Evaluating ChatGPT's efficacy in assessing the safety of non-prescription medications and supplements in patients with kidney disease.

Background: This study investigated the efficacy of ChatGPT-3.5 and ChatGPT-4 in assessing drug safety for patients with kidney diseases, comparing their performance to Micromedex, a well-established drug information source. Despite the perception of non-prescription medications and supplements as safe, risks exist, especially for those with kidney issues. The study's goal was to evaluate ChatGPT's versions for their potential in clinical decision-making regarding kidney disease patients. Method: The research involved analyzing 124 common non-prescription medications and supplements using ChatGPT-3.5 and ChatGPT-4 with queries about their safety for people with kidney disease. The AI responses were categorized as "generally safe," "potentially harmful," or "unknown toxicity." Simultaneously, these medications and supplements were assessed in Micromedex using similar categories, allowing for a comparison of the concordance between the two resources. Results: Micromedex identified 85 (68.5%) medications as generally safe, 35 (28.2%) as potentially harmful, and 4 (3.2%) of unknown toxicity. ChatGPT-3.5 identified 89 (71.8%) as generally safe, 11 (8.9%) as potentially harmful, and 24 (19.3%) of unknown toxicity. GPT-4 identified 82 (66.1%) as generally safe, 29 (23.4%) as potentially harmful, and 13 (10.5%) of unknown toxicity. The overall agreement between Micromedex and ChatGPT-3.5 was 64.5% and ChatGPT-4 demonstrated a higher agreement at 81.4%. Notably, ChatGPT-3.5's suboptimal performance was primarily influenced by a lower concordance rate among supplements, standing at 60.3%. This discrepancy could be attributed to the limited data on supplements within ChatGPT-3.5, with supplements constituting 80% of medications identified as unknown. Conclusion: ChatGPT's capabilities in evaluating the safety of non-prescription drugs and supplements for kidney disease patients are modest compared to established drug information resources. Neither ChatGPT-3.5 nor ChatGPT-4 can be currently recommended as reliable drug information sources for this demographic. The results highlight the need for further improvements in the model's accuracy and reliability in the medical domain.

In vivo activity of the second-generation proteasome inhibitor ixazomib against pediatric T-cell acute lymphoblastic leukemia xenografts.

The overall survival rate of patients with T-cell acute lymphoblastic leukemia (T-ALL) is now 90%, although patients with relapsed T-ALL face poor prognosis. The ubiquitin-proteasome system maintains normal protein homeostasis, and aberrations in this pathway are associated with T-ALL. Here we demonstrate the in vitro and in vivo activity of ixazomib, a second-generation orally available, reversible, and selective proteasome inhibitor against pediatric T-ALL cell lines and patient-derived xenografts (PDXs) grown orthotopically in immunodeficient NOD.Cg-PrkdcscidIL2rgtm1Wjl/SzJAusb (NSG) mice. Ixazomib was highly potent in vitro, with half-maximal inhibitory concentration (IC50) values in the low nanomolar range. As a monotherapy, ixazomib significantly extended mouse event-free survival of five out of eight T-ALL PDXs in vivo.

A proteogenomic surfaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma.

Cancer immunotherapies have produced remarkable results in B-cell malignancies; however, optimal cell surface targets for many solid cancers remain elusive. Here, we present an integrative proteomic, transcriptomic, and epigenomic analysis of tumor specimens along with normal tissues to identify biologically relevant cell surface proteins that can serve as immunotherapeutic targets for neuroblastoma, an often-fatal childhood cancer of the developing nervous system. We apply this approach to human-derived cell lines (N=9) and cell/patient-derived xenograft (N=12) models of neuroblastoma. Plasma membrane-enriched mass spectrometry identified 1,461 cell surface proteins in cell lines and 1,401 in xenograft models, respectively. Additional proteogenomic analyses revealed 60 high-confidence candidate immunotherapeutic targets and we prioritized Delta-like canonical notch ligand 1 (DLK1) for further study. High expression of DLK1 directly correlated with the presence of a super-enhancer spanning the DLK1 locus. Robust cell surface expression of DLK1 was validated by immunofluorescence, flow cytometry, and immunohistochemistry. Short hairpin RNA mediated silencing of DLK1 in neuroblastoma cells resulted in increased cellular differentiation. ADCT-701, a DLK1-targeting antibody-drug conjugate (ADC), showed potent and specific cytotoxicity in DLK1-expressing neuroblastoma xenograft models. Moreover, DLK1 is highly expressed in several adult cancer types, including adrenocortical carcinoma (ACC), pheochromocytoma/paraganglioma (PCPG), hepatoblastoma, and small cell lung cancer (SCLC), suggesting potential clinical benefit beyond neuroblastoma. Taken together, our study demonstrates the utility of comprehensive cancer surfaceome characterization and credentials DLK1 as an immunotherapeutic target. Highlights: Plasma membrane enriched proteomics defines surfaceome of neuroblastomaMulti-omic data integration prioritizes DLK1 as a candidate immunotherapeutic target in neuroblastoma and other cancersDLK1 expression is driven by a super-enhancer DLK1 silencing in neuroblastoma cells results in cellular differentiation ADCT-701, a DLK1-targeting antibody-drug conjugate, shows potent and specific cytotoxicity in DLK1-expressing neuroblastoma preclinical models.

In vivo activity of the dual SYK/FLT3 inhibitor TAK-659 against pediatric acute lymphoblastic leukemia xenografts.

BACKGROUND: While children with acute lymphoblastic leukemia (ALL) experience close to a 90% likelihood of cure, the outcome for certain high-risk pediatric ALL subtypes remains dismal. Spleen tyrosine kinase (SYK) is a prominent cytosolic nonreceptor tyrosine kinase in pediatric B-lineage ALL (B-ALL). Activating mutations or overexpression of Fms-related receptor tyrosine kinase 3 (FLT3) are associated with poor outcome in hematological malignancies. TAK-659 (mivavotinib) is a dual SYK/FLT3 reversible inhibitor, which has been clinically evaluated in several other hematological malignancies. Here, we investigate the in vivo efficacy of TAK-659 against pediatric ALL patient-derived xenografts (PDXs). METHODS: SYK and FLT3 mRNA expression was quantified by RNA-seq. PDX engraftment and drug responses in NSG mice were evaluated by enumerating the proportion of human CD45+ cells (%huCD45+ ) in the peripheral blood. TAK-659 was administered per oral at 60 mg/kg daily for 21 days. Events were defined as %huCD45+ ≥ 25%. In addition, mice were humanely killed to assess leukemia infiltration in the spleen and bone marrow (BM). Drug efficacy was assessed by event-free survival and stringent objective response measures. RESULTS: FLT3 and SYK mRNA expression was significantly higher in B-lineage compared with T-lineage PDXs. TAK-659 was well tolerated and significantly prolonged the time to event in six out of eight PDXs tested. However, only one PDX achieved an objective response. The minimum mean %huCD45+ was significantly reduced in five out of eight PDXs in TAK-659-treated mice compared with vehicle controls. CONCLUSIONS: TAK-659 exhibited low to moderate single-agent in vivo activity against pediatric ALL PDXs representative of diverse subtypes.

In vivo activity of the dual PI3Kδ and PI3Kγ inhibitor duvelisib against pediatric acute lymphoblastic leukemia xenografts.

BACKGROUND: Acute lymphoblastic leukemia (ALL) remains one of the most common causes of cancer-related mortality in children. Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases, and aberrations in the PI3K pathway are associated with several hematological malignancies, including ALL. Duvelisib (Copiktra) is an orally available, small molecule dual inhibitor of PI3Kδ and PI3Kγ, that is Food and Drug Administration (FDA) approved for the treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma. Here, we report the efficacy of duvelisib against a panel of pediatric ALL patient-derived xenografts (PDXs). PROCEDURES: Thirty PDXs were selected for a single mouse trial based on PI3Kδ (PIK3CD) and PI3Kγ (PIK3CG) expression and mutational status. PDXs were grown orthotopically in NSG (NOD.Cg-Prkdcscid IL2rgtm1Wjl /SzJAusb) mice, and engraftment was evaluated by enumerating the proportion of human versus mouse CD45+ cells (%huCD45+ ) in the peripheral blood. Treatment commenced when the %huCD45+ reached greater than or equal to 1%, and events were predefined as %huCD45+ greater than or equal to 25% or leukemia-related morbidity. Duvelisib was administered per oral (50 mg/kg, twice daily for 28 days). Drug efficacy was assessed by event-free survival and stringent objective response measures. RESULTS: PI3Kδ and PI3Kγ mRNA expression was significantly higher in B-lineage than T-lineage ALL PDXs (p-values <.0001). Duvelisib was well-tolerated and reduced leukemia cells in the peripheral blood in four PDXs, but with only one objective response. There was no obvious relationship between duvelisib efficacy and PI3Kδ or PI3Kγ expression or mutation status, nor was the in vivo response to duvelisib subtype dependent. CONCLUSIONS: Duvelisib demonstrated limited in vivo activity against ALL PDXs.

Sources of variation in estimates of Duchenne and Becker muscular dystrophy prevalence in the United States.

BACKGROUND: Direct estimates of rare disease prevalence from public health surveillance may only be available in a few catchment areas. Understanding variation among observed prevalence can inform estimates of prevalence in other locations. The Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) conducts population-based surveillance of major muscular dystrophies in selected areas of the United States. We identified sources of variation in prevalence estimates of Duchenne and Becker muscular dystrophy (DBMD) within MD STARnet from published literature and a survey of MD STARnet investigators, then developed a logic model of the relationships between the sources of variation and estimated prevalence. RESULTS: The 17 identified sources of variability fell into four categories: (1) inherent in surveillance systems, (2) particular to rare diseases, (3) particular to medical-records-based surveillance, and (4) resulting from extrapolation. For the sources of uncertainty measured by MD STARnet, we estimated each source's contribution to the total variance in DBMD prevalence. Based on the logic model we fit a multivariable Poisson regression model to 96 age-site-race/ethnicity strata. Age accounted for 74% of the variation between strata, surveillance site for 6%, race/ethnicity for 3%, and 17% remained unexplained. CONCLUSION: Variation in estimates derived from a non-random sample of states or counties may not be explained by demographic differences alone. Applying these estimates to other populations requires caution.

Tailoring the Host Range of Ackermannviridae Bacteriophages through Chimeric Tailspike Proteins.

Host range is a major determinant in the industrial utility of a bacteriophage. A model host range permits broad recognition across serovars of a target bacterium while avoiding cross-reactivity with commensal microbiota. Searching for a naturally occurring bacteriophage with ideal host ranges is challenging, time-consuming, and restrictive. To address this, SPTD1.NL, a previously published luciferase reporter bacteriophage for Salmonella, was used to investigate manipulation of host range through receptor-binding protein engineering. Similar to related members of the Ackermannviridae bacteriophage family, SPTD1.NL possessed a receptor-binding protein gene cluster encoding four tailspike proteins, TSP1-4. Investigation of the native gene cluster through chimeric proteins identified TSP3 as the tailspike protein responsible for Salmonella detection. Further analysis of chimeric phages revealed that TSP2 contributed off-target Citrobacter recognition, whereas TSP1 and TSP4 were not essential for activity against any known host. To improve the host range of SPTD1.NL, TSP1 and TSP2 were sequentially replaced with chimeric receptor-binding proteins targeting Salmonella. This engineered construct, called RBP-SPTD1-3, was a superior diagnostic reporter, sensitively detecting additional Salmonella serovars while also demonstrating improved specificity. For industrial applications, bacteriophages of the Ackermannviridae family are thus uniquely versatile and may be engineered with multiple chimeric receptor-binding proteins to achieve a custom-tailored host range.

Gene-Folic Acid Interactions and Risk of Conotruncal Heart Defects: Results from the National Birth Defects Prevention Study.

Conotruncal heart defects (CTDs) are heart malformations that affect the cardiac outflow tract and typically cause significant morbidity and mortality. Evidence from epidemiological studies suggests that maternal folate intake is associated with a reduced risk of heart defects, including CTD. However, it is unclear if folate-related gene variants and maternal folate intake have an interactive effect on the risk of CTDs. In this study, we performed targeted sequencing of folate-related genes on DNA from 436 case families with CTDs who are enrolled in the National Birth Defects Prevention Study and then tested for common and rare variants associated with CTD. We identified risk alleles in maternal MTHFS (ORmeta = 1.34; 95% CI 1.07 to 1.67), maternal NOS2 (ORmeta = 1.34; 95% CI 1.05 to 1.72), fetal MTHFS (ORmeta = 1.35; 95% CI 1.09 to 1.66), and fetal TCN2 (ORmeta = 1.38; 95% CI 1.12 to 1.70) that are associated with an increased risk of CTD among cases without folic acid supplementation. We detected putative de novo mutations in genes from the folate, homocysteine, and transsulfuration pathways and identified a significant association between rare variants in MGST1 and CTD risk. Results suggest that periconceptional folic acid supplementation is associated with decreased risk of CTD among individuals with susceptible genotypes.

Evaluation of the pan-class I phosphoinositide 3-kinase (PI3K) inhibitor copanlisib in the Pediatric Preclinical Testing Consortium in vivo models of osteosarcoma.

Copanlisib is a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, with activity against all four PI3K class I isoforms (PI3Kα, PI3Kß, PI3Kγ, and PI3Kδ). Whole-genome and RNA sequencing data have revealed several PI3K aberrations in osteosarcoma tumor samples. The in vivo anticancer effects of copanlisib were assessed in a panel of six osteosarcoma models. Copanlisib induced prolonged event-free survival in five of six osteosarcoma models; however, all models demonstrated progressive disease suggesting minimal activity. While copanlisib did not result in tumor regression, more data are needed to fully explore the role of the PI3K pathway in the pathogenesis of osteosarcoma.

Development of a Replication-Deficient Bacteriophage Reporter Lacking an Essential Baseplate Wedge Subunit.

Engineered bacteriophages (phages) can be effective diagnostic reporters for detecting a variety of bacterial pathogens. Although a promising biotechnology, the large-scale use of these reporters may result in the unintentional release of genetically modified viruses. In order to limit the potential environmental impact, the ability of these phages to propagate outside the laboratory was targeted. The phage SEA1 has been previously engineered to facilitate food safety as an accurate and sensitive reporter for Salmonella contamination. In this study, homologous recombination was used to replace the expression of an essential baseplate wedge subunit (gp141) in SEA1 with a luciferase, NanoLuc®. This reporter, referred to as SEA1Δgp141.NL, demonstrated a loss of plaque formation and a failure to increase in titer following infection of Salmonella. SEA1Δgp141.NL was thus incapable of producing infectious progeny in the absence of gp141. In contrast, production of high titer stocks was possible when gp141 was artificially supplied in trans during infection. As a reporter, SEA1Δgp141.NL facilitated rapid, sensitive, and robust detection of Salmonella despite an inability to replicate. These results suggest that replication-deficient reporter phages are an effective method to obtain improved containment without sacrificing significant performance or the ease of production associated with many phage-based diagnostic methods.

Evaluation of the DLL3-targeting antibody-drug conjugate rovalpituzumab tesirine in preclinical models of neuroblastoma.

Neuroblastomas have neuroendocrine features and often show similar gene expression patterns to small cell lung cancer including high expression of delta-like ligand 3 (DLL3). Here we determine the efficacy of rovalpituzumab tesirine (Rova-T), an antibody drug conjugated (ADC) with a pyrrolobenzodiazepine (PBD) dimer toxin targeting DLL3, in preclinical models of human neuroblastoma. We evaluated DLL3 expression in RNA sequencing data sets and performed immunohistochemistry (IHC) on neuroblastoma patient derived xenograft (PDX), human neuroblastoma primary tumor and normal childhood tissue microarrays (TMAs). We then evaluated the activity of Rova-T against 11 neuroblastoma PDX models using varying doses and schedules and compared anti-tumor activity to expression levels. DLL3 mRNA was differentially overexpressed in neuroblastoma at comparable levels to small cell lung cancer, as well as Wilms and rhabdoid tumors. DLL3 protein was robustly expressed across the neuroblastoma PDX array, but membranous staining was variable. The human neuroblastoma array, however, showed staining in only 44% of cases, whereas no significant staining was observed in the normal childhood tissue array. Rova-T showed a clear dose response effect across the 11 models tested, with a single dose inducing a complete or partial response in 3/11 and stable disease in another 3/11 models. No overt signs of toxicity were observed, and there was no treatment-related mortality. Strong membranous staining was necessary, but not sufficient, for anti-tumor activity. Rova-T has activity in a subset of neuroblastoma preclinical models, but heterogeneous expression in these models and the near absence of expression seen in human tumors suggests that any DLL3-targeting clinical trial should be only performed with a robust companion diagnostic to evaluate DLL3 expression for patient selection.

Identifying Datasets for Cross-Study Analysis in dbGaP using PhenX.

Identifying relevant studies and harmonizing datasets are major hurdles for data reuse. Common Data Elements (CDEs) can help identify comparable study datasets and reduce the burden of retrospective data harmonization, but they have not been required, historically. The collaborative team at PhenX and dbGaP developed an approach to use PhenX variables as a set of CDEs to link phenotypic data and identify comparable studies in dbGaP. Variables were identified as either comparable or related, based on the data collection mode used to harmonize data across mapped datasets. We further added a CDE data field in the dbGaP data submission packet to indicate use of PhenX and annotate linkages in the future. Some 13,653 dbGaP variables from 521 studies were linked through PhenX variable mapping. These variable linkages have been made accessible for browsing and searching in the repository through dbGaP CDE-faceted search filter and the PhenX variable search tool. New features in dbGaP and PhenX enable investigators to identify variable linkages among dbGaP studies and reveal opportunities for cross-study analysis.

Bacteriophage-Based Detection of Staphylococcus aureus in Human Serum.

Bacteriophages have been investigated for clinical utility, both as diagnostic tools and as therapeutic interventions. In order to be applied successfully, a detailed understanding of the influence of the human matrix on the interaction between bacteriophage and the host bacterium is required. In this study, a cocktail of luciferase bacteriophage reporters was assessed for functionality in a matrix containing human serum and spiked with Staphylococcus aureus. The inhibition of signal and loss of sensitivity was evident with minimal amounts of serum. This phenotype was independent of bacterial growth and bacteriophage viability. Serum-mediated loss of signal was common, albeit not universal, among S. aureus strains. Immunoglobulin G was identified as an inhibitory component and partial inhibition was observed with both the f(ab')2 and Fc region. A modified bacteriophage cocktail containing recombinant protein A was developed, which substantially improved signal without the need for additional sample purification. This study highlights the importance of assessing bacteriophage activity in relevant host matrices. Furthermore, it identifies an effective solution, recombinant protein A, for promoting bacteriophage-based detection of S. aureus in matrices containing human serum.

Perioperative Practices in Dermatologic Surgery.

BACKGROUND: Mohs micrographic surgery is generally safe and well tolerated. Various perioperative practices are employed with the aim of reducing adverse events; however, implementation is variable, and limited efficacy data are available. OBJECTIVE: This study sought to assess perioperative practice patterns among dermatologic surgeons with regards to antibiotic prophylaxis (AP), anticoagulation, activity restrictions, and antiseptic choice. METHODS AND MATERIALS: Two surveys were distributed by the American College of Mohs Surgery (ACMS) and the American Society for Mohs Surgery (ASMS) to their membership via email. RESULTS: One hundres seventy-seven surgeons participated, with membership from ACMS (61%), ASMS (35%), or both organizations (4%) represented. Systemic AP is prescribed preoperatively by 96% (162/168) and postoperatively by 91% (161/177) of surgeons for variable clinical indications. Therapeutic antiplatelet and anticoagulant medications are rarely held (3%-5%, 4-7/149), whereas preventative aspirin (30%, 45/149), NSAIDs (25%, 36/145), and supplements known to have an anticoagulant effect (54%, 80/149) are more commonly held. Antiseptic choice and recommended activity restrictions vary. CONCLUSION: Perioperative practices of dermatologic surgeons are variable and, where applicable, may deviate from guidelines. These findings underscore the need for standardization and updated guidelines for perioperative practices in dermatologic surgery.

Trastuzumab Deruxtecan, Antibody-Drug Conjugate Targeting HER2, Is Effective in Pediatric Malignancies: A Report by the Pediatric Preclinical Testing Consortium.

HER2 is expressed in many pediatric solid tumors and is a target for innovative immune therapies including CAR-T cells and antibody-drug conjugates (ADC). We evaluated the preclinical efficacy of trastuzumab deruxtecan (T-DXd, DS-8201a), a humanized monoclonal HER2-targeting antibody conjugated to a topoisomerase 1 inhibitor, DXd, in patient- and cell line-derived xenograft (PDX/CDX) models. HER2 mRNA expression was determined using RNA-seq and protein expression via IHC across multiple pediatric tumor PDX models. Osteosarcoma (OS), malignant rhabdoid tumor (MRT), and Wilms tumor (WT) models with varying HER2 expression were tested using 10 mice per group. Additional histologies such as Ewing sarcoma (EWS), rhabdomyosarcoma (RMS), neuroblastoma (NB), and brain tumors were evaluated using single mouse testing (SMT) experiments. T-DXd or vehicle control was administered intravenously to mice harboring established flank tumors at a dose of 5 mg/kg on day 1. Event-free survival (EFS) and objective response were compared between treatment and control groups. HER2 mRNA expression was observed across histologies, with the highest expression in WT (median = 22 FPKM), followed by MRT, OS, and EWS. The relationship between HER2 protein and mRNA expression was inconsistent. T-DXd significantly prolonged EFS in 6/7 OS, 2/2 MRT, and 3/3 WT PDX models. Complete response (CR) or maintained CR (MCR) were observed for 4/5 WT and MRT models, whereas stable disease was the best response among OS models. SMT experiments also demonstrated activity across multiple solid tumors. Clinical trials assessing the efficacy of a HER2-directed ADC in pediatric patients with HER2-expressing tumors should be considered.

High-Fidelity Indirect Readout of Trapped-Ion Hyperfine Qubits.

We propose and demonstrate a protocol for high-fidelity indirect readout of trapped ion hyperfine qubits, where the state of a ^{9}Be^{+} qubit ion is mapped to a ^{25}Mg^{+} readout ion using laser-driven Raman transitions. By partitioning the ^{9}Be^{+} ground-state hyperfine manifold into two subspaces representing the two qubit states and choosing appropriate laser parameters, the protocol can be made robust to spontaneous photon scattering errors on the Raman transitions, enabling repetition for increased readout fidelity. We demonstrate combined readout and back-action errors for the two subspaces of 1.2_{-0.6}^{+1.1}×10^{-4} and 0_{-0}^{+1.9}×10^{-5} with 68% confidence while avoiding decoherence of spectator qubits due to stray resonant light that is inherent to direct fluorescence detection.

Role Attainment in Emerging Adulthood: Subjective Evaluation by Male Adolescents and Adults with Duchenne and Becker Muscular Dystrophy.

BACKGROUND: Youth with Duchenne and Becker muscular dystrophy (DBMD) experience challenges in attaining adult roles, which may impact quality of life. New interventions and treatments may facilitate adult role attainment through improved function. Historical data on adult role attainment is important to assess the impact of new interventions on teens and young adults with DBMD. This study assesses medical knowledge, independence and employment, and relationships among adolescents and young adults with DBMD. METHODS: This study uses data from a 2013 Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) survey on adult transition. Males with DBMD aged 16-30 years were included. RESULTS: Sixty-five of 258 eligible males participated; we report results on 60 participants with an MD STARnet case definition of DMD or BMD. Individuals with BMD reported higher rates than those with DMD of frequently staying home without supervision (50% BMD; 14% DMD), independently performing daily physical needs (93% BMD; 7% DMD) and being employed full or part time (33% BMD; 4% DMD). Most participants understood medication and physical therapy goals; less than half indicated being often or always responsible for scheduling DMBD-related management and refilling medications. Most had not been in a romantic relationship but reported desiring such relationships. CONCLUSIONS: Our data reinforce the impact of DMD (and to a lesser extent, BMD) on transition to adult roles. These results provide an important historical comparator for teen and adult patients who are trying new interventions and therapies. Such data are important for assessing the quality-of-life impact of new treatments and to inform support and training programs for people with DBMD as they transition to new adult roles and responsibilities.