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Introduction: High-grade serous ovarian cancer (HGSOC) is driven by loss of TP53 and genome instability . Despite the recent success of PARP inhibitors, advanced BRCA mutant and homologous recombination repair deficient (HRD) HGSOC, chemotherapy remains the first line treatment. Little is known about how chemotherapy exposure alters tumor heterogeneity and subsequent response to targeted therapies. Certain mutations may survive the exposure of chemotherapy better than others. The question of whether targeted therapies should be given before or after response to chemotherapy also remains unanswered. We use the principles of natural selection to investigate how HGSOC evolves over time and selection operates on clones in the context of cytotoxic/non-cytotoxic combination therapies, and what changes in genomes/transcriptomes at the single cell level drive tumor progression. Methods: Cell lines ID8 Trp53 −/−; Brca1 −/− and WT were used to represent defective/proficient homologous recombination were given intraperitoneally to C57B6 mice to develop HGSOC models. Transfected Luciferase expression in the cells used to monitor tumor response to olaparib (Ola)+/- Bevacizumab (BEV-various doses) +/- Atezolizumab (ATz) combinations by bioluminescence imaging (BLI). Ascitic fluid and mouse organs were harvested for the evidence of seeding and identification of biomarkers. In addition, 10 treatment naïve HGSOC PDX were developed in immunodeficient mice and treated with either cisplatin or olaparib. Single-cell whole-genome sequencing (scWGS) was performed using direct library preparation (DLP+). Hierarchical clustering and Sitka are used to identify the clonal structure of each condition following treatment. Phylogenetic tree was computed using copy number data. Results: In the BRCA WT HRp study group, the greatest response was seen in the triplet Ola+BEV+ATz combinations and interestingly no significant differences were observed using a lower dose of BEV. Furthermore, from scWGS data of PDX passages we captured initial clonal heterogeneity leading to emergent clones. We found evolving copy number changes on chromosome 19, 8, 3 and loss of heterozygosity of TP53. Conclusion: The triplet combination of low-dose-intensity bevacizumab with other non-cytotoxic drugs was an effective regimen for BRCA WT syngeneic mouse tumors. In HGSOC PDX, we are able to capture diversification between HGSOC PDX passages-specifically after drug exposures. Citation Format: Farhia Kabeer, Goldman Lam, Naila Adam, Maxwell Douglas, Amal El-Naggar, Forouh Kalantari, Mengke Han, Vinci Au, Michael Van Vliet, Cindy Shen, Sean Beaty, Daniel Lai, Andy Mungall, Richard Moore, Sam Aparicio, Andrew Roth, David Huntsman, Yvette Drew. The evolution of high grade serous ovarian cancer under the pressure of non-cytotoxic and cytotoxic treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2182.

How cell-to-cell copy number alterations that underpin genomic instability

Introduction Partial thickness burns not undergoing surgical excision are treated with topical silver products including silver sulfadiazine (SSD) and Mepilex Ag. Skin allograft is a more costly alternative that acts as definitive wound coverage until autogenous epithelialization. Economic constraints and the movement toward value-based care demand cost and outcome justification prior to adopting more costly products. Methods A cost-utility analysis was performed comparing skin allograft to SSD and Mepilex Ag using decision tree analysis. The base case modeled a superficial partial thickness 20% total body surface area burn. Utilities were derived from expert opinion on the basis of personal experience. Costs were derived from 2019 Medicare payments. Quality adjusted life years were calculated using rollback method assuming standard life expectancies in the United States. Probabilistic sensitivity analysis was performed to asses model robustness. Results The incremental costs of skin allograft to Mepilex Ag and SSD were $907.71 and $1257.86, respectively. The incremental quality adjusted life year (QALY) gains from allograft over Mepilex Ag and SSD were 0.011 and 0.016. This yielded an incremental cost-utility ratio for allograft vs. Mepilex Ag of $84,189.29/QALY compared with an incremental cost-utility ratio of $79,684.63/QALY for allograft vs. SSD. Assuming willingness-to-pay thresholds of $100,000/QALY, probabilistic sensitivity analysis demonstrated that allograft was cost effective to Mepilex Ag in 62.1% of scenarios, and cost effective to SSD in 64.9% of simulations. Conclusion Skin allograft showed greater QALYs compared with topical silver dressings at a higher cost. Depending on willingness-to-pay thresholds, skin allograft may be a considered a cost-effective treatment of partial-thickness burns.

Motivation Developing a robust and performant data analysis workflow that integrates all necessary components whilst still being able to scale over multiple compute nodes is a challenging task. We introduce a generic method based on the microservice architecture, where software tools are encapsulated as Docker containers that can be connected into scientific workflows and executed using the Kubernetes container orchestrator. Results We developed a Virtual Research Environment (VRE) which facilitates rapid integration of new tools and developing scalable and interoperable workflows for performing metabolomics data analysis. The environment can be launched on-demand on cloud resources and desktop computers. IT-expertise requirements on the user side are kept to a minimum, and workflows can be re-used effortlessly by any novice user. We validate our method in the field of metabolomics on two mass spectrometry, one nuclear magnetic resonance spectroscopy and one fluxomics study. We showed that the method scales dynamically with increasing availability of computational resources. We demonstrated that the method facilitates interoperability using integration of the major software suites resulting in a turn-key workflow encompassing all steps for mass-spectrometry-based metabolomics including preprocessing, statistics and identification. Microservices is a generic methodology that can serve any scientific discipline and opens up for new types of large-scale integrative science. Availability and implementation The PhenoMeNal consortium maintains a web portal (https://portal.phenomenal-h2020.eu) providing a GUI for launching the Virtual Research Environment. The GitHub repository https://github.com/phnmnl/ hosts the source code of all projects. Supplementary information Supplementary data are available at Bioinformatics online.

International audience; Background Metabolomics is the comprehensive study of a multitude of small molecules to gain insight into an organism's metabolism. The research field is dynamic and expanding with applications across biomedical, biotechnological, and many other applied biological domains. Its computationally intensive nature has driven requirements for open data formats, data repositories, and data analysis tools. However, the rapid progress has resulted in a mosaic of independent, and sometimes incompatible, analysis methods that are difficult to connect into a useful and complete data analysis solution. Findings PhenoMeNal (Phenome and Metabolome aNalysis) is an advanced and complete solution to set up Infrastructure-as-a-Service (IaaS) that brings workflow-oriented, interoperable metabolomics data analysis platforms into the cloud. PhenoMeNal seamlessly integrates a wide array of existing open-source tools that are tested and packaged as Docker containers through the project's continuous integration process and deployed based on a kubernetes orchestration framework. It also provides a number of standardized, automated, and published analysis workflows in the user interfaces Galaxy, Jupyter, Luigi, and Pachyderm. Conclusions PhenoMeNal constitutes a keystone solution in cloud e-infrastructures available for metabolomics. PhenoMeNal is a unique and complete solution for setting up cloud e-infrastructures through easy-to-use web interfaces that can be scaled to any custom public and private cloud environment. By harmonizing and automating software installation and configuration and through ready-to-use scientific workflow user interfaces, PhenoMeNal has succeeded in providing scientists with workflow-driven, reproducible, and shareable metabolomics data analysis platforms that are interfaced through standard data formats, representative datasets, versioned, and have been tested for reproducibility and interoperability. The elastic implementation of PhenoMeNal further allows easy adaptation of the infrastructure to other application areas and omics research domains.

The possible presence of matrix effect is one of the main concerns in liquid chromatography-mass spectrometry (LC-MS)-driven bioanalysis due to its impact on the reliability of the obtained quantitative results. Here we propose an approach to correct for the matrix effect in LC-MS with electrospray ionization using postcolumn infusion of eight internal standards (PCI-IS). We applied this approach to a generic ultraperformance liquid chromatography-time-of-flight (UHPLC-TOF) platform developed for small-molecule profiling with a main focus on drugs. Different urine samples were spiked with 19 drugs with different physicochemical properties and analyzed in order to study matrix effect (in absolute and relative terms). Furthermore, calibration curves for each analyte were constructed and quality control samples at different concentration levels were analyzed to check the applicability of this approach in quantitative analysis. The matrix effect profiles of the PCI-ISs were different: this confirms that the matrix effect is compound-dependent, and therefore the most suitable PCI-IS has to be chosen for each analyte. Chromatograms were reconstructed using analyte and PCI-IS responses, which were used to develop an optimized method which compensates for variation in ionization efficiency. The approach presented here improved the results in terms of matrix effect dramatically. Furthermore, calibration curves of higher quality are obtained, dynamic range is enhanced, and accuracy and precision of QC samples is increased. The use of PCI-ISs is a very promising step toward an analytical platform free of matrix effect, which can make LC-MS analysis even more successful, adding a higher reliability in quantification to its intrinsic high sensitivity and selectivity.

The standard treatment of partial-thickness burns includes topical silver products such as silver sulfadiazine (SSD) cream and enclosed dressings including silver-impregnated foam (Mepilex Ag; Molnlycke Health Care, Gothenburg, Sweden) and silver-laden sheets (Aquacel Ag; ConvaTec, Skillman, NJ). The current state of health care is limited by resources, with an emphasis on evidence-based outcomes and cost-effective treatments. This study includes a decision analysis with an incremental cost-utility ratio comparing enclosed silver dressings with SSD in partial-thickness burn patients with TBSA less than 20%. A comprehensive literature review was conducted to identify clinically relevant health states in partial-thickness burn patients. These health states include successful healing, infection, and noninfected delayed healing requiring either surgery or conservative management. The probabilities of these health states were combined with Medicare CPT reimbursement codes (cost) and patient-derived utilities to fit into the decision model. Utilities were obtained using a visual analog scale during patient interviews. Expected cost and quality-adjusted life years (QALYs) were calculated using the roll-back method. The incremental cost-utility ratio for enclosed silver dressing relative to SSD was $40,167.99/QALY. One-way sensitivity analysis of complication rates confirmed robustness of the model. Assuming a maximum willingness to pay $50,000/QALY, the complication rate for SSD must be 22% or higher for enclosed silver dressing to be cost effective. By varying complication rates for SSD and enclosed silver dressings, the two-way sensitivity analysis demonstrated the cost effectiveness of using enclosed silver dressing at the majority of complication rates for both treatment modalities. Enclosed silver dressings are a cost-effective means of treating partial thickness burns.

Damage control surgery and resuscitation is the concept of abbreviating interventions in severely injured patients to prevent physiologic exhaustion and optimize outcome. The concept has been expanded from the operative technique to principles underlying the logistical flow of a trauma patient from the scene through the emergency department to the operating room then ICU for resuscitation, and back to the OR for definitive repair. Patients with multiple cavity injuries, blast injuries, burns, traumatic brain injuries, and crush injury are especially challenging. To implement damage control and salvage a severely injured patient, the team—EMS, emergency department personnel, surgeons, and ICU staff—must recognize patients that benefit from damage control and effectively communicate to ensure smooth transitions through the hospital system while providing quality care in each setting.

Metabolomics has become a crucial phenotyping technique in a range of research fields including medicine, the life sciences, biotechnology and the environmental sciences. This necessitates the transfer of experimental information between research groups, as well as potentially to publishers and funders. After the initial efforts of the metabolomics standards initiative, minimum reporting standards were proposed which included the concepts for metabolomics databases. Built by the community, standards and infrastructure for metabolomics are still needed to allow storage, exchange, comparison and re-utilization of metabolomics data. The Framework Programme 7 EU Initiative ‘coordination of standards in metabolomics’ (COSMOS) is developing a robust data infrastructure and exchange standards for metabolomics data and metadata. This is to support workflows for a broad range of metabolomics applications within the European metabolomics community and the wider metabolomics and biomedical communities’ participation. Here we announce our concepts and efforts asking for re-engagement of the metabolomics community, academics and industry, journal publishers, software and hardware vendors, as well as those interested in standardisation worldwide (addressing missing metabolomics ontologies, complex-metadata capturing and XML based open source data exchange format), to join and work towards updating and implementing metabolomics standards.

There are various treatment modalities for acne vulgaris including topical and oral therapy as well as microdermabrasion and chemical peels. Recently, there has been an emergence of novel laser and light sources as a means for treating acne vulgaris. This article will review the advances of laser and light sources in the treatment of acne vulgaris.

International audience; Metabolomics has become a crucial phenotyping technique in a range of research fields including medicine, the life sciences, biotechnology and the environmental sciences. This necessitates the transfer of experimental information between research groups, as well as potentially to publishers and funders. After the initial efforts of the metabolomics standards initiative, minimum reporting standards were proposed which included the concepts for metabolomics databases. Built by the community, standards and infrastructure for metabolomics are still needed to allow storage, exchange, comparison and re-utilization of metabolomics data. The Framework Programme 7 EU Initiative ‘coordination of standards in metabolomics’ (COSMOS) is developing a robust data infrastructure and exchange standards for metabolomics data and metadata. This is to support workflows for a broad range of metabolomics applications within the European metabolomics community and the wider metabolomics and biomedical communities’ participation. Here we announce our concepts and efforts asking for re-engagement of the metabolomics community, academics and industry, journal publishers, software and hardware vendors, as well as those interested in standardisation worldwide (addressing missing metabolomics ontologies, complex-metadata capturing and XML based open source data exchange format), to join and work towards updating and implementing metabolomics standards.

Autologous split-thickness skin grafting has been proven to provide the best cosmetic and functional outcome after cutaneous burn injuries and thus is the standard of care. Clinical observations have shown that female burn patients frequently have greater difficulty choosing a donor site than do male burn patients. However, there is a lack of data characterizing donor-site preferences among women with burns. The purpose of this study was to examine donor-site preferences among women using an online survey that included 356 responders between January 4, 2012, and April 4, 2012. This study found that there was a preference for posterior donor sites, with lower back, left buttock, and left posterior thigh being the most preferred sites. The least preferred locations were the right anterior upper arm, any aspect of the forearms, and the chest. Those surveyed and reporting a higher education level or concerns with scarring were least likely to choose anterior locations. Age, concern for color changes, and prior surgery or grafting had no statistically significant effect on donor-site preference. Given these strong preferences among female patients, posterior donor sites should be considered and discussed as compared with the current standard of using lateral or anterior thigh donor sites.

A discussion of the ethics of performing anti-aging interventions for older patients. Virtual Mentor is a monthly bioethics journal published by the American Medical Association.

Laser-assisted indocyanine green angiography is a U.S. Food and Drug Administration-approved technology used to assess tissue viability and perfusion. Its use in plastic and reconstructive surgery to assess flap perfusion in autologous breast reconstruction is relatively new. There have been no previous studies evaluating the cost-effectiveness of this new technology compared with the current practice of clinical judgment in evaluating tissue perfusion and viability in free autologous breast reconstruction in patients who have undergone mastectomy.A comprehensive literature review was performed to identify the complication rate of the most common complications with and without laser-assisted indocyanine green angiography in free autologous breast reconstruction after mastectomy. These probabilities were combined with Medicare Current Procedural Terminology provider reimbursement codes (cost) and utility estimates for common complications from a survey of 10 plastic surgeons to fit into a decision model to evaluate the cost-effectiveness of laser-assisted indocyanine green angiography.The decision model revealed a baseline cost difference of $773.66 and a 0.22 difference in the quality-adjusted life-years, yielding an incremental cost-utility ratio of $3516.64 per quality-adjusted life year favoring laser-assisted indocyanine green angiography. Sensitivity analysis showed that using laser-assisted indocyanine green angiography was more cost-effective when the complication rate without using laser-assisted indocyanine green angiography (clinical judgment alone) was 4 percent or higher.The authors' study demonstrates that laser-assisted indocyanine green angiography is a cost-effective technology under the most stringent acceptable thresholds when used in immediate free autologous breast reconstruction.

The use of acellular dermal matrix has allowed for single-stage immediate breast reconstruction after mastectomy at a significantly decreased cost compared with two-stage expander/implant reconstruction. The use of a pedicled autologous dermal flap in the same fashion as acellular dermal matrix in women with larger, ptotic breasts has also allowed for single-stage immediate breast reconstruction with similarly low complication rates and without the added procedural cost of using acellular dermal matrix. There have been no prior studies evaluating whether the added procedural cost for acellular dermal matrix is cost-effective relative to using an autologous dermal flap in single-stage immediate breast reconstruction following mastectomy.A comprehensive literature review was conducted to identify published complication rates for single-stage, implant-based immediate breast reconstruction using either acellular dermal matrix or an autologous dermal flap. The probabilities of the most common complications were combined with Medicare Current Procedural Terminology reimbursement codes and expert utility estimates to fit into a decision model to evaluate the cost-effectiveness of acellular dermal matrix.: The decision model revealed a baseline cost difference of $261.72 and a 0.001 increase in the quality-adjusted life years when using acellular dermal matrix, yielding an incremental cost-utility ratio of $261,720 per quality-adjusted life year. Sensitivity analysis showed that acellular dermal matrix was not cost-effective when the complication rate for autologous dermal flaps was below 20 percent.The authors' study demonstrates that acellular dermal matrix is not a cost-effective technology in patients who can have an autologous dermal flap in single-stage immediate breast reconstruction.

BACKGROUND The authors assessed the diagnostic potential of commonly used patient-reported measures, namely, the Boston Carpal Tunnel Questionnaire (function and symptom severity), QuickDASH (a shortened version of the Disabilities of the Arm, Shoulder and Hand questionnaire), and the Short Form-8. METHODS Measure scores were extracted retrospectively from the records of 262 patients (397 hands) and compared using analysis of variance to determine statistical differences among diagnoses assigned by the same surgeon at the time of visit. Patients were grouped into one of two diagnostic groups: those with Dupuytren disease and those with carpal tunnel, osteoarthritis, and tenosynovitis conditions. Logistic regression analysis was performed, and a receiver operating characteristic curve was used in data analysis. RESULTS Analysis of variance showed statistical differences among the five diagnoses for each patient-reported measure. Results showed that Dupuytren disease was significantly different from the other diagnoses. Carpal tunnel, osteoarthritis, and tenosynovitis conditions were statistically associated with higher Boston Carpal Tunnel Questionnaire function and symptom severity and QuickDASH scores compared with Dupuytren disease. Lower physical and mental summary Short Form-8 scores were associated with the carpal tunnel, osteoarthritis, and tenosynovitis conditions. QuickDASH scores of 25 or higher and Boston Carpal Tunnel Questionnaire symptom severity scores and function scores of 2.5 or higher and of 2 or higher, respectively, are the best patient-reported measure threshold values for distinguishing between the two diagnostic groups. CONCLUSIONS The QuickDASH and Boston Carpal Tunnel Questionnaire patient-reported measures have diagnostic potential. Establishing threshold values for predicting a diagnostic group may prove to be a useful tool for referring providers. CLINICAL QUESTION/LEVEL OF EVIDENCE Diagnostic, IV.

Summary: Identification of metabolites using high-resolution multi-stage mass spectrometry (MSn) data is a significant challenge demanding access to all sorts of computational infrastructures. MetiTree is a user-friendly, web application dedicated to organize, process, share, visualize and compare MSn data. It integrates several features to export and visualize complex MSn data, facilitating the exploration and interpretation of metabolomics experiments. A dedicated spectral tree viewer allows the simultaneous presentation of three related types of MSn data, namely, the spectral data, the fragmentation tree and the fragmentation reactions. MetiTree stores the data in an internal database to enable searching for similar fragmentation trees and matching against other MSn data. As such MetiTree contains much functionality that will make the difficult task of identifying unknown metabolites much easier. Availability: MetiTree is accessible at http://www.MetiTree.nl. The source code is available at https://github.com/NetherlandsMetabolomicsCentre/metitree/wiki. Contact: m.rojas@lacdr.leidenuniv.nl or t.reijmers@lacdr.leidenuniv.nl

There are numerous treatments for cellulite including topical, surgical, laser and other therapies. Many of these treatments are expensive. Part of the difficulty in treating cellulite arises from our incomplete understanding of this phenomenon. As noted previously in this journal, there is no consensus as to the etiology of cellulite. This article will focus on both traditional and novel treatments for cellulite and assess their efficacy based on the scientific literature.