bluuebunny/crossref_metadata_2025 huggingface dataset:
E-bike riding: A metabolic evaluation in the context of exercise intensity domains
Authors: Bonardi Alberto , Negro Francesco , Iannetta Danilo
Published: November 2024

Introduction

E-bikes are being promoted as a mode of transportation that can aid with meeting current physical activity guidelines. This study evaluated exertional intensity associated with E-Biking within the exercise intensity domain framework. We hypothesized that exertional intensity of E-bikes is insufficient to evoke a metabolic demand associated with the minimum intensity needed to improve cardiorespiratory fitness.

Methods

Forty-four participants (22 females) of varying activity levels completed two experimental sessions. The first session involved a lab-based ramp-incremental exercise test to determine V̇O2max, gas exchange threshold (GET), and respiratory compensation point (RCP). The second session involved the completion of two outdoor rides on the same bike equipped with an electrical motor E-bike. The first ride was completed without electrical assistance, while the second was. The power output (PO) and speed were set at an intensity corresponding to ∼10% above GET.

Results

As expected, using E-bike assistance resulted in a lower metabolic demand, falling well below GET. While the absolute power output (PO) was different between sexes, relative heart rate (HR) and relative PO were similar between the rides without and with assistance. This suggests that when riding an E-bike, the internal load is similar between sexes.

Conclusion

Despite E-bikes facilitate a more active lifestyle and help to reduce the emission of pollutants, when interpreted within the context of the exercise intensity domain schema, their associated exertional intensity is likely insufficient to confidently elicit cardiorespiratory benefits.
An Open-Source Neurodynamic Model of the Bladder
Authors: Lister Elliot , McConnell-Trevillion Aidan , Jabbari Milad , Erfanian Abbas , Nazarpour Kianoush
Published: November 2024

Background

Lower urinary tract (LUT) symptoms affect a significant proportion of the population. In-silico medicine can help understand these conditions and develop treatments. However, current LUT computational models are closed source, too deterministic, and do not allow for simple use of modelling neural intervention.

Methods

An open-source Python-based model was developed to simulate bladder, sphincter, and kidney dynamics using normalised neural signals to predict pressure and volume. The model was verified against animal bladder data, assessed for noise sensitivity, and evaluated against known physiological factors.

Results

The animal data comparison yielded a significantly more similar pattern than existing models, with a correlation coefficient ofr= 0.93 (p< 0.001). All physiological factors were within bounds, and the model remained stable with noise under the described boundaries.

Conclusion

The proposed model advances the field of computational medicine by providing an open-source model for researchers and developers. It improves upon existing models by being accessible, including a built-in neural model that better replicates smooth bladder filling results, and incorporating a novel kidney function that alters bladder function by time of day in line with circadian rhythm. Future applications include personalised medicine, treating LUT symptoms with in-silico models and adaptive neural interventions.
In depth sequencing of a serially sampled household cohort reveals the within-host dynamics of Omicron SARS-CoV-2 and rare selection of novel spike variants
Authors: Bendall Emily E. , Dimcheff Derek , Papalambros Leigh , Fitzsimmons William J. , Zhu Yuwei , Schmitz Jonathan E. , Halasa Natasha , Chappell James D. , Martin Emily Toth , Biddle Jessica E. , Smith-Jeffcoat Sarah E. , Rolfes Melissa A. , Mellis Alexandra , Talbot H. Keipp , Grijalva Carlos G. , Lauring Adam S.
Published: November 2024

SARS-CoV-2 has undergone repeated and rapid evolution to circumvent host immunity. However, outside of prolonged infections in immunocompromised hosts, within-host positive selection has rarely been detected. The low diversity within-hosts and strong genetic linkage among genomic sites make accurately detecting positive selection difficult. Longitudinal sampling is a powerful method for detecting selection that has seldom been used for SARS-CoV-2. Here we combine longitudinal sampling with replicate sequencing to increase the accuracy of and lower the threshold for variant calling. We sequenced 577 specimens from 105 individuals from a household cohort primarily during the BA.1/BA.2 variant period. There was extremely low diversity and a low rate of divergence. Specimens had 0-12 intrahost single nucleotide variants (iSNV) at >0.5% frequency, and the majority of the iSNV were at frequencies <2%. Within-host dynamics were dominated by genetic drift and purifying selection. Positive selection was rare but highly concentrated in spike. Two individuals with BA.1 infections had S:371F, a lineage defining substitution for BA.2. A Wright Fisher Approximate Bayesian Computational model identified positive selection at 14 loci with 7 in spike, including S:448 and S:339. We also detected significant genetic hitchhiking between synonymous changes and nonsynonymous iSNV under selection. The detectable immune-mediated selection may be caused by the relatively narrow antibody repertoire in individuals during the early Omicron phase of the SARS-CoV-2 pandemic. As both the virus and population immunity evolve, understanding the corresponding shifts in SARS-CoV-2 within-host dynamics will be important.
M2 Macrophages are Major Mediators of Germline Risk of Endometriosis and Explain Pleiotropy with Comorbid Traits
Authors: Ochoa Soledad , Rasquel-Oliveira Fernanda S. , McKinnon Brett , Haro Marcela , Subramaniam Sugarniya , Yu Pak , Coetzee Simon , Anglesio Michael S. , Wright Kelly N. , Meyer Raanan , Gargett Caroline E. , Mortlock Sally , Montgomery Grant W. , Rogers Michael S. , Lawrenson Kate
Published: November 2024

Endometriosis is a common gynecologic condition that causes chronic life-altering symptoms including pain, infertility, and elevated cancer risk. There is an urgent need for new non-hormonal targeted therapeutics to treat endometriosis, but until very recently, the cellular and molecular signatures of endometriotic lesions were undefined, severely hindering the development of clinical advances. Integrating inherited risk data from analyses of >450,000 individuals with ∼350,000 single cell transcriptomes from 21 patients, we uncover M2-macrophages as candidate drivers of disease susceptibility, and nominate IL1 signaling as a central hub impacted by germline genetic variation associated with endometriosis. Extensive functional follow-up confirmed these associations and revealed a pleiotropic role for this pathway in endometriosis. Population-scale expression quantitative trail locus analysis demonstrated that genetic variation controllingIL1Aexpression is also associated with endometriosis risk variants. Manipulation of IL1 signaling in state-of-the-artin vitrodecidualized assembloids impacted epithelial differentiation, and in anin vivoendometriosis model, treatment with anakinra (an interleukin-1 receptor antagonist) resulted in a significant, dose-dependent reduction in both spontaneous pain and evoked pain. Together these studies highlight non-diagnostic cell types as central to endometriosis susceptibility and support IL1 signaling as an important actionable pathway for this disease.
Phylogeographic patterns ofEscherichia coliisolated from white-tailed deer,Odocoileus virginianus, during necropsy in a farmed deer surveillance program
Authors: Metrailer Morgan C. , Cheng An-Chi , Bluhm Andrew P. , Jiranantasak Treenate , Norris Michael H. , Surphlis Austin , Subramaniam Kuttichantran , Jeong Kwangcheol Casey , Wisely Samantha M. , Krauer Juan Campos , Blackburn Jason K.
Published: November 2024

White-tailed deer (Odocoileus virginianus) (WTD) farms are distributed throughout Florida and number nearly 400. The Cervidae Health Research Initiative (CHeRI) is an initiative that investigates disease and health of farmed cervids statewide. Within the Florida industry, Epizootic Hemorrhagic disease virus (EHDV) and Bluetongue virus (BTV) are major causes of disease and associated economic losses. Often, deer survive EHDV or BTV infections but succumb to secondary bacterial infections, includingEscherichia coli. E. colican be opportunistic with severe illness or death occurring in hosts weakened from viral infection. We investigated presumptiveE. colistrains isolated from WTD during necropsy investigations. Genomic DNA was extracted and whole genome sequenced from 61 suspectE. coliisolates. Exploratory spatial data analysis (ESDA) of the distribution ofE. coliphylotypes, distribution ofE. coli, and deer between ranches was performed. We examined phylogenetic relationships between isolates, categorized by ranch and year and compared to all reportedE. coliisolates in Florida from EnteroBase. One strain wasEnterobacter hormaecheiand the other 60 wereE. coli. TwoE. colistrains were toxigenic. Deer isolates represented 7 phylogroups with B1 being the most prevalent (45/60) and geographically widespread (14/16 counties reportingE. coli). Phylogroup A was the second most prevalent phylogroup. In at least two instances two phylogroups were present within a single animal. We found that deer isolates spanned many of known phylotypes in Florida from animals and humans. Diversity patterns suggest deer are infected locally with most animals on ranches having high genomic similarity within phylogroups.

*Sequence data from this article have been deposited in the National Center for Biotechnology Information (NCBI) database under BioProject PRJNA1183872.
Identifying genomic adaptation to local climate using a mechanistic evolutionary model
Authors: Goel Nikunj , Bossu Christen M. , Van Ee Justin J. , Zavaleta Erika , Ruegg Kristen C. , Hooten Mevin B.
Published: November 2024

Identifying genomic adaptation is key to understanding species’ evolutionary responses to climate change. However, current methods to identify adaptive variation have two major limitations. First, when estimating genetic variation, most methods do not account for observational uncertainty in genetic data because of finite sampling and missing genotypes. Second, current methods use phenomenological models to partition genetic variation into adaptive and non-adaptive components. These phenomenological models are not mechanistic models of evolution and, therefore, do not faithfully capture the demographic history of the species.

We address these limitations by developing a hierarchical Bayesian model that explicitly accounts for both the observational uncertainty and underlying evolutionary processes. The first layer of the hierarchy is the data model that captures observational uncertainty by probabilistically linking RAD-sequence data to genetic variation. The second layer is a process model that provides a mechanistic explanation of how evolutionary forces, such as local adaptation, mutation, migration, and drift, maintain genetic variation. The third layer is the parameter model, which incorporates our knowledge about biological processes. For example, because most loci in the genome are expected to be neutral, the environmental sensitivity coefficients are assigned a regularized prior centered at zero. Together, the three models provide a rigorous probabilistic framework to identify local adaptation in wild organisms.

Analysis of simulated RAD-seq data shows that our statistical model can reliably infer adaptive genetic variation. To show the real-world applicability of our method, we re-analyzed RAD-seq data from Willow Flycatchers (Empidonax traillii) in the USA. We found 30 genes close to loci that showed a statistically significant association with temperature seasonality. Gene ontology suggests that several of these genes play a crucial role in egg mineralization, feather development, and the ability to withstand extreme temperatures.

Moreover, biogeographers can easily modify the data and process models to accommodate a wide range of genetic datasets (e.g., pool and low coverage genome sequencing) and demographic histories (e.g., range shifts), allowing them to construct statistical models specific to their study system.
The role of carbonic anhydrase in rock weathering and pH regulation by the soil bacteriumBurkholderia thailandensisE264
Authors: Bell Derek S. , Leake Jonathan R. , Beerling David J. , Ton Jurriaan , Epihov Dimitar Z.
Published: November 2024

Enhanced rock weathering (ERW) is increasingly recognized as a way to sequester atmospheric carbon dioxide (CO2) to slow global warming, but its effectiveness needs to be optimized. Carbonic anhydrase (CA), an enzyme capable of accelerating rock weathering bothin vitroand in soil, offers a valuable target due to its ability to convert CO2into carbonic acid. This conversion promotes rock dissolution, enabling immediate CO2absorption through cation release and charge-balance mechanisms. Studies have shown that bacteria grown in axenic, rock-amended media increase CA gene expression, but the influence of bacterial CA on rock dissolution rates remains unclear. To investigate this, we used a reverse genetics approach with the phosphate-solubilizing bacteriumBurkholderia thailandensisE264. We examined three CA-inactivated mutants alongside the wildtype, growing them in minimal media with basalt rock dust (0-10% w/v) at an initial pH of 6.0. After 7 days, we measured weathering potential through elemental concentrations, pH, and dissolved inorganic carbon. In 1% basalt medium, inactivation of the CA1 gene (BTH_I1052) significantly reduced base cation weathering by 41% compared to the wildtype, whereas inactivation of CA2 (BTH_I0345) and CA3 (BTH_I1199) had no significant effect. In the highly buffered, 10% basalt medium, CA1 had a minor role in weathering, and both CA2 and CA3 had no effect. These findings suggest that CA genes inB. thailandensisoperate differently and that CA1’s effect is pH-dependent. Surprisingly, CA1 was localized intracellularly, raising questions about how intracellular CAs might influence mineral dissolution, potentially through acidity export or abiontic enzyme activity after cell lysis.

Importance

While purified carbonic anhydrase (CA) protein has been shown to increase mineral dissolution rates in mineral-amended mediain vitro, it remains unclear if the bacterial CA gene directly drives this process. This study used CA-inactivated mutants of the soil bacteriumBurkholderia thailandensisin basalt-amended liquid media and found that only one of the three CA genes influenced mineral dissolution rates. This finding supports prior evidence that bacterial CAs may contribute to mineral dissolution in soils. Importantly, it also showed that not all CA genes in a bacterium may activate under the same conditions, which could impact how soil bacterial CAs are leveraged to enhance weathering. Furthermore, cellular localisation predictions indicated that all three CA genes inB. thailandensisare cytosolic, challenging the common focus on extracellular CAs and suggesting that CA proteins may influence the external environment without needing to be actively exported from the cell.
Conformational ensemble-based framework enables rapid development of Lassa virus vaccine candidates
Authors: Mishra Nitesh , Avillion Gabriel , Callaghan Sean , DiBiase Charlotte , Hurtado Jonathan , Liendo Nathan , Burbach Sarah , Messmer Terrence , Briney Bryan
Published: November 2024

Lassa virus (LASV), an arenavirus endemic to West Africa, poses a significant public health threat due to its high pathogenicity and expanding geographic risk zone. LASV glycoprotein complex (GPC) is the only known target of neutralizing antibodies, but its inherent metastability and conformational flexibility have hindered the development of GPC-based vaccines. We employed a variant of AlphaFold2 (AF2), called subsampled AF2, to generate diverse structures of LASV GPC that capture an array of potential conformational states using MSA subsampling and dropout layers. Conformational ensembles identified several metamorphic domains—areas of significant conformational flexibility—that could be targeted to stabilize the GPC in its immunogenic prefusion state. ProteinMPNN was then used to redesign GPC sequences to minimize the mobility of metamorphic domains. These redesigned sequences were further filtered using subsampled AF2, leading to the identification of promising GPC variants for further testing. A small library of redesigned GPC sequences was experimentally validated and showed significantly increased protein yields compared to controls. Antigenic profiles indicated these variants preserved essential epitopes for effective immune response, suggesting their potential for broad protective efficacy. Our results demonstrate that AI-driven approaches can predict the conformational landscape of complex pathogens. This knowledge can be used to stabilize viral proteins, such as LASV GPC, in their prefusion conformation, optimizing them for stability and expression, and offering a streamlined framework for vaccine design. Our deep learning / machine learning enabled framework contributes to global efforts to combat LASV and has broader implications for vaccine design and pandemic preparedness.
Genetic screen identifies cell wall enzyme is key for freshwater survival ofFrancisella tularensis
Authors: Macaraeg Aisling , Trautmann Hannah S. , Ramsey Kathryn M.
Published: November 2024

Human infection withFrancisella tularensis, a potentially lethal bacterial pathogen, typically occurs after exposure to contaminated water, soil, food, or an infected animal. WhileF. tularensiscan persist in environmental sources over long periods of time, the genetic requirements that permit its long-term viability are not understood. To address this question, we developed a laboratory model for persistence ofF. tularensisin fresh water, finding that viable cells could be recovered for 3 – 8 weeks after incubation at 4°C. Using this model, we took an unbiased, transposon insertion sequencing approach to identify genes critical for this persistence ofF. tularensiscells. We found that mutants inmpl, a gene encoding murein peptide ligase, are defective for persistence in fresh water. Previous studies had identifiedmplas critical for intramacrophage survival. Murein peptide ligase plays a role in peptidoglycan recycling, suggesting thatF. tularensisuses this enzyme to maintain cell wall integrity during hypoosmotic and intramacrophage stress conditions. Our results highlight the importance of understanding how bacterial cell envelopes have evolved and adapted to maintain their integrity in a variety of stress conditions.
Developmental functions ofrapgef1bin neural crest specification and presomitic mesoderm patterning
Authors: Prasad Tuhina , Iyer Sharada , D’silva Sian , Mathew Reuben J. , Sowpati Divya Tej , Radha Vegesna , Kumar Megha
Published: November 2024

Rapgef1, a cell fate determinant and effector of multiple signaling events is essential for mammalian embryonic development. Here, we investigated the developmental role ofrapgef1using zebrafish as a model. We show thatrapgef1is maternally expressed and alternately spliced isoforms of its two paralogs,rapgef1aandrapgef1bshow development and tissue-specific expression. CRISPR-Cas9 and morpholino-based targeting ofrapgef1bresulted in developmental defects in the embryonic brain and somites. Therapgef1bmorphants showed altered expression of lineage determinants of the cranial neural crest. Comparative transcriptome and altered expression analysis of morphants revealed fresh insights into the developmental functions ofrapgef1bin presomitic mesoderm, and somitogenesis. During early embryonic mitoses, the morphants showed mitotic defects such as diffused spindle poles and chromosome mis-congression. Our results demonstrate thatrapgef1bis required for normal embryonic mitoses, cranial neural crest specification, somitogenesis, and myogenesis during embryonic development.

Significance

RAPGEF1 is an important signaling factor, essential for cytoskeletal remodeling, signaling, and cell adhesion in cultured mammalian cells. TheRapgef1knockout mice embryos fail to survive beyond implantation, strongly suggesting its essential role in embryonic development. Further, mutations inRAPGEF1are associated with many neurological disorders like schizophrenia and intellectual disability with behavioral defects. However, the role of rapgef1 in regulating embryonic events is poorly understood. This study highlights the developmental functions ofrapgef1in lineage determination during embryonic development. We show thatrapgef1bacts as an activator of canonical Wnt signaling and is essential for early neurodevelopment and somite formation. Further,rapgef1bis also required to maintain mitotic fidelity, spindle pole integrity, and chromosome congression during embryonic mitoses.
The sicker sex is plastic: Thermal plasticity determines sex biases in pathogen transmission
Authors: Butterworth Nathan J. , Lush Jared , Moore Kerri J. , Hall Matthew D.
Published: November 2024

Sex differences are predicted to play an important role in the spread and evolution of pathogens. However, attempts to generalize the ‘sicker’ sex have been challenged by intraspecific variability of sex-biases across the infection process. Sex specific plasticity provides a framework to resolve this by elucidating how infection is shaped at the sex-pathogen-environment interface. Using theDaphnia magnaandPasteuria ramosasystem, we measure infection outcomes for males and females across three temperatures and seven pathogen densities to quantify how sex specific plasticity shapes susceptibility, pathogen loads, and ultimately transmission. We find unique forms of plasticity at each stage of infection – including equivalent, sex-specific, and divergent plasticity. Integrating these into a single estimate of transmission reveals a clear pattern – male-biased transmission at cold temperatures, and female-biased transmission at warm temperatures. Sex specific thermal plasticity thus determines the ‘sicker’ sex, with implications for pathogen spread and evolution in a warming world.
Trait-space patterning is dictated by the tempo and mode of mutation
Authors: Martis Stephen , Schwab David J. , GrandPre Trevor
Published: November 2024

In large, natural ecosystems, many (≳ 1) phenotypically relevant mutants can emerge over the characteristic turnover time of the population. When this is the case, there can be ‘eco-evolutionary feedback’ between the dynamical processes that underlie mutation, selection and ecology. In this paper, we show that, owing to such feedback, the precise details of the mutational process can have a qualitative impact on the long-term behavior of an eco-evolutionary system, in contrast to the classical population genetic assumption that all mutations can be modeled with an effective, homogeneous rate. We demonstrate this in the context of a version of MacArthur’s consumer-resource model in which consumers mutate along a resource preference trait-space. Starting from a stochastic individual-based model, we simulate the system in the case where mutations are exogenously generated at a fixed rate (e.g. via external mutagens) and in the case where mutations are coupled to replication (e.g. via DNA copying errors). We find that, surprisingly, replication-coupled mutations are capable of generating a patterned phase in the limit of fast ecological relaxation – precisely the regime where classical population genetic models are expected to operate. We derive the appropriate mean-field description of the stochastic model and use it to show that the patterned phase comes about due to a Turing-like mechanism driven by the non-reciprocal and nonlinear nature of replicative mutations. We demonstrate that these results are robust to demographic noise and model choices and we discuss systems in which this phenomenology might be relevant.
Semi-Automated High Content Analysis of Pollen Performance Using TubeTracker
Authors: Yimga Ouonkap Sorel V. , Oseguera Yahir , Okihiro Bryce , Johnson Mark A.
Published: November 2024

Pollen function is critical for successful plant reproduction and crop productivity and it is important to develop accessible methods to quantitatively analyze pollen performance to enhance reproductive resilience. Here we introduce TubeTracker as a method to quantify key parameters of pollen performance such as, time to pollen grain germination, pollen tube tip velocity and pollen tube survival. TubeTracker integrates manual and automatic image processing routines and the graphical user interface allows the user to interact with the software to make manual corrections of automated steps. TubeTracker does not depend on training data sets required to implement machine learning approaches and thus can be immediately implemented using readily available imaging systems. Furthermore, TubeTracker is an excellent tool to produce the pollen performance data sets necessary to take advantage of emerging AI-based methods to fully automate analysis. We tested TubeTracker and found it to be accurate in measuring pollen tube germination and pollen tube tip elongation across multiple cultivars of tomato.

Abstract Figure

Graphical Abstract

Graphical user interface of TubeTracker showing all supported functionalities.
Investigation of electrochromic band-shifts in the Soret region induced by the formation of TyrD•, TyrZ•, and QA•-in Photosystem II
Authors: Boussac Alain , Noguchi Takumi , Rutherford A. William , Sellés Julien , Sugiura Miwa , Viola Stefania
Published: November 2024

The effects of TyrD•, TyrZ•, and QA•-radical formation on the absorption spectrum in the Soret region were studied in Mn-depleted Photosystem II at pH 8.6 (in order to be in the TyrDstate after dark adaptation). Flash-induced difference spectra were recorded in several PSII samples from:i)Thermosynechococcus vestitus(formerlyT. elongatus),ii)Synechocystis sp.PCC 6803,iii)Chroococcidiopsis thermalisPCC 7203 grown under far-red light, andiv)Acaryochloris marina. In the case ofT. vestitus, mutants D1/H198Q, D1/T1789H, D2/I178H, and D2/Y160F, with PsbA1/Q130 instead of PsbA3/E130, were also studied for possible contributions from PD1, ChlD1, ChlD2, and PheD1, respectively. For a possible contribution from PD2, the D2/H197A mutant was studied inS. 6803. While PD1is clearly the species whose spectrum is blue-shifted by ∼3nm in the presence of QA•-, as has already been well documented in the literature, the species whose spectra shift upon the formation of TyrD•and TyrZ•remain to be clearly identified, as they appear different from PD1, PD2, PheD1, ChlD1, and ChlD2, as concluded by the lack of different light-induced difference spectra in the mutants listed above. Although we cannot rule out a weak effect, considering the accuracy of the experiments, it is proposed that other pigments, such as antenna Chl and/or Car, near the reaction center are involved. Additionally, it is shown that:i) there is no proton release into the bulk upon the oxidation of TyrDat pH 8.6, andii) the rearrangement of the electrostatic environment of the pigments involved in the light-induced difference spectra in the samples studied, upon the formation of TyrD•, TyrZ•, and QA•-, likely occurs differently from both a kinetic and structural perspective.
Pilot: Salivary Lactoferrin as a Biomarker of Alzheimer’s Disease
Authors: Hammerschlag BL , Butts B , Likos KDS , Verble DD , Nimmagadda N , Virani R , Ramanathan S , Wharton W.
Published: November 2024

Background

Alzheimer’s disease (AD) research has focused on developing accessible biomarkers that accurately detect disease pathology and progression before symptoms present. Lactoferrin (Lf) is an iron-binding antimicrobial glycoprotein found in all biological fluids, and its concentration in saliva has been correlated with AD symptoms. This pilot project aimed to determine whether salivary lactoferrin (sLF) has potential as a biomarker for AD.

Methods

Participants were middle to older-aged non-Hispanic white (NHW) and Black Americans (BA) at risk for AD due to parental history. We collected saliva samples after an 8-hour fast and administered a cognitive battery assessing executive function, memory, visuospatial ability, attention, and verbal fluency. We examined the relationship between sLF and cognitive performance and evaluated protein concentration across races.

Results

Seventeen middle-to-older-aged (age = 60.29 ± 9.7 years) BA and NHWs were enrolled. After controlling for age, sex, race, and years of education, we found a significant r between sLF and Digit Span Memory Test (DSMT) scores (P= 0.013) and a modest correlation with Mental Rotation Test scores (P= 0.194). We found no difference in average concentration across races.

Conclusions

Memory concerns and a worsening in visuospatial ability are early signs of cognitive decline in AD patients, and this pilot suggests a correlation of these symptoms with sLF. Bigger-scale longitudinal studies to examine the relationship between sLF and established AD biomarkers in diverse populations are needed to assess its clinical usefulness as an early biomarker for AD.
Use of the test-negative design to estimate the protective effect of a scalar immune measure: A simulation analysis
Authors: Zhang Ziyuan , Boyer Christopher Brian , Lipsitch Marc
Published: November 2024

Background

The relationship between antibody levels (more generally, a scalar measure of immune protection) at the time of exposure to infection (so-called exposure-proximal correlates of protection) and the risk of infection given exposure is of central interest in evaluating the evolution of immune protection conferred by prior infection and/or vaccination. A version of the test-negative study design (TND), adapted from vaccine effectiveness studies, has been used to assess this relationship. However, the conditions under which such a study identifies the relationship between immune measurements and protection have not been defined.

Objective

To evaluate the conditions for TNDs to estimate the relationship between antibody levels or a similar scalar measurement of immunity (hereafter exposure-proximal correlates of protection, COP) and the relative incidence rate of infection given exposure.

Method

Individual-based transmission models, linking infection risk linearly and nonlinearly with COP value and accounting for waning immunity post-vaccination and –infection, were used. Simulations were performed of a TND with sampling on predetermined dates. Data from either one or multiple simulation days were analyzed using logistic regression and generalized additive models.

Result

A correctly specified logistic regression model provided an unbiased estimate of the effectiveness of specific COP levels (analogous to vaccine effectiveness). Aggregating data across different simulation dates with incidence-density sampling also provided reliable estimates of protection. When, as is generally the case, the functional form relating COP level to protection is unknown, generalized additive models offer a more flexible alternative to traditional logistic regression approaches.

Conclusion

A TND can validly estimate the relative effect of an immune COP at the time of exposure on the incidence rate of infection via logistic regression if the functional form of the effect is known and appropriately modeled or unknown a semiparametric approach. Future research should further examine the dynamics of immunity waning and boosting for more reliable inference.
Novel Domain V mutation incfr-positive clinicalStaphylococcus haemolyticusisolates causing linezolid resistance in Egyptian ICU patients
Authors: Maghraby Saber , Dawoud Mohamed Ez El-Din , Eweis Mohamed , El-nagish Abdullah , Ghaith Doaa
Published: November 2024

Linezolid resistance has become a focal point worldwide, particularly as linezolid stands as one of the last resort antibiotics against multiple-drug resistant bacterial strains. Despite its critical importance, the situation in Egypt remains relatively unexplored. As various linezolid resistance mechanisms have been identified in staphylococci, our investigation aims to uncover the molecular characteristics of staphylococci showing reduced susceptibility to Linezolid at Kasr-El-Eini Teaching Hospital. Thirty isolates were investigated in this study. The selected samples, identified by Vitek 2 system and confirmed by 16S rRNA, were examined by disc diffusion method. Of the 30 isolates, two were confirmed as linezolid resistant and screened for the presence of cfr gene and mutations in the Domain V of the 23S rRNA gene. Both of the studied strains, identified asStaphylococcus haemolyticus, SZ-2 and SZ-7 harbored two point mutations G2576T and G2602T in the Domain V of the 23S rRNA gene. A novel G2694C mutation reported for the first time was detected in strain SZ-7. The presence of cfr gene was confirmed in both isolates. Linezolid-resistantStaphylococcus haemolyticushad emerged in ICU patients with prior antibiotic exposure. The exact role of the novel G2694C mutation in linezolid resistance needs further investigations. The study underscores the importance of proper surveillance ofcfr-carrying strains in the healthcare settings in Egypt.
Index microvascular resistance (IMR)-guided management of heart transplantation (IMR-HT study): Study Protocol
Authors: Pérez-Guerrero Ainhoa , Vilchez-Tschischke Jean Paul , Almenar Bonet Luis , Diez Gil Jose Luis , Blasco Peiró Teresa , Brugaletta Salvatore , Gomez-Lara Josep , González Costello José , Antuña Paula , Alonso Fernández Vanesa , Sarnago Cebada Fernando , García-Cosio María Dolores , Hidalgo Lesmes Francisco , López Granados Amador , López-Palop Ramón , Paula Garrido Iris , Cardenal Piris Rosa María , Rangel Sousa Diego , Fuertes Ferre Georgina
Published: November 2024

Background

Acute allograft rejection (AAR) is an important cause of morbi-mortality in heart transplant (HT) patients, particularly during the first year. Endomyocardial biopsy (EMB) is the “gold standard” to guide post-heart transplantation treatment. However, it is associated with complications that can be potentially serious. Index of microvascular resistance (IMR) is a specific physiological parameter to measure microvascular function. An increased IMR measured early after HT has been associated with acute cellular rejection (ACR), higher all-cause mortality and adverse cardiac events. As far as we know, no study has evaluated IMR impact on post-HT management (number of EMB performed). Our aim will be to assess if post-HT patient management may be modified based on IMR value.

Study design

The IMR-HT study (NCT 06656065) is a multicenter, prospective study that will include post-HT consecutive stable patients undergoing coronary physiological assessment in the first three months and one year. Depending on IMR values the physician will be able to reduce the number of biopsies established in each center protocol.

Conclusions

Management after heart transplant (number of biopsies) could be modified depending on IMR values.
Risk prediction models for pneumonia in hospitalized stroke patients: A systematic review
Authors: Yan Manlin , Huang Weirong , Zhang Zhihui , Song Meixuan , Li Xianrong
Published: November 2024

Objective

To systematically evaluate risk prediction models for pneumonia occurrence during hospitalization in stroke patients.

Methods

Computer searches were conducted in the PubMed, Embase, Web of Science, Cochrane Library, and EBSCO databases for literature related to risk prediction models for pneumonia in hospitalized stroke patients, with search dates ranging from database inception to June 13, 2024. Two researchers independently screened the literature, extracted the data, and evaluated the risk of bias and applicability of the included studies via the Prediction Model Risk of Bias ASsessment Tool (PROBAST).

Results

A total of 43 studies were included, among which 33 studies developed a total of 56 new models, and 25 studies externally validated 19 models. Among the 56 new models, 29 used a logistic regression model (LR), 25 used a machine learning model (ML), 1 used a classification and regression tree model (CART), and 1 used a linear regression model. The reported area under the curve (AUC) ranged from 0.565 to 0.960. The number of predictors explicitly reported for one model was 1,046, with the top three predictors most commonly used being age, the National Institutes of Health Stroke Scale (NIHSS) score, and dysphagia. The PROBAST results revealed that all 43 studies had a high risk of bias, and 27 studies had poor applicability.

Conclusion

Although the pneumonia risk prediction models for hospitalized stroke patients in the included studies achieved good predictive performance, the overall quality needs improvement. Future research should follow stricter study designs, standardized reporting practices, and multicenter large-sample external validation.
A generalised vision transformer-based self-supervised model for diagnosing and grading prostate cancer using histological images
Authors: Chaurasia Abadh K , Harris Helen C , Toohey Patrick W , Hewitt Alex W
Published: November 2024

Background

Gleason grading remains the gold standard for prostate cancer histological classification and prognosis, yet its subjectivity leads to grade variability between pathologists, potentially impacting clinical decision-making. Herein, we trained and validated a generalised AI-driven system for diagnosing prostate cancer using diverse datasets from tissue microarray (TMA) core and whole slide images (WSIs) with Hematoxylin and Eosin staining.

Methods

We analysed eight prostate cancer datasets, which included 12,711 histological images from 3,648 patients, incorporating TMA core images and WSIs. The Macenko method was used to normalise colours for consistency across diverse images. Subsequently, we trained a multi-resolution (5x, 10x, 20x, and 40x) binary classifier to identify benign and malignant tissue. We then implemented a multi-class classifier for Gleason patterns (GP) sub-categorisation from malignant tissue. Finally, the models were externally validated on 11,132 histology images from 2,176 patients to determine the International Society of Urological Pathology (ISUP) grade. Models were assessed using various classification metrics, and the agreement between the model’s predictions and the ground truth was quantified using the quadratic weighted Cohen’s Kappa (κ) score.

Results

Our multi-resolution binary classifier demonstrated robust performance in distinguishing malignant from benign tissue withκscores of 0.967 on internal validation. The model achievedκscores ranging from 0.876 to 0.995 across four unseen testing datasets. The multi-class classifier also distinguished GP3, GP4, and GPs with an overallκscore of 0.841. This model was further tested across four datasets, obtainingκscores ranging from 0.774 to 0.888. The models’ performance was compared against an independent pathologist’s annotation on an external dataset, achieving aκscore of 0.752 for four classes.

Conclusion

The self-supervised ViT-based model effectively diagnoses and grades prostate cancer using histological images, distinguishing benign and malignant tissues and classifying malignancies by aggressiveness. External validation highlights its robustness and clinical applicability in digital pathology.
Smallpox bioterrorism scenarios and reactive intervention protocol: mathematical model-based analysis
Authors: Ko Youngsuk , Seo Yubin , Park Jin Ju , Kim Eun Jung , Moon Jong Youn , Kim Tark , Eom Joong Sik , Oh Hong Sang , Kim Arim , Kim Jin Yong , Lee Jacob , Jung Eunok
Published: November 2024

Smallpox, caused by the variola virus, is one of the most devastating diseases in human history and was eradicated through global vaccination efforts by 1980. Despite its eradication, the virus remains in high-security laboratories for research purposes, posing the potential risk of bioterrorism. This study developed a mathematical model to analyze potential smallpox epidemics by incorporating factors such as age groups, heterogeneous contact patterns, and various intervention strategies including contact tracing, ring vaccination, and mass vaccination. The model simulations indicated that the Republic of Korea’s current plans for negative-pressure isolation beds should suffice under most scenarios, but extreme worst-case scenarios could overwhelm healthcare capacity. This study highlights the critical importance of non-pharmaceutical interventions and strategic vaccination prioritization for controlling outbreaks. These findings provide valuable guidance for public health officials and policymakers in preparing for potential bioterrorism threats and emerging infectious diseases. Furthermore, emphasizes the need for comprehensive preparedness and robust response strategies. The proposed framework applies to smallpox and to other infectious diseases, offering insights for future outbreak management.
Article Processing Charges Threaten Global Health Equity: Open Access is Closed Science
Authors: Hyman Gabriella Y. , Wurdeman Taylor , Kumar Nikathan , Alty Isaac G. , Forbes Callum , Riviello Robert , Raykar Nakul P.
Published: November 2024

Introduction

The shift from subscription-based to open-access (OA) publishing sought to democratize scientific knowledge by eliminating access barriers. However, article processing charges (APCs) have raised concerns about equity, particularly for researchers from low- and middle-income countries (LMICs). APCs shift costs from readers to authors, potentially limiting the ability of researchers to disseminate their work. This study aimed to quantify the effect of APCs on equity in global surgery by examining current APC costs and their association with journal metrics and LMIC authorship.

Methods

A structured review was conducted on journals’ APCs and bibliometrics using data from the Scientific Journal Rankings (SJR) and PubMed. Journals were included if they actively published human health research and had at least 100 articles with first author information. APC data were obtained from five major publishers (Elsevier, Wiley, Oxford, Sage, and Springer Nature) and supplemented manually. Journals were categorized into surgery, public health, and other groups. Data on APCs, bibliometrics (SJR ranking, H-index), and first author affiliations were analyzed using linear regression models to assess their relationship with APC costs and LMIC authorship.

Results

The study included 2,001 journals with a median APC of $3,700 USD showing no significant cost differences across journal categories. The median percentage of LMIC first authors was 4%, with a significant negative association between APCs and LMIC authorship: each $500 increase in APC was linked to a 0.7% decrease in LMIC first authorship. While higher APCs correlated with slightly higher bibliometric indices, the academic impact was limited.

Conclusion

APCs present a significant barrier to LMIC authors, undermining the equity goals of OA publishing. Alternative funding models, such as tiered pricing or expanded waivers, are needed to ensure OA remains accessible and equitable across all economic contexts.
Mutation Spectrum and Associated Risks of Medullary Thyroid Cancer and All-Cause Mortality in Incidentally Identified MEN2A-CausingRETVariants
Authors: West Courtney E. , Mirshahi Uyenlinh L. , Ruth Katherine S. , Sharp Luke N. , Arni Ankit M. , Turnbull Clare , Wright Caroline F. , Vaidya Bijay , Owens Martina M. , Carey David J. , Patel Kashyap A.
Published: November 2024

Importance

RETpathogenic variants cause Multiple Endocrine Neoplasia type 2 (MEN2), characterised by medullary thyroid cancer (MTC). With increasing incidental identification of these variants in asymptomatic individuals outside family screening, their risk of MTC and all-cause mortality without intervention remain unknown in this context.

Objective

To determine the risk of MTC and all-cause mortality in clinically unselected individuals and assess how the risk of MTC differ from clinically ascertained cases.

Design, Setting, and Participants

Prospective cohort study of 383,914 unrelated individuals from the clinically unselected UK population (UK Biobank) and 122,640 from the US health system (Geisinger cohort). We compared MTC risk in these cohorts to 1,078 individuals who were clinically ascertained with suspicion of MEN2 from UK routine practice.

Exposures

RETpathogenic variants causing MEN2

Main Outcomes and Measures

Frequency and the spectrum of pathogenicRETvariants, Risk of clinically presented MTC, all-cause mortality without thyroidectomy.

Results

PathogenicRETvariants were found in 0.04% of individuals from UK population cohort and 0.08% of individuals from US health system cohort. They were predominantly from moderate-risk category as per American Thyroid Association guideline (99.4% and 94.8% respectively). MTC risk by age 75 in variant carriers in the UK population was 2.2% (95% CI 0.7-6.8) and 19% (95% CI 5.7-30) in US health system cohort. This was significantly lower than the clinically ascertained cohort with the matched variants (95.7%, 95% CI 82.1-99.7 p<0.0001). In the UK Biobank, most variant carriers (98.2%) did not undergo thyroidectomy and their all-cause mortality by age 75 was similar to non-carriers (6.1%, 95% CI 2.7-13.8 vs 5.7%, 5.6-5.8, p=0.79), with consistent findings in the US health system cohort.

Conclusions and Relevance

Moderate-riskRETvariants are most common in incidental cases. These variants carry substantially lower MTC risk than clinically ascertained cases. This evidence addresses a current knowledge gap, enabling more informed clinical decision-making.
CharacterisingStreptococcus pneumoniaeTransmission Patterns in Malawi Through Genomic and Statistical Modelling
Authors: Cave Rory , Chirombo James , Obolski Uri , Belman Sophie , Kalizang’oma Akuzike , Mwalukomo Thandie S. , Kamng’ona Arox , Brown Comfort , Msefula Jacquline , Bonomali Farouck , Nyirenda Roseline , Swarthout Todd D. , Kwambana-Adams Brenda , French Neil , Heyderman Robert S.
Published: November 2024

Controlling the carriage and transmission ofStreptococcus pneumoniaein children from high- disease burden countries is crucial for disease prevention. To assess the rate of spread, and the factors associated with the high frequency of transmission despite pneumococcal conjugate vaccine (PCV) introduction, we measured evolution divergence time using the whole genome sequences ofS. pneumoniaecollected from 1,617 child participants from Blantyre, Malawi between 2015 and 2019. These children included both PCV13 vaccinated children aged 2 to 7 years and PCV13 unvaccinated children aged 5 to 10 years who were age ineligible when PCV was introduced. Using a generalized additive mixed model (GAMM) and relative risk (RR) frameworks, while accounting for household geospatial distances, we found that the spread of lineages became widespread across the population of Blantyre over approximately four years, with transmission being more likely between neighbouring households. Logistic regression and random forest models predicted a higher incidence of events among preschool children in densely populated, higher socioeconomic areas. Additionally, recent transmission was linked to recently expanding, non-vaccine serotype lineages that are penicillin non-susceptible. Our findings suggest that enhancing vaccine-mediated immunity among preschool-aged children in high density settings could reduce transmission of disease-causing and antimicrobial-resistant pneumococcal lineages, therefore strengthening herd protection for vulnerable individuals (e.g. very young children and people living with HIV).