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Background/Objectives: Locally advanced and metastatic leiomyosarcoma (LMS) is an aggressive cancer with limited treatment options. This single-institution, retrospective study evaluated the efficacy of first-line chemotherapy regimens in patients with advanced or metastatic LMS treated at Stanford Medical Center. Methods: Seventy-four patients with unresectable or metastatic LMS were deemed eligible and treated with first-line chemotherapy regimens, including gemcitabine plus docetaxel, dacarbazine, doxorubicin combinations (with evofosfamide or ifosfamide), and doxorubicin monotherapy. Progression-free survival (PFS), overall survival (OS), and disease control rate (DCR) were assessed using RECIST v1.1, with survival analyses performed using Kaplan–Meier and Cox proportional hazards methods. Results: The cohort consisted of 56 females (75.7%) and 18 males (24.3%), with a median age of 55.5 years. The majority (93.2%) had metastatic disease. The median PFS for the entire cohort was 4.9 months (range: 0.6–28.1 mo), and the median OS was 27.3 months (range: 1.9–140.2 mo). The doxorubicin combination (DC) group had the highest median PFS of 7.9 months (range: 0.6–15.8 mo). Doxorubicin alone had the highest median OS of 33.8 months (4.2–100.2 mo). Doxorubicin combinations demonstrated superior PFS in both uterine and non-uterine LMS subgroups. Conclusions: These findings reaffirm the efficacy of doxorubicin-based combination regimens as a first-line treatment for locally advanced and metastatic LMS, particularly in non-uterine LMS.

ObjectivesThis study investigated the association between vaccine stockout and immunisation coverage, and infant/under 5 mortality rates.DesignA retrospective cohort study.SettingLow-income and middle-income countries.ParticipantsA cohort of 131 low-income and middle-income countries from 2004 to 2019.Primary outcome measuresMain outcomes included immunisation coverages of (1) diphtheria-tetanus-pertussis containing vaccine (DTP), (2) measles containing vaccine (MCV), (3) BCG and (4) oral polio vaccine (OPV). We also included infant and under 5 mortality rates as secondary outcomes.ResultsThe countries that experienced national-level stockouts of DTP and MCV had 3.7 and 4 percentage points lower coverage rates of DTP3 and MCV1, respectively, compared with the countries without the stockout events (p<0.01). Moreover, the statistically significant differences in the immunisation coverage rates across the countries with and without the stockout events are 2.4 percentage points and 2.6 percentage points for BCG and OPV, respectively (p<0.01).ConclusionOur findings show that the incidence of vaccine stockout events is associated with the decreased immunisation coverages for children in low-income and middle-income countries. However, we did not observe a statistically significant association between the increasing frequency of vaccine stockout and infant and under 5 mortality rates.

The chronic opportunistic multi-drug-resistant pathogen Pseudomonas aeruginosa is persistently infected by temperate phages. We assess the contribution of temperate phage infection to the evolution of the clinically relevant strain UCBPP-PA14. We found that a low level of clustered regularly interspaced short palindromic repeat (CRISPR)-mediated self-targeting resulted in polylysogeny evolution and large genome rearrangements in lysogens; we also found extensive diversification in CRISPR spacers and cas genes. These genomic modifications resulted in decreased spontaneous induction in both exponential and stationary phase growth, increasing lysogen fitness. This work shows the importance of considering latent phage infection in characterizing the evolution of bacterial populations.

ObjectivesTo evaluate the safeguarding impact of government commitment (defined as the proportion of government expenditure relative to total expenditure) to health and immunisation financing in mitigating the disruptions to routine childhood vaccination during the COVID-19 pandemic.DesignA quasi-experimental difference-in-differences study with country fixed effect, leveraging the COVID-19 pandemic as a natural experiment.SettingLow-income and middle-income countries.ParticipantsA cohort of 131 low- and middle-income countries from 2010 to 2023.Primary outcome measuresOur primary outcomes included the coverage rates for the third dose of the diphtheria-tetanus-pertussis containing vaccine (DTP3) and the first dose of the measles containing vaccine (MCV1).ResultsBoth high government commitment countries (ie, above the upper 20th percentile) and low government commitment countries (ie, below the upper 20th percentile) experienced declines in immunisation coverage over the 4 years following the COVID-19 pandemic, with DTP3 and MCV1 decreasing by 4 and 5 percentage points, respectively (p<0.001). However, the differences in these declines between the two groups were not statistically significant during this period.ConclusionGreater government commitment to health and immunisation financing may not be sufficient on its own to mitigate pandemic-related disruptions in routine childhood vaccination.

Pseudomonas aeruginosa is a widespread opportunistic pathogen and a major cause of morbidity and mortality in cystic fibrosis patients. Microbe-virus interactions play a critical role in shaping microbial populations, as viral infections can kill microbial populations or contribute to gene flow among microbes. Investigating how P. aeruginosa uses its CRISPR immune system to evade viral infection aids our understanding of how this organism spreads and evolves alongside its viruses in humans and the environment. Here, we identify patterns of CRISPR targeting and immunity that indicate P. aeruginosa and its viruses evolve in both a broad global population and in isolated human “islands.” These data set the stage for exploring metapopulation dynamics occurring within and between isolated “island” populations associated with CF patients, an essential step to inform future work predicting the specificity and efficacy of virus therapy and the spread of invasive viral elements and pathogenic epidemic bacterial strains. Viruses that infect the widespread opportunistic pathogen Pseudomonas aeruginosa have been shown to influence physiology and critical clinical outcomes in cystic fibrosis (CF) patients. To understand how CRISPR-Cas immune interactions may contribute to the distribution and coevolution of P. aeruginosa and its viruses, we reconstructed CRISPR arrays from a highly sampled longitudinal data set from CF patients attending the Copenhagen Cystic Fibrosis Clinic in Copenhagen, Denmark (R. L. Marvig, L. M. Sommer, S. Molin, and H. K. Johansen, Nat Genet 47:57–64, 2015, https://doi.org/10.1038/ng.3148 ). We show that new spacers are not added to or deleted from CRISPR arrays over time within a single patient but do vary among patients in this data set. We compared assembled CRISPR arrays from this data set to CRISPR arrays extracted from 726 additional publicly available P. aeruginosa sequences to show that local diversity in this population encompasses global diversity and that there is no evidence for population structure associated with location or environment sampled. We compare over 3,000 spacers from our global data set to 98 lytic and temperate viruses and proviruses and find a subset of related temperate virus clusters frequently targeted by CRISPR spacers. Highly targeted viruses are matched by different spacers in different arrays, resulting in a pattern of distributed immunity within the global population. Understanding the multiple immune contexts that P. aeruginosa viruses face can be applied to study of P. aeruginosa gene transfer, the spread of epidemic strains in cystic fibrosis patients, and viral control of P. aeruginosa infection. IMPORTANCE Pseudomonas aeruginosa is a widespread opportunistic pathogen and a major cause of morbidity and mortality in cystic fibrosis patients. Microbe-virus interactions play a critical role in shaping microbial populations, as viral infections can kill microbial populations or contribute to gene flow among microbes. Investigating how P. aeruginosa uses its CRISPR immune system to evade viral infection aids our understanding of how this organism spreads and evolves alongside its viruses in humans and the environment. Here, we identify patterns of CRISPR targeting and immunity that indicate P. aeruginosa and its viruses evolve in both a broad global population and in isolated human “islands.” These data set the stage for exploring metapopulation dynamics occurring within and between isolated “island” populations associated with CF patients, an essential step to inform future work predicting the specificity and efficacy of virus therapy and the spread of invasive viral elements and pathogenic epidemic bacterial strains.

Clinical decision-making is driven by multimodal data, including clinical notes and pathological characteristics. Artificial intelligence approaches that can effectively integrate multimodal data hold significant promise in advancing clinical care 1 , 2 . However, the scarcity of well-annotated multimodal datasets in clinical settings has hindered the development of useful models. In this study, we developed the Multimodal transformer with Unified maSKed modeling (MUSK), a vision–language foundation model designed to leverage large-scale, unlabelled, unpaired image and text data. MUSK was pretrained on 50 million pathology images from 11,577 patients and one billion pathology-related text tokens using unified masked modelling. It was further pretrained on one million pathology image–text pairs to efficiently align the vision and language features. With minimal or no further training, MUSK was tested in a wide range of applications and demonstrated superior performance across 23 patch-level and slide-level benchmarks, including image-to-text and text-to-image retrieval, visual question answering, image classification and molecular biomarker prediction. Furthermore, MUSK showed strong performance in outcome prediction, including melanoma relapse prediction, pan-cancer prognosis prediction and immunotherapy response prediction in lung and gastro-oesophageal cancers. MUSK effectively combined complementary information from pathology images and clinical reports and could potentially improve diagnosis and precision in cancer therapy. Trained on unlabelled, unpaired image and text data, the Multimodal transformer with Unified maSKed modeling excelled in outcome prediction, image-to-text retrieval and visual question answering, potentially improving cancer diagnosis and therapy precision.

Antibiotic resistance is a growing concern for management of common bacterial infections. Here, we show that antibiotics can be effective at subinhibitory levels when bacteria carry latent phage. Our findings suggest that specific treatment strategies based on the identification of latent viruses in individual bacterial strains may be an effective personalized medicine approach to antibiotic stewardship. Most bacteria and archaea are infected by latent viruses that change their physiology and responses to environmental stress. We use a population model of the bacterium-phage relationship to examine the role that latent phage play in the bacterial population over time in response to antibiotic treatment. We demonstrate that the stress induced by antibiotic administration, even if bacteria are resistant to killing by antibiotics, is sufficient to control the infection under certain conditions. This work expands the breadth of understanding of phage-antibiotic synergy to include both temperate and chronic viruses persisting in their latent form in bacterial populations. IMPORTANCE Antibiotic resistance is a growing concern for management of common bacterial infections. Here, we show that antibiotics can be effective at subinhibitory levels when bacteria carry latent phage. Our findings suggest that specific treatment strategies based on the identification of latent viruses in individual bacterial strains may be an effective personalized medicine approach to antibiotic stewardship.

Soft tissue sarcomas (STS) are a rare, complex, heterogeneous group of mesenchymal neoplasms with over 150 different histological subtypes. Treatments for this malignancy have been especially challenging due to the heterogeneity of the disease and the modest efficacy of conventional chemotherapy. The next frontier lies in discerning the molecular pathways in which these mesenchymal neoplasms arise, metastasize, and develop drug-resistance, thereby helping guide new therapeutic targets for the treatment of STS. This comprehensive review will discuss the current understanding of tumorigenesis of specific STS subtypes, including oncogenic pathway alterations involved in cell cycle regulation, angiogenesis, NOTCH signaling, and aberrant genetic rearrangements. It will then review current therapies that have been recently developed to target these pathways, including a review of ongoing clinical studies for targeted sarcoma treatment, as well as discuss new potential avenues for therapies against known molecular pathways of sarcomagenesis.

It has been demonstrated that virtual prototypes can be used productively in usability testing. Virtual prototypes, Augmented Reality (AR) in particular, has received some attention as platforms that support AR such as cell phones and iPads, which combine both the real and virtual worlds, become ubiquitous.Structured AR usability testing in the product development phase enables obtaining early user feedback, allowing companies to focus on UX from the early design phase. Therefore, several studies of usability testing using AR have been conducted, and there have been attempts to perform AR usability testing with remote settings. However, the authentic AR experience has not been provided to the participants due to complicated setup and logistics problems. They revealed many challenges such as different experimental mindsets, communication with participants, a sense of distance from the actual AR experience, and technical issues.This study was aimed to make such a direct comparison between the conventional lab-based (as a control group) usability testing, conventional lab-based AR usability testing, and a remote synchronous AR usability testing method to determine whether typical outcome variables (e.g. performance, satisfaction, accuracy) of usability tests would be affected by the reduced experiment control (e.g. presence of experimenter, user environment). To compare the assessment of the usability for each setup, SUS score, task time/experiment time, and error rate data were collected. Seventy-five usability studies were conducted to evaluate the three respective setups, and it was found that the conventional lab-based usability testing is significantly more efficient and effective, but it also revealed that the SUS scores of all groups were not big enough to be statistically significant.