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Adherens junction-associated protein 1 (AJAP1) has been implicated in brain diseases; however, a pathogenic mechanism has not been identified. AJAP1 is widely expressed in neurons and binds to γ-aminobutyric acid type B receptors (GBRs), which inhibit neurotransmitter release at most synapses in the brain. Here, we show that AJAP1 is selectively expressed in dendrites and trans-synaptically recruits GBRs to presynaptic sites of neurons expressing AJAP1. We have identified several monoallelic AJAP1 variants in individuals with epilepsy and/or neurodevelopmental disorders. Specifically, we show that the variant p.(W183C) lacks binding to GBRs, resulting in the inability to recruit them. Ultrastructural analysis revealed significantly decreased presynaptic GBR levels in Ajap1-/- and Ajap1W183C/+ mice. Consequently, these mice exhibited reduced GBR-mediated presynaptic inhibition at excitatory and inhibitory synapses, along with impaired synaptic plasticity. Our study reveals that AJAP1 enables the postsynaptic neuron to regulate the level of presynaptic GBR-mediated inhibition, supporting the clinical relevance of loss-of-function AJAP1 variants.

Being bullied is associated with anxiety, depression symptoms, and long-term negative health outcomes. The aim of this qualitative pilotstudy was to explore bullied children's experiences of support groups and how participating in a group affected the children. The sample consisted of 24 children aged 11-13 years. Four of them were bullied, while 20 participated in support groups. Individual and focus group interviews were conducted. The main theme identified was that support groups provide an opportunity for change and can help children to be included among peers. The changes were achieved through encouragement and support from peers. The children participating in the support groups reported a feeling of being selected. The groups provided fellowship, and an opportunity for change. Both getting support from and being part of a support group contributed to inclusion, strength, and valuable experiences. The findings suggest that a systemic approach to bullying is advantageous.

Abstract An influenza vaccine approach that overcomes the problem of viral sequence diversity and provides long-lived heterosubtypic protection is urgently needed to protect against pandemic influenza viruses. Here, to determine if lung-resident effector memory T cells induced by cytomegalovirus (CMV)-vectored vaccines expressing conserved internal influenza antigens could protect against lethal influenza challenge, we immunize Mauritian cynomolgus macaques (MCM) with cynomolgus CMV (CyCMV) vaccines expressing H1N1 1918 influenza M1, NP, and PB1 antigens (CyCMV/Flu), and challenge with heterologous, aerosolized avian H5N1 influenza. All six unvaccinated MCM died by seven days post infection with acute respiratory distress, while 54.5% (6/11) CyCMV/Flu-vaccinated MCM survived. Survival correlates with the magnitude of lung-resident influenza-specific CD4 + T cells prior to challenge. These data demonstrate that CD4 + T cells targeting conserved internal influenza proteins can protect against highly pathogenic heterologous influenza challenge and support further exploration of effector memory T cell-based vaccines for universal influenza vaccine development.

Going through an era where sustainability and definitions of fairness have been extended and integrated into the agri-food chain, there is a need to understand, on a multi-dimensional and multinational level, the structure of agri-food value chain revenues and consumers’ intentions regarding necessity foods. The study analyzed 1,020 questionnaires from Algeria, Germany, Greece, Italy, and Tunisia revealing that taste prioritizes brand and packaging. Social networks, including family and friends, significantly influence the purchase of fair products. Furthermore, a choice experiment revealed the consumer preferences around attributes of the olive oil case as local, traditional, or organic, from a family or farmer association, in a glass bottle, purchased in small local shops/markets, typical and/or extensive nutritional labeling and health claims, non-relevant branding, and finally a fair price reflecting the reasonable quality of the olive oil product. Regarding the agri-food value chain, the results highlight the revenue distribution among stakeholders as unequal and unfair from consumer perceptions, with an imperative need for transparency. The study investigates in-depth the multifaceted dimensions of the fairness concept in the food market from a consumer’s perception, showing their willingness to pay for necessities based on fair pricing and sustainable practices.

ABSTRACT: Background: Spine surgical training faces increasing challenges due to restricted working hours and greater sub specialization. Modern simulators offer a promising approach to teaching both simple and complex spinal procedures. This study evaluated the acceptance and efficacy of spine simulator training using a lumbar herniated disc model tested by 16 neurosurgical residents (PGY-1-6), and compared 3D and 2D teaching methods. Methods: Sixteen residents utilized the Realists RealSpine L4/L5 disc simulator with both microscope and exoscope. A mixed-methods analysis assessed the efficacy and acceptance of the training. Six PGY-1 residents participated in a learning curve study, divided into exoscopic and microscopic cohorts. Each group watched a tutorial in either 3D or 2D, followed by 3 surgical sessions. Endpoints included surgical progress within 30 minutes and complication rates. Microsurgical skills and mental concepts were evaluated on a numeric Likert Scale. Results: Participants rated the simulator training favorably, with a median score of 8/10 across 6 categories. The learning curve study showed a 30% improvement in microsurgical performance. The completion rate of herniated disc removal increased from 50% at T2 to 100% at T3 and T4. Significant improvement in mental concept was observed (p=.035), with slightly better consolidation in the exoscope group. Self-assessments revealed significantly improved skills across all participants. Conclusions: Spine simulator training was well-received and resulted in improvements in both mental concept and microsurgical performance, with enhanced outcomes in the 3D teaching/exoscope group. This study supports the integration of spine simulators into spine surgical residency, particularly for early-stage training, to improve both cognitive and practical surgical skills.

Carbon emissions are increasing due to continued urban developments and the growth of the human population, leading to environmental issues such as global warming. Moving towards the future, projected population growth will cause an increase in energy demand. Without the transition to cleaner energy generation, a high dependency on electricity generation by fossil fuels will emit more harmful gases, worsening the impacts of global warming. Therefore, the energy industry is moving towards cleaner alternatives through renewable energy (RE) technologies. However, in the future power grid, more technological development and implementation of cutting-edge research methods will be required to upsurge the percentage of clean electricity generation to attain net zero. Renewables, energy storage systems (ESS), grid technologies, and building energy management systems (BEMS) are key technologies emerging to aid green electrification in the electricity, industry, commercial and transportation sectors. This review discusses the technical challenges and solutions that contribute towards achieving net-zero energy systems. A systematic review was conducted on research methods related to the optimal planning of renewable energy systems, ESS, power system devices, and BEMS which are research areas that are moving towards being optimally integrated in the future energy system. Based on the review, we propose new gaps to be addressed in the development of energy system modelling tools. These tools should seamlessly integrate methods for energy storage related to voltage support, microgrid dispatch strategies, optimal reactive power flow in electrical networks, and energy management in buildings. This integration will enhance the capability of these tools to incorporate detailed analyses into broader energy balance simulations for large geographical regions. This review paper aims to guide researchers in identifying and addressing specific gaps in future research directions within these research areas, thereby advancing the knowledge base and informing subsequent studies.

Objectives: On the basis of the positive results of CheckMate-743, first-line (1L) treatment of malignant pleural mesothelioma (MPM) with the combination of ipilimumab and nivolumab (ipi-nivo) has become a standard-of-care. Furthermore, patients who received 1L platinum/pemetrexed chemotherapy are often considered for second or further-line (2L+) ipi-nivo on the basis of MAPS2 results. Here we report on real-world survival and safety outcomes of ipi-nivo for patients with MPM in Switzerland. Methods: Twelve cancer centers contributed data to this retrospective cohort. Baseline characteristics including age, sex, histology, programmed death-ligand 1 expression, Eastern Cooperative Oncology Group performance status (ECOG PS), and previous/subsequent therapies were collected. The efficacy and safety outcomes were assessed by local investigators. Results: Of the 109 patients with MPM treated with ipi-nivo between November 2017 and March 2023 (median follow-up of 16.6 months) 75% had epithelioid, 9% biphasic, and 16% sarcomatoid histology. The median age was 72 years; 91% were males, and 83% had an ECOG PS of 0 to 1. Ipilimumab in combination with nivolumab was given as 1L in 43% and as 2L+ treatment in 57% of patients. The objective response rate was 21% in 1L and 15% in 2L+. Median progression-free survival was 6.5 and 2.8 months, respectively. Median overall survival (OS) from the start of ipi-nivo was 12.6 months for 1L and 6.9 months for 2L+. No differences in OS were observed depending on age and programmed death-ligand 1 expression. Nevertheless, the median OS was significantly worse in patients with an ECOG PS of 2 or higher than those with an ECOG PS of 0 to 1 (2.4 versus 11.9 months, p < 0.001). Treatment-related adverse events (TRAEs) of any grade related to ipi-nivo treatment occurred in 65 patients (62%). The highest-grade TRAE was 1 to 2 in 58% of these patients and 3 or higher in 42% Treatment discontinuation due to a TRAE occurred in 22% of patients. Conclusion: In this real-world cohort of patients with MPM treated with ipi-nivo survival outcomes were inferior to those reported in the CheckMate-743 and MAPS2 trials, whereas safety outcomes were similar.

Introduction: SCLC is characterized by aggressiveness and limited treatment options, especially in extensive-stage SCLC (ES-SCLC). Immunotherapy added to the platinum-etoposide combination has recently become standard in this setting. This retrospective study aims to evaluate the real-world effectiveness of chemo-immunotherapy in patients with ES-SCLC, focusing on subpopulations excluded from clinical trials. Methods: A retrospective binational multicenter study was conducted, involving consecutive patients with ES-SCLC from 10 British and 10 Swiss institutions. Patients received platinum-etoposide chemotherapy in combination with immunotherapy (atezolizumab or durvalumab). Patient, tumor, and treatment details were collected. Overall survival (OS), progression-free survival, objective response rate, and safety outcomes were analyzed. Results: A total of 436 patients were included. One hundred forty-two patients (32.6%) in our cohort would not have been eligible for the pivotal registrational trials owing to an Eastern Cooperative Oncology Group performance status of 2 or higher, autoimmune disease, active brain metastases, or steroid use. Most patients received carboplatin (96.8%) and atezolizumab (97.9%). The median progression-free survival was 5.5 months and the median OS was 9.3 months. The two-year OS was 14%. Patients with liver or bone metastases or an Eastern Cooperative Oncology Group performance status of 2 or higher had worse survival outcomes. Treatment-related adverse events were reported in 222 patients (51%) whereas immune-related adverse events occurred in 95 patients (22%). Three out of five grade 5 immune-related adverse events were caused by pneumonitis. Conclusions: To our knowledge, this is the largest real-world cohort of patients treated with chemo-immunotherapy for ES-SCLC. Although one-third of patients would not have been eligible for pivotal trials, the survival outcomes in our cohort are similar to those in registrational trials. In particular, the number of long-term survivors and the safety data are comparable, supporting the use of chemo-immunotherapy as first-line treatment for ES-SCLC in daily clinical practice.

In the central nervous system of vertebrates, glutamate serves as the primary excitatory neurotransmitter. However, in the retina, glutamate released from photoreceptors causes hyperpolarization in post-synaptic ON-bipolar cells through a glutamate-gated chloride current, which seems paradoxical. Our research reveals that this current is modulated by two excitatory glutamate transporters, EAAT5b and EAAT7. In the zebrafish retina, these transporters are located at the dendritic tips of ON-bipolar cells and interact with all four types of cone photoreceptors. The absence of these transporters leads to a decrease in ON-bipolar cell responses, with eaat5b mutants being less severely affected than eaat5b/eaat7 double mutants, which also exhibit altered response kinetics. Biophysical investigations establish that EAAT7 is an active glutamate transporter with a predominant anion conductance. Our study is the first to demonstrate the direct involvement of post-synaptic glutamate transporters in inhibitory direct synaptic transmission at a central nervous system synapse.

Abstract Background The prevalence of sacroiliac joint pain (SIJP) is estimated to be 10–30% in patients with chronic low back pain. Numerous conservative and surgical treatment modalities for SIJP have been described with limited evidence regarding long-term pain relief. Spinal cord stimulation (SCS) is a well-established technique to treat patients with chronic low back pain. However, the effect on patients with SIJP is not consistent. Therefore, peripheral nerve stimulation (PNS) for chronic SIJP was implemented in experimental trials. Clinical data on PNS for SIJP is still lacking. The authors present a case series and a protocol for a prospective, multicenter study to determine the effect of PNS in patients with chronic intractable SIJP. Method A multicenter, prospective randomized controlled trial was designed. Patients with chronic intractable SIJP will be recruited and randomized in a 4:3 ratio to either the peripheral nerve stimulation group or to the best medical treatment group. A total of 90 patients are planned to be enrolled (52 in the PNS group and 38 in the BMT group). Patients in the intervention group receive a percutaneous implantation of a unilateral or bilateral lead which is externalized for a trial phase for 3–14 days. After trial phase only patients with at least 50% reduction of pain receive an impulse generator for permanent stimulation. Regular visits for participants are planned on day 0, after 3 months (± 30 days), 6 months (± 30 days), and 12 months (± 60 days). The primary outcome measurements is the difference in Numeric Pain Rating Scale (NRS) between baseline and after 6 months. Secondary outcomes is improvement of pain associated disability (ODI) and improvement of health-related quality of life after 6 and 12 months. Discussion We have described the protocol for a prospective, multicenter, randomized trial evaluating the influence of PNS on patients with chronic sacroiliac joint syndrome. We believe that PNS on patients with chronic sacroiliac joint syndrome will show promising results regarding pain relief and quality of life in comparison to BMT after 12 months. The design of this trial promises high evidence in comparison to the data to date. Trial registration ClinicalTrials.gov, NCT05357300. Registered on April 26, 2022.

T cell receptor (TCR) repertoire sequencing has emerged as a powerful tool for understanding the diversity and functionality of T cells within the host immune system. Yet, the chicken TCR repertoire remains poorly understood due to incomplete genome annotation of the TCR loci, despite the importance of chickens in agriculture and as an immunological model. Here, we addressed this critical issue by employing 5’ rapid amplification of complementary DNA ends (5’RACE) TCR repertoire sequencing with molecular barcoding of complementary DNA (cDNA) molecules. Simultaneously, we enhanced the genome annotation of TCR Variable (V), Diversity (D, only present in β and δ loci) and Joining (J) genes in the chicken genome. To enhance the efficiency of TCR annotations, we developed VJ-gene-finder, an algorithm designed to extract VJ gene candidates from deoxyribonucleic acid (DNA) sequences. Using this tool, we achieved a comprehensive annotation of all known chicken TCR loci, including the α/δ locus on chromosome 27. Evolutionary analysis revealed that each locus evolved separately by duplication of long homology units. To define the baseline TCR diversity in healthy chickens and to demonstrate the feasibility of the approach, we characterized the splenic α/β/γ/δ TCR repertoire. Analysis of the repertoires revealed preferential usage of specific V and J combinations in all chains, while the overall features were characteristic of unbiased repertoires. We observed moderate levels of shared complementarity-determining region 3 (CDR3) clonotypes among individual birds within the α and γ chain repertoires, including the most frequently occurring clonotypes. However, the β and δ repertoires were predominantly unique to each bird. Taken together, our TCR repertoire analysis allowed us to decipher the composition, diversity, and functionality of T cells in chickens. This work not only represents a significant step towards understanding avian T cell biology, but will also shed light on host-pathogen interactions, vaccine development, and the evolutionary history of avian immunology.

Introduction Syndromic panel assays, that is, using one test to simultaneously target multiple pathogens with overlapping signs and symptoms, have been integrated into routine paediatric care over the past decade, mainly for more severely ill and hospitalised patients. Their wider availability and short turnaround times open the possibility to apply them to non-hospitalised patients as well. In this context, it is important to trial how clinicians make use of pathogen detection data and if their early availability influences management decisions, particularly antibiotic use and hospitalisation.Methods and analysis Advanced Diagnostics for Enhanced QUality of Antibiotic prescription in respiratory Tract infections in Emergency rooms is an individually randomised, controlled, open-label effectiveness trial comparing the impact of a respiratory pathogen panel assay (BIOFIRE Respiratory Panel 2.1plus) used as a rapid syndromic test on nasopharyngeal swabs in addition to the standard of care versus standard of care alone. The trial will 1:1 randomise 520 participants under the age of 18 at 7 paediatric emergency departments in 5 European countries. Inclusion criteria for the trial consist of two sets, with the first describing respiratory tract infections in paediatric patients and the second describing the situation of potential management uncertainty in which test results may immediately affect management decisions. Enrolment started in July 2021 and is expected to be completed in early 2024. We will perform a two-sample t-test assuming a pooled variance estimate to compare the log-transformed mean time on antibiotic treatment (in hours) and number of days alive out of the hospital within 14 days after study enrolment between the control and intervention arms.Ethics and dissemination The trial protocol and materials were approved by research ethics committees in all participating countries. The respiratory pathogen panel assay is CE marked (assessed to meet European regulations) and FDA (United States Food and Drug Administration) cleared for diagnostic use. Participants and caregivers provide informed consent prior to study procedures commencing. The trial results will be published in peer-reviewed journals and at national and international conferences. Key messages will also be disseminated via press and social media where appropriate.Trial registration number NCT04781530.

Background: Despite recent awareness of institutional racism, there are still important racial disparities in prostate cancer medical research. We investigated the historical development of research on racial disparities and bias. Methods: PubMed was searched for the term ‘prostate cancer race’ and added key terms associated with racial disparity. As an indicator of scientific interest in the topic, we analyzed whether the number of publications increased linearly as an indicator of growing interest. The linearity is expressed as R2. Results: The general search term “prostate cancer race” yielded 4507 publications. More specific search terms with ≥12 publications showing a higher scientific interest were found after 2005. The terms with the most publications when added to the general term were “genetic” (n = 1011), “PSA” (n = 995), and “detection” (n = 861). There was a linear increase in publications for “prostate cancer race” (R2 = 0.75) since 1980. Specific terms added to the general terms with a high linear increase (R2 ≥ 0.7) were “screening” (R2 = 0.82), “detection” (R2 = 0.72), “treatment access” (R2 = 0.71), and “trial underrepresentation” (R2 = 0.71). However, only a few studies have investigated its association with sexual activity. A combination with “sexual” showed 157 publications but only two years with ≥12 publications/year. Conclusion: The terms “genetic”, “PSA”, and “detection” have been the focus of recent research on racial differences in prostate cancer. We found that old stereotypes are still being mentioned but seem to find little interest in the current literature. Further research interest was found in “treatment access”. Recently, interest in socioeconomic factors has decreased.

Autoethnography, the narrative exploration of one’s own cultural context and experience, has been proposed as a pedagogical method of tapping the knowledge of diverse groups of students for mutual cultural learning (Kumaravadivelu, 2008). With this in mind, we set up a virtual exchange (VE) between second-year students from the University of Galway, Ireland, preparing for their Erasmus year in Germany, and students studying Irish literature and culture in their final year at a northern German grammar school. In this exchange the students themselves were to complete an autoethnographic task. The VE showed that autoethnography can serve as an instrument to address some of the problems that O’Dowd (2006) identified while using ethnographic methods in telecollaboration: the emergence of an asymmetrical relationship with conflicting roles and communicative styles, overgeneralisation, and the inability to suspend judgement. Furthermore, autoethnography as a dialogic form appears to be moreappropriate than traditional ethnographic methods for Global Education, which, in contrast to Intercultural Learning, does not mainly aim at understanding other cultures distinct from one’s own, but at preparing students for “effective interactions across cultures” (OECD, 2018, p. 10, our emphasis) in a highly connected, endangered global society. By moving between the individual and the cultural, students can become aware of different but also interdependent local, national, transnational, and global cultural structures in which they live, partly connecting them to and partly distinguishing them from each other.

CD8+ T cells are key mediators of antiviral and antitumor immunity. The isolation and study of Ag-specific CD8+ T cells, as well as mapping of their MHC restriction, has practical importance to the study of disease and the development of therapeutics. Unfortunately, most experimental approaches are cumbersome, owing to the highly variable and donor-specific nature of MHC-bound peptide/TCR interactions. Here we present a novel system for rapid identification and characterization of Ag-specific CD8+ T cells, particularly well suited for samples with limited primary cells. Cells are stimulated ex vivo with Ag of interest, followed by live cell sorting based on surface-trapped TNF-α. We take advantage of major advances in single-cell sequencing to generate full-length sequence data from the paired TCR α- and β-chains from these Ag-specific cells. The paired TCR chains are cloned into retroviral vectors and used to transduce donor CD8+ T cells. These TCR transductants provide a virtually unlimited experimental reagent, which can be used for further characterization, such as minimal epitope mapping or identification of MHC restriction, without depleting primary cells. We validated this system using CMV-specific CD8+ T cells from rhesus macaques, characterizing an immunodominant Mamu-A1*002:01-restricted epitope. We further demonstrated the utility of this system by mapping a novel HLA-A*68:02-restricted HIV Gag epitope from an HIV-infected donor. Collectively, these data validate a new strategy to rapidly identify novel Ags and characterize Ag-specific CD8+ T cells, with applications ranging from the study of infectious disease to immunotherapeutics and precision medicine.