Influence of quitting smoking on diabetes-related complications: A scoping review with a systematic search strategy.

INTRODUCTION: Smoking in people with diabetes markedly elevates their risk of developing complications and increases the likelihood of cardiovascular mortality. This review is the first to specifically provide evidence-based analysis about the influence of quitting smoking on diabetes-related complications in people with type 2 diabetes. METHOD: The present review was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Extension for Scoping Reviews. All human clinical studies assessing the effects of stopping smoking cessation on diabetes-related complications were included. PubMed and Embase were screened until January 2024. References of primary studies and principal peer-reviewed scientific journals in the field were manually screened. RESULTS: We identified a total of 1023 studies. Only 26 met the criteria for eligibility. In general quitting smoking is associated with decreased risks of myocardial infarction and ischemic stroke. Regarding microvascular complications, the strongest evidence for the beneficial effects of smoking cessation is observed in diabetic nephropathy. However, the relationship between smoking cessation and retinopathy, neuropathy, diabetic foot complications and diabetic-related erectile dysfunction, is poorly investigated. CONCLUSION: Quitting smoking offers significant advantages in managing diabetes-related complications, significantly lowering the risks of myocardial infarction, ischemic stroke, and diabetic nephropathy. This underscores the importance of cessation. Providing evidence-based information on the benefits of stopping smoking for people with type 2 diabetes who smoke, can bolster smoking cessation efforts in the context of diabetes management.

Inhalation of ACE2-expressing lung exosomes provides prophylactic protection against SARS-CoV-2.

Continued emergence of SARS-CoV-2 variants of concern that are capable of escaping vaccine-induced immunity highlights the urgency of developing new COVID-19 therapeutics. An essential mechanism for SARS-CoV-2 infection begins with the viral spike protein binding to the human ACE2. Consequently, inhibiting this interaction becomes a highly promising therapeutic strategy against COVID-19. Herein, we demonstrate that ACE2-expressing human lung spheroid cells (LSC)-derived exosomes (LSC-Exo) could function as a prophylactic agent to bind and neutralize SARS-CoV-2, protecting the host against SARS-CoV-2 infection. Inhalation of LSC-Exo facilitates its deposition and biodistribution throughout the whole lung in a female mouse model. We show that LSC-Exo blocks the interaction of SARS-CoV-2 with host cells in vitro and in vivo by neutralizing the virus. LSC-Exo treatment protects hamsters from SARS-CoV-2-induced disease and reduced viral loads. Furthermore, LSC-Exo intercepts the entry of multiple SARS-CoV-2 variant pseudoviruses in female mice and shows comparable or equal potency against the wild-type strain, demonstrating that LSC-Exo may act as a broad-spectrum protectant against existing and emerging virus variants.

Elemental Sulfur Promoted Cyclization of Aryl Hydrazones and Aryl Isothiocyanates Yielding 2-Imino-1,3,4-thiadiazoles.

We report a method for using elemental sulfur to facilitate the cyclization of aryl hydrazones and aryl isothiocyanates, affording biorelated 2-imino-1,3,4-thiadiazoles. Reactions progressed in the presence of elemental sulfur, N-methylmorpholine base, and DMSO solvent, while were tolerant of a wide range of functionalities including halogen, nitro, cyano, methylsulfonyl, and heterocyclic groups. The method appears to offer a general pathway for using simple, cheap, and stable reagents to afford triaryl-substituted 2-imino-1,3,4-thiadiazoles under relatively mild conditions.

Osteosarcoma PDX-Derived Cell Line Models for Preclinical Drug Evaluation Demonstrate Metastasis Inhibition by Dinaciclib through a Genome-Targeted Approach.

PURPOSE: Models to study metastatic disease in rare cancers are needed to advance preclinical therapeutics and to gain insight into disease biology. Osteosarcoma is a rare cancer with a complex genomic landscape in which outcomes for patients with metastatic disease are poor. As osteosarcoma genomes are highly heterogeneous, multiple models are needed to fully elucidate key aspects of disease biology and to recapitulate clinically relevant phenotypes. EXPERIMENTAL DESIGN: Matched patient samples, patient-derived xenografts (PDX), and PDX-derived cell lines were comprehensively evaluated using whole-genome sequencing and RNA sequencing. The in vivo metastatic phenotype of the PDX-derived cell lines was characterized in both an intravenous and an orthotopic murine model. As a proof-of-concept study, we tested the preclinical effectiveness of a cyclin-dependent kinase inhibitor on the growth of metastatic tumors in an orthotopic amputation model. RESULTS: PDXs and PDX-derived cell lines largely maintained the expression profiles of the patient from which they were derived despite the emergence of whole-genome duplication in a subset of cell lines. The cell lines were heterogeneous in their metastatic capacity, and heterogeneous tissue tropism was observed in both intravenous and orthotopic models. Single-agent dinaciclib was effective at dramatically reducing the metastatic burden. CONCLUSIONS: The variation in metastasis predilection sites between osteosarcoma PDX-derived cell lines demonstrates their ability to recapitulate the spectrum of the disease observed in patients. We describe here a panel of new osteosarcoma PDX-derived cell lines that we believe will be of wide use to the osteosarcoma research community.

Comparison of accuracy of breeding value for cow from three methods in Hanwoo (Korean cattle) population.

In Korea, Korea Proven Bulls (KPN) program has been well-developed. Breeding and evaluation of cows are also an essential factor to increase earnings and genetic gain. This study aimed to evaluate the accuracy of cow breeding value by using three methods (pedigree index [PI], pedigree-based best linear unbiased prediction [PBLUP], and genomic-BLUP [GBLUP]). The reference population (n = 16,971) was used to estimate breeding values for 481 females as a test population. The accuracy of GBLUP was 0.63, 0.66, 0.62 and 0.63 for carcass weight (CWT), eye muscle area (EMA), back-fat thickness (BFT), and marbling score (MS), respectively. As for the PBLUP method, accuracy of prediction was 0.43 for CWT, 0.45 for EMA, 0.43 for MS, and 0.44 for BFT. Accuracy of PI method was the lowest (0.28 to 0.29 for carcass traits). The increase by approximate 20% in accuracy of GBLUP method than other methods could be because genomic information may explain Mendelian sampling error that pedigree information cannot detect. Bias can cause reducing accuracy of estimated breeding value (EBV) for selected animals. Regression coefficient between true breeding value (TBV) and GBLUP EBV, PBLUP EBV, and PI EBV were 0.78, 0.625, and 0.35, respectively for CWT. This showed that genomic EBV (GEBV) is less biased than PBLUP and PI EBV in this study. In addition, number of effective chromosome segments (Me) statistic that indicates the independent loci is one of the important factors affecting the accuracy of BLUP. The correlation between Me and the accuracy of GBLUP is related to the genetic relationship between reference and test population. The correlations between Me and accuracy were -0.74 in CWT, -0.75 in EMA, -0.73 in MS, and -0.75 in BF, which were strongly negative. These results proved that the estimation of genetic ability using genomic data is the most effective, and the smaller the Me, the higher the accuracy of EBV.

Identification of Missense Variants Affecting Carcass Traits for Hanwoo Precision Breeding.

This study aimed to identify causal variants associated with important carcass traits such as weight and meat quality in Hanwoo cattle. We analyzed missense mutations extracted from imputed sequence data (ARS-UCD1.2) and performed an exon-specific association test on the carcass traits of 16,970 commercial Hanwoo. We found 33, 2, 1, and 3 significant SNPs associated with carcass weight (CW), backfat thickness (BFT), eye muscle area (EMA), and marbling score (MS), respectively. In CW and EMA, the most significant missense SNP was identified at 19,524,263 on BTA14 and involved the PRKDC. A missense SNP in the ZFAND2B, located at 107,160,304 on BTA2 was identified as being involved in BFT. For MS, missense SNP in the ACVR2B gene, located at 11,849,704 in BTA22 was identified as the most significant marker. The contribution of the most significant missense SNPs to genetic variance was confirmed to be 8.47%, 2.08%, 1.73%, and 1.19% in CW, BFT, EMA, and MS, respectively. We generated favorable and unfavorable haplotype combinations based on the significant SNPs for CW. Significant differences in GEBV (Genomic Estimated Breeding Values) were observed between groups with each favorable and unfavorable haplotype combination. In particular, the missense SNPs in PRKDC, MRPL9, and ANKFN1 appear to significantly affect the protein's function and structure, making them strong candidates as causal mutations. These missense SNPs have the potential to serve as valuable markers for improving carcass traits in Hanwoo commercial farms.

Cardiac sarcoma presenting as paraneoplastic arthritis and clubbing: a case report and literature review.

BACKGROUND: Cardiac tumours are rare, and clinical manifestations depend on the anatomical location. Symptoms can be the result of cardiac outflow anomalies, constitutional features such as fever, loss of weight, and/or paraneoplastic manifestations such as arthritis. To date, there has only been one other case report in the literature of cardiac sarcoma presenting as paraneoplastic arthropathy. CASE PRESENTATION: A 52-year-old woman presented with acute onset corticosteroid-resistant inflammatory polyarthralgia, clubbing and a systolic murmur. Transthoracic echocardiogram revealed a dilated left atrium with an echogenic mass and brain magnetic resonance imaging revealed multiple embolic infarcts. Histopathology following emergency resection showed a Grade 3 left atrial intimal sarcoma. The polyarthralgia and clubbing resolved soon after tumour removal. The patient went on to receive chemotherapy and remains in remission. CONCLUSIONS: This case highlights the rare paraneoplastic association of cardiac sarcoma and arthropathy.

UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma.

KRAS is a frequent driver in lung cancer. To identify KRAS-specific vulnerabilities in lung cancer, we performed RNAi screens in primary spheroids derived from a Kras mutant mouse lung cancer model and discovered an epigenetic regulator Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). In human lung cancer models UHRF1 knock-out selectively impaired growth and induced apoptosis only in KRAS mutant cells. Genome-wide methylation and gene expression analysis of UHRF1-depleted KRAS mutant cells revealed global DNA hypomethylation leading to upregulation of tumor suppressor genes (TSGs). A focused CRISPR/Cas9 screen validated several of these TSGs as mediators of UHRF1-driven tumorigenesis. In vivo, UHRF1 knock-out inhibited tumor growth of KRAS-driven mouse lung cancer models. Finally, in lung cancer patients high UHRF1 expression is anti-correlated with TSG expression and predicts worse outcomes for patients with KRAS mutant tumors. These results nominate UHRF1 as a KRAS-specific vulnerability and potential target for therapeutic intervention.

A SARS-CoV-2 and influenza double hit vaccine based on RBD-conjugated inactivated influenza A virus.

The circulating flu viruses merging with the ongoing COVID-19 pandemic raises a more severe threat that promotes the infectivity of SARS-CoV-2 associated with higher mortality rates. Here, we conjugated recombinant receptor binding domain (RBD) of SARS-CoV-2 spike protein onto inactivated influenza A virus (Flu) to develop a SARS-CoV-2 virus-like particle (VLP) vaccine with two-hit protection. This double-hit vaccine (Flu-RBD) not only induced protective immunities against SARS-CoV-2 but also remained functional as a flu vaccine. The Flu core improved the retention and distribution of Flu-RBD vaccine in the draining lymph nodes, with enhanced immunogenicity. In a hamster model of live SARS-CoV-2 infection, two doses of Flu-RBD efficiently protected animals against viral infection. Furthermore, Flu-RBD VLP elicited a strong neutralization activity against both SARS-CoV-2 Delta pseudovirus and wild-type influenza A H1N1 inactivated virus in mice. Overall, the Flu-RBD VLP vaccine is a promising candidate for combating COVID-19, influenza A, and coinfection.

A genome-wide association study for eumelanin pigmentation in chicken plumage using a computer vision approach.

Chicken plumage colouration is an important trait related to productivity in poultry industry. Therefore, the genetic basis for pigmentation in chicken plumage is an area of great interest. However, the colour trait is generally regarded as a qualitative trait and representing colour variations is difficult. In this study, we developed a method to quantify and classify colour using an F2 population crossed from two pure lines: White Leghorn and the Korean indigenous breed Yeonsan Ogye. Using red, green, and blue values in the cropped body region, we identified significant genomic regions on chromosomes 33:3 160 480-7 447 197 and Z:78 748 287-79 173 793. Furthermore, we identified two potential candidate genes (PMEL and MTAP) that might have significant effects on melanin-based plumage pigmentation. Our study presents a new phenotyping method using a computer vision approach and provides new insights into the genetic basis of melanin-based feather colouration in chickens.

A facilitated social innovation: stakeholder groups using Plan-Do-Study-Act cycles for perinatal health across levels of the health system in Cao Bang province, Vietnam.

BACKGROUND: Universal coverage of evidence-based interventions for perinatal health, often part of evidence-based guidelines, could prevent most perinatal deaths, particularly if entire communities were engaged in the implementation. Social innovations may provide creative solutions to the implementation of evidence-based guidelines, but successful use of social innovations relies on the engagement of communities and health system actors. This proof-of-concept study aimed to assess whether an earlier successful social innovation for improved neonatal survival that employed regular facilitated Plan-Do-Study-Act meetings on the commune level was feasible and acceptable when implemented on multiple levels of the health system (52 health units) and resulted in actions with plausibly favourable effects on perinatal health and survival in Cao Bang province, northern Vietnam. METHODS: The Integrated Promoting Action on Research Implementation in Health Services (i-PARIHS) framework guided the implementation and evaluation of the Perinatal Knowledge-Into-Practice (PeriKIP) project. Data collection included facilitators' diaries, health workers' knowledge on perinatal care, structured observations of antenatal care, focus group discussions with facilitators, their mentors and representatives of different actors of the initiated stakeholder groups and an individual interview with the Reproductive Health Centre director. Clinical experts assessed the relevance of the identified problems and actions taken based on facilitators' diaries. Descriptive statistics included proportions, means, and t-tests for the knowledge assessment and observations. Qualitative data were analysed by content analysis. RESULTS: The social innovation resulted in the identification of about 500 relevant problems. Also, 75% of planned actions to overcome prioritised problems were undertaken, results presented and a plan for new actions to achieve the group's goals to enhance perinatal health. The facilitators had significant roles, ensuring that the stakeholder groups were established based on principles of mutual respect. Overall, the knowledge of perinatal health and performance of antenatal care improved over the intervention period. CONCLUSIONS: The establishment of facilitated local stakeholder groups can remedy the need for tailored interventions and grassroots involvement in perinatal health and provide a scalable structure for focused efforts to reduce preventable deaths and promote health and well-being.

Persistence and fading of the cognitive and socio-emotional benefits of preschool education in a low-resource setting: Group differences and dose-dependent associations in longitudinal data from Vietnam.

Introduction: Four analytic approaches examined the effectiveness of preschool education in Vietnam, which provides a context in which national curricula and teaching standards for preschools and schools, high levels of preschool attendance, and fee subsidies for disadvantaged children, limit the heterogeneity in children's experiences that often obscure the outcomes associated with preschool attendance. Methods: The Young Lives Study provided longitudinal data on children's receptive vocabulary, mathematics, and life satisfaction at 5, 8, 12, and 15 years of age, and on their self-concept and relationships at 12 and 15 years. Results: The first analysis found that children who attended preschool (n = 1,562 at 5 years of age) had larger vocabularies at 5, 8, 12, and 15 years, greater mathematics knowledge at 5, 8, and 12 years, and higher life satisfaction at 5 and 12 years of age than the small number of children who did not attend preschool (n = 164 at 5 years of age). The second, found that the dose of preschool education (hours per week × 4 × months) received by children who attended preschool was positively associated with their receptive vocabulary and mathematics scores at 5, 8, 12, and 15 years of age, and with their life satisfaction at 5 and 15 years of age. Although the magnitude of the effect for vocabulary declined over time, it remained stable for mathematics. The third analysis found that a high dose of preschool education allowed disadvantaged rural children to achieve comparable or better scores than their urban peers for receptive vocabulary at 8, 12, and 15 years, mathematics at 12 years, and life satisfaction at all ages. The final analysis found that even a low dose of preschool education improved rural children's receptive vocabulary at 5, 8, and 15 years, and their numeracy/mathematics scores at 5, 8, and 12 years. Discussion: Together, the results suggest that preschool attendance had a small but meaningful positive association with Vietnamese children's cognitive skills and life satisfaction that persisted for at least 10 years. These findings provide insights into the scale, scope, and longevity of effects that can be achieved from scaled-up preschool programs under resource-constrained conditions.

Development and characterization of new patient-derived xenograft (PDX) models of osteosarcoma with distinct metastatic capacities.

Models to study metastatic disease in rare cancers are needed to advance preclinical therapeutics and to gain insight into disease biology, especially for highly aggressive cancers with a propensity for metastatic spread. Osteosarcoma is a rare cancer with a complex genomic landscape in which outcomes for patients with metastatic disease are poor. As osteosarcoma genomes are highly heterogeneous, a large panel of models is needed to fully elucidate key aspects of disease biology and to recapitulate clinically-relevant phenotypes. We describe the development and characterization of osteosarcoma patient-derived xenografts (PDXs) and a panel of PDX-derived cell lines. Matched patient samples, PDXs, and PDX-derived cell lines were comprehensively evaluated using whole genome sequencing and RNA sequencing. PDXs and PDX-derived cell lines largely maintained the expression profiles of the patient from which they were derived despite the emergence of whole-genome duplication (WGD) in a subset of cell lines. These cell line models were heterogeneous in their metastatic capacity and their tissue tropism as observed in both intravenous and orthotopic models. As proof-of-concept study, we used one of these models to test the preclinical effectiveness of a CDK inhibitor on the growth of metastatic tumors in an orthotopic amputation model. Single-agent dinaciclib was effective at dramatically reducing the metastatic burden in this model.

High doses of a national preschool program are associated with the long-term mitigation of adverse outcomes in cognitive development and life satisfaction among children who experience early stunting: a multi-site longitudinal study in Vietnam.

Background: Stunting (low height-for-age) is a marker of cumulative developmental disadvantage that can also contribute to impaired cognitive development and poor psychological wellbeing. Several interventions designed to preserve stunted children's developmental potential through increasing their cognitive stimulation have proven to be effective. However, their resource-intensive nature limits their sustainability and scalability in the low-and middle-income countries in which 98% of stunted children live. The current study had three aims: to identify the domains of developmental disadvantage associated with stunting at 5 years of age in the Vietnamese context; to examine the relationship between Vietnamese children's stunting status at 5 years of age, the dose of the national preschool program they received, and their cognitive skills and psychological well-being at 4 ages; and to determine whether some doses of the national preschool program were associated with the mitigation of adverse cognitive and wellbeing outcomes among stunted children. Method: The Young Lives Study in Vietnam (n = 2,000; 31 sites) provided archival data that allowed calculation of the approximate dose (in hours) of the preschool program received by children, and longitudinal data on children's growth (1, 5, 8, 12, and 15 years), receptive vocabulary (5, 8, 12 and 15 years), reading skills, mathematics skills and life satisfaction (each at 8, 12, and 15 years). Results: Stunting at 5 years of age was associated with diverse aspects of financial and social disadvantage, greater exposure to health risks, lower preventive health care, and constraints on maternal care. Scores for all cognitive variables at all ages were positively associated with preschool dose and negatively associated with stunted growth at 5 years of age. That is, effects associated with stunting and preschool dose at 5 years of age continued to be found during the subsequent 10 years. High doses of preschool education (3,000 h or more) were associated with the mitigation of adverse outcomes for most cognitive variables at most ages. Conclusion: The current findings raise the possibility that generic preschool programs delivered at high dose may provide a scalable and sustainable intervention to support the life opportunities of children who experience early stunting.

Inhalable exosomes outperform liposomes as mRNA and protein drug carriers to the lung.

Respiratory diseases are among the leading causes of morbidity and mortality worldwide, coupled with the ongoing coronavirus disease 2019 (COVID-19) pandemic. mRNA lipid nanoparticle (LNP) vaccines have been developed, but their intramuscular delivery limits pulmonary bioavailability. Inhalation of nanoparticle therapeutics offers localized drug delivery that minimizes off targeted adverse effects and has greater patient compliance. However, LNP platforms require extensive reformulation for inhaled delivery. Lung-derived extracellular vesicles (Lung-Exo) offer a biological nanoparticle alternative that is naturally optimized for mRNA translation and delivery to pulmonary cells. We compared the biodistribution of Lung-Exo against commercially standard biological extracellular vesicles (HEK-Exo) and LNPs (Lipo), where Lung-Exo exhibited superior mRNA and protein cargo distribution to and retention in the bronchioles and parenchyma following nebulization administration. This suggests that inhaled Lung-Exo can deliver mRNA and protein drugs with enhanced pulmonary bioavailability and therapeutic efficacy.

Exosomes decorated with a recombinant SARS-CoV-2 receptor-binding domain as an inhalable COVID-19 vaccine.

The first two mRNA vaccines against infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that were approved by regulators require a cold chain and were designed to elicit systemic immunity via intramuscular injection. Here we report the design and preclinical testing of an inhalable virus-like-particle as a COVID-19 vaccine that, after lyophilisation, is stable at room temperature for over three months. The vaccine consists of a recombinant SARS-CoV-2 receptor-binding domain (RBD) conjugated to lung-derived exosomes which, with respect to liposomes, enhance the retention of the RBD in both the mucus-lined respiratory airway and in lung parenchyma. In mice, the vaccine elicited RBD-specific IgG antibodies, mucosal IgA responses and CD4+ and CD8+ T cells with a Th1-like cytokine expression profile in the animals' lungs, and cleared them of SARS-CoV-2 pseudovirus after a challenge. In hamsters, two doses of the vaccine attenuated severe pneumonia and reduced inflammatory infiltrates after a challenge with live SARS-CoV-2. Inhalable and room-temperature-stable virus-like particles may become promising vaccine candidates.

Inhalable dry powder mRNA vaccines based on extracellular vesicles.

Respiratory diseases are a global burden, with millions of deaths attributed to pulmonary illnesses and dysfunctions. Therapeutics have been developed, but they present major limitations regarding pulmonary bioavailability and product stability. To circumvent such limitations, we developed room-temperature-stable inhalable lung-derived extracellular vesicles or exosomes (Lung-Exos) as mRNA and protein drug carriers. Compared with standard synthetic nanoparticle liposomes (Lipos), Lung-Exos exhibited superior distribution to the bronchioles and parenchyma and are deliverable to the lungs of rodents and nonhuman primates (NHPs) by dry powder inhalation. In a vaccine application, severe acute respiratory coronavirus 2 (SARS-CoV-2) spike (S) protein encoding mRNA-loaded Lung-Exos (S-Exos) elicited greater immunoglobulin G (IgG) and secretory IgA (SIgA) responses than its loaded liposome (S-Lipo) counterpart. Importantly, S-Exos remained functional at room-temperature storage for one month. Our results suggest that extracellular vesicles can serve as an inhaled mRNA drug-delivery system that is superior to synthetic liposomes.

Ductal Carcinoma in Situ: Molecular Changes Accompanying Disease Progression.

Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive ductal carcinoma (IDC), whereby if left untreated, approximately 12% of patients develop invasive disease. The current standard of care is surgical removal of the lesion, to prevent potential progression, and radiotherapy to reduce risk of recurrence. There is substantial overtreatment of DCIS patients, considering not all DCIS lesions progress to invasive disease. Hence, there is a critical imperative to better predict which DCIS lesions are destined for poor outcome and which are not, allowing for tailored treatment. Active surveillance is currently being trialed as an alternative management practice, but this approach relies on accurately identifying cases that are at low risk of progression to invasive disease. Two DCIS-specific genomic profiling assays that attempt to distinguish low and high-risk patients have emerged, but imperfections in risk stratification coupled with a high price tag warrant the continued search for more robust and accessible prognostic biomarkers. This search has largely turned researchers toward the tumor microenvironment. Recent evidence suggests that a spectrum of cell types within the DCIS microenvironment are genetically and phenotypically altered compared to normal tissue and play critical roles in disease progression. Uncovering the molecular mechanisms contributing to DCIS progression has provided optimism for the search for well-validated prognostic biomarkers that can accurately predict the risk for a patient developing IDC. The discovery of such markers would modernize DCIS management and allow tailored treatment plans. This review will summarize the current literature regarding DCIS diagnosis, treatment, and pathology.

Impact of the EndoPredict genomic assay on treatment decisions for oestrogen receptor-positive early breast cancer patients: benefits of physician selective testing.

PURPOSE: Genomic tests improve accuracy of risk prediction for early breast cancers but these are expensive. This study evaluated the clinical utility of EndoPredict®, in terms of impact on adjuvant therapy recommendations and identification of parameters to guide selective application. METHODS: Patients with ER-positive, HER2-negative, and early-stage invasive breast cancer were tested with EndoPredict®. Two cohorts were recruited: one consecutively and another at clinical team discretion. Systemic treatment recommendations were recorded before and after EndoPredict® results were revealed to the multidisciplinary team. RESULTS: 233 patients were recruited across five sites: 123 consecutive and 110 at clinical team discretion. In the consecutive cohort 50.6% (62/123) cases were classified high risk of recurrence by EndoPredict®, compared with 62.7% (69/110) in the selective cohort. A change in treatment recommendation was significantly more likely (p < 0.0001) in the selective cohort (43/110, 39.1%) compared to the consecutive group (11/123, 8.9%). The strongest driver of selective recruitment was intermediate grade histology, whilst logistic regression modelling demonstrated that nodal status (p < 0.001), proliferative rate (p = 0.001), and progesterone receptor positivity (p < 0.001) were the strongest discriminators of risk. CONCLUSION: Whilst molecular risk can be predicted by traditional variables in a high proportion of cases, EndoPredict® had a greater impact on treatment decisions in those cases selected for testing at team discretion. This is indicative of the robust ability of the clinical team to identify cases most likely to benefit from testing, underscoring the value of genomic tests in the oncologists' tool kit.