Deciphering the clinical spectrum of gastric disease in patients with Juvenile Polyposis Syndrome.

BACKGROUND AND AIMS: Juvenile Polyposis Syndrome (JPS) is a rare hereditary autosomal dominant cancer-predisposition syndrome caused by germline pathogenic variants (PV) located in SMAD4 or BMPR1A genes. Precise clinical and endoscopic presentation as the evolution of gastric lesions remain ill-known. METHODS: Clinical, endoscopic, genetic, pathological data from patients with SMAD4 or BMPR1A PVs included between 2007 and 2020 in the French network on rare digestive polyposis (RENAPOL) database were prospectively collected to address uncertainties regarding gastric involvement. RESULTS: Thirty-six patients were included: 25 (69.5%) had SMAD4 PVs, 11 had BMPR1A PVs. For SMAD4 PV carriers, median age at inclusion was 43.0 years [range 10-78]. At baseline esophagogastroduodenoscopy (EGD), 22/25 (88%) exhibited at least one gastric juvenile polyp, 5/25 (20%) had macroscopic signs of inflammatory gastritis. Early gastric disease was mostly located under the cardia, then progressed to gastric antrum and body. During a mean follow-up period of 55.0 months, 12/25 had gastric disease progression (i.e. new juvenile polyps (91.6%), diffuse gastric involvement (41.6%), inflammatory flat progression (25%)). Among 62 biopsies, low-grade dysplasia was observed in 5 (7.5%) samples from 2 patients. Nine carriers (36%) underwent gastrectomy (mean age of 47.2 years) due to diffuse gastric involvement or worsening clinical symptoms. Gastric adenocarcinoma (T1) was found in one gastrectomy specimen. Among the 11 patients with BMPR1A PVs, 2 had gastric hamartomatomas at baseline EGD, none with dysplasia or symptoms. CONCLUSION: Gastric involvement in JPS appears to be progressive during life, initiating in the cardia area, and mostly concerns SMAD4 PV carriers.

Hyperangulated vs. Macintosh videolaryngoscopy in adults with anticipated difficult airway management: a randomised controlled trial.

BACKGROUND: It is not certain whether the blade geometry of videolaryngoscopes, either a hyperangulated or Macintosh shape, affects glottic view, success rate and/or tracheal intubation time in patients with expected difficult airways. We hypothesised that using a hyperangulated videolaryngoscope blade would visualise a higher percentage of glottic opening compared with a Macintosh videolaryngoscope blade in patients with expected difficult airways. METHODS: We conducted an open-label, patient-blinded, randomised controlled trial in adult patients scheduled to undergo elective ear, nose and throat or oral and maxillofacial surgery, who were anticipated to have a difficult airway. All airway operators were consultant anaesthetists. Patients were allocated randomly to tracheal intubation with either hyperangulated (C-MAC D-BLADE™) or Macintosh videolaryngoscope blades (C-MAC™). The primary outcome was the percentage of glottic opening. First attempt success was designated a key secondary outcome. RESULTS: We assessed 2540 adults scheduled for elective head and neck surgery for eligibility and included 182 patients with expected difficult airways undergoing orotracheal intubation. The percentage of glottic opening visualised, expressed as median (IQR [range]), was 89 (69-99 [0-100])% with hyperangulated videolaryngoscope blades and 54 (9-90 [0-100])% with Macintosh videolaryngoscope blades (p < 0.001). First-line hyperangulated videolaryngoscopy failed in one patient and Macintosh videolaryngoscopy in 12 patients (13%, p = 0.002). First attempt success rate was 97% with hyperangulated videolaryngoscope blades and 67% with Macintosh videolaryngoscope blades (p < 0.001). CONCLUSIONS: Glottic view and first attempt success rate were superior with hyperangulated videolaryngoscope blades compared with Macintosh videolaryngoscope blades when used by experienced anaesthetists in patients with difficult airways.

Elemental Profiling for the Detection of Food Mixtures: A Proof of Principle Study on the Detection of Mixed Walnut Origins Using Measured and Calculated Data.

Element profiling is a powerful tool for detecting fraud related to claims of geographical origin. However, these methods must be continuously developed, as mixtures of different origins in particular offer great potential for adulteration. This study is a proof of principle to determine whether elemental profiling is suitable for detecting mixtures of the same food but from different origins and whether calculated data from walnut mixtures could help to reduce the measurement burden. The calculated data used in this study were generated based on measurements of authentic, unadulterated samples. Five different classification models and three regression models were applied in five different evaluation approaches to detect adulteration or even distinguish between adulteration levels (10% to 90%). To validate the method, 270 mixtures of walnuts from different origins were analyzed using inductively coupled plasma mass spectrometry (ICP-MS). Depending on the evaluation approach, different characteristics were observed in mixtures when comparing the calculated and measured data. Based on the measured data, it was possible to detect admixtures with an accuracy of 100%, even at low levels of adulteration (20%), depending on the country. However, calculated data can only contribute to the detection of adulterated walnut samples in exceptional cases.

The respective and dependent effects of scattering and bone matrix absorption on ultrasound attenuation in cortical bone.

Cortical bone is characterized by a dense solid matrix permeated by fluid-filled pores. Ultrasound scattering has potential for the non-invasive evaluation of changes in bone porosity. However, there is an incomplete understanding of the impact of ultrasonic absorption in the solid matrix on ultrasound scattering. In this study, maps were derived from scanning acoustic microscopy images of human femur cross-sections. Finite-difference time domain ultrasound scatter simulations were conducted on these maps. Pore density, diameter distribution of the pores, and nominal absorption values in the solid and fluid matrices were controlled. Ultrasound pulses with a central frequency of 8.2 MHz were propagated, both in through-transmission and backscattering configurations. From these data, the scattering, bone matrix absorption, and attenuation extinction lengths were calculated. The results demonstrated that as absorption in the solid matrix was varied, the scattering, absorption, and attenuation extinction lengths were significantly impacted. It was shown that for lower values of absorption in the solid matrix (less than 2 dB mm-1), attenuation due to scattering dominates, whereas at higher values of absorption (more than 2 dB mm-1), attenuation due to absorption dominates. This will impact how ultrasound attenuation and scattering parameters can be used to extract quantitative information on bone microstructure.

Design Optimization and Tradeoff Analysis of an Actuated Continuum Probe for Pulmonary Nodule Localization and Resection.

Pulmonary nodules are abnormal tissue masses in the lungs, typically less than 3.0 cm in diameter, commonly detected during imaging of the chest and lungs. While most pulmonary nodules are not cancerous, surgical resection may be required if growth is detected between scans. This resection is typically performed without the benefit of intraoperative imaging, making it difficult for surgeons to confidently provide appropriate margins. To enhance the efficacy of wedge resection, researchers have developed a modified ultrasound imaging approach that utilizes both multiple scattering (MS) and single scattering (SS) to enhance the accuracy of margin delineation. Clinical deployment of this novel ultrasound technology requires a highly maneuverable ultrasound probe, ideally one that could be deployed and actuated with minimal invasiveness. This study details the design optimization and tradeoff analysis of an actuated continuum probe for pulmonary nodule localization and resection. This device, deployed through intercostal ports, would enable the intraoperative imaging and precise mapping of nodules for improved margin delineation and patient outcomes. To achieve this objective, multiple objective genetic algorithms (MOGAs) and a design of experiments (DOE) study are used to explore the design space and quantify key dimensional relationships and their effects on probe actuation.

Digitally managing depression: A fully remote randomised attention-placebo controlled trial.

Background: Depression is a common and disabling condition. Digital apps may augment or facilitate care, particularly in under-served populations. We tested the efficacy of juli, a digital self-management app for depression in a fully remote randomised controlled trial. Methods: A pragmatic randomised controlled trial that included participants aged > 18 who self-identified as having depression and scored > 5 on the Patient Health Questionnaire-8. Participants were randomly assigned (1:1) to receive juli for 8 weeks or a limited attention-placebo control app. Our primary outcome was the difference in Patient Health Questionnaire-8 scores at 8 weeks. Secondary outcomes were remission, minimal clinically important difference, worsening of depression, and health-related quality of life. Analyses were per-protocol (primary), and modified and full intention-to-treat (secondary). The trial was registered at ISRCTN (ISRCTN12329547). Results: Between May 2021 and January 2023, we randomised 908 participants. 662 completed the week 2 outcome assessment and were included in the modified intention-to-treat analysis, and 456 completed the week 8 outcome assessments (per-protocol). In the per-protocol analysis, the juli group had a greater reduction in Patient Health Questionnaire-8 score (10.78, standard deviation 6.26) than the control group (11.88, standard deviation 5.73) by week 8 (baseline adjusted ß-coefficient -0.94, 95% CI: -1.87 to -0.22, p = 0.045). Achieving remission and a minimal clinically important difference was more likely in the juli group at 8 weeks (adjusted odds ratios 2.22, 95% CI: 1.45-3.39, p < 0.001 and 1.56, 95% CI: 1.08-2.27, p = 0.018, respectively). There were no between-group differences in health-related quality of life or worsening of depression. Modified and full intention-to-treat analyses found similar results, but the primary outcome was non-significant. Conclusion: The use of juli for 8 weeks resulted in a small reduction in symptoms of depression compared with an attention-placebo control. The juli app is a digital self-management tool that could increase the accessibility of evidence-based depression treatments.

Differences in regulation mechanisms of glutamine synthetases from methanogenic archaea unveiled by structural investigations.

Glutamine synthetases (GS) catalyze the ATP-dependent ammonium assimilation, the initial step of nitrogen acquisition that must be under tight control to fit cellular needs. While their catalytic mechanisms and regulations are well-characterized in bacteria and eukaryotes, only limited knowledge exists in archaea. Here, we solved two archaeal GS structures and unveiled unexpected differences in their regulatory mechanisms. GS from Methanothermococcus thermolithotrophicus is inactive in its resting state and switched on by 2-oxoglutarate, a sensor of cellular nitrogen deficiency. The enzyme activation overlays remarkably well with the reported cellular concentration for 2-oxoglutarate. Its binding to an allosteric pocket reconfigures the active site through long-range conformational changes. The homolog from Methermicoccus shengliensis does not harbor the 2-oxoglutarate binding motif and, consequently, is 2-oxoglutarate insensitive. Instead, it is directly feedback-inhibited through glutamine recognition by the catalytic Asp50'-loop, a mechanism common to bacterial homologs, but absent in M. thermolithotrophicus due to residue substitution. Analyses of residue conservation in archaeal GS suggest that both regulations are widespread and not mutually exclusive. While the effectors and their binding sites are surprisingly different, the molecular mechanisms underlying their mode of action on GS activity operate on the same molecular determinants in the active site.

Lung Quantitative Ultrasound to Stage and Monitor Interstitial Lung Diseases.

Chronic interstitial lung diseases (ILDs) require frequent point-of-care monitoring. X-ray-based methods lack resolution and are ionizing. Chest computerized tomographic (CT) scans are expensive and provide more radiation. Conventional ultrasound can detect severe lung damage via vertical artifacts (B-lines). However, this information is not quantitative, and the appearance of B-lines is operator- and system-dependent. Here we demonstrate novel ultrasound-based biomarkers to assess severity of ILDs. Lung alveoli scatter ultrasound waves, leading to a complex acoustic signature, which is affected by changes in alveolar density due to ILDs. We exploit ultrasound scattering in the lung and combine Quantitative Ultrasound (QUS) parameters, to develop ultrasound-based biomarkers that significantly correlate to the severity of pulmonary fibrosis and edema in rodent lungs. These innovative QUS biomarkers will be very significant for monitoring severity of chronic ILDs and response to treatment, especially in this new era of miniaturized and highly portable ultrasound devices.

Lung quantitative ultrasound to stage and monitor interstitial lung diseases.

Chronic interstitial lung diseases (ILDs) require frequent point-of-care monitoring. X-ray-based methods lack resolution and are ionizing. Chest computerized tomographic (CT) scans are expensive and provide more radiation. Conventional ultrasound can detect severe lung damage via vertical artifacts (B-lines). However, this information is not quantitative, and the appearance of B-lines is operator- and system-dependent. Here we demonstrate novel ultrasound-based biomarkers to assess severity of ILDs. Lung alveoli scatter ultrasound waves, leading to a complex acoustic signature, which is affected by changes in alveolar density due to ILDs. We exploit ultrasound scattering in the lung and combine quantitative ultrasound (QUS) parameters, to develop ultrasound-based biomarkers that significantly correlate (p = 1e-4 for edema and p = 3e-7 for fibrosis) to the severity of pulmonary fibrosis and edema in rodent lungs. These innovative QUS biomarkers will be very significant for monitoring severity of chronic ILDs and response to treatment, especially in this new era of miniaturized and highly portable ultrasound devices.

Pancreatic neuroendocrine tumors in French VHL mutation carriers: a multicentric retrospective study.

BACKGROUND: Von Hippel-Lindau disease (VHL) is a rare autosomal dominant hereditary cancer-predisposition syndrome caused by germline pathogenic variants (PV) in VHL gene. It is associated with a high penetrance of benign and malignant vascular tumors in multiples organs, including pancreatic neuroendocrine tumors (PanNETs), whose long-term natural history is ill-known. METHODS: Patients with both documented germline PV in VHL gene and PanNETs included in the French PREDIR database between 1995 and 2022 were included. Primary endpoint was the proportion of patients with PanNET-related metastases and secondary endpoint was overall survival (OS). Genotype/phenotype correlations were studied. RESULTS: We included 121 patients with 259 PanNETs. Median age at diagnosis was 38 years. Median follow-up was 89.5 months. PanNET surgical resection was performed in 51 patients. Overall, 29 patients (24%) had metastases (5 synchronous, 10 metachronous), with a higher risk in case of larger PanNET size (p=0.0089; best threshold 28 mm) and grade 2 PanNET (p=0.048), and a pejorative prognostic impact (p=0.043). Patients with PV in VHL exon 1 had larger PanNETs (p=0.018), more often metastatic disease (48% vs 11.5%; p < 0.001) and a trend toward shorter OS (p=0.16). CONCLUSION: The risk of metastases associated to VHL-related PanNETs remains low (24%) but increases with tumor size >28 mm, higher grade and in case of PV located VHL exon 1. These data might help improving the management of these patients, who should be referred to an expert center.

High-Performance PMN-PT Single-Crystal-Based 1-3 Composite Transducer Integrated with a Biopsy Needle.

To address the need for high-resolution imaging in lung nodule detection and overcome the limitations of the shallow imaging depth associated with high-frequency ultrasound and the complex structure of lung tissue, we successfully integrated 50 MHz ultrasound transducers with 18-gauge biopsy needles. Featuring a miniaturized size of 0.6 × 0.5 × 0.5 mm3, the 50 MHz micromachined 1-3 composite transducer was tested to perform mechanical scanning of a nodule within a lung-tissue-mimicking phantom in vitro. The high-frequency transducer demonstrated the ability to achieve imaging with an axial resolution of 30 µm for measuring nodule edges. Moreover, the integrated biopsy needle prototype exhibited high accuracy (1.74% discrepancy) in estimating nodule area compared to actual dimensions in vitro. These results underscore the promising potential of biopsy-needle-integrated transducers in enhancing the accuracy of endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNA) for clinical applications.

Development, feeding, and sex shape the relative quantity of the nutritional obligatory symbiont Wolbachia in bed bugs.

The common bed bug, Cimex lectularius, is a hemipteran insect that feeds only on blood, and whose bites cause public health issues. Due to globalization and resistance to insecticides, this pest has undergone a significant and global resurgence in recent decades. Blood is an unbalanced diet, lacking notably sufficient B vitamins. Like all strict hematophagous arthropods, bed bugs host a nutritional symbiont supplying B vitamins. In C. lectularius, this nutritional symbiont is the intracellular bacterium Wolbachia (wCle). It is located in specific symbiotic organs, the bacteriomes, as well as in ovaries. Experimental depletion of wCle has been shown to result in longer nymphal development and lower fecundity. These phenotypes were rescued by B vitamin supplementation. Understanding the interaction between wCle and the bed bug may help to develop new pest control methods targeting the disruption of this symbiotic interaction. The objective of this work was thus to quantify accurately the density of wCle over the life cycle of the host and to describe potential associated morphological changes in the bacteriome. We also sought to determine the impact of sex, feeding status, and aging on the bacterial population dynamics. We showed that the relative quantity of wCle continuously increases during bed bug development, while the relative size of the bacteriome remains stable. We also showed that adult females harbor more wCle than males and that wCle relative quantity decreases slightly in adults with age, except in weekly-fed males. These results are discussed in the context of bed bug ecology and will help to define critical points of the symbiotic interaction during the bed bug life cycle.

Deep dive into the chronic toxicity of tyre particle mixtures and their leachates.

Particles from the tread of vehicle tyres are a global pollutant, which are emitted into the environment at an approximate rate of 1.4 kg.year-1 for an average passenger-car. In this study, popular tyre brands were used to generate a tyre tread microparticle mixture. The chronic toxicity of both particles and chemical leachates were compared on a planktonic test species (Daphnia magna). Over 21 days of exposure, pristine tyre tread microparticles were more toxic (LC50 60 mg.L-1) than chemical lechates alone (LC50 542 mg.L-1). Microparticles and leachates showed distinct effects on reproduction and morphological development at environmentally relevant concentrations, with dose-dependent uptake of particles visible in the digestive tract. Chemical characterization of leachates revealed a metal predominance of zinc, titanium, and strontium. Of the numerous organic chemicals present, at least 54 were shared across all 5 tyre brands, with many classified to be very toxic. Our results provide a critically needed information on the toxicity of tyre tread particles and the associated chemicals that leach from them to inform future mitigation measures. We conclude that tyre particles are hazardous pollutants of particular concern that are close to or possibly above chronic environmental safety limits in some locations.

Modeling HepaRG metabolome responses to pyrrolizidine alkaloid exposure for insight into points of departure and modes of action.

The new challenges in toxicology demand novel and innovative in vitro approaches for deriving points of departure (PODs) and determining the mode of action (MOA) of chemicals. Therefore, the aim of this original study was to couple in vitro studies with untargeted metabolomics to model the concentration-response of extra- and intracellular metabolome data on human HepaRG cells treated for 48 h with three pyrrolizidine alkaloids (PAs): heliotrine, retrorsine and lasiocarpine. Modeling revealed that the three PAs induced various monotonic and, importantly, biphasic curves of metabolite content. Based on unannotated metabolites, the endometabolome was more sensitive than the exometabolome in terms of metabolomic effects, and benchmark concentrations (BMCs) confirmed that lasiocarpine was the most hepatotoxic PA. Regarding its MOA, impairment of lipid metabolism was highlighted at a very low BMC (first quartile, 0.003 µM). Moreover, results confirmed that lasiocarpine targets bile acids, as well as amino acid and steroid metabolisms. Analysis of the endometabolome, based on coupling concentration-response and PODs, gave encouraging results for ranking toxins according to their hepatotoxic effects. Therefore, this novel approach is a promising tool for next-generation risk assessment, readily applicable to a broad range of compounds and toxic endpoints.

Trifluridine/tipiracil + oxaliplatin ± nivolumab vs FOLFOX ± nivolumab in HER2 negative advanced oesogastric adenocarcinoma: The PRODIGE73-UCGI40-LOGICAN trial.

BACKGROUND: Trifluridine/tipiracil (FTD/TPI) is approved in third-line treatment of patients with advanced/metastatic gastric and gastroesophageal junction adenocarcinomas (aGA/GEJA). The association of oxaliplatin with FTD/TPI is promising and the combination of FTD/TPI + oxaliplatin + nivolumab has shown a predictable and manageable safety profile. AIMS: The aim is to evaluate the efficacy and safety of FTD/TPI plus oxaliplatin with or without nivolumab in patients, with HER2 negative aGA/GEJA, unfit for triplet chemotherapy (TFOX/mFLOT regimen), in the first-line metastatic setting in comparison with the standard of care FOLFOX with or without nivolumab. METHODS: This study is a prospective randomised, open label, comparative, multicentre, phase II trial designed to include 118 patients. The primary objective is to evaluate the superiority of FTD/TPI plus oxaliplatin with or without nivolumab over FOLFOX regimen with or without nivolumab in terms of PFS in a population of patients non candidate for triplet chemotherapy. Nivolumab will be used for patients whose tumour express PD-L1 with a CPS score ≥5. DISCUSSION: PRODIGE73-UCGI40-LOGICAN study will provide efficacy and safety data on the association of FTD/TPI plus oxaliplatin with or without nivolumab versus FOLFOX regimen with or without nivolumab in first-line palliative setting, in patients with aGA/GEJA (NCT05476796).

Predicting Structural Properties of Cortical Bone by Combining Ultrasonic Attenuation and an Artificial Neural Network (ANN): 2-D FDTD Study.

The goal of this paper is to predict the micro-architectural parameters of cortical bone such as pore diameter (ϕ) and porosity (v) from ultrasound attenuation measurements using an artificial neural network (ANN). Slices from a 3-D CT scan of human femur are obtained. The micro-architectural parameters of porosity such as average pore size and porosity are calculated using image processing. When ultrasound waves propagate in porous structures, attenuation is observed due to scattering. Two-dimensional finite-difference time-domain simulations are carried out to obtain frequency dependent attenuation in those 2D structures. An artificial neural network (ANN) is then trained with the input feature vector as the frequency dependent attenuation and output as pore diameter (ϕ) and porosity (v). The ANN is composed of one input layer, 3 hidden layers and one output layer, all of which are fully connected. 340 attenuation data sets were acquired and trained over 2000 epochs with a batch size of 32. Data was split into train, validation and test. It was observed that the ANN predicted the micro-architectural parameters of the cortical bone with high accuracies and low losses with a minimum R2 (goodness of fit) value of 0.95. ANN approaches could potentially help inform the solution of inverse-problems to retrieve bone porosity from ultrasound measurements. Ultimately, those inverse-problems could be used for the non-invasive diagnosis and monitoring of osteoporosis.

Influence of micro-structural parameters on apparent absorption coefficient in porous structures mimicking cortical bone.

Ultrasound wave propagation in porous media is associated with energy loss and attenuation. Attenuation is caused by both scattering and absorption, and is influenced by the microstructure as well as the operating frequency. In the present simulation study, we calculate the attenuation coefficient in porous structures mimicking cortical bone both in presence and absence of absorption to isolate the effects of scattering and absorption on the total attenuation. A parameter called apparent absorption α a p p . a b s is defined as the difference between the total attenuation α total and the attenuation exclusively due to scattering α scat . α total , α scat and α app.abs are estimated in porous structures with varying pore diameters ( ϕ ∈ [ 40, 120 ] µ m ) and pore densities ( ρ ∈ [ 5, 25 ] pore / m m 2 ) at 5MHz and 8MHz. Results show that both scattering and absorption contribute to the total attenuation. They also illustrate that, although absorption only occurs in the solid matrix, the apparent absorption α a p p . a b s is a function of porosity, presumably due to the presence of multiple scattering. For large values of k ϕ , an increase in pore size or density does not lead to increase in α s c a t and only results in an increase of the total attenuation as a result of increase in α app.abs. . On the other hand, in low/intermediate scattering regimes ( k ϕ ≤ 1 ) , an increase in either pore size or pore density results in increase in α scat while α app.abs remains constant.

Inferring porosity from frequency dependent attenuation in cortical bone mimicking porous media.

Osteoporosis affects porosity in cortical bone. Quantifying levels of osteoporosis by inferring the micro-architectural properties from ultrasonic wave attenuation in cortical bone has yet to be done. In this work we use a phenomenological, power law model to describe the frequency dependent attenuation in non-absorbing porous media mimicking a simplified cortical bone structure. We optimize this model to fit data generated using a finite-difference, time domain (FDTD) numerical simulation. Model parameters are estimated using an ordinary least squares (OLS) formulation of the inverse problem. With these we determine linear, functional relationships between the model parameter estimates and the micro-architectural parameters, pore density and pore diameter. These relationships allow us to infer ranges of porosity from simulated attenuation data. Repeating this process for attenuation data collected from cortical bone samples could allow one to characterize the micro-architectural properties of bone.