What are the information needs of people with dementia and their family caregivers when they are admitted to a mental health ward and do current ward patient information leaflets meet their needs?

INTRODUCTION: An admission to a mental health ward is an uncertain and unexpected part of a person's journey with dementia and consequently, families require information about what to expect and how to prepare. This study aimed to establish the information needs of people with dementia and their families at the point of admission to a mental health ward and to collate existing ward information leaflets to explore if they meet these information needs. METHODS: This research was conducted in two parts: (1) a qualitative study using focus groups, one with people with dementia and family carers with lived experience of such an admission (n = 6), and another with Admiral Nurses (n = 6) to explore information needs at the point of admission. (2) Each National Health Service (NHS) mental health trust (n = 67) was asked to provide a copy of their ward information shared at admission. A total of 30 leaflets were received from 15 NHS trusts; after removing duplicates, 22 were included. A content analysis was conducted to evaluate to what extent leaflets met the information needs identified by focus groups. RESULTS: Two main categories 'honest, accurate and up-to-date information' and 'who is the information for' and four subcategories were derived from focus group data. Participants felt that people with dementia and their families were likely to have different information needs. Material for people with dementia needed to be in an accessible format. Information should cover the aim of the admission, a timeline of what to expect and details about how families will be involved in care. Practical information about what to pack and ward facilities was valued. Participants spoke about the need to consider the tone of the information, given that people are likely to be distressed. The information leaflets reviewed did not meet the information needs identified by focus group participants. CONCLUSIONS: People with dementia and family carers have different information needs at the point of admission to a mental health ward. Information provided to people with dementia needs to be in an accessible format with content relevant to these needs. Wards should aim to co-create information to ensure that they meet people's information needs. PATIENT OR PUBLIC CONTRIBUTION: This research was supported by a patient and public involvement (PPI) group of people with dementia and carers who have experience in mental health wards. The idea for the study came from the group and was motivated by their experiences. The PPI group helped with the design of the study and took part in the focus groups. The information generated has been written up in this paper, and the knowledge generated has also been used to co-create a guide for wards on writing their information leaflets and to support the co-creation of a public information leaflet by Dementia UK about mental health admissions for people with dementia.

ECMO simulation: How much, who to train, and a review of cost, fidelity and performance.

BACKGROUND: Extracorporeal Membrane Oxygenation (ECMO) is a high-risk, low-volume procedure requiring repetition, skill and multiple disciplines with fidelity of communication. Yet many barriers exist to maintain proficiency and skills with variable cost and fidelity. We designed and implemented a low-cost monthly ECMO simulation and hypothesized providers would have increased familiarity and improved teamwork. We also review some key elements of cost, fidelity and evaluation of effectiveness. METHODS: A structured, 1-hour ECMO simulation was performed on a customized mannikin on a monthly basis in 2022. Qualitative surveys were administered to each member post-simulation. Answers were categorized by theme, including satisfaction of patient care, evaluation of self and team dynamics, and areas for improvement. RESULTS: Most participants were satisfied with their ability to take care of the patient, with common themes of communication and coordination of roles. Identified areas of improvement were mostly limited to technical skills, and soft skills such as communication and teamwork. CONCLUSIONS: We designed and implemented a low-cost, monthly and multi-disciplinary ECMO simulation program with overall positive feedback and identified areas for improvement. There remains variability in cost, fidelity and evaluation of performance and retention. There may be a need to create guidelines for ECMO simulation training that can be applied at all institutions utilizing ECMO for patient care.

In vitro mutagenicity of selected environmental carcinogens and their metabolites in MutaMouse FE1 lung epithelial cells.

Chemicals in commerce or under development must be assessed for genotoxicity; assessment is generally conducted using validated assays (e.g. Tk mouse lymphoma assay) as part of a regulatory process. Currently, the MutaMouse FE1 cell mutagenicity assay is undergoing validation for eventual use as a standard in vitro mammalian mutagenicity assay. FE1 cells have been shown to be metabolically competent with respect to some cytochrome P450 (CYP) isozymes; for instance, they can convert the human carcinogen benzo[a]pyrene into its proximate mutagenic metabolite. However, some contradictory results have been noted for other genotoxic carcinogens that require two-step metabolic activation (e.g. 2-acetylaminofluorene and 2-amino-3-methylimidazo[4,5-f]quinoxaline). Here, we examined three known or suspected human carcinogens, namely acrylamide, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 4-aminobiphenyl (4-ABP), together with their proximate metabolites (i.e. glycidamide, N-OH-PhIP and N-OH-4-ABP), to aid in the validation of the FE1 cell mutagenicity assay. Assessments of the parent compounds were conducted both in the presence and absence of an exogenous metabolic activation mixture S9; assessments of the metabolites were in the absence of S9. The most potent compound was N-OH-PhIP -S9, which elicited a mutant frequency (MF) level 5.3-fold over background at 5 µM. There was a 4.3-fold increase for PhIP +S9 at 5 µM, a 1.7-fold increase for glycidamide -S9 at 3.5 mM and a 1.5-fold increase for acrylamide +S9 at 4 mM. Acrylamide -S9 elicited a marginal 1.4-fold MF increase at 8 mM. Treatment with PhIP -S9, 4-ABP ±S9 and N-OH-4-ABP -S9 failed to elicit significant increases in lacZ MF with any of the treatment conditions tested. Gene expression of key CYP isozymes was quantified by RT-qPCR. Cyp1a1, 1a2 and 1b1 are required to metabolise PhIP and 4-ABP. Results showed that treatment with both compounds induced expression of Cyp1a1 and Cyp1b1 but not Cyp1a2. Cyp2e1, which catalyses the bioactivation of acrylamide to glycidamide, was not induced after acrylamide treatment. Overall, our results confirm that the FE1 cell mutagenicity assay has the potential for use alongside other, more traditional in vitro mutagenicity assays.

Radiology and patient communication: if not now, then when?

KEY POINTS: • Communication with patients in radiology is, in general, indirect using the referrer as a conduit. • Direct patient communication may be beneficial for radiology departments and radiologists to improve patient awareness about the nature of our role and also to provide correct and measured information about the nature and frequency of discrepancies in radiology.

Clinicians' perceptions of the quality of outsourced radiology and actions taken around perceived imaging errors in practice.

OBJECTIVES: Outsourcing of radiological reporting services has fundamentally altered communication between radiologists and clinicians in clinical decision making, which relies heavily on diagnostic imaging. The aim of this study was to understand clinicians' perspectives and experiences of interpretation of outsourced reports in clinical practice, if the author of imaging reports matters to clinicians, and actions taken to deal with perceived errors. METHODS: A printed survey was distributed to a purposive sample of 50 of the 250 senior medical and surgical staff of a large National Health Service hospital in the UK who regularly engaged with the Radiology Department between May and October 2017, representing 20% of this hospital workforce. The survey consisted of ten questions examining clinicians' opinions on radiology reporting, with comment options to encourage respondents to give further detail. Participants were requested to return the survey to the study investigators. RESULTS: The survey elicited a 100% response rate (n = 50). A constant comparative framework was used to guide analysis, revealing themes relevant to the ongoing inter-professional relationship between clinicians and radiologists. The disparity between in-house and externally sourced radiology reports and underlying issues of trust surrounding outsourced reports were the most significant themes identified. CONCLUSIONS: This study found outsourcing of radiology reporting needs multi-disciplinary team availability regarding the interpretation and discussions around capacity for effective communication. It raises important issues around often under-acknowledged additional workloads imposed on in-house radiologists. There are financial and pragmatic clinical aspects in pathways of radiology practice which require further research and examination. KEY POINTS: • Utilisation of outsourcing is increasing in practice in response to imaging demands. • Outsourcing increases departmental primary reporting capacity but may increase the workload of the local radiologist. • The development of strategies for outsourcing examinations may lessen demands on the in-house workforce.

The utility of metabolic activation mixtures containing human hepatic post-mitochondrial supernatant (S9) for in vitro genetic toxicity assessment.

In vitro genotoxicity assessment routinely employs an exogenous metabolic activation mixture to simulate mammalian metabolism. Activation mixtures commonly contain post-mitochondrial liver supernatant (i.e. S9) from chemically induced Sprague Dawley rats. Although Organization for Economic Cooperation and Development (OECD) test guidelines permit the use of other S9 preparations, assessments rarely employ human-derived S9. The objective of this study is to review and evaluate the use of human-derived S9 for in vitro genetic toxicity assessment. All available published genotoxicity assessments employing human S9 were compiled for analysis. To facilitate comparative analyses, additional matched Ames data using induced rat liver S9 were obtained for certain highly cited chemicals. Historical human and induced rat S9 quality control reports from Moltox were obtained and mined for enzyme activity and mutagenic potency data. Additional in vitro micronucleus data were experimentally generated using human and induced rat S9. The metabolic activity of induced rat S9 was found to be higher than human S9, and linked to high mutagenic potency results. This study revealed that human S9 often yields significantly lower Salmonella mutagenic potency values, especially for polycyclic aromatic hydrocarbons, aflatoxin B1 and heterocyclic amines (~3- to 350-fold). Conversely, assessment with human S9 activation yields higher potency for aromatic amines (~2- to 50-fold). Outliers with extremely high mutagenic potency results were observed in the human S9 data. Similar trends were observed in experimentally generated mammalian micronucleus cell assays, however human S9 elicited potent cytotoxicity L5178Y, CHO and TK6 cell lines. Due to the potential for reduced sensitivity and the absence of a link between enzyme activity levels and mutagenic potency, human liver S9 is not recommended for use alone in in vitro genotoxicity screening assays; however, human S9 may be extremely useful in follow-up tests, especially in the case of chemicals with species-specific metabolic differences, such as aromatic amines.

Mouthguard Use and Awareness of Junior Rugby League Players in the Gold Coast, Australia: A Need for More Education.

OBJECTIVE: To investigate knowledge, attitude, and awareness of appropriate mouthguard use, as well as the management of traumatic dental injuries (TDIs). DESIGN: Cross-sectional survey. SETTING: Community survey. PARTICIPANTS: Four hundred ninety-four junior rugby league players and their coaches in the Gold Coast, Australia. INTERVENTIONS: Data were collected anonymously during training sessions by means of a survey questionnaire, followed by a presentation on mouthguards and the management of TDIs. MAIN OUTCOME MEASURES: Descriptive statistics on the frequency distribution of the demographic characteristics, knowledge, and use of mouthguards as well as the relationships between the type of mouthguard worn and questions related to mouthguard use. RESULTS: The majority of players surveyed reported wearing a mouthguard (68.2%). Cost (40.1%) and not believing that they work (35.7%) were listed as the main reasons for not doing so. The boil-and-bite type was the most used by players (64.7%). Almost 44% of coaches and 50% of players responded that only a dentist can manage an avulsed tooth, that a tooth had to be reinserted within 15 minutes (40.6% and 21.9%, respectively), and that either water or milk can be used to transport an avulsed tooth to the dentist (100% and 82.2%, respectively). CONCLUSIONS: Education related to the correct use of mouthguards and the management of TDIs should be ongoing for players, their caregivers, and their coaches and should be required as part of the training of coaches to prevent injury in rugby league. CLINICAL RELEVANCE: This study found that although the overwhelming majority of junior rugby league coaches encourage the wearing of mouthguards, only two-thirds of the players do so. Players' compliance to wear mouthguards is largely influenced by their perception of efficacy and its comfort. Educational campaigns with involvement of dental practitioners, related to the correct use of mouthguards and the management of TDIs, should be ongoing for players, their caregivers, and their coaches and should also be required as part of the training of coaches.

The Impact of Social Media on Dissemination and Implementation of Clinical Practice Guidelines: A Longitudinal Observational Study.

BACKGROUND: Evidence-based clinical practice guidelines (CPGs) are statements that provide recommendations to optimize patient care for a specific clinical problem or question. Merely reading a guideline rarely leads to implementation of recommendations. The American Academy of Neurology (AAN) has a formal process of guideline development and dissemination. The last few years have seen a burgeoning of social media such as Facebook, Twitter, and LinkedIn, and newer methods of dissemination such as podcasts and webinars. The role of these media in guideline dissemination has not been studied. Systematic evaluation of dissemination methods and comparison of the effectiveness of newer methods with traditional methods is not available. It is also not known whether specific dissemination methods may be more effectively targeted to specific audiences. OBJECTIVE: Our aim was to (1) develop an innovative dissemination strategy by adding social media-based dissemination methods to traditional methods for the AAN clinical practice guidelines "Complementary and alternative medicine in multiple sclerosis" ("CAM in MS") and (2) evaluate whether the addition of social media outreach improves awareness of the CPG and knowledge of CPG recommendations, and affects implementation of those recommendations. METHODS: Outcomes were measured by four surveys in each of the two target populations: patients and physicians/clinicians ("physicians"). The primary outcome was the difference in participants' intent to discuss use of complementary and alternative medicine (CAM) with their physicians or patients, respectively, after novel dissemination, as compared with that after traditional dissemination. Secondary outcomes were changes in awareness of the CPG, knowledge of CPG content, and behavior regarding CAM use in multiple sclerosis (MS). RESULTS: Response rates were 25.08% (622/2480) for physicians and 43.5% (348/800) for patients. Awareness of the CPG increased after traditional dissemination (absolute difference, 95% confidence interval: physicians 36%, 95% CI 25-46, and patients 10%, 95% CI 1-11) but did not increase further after novel dissemination (physicians 0%, 95% CI -11 to 11, and patients -4%, 95% CI -6 to 14). Intent to discuss CAM also increased after traditional dissemination but did not change after novel dissemination (traditional: physicians 12%, 95% CI 2-22, and patients 19%, 95% CI 3-33; novel: physicians 11%, 95% CI -1 to -21, and patients -8%, 95% CI -22 to 8). Knowledge of CPG recommendations and behavior regarding CAM use in MS did not change after either traditional dissemination or novel dissemination. CONCLUSIONS: Social media-based dissemination methods did not confer additional benefit over print-, email-, and Internet-based methods in increasing CPG awareness and changing intent in physicians or patients. Research on audience selection, message formatting, and message delivery is required to utilize Web 2.0 technologies optimally for dissemination.

Intellectual development is positively related to intrinsic motivation and course grades for female but not male students.

We hypothesized that the intellectual development of students, i.e., their beliefs about the nature of knowledge and learning, affects their intrinsic motivation and class performance. Specifically, we hypothesized that students with low intellectual development (i.e., the naive beliefs that knowledge is simple, absolute, and certain) have low intrinsic motivation and low class performance, whereas students with high intellectual development (i.e., more sophisticated beliefs that knowledge is complex, tentative, and evolving) have high intrinsic motivation and class performance. To test this hypothesis, we administered the Learning Context Questionnaire to measure intellectual development. In addition, we administered the Intrinsic Motivation Inventory to assess our students' intrinsic motivation. Furthermore, we performed regression analyses between intellectual development with both intrinsic motivation and class performance. The results document a positive relationship among intellectual development, intrinsic motivation, and class performance for female students only. In sharp contrast, there was a negative relationship between intellectual development, intrinsic motivation, and class performance for male students. The slope comparisons documented significant differences in the slopes relating intellectual development, intrinsic motivation, and class performance between female and male students. Thus, female students with more sophisticated beliefs that knowledge is personally constructed, complex, and evolving had higher intrinsic motivation and class performance. In contrast, male students with the naive beliefs that the structure of knowledge is simple, absolute, and certain had higher levels of intrinsic motivation and class performance. The results suggest that sex influences intellectual development, which has an effect on intrinsic motivation for learning a specific topic.

Resistance to two heterologous neurotropic oncolytic viruses, Semliki Forest virus and vaccinia virus, in experimental glioma.

Attenuated Semliki Forest virus (SFV) may be suitable for targeting malignant glioma due to its natural neurotropism, but its replication in brain tumor cells may be restricted by innate antiviral defenses. We attempted to facilitate SFV replication in glioma cells by combining it with vaccinia virus, which is capable of antagonizing such defenses. Surprisingly, we found parenchymal mouse brain tumors to be refractory to both viruses. Also, vaccinia virus appears to be sensitive to SFV-induced antiviral interference.

Uncertainty-aware image classification on 3D CT lung.

Early detection is crucial for lung cancer to prolong the patient's survival. Existing model architectures used in such systems have shown promising results. However, they lack reliability and robustness in their predictions and the models are typically evaluated on a single dataset, making them overconfident when a new class is present. With the existence of uncertainty, uncertain images can be referred to medical experts for a second opinion. Thus, we propose an uncertainty-aware framework that includes three phases: data preprocessing and model selection and evaluation, uncertainty quantification (UQ), and uncertainty measurement and data referral for the classification of benign and malignant nodules using 3D CT images. To quantify the uncertainty, we employed three approaches; Monte Carlo Dropout (MCD), Deep Ensemble (DE), and Ensemble Monte Carlo Dropout (EMCD). We evaluated eight different deep learning models consisting of ResNet, DenseNet, and the Inception network family, all of which achieved average F1 scores above 0.832, and the highest average value of 0.845 was obtained using InceptionResNetV2. Furthermore, incorporating the UQ demonstrated significant improvement in the overall model performance. Upon evaluation of the uncertainty estimate, MCD outperforms the other UQ models except for the metric, URecall, where DE and EMCD excel, implying that they are better at identifying incorrect predictions with higher uncertainty levels, which is vital in the medical field. Finally, we show that using a threshold for data referral can greatly improve the performance further, increasing the accuracy up to 0.959.

Higher levels of intrinsic motivation are related to higher levels of class performance for male but not female students.

Our students are naturally curious, with powerful intrinsic motives to understand their world. Accordingly, we, as teachers, must capitalize on this inherently active and curious nature so that learning becomes a lifelong activity where students take initiative for learning, are skilled in learning, and want to learn new things. Achieving this goal requires an understanding of student attitudes, beliefs, characteristics, and motivations. To achieve this goal, we administered the intrinsic motivation inventory (IMI) to assess our students' interest and enjoyment, perceived choice, and perceived competence while taking our undergraduate exercise physiology class (46 students; 20 female students and 26 male students). The interest and enjoyment subscale is considered the self-reported measure of intrinsic motivation. The perceived choice and perceived competence concepts are theorized to be positive predictors of both self-reported and behavioral measures of intrinsic motivation. Our results documented a significant increase in course grade with an increase in survey score for the interest and enjoyment subscale of the IMI when female and male students were combined. Specifically, each increase in survey score for the interest and enjoyment subscale of the IMI was associated with a significant (P < 0.05) increase of 3.9% in course grade. However, the increase in survey score was associated with a significantly greater (P < 0.05) increase in course grade for male (6.1%) compared with female (0.3%) students. These results have implications for both classroom practice and educational reform policies.

Application of a new approach methodology (NAM)-based strategy for genotoxicity assessment of data-poor compounds.

The conventional battery for genotoxicity testing is not well suited to assessing the large number of chemicals needing evaluation. Traditional in vitro tests lack throughput, provide little mechanistic information, and have poor specificity in predicting in vivo genotoxicity. New Approach Methodologies (NAMs) aim to accelerate the pace of hazard assessment and reduce reliance on in vivo tests that are time-consuming and resource-intensive. As such, high-throughput transcriptomic and flow cytometry-based assays have been developed for modernized in vitro genotoxicity assessment. This includes: the TGx-DDI transcriptomic biomarker (i.e., 64-gene expression signature to identify DNA damage-inducing (DDI) substances), the MicroFlow® assay (i.e., a flow cytometry-based micronucleus (MN) test), and the MultiFlow® assay (i.e., a multiplexed flow cytometry-based reporter assay that yields mode of action (MoA) information). The objective of this study was to investigate the utility of the TGx-DDI transcriptomic biomarker, multiplexed with the MicroFlow® and MultiFlow® assays, as an integrated NAM-based testing strategy for screening data-poor compounds prioritized by Health Canada's New Substances Assessment and Control Bureau. Human lymphoblastoid TK6 cells were exposed to 3 control and 10 data-poor substances, using a 6-point concentration range. Gene expression profiling was conducted using the targeted TempO-Seq™ assay, and the TGx-DDI classifier was applied to the dataset. Classifications were compared with those based on the MicroFlow® and MultiFlow® assays. Benchmark Concentration (BMC) modeling was used for potency ranking. The results of the integrated hazard calls indicate that five of the data-poor compounds were genotoxic in vitro, causing DNA damage via a clastogenic MoA, and one via a pan-genotoxic MoA. Two compounds were likely irrelevant positives in the MN test; two are considered possibly genotoxic causing DNA damage via an ambiguous MoA. BMC modeling revealed nearly identical potency rankings for each assay. This ranking was maintained when all endpoint BMCs were converted into a single score using the Toxicological Prioritization (ToxPi) approach. Overall, this study contributes to the establishment of a modernized approach for effective genotoxicity assessment and chemical prioritization for further regulatory scrutiny. We conclude that the integration of TGx-DDI, MicroFlow®, and MultiFlow® endpoints is an effective NAM-based strategy for genotoxicity assessment of data-poor compounds.

The lack of effect of low temperature and high turbidity on operational Bacillus thuringiensis subsp. israelensis activity against larval black flies (Diptera: Simuliidae).

Black fly suppression programs are conducted across a wide range of environmental conditions, targeting a variety of pest species with diverse life histories. Operational applications of Vectobac 12AS (Bacillus thuringiensis subsp. israelensis) were conducted during times characterized by water temperature and turbidity extremes. Applications were conducted in the Yellow River in central Wisconsin targeting Simulium annulus and S. johannseni when water temperatures were 1-2 degrees C. Applications were conducted in the Green River in western North Carolina targeting the S. jenningsi group after a rain event, when portions of the treatment zone experienced turbidities of 276 nephelometric turbidity units. Excellent larvicidal activity was observed in both programs, with 97% mortality or greater being observed at distances over 5 km downstream of a treatment site. Mortality data for larval black flies in 2 operational suppression programs conducted in 2011 demonstrated a negligible effect of near-freezing water temperatures and exceptionally high turbidity on Bti activity.

Division of Labor by the HELQ, BLM, and FANCM Helicases during Homologous Recombination Repair in Drosophila melanogaster.

Repair of DNA double-strand breaks by homologous recombination (HR) requires a carefully orchestrated sequence of events involving many proteins. One type of HR, synthesis-dependent strand annealing (SDSA), proceeds via the formation of a displacement loop (D-loop) when RAD51-coated single-stranded DNA invades a homologous template. The 3' end of the single-stranded DNA is extended by DNA synthesis. In SDSA, the D-loop is then disassembled prior to strand annealing. While many helicases can unwind D-loops in vitro, how their action is choreographed in vivo remains to be determined. To clarify the roles of various DNA helicases during SDSA, we used a double-strand gap repair assay to study the outcomes of homologous recombination repair in Drosophila melanogaster lacking the BLM, HELQ, and FANCM helicases. We found that the absence of any of these three helicases impairs gap repair. In addition, flies lacking both BLM and HELQ or HELQ and FANCM had more severe SDSA defects than the corresponding single mutants. In the absence of BLM, a large percentage of repair events were accompanied by flanking deletions. Strikingly, these deletions were mostly abolished in the blm helq and blm fancm double mutants. Our results suggest that the BLM, HELQ, and FANCM helicases play distinct roles during SDSA, with HELQ and FANCM acting early to promote the formation of recombination intermediates that are then processed by BLM to prevent repair by deletion-prone mechanisms.

A systematic review of obesity as a barrier to accessing cancer screening services.

Introduction: Obesity is a known risk factor for the development of cancers, and a significant proportion of the population may be at risk of developing cancer owing to their weight status. There is acknowledged societal stigma towards people living with obesity, which can influence health behaviors and deter help seeking, such as cancer screening. Healthcare professionals' attitudes and views toward people living with obesity may adversely affect the patient-professional interface and treatment. Methods: A systematic review was carried out which aimed to explore the impact of living with obesity on the uptake of three main cancer-screening services: breast, cervical, and colorectal. Results: Ten studies were included in the review. Three main areas were identified from both a patient and healthcare professional perspective: barriers and challenges to screening, gender issues, and disparities in the population living with obesity. Conclusion: Further research is needed to improve uptake of cancer screening services, and for education on weight bias, which is often unconscious, to be considered for healthcare professionals working in cancer screening services. This may help to increase the incidence of early differential diagnosis of potential cancers and improve health outcomes for people living with obesity.

Progesterone increases skeletal muscle mitochondrial H2O2 emission in nonmenopausal women.

The luteal phase of the female menstrual cycle is associated with both 1) elevated serum progesterone (P4) and estradiol (E2), and 2) reduced insulin sensitivity. Recently, we demonstrated a link between skeletal muscle mitochondrial H(2)O(2) emission (mE(H2O2)) and insulin resistance. To determine whether serum levels of P4 and/or E(2) are related to mitochondrial function, mE(H2O2) and respiratory O(2) flux (Jo(2)) were measured in permeabilized myofibers from insulin-sensitive (IS, n = 24) and -resistant (IR, n = 8) nonmenopausal women (IR = HOMA-IR > 3.6). Succinate-supported mE(H2O2) was more than 50% greater in the IR vs. IS women (P < 0.05). Interestingly, serum P4 correlated positively with succinate-supported mE(H2O2) (r = 0. 53, P < 0.01). To determine whether P4 or E2 directly affect mitochondrial function, saponin-permeabilized vastus lateralis myofibers biopsied from five nonmenopausal women in the early follicular phase were incubated in P4 (60 nM), E2 (1.4 nM), or both. P4 alone inhibited state 3 Jo(2), supported by multisubstrate combination (P < 0.01). However, E2 alone or in combination with P4 had no effect on Jo(2). In contrast, during state 4 respiration, supported by succinate and glycerophosphate, mE(H2O2) was increased with P4 alone or in combination with E2 (P < 0.01). The results suggest that 1) P4 increases mE(H2O2) with or without E2; 2) P4 alone inhibits Jo(2) but not when E2 is present; and 3) P4 is related to the mE(H2O2) previously linked to skeletal muscle insulin resistance.

A high-throughput pharmacoviral approach identifies novel oncolytic virus sensitizers.

Oncolytic viruses (OVs) are promising anticancer agents but like other cancer monotherapies, the genetic heterogeneity of human malignancies can lead to treatment resistance. We used a virus/cell-based assay to screen diverse chemical libraries to identify small molecules that could act in synergy with OVs to destroy tumor cells that resist viral infection. Several molecules were identified that aid in viral oncolysis, enhancing virus replication and spread as much as 1,000-fold in tumor cells. One of these molecules we named virus-sensitizers 1 (VSe1), was found to target tumor innate immune response and could enhance OV efficacy in animal tumor models and within primary human tumor explants while remaining benign to normal tissues. We believe this is the first example of a virus/cell-based "pharmacoviral" screen aimed to identify small molecules that modulate cellular response to virus infection and enhance oncolytic virotherapy.