Search

New treatment strategies are urgently needed for pancreatic ductal adenocarcinoma (PDAC), which is one of the deadliest tumors nowadays. PDAC is marked by hypoxia, intrinsic chemoresistance, a “cold” tumor microenvironment, and dense desmoplastic stroma, which hinders drug penetration. This study investigates the combined effect of iron-doped, lipid-coated zinc oxide nanoparticles enhanced with a fluorescent sonosensitizer and local ultrasound stimulation in treating PDAC. Nanoparticles were synthesized and coated by lipids, and their physiochemical properties were characterized by assessing reproducibility, stability, and efficient inclusion of the sonosensitizer. In vitro, sonosensitizer-enhanced nanoconstructs were tested on a KPC murine PDAC cell line in combination with ultrasound to evaluate their cytotoxicity and assess their efficacy. In vivo, NPs were further coupled with AlexaFluor 700 to allow their localization over time, and the nanoconstructs were intratumorally administered to a subcutaneous murine PDAC model to enhance local bioavailability and tumor visualization and minimize off-target effects of systemic delivery. Biodistribution, efficacy, flow cytometry, and survival studies were carried out on different cohorts of mice. The sonosensitizer-enhanced nanoconstructs, combined with ultrasound, triggered significant reactive oxygen species (ROS) production, reducing the KPC cell viability. In vivo, the antitumor efficacy was particularly pronounced with ultrasound stimulation, demonstrating a synergistic interaction between the nanoparticles and ultrasound. Moreover, increased immune cell infiltration, enhanced cancer cell apoptosis, and prolonged survival of the treated animals were achieved. These findings highlight the potential of a synergistic therapeutic approach combining lipid-coated sonosensitizer-loaded nanoparticles and ultrasound stimulation as an effective therapy for PDAC and in situ monitoring.

Intraoperative frozen section (FS) examination of oncologic surgical specimens is frequently performed to ensure complete surgical resection. Data on the gross evaluation of surgical margins are limited. We recently published a study suggesting the use of a macroscopic 2.0 cm tumor-margin cutoff during intraoperative evaluation to decrease the number of unnecessary FS. This study aimed to validate the safety and the clinical impacts of implementing a 2.0 cm tumor-margin threshold for FS diagnosis in evaluating surgical margins during oncologic lung surgery. This retrospective analysis included patients who underwent lung resection for primary or metastatic neoplasms between 2018 and 2022 at the Institut Universitaire de Cardiologie et de Pneumologie de Québec, following the implementation of this practice. Clinicopathological data were retrieved from the medical files. Univariate and multivariate analyses were used to identify the variables associated with positive margins. This study included 1575 tumors in 1299 patients. FS evaluations were performed in 24.4% of patients. No positive margins were observed when the tumor-margin distance was >2.0 cm. The incidence rate of positive margins was 2.95%, with parenchymal margins being the most affected. Multivariate analysis identified the tumor-margin distance as a significant predictor of positive margin status. This practice led to a 79.9% reduction in FS evaluations without compromising the margin assessment accuracy or patient safety. A 2.0 cm tumor-margin distance threshold for intraoperative FS evaluation in oncologic lung surgery is safe and effective in reducing unnecessary FS evaluations while maintaining accurate margin assessments.

In eukaryotic cells, the phospholipid cardiolipin (CL) is a crucial component that influences the function and organization of the mitochondrial inner membrane. In this study, we examined its potential role in passive proton transmembrane flux using unilamellar vesicles composed of natural egg phosphatidylcholine (PC) alone or with the inclusion of 18 or 34 mol % CL. A membrane potential was induced by a potassium gradient, and oxonol VI dye was used to monitor membrane potential dissipation resulting from proton transmembrane efflux. Increasing the CL content led to a net increase in proton efflux, which was also dependent on the magnitude of the membrane potential. The same increase in proton efflux was measured in the presence of the equally negatively charged phosphatidylglycerol, indicating that the charge of CL plays a more important role than its structure in this mechanism. When varying the proton membrane permeability (pH) using the protonophore CCCP, we observed that unlike PC liposomes, where a small amount of CCCP was sufficient to achieve maximum flux, a significantly larger amount of protonophore was required in the presence of CL. Conversely, increasing the buffer capacity increased proton flux, indicating that proton availability, rather than membrane permeability, may be the limiting factor for proton leak. Our findings demonstrated that a higher proton content associated with the membrane was correlated with an increasing leak in the presence of CL. Additionally, smaller liposome diameters appeared to favor proton leak. Taken together, our results suggest that the presence of negatively charged CL in a membrane traps protons and increases their leakage, potentially in a manner dependent on membrane curvature. We discuss the possible mechanisms and implications of these findings for mitochondrial respiration function.

Disease tolerance is an evolutionarily conserved host defense strategy that preserves tissue integrity and physiology without affecting pathogen load. Unlike host resistance, the mechanisms underlying disease tolerance remain poorly understood. In the present study, we investigated whether an adjuvant (β-glucan) can reprogram innate immunity to provide protection against influenza A virus (IAV) infection. β-Glucan treatment reduces the morbidity and mortality against IAV infection, independent of host resistance. The enhanced survival is the result of increased recruitment of neutrophils via RoRγt+T cells in the lung tissue. β-Glucan treatment promotes granulopoiesis in a type 1 interferon-dependent manner that leads to the generation of a unique subset of immature neutrophils utilizing a mitochondrial oxidative metabolism and producing interleukin-10. Collectively, our data indicate that β-glucan reprograms hematopoietic stem cells to generate neutrophils with a new ‘regulatory’ function, which is required for promoting disease tolerance and maintaining lung tissue integrity against viral infection.

Background Diet quality indexes (DQIs) consist of combinations of foods and/or nutrient components that represent adherence to dietary guidelines. A high-quality diet during pregnancy contributes to optimal birth outcomes.Objective We developed and validated the first DQI for pregnancy for South African women.Methods The South African Food Based Dietary Guidelines and pregnancy dietary guidelines were used as theoretical basis for the a prioridevelopment of the South African Diet Quality Index for Pregnancy (SA-DQI-P). To validate the SA-DQI-P, we applied it to data collected for the Nutritional status of Expectant Mothers and their newborn Infants (NuEMI) study (N= 682). We determined the associations between SA-DQI-P scores in tertiles with nutrient intakes, sociodemographic factors, household food security level, and biochemical values.Results A lower household density ratio, household access to a toilet, refrigerator, and microwave, a higher educational level, being employed and being food secure were significantly associated with a higher score. After correcting for energy intake, higher scores were significantly associated with higher intakes of protein, total fat, saturated fat, cholesterol, calcium, vitamin A, vitamin E, folic acid, vitamin B12, and vitamin C. Significantly more participants who were vitamin A deficient scored in the lowest tertile than those in higher tertiles.Conclusion The SA-DQI-P is the first DQI developed for a South African population and has proven to be valid in ranking diet quality in pregnant women in our sample. Information regarding diet quality of this vulnerable group can assist with planning nutrition intervention programs to improve nutritional status.

CASPR2-associated neurological disorders encompass a wide clinical spectrum broadly divided into overlapping three autoimmune syndromes: CASPR2 limbic encephalitis, Morvan syndrome, and Isaacs syndrome. CASPR2 is a neuronal protein expressed at different sites in the central and peripheral nervous system and has a variety of roles and functions regarding neuronal excitability, synaptic plasticity, and homeostasis of inhibitory networks, most of which are only partially understood. CASPR2 antibodies have various pathogenic effects including internalization of CASPR2, disruption of protein-protein interactions, and, possibly, complement activation. Their pathogenic effect is well demonstrated in the limbic encephalitis phenotype, but the role of pathogenic antibodies in the development of other clinical manifestations is less clear. CASPR2 limbic encephalitis also differ from the other CASPR2-associated disorders in regard to HLA allele and paraneoplastic associations, suggesting it has immunological mechanisms distinct from the other clinical forms. Future studies are needed to better understand how the immunological alterations lead to the different phenotypes associated with CASPR2 antibodies.

Immune checkpoint inhibitors lead to effective antitumour responses but also to immune-related adverse events (irAEs), which affect the nervous system in 1–5% of patients. Encephalitis is the most frequent central nervous system irAE and is clinically relevant due to its high severity and mortality. Early diagnosis is crucial but is hampered by the broad list of alternative diagnoses, the lack of established diagnostic criteria, and the need of extensive diagnostic procedures (e.g., spinal tap, brain MRI) alongside expert neurological evaluation. Additionally, the response to corticosteroids is inconsistent, and the management of corticosteroid-refractory patients remains poorly defined. This mini-review discusses the role of various soluble biomarkers in the diagnosis, prognostication, and management of ICI-encephalitis. Neural antibodies, which are well-established biomarkers of autoimmune and paraneoplastic encephalitis, are found in only a subset of ICI-encephalitis, in which they can aid to establish the diagnosis. The most prevalent are paraneoplastic neurological syndromes (PNS)-associated antibodies, which are found almost exclusively in focal ICI-encephalitis syndromes and are associated with poor outcomes, possibly due to predominantly cytotoxic T cell involvement leading to irreversible neuronal loss. Beside antibodies, serum brain injury biomarkers such as NfL and S100B are elevated in ICI-encephalitis and, even if non-specific, may be useful as a routine test to quickly identify patients in whom neurological evaluation and second-level diagnostic procedures should be prioritized. Additionally, higher serum and CSF NfL levels have been associated with lack of treatment response in ICI-encephalitis, suggesting they may have a prognostic role. Among cytokines, elevated interleukin 6 (IL6) levels have been observed in serum and/or CSF samples of some patients with ICI-encephalitis, but the role of IL6 as a biomarker for response to IL6-directed therapies requires further investigation. Likewise, the value of other biomarkers, including T cells markers and HLA haplotypes, still needs to be evaluated in large cohorts. Overall, neural antibodies are important diagnostic and prognostic biomarkers in ICI-encephalitis, and other soluble biomarkers, especially NfL, deserve further investigation since they have a promising application in clinical practice.

La perte de sensibilité aux hypoglycémies (PSH) est une réduction de la capacité à reconnaître les signes avant-coureurs de l’hypoglycémie qui concerne environ 25 % des diabétiques de type 1 avec une physiopathologie complexe et des conséquences potentiellement graves, dont la survenue d’hypoglycémies sévères. Plusieurs scores/questionnaires sont à disposition même s’il importe en premier lieu d’interroger les patients. Les nouveaux outils technologiques, flash glucose monitoring(FGM) et mesure continue du glucose (MCG), peuvent fournir des informations en temps réel sur la glycémie et générer des alertes en cas de baisse rapide de la glycémie. Il existe désormais des FGM avec alerte de seuil glycémique, de même que des MCG disposant d’alertes prédictives. Ce sont des outils essentiels pour aider à prévenir les hypoglycémies sévères et à en atténuer les conséquences chez les patients vivant avec un diabète.

•Patients with MM patients have increased CD16/CD226LowNK cell subsets characterized by adhesion defects and reduced effector functions.•The frequency of CD16/CD226LowNK cells correlates with clinical outcomes in patients MM.

Atractylis flavaDesf. (AF) is common plant that is widely used for its anti- inflammatory and antioxidant properties. The purpose of this study was, therefore, to evaluate the cytotoxic effect and the molecular basis of antioxidant and anti-inflammatory effects of the ethyl acetate extract (AFEAE) obtained from the whole plant A. flava. This was accomplished throughthe use of NR8383 alveolar rat macrophage cells. Cultures of alveolar rat macrophage cells were treated with AFEAE(25–800 μg/mL), and cell viability was determined via WST-1 and LDH tests. In turn, the gene expression levels of nuclear factor κB (NF-κB), tumor necrosis factor-alpha (TNFα), interleukin 1 beta (IL1-β), interleukin 6 (IL-6), mitochondrial dynamin like GTPase (OPA1), Succinate dehydrogenase complex subunit A (SDHA) and neutrophil cytosolic factor 1 (NCF1) were assessed by applying RT-qPCR. The results show that ethyl acetate extracts of A. flavahave non-cytotoxic effects, and the gene expression analysis demonstrates that AFEAF extracts generate significant downregulation of NF-κB, TNFα, IL-1 β, IL-6, NCF1, OPA1 and SDHA, compared to untreated cells. This study reveals that Atractylis flavaethyl acetate extract administration may be considered as a potential therapeutic strategy for inflammatory related diseases.

La mesure en continu du glucose (MCG) interstitiel, désormais largement adoptée par les patients et par les professionnels de santé, a fait apparaître de nouveaux paramètres de suivi du diabète : le temps dans la cible (TIR), le temps en hypoglycémie (TBR) ou encore le coefficient de variation (CV) sont utilisés quotidiennement en consultation de diabétologie pour évaluer l’équilibre métabolique des patients équipés de capteurs de glucose. De nouveaux paramètres de suivi issus des données des capteurs, notamment le temps dans la cible étroite (TITR) et le GRI (glycemic risk index), ont été développés pour affiner encore l’analyse métabolique et seront peut-être prochainement disponibles sur les rapports MCG standardisés.

In the realm of medicinal chemistry, the primary objective is to swiftly optimize a multitude of chemical properties of a set of compounds to yield a clinical candidate poised for clinical trials. In recent years, two computational techniques, machine learning (ML) and physics-based methods, have evolved substantially and are now frequently incorporated into the medicinal chemist’s toolbox to enhance the efficiency of both hit optimization and candidate design. Both computational methods come with their own set of limitations, and they are often used independently of each other. ML’s capability to screen extensive compound libraries expediently is tempered by its reliance on quality data, which can be scarce especially during early-stage optimization. Contrarily, physics-based approaches like free energy perturbation (FEP) are frequently constrained by low throughput and high cost by comparison; however, physics-based methods are capable of making highly accurate binding affinity predictions. In this study, we harnessed the strength of FEP to overcome data paucity in ML by generating virtual activity data sets which then inform the training of algorithms. Here, we show that ML algorithms trained with an FEP-augmented data set could achieve comparable predictive accuracy to data sets trained on experimental data from biological assays. Throughout the paper, we emphasize key mechanistic considerations that must be taken into account when aiming to augment data sets and lay the groundwork for successful implementation. Ultimately, the study advocates for the synergy of physics-based methods and ML to expedite the lead optimization process. We believe that the physics-based augmentation of ML will significantly benefit drug discovery, as these techniques continue to evolve.

ABSTRACTIntroductionHistone deacetylases (HDACs) are a class of zinc-dependent enzymes. They maintain acetylation homeostasis, with numerous biological functions and are associated with many diseases. HDAC3 strictly requires multi-subunit complex formation for activity. It is associated with the progression of numerous non-communicable diseases. Its widespread involvement in diseases makes it an epigenetic drug target. Preexisting HDAC3 inhibitors have many uses, highlighting the need for continued research in the discovery of HDAC3-selective inhibitors.Area coveredThis review provides an overview of 24 patents published from 2010 to 2023, focusing on compounds that inhibit the HDAC3 isoenzyme.Expert opinionHDAC3-selective inhibitors – pivotal for pharmacological applications, as single or combination therapies – are gaining traction as a strategy to move away from complications laden pan-HDAC inhibitors. Moreover, there is an unmet need for HDAC3 inhibitors with alternative zinc-binding groups (ZBGs) because some preexisting ZBGs have limitations related to toxicity and side effects. Difficulties in achieving HDAC3 selectivity may be due to isoform selectivity. However, advancements in computer-aided drug design and experimental data of HDAC3 3D co-crystallized models could lead to the discovery of novel HDAC3-selective inhibitors, which bear alternative ZBGs with balanced selectivity for HDAC3 and potency.

Pour les personnes vivant avec un diabète de type 1 (DT1), l’insulinothérapie fonctionnelle (IF), et notamment la quantification des glucides, permettent d’obtenir conjointement un meilleur équilibre glycémique et une plus grande liberté dans la composition des repas. Le GluciQuizz est le premier outil d’évaluation en langue française de ces connaissances. Il a été développé à partir d’un questionnaire américain validé qui a été traduit et adapté aux habitudes alimentaires françaises. Le GluciQuizz a été soumis à un processus complet de validation avec l’aide de patients experts et de diabétologues indépendants. Sa cohérence interne a été évaluée pour chaque item et son évaluation par un panel de 190 personnes vivant avec un DT1 a montré une corrélation positive du score GluciQuizz au temps dans la cible (Time in Range[TIR]) de cette population. Le GluciQuizz, disponible gratuitement, est ainsi le premier questionnaire français validé d’évaluation des connaissances en insulinothérapie fonctionnelle.

Tumor grading enables better management of patients and treatment options. The International Association for the Study of Lung Cancer (IASLC) Pathology Committee has recently released a 3-tier grading system for invasive pulmonary adenocarcinoma consisting of predominant histologic patterns plus a cutoff of 20% of high-grade components including solid, micropapillary, and complex glandular patterns. The goal of this study was to validate the prognostic value of the new IASLC grading system and to compare its discriminatory performance to the predominant pattern–based grading system and a simplified version of the IASLC grading system without complex glandular patterns. This was a single-site retrospective study based on a 20-year data collection of patients that underwent lung cancer surgery. All invasive pulmonary adenocarcinomas confirmed by the histologic review were evaluated in a discovery cohort (n=676) and a validation cohort (n=717). The median duration of follow-up in the combined dataset (n=1393) was 7.5 years. The primary outcome was overall survival after surgery. The 3 grading systems had strong and relatively similar predictive performance, but the best parsimonious model was the simplified IASLC grading system (log-rank P=1.39E−13). The latter was strongly associated with survival in the validation set (P=1.1E−18) and the combined set (P=5.01E−35). We observed a large proportion of patients upgraded to the poor prognosis group using the IASLC grading system, which was attenuated when using the simplified IASLC grading system. In conclusion, we identified a histologic simpler classification for invasive pulmonary adenocarcinomas that outperformed the recently proposed IASLC grading system. A simplified grading system is clinically convenient and will facilitate widespread implementation.

Reliable water quality monitoring requires on-site processing and assessment of water quality data in near real-time. This helps to promptly detect changes in water quality, prevent biodiversity loss, safeguard the health and well-being of communities, and mitigate agricultural problems. To this end, we proposed a highway-bidirectional long short-term memory (Highway-BiLSTM)-based water quality classification tool for potential integration into an edge-enabled water quality monitoring system to facilitate on-site water quality classification. The performance of the proposed classifier was validated by comparing it with several baseline water quality classifiers. The proposed classifier outperformed the baseline water classifier in terms of accuracy, precision, sensitivity, ${F}1$ -score, and confusion matrix. Specifically, the proposed water classifier surpassed the random forest (RF) classifier with 2% accuracy, precision, sensitivity, and ${F}1$ -score. Moreover, the proposed classifier achieved an increase of 4% in accuracy, precision, sensitivity, and ${F}1$ -score for classifying water quality compared with the gradient-boosting classifier. Additionally, the proposed method has a 4% increase in accuracy, sensitivity, ${F}1$ -score, and a 3% increase in precision compared to the support vector machine (SVM) water quality classifier. The proposed method outperformed the artificial neural network (ANN) classifier by 1% accuracy, precision, sensitivity, and ${F}1$ -score. Finally, the proposed method demonstrated rare errors in accurately classifying complex water quality samples. These findings suggest that our proposed method could be used to effectively classify water quality to aid accurate decision-making and environmental management.

Neurodegenerative disorders pose a significant challenge to global healthcare systems due to their progressive nature and the resulting loss of neuronal cells and functions. Excitotoxicity, characterized by calcium overload, plays a critical role in the pathophysiology of these disorders. In this review article, we explore the involvement of calcium dysregulation in neurodegeneration and neurodegenerative disorders. A promising therapeutic strategy to counter calcium dysregulation involves the use of calcium modulators, particularly polycyclic cage compounds. These compounds, structurally related to amantadine and memantine, exhibit neuroprotective properties by attenuating calcium influx into neuronal cells. Notably, the pentacycloundecylamine NGP1-01, a cage-like structure, has shown efficacy in inhibiting both N-methyl-D-aspartate (NMDA) receptors and voltage- gated calcium channels (VGCCs), making it a potential candidate for neuroprotection against excitotoxic-induced neurodegenerative disorders. The structure-activity relationship of polycyclic cage compounds is discussed in detail, highlighting their calcium-inhibitory activities. Various closed, open, and rearranged cage compounds have demonstrated inhibitory effects on calcium influx through NMDA receptors and VGCCs. Additionally, these compounds have exhibited neuroprotective properties, including free radical scavenging, attenuation of neurotoxicities, and reduction of neuroinflammation. Although the calcium modulatory activities of polycyclic cage compounds have been extensively studied, apart from amantadine and memantine, none have undergone clinical trials. Further in vitro and in vivo studies and subsequent clinical trials are required to establish the efficacy and safety of these compounds. The development of polycyclic cages as potential multifunctional agents for treating complex neurodegenerative diseases holds great promise.

When carriers consider electrifying their delivery fleets, it is not only a societal and moral obligation, given road traffic's impact on emissions. It has also become an economic consideration as sustainability metrics can result in investment, and the life-cycle cost of electric vehicles is becoming more attractive. In this paper, we report on an actual case of a South African pharmaceutical company considering replacing and electrifying its current delivery fleet. The paper uses an agent-based simulation approach that models each delivery vehicle on an existing road network. Each vehicle's emissions characteristics are known, and its spatiotemporal movement results from solving a variant of the well-known routing problem. Vehicle movements are coupled with a detailed database of emissions factors to estimate the total emissions per vehicle per link, which can then be aggregated to any required level. The results show that electrifying an entire fleet may not be viable initially, suggesting a hybrid fleet as a more practical intervention in the foreseeable future.

Several city logistics initiatives focus on lowering last-mile deliveries’ environmental impacts. And here, the impact is often the total (absolute) pollutants emitted by urban goods vehicles and the population's exposure to those pollutants. Some of these interventions include the conversion of traditional fleets to clean(er) fuels or imposing vehicle access restrictions, based on emission standards, in the form of (ultra) low emission zones. Many of these interventions rely on models to predict and evaluate, a priori, what the impact will be. But, like all models, assumptions must be made, resulting in predicted results underestimating actual emissions. For urban logistics, more than for private cars, the literature shows a substantial difference between the predicted and tail-pipe emissions for most pollutants. This paper builds on prior research and shows the cargo load's nonlinear effect on emissions in an urban environment.

L’hidradénite suppurée (HS) altère considérablement la vie quotidienne des patients, entraînant une stigmatisation sociale et affectant leur vie professionnelle. Cet impact est principalement dû à la localisation anatomique des lésions, à leur nature ainsi qu’à la chronicité et à l’imprévisibilité des poussées. Peu de recherches ont évalué les conséquences de l’HS sur la sexualité et le désir de parentalité des femmes atteintes.

•Platelet mitochondria undergo a fission step during platelet activation.•The fission of platelet mitochondria correlates with a switch from a predominant mitochondrial to a more glycolytic energy production.

Supramolecular hybrids of DNA and single-walled carbon nanotubes (SWCNTs) have been introduced in numerous biosensing applications due to their unique optical properties. Recent aqueous two-phase (ATP) purification methods for SWCNTs have gained popularity by introducing specificity and homogeneity into the sensor design process. Using murine macrophages probed by near-infrared and Raman microscopies, we show that ATP purification increases the retention time of DNA-SWCNTs within cells while simultaneously enhancing the optical performance and stability of the engineered nanomaterial. Over a period of 6 h, we observe 45% brighter fluorescence intensity and no significant change in emission wavelength of ATP-purified DNA-SWCNTs relative to as-dispersed SWCNTs. These findings provide strong evidence of how cells differentially process engineered nanomaterials depending on their state of purification, lending to the future development of more robust and sensitive biosensors with desirable in vivooptical parameters using surfactant-based ATP systems with a subsequent exchange to biocompatible functionalization.

ABSTRACTPerson-centeredness is an important aspect of healthcare service delivery endorsed by the World Health Organization. To instill person-centered care (PCC) in health training requires prioritization of PCC concepts. Focusing on Speech-Language Pathology and/or Audiology (SLP/A) this study aimed to (i) measure student preferences towards PCC using the modified Patient-Practitioner Orientation Scale (mPPOS) (ii) to determine predictors towards these preferences and (iii) describe students’ views and experiences towards PCC. A mixed-method design was followed utilizing an online survey and four focus group discussions. The survey included demographic questions, the modified Patient-Practitioner-Orientation Scale (mPPOS), the Ten-Item-Personality-Inventory (TIPI) and an open-ended question. The focus group discussions included prompting questions which facilitated an open-ended discussion. A total of 321 students (54.5% SLP) completed the online survey across all seven South African Universities, and 16 students (39% Audiology students) participated in the focus group discussions. High preference towards person-centeredness with a mean mPPOS score of 4.3 (SD 0.6) was obtained. Quantile regression analysis revealed eight common predictors towards PCC preferences. Three main categories emerged from the open-ended question and focus group discussions: (i) client-clinician relationship (ii) barriers towards PCC and (iii) PCC training. Although students have a preference for and an understanding of PCC, there are important factors to consider during training. Curriculum enhancement can nurture and foster the skills required to provide care that is more person-centered.

Short wave infrared hyperspectral imaging was tested for its ability to distinguish rooibos tea (Aspalathus linearis) based on production area and quality grade, with the aim to replace time-consuming sensory analysis in the industry. The number of latent variables and model parameters of the calibration model were optimised by cross-validation. Classification error rates were used to evaluate the performance of the models in classifying rooibos based on production area and quality grade. The production area of rooibos was distinguished by applying a partial least square-discriminant analysis model with second derivative pre-processing, followed by mean centering and inclusion of nine LVs. The model could successfully distinguish between the two production areas and had a classification accuracy of 100% for the prediction set. To distinguish between different quality grades, a hierarchical model with second derivative pre-processing was developed. Grade A could be distinguished successfully from grades B, C and D (class BCD) with 100% accuracy and grade D could be distinguished from grades B and C (class BC) with 96% accuracy. However, the model was less accurate to distinguish between grade B and C samples, with prediction accuracies of 82 and 66% for B and C, respectively. Application of near infrared hyperspectral imaging therefore offers the potential to replace the use of sensory analysis in the rooibos tea industry to predict production area and quality grade of this herbal tea.

Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer.

Public transport network design deals with finding efficient network solution(s) from a set of alternatives that best satisfies the often-conflicting objectives of stakeholders like passengers and operators. This work presents a simulation-based optimization (SBO) model for designing public transport networks. The work’s novelty is in developing such a network design model that fully accounts for the stochastic behavior of commuters on the transit network. The SBO discipline solves decision-based problems like the transit network design problem (TNDP) by combining simulation and optimization models. The proposed model integrates a disaggregated activity-based travel demand simulation with a multi-objective network optimization algorithm. Trip-based travel demand models are commonly used to represent traveler behavior in the literature. The approach limits its ability to accommodate the stochastic realities of traveler behavior in a transit network design solution. Using activity-based simulation instead makes it possible to account for a more realistic traveler behavior, especially real-time decisions made in response to changing network dynamics which ultimately affect the distribution of demand over time on the network. The proposed model is applied to the improved design of the integrated public transport network in the City of Cape Town, South Africa. The results show SBO can design efficient network solutions that reflect the objectives of network stakeholders.

•The continuous development of new oncological treatments have led to the emergence of new neurological side effects.•The neurological side effects of oncological treatments can be life threatening or can impair greatly the quality of life; their management should be performed by specialized teams.•Classical oncological treatments as brain radiotherapy are subjected to toxicity mitigating strategies and improvement of neurological complication diagnosis and management.•Innovating oncological treatments as the immune checkpoint inhibitors and the CAR-T cells are responsible for immune-mediated toxicities.•Molecularly targeted therapies represent an expanding class associated to both cytotoxic and immune-mediated adverse events.

Thyrotoxic periodic paralysis (TPP) is a complication of hyperthyroidism commonly seen in Asian populations. It presents as sudden-onset muscle paralysis and hypokalaemia. Diagnosis is often delayed due to the rarity of the disease, the subtlety of the hyperthyroidism and the fleeting nature of the clinical presentation. With global expansion, physicians outside Asia should be aware of this disease for early recognition and treatment as severe cardiac arrhythmias, which may prove fatal, can occur. Several breakthroughs have been made in identifying the pathophysiological mechanism resulting in the severe hypokalaemia, including mutations in the Kir2.6 channel, an inwardly rectifying potassium channel, which results in a massive intracellular potassium shift. Treating the underlying hyperthyroidism is the definitive treatment; however, beta blockers and potassium supplementation are vital in acute management of this condition. This is a report of a case seen in Cape Town, South Africa with a review of the literature regarding the clinical features, pathophysiology and treatment.

In the past 20 years, the International Association for the Study of Lung Cancer (IASLC) has been working on a global project to revise the TNM classification of lung cancer. The first and second phases of the staging projects proposed recommendations for revision of the TNM classification, which were adopted by the Union for International Cancer Control and the American Joint Committee on Cancer as their seventh and eighth editions of the TNM classifications of lung cancer. For the third phase of the IASLC Staging Project, a new database of lung cancer cases diagnosed between January 2011 and December 2019 has been established. The Staging and Prognostic Factors Committee of the IASLC is in charge of the process of proposing new recommendations. The newly established database consisted of 124,581 cases. The data were obtained from Asia and Australia (56.0%), Europe (24.7%), North America (15.7%), South/Central America (3.4%), and Africa and the Middle East (0.1%). After cases with incomplete data are excluded, 87,043 cases were enrolled in the analysis, of which 52,069 (59.8%) were invasive adenocarcinoma and 15,872 (18.2%) were squamous cell carcinoma. Both clinical and pathologic stages were available in 44,831 (51.5%) cases. Analyses of this database are expected to provide proposals for changing the TNM classification toward the ninth edition, which is scheduled to be in use in January 2024. This newly established global database on lung cancer is described to provide fundamental elements for revisions of the TNM rules for staging lung cancer.

Comme c’est souvent le cas dans les enquêtes en ligne, et a fortioridans celles reposant sur des échantillons « spontanés », celui de l’enquête Vico est caractérisé par un certain nombre de biais : les répondant·es sont beaucoup plus souvent issu·es des catégories favorisées et diplômées que l’ensemble de la population, et les femmes y sont également bien plus nombreuses que les hommes. Cet article propose une technique de redressement de ces biais, et en discute l’efficacité.

Photochemical internalization (PCI) is a novel, minimally invasive drug delivery technology that facilitates the delivery of therapeutic molecules into the cytosol of cells. In this work, PCI was utilized in an effort to enhance the therapeutic index of the existing anticancer drugs as well as novel nanοformulations against breast and pancreatic cancer cells. Frontline anticancer drugs were tested with bleomycin as a benchmark PCI control; namely, three vinca alkaloids (vincristine, vinorelbine, and vinblastine), two taxanes (docetaxel and paclitaxel), two antimetabolites (gemcitabine and capecitabine), a combination of taxanes with antimetabolites, and two nano-sized formulations (squalene- and polymer-bound gemcitabine derivatives) were tested in a 3D PCI in vitro model. Strikingly, we discovered that several drug molecules exhibited remarkably augmented therapeutic activity by several orders of magnitude compared to their respective controls (without PCI technology or directly compared with bleomycin controls). Nearly all drug molecules showed enhanced therapeutic efficiency, but more interestingly, we traced several drug molecules that showed multi-fold enhancement (ranging from 5000- up to 170,000-fold enhancement) in their IC70indices. Interestingly, PCI delivery of the vinca alkaloids (especially PCI–vincristine), and some of the nanoformulations tested, was seen to perform impressively across all of the treatment outcomes of potency, efficacy, and synergy─as determined by means of a cell viability assay. The study constitutes a systematic guide for the development of future PCI-based therapeutic modalities for precision oncology.

Les patients atteints de diabète de type 1 ou de diabète de type 2 insulinorequérants représentent en France plusieurs centaines de milliers de personnes. Bien que la plupart de ces patients soient maintenant équipés de capteur de glucose interstitiel, apportant au clinicien une mine d'information concernant les profils de glucose, l'absence de données fiables concernant l'insulinothérapie limite l'analyse de la situation et rend difficile l'optimisation thérapeutique. Afin de répondre à ce besoin non couvert, des stylos à insuline connectés, de différentes technologies et ergonomies, ont été développés, permettant une remontée des données d'insuline (dose, timing) sur différentes plateformes de reporting. Les premières études cliniques avec ces stylos montrent que leur utilisation permet d'améliorer l'observance thérapeutique des injections d'insuline, quantitativement et qualitativement, avec un bénéfice associé sur l'équilibre métabolique. L'initiation de ces stylos nécessite bien sûr un accompagnement et une éducation des patients qui doivent s'approprier ce dispositif afin d'en tirer le meilleur profit.

Intermittent (on 4 days per week) antiretroviral therapy (ART) for patients with HIV-1 might be more convenient, better tolerated, and cheaper than continuous treatment. We aimed to establish the efficacy and safety of a 4-days-on and 3-days-off (intermittent) maintenance regimen versus a standard 7 day (continuous) maintenance regimen.

Data generated from telemetry devices, such as acceleration and speed, are used in a variety of industries to determine the risk profile of a driver. This paper considers the addition of road gradient as a contextual variable to a driving behavior model to determine specifically if the risk of a driver is influenced by different road grades. This behavioral risk is demonstrated by comparing the performance of heavy vehicle drivers with and without the addition of road grade as a variable. This is done by using accelerometer data of 48 heavy goods vehicles over an entire month, and appending elevation data from digital elevation model (DEM) data, specifically that of the Shuttle Radar Topography Mission (SRTM), to the vehicles’ GPS traces. The elevation values are used to calculate road grade values which are then categorized in five grade levels. The results show that there is a clear influence of gradient on the behavior of the drivers studied. There is also evidence that steeper sections on a road can cause a change in an individual’s performance when compared with the group.

African logistics and supply chain management capabilities are essential to the performance of the continent's commercial and humanitarian supply chains (SCs). This article reviewed the challenges for researchers and practitioners in advancing logistics and SC performance through developing appropriate capabilities. A literature review and landscape mapping were followed by semistructured interviews with 45 stakeholders from industry bodies, academia, funding bodies, consultants, specialists, and academics, confirming the capability and opportunity gaps in the current landscape. A meta-framework for sustainable institutional capacity development was constructed based on the empirical data that were gathered, and SC capacity development recommendations were proposed.

Single-cell technologies have revealed the complexity of the tumour immune microenvironment with unparalleled resolution1–9. Most clinical strategies rely on histopathological stratification of tumour subtypes, yet the spatial context of single-cell phenotypes within these stratified subgroups is poorly understood. Here we apply imaging mass cytometry to characterize the tumour and immunological landscape of samples from 416 patients with lung adenocarcinoma across five histological patterns. We resolve more than 1.6 million cells, enabling spatial analysis of immune lineages and activation states with distinct clinical correlates, including survival. Using deep learning, we can predict with high accuracy those patients who will progress after surgery using a single 1-mm2tumour core, which could be informative for clinical management following surgical resection. Our dataset represents a valuable resource for the non-small cell lung cancer research community and exemplifies the utility of spatial resolution within single-cell analyses. This study also highlights how artificial intelligence can improve our understanding of microenvironmental features that underlie cancer progression and may influence future clinical practice.