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Abstract Background In large asexual populations where beneficial mutations may co-occur and recombination is absent, the fate of beneficial mutations can be significantly affected by competition (i.e., clonal interference). Theoretical models predict that clonal interference (CI) can slow adaptation, alter the distribution of fixed beneficial mutations, and affect disease progression by impacting within-host evolution of pathogens. While phenotypic data support that CI is a significant determinant of adaptive outcome, genetic data are needed to verify the patterns and to inform evolutionary models. We adapted replicate populations of the bacteriophage φX174 under two levels of CaCl2 to create benign and harsh environments. Genomic sequences of multiple individuals from evolved populations were used to detect competing beneficial mutations. Results There were several competing genotypes in most of the populations where CaCl2 was abundant, but no evidence of CI where CaCl2 was scarce, even though rates of adaptation and population sizes among the treatments were similar. The sequence data revealed that observed mutations were limited to a single portion of one gene in the harsh treatment, but spanned a different and larger region of the genome under the benign treatments, suggesting that there were more adaptive solutions to the benign treatment. Conclusion Beneficial mutations with relatively large selection coefficients can be excluded by CI. CI may commonly determine the fate of beneficial mutations in large microbial populations, but its occurrence depends on selective conditions. CI was more frequent in benign selective conditions possibly due to a greater number of adaptive targets under this treatment. Additionally, the genomic sequence data showed that selection can target different types and numbers of phenotypes in environments that differ by only a single continuous variable.

Abstract Background Within-host competition between strains of a vector-borne pathogen can affect strain frequencies in both the host and vector, thereby affecting viral population dynamics. However little is known about inter-strain competition in one of the most genetically diverse and epidemiologically important mosquito-borne RNA virus: dengue virus (DENV). To assess the strength and symmetry of intra-host competition among different strains of DENV, the effect of mixed infection of two DENV serotypes, DENV2 and DENV4, on the replication of each in cultured mosquito cells was tested. The number of infectious particles produced by each DENV strain in mixed infections was compared to that in single infections to determine whether replication of each strain was decreased in the presence of the other strain (i.e., competition). The two DENV strains were added to cells either simultaneously (coinfection) or with a 1 or 6-hour time lag between first and second serotype (superinfection). Results DENV2 and DENV4 showed significantly reduced replication in mixed infection relative to single infection treatments. In superinfection treatments, replication was suppressed to a greater extent when the interval between addition of each strain was longer, and when a strain was added second. Additionally, competitive effects were asymmetric: although both strains replicated to similar peak population sizes in single infections, DENV2 was more suppressed than DENV4 in mixed infections. Superinfection treatments yielded significantly lower combined virus titers than coinfection or single infection treatments. Conclusion Competition between DENV strains in cultured mosquito cells can cause a significant decrease in peak viral population sizes, which could translate to decreased transmission by the vector. Effects of competition were asymmetric between DENV2 and DENV4, probably reflecting significant variation in the competitive ability of DENV strains in nature. Competition was strongest in superinfection treatments, suggesting that colonization of new DENV strains could be impeded in areas where numerous mosquitoes are infected with endemic DENV strains.

Discusses strategies used to analyze the content of human Chromosome 7 for the International Human Genome Project. Significance of identifying the parts of the genome; Description of the clone-based hierarchical shotgun strategy; Use of the fluorescence-based DNA sequencing instruments in the analysis.

Study Objective: Use machine learning to characterize the content of endometriosis online community posts and comments., Design: Retrospective Descriptive Study., Setting: Endometriosis online health communities (OHCs) on the platform Reddit., Participants: Users of the endometriosis OHCs r/Endo and r/endometriosis., Interventions: Machine learning was used to analyze thousands of posts made to endometriosis OHCs. Content of posts and comments was interpreted using topic modeling, persona identification, and intent labeling. Measurements included baseline characteristics of users, posts, and comments to the OHCs. Machine-learning techniques; topic modeling, intent labeling, and persona identification were used to identify the most common topics of conversation, the intents behind the posts, and the subjects of people discussed in posts. System performance was assessed via accuracy at F 1 -score., Results: A total of 34 715 posts and 353 162 comments responding to posts were evaluated. The topics most likely to be a subject of a post were menstruation (8%), sharing symptoms (8%), medical appointments (8%), medical story (9%), and empathy (7%). The majority of posts were written with the intent of seeking information about endometriosis (49%) or seeking the experiences of others with endometriosis (29%). Users expressed a strong preference for surgeons performing excision rather than ablation of endometriosis., Conclusion: Endometriosis OHCs are mostly used to learn about symptoms of endometriosis and share one's medical experiences. Posts and comments from users highlight the need for more empathy in the clinical care of endometriosis and easier access for patients to high-quality information about endometriosis., (Copyright © 2024 AAGL. Published by Elsevier Inc. All rights reserved.)

Gynecological pathologies account for approximately 4.5% of the overall global disease burden. Although cancers of the female reproductive system have understandably been the focus of a great deal of research, benign gynecological conditions-such as endometriosis, polycystic ovary syndrome, and uterine fibroids-have remained stubbornly understudied despite their astonishing ubiquity and grave morbidity. This historical inattention has frequently become manifested in flawed diagnostic and treatment paradigms. Molecular imaging could be instrumental in improving patient care on both fronts. In this Focus on Molecular Imaging review, we will examine recent advances in the use of PET, SPECT, MRI, and fluorescence imaging for the diagnosis and management of benign gynecological conditions, with particular emphasis on recent clinical reports, areas of need, and opportunities for growth., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Study Objective: Although medical, interventional, and surgical treatment options for fibroids have expanded over the last decade, many patients are not thoroughly counseled about all available therapies. Patients desire a more comprehensive approach with shared decision-making tailored to their health goals. The aim of this study is to assess patient knowledge regarding treatment options before and after consultation with a multidisciplinary fibroid center., Design: Prospective survey study., Setting: Academic medical center in New York, NY., Patients and Participants: Patients who presented for initial consultation with a multidisciplinary fibroid program from July 2021 through January 2022., Interventions: Patients were offered same-day office consultation with a minimally invasive gynecologic surgeon (MIGS) followed by a telemedicine visit with an interventional radiologist (IR) within 3 weeks of the appointment request. Collaborative discussions were held between providers regarding patient care. Patients were asked to complete the survey following both appointments. Data was collected regarding demographics, prior evaluation of fibroids, knowledge about treatment options, and overall experience., Results: A total of 102 patients completed the survey (response rate 77%). A majority (55.9%) had known about their fibroids for at least 2 years. Most patients sought out the fibroid program for a 2nd (28.4%), 3rd (22.5%) or 4th (7.8%) opinion. Notably, 35.3% of patients who had previously been seen by an obstetrician-gynecologist (OB/GYN) were not offered any treatment. Of those who had been offered treatment, 24.5% were counseled on medical management with oral contraceptives, 28.4% on surgical options, and 5.9% on uterine artery embolization. Nearly all patients (86.3%) endorsed that they would not have sought 2 separate consultations had it not been for the program. Patients were overall well-informed after their experience, with 95.1% reporting they were more knowledgeable about their options and none reporting the 2 separate consults created more confusion for them., Conclusion: Many patients with symptomatic fibroids seeking secondary opinions have not been adequately counseled on fibroid management options. A collaborative approach to fibroid management better educates patients, provides an opportunity to be thoroughly counseled by the specialists performing either surgical or interventional procedures, and increases patient knowledge about fibroid treatment options., (Copyright © 2024 AAGL. Published by Elsevier Inc. All rights reserved.)

Background/Objectives : Our objective was to evaluate changes in the management of symptomatic fibroids after establishing a multidisciplinary fibroid center with minimally invasive gynecologic surgery (MIGS) and interventional radiology (IR). Methods : A retrospective cohort study was conducted at the fibroid center created in September 2020. Patients were offered same-day consults with both MIGS and IR providers. Data were collected for patients with initial consultations from January to June 2019 (pre-fibroid center) and from January to June 2021 (post-fibroid center). Results : Among 615 patients meeting inclusion criteria, 273 had consultations pre-center and 342 post-center. More patients seen post-center had previously attempted medical management (30.1% vs. 20.2%), with a significant proportion having no prior medical or surgical treatment (53.2% vs. 61.5%). Post-center, there were more MIGS consultations (65.5% vs. 53.1%) and a decrease in general gynecology (GYN) consultations (19.0% vs. 25.6%). More patients sought additional opinions post-center (83.6% vs. 67.0%), particularly with MIGS (58.8% vs. 37.0%). General GYNs referred to MIGS (79.3% vs. 73.1%) and IR specialists (16.0% vs. 13.0%) more often in 2021. In 2021, use of MRI increased (66.5% vs. 52.4%), and more patients underwent uterine artery embolization (UAE) within 1 year of consultation compared to the pre-center period (13.8% vs. 6.9%). Conclusions : Patients with symptomatic fibroids often seek the expertise of specialists to explore treatment options. A multidisciplinary fibroid center that integrates efforts of MIGS and IR enables thorough counseling and a rise in the utilization of minimally invasive procedures, including UAE.

Gastrointestinal nematode (GIN) infections are a major concern for the ruminant industry worldwide and result in significant production losses. Naturally occurring polyparasitism and increasing drug resistance that potentiate disease outcomes are observed among the most prevalent GINs of veterinary importance. Within the five major taxonomic clades, clade Va represents a group of GINs that predominantly affect the abomasum or small intestine of ruminants. However, the development of effective broad-spectrum anthelmintics against ruminant clade Va GINs has been challenged by a lack of comprehensive druggable genome resources. Here, we first assembled draft genomes for three clade Va species ( Cooperia oncophora , Trichostrongylus colubriformis , and Ostertagia ostertagi ) and compared them with closely related ruminant GINs. Genome-wide phylogenetic reconstruction showed a relationship among ruminant GINs structured by taxonomic classification. Orthogroup (OG) inference and functional enrichment analyses identified 220 clade Va-specific and Va-conserved OGs, enriched for functions related to cell cycle and cellular senescence. Further transcriptomic analysis identified 61 taxonomically and functionally conserved clade Va OGs that may function as drug targets for new broad-spectrum anthelmintics. Chemogenomic screening identified 11 compounds targeting homologs of these OGs, thus having potential anthelmintic activity. In in vitro phenotypic assays, three kinase inhibitors (digitoxigenin, K-252a, and staurosporine) exhibited broad-spectrum anthelmintic activities against clade Va GINs by obstructing the motility of exsheathed L3 (xL3) or molting of xL3 to L4. These results demonstrate valuable applications of the new ruminant GIN genomes in gaining better insights into their life cycles and offer a contemporary approach to discovering the next generation of anthelmintics.IMPORTANCEGastrointestinal nematode (GIN) infections in ruminants are caused by parasites that inhibit normal function in the digestive tract of cattle, sheep, and goats, thereby causing morbidity and mortality. Coinfection and increasing drug resistance to current therapeutic agents will continue to worsen disease outcomes and impose significant production losses on domestic livestock producers worldwide. In combination with ongoing therapeutic efforts, advancing the discovery of new drugs with novel modes of action is critical for better controlling GIN infections. The significance of this study is in assembling and characterizing new GIN genomes of Cooperia oncophora , Ostertagia ostertagi, and Trichostrongylus colubriformis for facilitating a multi-omics approach to identify novel, biologically conserved drug targets for five major GINs of veterinary importance. With this information, we were then able to demonstrate the potential of commercially available compounds as new anthelmintics., Competing Interests: The authors declare no conflict of interest.

Background: Spinal metastases are a significant cause of morbidity in patients with advanced cancer, and management often requires surgical intervention. Although prior studies have identified factors that influence outcomes with surgery, the ability of these factors to predict outcomes remains unclear in the era of contemporary therapies, and there is a need to better identify patients who are likely to benefit from surgery., Methods: We performed a single-center, retrospective analysis to evaluate risk factors for poor outcomes in patients with spinal metastases treated with surgery. The primary outcome was mortality at 180 days., Results: A total of 128 patients were identified. Age ≥ 65 years at surgery ( p = 0.0316), presence of extraspinal metastases ( p = 0.0110), and ECOG performance scores >1 ( p = 0.0397) were associated with mortality at 180 days on multivariate analysis. These factors and BMI ≤ 30 mg/kg 2 ( p = 0.0008) were also associated with worse overall survival., Conclusions: Age > 65, extraspinal metastases, and performance status scores >1 are factors associated with mortality at 180 days in patients with spinal metastases treated with surgery. Patients with these factors and BMI ≤ 30 mg/kg 2 had worse overall survival. Our results support multidisciplinary discussions regarding the benefits and risks associated with surgery in patients with these risk factors.

Non-alcoholic fatty liver disease (NAFLD) is the liver manifestation of the metabolic syndrome with global prevalence reaching epidemic levels. Despite the high disease burden in the population only a small proportion of those with NAFLD will develop progressive liver disease, for which there is currently no approved pharmacotherapy. Identifying those who are at risk of progressive NAFLD currently requires a liver biopsy which is problematic. Firstly, liver biopsy is invasive and therefore not appropriate for use in a condition like NAFLD that affects a large proportion of the population. Secondly, biopsy is limited by sampling and observer dependent variability which can lead to misclassification of disease severity. Non-invasive biomarkers are therefore needed to replace liver biopsy in the assessment of NAFLD. Our study addresses this unmet need. The LITMUS Imaging Study is a prospectively recruited multi-centre cohort study evaluating magnetic resonance imaging and elastography, and ultrasound elastography against liver histology as the reference standard. Imaging biomarkers and biopsy are acquired within a 100-day window. The study employs standardised processes for imaging data collection and analysis as well as a real time central monitoring and quality control process for all the data submitted for analysis. It is anticipated that the high-quality data generated from this study will underpin changes in clinical practice for the benefit of people with NAFLD. Study Registration: clinicaltrials.gov: NCT05479721., Competing Interests: Declaration of Competing Interest FEM, SA, KW, JC, MA, EMG, SF, MRG, JC, IFL, RA, RSG, JMP, JB, VR, MW, SP, MA, RF, LM, ET, ME, PL, ATH, GP, HYJ, KP and PMB declare no conflicts of interest. MP is a shareholder in Perspectum Ltd. EMT is a shareholder in Perspectum Ltd. SA is currently employed by Boehringer Ingelheim (but was not during his participation in the project). GPA has served as a consultant and an advisory board member for Pfizer Inc., Inventiva Pharma, GlaxoSmithKline and KaNDy Therapeutics; he has been a consultant to BerGenBio ASA, Median Technologies, FRACTYL, Amryt Pharmaceuticals and AstraZeneca; and has given presentations on behalf of Roche Diagnostics and Medscape all through the University of Nottingham contract. CA declares the following potential conflicts of interest: Hologic: Support of study and expert; Guerbet: Member of board, PI of study; Siemens: Expert. EB has served as a consultant or advisory board member for Boehringer Ingelheim, Gilead Sciences, Intercept, Merck, Novo Nordisk, Pfizer, ProSciento; and a speaker for Gilead Sciences, Intercept, Merck, Novo Nordisk, Pfizer. She has also received a research grant from Gilead Sciences for fatty liver research. AG served as a speaker and consultant for AbbVie, Alexion, AstraZeneca, Bayer, BMS, CSL Behring, Eisai, Falk, Gilead, Heel, Intercept, Ipsen, Merz, MSD, Novartis, Pfizer, Roche, Sanofi-Aventis, Sequana; received research funding from Intercept, Falk, Novartis. JMS reports consultancy for BMS, Boehringer Ingelheim, Echosens, Genfit, Gilead Sciences, Intercept Pharmaceuticals, Madrigal, Novartis, Pfizer, Roche, Sanofi; received research funding from Gilead Sciences and was on the speaker's bureau for Falk Foundation MSD Sharp & Dohme GmbH. MJS and PH are employed by Antaros Medical AB, Mölndal, Sweden. ES is employed by Perspectum Ltd., Oxford, UK. RB is a shareholder and employed (CEO) by Perspectum Ltd., Oxford, UK. KP and MK are employed by Resoundant Inc., Rochester, MN, USA. RLE and the Mayo Clinic have intellectual property rights and a financial interest in magnetic resonance elastography technology. AT is employed by ADVANZPHARMA, Capital House, 1st Floor, 85 King William Street, London, EC4N 7BL, United Kingdom. HC is employed by Boehringer Ingelheim Pharma GmbH & Co. MM is employed by Novartis AG, Basel, Switzerland. CY is employed by Pfizer Inc., Lake Mary, FL, USA. TT was employed by Pfizer at the time of her involvement with the project. QMA is coordinator of the EU IMI-2 LITMUS consortium, which is funded by the EU Horizon 2020 programme and EFPIA. This multistakeholder consortium includes industry partners. QMA has received research grant funding from AstraZeneca, Boehringer Ingelheim, and Intercept Pharmaceuticals, Inc.; has served as a consultant on behalf of Newcastle University for Alimentiv, Akero, AstraZeneca, Axcella, 89bio, Boehringer Ingelheim, Bristol Myers Squibb, Galmed, Genfit, Genentech, Gilead, GSK, Hanmi, HistoIndex, Intercept Pharmaceuticals, Inc., Inventiva, Ionis, IQVIA, Janssen, Madrigal, Medpace, Merck, NGM Bio, Novartis, Novo Nordisk, PathAI, Pfizer, Poxel, Resolution Therapeutics, Roche, Ridgeline Therapeutics, RTI, Shionogi, and Terns; has served as a speaker for Fishawack, Integritas Communications, Kenes, Novo Nordisk, Madrigal, Medscape, and Springer Healthcare; and receives royalties from Elsevier Ltd. SN is a shareholder in Perspectum Ltd. SAH has research grants from Akero, Altimmune, Axcella-Cirius, CiVi Biopharma, Cymabay, Galectin, Genfit, Gilead Sciences, Hepion Pharmaceuticals, Hightide Therapeutics, Intercept, Madrigal, Metacrine, NGM Bio, Northsea Therapeutics, Novartis, Novo Nordisk, Poxel, Sagimet, Viking. He has received consulting fees from Akero, Altimmune, Alentis, Arrowhead, Axcella, Echosens, Enyo, Foresite Labs, Galectin, Genfit, Gilead Sciences, Hepion, HIghtide, HistoIndex, Intercept, Kowa, Madrigal, Metacrine, NeuroBo, NGM, Northsea, Novartis, Novo Nordisk, Poxel, Perspectum, Sagimet, Terns, and Viking., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background There is a need for reliable noninvasive methods for diagnosing and monitoring nonalcoholic fatty liver disease (NAFLD). Thus, the multidisciplinary Non-invasive Biomarkers of Metabolic Liver disease (NIMBLE) consortium was formed to identify and advance the regulatory qualification of NAFLD imaging biomarkers. Purpose To determine the different-day same-scanner repeatability coefficient of liver MRI biomarkers in patients with NAFLD at risk for steatohepatitis. Materials and Methods NIMBLE 1.2 is a prospective, observational, single-center short-term cross-sectional study (October 2021 to June 2022) in adults with NAFLD across a spectrum of low, intermediate, and high likelihood of advanced fibrosis as determined according to the fibrosis based on four factors (FIB-4) index. Participants underwent up to seven MRI examinations across two visits less than or equal to 7 days apart. Standardized imaging protocols were implemented with six MRI scanners from three vendors at both 1.5 T and 3 T, with central analysis of the data performed by an independent reading center (University of California, San Diego). Trained analysts, who were blinded to clinical data, measured the MRI proton density fat fraction (PDFF), liver stiffness at MR elastography (MRE), and visceral adipose tissue (VAT) for each participant. Point estimates and CIs were calculated using χ 2 distribution and statistical modeling for pooled repeatability measures. Results A total of 17 participants (mean age, 58 years ± 8.5 [SD]; 10 female) were included, of which seven (41.2%), six (35.3%), and four (23.5%) participants had a low, intermediate, or high likelihood of advanced fibrosis, respectively. The different-day same-scanner mean measurements were 13%-14% for PDFF, 6.6 L for VAT, and 3.15 kPa for two-dimensional MRE stiffness. The different-day same-scanner repeatability coefficients were 0.22 L (95% CI: 0.17, 0.29) for VAT, 0.75 kPa (95% CI: 0.6, 0.99) for MRE stiffness, 1.19% (95% CI: 0.96, 1.61) for MRI PDFF using magnitude reconstruction, 1.56% (95% CI: 1.26, 2.07) for MRI PDFF using complex reconstruction, and 19.7% (95% CI: 15.8, 26.2) for three-dimensional MRE shear modulus. Conclusion This preliminary study suggests that thresholds of 1.2%-1.6%, 0.22 L, and 0.75 kPa for MRI PDFF, VAT, and MRE, respectively, should be used to discern measurement error from real change in patients with NAFLD. ClinicalTrials.gov registration no. NCT05081427 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Kozaka and Matsui in this issue.

Purpose: To review cases of uterine rupture and identify risk factors associated with adverse outcomes., Methods: This study is a retrospective cohort of complete uterine ruptures diagnosed in a large hospital system in Massachusetts between 2004 and 2018. Baseline demographics, labor characteristics and outcomes of uterine rupture were collected from medical records., Results: A total of 173 cases of uterine rupture were identified. There were 30 (17.3%) women with an unscarred uterus, while 142 (82.1%) had a scarred uterus. Adverse outcomes (n = 89, 51.4% of cases) included 26 (15.0%) hysterectomies, 55 (31.8%) blood transfusions, 18 (10.4%) bladder/ureteral injuries, 5 (2.9%) reoperations, 25 (14.5%) Apgar scores lower than 5 at 5 min and 9 (5.2%) perinatal deaths. Uterine rupture of a scarred uterus was associated with decreased risk of hemorrhage (OR 0.40, 95% CI 0.17-0.93), blood transfusion (OR 0.27, 95% CI 0.11-0.69), hysterectomy (OR 0.23, 95% CI 0.08-0.69) and any adverse outcome (OR 0.34, 95% CI 0.13-0.91) compared with unscarred rupture. Uterine rupture during vaginal delivery was associated with increased risk of transfusion (OR 6.55, 95% CI 1.53-28.05) and hysterectomy (OR 8.95, 95% CI 2.12-37.72) compared with emergent C-section., Conclusions: Although rare, uterine rupture is associated with adverse outcomes in over half of cases. Unscarred rupture and vaginal delivery demonstrate increased risk of adverse outcomes, highlighting the need for early diagnosis and operative intervention., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)