bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction of Pediatric No-Show Rates Before and During the COVID-19 Pandemic Utilizing Machine Learning
Authors: Hathaway Quincy A. , Yanamala Naveena , Narumanchi TaraChandra , Narumanchi Janani
Published: November 2024

Background

Patient no-shows significantly disrupt pediatric healthcare delivery, highlighting the necessity for precise predictive models, especially during the dynamic shifts caused by the SARS-CoV-2 pandemic. In outpatient settings, these no-shows result in medical resource underutilization, increased healthcare costs, reduced access to care, and lower clinic efficiency and productivity.

Methods

The objective is to develop a predictive model for patient no-shows using data-driven techniques. We analyzed five years of historical data retrieved from both a scheduling system and electronic health records from a general pediatrics clinic within the WVU Health systems. This dataset comprises a total of 209,408 visits from 2015 to 2018, 82,925 visits in 2019, and 58,820 visits in 2020, spanning both pre-pandemic and pandemic periods. The data includes variables such as patient demographics, appointment details, timing, hospital characteristics, appointment types, and environmental factors.

Results

Our XGBoost model demonstrated robust predictive capabilities, notably outperforming traditional "no-show rate" metrics. Precision and recall metrics for all features were 0.82 and 0.88, respectively. Receiver Operator Characteristic (ROC) analysis yielded AUCs of 0.90 for all features and 0.88 for the top 5 predictors when evaluated on the 2019 cohort. Furthermore, model generalization across racial/ethnic groups was also observed. Evaluation on 2020 telehealth data reaffirmed model efficacy (AUC: 0.90), with consistent top predictive features.

Conclusions

Our study presents a sophisticated predictive model for pediatric no-show rates, offering insights into nuanced factors influencing attendance behavior. The model’s adaptability to evolving healthcare landscapes, including telehealth, underscores its potential for enhancing clinical practice and resource allocation.
Caregiver Mind-Mindedness Training as an Early Intervention for Social Anxiety in Children: A protocol for an RCT intervention
Authors: Javadian Hiva , Stewart Mary E. , Mathews Minu , Williams Andrew James , Hale Daniel
Published: November 2024

Background

This paper describes a randomised controlled trial (RCT) protocol aimed at investigating the efficacy of caregivers’ Mind-Mindedness training as an early intervention for preschoolers with social anxiety. Mind-mindedness, a caregiver’s ability to recognise and respond to a child as an individual with their own thoughts, feelings, and intentions, is associated with secure attachment and socioemotional skills. While previous studies indicate brief Mind-Mindedness training may increase caregiver mentalisation in high-risk groups, rigorous research on the impacts of social anxiety in children is limited. Building on the well-established link between caregiver’s Mind-Mindedness and positive socioemotional outcomes in children, this study aims to bridge the existing research gap by directly testing the impact of Mind-Mindedness training on social anxiety.

Methods

This randomized controlled trial aims to recruit 100 caregivers of preschool-aged 4 to 7-year-old children with social anxiety from the UK and Iran. The caregivers will be randomly assigned to either a mind-mindedness training group (n=50) or a peer support (control) group(n=50). The mind-mindedness training will involve three online sessions focused on teaching strategies for using mind-minded comments, the program will consist of three online sessions, each lasting one hour and conducted over three consecutive weeks. The peer support (control) group will have access to a private online peer-support platform for sharing experiences. Measures of mind-mindedness, child social anxiety, attachment, and theory of mind will be assessed at baseline, post-intervention, and 3-month follow-up using established assessment tools.

Discussion

The study aims to evaluate the effectiveness of a mind-mindedness parental intervention for social anxiety in children and to uncover the potential mediating roles of attachment and theory of mind in the relationship between mind-mindedness and child anxiety. The cross-cultural design, involving participants from the UK and Iran, will offer valuable information on the cultural aspect of the intervention. The training group is hypothesized to lead to increased mind-mindedness and reduced child social anxiety versus a peer support (control) group. This research can establish evidence for mind-mindedness training as an early intervention approach for childhood social anxiety.

Trial registration

Prospectively registered onClinicalTrials.gov(ID:NCT06657014; registered on 23rd October 2024) and on the Iranian Registry of Clinical Trials (IRCT) Version1(ID: 80088; approved on 2nd November 2024). These registrations promote transparency and ensure compliance with international standards for reporting clinical trials.
The East London Parkinson’s Disease Project – A case-control study in a diverse population
Authors: Zirra Alexandra , Dey Kamalesh C. , Camboe Ellen , Waters Sheena , Haque Tahrina , Huxford Brook , Chohan Harneek , Donkor Natalie , Kahan Joshua , Ben-Joseph Aaron , Gallagher David A. , Budu Caroline , Boyle Thomas , Simonet Cristina , Lees Andrew J , Marshall Charles R. , Noyce Alastair J.
Published: November 2024

Background

There is a relative dearth of research on patients with Parkinson’s disease (PD) from under-represented ethnic groups in the United Kingdom.

Objectives

The East London Parkinson Disease project seeks to understand the clinical manifestations and determinants of PD in a diverse population.

Methods

Patients with PD were recruited from the Royal London Hospital. Healthy controls came from community engagement events and partners of patients. Data on clinical features assessed by motor and non-motor scales were collected between January 2019 and February 2024, and compared between groups. Parametric, non-parametric tests, and unmatched logistic models, adjusted for age, gender and duration of disease were used.

Results

We assessed 218 patients with PD and 90 controls. Among them, 50% of patients and 64% controls identified as South Asian or Black. Males comprised 63% of patients and 70% of controls. After adjusting for age, gender, disease duration and treatment burden, South Asian and Black patients had significantly worse motor scores compared to White patients (mean [SD], 42.2 [18.8], and 47 [16.6] vs 35.2 [16.4], p<0.001 and p<0.001). Cognitive impairment was more prevalent in South Asian (73%) and Black patients (75%) than in White patients (45%, p=0.002).

Conclusions

Our results suggest that patients with PD from South Asian and Black ethnic groups may have more severe motor and certain non-motor features, including cognitive impairment, compared to White patients.
Cohort Profile Update: Expanding the Cardiovascular Risk in Young Finns Study into a multigenerational cohort
Authors: Pahkala Katja , Rovio Suvi , Auranen Kari , Bourgery Matthieu , Elovainio Marko , Fogelholm Mikael , Haapala Johanna , Hirvensalo Mirja , Hutri Nina , Jokinen Eero , Jula Antti , Juonala Markus , Kaikkonen Jari , Kartiosuo Noora , Kiviranta Hannu , Koskinen Juhani S. , Kotaja Noora , Kähönen Mika , Laitinen Tomi P. , Lehtimäki Terho , Lisinen Irina , Loo Britt-Marie , Lyytikäinen Leo-Pekka , Magnussen Costan G. , Mishra Pashupati P. , Mykkänen Juha , Mäkelä Juho-Antti , Männistö Satu , Nevalainen Jaakko , Pulkki-Råback Laura , Raitoharju Emma , Rantakokko Panu , Rönnemaa Tapani , Stenbacka Sini , Taittonen Leena , Tammelin Tuija H. , Toppari Jorma , Tossavainen Päivi , Viikari Jorma , Raitakari Olli
Published: November 2024

Cardiovascular Risk in Young Finns Study (YFS) is a prospective cohort of 3596 males and females (baseline age 3-18 years) that was established in 1980 to study cardiovascular risk factors in children and adolescents. The YFS has been instrumental in demonstrating the links between childhood risk factors and adult cardiovascular outcomes with implications on paediatric cardiovascular preventive practise.

In the latest follow-up in 2018-2020, the study was expanded into a three-generation cohort, including the original cohort members, as well as their parents and offspring. Altogether 7341 individuals aged 3-92 years participated; 2127 original cohort members (now aged 40-58 years), 2452 parents (aged 58-92 years) and 2762 offspring (aged 3-37 years) of the original cohort members.

The main aim was to establish a multigenerational population data base, sample biobank and links to national health registries that would offer a unique platform to study familial transmission of health-related traits. The field studies and data collections were conducted as part of the ERC funded MULTIEPIGEN project designed testing a specific hypothesis that epigenetic markers in the semen play a role in the transmission of intergenerational information in the paternal lineage. It is a firsta prioridesigned epidemiologic study assessing the role of paternal life exposures, including chemical and psychosocial stress, in the development of cardio-metabolic, cognitive and psychosocial outcomes in their offspring.
The 14-Day Incidence and Risk Factors of Gastrointestinal Anastomotic Leak Among Adult Patients in Mulago Hospital
Authors:   A PROSPECTIVE COHORT STUDY, Omare Isaac , Mbiine Ronald , Kasagga Brian , Kabweru Wilberforce Musoga , Okeny Paul
Published: November 2024

Introduction

Anastomotic leak is a dreaded complication following gastrointestinal (GI) anastomotic surgery. It increases morbidity and mortality of patients undergoing GI surgery. However, there is paucity of data on the incidence and risk factors of anastomotic leak following gastrointestinal surgery in Uganda. The main objective of this study was to determine the incidence and risk factors of anastomotic leak following gastrointestinal surgery in Mulago Hospital.

Methods

We consecutively recruited adult patients admitted to the general surgery wards in Mulago Hospital, 24 hours following gastrointestinal surgery. The recruitment process started on 22ndApril 2024 and ended on 11thJuly 2024. The participants provided informed written consent prior to enrolment into the study. Patient related factors including preoperative anemia, preoperative albumin level, and ASA status were recorded on entry, while the outcome (anastomotic leak) was obtained upon 14 day’s follow-up. Data were analysed using SPSS version 26. Multivariate logistic regression was used to determine the independent risk factors for anastomotic leak, p< 0.05 was considered statistically significant.

Results

Eighty-five participants were studied. The incidence of anastomotic leak was 8.2% (n=7). Hemoglobin level less than 10 g/dl was the only independent predictor for anastomotic leak in this study. (RR, 8.15; 95% C.I, 1.16 - 57.48; p=0.035).

Conclusion

The incidence of anastomotic leak in Mulago National Referral Hospital was low. Low Hemoglobin (Hb<10g/dl) was associated with increased rates of anastomotic leak.
Intracranial Atherosclerotic Disease in Acute Ischemic Stroke: Clinical Predictors, Imaging Profiles, and Treatment Outcomes: An Analysis from RITE Registry
Authors: Alotaibi Fawaz F. , Mlynash Michael , Muteb M. Aldawsari , AlAbidien Nowar Z. , Alqahtani Mohammed , BinAmir Hussain , AlKawi Ammar , Alreshaid Abdulrahman A. , AlZawahmah Mohamed , Alhazzani Adel , Alabdaly Hani , Alanazi Abdulmajeed , Almansour Nouf , Albers Gregory W. , Shuaib Ashfaq , Al-Ajlan Fahad S.
Published: November 2024

Background

Intracranial atherosclerotic disease (ICAD) is a leading cause of ischemic stroke worldwide, with a significant prevalence in specific populations. This study aims to compare the clinical characteristics, imaging profiles, and outcomes of stroke patients with large vessel occlusion (LVO) caused by ICAD versus non-ICAD etiologies, particularly in those transferred for endovascular treatment (EVT).

Methods

A retrospective analysis was conducted using data from the Riyadh Thrombectomy Registry, including 219 patients with acute ischemic stroke who underwent EVT between January 2019 and March 2024. Clinical, demographic, and imaging data were collected and compared between ICAD and non-ICAD groups. Imaging modalities included computed tomography perfusion (CTP) and angiography, with key metrics such as the hypoperfusion intensity ratio (HIR) and cerebral blood volume (CBV) index evaluated for prognostic utility.

Results

Patients with ICAD were older and demonstrated a higher prevalence of vascular risk factors. ICAD patients presented with better ASPECTS scores, smaller ischemic core volumes, and higher mismatch ratios, reflecting better collateral circulation. However, despite favorable imaging profiles, ICAD patients exhibited higher mortality rates, particularly in cases involving basilar artery occlusion. HIR and CBV indices demonstrated modest diagnostic performance in distinguishing ICAD from non-ICAD, with an area under the curve (AUC) of 0.62 for HIR and 0.57 for CBV.

Conclusions

ICAD patients undergoing EVT showed distinct clinical and imaging characteristics compared to non-ICAD patients. Despite better collateral circulation, ICAD is associated with higher mortality, especially in posterior circulation strokes. Further research is required to optimize EVT strategies and explore adjunctive therapies tailored to this challenging patient population.
Molecular architecture of thylakoid membranes within intact spinach chloroplasts
Authors: Wietrzynski Wojciech , Lamm Lorenz , Wood William H.J. , Loukeri Matina-Jasemi , Malone Lorna , Peng Tingying , Johnson Matthew P. , Engel Benjamin D.
Published: November 2024

Thylakoid membranes coordinate the light reactions of photosynthesis across multiple scales, coupling the architecture of an elaborate membrane network to the spatial organization of individual protein complexes embedded within this network. Previously, we usedin situcryo- electron tomography (cryo-ET) to reveal the native thylakoid architecture of the green algaChlamydomonas reinhardtii[1] and then map the molecular organization of these thylakoids with single-molecule precision [2]. However, it remains to be shown how generalizable this green algal blueprint is to the thylakoids of vascular plants, which possess distinct membrane architecture subdivided into grana stacks interconnected by non-stacked stromal lamellae. Here, we continue our cryo-ET investigation to reveal the molecular architecture of thylakoids within intact chloroplasts isolated from spinach (Spinacia oleracea). We visualize the fine ultrastructural details of grana membranes, as well as interactions between thylakoids and plastoglobules. We apply and further develop AI-based computational approaches for automated membrane segmentation and membrane protein picking [3], enabling us to quantify the organization of photosynthetic complexes within the plane of the thylakoid membrane and across adjacent stacked membranes. Our analysis reveals that, despite different 3D architecture, the molecular organization of thylakoid membranes in vascular plants and green algae is strikingly similar. In contrast to isolated plant thylakoids, where semi- crystalline arrays of photosystem II (PSII) appear to hold some membranes together, we find in intact chloroplasts that PSII is non-crystalline and has uniform concentration both within the membrane plane and across stacked grana membranes. Similar toC. reinhardtii, we observe strict lateral heterogeneity of PSII and PSI at the boundary between appressed and non-appressed thylakoid domains, with no evidence for a distinct grana margin region where these complexes have been proposed to intermix. Based on these measurements, we support a simple two-domain model for the molecular organization of thylakoid membranes in both green algae and plants.
Effects of Primed Adipose Mesenchymal Stem Cell-Derived Exosomes on Immunomodulation in Behcet Uveitis
Authors: Gozel Merve , Aydemir Dilara , Kaleli Humeyra Nur , Cosar Feray , Guleser Umit Yasar , Unlu Eda Kusan , Kesim Cem , Sezgin Billur , Sahin Afsun , Ucar Didar , Hatemi Gulen , Hasanreisoglu Murat
Published: November 2024

Purpose

This study sought to investigate the potential role of exosomes of interferon-gamma (IFN-γ) primed (IFN+Exo) and non-primed (IFN-Exo) adipose-derived mesenchymal stem cells (AdMSCs) for the treatment of Behçet Disease (BD) uveitis (BU).

Methods

AdMSCs were isolated from adipose tissue. Characterization and multipotency analyses were performed. Exosomes were isolated from the media of AdMSCs and then characterized. Peripheral blood mononuclear cells (PBMC) were isolated from patients with BU and healthy individuals. AdMSCs were preincubated with or without IFN-γ for 48 h. PBMC of patients with BU and healthy controls separately cultured with exosomes for 72 h. After the culture period, lymphocyte proliferation, viability, and apoptosis were carried out via flow cytometry. The expression of interleukin (IL)-10, IL-17, transforming growth factor (TGF)-β, and interferon (IFN)-γ levels were measured by real-time polymerase chain reaction (RT-PCR).

Results

IFN+Exo promoted lymphocyte apoptosis in patients with BU. IFN+Exo suppressed cell viability of T lymphocytes of BU. Exosomes alone did not affect on T lymphocyte proliferation. Additionally, exosomes increased anti-inflammatory cytokine levels and reduced pro-inflammatory cytokine levels of T lymphocytes in patients with BU.

Conclusion

This study’s findings can open a new pathway in MSCs/exosome therapy in BU.
Can AI modelling of protein structures distinguish between sensor and helper NLR immune receptors?
Authors: Toghani AmirAli , Frijters Raoul , Bozkurt Tolga O. , Terauchi Ryohei , Kamoun Sophien , Sugihara Yu
Published: November 2024

NLR immune receptors can be functionally organized in genetically linked sensor-helper pairs. However, methods to categorize paired NLRs remain limited, primarily relying on the presence of non-canonical domains in some sensor NLRs. Here, we propose that the AI system AlphaFold 3 can classify paired NLR proteins into sensor or helper categories based on predicted structural characteristics. Helper NLRs showed higher AlphaFold 3 confidence scores than sensors when modelled in oligomeric configurations. Furthermore, funnel-shaped structures—essential for activating immune responses—were reliably predicted in helpers but not in sensors. Applying this method to uncharacterized NLR pairs from rice, we found that AlphaFold 3 can differentiate between putative sensors and helpers even when both proteins lack non-canonical domain annotations. These findings suggest that AlphaFold 3 offers a new approach to categorize NLRs and enhances our understanding of the functional configurations in plant immune systems, even in the absence of non-canonical domain annotations.
Assembly and lipid-gating of LRRC8A:D volume-regulated anion channels
Authors: Lurie Antony , Kern David M. , Henn Katharine , Brohawn Stephen G.
Published: November 2024

Volume-regulated anion channels (VRACs) are ubiquitously expressed vertebrate ion channels that open in response to hypotonic swelling. VRACs assemble as heteromers of LRRC8A and LRRC8B-E subunits, with different subunit combinations resulting in channels with different properties. Recent studies have described the structures of LRRC8A:C VRACs, but how other VRACs assemble, and which structural features are conserved or variant across channel assemblies remains unknown. Herein, we used cryo-EM to determine structures of a LRRC8A:D VRAC with a 4:2 subunit stoichiometry, which we captured in two conformations. The presence of LRRC8D subunits increases hydrophobicity and widens the selectivity filter, which may explain the unique substrate selectivity of LRRC8D-containing VRACs. The structures reveal lipids bound inside the channel pore, similar to those observed in LRRC8A:C VRACs. Using electrophysiological experiments, we confirmed that pore lipids block conduction in the closed state, demonstrating that lipid-gating is a general property of VRACs. Finally, we observe that LRRC8D subunit incorporation disrupts packing of the cytoplasmic LRR domains, increasing channel dynamics and opening lateral fenestrations, which we speculate are necessary for pore lipid evacuation and channel activation.
Intraoperative Augmented Reality for Vitreoretinal Surgery using Edge Computing
Authors: Ye Run Zhou , Iezzi Raymond
Published: November 2024

Purpose

Augmented reality (AR) may allow vitreoretinal surgeons to leverage microscope-integrated digital imaging systems to analyze and highlight key retinal anatomic features in real-time, possibly improving safety and precision during surgery. By employing convolutional neural networks (CNNs) for retina vessel segmentation, a retinal coordinate system can be created that allows pre-operative images of capillary non-perfusion or retinal breaks to be digitally aligned and overlayed upon the surgical field in real-time. Such technology may be useful in assuring thorough laser treatment of capillary non-perfusion or in using pre-operative optical coherence tomography (OCT) to guide macular surgery when microscope-integrated OCT (MIOCT) is not available.

Methods

This study is a retrospective analysis involving the development and testing of a novel image registration algorithm for vitreoretinal surgery. Fifteen anonymized cases of pars plana vitrectomy with epiretinal membrane peeling, along with corresponding preoperative fundus photographs and optical coherence tomography (OCT) images, were retrospectively collected from the Mayo Clinic database. We developed a TPU (Tensor-Processing Unit)-accelerated CNN for semantic segmentation of retinal vessels from fundus photographs and subsequent real-time image registration in surgical video streams. An iterative patch-wise cross-correlation (IPCC) algorithm was developed for image registration, with a focus on optimizing processing speeds and maintaining high spatial accuracy. The primary outcomes measured were processing speed in frames per second (FPS) and the spatial accuracy of image registration, quantified by the Dice coefficient between registered and manually aligned images.

Results

When deployed on an Edge TPU, the CNN model combined with our image registration algorithm processed video streams at a rate of 14 FPS, which is superior to processing rates achieved on other standard hardware configurations. The IPCC algorithm efficiently aligned pre-operative and intraoperative images, showing high accuracy in comparison to manual registration.

Conclusion

This study demonstrates the feasibility of using TPU-accelerated CNNs for enhanced AR in vitreoretinal surgery.
Repeated administration of pharmaceutical-grade medium chain triglycerides, a common pharmacologic excipient, confers dose-dependent toxicity by the intraperitoneal but not oral route in mice*
Authors: Adler-Wachter Mitzi , Tsai Julia Y. , Schweitzer Brendan N. , McDonough Ashley , Snyder Jessica M. , Barker-Haliski Melissa , Weinstein Jonathan R.
Published: November 2024

Pharmaceutical-grade medium chain triglycerides (MCTs) are common excipients for in vivo pharmacological studies in laboratory animals, and as an experimental therapeutic in certain metabolic and neurological disorders. In this study, we examined the tolerability of repeated administration of a pharmaceutical-grade formulation of three MCTs—caprylic, capric, and lauric acid - in mice via the oral (PO) and intraperitoneal (IP) routes. We administered either 8 or 4 µL of 100% MCTs or saline/gram of body weight twice daily for seven days. During administration and for seven days after, we monitored weight change and clinical presentation. On day 14, or upon meeting euthanasia criteria, animals were sacrificed for gross necropsy, histology, and complete blood count. We observed significant weight loss, clinical decline and 100% mortality in animals receiving 8 µL/g of MCTs via the IP route of administration. Gross necropsy revealed serosanguinous fluid in the thoracic cavity, dark red mottled lungs, and adhesions in the abdominal cavity. Histology confirmed inflammation of the lungs, mediastinum, and peritoneum. Mild gross lesions and initial weight loss (through day 3) were also present in mice receiving 4 µL/g of MCTs IP. However, these animals regained weight by day seven and exhibited no clinical decline or mortality. None of these adverse effects were seen in animals receiving either 8 µL/g of MCTs PO or 8 µL/g of saline IP. These findings suggest repeated IP administration of MCTs may cause dose-dependent toxicity, and mortality at high doses, but confers no adverse effects when administered via the PO route.

SIGNIFICANCE STATEMENT

Medium chain triglycerides (MCTs) are commonly used as an excipient in pharmacological studies involving laboratory animals. Our work provides much needed safety information regarding adverse effects of repeated MCTs administration via the intraperitoneal, but not the oral, route in mice.
Intraspecific and intraindividual trait variability decrease with tree species richness in a subtropical tree biodiversity experiment
Authors: Sánchez-Bermejo Pablo Castro , Carmona Carlos Pérez , Schuman Meredith Christine , Benavides Raquel , Sachsenmaier Lena , Li Shan , Liu Xiaojuan , Haider Sylvia
Published: November 2024

Phenotypic variability within tree species responds to local tree species richness. However, we lack evidence on how different sources of trait variation shape tree-tree interactions. Along a diversity gradient from one to eight tree species, we sampled 4,568 leaves from 381 trees to study changes in intraspecific and intraindividual leaf trait variability and assessed their contribution to community functional diversity. Intraspecific variability decreased with tree species richness, while intraindividual variability barely responded. Functional overlap between conspecific trees increased with tree species richness and through intraindividual variation, but was reduced through intraspecific variability, meaning that intraspecific variability may reduce intraspecific competitive interactions while intraindividual variability could arise due to varying microenvironmental conditions within the canopy. Last, intraspecific and intraindividual variability explained high community functional richness and divergence, respectively, especially in mixtures. Our findings emphasize that fine-scale variability influences tree-tree interactions and can be a driver of local functional diversity.

Teaser

Trait variability within tree species decreases with diversity and explains high forest functional diversity.
Beyond HER2 expression in breast cancer: Investigating alternative splicing profiles as a mechanism of resistance to anti-HER2 therapies
Authors: Guardia Gabriela D A , dos Anjos Carlos Henrique , Pozzo Aline Rangel , dos Santos Filipe Ferreira , Birbrair Alexander , Asprino Paula , Camargo Anamaria A , GALANTE PEDRO A F
Published: November 2024

Breast cancer is a heterogeneous disease that can be molecularly classified based on the expression of hormone receptors and the overexpression of the HER2 receptor (ERBB2). Targeted therapies for HER2-positive breast cancer, including trastuzumab, antibody drug conjugates (ADCs) and tyrosine kinase inhibitors, have significantly improved patient outcomes. However, both primary and acquired resistance to these treatments pose challenges that can limit their long-term efficacy. Addressing these obstacles is vital for enhancing therapeutic strategies and patient care. Alternative splicing, a post-transcriptional mechanism that enhances transcript diversity (isoforms) within a cell, can result in isoform-encoded proteins with varied functions, cellular localizations, or binding properties. In this study, we undertook a comprehensive characterization of the alternative splicing isoforms of HER2, assessed their expression levels in primary breast tumors and cell lines, and explored their role in resistance to anti-HER2 therapies. Our results have significantly expanded the catalog of known HER2 protein-coding isoforms from 13 to 90, revealing distinct patterns of protein domains, cellular localization, and protein structures, as well as mapping their antibody-binding sites. Additionally, by profiling expression in 561 primary breast cancer samples and analyzing mass spectrometry data for translation evidence, we discovered a complex landscape of splicing isoform expression in primary tumors, revealing novel isoforms that were previously unrecognized and are not evaluated in routine clinical practice. This extends beyond the traditional profile based solely on HER2 gene expression and translation. Finally, by assessing HER2 isoform expression in cell cultures that are either sensitive or resistant to trastuzumab and ADCs (T-DM1 or T-DXd), we found that drug-resistant tumor cells shifted their expression toward splicing isoforms that lack the antibody-binding domains. Our results substantially broaden the understanding of HER2 protein-coding isoforms, revealing distinct mechanisms of potential resistance to anti-HER2 therapies, particularly ADCs, by uncovering a new dimension of splicing isoform diversity. This expanded landscape of HER2 isoforms, marked by unique domain patterns and altered antibody-binding sites, emphasizes the crucial role of alternative splicing investigations in advancing precision-targeted cancer therapies.
De novoprotein-coding gene variants in developmental stuttering
Authors: Eising Else , Dzinovic Ivana , Vino Arianna , Stipdonk Lottie , Pavlov Martin , Winkelmann Juliane , Sommer Martin , Franken Marie-Christine J.P. , Oexle Konrad , Fisher Simon E.
Published: November 2024

Stuttering is a common neurodevelopmental condition characterized by disfluencies in speech, such as blocks, prolongations, and repetitions. While most children who stutter do so only transiently, there are some for whom stuttering persists into adulthood. Rare-variant screens in families including multiple relatives with persistent stuttering have so far identified six genes carrying putative pathogenic variants hypothesized to act in a monogenic fashion. Here, we applied a complementary study design, searching instead forde novovariants in exomes of 85 independent parent-child trios, each with a child with transient or persistent stuttering. Exome sequencing analysis yielded a pathogenic variant inSPTBN1as well as likely pathogenic variants inPRPF8,TRIO, andZBTB7A- four genes previously implicated in neurodevelopmental disorders with or without speech problems. Our results also highlighted two further genes of interest for stuttering:FLT3andIREB2. We used extensive bioinformatic approaches to investigate overlaps in brain-related processes among the twelve genes associated with monogenic forms of stuttering. Analyses of gene-expression datasets of the developing and adult human brain, and data from a genome-wide association study of human brain structural connectivity, did not find links of monogenic stuttering to specific brain processes. Overall, our results provide the first direct genetic link between stuttering and other neurodevelopmental disorders, including speech delay and aphasia. In addition, we systematically demonstrate a dissimilarity in biological pathways associated with the genes thus far implicated in monogenic forms of stuttering, indicating heterogeneity in the etiological basis of this condition.
Genomic predictors of response to antidepressants in Major depressive disorder (MDD): A GWAS-Based Study on Indian cohort
Authors: Goel Isha , Hans Gagan , Kumar Nand , Karmakar Subhradip
Published: November 2024

Background

Major depressive disorder (MDD) affects a significant portion of the population, with approximately 70% of patients not achieving adequate remission using anti-depressant monotherapy, a condition known as inadequate treatment response (ITR). In the Indian population, few studies have explored the genetic associations of this response, and those that exist are underpowered. This study aims to identify single nucleotide variations associated with ITR in the Indian population. The goal is to develop a population-specific gene panel that can identify subjects at risk for ITR, allowing alternative treatment modalities.

Methods

Subjects satisfying inclusion-exclusion criteria were enrolled for the study following institutional ethical approval. We recruited 120 subjects with MDD and assessed their response to monotherapy (Escitalopram) using the Hamilton Depression Rating Scale (HAMD) before and 4-6 weeks after medication. Responders (n=45) and non-responders (n=75) were genotyped using the Infinium Global Screening SNP-Array-24 v3.0. A genome-wide association study (GWAS) was performed to identify SNPs associated with ITR.

Results

Twelve lead-significant SNPs with a threshold of < 1E-05 were identified, suggesting an association with ITR. Among these, four SNPs were located in the intronic/regulatory regions of the genesLRSAM1, EFCAB2, TRIM56andZNF17. The remaining eight SNPs were near genesALDH1A2, LIPC, MYOCD, SPRY2, ANKRD18B, CCDC54, TNS3, ANKRD46, andFCRL2. These genes are involved in critical functions related to cell signalling, immune response, neurodevelopment, regulating intracellular levels, and transcription factor binding.

Conclusions

Our study identified several novel SNPs that may be associated with ITR in MDD patients, reported for the first time in an Indian cohort. Further investigations are underway to determine their clinical significance and potential to be used for screening individuals responding to drug interventions as user-friendly gene panels.
Relationships between 25-Hydroxyvitamin D and Alpha-synucleinopathies: A Mendelian Randomization Study
Authors: Li Fu-Jia , Geng Ru-Lin , Wen Cheng , Huang Kai-Xun , Lin Dan-Yu , Li Zhong-Gui , Zhang Jie-Li , Xu Chuan-Ying , Zhang Wei , Zu Jie , Dong Li-Guo , Wang Wen-Xin , Ruan Zhi-Jia , Yin Pei-Xiao , Guan Chen-Yang , Cui Gui-Yun , Tao En-Xiang
Published: November 2024

Background

Alpha-synucleinopathies, including Parkinson’s disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), are neurodegenerative diseases characterized by abnormal aggregation of alpha-synuclein. Isolated REM sleep behavior disorder (iRBD) is a prodromal stage of these disorders. While 25-hydroxyvitamin D (25[OH]D) has been linked to PD in previous studies, its causal role remains unclear, and its relationship with iRBD, MSA, and DLB is rarely explored.

Objectives

This study used Mendelian randomization (MR) to investigate the causal relationship between 25(OH)D and iRBD, PD, MSA, and DLB.

Methods

GWAS data for 25(OH)D were sourced from the UK Biobank, and outcome data for PD were obtained from the latest FinnGen R12 database. Data for iRBD, PD onset age, PD clinical progression, MSA, and DLB were derived from a broader European population. The study had two steps: univariable MR (UVMR) using genome-wide IV selection as the primary analysis, with replication analyses using biological function-based IV selection and sunlight exposure and vitamin D supplementation-related factors as exposures. Multivariable MR (MVMR) was then conducted to adjust for 13 covariates, testing the robustness of findings.

Results

25(OH)D showed a significant protective effect on MSA across all UVMR (both primary and replication) and MVMR analyses. It also exhibited a nominal protective effect on PD in the Finnish population in primary UVMR analysis, but this was not replicated. No associations were found between 25(OH)D and iRBD, PD onset age, PD clinical progression, or DLB. Power analyses indicated insufficient sensitivity to detect weak effects of 25(OH)D on iRBD and DLB.

Conclusions

MR analysis supports a protective role of 25(OH)D against MSA. While nominally protective for PD in the Finnish population, the effect was not robust. Weak effects on iRBD and DLB cannot be excluded.
Impact of Scabies on Quality of Life and Recent Advances in Management: A Systematic Review
Authors: Kumari Sakshi , Srinivas Swathi , Siddiqua Zainab , Qazi Muhammad Saeed , Sheikh Mahin , Rath Shree , Khan Maham , Jawaid Muhammad Daim , Tummala Nayanika , Mal Madho
Published: November 2024

Introduction

Scabies are a highly transmittable disease of the skin. It is caused by a specific mite named Sarcoptes scabiei. Individuals who are infected with scabies have a miserable life, and their quality of life is poor. It impacts the quality of life by causing physical discomfort due to itching. Not only does it lead to the mental distress of a diseased individual, but it also leads to social isolation due to the stigma associated with this condition. This systematic review highlights the profound effect of scabies on the lives of affected individuals and the recent breakthroughs in the management of scabies.

Purpose

The purpose of this article is to shed light on the impact of scabies on the quality of life. We also discussed the advancements in the management of this disease, which impacts life physically and socially.

Method

We included randomized controlled trials, clinical trials, and observational studies. Studies with full-text access were included. Case reports, letters, and systematic/narrative reviews were excluded from the search. 180 records were screened up to March 2024, of which 129 articles were from PubMed and 51 from Google Scholar. 22 articles were thoroughly screened by two different reviewers independently and included in the review. Studies were carried out with no restrictions on age or sex, including the pediatric and adult populations.

Conclusion

Findings indicate a significant correlation between scabies and poor quality of life. Scabies most commonly affect children of lower socioeconomic status and in resource-limited settings. Scabies can lead to severe complications such as rheumatic heart disease, kidney diseases, and a variety of secondary bacterial infections; therefore, advances in treatment strategies are needed. Currently, permethrin and ivermectin have been used for treatment. Moxidectin, a new drug, is undergoing clinical trials to replace permethrin in regions with high resistance. The interventions need to be patient-centered, and new drugs need to be developed that have anti-parasitic actions and also lead to the prevention of secondary bacterial infections.
Computational modeling enables individual assessment of postprandial glucose and insulin responses after bariatric surgery
Authors: Poyraz Onur , Heinonen Sini , John S. T. , Saarinen Tuure , Juuti Anne , Marttinen Pekka , Pietiläinen Kirsi H.
Published: November 2024

Bariatric surgery enhances glucose metabolism, yet the detailed postprandial joint glucose and insulin responses, variability in individual outcomes and differences in surgical approaches remain poorly understood. To address this, we used hierarchical multi-output Gaussian process (HMOGP) regression to model the individual postprandial glucose and insulin responses and to estimate the average response curves from individual data. Our study included 44 patients with obesity who underwent either Roux-en-Y gastric bypass (RYGB) (n=24) or One-Anastomosis gastric bypass (OAGB) (n=20) surgery. The patients were followed up at 6th and 12th months after the operation, during which they underwent an oral glucose tolerance test (OGTT) and a mixed meal test (MMT). A marked reduction in glycaemia, an earlier glucose peaking time and increase and sharpening in the postprandial glucose and insulin responses were evident in both metabolic tests after the operations. MMT resulted in higher postprandial glucose and insulin peaks compared with OGTT and higher glucose and insulin responses were observed after RYGB compared with OAGB. Women and persons without T2DM had a healthier postprandial response before and after surgery. Computational modeling with HMOGP regression can be used to, in detail, predict the combined responses of patient cohorts to ingested glucose or a mixed meal, and help in assessing individual metabolic improvement after weight loss. This can lead to new knowledge in personalized metabolic interventions.
Bayesian Mendelian Randomization Analysis for Latent Exposures Leveraging GWAS Summary Statistics for Traits Co-Regulated by the Exposures
Authors: Yu Yue , Lakkis Andrew , Zhao Bingxin , Jin Jin
Published: November 2024

Mendelian Randomization analysis is a popular method to infer causal relationships between exposures and outcomes, utilizing data from genome-wide association studies (GWAS) to overcome limitations of observational research by treating genetic variants as instrumental variables. This study focuses on a specific problem setting, where causal signals may exist among a series of correlated traits, but the exposures of interest, such as biological functions or lower-dimensional latent factors that regulate the observable traits, are not directly observable. We propose a Bayesian Mendelian randomization analysis framework that allows joint analysis of the causal effects of multiple latent exposures on a disease outcome leveraging GWAS summary-level association statistics for traits co-regulated by the exposures. We conduct simulation studies to show the validity and superiority of the method in terms of type I error control and power due to a more flexible modeling framework and a more stable algorithm compared to an alternative approach and traditional single- and multi-exposure analysis approaches not specifically designed for the problem. We have also applied the method to reveal evidence of the causal effects of psychiatric factors, including compulsive, psychotic, neurodevelopmental, and internalizing factors, on neurodegenerative, autoimmune, digestive, and cardiometabolic diseases.
Demographic Representation of a Decentralized Long COVID Trial: A Comparison with the 2023 National Health Interview Survey
Authors: Sawano Mitsuaki , Warner Frederick , Henriquez Yashira , Bhattacharjee Bornali , Iwasaki Akiko , Krumholz Harlan M.
Published: November 2024

Importance

Clinical trials can be a chokepoint to progress in medicine. They are commonly expensive, slow, and not participant-centric. Ensuring patient-centric, equitable trials with diverse demographic representation is essential for developing generalizable treatments and reducing healthcare disparities. Thus, there is an urgent need to test new ways of conducting clinical trials. The PAX LC trial is a novel Phase II decentralized, digital, and participant-centric double-blind randomized trial of Paxlovid for long COVID and is a test case for a new approach. There is a need to determine how well the trial enrolled a representative population with long COVID.

Objective

To compare the demographic characteristics of participants in the PAX LC trial with those reported in the National Health Interview Survey (NHIS) to assess how well the decentralized recruitment reflects the broader population in the US with long COVID.

Design

Descriptive analysis comparing 2 databases: a Phase 2, 1:1 randomized, double-blind, superiority, placebo-controlled trial conducted in community-dwelling adults with long COVID, and a nationwide observational cross-sectional survey.

Setting

Decentralized clinical trial with participants recruited from 48 contiguous states in the US. The NHIS survey participants were recruited from all 50 states.

Participants

100 highly symptomatic adults with long COVID in the PAX LC trial, compared with 575 from NHIS.

Intervention(s) or Exposure(s)

None.

Main Outcome(s) and Measure(s)

Percentage distribution by age group, gender, race and ethnicity, and region for each group.

Results

PAX LC included 100 participants and NHIS 575, with PAX LC participants being younger (median 42 vs. 53 years). There was an equal proportion of women. Non-Hispanic White representation was higher in PAX LC (89% vs. 61% in NHIS), while the Hispanic and Non-Hispanic Black groups were underrepresented (5% vs. 20% and 1% vs. 12%, respectively). More PAX LC participants were from the Northeast (51% vs. 15%) due to earlier enrollment in this region.

Conclusions and Relevance

The PAX LC trial highlights the potential of decentralized trials to achieve geographic diversity and balanced age and gender representation. However, to maximize the benefits of this approach, further efforts are warranted to improve racial and ethnic diversity.

Trial Registration

NCT05668091.
Long-term Outcomes of Poor-grade Aneurysmal Subarachnoid Haemorrhage: A Multicentre Observational Cohort Study
Authors: Wang Bangyue , Li Tianxing , Zhao Yan , Zhou Tian , Wang Ruyi , Li Yang , An Xiuhu , Hao Jiheng , Wang Kaijie , Yang Xinyu
Published: November 2024

BACKGROUND

Despite advancements in neurosurgery and intensive care that reduce overall mortality, poor-grade aneurysmal subarachnoid haemorrhage (aSAH) (World Federation of Neurosurgical Societies [WFNS] grades IV and V) remains a significant clinical challenge and is associated with persistently high mortality rates. The aim of this study was to assess the long-term outcomes of poor-grade aSAH and to identify factors influencing patient prognosis to guide clinical management.

METHODS

A multicentre, observational cohort study was conducted across 12 regional centres in northern China. The study included patients with poor-grade aSAH admitted from 2017 to 2020. The baseline data included demographics, clinical presentation, aneurysm characteristics, and treatment modalities. Outcome data, including survival status, mortality along with its associated causes and timing, and modified Rankin scale (mRS) scores, were collected prospectively at the last medical follow-up. Changes in case fatality over time were quantified with weighted linear regression. Survival analysis was performed to estimate survival and hazard ratios for death. Binary logistic regression was performed to estimate the odds ratio for dependency (mRS=3-5).

RESULTS

Among the 1,589 enrolled patients, 1,339 were successfully followed, with an average follow-up of 26.37 months. Among them, 61.5% (824/1,339) were dependent or died. The overall mortality rate was 51% (684/1,339), and 21.3% (140/655) of the survivors were dependent. The risk factors for mortality included age ≥65 years, previous history of stroke, and WFNS grade V. Additionally, conservative treatment and endovascular treatment were identified as risk factors and protective factors, respectively, compared with surgical treatment. WFNS grade V and middle cerebral artery aneurysms are independent risk factors for dependency.

CONCLUSIONS

Although there has been a downward trend in recent years, the long-term mortality rate for poor-grade aSAH has remained significantly high at 51%, with 21.3% of survivors being dependent. Active aneurysm treatment, to the extent possible, is crucial for improving the prognosis of these patients.
Structured and random interactions interplay in complex ecosystems dynamics
Authors: Martínez Juan Giral , Barbier Matthieu , De Monte Silvia
Published: November 2024

Minimal models for complex ecosystems often assume random interactions, whose statistics suffice to predict dynamical and macroecological patterns. However, interaction networks commonly possess large-scale structures, such as hierarchies or functional groups. Here, we ask how conclusions from random interaction models are altered by the presence of such large-scale network structures. We consider a simple superposition of structured and random interactions in a classic population dynamics model, and study macroscopic observables, abundance distributions and dynamical regimes. Randomness and structure combine in a surprisingly yet deceptively straightforward way: contributions from each component to the patterns are largely independent, and yet their interplay has non-trivial consequences, notably out of equilibrium. We conclude that whether interaction structure matters depends on the pattern: conclusions from randomly interacting models are less robust when considering static patterns of species presence and abundance, and more robust in the dynamical nature of their ecological regimes.