Reporting System Research Articles

Post-marketing safety concern of PI3K inhibitors in the cancer therapies: an 8-year disproportionality analysis from the FDA Adverse Event Reporting System

ABSTRACT Background The Phosphoinositide 3-kinases (PI3Ks) family plays a crucial role in tumorigenesis. Alpelisib (inhibiting PI3Kα), copanlisib (inhibiting PI3Kα andPI3Kδ), duvelisib (inhibiting PI3Kδ and PI3Kγ), and idelalisib (inhibiting PI3Kδ) were developed to target the PI3K pathway. However, the toxicity limits their application to some extent. It’s necessary to investigate the adverse effects (AEs) of these inhibitors. Research design and methods We conducted a comparative analysis of the safety signals of AEs in PI3K inhibitors using disproportionality analysis in the FDA Adverse Event Reporting System database(FAERS). Results Our study identified significant safety signals for metabolic disorders with all PI3K inhibitors. Notable safety signals for gastrointestinal disorders were observed with most PI3K inhibitors, with the exception of copanlisib. Common AEs shared among all PI3K inhibitors included colitis and dehydration. Alpelisib displayed unique AEs associated with metabolic disorders, whereas copanlisib exhibited idiosyncratic AEs linked to cardiac and vascular disorders. Stevens-Johnson syndrome emerged as a common severe adverse event (SAE) among alpelisib, copanlisib, and idelalisib, while febrile neutropenia was prevalent among copanlisib, duvelisib, and idelalisib. Intestinal perforation was solely associated with alpelisib. Conclusions The safety profiles of the five PI3K inhibitors vary concerning adverse events. These findings could guide drug selection and inform future prospective research.

Integration of Business Unit Financial Reporting Systems in Village-Owned Enterprises (BUMDes)

BUMDes is a village government-owned business institution established in an effort to strengthen the village economy, based on the needs and potential of the village concerned. In its operations, BUMDes can have various business units with autonomous management in one business entity. Each business unit makes its own financial report according to the type of business it runs. The resulting financial report will be submitted to the head office for merger and consolidation. Although each business unit has a different type of business, the process and provisions for preparing financial reports in each business unit are the same, because they are regulated in government regulations. The only differences are related to operational reporting and components/account names in the financial report. To improve the ease of preparation and accountability of its financial reports, the existence of an integrated accounting information system is a must. As an initial step, a design process is carried out which will be used as the basis or technical reference for the development process. The design process is carried out with an object-oriented approach, with the results in the form of classes/components and interactions between them which are the foundation of the system building. This will facilitate the development process and this integrated system can then be built/developed in stages according to the development/addition of business units from BUMDes.

A simple and efficient method for betalain quantification in RUBY-expressing plant samples

The RUBY reporter system has demonstrated great potential as a visible marker to monitor gene expression in both transiently and stably transformed plant tissues. Ectopic expression of the RUBY reporter leads to bright red pigmentation in plant tissues that do not naturally accumulate betalain. Unlike traditional visual markers such as β-glucuronidase (GUS), luciferase (LUC), and various fluorescent proteins, the RUBY reporter system does not require sample sacrifice or special equipment for visualizing the gene expression. However, a robust quantitative analysis method for betalain content has been lacking, limiting accurate comparative analyses. In this work, we present a simple and rapid protocol for quantitative evaluation of RUBY expression in transgenic plant tissues. Using this method, we demonstrate that differential RUBY expression can be quantified in transiently transformed leaf tissues, such as agroinfiltrated Nicotiana benthamiana leaves, and in stable transgenic maize tissues, including seeds, leaves, and roots. We found that grinding fresh tissues with a hand grinder and plastic pestle, without the use of liquid nitrogen, is an effective method for rapid betalain extraction. Betalain contents estimated by spectrophotometric and High-Performance Liquid Chromatography (HPLC) analyses were highly consistent, validating that our rapid betalain extraction and quantification method is suitable for comparative analysis. In addition, betalain content was strongly correlated with RUBY expression level in agroinfiltrated N. benthamiana leaves, suggesting that our method can be useful for monitoring transient transformation efficiency in plants. Using our rapid protocol, we quantified varying levels of betalain pigment in N. benthamiana leaves, ranging from 110 to 1066 mg/kg of tissue, and in maize samples, ranging from 15.3 to 1028.7 mg/kg of tissue. This method is expected to streamline comparative studies in plants, providing valuable insights into the effectiveness of various promoters, enhancers, or other regulatory elements used in transgenic constructs.

Split Reporters Facilitate Monitoring of Gene Expression and Peptide Production in Linear Cell-Free Transcription-Translation Systems.

Cell-free transcription-translation (TXTL) systems expressing genes from linear dsDNA enable the rapid prototyping of genetic devices while avoiding cloning steps. However, repetitive inclusion of a reporter gene is an incompressible cost and sometimes accounts for most of the synthesized DNA length. Here we present reporter systems based on split-GFP systems that reassemble into functional fluorescent proteins and can be used to monitor gene expression in E. coli TXTL. The 135 bp GFP10-11 fragment produces a fluorescent signal comparable to its full-length GFP counterpart when reassembling with its complementary protein synthesized from the 535 bp fragment expressed in TXTL. We show that split reporters can be used to characterize promoter libraries, with data qualitatively comparable to full-length GFP and matching in vivo expression measurements. We also use split reporters as small fusion tags to measure the TXTL protein and peptide production yield. Finally, we generalize our concept by providing a luminescent split reporter based on split-nanoluciferase. The ∼80% gene sequence length reduction afforded by split reporters lowers synthesis costs and liberates space for testing larger devices while producing a reliable output. In the peptide production context, the small size of split reporters compared with full-length GFP is less likely to bias peptide solubility assays. We anticipate that split reporters will facilitate rapid and cost-efficient genetic device prototyping, protein production, and interaction assays.

Mechanistic analysis of Riboswitch Ligand interactions provides insights into pharmacological control over gene expression

Riboswitches are structured RNA elements that regulate gene expression upon binding to small molecule ligands. Understanding the mechanisms by which small molecules impact riboswitch activity is key to developing potent, selective ligands for these and other RNA targets. We report the structure-informed design of chemically diverse synthetic ligands for PreQ1 riboswitches. Multiple X-ray co-crystal structures of synthetic ligands with the Thermoanaerobacter tengcongensis (Tte)-PreQ1 riboswitch confirm a common binding site with the cognate ligand, despite considerable chemical differences among the ligands. Structure probing assays demonstrate that one ligand causes conformational changes similar to PreQ1 in six structurally and mechanistically diverse PreQ1 riboswitch aptamers. Single-molecule force spectroscopy is used to demonstrate differential modes of riboswitch stabilization by the ligands. Binding of the natural ligand brings about the formation of a persistent, folded pseudoknot structure, whereas a synthetic ligand decreases the rate of unfolding through a kinetic mechanism. Single round transcription termination assays show the biochemical activity of the ligands, while a GFP reporter system reveals compound activity in regulating gene expression in live cells without toxicity. Taken together, this study reveals that diverse small molecules can impact gene expression in live cells by altering conformational changes in RNA structures through distinct mechanisms.

Sodium-glucose cotransporter 2 inhibitors and renal cancer in the US FDA adverse event reporting system.

Recent evidence suggests an association between sodium-glucose cotransporter 2 (SGLT2) inhibitors and a higher risk of renal cancer. We conducted a pharmacovigilance analysis using the US FDA Adverse Event Reporting System (FAERS) to investigate the disproportionate association between SGLT2 inhibitors and renal cancer. We used AERSMine to mine data from FAERS, covering the period from 2014 Q1 to 2023 Q3. The control group was treated with other glucose-lowering medications (ATC-A10B). Disproportionality analysis results were performed using a proportional reporting ratio (PRR) with a 95% confidence interval (CI) and an information component (IC) with 95% credible interval. Compared to the control group, the SGLT2 inhibitor group had a higher disproportionate renal cancer reporting frequency (0.92 vs 0.27/1000 reports; PRR 3.38; 95% CI 2.68-4.25; p < 0.001) with an IC of 1.36 (0.60-2.06), comprising dapagliflozin (PRR 4.14; 2.95-5.80; p < 0.001), empagliflozin (PRR 2.74; 1.94-3.89; p < 0.001), and canagliflozin (PRR 3.56; 2.48-5.12; p < 0.001). Consistent results were obtained in the diabetes indication with the primary outcomes only for the SGLT2 inhibitors group (not individual molecule). The results of the sensitivity analysis (excluding hypertension indication or antihypertensive drugs, obesity, smoking, alpha-1 blockers, or anti-renal cancer drugs) were highly consistent with the main outcomes, indicating good robustness of the results. The results from 2004 Q1 to 2023 Q3 were similar to those from 2014 Q1 to 2023 Q3, with the exception of empagliflozin. There was a disproportionate association between SGLT2 inhibitors and renal cancer, which supports the current meta-analysis results indicating an increased risk of renal cancer associated with SGLT2 inhibitors.

The surface interface and swimming motility influence surface-sensing responses in Pseudomonas aeruginosa

Bacterial biofilms have been implicated in several chronic infections. After initial attachment, a critical first step in biofilm formation is a cell inducing a surface-sensing response. In the Gram-negative opportunistic pathogen Pseudomonas aeruginosa, two second messengers, cyclic diguanylate monophosphate (c-di-GMP) and cyclic adenosine monophosphate (cAMP), are produced by different surface-sensing mechanisms. However, given the disparate cellular behaviors regulated by these second messengers, how newly attached cells coordinate these pathways remains unclear. Some of the uncertainty relates to studies using different strains, experimental systems, and usually focusing on a single second messenger. In this study, we developed a tricolor reporter system to simultaneously gauge c-di-GMP and cAMP levels in single cells. Using PAO1, we show that c-di-GMP and cAMP are selectively activated in two commonly used experimental systems to study surface sensing. By further examining the conditions that differentiate a c-di-GMP or cAMP response, we demonstrate that an agarose-air interface activates cAMP signaling through type IV pili and the Pil-Chp system. However, a liquid-agarose interface favors the activation of c-di-GMP signaling. This response is dependent on flagellar motility and correlated with higher swimming speed. Collectively, this work indicates that c-di-GMP and cAMP signaling responses are dependent on the surface context.

Antigenic peptide–thioredoxin fusion chimeras for &lt;i&gt;in vitro&lt;/i&gt; stimulus of CD4&lt;sup&gt;+&lt;/sup&gt; TCR&lt;sup&gt;+&lt;/sup&gt; Jurkat T-cells

Study of CD4+ T-cell response and T-cell receptor (TCR) specificity is crucial for understanding etiology of immune-mediated diseases and developing targeted therapies. However, solubility, accessibility, and stability of synthetic antigenic peptides used in T-cell assays may be a critical point in such studies. Here we present a T-cell activation reporter system using recombinant proteins containing antigenic epitopes fused with bacterial thioredoxin (trx-peptides) and obtained by bacterial expression. We report that co-incubation of CD4+ HA1.7 TCR+ reporter Jurkat 76 TRP-cells with CD80+ HLA-DRB1*01:01+ HeLa-cells or CD4+ Ob.1A12 TCR+ Jurkat 76 TRP with CD80+ HLA-DRB1*15:01+ HeLa-cells resulted in activation of reporter Jurkat 76 TPR after addition of recombinant trx-peptide fusion proteins, containing TCR-specific epitopes. Trx-peptides were comparable with corresponding synthetic peptides in their capacity to activate Jurkat 76 TPR. These data demonstrate that thioredoxin as a carrier protein (trx) for antigenic peptides exhibits minimal interference with recognition of MHC-specific peptides by TCRs and consequent T-cell activation. Our findings highlight potential feasibility of trx-peptides as a reagent for assessing the immunogenicity of antigenic fragments.

Abstract A060: Dysregulation of PTEN expression in a subset of Cancer Associated Fibroblasts by Tumor Secreted Factors in PDAC

Abstract Pancreatic Ductal Adenocarcinoma (PDAC) is a deadly malignancy. Cancer associated fibroblasts (CAFs) play a complex role in the PDAC tumor microenvironment (TME), with a subset contributing significantly to tumor progression. Phosphatase and tensin homolog (PTEN) is a tumor suppressor and its loss is associated with increased tumor aggressiveness. Our group previously demonstrated PTEN loss in SMA+ positive CAFS correlated with worsened outcomes in patients and in mouse PDAC models. Our group previously demonstrated the loss of PTEN in CAFS led to activation of Stat3, resulting in an immunosuppressive microenvironment (Lefler et al, 2022 PMID: 35803738). However, little is known of the signals produced by tumor cells or other cell types in the TME that trigger loss of PTEN in CAFs. This study aims to to elucidate the molecular mechanisms underlying PTEN loss in CAFs in PDAC. To address this gap, we employed single cell RNA sequencing of tumors from a mouse PDAC model and identified a (PDRGFRa+Lys6+Stat3+Pten-low) CAF subpopulation. Comparing normal pancreas epithelial cells to tumor cells in this data set, we identified the IL6 family of cytokines, (IL6; Oncostatin-M, OSM; and Leukemia Inhibitory Factor, LIF) and Transforming Growth Factor beta 1 (TGFb1) as potential ligands that regulated PTEN, while myeloid cells were a source of the IL6 family member Oncostatin M (OSM). Treatment of isolated CAFs with these factors revealed no significant difference in PTEN mRNA expression. Thus, we developed an in vitro reporter system in which a PTEN-GFP fusion protein is expressed in CAFs. Treating these CAFs with IL6, OSM and TGFb1 (but not LIF) led to a significant decrease in GFP fluorescence. Analysis of endogenous PTEN by western blot confirmed these results. We posited that expression of PTEN E3 ligases might be increased by treatment with these factors, leading to destruction of PTEN. In support of this hypothesis, the expression of E3 ligases WWP1 and WWP2 was increased by treatment with IL6 and OSM. Additionally, preliminary data has revealed that PTEN is oxidized in isolated CAFs, which causes loss of PTEN activity and potentially increased protein turnover. Current experiments are aimed at testing these potential mechanisms. To conclude, PTEN is dysregulated post-transcriptionally in CAFs. The mechanism of PTEN dysregulation could be via increased expression of E3 ligases that target PTEN and/or PTEN oxidation. Future efforts will be aimed at testing whether inhibition of these pathways can restore PTEN expression in mouse PDAC models. These pathways and interactions could be further exploited for therapeutic benefit in curbing PDAC progression. Citation Format: Ivo N. Woogeng, Lu Han, Samaneh Saberi, Cameron Bumbleburg, Joseph Beaudet, Sudarshana Sharma, Michael Ostrowski. Dysregulation of PTEN expression in a subset of Cancer Associated Fibroblasts by Tumor Secreted Factors in PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A060.

A real-world disproportionality analysis of baloxavir marboxil: post-marketing pharmacovigilance data

ABSTRACT Objective Baloxavir marboxil (hereafter referred to as baloxavir) is the only cap-dependent endonuclease inhiabitor approved for the treatment and prevention of influenza. However, as a new drug marketed in 2018, the long-term safety of baloxavir in large sample population was unclear. This study aims to evaluate baloxavir-associated adverse events (AEs) through data mining of the international pharmacovigilance database of US FDA Adverse Event Reporting System (FAERS). Methods Disproportionality analysis was conducted to assess the association between baloxavir and its AEs. Data were collected from FAERS from March 2018 to June 2023. After standardizing the data, signal quantification techniques including ROR, PRR, BCPNN and MGPS were used for analysis. Results A total of 49 significant baloxavir-related preferred terms (PTs) in 20 system organ classes (SOCs) were identified in our data analysis. Compared to baloxavir’s FDA label, some new PTs emerged, with the top 10 being pneumonia, loss of consciousness, rhabdomyolysis, seizure, altered state of consciousness, hepatic function abnormal, delirium, depressed level of consciousness, encephalopathy and cardio-respiratory arrest. Conclusion In clinical application of baloxavir, attention should be paid to the new AE signals in addition to the those recorded in the labels, so as to ensure the safety of the patients.

Adverse events associated with Atogepant: a FAERS-based pharmacovigilance analysis

ABSTRACT Background Migraine, a prevalent neurovascular disorder, can significantly disrupt an individual’s daily life. Atogepant (AGN-241689), an orally administered small-molecule drug classified as a calcitonin gene-related peptide receptor antagonist, is utilized for prophylactic migraine treatment. The objective of this study was to investigate adverse events (AEs) associated with atogepant through data mining in the FDA Adverse Event Reporting System (FAERS) to enhance clinical safety. Methods Data for atogepant were obtained from the FAERS database covering Q3 2021 through Q4 2023. Disproportionality analysis was employed to quantify relevant AEs associated with atogepant. Reported Ratio of Ratios (ROR) was utilized for identifying risk signals within the FAERS data. This methodology relies on the System Organ Class (SOC) and Preferred Terminology (PT) of the Medical Dictionary for Regulatory Activities (MedDRA). Results From the FAERS database, a collection of 7,991,243 reports was obtained. Among these reports, a subset of 3015 was identified as ‘primary suspected (PS)’ AEs specifically related to atogepant. AEs induced by atogepant were observed across 27 organ systems. A total of 48 significantly disproportionate Preferred Terminologies (PTs) meeting all four algorithms were identified. Conclusion Our study has identified adverse events (AEs) associated with atogepant, potentially providing crucial support for the clinical monitoring and risk identification of atogepant.

Antibody-drug conjugates-related interstitial lung diseases: data mining of the FAERS database

ABSTRACT Background Interstitial lung diseases (ILD) is a serious adverse event (AE) associated with antibody-drug conjugates (ADCs). This study aims to delve deeply into the signals of AE associated with ILD linked to ADCs. Research design and methods The AE reports were extracted from the first quarter of 2004 to the fourth quarter of 2023 based on the FDA Adverse Event Reporting System (FAERS) database. Signal mining was performed using the reporting odds ratio (ROR) method and the multi‐item gamma Poisson shrinker (MGPS) method. Data management, analysis, and visualization were carried out using Python, R software, and MySQL. Results A total of 1389 AE reports related to ILD with 11 types of ADCs as the primary suspected drugs were obtained. The age groups most represented were 61–80 age group. ILD-related AE signals were detected for 11 ADCs in the study. Trastuzumab deruxtecan showed the strongest signals in both for ROR and MGPS methods. The median onset time vary from 8 days to 207 days. Conclusions The signals of ILD AE associated with ADCs are notably strong. ILD should be closely monitored and assessed in the clinical use of ADCs taking full account of the efficacy and risks of these drugs.

Diagnostic utility of prostate health index density prior to MRI-ultrasound fusion targeted biopsy

Aim: Prostate biopsy can be prone to complications and thus should be avoided when unnecessary. Although the combination of magnetic resonance imaging (MRI), the prostate health index (PHI), and PHI density (PHID) has been shown to improve detection of clinically significant prostate cancer (csPCa), there is limited information available assessing its clinical utility. We sought to determine whether using PHID could enhance the detection of PCa on MRI ultrasound fusion-targeted biopsy (MRF-TB) compared to other biomarker cutoffs. Methods: Between June 2015 and December 2020, 302 men obtained PHI testing before MRF-TB at a single institution. We used descriptive statistics, multivariable logistic regression, and receiver operating characteristic curves to determine the predictive accuracy of PHID and PHI to detect ≥ Gleason grade group (GGG) 2 PCa and identify cutoff values. Results: Any cancer grade was identified in 75.5% of patients and ≥ GGG2 PCa was identified in 45% of patients. The median PHID was 1.05 [interquartile range (IQR) 0.59–1.64]. A PHID cutoff of 0.91 had a higher discriminatory ability to predict ≥ GGG2 PCa compared to PHI &gt; 27, PHI &gt; 36, and prostate specific-antigen (PSA) density &gt; 0.15 (AUC: 0.707 vs. 0.549 vs. 0.620 vs. 0.601), particularly in men with Prostate Imaging Reporting and Data System (PI-RADS) 1–2 lesions on MRI (AUC: 0.817 vs. 0.563 vs. 0.621 vs. 0.678). At this cutoff, 35.0% of all the original biopsies could be safely avoided (PHID &lt; 0.91 and no ≥ GGG2 PCa) and csPCa would be missed in 9.67% of patients who would have been biopsied. In patients with PI-RADS 1–2 lesions using a PHID cutoff of 0.91, 56.8% of biopsies could be safely avoided while missing 0 csPCa. Conclusions: These findings suggest that a PHID cutoff of 0.91 improves the selection of patients with elevated prostate-specific antigen who are referred for prostate biopsy, and potentially in patients with PI-RADS 1–2 lesions.

An Analysis of the Results of Breast Imaging Reporting and Data System 4 Lesions in Tertiary Care Center in South India

An Analysis of the Results of Breast Imaging Reporting and Data System 4 Lesions in Tertiary Care Center in South India

Risk of Suicide, Hair Loss, and Aspiration with GLP1-Receptor Agonists and Other Diabetic Agents: A Real-World Pharmacovigilance Study.

With the increasing popularity of glucagon-like peptide 1 receptor agonists (GLP1-RAs), numerous safety concerns arose pertaining to suicide, hair loss, and aspiration risks. We attempted to validate these concerns. We queried four pharmacovigilance databases to compare GLP1-RAs to sodium-glucose transporter 2 inhibitors (SGLT2is) with respect to these adverse events (AE): the FDA Adverse Event Reporting System (FAERS), the Australian Database of Adverse Event Notifications (DAEN), the European Medicines Agency's (EudraVigilance), and the World Health Organization-Vigibase. OpenVigil 2.1 was utilized to perform a disproportionality analysis for GLP1-RAs, SGLT2is, dipeptidyl peptidase 4 inhibitors (DPP4is), sulfonylureas, metformin, and insulin. The following indices were extracted from the FAERS database from Q4/2003 until Q3/2023: relative reporting ratio (RRR), proportional reporting ratio (PRR), reporting odds ratio (ROR), and chi-squared (χ2). A positive signal was detected if PRR > 2 and χ2 > 4 for any drug-event pair. No positive signals were observed between GLP1-RAs and either suicide, hair loss, or aspiration risks. Semaglutide [ROR = 0.60 (0.51-0.71)] and liraglutide [ROR = 0.28 (0.23-0.35)] had higher suicidal events than DPP4is and SGLT2is. GLP1-RAs were the most reported class with hair loss [ROR = 0.61 (0.60-0.64)], and semaglutide, liraglutide, and dulaglutide were the three leading medications. GLP1-RAs ranked lower with aspiration events, which were led by sitagliptin and DPP4is as a group. GLP1-RAs exhibit higher reporting of suicide, hair loss, and aspiration events when compared to several other antidiabetic medications despite not meeting the criteria for positive signals yet. This warrants intensive monitoring and reporting.

Lacidipine Inhibits NF-κB and Notch Pathways and Mitigates DSS-Induced Colitis.

Ulcerative colitis (UC) is a chronic inflammatory condition affecting the colon, with a global incidence that is rising. Despite the increasing prevalence, effective treatment options for UC remain limited. We utilized an NF-κB promoter dual fluorescence reporter system to screen for compounds that could inhibit p65 and IκBα phosphorylation. The anti-hypertension drug lacidipine was identified as a candidate. Its efficacy was further evaluated in a murine model of dextran sulfate sodium (DSS)-induced colitis. The analysis included the assessment of colon lesions, inflammation markers, and signal pathway activation, with a focus on NF-κB and Notch signaling. Lacidipine effectively inhibited p65 and IκBα phosphorylation in the reporter system. In the DSS-induced colitis murine model, lacidipine treatment led to a reduction in colon lesions and inflammatory markers. Target analysis showed significant enrichment of the Notch signaling pathway. Additionally, lacidipine inhibited both NF-κB and Notch activation in DSS-stimulated colons. Lacidipine demonstrated a protective effect in UC, reducing inflammation and modulating key signaling pathways. These findings suggest that lacidipine could be a promising candidate for the treatment of UC.

A national analysis of systemic adverse events of beta-blockers used for glaucoma therapy

Purpose To evaluate systemic complications for timolol, carteolol, levobunolol, and/or betaxalol by using an FDA Federal Adverse Event Reporting System (FAERS) Methods We evaluated FAERS for adverse events associated with β-blocker use for glaucoma. All reported symptoms were reviewed to identify systemic adverse events and to detect safety signals, defined as information on a new or known side effect that may be caused by a medicine. We used the proportional reporting ratio (PRR), reporting odds ratio (ROR), empirical Bayes geometric mean (EBGM), and information component (IC) as a part of a disproportionality analysis comparing the frequency of β-blocker symptoms with all other adverse event reports. We considered a signal to be detected when all four disproportionality analysis metrics were positive. Results We found 10,500,309 total adverse event reports from the FAERS database 2004-2022Q3, which included 8,793 case reports with a primary suspect of a β-blocker use for glaucoma. 1,838 unique adverse symptoms were reported were associated with β-blocker. Regarding outcomes, there were 165 (1.88%) reports of disability, 671 (7.63%) reports of hospitalisation, and 1,934 (21.99%) reports of some other unspecified complication. Regarding adverse events, the most reported general, cardiac, and respiratory symptoms were respectively dizziness (n = 281), bradycardia (n = 145), and dyspnoea (n = 195). 256 (2.91%) cases of death were reported. We found significant signals on bradycardia (n = 145), complete atrioventricular block (n = 38), and bronchospasm (n = 23). No allergic, endocrine, constitutional, or gastrointestinal symptoms generated positive signals. Conclusion β-blocker use in glaucoma therapy can be rarely associated with serious systemic and life-threatening complications.

Explainable artificial intelligence-driven prostate cancer screening using exosomal multi-marker based dual-gate FET biosensor

Prostate Imaging Reporting and Data System (PI-RADS) score, a reporting system of prostate MRI cases, has become a standard prostate cancer (PCa) screening method due to exceptional diagnosis performance. However, PI-RADS 3 lesions are an unmet medical need because PI-RADS provides diagnosis accuracy of only 30–40% at most, accompanied by a high false-positive rate. Here, we propose an explainable artificial intelligence (XAI) based PCa screening system integrating a highly sensitive dual-gate field-effect transistor (DGFET) based multi-marker biosensor for ambiguous lesions identification. This system produces interpretable results by analyzing sensing patterns of three urinary exosomal biomarkers, providing a possibility of an evidence-based prediction from clinicians. In our results, XAI-based PCa screening system showed a high accuracy with an AUC of 0.93 using 102 blinded samples with the non-invasive method. Remarkably, the PCa diagnosis accuracy of patients with PI-RADS 3 was more than twice that of conventional PI-RADS scoring. Our system also provided a reasonable explanation of its decision that TMEM256 biomarker is the leading factor for screening those with PI-RADS 3. Our study implies that XAI can facilitate informed decisions, guided by insights into the significance of visualized multi-biomarkers and clinical factors. The XAI-based sensor system can assist healthcare professionals in providing practical and evidence-based PCa diagnoses.

Stakeholder perspectives on border carbon adjustments: Trinidad and Tobago's balancing act between competitiveness and climate action

ABSTRACT Introduction This policy analysis paper explores stakeholder perspectives on the potential impact of Border Carbon Adjustments (BCAs) as an external climate policy instrument on Trinidad and Tobago. The research is based on data collected through a questionnaire and two workshops.Discussion The study finds that while the majority of stakeholders are aware of BCAs and generally support their implementation for environmental reasons, there are concerns about their impact on the competitiveness of the country's exports and the social consequences. Stakeholders expressed concerns about potential job losses, increased costs for consumers, and reduced competitiveness of local industries.Conclusion The research recommends the participation of Trinidad and Tobago in international discussions on BCA design to advocate for phased exemptions as the country decarbonizes and to influence key BCA design features such as geographic coverage, product coverage, emissions scope, fees and application of the fees and crediting for foreign policy. The country should also develop robust Measurement, Reporting, and Verification (MRV) systems to measure and verify domestic carbon emissions accurately. Additionally, the country should introduce policies like a carbon tax to potentially reduce emissions and the amount of taxes paid.

Evaluating text and visual diagnostic capabilities of large language models on questions related to the Breast Imaging Reporting and Data System Atlas 5th edition.

This study aimed to evaluate the performance of large language models (LLMs) and multimodal LLMs in interpreting the Breast Imaging Reporting and Data System (BI-RADS) categories and providing clinical management recommendations for breast radiology in text-based and visual questions. This cross-sectional observational study involved two steps. In the first step, we compared ten LLMs (namely ChatGPT 4o, ChatGPT 4, ChatGPT 3.5, Google Gemini 1.5 Pro, Google Gemini 1.0, Microsoft Copilot, Perplexity, Claude 3.5 Sonnet, Claude 3 Opus, and Claude 3 Opus 200K), general radiologists, and a breast radiologist using 100 text-based multiple-choice questions (MCQs) related to the BI-RADS Atlas 5th edition. In the second step, we assessed the performance of five multimodal LLMs (ChatGPT 4o, ChatGPT 4V, Claude 3.5 Sonnet, Claude 3 Opus, and Google Gemini 1.5 Pro) in assigning BI-RADS categories and providing clinical management recommendations on 100 breast ultrasound images. The comparison of correct answers and accuracy by question types was analyzed using McNemar's and chi-squared tests. Management scores were analyzed using the Kruskal- Wallis and Wilcoxon tests. Claude 3.5 Sonnet achieved the highest accuracy in text-based MCQs (90%), followed by ChatGPT 4o (89%), outperforming all other LLMs and general radiologists (78% and 76%) (P < 0.05), except for the Claude 3 Opus models and the breast radiologist (82%) (P > 0.05). Lower-performing LLMs included Google Gemini 1.0 (61%) and ChatGPT 3.5 (60%). Performance across different categories of showed no significant variation among LLMs or radiologists (P > 0.05). For breast ultrasound images, Claude 3.5 Sonnet achieved 59% accuracy, significantly higher than other multimodal LLMs (P < 0.05). Management recommendations were evaluated using a 3-point Likert scale, with Claude 3.5 Sonnet scoring the highest (mean: 2.12 ± 0.97) (P < 0.05). Accuracy varied significantly across BI-RADS categories, except Claude 3 Opus (P < 0.05). Gemini 1.5 Pro failed to answer any BI-RADS 5 questions correctly. Similarly, ChatGPT 4V failed to answer any BI-RADS 1 questions correctly, making them the least accurate in these categories (P < 0.05). Although LLMs such as Claude 3.5 Sonnet and ChatGPT 4o show promise in text-based BI-RADS assessments, their limitations in visual diagnostics suggest they should be used cautiously and under radiologists' supervision to avoid misdiagnoses. This study demonstrates that while LLMs exhibit strong capabilities in text-based BI-RADS assessments, their visual diagnostic abilities are currently limited, necessitating further development and cautious application in clinical practice.