Diagnosis in Bytes: Comparing the Diagnostic Accuracy of Google and ChatGPT 3.5 as an Educational Support Tool.

BACKGROUND: Adopting advanced digital technologies as diagnostic support tools in healthcare is an unquestionable trend accelerated by the COVID-19 pandemic. However, their accuracy in suggesting diagnoses remains controversial and needs to be explored. We aimed to evaluate and compare the diagnostic accuracy of two free accessible internet search tools: Google and ChatGPT 3.5. METHODS: To assess the effectiveness of both medical platforms, we conducted evaluations using a sample of 60 clinical cases related to urological pathologies. We organized the urological cases into two distinct categories for our analysis: (i) prevalent conditions, which were compiled using the most common symptoms, as outlined by EAU and UpToDate guidelines, and (ii) unusual disorders, identified through case reports published in the 'Urology Case Reports' journal from 2022 to 2023. The outcomes were meticulously classified into three categories to determine the accuracy of each platform: "correct diagnosis", "likely differential diagnosis", and "incorrect diagnosis". A group of experts evaluated the responses blindly and randomly. RESULTS: For commonly encountered urological conditions, Google's accuracy was 53.3%, with an additional 23.3% of its results falling within a plausible range of differential diagnoses, and the remaining outcomes were incorrect. ChatGPT 3.5 outperformed Google with an accuracy of 86.6%, provided a likely differential diagnosis in 13.3% of cases, and made no unsuitable diagnosis. In evaluating unusual disorders, Google failed to deliver any correct diagnoses but proposed a likely differential diagnosis in 20% of cases. ChatGPT 3.5 identified the proper diagnosis in 16.6% of rare cases and offered a reasonable differential diagnosis in half of the cases. CONCLUSION: ChatGPT 3.5 demonstrated higher diagnostic accuracy than Google in both contexts. The platform showed satisfactory accuracy when diagnosing common cases, yet its performance in identifying rare conditions remains limited.

Exploring countermovement jump variables across competitive levels and playing positions in futsal.

Introduction: The aims of this study were to compare several countermovement jump (CMJ) kinetic variables between professional (PRO) and semi-professional (SEMI-PRO) futsal players and examine the differences amongst playing positions. Methods: CMJ performance from 56 male futsal players (25.2 ± 4.8 years; weight: 74.4 ± 6.4 kg) was analysed. Players were separated into PRO (n = 29; 27.0 ± 4.4 years; 75.4 ± 6.0 kg) and SEMI-PRO (n = 27; 22.7 ± 4.3 years; 73.1 ± 6.8 kg), and according to playing position: defenders (n = 16; 25.4 ± 3.7 years; 75.2 ± 6.0 kg), wingers (n = 26; 23.5 ± 4.5 years; 72.0 ± 6.9 kg), and pivots (n = 14; 28.0 ± 5.6 years; 77.8 ± 4.3 kg). Linear mixed models and effect sizes were used for the analyses based on the mean of two jumps for each variable. Results: PRO players presented a deeper center of mass (COM) displacement (p = 0.002, ES = 0.83), greater eccentric (Ecc) absolute (p = 0.019, ES = 0.61) and relative peak power (p = 0.046, ES = 0.52), and achieved greater Ecc peak velocities (p = 0.004, ES = 0.76) when compared to SEMI-PRO. Non-significant and trivial-to-small differences were observed in all the other CMJ variables according to the competitive level and playing position. Discussion: Ecc capabilities (i.e., deeper COM displacement, greater Ecc absolute and relative peak power, and peak velocity) during vertical jump seem to differentiate PRO and SEMI-PRO players. However, CMJ variables do not discriminate amongst playing positions in futsal players.

Moderately lipophilic 2-(Het)aryl-6-dithioacetals, 2-phenyl-1,4-benzodioxane-6-dithioacetals and 2-phenylbenzofuran-5-dithioacetals: Synthesis and primary evaluation as potential antidiabetic AMPK-activators.

Since the 1950's, AMP-kinase (AMPK) has been used as a promising target for the development of antidiabetic drugs against Type 2 diabetes mellitus (T2D). Indeed, the canonical antidiabetic drug metformin recruits, at least partially, AMPK activation for its therapeutic effect. Herein we present design and synthesis of 20 novel relatively polar cyclic and acyclic dithioacetals of 2-(Het)arylchroman-6-carbaldehydes, 2-phenyl-1,4-benzodioxane-6-carbaldehyde, and 2-phenylbenzofuran-5-carbaldehyde, which were developed as potential AMPK activators. Three of the synthesized dithioacetals demonstrated significant enhancement (≥70%) of glucose uptake in rat L6 myotubes. Noteworthy, one of the dithioacetals, namely 4-(6-(1,3-dithian-2-yl)chroman-2-yl)pyridine, exhibited high potency comparing to other molecules. It increased the rate of glucose uptake in rat L6 myotubes and augmented insulin secretion from rat INS-1E cells in pharmacological relevant concentrations (up to 2 µM). Both effects were mediated by activation of AMPK. In addition, the compound showed excellent pharmacokinetic profile in healthy mice, including maximal oral bioavailability. Such bifunctionality (increased glucose uptake and insulin secretion) can be used as a starting point for the development of a novel class of antidiabetic drugs with dual activity that is relevant for T2D treatment.

Inhibitors of DNA Methylation.

DNA methylation is involved in numerous biological processes and is deregulated in human diseases. The modulation of the activity of the enzymes and proteins in charge of DNA methylation, for example, DNA methyltransferases (DNMTs), can represent a powerful strategy to alter DNA methylation patterns and restore biological processes that are aberrant in diseases. In this chapter, we present examples of inhibitors of DNMTs (DNMTi). We review their fields of application either as therapeutic molecules, for example, in cancers, cardiovascular, neurological, and infectious diseases or as bioengineering tools. Finally, novel strategies to target DNA methylation and overcome the limits of single DNMT inhibitors will be described. These strategies consist in either targeting the methyl group reader proteins rather than targeting directly DNMTs or to combine within the same molecule a DNMT inhibitor with an additional active moiety, e.g., HDAC inhibitor, to improve efficacy and lower secondary effect of such drug.

Identification of Chemical Probes Targeting MBD2.

Epigenetics has received much attention in the past decade. Many insights on epigenetic (dys)regulation in diseases have been obtained, and clinical therapies targeting them are in place. However, the readers of the epigenetic marks are lacking enlightenment behind this revolution, and it is poorly understood how DNA methylation is being read and translated to chromatin function and cellular responses. Chemical probes targeting the methyl-CpG readers, such as the methyl-CpG binding domain proteins (MBDs), could be used to study this mechanism. We have designed analogues of 5-methylcytosine to probe the MBD domain of human MBD2. By setting up a protein thermal shift assay and an AlphaScreen-based test, we were able to identify three fragments that bind MBD2 alone and disrupt the MBD2-methylated DNA interactions. Two-dimensional NMR experiments and virtual docking gave valuable insights into the interaction of the ligands with the protein showing that the compounds interact with residues that are important for DNA recognition. These constitute the starting point for the design of potent chemical probes for MBD proteins.

1,2,3-Triazole-gold(I)-triethylposphine derivatives active against resistant Gram-positive pathogens.

Innovative organogold(I) antibacterial compounds were synthesized by click chemistry with triethylphosphine-gold(I) azides and an alkyne derivative. The resulting organo-gold(I) compounds exhibit high levels of antibacterial activity against Gram-positive pathogens, with particularly low MICs against Clostridium difficile.

Approved drugs screening against the nsP1 capping enzyme of Venezuelan equine encephalitis virus using an immuno-based assay.

Alphaviruses such as the Venezuelan equine encephalitis virus (VEEV) are important human emerging pathogens transmitted by mosquitoes. They possess a unique viral mRNA capping mechanism catalyzed by the viral non-structural protein nsP1, which is essential for virus replication. The alphaviruses capping starts by the methylation of a GTP molecule by the N7-guanine methyltransferase (MTase) activity; nsP1 then forms a covalent link with m7GMP releasing pyrophosphate (GT reaction) and the m7GMP is next transferred onto the 5'-diphosphate end of the viral mRNA to form a cap-0 structure. The cap-0 structure decreases the detection of foreign viral RNAs, prevents RNA degradation by cellular exonucleases, and promotes viral RNA translation into proteins. Additionally, reverse-genetic studies have demonstrated that viruses mutated in nsP1 catalytic residues are both impaired towards replication and attenuated. The nsP1 protein is thus considered an attractive antiviral target for drug discovery. We have previously demonstrated that the guanylylation of VEEV nsP1 can be monitored by Western blot analysis using an antibody recognizing the cap structure. In this study, we developed a high throughput ELISA screening assay to monitor the GT reaction through m7GMP-nsP1 adduct quantitation. This assay was validated using known nsP1 inhibitors before screening 1220 approved compounds. 18 compounds inhibiting the nsP1 guanylylation were identified, and their IC50 determined. Compounds from two series were further characterized and shown to inhibit the nsP1 MTase activity. Conversely, these compounds barely inhibited a cellular MTase demonstrating their specificity towards nsP1. Analogues search and SAR were also initiated to identify the active pharmacophore features. Altogether the results show that this HT enzyme-based assay is a convenient way to select potent and specific hit compounds targeting the viral mRNA capping of Alphaviruses.

N-Acetyl-3-aminopyrazoles block the non-canonical NF-kB cascade by selectively inhibiting NIK.

NF-κB-inducing kinase (NIK), an oncogenic drug target that is associated with various cancers, is a central signalling component of the non-canonical pathway. A blind screening process, which established that amino pyrazole related scaffolds have an effect on IKKbeta, led to a hit-to-lead optimization process that identified the aminopyrazole 3a as a low µM selective NIK inhibitor. Compound 3a effectively inhibited the NIK-dependent activation of the NF-κB pathway in tumour cells, confirming its selective inhibitory profile.

Toward the identification of viral cap-methyltransferase inhibitors by fluorescence screening assay.

Two highly pathogenic human coronaviruses associated with severe respiratory syndromes emerged since the beginning of the century. The severe acute respiratory syndrome SARS-coronavirus (CoV) spread first in southern China in 2003 with about 8000 infected cases in few months. Then in 2012, the Middle East respiratory syndrome (MERS-CoV) emerged from the Arabian Peninsula giving a still on-going epidemic associated to a high fatality rate. CoVs are thus considered a major health threat. This is especially true as no vaccine nor specific therapeutic are available against either SARS- or MERS-CoV. Therefore, new drugs need to be identified in order to develop antiviral treatments limiting CoV replication. In this study, we focus on the nsp14 protein, which plays a key role in virus replication as it methylates the RNA cap structure at the N7 position of the guanine. We developed a high-throughput N7-MTase assay based on Homogenous Time Resolved Fluorescence (HTRF®) and screened chemical libraries (2000 compounds) on the SARS-CoV nsp14. 20 compounds inhibiting the SARS-CoV nsp14 were further evaluated by IC50 determination and their specificity was assessed toward flavivirus- and human cap N7-MTases. Our results reveal three classes of compounds: 1) molecules inhibiting several MTases as well as the dengue virus polymerase activity unspecifically, 2) pan MTases inhibitors targeting both viral and cellular MTases, and 3) inhibitors targeting one viral MTase more specifically showing however activity against the human cap N7-MTase. These compounds provide a first basis towards the development of more specific inhibitors of viral methyltransferases.

4-Hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]-1,2,5-thiadiazole-3-carboxamide: a novel inhibitor of the canonical NF-κB cascade.

The NF-κB signaling pathway is a validated oncological target. Here, we applied scaffold hopping to IMD-0354, a presumed IKKß inhibitor, and identified 4-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]-1,2,5-thiadiazole-3-carboxamide (4) as a nM-inhibitor of the NF-κB pathway. However, both 4 and IMD-0354, being potent inhibitors of the canonical NF-κB pathway, were found to be inactive in human IKKß enzyme assays.

Use of hindered silyl ethers as protecting groups for the non-aldol aldol process.

[reaction: see text] Bulky epoxy bis-silyl ethers, e.g., 15, derived from 5-trialkylsilyloxy-2-alken-1-ols by epoxidation and silylation were treated with TMSOTf to afford non-aldol aldol rearrangement products, the 3,5-bis(silyloxy)alkanals, e.g., 16, with little to none of the corresponding tetrahydrofurans.