Search

The majority of oncogenic drivers are intracellular proteins, constraining their immunotherapeutic targeting to mutated peptides (neoantigens) presented by individual human leukocyte antigen (HLA) allotypes1. However, most cancers have a modest mutational burden that is insufficient for generating responses using neoantigen-based therapies2,3. Neuroblastoma is a paediatric cancer that harbours few mutations and is instead driven by epigenetically deregulated transcriptional networks4. Here we show that the neuroblastoma immunopeptidome is enriched with peptides derived from proteins essential for tumorigenesis. We focused on targeting the unmutated peptide QYNPIRTTF discovered on HLA-A*24:02, which is derived from the neuroblastoma-dependency gene and master transcriptional regulator PHOX2B. To target QYNPIRTTF, we developed peptide-centric chimeric antigen receptors (PC-CARs) through a counter panning strategy using predicted potentially cross-reactive peptides. We further proposed that PC-CARs can recognize peptides on additional HLA allotypes when presenting a similar overall molecular surface. Informed by our computational modelling results, we show that PHOX2B PC-CARs also recognize QYNPIRTTF presented by HLA-A*23:01, the most common non-A2 allele in people with African ancestry. Finally, we demonstrate potent and specific killing of neuroblastoma cells expressing these HLAs in vitro and complete tumour regression in mice. These data suggest that PC-CARs have the potential to expand the pool of immunotherapeutic targets to include non-immunogenic intracellular oncoproteins and allow targeting through additional HLA allotypes in a clinical setting.

Abstract Despite hundreds of studies examining belief in conspiracy theories, it is still unclear who—demographically—is most likely to believe such theories. To remedy this knowledge gap, we examine survey data containing various operationalizations of conspiracism across diverse sociopolitical contexts. Study 1 employs a 2021 U.S. survey (n = 2021) to examine associations between sociodemographic characteristics and beliefs in 39 conspiracy theories. Study 2 similarly employs a survey of 20 countries (n = 26,416) and 11 conspiracy theory beliefs. Study 3 reports results from a 2020 U.S. survey (n = 2015) measuring perceptions about which groups are engaging in conspiracies. Study 4 interrogates data from nine U.S. surveys (2012–2022; n = 14,334) to examine the relationships between sociodemographic characteristics and generalized conspiracy thinking. Study 5 synchronizes studies 1–4 to provide an intersectional analysis of conspiracy theory belief. Across studies, we observe remarkably consistent patterns: education, income, age (older), and White identification are negatively related to conspiracism, while Black identification is positively related. We conclude by discussing why conspiracy theories may appeal most to historically marginalized groups and how our findings can inform efforts to mitigate the negative effects of conspiracy theories.

In recent years, the growing interest in automatic speech recognition (ASR) has been driven by its wide-ranging applications across various domains. Integrating speech recognition technologies into smart systems highlights the pivotal role of human-machine interaction. This study introduces a robust ASR system that leverages convolutional neural networks (CNNs) in conjunction with Mel-frequency cepstral coefficients (MFCCs). The model's architecture was improved by extensively examining hyperparameters, effectively recognizing ten different spoken commands. The model conducted training and evaluation using the Google Speech dataset, comprising 65,000 audio clips collected from a wide range of speakers across the globe. This dataset accurately represents the natural variations in speech found in real-world scenarios. The design comprises eight storage layers, encompassing convolutional and fully connected layers. It consists of a total of 183,345 weights and utilizes ReLU activation. It is worth mentioning that the average F1-score obtained during the training, validation, and testing stages is 99.06 %, 94.68%, and 95.27%, respectively. Furthermore, the proposed model exhibits about 1.3% improvement in experimental test accuracy over existing methods, confirming its effectiveness in real-world applications.

ObjectivesBalloon dilation followed by balloon-expandable stent implantation is an effective treatment for improving hemodynamic status in patients with coarctation of the aorta (CoA). However, limited evidence exists regarding the safety and efficacy of covered balloon-expandable stents (CBSs) in a large cohort. In this meta-analysis, we aimed to evaluate the overall success rates, hemodynamic and anatomical benefits, complications, and mid-term results of CBSs in treating CoA.MethodsThe PubMed, Embase, and Cochrane Library databases were systemically searched for studies reporting outcomes of CBSs in treating CoA. Single-group rate meta-analyses were performed to calculate estimated pooled procedural success rates, the incidence of complications, and re-coarctation rates. A meta-analysis using standardized mean differences was conducted to compare pre- and postoperative trans-coarctation pressure gradients (PGs), coarctation diameter, and overall changes in systolic blood pressure (SBP). Subgroup analyses were performed to identify potential sources of heterogeneity.ResultsThe final analysis included 12 studies with a total of 411 patients. The estimated pooled procedural success rate was 100% [95% confidence interval (CI): 98%–100%, I2 = 0, P = 0.78]. Significant decreases in trans-coarctation PGs and SBP were observed. The pooled incidences of stent-related, aortic, and access site complications were 2% (95% CI: 0%–5%, I2 = 30.4%, P = 0.15), 2% (95% CI: 0%–4%, I2 = 0%, P = 0.76), and 3% (95% CI: 1%–7%, I2 = 52.9%, P = 0.02), respectively. Subgroup analyses showed that implantation of BeGraft stents was related to a significantly higher incidence of access site complications.ConclusionCovered balloon-expandable stent implantation in treating CoA is safe and effective with high procedural success rates, an acceptable incidence of complications, and a low incidence of re-coarctation.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, PROSPERO (CRD42023430356).

In recent years, integrating quantum feedback mechanisms into thermal machines has gained attention due to its benefits in manipulating the system states and energy flows. This is particularly advantageous for quantum thermal transistors in preserving their inherent quantum properties as they lose the purity of the system states due to decoherence and relaxation from interactions with thermal baths, within the subsystems, and monitoring. In the literature, studies have demonstrated that preserving quantum coherence can enhance the performance of quantum thermal machines, improving their efficiency. In our paper, we present a model that proposes engineering baths to be equipped with detectors and a controller to enable feedback in a quantum thermal transistor that emulates a role played by a feedback resistor in an electronic transistor. We use the framework of quantum feedback control via weak monitoring. We modify the system evolution trajectories by using a weak monitoring record from a detector. By taking the ensemble average of these trajectories, we unveil the evolution of the system density matrix that corresponds to the Markovian dynamics of the transistor. This type of feedback introduces minimal perturbation to the system and, once tuned, enhances the system coherence that would otherwise degrade due to bath interactions. Furthermore, there will be no change in the relaxation times. The probabilities of population terms remain unchanged. We treat this an enhancement in the operational characteristics of the quantum thermal transistor as it maintains its quantum features with an added benefit of improved amplification capabilities.

The thalamus is a deep structure located in the diencephalon, whose arterial blood supply is mainly from four branches of posterior cerebral artery. The artery of percheron (AOP) is an infrequent variation of thalamic perfusion, occlusion of which presents with a heterogenous, atypical list of symptoms without focal signs. This is in contrast to the typical, easily recognizable focal neurology of other ischemic infarcts. Therefore, AOP infarctions may be misdiagnosed, delayed in diagnosis or missed altogether. It is a rare, but vital area of neurology that needs to be studied by clinicians to facilitate an overall care for patients. We report the case of a 59-year-old lady who presented to us with bilateral complete ptosis with bilateral vertical gaze palsy and nystagmus, whose initial NCCT brain was normal. Subsequent MRI showed bilateral thalamic and midbrain ischemic infarctions in the artery of Percheron distribution. Our case highlights the importance of high degree of suspicion, early diagnosis and role of MRI in the diagnosis when initial CT is normal.

The paper focuses on the impact of informal economy and Islamic finance development on sustainable development using a panel dataset of 15 Muslim-majority countries from 2016 to 2022. The results based on the feasible GLS and panel quantile regression methods reveal that Islamic finance development has a positive impact on sustainable development. Meanwhile, the informal economy has a negative impact on sustainable development. Assessing the components of Islamic finance development, we further note that only quantitative development/financial performance and knowledge indicators are effective in achieving sustainable development. Besides these key results, GDP per capita, trade openness, and foreign direct investment emerge to be positive factors while the natural resource rents a negative factor in sustainable development. We reason that low productivity and precarious working conditions associated with informal economy may have hindered economic, social, and environmental wellbeing. The positive contribution of the Islamic finance development especially those related to Islamic financial performance and knowledge sharing to sustainable development hints the importance of further development of the Islamic financial sector in these countries.

Abstract Background Sri Lanka after eliminating malaria in 2012, is in the prevention of re-establishment (POR) phase. Being a tropical country with high malariogenic potential, maintaining vigilance is important. All malaria cases are investigated epidemiologically and followed up by integrated drug efficacy surveillance (iDES). Occasionally, that alone is not adequate to differentiate Plasmodium falciparum reinfections from recrudescences. This study evaluated the World Health Organization and Medicines for Malaria Venture (MMV) recommended genotyping protocol for the merozoite surface proteins (msp1, msp2) and the glutamate-rich protein (glurp) to discriminate P. falciparum recrudescence from reinfection in POR phase. Methods All P. falciparum patients detected from April 2014 to December 2019 were included in this study. Patients were treated and followed up by iDES up to 28 days and were advised to get tested if they develop fever at any time over the following year. Basic socio-demographic information including history of travel was obtained. Details of the malariogenic potential and reactive entomological and parasitological surveillance carried out by the Anti Malaria Campaign to exclude the possibility of local transmission were also collected. The msp1, msp2, and glurp genotyping was performed for initial and any recurrent infections. Classification of recurrent infections as recrudescence or reinfection was done based on epidemiological findings and was compared with the genotyping outcome. Results Among 106 P. falciparum patients, six had recurrent infections. All the initial infections were imported, with a history of travel to malaria endemic countries. In all instances, the reactive entomological and parasitological surveillance had no evidence for local transmission. Five recurrences occurred within 28 days of follow-up and were classified as recrudescence. They have not travelled to malaria endemic countries between the initial and recurrent infections. The other had a recurrent infection after 105 days. It was assumed a reinfection, as he had travelled to the same malaria endemic country in between the two malaria attacks. Genotyping confirmed the recrudescence and the reinfection. Conclusions The msp1, msp2 and glurp genotyping method accurately differentiated reinfections from recrudescence. Since reinfection without a history of travel to a malaria endemic country would mean local transmission, combining genotyping outcome with epidemiological findings will assist classifying malaria cases without any ambiguity.

Abstract Artificial neural networks are becoming an integral part of digital solutions to complex problems. However, employing neural networks on quantum processors faces challenges related to the implementation of non-linear functions using quantum circuits. In this paper, we use repeat-until-success circuits enabled by real-time control-flow feedback to realize quantum neurons with non-linear activation functions. These neurons constitute elementary building blocks that can be arranged in a variety of layouts to carry out deep learning tasks quantum coherently. As an example, we construct a minimal feedforward quantum neural network capable of learning all 2-to-1-bit Boolean functions by optimization of network activation parameters within the supervised-learning paradigm. This model is shown to perform non-linear classification and effectively learns from multiple copies of a single training state consisting of the maximal superposition of all inputs.

Abstract The ability to finely control the surface plasmon polariton (SPP) modes of plasmonic waveguides unveils many potential applications in nanophotonics. This work presents a comprehensive theoretical framework for predicting the propagation characteristics of SPP modes at a Schottky junction exposed to a dressing electromagnetic field. Applying the general linear response theory towards a periodically driven many-body quantum system, we obtain an explicit expression for the dielectric function of the dressed metal. Our study demonstrates that the dressing field can be used to alter and fine-tune the electron damping factor. By doing so, the SPP propagation length could be controlled and enhanced by appropriately selecting the intensity, frequency and polarization type of the external dressing field. Consequently, the developed theory reveals an unexplored mechanism for enhancing the SPP propagation length without altering other SPP characteristics. The proposed improvements are compatible with existing SPP-based waveguiding technologies and could lead to breakthroughs in the design and fabrication of state-of-the-art nanoscale integrated circuits and devices in the near future.

Purpose: The purpose of this study is to identify opportunities to improve processes within a paediatric feeding clinic to enhance timely patient access to healthcare through effective and efficient resource use. Design/methodology/approach: The study involved three interrelated methods. First, de-identified feeding clinic data, collected over seven years, were analysed to understand patient appointments. Second, clinician workshops and the swim lane method were used to map feeding clinic processes. Third, root cause analysis was conducted to identify bottlenecks and identify improvement opportunities. Findings: The results revealed three, poorly connected sub-processes within the feeding clinic – namely: the patient triaging and appointment scheduling or allocation process; the clinic reporting process; and the cancellation and rescheduling process. These sub-processes were poorly connected because of inadequate resources, few standardised processes, and limited coordination between the different processes. Consequently, patient appointments were typically delayed, and patient reports were not always completed in a timely manner. Processes within the paediatric feeding clinic could therefore be improved by using digital tools, patient portals and telehealth, online interventions, an automated appointment confirmation system, and/or an automated transcription of each appointment. Originality/value: This is the first published study to apply business process management to a paediatric feeding clinic. By using three methods to clarify opportunities to improve clinic processes, it highlights the potential value of health information technology in this context. This evidence will enable health service managers to ensure that children with feeding difficulties have timely access to appropriate care.