all relevant AR apps in the Apple App and Google Play stores, with high sensitivity and specificity. This approach has the potential to unveil the gaps and unmet needs of the apps developed so far.

Background There is substantial heterogeneity between trial outcomes in pressure ulcer prevention research. The development of core outcome sets is one strategy to improve comparability between trial results and thus increase the quality of evidence.

Objectives To identify core outcomes for pressure ulcer prevention trials.

Methods A workshop was held with service users to discuss their views and understanding of the outcomes identified by a scoping review and to identify any missing outcomes. In a next step, a Delphi survey comprising three rounds was conducted to evaluate a compiled list of outcomes by their importance. Afterwards the preselection from the Delphi survey was discussed in a virtual consensus meeting with the aim of agreeing on a final set of core outcomes. Individuals who had completed all three rounds of the Delphi survey were eligible to participate in this meeting. Participants included practitioners, service users, researchers and industry representatives. The OUTPUTs project is registered in the COMET database and is part of the Cochrane Skin Core Outcome Set Initiative.

Results The workshop did not reveal any missing outcomes, but highlighted the need for further efforts to make lay people understand what an outcome is in a study setting. The Delphi survey took place between December 2020 and June 2021. After the three rounds, 18 out of 37 presented outcomes were rated to be critically important. In the following consensus meeting, six outcomes were prioritized to be included in the core outcome set for pressure ulcer prevention trials: (i) pressure ulcer occurrence; (ii) pressure ulcer precursor signs and symptoms; (iii) mobility; (iv) acceptability and comfort of intervention; (v) adherence/compliance; and (vi) adverse events/safety.

Conclusions Based on a comprehensive list of outcomes in pressure ulcer prevention research, there was clear agreement on the six identified core outcomes in three international Delphi rounds and in the consensus meeting. Although outcome measurement instruments need to be identified next, the six identified core outcomes should already be considered in future trials, as service users, practitioners, researchers and industry representatives have agreed that they are critically important.

Background Melasma is a common dermatological condition. Although its relevance as a skin condition is primarily of a cosmetic nature, it may affect the patient’s wellbeing and quality of life. A broad range of treatment options is available, which makes it difficult to choose the most appropriate of those treatments.

Objectives To summarize and critically appraise evidence from investigator‐blinded randomized controlled trials (RCTs) on the efficacy and safety of self‐applied topical interventions for melasma.

Methods We systematically searched MEDLINE and the Cochrane CENTRAL trials database for RCTs on topical, self‐administered interventions for patients diagnosed with melasma. Eligibility was limited to RCTs that explicitly stated in their methods section (i) how they generated the random allocation sequence, and (ii) that the study outcome assessor was blinded to the participants’ group allocation. Outcomes of interest included evaluator‐assessed clinical scores (such as the Melasma Area and Severity Index), quality of life and patient‐reported outcomes, as well as safety outcomes. The study findings were meta‐analysed, pooling data from studies on the same comparisons, if this was possible. We assessed confidence in effect estimates using the GRADE approach.

Results Our searches yielded 1078 hits. We included 36 studies reporting on 47 different comparisons of interventions. These included medical treatments such as ‘triple combination cream’ (TCC), over‐the‐counter cosmetic and herbal products, as well as sun creams covering different light spectra. Pooling data was possible for only two comparisons, topical tranexamic acid (TXA) vs. hydroquinone (HQ) and cysteamine vs. placebo. Direct comparisons were available for a variety of interventions; however, the reported outcomes varied greatly. Overall, our confidence in the effect estimates ranged from very low to high.

Conclusions Our findings indicate that TCC and its individual components HQ and tretinoin are effective in lightening melasma. Besides these established self‐applied treatment options, we identified further medical treatments as well as promising cosmetic and herbal product treatment approaches. Furthermore, evidence suggests that using broad‐spectrum sunscreen covering both the visible and ultraviolet‐light spectrum enhances the treatment efficacy of HQ. However, with mostly small RCTs comparing treatments directly using a broad range of outcomes, further research is needed to draw conclusions about which treatment is most effective.

Aims Research ethics committees and regulatory agencies assess whether the benefits of a proposed early-stage clinical trial outweigh the risks based on preclinical studies reported in investigator's brochures (IBs). Recent studies have indicated that the reporting of preclinical evidence presented in IBs does not enable proper risk-benefit assessment. We interviewed different stakeholders (regulators, research ethics committee members, preclinical and clinical researchers, ethicists, and metaresearchers) about their views on measures to increase the completeness and robustness of preclinical evidence reporting in IBs.

Methods This study was preregistered (https://osf.io/nvzwy/). We used purposive sampling and invited stakeholders to participate in an online semistructured interview between March and June 2021. Themes were derived using inductive content analysis. We used a strengths, weaknesses, opportunities and threats matrix to categorize our findings.

Results Twenty-seven international stakeholders participated. The interviewees pointed to several strengths and opportunities to improve completeness and robustness, mainly more transparent and systematic justifications for the included studies. However, weaknesses and threats were mentioned that could undermine efforts to enable a more thorough assessment: The interviewees stressed that current review practices are sufficient to ensure the safe conduct of first-in-human trials. They feared that changes to the IB structure or review process could overburden stakeholders and slow drug development.

Conclusion In principle, more robust decision-making processes align with the interests of all stakeholders and with many current initiatives to increase the translatability of preclinical research and limit uninformative or ill-justified trials early in the development process. Further research should investigate measures that could be implemented to benefit all stakeholders.

Introduction A positive childbirth experience promotes women’s health, both during and beyond the perinatal period. Understanding what constitutes a positive childbirth experience is thus critical to providing high-quality maternity care. Currently, there is no clear, inclusive, woman-centered definition of a positive childbirth experience to guide practice, education, and research.

Aim To formulate an inclusive woman-centered definition of a positive childbirth experience.

Methods A six-step process was undertaken: (a) Key concepts associated with a positive childbirth were derived from a rapid literature review; (b) The key concepts were used by interdisciplinary experts in the author group to create a draft definition; (c) The draft definition was presented to clinicians and researchers during a European research meeting on perinatal mental health; (d) The authors integrated the expert feedback to refine the working definition; (e) A revised definition was shared with women from consumer groups in six countries to confirm its face validity; and (f) A final definition was formulated based on the women’s feedback (n = 42).

Results The following definition was formulated: “A positive childbirth experience refers to a woman’s experience of interactions and events directly related to childbirth that made her feel supported, in control, safe, and respected; a positive childbirth can make women feel joy, confident, and/or accomplished and may have short and/or long-term positive impacts on a woman’s psychosocial well-being.”

Conclusions This inclusive, woman-centered definition highlights the importance of provider interactions for facilitating a positive childbirth experience. Feeling supported and having a sense of control, safety, and respect are central tenets. This definition could help to identify and validate positive childbirth experience(s), and to inform practice, education, research, advocacy, and policy-making.

Introduction Many women experience giving birth as traumatic. Although women's subjective experiences of trauma are considered the most important, currently there is no clear inclusive definition of a traumatic birth to help guide practice, education, and research.

Aim To formulate a woman-centered, inclusive definition of a traumatic childbirth experience.

Methods After a rapid literature review, a five-step process was undertaken. First, a draft definition was created based on interdisciplinary experts’ views. The definition was then discussed and reformulated with input from over 60 multidisciplinary clinicians and researchers during a perinatal mental health and birth trauma research meeting in Europe. A revised definition was then shared with consumer groups in eight countries to confirm its face validity and adjusted based on their feedback.

Results The stepwise process confirmed that a woman-centered and inclusive definition was important. The final definition was: “A traumatic childbirth experience refers to a woman's experience of interactions and/or events directly related to childbirth that caused overwhelming distressing emotions and reactions; leading to short and/ or long-term negative impacts on a woman's health and wellbeing.”

Conclusions This definition of a traumatic childbirth experience was developed through consultations with experts and consumer groups. The definition acknowledges that low-quality provider interactions and obstetric violence can traumatize individuals during childbirth. The women-centered and inclusive focus could help women to identify and validate their experiences of traumatic birth, offering benefits for practice, education, and research, as well as for policymaking and activism in the fields of perinatal mental health and respectful maternity care.

Any experiment involving living organisms requires justification of the need and moral defensibleness of the study. Statistical planning, design, and sample size calculation of the experiment are no less important review criteria than general medical and ethical points to consider. Errors made in the statistical planning and data evaluation phase can have severe consequences on both results and conclusions. They might proliferate and thus impact future trials-an unintended. outcome of fundamental research with profound ethical consequences. Unified statistical standards are currently missing for animal review boards in Germany. In order to accompany, we developed a biometric form to be filled and handed in with the proposal at the concerned local authority on animal welfare. It addresses relevant points to consider for biostatistical planning of animal experiments and can help both the applicants and the reviewers in overseeing the entire experiment(s) planned. Furthermore, the form might also aid in meeting the current standards set by the 3+3R's principle of animal experimentation: Replacement, Reduction, Refinement as well as Robustness, Registration, and Reporting. The form has already been in use by the concerned local authority of animal welfare in Berlin, Germany. In addition, we provide reference to our user guide giving more detailed explanation and examples for each section of the biometric form. Unifying the set of biostatistical aspects will help both the applicants and the reviewers to equal standards and increase quality of preclinical research projects, also for translational, multicenter, or international studies.

Background and Aims: Nucleotide‐binding oligomerization domain‐like receptor‐family pyrin domain‐containing 3 (NLRP3) inflammasome activation has been shown to result in liver fibrosis. Mechanisms and downstream signaling remain incompletely understood. Here, we studied the role of IL‐18 in hepatic stellate cells (HSCs), and its impact on liver fibrosis.

Approach and Results: We observed significantly increased serum levels of IL‐18 (128.4 pg/ml vs. 74.9 pg/ml) and IL‐18 binding protein (BP; 46.50 ng/ml vs. 15.35 ng/ml) in patients with liver cirrhosis compared with healthy controls. Single cell RNA sequencing data showed that an immunoregulatory subset of murine HSCs highly expresses Il18 and Il18r1. Treatment of cultured primary murine HSC with recombinant mouse IL‐18 accelerated their transdifferentiation into myofibroblasts. In vivo, IL‐18 receptor‐deficient mice had reduced liver fibrosis in a model of fibrosis induced by HSC‐specific NLRP3 overactivation. Whole liver RNA sequencing analysis from a murine model of severe NASH‐induced fibrosis by feeding a choline‐deficient, L‐amino acid‐defined, high fat diet showed that genes related to IL‐18 and its downstream signaling were significantly upregulated, and Il18−/− mice receiving this diet for 10 weeks showed protection from fibrotic changes with decreased number of alpha smooth muscle actin‐positive cells and collagen deposition. HSC activation triggered by NLRP3 inflammasome activation was abrogated when IL‐18 signaling was blocked by its naturally occurring antagonist IL‐18BP. Accordingly, we observed that the severe inflammatory phenotype associated with myeloid cell‐specific NLRP3 gain‐of‐function was rescued by IL‐18BP.

Conclusions: Our study highlights the role of IL‐18 in the development of liver fibrosis by its direct effect on HSC activation identifying IL‐18 as a target to treat liver fibrosis.

Background We describe here the first patient with recurrent hemolysis related to disinfectant containing silver nanoparticles (AgNps).

Methods A 58-year-old chemist repeatedly experienced DAT-negative (Coombs-negative) hemolysis during the last 5 years. He was treated with a number of immunosuppressive drugs including 18 times rituximab. The attempt to treat him with cyclosporine A served only to increase the rate of hemolysis. Only by chance, we revealed that the patient regularly used a hand disinfectant containing AgNps. Serological testing was performed using standard techniques. Eryptosis was measured by binding annexin to exposed phosphatidylserine (PS) of the circulating red blood cells (RBCs).

Results Antiglobulin tests remained negative, and PS exposing RBCs were detected two times during the last hemolytic episodes. Hemolysis completely disappeared following discontinuation of AgNp containing products.

Conclusion AgNps are increasingly being used in a large variety of products. Recently, it was reported that they induce in vitro prohemolytic and procoagulant effects via oxidative stress and eryptosis. The clinical findings imply the hemolysis was provoked by the patient's regular use of cleansing products containing AgNps. Our finding might help to explain the etiology of hemolytical disorders that may remain obscure in many cases.

The study of cerebellar development has been at the forefront of neuroscience since the pioneering work of Wilhelm His Sr., Santiago Ramon y Cajal and many others since the 19th century. They laid the foundation to identify the circuitry of the cerebellum, already revealing its stereotypic three-layered cortex and discerning several of its neuronal components. Their work was fundamental in the acceptance of the neuron doctrine, which acknowledges the key role of individual neurons in forming the basic units of the nervous system. Increasing evidence shows that the cerebellum performs a variety of homeostatic and higher order neuronal functions beyond the mere control of motor behaviour. Over the last three decades, many studies have revealed the molecular machinery that regulates distinct aspects of cerebellar development, from the establishment of a cerebellar anlage in the posterior brain to the identification of cerebellar neuron diversity at the single cell level. In this review, we focus on summarizing our current knowledge on early cerebellar development with a particular emphasis on the molecular determinants that secure neuron specification and contribute to the diversity of cerebellar neurons.

Human cytomegalovirus (CMV) is a ubiquitously distributed pathogen whose rodent counterparts such as mouse and rat CMV serve as common infection models. Here, we conducted global proteome profiling of rat CMV-infected cells and uncovered a pronounced loss of the transcription factor STAT2, which is crucial for antiviral interferon signalling. Via deletion mutagenesis, we found that the viral protein E27 is required for CMV-induced STAT2 depletion. Cellular and in vitro analyses showed that E27 exploits host-cell Cullin4-RING ubiquitin ligase (CRL4) complexes to induce poly-ubiquitylation and proteasomal degradation of STAT2. Cryo-electron microscopy revealed how E27 mimics molecular surface properties of cellular CRL4 substrate receptors called DCAFs (DDB1- and Cullin4-associated factors), thereby displacing them from the catalytic core of CRL4. Moreover, structural analyses showed that E27 recruits STAT2 through a bipartite binding interface, which partially overlaps with the IRF9 binding site. Structure-based mutations in M27, the murine CMV homologue of E27, impair the interferon-suppressing capacity and virus replication in mouse models, supporting the conserved importance of DCAF mimicry for CMV immune evasion.

Background Cold urticaria (ColdU) is a form of inducible urticaria where cold induces wheals and/or angioedema. The burden of disease is high and linked to trigger thresholds, exposure, and avoidance. There are presently no validated patient-reported outcome measures (PROMs) to assess and monitor disease activity. Our objective was to develop a disease-specific activity score for ColdU that is easy to administer and evaluate.

Methods A Cold Urticaria Activity Score (ColdUAS) questionnaire was developed, directed by PROM developing guidelines. After the generation of a conceptional framework, the item generation phase included the literature research on ColdU signs and symptoms and on comparable tools for similar diseases and 47 ColdU patient interviews. Subsequently, an impact analysis for content validity was performed. The final selection of items underwent expert review for face validity and cognitive debriefing.

Results The ColdUAS, a self-administered questionnaire for the prospective assessment of disease activity in patients with ColdU, consists of 4 items: 1. the frequency and severity of the signs (wheals and/or angioedema), 2. the frequency and severity of the symptoms (e.g., itch and burn), 3. the exposure to specific triggers, and 4. the avoidance of these triggers. The recall period for each item is the last 24 h.

Conclusions The ColdUAS is the first disease-specific PROM to assess ColdU disease activity. It may help to better assess patients' disease status in routine clinical practice as well as in clinical trials. Anchor-based approaches are currently used to validate the ColdUAS.