bluuebunny/crossref_metadata_2025 huggingface dataset:
Acetaminophen in Pregnancy and Attention-Deficit and Hyperactivity Disorder and Autism Spectrum Disorder
Authors: Damkier Per , Gram Erika B. , Ceulemans Michael , Panchaud Alice , Cleary Brian , Chambers Christina , Weber-Schoendorfer Corinna , Kennedy Debra , Hodson Ken , Grant Kimberly S. , Diav-Citrin Orna , Običan Sarah G. , Shechtman Svetlana , Alwan Sura
Published: December 2024

Acetaminophen is a common over-the-counter medication that recently gained substantial media attention regarding its use by pregnant individuals. In this clinical perspective, we discuss the strengths and limitations of the published literature on the effect of maternal acetaminophen use in pregnancy on the child's risk of developing attention-deficit and hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Studies included were specifically selected on the basis of the quality and validity of ADHD or ASD outcome definitions. From a total of 56 identified studies, commentaries, and editorials of relevance, we critically reviewed nine studies with original data that satisfied our inclusion criteria and three meta-analyses. Most studies that have reported positive findings are difficult to interpret because they have important biases, notably a high degree of selection bias, variability in selection and adjustment for various potential confounders, and unmeasured familial confounding. When unobserved familial confounding through sibling analysis was controlled for, associations weakened substantially. This suggests that residual confounding from shared genetic and environmental factors may have caused an upward bias in the original observations. According to the current scientific evidence, in utero exposure to acetaminophen is unlikely to confer a clinically important increased risk of childhood ADHD or ASD. The current level of evidence does not warrant changes to clinical guidelines on the treatment of fever or pain in pregnancy. Prospective research designed to account for familial and psychosocial environmental factors related to both maternal use of acetaminophen and children's neurodevelopment should be undertaken.
Efficacy and Safety of Immune Checkpoint Inhibitors on Advanced Cervical Cancer: A Systematic Review and Meta-analysis
Authors: Wang Wenhui , Bi Xiaoning , Feng Ye , Ming Xue , Saina Guo , Kun Wang , Ling Bin , Yu Huan
Published: December 2024

This study aims to evaluate the efficacy and safety of immune checkpoint inhibitors (ICIs) in patients with histologically proven advanced cervical cancer. MEDLINE (through PubMed), Web of Science, Embase, and the Cochrane Library were comprehensively searched. Eligible studies were clinical trials investigating the efficacy and safety on ICIs in patients with confirmed advanced cervical cancer. Response rates and adverse events rates were pooled using either a random-effects model or a fixed-effects model based on the I
2 value. A total of 12 clinical trials with 523 women diagnosed with advanced cervical cancer were included. Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors were identified. The pooled objective response (OR) rate, complete response (CR) rate, partial response (PR) rate, and stable disease (SD) rate of PD1 antibodies were 0.24 (95% CIs: 0.11–0.39; I
2=90%, P<0.01), 0.03 (95% CIs: 0.02–0.05; I
2=0%, P =0.92), 0.20 (95% CIs: 0.08–0.36; I
2=91%, P<0.01), 0.31 (95% CIs: 0.23–0.40; I
2=79%, P<0.01), respectively. Adverse events (AEs) rate of any grade was 0.81 (95% CIs: 0.72–0.88; I
2=83%, P<0.01). This study indicates that PD-1/PD-L1 inhibitors reveal acceptable clinical responses and tolerable adverse events in the treatment of advanced cervical cancer. Well-designed clinical trials investigating the efficacy and safety of immune checkpoint inhibitors (ICIs) are needed.
Why is roll-out of long-acting PrEP agents so slow?
Authors: Patel Rupa R. , Mayer Kenneth H.
Published: December 2024

Purpose of review

Injectable cabotegravir for HIV preexposure prophylaxis (PrEP) is effective, yet global implementation has been slow. We review factors which have contributed to the delayed roll-out of this medication.

Recent findings

Fifty-three countries have approved cabotegravir for HIV prevention yet roll-out has been slow. Cabotegravir made up 2.5% of all U.S. PrEP prescriptions in 2023 and is very slowly increasing after FDA approval in 2021. Medication has not been available outside of implementation science studies in Africa and Asia. There is a lengthy process for generic medication production despite agreements signed in 2021; the first available generic dose is not anticipated until 2027. In the United States, where some of the cabotegravir medication costs can be covered under individual insurance plans, high costs and medication acquisition pathways for health centers have been complex, contributing to national implementation delays. The intensity of the staffing required for medication acquisition, insurance paperwork filing, process documentation, billing, injection administration, appointment scheduling, missed appointment monitoring and client follow up has burdened healthcare organizations.

Injectable cabotegravir PrEP has not reaped its potential to be an alternative in those for whom adherence to a daily PrEP pill is challenging. Lessons learned regarding cabotegravir medication acquisition pathways and clinical delivery strategies can inform the rollout of future HIV prevention long-acting agents.
Postnatal Zika and Dengue Infection and their Effects on Neurodevelopment Among Children Living in Rural Guatemala
Authors: Asturias Edwin J. , Connery Amy K. , Olson Daniel , Lamb Molly M. , Paniagua-Avila Alejandra , Anderson Evan J. , Focht Chris , Colbert Alison M. , Natrajan Muktha , Waggoner Jesse J. , Scherer Erin , Calvimontes D. Mirella , Bolaños Guillermo A. , Bauer Desirée , Arroyave Paola , Hernández Sara , Martinez Maria A. , Ralda Aida V. , Rojop Neudy , Barrios Edgar E. , Chacon Andrea , Dempsey Walla , Tomashek Kay M. , Keitel Wendy A. , El Sahly Hana M. , Muñoz Flor M.
Published: December 2024

Background:

Prenatal Zika virus (ZIKV) infection leads to microcephaly and adverse neurodevelopment. The effects of postnatal ZIKV infection on the developing brain are unknown. We assessed the neurodevelopmental outcomes of children exposed postnatally during the ZIKV epidemic.

Methods:

A prospective study enrolled infants 0–3 months of age and their mothers, and children 1.5–3.5 years of age in rural Guatemala from 2017 and were followed for 12 months until 2019. Neurodevelopment was evaluated using the Mullen Scales of Early Learning (MSEL). ZIKV and dengue virus (DENV) infections were identified by polymerase chain reaction (PCR) using active surveillance. Serological analyses, stratified by age group flavivirus serostatus at enrollment, were conducted using a focus reduction neutralization test.

Results:

Of 1371 enrolled participants, 1187 (86.6%) completed the study. No PCR-confirmed ZIKV infections were identified during the study period. One-third of 1.5–3.5-year-old children were ZIKV-seropositive at enrollment (likely postnatal infection). Twenty participants (5.8%) tested positive for DENV by PCR (11 infants, 5 children and 4 mothers); 15 (75%) were DENV-3 infections and 5 were DENV-2. The incidence of DENV infection in infants was 2.6%. No significant differences in MSEL scores were found between infants born seropositive versus seronegative for ZIKV or DENV. DENV seropositivity at enrollment in 1.5–5-year-old children was associated with lower MSEL scores for fine motor, visual reception and language, and microcephaly at 12 months versus seronegative children (all P < 0.05).

Conclusions:

Postnatal ZIKV infection in children from rural Guatemala was not associated with worse neurodevelopmental outcomes. DENV seropositivity was associated with a higher risk of microcephaly in infants and worse neurodevelopmental outcomes in children.
Voices of Care
Authors: Aaron Siobhan P. , Supiano Katherine , DeSimio Samantha
Published: December 2024

This qualitative study examines the distinct experiences of Black/African American nurses in providing end-of-life care to patients of the same racial background and their families. It fills a significant gap in existing research by focusing on the lived experiences and perceptions of Black/African American nurses, gathered through semistructured interviews. Using phenomenological analysis with Colaizzi's method, the study identified principal themes such as racial and ethnic disparities in treatment, challenges in pain management, the need for cultural sensitivity, and the significant influence of historical Black/African American patients' mistrust in health care interactions. The findings illustrate pervasive health care disparities, which are intensified by socioeconomic variables, cultural incompetence, and systemic bias. The nurses highlighted the urgent need for enhanced cultural competence in health care practices to ensure equitable treatment and patient-centric care. This research underscores the necessity for systemic reforms to improve cultural sensitivity and trust within health care services, advocating for comprehensive cultural competency training, greater diversity in health care representation, and effective mechanisms for reporting and addressing disparities. These measures are critical for improving health care outcomes and trust among Black/African American communities at the end of life.
New Approach in the Interpretation of Complex Triple-negative Breast Cancer Immunohistochemistry Specimens Processed With VENTANA PD-L1 (SP142) Assay
Authors: Peg Vicente , Abengozar-Muela Marta , Acosta Jesús , Andrés Leire , García-Rojo Marcial , Hardisson David , Nicolau María Jesús , Ramos-Oliver Irma , Rodrigo Maximiliano , Sánchez-Bernal María Luisa , Sanz Julián , Garrote Leia , Ramírez Ignacio , Rojo Federico
Published: December 2024

Triple-negative breast cancer (TNBC) is challenging to treat because of its lack of specific molecular targets. The IMMUNOPEG study aimed to evaluate a novel structured method for interpreting TNBC immunohistochemistry specimens processed with VENTANA PD-L1 (SP142) assay. The study involved 10 pathologists who evaluated 50 different immunohistochemistry specimens of TNBC with programmed death ligand 1 (PD-L1) expression considered challenging and that were previously evaluated by the scientific committee, using the NAVIFY Digital Pathology platform. Initially, the overall percent agreement (OPA) was 74%, with a negative percent agreement (NPA) of 68.2% for samples classified as negative, and a positive percent agreement (PPA) of 94.5% for positive samples. After training on the method, the OPA improved significantly to 81.6%, with the NPA increasing to 80.5% and the PPA decreasing to 85.5%. The mean percentage of the tumor area occupied by PD-L1-stained immune cells decreased from 2.5% to 1.6% post-training, approaching to the scientific committee’s consensus of 1.029%. The study found that the pathologists’ confidence in their assessments increased significantly when using the structured method, which was found to be easy to use by 9 out of 10 pathologists. All pathologists agreed that the structured method was useful for assessing PD-L1 expression. The study suggests that this method has potential value in interpreting challenging cases of PD-L1 immunohistochemistry (IHC) in TNBC. Further refinement and a training protocol may be necessary to enhance the method's efficiency. The potential for generalizing this structured method to other IHC procedures and pathologies warrants additional research.
Physical Activity Monitoring in Children in the 1-Year After 3 or More Days of Invasive Ventilation: Feasibility of Using Accelerometers
Authors: Maddux Aline B. , Miller Kristen R. , Sierra Yamila L. , Bennett Tellen D. , Watson R. Scott , Spear Matthew , Pyle Laura L. , Mourani Peter M.
Published: December 2024

Objectives:

To measure physical activity in a cohort of children who survived greater than or equal to 3 days of invasive ventilation.

Design:

Prospective cohort study (2018–2021).

Setting:

Quaternary children’s hospital PICU.

Patients:

Children (2–17 yr old) without a preexisting tracheostomy who were ambulatory pre-illness and received greater than or equal to 3 days of invasive ventilation.

Interventions:

None.

Measurements and Main Results:

We measured duration and intensity of physical activity using hip- (< 6 yr old) or wrist- (≥ 6 yr old) worn ActiGraph GT3XP-BTLE accelerometers (ActiGraph, Pensacola, FL) for 7 days at three timepoints: hospital discharge, 3 months, and 12 months post-discharge. We measured duration of moderate or vigorous physical activity (MVPA) and nonsedentary activity, both characterized as percent of total awake wear time and total minutes per day. We categorized participants based on when they first attained a “high activity” day defined as greater than or equal to 60 minutes of MVPA or a day with percent of MVPA in the top quartile of all days measured. We evaluated 55 children of whom 43 (78%) had data from greater than or equal to 1 timepoint including 19 (35%) with data from all timepoints. Maximum daily MVPA increased across the three post-discharge timepoints (median, 16.0 min [interquartile range (IQR), 8.0–42.8 min], 48.3 min [27.8–94.3 min], and 68.4 min [34.7–111.0 min], respectively) as did maximum daily percent of awake wear time in MVPA (median, 4.3% [IQR, 2.8–9.0%], 10.1% [5.7–14.4%], and 11.1% [7.1–17.5%], respectively). Of the 43 participants, 27 achieved a high activity day: nine of 43 during the hospital discharge period, 14 of 43 during the 3 months post-discharge period, and four of 43 during the 12 months post-discharge period; 16 of 43 did not demonstrate high activity during the post-discharge year.

Conclusions:

In the 1-year after PICU discharge measuring physical activity with accelerometers in children 2–17 years old is feasible. Furthermore, demonstration of variable recovery trajectories in our pilot cohort suggests it has potential to be an outcome measure in clinical trials.
T1WI Radiomics Analysis of Anterior Scalene Muscle: A Preliminary Application in Neurogenic Thoracic Outlet Syndrome
Authors: Sun Meng , Fang Le , Tang Peiyun , Wang Fangruyue , Jiang Ling , Wang Tianwei
Published: December 2024

Aim

This study aimed to analyze the differences in radiomic features of the anterior scalene muscle and evaluate the diagnostic performance of MRI-based radiomics model for neurogenic thoracic outlet syndrome (NTOS).

Materials and Methods

Imaging data of patients with NTOS who underwent preoperative brachial plexus magnetic resonance neurography were collected and were randomly divided into training and test groups. The anterior scalene muscle area was sliced in the T1WI sequence as the region of interest for the extraction of radiomics features. The most significant features were identified using feature selection and dimensionality-reduction methods. Various machine learning algorithms were applied to construct regression models. Model performance was evaluated using area under the receiver operating characteristic curve (AUROC).

Results

Totally, 267 radiomics features were extracted, of which 57 showed significant differences (P ≤ 0.05) between the abnormal and normal anterior scalene muscle groups. The least absolute shrinkage and selection operator regression model identified 13 optimal radiomic features with nonzero coefficients for constructing the model. In the training set, the AUROCs of diagnostic models built by different machine learning algorithms, ranked from highest to lowest, were as follows: support vector machine (SVM), 0.953; multilayer perception (MLP), 0.936; logistic regression (LR), 0.926; light gradient boosting machine (LightGBM), 0.906; and K-nearest neighbors (KNN), 0.813. In the testing set, the rankings were as follows: LR, 0.933; SVM, 0.886; KNN, 0.843; LightGBM, 0.824; and MLP, 0.706.

Conclusions

NTOS is attributed to anterior scalene muscle abnormalities and exhibits distinct radiomic features. Integrating these features with machine learning can improve traditional manual image interpretation, offering further clarity in NTOS diagnosis.
Intestinal epithelial-specific occludin deletion worsens gut permeability and survival following sepsis
Authors: Yumoto Tetsuya , Oami Takehiko , Liang Zhe , Burd Eileen M. , Ford Mandy L. , Turner Jerrold R. , Coopersmith Craig M.
Published: December 2024

Sepsis induces intestinal hyperpermeability, which is associated with higher mortality. Occludin is a tight junction protein that plays a critical role in regulating disease-associated intestinal barrier loss. This study examined the role of intestinal occludin on gut barrier function and survival in a pre-clinical model of sepsis. Intestinal epithelial-specific occludin knockout (occludin KOIEC) mice and wild type controls were subjected to intra-abdominal sepsis and sacrificed at pre-determined endpoints for mechanistic studies or followed for survival. Occludin KOIEC mice had a significant increase in intestinal permeability, that was induced only in the setting of sepsis as knockout mice and control mice had similar baseline permeability. The worsened barrier was specific to the leak pathway of permeability, without changes in either the pore or unrestricted pathways. Increased sepsis-induced permeability was associated with increased levels of the tight junction ZO-1 in occludin KOIEC mice. Occludin KOIEC mice also had significant increases in systemic cytokines IL-6 and MCP-1and increased bacteremia. Further, occludin KOIEC mice had higher levels of jejunal IL-1β and MCP-1 as well as increased MCP-1 and IL-17A in the peritoneal fluid although peritoneal bacteria levels were unchanged. Notably, 7-day mortality was significantly higher in occludin KOIEC mice following sepsis. Occludin thus plays a critical role in preserving gut barrier function and mediating survival during sepsis, associated with alterations in inflammation and bacteremia. Agents that preserve occludin function may represent a new therapeutic strategy in the treatment of sepsis.
Biomechanical Evaluation of Femoral Neck Fracture Fixation Based on Finite Element Analysis
Authors: Rao Laureb , Mittal Samarth , Kabra Apoorva , Trikha Vivek , Chawla Anoop , Mukherjee Kaushik
Published: December 2024

Pauwels type III fracture, wherein the fracture plane makes an angle of 50°-70° with the transverse plane, is the most unstable femoral neck fracture. Although there are various types of internal fixation devices, including Cannulated cancellous screws (CCS), dynamic hip screw (DHS), dynamic hip screw along with anti-rotation screws (DHS+ARS), and a newly introduced femoral neck system (FNS), patients with Pauwels type III fracture often experience implant failure. There was no study investigating the performance of these internal fixators under physiological musculoskeletal loading. The objective of the present study was to compare the biomechanical performance of CCS, DHS, DHS+ARS and FNS under daily physiological activities like normal walking and stair climbing.

The unstable Pauwels type III fracture was virtually induced in a composite femur bone model and was fixed with all four internal fixators. Second-order tetrahedral elements were used to develop the FE models. The stresses, strains, and deformations of intact and reconstructed femur and implant components were compared to understand the biomechanical efficacy.

FNS showed the highest inferior axial displacement of the femoral head while DHS+ARS exhibited the least inferior axial displacement. Among the four fracture fixation systems, DHS+ARS offered the highest post-fixation stability in terms of fracture gap opening (normal walking: 0.82mm and stair climbing: 0.95mm) and contact sliding, while the performance of single hole locking plated FNS was the worst (normal walking: 2.65mm, stair climbing: 3.72mm). Based on this computational study, DHS+ARS seems to be a better performing system in Pauwels type III fracture fixation.
Defining Mechanistic Links Between the Non-Coding Variant rs17673553 inCLEC16Aand Lupus Susceptibility
Authors: Reddy-Rallabandi Harikrishna , Singh Manish K. , Looger Loren L. , Nath Swapan K.
Published: December 2024

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder characterized by widespread inflammation and autoantibody production. Its development and progression involve genetic, epigenetic, and environmental factors. Although genome-wide association studies (GWAS) have repeatedly identified a susceptibility signal at 16p13, its fine-scale source and its functional and mechanistic role in SLE remain unclear. We used bioinformatics to prioritize likely functional variants and validated the top candidate through various experimental techniques, including CRISPR-based genome editing in B cells. To assess the functional impact of the proposed causal variant inCLEC16A, we compared autophagy levels between wild-type (WT) and knock-out (KO) cells. Systematic bioinformatics analysis identified the highly conserved non-coding intronic variant rs17673553, with the risk allele apparently affecting enhancer function and regulating several target genes, includingCLEC16Aitself. Luciferase reporter assays followed by ChIP-qPCR validated this enhancer activity, demonstrating that the risk allele increases the binding of enhancer histone marks (H3K27ac and H3K4me1), CTCF-binding factor, and key immune transcription factors (GATA3 and STAT3). Knock-down ofGATA3andSTAT3 viasiRNA led to a significant decrease inCLEC16Aexpression. These regulatory effects on the target gene were further confirmed using CRISPR-based genome editing and CRISPR-dCas9-based epigenetic activation/silencing. Functionally, WT cells exhibited higher levels of starvation-induced autophagy compared to KO cells, highlighting the role ofCLEC16Aand the rs17673553 locus in autophagy regulation. These findings suggest that the rs17673553 locus – particularly the risk allele – drives significant allele-specific chromatin modifications and binding of multiple transcription factors, thereby mechanistically regulating the expression of target autophagy-associated genes, includingCLEC16Aitself. This mechanism could potentially explain the association between rs17673553 and SLE, and underlie the signal at 16p13.
A minimalist binary/digital approach to large-scale single molecule protein identification with optically labeled tRNAs and multiple carboxypeptidases and its extension to peptide sequencing
Authors: Sampath G.
Published: December 2024

Recently a binary/digital scheme based on the superspecificity property of transfer RNAs (tRNAs) was proposed for the identification of single amino acids (AAs) from binary-valued measurements (Eur. Phys. J. E45, 94, 2022). There are two formulations, they can be used to sequence short peptides and/or identify their parent proteins. In one of them an array of peptides is sequenced in 20 cycles by adding 20 different tRNAs carrying a fluorescent tag, optically recognizing the C-terminal residues, and cleaving the latter with a carboxypeptidase; the process is repeated over the peptides in parallel. Here this scheme is used to develop in theory a minimalist approach to protein identification that uses only two tRNAs and the carboxypeptidases A, B, and C. The latter form a complete and mutually exclusive set capable of cleaving all 20 AA types; this divides the 20 AAs into three classes. The sequences obtained are partial sequences in the reduced alphabet, their parent proteins can be obtained by search through a proteome database. The AA class of the terminal residue of every peptide in the array can be identified in a single cycle by using the three carboxypeptidases in the order C-B-A. With peptide lengths of ∼20 and a cycle time of ∼1 hour, the parent proteins of K peptides can be obtained in about 20 hours. This is independent of K (within the limits imposed by the imaging method used) and the dynamic range of a proteome; thus in theory a whole proteome can be processed in less than a day. Computational results suggest that the parent proteins of over 92% of peptides from the human proteome (Uniprot id UP000005640_9606) can be identified. The identification rate when residues are skipped due to carboxypeptidases cleaving the second and later residues in delayed reactions is about ∼90% with 1 or 2 skips. Full sequencing without skipped residues can be done by using all 20 tRNA types over 20 cycles in increasing order of cleavage time of the 20 AA types; a recursive procedure is given.
PTTG1-Mediated Pericyte Dysfunction Drives Diabetes-Induced Microvascular Dysfunction
Authors: Zhang Linyu , Ren Ling , Zhang Jingyue , Xia Min , Li Xiaosa , Yao Mudi , Ma Fanfei , Jiang Chang , Yao Jin , Yan Biao
Published: December 2024

Background

Pericytes are crucial for the development, stabilization, and functional regulation of microvasculature, especially in the retina. In diabetic retinopathy (DR), early loss of pericytes is a key event that drives microvascular dysfunction. Despite their critical role, the mechanisms underlying the functional heterogeneity of pericytes in DR remain poorly understood, impeding the development of effective therapeutic strategies.

Methods

We employed single-cell RNA sequencing to construct a comprehensive single- cell atlas of non-diabetic and diabetic retinas. Using bioinformatic clustering and subcluster analysis, we identified a specific pericyte subcluster associated with diabetic microvascular complications. Differential gene expression analysis and immunofluorescence validation highlighted PTTG1 as a potential key regulator of pericyte dysfunction. To investigate its functional role, we emplyed CRISPR/Cas9 and adenoviral vectors to modulate PTTG1 expression in vitro and in vivo. Combined transcriptomic and metabolomic approaches were used to explore the mechanistic pathways through which PTTG1 influences pericyte biology and vascular function.

Results

We identified a novel pericyte subcluster characterized by elevated expression of PTTG1, which was strongly correlated with diabetic microvascular dysfunction. Silencing PTTG1 using CRISPR/Cas9 and siRNA in vitro mitigated pericyte dysfunction under high- glucose conditions. Targeted knockdown of PTTG1 using viral vectors improved retinal vascular integrity and reduced neovascularization in diabetic mice. Transcriptomic and untargeted metabolomic analyses revealed that PTTG1 knockdown reprogrammed pericyte energy metabolism by modulating glycolysis pathway genes, reducing oxidative stress, and restoring pericyte function, ultimately alleviating microvascular dysfunction in DR.

Conclusions

PTTG1 plays a critical role in regulating pericyte dysfunction and maintaining vascular homeostasis in diabetic retinopathy. By modulating key metabolic pathways and pericyte phenotypes, PTTG1 represents a promising therapeutic target for treating diabetic microvascular complications. These insights offer a novel molecular framework for developing targeted therapies aimed at restoring retinal vascular health in diabetic patients.
Conflicting Timelines: Exploring patterns of mito-nuclear discordance in divergence estimates among tetrapods
Authors: Ranganathan Ekadh , Karanth Praveen
Published: December 2024

Phylogenetic studies across a range of tetrapod groups have historically utilised either mitochondrial DNA, concatenated mito-nuclear matrices, or nuclear loci to infer divergence estimates. As such, the discordance between estimates inferred using differing data types has been a topic of interest over the past decade. Although several studies have looked into divergence disparities in smaller taxonomic groups, often with mixed results, a systematic investigation of the pattern of mito-nuclear divergence discordance in tetrapods across deep-time remains to be undertaken. In this study, we aimed to quantify the extent of divergence disparity inferred by the aforementioned data types in each of the four major tetrapod groups, namely primates (OrderPrimates), birds (ClassAves), squamates (OrderSquamata), and anurans (OrderAnura), while controlling for calibration strategies, taxon sampling and othera prioridistributions. We also calculated substitution saturation for all groups across data types in order to elucidate its role in generating unreliable divergence estimates. Our findings indicate that mitochondrial estimates consistently underestimate basal divergence times and overestimate recent divergences across all groups (apart from anurans) as compared to the nuclear datasets. We also find that divergence times estimated using concatenated matrices skew in favour of the nuclear tree. Furthermore, substitution saturation is substantial in all of the mitochondrial datasets across groups, and interestingly present in the nuclear dataset for Anurans, resulting in a reduction in overall mito-nuclear divergence disparity for the crown ages of the group. These results call for a revisit of divergence dates estimated using mitochondrial DNA, while advocating for saturation testing prior to divergence dating and highlighting the inherent bias in divergence dates estimated using concatenated mito-nuclear matrices.
Safety and efficacy of high frequency jet ventilation: a systematic and narrative review
Authors: Spaar Jasmin , Biro Peter , Sander Michael , Gross Volker , Scholtes Michael , Sohrabi Keywan
Published: December 2024

High frequency jet ventilation (HFJV) is an unconventional mechanical ventilation technique increasingly utilized in complex medical fields such as airway surgery and intensive care.

This systematic review analyzes the safety and efficacy of HFJV, focusing on its application in both adult and pediatric populations. Through systematic searches of PubMed, Cochrane Library, and Livivo databases, 41 studies meeting the inclusion criteria were identified. Key parameters analyzed included complications, CO₂ and O₂ levels, pH values, FiO₂, treatment course, and duration. Studies were selected that evaluated HFJV both as a standalone method and in comparison, with conventional ventilation techniques.

The findings suggest that HFJV offers significant advantages in maintaining low alveolar pressures and improving surgical conditions, particularly in procedures requiring minimal organ movement. While most studies reported no significant difference in complication rates between HFJV and conventional ventilation, HFJV was associated with a more favorable treatment course and duration. Despite these positive outcomes, the data highlight challenges in the use of HFJV, particularly the complexity of the technique and the necessity for precise ventilatory parameter settings. Inappropriate settings can lead to suboptimal ventilation and oxygenation, increasing the risk of complications such as pneumothorax.

This review underscores the need for further research to optimize HFJV application and better understand its long-term clinical impacts. The insights gained provide valuable guidance for future clinical use.

Key Message

This systematic review examines the safety and efficacy of high frequency jet ventilation in adult and paediatric patients. The findings indicate that HFJV offers advantages in complex procedures, such as airway surgery and intensive care, by providing lower alveolar pressures and improved surgical conditions without significantly increased complication rates compared to conventional ventilation. However, HFJV requires precise parameter controls to avoid complications such as pneumothorax. Further research is needed to optimise its long-term clinical effects.
Deciphering Risk of Recurrent Bone Stress Injury in Female Runners Using Serum Proteomics Analysis and Predictive Models
Authors: Romanowicz Genevieve E. , Popp Kristin , Dinh Ethan , Harker Isabella R. , Leguineche Kelly , Hughes Julie M. , Ackerman Kathryn E. , Bouxsein Mary L. , Guldberg Robert E.
Published: December 2024

Up to 40% of elite athletes experience bone stress injuries (BSIs), with 20-30% facing reinjury. Early identification of runners at high risk of subsequent BSI could improve prevention strategies. However, the complex etiology and multifactorial risk factors of BSIs makes identifying predictive risk factors challenging. In a study of 30 female recreational athletes with tibial BSIs, 10 experienced additional BSIs over a 1-year period, prompting investigation of systemic biomarkers of subsequent BSIs using aptamer-based proteomic technology. We hypothesized that early proteomic signatures could discriminate runners who experienced subsequent BSIs. 1,500 proteins related to metabolic, immune, and bone healing pathways were examined. Using supervised machine learning and genetic programming methods, we analyzed serum protein signatures over the 1-year monitoring period. Models were also created with clinical metrics, including standard-of-care blood analysis, bone density measures, and health histories. Protein signatures collected within three weeks of BSI diagnosis achieved the greatest separation by sparse partial least squares discriminant analysis (sPLS-DA), clustering single and recurrent BSI individuals with a mean accuracy of 96 ± 0.02%. Genetic programming models independently verified the presence of candidate biomarkers, including fumarylacetoacetase, osteopontin, and trypsin-2, which significantly outperformed clinical metrics. Time-course differential expression analysis highlighted 112 differentially expressed proteins in individuals with additional BSIs. Gene set enrichment analysis mapped these proteins to pathways indicating increased fibrin clot formation and decreased immune signaling in recurrent BSI individuals. These findings provide new insights into biomarkers and dysregulated protein pathways associated with recurrent BSI and may lead to new preventative or therapeutic intervention strategies.

One Sentence Summary

Our study identified candidate serum biomarkers to predict subsequent bone stress injuries in female runners, offering new insights for clinical monitoring and interventions.
Sex-specific proteomic signatures improve cardiovascular risk prediction for the general population without cardiovascular disease or diabetes
Authors: Xie Ruijie , Vlaski Tomislav , Sha Sha , Brenner Hermann , Schöttker Ben
Published: December 2024

Importance

Accurate prediction of 10-year major adverse cardiovascular events (MACE) is crucial for effective cardiovascular disease prevention and management.

Objective

To evaluate whether adding sex-specific proteomic profiles to the SCORE2 model enhances 10-year MACE risk prediction in the large UK Biobank (UKB) cohort.

Design, Setting, and Participants

Data from 47,382 UKB participants, aged 40 to 69 years without prior cardiovascular disease or diabetes, were utilized. The cohort was randomly divided into derivation (70%) and validation (30%) sets.

Exposures

Proteomic profiling of plasma samples was conducted using the Olink Explore 3072 platform, measuring 2,923 unique proteins, of which 2,085 could be used. Sex-specific Least Absolute Shrinkage and Selection Operator (LASSO) regression was used for biomarker selection.

Main Outcomes and Measures

The primary outcome was 10-year MACE incidence, defined as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Model performance was assessed by changes in Harrell’s C-index, net reclassification index (NRI), and integrated discrimination index (IDI).

Results

During 10-year follow-up, 2,163 participants experienced MACE. Overall, 18 proteins were selected by LASSO regression, with 5 of them identified in both sexes, 7 only in males, and 6 only in females. Incorporating these proteins, significantly improved the C-index of the SCORE2 model from 0.713 to 0.778 (P□<□0.001) in the total population. The improvement was greater in males (C-index increase from 0.684 to 0.771; Δ□=□+0.087) than in females (from 0.720 to 0.769; Δ□=□+0.049). The NRI was 19.9% for the total population, 36.3% for males, and 18.2% for females. The WAP four-disulfide core domain protein (WFDC2), which modulates extracellular matrix degradation, impacting fibrosis and plaque stability, and the growth/differentiation factor 15 (GDF15), reflecting increased inflammatory activity, were the proteins contributing the strongest C-index increase in both sexes; even more than the N-terminal prohormone of brain natriuretic peptide (NTproBNP), which was also selected.

Conclusions and Relevance

The derivedsex-specific 10-year MACE risk prediction models, combining 12 protein concentrations among men and 11 protein concentrations among women with the SCORE2 model, significantly improved the discriminative abilities of the SCORE2 model. This study shows the potential of sex-specific proteomic profiles for enhanced cardiovascular risk stratification and personalized prevention strategies.
Multi-omic analysis identifies a multi-step pathology in a case of multiple chorangioma syndrome in monochorionic twins
Authors: Wilk Brandon M. , Gajapathy Manavalan , Brown Donna M. , Duncan Virginia E. , Worthey Elizabeth A.
Published: December 2024

Background

Chorangiomas, benign proliferative capillary lesions in the placenta, occur in approximately 1% of births, typically as a solitary nodule. In rare cases, multiple nodules develop, posing risks of fetal heart failure, hydrops fetalis, and intrauterine death due to altered placental hemodynamics. Although genetic and hypoxic factors have been hypothesized to drive aberrant angiogenesis, definitive evidence has been lacking. We report on a unique case of multiple chorangiomas in half of a shared placenta in monozygotic, monochorionic diamniotic (MCDA) twins, providing an unprecedented opportunity to explore impacts that molecular variation has on chorangioma formation.

Results

Whole genome and bulk RNA sequencing supported identification of early embryonic or germline and somatic variation. It revealed a likely pathogenic heterozygous frameshift deletion in EPAS1, a hypoxia-sensing transcription factor, with an early embryonic or germline origin. This variant likely impaired placental oxygen regulation and angiogenesis through its impact on VEGF-related pathways. Deleterious somatic mutations in COL1A1, FBXO11, and TRIM71 were observed within the chorangioma-affected tissue, along with increased expression of Leptin and DNA damage signatures consistent with oxidative stress. In contrast, the unaffected twin’s placental territory showed a different pattern of pathogenic somatic variation with the presence of a known pathogenic variant in MUTYH and signs of repair deficiencies. These findings highlight the presence of predisposing events and distinct molecular processes within each domain of the shared placenta. We propose that these molecular events, combined with environmental factors intensified by the MCDA pregnancy, likely contributed to chorangioma development..

Conclusions

Our study provides novel insights into the molecular basis of multiple chorangioma syndrome. To our knowledge, this is the first molecular evidence implicating both germline and somatic genetic involvement in this condition. The identification of molecular signatures previously associated with malignancy suggests that chorangiomas may share pathways with oncogenic processes. These findings highlight the importance of considering both genetic and environmental interactions in placental pathologies, offering potential implications for understanding and managing complex vascular and placental conditions, including preeclampsia, intrauterine growth restriction, and fetal vascular malperfusion.
Is the Official Development Assistance in Guinea-Bissau “emergency” or “indispensable”? Perceptions of key stakeholders in the healthcare sector
Authors: Casimiro Anaxore , Cane Réka Maulide , Jareski Andrade Michel , Varandas Luís , Craveiro Isabel
Published: December 2024

Official Development Assistance (ODA) is a type of financial support for low and medium-income countries to promote economic development and well-being. This study explores the perceptions of key healthcare stakeholders on the role of ODA in the health sector in Guinea-Bissau, focusing on maternal and child health. This qualitative study, conducted in May 2022 and February 2024, utilized semi-structured interviews with ten national and international healthcare stakeholders. Participants included present and past Ministry of Public Health officials and global partners in Guinea-Bissau. An interview script was used, including questions about the role and effectiveness of ODA in development, challenges in implementing health programs, coordination mechanisms, alignment of assistance with countries’ strategic documents, and recommendations for future improvements. Thematic categorical analysis, identification of standards, themes, and emerging relationships were identified in the participants’ responses. Findings reveal as main topics: (1) Participants considered that foreign aid is seen as a “humanitarian” or “emergency” assistance that complements the government and has been indispensable for project implementation and improvement of health indicators (2) Stakeholders reported significant challenges, including inadequate alignment of donor agendas with national health strategies, insufficient coordination among actors, and limited government ownership. Political instability undermines projects’ sustainability and long-term impact (3). It is necessary to reinforce the management capacity of the Ministry of Health and ensure that the guiding tools are used. ODA has been crucial to avoid the collapse of the health sector in Guinea-Bissau. However, a more cohesive strategy is essential to enhance ODA effectiveness in Guinea-Bissau. Recommendations include strengthening government leadership, aligning donor programs with national health priorities, and fostering improved coordination among health actors. Increasing government ownership of ODA projects could improve sustainability. This research offers crucial insights for policymakers, emphasizing the balance between ODA and long-term health improvements in Guinea-Bissau.
Master protocols in Low-and-Middle income countries: A review of current use, limitations, and opportunities for precision medicine
Authors: Ouma Luke , Al-Ashmori Sarah , Sarkodie Samuel , Whitehead Lou , Konkoth Ann Breeze , Hiu Shaun , Bigirumurame Theophile , Kareithi Dorcas , Lozano-Kuehne Jingky , Shahmandi Marzieh , Wason James M.S.
Published: December 2024

Background

Master protocols - umbrella, basket and platform trials that study multiple therapies, multiple diseases or both, offer many advantages, most profoundly that they answer multiple treatment related questions, that would otherwise take multiple trials. We conducted a review of trial registries to characterise their use in advancing precision medicine in low and middle income countries (LMICs).

Methods

We searched trial records available in 20 trial registries globally, includingClinicalTrials.govand WHO ICTRP, to identify umbrella, basket and platform trials launched until 30 September 2023.

Results

We identified 102 master protocols - 29 umbrella trials, 31 basket trials, 36 platform trials, as well as 6 other designs that partially aligned with the working definition of master protocols run in 54 different LMICs. Most trials were pharmaceutical industry-sponsored studies (60/102, 58.8%), conducted in oncology settings (56/102, 54.9%), currently ongoing (69/102, 67.6%) in early phase (phase I and II) settings (70/102, 68.6%). There was a greater representation of upper middle-income countries, particularly China that was a site to more than half of all master protocols (53/102, 52%). Other common countries included Brazil, Russia, Turkey and Argentina. Most master protocols (93/102 91.2%) have been planned or launched in the last five years (2019 onwards), mainly with international collaborations in high-income countries. Only a small proportion of trials (5/102, 4.9%) launched exclusively in LMICs excluding china and European LMICs. For most studies, the statistical aspects of trial design and trial documentation (including study protocols and statistical analysis plans) were not publicly accessible.

Conclusion

Unlike high-income countries, where several hundreds of master protocols are ongoing or completed, there is limited use of master protocols in LMICs, partly owing to low penetration of precision medicine research and limited clinical trial infrastructure in most LMICs. The evidence presented herein create a case for supporting precision medicine initiatives in LMICs (especially Africa), and training and capacity building initiatives focused on innovative clinical trial designs like master protocols, especially in therapeutic areas outside oncology.
Oral supplementation with Nicotinamide Riboside treatment protects RGCs in DBA/2J mouse model
Authors: Zhang Nan , Li Ying , Zhang Xian , Chrenek Micah A. , Wang Jiaxing , Girardot Preston E. , Sellers Jana T. , Brenner Charles , Cui Xiangqin , Geisert Eldon E. , Nickerson John , Boatright Jeffrey H.
Published: December 2024

Purpose

The aim of this study was to test whether oral administration of nicotinamide riboside (NR), the nicotinamide adenine dinucleotide (NAD+) precursors, protect retina ganglion cells (RGCs) from neurodegeneration in DBA/2J (D2) mice, which is a widely used mouse model of age-related inherited glaucoma.

Method

Oral NR or NAM administration (NR low dose: 1150mg/kg; NR high dose: 4200mg/kg; NAM low dose group: 500mg/kg; NAM high dose: 2000mg/kg of body weight per day) essentially started when D2 mice were 4 or 9 months old and continued up to 12 months old. Control cohort identically received food/water without NAM or NR. Intraocular pressure (IOP) was measured every month until experiment completion. Pattern electroretinography (PERG) was recorded. Retinas were harvested for whole mount immunofluorescence staining with RGCs marker Brn3a and imaged by fluorescent confocal microscopy. Optic nerves were harvested for axon staining and quantification. Retinal NAD+ levels were enzymatically assayed.

Results

NR oral supplementary treatment started at 4 months old robustly increased retinal NAD+ levels in D2 mice (NRHighvs. vehicle: 273.7±23.59% vs. 108.70±12.10%,p<0.001). In aged vehicle group (12 months old), there was significantly diminution of the P1 and N2 components of PERG response compare with naïve group (naïve vs. vehicle: P1: 7.82± 0.70uV vs 1.63± 0.17uV,p<0.0001; N2: -13.29± 0.83uV vs. -3.22± 0.27uV,p<0.0001; Kruskal-Wallis test with Dunn‘s multiple comparison test). NR treatment preserved aged D2 visual function when mice were 9 and 12 months old. In addition, long-term NR high dose treatment significantly protected against total RGCs loss and optic nerve atrophy (RGC: NRHighvs. vehicle: 1412±62.00vs 475.2±94.68 cells/field,p<0.00001; axon numbers: NRHighvs. vehicle: 23990±1159 vs 8573±1160, n=41-53,p<0.0001). Furthermore, long-term NR supplementation prevent iris depigmentation and delayed IOP elevation.

Conclusion

NR oral supplementary treatment significantly preserved RGC and axon numbers, potentially preserves retinal function via elevated retinal NAD+ level in aged D2 mice. Interestingly, NR treatment also prevented iris atrophy, delayed IOP elevation associated with this glaucoma model. NR oral supplementation thus treated several aspects of murine pigment dispersion glaucoma. Given parallels between this model and glaucoma in human, out data indicate that NR is worth exploring as a therapeutic candidate in treatment of glaucoma.