Tri-State Evaluation of the Effects of the COVID-19 Pandemic on Routine Vaccine Uptake in Iowa, Minnesota, and North Dakota, 2017-2021.

The objective of this analysis was to evaluate and compare the effects of the COVID-19 pandemic on routine and annual influenza vaccination in Iowa, Minnesota, and North Dakota. Routine and annual influenza vaccination uptake and coverage between 2017 and 2021 was collected from each state's immunization information system (IIS) by age group and stratified by provider and vaccine type. Data from 2017 to 2019 were averaged to obtain a pre-pandemic baseline and compared to 2020 and 2021 data. Percent changes were calculated to evaluate differences in uptake and coverage. Changes in coverage and administration varied by state, but each state had some level of decreased administration across the different age groups and vaccine types. The most consistent decreases in vaccine administration occurred in the 15-year-old cohort with each state finding decreased administrations in 2020 and 2021. The 12-year-old age group had decreased administration of hepatitis B, measles, mumps, and rubella, and varicella vaccine while the 2-year-old age group had the most consistent decrease in coverage across all vaccines analyzed. Trends by provider type were also noted in all three states, with local public health (LPH) experiencing the largest and most consistent declines in vaccine administrations by age group. Adult influenza coverage improved to varying degrees in 2020 (+ 14.1% IA, + 2.1% MN, + 1.5% ND), but either decreased or approached the 2017-19 average in 2021. All three states saw some level of decreased vaccine administration across the age groups, vaccines, and provider types assessed. The COVID-19 pandemic affected how many children and adults received recommended immunizations, leaving communities vulnerable to vaccine-preventable diseases.

Benefits and Challenges of Sealing Deceased Individual Immunization Records in Immunization Information Systems (IIS): An Overview of Iowa's Process.

Data cleansing practices aimed to improve data quality in immunization information systems (IIS) continue to be identified and evaluated by immunization programs to generate accurate and reliable immunization coverage rates. The Iowa Immunization Program has implemented several automated, daily data cleansing practices to improve the quality of records in Iowa's Immunization Registry Information System (IRIS), including the process of sealing records of deceased individuals through vital records matching. This process removes deceased individual records from the active IIS population, which helps reduce denominator inflation and improve the accuracy of immunization rate calculations. Other benefits to this process include decreasing record fragmentation, increasing completeness and accuracy of IIS data, improving reminder/recall functionality, and supporting better clinical decision-making for providers. This process is one of multiple practices implemented in IIS to improve data quality and is limited by several factors, including the inability to capture deaths for out-of-state records.

Influenza Vaccinations During the COVID-19 Pandemic - 11 U.S. Jurisdictions, September-December 2020.

Influenza causes considerable morbidity and mortality in the United States. Between 2010 and 2020, an estimated 9-41 million cases resulted in 140,000-710,000 hospitalizations and 12,000-52,000 deaths annually (1). As the United States enters the 2021-22 influenza season, the potential impact of influenza illnesses is of concern given that influenza season will again coincide with the ongoing COVID-19 pandemic, which could further strain overburdened health care systems. The Advisory Committee on Immunization Practices (ACIP) recommends routine annual influenza vaccination for the 2021-22 influenza season for all persons aged ≥6 months who have no contraindications (2). To assess the potential impact of the COVID-19 pandemic on influenza vaccination coverage, the percentage change between administration of at least 1 dose of influenza vaccine during September-December 2020 was compared with the average administered in the corresponding periods in 2018 and 2019. The data analyzed were reported from 11 U.S. jurisdictions with high-performing state immunization information systems.* Overall, influenza vaccine administration was 9.0% higher in 2020 compared with the average in 2018 and 2019, combined. However, in 2020, the number of influenza vaccine doses administered to children aged 6-23 months and children aged 2-4 years, was 13.9% and 11.9% lower, respectively than the average for each age group in 2018 and 2019. Strategic efforts are needed to ensure high influenza vaccination coverage among all age groups, especially children aged 6 months-4 years who are not yet eligible to receive a COVID-19 vaccine. Administration of influenza vaccine and a COVID-19 vaccine among eligible populations is especially important to reduce the potential strain that influenza and COVID-19 cases could place on health care systems already overburdened by COVID-19.

Impact of the COVID-19 Pandemic on Administration of Selected Routine Childhood and Adolescent Vaccinations - 10 U.S. Jurisdictions, March-September 2020.

After the March 2020 declaration of the COVID-19 pandemic in the United States, an analysis of provider ordering data from the federally funded Vaccines for Children program found a substantial decrease in routine pediatric vaccine ordering (1), and data from New York City and Michigan indicated sharp declines in routine childhood vaccine administration in these areas (2,3). In November 2020, CDC interim guidance stated that routine vaccination of children and adolescents should remain an essential preventive service during the COVID-19 pandemic (4,5). To further understand the impact of the pandemic on routine childhood and adolescent vaccination, vaccine administration data during March-September 2020 from 10 U.S. jurisdictions with high-performing* immunization information systems were assessed. Fewer administered doses of routine childhood and adolescent vaccines were recorded in all 10 jurisdictions during March-September 2020 compared with those recorded during the same period in 2018 and 2019. The number of vaccine doses administered substantially declined during March-May 2020, when many jurisdictions enacted stay-at-home orders. After many jurisdictions lifted these orders, the number of vaccine doses administered during June-September 2020 approached prepandemic baseline levels, but did not increase to the level that would have been necessary to catch up children who did not receive routine vaccinations on time. This lag in catch-up vaccination might pose a serious public health threat that would result in vaccine-preventable disease outbreaks, especially in schools that have reopened for in-person learning. During the past few decades, the United States has achieved a substantial reduction in the prevalence of vaccine-preventable diseases driven in large part to the ongoing administration of routinely recommended pediatric vaccines. These efforts need to continue even during the COVID-19 pandemic to reduce the morbidity and mortality from vaccine-preventable diseases. Health care providers should assess the vaccination status of all pediatric patients, including adolescents, and contact those who are behind schedule to ensure that all children are fully vaccinated.

Recovery and analysis of transcriptome subsets from pooled single-cell RNA-seq libraries.

Single-cell RNA sequencing (scRNA-seq) methods generate sparse gene expression profiles for thousands of single cells in a single experiment. The information in these profiles is sufficient to classify cell types by distinct expression patterns but the high complexity of scRNA-seq libraries often prevents full characterization of transcriptomes from individual cells. To extract more focused gene expression information from scRNA-seq libraries, we developed a strategy to physically recover the DNA molecules comprising transcriptome subsets, enabling deeper interrogation of the isolated molecules by another round of DNA sequencing. We applied the method in cell-centric and gene-centric modes to isolate cDNA fragments from scRNA-seq libraries. First, we resampled the transcriptomes of rare, single megakaryocytes from a complex mixture of lymphocytes and analyzed them in a second round of DNA sequencing, yielding up to 20-fold greater sequencing depth per cell and increasing the number of genes detected per cell from a median of 1313 to 2002. We similarly isolated mRNAs from targeted T cells to improve the reconstruction of their VDJ-rearranged immune receptor mRNAs. Second, we isolated CD3D mRNA fragments expressed across cells in a scRNA-seq library prepared from a clonal T cell line, increasing the number of cells with detected CD3D expression from 59.7% to 100%. Transcriptome resampling is a general approach to recover targeted gene expression information from single-cell RNA sequencing libraries that enhances the utility of these costly experiments, and may be applicable to the targeted recovery of molecules from other single-cell assays.

New generation breast cancer cell lines developed from patient-derived xenografts.

BACKGROUND: Breast cancer is a highly heterogeneous disease characterized by multiple histologic and molecular subtypes. While a myriad of breast cancer cell lines have been developed over the past 60 years, estrogen receptor alpha (ER)+ disease and some mutations associated with this subtype remain underrepresented. Here we describe six breast cancer cell lines derived from patient-derived xenografts (PDX) and their general characteristics. METHODS: Established breast cancer PDX were processed into cell suspensions and placed into standard 2D cell culture; six emerged into long-term passageable cell lines. Cell lines were assessed for protein expression of common luminal, basal, and mesenchymal markers, growth assessed in response to estrogens and endocrine therapies, and RNA-seq and oncogenomics testing performed to compare relative transcript levels and identify putative oncogenic drivers. RESULTS: Three cell lines express ER and two are also progesterone receptor (PR) positive; PAM50 subtyping identified one line as luminal A. One of the ER+PR+ lines harbors a D538G mutation in the gene for ER (ESR1), providing a natural model that contains this endocrine-resistant genotype. The third ER+PR-/low cell line has mucinous features, a rare histologic type of breast cancer. The three other lines are ER- and represent two basal-like and a mixed ductal/lobular breast cancer. The cell lines show varied responses to tamoxifen and fulvestrant, and three were demonstrated to regrow tumors in vivo. RNA sequencing confirms all cell lines are human and epithelial. Targeted oncogenomics testing confirmed the noted ESR1 mutation in addition to other mutations (i.e., PIK3CA, BRCA2, CCND1, NF1, TP53, MYC) and amplifications (i.e., FGFR1, FGFR3) frequently found in breast cancers. CONCLUSIONS: These new generation breast cancer cell lines add to the existing repository of breast cancer models, increase the number of ER+ lines, and provide a resource that can be genetically modified for studying several important clinical breast cancer features.

The secreted MSP domain of C. elegans VAPB homolog VPR-1 patterns the adult striated muscle mitochondrial reticulum via SMN-1.

The major sperm protein domain (MSPd) has an extracellular signaling function implicated in amyotrophic lateral sclerosis. Secreted MSPds derived from the C. elegans VAPB homolog VPR-1 promote mitochondrial localization to actin-rich I-bands in body wall muscle. Here we show that the nervous system and germ line are key MSPd secretion tissues. MSPd signals are transduced through the CLR-1 Lar-like tyrosine phosphatase receptor. We show that CLR-1 is expressed throughout the muscle plasma membrane, where it is accessible to MSPd within the pseudocoelomic fluid. MSPd signaling is sufficient to remodel the muscle mitochondrial reticulum during adulthood. An RNAi suppressor screen identified survival of motor neuron 1 (SMN-1) as a downstream effector. SMN-1 acts in muscle, where it colocalizes at myofilaments with ARX-2, a component of the Arp2/3 actin-nucleation complex. Genetic studies suggest that SMN-1 promotes Arp2/3 activity important for localizing mitochondria to I-bands. Our results support the model that VAPB homologs are circulating hormones that pattern the striated muscle mitochondrial reticulum. This function is crucial in adults and requires SMN-1 in muscle, likely independent of its role in pre-mRNA splicing.

The C. elegans VAPB homolog VPR-1 is a permissive signal for gonad development.

VAMP/synaptobrevin-associated proteins (VAPs) contain an N-terminal major sperm protein domain (MSPd) that is associated with amyotrophic lateral sclerosis. VAPs have an intracellular housekeeping function, as well as an extracellular signaling function mediated by the secreted MSPd. Here we show that the C. elegans VAP homolog VPR-1 is essential for gonad development. vpr-1 null mutants are maternal effect sterile due to arrested gonadogenesis following embryo hatching. Somatic gonadal precursor cells and germ cells fail to proliferate fully and complete their respective differentiation programs. Maternal or zygotic vpr-1 expression is sufficient to induce gonadogenesis and fertility. Genetic mosaic and cell type-specific expression studies indicate that vpr-1 activity is important in the nervous system, germ line and intestine. VPR-1 acts in parallel to Notch signaling, a key regulator of germline stem cell proliferation and differentiation. Neuronal vpr-1 expression is sufficient for gonadogenesis induction during a limited time period shortly after hatching. These results support the model that the secreted VPR-1 MSPd acts at least in part on gonadal sheath cell precursors in L1 to early L2 stage hermaphrodites to permit gonadogenesis.

A Novel Model Incorporating Pectoralis Muscle Measures to Predict Mortality After Ventricular Assist Device Implantation.

BACKGROUND: We have previously demonstrated that pectoralis muscle mass and tissue attenuation obtained on preoperative CT scans were powerful predictors of mortality after left ventricular assist device implantation. In this analysis, we confirm our findings in a separate left ventricular assist device implantation cohort, and we present a novel, user-friendly mortality-prediction model incorporating these measures. METHODS AND RESULTS: Patients with chest CTs performed ≤ 3 months prior to left ventricular assist device implantation at University of Minnesota (n = 143) and Houston Methodist Hospital (n = 133) were identified. Unilateral pectoralis muscle mass indexed to body surface area (PMI) and attenuation (approximated by mean Hounsfield units) (PHUm) were measured on preoperative chest CT scans. To develop a prediction model incorporating pectoralis muscle measures, we implemented a cross-validated model-selection approach using Cox proportional hazards regression models. The final model included PHUm, PMI, African American race, creatinine, total bilirubin, body mass index, bridge to transplant, and presence or absence of contrast. Receiver-operating characteristic curves for 30-, 90- and 365-day survival were generated. The area under the curve for the model at 30, 90 and 365 days was 0.78, 0.76 and 0.76, respectively. CONCLUSIONS: The Minnesota Pectoralis Risk Score had favorable discrimination in this multicenter dataset. These skeletal-muscle measures appear to add important information to preoperative risk assessment.

Correction: Glutamate sensing in biofluids: recent advances and research challenges of electrochemical sensors.

Correction for 'Glutamate sensing in biofluids: recent advances and research challenges of electrochemical sensors' by Jessica Schultz et al., Analyst, 2020, 145, 321-347. DOI: 10.10.1039/C9AN01609K.

Glutamate sensing in biofluids: recent advances and research challenges of electrochemical sensors.

Glutamate is a nonessential amino acid and a putative neurotransmitter. When its consumption exceeds its synthesis, it becomes necessary to monitor its levels. Hence, a low-cost, sensitive and real-time monitoring of glutamate to quantify pain and detect neurodegenerative diseases is imperative to improve pharmacotherapy and early diagnosis for health care. While enzymatic electrochemical sensors are promising to address issues in lab-based detection techniques, non-enzymatic sensors are better due to their higher stability and lower cost. In this review, we aim to discuss the recent advances and remaining challenges of sensing glutamate in biofluids. First, we discuss the metabolic routes of glutamate, followed by its transmission processes to the biofluids. Second, we identify the connection of glutamate to pathologies as a potential biomarker. Third, we emphasize electrochemical sensors instantaneously detect glutamate in biofluids in real-time, quantifying pain and monitoring neurodegenerative diseases. The literature shows the concentration of glutamate in biofluids, such as plasma, cerebral spinal fluid, urine, and saliva are in the range of 5-100 µM, 0.5-2 µM, 8.5 (3.3-18.4) µM mM-1 creatinine, and 0.232 ± 0.177 µM respectively. While these concentration levels are sometimes lower than the detection limit of electrochemical sensors, functionalization of the nanomaterials currently being used such as NiO and Co3O4 with carbon nanotubes or beta-cyclodextrin may improve the sensing performance. Another key challenge in the research is to develop relationships between glutamate and biofluids. Finally, we have to advance electrochemical sensors that are compatible to detect glutamate in physiological conditions for long durations of time.

A New Community-Based Model for Training in Evidence-Based Psychotherapy Practice.

It is critical that evidence-based practices (EBP's) be provided to patients. Efforts to train clinicians in the community in EBP's, however, has been hindered by a lack of resources and rigid and resource intensive models of training. We describe efforts to overcome these barriers in a large scale community-based training program for Interpersonal Psychotherapy implemented with over 1400 clinicians in Los Angeles working within the Los Angeles County Department of Mental Health public system of care. The program, described in detail, is a potential template for training for community-based clinicians in evidence-based psychotherapy practices.

The glucose transporter GLUT1 is required for ErbB2-induced mammary tumorigenesis.

BACKGROUND: Altered tumor cell metabolism is an emerging hallmark of cancer; however, the precise role for glucose in tumor initiation is not known. GLUT1 (SLC2A1) is expressed in breast cancer cells and is likely responsible for avid glucose uptake observed in established tumors. We have shown that GLUT1 was necessary for xenograft tumor formation from primary mammary cells transformed with the polyomavirus middle-T antigen but that it was not necessary for growth after tumors had formed in vivo, suggesting a differential requirement for glucose depending on the stage of tumorigenesis. METHODS: To determine whether GLUT1 is required early during mammary tumorigenesis, we crossed MMTV-NIC mice, which express activated HER2/NEU/ERBB2 and Cre recombinase, to Slc2a1 Flox/Flox (GLUT1Flox/Flox) mice to generate NIC-GLUT1+/+, NIC-GLUT1Flox/+, and NIC-GLUT1Flox/Flox mice. In addition, we evaluated effects of glucose restriction or GLUT1 inhibition on transformation in MCF10A-ERBB2 breast epithelial cells in three-dimensional culture. Finally, we utilized global gene expression profiling data of primary human breast tumors to determine the relationship between SLC2A1 and stage of tumorigenesis. RESULTS: All of the NIC-GLUT1+/+ mice developed tumors in less than 200 days. In contrast, only 1 NIC-GLUT1Flox/Flox mouse and 1 NIC-GLUT1Flox/+ mouse developed mammary tumors, even after 18 months. Mammary gland development was not disrupted in NIC mice lacking GLUT1; however, epithelial content of mature glands was reduced compared to NIC-GLUT1Flox/+ mice. In MCF10A-ERBB2 cells, glucose restriction or GLUT1 inhibition blocked transformation induced by activated ERBB2 through reduced cell proliferation. In human breast cancers, SLC2A1 was higher in ductal carcinoma in situ compared to the normal breast, but lower in invasive versus in situ lesions, suggesting the requirement for GLUT1 decreases as tumors progress. CONCLUSIONS: This study demonstrates a strict requirement for GLUT1 in the early stages of mammary tumorigenesis in vitro and in vivo. While metabolic adaptation has emerged as a hallmark of cancer, our data indicate that early tumor cells rely heavily on glucose and highlight the potential for glucose restriction as a breast cancer preventive strategy.

Steroid hormones, steroid receptors, and breast cancer stem cells.

The ovarian hormones progesterone and estrogen play important roles in breast cancer etiology, proliferation, and treatment. Androgens may also contribute to breast cancer risk and progression. In recent years, significant advances have been made in defining the roles of these steroid hormones in stem cell homeostasis in the breast. Stem cells are potential origins of breast cancer and may dictate tumor phenotype. At least a portion of breast cancers are proposed to be driven by cancer stem cells (CSCs), cells that mimic the self-renewing and repopulating properties of normal stem cells, and can confer drug resistance. Progesterone has been identified as the critical hormone regulating normal murine mammary stem cell (MaSC) populations and normal human breast stem cells. Synthetic progestins increase human breast cancer risk; one theory speculates that this occurs through increased stem cells. Progesterone treatment also increases breast CSCs in established breast cancer cell lines. This is mediated in part through progesterone regulation of transcription factors, signal transduction pathways, and microRNAs. There is also emerging evidence that estrogens and androgens can regulate breast CSC numbers. The evolving concept that a breast CSC phenotype is dynamic and can be influenced by cell signaling and external cues emphasizes that steroid hormones could be crucial players in controlling CSC number and function. Here we review recent studies on steroid hormone regulation of breast CSCs, and discuss mechanisms by which this occurs.

Cytokeratin 5-Positive Cells Represent a Therapy Resistant subpopulation in Epithelial Ovarian Cancer.

OBJECTIVE: Cytokeratin 5 (CK5) is an epithelial cell marker implicated in stem and progenitor cell activity in glandular reproductive tissues and endocrine and chemotherapy resistance in estrogen receptor (ER)(+) breast cancer. The goal of this study was to determine the prevalence of CK5 expression in ovarian cancer and the response of CK5(+) cell populations to cisplatin therapy. MATERIALS AND METHODS: Cytokeratin 5 expression was evaluated in 2 ovarian tissue microarrays, representing 137 neoplasms, and 6 ovarian cancer cell lines. Cell lines were treated with IC(50) (half-maximal inhibitory concentration) cisplatin, and the prevalence of CK5(+) cells pretreatment and posttreatment was determined. Proliferation of CK5(+) versus CK5(-) cell populations was determined using 5-bromo-2'-deoxyuridine incorporation. Chemotherapy-induced apoptosis in CK5(+) versus CK5(-) cells was measured using immunohistochemical staining for cleaved caspase-3. RESULTS: Cytokeratin 5 was expressed in 39.3% (42 of 107) of epithelial ovarian cancers with a range of 1% to 80% positive cells. Serous and endometrioid histologic subtypes had the highest percentage of CK5(+) specimens. Cytokeratin 5 expression correlated with ER positivity (38 of 42 CK5(+) tumors were also ER(+)). Cytokeratin 5 was expressed in 5 of 6 overall and 4 of 4 ER(+) epithelial ovarian cancer cell lines ranging from 2.4% to 52.7% positive cells. Cytokeratin 5(+) compared with CK5(-) cells were slower proliferating. The prevalence of CK5(+) cells increased after 48-hour cisplatin treatment in 4 of 5 cell lines tested. Cytokeratin 5(+) ovarian cancer cells compared with CK5(-) ovarian cancer cells were more resistant to cisplatin-induced apoptosis. CONCLUSIONS: Cytokeratin 5 is expressed in a significant proportion of epithelial ovarian cancers and represents a slower proliferating chemoresistant subpopulation that may warrant cotargeting in combination therapy.

Missed opportunities for human papillomavirus vaccination using Iowa's Immunization Registry Information System.

PURPOSE: Adolescent human papillomavirus (HPV) vaccination rates continue to remain lower than other adolescent vaccines, both nationwide and in Iowa. This study examined predictors of missed opportunities for first-dose HPV vaccine administrations in Iowa in order to conduct more targeted outreach and improve adolescent HPV vaccine uptake. METHODS: A retrospective study was conducted to identify predictors of missed opportunities for first-dose HPV vaccination in Iowa adolescents using Iowa's Immunization Registry Information System. The study population included 154,905 adolescents aged 11-15 years between 2019 and 2022. Missed opportunity for first-dose HPV vaccination was defined as a vaccination encounter where an adolescent received a Tdap and/or MenACWY vaccine but did not receive the first-dose HPV vaccine during the same encounter. FINDINGS: Over a third of the study population experienced a missed opportunity for HPV vaccination between 2019 and 2022. Missed opportunity for vaccination was most common among individuals living in a rural county (aOR = 1.36), underinsured adolescents (aOR = 1.74), males (aOR = 1.12), teens 13-15 years of age (aOR = 1.76), and White race and non-Hispanic ethnicity. CONCLUSION: This study builds on previously reported predictors of missed opportunity for HPV vaccination in adolescents. Increased understanding of provider needs and barriers to administering HPV vaccination and further analysis of how the Vaccines for Children Program can play a role in HPV vaccination uptake is necessary to improve HPV vaccination rates among adolescents in Iowa and more specifically in rural communities.

Fishing damage to cloud sponges may lead to losses in associated fish communities in Pacific Canada.

Glass sponge gardens are important biogenic habitats that support fish communities in Pacific Canada. However, glass sponges (class Hexactinellida) are delicate and susceptible to damage from fishing gear such as downriggers. In this study we document changes in a fish community before -and after damage from a presumed fishing event that resulted in a reduction of 58.9% of the available sponge habitat in a small cloud sponge garden in British Columbia. This habitat loss coincided with a decline of 76.9% of the relative abundance of rockfish, an economically important group of fishes, at the garden. This decline was particularly pronounced in small size classes with the disappearance of juvenile rockfish after the sponge loss. Although based on a single site, this is the first documentation of how anthropogenic damage in a sponge aggregation may impact the associated fish community. Damage from fishing gear is likely most pronounced in small sponge aggregations, like nearshore gardens, where a single event may result in a disproportionately large loss of available fish habitat. Slow regrowth of sponges suggests the habitat availability may be permanently altered at these sites and can coincide with shifts in the localized fish community that may be long lasting on a local scale. Currently sponge gardens do not have any direct spatial protections in the Pacific Northwest, and this work highlights the importance of considering them in future protection initiatives.

Validation of the Minnesota Pectoralis Risk Score to predict mortality in the HeartMate 3 population.

BACKGROUND: The Minnesota Pectoralis Risk Score (MPRS) utilizes computed tomography-quantified thoracic muscle and clinical variables to predict survival after left ventricular assist device (LVAD) implantation. The model has not been prospectively tested in HeartMate 3 recipients. METHODS: A single-center HeartMate 3 cohort from July 2016 to July 2021 (n = 108) was utilized for this analysis. Cohort subjects with complete covariates for MPRS calculation (pectoralis muscle measures, Black race, creatinine, total bilirubin, body mass index, bridge to transplant status, and presence/absence of contrast) implanted after MPRS development were included. MPRS were calculated on each subject. Receiver operating characteristic curves were generated to test model discrimination at 30-day, 90-day, and 1-year mortality post-LVAD. Next, the performance of the 1-year post-LVAD outcome was compared to the HeartMate 3 survival risk score (HM3RS). RESULTS: The mean age was 58 (15 years), 80% (86/108) were male, and 26% (28/108) were destination therapy. The area under the curve (AUC) for the MPRS model to predict post-LVAD mortality was 0.73 at 30 days, 0.78 at 90 days, and 0.81 at 1 year. The AUC for the HM3RS for the 1-year outcome was 0.693. Each 1-unit point of the MPRS was associated with a significant increase in the hazard rate of death after LVAD (hazard ratio 2.1, 95% confidence interval 1.5-3.0, p < 0.0001). CONCLUSIONS: The MPRS had high performance in this prospective validation, particularly with respect to 90-day and 1-year post-LVAD mortality. Such a tool can provide additional information regarding risk stratification to aid informed decision-making.

Targeting aberrant fatty acid synthesis and storage in endocrine resistant breast cancer cells.

Background: Lipid metabolic reprogramming is an emerging characteristic of endocrine therapy (ET) resistance in estrogen receptor-positive (ER+) breast cancer. We explored changes in lipid metabolism in ER+ breast cancer cell lines following acquired resistance to common endocrine treatments and tested efficacy of an inhibitor in current clinical trials. Methods: We derived ER+ breast cancer cell lines resistant to Tamoxifen (TamR), Fulvestrant (FulvR), and long-term estrogen withdrawal (EWD). Parental and ET resistant cells were subjected to global gene expression and unbiased lipidomic profiling. Lipid storage changes were assessed via neutral lipid staining with Oil Red O (ORO). The impact of the fatty acid synthase (FASN) inhibitor TVB-2640 on the growth and lipid storage of these cell lines was evaluated. Additionally, 13 C 2 -acetate tracing was used to examine FASN activity in parental and ET resistant cells in the absence or presence of TVB-2640. Results: Compared to parental cells, lipid metabolism and processing pathways were notably enriched in ET resistant cells, which exhibited distinct lipidomes characterized by increased triglyceride and polyunsaturated FA (PUFA) species. ET-resistant cells displayed enhanced cytoplasmic lipid droplets. Increased FASN protein levels were observed in ET-resistant cells, and TVB-2640 effectively inhibited FASN activity. FASN inhibition reduced cell growth in some but not all cell lines and ET resistance types and did not correlate to lipid storage reduction. 13 C 2 -acetate tracing confirmed reduced palmitate synthesis and enhanced PUFA synthesis in ET-resistant cells, especially when combined with FulvR. Conclusion: ET resistant breast cancer cells exhibit a shift towards enhanced triglyceride storage and complex lipids enriched with PUFA acyl chains. While targeting FASN alongside ET may not fully overcome ET resistance in our models, focusing on the unique lipid metabolic dependencies, such as PUFA pathways, may present a promising alternative strategy for treating ET resistant breast cancer.