Factors influencing COVID-19 vaccine uptake among Latinos: A cross-sectional study.

Vaccination against COVID-19 can prevent severe illness and reduce hospitalizations and deaths. Understanding and addressing determinants contributing to vaccine uptake among high-risk groups, such as Latinos, are pivotal in ensuring equitable vaccine distribution, promoting health equity, and fostering community engagement to bridge the gap in vaccine acceptance and ultimately enhance public health. This study aimed to examine factors influencing vaccine uptake among Latinos. We conducted a cross-sectional study using an online platform (n = 242). The survey was administered using a multimodal approach. Strategies for recruitment included community outreach, social media, and targeting community networks serving Latinos. Descriptive statistics, chi-square, and multivariable analysis were performed. Overall, 81.4% of respondents had received at least one dose of the COVID-19 vaccine, with 77.0% recommending it and 70.6% believing it to be safe, 66.7% believing in its efficacy, 62.3% able to find trustful information in Spanish or Portuguese, and almost 40% who relied on health organizations as their primary resource for COVID-19 vaccine information. Factors significantly associated with vaccine uptake included higher education level (p<0.001), English level (p = 0.023), living in an urban area (p = 0.048), having insurance (p<0.001), and having a healthcare provider (p = 0.007). Furthermore, belief in vaccine safety and efficacy, trust in public health authorities, concerns about COVID-19, the ability to determine true/false vaccine information during the pandemic, and the availability of trustworthy information in Spanish/Portuguese had statistically significant associations (p<0.05) with COVID-19 vaccine uptake. COVID-19 vaccine uptake differed based on sociodemographic and other modifiable factors. Our findings emphasize the importance of implementing targeted interventions and culturally sensitive communication strategies to improve vaccination uptake among the Latino community in the United States.

The Impact of the Communities that Care Approach in Reducing Violence and Crime Within an Urban, High-Burden Community.

Community violence and crime are significant public health problems with serious and lasting effects on young people, families, and communities. This violence and crime have significant ripple effects, affecting not just those who are directly physically injured, but also those who witness violent episodes, those who have friends or loved ones killed or injured, and those who must everyday navigate streets that they know have been frequent sites of serious violence and crime. The current study presents evidence of the impact that a data-driven, collective impact approach - the Communities that Care prevention system - can have on violence and crime outcomes within a large urban, high-burden community. Established as one of the national Youth Violence Prevention Centers (YVPC) funded by the Centers for Disease Control and Prevention, the Chicago Center for Youth Violence Prevention is among the first to implement the CTC approach in a large, urban community. The current study's findings show reductions in violence (i.e., aggravated assaults and robberies) in the Bronzeville community, compared to similar communities in Chicago.

Design and Synthesis of Clinical Candidate PF-06852231 (CVL-231): A Brain Penetrant, Selective, Positive Allosteric Modulator of the M4 Muscarinic Acetylcholine Receptor.

Selective activation of the M4 muscarinic acetylcholine receptor subtype offers a novel strategy for the treatment of psychosis in multiple neurological disorders. Although the development of traditional muscarinic activators has been stymied due to pan-receptor activation, muscarinic receptor subtype selectivity can be achieved through the utilization of a subtype of a unique allosteric site. A major challenge in capitalizing on this allosteric site to date has been achieving a balance of suitable potency and brain penetration. Herein, we describe the design of a brain penetrant series of M4 selective positive allosteric modulators (PAMs), ultimately culminating in the identification of 21 (PF-06852231, now CVL-231/emraclidine), which is under active clinical development as a novel mechanism and approach for the treatment of schizophrenia.

Risk Factors for Early Lower Limb Re-Amputation in Vascular Diseases.

BACKGROUND: Numerous risk factors for lower limb amputations are known; however, this study aimed to identify risk factors for re-amputation in patients within 6 months from an initial lower limb amputation procedure. METHODS: This single-center retrospective cohort study was performed at the Hospital Regional Hans Dieter Schmidt in Brazil. The study included patients who were aged at least 18 years and had undergone lower limb amputation between 2013 and 2022. Patients who died while hospitalized and patients who were lost to follow-up after hospital discharge were excluded from the study. Patient age, sex, number of amputations, revision time, comorbidities, and potential risk factors were extracted from the physical therapy service database and electronic medical records of the hospital. Chi-squared test and student's t-test were used to identify statistical significance. RESULTS: A total of 652 patients were included, of which 35.2% (230) patients underwent re-amputation within 6 months of the first operation. We found that dialysis (P = 0.004; odds ratio [OR] 8.36, 95% confidence interval [CI] 3.09-20.5), smoking (P = 0.004; OR 1.67, 95% CI 1.18-2.35), and hypertension (P = 0.02; OR 1.55, 95% CI 1.09-2.19) were predictive factors for re-amputation within 6 months of lower limb amputation. CONCLUSIONS: Therefore, it is important to intervene early and provide additional support to patients undergoing lower limb amputation with these risk factors to reduce the potential for re-amputation in the future.

Seven new species of the segmented spider genus Liphistius (Mesothelae, Liphistiidae) in Thailand and Myanmar.

Seven new species of the primitive segmented spider genus Liphistius are described and assigned to species groups based on characters of the male palp and vulva plate. The bristowei group includes L.dawei Sivayyapram & Warrit, sp. nov. (♂♀) from southeastern Myanmar, L.choosaki Sivayyapram & Warrit, sp. nov. (♀) from northwestern Thailand, and L.lansak Sivayyapram & Warrit, sp. nov. (♀) from western Thailand; the trang group (Complex A) contains L.kaengkhoi Sivayyapram & Warrit, sp. nov. (♂♀), L.hintung Sivayyapram & Warrit, sp. nov. (♂♀), L.buyphradi Sivayyapram & Warrit, sp. nov. (♂♀), and L.champakpheaw Sivayyapram & Warrit, sp. nov. (♂♀) from central Thailand.

Exploring recent trends (2014-21) in preferencing and accepting Queensland medical internships in rural hospitals.

BACKGROUND: Medical internship is a key transition point in medical training from student to independent (junior) doctor. The national Regional Training Hubs (RTH) policy began across Australia in late 2017, which aims to build medical training pathways for junior doctors within a rural region and guide students, interns and trainees towards these. This study aims to explore preferencing and acceptance trends for rural medical internship positions in Queensland. Moreover, it focuses on internship preference and acceptance outcomes prior to and following the establishment of RTHs, and their association with key covariates such as rural training immersions offered by medical schools. METHODS: Data from all applicants to Queensland Health intern positions between 2014-2021 were available, notably their preference order and location of accepted internship position, classified as rural or metropolitan. Matched data from Queensland's medical schools were added for rural training time and other key demographics. Analyses explored the statistical associations between these factors and preferencing or accepting rural internships, comparing pre-RTH and post-RTH cohorts. RESULTS: Domestic Queensland-trained graduates first preferencing rural intern positions increased significantly (pre-RTH 21.1% vs post-RTH 24.0%, p = 0.017), reinforced by a non-significant increase in rural acceptances (27.3% vs 29.7%, p = 0.070). Rural interns were more likely to have previously spent ≥ 11-weeks training in rural locations within medical school, be rurally based in the year applying for internship, or enrolled in the rural generalist pathway. CONCLUSIONS: The introduction of the RTH was associated with a moderate increase of graduates both preferencing and accepting a rural internship, though a richer understanding of the dominant reasons for and against this remain less clear. An expansion of graduates who undertook longer periods of undergraduate rural training in the same period did not diminish the proportion choosing a rural internship, suggesting there remains an appetite for these opportunities. Overall, domestic graduates are identified as a reliable source of intern recruitment and retention to rural hospitals across Queensland, with entry to the rural generalist pathway and extended rural placement experiences enhancing uptake of rural practice.

Virtual Molecular and Precision Medicine Clinic to Improve Access to Clinical Trials for Patients With Metastatic Breast Cancer: An Academic/Community Collaboration.

PURPOSE: There is a demand for improved care delivery surrounding genomic testing and clinical trial enrollment among patients with metastatic breast cancer (MBC). We sought to improve the current process via real-time informal consultation and prescreening assessment for patients with MBC treated by community and academic medical oncologists by implementing a virtual molecular and precision medicine (vMAP) clinic. METHODS: The vMAP program used a virtual referral system directed to a multidisciplinary team with precision medicine expertise. Providers contacted vMAP regarding patients with MBC, and on receipt of referral, the vMAP team engaged in discussion to identify if further diagnostics were needed (including genomic testing) and to identify potential clinical trials or standard treatment options. Recommendations were then sent to the referring provider within 72 hours. Pre-/postsurveys were issued to network physicians to assess for barriers, clinical trial access, and vMAP referral experience. Program implementation was evaluated with the Squire 2.0 reporting guidelines for quality improvement in health care as a framework. RESULTS: Eighty-one cases from 22 providers were referred to vMAP over a 26-month period. The average response time to the referring provider with a finalized recommendation was 1.90 ± 1.82 days. A total of 86.4% of cases had clinical trial options on vMAP prescreen, with 40.7% initiating formal screening assessments and 27 patients (33.3%) ultimately enrolling on trials. On resurvey, 92% of survey responses across community oncology referring providers said that they were very likely to use vMAP again. CONCLUSION: In the initial 2-year period, vMAP demonstrated an efficient means to offer real-time interpretation of genomic testing and identification of clinical trials for patients with MBC, with effective clinical trial enrollment and high rates of referring provider satisfaction.

Endometrial cancer PDX-derived organoids (PDXOs) and PDXs with FGFR2c isoform expression are sensitive to FGFR inhibition.

Endometrial cancer (EC) patients with metastatic/recurrent disease have limited treatment options and poor survival outcomes. Recently, we discovered the FGFR2c splice isoform is associated with poor prognosis in EC patients. Here we report the establishment of 16 EC patient-derived xenografts (PDX)-derived organoids (PDXOs) with or without FGFR2c expression. In vitro treatment of 5 EC PDXOs with BGJ398 showed significant cell death in 3 models with FGFR2c expression. PDXs with high/moderate FGFR2c expression showed significant tumour growth inhibition (TGI) following 21-day treatment with FGFR inhibitors (BGJ398 or pemigatinib) and significantly prolonged survival in 4/5 models. Pemigatinib + cisplatin combination therapy (n = 5) resulted in significant TGI and prolonged survival in one of two p53abn PDXs. All five models treated with cisplatin alone showed de novo resistance and no survival benefit. Seven-day treatment with BGJ398 revealed a significant reduction in angiogenesis and CD206 + M2 macrophages. These data collectively support the evaluation of FGFR inhibitors in a clinical trial.

Democratising data to address health system inequities in Australia.

Understanding the health status of a population or community is crucial to equitable service planning. Among other uses, data on health status can help local and national planners and policy makers understand patterns and trends in current or emerging health and well-being, especially how disparities relating to geography, ethnicity, language and living with disability influence access to services. In this practice paper we draw attention to the nature of Australia's health data challenges and call for greater 'democratisation' of health data to address health system inequities. Democratisation implies the need for greater quality and representativeness of health data as well as improved access and usability that enable health planners and researchers to respond to health and health service disparities efficiently and cost-effectively. We draw on learnings from two practice examples, marred by inaccessibility, reduced interoperability and limited representativeness. We call for renewed and urgent attention to, and investment in, improved data quality and usability for all levels of health, disability and related service delivery in Australia.

Highly socially vulnerable communities exhibit disproportionately increased viral loads as measured in community wastewater.

Wastewater surveillance has proven to be a useful tool for evidence-based epidemiology in the fight against the SARS-CoV-2 virus. It is particularly useful at the population level where acquisition of individual test samples may be time or cost-prohibitive. Wastewater surveillance for SARS-CoV-2 has typically been performed at wastewater treatment plants; however, this study was designed to sample on a local level to monitor the spread of the virus among three communities with distinct social vulnerability indices in Shreveport, Louisiana, located in a socially vulnerable region of the United States. Twice-monthly grab samples were collected from September 30, 2020, to March 23, 2021, during the Beta wave of the pandemic. The goals of the study were to examine whether: 1) concentrations of SARS-CoV-2 RNA in wastewater varied with social vulnerability indices and, 2) the time lag of spikes differed during wastewater monitoring in the distinct communities. The size of the population contributing to each sample was assessed via the quantification of the pepper mild mottle virus (PMMoV), which was significantly higher in the less socially vulnerable community. We found that the communities with higher social vulnerability exhibited greater viral loads as assessed by wastewater when normalized with PMMoV (Kruskal-Wallis, p < 0.05). The timing of the spread of the virus through the three communities appeared to be similar. These results suggest that interconnected communities within a municipality experienced the spread of the SARS-CoV-2 virus at similar times, but areas of high social vulnerability experienced more intense wastewater viral loads.

Using the social vulnerability index to assess COVID-19 vaccine uptake in Louisiana.

Using data from the Louisiana Department of Public Health, we explored the spatial relationships between the Social Vulnerability Index (SVI) and COVID-19-related vaccination and mortality rates. Publicly available COVID-19 vaccination and mortality data accrued from December 2020 to October 2021 was downloaded from the Louisiana Department of Health website and merged with the SVI data; geospatial analysis was then performed to identify the spatial association between the SVI and vaccine uptake and mortality rate. Bivariate Moran's I analysis revealed significant clustering of high SVI ranking with low COVID-19 vaccination rates (1.00, p < 0.001) and high smoothed mortality rates (0.61, p < 0.001). Regression revealed that for each 10% increase in SVI ranking, COVID-19 vaccination rates decreased by 3.02-fold (95% CI = 3.73-2.30), and mortality rates increased by a factor of 1.19 (95% CI = 0.99-1.43). SVI values are spatially linked and significantly associated with Louisiana's COVID-19-related vaccination and mortality rates. We also found that vaccination uptake was higher in whites than in blacks. These findings can help identify regions with low vaccination rates and high mortality, enabling the necessary steps to increase vaccination rates in disadvantaged neighborhoods.

HIV testing inside Brazilian female prisons: results of a national survey.

This study aimed to identify the prevalence of women in prisons who have already had an HIV test inside prison and the factors associated with this test. A cross-sectional study was carried out with 1327 women in 15 prisons in 9 states in Brazil. Almost 60% (95% CI: 57.8-63.7) of women have already been tested for HIV in prison. The factors associated with this HIV test were age ≥41 years (OR = 1.9; 95% CI = 1.2-2.9), highest level of education (OR = 1.9; 95% CI = 1.3-2.8), having been arrested 3 or more times (OR = 1.9; 95% CI = 1.3-2.8), having received information about HIV/STI in the lifetime (OR = 1.4; 95% CI = 1.1-1.9) and perceived themselves to be at no risk for HIV infection (OR = 1.7; 95% CI = 1.2-2.5), black or mixed race (OR = 0.7; 95% CI = 0.5-0.9) and having a male sexual partner (OR = 0.6; 95% CI = 0.5-0.9). The routine HIV testing in prisons needs to be expanded to promote HIV prevention for a population with limited access to these services outside of prison.

COVID-19 drive-through mass vaccination in Northwest Louisiana.

Background: Vaccinating susceptible populations quickly and safely is vital during a pandemic. Mass vaccination programs using a drive-through method have been shown to reach large numbers of people efficiently during vaccine campaigns. Methods: We performed a quantitative, cross-sectional study analyzing data collected by the COVID-19 mass vaccination program conducted by Louisiana State University Health Shreveport (LSUSH). Results: Between December 2020 and September 2021, the vaccination program administered 90,655 COVID-19 vaccines. Among those who received at least the first dose of the vaccine, there were 21,700 men and 28,269 women; 22,820 were ≥60 years of age; 28,031 identified as Caucasian, 19,249 as African American, 47,916 as non-Hispanic, and most of them reported that they had not tested positive for COVID-19 before vaccination. Discussion: The LSUHS vaccination center served people from different regions within Louisiana as well as those from outside Louisiana. Vaccination is a crucial public health measure in the fight against the COVID-19 pandemic. Conclusions: Our study showed that the mass vaccination program conducted by LSUHS had a considerable positive impact on communities in Northwest Louisiana. This drive-through method is an effective strategy with which to reach a significant number of people during a pandemic.

Spatial expression of the FGFR2b splice isoform and its prognostic significance in endometrioid endometrial carcinoma.

Endometrial carcinoma (EC) is the most common gynecological malignancy and fibroblast growth factor receptor 2 (FGFR2) is a frequently dysregulated receptor tyrosine kinase. FGFR2b and FGFR2c are the two main splice isoforms of FGFR2 and are normally localized in epithelial and mesenchymal cells, respectively. Previously, we demonstrated that FGFR2c mRNA expression was associated with aggressive tumor characteristics, shorter progression-free survival (PFS), and disease-specific survival (DSS) in endometrioid ECs (EECs). The objectives of this study were to investigate the spatial expression of FGFR2b in normal and hyperplasia with and without atypia of human endometrium and to assess the prognostic significance of FGFR2b expression in EC. FGFR2b and FGFR2c mRNA expression was evaluated in normal (proliferative [n = 10], secretory [n = 15], and atrophic [n = 10] endometrium), hyperplasia with and without atypia (n = 19) as well as two patient cohorts of EC samples (discovery [n = 78] and Vancouver [n = 460]) using isoform-specific BaseScope RNA in situ hybridization assays. Tumors were categorized based on FGFR2 isoform expression (one, both, or neither) and categories were correlated with clinicopathologic markers, molecular subtypes, and clinical outcomes. The FGFR2b splice isoform was exclusively expressed in the epithelial compartment of normal endometrium and hyperplasia without atypia. We observed FGFR2c expression at the basalis layer of glands in 33% (3/9) of hyperplasia with atypia. In patients with EEC, FGFR2b+/FGFR2c- expression was found in 48% of the discovery cohort and 35% of the validation Vancouver cohort. In univariate analyses, tumors with FGFR2b+/FGFR2c- expression had longer PFS (hazard ratio [HR] 0.265; 95% CI 0.145-0.423; log-rank p < 0.019) and DSS (HR 0.31; 95% CI 0.149-0.622; log-rank p < 0.001) compared to tumors with FGFR2b-/FGFR2c+ expression in the large EEC Vancouver cohort. In multivariable Cox regression analyses, tumors with FGFR2b+/FGFR2c- expression were significantly associated with longer DSS (HR 0.37; 95% CI 0.153-0.872; log-rank p < 0.023) compared to FGFR2b-/FGFR2c+ tumors. In conclusion, FGFR2b+/FGFR2c- expression is associated with favorable clinicopathologic markers and clinical outcomes suggesting that FGFR2b could play a role in tailoring the management of EEC patients in the clinic if these findings are confirmed in an independent cohort.

Polypharmacy in Children and Young People With Life-limiting Conditions From 2000 to 2015: A Repeated Cross-sectional Study in England.

CONTEXT: Polypharmacy is often appropriate for children with life-limiting conditions but is associated with an increase in hospitalizations and inappropriate prescribing, and can affect the quality of life of children and their families as they manage complex medication schedules. Despite this, little is known about polypharmacy in this population. OBJECTIVE: To describe the prevalence and patterns of polypharmacy in children with a life-limiting condition in a nationally representative cohort in England. METHODS: Observational study of children (age 0-19 years) with a life-limiting condition in a national database from 2000 to 2015. Common definitions of polypharmacy were used to determine polypharmacy prevalence in each year based on unique medications and regular medications. Hierarchical regression analyses were used to explore factors associated with polypharmacy. RESULTS: Data on 15,829 individuals were included. Each year 27%-39% of children were prescribed ≥5 unique medications and 8%-12% were prescribed ≥10. Children with a respiratory (OR 7.6, 95%CI 6.4-9.0), neurological (OR 2.8, 95%CI 2.4-3.2), or metabolic (OR 2.2, 95%CI 1.7-2.8) condition were more likely than those with a congenital condition to experience polypharmacy. Increasing age, being diagnosed with a LLC under one year of age, having >1 life-limiting or chronic condition or living in areas of higher deprivation were also associated with higher prevalence of polypharmacy. CONCLUSION: Children with life-limiting conditions have a high prevalence of polypharmacy and some children are at greater risk than others. More research is needed to understand and address the factors that lead to problematic polypharmacy in this population.

Enablers and barriers to non-dispensing pharmacist integration into the primary health care teams of Aboriginal community-controlled health services.

BACKGROUND: The primary health care management of chronic disease affecting Aboriginal and Torres Strait Islander peoples requires healthcare quality and equity demands to be met, and systems that foster better team-based care. Non-dispensing pharmacists (NDPs) integrated within primary healthcare settings can enhance the quality of patient care, although factors that enable or challenge integration within these settings need to be better understood. OBJECTIVES: To investigate enabling factors and barriers influencing integration of NDPs within Aboriginal community-controlled health services delivering primary health care. This was achieved through qualitative evaluation of the Integrating Pharmacists within Aboriginal Community Controlled Health Services (IPAC) Trial exploring the perceptions of NDPs, community pharmacists, healthcare staff, managers, and Aboriginal and Torres Strait Islander patients of these services. METHODS: NDPs were employed across twenty urban, rural, and remote services in three Australian states and provided pre-defined medication-related roles to adult Aboriginal and Torres Strait Islander patients. Perceptions were elicited from online surveys, interviews, and focus groups. Transcripts were thematically analyzed using the constant comparison method to identify, compare, and refine emerging themes. RESULTS: One hundred and four participants informed the findings, including 24 NDPs, 13 general practitioners, 12 service managers, 10 community pharmacists, 17 health service staff, and 17 patients. Enablers of integration included: personal (previous experience with Aboriginal and Torres Strait Islander peoples, cultural awareness, skills, individual attributes); health service-related (induction programs, Aboriginal Health Worker support, team-building initiatives); and community-related factors (engaged community elders, leaders, cultural mentors, community pharmacy champions). Barriers to NDP integration included a lack of systems supports for patients and staff to adapt to NDP roles, health service factors, travel requirements, a lack of community linkages, and time and budget constraints. CONCLUSIONS: NDP integration within primary health care services has potential to enhance medication-related services to Aboriginal and Torres Strait Islander peoples if enabling factors are supported and health systems and adequate resources facilitate the integration of pharmacists within these settings.

Target occupancy study and whole-body dosimetry with a MAGL PET ligand [11C]PF-06809247 in non-human primates.

BACKGROUND: Monoacylglycerol lipase (MAGL) is a key serine hydrolase which terminates endocannabinoid signaling and regulates arachidonic acid driven inflammatory responses within the central nervous system. To develop [11C]PF-06809247 into a clinically usable MAGL positron emission tomography (PET) radioligand, we assessed the occupancy of MAGL by an inhibitor in the non-human primate (NHP) brain. Additionally, we measured the whole-body distribution of [11C]PF-06809247 in NHP and estimated human effective radiation doses. METHODS: Seven cynomolgus monkeys were enrolled for brain PET measurements. Two PET measurements along with arterial blood sampling were performed in each NHP: one baseline and one pretreatment condition with intravenous administration of PF-06818883, a pro-drug of a selective MAGL inhibitor (total of seven doses between 0.01 and 1.27 mg/kg). Kinetic parameters K1, k2 and k3 were estimated by a two tissue compartment (2TC) model using metabolite corrected plasma radioactivity as the input function. k4 was set as 0 according to the irreversible binding of [11C]PF-06809247. Ki by 2TC and Patlak analysis were calculated as the influx constant. The target occupancy was calculated using Ki at baseline and pretreatment conditions. Two cynomolgus monkeys were enrolled for whole-body PET measurements. Estimates of the absorbed radiation dose in humans were calculated with OLINDA/EXM 1.1 using the adult male reference model. RESULTS: Radioactivity retention was decreased in all brain regions following pretreatment with PF-06818883. Occupancy was measured as 25.4-100.5% in a dose dependent manner. Whole-body PET showed high radioactivity uptake values in the liver, small intestine, kidney, and brain. The effective dose of [11C]PF-06809247 was calculated as 4.3 µSv/MBq. CONCLUSIONS: [11C]PF-06809247 is a promising PET ligand for further studies of MAGL in the human brain.

Acute exposure to sublethal doses of neonicotinoid insecticides increases heat tolerance in honey bees.

The European honey bee, Apis mellifera L., is the single most valuable managed pollinator in the world. Poor colony health or unusually high colony losses of managed honey bees result from a myriad of stressors, which are more harmful in combination. Climate change is expected to accentuate the effects of these stressors, but the physiological and behavioral responses of honey bees to elevated temperatures while under simultaneous influence of one or more stressors remain largely unknown. Here we test the hypothesis that exposure to acute, sublethal doses of neonicotinoid insecticides reduce thermal tolerance in honey bees. We administered to bees oral doses of imidacloprid and acetamiprid at 1/5, 1/20, and 1/100 of LD50 and measured their heat tolerance 4 h post-feeding, using both dynamic and static protocols. Contrary to our expectations, acute exposure to sublethal doses of both insecticides resulted in higher thermal tolerance and greater survival rates of bees. Bees that ingested the higher doses of insecticides displayed a critical thermal maximum from 2 ˚C to 5 ˚C greater than that of the control group, and 67%-87% reduction in mortality. Our study suggests a resilience of honey bees to high temperatures when other stressors are present, which is consistent with studies in other insects. We discuss the implications of these results and hypothesize that this compensatory effect is likely due to induction of heat shock proteins by the insecticides, which provides temporary protection from elevated temperatures.

Patient-derived xenograft models capture genomic heterogeneity in endometrial cancer.

BACKGROUND: Endometrial cancer (EC) is a major gynecological cancer with increasing incidence. It comprises four molecular subtypes with differing etiology, prognoses, and responses to chemotherapy. In the future, clinical trials testing new single agents or combination therapies will be targeted to the molecular subtype most likely to respond. As pre-clinical models that faithfully represent the molecular subtypes of EC are urgently needed, we sought to develop and characterize a panel of novel EC patient-derived xenograft (PDX) models. METHODS: Here, we report whole exome or whole genome sequencing of 11 PDX models and their matched primary tumor. Analysis of multiple PDX lineages and passages was performed to study tumor heterogeneity across lineages and/or passages. Based on recent reports of frequent defects in the homologous recombination (HR) pathway in EC, we assessed mutational signatures and HR deficiency scores and correlated these with in vivo responses to the PARP inhibitor (PARPi) talazoparib in six PDXs representing the copy number high/p53-mutant and mismatch-repair deficient molecular subtypes of EC. RESULTS: PDX models were successfully generated from grade 2/3 tumors, including three uterine carcinosarcomas. The models showed similar histomorphology to the primary tumors and represented all four molecular subtypes of EC, including five mismatch-repair deficient models. The different PDX lineages showed a wide range of inter-tumor and intra-tumor heterogeneity. However, for most PDX models, one arm recapitulated the molecular landscape of the primary tumor without major genomic drift. An in vivo response to talazoparib was detected in four copy number high models. Two models (carcinosarcomas) showed a response consistent with stable disease and two models (one copy number high serous EC and another carcinosarcoma) showed significant tumor growth inhibition, albeit one consistent with progressive disease; however, all lacked the HR deficiency genomic signature. CONCLUSIONS: EC PDX models represent the four molecular subtypes of disease and can capture intra-tumor heterogeneity of the original primary tumor. PDXs of the copy number high molecular subtype showed sensitivity to PARPi; however, deeper and more durable responses will likely require combination of PARPi with other agents.

Results of PD-L1 Analysis of Women Treated with Durvalumab in Advanced Endometrial Carcinoma (PHAEDRA).

Women with advanced endometrial carcinoma (EC) with mismatch repair (MMR) deficiency have improved outcomes when treated with immune checkpoint inhibitors; however, additional biomarkers are needed to identify women most likely to respond. Scores for programmed death ligand 1 (PD-L1), immunohistochemical staining of tumor (TC+), immune cells (IC+) and presence of tumor-associated immune cells (ICP) on MMR deficient (n = 34) and proficient (n = 33) EC from women treated with durvalumab in the PHAEDRA trial (ANZGOG1601/CTC0144) (trial registration number ACTRN12617000106336, prospectively registered 19 January 2017) are reported and correlated with outcome. Receiver operating characteristic (ROC) analyses and area under the ROC curve were used to determine optimal cutpoints. Performance was compared with median cutpoints and two algorithms; a novel algorithm derived from optimal cutpoints (TC+ ≥ 1 or ICP ≥ 10 or IC+ ≥ 35) and the Ventana urothelial carcinoma (UC) algorithm (either TC+ ≥ 25, ICP > 1 and IC+ ≥ 25 or ICP = 1 and IC+ = 100). The cutpoint ICP ≥ 10 had highest sensitivity (53%) and specificity (82%), being prognostic for progression-free survival (PFS) (p = 0.01), while the optimal cutpoints algorithm was associated with overall survival (p = 0.02); these results were not significant after adjusting for MMR status. The optimal cutpoints algorithm identified non-responders (p = 0.02) with high sensitivity (88%) and negative predictive value (92%), remaining significant after adjustment for MMR. Although MMR status had the strongest association with response, further work to determine the significance of ICP ≥ 10 and the novel optimal cutpoint algorithm is needed.