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Introduction Intratympanic corticosteroids are commonly used in the treatment of Menière’s disease (MD). However, few and small randomised controlled trials (RCT) on the effectiveness of intratympanic corticosteroids have been performed. A recent Cochrane review suggested that a well-conducted placebo-controlled RCT with a large study population is required to evaluate the effectiveness of the use of intratympanic corticosteroids in MD. The following protocol describes a phase-3 multicentre, double-blinded, randomised, placebo-controlled trial to compare the effectiveness of methylprednisolone (62.5 mg/mL) to a placebo (sodium chloride 0.9%).Methods and analysis We aim to recruit 148 patients with unilateral MD from six hospitals in the Netherlands. Patients will be randomly assigned to either the methylprednisolone or the placebo group. Two injections will be given, one at baseline and one after 2 weeks. Follow-up assessments will be done at 3, 6, 9 and 12 months. The primary outcome will be the frequency of vertigo attacks. Attacks will be evaluated daily with the DizzyQuest app. Secondary outcomes include hearing loss, tinnitus, health-related quality of life, use of co-interventions and escape medication, (serious) adverse events and cost-effectiveness. These will be evaluated with audiometry and multiple commonly used, validated questionnaires. For the primary and secondary outcomes mixed model analysis, generalised estimating equation analysis and logistic regression analysis will be used.Ethics and dissemination This study was submitted via the Clinical Trials Information System, reviewed and approved by the Medical Research Ethics Committee Leiden The Hague Delft and the local institutional review board of each participating centre. All data will be presented ensuring the integrity and anonymity of patients. Results will be published in scientific journals and presented on (inter)national conferences.Trial registration number This study is registered at ClinicalTrials.gov Protocol Registration and Results System, with the registration ID: NCT05851508.

The sitcom "The Good Place" can be used by management instructors to teach ethical frameworks and concepts. This series, familiar to many undergraduate students in the US, features a Professor of Ethics and Moral Philosophy who gives mini lectures applied to what the characters are experiencing. These mini lectures can be shown to undergraduates studying ethics in a full course or as a subsection of courses such as management, organizational behavior, or leadership. This article provides information on particular clips that management instructors can use, recommendations for discussion topics with prompts provided, and a comparative pedagogical analysis of using this resource.

Abstract Background In addition to the elimination diet, dietary composition may influence disease severity in patients with eosinophilic esophagitis (EoE) through modulation of the immune response. Aim To explore the immunomodulatory role of nutrition before and during elimination diet in adult EoE patients. Methods Nutritional intake was assessed in 39 Dutch adult EoE patients participating in the Supplemental Elemental Trial (Dutch trial registry NL6014, NTR6778) using 3‐day food diaries. In this randomized controlled trial, diagnosed patients received either a four‐food elimination diet alone (FFED) or FFED with addition of an amino acid‐based formula for 6 weeks. Multiple linear regression analyses were performed to assess associations between the intake of nutrients and food groups per 1000 kCal and peak eosinophil count/high power field (PEC), both at baseline and after 6 weeks. Results At baseline, we found a statistically significant negative (thus favorable) relationship between the intake of protein, total fat, phosphorus, zinc, vitamin B12, folate, and milk products and PEC (p

Purpose: ARID1B is one of the most frequently mutated genes in intellectual disability cohorts. Thus, far few adult-aged patients with ARID1B-related disorder have been described, which limits our understanding of the disease’s natural history and our ability to counsel patients and their families. Methods: Data on patients aged 18+ years with ARID1B-related disorder were collected through an online questionnaire completed by clinicians and parents. Results: Eighty-seven adult patients with ARID1B were included. Cognitive functioning ranged from borderline to severe intellectual disability. Patients identified through the genetic workup of their child were either mosaic or had a variant in exon 1. New clinical features identified in this population are loss of skill (16/64, 25%) and recurrent patella luxation (12/45, 32%). Self-sustainability data showed that 88% (45/51) could eat independently, and 16% (7/45) could travel alone by public transport. Facial photo analysis showed that patients’ photographs taken at different ages clustered consistently, separate from matched controls. Conclusion: The ARID1B spectrum is broad, and as patients age, there is a significant shift in the medical aspects requiring attention. To address the changing medical needs with increasing age, we have formulated recommendations to promote timely intervention in an attempt to mitigate disease progression.

Abstract Safety and efficacy of coronary drug-eluting stents (DES) are often preclinically tested using healthy or minimally diseased swine. These generally show significant fibrotic neointima at follow-up, while in patients, incomplete healing is often observed. The aim of this study was to investigate neointima responses to DES in swine with significant coronary atherosclerosis. Adult familial hypercholesterolemic swine (n = 6) received a high fat diet to develop atherosclerosis. Serial OCT was performed before, directly after, and 28 days after DES implantation (n = 14 stents). Lumen, stent and plaque area, uncovered struts, neointima thickness and neointima type were analyzed for each frame and averaged per stent. Histology was performed to show differences in coronary atherosclerosis. A range of plaque size and severity was found, from healthy segments to lipid-rich plaques. Accordingly, neointima responses ranged from uncovered struts, to minimal neointima, to fibrotic neointima. Lower plaque burden resulted in a fibrotic neointima at follow-up, reminiscent of minimally diseased swine coronary models. In contrast, higher plaque burden resulted in minimal neointima and more uncovered struts at follow-up, similarly to patients’ responses. The presence of lipid-rich plaques resulted in more uncovered struts, which underscores the importance of advanced disease when performing safety and efficacy testing of DES.

This study aims to refine our understanding of the inherent heterogeneity in cervical cancer by exploring differential gene expression profiles, immune cell infiltration dynamics, and implicated signaling pathways in the two predominant histological types of cervix carcinoma, Squamous Cell Carcinoma (SCC) and Adenocarcinoma (ADC). Targeted gene expression data that were previously generated from samples of primary cervical cancer were re-analyzed. The samples were grouped based on their histopathology, comparing SCC to ADC. Each tumor in the study was confirmed to be high risk human papilloma virus (hrHPV) positive. A total of 21 cervical cancer samples were included, with 11 cases of SCC and 10 of ADC. Data analysis revealed a total of 26 differentially expressed genes, with 19 genes being overexpressed in SCC compared to ADC (Benjamini–Hochberg (BH)-adjusted p-value < 0.05). Importantly, the immune checkpoint markers CD274 and CTLA4 demonstrated significantly higher expression in SCC compared to ADC. In addition, SCC showed a higher infiltration of immune cells, including B and T cells, and cytotoxic cells. Higher activation of a variety of pathways was found in SCC samples including cytotoxicity, interferon signaling, metabolic stress, lymphoid compartment, hypoxia, PI3k-AKT, hedgehog signaling and Notch signaling pathways. Our findings show distinctive gene expression patterns, signaling pathway activations, and trends in immune cell infiltration between SCC and ADC in cervical cancer. This study underscores the heterogeneity within primary cervical cancer, emphasizing the potential benefits of subdividing these tumours based on histological and molecular differences.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) can occur due to maternal IgG antibodies targeting platelet antigens, causing life-threatening bleeding in the neonate. However, the disease manifests itself in only a fraction of pregnancies, most commonly with anti-HPA-1a antibodies. We found that in particular, the core fucosylation in the IgG-Fc tail is highly variable in anti-HPA-1a IgG, which strongly influences the binding to leukocyte IgG-Fc receptors IIIa/b (FcγRIIIa/b). Currently, gold-standard IgG-glycoanalytics rely on complicated methods (e.g., mass spectrometry (MS)) that are not suited for diagnostic purposes. Our aim was to provide a simplified method to quantify the biological activity of IgG antibodies targeting cells. We developed a cellular surface plasmon resonance imaging (cSPRi) technique based on FcγRIII-binding to IgG-opsonized cells and compared the results with MS. The strength of platelet binding to FcγR was monitored under flow using both WT FcγRIIIa (sensitive to Fc glycosylation status) and mutant FcγRIIIa-N162A (insensitive to Fc glycosylation status). The quality of the anti-HPA-1a glycosylation was monitored as the ratio of binding signals from the WT versus FcγRIIIa-N162A, using glycoengineered recombinant anti-platelet HPA-1a as a standard. The method was validated with 143 plasma samples with anti-HPA-1a antibodies analyzed by MS with known clinical outcomes and tested for validation of the method. The ratio of patient signal from the WT versus FcγRIIIa-N162A correlated with the fucosylation of the HPA-1a antibodies measured by MS (r=-0.52). Significantly, FNAIT disease severity based on Buchanan bleeding score was similarly discriminated against by MS and cSPRi. In conclusion, the use of IgG receptors, in this case, FcγRIIIa, on SPR chips can yield quantitative and qualitative information on platelet-bound anti-HPA-1a antibodies. Using opsonized cells in this manner circumvents the need for purification of specific antibodies and laborious MS analysis to obtain qualitative antibody traits such as IgG fucosylation, for which no clinical test is currently available.

This article examines teammates' perceptions of individual expert and referent power (personal power) in student teams working on a semester-long project. In our study, we found a positive relationship between being perceived as high in personal power (expert and referent power) by teammates and faculty advisor-rated performance, measured by quality and quantity of work, efficiency, meeting team goals, meeting deadlines, and overall performance. To examine the mechanism behind this relationship, we also examined and found that expressed humility mediated the effect between teammates' power perceptions and individual performance. These findings suggest that power plays an important role in teammates' perceptions of individuals, in the individual's own performance, and in how humility functions in team settings. We further discuss these results in terms of practical implications as well as implications for management educators.

Experiential learning has been documented as an effective method for student learning, yet its use in large-enrollment classes remains limited. Kolb's experiential learning theory emphasizes that experiential learning requires a hospitable learning space (HLS) that is conducive to learning. In this article, we reframe the challenges to experiential learning in large classes as a failure to create and maintain an HLS, and we propose Appreciative inquiry as one solution to this problem. Appreciative inquiry is an organizational development methodology that practitioners have successfully used to engage large groups to leverage their strengths and resources. First, we describe the HLS as an overarching theoretical framework to address the lack of engagement when conducting experiential learning in large classes. Second, we use the principles of Appreciative inquiry to provide actionable suggestions to instructors facing these challenges. Finally, through the use of appreciative inquiry, we argue that some characteristics of large classes can instead be viewed in an appreciative way as available resources to generate an engaging experiential learning process for students.

In the Netherlands, the trend towards inclusion has led to the development of a 'To School Together' programme in which students with profound intellectual and multiple disabilities (PIMD) receive tailored care and education during the school day in a special classroom ('To School Together' class) within a mainstream school. Besides shared activities with other students with disabilities in the 'To School Together' classroom, inclusion moments are organised in which students with PIMD engage in activities with typically developing peers. A teaching assistant (TA) is present to support the student with PIMD. In this study, we explored the type of activities offered during these inclusion moments, the interaction between students with PIMD and their peers, and the role of TAs. Video recordings were made of three inclusion moments for eight students with PIMD. We coded the contact initiations of students with PIMD, their peers and TAs, and the responses to these initiations. The results show a total of 246 contact initiations by peers where students with PIMD responded positively 82 times, TAs attempted to facilitate interactions 55 times and students with PIMD responded positively 11 times. Based on our findings, we make several recommendations that can guide inclusive practices for students with PIMD.

Introduction: Intellectual disability is a key subject in all mental healthcare institutions, including the forensic mental health services. The Screener for Intelligence and Learning Disability (SCIL) is designed to screen for intellectual disability in forensic populations. So far, this assessment method is only validated in "detention fit prisoners" with low need of care. The aim of the present study was to investigate the psychometric properties of the SCIL in a population of mentally ill detainees with high need of care. Materials and methods: Screener for Intelligence and Learning Disability scores, mental health reports including intelligence assessment, and criminal records of detainees were obtained. Reliability and validity of the SCIL were calculated, using the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) and prior studies of the SCIL as a reference. Results: Cronbach's alpha coefficient for the total SCIL was 0.72. The area under the receiver operating characteristics (ROC) curve was 0.84. Different cut-off values than the original were determined when achieving the optimum in true positives and negatives. The mean intelligence quotient (IQ) score of the study population was 82.6, and 60.3% could be classified with an IQ < 85. Discussion: The SCIL gives a quick and accurate indication of whether a person is at risk for intellectual disabilities. Although both the reliability and validity of the SCIL are lower in the study population than in regular prison populations, for application of the SCIL in mentally ill detainees all psychometric properties could be classified as acceptable. When assessing the latter populations, it is recommended to use a cut-off value of 20.5 instead of the original 19.5. Additionally, it is advised to revise item 4. Finally, it is important to mention that the estimated prevalence of intellectual disability is the forensic population seems to be larger than expected.

Diversity, equity and inclusion (DEI) in marketing– defined as the composition of an organisation's marketing reflects diverse, equitable representation of its consumer base, especially with respect to the use of inclusive, bias-free imagery, language and messaging among underrepresented, underserved and marginalised consumer segments – has led to the advancement of AI-enabled technologies to aid marketers improve the DEI of their marketing materials. To ensure DEI marketing strategies are fully considered and that the use of AI is implemented effectively, we suggest marketers to utilise our CONSIDER framework (comprehend current state, operationalise with openness, nurture dynamic relevance, set standards, involve stakeholders, diversify data, elevate literacy and regular monitoring). We then highlight the pros and cons for using AI to implement DEI into marketing materials and provide several AI-enabled metrics (accessibility, allyship, cultural sensitivity, diversity, gender parity, inclusivity intersectionality and representation) that offer a more objective and quantitative approach for marketers to assess how well they are meeting their DEI goals and identifying gaps in representation to make changes to improve the DEI of their marketing materials. [ABSTRACT FROM AUTHOR]

This article focuses on using the cooperative board game "Pandemic"® to teach management. In "Pandemic," players must work together to cure four diseases and save the world. In this article, we suggest how it can be used in the classroom to teach decision making and also give guidance on how the game can help students learn how to reflect and put into practice the leadership, teamwork, goal setting, and ethical theories presented during management, leadership, and organizational behavior courses. "Pandemic" is a useful experiential teaching tool that engages students in complex decisions.

We report on an experiment to investigate the effect of an online asynchronous marketing simulation on student engagement and GPA. Engagement was measured in terms of conscious attention, enthused participation and social connection. The participants were 45 students undertaking marketing management at an American university over one semester. Half the students (the treatment group) were required to undertake the simulation in addition to their regular assessments. The results support the idea that online asynchronous marketing simulations contribute to increasing a student's GPA score, and that factors other than engagement may be driving this learning and achievement. Evidence for this included (1) relatively higher post-treatment GPA scores for the treatment group; (2) relatively lower post-treatment levels of enthused participation for the treatment group; (3) lack of significant differences between the groups in terms of conscious attention and social connection.

RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D. rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome.

The increasing amount of globally seized controlled substances in combination with the more diverse drugs-of-abuse market encompassing many new psychoactive substances (NPS) provides challenges for rapid and reliable on-site presumptive drug testing. Long-established colorimetric spot tests tend to fail due to the unavailability of reliable tests for novel drugs and to false-positive reactions on commonly encountered substances. In addition, handling of samples and chemicals is required. Spectroscopic techniques do not have these disadvantages as spectra are compound-specific and non-invasive tests are possible. Near-infrared (NIR) spectroscopy is a promising technique for on-scene forensic drug detection. Numerous portable devices were introduced in the market in recent years. However, most handheld spectrometers operate in different and relatively confined wavelength ranges compared to the full 780 – 2500 nm NIR wavelength range. In addition, their spectral resolution is limited compared to benchtop instruments. This dataset presents the NIR spectra of 430 forensic samples, including regularly encountered illicit-drugs, NPS, commonly used adulterants, bulking-agents and excipients, and seized casework materials (powders and tablets). Data is available from 5 different NIR spectrometers; including a benchmark high-resolution, full range 350–2500 nm laboratory grade instrument and 4 portable spectrometers operating in the ranges of 1300–2600 nm, 1550–1950 nm, 950–1650 nm and 740–1070 nm. Via this dataset, spectra of illicit-drugs become available to institutes that typically do not have access to controlled substances. This data can be used to develop chemometric detection and classification models for illicit-drugs and provide insight in diagnostic spectral features that need to be recorded for reliable detection models. Additionally, the high-resolution, full range VIS-NIR spectra of the benchmark ASD instrument can be used for in-silica predictions of spectra in a certain wavelength range to provide insight in the optimal resolution and wavelength range of a prospective portable device.

Background The complete response rate of cervical high-grade squamous intraepithelial lesion (cHSIL) patients to imiquimod immunotherapy is approximately 60%. Consequently, many patients are exposed to unnecessary adverse effects of imiquimod. On the other hand, conventional surgical large loop excision therapy is associated with increased risk of premature births in subsequent pregnancies. An in-depth analysis of the cHSIL immune microenvironment was performed in order to identify and develop a predictive biomarker for response to imiquimod, to maximize therapy efficacy and to avoid adverse effects in patients unlikely to respond.Methods Biopsies of 35 cHSIL patients, before and 10 weeks on imiquimod treatment, were analyzed by two multispectral seven-color immunofluorescence panels for T cell and myeloid cell composition in relation to treatment response. Based on these results a simplified immunohistochemical detection protocol was developed. Samples were scanned with the Vectra multispectral imaging system and cells were automatically identified using machine learning.Results The immune microenvironment of complete responders (CR) is characterized by a strong and coordinated infiltration by T helper cells (activated PD1+/type 1 Tbet+), M1-like macrophages (CD68+CD163-) and dendritic cells (CD11c+) prior to imiquimod. The lesions of non-responders (NRs) displayed a high infiltration by CD3+FOXP3+ regulatory T cells. At 10 weeks on imiquimod, a strong influx of intraepithelial and stromal CD4+ T cells was observed in CR but not NR patients. A steep decrease in macrophages occurred both in CR and NR patients, leveling the pre-existing differences in myeloid cell composition between the two groups. Based on the pre-existing immune composition differences, the sum of intraepithelial CD4 T cell, macrophage and dendritic cell counts was used to develop a quantitative simplified one color immunohistochemical biomarker, the CHSIL immune biomarker for imiquimod (CIBI), which can be automatically and unbiasedly quantified and has an excellent predictive capacity (receiver operating characteristic area under the curve 0.95, p