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Liquid biopsies have the potential to revolutionize cancer care through non-invasive early detection of tumors. Developing a robust liquid biopsy test requires collecting high-dimensional data from a large number of blood samples across heterogeneous groups of patients. We propose that the generative capability of variational auto-encoders enables learning a robust and generalizable signature of blood-based biomarkers. In this study, we analyze orphan non-coding RNAs (oncRNAs) from serum samples of 1050 individuals diagnosed with non-small cell lung cancer (NSCLC) at various stages, as well as sex-, age-, and BMI-matched controls. We demonstrate that our multi-task generative AI model, Orion, surpasses commonly used methods in both overall performance and generalizability to held-out datasets. Orion achieves an overall sensitivity of 94% (95% CI: 87%-98%) at 87% (95% CI: 81%-93%) specificity for cancer detection across all stages, outperforming the sensitivity of other methods on held-out validation datasets by more than  ~ 30%.

Tick-transmitted Babesia are a major global veterinary threat and an emerging risk to humans. Unlike their Plasmodium relatives, these erythrocyte-infecting Apicomplexa have been largely overlooked and lack specific treatment. Selective targeting of the Babesia proteasome holds promise for drug development. In this study, we screened a library of peptide epoxyketone inhibitors derived from the marine natural product carmaphycin B for their activity against Babesia. Several of these compounds showed activity against both the asexual and sexual blood stages of Plasmodium falciparum. These compounds inactivate β5 proteasome subunit activity in the lysates of Babesia divergens and Babesia microti in the low nanomolar range. Several compounds were tested with the purified B. divergens proteasome and showed IC50 values comparable to carfilzomib, an approved anticancer proteasome inhibitor. They also inhibited B. divergens growth in bovine erythrocyte cultures with solid EC50 values, but importantly, they appeared less toxic to human cells than carfilzomib. These compounds therefore offer a wider therapeutic window and provide new insights into the development of small proteasome inhibitors as selective drugs for babesiosis.

Metals are important cofactors in the metabolic processes of cyanobacteria, including photosynthesis, cellular respiration, DNA replication, and the biosynthesis of primary and secondary metabolites. In adaptation to the marine environment, cyanobacteria use metallophores to acquire trace metals when necessary as well as to reduce potential toxicity from excessive metal concentrations. Leptochelins A-C were identified as structurally novel metallophores from three geographically dispersed cyanobacteria of the genus Leptothoe. Determination of the complex structures of these metabolites presented numerous challenges, but they were ultimately solved using integrated data from NMR, mass spectrometry and deductions from the biosynthetic gene cluster. The leptochelins are comprised of halogenated linear NRPS-PKS hybrid products with multiple heterocycles that have potential for hexadentate and tetradentate coordination with metal ions. The genomes of the three leptochelin producers were sequenced, and retrobiosynthetic analysis revealed one candidate biosynthetic gene cluster (BGC) consistent with the structure of leptochelin. The putative BGC is highly homologous in all three Leptothoe strains, and all possess genetic signatures associated with metallophores. Postcolumn infusion of metals using an LC-MS metabolomics workflow performed with leptochelins A and B revealed promiscuous binding of iron, copper, cobalt, and zinc, with greatest preference for copper. Iron depletion and copper toxicity experiments support the hypothesis that leptochelin metallophores may play key ecological roles in iron acquisition and in copper detoxification. In addition, the leptochelins possess significant cytotoxicity against several cancer cell lines.

Objectives: The aim of this systematic review and meta-analysis was to evaluate the current literature on the effect of implant surface characteristics on peri-implant marginal bone levels (MBL), soft tissue periodontal parameters, peri-implantitis, and implant failure rates. Materials and Methods: Randomized controlled trials were searched in electronic databases. Risk of bias within the selected studies was assessed using the Risk of Bias Tool 2. Meta-analyses were performed using Review Manager software for studies with similar comparisons reporting same outcome measures. Results: Ten randomized control trials were included in the present review. The primary outcome of changes in peri-implant MBL favoured implants with machined surfaces, however, the difference was not statistically significant (P = .18). The changes in probing pocket depths significantly favoured the use of machined surfaces (P = .01), while the implant failure rates favoured roughened surface implants. However, the difference was not statistically significant (P = .09). Conclusion: Machined surface implants were favoured in terms of lesser peri-implant MBL, though the difference was not significant. The analysis also demonstrated limited favourable outcomes in terms of periodontal parameters for machined surfaces, with slightly significantly better outcomes in terms of probing pocket depths. However, rough surface implants tended to display a lower implant failure.

Abstract Neuromuscular diseases (NMD) are a group of neurological diseases that manifest with various clinical symptoms affecting different components of the peripheral nervous system, which play a role in voluntary body movements control. The primary objective of this study is to explore the diagnostic efficacy of a combined genetic and biochemical testing approach for patients with neuromuscular diseases with diverse presentations in a population with high rate of consanguinity. Genetic testing was performed using selected Next Generation Sequencing (NGS) gene panels and whole exome sequencing on the peripheral blood sample from the patients. The study results revealed that the majority of patients in our cohort had a history of consanguinity (83%). Genetic testing through gene panels and Whole Exome Sequencing yielded similar result. Out of the patients tested, 66% underwent gene panels testing, 56% had Whole Exome Sequencing, 32% received array Comparative Genomic Hybridization (CGH) assays, and 40% underwent metabolic testing. Overall, 58 patients (61%) received definitive results after following all tests. Among the remaining 36 patients, 19 exhibited variants of unknown significance (VOUS) (21%).

Abstract Non-contact anterior cruciate ligament (ACL) rupture is a common serious orthopaedic disease in humans and dogs. Familial risk has been recognized in both species but interactions between genetic effects and environmental risk are not understood. We investigated ACL rupture heritability, genetic architecture, selection pressure, sharing of risk genes and biological pathways, and polygenic risk score (PRS) prediction of disease risk. In both species, ACL rupture has moderate heritability, is likely under negative selection, and has a highly polygenic architecture where thousands of variant effects act together to influence disease risk. In dogs, we found hotspots of regional heritability. We also confirmed sharing of multiple risk genes. Our findings challenge the dogma that non-contact ACL rupture is predominantly due to a single overload injury event. Our results also suggest that accurate PRS prediction of ACL rupture risk is an achievable goal in both species, enabling identification of individuals for personalized medical care.

Protecting groups (PGs) in peptide synthesis have inspired advanced design principles that incorporate orthogonality for selective C- and N-terminus and side-chain deprotections. The conventionally acid-stable 9-fluorenylmethoxycarbonyl (Fmoc) group is one of the most widely used N-protection groups in solid- and solution-phase synthesis. Despite the versatility of Fmoc, deprotection by the removal of the Fmoc group to unmask primary amines requires the use of a basic secondary amine nucleophile, but this stratagem poses challenges in sensitive molecules that bear reactive electrophilic groups. An expansion of PG versatility, a tunable orthogonality, in the late-stage synthesis of peptides would add flexibility to the synthetic design and implementation. Here, we report a novel Fmoc deprotection method using hydrogenolysis under mildly acidic conditions for the synthesis of Z-Arg-Lys-acyloxymethyl ketone (Z-R-K-AOMK). This new method is not only valuable for Fmoc deprotection in the synthesis of complex peptides that contain highly reactive electrophiles, or other similar sensitive functional groups, that are incompatible with traditional Fmoc deprotection conditions but also tolerant of N-Boc groups present in the substrate.

While pancreatic β and α cells are considered the main drivers of blood glucose homeostasis through insulin and glucagon secretion, the contribution of δ cells and somatostatin (SST) secretion to glucose homeostasis remains unresolved. Here we provide a quantitative assessment of the physiological contribution of δ cells to the glycaemic set point in mice. Employing three orthogonal mouse models to remove SST signalling within the pancreas or transplanted islets, we demonstrate that ablating δ cells or SST leads to a sustained decrease in the glycaemic set point. This reduction coincides with a decreased glucose threshold for insulin response from β cells, leading to increased insulin secretion to the same glucose challenge. Our data demonstrate that β cells are sufficient to maintain stable glycaemia and reveal that the physiological role of δ cells is to provide tonic feedback inhibition that reduces the β cell glucose threshold and consequently lowers the glycaemic set point in vivo.

Paediatric Femoral Neck Fracture (PFNF) is rare, and its repair is challenging for orthopaedists. Surgical treatment should be performed, as soon as, possible with anatomical repair to avoid postoperative complications, including Avascular Head Necrosis (AVN) and bone deformity. In the present case scenario, a 14-year-old male patient presented to the Orthopaedic Emergency Department with hip pain and an inability to bear weight or move his right lower extremity. He arrived at the hospital at night and was examined immediately. The patient reported a fall from the second floor two days prior. Due to the unavailability of some necessary surgical instruments at the time of the emergency surgery, orthopaedic surgeons adopted a new procedure for treating a PFNF. The fracture reduction was maintained under general anaesthesia, and the incision site was properly sterilised before using a 3 mm Kirschner wire (K-wire). The 3 mm K-wire was removed before compressing the fracture site with screws. The wires were cut to a length that allows them to be bent over the femoral shaft and secured to the shaft using ligature wires. This is a modification of the Wagner technique, which involves passing the ligature wire around the femoral shaft.

Abstract Background Acute respiratory infections are a common presentation in clinical practice and medical interns must learn proper diagnosis and antibiotic prescribing. Traditional lecture-based teaching may not provide sufficient opportunities for students to apply their knowledge in realistic scenarios, whereas computer case-based simulations offer an alternative approach that allows active learning and decision-making in simulated patient cases. This study investigated the effectiveness of computer case-based reasoning simulation versus traditional lectures for medical interns teaching of diagnosis and antibiotic prescribing for acute respiratory infections. Methods This comparative quasi-experimental study was conducted from 2020 to 2022 in the Department of Infectious Diseases at Shahid Beheshti Hospital, affiliated to Kashan University of Medical Sciences. The samples were selected using a convenience method and assigned to the intervention and control groups using a permuted block randomization approach. Over a period of ten months (Each month, an average of eight medical interns), a total of 40 medical interns received traditional lecture-based teaching, while another 40 medical interns were taught using a Computer Case-based Reasoning simulation. The medical interns’ knowledge in both groups was assessed using pre- and post-tests. The collected data from the pre- and post-tests were then analyzed statistically using paired t-tests, independent t-tests, and ANCOVA. Results The posttest scores of the medical interns in both groups were significantly higher than the pretest scores (P 0.21). The results of the ANCOVA, after controlling for pre-test scores, showed no statistically significant difference between the two teaching methods in their effect on medical interns’ diagnostic and antibiotic prescribing performance (P > 0.33). Conclusion The study found that both computer case-based reasoning simulation and traditional lectures were effective in improving medical interns’ knowledge of diagnosis and antibiotic prescribing practices for acute respiratory infections. However, no statistically significant differences were observed between the two teaching methods. Thus, computer- based simulation could replace face-to-face teaching when this method is impractical or computerized methods are more cost-effective.

Abstract Antibiotics become less effective in treating infectious diseases as resistance increases. Staphylococcus aureus is a global problem due to its ability to form biofilms and resistance mechanisms. Phage endolysin is one of the most promising methods for combating antibiotic resistance. ZAM-MSC chimeric endolysin has three domains derived from SAL1 and lysostaphin, which target the peptide bridge of peptidoglycan. In this study purified ZAM-MSC (with yield of 30 mg/lit) had bactericidal activity against methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) at low concentrations (2.38 μg/ml and 1.88 μg/ml, respectively). The antibacterial spectrum revealed that ZAM-MSC was active against diverse Staphylococci. it has maintained 100% stability after 24 h incubation in pH 5 to 10 against S. aureus, as well as demonstrated significant thermostability and maintained nearly its full activity at different temperatures (4–42 °C) up to 1 day of incubation. The anti-biofilm activity of various concentrations of ZAM-MSC against MSSA and MRSA biofilms was not dose-dependent, and antibiofilm activity was observed even at low concentrations (14 μg/ml). Further, the molecular dynamics simulations demonstrated that the ZAM-MSC chimer and its parent proteins remained dynamically stable, showing similar flexibility despite the size and hydrogen bond number differences. In conclusion, the study reveals that chimeric ZAM-MSC is a distinctive enzyme with exceptional biochemical properties and rapid lytic activity against Staphylococci.

Background: Breast cancer ranks as one of the most prevalent cancers among women worldwide and remains a major cause of mortality. The axillary lymph node (ALN) status, especially in the absence of distant metastasis, is a significant prognostic indicator in breast cancer management. Non-invasive methods, such as ultrasound, have gained prominence in the diagnostic landscape, particularly for evaluating dense breast tissue where traditional imaging may have limitations. This study was conducted to assess the diagnostic accuracy of ultrasound in detecting malignant ALNs among breast cancer patients. Methods: This descriptive-analytical study was conducted on 150 women diagnosed with breast cancer who visited Golestan Hospital in Ahvaz, Iran, between 2021 and 2022. Patients were initially examined clinically, and subsequently, ALN evaluations were performed using a GE S6 logic ultrasound machine. Key radiologic parameters including lymph node size, morphology, cortical thickness, and vascular distribution were assessed. Stata software was used for data analysis, and pathology results were considered the gold standard to determine ultrasound’s sensitivity and specificity in detecting malignancy. Results: We found 77.7% of the 150 patients had metastatic ALNs, indicating a high rate of lymphatic spread in this population. Ultrasound showed a sensitivity of 86.09% and a specificity of 51.52% in detecting malignant nodes. Radiological signs of cancer, like abnormal morphology and increased cortical thickness, were strongly linked to positive pathological findings. This shows that ultrasound is a useful tool for diagnosis. Conclusion: The results indicate that ultrasound, as a non-invasive and accessible modality, can serve as a valuable diagnostic tool for identifying malignant ALNs in breast cancer patients. Integrating ultrasound with physical examination could enhance diagnostic precision, potentially reducing the need for invasive procedures such as biopsies. However, more research is necessary to establish the role of ultrasound in clinical protocols and investigate its potential to guide customized treatment strategies. Such advancements could optimize patient outcomes, enhance resource allocation, and ultimately contribute to more effective breast cancer management.

Background Fungal rhinosinusitis is subdivided into two subtypes, invasive and noninvasive variants, with allergic fungal rhinosinusitis (AFRS) being the most prevalent noninvasive variant. The most common clinical features of AFRS are nasal polyposis, rhinorrhea, facial pressure, and periorbital edema.Objective This study aimed to report a rare clinical presentation and serious complications of AFRS.Method and result The patient was presented to the Otorhinolaryngology Department of Qatif Central Hospital, Eastern Region, Saudi Arabia. We reported a rare presentation of a patient diagnosed with untreated AFRS complicated by basilar artery thrombosis. The patient was urgently managed with endoscopic sinus surgery, postoperative antifungal, and local nasal steroids.Conclusion Allergic fungal rhinosinusitis is a chronic disorder associated with significant morbidity that requires early diagnosis and management. The treatment protocol was based on surgical debridement of the paranasal sinuses from the fungal material and postoperative steroid therapy. Allergic fungal sinusitis with granuloma was more aggressive and needed to be treated cautiously by adding antifungal treatments.

Abstract Liquid biopsies have the potential to revolutionize cancer care through non-invasive early detection of tumors. Developing a robust liquid biopsy test requires collecting high-dimensional data from a large number of blood samples across heterogeneous groups of patients. We propose that the generative capability of variational auto-encoders enables learning a robust and generalizable signature of blood-based biomarkers. In this study, we analyze orphan non-coding RNAs (oncRNAs) from serum samples of 1050 individuals diagnosed with non-small cell lung cancer (NSCLC) at various stages, as well as sex-, age-, and BMI-matched controls. We demonstrate that our multi-task generative AI model, Orion, surpasses commonly used methods in both overall performance and generalizability to held-out datasets. Orion achieves an overall sensitivity of 94% (95% CI: 87%–98%) at 87% (95% CI: 81%–93%) specificity for cancer detection across all stages, outperforming the sensitivity of other methods on held-out validation datasets by more than ~ 30%.

Abstract Background Infections caused by biofilm-forming bacteria have significantly linked to dental plaque and caries. The aim of this study is to assess efficacy of some natural compounds in inhibition and eradication of biofilm formed by bacterial isolates from dental infections. Results Bacterial isolates were recovered from dental plaque/caries and identified using standard microbiological tests and 16S rDNA sequencing. The isolated bacterial strains include Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Klebsiella pneumoniae, and Escherichia coli. The antibiotic susceptibility was determined by disk diffusion method and revealed that the majority of isolates showed high antibiotic resistance, and 61% of isolates were found to be multidrug resistant. The biofilm formation capacity of isolates was investigated using microtiter plate assay. Among the 77 bacterial isolates, seventeen showed moderate biofilm formation capacity, twenty-two showed near-moderate, thirty-four had weak biofilm-forming capacity, and four were non-biofilm producers. The antibiofilm activity of tested compounds (rose and jasmine oils, propolis, vanillin, and vinegar) was evaluated against isolates with highest biofilm-forming capacity. The in vitro antibiofilm ability of tested substances were investigated alone or in combination with each other to evaluate their ability to prevent biofilm formation or destroy preformed single-/multispecies biofilms. Finally, antibiofilm ability of tested combination was evaluated ex vivo on natural teeth. Our results showed that vanillin in combination with rose or jasmine oils showed promising biofilm inhibition and biofilm eradication activities in both the in vitro and ex vivo models. Conclusions Dental plaque and caries can be successfully prevented using combination of vanillin with rose or jasmine oils, and these compounds can be incorporated in new anticaries dental formulations.

Abstract This research explores the challenges posed by variations in cystic duct anatomy during laparoscopic cholecystectomy and the potential use of stapler devices to address such complexities. It aims to assess the safety and efficacy of stapler devices, particularly in cases involving short, and wide cystic duct. The study, conducted at King Abdulaziz Medical City in Riyadh, Saudi Arabia, between 2021 and 2023. The study design involved a retrospective cohort approach, and the sample size encompassed all cases meeting the inclusion criteria during the study period. Data was analyzed using SPSS program. The study involving 568 patients, with the predominant technique for ligation being clipping (89.3%). The primary indication for using the Endo GIA stapler was a wide cystic duct (6.2%). Analysis revealed a significant association between stapler device use and hypertension (p = 0.042), diabetes (p = 0.001), CKD (p = 0.011), and obstructive jaundice (p = 0.006). Multivariate regression demonstrated that older patients were 2.1 times more likely to use stapler devices (AOR = 2.125; p = 0.039), while those with obstructive jaundice had a 2.2 times higher likelihood (AOR = 2.168; p = 0.049). Throughout the years, metal clips have shown the best prognosis compared to any other method for securing the cystic duct during closure in laparoscopic cholecystectomy. However, to avoid incomplete sealing of wide, short, or inflamed ducts, other instruments have emerged as possible alternatives for such conditions. Use of Endo-GIA is a safe and effective method for patients with wide, short cystic duct. Selective usage of endo-GIA is considered cost effective and may add a positive impact in decreasing post operative biliary leak.

This article examined student experiences before and after an essay writing assignment that required the use of ChatGPT within an undergraduate engineering course. Utilizing a pre-post study design, we gathered data from 24 participants to evaluate ChatGPT's support for both completing and grading an essay assignment, exploring its educational value and impact on the learning process. Our quantitative and thematic analyses uncovered that ChatGPT did not simplify the writing process. Instead, the tool transformed the student learning experience yielding mixed responses. Participants reported finding ChatGPT valuable for learning, and their comfort with its ethical and benevolent aspects increased postuse. Concerns with ChatGPT included poor accuracy and limited feedback on the confidence of its output. Students preferred instructors to use ChatGPT to help grade their assignments, with appropriate oversight. They did not trust ChatGPT to grade by itself. Student views of ChatGPT evolved from a perceived "cheating tool" to a collaborative resource that requires human oversight and calibrated trust. Implications for writing, education, and trust in artificial intelligence are discussed.