bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Surgical Timing to Dental Health in Secondary Alveolar Bone Grafting: Three-Dimensional Outcomes
Authors: Kwon Donghwan , Shin Youngmin , Jo Taehee , Choi Jaehoon , Kim Junhyung , Jeong Woonhyeok
Published: September 2024

Background:

There are various opinions on the optimal timing for performing secondary alveolar bone grafting (SABG). This study compared dental health and 3-dimensional outcomes according to the timing of SABG surgery.

Patients and Methods:

A retrospective chart review was performed in patients who underwent SABG between January 1996 and October 2020. Patients were divided into early SABG (6–8 y old) and traditional SABG (9–13 y old) groups. The final dental survival of the lateral incisor and canine teeth, survival of the bone graft, and maxillary growth were analyzed using plain radiographs and computed tomography with a 3-dimensional volumetric analysis tool.

Results:

Thirty-six patients were divided into an early group (15 patients) and a traditional group (21 patients). Five patients had bilateral cleft lip, and 26 patients had unilateral cleft lip and palate; therefore, 36 alveolar clefts were analyzed in this study. Lateral incisor survival was significantly greater in the early group than in the traditional group (60% vs. 23.5%; P<0.05). Compared with that in the traditional group, graft success in the early group was greater (80% vs. 57.1%; P<0.05). Three-dimensional volumetric analysis revealed superior bone graft efficiency in the early group compared with the traditional group (55.2 vs. 38.5%; P<0.05). There was no significant difference in maxillary growth between the 2 groups.

Conclusions:

In our study, superior dental and clinical outcomes were observed in the early SABG group without any long-term complications or maxillary retrusion. Our institution cautiously indicated that SABG could be performed at an age earlier than the existing SABG performed after 9 years old.
Transarterial Radioembolization Can Downstage Intermediate and Advanced Hepatocellular Carcinoma to Liver Transplantation
Authors: Berardi Giammauro , Guglielmo Nicola , Cucchetti Alessandro , Usai Sofia , Colasanti Marco , Meniconi Roberto Luca , Ferretti Stefano , Mariano Germano , Angrisani Marco , Sciuto Rosa , Di Stefano Federica , Ventroni Guido , Riu Pascale , Giannelli Valerio , Pellicelli Adriano , Lionetti Raffaella , D’Offizi Giampiero , Vennarecci Giovanni , Maritti Micaela , Tritapepe Luigi , Cianni Roberto , Ettorre Giuseppe Maria
Published: September 2024

Background.

Transarterial radioembolization (TARE) is an effective treatment to control tumor growth and improve survival in hepatocellular carcinoma (HCC). The role of TARE in downstaging patients to liver transplantation (LT) is unclear. The aim of this study was to investigate the downstaging efficacy of TARE for intermediate and advanced HCC.

Methods.

Intention-to-treat analysis with multistate modeling was performed. Patients moved through 5 health states: (1) from TARE to listing, (2) from TARE to death without listing, (3) from listing to LT, (4) from listing to death without LT, and (5) from transplant to death. Factors affecting the chance of death after TARE were considered to stratify outcomes.

Results.

Two hundred fourteen patients underwent TARE. Of those, 43.9% had radiological response, 29.9% were listed, and 22.8% were transplanted. The probability of being alive without LT was 40.5% 1 y after TARE and 11.5% at 5 y. The chance of being listed was 9.4% at 1 y and 0.9% at 5 y. The probability of dying after TARE without LT was 38% at 1 y and 73% at 5 y. The overall survival of patients receiving LT was 61% at 5 y after transplant. Tumor beyond up-to-seven criteria, alfafetoprotein >400 ng/mL, and albumin-bilirubin ≥2 were associated with death. Three risk groups were associated with different response, chances of being listed, and receiving LT. Median survival was 3 y for low-risk, 1.9 y for intermediate-risk, and 9 mo for high-risk patients (P < 0.001).

Conclusions.

In intermediate and advanced HCC, TARE allows for a 44% chance of response, 30% downstaging, and 23% probability of permitting LT. Patient’s and tumor’s characteristics allow for risk stratification and predict survival from TARE.
Donor-derived Cell-free DNA Evaluation in Pediatric Heart Transplant Recipients: A Single-center 12-mo Experience
Authors: Sorbini Monica , Aidala Enrico , Carradori Tullia , Vallone Francesco Edoardo , Togliatto Gabriele Maria , Caorsi Cristiana , Mansouri Morteza , Burlo Paola , Vaisitti Tiziana , Amoroso Antonio , Deaglio Silvia , Pace Napoleone Carlo
Published: September 2024

Background.

Endomyocardial biopsy (EMB) is considered the gold-standard method to diagnose rejection after heart transplantation. However, the many disadvantages and potential complications of this test restrict its routine application, particularly in pediatric patients. Donor-derived cell-free DNA (dd-cfDNA), released by the transplanted heart as result of cellular injury, is emerging as a biomarker of tissue damage involved in ischemia/reperfusion injury and posttransplant rejection. In the present study, we systematically evaluated dd-cfDNA levels in pediatric heart transplant patients coming for follow-up visits to our clinic for 12 mo, with the aim of determining whether dd-cfDNA monitoring could be efficiently applied and integrated into the posttransplant management of rejection in pediatric recipients.

Methods.

Twenty-nine patients were enrolled, and cfDNA was obtained from 158 blood samples collected during posttransplant follow-up. dd-cfDNA% was determined with a droplet-digital polymerase chain reaction assay. EMB scores, donor-specific antibody measurements, and distress marker quantification were correlated with dd-cfDNA, together with echocardiogram information.

Results.

The percentage of dd-cfDNA increased when EMBs scored positive for rejection (P = 0.0002) and donor-specific antibodies were present (P = 0.0010). N-terminal pro-B-type natriuretic peptide and high-sensitive troponin I elevation were significantly associated with dd-cfDNA release (P = 0.02 andP < 0.0001, respectively), as were reduced isovolumetric relaxation time (P = 0.0031), signs of heart failure (P = 0.0018), and treatment for rejection (P = 0.0017). By determining a positive threshold for rejection at 0.55%, the test had a negative predictive value maximized at 100%.

Conclusions.

Collectively, results indicate that dd-cfDNA monitoring has a high negative prognostic value, suggesting that in heart transplanted children with dd-cfDNA levels of <0.55% threshold, protocol EMBs may be postponed.
Are agricultural commodity production systems at risk from local biodiversity loss?
Authors: Maney Calum , Sassen Marieke , Giller Ken E.
Published: September 2024

Compelling evidence for feedbacks between commodity crop production systems and local ecosystems has led to predictions that biodiversity loss could threaten food security. However, for this to happen agricultural production systems must both impact and depend on the same components of biodiversity. Here, we review the evidence for and against the simultaneous impacts and dependencies of eight important commodity crops on biodiversity. We evaluate the risk that pollination, pest control or biodiversity-mediated soil health maintenance services are at risk from local biodiversity loss. We find that for key species groups such as ants, bees and birds, the production of commodities including coffee, cocoa and soya bean is indeed likely to be at risk from local biodiversity loss. However, we also identify several combinations of commodity, ecosystem service and component of biodiversity that are unlikely to lead to reinforcing feedbacks and lose–lose outcomes for biodiversity and agriculture. Furthermore, there are significant gaps in the evidence both for and against a mutualism between biodiversity and agricultural commodity production, highlighting the need for more evaluation of the importance of specific biodiversity groups to agricultural systems globally.
Quantifying indirect and direct vaccination effects arising in the SIR model
Authors: Lin Lixin , Hamedmoghadam Homayoun , Shorten Robert , Stone Lewi
Published: September 2024

Vaccination campaigns have both direct and indirect effects that act to control an infectious disease as it spreads through a population. Indirect effects arise when vaccinated individuals block disease transmission in any infection chain they are part of, and this in turn can benefit both vaccinated and unvaccinated individuals. Indirect effects are difficult to quantify in practice but, in this article, working with the susceptible–infected–recovered (SIR) model, they are analytically calculated in important cases, through pivoting on the final size formula for epidemics. Their relationship to herd immunity is also clarified. The analysis allows us to identify the important distinction between quantifying the indirect effects of vaccination at the ‘population level’ versus the ‘per capita’ level, which often results in radically different conclusions. As an example, our analysis unpacks why the population-level indirect effect can appear significantly larger than its per capita analogue. In addition, we consider a recently proposed epidemiological non-pharmaceutical intervention (by the means of recovered individuals) used over the COVID-19 pandemic, referred to as ‘shielding’, and study its impact on our mathematical analysis. The shielding scheme is extended to take advantage of vaccination including imperfect vaccination.
Rethinking the physiological cross-sectional area of skeletal muscle reveals the mechanical advantage of pennation
Authors: Rockenfeller Robert , Günther Michael , Clemente Christofer J. , Dick Taylor J. M.
Published: September 2024

The shape of skeletal muscle varies remarkably—with important implications for locomotor performance. In many muscles, the fibres are arranged at an angle relative to the tendons’ line of action, termed the pennation angle. These pennate muscles allow more sarcomeres to be packed side by side, enabling the muscle to generate higher maximum forces for a given muscle size. Historically, the physiological cross-sectional area (PCSA) has been used to capture both the size and arrangement of muscle fibres, and is one of the best predictors of a muscles capacity to produce force. However, the anatomical and mechanical implications of PCSA remain ambiguous as misinterpretations have limited our ability to understand the mechanical advantage of pennate muscle designs. We developed geometric models to resolve the mechanistic and functional impacts of pennation angle across a range of muscle shapes and sizes. Comparisons among model predictions and empirical data on human lower limb muscles demonstrated how a pennate arrangement of fibres allows muscles to produce up to six times more isometric force when compared with non-pennate muscles of the same volume. We show that in muscles much longer than thick, an optimal pennation angle exists at which isometric force is maximized. Using empirically informed geometric models we demonstrate the functional significance of a pennate muscle design and provide a new parameter, pennation mechanical advantage, which quantifies this performance improvement.
Silver nanoparticles incorporated dental restorative resin and its antibiofilm effect
Authors: Campos-Ibarra Verónica , Rodríguez-Moreno Andrea , Zavala-Alonso Norma Verónica , Vargas-Sanchez Luis Octavio , Loredo-Tobias Marcos , García-Arreola María Elena , Aranda-Herrera Benjamin , Ruiz-Garcia Jaime , Manisekaran Ravichandran
Published: September 2024

Dental restoration materials are susceptible to bacterial biofilm formation, which damages the restorations and causes oral health problems. Therefore, to overcome this, silver nanoparticles (AgNPs) are studied widely due to their antimicrobial, anti-inflammatory and healing properties. The purpose of this study was to develop a strategy for incorporating AgNPs onto the surface of bisacrylic resin (Bis) to evaluate its antibiofilm effects using
Streptococcus sanguinis
and
Actinomyces naeslundii
. AgNPs with an average size of 25 nm at two different concentrations were dispersed on the Bis surface (Bis-AgNPs) by mechanical deposition. Ag release was quantified until 7 days of incubation. Bacterial growth was assessed using a viability assay kit and observed using confocal microscopy. The biofilm biomass was quantified using arbitrary fluorescence units. Cell viability was evaluated using an MTT assay. The results showed that Bis-AgNPs significantly inhibited biofilm formation along with a significant difference in the viability of human gingival fibroblasts. The quantification confirmed a decrease in Ag release over time, and elemental mapping showed AgNP penetration up to 10 µm from the surface. Therefore, it was concluded that Bis-AgNPs presented enhanced antibiofilm properties, even at a concentration with no adverse effects. Therefore, this nanocomposite may be a promising alternative for biofilm control in temporary restorative materials.
Acoelomorph flatworm monophyly is a long-branch attraction artefact obscuring a clade of Acoela and Xenoturbellida
Authors: Redmond Anthony K.
Published: September 2024

Acoelomorpha is a broadly accepted clade of bilaterian animals made up of the fast-evolving, morphologically simple, mainly marine flatworm lineages Acoela and Nemertodermatida. Phylogenomic studies support Acoelomorpha’s close relationship with the slowly evolving and similarly simplistic
Xenoturbella
, together forming the phylum Xenacoelomorpha. The phylogenetic placement of Xenacoelomorpha amongst bilaterians is controversial, with some studies supporting Xenacoelomorpha as the sister group to all other bilaterians, implying that their simplicity may be representative of early bilaterians. Others propose that this placement is an error resulting from the fast-evolving Acoelomorpha, and instead suggest that they are the degenerate sister group to Ambulacraria. Perhaps as a result of this debate, internal xenacoelomorph relationships have been somewhat overlooked at a phylogenomic scale. Here, I employ a highly targeted approach to detect and overcome possible phylogenomic error in the relationship between
Xenoturbella
and the fast-evolving acoelomorph flatworms. The results indicate that the subphylum Acoelomorpha is a long-branch attraction artefact obscuring a previously undiscovered clade comprising
Xenoturbella
and Acoela, which I name Xenacoela. The findings also suggest that Xenacoelomorpha is not the sister group to all other bilaterians. This study provides a template for future efforts aimed at discovering and correcting unrecognized long-branch attraction artefacts throughout the tree of life.
Computational account for the naturalness perception of others’ jumping motion based on a vertical projectile motion model
Authors: Yokosaka Takumi , Ujitoko Yusuke , Kawabe Takahiro
Published: September 2024

The visual naturalness of a rendered character’s motion is an important factor in computer graphics work, and the rendering of jumping motions is no exception to this. However, the computational mechanism that underlies the observer’s judgement of the naturalness of a jumping motion has not yet been fully elucidated. We hypothesized that observers would perceive a jumping motion as more natural when the jump trajectory was consistent with the trajectory of a vertical projectile motion based on Earth’s gravity. We asked human participants to evaluate the naturalness of point-light jumping motions whose height and duration were modulated. The results showed that the observers’ naturalness rating varied with the modulation ratios of the jump height and duration. Interestingly, the ratings were high even when the height and duration differed from the actual jump. To explain this tendency, we constructed computational models that predicted the theoretical trajectory of a jump based on the projectile motion formula and calculated the errors between the theoretical and observed trajectories. The pattern of the errors correlated closely with the participants’ ratings. Our results suggest that observers judge the naturalness of observed jumping motion based on the error between observed and predicted jump trajectories.
The resolution of evolutionary conflicts within species
Authors: Ågren J. Arvid , Arnqvist Göran , Rowe Locke
Published: September 2024

Evolutionary conflicts of interest occur at all levels, scales and forms of biological organization. They are a fundamental component of the living world and range from conflicts between genetic elements and cells, to conflicts between the sexes and between competing individuals. Yet, the existence of admirably well functioning genomes, bodies, mating pairs and societies suggests that processes must exist to resolve or mitigate such conflicts. We organized this special feature ‘The resolution of evolutionary conflicts within species’ to encourage the flow of knowledge between fields that traditionally have often taken different approaches to study evolutionary conflicts. Contributed papers discuss data from bacteria, plants and animals (including humans) and present theory, molecular mechanisms and population dynamics of how conflicts are resolved in nature. Together, they contribute to a synthetic theory of conflict resolution.
Two real-time TaqMan PCRs for the detection of Alongshan Virus (ALSV), a new member of the tick-borne Flaviviridae family
Authors: Opota Onya , Tagini Florian , Cagno Valeria , Kubacki Jakub , Greub Gilbert
Published: September 2024

Introduction: Alongshan Virus (ALSV) is a tick-borne Flaviviridae. Ticks carrying ALSV have been identified in various regions, including China, Russia, Finland, Switzerland, and Germany, mainly within Ixodes ricinus and Ixodes persulcatus species. Hypothesis/Gap Statement: However, the clinical relevance and the pathogenicity of ALSV in humans is still unknown. Aim: We aimed to validate and integrate a real-time polymerase chain reaction (PCR) assay on our in-house molecular diagnostic platform to accurately detect ALSV and then further investigate its clinical relevance and its potential role as agent of meningoencephalitis in humans. Methodology: We customized two ALSV-specific Taqman RT-PCR assays targeting the NS3 and NS5 genes to align with the genetic diversity of ALSV sequences and the technical features of TaqMan probes-related technologies. Positive controls included ALSV RNA from infected Swiss ticks and synthetic plasmids including the target region of the RT-PCR assays. Results: To determine the limit of detection of the ALSV PCR assay, we used serial dilutions of the synthetic plasmid. Amplification rates of 100%, 92%, and 20% were respectively achieved for 1000, 100, and 10 copies per reaction for the NS3 PCR and 100%, 100%, 20% for the NS5 PCR. Intra- and inter-run reproducibility, evaluated over five independent runs with plasmid dilutions representing 100 and 10 DNA copies per reaction, met diagnostic standards. The assay exhibited 100% specificity (71/71) when tested against (i) a panel of cerebrospinal fluid pathogens (n=41), including bacteria, viruses, and fungi, and (ii) CSF specimens from our biobank (n=30), collected during winter when local tick exposure is unlikely due to low temperatures. In contrast specific amplification was obtained in ALSV-infected tick samples. Conclusions: Two ALSV real-time PCRs were validated for rapid, sensitive, and specific detection of ALSV RNA. Integration of ALSV PCR into open molecular diagnostic platform such as our, allows for syndromic testing alongside other encephalitis-associated viruses, such as Tick-Borne encephalitis virus or West Nile virus. This PCR will facilitate high-throughput screening of ticks for surveillance purposes. Moreover, this assay could be integrated into other in-house molecular diagnostic platform, in order to accurately detect ALSV to further explore ALSV pathogenic role.
Interpretable high-resolution dimension reduction of spatial transcriptomics data by SpaHDmap
Authors: Tang Junjie , Chen Zihao , Qian Kun , Huang Siyuan , He Yang , Yin Shenyi , He Xinyu , Ye Buqing , Zhuang Yan , Meng Hongxue , Xi Jianzhong Jeff , Xi Ruibin
Published: September 2024

Spatial transcriptomics (ST) technologies have revolutionized tissue architecture studies by capturing gene expression with spatial context. However, high-dimensional ST data often have limited spatial resolution and exhibit considerable noise and sparsity, posing significant challenges in deciphering subtle spatial structures and underlying biological activities. Here, we introduce SpaHDmap, an interpretable dimension reduction framework that enhances spatial resolution by integrating ST gene expression with high-resolution histology images. SpaHDmap incorporates non-negative matrix factorization into a multimodal fusion encoder-decoder architecture, enabling the identification of interpretable, high-resolution embeddings. Furthermore, SpaHDmap can simultaneously analyze multiple samples and is compatible with various types of histology images. Extensive evaluations on synthetic and real ST datasets from various technologies and tissue types demonstrate that SpaHDmap can effectively produce highly interpretable, high-resolution embeddings, and detects refined spatial structures. SpaHDmap represents a powerful approach for integrating ST data and histology images, offering deeper insights into complex tissue structures and functions.
Loss of PRICKLE1 in the myometrium leads to reduced fertility, abnormal myometrial architecture, and aberrant extracellular matrix deposition in mice
Authors: Roberts Emily R , Ganeshkumar Sornakala , Gunewardena Sumedha , Chennathukuzhi Vargheese M
Published: September 2024

Uterine leiomyomas (UL) are the most prevalent benign tumors of the female reproductive tract, originating from the myometrium and affecting over 75% of reproductive-age women. Symptoms of UL include pelvic pain, pressure, dysmenorrhea, menorrhagia, anemia, and reproductive dysfunction. Currently, there is no effective long-term pharmacotherapy for UL, making them the leading cause of hysterectomies in the United States. The lack of treatment options is attributed to the absence of accurate animal models and a limited understanding of UL pathogenesis. Previous research has shown the loss of repressor of element 1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) within the myometrium promotes UL pathogenesis. In addition, deletion ofRestin the mouse myometrium leads to a UL phenotype. PRICKLE1, also known as Rest-interacting LIM-domain Protein (RILP), is required for nuclear localization of REST and Wnt/planar cell polarity (PCP) signaling, making it a critical target for UL studies. In the context of PCP, smooth muscle cells in UL show abnormal organization, aberrant ECM structure, and expression levels, potentially influenced by PRICKLE1 loss. The exact role of PRICKLE1 and Wnt/PCP in UL pathogenesis remains unclear.

To explore PRICKLE1’s role in UL, we deletedPrickle1using our myometrial-specific icre. Our findings demonstrate thatPrickle1loss in the myometrium results in a UL phenotype characterized by altered collagen expression, excessive extracellular matrix (ECM) deposition, aberrant smooth muscle cell organization, increasedEsr1andPgrexpression, and dysregulated Wnt/PCP signaling. This novel mouse model serves as a valuable preclinical tool for understanding UL pathogenesis and developing future pharmacotherapies.
Development in the cold renders bird mitochondria more susceptible to heat stress
Authors: Correia Maria , Thoral Elisa , Persson Elin , Chamkha Imen , Elmér Eskil , Nord Andreas
Published: September 2024

Research on birds suggests that extreme weather events during development may have long-lasting consequences on form and function. The underlying cellular mechanisms mediating such phenotypic effects are poorly studied. We raised Japanese quail in warm (30°C) or cold (10°C) temperatures from hatching until adulthood, and then measured mitochondrial metabolism in intact blood cells at representative normothermic body temperature (41°C) and a hyperthermic temperature (45°C) that quail commonly attain when heat stressed. To investigate whether any developmental effects were reversible, half of the cold- and warm-acclimated birds were assigned to a common garden (20°C) 3 weeks before the measurements. Across groups, hyperthermia was associated with increased proton leak, but decreases in both phosphorylating respiration (where ATP is produced) and working capacity of the mitochondria. Cold-acclimated birds were more strongly affected by heat stress: the increase in proton leak was 1.6-fold higher, and the decrease in phosphorylating capacity during endogenous respiration was 1.7-fold greater, compared to warm-acclimated birds. These differences did not remain in the common-garden birds. Our study suggests that developmental cold acclimation is traded off against heat tolerance at the level of cellular metabolism, with implications for our understanding of avian responses to climate change.
Contraceptive Outcomes of the Natural Cycles Birth Control App: A Study of Canadian Women
Authors: Benhar Eleonora , van Lamsweerde Agathe , Krauss Kerry , Berglund Scherwitzl Elina , Scherwitzl Raoul
Published: September 2024

Objective

This study aimed to investigate the key demographics and evaluate the real-world contraceptive failure and continuation rates of the Natural Cycles app in a cohort of women from Canada.

Methods

This was a real-world, prospective cohort study. Demographics were assessed via in-app questionnaires. Contraceptive failure rates in typical and perfect use were calculated using the 13-cycle cumulative pregnancy probability (Kaplan-Meier survival analysis) and the one-year Pearl Index (PI). One-year continuation rates were estimated through survival analysis.

Results

The study included 8 ‘798 women who contributed an average of 9.2 months of data, amounting to a total of 7’ 063 woman-years of exposure. The average user was 27.3 years old, had a body mass index of 24.6, and reported being in a stable relationship. With typical use, the app demonstrated a 13-cycle cumulative pregnancy probability of 4.8 [95% CI: 4.3, 5.4] and a Pearl Index of 4.3 [95% CI: 3.9, 4.8]. Under perfect use, the contraceptive failure rate was 2.3 [95% CI: 0.7, 3.9] for life table analysis and 1.7 [95% CI: 0.5, 2.8] for the 1-year PI. The contraceptive method’s continuation rate after one year was 62.4%.

Conclusions

The data presented in this study offer valuable insights into the cohort of women using the Natural Cycles app in Canada and provide country-specific effectiveness estimates. The app’s contraceptive effectiveness aligns with previously published data on Natural Cycles.
Tucaresol: A Clinical Stage Oral Candidate Drug With Two Distinct Antiviral Mechanisms
Authors: Penney Christopher L. , Zacharie Boulos , Duceppe Jean-Simon
Published: September 2024

Globally, approximately 39 million people are living with Human Immunodeficiency Virus, HIV, arising from approximately 86 million infections since this epidemic began in 1981. However, the number of HIV infections is unevenly distributed with two thirds of global infections confined to Sub-Saharan Africa. Due to viral drug resistance, the most effective treatment requires a triple drug combination thereby adding to the complexity and cost of therapy. As such, many people living with HIV or at risk of infection do not have access to prevention or treatment of this potentially fatal disease. There is no cure for HIV [1]. Tucaresol is an orally active clinical stage drug which functions as a host targeted antiviral agent by protection or reconstitution of CD4+ T helper immune cells. We report herein that Tucaresol also displays in-vitro activity against HIV in infected human peripheral blood mononuclear cells. Although this in-vitro antiviral activity is not potent, the excellent safety profile and bioavailability of Tucaresol, along with its low Molecular Weight, support attainment of relevant drug concentrations in man to achieve significant in-vivo activity. This is demonstrated by previously reported stabilization of viremia in a prior proof of concept phase 1b/2a HIV clinical trial [2]. It is possible that the significant in-vivo activity of Tucaresol arises from synergy between co-stimulation of CD4+ T helper cells and the direct activity against virally infected cells. A pan in-vitro viral screen of Tucaresol further revealed a weak, direct antiviral activity against human herpes virus 6B, human papillomavirus 11, measles virus and hepatitis B virus.
p53 Regulates Nuclear Architecture to Reduce Carcinogen Sensitivity and Mutagenic Potential
Authors: King Devin A. , McCoy Dakota E. , Perdyan Adrian , Mieczkowski Jakub , Douki Thierry , Dionne Jennifer A. , Herrera Rafael E. , Morrison Ashby J.
Published: September 2024

The p53 tumor suppressor is an indispensable regulator of DNA damage responses that accelerates carcinogenesis when mutated. In this report, we uncover a new mechanism by which p53 maintains genomic integrity in the absence of canonical DNA damage response activation. Specifically, loss of p53 dramatically alters chromatin structure at the nuclear periphery, allowing increased transmission of an environmental carcinogen, ultraviolet (UV) radiation, into the nucleus. Genome-wide mapping of UV-induced DNA lesions in p53-deficient primary cells reveals elevated lesion abundance in regions corresponding to locations of high mutation burden in malignant melanomas. These findings uncover a novel role of p53 in the suppression of mutations that contribute to cancer and highlight the critical influence of nuclear architecture in regulating sensitivity to carcinogens.

One-Sentence Summary

The p53 tumor suppressor reduces carcinogen sensitivity and mutagenic potential by maintaining nuclear architecture.
Viral transcript and tumor immune microenvironment-based transcriptomic profiling of HPV-associated head and neck squamous cell carcinoma identifies subtypes associated with prognosis
Authors: Nikitina Anastasia , Kiriy Daria , Tyshevich Andrey , Tychinin Dmitry , Antysheva Zoia , Sobol Anastasia , Kushnarev Vladimir , Shin Nara , Brown Jessica H. , Lewis James , Kuhs Krystle A. Lang , Ferris Robert , Wirth Lori , Kotlov Nikita , Faden Daniel L.
Published: September 2024

Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HPV-positive HNSCC) has distinct biological characteristics from HPV-negative HNSCC. Using an AI-based analytical platform on meta cohorts, we profiled expression patterns of viral transcripts and HPV viral genome integration, and classified the tumor microenvironment (TME). Unsupervised clustering analysis revealed 5 distinct and novel TME subtypes across patients (immune-enriched, highly immune and B-cell enriched, fibrotic, immune-desert, and immune-enriched luminal). These TME subtypes were highly correlated with patient prognosis. In order to understand specific factors associated with prognosis, we used unsupervised clustering of a HPV-positive HNSCC cohort from The Cancer Genome Atlas (TCGA) (n = 53) based on HPV transcript expression, and identified 4 HPV-related subtypes (E2/E5, E6/E7, E1/E4 and L1/L2). Utilizing both viral transcript and TME subtypes, we found that the E2/E5 HPV subtype was associated with an immune-enriched TME and had a higher overall survival compared to other subtypes. The E2/E5 subtype was also enriched for samples without HPV-genome integration, suggesting that episomal HPV status and E2/E5 expression pattern may be associated with an inflamed microenvironment and improved prognosis. In contrast, E6/E7 subtype samples were associated with the fibrotic and immune-desert TME subtypes, with lower values of T-cell and B-cell gene expression signatures and lower overall survival. Both E1/E4 and L1/L2 subtypes were associated with the immune-enriched luminal subtype. Our results suggest that HPV- transcript expression patterns may drive modulation of the TME and thereby impact prognosis.
Perceived barriers to research and scholarship among physicians
Authors: Lagerman Makayla , Dennis Lauren , Deaner Traci , Sigal Adam , Rabago David , Dong Huamei , Wiedemer Joseph P. , Reedy-Cooper Alexis , Parascando Jessica , Clebak Karl T. , Cassidy-Smith Tara , Lennon Robert P. , Simoyan Olapeju
Published: September 2024

Introduction

Inadequate scholarship is a common concern in graduate medical education. Many barriers to scholarship have been identified, but there are limited data on which are most important. A rank-order of barriers from learners’ perspectives would better enable programs to address perceived barriers.

Methods

Given that learners are experts in their own perceptions, we applied the Delphi method of generating consensus expert opinion to construct ranked lists of physician-perceived barriers to scholarly activity at various sites. The survey was conducted within three separate health systems. Respondents were asked to identify their perceived barriers via free text and the listed barriers were consolidated by the research team. In the second round, respondents were presented with the consolidated lists and asked to rank them. In the third and final round, each respondent was shown a comparison of their own rankings to that of their peers and given an opportunity to make changes. Ranking differences between programs were compared using Rank Biased Overlap (RBO).

Results

The Delphi method is a straightforward method to obtain a ranked list of perceived learner barriers to scholarly activity; its primary limitation is learner engagement and, of note in our study, high dropout rates. RBO is an effective method of ranking differences between programs and specialties. Top barriers across programs included time, overwhelm with the research process, and lack of interest or energy.

Discussion

Several of the identified barriers may be addressed with enthusiastic mentors, streamlined administrative processes, and education. This could be done within a hospital system or on a national level through specialty organizations.
Linking the plasma proteome to genetics in individuals from continental Africa provides insights into type 2 diabetes pathogenesis
Authors: Soremekun Opeyemi , Park Young-Chan , Tutino Mauro , Kalungi Allan , Rayner N. William , Nyirenda Moffat , Fatumo Segun , Zeggini Eleftheria
Published: September 2024

Individuals of African ancestry remain largely underrepresented in genetic and proteomic studies. Here, we measure the levels of 2,873 proteins using the Olink proximity extension assay in plasma samples from 163 individuals with type 2 diabetes (T2D) or prediabetes and 362 normoglycemic controls from the Ugandan population for the first time. We identify 88 differentially expressed proteins between the two groups and 208 proteins associated with cardiometabolic traits. We link genome-wide data to protein expression levels and construct the first protein quantitative trait locus (pQTL) map in this population. We identify 399 independent associations with 346 (86.7%) cis-pQTLs and 53 (13.3%) trans-pQTLs. 16.7% of the cis-pQTLs and all of the trans-pQTLs have not been previously reported in African-ancestry individuals. Of these, 37 pQTLs have not been previously reported in any population. We find evidence for colocalization between a pQTL for SIRPA and T2D genetic risk. Mendelian randomization analysis identified 20 proteins causally associated with T2D. Our findings reveal proteins causally implicated in the pathogenesis of T2D, which may be leveraged for personalized medicine tailored to African-ancestry individuals.
Health professionals’ beliefs and attitudes towards preconception care: A systematic review
Authors: Caut Cherie , Schoenaker Danielle , McIntyre Erica , Steel Amie
Published: September 2024

Background

Health professionals have previously identified various barriers and factors that would help facilitate preconception care services in healthcare settings. Clinically relevant preconception information and clinical practice guidelines have since been developed to aid health professionals in preconception care delivery. This systematic review aimed to 1) synthesise recent literature (past 8 years) describing health professionals’ beliefs and attitudes towards preconception care services or programmes and 2) determine if the experience of health professionals providing preconception care has changed compared to literature reviews conducted more than 8 years ago.

Methods

Five databases were searched between 27/01/2016 and 20/11/2024. Primary quantitative and qualitative research studies were included if they examined health professionals’ beliefs and attitudes towards delivering preconception care services or programmes. Study quality was assessed using the CASP Checklist (qualitative studies) and AXIS tool (quantitative studies). Data synthesis used thematic categorisation adapted from the framework approach.

Results

Twenty-seven studies were included (n=11 qualitative, n=14 quantitative, n=2 mixed-methods studies). Methodological quality was generally good for qualitative studies but varied for quantitative studies. The results covered three categories: 1)addressing preconception care health literacy(i.e. lack of knowledge, awareness, training and resources), 2)clinical practicalities of preconception care (i.e. need for coordination of care and clarity on role responsibility), and 3)the role of the patient(i.e. need for public health education to support patient-led conversations).

Conclusions

Little has changed regarding the barriers and facilitators to providing preconception care reported by health professionals. To improve the provision of preconception care, there is a need to co-develop professional and public preconception health education, clinical resources, and a coordinated preconception healthcare service model.
First-in-human evaluation of memory-like NK cells with an IL-15 super-agonist and CTLA-4 blockade in advanced head and neck cancer
Authors: Shapiro Roman M. , Sheffer Michal , Booker Matthew A. , Tolstorukov Michael Y. , Birch Grace C. , Sade-Feldman Moshe , Fang Jacy , Li Shuqiang , Lu Wesley , Ansuinelli Michela , Dulery Remy , Tarannum Mubin , Baginska Joanna , Dwivedi Nishant , Kothari Ashish , Penter Livius , Abdulhamid Yasmin Z. , Kaplan Isabel E. , Khanhlinh Dinh , Uppaluri Ravindra , Redd Robert A. , Nikiforow Sarah , Koreth John , Ritz Jerome , Wu Catherine J. , Soiffer Robert J. , Hanna Glenn J. , Romee Rizwan
Published: September 2024

Cytokineinducedmemory-like natural killer (CIML NK) cells combined with an IL-15 super-agonist (N-803) are a novel modality to treat relapsed/refractory head and neck cancer. We report data from a phase I trial of haploidentical CIML NK cells combined with N-803 with or without ipilimumab (IPI) in relapsed/refractory head and neck cancer patients after a median of 6 prior lines of therapy. The primary endpoint was safety, which was established, with dose-limiting toxicity in 1/10 patients. A promising though transient disease control rate of 70% correlated with donor NK cell expansion, the latter occurring irrespective of IPI. High-resolution immunophenotypic and transcriptional profiling characterized the NK cells and their interacting partnersin vivo. IPI was associated with contraction of Treg:Tcon, rapid recovery of recipient CD8+T cells, and accelerated rejection of donor NK cells. These results inform evaluation of CIML NK therapy for advanced malignancies, with considerations for combination with IPI.

Significance

CIML NK cells combined with N-803 and ipilimumab to treat head and neck cancer is safe, and associated with a more proliferative NK cell phenotype. However, the combination leads to reduced HLA mismatched NK cell persistence, resulting in an important limitation informing future NK cell combination therapies in clinical trials.

Trial Registration

NCT04290546

Funding

Gateway for Cancer Research, Ted and Eileen Pasquarello Research Fund, Goldfarb and Rudkin Family Fellowship, Dr. Antin’s Research Fund, Massey Family Fund. MS is funded by the Sidney Farber Scholar Program, Dana Farber, and RR is a recipient of the Career Development Award from the Leukemia and Lymphoma Society and is a member of the Parker Institute for Cancer Immunotherapy at Dana-Farber Cancer Institute.
WITHDRAWN: EpiSemoLLM: A Fine-tuned Large Language Model for Epileptogenic Zone
Authors: Yang Shihao , Luo Yaxi , Jiao Meng , Fotedar Neel , Rao Vikram R. , Ju Xinglong , Wu Shasha , Xian Xiaochen , Sun Hai , Karakis Ioannis , Bernardo Danilo , Laing Josh , Kwan Patrick , Rosenow Felix , Liu Feng
Published: September 2024

Withdrawal statement

medRxiv has withdrawn this manuscript due to a duplicate posting of manuscript number MEDRXIV/2024/307955. Therefore, this work should not be cited as reference for the project. If you have any questions, please contact the corresponding author. The correct preprint can be found at doi: 10.1101/2024.05.26.24307955
Prenatal Exposure of Pesticide Mixtures and the Placental Transcriptome: Insights from Trimester-specific, Sex-Specific and Metabolite-Scaled Analyses in the SAWASDEE Cohort
Authors: Wang Yewei , Hermetz Karen , Burt Amber , Lesseur Corina , Panuwet Parinya , Fiedler Nancy , Prapamontol Tippawan , Suttiwan Panrapee , Nimmapirat Pimjuta , Sittiwang Supattra , Naksen Warangkana , Yakimavets Volha , Barr Dana Boyd , Hao Ke , Chen Jia , Marsit Carmen J.
Published: September 2024

We investigated the effect of exposure to pesticide mixtures during pregnancy on the placental transcriptome, to link these exposures and placental functions. The Study of Asian Women and their Offspring’s Development and Environmental Exposures (SAWASDEE) enrolled pregnant farmworkers from Thailand (n=248), who were primarily exposed to organophosphate (OP) and pyrethroid pesticides. We measured maternal urinary levels of six non-specific OP metabolites expressed as three summary measures (dimethylalkylphosphates (DMAP), diethylalkylphosphates (DEAP), and dialkylphosphates (DAP) and three pyrethroid metabolites (3-phenoxybenzoic acid (3-PBA),cis- andtrans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (Cis-DCCA, Trans-DCCA) during early, middle, and late pregnancy, and adjusted for urine dilution using creatinine. RNA-sequencing was used to profile the placental transcriptome from which 21 co-expression network modules were identified by Weighted Gene Co-expression Network Analysis. Quantile g-computation analysis identified an average pregnancy positive mixture exposure effect on the E2f Target Module (β = 0.013, p = 0.012) and a negative mixture exposure effect (β = −0.016, p = 0.008) on the Myogenesis Module. The pesticide metabolites driving the associations differed for each module, highlighting differential susceptibilities within the placental transcriptome to various pesticides. When stratifying by infant sex, the average pregnancy mixture exhibited a significant negative effect (β= −0.018, P=0.016) on the Myogenesis Module only in females; other modules, such as epithelial-mesenchymal transition, though not demonstrating an overall mixture effect, did demonstrate differential impacts of the mixture by sex. Pesticide mixtures in both the second trimester (β = −0.013, p = 0.015) and the third trimester (β = −0.012, p = 0.028) exhibited consistently significant negative associations with the Myogenesis module. These findings underscore the importance of considering the prenatal environment more holistically, understanding the placenta’s susceptibility to contaminants, and incorporating sex-specific analyses to understand differential impacts.
Association Between Life’s Essential 8 and Atherogenic Index of Plasma in Adults: Insights from NHANES 2007-2018
Authors: Xu Long-hui , Ding Kai-wen , Yang Guo-dong , Han Xiao-xuan , Cong Xiao , Wang Rong-hui , Liu Xin-ru , Li Na , Xu Cui-ping
Published: September 2024

Objectives

This study aimed to investigate the relationship between Life’s Essential 8 (LE8) and the Atherogenic Index of Plasma (AIP).

Methods

We conducted an analysis of data from 8,215 U.S. adults aged 20 years and older, utilizing the National Health and Nutrition Examination Survey data from 2007 to 2018. Based on LE8 scores, Cardiovascular Health (CVH) was stratified into three levels—low, moderate, and high—while AIP was categorized into four risk levels: extremely low (AIP<-0.3), low (−0.3≤AIP<0.1), medium (0.1≤AIP<0.24), and high (AIP≥0.24). Weighted ordinal logistic regression analysis was utilized to examine the association between CVH scores and AIP risk levels, adjusting for potential confounding variables.

Results

A significant inverse correlation exists between CVH scores and AIP risk levels (OR=0.51,95%CI: 0.49-0.54,P<0.001). Higher CVH scores were associated with lower AIP risk levels, while lower CVH scores corresponded to elevated AIP risk levels. Notably, improvements in specific CVH components—such as Body Mass Index and Blood Lipids—exhibited a strong relationship with reductions in AIP risk levels.

Conclusions

Enhancing CVH is vital for effectively reducing AIP risk levels, thus underscoring the critical importance of health management strategies in the prevention of cardiovascular diseases.
Effect of Monitoring and Evaluation Systems on the Performance of Neonatal Intensive Care Unit at Yumbe Regional referral hospital; A Pre-post quasi-experimental study design
Authors: Ssemanda Innocent , Odong Patrick E. , Nasur Mubaraka , Ejalu David , Mwengwe Karen , Tukei JMO
Published: September 2024

Purpose

This study explored the effect of implementing monitoring and Evaluation (M&E) systems on the performance of the Neonatal Intensive care Unit at Yumbe regional referral hospital.

Methods

A pretest-posttest quasi-experimental design was employed involving 236 neonates, with 103 in the pretest group (Before the implementation monitoring and evaluation systems) and 130 in the posttest group (after the implementation of monitoring and evaluation). The intervention lasted 105 days. Key performance indicators (KPIs) such as; neonatal mortality rates, length of stay, neonatal intensive care’s effectiveness, morbidity rate, survival rates, and infection control were measured. Patient satisfaction as a secondary outcome was also explored through questionnaire surveys. Data collected was entered directly in Micro software, and exported to the STATA version 18 for analysis

Results

Neonatal mortality rates significantly decreased from 19.4% in the pretest group to 7.7% in the posttest group (P<0.01). The survival rates improved from 80.6% in the pretest group to 92.3% in the posttest group. The average length of stay was reduced from 10 days (SD=4) to 8 days (SD=3) (P<0.05). Neonatal intensive care effectiveness scores improved from a mean of 2.8 to 3.5 (P<0.01). Compliance with Neonatal intensive care unit protocols increased from 70% to 80% (P<0.01). The reliability of monitoring and evaluation components was high, with Cronbach’s alpha values ranging from 0.754 to 0.915

Conclusion

Implementation of monitoring and evaluation systems significantly enhanced NICU’s performance, reduced mortality rate, improved survival rates and improved patient satisfaction. These findings underline the importance of M&E frameworks in optimizing neonatal care.