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Primary care providers are often the first to identify concerns for autism through routine screening in the first 2 years of life. However, most children do not receive a diagnosis until years later resulting in delays accessing appropriate intervention. Delays in diagnosis disproportionately impact those who are otherwise disadvantaged by society based on race or socioeconomic status. Embedding mental health clinicians into primary care clinics offers a promising opportunity to address barriers to accessing diagnostic and intervention services once primary care providers identify concerns. The goal of this study was to assess the Autism in Primary Care program through which embedded mental health professionals in an urban primary care setting, primarily serving Black and Latinx families with Medicaid, were trained to provide autism diagnostic evaluations. Two hundred and fifty children completed evaluations through Autism in Primary Care program. Wait times to access evaluations in primary care were found to be significantly shorter than through standard avenues of care (e.g. tertiary care clinics). Referring primary care providers and caregivers endorsed high levels of satisfaction with the program. Embedding autism evaluations into primary care settings offers a promising opportunity to improve earlier diagnosis and treatment access for families, reduce inequities in care, and increase caregiver and child well-being.

The fact that neutrinos carry a non-vanishing rest mass is evidence ofphysics beyond the Standard Model of elementary particles. Their absolute massbears important relevance from particle physics to cosmology. In this work, wereport on the search for the effective electron antineutrino mass with theKATRIN experiment. KATRIN performs precision spectroscopy of the tritium$\beta$-decay close to the kinematic endpoint. Based on the first fiveneutrino-mass measurement campaigns, we derive a best-fit value of $m_u^{2} ={-0.14^{+0.13}_{-0.15}}~\mathrm{eV^2}$, resulting in an upper limit of $m_u <{0.45}~\mathrm{eV}$ at 90 % confidence level. With six times the statistics ofprevious data sets, amounting to 36 million electrons collected in 259measurement days, a substantial reduction of the background level and improvedsystematic uncertainties, this result tightens KATRIN's previous bound by afactor of almost two.

PurposeTo report on cases of unilateral perimacular atrophy after treatment with voretigene neparvovec-rzyl, in the setting of previous contralateral eye treatment with a different viral vector.DesignSingle-center, retrospective chart review.MethodsIn this case series, four patients between the ages of six and 11 years old with RPE65-related retinopathy were treated unilaterally with rAAV2-CB-hRPE65 as part of a gene augmentation clinical trial (NCT00749957). Six to 10 years later the contralateral eyes were treated with the Food and Drug Administration-approved drug, voretigene neparvovec-rzyl. Best-corrected visual acuity (BCVA), fundus photos, ocular coherence tomography, two-color dark-adapted perimetry, full field stimulus threshold testing (FST), and location of subretinal bleb and chorioretinal atrophy were evaluated.ResultsThree out of four patients showed unilateral perimacular atrophy after treatment with voretigene, ranging from five to 22 months after treatment. Areas of robust visual field improvement were followed by areas of chorioretinal atrophy. Despite perimacular changes, BCVA, FST, and subjective improvements in vision and nyctalopia were maintained. Perimacular atrophy was not observed in the first eye treated with the previous viral vector.ConclusionsWe observed areas of robust visual field improvement followed by perimacular atrophy in voretigene treated eyes, as compared to the initially treated contralateral eyes.Translational relevanceCaution is advised when using two different viral vectors between eyes in gene therapy. This may become an important issue in the future with increasing gene therapy clinical trials for inherited retinal dystrophies.

Background: We now have sufficient evidence demonstrating inequalities in specific avoidable causes of death for adults with intellectual disability compared to their peers without intellectual disability. Apart from COVID-19, the largest differentials that disadvantage people with intellectual disability are in relation to pneumonia, aspiration pneumonia, epilepsy, cerebrovascular disease, ischaemic heart disease, deep vein thrombosis, diabetes and sepsis. The aim of this systematic review is to report on strategies at the individual, population or policy levels aimed at preventing these conditions that are applicable to adults with intellectual disability and that have been based on or recommended by research. Methods: Systematic review of PUBMED, EMBASE, CINAHL, PsychInfo, Social Care Online, International Bibliography of the Social Sciences (IBSS), Web of Science, Scopus, Overton, the Cochrane Library and Google Scholar databases was carried out. Searches were completed on 30 June 2023. Quantitative, qualitative and mixed-methods research; systematic, scoping or evidence-based reviews; and audit and reports of mortality reviews were included. Publications included in the review were about preventing the eight potentially avoidable causes of death. Findings: Ninety-four papers were included in the review (9 in relation to pneumonia; 11 for aspiration pneumonia; 18 for sudden unexpected death in epilepsy; 7 for cerebrovascular disease; 8 for ischaemic heart disease; 4 for deep vein thrombosis; 31 for diabetes; 6 for sepsis). The eight most frequently occurring potentially avoidable causes of death in people with intellectual disability are very different medical conditions, but they shared striking similarities in how they could be prevented. The literature overwhelmingly implicated the need to make lifestyle changes to address obesity, lack of exercise and poor nutrition, and to have regular medical reviews. In addition, 'whole-population' approaches are required that look beyond the individual to the social determinants of health. Conclusions: We found little peer-reviewed evidence specifically about preventing these conditions in people with intellectual disability. However, most of the literature about preventative strategies pertaining to the general population was applicable to people with intellectual disability, albeit that some 'reasonable adjustments' would be required.

Abstract Rare cancers present significant challenges in diagnosis, treatment, and research, accounting for up to 25% of global cancer cases. Due to their rarity and atypical presentations, they are often misdiagnosed, resulting in late-stage detection and poor outcomes. Here, we describe a patient case with advanced metastatic nasopharynx NUT carcinoma, one of the rarest and most aggressive cancers. We conducted a comprehensive analysis of this patient’s tumor, including Tumor Mutation Burden, Microsatellite Instability, and genetic profiling to explore further putative druggable targets. The tumor exhibited high PD-L1 expression and showed a notable response to immune checkpoint inhibitors when combined with platinum-based radio-chemotherapy. Our findings indicate that checkpoint inhibitors could play a critical role in treating NUT carcinoma, offering new therapeutic avenues and hope for patients with this challenging diagnosis. Whether PD-L1 expression may be a useful predictor of immune checkpoint inhibitor efficacy warrants further research.

Abstract Accurate diagnosis and monitoring of neurodegenerative diseases require reliable biomarkers. Cerebrospinal fluid (CSF) proteins are promising candidates for reflecting brain pathology; however, their diagnostic utility may be compromised by natural variability between individuals, weakening their association with disease. Here, we measured the levels of 69 pre-selected proteins in cerebrospinal fluid using antibody-based suspension bead array technology in a multi-disease cohort of 499 individuals with neurodegenerative disorders including Alzheimer’s disease (AD), behavioral variant frontotemporal dementia, primary progressive aphasias, amyotrophic lateral sclerosis (ALS), corticobasal syndrome, primary supranuclear palsy, along with healthy controls. We identify significant inter-individual variability in overall CSF levels of brain-derived proteins, which could not be attributed to specific disease associations. Using linear modelling, we show that adjusting for median CSF levels of brain-derived proteins increases the diagnostic accuracy of proteins previously identified as altered in CSF in the context of neurodegenerative disorders. We further demonstrate a simplified approach for the adjustment using pairs of correlated proteins with opposite alteration in the diseases. With this approach, the proteins adjust for each other and further increase the biomarker performance through additive effect. When comparing the diseases, two proteins—neurofilament medium and myelin basic protein—showed increased levels in ALS compared to other diseases, and neurogranin showed a specific increase in AD. Several other proteins showed similar trends across the studied diseases, indicating that these proteins likely reflect shared processes related to neurodegeneration. Overall, our findings suggest that accounting for inter-individual variability is crucial in future studies to improve the identification and performance of relevant biomarkers. Importantly, we highlight the need for multi-disease studies to identify disease-specific biomarkers.

Abstract The proline-rich antimicrobial designer peptide Api137 inhibits protein expression in bacteria by binding simultaneously to the ribosomal polypeptide exit tunnel and the release factor (RF), depleting the cellular RF pool and leading to ribosomal arrest at stop codons. This study investigates the additional effect of Api137 on the assembly of ribosomes using an Escherichia coli reporter strain expressing one ribosomal protein per 30S and 50S subunit tagged with mCherry and EGFP, respectively. Separation of cellular extracts derived from cells exposed to Api137 in a sucrose gradient reveals elevated levels of partially assembled and not fully matured precursors of the 50S subunit (pre-50S). High-resolution structures obtained by cryogenic electron microscopy demonstrate that a large proportion of pre-50S states are missing up to five proteins (uL22, bL32, uL29, bL23, and uL16) and have misfolded helices in 23S rRNA domain IV. These data suggest a second mechanism for Api137, wherein it disrupts 50S subunit assembly by inducing the formation of misfolded precursor particles potentially incapable of evolving into active ribosomes, suggesting a bactericidal mechanism.

Background: Allogenic kidney transplantation has been the gold standard treatment for end-stage renal disease. In the research setting, rat models are widely utilized to refine surgical techniques and enhance graft viability. One critical factor affecting transplantation outcomes is the efficiency of the venous anastomosis. This study evaluates the utility of a microvascular coupling device for venous anastomosis in a rat kidney transplantation model. Material and methods: Experimental allogenic kidney transplantations were conducted in male Brown Norway rats (n = 10) as donors and Lewis rats as recipients (n = 17), housed according to institutional guidelines. A microvascular coupling device was used for renal venous anastomosis, and creatinine levels were measured postoperatively to assess kidney function. Procedure times, ischemia duration, and postoperative complications were recorded and analyzed. Results: The venous anastomosis time averaged 6.6 ± 2.2 min. Total ischemia time averaged 42.4 ± 4.9 min. Early postoperative serum creatinine levels were slightly elevated about references thresholds, which normalized by postoperative day 3. Four animals died after successful transplantation due to urethral complications and postrenal failure (23.5 %). Other postoperative mortality was primarily linked to complications unrelated to thrombosis (n = 3, 17.6 %). Conclusion: The use of a microvascular coupling device for venous anastomosis in rat kidney transplantation significantly reduces procedure time and ischemia duration, contributing to more consistent graft outcomes. The simplification of the venous anastomosis process and reduced operative time justify the use of coupling devices. This technique holds promise for advancing preclinical transplant research and improving reproducibility in microsurgical procedures.

Aims. Multiple sclerosis treatment strategies are changing in the Czech Republic. According to data from 2013-2021, the proportion of patients starting high-efficacy disease-modifying therapies is increasing. In this survey, we describe the actual data trends in multiple sclerosis (MS) patients beginning their first disease‑modifying therapies (DMTs) from 2013 to 2021. The secondary objective was to present the history, data collection, and scientific potential of the Czech National MS registry (ReMuS). Methods. First, using descriptive statistics, we analysed the data for patients starting their first DMTs, either platform (including dimethyl fumarate) or high-efficacy DMTs (HE-DMTs), for each successive year. Second, a detailed description of the history, data collection, completeness, quality optimising procedures, and legal policies of ReMuS is provided. Results. Based on the dataset from December 31, 2021, the total number of monitored patients with MS in ReMuS increased from 9,019 in 2013 (referred from 7 of 15 MS centres) to 12,940 in 2016 (referred from all 15 Czech MS centres) to 17,478 in 2021. In these years, the percentage of patients treated with DMTs in the registry ranged from 76 to 83%, but the proportion of patients treated with HE-DMTs changed from 16.2% in 2013 to 37.1% in 2021. During the follow-up period, a total of 8,491 treatment-naive patients received DMTs. The proportion of patients (all MS phenotypes) starting HE-DMTs increased from 2.1% in 2013 to 18.5% in 2021. Conclusion. Patient registries, including ReMuS, provide an essential quality data source, especially in light of the increasing percentage of patients on HE-DMTs. Although early initiation of HE-DMT can provide considerable benefits, it also carries greater potential risks. Consistent long-term follow-up of patients in real‑world clinical practice, which only registries allow, is therefore crucial to evaluate the efficacy and safety of therapeutic strategies, for epidemiological research and to assist decision making by healthcare providers and regulatory bodies.

This article describes how and why the Dunning-Kruger effect, in which novice students fail to recognize their own lack of research skills, often occurs with the one-shot library instruction mode. In contrast, we offer a holistic model of instruction that emphasizes closer information literacy connections to higher education curricula. Through collaboration, embedded librarianship, and using class time to address ACRL Framework concepts, such instruction promotes deeper, student-centered, authentic inquiry. A case study using research logs and a learning community approach indicated that students acquired a deeper understanding of the research process. The collaborative use of research logs highlights one approach to avoiding the Dunning-Kruger effect, even with limited class time.