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Journal For Immunotherapy of Cancer May 2024Artificial intelligence (AI) chatbots have become a major source of general and medical information, though their accuracy and completeness are still being assessed....
BACKGROUND
Artificial intelligence (AI) chatbots have become a major source of general and medical information, though their accuracy and completeness are still being assessed. Their utility to answer questions surrounding immune-related adverse events (irAEs), common and potentially dangerous toxicities from cancer immunotherapy, are not well defined.
METHODS
We developed 50 distinct questions with answers in available guidelines surrounding 10 irAE categories and queried two AI chatbots (ChatGPT and Bard), along with an additional 20 patient-specific scenarios. Experts in irAE management scored answers for accuracy and completion using a Likert scale ranging from 1 (least accurate/complete) to 4 (most accurate/complete). Answers across categories and across engines were compared.
RESULTS
Overall, both engines scored highly for accuracy (mean scores for ChatGPT and Bard were 3.87 vs 3.5, p<0.01) and completeness (3.83 vs 3.46, p<0.01). Scores of 1-2 (completely or mostly inaccurate or incomplete) were particularly rare for ChatGPT (6/800 answer-ratings, 0.75%). Of the 50 questions, all eight physician raters gave ChatGPT a rating of 4 (fully accurate or complete) for 22 questions (for accuracy) and 16 questions (for completeness). In the 20 patient scenarios, the average accuracy score was 3.725 (median 4) and the average completeness was 3.61 (median 4).
CONCLUSIONS
AI chatbots provided largely accurate and complete information regarding irAEs, and wildly inaccurate information ("hallucinations") was uncommon. However, until accuracy and completeness increases further, appropriate guidelines remain the gold standard to follow.
Topics: Humans; Artificial Intelligence; Immunotherapy; Neoplasms; Drug-Related Side Effects and Adverse Reactions
PubMed: 38816231
DOI: 10.1136/jitc-2023-008599 -
PloS One 2024The push towards research commercialisation at universities has highlighted the importance of intellectual property (IP) policies in fostering innovation and guiding and... (Comparative Study)
Comparative Study
The push towards research commercialisation at universities has highlighted the importance of intellectual property (IP) policies in fostering innovation and guiding and managing research commercialisation activities. This paper undertakes a content analysis of intellectual property policies of all (37) Australian public universities, focusing on policy objectives, definition of IP, ownership of IP created by different creators, and distribution of net commercialisation revenues. It is found that all universities assert ownership over staff-created IP, particularly when related to employment or utilisation of university resources. For students, policies tend to balance their rights with university interests, with nuanced approaches for different types of student participation, but the focus of most policies was on postgraduate students engaging in research activities. While some policies had clear arrangements for IP created by visitors and affiliates and Indigenous cultural and intellectual property (ICIP), about a quarter of policies did not specify arrangements for these groups. Revenue sharing arrangements vary but generally award something between a third to a half of net revenue to creators, to both acknowledge their contribution and incentivise further innovation. Policies included a broad spectrum of objectives, from protecting and commercialising IP to fostering innovation and societal benefit, reflecting varying strategies across the higher education sector. Policies could benefit from further clarity in certain areas such as the rights of students or other creator groups. Research is needed to assess the effectiveness of these policies and their influence on innovation and commercialisation activities.
Topics: Intellectual Property; Universities; Australia; Humans; Ownership; Students; Policy
PubMed: 38814965
DOI: 10.1371/journal.pone.0304647 -
PloS One 2024This research investigates the glass cliff effect and the positions held by women in leadership roles, focusing on their impact on operational liquidity. The study...
This research investigates the glass cliff effect and the positions held by women in leadership roles, focusing on their impact on operational liquidity. The study delves into the relationship between corporate governance attributes and operational liquidity in 60 non-financial companies listed on the Pakistan Stock Exchange during Covid-19. Utilizing Quine-McCluskey technique and fuzzy set Qualitative Comparative Analysis (fsQCA), it examines the combined effect of Women on the Board, Board Size, Ownership by Blockholders, Board Qualifications and Busy Directors on Operational Liquidity. The necessary condition analysis (NCA) emphasises that firms can operate without reliance on any particular variable taken in the study. The sufficiency analysis provided an expanded understanding of the three conditions leading to the same outcome both before and during the pandemic. This research highlights the significance of the glass cliff effect and emphasizes the pivotal role of women in effectively managing liquidity during times of crisis. Additionally, it provides valuable insights for policymakers regarding the impact of Covid-19 on the interplay between corporate governance characteristics and operational liquidity.
Topics: Leadership; Humans; Female; COVID-19; Pakistan; SARS-CoV-2; Pandemics
PubMed: 38814963
DOI: 10.1371/journal.pone.0302210 -
MMWR. Morbidity and Mortality Weekly... May 2024
Topics: Humans; United States; Aged; Respiratory Syncytial Virus Vaccines; Middle Aged; Respiratory Syncytial Virus Infections; Female; Male; Aged, 80 and over; Adverse Drug Reaction Reporting Systems
PubMed: 38814851
DOI: 10.15585/mmwr.mm7321a3 -
Heliyon May 2024This study aims to explore the effect of eco-innovation and renewable energy on carbon dioxide emissions (CDE) for G7 countries. Using regression models, the results...
This study aims to explore the effect of eco-innovation and renewable energy on carbon dioxide emissions (CDE) for G7 countries. Using regression models, the results reveal that eco-innovation and renewable energy lead to reducing CDE in the presence of governance variables. Additional analysis is conducted to examine whether Hofstede national culture dimensions moderate the nexus of "eco-innovation- carbon emission" and "renewable energy-carbon emission". The results show that individualism, long-term orientation, and indulgence dimensions moderate positively the eco-innovation-carbon emission relationship. Moreover, power distance and uncertainty avoidance dimensions moderate the relationship between renewable energy and CDE and help reduce carbon emissions. The outcomes of this study provide new insights and directives for policymakers and regulators. In fact, increased investment in eco-innovation and renewable energy will support the environmental agenda of G7 countries. National cultural dimensions should be taken into consideration to improve awareness of environmental quality. Moreover, the combination of governance indicators plays a key role in environmental sustainability.
PubMed: 38813154
DOI: 10.1016/j.heliyon.2024.e31142 -
Future Science OA 2024Recently, the emergency of multidrug-resistant organisms (MDRO) has complicated the management of bacterial infections (BI) in cirrhosis. We aimed to assess their...
Recently, the emergency of multidrug-resistant organisms (MDRO) has complicated the management of bacterial infections (BI) in cirrhosis. We aimed to assess their clinical impact on patients with decompensated cirrhosis. A retrospective study included consecutive cirrhotic patients hospitalized for acute decompensation (AD) between January 2010 and December 2019. A total of 518 AD admissions in 219 patients were included, with 260 BI episodes (50.2%). MDRO prevalence was 38.2% of the total isolates. Recent antibiotic use (OR = 4.91), nosocomial infection (OR = 2.95), and healthcare-associated infection (OR = 3.45) were their main risk factors. MDROs were associated with empiric treatment failure (OR = 23.42), a higher prevalence of sepsis (OR = 4.93), ACLF (OR = 3.42) and mortality. The clinical impact of MDROs was pejorative, with an increased risk of empiric treatment failure, organ failure and death.
PubMed: 38813115
DOI: 10.2144/fsoa-2023-0160 -
Frontiers in Oncology 2024Anti-GD2 monoclonal antibodies (mAbs) have shown to improve the overall survival of patients with high-risk neuroblastoma (HR-NB). Serious adverse events (AEs),...
BACKGROUND
Anti-GD2 monoclonal antibodies (mAbs) have shown to improve the overall survival of patients with high-risk neuroblastoma (HR-NB). Serious adverse events (AEs), including pain, within hours of antibody infusion, have limited the development of these therapies. In this study, we provide evidence of Autonomic Nervous System (ANS) activation as the mechanism to explain the main side effects of anti-GD2 mAbs.
METHODS
Through confocal microscopy and computational super-resolution microscopy experiments we explored GD2 expression in postnatal nerves of infants. In patients we assessed the ANS using the Sympathetic Skin Response (SSR) test. To exploit tachyphylaxis, a novel infusion protocol (the Step-Up) was mathematically modelled and tested.
RESULTS
Through confocal microscopy, GD2 expression is clearly visible in the perineurium surrounding the nuclei of nerve cells. By computational super-resolution microscopy experiments we showed the selective expression of GD2 on the cell membranes of human Schwann cells in peripheral nerves (PNs) significantly lower than on NB. In patients, changes in the SSR were observed 4 minutes into the anti-GD2 mAb naxitamab infusion. SSR latency quickly shortened followed by gradual decrease in the amplitude before disappearance. SSR response did not recover for 24 hours consistent with tachyphylaxis and absence of side effects in the clinic. The Step-Up protocol dissociated on-target off-tumor side effects while maintaining serum drug exposure.
CONCLUSION
We provide first evidence of the ANS as the principal non-tumor target of anti-GD2 mAbs in humans. We describe the development and modeling of the Step-Up protocol exploiting the tachyphylaxis phenomenon we demonstrate in patients using the SSR test.
PubMed: 38812778
DOI: 10.3389/fonc.2024.1380917 -
Frontiers in Oncology 2024Molecular profiling of metastatic breast cancer (MBC) through the widespread use of next-generation sequencing (NGS) has highlighted actionable mutations and driven...
INTRODUCTION
Molecular profiling of metastatic breast cancer (MBC) through the widespread use of next-generation sequencing (NGS) has highlighted actionable mutations and driven trials of targeted therapy matched to tumour molecular profiles, with improved outcomes reported using such an approach. Here, we review NGS results and treatment outcomes for a cohort of Asian MBC patients in the phase I unit of a tertiary centre.
METHODS
Patients with MBC referred to a phase I unit underwent NGS via Ion AmpliSeq Cancer Hotspot v2 (ACH v2, 2014-2017) prior to institutional change to FoundationOne CDx (FM1; 2017-2022). Patients were counselled on findings and enrolled on matched therapeutic trials, where available. Outcomes for all subsequent treatment events were recorded to data cut-off on January 31, 2022.
RESULTS
A total of 215 patients were enrolled with successful NGS in 158 patients. The PI3K/AKT/PTEN pathway was the most altered with one or more of the pathway member genes affected in 62% (98/158) patients and 43% of tumours harbouring a alteration. Tumour mutational burden (TMB) was reported in 96/109 FM1 sequenced patients, with a mean TMB of 5.04 mt/Mb and 13% (12/96) with TMB ≥ 10 mt/Mb. Treatment outcomes were evaluable in 105/158 patients, with a pooled total of 216 treatment events recorded. Matched treatment was administered in 47/216 (22%) events and associated with prolonged median progression-free survival (PFS) of 21.0 weeks [95% confidence interval (CI) 11.7, 26.0 weeks] 12.1 weeks (95% CI 10.0, 15.4 weeks) in unmatched, with hazard ratio (HR) for progression or death of 0.63 (95% CI 0.41, 0.97; p = 0.034). In the subgroup of -altered MBC, the HR for progression or death was 0.57 (95% CI 0.35, 0.92; p = 0.02), favouring matched treatment. Per-patient overall survival (OS) analysis (n = 105) showed improved survival for patients receiving matched treatment unmatched, with median OS (mOS) of 30.1 11.8 months, HR = 0.45 (95% CI 0.24, 0.84; p = 0.013). Objective response rate (ORR) in the overall population was similar in matched and unmatched treatment events (23.7% 17.2%, odds ratio of response 1.14 95% CI 0.50, 2.62; p = 0.75).
CONCLUSIONS
Broad-panel NGS in MBC is feasible, allowing therapeutic matching, which was associated with improvements in PFS and OS.
PubMed: 38812774
DOI: 10.3389/fonc.2024.1342346 -
Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles.Genome Medicine May 2024We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney,...
BACKGROUND
We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative mode of action, wherein an increased level of AFF3 resulted in pathological effects.
METHODS
Evolutionary constraints suggest that other modes-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be damaging variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants.
RESULTS
We identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous Loss-of-Function (LoF) or biallelic missense variants in AFF3. Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA, confirming their association with the ablation of aff3. Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not rescue these phenotypes. Overexpression of mutated AFF3 mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness. To further assess the effect of AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring + / + , KINSSHIP/KINSSHIP, LoF/ + , LoF/LoF or KINSSHIP/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the KINSSHIP/KINSSHIP or the LoF/LoF lines. While the same pathways are affected, only about one third of the differentially expressed genes are common to the homozygote datasets, indicating that AFF3 LoF and KINSSHIP variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation.
CONCLUSIONS
Our results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious.
Topics: Humans; Animals; Zebrafish; Transcriptome; Intellectual Disability; Phenotype; Female; Male; Mutation, Missense; Loss of Function Mutation
PubMed: 38811945
DOI: 10.1186/s13073-024-01339-y -
Nature Communications May 2024The intestinal anaerobic bacterium Akkermansia muciniphila is specialized in the degradation of mucins, which are heavily O-glycosylated proteins that constitute the...
The intestinal anaerobic bacterium Akkermansia muciniphila is specialized in the degradation of mucins, which are heavily O-glycosylated proteins that constitute the major components of the mucus lining the intestine. Despite that adhesion to mucins is considered critical for the persistence of A. muciniphila in the human intestinal tract, our knowledge of how this intestinal symbiont recognizes and binds to mucins is still limited. Here, we first show that the mucin-binding properties of A. muciniphila are independent of environmental oxygen concentrations and not abolished by pasteurization. We then dissected the mucin-binding properties of pasteurized A. muciniphila by use of a recently developed cell-based mucin array that enables display of the tandem repeats of human mucins with distinct O-glycan patterns and structures. We found that A. muciniphila recognizes the unsialylated LacNAc (Galβ1-4GlcNAcβ1-R) disaccharide selectively on core2 and core3 O-glycans. This disaccharide epitope is abundantly found on human colonic mucins capped by sialic acids, and we demonstrated that endogenous A. muciniphila neuraminidase activity can uncover the epitope and promote binding. In summary, our study provides insights into the mucin-binding properties important for colonization of a key mucin-foraging bacterium.
Topics: Akkermansia; Humans; Mucins; Polysaccharides; Neuraminidase; Protein Binding; Glycosylation; Disaccharides; Verrucomicrobia; Epitopes; Bacterial Adhesion
PubMed: 38811534
DOI: 10.1038/s41467-024-48770-8