bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Rate of Secondary Speech Surgery After Cleft Palate Repair: A Systematic Review
Authors: Plonkowski Alexander T. , Choi Dylan G. , Naidu Priyanka , Turk Marvee , Yao Caroline A. , Magee William P. 
Published: February 2025

Background:
Reported rates of velopharyngeal insufficiency (VPI) after primary palatoplasty for cleft palate (CP) range from 5% to 30%. Although some cases are managed with speech therapy, many patients with VPI require surgical intervention. In this study, we investigate the rate of VPI surgery in patients with CP.

Methods:
A systematic review was undertaken following PRISMA guidelines. PubMed, Scopus, and Cochrane databases were used. Studies reporting the rate of VPI surgery in patients with CP were included. Studies containing patients with submucous clefts and/or lacking 6 months follow-up were excluded. Rates of VPI surgery were calculated through weighted means.

Results:
Fifty-eight articles were included. The overall rate of VPI surgery was 17.5% ± 9.2% (range, 0%–59%). When stratified by phenotype, the rate of VPI surgery was 20.0% ± 13.1% for unilateral cleft lip and palate (range, 0%–39.6%), 27.1% ± 17.2% for bilateral cleft lip and palate (range, 0%–59%), and 14.4% ± 7.2% for isolated CP (range, 0%–47.4%, P > 0.05). When segregated by the palatoplasty technique, the surgical rate was 7.2% ± 3.7% for Furlow, 20.3% ± 19.8% for 2-flap, 5.0% ± 2.8% for Sommerlad, and 23.4% ± 8.0% for 2-stage (P > 0.05). Of studies reporting VPI assessment criteria, speech pathology assessment alone (n = 11, 34.4%) was the most common.

Conclusions:
Significant variability exists in reported rates of VPI surgery after CP repair. Initial results suggest a higher rate of VPI surgery in association with certain phenotypes and repair techniques, but data are insufficient for robust conclusions.
Timing of neurosurgical interventions for intracranial hypertension: the intensivists’ and neurosurgeons’ view
Authors: Lin Victor , Hutchinson Peter John , Kolias Angelos , Robba Chiara , Wahlster Sarah 
Published: February 2025

Purpose of review
The aim of this study was to highlight clinical considerations regarding medical versus surgical management of elevated intracranial pressure (ICP), describe limitations of medical management, and summarize evidence regarding timing of neurosurgical interventions.

Recent findings
The optimal ICP management strategy remains elusive, and substantial practice variations exist. Common risks of medical treatments include hypotension/shock, cardiac arrhythmias and heart failure, acute renal failure, volume overload, hypoxemia, and prolonged mechanical ventilation.
In traumatic brain injury (TBI), recent randomized controlled trials (RCT) did not demonstrate outcome benefits for early, prophylactic decompressive craniectomy, but indicate a role for secondary decompressive craniectomy in patients with refractory elevated ICP. A recent meta-analysis suggested that when an extraventricular drain is required, insertion 24 h or less post-TBI may result in better outcomes.
In large ischemic middle cerebral artery strokes, pooled analyses of three RCTs showed functional outcome benefits in patients less than 60 years who underwent prophylactic DC within less than 48 h. In intracranial hemorrhage, a recent RCT suggested outcome benefits for minimally invasive hematoma evacuation within less than 24 h.

Summary
More data are needed to guide ICP targets, treatment modalities, predictors of herniation, and surgical triggers; clinical decisions should consider individual patient characteristics, and account for risks of medical and surgical treatments.
Gastrointestinal dysmotility in the ICU
Authors: Pachisia Anant Vikram , Pal Divya , Govil Deepak 
Published: February 2025

Purpose of review
This review aims to provide a comprehensive overview of gastrointestinal dysmotility, particularly in critically ill patients within the ICU. It highlights the pathophysiology, prevalence, and clinical implications of conditions, such as oesophageal dysmotility, gastroparesis, ileus, and Ogilvie's syndrome. By examining current diagnostic and treatment approaches, the review emphasizes the importance of recognizing and managing gastrointestinal dysmotility to improve patient outcomes.

Recent finding
Recent literature indicates that up to 60% of ICU patients experience some form of gastrointestinal dysmotility, with those on mechanical ventilation being particularly at risk. The review identifies key contributors to gastrointestinal dysmotility, including inflammatory states, electrolyte imbalances, and the effects of certain medications. Nonpharmacological strategies, such as early enteral feeding, correcting electrolyte abnormalities, and mobilization are critical. Prokinetic agents have shown promise in alleviating feeding intolerance and improving gastric emptying, though their effects on overall mortality remain inconclusive.

Summary
Gastrointestinal dysmotility presents a significant challenge in critically ill patients, leading to various complications that hinder recovery. Understanding the underlying pathophysiology, coupled with effective diagnostic and treatment strategies, is essential for enhancing patient care. This review underscores the need for continued research and clinical focus on gastrointestinal motility disorders in the ICU to improve health outcomes for this vulnerable population.
Advancements in nutritional support for critically ill patients
Authors: Huynen Philippe , Casaer Michael P. , Gunst Jan 
Published: February 2025

Purpose of review
To summarize the clinical evidence on nutritional support for critically ill patients, the (patho)physiological mechanisms involved, and areas of future research.

Recent findings
Large randomized controlled trials have shown that early nutrition induces dose-dependent harm in critically ill patients, regardless of the feeding route, and that early high-dose amino acids are harmful. Harm has been attributed to feeding-induced suppression of cellular repair pathways including autophagy and ketogenesis, to aggravation of hyperglycemia and insulin needs, and to increased urea cycle activity. Additionally, acute critical illness was shown to be a state of anabolic resistance. The absence of benefit of early enhanced nutritional support on short- and long-term outcomes was observed in all studied subgroups.

Summary
While early high-dose nutrition should be avoided in all critically ill patients, the optimal initiation time of nutrition support for the individual patient, as well as ideal composition and dosing of nutrition over time remain unclear. Future studies should elucidate how fasting-induced repair pathways can be activated while avoiding prolonged starvation, and how hyperglycemia and high insulin need could be prevented. Potential strategies include intermittent fasting, ketogenic diets, ketone supplements, and alternative glucose-lowering agents, whether or not in combination with exercise.
Cell-penetrating peptide-mediated mouse oocyte activation
Authors: Suzuki Toru 
Published: February 2025

AbstractIntroductionThe cell cycle of ovulated oocytes from various animal species, including mice, is arrested in the second meiotic metaphase until fertilization. The meiotic cell cycle must be initiated to initiate embryonic development. Besides natural fertilization, several other methods have been developed to activate unfertilized oocytes without using sperm. These methods are not only utilized for animal production but have also proven effective in studying the molecular mechanisms that regulate the meiotic cell cycle, oocyte activation, and embryonic development. This study aimed to develop a method to activate mouse oocytes using a cell-penetrating peptide based on the knowledge that the C-terminal domain of the meiotic protein Emi2 can resume the arrested meiotic cell cycle.MethodsThis study used female B6D2F1 mice to investigate the effects of a CPP-fused Emi2 peptide on oocyte activation. Second meiotic metaphase oocytes were collected, cultured, and treated with the peptide or strontium chloride. Pronuclear formation, second polar body extrusion, and blastocyst development were assessed, and statistical significance was determined using Fisher’s exact test.ResultsThe cell-penetrating peptide activated zona-intact oocytes in a manner dependent on specific amino acid residues and peptide concentrations, which are critical components for cell membrane penetration. It has also been confirmed that oocytes activated using this method can develop to the blastocyst stage.DiscussionThe introduction of peptides or functional amino acid sequences using CPP or related methods could be an alternative for easily performing functional analyses of the activity of target proteins in oocytes.
A MULTI-MINERAL INTERVENTION TO IMPROVE DISEASE-RELATED AND MECHANISTIC BIOMARKERS IN ULCERATIVE COLITIS PATIENTS
Authors: Aslam Muhammad N. , Turgeon Danielle (Kim) , Appelman Henry D. , Stidham Ryan , McClintock Shannon , Allen Ron , Moraga Gillian , Harber Isabelle , Jencks Kara J. , McNeely Molly M. , Sen Ananda , Jepsen Karl J. , Varani James 
Published: February 2025

ABSTRACTIntroductionThe long-term goal of our studies is to determine if, and to what extent, a multi-mineral product (Aquamin) could have beneficial impact on individuals with ulcerative colitis (UC). As a step toward achieving that goal, we carried out a 180-day biomarker trial in patients with UC in remission or at the mild stage.ApproachA total of 28 subjects were included in the study. Each was randomized to receive either Aquamin for 180 days or placebo for the first 90 days. At day-90, placebo subjects crossed over to Aquamin for the final 90 days. At days-0, −90 and −180, serum samples were assessed for alkaline phosphatase (ALP), intestine-specific ALP (ALPI), C-reactive protein (CRP) and for biomarkers of bone turnover (osteocalcin, TRAP5b and bone-specific ALP [e.g., BALP]). Stool specimens were assessed for fecal calprotectin at the same time points and colon biopsies were examined histologically. Each subject underwent DEXA scanning (day-0 and −180 only). In addition, a mass spectrometry-based proteomic assessment was performed using colon biopsy specimens obtained at each time point.ResultsSubjects receiving Aquamin for the complete 180-day period (a total of 12) demonstrated improvement in all biomarkers; this was not seen in the placebo group (16 subjects). Subjects who received Aquamin for 90-days were intermediary in their responses. Subjects receiving Aquamin for 180-days also demonstrated increases in bone mineral density (BMD) and bone mineral content (BMC) resulting in a statistically-significant increase in the hip strength index over the period of treatment. This was accompanied by increases in osteocalcin and TRAP5b and by a decrease in BALP. The proteomic screen demonstrated up-regulation of multiple gut barrier proteins, cell surface transporter molecules and certain proteins with anti-inflammatory potential in response to Aquamin. Aquamin treatment also led to down-regulation of several proteins associated with the pro-inflammatory state.ConclusionThese findings suggest the potential value of multi-mineral intervention (Aquamin) as a low-cost, non-toxic adjuvant therapy for mild UC or for individuals with UC in remission.
The Austrian MS Database and the Austrian MS Cohort – a national effort towards data harmonization and prospective data collection
Authors: Bsteh Gabriel , Föttinger Fabian , Ponleitner Markus , Berek Klaus , Di Pauli Franziska , Heschl Bettina , Wurth Sebastian , Deisenhammer Florian , Enzinger Christian , Berger Thomas , Khalil Michael , Hegen Harald ,   the Austrian Multiple Sclerosis Database and Austrian MS cohort study group
Published: February 2025

AbstractBackgroundA variety of disease-modifying therapies (DMTs) are now available for multiple sclerosis (MS), each with distinct efficacy and risk profiles. However, the clinical course of MS varies significantly both within and between individuals, and the optimal treatment strategy remains uncertain at the group and individual levels. Addressing questions about treatment strategies through traditional randomized controlled trials is unrealistic due to the large sample sizes and high costs required. Instead, large-scale multicenter registries and well-characterized prospective observational cohorts offer a feasible approach to generating meaningful insights. For valid results, such registries and cohorts require harmonization across centers to support comprehensive, standardized, user-friendly data collection while meeting data protection standards and ensuring quality control.ObjectiveThis project aims to establish standardized, nationwide MS data collection in Austria.MethodsThe project consists of five key components: i) harmonization of data collection, ii) creation of infrastructure for data sharing, iii) retrospective harmonized data collection (Austrian MS Database, AMSD), iv) prospective harmonized data collection (Austrian MS Cohort, AMSC), and v) aggregated analyses.ResultsA comprehensive set of harmonized common data elements (CDE) comprising clinical and paraclinical data was developed and a common data collection infrastructure was generated using the web-based Research, Documentation, and Analysis platform (webRDA), an innovative data capture, processing, and analysis system provided by the Medical University of Vienna offering pseudonymized storage of data supported by a robust permissions system sufficing legal data protection and ethical requirements.The AMSC is set up as a standardized prospective collection of demographic, clinical, epidemiological, psycho-socio-economic, MRI, and OCT data as well as body fluids.ConclusionThe AMSD and AMSC will facilitate the evidence-based development of prognostic biomarkers, individualized therapy strategies and treatment sequences based on a high-quality, population-based dataset of more than 8,000 people with MS.
Rare gain-of-function regulatory mutations explain the missing heritability of bicuspid aortic valve
Authors: Zhigulev Artemy , Petersson Sjögren Madeleine , Buyan Andrey , Nozdrin Vladimir , Lázár Enikő , Mauron Raphaël , Lång Karin , Spalinskas Rapolas , Schwochow Doreen , Pradhananga Sailendra , Franco-Cereceda Anders , Lundeberg Joakim , Kulakovskiy Ivan V. , Eriksson Per , Björck Hanna M , Sahlén Pelin 
Published: February 2025

AbstractBicuspid aortic valve (BAV), a prevalent congenital cardiac defect, predisposes patients to severe complications. Despite its high heritability, previously identified protein-coding and common regulatory mutations account for only a small fraction of cases. To address this gap, we investigated the role of rare regulatory mutations. By integrating high-resolution three-dimensional genome organization profiling with whole-genome sequencing, we analyzed sixteen patients with BAV and normal tricuspid aortic valves. Our findings reveal a 1.5-fold enrichment of gain-of-function regulatory mutations in previously implicated genes among BAV patients. Genome-wide, moderately rare mutations (allele frequencies below 3%) were predicted to alter the transcriptome of specific developmental valve mesenchymal cell and fibroblast populations. Expanding the BAV pathway network with newly implicated genes uncovered substantial genetic heterogeneity underlying the disease. These results position rare regulatory mutations as pivotal contributors to missing BAV heritability and emphasize the need for further research of their mechanistic roles.
Kupffer cells control neonatal hepatic metabolism via Igf1 signaling
Authors: Makdissi Nikola , Hirschmann Daria , Frolov Aleksej , Sado Inaam , Nikolka Fabian , Cheng Jingyuan , Blank-Stein Nelli , Viola Maria Francesca , Yaghmour Mohamed , Arnold Philipp , Bonaguro Lorenzo , Becker Matthias , Thiele Christoph , Meissner Felix , Hiller Karsten , Beyer Marc D. , Mass Elvira 
Published: February 2025

AbstractDuring perinatal development, liver metabolism is tightly regulated to ensure energy supply for the newborn. Before birth, glycogen is stored in hepatocytes and later metabolized to glucose, meeting the energy demands of the neonate. Shortly after birth, lipogenesis begins, driven by the transcriptional activation of enzymes involved in fatty acid oxidation. These processes are thought to be largely regulated by systemic insulin and glucagon levels. However, the role of liver-derived local factors in neonatal hepatocyte metabolism remains unexplored. Kupffer cells (KCs), the liver’s resident macrophages, colonize the fetal liver early in embryogenesis and support liver metabolism in adulthood. Yet, whether KCs influence neonatal hepatocyte metabolism is unknown. Here, using conditional knockout mouse models targeting macrophages, we demonstrate that yolk sac-derived KCs play a critical role in hepatocyte glycogen storage and function by regulating the tricarboxylic acid (TCA) cycle - a role that monocyte-derived KC-like cells cannot substitute. Newborn pups lacking yolk sac-derived KCs mobilize glycogen more rapidly, a process regulated by insulin-like growth factor 1 (Igf1) production. Our findings reveal that macrophages are a major source of Igf1 at birth and that local Igf1 production by KCs is essential for balanced hepatocyte metabolism.
AFD Thermosensory Neurons Mediate Tactile-Dependent Locomotion Modulation inC. elegans
Authors: Rosero Manuel , Bai Jihong 
Published: February 2025

ABSTRACTSensory neurons drive animal behaviors by detecting environmental stimuli and relaying information to downstream circuits. Beyond their primary roles in sensing, these neurons often form additional synaptic connections outside their main sensory modality, suggesting broader contributions to behavior modulation. Here, we uncover an unexpected role for the thermosensory neuron AFD in coupling tactile experience to locomotion modulation inCaenorhabditis elegans. We show that while AFD employs cGMP signaling for both thermotaxis and tactile-dependent modulation, the specific molecular components of the cGMP pathway differ between these two processes. Interestingly, disrupting the dendritic sensory apparatus of AFD, which is essential for thermotaxis, does not impair tactile-based locomotion modulation, indicating that AFD can mediate tactile-dependent behavior independently of its thermosensory apparatus. In contrast, ablating the AFD neuron eliminates tactile-dependent modulation, pointing to an essential role for AFD itself, rather than its sensory dendritic endings. Further, we find tactile-dependent modulation requires the AIB interneuron, which connects AFD to touch circuits via electrical synapses. Removing innexins expressed in AFD and AIB abolishes this modulation, while re-establishing AFD-AIB connections with engineered electrical synapses restores it. Collectively, these findings uncover a previously unrecognized function of AFD beyond thermosensation, highlighting its influence on context-dependent neuroplasticity and behavioral modulation through broader circuit connectivity.
Mapping the Landscape of Allele-Specific Expression In Porcine Genomes
Authors: Yao Wen-ye , Gòdia Marta , Fang Lingzhao , Groenen Martien A. M. , Bai Lijing , Li Kui , Madsen Ole 
Published: February 2025

AbstractAllele-specific expression (ASE) is the imbalanced expression of two alleles of the same locus. It is quite pervasive among mammals and is associated with healthy and economically relevant traits. ASE is often used to support the identification of variants related to gene expression (cis-eQTLs). Thus, profiling ASE represents a significant step in elucidating the mechanism underlying gene expression regulation. In this study, we developed an ASE pipeline using public available RNA-seq data and open-source software. Using this pipeline, we were able to profile pervasive allelic imbalance across 42 tissues and 34 breeds from the Farm-GTEX-pig consortium at both SNP and gene levels without the need for parental genotype or whole genome sequence data. ASE was widely, but not evenly, spread across the genome. We also observed considerable variation in ASE profiles among various tissues, in which the ASE fraction ranged from 1.3% to 54.1%. ASE tends to be highly tissue-specific, and the overlap across tissues is limited. The functional analysis of tissue-specific ASE sites indicates that they are involved in the critical maintenance of these tissues. Our ASE pipeline can be readily applied to other RNA-seq data sets for livestock, thereby significantly expanding its potential utility. The wealth of available ASE resources provides a solid foundation for identifying regulatory elements within the genome that drive complex traits in livestock, making our pipeline and results valuable resources for researchers in this field.
Altered mechanical properties of astrocytes lacking MLC1; implications for the leukodystrophy MLC
Authors: Bisseling Quinty , Passchier Emma M.J. , Antonovaite Nelda , Camerini Serena , Brignone Maria S. , Freal Amélie , Mansvelder Huibert D. , Ambrosini Elena , van der Knaap Marjo S. , Min Rogier 
Published: February 2025

ABSTRACTLoss of function of the astrocyte protein MLC1 causes Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC), a leukodystrophy characterized by white matter edema and slow neurological deterioration. MLC1 dysfunction leads to swelling of perivascular astrocyte endfeet and an impaired attachment of endfeet to blood vessels. In isolated primary astrocytes, loss of MLC1 hinders recovery of astrocytes from cell swelling, but the cellular function of MLC1 is not completely understood. MLC1 modulates gating of mechanosensitive ion channels involved in volume regulation. The cytoskeleton plays a crucial role in cell volume regulation, and interactions between the cytoskeleton and cell membrane affect the properties of mechanosensitive ion channels. Therefore, we investigated whether primaryMlc1-null mouse astrocytes show a disruption in their mechanical properties. We measured mechanical properties of cultured primary astrocytes with an indentation technique and demonstrated thatMlc1-null astrocytes are softer than wild-type astrocytes. Proteomic analysis confirmed dysregulation of several cytoskeleton-related pathways inMlc1-null astrocytes. Confocal imaging revealed that organization of the actin cytoskeleton is unaffected. Instead, we observed alterations in focal adhesions, which aid in relaying mechanical forces between the cytoskeleton, cell membrane, and the extracellular matrix (ECM). Together, our findings reveal that the mechanical properties ofMlc1-null astrocytes are altered, and that disrupted cytoskeleton-membrane-ECM interactions potentially play a role in the disease. Modulators of astrocyte mechanobiology might therefore hold promise for MLC therapy development.
A discrete region of the D4Z4 is sufficient to initiate epigenetic silencing
Authors: Paatela Ellen M. , St. Amant Faith G. , Hamm Danielle C. , Bennett Sean R. , Gujral Taranjit S. , van der Maarel Silvère M. , Tapscott Stephen J. 
Published: February 2025

AbstractThe DUX4 transcription factor is briefly expressed in the early embryo and is epigenetically repressed in somatic tissues. Loss of epigenetic repression can result in the aberrant expression of DUX4 in skeletal muscle and can cause facioscapulohumeral dystrophy (FSHD). Multiple factors have been identified as necessary to maintain epigenetic silencing ofDUX4in skeletal muscle, but whether specific sequences at theDUX4locus are sufficient for epigenetic silencing has been unknown. We cloned fragments of the D4Z4 macrosatellite repeat, the DNA region that encompasses theDUX4retrogene, adjacent to a reporter driven by a constitutive promoter and identified a single fragment sufficient to epigenetically repress reporter gene expression. Previously identified suppressors ofDUX4expression—SETDB1, ATF7IP, SIN3A/B, and LRIF1—were necessary for silencing activity and p38 inhibitors enhanced suppression. These findings identify a key regulatory sequence for D4Z4 epigenetic repression and establish a model system for mechanistic and discovery studies.