bluuebunny/crossref_metadata_2025 huggingface dataset:
Violence in the healthcare workplace
Authors: Hargreaves Courtney , Wax Joseph R.
Published: June 2024

Purpose of review

Healthcare workers experience a disproportionate frequency of workplace violence. Identifying commonalities among incidents of workplace violence provides an opportunity for change to prevent and mitigate future violence.

Recent findings

Despite a continued decline in overall workplace violence, the rate of violence in the healthcare sector is steadily rising. While healthcare workers make up 13% of the workforce, they experience 60% of all workplace assaults. Environmental, structural, and staffing issues may all contribute to the increased rates of workplace violence affecting healthcare workers.

Comprehensive proactive workplace violence prevention programs can significantly reduce the frequency of violence and the negative impact on employees and institutions. Analyzing the factors that contribute to violence in the healthcare workplace provides the potential to mitigate these risks and reduce episodes of violence.
Emerging data on diagnosis and management of uterine isthmoceles: a rapid review
Authors: Cook Elizabeth N. , Jesse Nicholas , Harvey Lara
Published: June 2024

Purpose of review

With a rising number of cesarean sections, the prevalence of uterine isthmoceles is increasing. We performed a rapid review to assess the most recent data on the diagnosis and management of uterine isthmoceles over the past 18 months to identify current trends and directions for continued research.

Recent findings

A comprehensive search was conducted in PubMed (NLM), Embase (Ovid), CINAHL (EBSCOhost) to find English written articles discussing the diagnosis or management of uterine isthmoceles published in the previous 18 months. Data extraction was performed on one hundred articles that met inclusion criteria.

This rapid review highlights agreement regarding diagnostic methods, symptoms, and recommended treatment paths for patients with symptomatic uterine niches. However, the diversity in definitions hampers the capacity to formulate detailed conclusions regarding the features of uterine niches and their impact on women's health.
Ergonomic considerations for unique surgeon populations
Authors: Olig Emily , Ranieri Gina , Louie Michelle
Published: June 2024

Purpose of review

Surgeons are rapidly diversifying as a population, introducing new ergonomic challenges. This review describes the challenges that are experienced by special populations of surgeons including small-handed surgeons, pregnant surgeons, and trainees, and evidence-based solutions to overcome them.

Recent findings

Small-handed and female surgeons report more musculoskeletal complaints compared with their male counterparts. Pregnant surgeons frequently report development or worsening of musculoskeletal disorders such as carpal tunnel syndrome and low back pain. Trainees also report high rates of musculoskeletal complaints with minimal autonomy to alter their environment. Limited objective data exists regarding the ideal instruments currently available for special populations. Several small, randomized studies have proposed exercise regimens targeting the upper extremities and pregnancy-related pain syndromes with improvements in symptoms. Various methods of ergonomic education have been studied in trainees with improvements in operating room posture and performance.

Limited objective data is available to recommend specific surgical instruments for high-risk surgeon populations. Beneficial exercise regimens have been described for musculoskeletal disorders commonly plaguing surgeons but have yet to be studied explicitly in small-handed or pregnant surgeons and trainees.
Alternative treatments of adenomyosis – an update in procedural management and clinical outcomes
Authors: Zeccola Alison M. , Allen Sarah E.
Published: June 2024

Purpose of review

Adenomyosis is a common cause of abnormal uterine bleeding (AUB), dysmenorrhea, and pelvic pain. Definitive diagnosis and treatment have historically been by uterine histopathology at time of hysterectomy; however, advances in imaging have supported earlier diagnosis and subsequent conservative treatment. This review aims to update the evidence supporting the uterine-sparing, procedural management options with a focus on clinical outcomes.

Recent findings

Uterine artery embolization (UAE), radiofrequency ablation (RFA), high-intensity focused ultrasound (HIFU), percutaneous microwave ablation (PMWA), and adenomyomectomy are minimally invasive interventions proven to be effective in reducing AUB and dysmenorrhea due to adenomyosis. Symptom improvement is associated with a decrease in uterine volume. Studies support the use of alternative treatment options given the overall low rates of symptom recurrence and reintervention. Combination therapy may be more effective than monotherapy.

This review provides the current evidence for use of alternative treatment options for adenomyosis. Access to ablative therapies in the USA is limited and primarily off label, given lack of FDA approval. High-quality prospective and randomized controlled trials are needed in order to further delineate treatment comparisons, efficacy, safety, and ideal patient selection for these treatments. More data are needed to assess safety and utility in those desiring future fertility.
Circulating bacterial peptides and linked metabolomic signatures are indicative of early mortality in pediatric cirrhosis
Authors: Mathew Babu , Tripathi Gaurav , Gautam Vipul , Bindal Vasundhra , Sharma Nupur , Yadav Manisha , Pandey Sushmita , Sharma Neha , Gupta Abhishak C. , Bhat Sadam H. , Saini Akhilesh K. , Sood Vikrant , Lal Bikrant Bihari , Alam Seema , Khanna Rajeev , Maras Jaswinder Singh
Published: June 2024

Background:

Patients with pediatric cirrhosis-sepsis (PC-S) attain early mortality. Plasma bacterial composition, the cognate metabolites, and their contribution to the deterioration of patients with PC-S to early mortality are unknown. We aimed to delineate the plasma metaproteome-metabolome landscape and identify molecular indicators capable of segregating patients with PC-S predisposed to early mortality in plasma, and we further validated the selected metabolite panel in paired 1-drop blood samples using untargeted metaproteomics-metabolomics by UHPLC-HRMS followed by validation using machine-learning algorithms.

Methods:

We enrolled 160 patients with liver diseases (cirrhosis-sepsis/nonsepsis [n=110] and noncirrhosis [n=50]) and performed untargeted metaproteomics-metabolomics on a training cohort of 110 patients (Cirrhosis-Sepsis/Nonsepsis, n=70 and noncirrhosis, n=40). The candidate predictors were validated on 2 test cohorts—T1 (plasma test cohort) and T2 (1-drop blood test cohort). Both T1 and T2 had 120 patients each, of which 70 were from the training cohort.

Results:

Increased levels of tryptophan metabolites and Salmonella enterica and Escherichia coli–associated peptides segregated patients with cirrhosis. Increased levels of deoxyribose-1-phosphate, N5-citryl-d-ornithine, and Herbinix hemicellulolytic and Leifsonia xyli segregated patients with PC-S. MMCN-based integration analysis of WMCNA-WMpCNA identified key microbial-metabolic modules linked to PC-S nonsurvivors. Increased Indican, Staphylobillin, glucose-6-phosphate, 2-octenoylcarnitine, palmitic acid, and guanidoacetic acid along with L. xyli, Mycoplasma genitalium, and Hungateiclostridium thermocellum segregated PC-S nonsurvivors and superseded the liver disease severity indices with high accuracy, sensitivity, and specificity for mortality prediction using random forest machine-learning algorithm.

Conclusions:

Our study reveals a novel metabolite signature panel capable of segregating patients with PC-S predisposed to early mortality using as low as 1-drop blood.
Shifting Patterns of Sputum Culture Testing and Antibiotic Usage Among Patients With Pneumonia Before and After the COVID-19 Pandemic
Authors: Ito Hiroshi , Kitagawa Yuki , Nakashima Toshiya , Kobanawa Satoshi , Uki Kento , Oshida Jura , Kodama Taisuke , Kobayashi Daiki
Published: June 2024

The coronavirus disease 2019 (COVID-19) pandemic has greatly shifted the attitude of the public and health care workers toward health care practices. Furthermore, this pandemic led to reduced diagnostic testing of various diseases worldwide. This study investigated the impact of the COVID-19 pandemic on health care practices, mainly focusing on sputum culture testing for pneumonia and how these changes affected antibiotic selection and health outcomes. We conducted a retrospective observational study at the Tokyo Medical University Ibaraki Medical Center between January 2018 and December 2021. We compared clinical outcomes during the pre–COVID-19 and post–COVID-19 periods. These outcomes included microbiological test implementation (eg, sputum culture test), length of hospital stay, and in-hospital mortality. Of the 698 patients, 384 (55.0%) were from the pre–COVID-19 period, and 314 (45.0%) were from the post–COVID-19 period. The post–COVID-19 period was associated with a lower ordering rate of sputum cultures (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.50–0.93). Furthermore, the post–COVID-19 period was associated with increased use of narrow-spectrum antibiotics (OR, 1.57; 95% CI, 1.12–2.21) and a higher rate of in-hospital death (OR, 1.78; 95% CI, 1.16–2.73). The COVID-19 pandemic has prompted changes in health care–seeking behaviors, affecting health care providers' diagnostic practices and potentially influencing patient outcomes. Our study outlines the importance of adapting health care strategies during pandemics. Further studies are required to understand the complex interplay among pandemic situations, diagnostic procedures, and patient prognosis.
Transcatheter Aortic Valve Replacement–Associated Prosthetic Valve Endocarditis Due to Pseudomonas aeruginosa
Authors: Boylan Kate E. , Myers Joseph P.
Published: June 2024

Introduction

In patients unsuitable for surgical aortic valve replacement (SAVR), transcatheter aortic valve replacement (TAVR) is an alternative treatment modality for severe aortic stenosis. Prosthetic valve endocarditis (PVE) is uncommon after TAVR, and TAVR-PVE due to Pseudomonas aeruginosa is rare. We report a patient with P. aeruginosa TAVR-PVE and review the literature on the topic.

Case

A 70-year-old woman with history of atrial fibrillation and severe aortic stenosis status post TAVR 4 months previously presented with a third episode of P. aeruginosa bacteremia. She initially developed P. aeruginosa bacteremia 18 days after TAVR. She failed two 6-week courses of intravenous cefepime treatment and then developed P. aeruginosa breakthrough bacteremia while on her third course of intravenous cefepime. Surgical intervention was declined by the patient. Two prior transesophageal echocardiograms (TEEs) were negative for vegetation, but after her breakthrough bacteremia, a repeat TEE showed a 1.5 × 0.8-cm vegetation on the aortic valve. Patient and family declined further therapy and transitioned to hospice and died 5 days later.

Discussion

This is the sixth reported case of P. aeruginosa TAVR-PVE. Enterococcus faecalis, coagulase-negative Staphylococcus and Staphylococcus aureus, and streptococci are the most common etiologic agents causing TAVR-PVE. Diagnosis is difficult, and TEE may be nondiagnostic. Of the 6 reported cases, the only 2 to survive underwent SAVR despite high Society of Thoracic Surgery risk calculator scores.

Conclusion

TAVR-PVE due to P. aeruginosa is rare and will likely not be cured by medical therapy alone. Surgical intervention with SAVR should be considered as the only available curative therapy despite high Society of Thoracic Surgery surgical risk scores.
Sick Leave and Absence Rate of Hospital Workers During the Sixth to Eighth Wave of COVID-19 in Japan
Authors: Seki Yoshitaka , Uchiyama Shota , Matsui Yuma , Baba Yuri , Kamii Yasuhiro , Shinohara Wakako , Yoshida Kazushi , Ichikawa Akihiro , Yoshikawa Koji , Araya Jun
Published: June 2024

Background

There are several reports of breakthrough infections of severe acute respiratory syndrome coronavirus 2 in vaccinated individuals and reinfections in previously infected individuals. Although the coronavirus disease (COVID-19) pandemic has increased the incidence of infections at healthcare facilities, the association between the increase in community spread and absence rate of hospital workers due to COVID-19 infection-related sick leave has not yet been fully elucidated.

Method

We reviewed the case files of patients with COVID-19 diagnosed at the Jikei University Katsushika Medical Center, Tokyo, Japan, between January 1, 2022, and February 28, 2023. The obtained data was used to determine the number of COVID-19 admissions and absence rate of hospital workers due to COVID-19 infection-related sick leave during the sixth to eighth wave of the COVID-19 pandemic.

Results

Of 1899 patients with confirmed COVID-19, 397 (20.9%) were hospital workers. Of the 397 patients, 71, 156, and 119 contracted the infection during the sixth (January–March 2022), seventh (July–September 2022), and eighth wave (November 2022–February 2023), respectively. The absence rate of hospital workers due to COVID-19 was 6.3%, excluding leaves of absence due to close contact in the seventh wave, which had the highest number of infections.

Conclusions

Given the difficulty of maintaining a usual work schedule during the COVID-19 outbreak, it may be necessary to re-evaluate the backgrounds of healthcare workers at high risk of contracting COVID-19 and to make aggressive adjustments to their work schedules by distributing assignments and restricting leave.
Soft tissue coverage for IIIB fractures: from timing to coverage options
Authors: Azad Ali , Hacquebord Jacques H.
Published: June 2024

Open tibia fractures are the most common open long bone injury. Most of these injuries involve a high-energy mechanism. Many standards for management have been created to provide guidance and a baseline for quality. There are several factors that must be considered when determining the timing of coverage for an open fracture with soft tissue compromise. Understanding the available options for soft tissue coverage, including local/rotational flaps and free tissue transfer, will allow for a tailored approach based on the personality of the injury. The aim of this review was to characterize the critical window of treatment based on the current literature and to provide a review of the available soft tissue coverage options.
Classification of open tibia fractures: the rationale for a new classification system
Authors: Resad Ferati Sehar , Ganta Abhishek
Published: June 2024

Open tibial shaft fractures are one of the most common long bone injuries encountered. Current existing classifications are designed to characterize the nature of the injury and guide clinical decision making. However, despite these advancements, there are areas in our current classification system that can be improved to not only make reliability more producible but also create prognostic factors that can help guide treatment.
Applications of Machine Learning in Prognostication of Mild Traumatic Brain Injury
Authors: Yao Patrick F. , Gandhi Pranjan A. , McMullen Eric P. , Manka Marlin , Liang Jason
Published: June 2024

Objective

The aim of the study is to review the literature regarding the current state and clinical applicability of machine learning models in prognosticating the outcomes of patients with mild traumatic brain injury in the early clinical presentation.

Design

Databases were searched for studies including machine learning and mild traumatic brain injury from inception to March 10, 2023. Included studies had a primary outcome of predicting post-mild traumatic brain injury prognosis or sequelae. The Prediction model study Risk of Bias for Predictive Models assessment tool was used for assessing the risk of bias and applicability of included studies.

Results

Out of 1235 articles, 10 met the inclusion criteria, including data from 127,929 patients. The most frequently used modeling techniques were support vector machine and artificial neural network and area under the curve ranged from 0.66 to 0.889. Despite promise, several limitations to studies exist such as low sample sizes, database restrictions, inconsistencies in patient presentation definitions, and lack of comparison to traditional clinical judgment or tools.

Conclusions

Machine learning models show potential in early stage mild traumatic brain injury prognostication, but to achieve widespread adoption, future clinical studies prognosticating mild traumatic brain injury using machine learning need to reduce bias, provide clarity and consistency in defining patient populations targeted and validate against established benchmarks.
Does Primary Cleft Palate Repair by Furlow Z-Plasty Technique With a Buccinator Myomucosal Flap Change Speech and Middle Ear Outcomes?
Authors: Elrouby Iman Mohamed , Aboulhassan Mamdouh Ahmed , Abdel Fattah Hassan Tarek , Refahee Shaimaa Mohsen
Published: June 2024

Background:

Children with repaired cleft lip and palate may present with middle ear effusion and disturbed speech due to velopharyngeal (VP) insufficiency. Furlow Z-palatoplasty with a buccinator myomucosal flap is one of the effective surgical techniques for primary cleft palate repair and lengthening of the palate.

Purpose of the study:

This study aimed to evaluate the effect of Furlow Z-palatoplasty with buccal myomucosal flap as a primary cleft palate repair technique on the VP function during speech and the Eustachian tube function.

Materials and methods:

Forty patients with non-syndromic cleft lip and palate aged 3 to 7 years surgically repaired with Furlow palatoplasty with a buccinator myomucosal flap were assessed. Perceptual speech assessment, nasopharyngoscopic examination, otoscopic examination, and tympanometry were done for all patients to assess the speech and middle ear function.

Results:

The percentage of mild hypernasality was significant in 22.5% of children with repaired cleft lip and palate, while 77.5% showed no hypernasality. Speech intelligibility was normal in 77.5% and mildly affected in 22.5% of children with repaired cleft palate. Compensatory misarticulations were recorded in 12.5% of children. Nasopharyngoscopic examination revealed adequate VP closure in 75% of children with repaired cleft palate. Twenty-five percent of children with repaired cleft lip and palate had middle ear effusion and required myringotomy with insertion of tympanostomy tubes.

Conclusion:

Primary cleft palate repair with Furlow Z-palatoplasty with buccal myomucosal flap had beneficial effects on speech outcomes. It was associated with a low prevalence of middle ear effusion, and a low number of tympanostomy tubes were needed.
Vimentin supports cell polarization by enhancing centrosome function and microtubule acetylation
Authors: Saldanha Renita , Ho Thanh Minh Tri , Krishnan Nikhila , Hehnly Heidi , Patteson Alison
Published: June 2024

Cell polarity is important for controlling cell shape, motility and cell division processes. Vimentin intermediate filaments are important for cell migration and cell polarization in mesenchymal cells and assembly of vimentin and microtubule networks is dynamically coordinated, but the precise details of how vimentin mediates cell polarity remain unclear. Here, we characterize the effects of vimentin on the structure and function of the centrosome and the stability of microtubule filaments in wild-type and vimentin-null mouse embryonic fibroblasts. We find that vimentin mediates the structure of the pericentriolar material, promotes centrosome-mediated microtubule regrowth and increases the level of stable acetylated microtubules in the cell. Loss of vimentin also impairs centrosome repositioning during cell polarization and migration processes that occur during wound closure. Our results suggest that vimentin modulates centrosome structure and function as well as microtubule network stability, which has important implications for how cells establish proper cell polarization and persistent migration.
Optimal sampling of spatial patterns improves deep learning-based early warning signals of critical transitions
Authors: Deb Smita , Mahendru Ekansh , Goyal Paras , Guttal Vishwesha , Dutta Partha Sharathi , Krishnan Narayanan C.
Published: June 2024

Complex spatio-temporal systems like lakes, forests and climate systems exhibit alternative stable states. In such systems, as the threshold value of the driver is crossed, the system may experience a sudden (discontinuous) transition or smooth (continuous) transition to an undesired steady state. Theories predict that changes in the structure of the underlying spatial patterns precede such transitions. While there has been a large body of research on identifying early warning signals of critical transitions, the problem of forecasting the type of transitions (sudden versus smooth) remains an open challenge. We address this gap by developing an advanced machine learning (ML) toolkit that serves as an early warning indicator of spatio-temporal critical transitions, Spatial Early Warning Signal Network (S-EWSNet). ML models typically resemble a black box and do not allow envisioning what the model learns in discerning the labels. Here, instead of naively relying upon the deep learning model, we let the deep neural network learn the latent features characteristic of transitions via an optimal sampling strategy (OSS) of spatial patterns. The S-EWSNet is trained on data from a stochastic cellular automata model deploying the OSS, providing an early warning indicator of transitions while detecting its type in simulated and empirical samples.
Associations between gas stove usage and childhood asthma symptoms, attacks, and ED visits among children in the 2020 Asthma Call-back Survey
Authors: LeSon Sydney , Rosenthal Samantha
Published: June 2024

Objective

To examine whether the use of gas stoves in the home is associated with increased asthma severity among children and adolescents ages 0-17 in the US.

Methods

Using the 2020 CDC Asthma Call-Back Survey for children, the association between gas stove usage and childhood asthma symptoms, asthma attack or episode, and emergency department visit for asthma was assessed. With a cross-sectional study design, bivariate analyses and multivariable logistic regression were conducted. Survey weights were used in the analyses for US population-based estimates.

Results

Children who live in a household that uses gas for cooking or has a gas stove had 1.133 (95% CI: 0.48, 2.68)) times the odds of having an asthma attack or episode within the past 12 months, 9.141 (95% CI: 1.99, 42.06) times the odds of having visited the emergency department or urgent care within the past 12 months, and 1.739 (95% CI: 1.02, 2.95) times the odds of recent symptoms of asthma compared to children who live in a household that does not use gas for cooking or does not have a gas stove, controlling for all confounders. There is an association between the usage of gas stoves and asthma symptoms, asthma attacks/episodes, and ED visits among asthmatic children. Reducing the exposure of gas stove usage should be a consideration in regards to existing and future interventions to prevent childhood asthma and reduce exacerbation of underlying childhood asthma.
Longitudinal risk prediction for pediatric glioma with temporal deep learning
Authors: Tak Divyanshu , Garomsa Biniam A. , Zapaishchykova Anna , Ye Zezhong , Vajapeyam Sri , Mahootiha Maryam , Climent Pardo Juan Carlos , Smith Ceilidh , Familiar Ariana M. , Chaunzwa Tafadzwa , Liu Kevin X. , Prabhu Sanjay , Bandopadhayay Pratiti , Nabavizadeh Ali , Mueller Sabine , Aerts Hugo JWL , Haas-Kogan Daphne , Poussaint Tina Y. , Kann Benjamin H.
Published: June 2024

Pediatric glioma recurrence can cause morbidity and mortality; however, recurrence pattern and severity are heterogeneous and challenging to predict with established clinical and genomic markers. Resultingly, almost all children undergo frequent, long-term, magnetic resonance (MR) brain surveillance regardless of individual recurrence risk. Deep learning analysis of longitudinal MR may be an effective approach for improving individualized recurrence prediction in gliomas and other cancers but has thus far been infeasible with current frameworks. Here, we propose a self-supervised, deep learning approach to longitudinal medical imaging analysis, temporal learning, that models the spatiotemporal information from a patient’s current and prior brain MRs to predict future recurrence. We apply temporal learning to pediatric glioma surveillance imaging for 715 patients (3,994 scans) from four distinct clinical settings. We find that longitudinal imaging analysis with temporal learning improves recurrence prediction performance by up to 41% compared to traditional approaches, with improvements in performance in both low- and high-grade glioma. We find that recurrence prediction accuracy increases incrementally with the number of historical scans available per patient. Temporal deep learning may enable point-of-care decision-support for pediatric brain tumors and be adaptable more broadly to patients with other cancers and chronic diseases undergoing surveillance imaging.
MIAI: Maturation of Immunity Against Influenza - a German birth cohort study with focus on the development of immunity against respiratory viral infections
Authors: Hartmann Carina R. , Khan Robin , Schöning Jennifer , Richter Maximilian , Willers Maike , Pirr Sabine , Heckmann Julia , Dirks Johannes , Morbach Henner , Konrad Monika , Fries Elena , Winkler Magdalene , Büchel Johanna , Seidenspinner Silvia , Fischer Jonas , Vollmuth Claudia , Meinhardt Martin , Marissen Janina , Schmolke Mirco , Haid Sibylle , Pietschmann Thomas , Backes Simone , Dölken Lars , Löber Ulrike , Keil Thomas , Heuschmann Peter U. , Wöckel Achim , Sagar  , Ulas Thomas , Forslund-Startceva Sofia K. , Härtel Christoph , Viemann Dorothee
Published: June 2024

Respiratory viral infections (RVIs) are a major global contributor to morbidity and mortality. The susceptibility and outcome of RVIs are strongly age-dependent and show considerable inter-population differences, pointing to genetically and/or environmentally driven developmental variability. The factors determining the age-dependency and shaping the age-related changes of human anti-RVI immunity after birth are still elusive. We are conducting a prospective birth cohort study aiming at identifying endogenous and environmental factors associated with the susceptibility to RVIs and their impact on cellular and humoral immune responses against the influenza A virus (IAV), respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The MIAI birth cohort enrolls healthy, full-term neonates born at the University Hospital Würzburg, Germany, with follow-up at four defined time-points during the first year of life. At each study visit, clinical metadata including diet, lifestyle exposures, sociodemographic information, and physical examinations, are collected along with extensive biomaterial sampling. Biomaterials are used to generate comprehensive, integrated multi-omics datasets including transcriptomic, epigenomic, proteomic, metabolomic and microbiomic methods. The results are expected to capture a holistic picture of the variability of immune trajectories with a focus on cellular and humoral key players involved in the defense of RVIs and the impact of host and environmental factors thereon. Thereby, MIAI aims at providing insights that allow unraveling molecular mechanisms that can be targeted to promote the development of competent anti-RVI immunity in early life and prevent severe RVIs.

Trial registration number:DRKS00034278
Genotype-first analysis in an unselected health system-based population reveals variable phenotypic severity ofCOL4A5variants
Authors: Zellers McKenzie , Solanki Kaushal , Kelly Melissa A , Murphy Karyn M , Retterer Kyle , Kirchner H. Les , Bucaloiu Ion Dan , Moore Bryn , Mirshahi Tooraj , Chang Alexander R
Published: June 2024

Introduction

Our knowledge of X-linked Alport Syndrome [AS] comes mostly from selected cohorts with more severe disease.

Methods

We examined the phenotypic spectrum of X-linked AS in males and females with a genotype-based approach using data from the Geisinger MyCode DiscovEHR study, an unselected health system-based cohort with exome sequencing and electronic health records. Patients withCOL4A5variants reported as pathogenic (P) or likely pathogenic (LP) in ClinVar, or protein-truncating variants (PTVs), were each matched with up to 5 controls withoutCOL4A3/4/5variants by sociodemographics, diabetes diagnosis, and year of first outpatient encounter. AS-related phenotypes included dipstick hematuria, bilateral sensorineural hearing loss (BSHL), proteinuria, decreased eGFR, and ESKD.

Results

Out of 170,856 patients, there were 29 hemizygous males (mean age 52.0 y [SD 20.0]) and 55 heterozygous females (mean age 59.3 y [SD 18.8]) with aCOL4A5P/LP variant, including 48 with the hypomorphic variant p.Gly624Asp. Overall, penetrance (having any AS phenotypic feature) was highest for non-p.Gly624Asp P/LP variants (males: 94%, females: 85%), intermediate for p.Gly624Asp (males: 77%, females: 69%), compared to controls (males: 32%; females: 50%). The proportion with ESKD was highest for males with P/LP variants (44%), intermediate for males with p.Gly624Asp (15%) and females with P/LP variants (10%), compared to controls (males: 3%, females 2%). Only 47% of individuals withCOL4A5had completed albuminuria screening, and a minority were taking renin-angiotensin aldosterone system (RAAS) inhibitors. Only 38% of males and 16% of females had a known diagnosis of Alport syndrome or thin basement membrane disease.

Conclusion

In an unselected cohort, we show increased risks of AS-related phenotypes in men and women compared to matched controls, while showing a wider spectrum of severity than has been described previously and variability by genotype. Future studies are needed to determine whether early genetic diagnosis can improve outcomes in Alport Syndrome.
Performance of a Protein Language Model for Variant Annotation in Cardiac Disease
Authors: Hochstadt Aviram , Barbhaiya Chirag , Aizer Anthony , Bernstein Scott , Cerrone Marina , Garber Leonid , Holmes Douglas , Knotts Robert J , Kushnir Alex , Martin Jacob , Park David , Spinelli Michael , Yang Felix , Chinitz Larry A , Jankelson Lior
Published: June 2024

Introduction

Genetic testing is a cornerstone in the assessment of many cardiac diseases. However, variants are frequently classified as Variants of Unknown Significance (VUS), limiting the utility of testing.

Recently, the DeepMind group (Google, USA) developed AlphaMissense, a unique Artificial Intelligence (AI) based model, based on language model principles for the prediction of missense variant pathogenicity.

Objective

To report on the performance of AlphaMissense, accessed by VarCardio, an open web-based variant annotation engine, in a real-world cardiovascular genetics center.

Methods

All genetic variants from an inherited arrhythmia program were examined using AlphaMissense via VarCard.io and compared to the ClinVar variant classification system, as well as another variant classification platform (Franklin by Genoox). The mutation reclassification rate and genotype phenotype concordance were examined for all variants in the study.

Results

We included 266 patients with heritable cardiac diseases, harboring 339 missense variants. Of those, 230 (67.8%) were classified by ClinVar as either VUS or non-classified. Using VarCard.io, 198 VUSs (86.1%, CI 80.9-90.3%) were reclassified to either Likely Pathgenic (LP) or Likely benign (LB). The reclassification rate was significantly higher for VarCard.io than for Franklin (86.1% vs 34.8%, p<0.001).

Genotype-Phenotype concordance was highly aligned using VarCard.io predictions, at 95.9% (CI 92.8-97.9%) concordance rate. For 109 variants classified as Pathogenic, LP, Benign or LB by ClinVar, concordance with VarCard.io was high (90.5%).

Conclusion

AlphaMissense, accessed via VarCard.io, may be a highly efficient tool for cardiac genetic variant interpretation. The engine’s notable performance in assessing variants that are classified as VUS in ClinVar, demonstrates its potential to enhance cardiac genetic testing.
Unravelling the Dynamics of Bacterial-Laden Respiratory Droplets: Epidemiological Transfer from Fomites to Susceptible Host
Authors: Rasheed Abdur , Parmar Kirti , Poopady Jason Joy , Jain Siddhant , Chakravortty Dipshikha , Basu Saptarshi
Published: June 2024

This study provides the first comprehensive investigation into how pathogen-laden respiratory droplets transfer diseases via inanimate surfaces. Respiratory fluid ejections containing pathogens pose a significant health threat, especially in high-traffic areas like hospitals, public transport, restaurants, and schools. When these droplets dry on surfaces, they form deposits that can transfer pathogens to healthy individuals through contact and can be ingested via the oral or nasal route. The study examined the effects of varying salt and mucin concentrations in respiratory fluid droplets containingPseudomonas aeruginosa(PA). Results showed that PA viability increased tenfold at elevated mucin concentrations, while changes in salt concentration had minimal impact. Adhesive properties of the deposits were analysed using atomic force spectroscopy and scotch tape test. Pathogen transfer from the deposit to a fingerprint patterned model thumb at different relative humidity (RH) levels was assessed using confocal microscopy, showing significant pathogen transfer at elevated RH. Out of 106CFU/ml pathogens in deposits, 17% to 38% are potentially transferable, with most of the transfer occurring from the droplet’s edge deposits. The study also explored evaporation, internal flow, and precipitation dynamics, with deposit and pathogen distribution characterized by optical profilometry, scanning electron microscopy, and confocal microscopy.
Studies of infused megakaryocytes into mice support a “catch-and-release” model of pulmonary-centric thrombopoiesis
Authors: Kim Hyunjun , Jarocha Danuta , Johnson Ian , Ahn Hyunsook , Hlinka Nicholas , French Deborah L. , Rauova Lubica , Lee Kiwon , Poncz Mortimer
Published: June 2024

Many aspects of thrombopoiesis, the release of platelets from megakaryocytes (Mks), remain under debate, including where this process occurs. Murine lungin situ-microscopy studies suggested that a significant fraction of circulating platelets were released from lung-entrapped, marrow-derived Mks. We now confirm thesein situstudies that endogenous mMks are entrapped in the lungs and show that intravenously infusedin vitro-differentiated, mature murine (m) and human (h) Mks are similarly entrapped followed by shedding of their cytoplasm over ∼30 minutes with a peak number of released platelets occurring 1.5-4 hours later. However, while infused Mks from both species shed large intrapulmonary cytoplasmic fragments that underwent further processing into platelet-sized fragments, the two differed: many mMks escaped from and then recycled back to the lungs, while most hMks were enucleated upon first intrapulmonary passage. Infused immature hMks, inflammatory hMks, umbilical cord-blood-derived hMks and immortalized Mk progenitor cell (imMKCL)-derived hMks were also entrapped in the lung of recipient mice, and released their cytoplasm, but did so to different degrees. Intraarterial infused hMks resulted in few Mks being entrapped in tissues other than the lungs and was accompanied by a blunted and delayed rise in circulating human platelets. These studies demonstrate that the lung entraps and processes both circulating Mks and released large cytoplasmic fragments consistent with a recent lung/heart murine study and support a pulmonary-centric “catch-and-release” model of thrombopoiesis. Thus, thrombopoiesis is a drawn-out process with the majority of cytoplasmic processing derived from Mks occurring in the pulmonary bed.

Key Points

Infusedin vitro-differentiated megakaryocytes synchronously release cytoplasmic fragments highly selectively in the pulmonary bed.

Large, released megakaryocyte fragments recycle to the lungs, undergo further fission, terminally form platelets.
Growth-induced physiological hypoxia correlates with growth deceleration during normal development
Authors: Zhao Yifan , Alexandre Cyrille , Kelly Gavin , Perez-Mockus Gantas , Vincent Jean-Paul
Published: June 2024

Growth deceleration is a universal feature of growth during development: most organs and tissues slow down their growth rate much before growth termination. Using transcriptomics analysis, we show that during their two-day period of growth deceleration, wing imaginal discs ofDrosophilaundergo a progressive metabolic shift away from oxidative phosphorylation and towards glycolysis. We then develop an ultra-sensitive reporter HIF-1α activity, which reveals that imaginal discs become increasingly hypoxic during development in normoxic conditions, suggesting that limiting oxygen supply could underlie growth deceleration. Growth is energetically expensive and thus expected to contribute, indirectly, to oxygen consumption. Indeed, excess TOR signalling, a key stimulator of growth, triggers hypoxia locally and systemically, highlighting the need to rein in growth when oxygen becomes limiting. This is achieved by a negative feedback loop whereby the classic TOR-inhibitory function of HIF-1α is deployed in response to developmental hypoxia. The absence of Sima/HIF-1α leads to cellular stress, which is alleviated by reduced TOR signalling. Conversely, a small increase in oxygen supply reduces the stress induced by excess TOR activity. We conclude that mild hypoxia is a normal feature of organ development and that Sima/HIF-1α prevents growth-induced oxygen demand from exceeding supply.
Heterogeneous shedding and susceptibility in aCaenorhabditis eleganstransmission model
Authors: Vega Nic M.
Published: June 2024

Variation in transmission plays a crucial role in shaping the dynamics of infectious diseases. Population heterogeneity is known to contribute to this variation and is often represented in epidemiological models. However, it is not always cleara prioriwhat sources of variation should contribute meaningfully to a given scenario, and it can be challenging to infer distributions of underlying processes from data. In this study, we demonstrate the use ofCaenorhabditis elegansas a tractable system in which high-quality data can be produced for experimental epidemics. We show that distributions of shedding and susceptibility in this host can be experimentally decoupled to measure heterogeneity in transmission processes. We observe and quantify super-shedding and heterogeneous susceptibility, and we show that distributions of population heterogeneity and transmission outcomes have features conserved with real-world epidemics. Our results quantify sources of heterogeneity in bacterial transmission in this small model organism and establishC. elegansas a promising quantitative model for experimental epidemics.
A frameshift mutation in the murinePrkragene causes dystonia and exhibits abnormal cerebellar development and reduced eIF2α phosphorylation
Authors: Burnett Samuel B. , Culver Allison M. , Simon Tricia A. , Rowson Taylor , Frederick Kenneth , Palmer Kristina , Murray Stephen A , Davis Shannon W. , Patel Rekha C.
Published: June 2024

Mutations inPrkragene, which encodes PACT/RAX cause early onset primary dystonia DYT-PRKRA, a movement disorder that disrupts coordinated muscle movements. PACT/RAX activates protein kinase R (PKR, aka EIF2AK2) by a direct interaction in response to cellular stressors to mediate phosphorylation of the α subunit of the eukaryotic translation initiation factor 2 (eIF2α). Mice homozygous for a naturally arisen, recessively inherited frameshift mutation,Prkralear-5Jexhibit progressive dystonia. In the present study, we investigate the biochemical and developmental consequences of thePrkralear-5Jmutation. Our results indicate that the truncated PACT/RAX protein retains its ability to interact with PKR, however, it inhibits PKR activation. Furthermore, mice homozygous for the mutation have abnormalities in the cerebellar development as well as a severe lack of dendritic arborization of Purkinje neurons. Additionally, reduced eIF2α phosphorylation is noted in the cerebellums and Purkinje neurons of the homozygousPrkralear-5Jmice. These results indicate that PACT/RAX mediated regulation of PKR activity and eIF2α phosphorylation plays a role in cerebellar development and contributes to the dystonia phenotype resulting from this mutation.

Summary Statement

This study shows, for the first time, a role of reduced eIF2α phosphorylation in DYT-PRKRA and the cerebellum development in a mouse model.
Combining Genetic Proxies of Drug Targets and Time-to-event analyses From Longitudinal Observational Data To Identify Target Patient Populations
Authors: Zhang Luke , Kulkarni Prachi , Farshidfar Farshad , Tingley Whit , Hoey Tim , Wang Whedy , Priest James R. , Figarska Sylwia M.
Published: June 2024

Background

Human genetics is an important tool for identifying genes as potential drug targets, and the extensive genetic study of cardiovascular disease provides an opportunity to leverage genetics to match specific patient populations to specific drug targets to improve prioritization of patient selection for clinical studies.

Methods

We selected well described genetic variants in the region ofPCSK9(rs11591147 and rs562556),ADRB1(rs7076938),ACE(rs4968782 and rs4363) andBAG3(rs2234962) for use as proxies for the effects of drugs. Time-to-event analyses were utilized to evaluate their effects on atrial fibrillation (AF) and heart failure (HF) death and/or re-hospitalization using real-world longitudinal dataset. To mitigate the effect of confounding factors for cardiovascular (CV) outcomes, we employed propensity score matching.

Results

After matching, a genetic proxy for PCSK9 inhibition (rs11591147) improved survival from CV death/heart transplant in individuals following a diagnosis of ischemic heart disease (Hazard Ratio (HR) 0.78,P=0.04). A genetic proxy for beta-blockade (rs7076938) improved freedom from rehospitalization or death in individuals with AF (HR 0.92,P=0.001), and a genetic proxy of ACE inhibition (rs7076938) improved freedom from death or rehospitalization for HF (HR 0.84,P=0.017) and AF (HR 0.85,P=0.0014). A protective variant in BAG3 (rs2234962) showed decreased risk of HF rehospitalization or CV death/heart transplant composite outcome within 10 years in HF patients (HR=0.96,P=0.033). Notably, despite smaller cohort sizes after matching, we often observed numerically smaller HRs and reduced P, indicating more pronounced effects and increased statistical association. However, not all genetic proxies replicated known treatment effects.

Conclusions

Genetic proxies for well-known drugs corroborate findings from clinical trials in cardiovascular disease. Our results may demonstrate a novel analytical approach that leverages genetic evidence from a large cohort to effectively select patient populations where specific drug targets may be most effective.
Long-read subcellular fractionation and sequencing reveals the translational fate of full-length mRNA isoforms during neuronal differentiation
Authors: Ritter Alexander J. , Draper Jolene M. , Vollmers Christopher , Sanford Jeremy R.
Published: June 2024

Alternative splicing (AS) alters thecis-regulatory landscape of mRNA isoforms, leading to transcripts with distinct localization, stability, and translational efficiency. To rigorously investigate mRNA isoform-specific ribosome association, we generated subcellular fractionation and sequencing (Frac-seq) libraries using both conventional short reads and long reads from human embryonic stem cells (ESCs) and neural progenitor cells (NPCs) derived from the same ESCs. We performed de novo transcriptome assembly from high-confidence long reads from cytosolic, monosomal, light, and heavy polyribosomal fractions and quantified their abundance using short reads from their respective subcellular fractions. Thousands of transcripts in each cell type exhibited association with particular subcellular fractions relative to the cytosol. Of the multi-isoform genes, 27% and 19% exhibited significant differential isoform sedimentation in ESCs and NPCs, respectively. Alternative promoter usage and internal exon skipping accounted for the majority of differences between isoforms from the same gene. Random forest classifiers implicated coding sequence (CDS) and untranslated region (UTR) lengths as important determinants of isoform-specific sedimentation profiles, and motif analyses reveal potential cell type–specific and subcellular fraction–associated RNA-binding protein signatures. Taken together, our data demonstrate that alternative mRNA processing within the CDS and UTRs impacts the translational control of mRNA isoforms during stem cell differentiation, and highlight the utility of using a novel long-read sequencing–based method to study translational control.
Renormalization of asymmetric staple-shaped Wilson-line operators in lattice and continuum perturbation theory
Authors: Spanoudes G. , Constantinou M. , Panagopoulos H.
Published: June 2024

In this work, we study the renormalization of nonlocal quark bilinear operators containing an asymmetric staple-shaped Wilson line at the one-loop level in both lattice and continuum perturbation theory. These operators enter the first-principle calculation of transverse momentum-dependent parton distribution functions (TMDPDFs) in lattice QCD using the formulation of large momentum effective theory. We provide appropriate RI′-type conditions that address the power and logarithmic divergences, as well as the mixing among staple operators of different Dirac structures, using a number of different possible projectors. A variant of RI′, including calculations of rectangular Wilson loops, which cancel the pinch-pole singularities of the staple operators at infinite length and reduce residual power divergences, is also employed. We calculate at one-loop order the conversion matrix, which relates the quasi-TMDPDFs in the RI′-type schemes to the reference scheme MS¯ for arbitrary values of the renormalization momentum scale and of the dimensions of the staple.

Published by the American Physical Society
2024