bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulatory trends of organophosphate and pyrethroid pesticides in cannabis and applications of the Comparative Toxicogenomics Database and Caenorhabditis elegans
Authors: Rivera Albert B , Stephens Ariell B , Conrow Kendra D , Griffith Symone T , Jameson Laura E , Cahill Thomas M , Sammi Shreesh R , Swinburne Mathew R , Cannon Jason R , Leung Maxwell C K
Published: January 2025

Organophosphate and pyrethroid pesticides are common contaminants in cannabis. Due to the status of cannabis as an illicit Schedule I substance at the federal level, there are no unified national guidelines in the United States to mitigate the health risk of pesticide exposure in cannabis. Here, we examined the change in the state-level regulations of organophosphate and pyrethroid pesticides in cannabis. The medians of pyrethroid and organophosphate pesticides specified by each state-level jurisdiction increased from zero pesticide in 2019 to 4.5 pyrethroid and 7 organophosphate pesticides in 2023, respectively. Next, we evaluated the potential connections between pyrethroids, organophosphates, cannabinoids, and Parkinson’s disease using the Comparative Toxicogenomics Database (CTD). Eleven pyrethroids, 30 organophosphates, and 14 cannabinoids were associated with 95 genes to form 3,237 inferred and curated Chemical-Gene-Phenotype-Disease tetramers. Using a behavioral repulsion assay with the whole organism model Caenorhabditis elegans, we examined the effect of cannabinoids and insecticides on depleting dopamine synthesis. Exposure to chlorpyrifos and permethrin, but not Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), results in dose-dependent effects on 1-nonanol repulsive behaviors in C. elegans, indicating dopaminergic neurotoxicity (P < 0.01). Dose-dependent effects of chlorpyrifos are different in the presence of Δ9-THC and CBD (P < 0.001). As a proof of concept, this study demonstrated how to use new approach methodologies such as C. elegans and the CTD to inform further testing and pesticide regulations in cannabis by chemical class.
Comparative Efficacy and Safety of Endovascular vs. Surgical Treatment in Spinal Dural Arteriovenous Fistulas
Authors: Musmar Basel , Roy Joanna M. , Orscelik Atakan , Bhaskar Sonu , Sizdahkhani Saman , Atallah Elias , Koduri Sravanthi , Tjoumakaris Stavropoula I. , Gooch Michael Reid , Rosenwasser Robert H. , Jabbour Pascal
Published: January 2025

Study Design.

Systematic Review and Meta-analysis.

Objective.

This study aims to compare the efficacy and safety of surgical and endovascular treatments for SDAVFs.

Summary of Background Data.

Spinal dural arteriovenous fistulas (SDAVFs) result from an abnormal connection between the radiculomeningeal artery and the radicular vein, leading to venous hypertension and potential neurological damage. The two primary treatment strategies are surgical closure and endovascular obliteration of the fistula.

Methods.

PubMed, Scopus, and Web of Science databases were searched from inception to July 2024. We defined the successful treatment as fistula occlusion with sufficient embolic material penetration or obliteration during surgery.

Results.

A total of 1192 articles were identified, with 40 studies meeting the inclusion criteria, comprising 1818 patients (surgical: 804, endovascular: 1014). The surgical group demonstrated higher rates of complete occlusion at last follow-up (96.8%, 363/375) compared to the endovascular group (72.5%, 470/648) (OR: 0.16; CI: 0.09 to 0.28, P<0.01). Surgical treatment also had higher successful treatment rates (97.5%, 392/402) compared to endovascular treatment (66.7%, 529/793) (OR: 0.11; CI: 0.06 to 0.19, P<0.01). Recurrence rates were lower in the surgical group (OR: 6.04; CI: 3.45 to 10.57, P<0.01) and retreatment rates were also lower (OR: 7.16; CI: 4.11 to 12.48, P<0.01). Initial treatment failure was significantly higher in the endovascular group (32.2%, 329/1023) compared to the surgical group (2.3%, 19/804) (OR: 8.97; CI: 5.56 to 14.45, P<0.01).

Conclusions.

Surgical treatment for SDAVFs achieves higher rates of complete occlusion and successful treatment compared to endovascular treatment, with lower rates of recurrence, retreatment, and initial treatment failure. Although both treatments show similar improvements in neurological status and periprocedural complications, surgery remains the preferred approach for definitive results. Treatment decisions should be individualized based on patient-specific factors and anatomical characteristics. Further research is needed to confirm these results.
Evaluation of Clinically Integrated Community Health Worker Support Interventions for Adults With Cardiovascular Disease
Authors: Orofo Cynthia , Gothe Neha P. , Huebner Torres Cristina , Yoo-Jeong Moka , Ye Lichuan
Published: January 2025

Background and Purpose:

Chronically ill individuals with cardiovascular diseases (CVDs) have been extensively challenged by the complexities of disease management. Although clinically integrated community health worker (cCHW) support interventions have been increasingly implemented to help manage CVDs, a comprehensive analysis of interventions implemented in real-world settings is lacking. Additionally, the influence of contextual factors (eg, patient/organization characteristics) on such interventions is underexplored. Guided by the PRISM framework, the purpose of this review is to understand cCHW interventions supporting individuals with CVDs in the clinical settings.

Methods:

PubMed, CINAHL and APA PsycInfo databases were searched using the following primary keywords: (community health worker), (integrat*), (chronic) and (cardiovascular disease). Studies investigating the integration of CHWs in the care of adults with CVD published from inception to 2023 were included.

Results:

A total of 25 studies were included in the review. Majority of studies (n = 23) measured intervention effectiveness and often positively impacted outcomes, including blood pressure and chronic disease control. Compared to effectiveness, the rest of the RE-AIM domains were underexplored.

Conclusion and Implications:

cCHW programs have demonstrated some evidence in improving health outcomes in individuals with CVD. However, less is known about their impact on other relevant multidimensional RE-AIM outcomes.
Traffic pollution, reproductive health, and depressive symptoms in a healthy multiethnic sample of reproductive age women in the Ovarian Aging Study
Authors: Pan Anwesha , Cromeens Martha Grace , Cedars Marcelle I. , Bleil Maria E.
Published: January 2025

Objective

This study aimed to determine whether exposure to traffic-related air pollution (TRAP) is associated with depressive symptoms while also characterizing the contribution of key explanatory factors related to sociodemographics and health. In addition, it aimed to also explore the role of reproductive health as a pathway through which exposure to TRAP may relate to depressive symptoms.

Methods

Participants were 688 healthy reproductive-age women in the Ovarian Aging Study. TRAP was derived from distance-weighted traffic counts using residential addresses. Depressive symptoms were assessed by the Center for Epidemiological Studies Depression scale. Explanatory factors were assessed by interview and clinic measures, including demographics (age, race/ethnicity), socioeconomic status (SES) (individual SES, neighborhood SES), general health (smoking, body mass index), and reproductive health (menarcheal age, contraceptive use, parity, menstrual cycle characteristics).

Results

In cross-sectional, step-wise multivariate regression analyses, greater exposure to TRAP was related to more depressive symptoms (b = 0.779, P = 0.015). Lower individual SES, longer menstrual cycle length, and experiencing change (vs no change) in menstrual cycle length were also related to more depressive symptoms (P's < 0.05). Examination of each model step showed that variance in depressive symptoms was attributable to TRAP (1.2%, P = 0.004), demographics (1.0%, P = 0.217), SES (1.4%, P = 0.007), general health (0.3%, P = 0.356), and reproductive health (2.0%, P = 0.015). Finally, menstrual cycle length, a marker of reproductive health status, partially mediated effects of TRAP on depressive symptoms (indirect effect: b = 0.064, P = 0.020).

Conclusions

Findings showed that exposure to TRAP is associated with depression, along with SES and reproductive health factors, and that reproductive health may be a pathway through which TRAP relates to depression.
“Doctor, I Want to Be Like This!”: Exploring Global Beauty Body Standards Through a Multicenter Survey
Authors: Tambasco Damiano , Mir Jordi , Hoyos Alfredo , Sieber David , Viaro Mauricio , Zamora Jack , Manfrim Carlos , Zara Edwin , Tomaselli Federica , Montes Christian , Isola Miriam , De Martino Maria , Parodi Pier Camillo , Albanese Roberta , Mendanha Mario
Published: January 2025

Background:

Plastic surgery aims to enhance patients’ positive features and improve perceived flaws without seeking complete transformation. The body is a living organism, not a sculptural object to be reshaped at will. Aesthetic standards are influenced by subjective factors, including technology and social media’s effect on self-perception and beauty ideals. Understanding body perception requires consideration of personal views, mirror reflections, and external perspectives.

Methods:

We analyzed data from more than 4000 patients to obtain objective insights into contemporary aesthetic preferences. We examined the influence of globalization on beauty standards, the relationship between physical activity and desired body definitions, and regional preferences for specific body shapes. In addition, we assessed how patients’ aesthetic preferences are shaped more by the surgical centers they choose than by their nationality.

Results:

Our findings indicate that globalization has diversified perceptions of beauty, highlighting personal and cultural differences. We noted a significant correlation between patients’ aesthetic preferences and the surgical center, reflecting the impact of medical tourism and social media on shaping beauty ideals.

Conclusions:

As patient opportunities expand, the remote management of complex procedures necessitates skilled surgeons to ensure safe and effective care. Our experience provides valuable data on current patient preferences, essential for adapting practices in the evolving landscape of plastic surgery.
Lateral Polydactyly of the Foot: Surgical Outcomes Based on a New Classification
Authors: Otsuka Junko , Horii Emiko , Koh Shukuki , Takeshige Hiroki
Published: January 2025

Background:

The objective of this study was to propose a novel classification for lateral polydactyly of the foot that integrates both visual appearance and radiographic findings and to delineate surgical techniques and their outcomes based on this classification.

Methods:

This study enrolled 148 feet from 126 patients who underwent initial surgery at our hospital between January 2009 and July 2021. The new classification system was derived from visual appearance according to the Hirase classification and radiological bifurcation level (D: distal or middle phalanx, P: proximal phalanx, and M: metatarsal). Incidence rates, surgical procedures, and surgical outcomes were compared across each type.

Results:

Morphologically, 25 cases were classified as type A, 43 cases as type B1, and 80 cases as type B2. The branching level was categorized as D in 81 feet, P in 41 feet, and M in 26 feet, with 68 feet (46%) classified as B2-D type. Excision of the sixth toes was performed in all type A cases, whereas the majority of type B cases required excision of the fifth toes. Revision procedures were conducted on 8 feet. Three patients with type A-P classification developed painful hammer toe deformities as a late sequela that necessitated extensor tenolysis and metatarsophalangeal joint contracture release during their school-age years.

Conclusions:

The classification system based on the combination of visual appearance and radiological branching level was both straightforward and beneficial for surgical planning and for predicting surgical outcomes and late sequelae.
Shifting Paradigms: A Deep Dive Into Public Perceptions of Gender-affirming Surgery
Authors: Camacho Justin M. , Alfertshofer Michael , Patel Heli S. , Najafali Daniel , Thompson Noelle , Stoffel Victoria , Reid Chris M. , Alperovich Michael , Knoedler Samuel , Knoedler Leonard
Published: January 2025

Background:

Given the growing demand for gender-affirming surgery (GAS) in recent years, it is essential to explore the public perceptions of GAS. Understanding the public’s opinions and attitudes toward GAS will provide valuable insights for shaping educational initiatives to enhance public knowledge and awareness.

Methods:

This cross-sectional study used the Prolific Academic platform to distribute an online survey among adult participants residing in the United States in August 2023.

Results:

Of 1005 completed survey responses, 50% of respondents were 41 years of age or older, 51% were women, and 73% were White. A total of 18% identified as part of the LGBTQIA+ community, and most (37%) resided in the southern United States. The majority of participants (78%) did not personally know anyone who underwent GAS, and 74% believed that plastic surgeons mainly perform GAS. Only 22% felt healthcare professionals were well qualified to provide gender-affirming care. Media’s effect on GAS acceptance was assessed to be mostly negative (33%) or very negative (12%). About 33% favored both public and private health insurance coverage for GAS, whereas 35% opposed insurance coverage. Most respondents strongly agreed (32% and 34%) or agreed (33% and 37%) that GAS aligns with gender identity and improves mental health. Regarding minimum age, most partakers (43%) supported 18 years, whereas 38% endorsed 21 years.

Conclusions:

This study sheds light on the public perceptions of GAS. These insights underscore the need for targeted educational efforts to increase awareness, rectify misconceptions, and promote a deeper understanding of GAS within society.
Evidence-based Algorithms for Free Deep Inferior Epigastric Perforator Flap Salvage in Autologous Breast Reconstruction
Authors: Todd Anna R. , Alrajraji Mawaddah , Sawa Kathryn , Lipa Joan E. , Snell Laura
Published: January 2025

Background:

Breast reconstruction with the deep inferior epigastric perforator (DIEP) free flap has become the gold standard for autologous breast reconstruction. Flap take-back to the operating room (OR) is an uncommon but difficult situation, requiring prompt and accessible resources. We conducted a literature review and independent expert review to inform evidence-based perioperative algorithms in the event of DIEP flap compromise.

Methods:

A review of the literature was conducted, including MEDLINE, Embase, Google Scholar, and Cochrane Controlled Register of Trials. Publications examining free flap re-exploration in breast reconstruction were used to inform evidence-based clinical algorithms. The algorithms then underwent expert review and revisions from 6 international experts in microsurgery.

Results:

Three evidence-based management algorithms were created. The first algorithm outlines perioperative management strategies to optimize patient care and prompt return to the OR. Nonconstricting flap inset after take-back, salvage medical strategies and postoperative management following flap failure were additionally included. Algorithms 2 (venous congestion) and 3 (vascular thrombosis) provide specific intraoperative strategies surrounding mechanical decompression, pedicle exposure, assessment and extraction of thrombosis, identification and use of alternative recipient vessels, and the usage of intraoperative thrombolytics.

Conclusions:

A coherent and stepwise approach to DIEP flap compromise in breast reconstruction was developed. These expert-reviewed algorithms provide an approachable and evidence-based structure to support return to the OR and serve as readily available resources.
Genetics, manifestations, and management of catecholaminergic polymorphic ventricular tachycardia
Authors: Desai Shubh , Moore Oliver M. , Wehrens Xander H.T.
Published: January 2025

Purpose of review

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a devastating heritable channelopathy that can lead to sudden cardiac death in children and young adults. This review aims to explore genetics, the cardiac and extracardiac manifestations of mutations associated with CPVT, and the challenges involved with managing phenotypically variable variants.

Recent findings

The understanding of the genetics and mechanisms of CPVT continues to grow with recent discoveries including alternative splicing of cardiac TRDN and calmodulin gene variants. Additionally, there is an increasing recognition of the extra-cardiac manifestations such as epilepsy, neurodevelopmental delay, and glucose homeostasis abnormalities in RyR2 variant carriers. Advances in precision medicine, including the development of iPSC-derived cardiomyocytes, are valuable models for developing targeted therapeutics.

CPVT remains a complex disorder with cardiac and neurological manifestations impacting management. Early genetic testing and personalized treatment, including beta-blockers, flecainide, and ICDs, is important in improving outcomes. Ongoing research into the mechanism of each mutation will help in developing more effective, personalized therapeutics.
Syncope Induced by Dynamic Head and Shoulder Motion in the Setting of Left Subclavian Stenosis
Authors: Fearington Forrest W. , Alajbegovic Katarina , Scott Jonathan M. , Brinjikji Waleed , Holmes Carmen R. , Khan Muhib
Published: January 2025

Introduction:

Dynamic vertebral artery insufficiency is a rare vascular phenomenon characterized by insufficient flow of the posterior cerebral circulation induced by dynamic motion of the head. Prior case reports have been limited to vertebral artery occlusion by cervical osteophytes or other structural impingements.

Case Report:

In this case report, we discuss the unusual case of a 61-year-old female with a history of vertigo, diplopia, nystagmus, and left subclavian stenosis admitted to the hospital for syncope elicited by a left head turn and left shoulder raise. Transcranial Doppler (TCD) ultrasound and angiography showed evidence of dynamic vertebrobasilar insufficiency elicited by a left-head turn. Percutaneous stenting of the left subclavian artery led to the resumption of normal vessel flow as assessed by TCD and the resolution of the patient’s symptoms.

Conclusions:

This case highlights an unusual cause of dynamic vertebrobasilar insufficiency induced by head turn and/or left shoulder raise due to subclavian stenosis, diagnosed by TCD and angiography, and successfully treated with subclavian artery stenting.
Topical neurokinin-1 receptor antagonism ameliorates ocular pain and prevents corneal nerve degeneration in an animal model of dry eye disease
Authors: Naderi Amirreza , Taketani Yukako , Wang Shudan , Kahale Francesca , Yung Ann , Surico Pier Luigi , Chen Yihe , Dana Reza
Published: January 2025

Introduction:

Ocular pain is a common complaint to eye care providers, associated with a variety of ocular conditions, among which dry eye disease (DED) is affecting millions of people worldwide. Despite being highly prevalent, ocular pain is not managed adequately in the clinic.

Objectives:

The aim of this study was to investigate the analgesic potential of neurokinin-1 receptor (NK1R) antagonism in DED.

Methods:

Dry eye disease was induced in mice, and an NK1R antagonist L-733,060 was topically administered twice daily throughout the study for 14 days. Hyperalgesia and allodynia were assessed using the eye-wiping test and palpebral ratio measurements. Corneas were collected for measuring substance P (SP) levels by enzyme-linked immunosorbent assay (ELISA) and imaging nerves by immunostaining. Trigeminal ganglions (TG) were collected to determine SP levels by ELISA and transient receptor potential cation channel subfamily V member 1 (TRPV1), transient receptor potential cation channel subfamily M (melastatin) member 8, c-Fos, and activating transcription factor 3 (ATF3) mRNA levels by real-time polymerase chain reaction.

Results:

Treating DED mice with L-733,060 resulted in a significant reduction in eye wipe behavior, a significant increase in palpebral ratio, and significant decreases in SP levels in both the cornea and TG compared with the vehicle-treated group. In addition, NK1R antagonist treatment significantly suppressed the upregulation of TRPV1, ATF3, and c-Fos and prevented corneal nerve loss.

Conclusion:

Neurokinin-1 receptor antagonism effectively reduced ocular nociception, decreased neuronal activation, and preserved corneal nerves in mice with DED. These findings suggest that blockade of SP signaling pathway is a promising therapeutic strategy for managing DED pain.
Evaluation of the efficacy of chlorous acid water and sodium hypochlorite solution against SARS-CoV-2 in the presence of organic matter
Authors: Lawal-Ayinde Basirat Mojisola , Oda Kosuke , Elsayed Abeer Mohamed Abdelfattah , Kurose Miuko , Sasaki Hiroaki , Nomura Toshihito , Yamamoto Akima , Higashiura Akifumi , Horiuchi Isanori , Goda Hisataka , Sakaguchi Takemasa
Published: January 2025

Chlorous acid water and sodium hypochlorite solution are effective disinfectants against SARS-CoV-2, the virus that caused the COVID-19 pandemic. Recent studies have shown that both compounds have equivalent inactivation effects when tested on purified viruses. However, in practical applications, the presence of organic matter is common and can significantly affect disinfectant performance. We conducted several experiments comparing these two disinfectants under different conditions to better understand their practical efficacy. When an infected cell culture medium (serum-free) was used as the test virus, chlorous acid water and sodium hypochlorite solution showed reduced efficacy. This decrease was attributed to the presence of amino acids in the medium. Notably, sodium hypochlorite solution showed a more pronounced reduction in potency compared to chlorous acid water. In addition, we evaluated the SARS-CoV-2 inactivation effects of chlorous acid water and sodium hypochlorite solution under various organic loading conditions simulating real-world contamination scenarios such as blood, vomit, and saliva. The organic materials used included bovine serum albumin, sheep red blood cells, polypeptone, fetal bovine serum, and artificial saliva. The results showed that chlorous acid water demonstrated superior resistance to organic matter interference compared to sodium hypochlorite solution. These results suggest that chlorous acid water may be more effective than sodium hypochlorite solution in inactivating viruses on contaminated surfaces, particularly in healthcare settings where organic contamination is common. In summary, our research suggests that chlorous acid water may be a more effective disinfectant in practical settings.
Literature review on eye trauma in Africa
Authors: Philémon Mapenzi Ndagonywa , Kakusu Daniel
Published: January 2025

Background

Ocular trauma is a relevant cause of monoocular blindness in Africa. Although once neglected, it has recently been incriminated as one of the main etiologies of non-congenital visual impairment throughout Africa, the epidemiology of ocular injuries varies across regions, and remains an increasing concern, hence the interest in highlighting its aspects.

Objective

This study aims to take stock of the overall situation on the epidemio-clinical, etiological and therapeutic aspects.

Methods

This study is a narrative literature review of articles on ocular trauma in Africa published in Medline via Pubmed and Semantic scholar from Research rabbit. After cross-referencing the keywords, we found, relative to our study period from 2012 to 2022, 215 articles in the literature on eye trauma, of which nine articles were thus retained according to the inclusion and exclusion criteria.

Results

In relation to the frequency, the highest frequency according to the regions is 44.1% observed in the studies carried out in Tanzania in 2019 and the lowest is observed in the studies carried out in Nigeria in 2017 while two years later still in Nigeria the results showed an increasing trend to 30.7%; which proves that the frequency of eye trauma in Africa varies in time and space. Clinically, the results illustrate the most common clinical signs. It emerges that each study has its particularity on the most common signs. Whatever the spatio-temporal particularities of eye trauma, the most commonly used management is medical treatment.
Understanding preconception care practices, beliefs, and attitudes in Australian primary care: A qualitative study of health professionals
Authors: Caut Cherie , Schoenaker Danielle , McIntyre Erica , Steel Amie
Published: January 2025

Background

Primary care is well placed to provide preconception care. To support primary care professionals in meeting the preconception care needs of prospective parents, an understanding of their perspectives and experiences of providing preconception care is needed. As women consult with a range of primary care health professionals for preconception care, including general practitioners (GPs), midwives, and naturopaths, this study aimed to explore these health professions’ beliefs and attitudes towards preconception care and describe their preconception care practice behaviours in Australia.

Methods

Qualitative methods were employed. Focus groups and interviews with health professionals (n=18) in clinical practice (more than 5 years) within Australia were conducted between May and August 2021. Health professionals comprised GPs (n=6), midwives (n=5), and naturopaths (n=7) and were recruited through professional organisations. Fieldwork explored the practice services provided, beliefs and attitudes towards preconception care, and preconception care practice behaviours. Data analysis used a framework thematic analysis approach.

Results

Three major themes were identified:Defining preconception health and care(subthemes:defining preconception healthanddefining preconception care), Understanding primary practitioners’ role in preconception care(subthemes:the GP’s role as central to preconception care,role is holistic, educational, and empoweringandrole of personal experience and gender in being a preconception care provider), andSituating preconception care in primary care practice(subthemes:preconception care patient populations,preconception care within broader health servicesandpreconception health information sources are varied).

Conclusions

While health professionals shared similar views on the factors that comprise preconception health, some components of preconception health differed among the health professional groups. Although it is universally agreed that GPs are key providers of preconception care, they are not the only health professionals with a role. A wider range of health professionals could aid in meeting the preconception care needs of people of reproductive age with greater coordination among them. To improve the provision of multi-disciplinary preconception care further insights into shared and complementary responsibilities among health professionals in primary care settings are needed.
Spectral normative modeling of brain structure
Authors: Mansour L Sina , Di Biase Maria A , Yan Hongwei , Xue Aihuiping , Venketasubramanian Narayanaswamy , Chong Eddie , Alexander-Bloch Aaron , Chen Christopher , Zhou Juan Helen , Yeo B.T. Thomas , Zalesky Andrew
Published: January 2025

Normative modeling in neuroscience aims to characterize interindividual variation in brain phenotypes and thus establish reference ranges, or brain charts, against which individual brains can be compared. Normative models are typically limited to coarse spatial scales due to computational constraints, limiting their spatial specificity. They additionally depend on fixed regions from fixed parcellation atlases, restricting their adaptability to alternative parcellation schemes. To overcome these key limitations, we propose spectral normative modeling (SNM), which leverages brain eigenmodes for efficient spatial reconstruction to generate normative ranges for arbitrary new regions of interest. Benchmarking against conventional counterparts, SNM achieves a 98.3% speedup in computing accurate normative ranges across spatial scales, from millimeters to the whole brain. We demonstrate its utility by elucidating high-resolution individual cortical atrophy patterns and characterizing the heterogeneous nature of neurodegeneration in Alzheimer's disease. SNM lays the groundwork for a new generation of spatially precise brain charts, offering substantial potential to drive advances in individualized precision medicine.
Alterations in Lipid Profiles in Children with Perinatally Acquired HIV Infection living in Ghana
Authors: Ayanful-Torgby Ruth , Shabanova Veronika , Essuman Akosua A. , Boafo Emmanuel , Amoah Linda E. , Paintsil Elijah
Published: January 2025

Children and adolescents who acquired HIV perinatally and are on lifelong antiretroviral therapy (ART) are at increased risk of lipid abnormalities, premature atherosclerosis, and early onset cardiovascular diseases (CVD). Majority of these children reside in sub-Saharan Africa, where monitoring of lipid profiles is not routine. In this study, we assessed the age dependent prevalence of dyslipidemia among children and adolescents who acquired HIV in Ghana.

In this cross-sectional study we examined lipid profiles of 397 children aged 6 to 18 years. Dyslipidemia was defined by elevated total cholesterol (TC) (≥200 mg/dL) or triglyceride (TG) levels (>150 mg/dL) or low-density lipoprotein cholesterol (LDL-C) (>130 mg/dL) or reduced high-density lipoprotein cholesterol (HDL-C) (<35 mg/dL). Dyslipidemia prevalence, by at least one criterion and for each criterion separately, was compared between age groups 6 - 12 (pre-teen) and 13 - 18 (teenage) years, as well as by sex.

The overall prevalence of dyslipidemia was 42.32%, and by individual criterion was 9.07% using LDL-C, 11.84% using TC, 15.87% using TG, and 24.00% using HDL-C. Additionaly, 5.04% (n=20) of the participants showed abnormalities across three parameters. Teenagers had a higher overall prevalence of dyslipidemia (46.75% vs. 39.04%, p=0.12). Criterion-based dyslipidemia prevalence varied across age groups, with TC-based (14.04% vs. 8.88%, p=0.12) being higher in the pre-teen group, while elevated TG-based (20.12% vs. 12.72%, p=0.05) and low levels of HDL- based (28.99% vs. 20.60%, p=0.05) were more prevalent in the teenagers. The mean levels of TC (p=0.04) and LDL-C (p=0.03) were significantly higher in the pre-teen age groups. Females had nearly twice as high as that of males with prevalence of abnormal LDL-C levels (11.39% vs. 6.67%, p=0.13).

This study showed a high prevalence of dyslipidemia among children who acquired HIV perinatally and are on ART, with age-related variations in lipid profiles. These findings emphasize the importance of implementing routine monitoring for lipid disorders within this population.
GALILEO Generatively Expands Chemical Space and Achieves One-Shot Identification of a Library of Novel, Specific, Next Generation Broad-Spectrum Antiviral Compounds at High Hit Rates
Authors: Umansky Tyler , Woods Virgil , Russell Sean M. , Garvey David S. , Smith Davey M. , Haders Daniel
Published: January 2025

The COVID-19 pandemic (2019-2023) demonstrated the need for safe and effective, stockpiled broad-spectrum antiviral drugs to suppress unexpected viral outbreaks. The inability of the pharmaceutical industry to create such a therapeutic in the 6 years since the onset of COVID-19 demonstrates antiviral drug development must undergo a paradigm shift for this to occur. AI-based target and medicinal chemistry discovery platforms such as GALILEO and its geometric graph convolutional network tool ChemPrint, which we recently published, hold promise in accelerating and reimagining the drug development process. GALILEO identified the Thumb-1 site (an allosteric subdomain of the viral RNA polymerase) to be structurally conserved across numerous viral species and MDL-001 (an orally available therapeutic with a favorable pharmacokinetics and safety profile in humans) to be a potent inhibitor thereof. Published preclinical proof-of-concept studies demonstrated MDL-001 as a first-in-class broad-spectrum antiviral drug. This study leverages GALILEO’s generative and multimodal discovery tools to create trillions of new chemical entities (NCEs) from MDL-001’s pharmacophoric scaffold and select a library of highly specific and optimized compounds for next-generation broad-spectrum antiviral development. Specifically, ChemPrint’s one-shot predictions identified 12 NCEs with predicted affinity to Thumb-1 and significantly reduced, or no, affinity to MDL-001’s original target.In vitrobioassays demonstrated a 100% hit rate, with all 12 NCEs having antiviral activity against Hepatitis C Virus (HCV) and/or human Coronavirus 229E.In vitrostudies also demonstrated reduced activity of 800-fold to greater than 15,000-fold relative to MDL-001’s originally designed mechanism of action (MoA). In Tanimoto similarity plots, the 12 NCEs lacked chemical relatedness to known antiviral drugs, including MDL-001 (average Tanimoto coefficient: 0.38) and Beclabuvir, (average Tanimoto coefficient: 0.13) a HCV Thumb-1 ligand that lacks broad-spectrum activity. This study showcases GALILEO’s ability to generate vast NCE libraries and ChemPrint’s extrapolative capabilities to discover large, potent NCE libraries of compounds, specific to a complex target that are novel to known chemistry at high hit-rates.
Domain Knowledge Augmented Contrastive Learning on Dynamic Hypergraphs for Improved Health Risk Prediction
Authors: Choudhuri Akash , Vu Hieu , Jha Kishlay , Adhikari Bijaya
Published: January 2025

Accurate health risk prediction is crucial for making informed clinical decisions and assessing the appropriate allocation of medical resources. While recent deep learning based approaches have shown great promise in risk prediction, they primarily focus on modeling the sequential information in Electronic Health Records (EHRs) and fail to leverage the rich mobility interactions among health entities. As a result, the existing approaches yield unsatisfactory performance in downstream risk prediction tasks, especially tasks such asClostridioides difficileInfection (CDI) incidence prediction that are primarily spread through mobility interactions. To address this issue, we propose a new approach that leverages Hypergraphs to explicitly model mobility interactions to improve predictive performance in health risk prediction tasks. Unlike regular graphs that are limited to modeling pairwise relationships, hypergraphs can effectively characterize the complex high-order semantic relationships between health entities. Moreover, we introduce a new contrastive learning strategy that exploits the domain knowledge to generate semantically meaningful positive (homologous) and negative (heterologous) pairs needed for contrastive learning. This unique contrastive pair augmentation strategy boosts the power of contrastive learning by generating feature representations that are both robust and well-aligned with the domain knowledge. Experiments on two real-world datasets demonstrate the advantage of our approach in both short-term and long-term risk prediction tasks, such asClostridioides difficileinfection incidence prediction and MICU transfer prediction. Our framework obtains gains in performance up to 29.49 % for PHOP, 30.64 % for MIMIC-IV for MICU transfer prediction, 13.17 % for PHOP, and 4.45 % for MIMIC-IV for CDI Incidence Prediction.
Impact of Digital Contact Tracing on Pandemic Control Analysed with Behaviour-driven Agent-based Modelling
Authors: Lopera González Luis Ignacio , Köber Göran , Kirchner Göran , Benzler Justus , Amft Oliver
Published: January 2025

We disentangle the efficacy of individual non-pharmaceutical interventions (NPIs), including digital contact tracing (DCT), with a novel behaviour-driven agent-based model (ABM) to inform ongoing pandemic preparedness efforts. Our model’s Zeitgeber architecture delineates contextual characteristics, including daytime, daily routines, locations, and activities. Our method determines each agent’s current location and behaviour in a realistic environment under the restrictions of NPIs. We model viral load transfer between agents from contact duration, distance, and the infected agent’s infectiousness level. We examine the effects of DCT adoption, adherence, and compliance, both individually and combined with other NPIs, on key pandemic indicators, thus providing novel insight into infection dynamics. DCT combined with other NPIs reduces the total infections up to 52% for realistic behaviour, whereas DCT alone yielded a 43% reduction. Surprisingly however, some NPI combinations do not improve pandemic parameters. Our approach offers fine-grained analysis capabilities on the effectiveness of NPI combinations that cannot be obtained in human studies due to confounding effects. Thus our approach can inform future pandemic control efforts and prioritisation in pandemic preparedness.
Genetic polymorphism and risk of anti-tuberculosis drug-induced liver injury (AT-DILI): a systematic review and meta-analysis
Authors: Tarazjani Amirreza Dehghan , Jouabadi Sima Mohammadi , Jouabadi Soroush Mohammadi , Naderi Elnaz , Sturkenboom Miriam , Ahmadizar Fariba
Published: January 2025

Anti-tuberculosis (TB) drugs like isoniazid and rifampin can cause hepatotoxicity leading to treatment termination. Although Genome-wide association studies (GWAS) have identified variants linked to the risk of developing anti-tuberculosis drug-induced liver injury (AT-DILI), findings remain inconsistent. This study aimed to systematically summarise previous observational studies and assess the association between genetic polymorphisms and AT-DILI risk in adults.

We conducted a comprehensive search of PubMed, EMBASE, and Cochrane Libraries until January 10, 2023. The Newcastle-Ottawa Scale checklist was used to assess the methodological quality of the included studies. Pooled odds ratios (OR) with 95% confidence intervals (CIs) were employed using a random-effect model with the I2statistic to estimate the heterogeneity of results.

Our study included 10 studies (n=3,322) of Asian ancestry. We identified genetic variants in drug-metabolizing enzymes, including NAT2, CYP2E1, and PXR, linked to AT-DILI risk. CYP2E1 C1/C1 and slow acetylators of NAT2*6A/6A, NAT26A/7B, NAT27B/7B, and NAT25B/7B genotypes were associated with increased risk, while rapid acetylators of NAT24/4 and NAT24/7B were linked to decreased risk. No significant association was found between CYP2E1B C1/C2, NAT2(*4/*6A, *4/*5B, *5B/*5B) and PXR with AT-DILI risk.

This study revealed that NAT2 slow acetylator genotypes or CYP2E1 C1/C1 are causally linked to AT-DILI risk. The findings suggest that genetic variants in drug-metabolizing enzymes regulated by NAT2 and CYP2E1 are involved in developing drug-induced liver injury in users of anti-TB drugs.
Psychiatric symptom improvement from adjunctive statin prescribing in severe mental illness: three target trial emulation studies
Authors: Launders Naomi , Richards-Belle Alvin , Man Kenneth KC , Wong Ian CK , Osborn David PJ , Hayes Joseph F
Published: January 2025

Background

Randomized controlled trials (RCTs) of statins as adjunct therapy for severe mental illness (SMI) have produced mixed results. Specific statin-antipsychotic combinations might improve psychiatric symptoms through: 1) blood-brain barrier (BBB) penetrant statins being anti-inflammatory/neuroprotective, and/or 2) statins that inhibit p-glycoprotein enhancing the effects of antipsychotics with high p-glycoprotein affinity.

Aim

To investigate these mechanisms via three target trial emulation studies.

Methods

We identified patients with SMI (schizophrenia, bipolar disorder, ‘other’ psychoses) prescribed antipsychotics/mood stabilisers and statins from 2000-2019 in English electronic health records. We defined three hypothetical RCTs and their observational analogues: 1) simvastatin (crosses BBB) vs. atorvastatin/pravastatin/rosuvastatin (non-penetrant); 2A) simvastatin/atorvastatin (p-glycoprotein inhibitors) vs. pravastatin in patients prescribed risperidone/olanzapine/aripiprazole (high p-glycoprotein affinity); 2B) risperidone/olanzapine/aripiprazole vs. quetiapine (low p-glycoprotein affinity) in patients prescribed simvastatin/atorvastatin. Primary outcome: 12-month psychiatric admissions. Secondary outcomes: self-harm, physical health, and accident/injury admissions.

Results

In 72,096 patients prescribed statins and antipsychotics/mood stabilisers, we found no reduction in psychiatric admissions at 12 months in patients prescribed: 1) BBB-penetrant vs. non-penetrant statins (HR:1.07; 95%CI:0.88-1.31); 2A) antipsychotics with p-glycoprotein affinity and p-glycoprotein inhibiting statins vs. statins without inhibition (HR:0.77; 95%CI:0.28-2.15); 2B) p-glycoprotein inhibiting statins with antipsychotics having p-glycoprotein affinity vs. antipsychotics without affinity (HR:0.93; 95%CI:0.79-1.09). In 2B we observed reduced self-harm (HR:0.60; 95%CI:0.38-0.97) in per-protocol analysis and reduced psychiatric admissions in the ‘other’ psychoses subgroup (HR:0.53; 95%CI:0.34-0.85).

Conclusions

BBB permeability is unlikely to be the mechanism by which statins improve SMI symptoms. Further research is needed to understand statin-antipsychotic interactions, and whether interaction with p-glycoprotein is a plausible mechanism.
A Novel Heme-Degrading Enzyme that Regulates Heme and Iron Homeostasis and Promotes Virulence inEnterococcus faecalis
Authors: Brunson Debra N. , Manzer Hader , Smith Alexander B. , Zackular Joseph P. , Kitten Todd , Lemos José A.
Published: January 2025

Enterococcus faecalis, a gut commensal, is a leading cause of opportunistic infections. Its virulence is linked to its ability to thrive in hostile environments, which includes host-imposed metal starvation. We recently showed thatE. faecalisevades iron starvation using five dedicated transporters that collectively scavenge iron from host tissues and other iron-deprived conditions. Interestingly, heme, the most abundant source of iron in the human body, supported growth of a strain lacking all five iron transporters (Δ5Fe). To release iron from heme, many bacterial pathogens utilize heme oxygenase enzymes to degrade the porphyrin that coordinates the iron ion of heme. AlthoughE. faecalislacks these enzymes, bioinformatics revealed a potential ortholog of the anaerobic heme-degrading enzyme anaerobilin synthase, found inEscherichia coliand a few other Gram-negative bacteria. Here, we demonstrated that deletion of OG1RF_RS05575 inE. faecalis(ΔRS05575) or in the Δ5Fe background (Δ5FeΔRS05575) led to intracellular heme accumulation and hypersensitivity under anaerobic conditions, suggestingRS05575encodes an anaerobilin synthase, the first of its kind described in Gram- positive bacteria. Additionally, deletion ofRS05575, either alone or in the Δ5Fe background, impairedE. faecaliscolonization in the mouse gastrointestinal tract and virulence in mouse peritonitis and rabbit infective endocarditis models. These results reveal that RS05575 is responsible for anaerobic degradation of heme and identify this relatively new enzyme class as a novel factor in bacterial pathogenesis. Findings from this study are likely to have broad implications, as homologues ofRS05575are found in other Gram-positive facultative anaerobes.

IMPORTANCE

Heme is an important nutrient for bacterial pathogens, mainly for its ability to serve as an iron source during infection. While bacteria are known to release iron from heme using enzymes called heme oxygenases, a new family of anaerobic heme-degrading enzymes has been described recently in Gram-negative bacteria. Here, we report the first description of anaerobic heme degradation by a Gram-positive bacterium, the opportunistic pathogenEnterococcus faecalis, and link activity of this enzyme to their ability to colonize and infect the host. We also show that homologues of this enzyme are found in many Gram-positive facultative anaerobes, implying that the ability to degrade heme under anaerobic conditions may be an overlooked fitness and virulence factor of bacterial pathogens.
Acute temporal, regional, and cell-type specific NKCC1 disruption following severe TBI in the developing gyrencephalic brain
Authors: Hochstetler Alexandra , Courtney Ya’el , Oloko Peace , Baskin Benjamin , Ding-Su Andrew , Stinson Tawny , McGuone Declan , Haynes Robin , Lehtinen Maria K. , Costine-Bartell Beth
Published: January 2025

Abstract

Traumatic brain injury (TBI) in children is a leading cause of morbidity and mortality, with no effective treatment and limited clinical management. We developed a multifactorial traumatic brain injury model in piglets which mirrors the evolving pathophysiology of severe pediatric TBI, showing age-dependent hypoxic-ischemic cerebral cortical injury and matrix metalloproteinase-driven vasogenic edema, with infant piglets experiencing less tissue damage than toddler piglets. Extracellular matrix breakdown can precipitate neuronal dysfunction, disrupting chloride homeostasis and the reversal potential for GABA. We hypothesized that ongoing tissue damage might be related to markers of “immature GABA”, evaluated by changes to the expression and phosphorylation of sodium-potassium-2-chloride cotransporter 1 (NKCC1), potassium-chloride cotransporter 2 (KCC2), and a regulatory kinase, (STE20/SPS1-related proline-alanine-rich protein kinase) SPAK. We mapped these markers in developing swine and infant human brain, identifying a postnatal pNKCC1 decrease in human infant hippocampus, and a perinatal cortical and hippocampal GABA switch in pigs, with no change in the thalamus. In infant piglets with severe TBI, upregulation of neuronal pNKCC1 correlated with hypoxic-ischemic injury and seizure duration. We also observed dysregulation of NKCC1, KCC2, and SPAK in cortex and hippocampus in infant and toddler piglets with severe TBI, with thalamus unchanged. We noted ectopic, non-apical localization of pNKCC1 signal in choroid plexus epithelium across ages in piglets and humans with severe TBI, indicating acute dysregulation of the CSF chloride milieu. These findings position swine as a useful model for pediatric TBI research and suggest that SPAK or NKCC1 inhibition in infants may be therapeutic.

Significance statement

Severe TBI in early childhood, the majority of which is due to abuse, remains an understudied area of neurotrauma. Our piglet model effectively replicates the pathophysiology of severe pediatric TBI, capturing age-dependent injury patterns and mechanisms of spreading hypoxic-ischemic injury throughout the cortical ribbon. We identified upregulation of neuronal-pNKCC1 in infant piglets, but not toddler piglets with severe TBI, and found this correlates with injury severity, seizure duration, and subarachnoid hemorrhage. Our findings indicate that treatments targeted to inhibit neuronal NKCC1 might alleviate evolving brain injury in infants with severe TBI. This model provides a valuable platform for studying mechanisms of TBI and testing new interventions, potentially advancing therapeutic strategies for pediatric brain injury where stopping traumatic seizures is difficult.