Ostschweizer Kinderspital

Genomic sequencing leaves >50% of dystonia-affected individuals without a diagnosis. Where DNA-oriented approaches remain insufficient, integrating multiomics is essential to advance genome interpretation. Herein, we incorporated RNA sequencing (RNA-seq) data from 167 patients with dystonia across a range of ages and presentations. We leveraged an RNA-seq analysis pipeline, focused on the identification of expression and splicing aberrations, on RNA-seq from skin biopsies. The recruited patients had early-onset dystonia in 85.0%, non-focal dystonia in 92.2%, and coexisting features in 76.0%. Thirty-six patient samples with pre-identified variants (36/167, 21.6%) and 131 samples with no previously prioritized diagnostic candidates from genomic sequencing (131/167, 78.4%) were evaluated. We found that >80% of dystonia-associated genes were detected by fibroblast RNA-seq. Expression and splicing aberration analyses produced a manageable number of significant RNA defects affecting dystonia-associated genes. The approach was especially successful in validating pathogenic effects of loss-of-function variants, with disease-relevant RNA-underexpression detected for 66.7% (10/15). Studying aberrant expression and splicing in the context of other pre-identified variant types yielded relevant results in 28.6% (6/21 samples). We obtained a 6.9% (9/131) diagnostic uplift for patients without prior candidates, all of whom exhibited combined dystonia with autosomal recessive inheritance. The new diagnoses from RNA-seq and genomic reanalysis were based on previously neglected splice-region (3/9) and deep(er) intronic (6/9) variants. For the observed events, integration of new machine-learning scores predicted corresponding aberrant gene expression in the brain. Fibroblast-based RNA-seq in our selected cohort improved variant interpretation and offered a modest yield in patients without prior candidate variants. ANN NEUROL 2026.

The spore-forming anaerobe Clostridioides difficile colonizes the highly dynamic gut environment early after birth, frequently without causing disease. In this study, we aimed to determine how environmental conditions indicative of the infant gut impacted prevalence and physiology of C. difficile. We examined the effect of pH, fermentation derived short-chain carboxylic acids (SCCA) and buffering systems combining in vitro and in vivo analysis, and experimental and modelling approaches. In vivo, the prevalence of Clostridioides significantly increased between 3months (30.2%) and 12months (56.2%) after birth. At 12months, the occurrence of Clostridioides was the highest in feces with near neutral pH (6.7 (IQR 6.5‒7.3). In vitro, C. difficile showed pH-dependent growth and metabolic activity with an optimum around pH 5.8-6.3. Most SCCA conferred antimicrobial activity at pH 5.2 and 6.1 while at pH 6.5, high concentrations of SCCA promoted growth. The presence of phosphate buffer enhanced antimicrobial activity of SCCA, particularly at lower pH values (5.2-5.8). Two multilinear regression models indicated that ionic strength was inversely related to optical density in vitro, while in vivo, the abundance of Clostridioides was inversely linked to the presence of undissociated SCCA. Together, this study highlights that the that occurrence and performance of the opportunistic pathogen C. difficile was affected by chemical systems such as pH, the presence of buffer systems and concentration and chemical state of SCCA. Our results suggest novel targets that could be modulated to impact C. difficile colonization.

186 Background: INCA33890 is an anti–PD-1/TGFβR2 bispecific antibody designed to antagonize TGFβR2/PD-1 signaling in immune cells co-expressing both targets. In the INCA33890-101 study (NCT05836324), patients (pts) with refractory non-MSI-H mCRC were treated with INCA33890 monotherapy at 3 expansion doses. Responses were observed in pts with and without active liver metastases. Here, we analyze associations between baseline biomarkers and clinical outcomes. Methods: Fresh or archival (≤3 years from study registration) baseline biopsies were required in the dose expansion part and assessed using immunohistochemistry (IHC) for CD8 and PD-L1 (SP263) and whole transcriptome and next-generation sequencing for DNA aberrations (both Tempus xT). Baseline ctDNA was analyzed using Predicine Atlas during dose escalation and expansion. Efficacy was assessed by investigators per RECIST v1.1. Results: As of July 25, 2025, efficacy data with INCA33890 monotherapy were available from 105 pts; 16 pts (15.2%) had a partial response (PR), including pts with liver and peritoneal metastases (Table). Of the 78 pts with evaluable baseline biopsies for IHC analysis, pts with PR or stable disease (SD) showed greater PD-L1 tumor area positivity scores than those with progressive disease (PD) (nominal p<0.05). mRNA expression of inflammatory genes (IFN-γ, CXCL9, CXCL10 and T-cell inflamed signature) were higher in pts with PR/SD vs PD. Pts with blood tumor mutation burden (bTMB) >20 mut/MB had a trend towards higher ORR (33.3%) vs pts with bTMB <20 mut/MB (12.5%). Consensus molecular subtypes (CMS) were assessed in 44 pts. Although CMS 4 is commonly associated with the presence of TGF-β, it was not associated with a higher ORR (7.7% [1/13]). Responses were also observed in CMS 2 (21.7% [5/23]) and CMS 1 (50% [1/2]), but not in CMS 3 (n=6). There was no relationship with tumor mRNA expression of TGFβ or TGFβ-associated signatures with clinical outcomes. In addition, SMAD4 mutations, determined by ctDNA, were present in both responders and non-responders. Mutations in KRAS (64%), TP53 (72%), and APC (47%) were the most common aberrations and had no impact on clinical outcomes. Conclusions: INCA33890 demonstrated preliminary efficacy in pts with non-MSI-H mCRC across a variety of subgroups. Higher baseline PD-L1 expression and mRNA expression of inflammatory genes enriched for clinical benefit while overexpression of TGF-β did not seem to enhance efficacy. Updated data will be presented. Clinical trial information: NCT05836324 . Efficacy across subgroups. N ORR, % DCR, % Overall 105 15.2 28.6 With/without Liver Metastases 75/30 12.0/23.3 20.0/50.0 Peritoneal Metastases 40 10.0 20.0 No Liver or Peritoneal Metastases 20 30.0 60.0 PD-L1 TAP <1% 22 9.1 22.7 PD-L1 TAP >1% 56 17.9 25.0 PD-L1 TAP >5% 13 38.5 61.5 bTMB high >20 mut/MB 15 33.3 40.0 bTMB <20 mut/MB 64 12.5 28.1

Teratomas are rare germ cell tumors composed of mature and/or immature tissues derived from all three germ cell layers. Oropharyngeal teratomas are especially uncommon and can cause life-threatening airway and feeding difficulties. This report presents an 11-month-old female patient with intermittent respiratory noise and early feeding challenges. Imaging revealed a polypoid mass in the left oropharynx, which was surgically excised. Histopathological examination confirmed a mature teratoma. Postoperatively, the patient showed marked improvement in both respiration and feeding, with no signs of recurrence after three months and one year of clinical follow-up. This case highlights the importance of including teratoma in the differential diagnosis of oropharyngeal masses. Early imaging, particularly MRI, is crucial for evaluating tumor composition and extent. Complete surgical resection is critical to prevent recurrence and resolve airway and feeding problems. Although typically benign, pharyngeal teratomas can be life-threatening if undiagnosed or inadequately managed. A multidisciplinary approach integrating pediatrics, otolaryngology, radiology, and pathology is vital for optimal outcomes.

Abstract Exome and genome sequencing leave >50% of dystonia-affected individuals without a molecular diagnosis. Where DNA-oriented approaches remain insufficient, integrating multiomics methods and bioinformatics is essential to advance genome interpretation. Herein, we incorporated RNA sequencing (RNA-seq) from a collection of 167 fibroblast samples from individuals affected with dystonic diseases. We leveraged an RNA-seq analysis pipeline, focused on the identification of expression and splicing aberrations, on RNA-seq from skin biopsies. We evaluated a “variant-positive” group of patient samples with preexisting information on variants (36/167, 21.6%), and a “variant-negative” group in which genomic sequencing alone had been unsuccessful in yielding a diagnostic candidate (78.4%). We found that at least 80% of dystonia-associated genes from databases were sufficiently detected by RNA-seq in fibroblasts, highlighting broad applicability. Expression and splicing aberration analyses then produced a manageable number of statistically significant RNA defects affecting dystonia-associated genes for effective case-by-case review. Our approach successfully detected RNA underexpression and mis-splicing for different types of pre-identified dystonia-related variants, providing both benchmarks and insights into mutational mechanisms. Applied to 131 samples from patients without candidate variants from exome and genome sequencing, RNA-seq aided the identification of previously unprioritized causative intronic alterations on reanalysis, providing an added diagnostic yield of 6.9% (9/131). For observed events, we also report the integration of new machine-learning scores predicting corresponding aberrant gene expression in the brain. Fibroblast-based RNA-seq in our selected cohort improved variant interpretation and enabled diagnoses missed by genomic analysis alone, suggesting this framework could be generalized to other dystonias.

Abstract Epileptic seizures are among the most common neurological manifestations in the neonatal period. A distinction is made between acute symptomatic (provoked) and unprovoked neonatal seizures: the former arise from brain injuries, such as hypoxic-ischemic encephalopathy (HIE), intracerebral hemorrhages, infections or metabolic disturbances. Unprovoked neonatal seizures typically occur in the context of genetic disorders or structural brain malformations. This distinction as well as the underlying etiology, are crucial as both significantly influence the prognosis. This review summarizes the current state of knowledge regarding the long-term outcomes of neonatal seizures and their predictive factors. Long-term neurological deficits depend not only on the seizures themselves but primarily on the underlying cause. Hypoxic-ischemic encephalopathy is frequently associated with severe long-term consequences such as cerebral palsy and cognitive impairments. Genetic epileptic encephalopathies are usually associated with lifelong epilepsy and neurocognitive deficits, while the extent and localization of structural brain malformations determine the severity of cognitive and motor impairments. Early diagnosis and prompt initiation of treatment are essential. In the short term, mortality is the primary concern and in the long term, neurological sequelae such as cerebral palsy, cognitive deficits, or post-neonatal epilepsy may occur. Identified prognostic factors include the underlying etiology, electroencephalography (EEG) and magnetic resonance imaging (MRI) findings and perinatal risk factors. Further prospective long-term studies are needed to improve care for affected neonates and sustainably optimize their long-term outcomes.

Switzerland's decentralised healthcare system delegates responsibility for paediatric hospital infrastructure to individual cantons. To date, official statistics on the number and types of paediatric hospital beds are lacking. This study sought to fill this gap by collecting and analysing data from all paediatric hospitals in Switzerland. A nationwide cross-sectional e-mail survey was conducted in January 2023. Data on both structurally available and operated beds were collected and descriptively analysed. The survey identified a total of 1751 beds in 29 paediatric hospitals or departments, of which 85% were operated. Of the total beds, 112 were paediatric intensive care unit beds (80% operated) and 339 were neonatology beds (86% operated). Significant regional disparities in bed availability were identified: the Lake Geneva region has the highest bed-to-child ratios, while Central Switzerland, Eastern Switzerland and Ticino show notably lower ratios. These findings highlight the current distribution of paediatric beds, the considerable proportion of non-operated beds, and the importance of continued, comprehensive data collection to inform healthcare planning.

To compare the development of the peripheral nervous systems of preterm- and term-born children from birth to 3years of age by imaging the median nerve. Measuring the cross-sectional area (CSA) of the median nerve at three locations along the arm in term-born (control group) and preterm-born children (study group) using high-resolution ultrasound imaging. The data revealed a steady myelination that follows a logarithmic curve when considering the increase of the CSA of the median nerve relative to body surface area (BSA) in preterm-born children. Therefore, while the CSA of the median nerve was smaller in premature babies at the time of birth, the maturation of the nerve is comparable for preterm- and term-born children. This study analyzed how the peripheral nervous system of preterm children develops compared to full-term children and found no differences in terms of median nerve development. Further, these findings align with previous research documenting a logarithmic increase in the CSA of the median nerve with age in full-term infants. This research could be helpful for enabling the use of high-resolution ultrasound imaging as a diagnostic tool for the peripheral nervous system of premature infants.

<bold>Introduction:</bold> In a recent publication, we introduced a new index for the quantification of dysfunctional breathing (DB) derived from the analysis of ventilation slopes obtained during cardiopulmonary exercise tests (CPET). Patients referred for a CPET typically have a variety of conditions and comorbidities. Our aim was to investigate the association between comorbidities and the prevalence of DB in patients referred for a CPET due to exertional dyspnea. <bold>Material and Methods:</bold> Data were retrospectively extracted from 961 consecutive patients referred for a CPET in our institution between January 2019 and July 2022. DB was assessed based on the proportional tidal volume variation index. The association between comorbidities and DB was assessed using Fisher's exact tests and principal component analysis. <bold>Results:</bold> Among 961 patients, the most prevalent comorbidities included breathing abnormalities (R06), essential primary hypertension (I10), COPD (J44), sleep apnea (G47), asthma (J45), obesity (E66), lung cancer (C34), and chronic ischaemic heart disease (I25). The prevalence of DB in the overall population was 53%. Significant associations between DB and comorbidities were found. Patient with COPD had a significantly higher DB prevalence of 65% (OR = 1.9 [95% CI: 1.4 to 2.7]; p < 0.001). Conversely, patients undergoing preoperative assessment prior to lung cancer resection had a lower DB prevalence of 41%. <bold>Conclusion:</bold> Using a newly developed DB diagnostic index, we could assess the association between DB and patient comorbidities. Over 50% of patients referred for a CPET had DB and COPD was significantly associated with a higher prevalence of DB.