bluuebunny/crossref_metadata_2025 huggingface dataset:
Preservation of coagulation function by normothermic machine perfusion in liver transplant as evidenced by thromboelastography parameters
Authors: Su Leon L. , Secor Daniel T. , McGary Alyssa K. , Nguyen Michelle C. , Jadlowiec Caroline C. , Williams Lance A. , Kinard Theresa N. , Adamski Jill , Stoker Alex D. , Frasco Peter E.
Published: October 2024

The use of normothermic machine perfusion (NMP) over static cold storage in liver transplantation has been shown to reduce posttransplant risks of early allograft dysfunction, primary nonfunction, and ischemic cholangiopathy, and its increasing use has played a role in the expanded utilization of marginal livers. While studies have demonstrated improved clinical outcomes using NMP over static cold storage preservation, real-time intraoperative data reflecting the quality and viability of NMP livers is limited. This retrospective, single-center study compared NMP versus static cold storage livers in first-time recipients of liver transplants through the evaluation of synthetic coagulation function as measured by thromboelastography and conventional coagulation testing. Secondarily, transfusion utilization between the 2 cohorts was reviewed. One hundred eighty-six recipients of liver transplants receiving allografts from donors after circulatory death were included in the study, of which 99 (53%) allografts were preserved in static cold storage, and 87 (47%) allografts were placed on the TransMedics Organ Care System. Study findings showed NMP livers supported with the TransMedics Organ Care System were associated with increased synthetic coagulation function and less excess fibrinolysis in the postreperfusion period compared to static cold storage livers, and that these findings were better reflected in real-time with thromboelastography monitoring versus conventional coagulation testing. Following reperfusion, there was a significant decrease in the transfusion of blood products in the NMP group compared with that in the static cold storage group. Overall, we determined that the use of intraoperative thromboelastography can provide real-time data to assess one aspect of reperfusion liver quality and viability.
Advances in colon-targeted drug technologies
Authors: Yeung Charlotte , McCoubrey Laura E. , Basit Abdul W.
Published: October 2024

Purpose of review

Herein, we present an overview of innovative oral technologies utilized in colonic drug delivery systems that have made significant translational and clinical advancements to treat inflammatory bowel disease (IBD) in recent years.

Recent findings

The colon is home to distinct physiological conditions, such as pH and microbiota, that have been exploited in the development of colonic drug delivery systems for the treatment of local and systemic diseases. However, given the intra and interindividual variability in the gastrointestinal tract of both healthy and diseased states, various systems have shown inconsistencies in targeted drug release to the colon. Recent breakthroughs have led to systems that incorporate multiple independent trigger mechanisms, ensuring drug release even if one mechanism fails due to physiological variability. Such advanced platforms have bolstered the development of oral biologics delivery, an especially promising direction given the lack of commercially available oral antibody medications for IBD. These concepts can be further enhanced by employing 3D printing which enables the personalisation of medicines.

Leveraging these novel technologies can accurately deliver therapeutics to the colon, allowing for treatments beyond gastrointestinal tract diseases. To realize the full potential of colonic drug delivery, it is paramount that research focuses on the clinical translatability and scalability of novel concepts.
Robotic-Assisted Lymphedema Surgery: Bridging the Gap in Training and Expanding Complex Surgical Options
Authors: Levin L. Scott , Payne Mary Margaret , Van Vleet John D , Azoury Saïd C.
Published: October 2024

The prevalence of lymphedema is likely to rise substantially in the coming decades, given projected increases in cancer. Lymphedema surgeries can improve patients’ quality of life, but the shortage of surgeons capable of performing these surgeries may be a barrier to treatment. Robotic platforms may elevate novice and less-seasoned surgeons’ skills, expediting their ability to perform lymphovenous anastomoses. At the same time, robotic systems may ameliorate work-related musculoskeletal stresses, which could extend the careers of microsurgeons. Moreover, as research progresses into novel applications, the integration of advanced robotic technology may become crucial. Continued exploration of these emerging fields will not only expand the possibilities for treatment but also necessitate further advancements in surgical techniques and training methodologies. The ongoing development and implementation of robotic systems like Symani could thus be instrumental in addressing the growing global burden of lymphedema and other complex surgical challenges.
Development and Validation of a Laparoscopic Sacrocolpopexy Training Model
Authors: Winn Heather M. , Tunitsky-Bitton Elena , O'Meara Amanda , Myers Erinn M. , Anderson-Montoya Brittany L. , Tarr Megan E.
Published: October 2024

Importance

Proper training is necessary to develop the highly specialized skills required to safely perform laparoscopic sacrocolpopexy. Currently, there is no validated training model for laparoscopic sacrocolpopexy that includes dissection of the presacral space, both vaginal and presacral mesh attachments, and peritoneal closure.

Objectives

This study aimed to create a procedure specific hierarchical task analysis for laparoscopic sacrocolpopexy and then develop and validate a corresponding laparoscopic sacrocolpopexy pelvic training model for the simulation environment.

Study Design

This was an observational simulation study that was divided into 5 phases: (1) development of hierarchical task analysis, (2) model construction, (3) participant recruitment and simulation testing, (4) reliability and validity testing, and (5) creation of a standard passing performance measure.

Results

Construct, face, and content validity were established for this model. According to the participating experts, the model was able to replicate the steps of presacral dissection, anterior vaginal and sacral mesh attachment, and peritoneal closure. Thirteen trainees and 5 experts completed the simulation, and all “agreed” or “strongly agreed” that the model seemed useful for improving suturing technique and learning the procedure. Additionally, a passing performance measure was determined through contrasting groups methodology.

Conclusions

We developed a novel, reusable, and validated training model that can be utilized as a training resource for the many critical skills necessary to safely and efficiently perform laparoscopic sacrocolpopexy.
Missing History: Anarcha, Betsey, and Lucy’s Legacy in Gynecologic Textbooks
Authors: Lee Jennifer H. , Sanchez Ciara , Johnson Bria , Woodburn Katherine L. , Iglesia Cheryl B.
Published: October 2024

The legacy of J. Marion Sims as the “father of gynecology” has become widely controversial among medical professionals and lay public because of ethical concerns surrounding the development of his surgical techniques and his exploitation of enslaved women for his experiments. Notably, in April 2018, the City of New York relocated a commemorative statue of Sims from Central Park following an art commission’s investigation of his controversial practices. The relocation was viewed by many as a public acknowledgement of the contributions of Anarcha, Betsey, Lucy, and the other enslaved women to the advancement of gynecologic surgery. However, despite the increased public awareness of the women’s sacrifices in recent years medical literature has not kept pace. We compared the portrayal of Sims and these enslaved women within current gynecology textbooks, prior editions, and historical medical literature. We found that gynecologic textbooks more often mention J. Marion Sims by name (74%) compared to the enslaved women he experimented on (24%). Neither current gynecologic surgery textbooks nor primary historical sources contain significant references to these women, meaning much of their story has been lost to history. While there has been increased public knowledge of the sacrifices of Anarcha, Betsey, and Lucy and other enslaved women, lay recognition is not enough. Full acknowledgment of their contributions necessitates crediting their roles in Sims’ experiments and stating their names in medical literature.
Protein profile of the Escherichia coli strain, BW25113, exposed to two novel iron-halide compounds: Fe(Hampy)2Cl4 and Fe(Hampy)2Br4.
Authors: Abedin Nusrat , Wagner Sarah , Khalkar Yukta Sanjay , Johnson Zulekha , Egbowon Biola F. , Hargreaves Alan J. , Fitzpatrick Anthony J. , Miles Amanda K. , Dafhnis-Calas Felix
Published: October 2024

The mortality rate and economic burden of infections caused by antimicrobial resistant pathogens are increasingly higher. This frustrating scenario emphasizes the urgent need for developing new antimicrobial drugs. We have previously addressed this problem by studying the antimicrobial activity of two novel iron-halide complexes, Fe(Hampy)2Cl4 (iron-tetrachloride) and Fe(Hampy)2Br4 (iron-tetrabromide). Both compounds showed bactericidal and antibiofilm activities against bacteria with an antimicrobial resistance phenotype. Herein, we used a proteomics approach to investigate the protein-expression profile  of bacterial cells previously exposed to both iron-halide complexes. For this study, the Escherichia coli strain, BW25113, was used as a model to facilitate the rapid identification of deregulated proteins. Heat map analysis of the common deregulated proteins highlighted that both complexes caused downregulation of proteins associated with key metabolic pathways, biofilm formation, cell-envelope biogenesis, and iron ion binding. In addition, network study suggested that the most influential proteins of the tetrachloride activity were those involved in TCA cycle, oxidative phosphorylation, iron ion homeostasis and carbon/secondary metabolism. This protein-protein interaction analysis also hinted that the main drivers of the tetrabromide activity were proteins involved in translation, ribosomal biogenesis, and cell motility. The above results strongly suggested how the presence of different halide ligands could be used to generate compounds with potentially different molecular mechanisms. Importantly, the findings of this study can also be used as a reference to compare with the protein profile of a bacteria exposed to future variants of the iron-halide complexes.
Anaerobic HgII reduction is driven by cellular HgII-thiol interactions

Authors: Lavoie Noemie C , Poulain Alexandre J
Published: October 2024

Redox reactions determine the availability of mercury species, HgII and Hg0, to anaerobic microbes responsible for the methylation of inorganic Hg into toxic methylmercury. Certain anaerobes also play an important role in Hg cycling in methylation hot spots by reducing HgII to its gaseous elemental form Hg0, yet their contributions remain unquantified due to a paucity of mechanistic information or genetic targets. In this work, we sought to uncover further mechanistic details on anaerobic HgII reduction by the versatile anoxygenic photoheterotroph and fermenter Heliomicrobium modesticaldumIce1. Due to HgII’s electrophilic attraction to thiols, we hypothesized that cellular thiol groups are likely interaction sites involved in HgII reduction. We exposed H. modesticaldum to the thiol-alkylating agent N-ethylmaleimide to irreversibly bind to thiols and found a concentration-dependent inhibition of Hg0 production during anoxygenic photoheterotrophy and fermentation. We propose updated insights into Heliobacterial HgII reduction where HgII-thiol interactions are a key step of the mechanism and discuss potential enzymatic coupling sites that merit further investigation.
Absence of measurable quantities of Candida auris and Cryptococcus spp. in the gut microbiota of Ghanaian individuals with and without HIV infection as confirmed by applying multiple real-time PCR assays
Authors: Fuchs Frieder , Frickmann Hagen , Hahn Andreas , Balczun Carsten , Hagen Ralf Matthias , Feldt Torsten , Sarfo Fred Stephen , Di Cristanziano Veronica , Loderstädt Ulrike , Ehrhardt Stephan , Schoppen Stefanie , Tagbor Harry , Eberhardt Kirsten Alexandra
Published: October 2024

Introduction. Fungal infections are relevant health risks for individuals with acquired immunodeficiency in the resource-limited tropics, but available surveillance data are scarce. For Candida auris and Cryptococcus spp., the evolution from environmental reservoirs to human pathogens causing life-threatening diseases is currently discussed as a public health concern in the context of climate change and limited treatment options.

Gap statement. Uncovering the gastrointestinal tract as an epidemiological niche of fungi emerging from the environment into individuals for whom fungal infections are not diagnosed.

Aim. To contribute to data on the local epidemiology of C. auris and Cryptococcus spp. in Western African Ghana by analysing gastrointestinal samples of Ghanaian individuals.

Methodology. Four real-time PCR assays targeting C. auris and five real-time PCR assays targeting Cryptococcus spp. were applied with stool samples of 875 non-age-stratified Ghanaian HIV patients and 30 Ghanaian control individuals without known HIV infection. Also, 664 samples from Ghanaian children under 2 years of age were investigated. The true abundance of the target micro-organism was considered as unlikely in the case of one or fewer positive signals, likely in the case of two to three positive signals and highly likely in the case of four or more positive signals per sample in the real-time PCR assays.

Results. The combined application of sensitive, target-specific real-time PCR assays indicates that neither C. auris, Cryptococcus neoformans complex nor Cryptococcus gattii complex were part of the gut microbiota of Ghanaian individuals with or without HIV infection.

Conclusion. Despite the significant disease burden from these pathogens in immunosuppressed Ghanaian individuals, detection from gastrointestinal samples was unlikely, which should be taken into account when discussing screening strategies for these fungi of public health concern. In contrast, the detection of these fungi from such samples should not routinely be considered as commensal colonization flora.
Depth-Dependent Contributions of Various Vascular Zones to Cerebral Autoregulation and Functional; Hyperemia: An In-Silico Analysis
Authors: Pashaie Ramin
Published: October 2024

Autoregulation and neurogliavascular coupling are key mechanisms that modulate myogenic tone (MT) in vessels to regulate cerebral blood flow (CBF) during resting state and periods of increased neural activity, respectively. To determine relative contributions of distinct vascular zones across different cortical depths in CBF regulation, we developed a simplified yet detailed and computationally efficient model of the mouse cerebrovasculature. The model integrates multiple simplifications and generalizations regarding vascular morphology, the hierarchical organization of mural cells, and potentiation/inhibition of MT in vessels. Our analysis showed that autoregulation is the result of the synergy between these factors, but achieving an optimal balance across all cortical depths and throughout the autoregulation range is a complex task. This complexity explains the non-uniformity observed experimentally in capillary blood flow at different cortical depths. In silico simulations of cerebral autoregulation support the idea that the cerebral vasculature does not maintain a plateau of blood flow throughout the autoregulatory range and consists of both flat and sloped phases. We learned that small-diameter vessels with large contractility, such as penetrating arterioles and precapillary arterioles, have major control over intravascular pressure at the entry points of capillaries and play a significant role in CBF regulation. However, temporal alterations in capillary diameter contribute moderately to cerebral autoregulation and minimally to functional hyperemia. In addition, hemodynamic analysis shows that while hemodynamics within capillaries remain relatively stable across all cortical depths throughout the entire autoregulation range, significant variability in hemodynamics can be observed within the first few branch orders of precapillary arterioles or transitional zone vessels. The computationally efficient cerebrovasculature model, proposed in this study, provides a novel framework for analyzing dynamics of the CBF regulation where hemodynamic and vasodynamic interactions are the foundation on which more sophisticated models can be developed.
Tracking gonadotropin-releasing hormone-mediated movement in-vivo using quantum dot nanoparticles: insights into pathways leading to sperm release
Authors: Julien A.R. , Kouba A.J. , Kabelik D. , Feugang J.M. , Willard S.T. , Kouba C.K.
Published: October 2024

As the number of conservation breeding programs for at-risk amphibians increase, application of assisted reproductive technologies (ARTs) has likewise grown, with hormone therapy being the most widely utilized technique. Significant interest has been raised for viable alternatives to traditional intracelomic injection for hormone treatment that may be simpler, require less hormone, induce a faster response and be more suitable for animals of different sizes or for minimal contact. We utilized quantum dot (QD) nanoparticles conjugated to GnRHa (GnRHa-QDs) as a means of monitoring exogenous GnRHa dispersal through living Fowler’s toads to investigate how delivery route may affect hormone pathway and efficacy after intracelomic, nasal, and oral administration. Real-time GnRHa-QD movement was tracked using in vivo imaging while hormone binding and QD aggregation were validated using fluorescence microscopy and measurements of spermiation responses following the administration of unconjugated GnRHa, unconjugated QDs, and GnRHa-QDs GnRHa alone was found to induce spermiation in 58.3%, 76.9% and 92.3% of males when administered by intracelomic, oral and nasal routes, respectively. When given through intracelomic injection GnRHa-QD caused spermiation and dispersed throughout the abdominal cavity to then aggregate within the brain, heart, liver, gastrointestinal (GI) tract, kidneys, and testes while unconjugated QDs did not. By contrast, GnRHa-QDs administered by oral or nasal routes were observed moving to the tympanic membrane and down the throat to the GI tract of the toads, but only nasal-administered GnRHa-QDs showed organ aggregation and were only found in the kidneys. Unconjugated QDs exhibited similar in vivo signal dispersal as their conjugated counterparts initially but did not aggregate in any organs over time nor induce spermiation. Through the use of novel QD hormone conjugates, in vivo imaging, and histology we were able to gain insight into how hormone pathways and efficacy might be impacted by delivery route which result in variations in physiological response to hormone treatment.
Well-resolved phylogeny supports repeated evolution of keel flowers as a synergistic contributor to papilionoid legume diversification
Authors: Cai Liming , Cardoso Domingos , Tressel Lydia G. , Lee Chaehee , Shrestha Bikash , Choi In-Su , de Lima Haroldo C. , de Queiroz Luciano P. , Ruhlman Tracey A. , Jansen Robert K. , Wojciechowski Martin F.
Published: October 2024

The butterfly-shaped keel flower is a highly successful floral form in angiosperms. These flowers steer the mechanical interaction with bees and thus are hypothesized to accelerate pollinator-driven diversification. The exceptionally labile evolution of keel flowers in Papilionoideae (Fabaceae) provides a suitable system to test this hypothesis.

Using 1,456 low-copy nuclear loci, we confidently resolve the early divergence history of Papilionoideae. Constrained by this backbone phylogeny, we generated a time tree for 3,326 Fabales to evaluate the tempo and mode of diversification within a state-dependent evolutionary framework.

The first keel flowers emerged around 59.0 Ma in Papilionoideae, predating the earliest fossil by 3–4 million years. The Miocene diversification of Papilionoideae coincided with rapid evolution of keel flowers. At least six independent origins and thirty-two losses of keel flowers were identified in Papilionoideae, Cercidoideae, and Polygalaceae. However, the state-dependent diversification model was not favored.

Lack of radiation associated with keel flowers suggests that diversification within Papilionoideae was not solely driven by pollinator-mediated selection, but instead an outcome of the synergistic effects of multiple innovations including nitrogen fixation and chemical defense as well as dispersal into subtropical and temperate regions.
Repertoire, function, and structure of serological antibodies induced by the R21/Matrix-M malaria vaccine
Authors: McDaniel Jonathan R. , Voss William N. , Bowyer Georgina , Rush Scott A. , Spencer Alexandra J. , Bellamy Duncan , Ulaszewska Marta , Goike Jule , Gregory Scott , King C. Richter , McLellan Jason S. , Hill Adrian V.S. , Georgiou George , Ewer Katie J. , Ippolito Gregory C.
Published: October 2024

The World Health Organization recently recommended the programmatic use of R21/Matrix-M vaccine forPlasmodium falciparummalaria prevention in children living in malaria-endemic areas. To determine its effects on humoral immunity, we conducted a proteomic analysis of polyclonal IgG antibodies directed against the NANP tetrapeptide of the circumsporozoite protein (CSP) which comprises the vaccine’s core immunogen. In ten malaria-naïve adult volunteers, R21/Matrix-M induced polarized IgG anti-NANP repertoires, heavily skewed forIGHV3-30/3-33genes bearing minimal somatic mutation, which remained static in composition following a controlled human malaria infection challenge. Notably, these vaccine-generated antibodies cross-reacted with another protective CSP epitope, the N-terminal junction region, despite its absence from the R21 construct. NANP-specificIGHV3-30/3-33monoclonal antibodies mined from polyclonal IgG repertoires blocked sporozoite invasionin vitroand prevented parasitemiain vivo. Overall, R21/Matrix-M elicits polarized, minimally mutated, polyclonal IgG responses that can target multiple protective CSP epitopes, offering molecular insight into the serological basis for its demonstrated efficacy againstP. falciparummalaria.
Vispro improves imaging analysis for Visium spatial transcriptomics
Authors: Ma Huifang , Qu Yilong , Zhang Anru R. , Ji Zhicheng
Published: October 2024

Spatial transcriptomics (ST) enables the comprehensive analysis of gene expression while preserving the spatial context of tissues. The histological images accompanying ST data provide spatially cohesive information that is often challenging to capture through gene expression alone. However, analyzing such images is challenging due to the presence of fiducial markers and background regions, which can obscure important features and complicate downstream analysis. To address these challenges, we developed Vispro, an end-to-end, fully automated image processing tool tailored for 10x Visium data. Vispro integrates four key modules of fiducial marker detection, fiducial marker removal and image restoration, tissue region detection, and segmentation of disconnected tissue areas. We demonstrated that Vispro enhances the quality of ST images and improves the performance of downstream analyses, including tissue segmentation, cell segmentation, image registration, and histology-based gene imputation.
Inhibition of Androgen Receptor Exposes Replication Stress Vulnerability in Prostate Cancer
Authors: Williams Carly S. , Li Xin , Jang Hongjun , Anand Jay Ramanlal , Lim Won Young , Lee Hyejin , Parks Julie , Zhang Xingyuan , Xie Jialiu , Zhao Jinshi , Wu Di , Armstrong Andrew J. , Bowser Jessica L. , Zou Lee , Hong Jiyong , Somarelli Jason A. , Vaziri Cyrus , Zhou Pei
Published: October 2024

Standard initial systemic treatment for patients with metastatic prostate cancer includes agents that target androgen receptor (AR) signaling. Despite an initial positive response to these AR pathway inhibitors (ARPIs), acquired resistance remains a significant challenge. We show that treatment of AR-positive prostate cancer cells with the frontline ARPI enzalutamide induces DNA replication stress. Such stress is exacerbated by suppression of translesion DNA synthesis (TLS), leading to aberrant accumulation of single-stranded DNA (ssDNA) gaps and persistent DNA damage biomarkers. We further demonstrate that the TLS inhibitor, JH-RE-06, markedly sensitizes AR-positive prostate cancer cells, but not AR-negative benign cells, to enzalutamidein vitro.Combination therapy with enzalutamide and JH-RE-06 significantly suppresses cancer growth in a syngeneic murine tumor model over vehicle control or individual treatment groups. These findings suggest that AR inhibition broadly triggers DNA replication stress in hormone-sensitive prostate cancer, thereby exposing a unique vulnerability that can be exploited by a TLS-disrupting adjuvant for targeted therapy.
Differences in Mean Diffusivity values in the Corona Radiata between patients with Alzheimer’s Disease and Healthy Controls
Authors: Asay Daniel J. , Hunsaker Naomi J.
Published: October 2024

Our understanding of Alzheimer’s disease (AD) is at an all time high. Despite the progress being made, AD is currently irreversible and the number of confirmed cases continues to grow world wide. There is a need for deeper understanding of the course of Alzheimer’s and the development of more sensitive diagnostic tools. In the present study, we performedDTI and TBSS analyses of the Corona Radiata (CR) and Uncinate Fasciculus (UF) in the brain. We extracted MD and FA values of 10 AD patients and compared them to 16 healthy controls using ENIGMA DTI protocol. We also analyzed the Mini-mental state examination (MMSE) scores of each subject. We predict that patients with AD will have lower FA scores and higher MD values compared to healthy controls. We also predict that higher MD scores will be predictive of lower MMSE scores. The results indicate a significant difference in MD values in the CR between groups, which indicates greater axonal necrosis in the CR in patients with AD. However, FA values were not different between groups and patients with higher MD values did not have lower MMSE scores.These results indicate that axonal necrosis in the CR does not have a significant effect on executive functioning as measured by the MMSE. However, these results provide support to the notion of using DTI methodologies as a means of diagnosing AD.
Outbreak of Chikungunya Fever in the Central Valley of Chiapas, Mexico
Authors: Gonzalez-Perez Ana Luz , Vazquez Ana , de Ory Fernando , Negredo Anabel , Plante Kenneth S. , Plante Jessica A. , Palermo Pedro M. , Watts Douglas , Sanchez-Seco Maria Paz , Weaver Scott C. , Estrada-Franco Jose Guillermo
Published: October 2024

Chikungunya virus (CHIKV) was isolated from humans in an outbreak of a febrile illness during July and August 2015 in the central valleys of Chiapas, Mexico. Sera obtained from 80 patients were tested for CHIKV RNA by reverse transcriptase polymerase chain reaction (RT-PCR) and for IgM and IgG antibodies by an enzyme linked immunoassay and a commercial indirect immunofluorescence test for CHIKV and dengue virus (DENV). Of the 80 patients, 67 were positive, including 50 for RNA and 17 for IgM. In addition, one patient was coinfected with CHIKV-DENV and 40 patients were positive for IgG antibody to DENV. The clinical manifestations included a high fever, polyarthralgia, headache, myalgia, rash, digestive disorders, conjunctivitis, and adenopathy associated with cervical and axillary inguinal regions. Complete nucleotide sequences of two of the CHIKV isolates showed that they belonged to the Asian lineage but did not group with other Mexican CHIKV isolates from the Chiapas coast. Our findings documented that different Asian lineage strains of CHIKV were circulating simultaneously during the 2015 outbreak in the Central Valley of Chiapas, Mexico. The 2024 cases suggest an explosive scenario of re-emergence of thousands of new Chikungunya and dengue fever (DENF) cases associated with deaths, and a dangerous increase of the four DENV serotypes throughout the Americas, especially in South American countries that have shown a high influx of human migration to southern Mexico. In Mexico, the state of Chiapas and other southern regions are the most vulnerable.

Author Summary

The first ever recorded outbreak of Chikungunya virus (CHIKV) in the highlands (central valley of Chiapas) Mexico took place in 2015. Clinical data from 80 infected patients together with information provided from virus isolates offered a vision of the diseased and their response linked to different variables such as age, gender, association with pre-existing diseases of some patients, including CHIKF-DENF co-infection. The origins of the Tuxtla Gutierrez CHIKV viruses isolated in the study, including other Mexican isolates, were traced to viruses circulating in regions of Asia in Micronesia and Philippines. Also, we call the attention of the influx of migrants coming from countries having current explosive outbreaks of CHIKV and DENV in the Americas and into southern Mexico. Further we discuss vulnerabilities and point out specially to the geographic location of Chiapas State and its strategic position for attracting the human migrant population.
Effectiveness and Safety of Propofol at Low Doses for Emergency Department Treatment of Migraine
Authors: Côté Stéphane , Simonyan David , Mallet Myriam , Baril Simon , Ouellet Laurie , Berthelot Simon
Published: October 2024

Introduction

A migraine treatment protocol implemented in the emergency department of an urban hospital allowed us to evaluate the effectiveness of propofol compared to metoclopramide as well as the safety of the protocol.

Methods

We reviewed the health records of all patients aged 16 years and older treated with propofol for migraine between May 2014 and August 2017 at a teaching hospital in Québec City (CHUL). The care protocol consisted of administering propofol (20 mg) every 5–10 minutes as needed (up to 6 doses), monitoring vital signs before and after each dose and continuous cardiac monitoring. The primary outcome measure was the mean reduction of pain following first-line therapy (propofol or metoclopramide). The secondary outcome measures were 1) adjusted relative risks of requiring rescue medication after first-line therapy; 2) incidence of the following side effects of propofol received as first or second-line therapy: low arterial pressure (< 90 systolic or < 65 mean), desaturation, excessive sedation, arrhythmia. The cohorts were paired for gender, age, triage priority, and month/year of ED visit.

Results

Files of 34 patients given propofol and 58 given metoclopramide as first-line treatment were analyzed. Five metoclopramide-treated patients received propofol as rescue medication. Among propofol-treated patients, 29.4% experienced pain relief compared to 66% in the metoclopramide group (p < 0.001). Rescue medication was more frequent in first-line propofol patients (82.4% versus 37.9%, p < 0.001). In this group, four participants (10.3%) received intravenous fluid bolus for mean blood pressure below 60, but no persistent desaturation, bradycardia, excessive sedation, or arrhythmia was recorded.

Conclusion

Though less effective than metoclopramide, propofol at low doses may be an alternative to treat migraine in the ED. Monitoring of vital signs (especially blood pressure) would be prudent but continuous nursing is likely unnecessary.
HospitalEnterococcus faeciumdemonstrates distinct environmental and patient reservoirs: a genomic point prevalence survey
Authors: Macesic Nenad , Cottingham Hugh , Wisniewski Jessica A. , Blakeway Luke V. , Theegala Ravali , Pragastis Katherine , Stewardson Andrew , Bass Pauline , Gritt Megan , Spilsbury Stephanie , Del Rosario-Kelly Denise , Dennison Amanda , Spelman Denis W. , Jenney Adam W.J. , Peleg Anton Y.
Published: October 2024

Objectives

Enterococcus faeciumis a common cause of hospital-acquired infections and is associated with vancomycin resistance. The hospital environment is often a reservoir forE. faeciumdue to its ability to survive on surfaces. In 2019 we noted increasing prevalence ofvanA E. faeciumcausing bloodstream infections. We aimed to assess the hospital environment as a reservoir ofvanA E. faecium.

Methods

We conducted a point prevalence survey of the environment at the Alfred Hospital, Melbourne, Australia. We sampled all wards (n=12), 10 surface types and 357 surfaces. ResultingE. faeciumisolates underwent short-read whole genome sequencing and were compared to invasive infection (bloodstream) isolates. Thevanoperon, multi-locus sequence type (MLST) and core genome MLST (cgMLST) were determined.

Results

Twenty percent (73/357) of surfaces isolatedE. faeciumwith a median of 20% positivity per ward (IQR 11.6-30.6%).vanAandvanBwere detected in 12/73 (16%) and 58/73 (79%) environmental genomes, respectively. In contrast, a higher proportion of bloodstream isolates carriedvanA(32/72 [44%],P<0.001). Environmental genomes belonged to 10 MLSTs and 10 cgMLSTs, with ST796/ST78 accounting for 54/73 (74%) genomes. Clinical STs and cgMLSTs overlapped with environmental but were more diverse. We noted 13 putative genomic transmission clusters. One cluster contained 25/44 (57%)vanAgenomes, with the majority being clinical (22/26 genomes, 85%). Environmental-clinical links were observed in 292/895 (33%) putative genomic transmission links. In completed assemblies, thevanAandvanBoperons were located on pRE25-like plasmids and the chromosome, respectively.

Conclusion

We noted a 20% prevalence ofE. faeciumenvironmental colonisation but thevanAoperon was detected in only 12/73 genomes. We identified distinct environmental and patient reservoirs, with most environmental genomes carrying thevanBoperon and having distinct STs/cgMLST clusters. Environment-clinical reservoir spillover was detected but accounted for a minority of putative transmission links.
UnveilingCrocosphaeraresponses to phosphorus depletion: insights from genome analysis and functional characterization
Authors: Caille Chloé , Rabouille Sophie , Ortega-Retuerta Eva , Denis Yann , Crispi Olivier , Marie Barbara , Pujo-Pay Mireille , Daric Vladimir , Talla Emmanuel , Latifi Amel
Published: October 2024

Unicellular, nitrogen-fixing cyanobacteria (UCYN) thrive and support primary production in oligotrophic oceans, playing a significant role in the marine nitrogen cycle.Crocosphaerasp, a model for studying marine nitrogen fixation, is adapted to low phosphate (Pi) conditions. Yet, howCrocosphaeracopes with Pidepletion is rather poorly understood. We present genomics analysis of Pistress-responsive genes in this genus, encompassing sixC. watsoniigenomes and two strains isolated in coastal environments,C. subtropicaandC. chwakensis. We identified genes involved in Pisignaling, uptake, and dissolved organic phosphorus (DOP) hydrolysis. Results showed different genetic potentials to cope with Piscarcity between theCrocosphaerastrains. Physiological monitoring of cultures ofC. watsoniiWH8501 exposed to Pidepletion highlighted a capacity to divide several times and survive for a few more days, albeit with a skewed C:N:P stoichiometry. Upon addition of DOP, cultures efficiently recovered to a growth rate and cell composition equivalent to those observed under favorable conditions. The concomitant transcription analysis revealed diel expression patterns of Pi-related genes and endogenous clock genes, suggesting a possible circadian regulation. Our data deepen our understanding of the growth strategiesCrocosphaeraemploys in Pi-limited environments, offering broader insights into microbial resilience in marine ecosystems.
Skeletal muscle ribosome analysis: a comparison of common assay methods and utilization of a novel RiboAb antibody cocktail
Authors: Godwin Joshua S. , Michel J. Max , Mobley C. Brooks , Nader Gustavo A. , Roberts Michael D.
Published: October 2024

Cellular and tissue total RNA concentrations have been widely reported to represent ribosome content, a metric that reflects the trophic state of skeletal muscle. Although various assays are used to assess total RNA concentrations, there is a need to homologize the various quantification approaches. Thus, we analyzed C2C12 myotubes and mouse skeletal muscle to determine if total RNA concentrations provided through UV-Vis spectroscopy (UV), fluorometry only (Fluor), and fluorometry-based microfluidic chip electrophoresis (MFGE) were representative of cellular and muscle tissue rRNA concentrations (i.e., MFGE 18S+28S rRNA, criterion metric of ribosome content). We also sought to determine whether a novel ribosomal protein antibody cocktail (termedRiboAb) corresponded with 18S+28S rRNA concentrations. Compared to non-treated C2C12 myotubes, 24-hour insulin-like growth factor-1 (IGF-1) treatments increased 18S+28S rRNA concentrations (∼2.0-fold; p<0.001) and total RNA concentrations based on UV (∼1.9-fold; p<0.001), Fluor (∼2.3 fold; p=0.001), and MFGE (∼2.1-fold, p<0.001). In C57BL/6 mice, 10 days of mechanical overload (MOV) via synergist ablation elevated plantaris 18S+28S rRNA concentrations (∼1.7-fold; p=0.017) and total RNA concentrations according to UV (∼1.5-fold; p=0.033), Fluor (∼1.6-fold; p=0.001), and MFGE (∼1.8-fold, p=0.017). In both experiments, total RNA concentration data yielded from all three techniques exhibited significant positive correlations to 18S+28S rRNA concentrations. Ribosome pelleting experiments indicated that the proteins assayed with the RiboAb cocktail (rps3/6 and rpl5/11) were exclusively associated with the ribosome pellet. Additionally, C2C12 myotube and mouse plantaris RiboAb levels were higher with IGF-1 treatments and MOV, respectively, relative to controls (1.3-fold and 1.7-fold, respectively, p<0.017), and values correlated with rRNA concentrations (r=0.637 and r=0.853, respectively, p<0.005). These data confirm that total RNA concentrations yielded from the UV, Fluor, MFGE techniques are valid surrogates of cell/tissue ribosome content. We also propose that the RiboAb cocktail may serve as a surrogate for changes in ribosome content in these models, although future research is needed to examine the feasibility of the RiboAb cocktail in humans as well as utility with other applications (e.g., immunohistochemistry and/or tissue fractionation experiments).
A FAN1 point mutation associated with accelerated Huntington’s disease progression alters its PCNA-mediated assembly on DNA
Authors: Aretz Jonas , Jeyasankar Gayathri , Salerno-Kochan Anna , Thomsen Maren , Thieulin-Pardo Gabriel , Haque Tasir , Monteagudo Edith , Felsenfeld Dan , Finley Michael , Vogt Thomas F. , Boudet Julien , Prasad Brinda C.
Published: October 2024

FAN1 is an endo- and exo-nuclease involved in DNA and interstrand crosslink repair. Genome-wide association studies of people with Huntington’s disease revealed a strong association between the FAN1 R507H mutation and early disease onset, however the underlying mechanism(s) remains unclear. FAN1 has previously been implicated in modulating triplet repeat expansion in a PCNA dependent manner. To examine the role of PCNA on FAN1 activation, we solved the cryo-EM structures of a PCNA–FAN1–DNA complex. Our findings reveal that the FAN1 R507 residue directly interacts with PCNA D232. Biophysical interaction studies demonstrated that FAN1 enhances the binding affinity of PCNA for DNA, a synergistic effect disrupted in mutants carrying the R507H mutation. In contrast, PCNA does not affect the affinity of FAN1 for DNA but does modulate FAN1 activity upon ternary complex formation. The weakened and functionally altered FAN1 R507H-PCNA-DNA complex may partly impair the FAN1-mediated repair of CAG extrahelical extrusions, providing a potential explanation for the mutation’s role in accelerating disease progression.
Mapping multiple RNA modifications simultaneously by proximity barcode sequencing
Authors: Sendinc Erdem , Yu Hua , Hwang Fu Yu Hsien , Santos Jerome , Johnson Zachary , Kirstein Justin R. , Niu Jiani , Chabot Michael B. , Cantu Vito Adrian , Džakula Željko , Lam Quan , Anmangandla Ananya , Burcham Timothy S. , Davis Eric M. , Miles Zachary D. , Price Andrew D. , Purse Byron W. , Gregory Richard I. , Stengel Gudrun
Published: October 2024

RNA is subject to a multitude of different chemical modifications that collectively represent the epitranscriptome. Individual RNA modifications including N6-methyladenosine (m6A) on mRNA play essential roles in the posttranscriptional control of gene expression. Recent technological advances have enabled the transcriptome-wide mapping of certain RNA modifications, to reveal their broad relevance and characteristic distribution patterns. However, convenient methods that enable the simultaneous mapping of multiple different RNA marks within the same sample are generally lacking. Here we present EpiPlex RNA modification profiling, a bead-based proximity barcoding assay with sequencing readout that expands the scope of molecular recognition-based RNA modification detection to multiple targets, while providing relative quantification and enabling low RNA input. Measuring signal intensity against spike-in controls provides relative quantification, indicative of the RNA mod abundance at each locus. We report on changes in the modification status of HEK293T cells upon treatment with pharmacological inhibitors separately targeting METTL3, the dominant m6A writer enzyme, and the EIF4A3 component of the exon junction complex (EJC). The treatments resulted in decreased or increased m6A levels, respectively, without effect on inosine levels. Inhibiting the helicase activity of EIF4A3 and EIF4A3 knockdown both cause a significant increase of m6A sites near exon junctions, consistent with the previously reported role of EIF4A3 in shaping the m6A landscape. Thus, EpiPlex offers a reliable and convenient method for simultaneous mapping of multiple RNA modifications to facilitate epitranscriptome studies.
Performance of and preference for saliva sampling for detection of SARS-COV-2 in the Bahamas
Authors: Martin Indira , McMillan Pearl
Published: October 2024

Implementing public health diagnostic modalities that are simultaneously accurate and acceptable is integral to effective pandemic response. In this regard, saliva has proven to be a reliable alternative to nasopharyngeal swabs (NPS) for the detection of SARS-COV-2 infections. In particular, the SalivaDirect protocol utilises untreated saliva as its sample type, and removes the need for RNA extraction, thereby decreasing the time and cost of diagnosis by RT-PCR. IN the current study we piloted SalivaDirect in the context of The Bahamas archipelago, where it demonstrated acceptable performance, with 95.2% concordance with NPS. However, there was discordance in 3 of the 8 total SARS-COV-2 positive samples,all of which were above Ct 30 and therefore presumably of low infectivity. Furthermore, a significant majority of survey respondents chose saliva as their preferred sample type and this was associated with citing ‘discomfort’ of NPS sampling as the reason for their choice. These results support the practical use of SalivaDirect in the Bahamas as a mass testing tool.
TikTok: Empowering Hidradenitis Suppurativa Patients through Social Media Education - A Cross-Sectional Content Analysis
Authors: Decker Paulina M. , Ezaldein Harib H.
Published: October 2024

Hidradenitis suppurativa (HS) is a chronic condition characterized by painful, inflamed lumps under the skin in intertriginous areas. While social media platforms like TikTok are increasingly raising public awareness about HS, the quality of the information presented remains challenging to assess. Our study aims to analyze the top one hundred TikTok videos focusing on HS clinical information, treatment options, and patient experiences from 2020 to 2024. We evaluate user engagement data, content characteristics, and assess the quality of health information using a validated DISCERN score. Overall, our study suggests that while TikTok serves as a valuable resource for raising awareness and accessing new information about HS, content from healthcare professionals and scientific research garners higher user engagement and contributes to greater awareness of HS.
Whole-genome sequencing reveals contribution of rare and common variation to structural kidney and urinary tract malformations
Authors: Chan Melanie MY , Sadeghi-Alavijeh Omid , Voinescu Catalin D , van der Zanden Loes FM , Groen in ’t Woud Sander , Schreuder Michiel F , Feitz Wout , Mingardo Enrico , Hilger Alina C , Reutter Heiko , Vendrig Lisanne M , Westland Rik , Stanescu Horia C , Levine Adam P , Böckenhauer Detlef , Gale Daniel P
Published: October 2024

Congenital anomalies of the kidneys and urinary tract (CAKUT) are the commonest cause of kidney failure in children and young adults with over 50 monogenic causes identified, largely in cohorts enriched for familial, syndromic, or consanguineous disease. We sought to better characterise the genomic architecture of these conditions using whole genome sequencing data from 992 unrelated individuals recruited to the UK’s 100,000 Genomes Project. The overall diagnostic yield was 4.3% with family history (P=7.4×10−3; OR 2.7; 95% CI 1.3-5.4) and extra-renal features (P=2.0×10−4; OR 3.4; 95% CI 1.8-6.6) independently predicting a monogenic diagnosis. Diagnostic yield was highest in cystic kidney dysplasia (10.7%) and kidney agenesis/hypodysplasia (5.9%). Exome-wide rare variant and genome-wide common variant (minor allele frequency ≥ 0.1%) testing was performed in a subset of 813 patients and 25,205 ancestry-matched controls with significant association detected at rs117473527 (P=3.93×10−8; OR 3.17; 95% CI 2.10-4.78; MAF 0.02). Heritability analysis estimated common variants explain 23% (standard error 11%) of phenotypic variance in those with European ancestry. Comparison of phenotype-specific genomic risk scores (GRS) demonstrated shared polygenic aetiology between upper urinary tract phenotypes but distinct patterns for both posterior urethral valves (PUV) and bladder exstrophy. A PUV-GRS consisting of 36,106 variants was validated in an independent European cohort of 77 cases and 2,746 controls (P=1×10−4) accounting for 37% of phenotypic variance. Together, these data demonstrate the importance of non-Mendelian genomic factors in the pathogenesis of CAKUT, evidenced by the fact that only a minority of patients in this large, unselected cohort received a monogenic diagnosis and that a substantial proportion of heritability can be attributed to common variation.

Lay Summary

This study looks at the DNA of patients with congenital anomalies of the kidneys and urinary tract (CAKUT), the most common cause of kidney failure in children. It finds that single gene (monogenic) causes are uncommon, and that genetic testing is more likely to find a cause in people with kidneys that have not formed properly (especially those with cysts), those with affected family members or with involvement of other organ systems. The study also supports the idea that many different common DNA changes (polygenic) together contribute to these conditions, particularly in posterior urethral valves, which is the leading cause of kidney failure in boys. Larger studies are needed to better understand the DNA changes and biological processes involved in kidney and urinary tract development and malformations.