Comparison of artificial intelligence large language model chatbots in answering frequently asked questions in anaesthesia.

Background: Patients are increasingly using artificial intelligence (AI) chatbots to seek answers to medical queries. Methods: Ten frequently asked questions in anaesthesia were posed to three AI chatbots: ChatGPT4 (OpenAI), Bard (Google), and Bing Chat (Microsoft). Each chatbot's answers were evaluated in a randomised, blinded order by five residency programme directors from 15 medical institutions in the USA. Three medical content quality categories (accuracy, comprehensiveness, safety) and three communication quality categories (understandability, empathy/respect, and ethics) were scored between 1 and 5 (1 representing worst, 5 representing best). Results: ChatGPT4 and Bard outperformed Bing Chat (median [inter-quartile range] scores: 4 [3-4], 4 [3-4], and 3 [2-4], respectively; P<0.001 with all metrics combined). All AI chatbots performed poorly in accuracy (score of ≥4 by 58%, 48%, and 36% of experts for ChatGPT4, Bard, and Bing Chat, respectively), comprehensiveness (score ≥4 by 42%, 30%, and 12% of experts for ChatGPT4, Bard, and Bing Chat, respectively), and safety (score ≥4 by 50%, 40%, and 28% of experts for ChatGPT4, Bard, and Bing Chat, respectively). Notably, answers from ChatGPT4, Bard, and Bing Chat differed statistically in comprehensiveness (ChatGPT4, 3 [2-4] vs Bing Chat, 2 [2-3], P<0.001; and Bard 3 [2-4] vs Bing Chat, 2 [2-3], P=0.002). All large language model chatbots performed well with no statistical difference for understandability (P=0.24), empathy (P=0.032), and ethics (P=0.465). Conclusions: In answering anaesthesia patient frequently asked questions, the chatbots perform well on communication metrics but are suboptimal for medical content metrics. Overall, ChatGPT4 and Bard were comparable to each other, both outperforming Bing Chat.

Gut microbiota composition is associated with the efficacy of Delta-24-RGDOX in malignant gliomas.

Glioblastoma, the most common primary brain tumor, has a 6.8% survival rate 5 years post diagnosis. Our team developed an oncolytic adenovirus with an OX-40L expression cassette named Delta-24-RGDOX. While studies have revealed the interaction between the gut microbiota and immunotherapy agents, there are no studies linking the gut microbiota with viroimmunotherapy efficacy. We hypothesize that gut bacterial signatures will be associated with oncolytic viral therapy efficacy. To test this hypothesis, we evaluated the changes in gut microbiota in two mouse cohorts: (1) GSC-005 glioblastoma-bearing mice treated orally with indoximod, an immunotherapeutic agent, or with Delta-24-RGDOX by intratumoral injection and (2) a mouse cohort harboring GL261-5 tumors used to mechanistically evaluate the importance of CD4+ T cells in relation to viroimmunotherapy efficacy. Microbiota assessment indicated significant differences in the structure of the gut bacterial communities in viroimmunotherapy-treated animals with higher survival compared with control or indoximod-treated animals. Moreover, viroimmunotherapy-treated mice with prolonged survival had a higher abundance of Bifidobacterium. The CD4+ T cell depletion was associated with gut dysbiosis, lower mouse survival, and lower antitumor efficacy of the therapy. These findings suggest that microbiota modulation along the gut-glioma axis contributes to the clinical efficacy and patient survival of viroimmunotherapy treated animals.

Erratum: Gut microbiota composition is associated with the efficacy of Delta-24-RGDOX in malignant gliomas.

[This corrects the article DOI: 10.1016/j.omton.2024.200787.].

Barriers and facilitators for family physicians prescribing opioid agonist therapy in Saskatchewan.

OBJECTIVE: To explore barriers and facilitators for family physicians in Saskatchewan prescribing opioid agonist therapy (OAT). DESIGN: Self-administered postal survey. SETTING: Family medicine practices in Saskatchewan. PARTICIPANTS: A total of 218 Saskatchewan family physicians who were not authorized to prescribe OAT as of June 2022. MAIN OUTCOME MEASURES: Descriptive and inferential statistics of physicians' self-reported barriers to and facilitators of prescribing OAT for opioid use disorder (OUD). RESULTS: Most respondents (84.8%) had some comfort with diagnosing OUD. However, more than half (58.3%) did not feel confident or knowledgeable about prescribing OAT. Barriers to OAT prescribing included lack of time, incomplete training requirements, lack of interest, insufficient funding or support, feeling overwhelmed, and perceiving that OAT does not work and thus is not necessary. Physicians working in core neighbourhoods and those receiving fee-for-service compensation reported the least available time to prescribe OAT. Conversely, physicians working in interdisciplinary team settings had increased time for OAT prescribing compared with physicians in other settings. Having a close personal relationship with someone with OUD was correlated with increased comfort in diagnosing OUD as well as with knowledge about and confidence in prescribing OAT. Themes identified as facilitators to increasing OAT prescribing included the addition of resources and supports, increased training, more awareness about OUD and OAT, enhanced compensation, and altered prescribing regulations. CONCLUSION: Despite the presence of several real and perceived barriers limiting OAT prescribing by Saskatchewan family physicians, there are family physicians interested in providing this therapy. Increased clinical resources and support, including increased interdisciplinary practice, are actionable steps that should be considered by policy decision makers to address this issue. Additionally, increased OUD and OAT education, which includes the perspectives of those with lived experience of OUD, would help address physician confidence, knowledge, and awareness in this area.

Chimeric oncolytic adenovirus evades neutralizing antibodies from human patients and exhibits enhanced anti-glioma efficacy in immunized mice.

Oncolytic viruses are a promising treatment for patients with high-grade gliomas, but neutralizing antibodies can limit their efficacy in patients with prior virus exposure or upon repeated virus injections. Data from a previous clinical trial using the oncolytic adenovirus Delta-24-RGD showed that generation of anti-viral neutralizing antibodies may affect the long-term survival of glioma patients. Past studies have examined the effects of neutralizing antibodies during systemic virus injections, but largely overlooked their impact during local virus injections into the brain. We found that immunoglobulins colocalized with viral proteins upon local oncolytic virotherapy of brain tumors, warranting a strategy to prevent virus neutralization and maximize oncolysis. Thus, we generated a chimeric virus, Delta-24-RGD-H43m, by replacing the capsid protein HVRs from the serotype 5-based Delta-24-RGD with those from the rare serotype 43. Delta-24-RGD-H43m evaded neutralizing anti-Ad5 antibodies and conferred a higher rate of long-term survival than Delta-24-RGD in glioma-bearing mice. Importantly, Delta-24-RGD-H43m activity was significantly more resistant to neutralizing antibodies present in sera of glioma patients treated with Delta-24-RGD during a phase 1 clinical trial. These findings provide a framework for a novel treatment of glioma patients that have developed immunity against Delta-24-RGD.

Pre-stroke exercise does not reduce atrophy in healthy young adult mice.

Stroke is the main cause of acquired disability in adults. Exercise reduces the risk for stroke and protects against functional loss after stroke. An exercise-induced reduction in key risk factors probably contributes to the protective effect, but direct effects on the brain may also contribute to stroke protection. We previously reported that exercise increases angiogenesis and neurogenesis through activation of the lactate receptor HCA1. Here we exposed young adult wild-type mice and HCA1 knockout mice to interval exercise at high or medium intensity, or to intraperitoneal injections of L-lactate or saline for seven weeks before we induced experimental stroke by permanent occlusion of the distal medial cerebral artery (dMCA). The resulting cortical atrophy measured three weeks after stroke was unaffected by exercise or L-lactate pre-treatments, and independent of HCA1 activation. Our results suggest that the beneficial effect of exercise prior to stroke where no reperfusion occurs is limited in individuals who do not carry risk factors.

Indigenous suicide rates in the United States, Australia and New Zealand between 2006 and 2019.

OBJECTIVE: Indigenous suicide prevention is an important focus for national health policies. Indigenous suicide rates in formerly colonial English-speaking countries such as the United States, Australia and New Zealand are considerably higher than the general population, particularly in young males. Given the similarities in their sociocultural history, a time series analysis was conducted to assess recent sex and age trends of suicide in the Indigenous and general populations in the United States, Australia and New Zealand. METHODS: Using the number of deaths by intentional self-harm and estimated resident population, suicide incidence rates were calculated for the years 2006-2019 and stratified by Indigenous status, year, time period, sex and age group (above 15 years). Incidence rates were plotted. Using the Poisson regression model, calculated suicide incidence rate ratios were used to make comparisons for sex and age. RESULTS: Across all countries studied, Indigenous suicide rates have increased over time, with Indigenous males having higher suicide rates than Indigenous females. However, the increase in Indigenous female suicides was greater than that for Indigenous males in Australia and New Zealand. Indigenous males aged 15-44 years have the highest suicide rates across all countries. CONCLUSION: Indigenous suicide rates have remained consistently high in the United States, Australia and New Zealand, with Indigenous males aged 15-44 years showing the highest rate. However, suicide rates for Indigenous females in Australia and New Zealand are increasing more rapidly than males. Given this, it is critical that further research is dedicated to understanding and addressing the issues driving this problem, particularly in youth.

The molecular basis of the antidepressant action of the magic mushroom extract, psilocin.

Magic mushrooms, and their extract psilocybin, are well-known for their psychedelic properties and recreational use. Psilocin, the bio-active form of psilocybin, can potentially treat various psychiatric diseases. Psilocin putatively exerts its psychedelic effect as an agonist to the serotonin 2A receptor (5-HT2AR), which is also the receptor for the neurological hormone serotonin. The two key chemical differences between the two molecules are first, that the primary amine in serotonin is replaced with a tertiary amine in psilocin, and second, the hydroxyl group is substituted differently on the aromatic ring. Here, we find that psilocin can bind to 5-HT2AR with an affinity higher than serotonin, and provide the molecular logic behind the higher binding affinity of psilocin using extensive molecular dynamics simulations and free energy calculations. The binding free energy of psilocin is dependent upon the protonation states of the ligands, as well as that of the key residue in the binding site: Aspartate 155. We find that the tertiary amine of psilocin, and not the altered substitution of the hydroxyl group in the ring is responsible for the increased affinity of psilocin. We propose design rules for effective antidepressants based on molecular insights from our simulations.

Performance of the fecal immunochemical test for colorectal cancer and advanced neoplasia in individuals under age 50.

The increased demand for colonoscopy combined with increased incidence of colorectal cancer (CRC) among younger populations presents a need to determine FIT performance among individuals in this age group. We conducted a systematic review to assess test performance characteristics of FIT in detecting CRC and advanced neoplasia in younger age populations. A search through December 2022 identified published articles assessing the sensitivity and specificity of FIT for advanced neoplasia or CRC among populations under age 50. Following the search, 3 studies were included in the systematic review. Sensitivity to detect advanced neoplasia ranged from 0.19 to 0.36 and specificity between 0.94 and 0.97 and the overall sensitivity and specificity were 0.23 (0.17-0.30) and 0.96 (0.94-0.98), respectively. Two studies that assessed these metrics in multiple age categories found similar sensitivity and specificity across all age groups 30-49. Sensitivity and specificity to detect CRC was assessed in one study and found no significant differences by age groups. These results suggest that FIT performance may be lower for younger individuals compared to those typically screened for CRC. However, there were few studies available for analysis. Given increasing recommendations to expand screening in younger age groups, more research is needed to determine whether FIT is an adequate screening tool in this population.

Durable responses to alectinib in murine models of EML4-ALK lung cancer requires adaptive immunity.

Lung cancers bearing oncogenic EML4-ALK fusions respond to targeted tyrosine kinase inhibitors (TKIs; e.g., alectinib), with variation in the degree of shrinkage and duration of treatment (DOT). However, factors that control this response are not well understood. While the contribution of the immune system in mediating the response to immunotherapy has been extensively investigated, less is known regarding the contribution of immunity to TKI therapeutic responses. We previously demonstrated a positive association of a TKI-induced interferon gamma (IFNγ) transcriptional response with DOT in EGFR-mutant lung cancers. Herein, we used three murine models of EML4-ALK lung cancer to test the role for host immunity in the alectinib therapeutic response. The cell lines (EA1, EA2, EA3) were propagated orthotopically in the lungs of immunocompetent and immunodeficient mice and treated with alectinib. Tumor volumes were serially measured by µCT and immune cell content was measured by flow cytometry and multispectral immunofluorescence. Transcriptional responses to alectinib were assessed by RNAseq and secreted chemokines were measured by ELISA. All cell lines were similarly sensitive to alectinib in vitro and as orthotopic tumors in immunocompetent mice, exhibited durable shrinkage. However, in immunodeficient mice, all tumor models rapidly progressed on TKI therapy. In immunocompetent mice, EA2 tumors exhibited a complete response, whereas EA1 and EA3 tumors retained residual disease that rapidly progressed upon termination of TKI treatment. Prior to treatment, EA2 tumors had greater numbers of CD8+ T cells and fewer neutrophils compared to EA1 tumors. Also, RNAseq of cancer cells recovered from untreated tumors revealed elevated levels of CXCL9 and 10 in EA2 tumors, and higher levels of CXCL1 and 2 in EA1 tumors. Analysis of pre-treatment patient biopsies from ALK+ tumors revealed an association of neutrophil content with shorter time to progression. Combined, these data support a role for adaptive immunity in durability of TKI responses and demonstrate that the immune cell composition of the tumor microenvironment is predictive of response to alectinib therapy.

Direct-to-consumer orthodontics: Exploring laypeople's perception of orthodontic treatment complexity.

BACKGROUND: The authors aimed to explore the treatment preferences of laypeople regarding direct-to-consumer (DTC) orthodontics and to identify whether case complexity, as perceived by laypeople, is one of the factors influencing interest in DTC orthodontics. METHODS: An online cross-sectional survey was conducted. Data analysis was performed using logistic regression models. RESULTS: A total of 1,362 surveys were completed. A significant inverse association was identified between the complexity of an orthodontic case, as measured using the American Board of Orthodontics' discrepancy index (DI) score, and the likelihood of choosing DTC treatment over an orthodontist. Participants were 3.53 times more likely to choose DTC treatment for a mild case (DI score, 0-10) compared with a complex case (DI score, > 20), although the likelihood of choosing DTC treatment for a moderate case (DI score, 11-20) was only 1.79 times higher than for a complex case. CONCLUSIONS: When laypeople were asked to consider each case as if it were their own dentition, there was a significant inverse association between the complexity of an orthodontic case, as measured using the DI score, and the likelihood of choosing DTC treatment over an orthodontist. Laypeople were seemingly more likely to choose DTC orthodontics for dentitions that did not appear crowded and were well aligned within the arches. Laypeople seemed to have an understanding that there are some limitations to DTC orthodontics. PRACTICAL IMPLICATIONS: Orthodontists should better understand the factors influencing consumers' decisions to select DTC orthodontics and dental organizations should focus their educational campaigns on these factors.

Novel EGFR-mutant mouse models of lung adenocarcinoma reveal adaptive immunity requirement for durable osimertinib response.

Lung cancers bearing oncogenically-mutated EGFR represent a significant fraction of lung adenocarcinomas (LUADs) for which EGFR-targeting tyrosine kinase inhibitors (TKIs) provide a highly effective therapeutic approach. However, these lung cancers eventually acquire resistance and undergo progression within a characteristically broad treatment duration range. Our previous study of EGFR mutant lung cancer patient biopsies highlighted the positive association of a TKI-induced interferon γ transcriptional response with increased time to treatment progression. To test the hypothesis that host immunity contributes to the TKI response, we developed novel genetically-engineered mouse models of EGFR mutant lung cancer bearing exon 19 deletions (del19) or the L860R missense mutation. Both oncogenic EGFR mouse models developed multifocal LUADs from which transplantable cancer cell lines sensitive to the EGFR-specific TKIs, gefitinib and osimertinib, were derived. When propagated orthotopically in the left lungs of syngeneic C57BL/6 mice, deep and durable shrinkage of the cell line-derived tumors was observed in response to daily treatment with osimertinib. By contrast, orthotopic tumors propagated in immune deficient nu/nu or Rag1-/- mice exhibited modest tumor shrinkage followed by rapid progression on continuous osimertinib treatment. Importantly, osimertinib treatment significantly increased intratumoral T cell content and decreased neutrophil content relative to diluent treatment. The findings provide strong evidence supporting the requirement for adaptive immunity in the durable therapeutic control of EGFR mutant lung cancer.

Phylogenomic analyses and host range prediction of cluster P mycobacteriophages.

Bacteriophages, infecting bacterial hosts in every environment on our planet, are a driver of adaptive evolution in bacterial communities. At the same time, the host range of many bacteriophages-and thus one of the selective pressures acting on complex microbial systems in nature-remains poorly characterized. Here, we computationally inferred the putative host ranges of 40 cluster P mycobacteriophages, including members from 6 subclusters (P1-P6). A series of comparative genomic analyses revealed that mycobacteriophages of subcluster P1 are restricted to the Mycobacterium genus, whereas mycobacteriophages of subclusters P2-P6 are likely also able to infect other genera, several of which are commonly associated with human disease. Further genomic analysis highlighted that the majority of cluster P mycobacteriophages harbor a conserved integration-dependent immunity system, hypothesized to be the ancestral state of a genetic switch that controls the shift between lytic and lysogenic life cycles-a temperate characteristic that impedes their usage in antibacterial applications.

Three tests of the Vulnerability-Stress-Adaptation Model: Independent prediction, mediation, and generalizability.

Objective: Efforts to understand why some marriages thrive while others falter are (a) not well integrated conceptually and (b) rely heavily on data collected from White middle-class samples. The Vulnerability-Stress-Adaptation Model (VSA; Karney and Bradbury, 1995) is used here to integrate prior efforts and is tested using data collected from couples living with low incomes. Background: The VSA Model assumes (a) that enduring vulnerabilities, stress, and couple communication account for unique variance in relationship satisfaction, (b) that communication mediates the effects of vulnerabilities and stress on satisfaction, and (c) that the predictors of satisfaction generalize across socioeconomic levels. To date, these assumptions remain untested. Materials and methods: With 388 couples from diverse backgrounds (88% Black or Hispanic), we used latent variable structural equation models to examine enduring vulnerabilities, chronic stress, and observed communication as predictors of 4-wave, 27-month satisfaction trajectories, first as main effects and then interacting with a validated 10-item index of sociodemographic risk. Results: (a) The three variable sets independently predict satisfaction trajectories; (b) couple communication does not mediate the effects of enduring vulnerabilities or stress on satisfaction; and (c) in 19% of tests, effects were stronger among couples with higher sociodemographic risk. Conclusion: Effects of established predictor domains on satisfaction replicate in a diverse sample of newlywed couples, and most findings generalize across levels of sociodemographic risk. The failure of couple communication to mediate effects of enduring personal vulnerabilities and stress raises new questions about how these two domains undermine committed partnerships.

Complete Genome Sequence of the Cluster P Mycobacteriophage Phegasus.

We characterized the complete genome of the cluster P mycobacteriophage Phegasus. Its 47.5-kb genome contains 81 protein-coding genes, 36 of which could be assigned a putative function. Phegasus is most closely related to two subcluster P1 bacteriophages, Mangethe and Majeke, with an average nucleotide identity of 99.63% each.

Reshaping the tumor microenvironment with oncolytic viruses, positive regulation of the immune synapse, and blockade of the immunosuppressive oncometabolic circuitry.

BACKGROUND: Oncolytic viruses are considered part of immunotherapy and have shown promise in preclinical experiments and clinical trials. Results from these studies have suggested that tumor microenvironment remodeling is required to achieve an effective response in solid tumors. Here, we assess the extent to which targeting specific mechanisms underlying the immunosuppressive tumor microenvironment optimizes viroimmunotherapy. METHODS: We used RNA-seq analyses to analyze the transcriptome, and validated the results using Q-PCR, flow cytometry, and immunofluorescence. Viral activity was analyzed by replication assays and viral titration. Kyn and Trp metabolite levels were quantified using liquid chromatography-mass spectrometry. Aryl hydrocarbon receptor (AhR) activation was analyzed by examination of promoter activity. Therapeutic efficacy was assessed by tumor histopathology and survival in syngeneic murine models of gliomas, including Indoleamine 2,3-dioxygenase (IDO)-/- mice. Flow cytometry was used for immunophenotyping and quantification of cell populations. Immune activation was examined in co-cultures of immune and cancer cells. T-cell depletion was used to identify the role played by specific cell populations. Rechallenge experiments were performed to identify the development of anti-tumor memory. RESULTS: Bulk RNA-seq analyses showed the activation of the immunosuppressive IDO-kynurenine-AhR circuitry in response to Delta-24-RGDOX infection of tumors. To overcome the effect of this pivotal pathway, we combined Delta-24-RGDOX with clinically relevant IDO inhibitors. The combination therapy increased the frequency of CD8+ T cells and decreased the rate of myeloid-derived suppressor cell and immunosupressive Treg tumor populations in animal models of solid tumors. Functional studies demonstrated that IDO-blockade-dependent activation of immune cells against tumor antigens could be reversed by the oncometabolite kynurenine. The concurrent targeting of the effectors and suppressors of the tumor immune landscape significantly prolonged the survival in animal models of orthotopic gliomas. CONCLUSIONS: Our data identified for the first time the in vivo role of IDO-dependent immunosuppressive pathways in the resistance of solid tumors to oncolytic adenoviruses. Specifically, the IDO-Kyn-AhR activity was responsible for the resurface of local immunosuppression and resistance to therapy, which was ablated through IDO inhibition. Our data indicate that combined molecular and immune therapy may improve outcomes in human gliomas and other cancers treated with virotherapy.

The efficacy of chemopreventive agents on the incidence of colorectal adenomas: A systematic review and network meta-analysis.

Colorectal cancer (CRC) is the fourth most common cancer and third leading cause of cancer-related death worldwide. Use of chemopreventive agents (CPAs) to reduce the incidence of precursor colorectal adenomas could lower the future burden of CRC. Many classes of potential CPAs have been investigated. To identify the most effective CPAs, we conducted a systematic review and a network meta-analysis (NMA). An electronic search was performed through August 2020 to identify all randomized controlled trials (RCTs) assessing the efficacy of CPAs in reducing the incidence of colorectal adenomas at the time of surveillance colonoscopy among patients who had previously undergone polypectomy during an index colonoscopy. In total, 33 RCTs were included in the NMA, which was conducted under a Bayesian inference framework. Random effects models were used with adjustment for follow-up length and control group event rates to yield relative risks (RRs) and 95% credible intervals (CrIs). Our full network consisted of 13 interventions in addition to a placebo arm. Of 20,925 included patients, 7766 had an adenoma. Compared to placebo, the combination of difluoromethylornithine (DFMO) + Sulindac (RR 0.24, CrI 0.10-0.55) demonstrated a protective effect, while aspirin had a RR of 0.77 (CrI 0.60-1.00), celecoxib 800 mg had a RR of 0.56 (CrI 0.31-1.01) and metformin had a RR of 0.56 (CrI 0.22-1.39). Our results suggest that select CPAs may be efficacious in preventing the development of adenomas. Further studies are needed to identify those patients most likely to benefit and the minimum effective dosages of CPAs.