P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage.

The P7C3 class of aminopropyl carbazole chemicals fosters the survival of neurons in a variety of rodent models of neurodegeneration or nerve cell injury. To uncover its mechanism of action, an active derivative of P7C3 was modified to contain both a benzophenone for photocrosslinking and an alkyne for CLICK chemistry. This derivative was found to bind nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme involved in the conversion of nicotinamide into nicotinamide adenine dinucleotide (NAD). Administration of active P7C3 chemicals to cells treated with doxorubicin, which induces NAD depletion, led to a rebound in intracellular levels of NAD and concomitant protection from doxorubicin-mediated toxicity. Active P7C3 variants likewise enhanced the activity of the purified NAMPT enzyme, providing further evidence that they act by increasing NAD levels through its NAMPT-mediated salvage.

FGFR redundancy limits the efficacy of FGFR4-selective inhibitors in hepatocellular carcinoma.

Aberrant fibroblast growth factor 19 (FGF19) signaling mediated by its receptor, FGF receptor 4 (FGFR4), and coreceptor, klotho ß (KLB), is a driver of hepatocellular carcinoma (HCC). Several potent FGFR4-selective inhibitors have been developed but have exhibited limited efficacy in HCC clinical trials. Here, by using HCC cell line models from the Cancer Cell Line Encyclopedia (CCLE) and the Liver Cancer Model Repository (LIMORE), we show that selective FGFR4 inactivation was not sufficient to inhibit cancer cell proliferation and tumor growth in FGF19-positive HCC. Moreover, genetic inactivation of KLB in these HCC cells resulted in a fitness defect more severe than that resulting from inactivation of FGFR4. By a combination of biochemical and genetic approaches, we found that KLB associated with FGFR3 and FGFR4 to mediate the prosurvival functions of FGF19. KLB mutants defective in interacting with FGFR3 or FGFR4 could not support the growth or survival of HCC cells. Genome-wide CRISPR loss-of-function screening revealed that FGFR3 restricted the activity of FGFR4-selective inhibitors in inducing cell death; the pan-FGFR inhibitor erdafitinib displayed superior potency than FGFR4-selective inhibitors in suppressing the growth and survival of FGF19-positive HCC cells. Among FGF19-positive HCC cases from The Cancer Genome Atlas (TCGA), FGFR3 is prevalently coexpressed with FGFR4 and KLB, suggesting that FGFR redundancy may be a common mechanism underlying the de novo resistance to FGFR4 inhibitors. Our study provides a rationale for clinical testing of pan-FGFR inhibitors as a treatment strategy for FGF19-positive HCC.

MFNet: Meta-learning based on frequency-space mix for MRI segmentation in nasopharyngeal carcinoma.

Deep learning techniques have been applied to medical image segmentation and demonstrated expert-level performance. Due to the poor generalization abilities of the models in the deployment in different centres, common solutions, such as transfer learning and domain adaptation techniques, have been proposed to mitigate this issue. However, these solutions necessitate retraining the models with target domain data and annotations, which limits their deployment in clinical settings in unseen domains. We evaluated the performance of domain generalization methods on the task of MRI segmentation of nasopharyngeal carcinoma (NPC) by collecting a new dataset of 321 patients with manually annotated MRIs from two hospitals. We transformed the modalities of MRI, including T1WI, T2WI and CE-T1WI, from the spatial domain to the frequency domain using Fourier transform. To address the bottleneck of domain generalization in MRI segmentation of NPC, we propose a meta-learning approach based on frequency domain feature mixing. We evaluated the performance of MFNet against existing techniques for generalizing NPC segmentation in terms of Dice and MIoU. Our method evidently outperforms the baseline in handling the generalization of NPC segmentation. The MF-Net clearly demonstrates its effectiveness for generalizing NPC MRI segmentation to unseen domains (Dice = 67.59%, MIoU = 75.74% T1W1). MFNet enhances the model's generalization capabilities by incorporating mixed-feature meta-learning. Our approach offers a novel perspective to tackle the domain generalization problem in the field of medical imaging by effectively exploiting the unique characteristics of medical images.

Helicobacter pylori CagA protein induces gastric cancer stem cell-like properties through the Akt/FOXO3a axis.

The presence of Helicobacter pylori (H. pylori) infection poses a substantial risk for the development of gastric adenocarcinoma. The primary mechanism through which H. pylori exerts its bacterial virulence is the cytotoxin CagA. This cytotoxin has the potential to induce inter-epithelial mesenchymal transition, proliferation, metastasis, and the acquisition of stem cell-like properties in gastric cancer (GC) cells infected with CagA-positive H. pylori. Cancer stem cells (CSCs) represent a distinct population of cells capable of self-renewal and generating heterogeneous tumor cells. Despite evidence showing that CagA can induce CSCs-like characteristics in GC cells, the precise mechanism through which CagA triggers the development of GC stem cells (GCSCs) remains uncertain. This study reveals that CagA-positive GC cells infected with H. pylori exhibit CSCs-like properties, such as heightened expression of CD44, a specific surface marker for CSCs, and increased ability to form tumor spheroids. Furthermore, we have observed that H. pylori activates the PI3K/Akt signaling pathway in a CagA-dependent manner, and our findings suggest that this activation is associated with the CSCs-like characteristics induced by H. pylori. The cytotoxin CagA, which is released during H. pylori infection, triggers the activation of the PI3K/Akt signaling pathway in a CagA-dependent manner. Additionally, CagA inhibits the transcription of FOXO3a and relocates it from the nucleus to the cytoplasm by activating the PI3K/Akt pathway. Furthermore, the regulatory function of the Akt/FOXO3a axis in the transformation of GC cells into a stemness state was successfully demonstrated.

Cobalt-Catalyzed Cascade C-H Activation/Annulation Polymerizations toward Diversified and Multifunctional Sulfur-Containing Fused Heterocyclic Polymers.

Transition-metal-catalyzed C-H activation has greatly benefited the synthesis and development of functional polymer materials, and the construction of multifunctional fused (hetero)cyclic polymers via novel C-H activation-based polyannulations has emerged as a charming but challenging area in recent years. Herein, we report the first cobalt(III)-catalyzed cascade C-H activation/annulation polymerization (CAAP) approach that can efficiently transform readily available aryl thioamides and internal diynes into multifunctional sulfur-containing fused heterocyclic (SFH) polymers. Within merely 3 h, a series of SFH polymers bearing complex and multisubstituted S,N-doped polycyclic units are facilely and efficiently produced with high molecular weights (absolute Mn up to 220400) in excellent yields (up to 99%), which are hard to achieve by traditional methods. The intermediate-terminated SFH polymer can be used as a reactive macromonomer to controllably extend or modify polymer main chains. The structural diversity can be further enriched through facile S-oxidation and N-methylation reactions of the SFH polymers. Benefiting from the unique structures, the obtained polymers exhibit excellent solution processability, high thermal and morphological stability, efficient and readily tunable aggregate-state fluorescence, stimuli-responsive properties, and high and UV-modulatable refractive indices of up to 1.8464 at 632.8 nm. These properties allow the SFH polymers to be potentially applied in diverse fields, including metal ion detection, photodynamic killing of cancer cells, fluorescent photopatterning, and gradient-index optical materials.

Mega-dose decitabine conditioning and prophylactic donor lymphocyte infusion for patients with relapsed/refractory AML with active disease at the time of allogeneic haematopoietic cell transplantation: A multicenter prospective phase II study.

Patients with relapsed/refractory acute myeloid leukaemia (R/R AML), especially those who failed in novel target agents are related to dismal survival. We developed a multi-institutional, single-arm, prospective phase II trial, to investigate intensified conditioning with 'Mega-Dose' decitabine (MegaDAC) following allogeneic haematopoietic cell transplantation (allo-HCT) for R/R AML. From 2019 to 2023, 70 heavily treated R/R AML patients in active disease were consecutively enrolled. Significantly, every patient (n = 18) harbouring specific mutations exhibited no response to their best available target agents (BATs). Moreover, 74.3% of the enrolled patients did not reach remission following venetoclax-based regimens. All patients underwent intravenous decitabine (400 mg/m2) along with busulfan and cyclophosphamide. Median follow-up was 26 months (8-65) after HCT. All engrafted patients achieved MRD negativity post-HCT, with a median 3.3-log reduction in recurrent genetic abnormalities. The regimen was well tolerated, without irreversible grades III-IV toxicity peri-engraftment. The estimated 2-year CIR was 29.6% (18.4%-41.7%) and the est-2-year NRM was 15.5% (7.8%-25.5%). The est-2-year LFS, OS, and GRFS were 55.0% (43.5%-69.4%), 58.6% (47.0%-73.0%), and 42.9% (31.9%-57.6%), respectively. Multivariate analysis showed that pre-HCT drug exposures had no significant impact on primary outcomes. MegaDAC is highlighted as an effective and safe option for R/R AML in the new era of targeted therapies.

Identification of SDG gene family members and exploration of flowering related genes in different cultivars of chrysanthemums and their wild ancestors.

The SET domain genes (SDGs) are significant contributors to various aspects of plant growth and development, mainly includes flowering, pollen development, root growth, regulation of the biological clock and branching patterns. To clarify the biological functions of the chrysanthemum SDG family, the SDG family members of four chrysanthemum cultivars and three related wild species were identified; their physical and chemical properties, protein domains and conserved motifs were predicted and analyzed. The results showed that 59, 67, 67, 102, 106, 114, and 123 SDGs were identified from Chrysanthemum nankingense, Chrysanthemum lavandulifolium, Chrysanthemum seticuspe, Chrysanthemum × morifolium cv. 'Hechengxinghuo', 'Zhongshanzigui', 'Quanxiangshuichang' and 'Jinbeidahong', respectively. The SDGs were divided into 5-7 subfamilies by cluster analysis; different conserved motifs were observed in particular families. The SDGs of C. lavandulifolium and C. seticuspe were distributed unevenly on 9 chromosomes. SDG promoters of different species include growth and development, photo-response, stress response and hormone responsive elements, among them, the cis-acting elements related to MeJA response had the largest proportion. The expression of chrysanthemum SDG genes was observed for most variable selected genes which has close association with important Arabidopsis thaliana genes related to flowering regulation. The qPCR results showed that the expression trend of SDG genes varied in different tissues at different growth stages with high expression in the flowering period. The ClSDG29 showed higher expression in the flower and bud tissues, which indicate that ClSDG29 might be associated with flowering regulation in chrysanthemum. In summary, the results of this study can provide a basis for subsequent research on chrysanthemum flowering time regulation.

Mini-dose methotrexate combined with methylprednisolone for the initial treatment of acute GVHD: a multicentre, randomized trial.

BACKGROUND: There is an urgent unmet need for effective initial treatment for acute graft-versus-host disease (aGVHD) adding to the standard first-line therapy with corticosteroids after allogeneic haematopoietic stem cell transplantation (allo-HSCT). METHODS: We performed a multicentre, open-label, randomized, phase 3 study. Eligible patients (aged 15 years or older, had received allo-HSCT for a haematological malignancy, developed aGVHD, and received no previous therapies for aGVHD) were randomly assigned (1:1) to receive either 5 mg/m2 MTX on Days 1, 3, or 8 and then combined with corticosteroids or corticosteroids alone weekly. RESULTS: The primary endpoint was the overall response rate (ORR) on Day 10. A total of 157 patients were randomly assigned to receive either MTX plus corticosteroids (n = 78; MTX group) or corticosteroids alone (n = 79; control group). The Day 10 ORR was 97% for the MTX group and 81% for the control group (p = .005). Among patients with mild aGVHD, the Day 10 ORR was 100% for the MTX group and 86% for the control group (p = .001). The 1-year estimated failure-free survival was 69% for the MTX group and 41% for the control group (p = .002). There were no differences in treatment-related adverse events between the two groups. CONCLUSIONS: In conclusion, mini-dose MTX combined with corticosteroids can significantly improve the ORR in patients with aGVHD and is well tolerated, although it did not achieve the prespecified 20% improvement with the addition of MTX. TRIAL REGISTRATION: The trial was registered with clinicaltrials.gov (NCT04960644).

Human amniotic epithelial cells improve uterine spiral artery remodeling to ameliorate preeclampsia in a rat model†.

Preeclampsia (PE) is a multisystem pregnancy disorder characterized by impaired remodeling of placental spiral arteries, which leads to the release of pro-inflammatory cytokines and anti-angiogenic agents. However, treatment options for PE are limited, with termination of pregnancy being the only curative option. In this work, we investigated the effects of human amniotic epithelial cells (hAECs) in PE rat model. The rats were induced with lipopolysaccharide (LPS) on gestational day 14.5 followed by injection of hAECs and human umbilical cord mesenchymal stem cells 24 h later. The hAECs treatment resulted in a reduction in blood pressure and proteinuria in the PE rat model. Furthermore, hAECs treatment decreased levels of pro-inflammatory cytokines, reduced inflammatory cells aggregation, and alleviated the damage to placental spiral arteries by downregulating the expression of anti-angiogenic factor and upregulating proangiogenic factor. In vitro experiments confirmed that hAECs treatment restored the proliferation, migration, and angiogenesis of LPS-damaged human umbilical vein endothelial cells. Additionally, hAECs treatment had positive effects on fetal weight and neurological development in the PE group, with no negative effects on the physical development or fertility of offspring rats. These results suggested that hAECs transplantation may be a novel adjuvant therapeutic strategy for PE by reducing the inflammatory and enhancing placental spiral artery angiogenesis.

Association Between Inability to Stand at ICU Discharge and Readmission: A Historical Cohort Study.

OBJECTIVES: The aim of this study was to determine if being unable to stand at ICU discharge was associated with an increased probability of ICU readmission. DESIGN: A multicenter retrospective cohort study was conducted using the Toronto Intensive Care Observational Registry (iCORE) project. SETTING: Nine tertiary academic ICUs in Toronto, Canada, affiliated with the University of Toronto. PATIENTS: All patients admitted to ICUs participating in iCORE from September 2014 to January 2020 were included. Patients had to be mechanically ventilated for more than 4 hours to be included in iCORE. Exclusion criteria were death during the initial ICU stay, transfer to another institution not included in iCORE at ICU discharge, and a short ICU stay defined as less than 2 days. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The main exposure in this study was the inability of the patient to stand at ICU discharge, documented daily in the database within the ICU Mobility Scale. The primary outcome of this study was readmission to the ICU. After adjusting for potential confounders, being unable to stand at ICU discharge was associated with increased odds of readmission (odds ratio, 1.85; 95% CI, 1.31-2.62; p < 0.001). CONCLUSIONS: In patients with an ICU stay of 2 days or more, being unable to stand at ICU discharge is associated with increased odds of readmission to the ICU.

Identification of Phosphodiesterase-7A (PDE7A) as a Novel Target for Reducing Ethanol Consumption in Mice.

BACKGROUND: Ethanol elicits a rapid stimulatory effect and a subsequent, prolonged sedative response, which are potential predictors of EtOH consumption by decreasing adenosine signaling; this phenomenon also reflects the obvious sex difference. cAMP (cyclic Adenosine Monophosphate)-PKA (Protein Kinase A) signaling pathway modulation can influence the stimulatory and sedative effects induced by EtOH in mice. This study's objective is to clarify the role of phosphodiesterase (PDE) in mediating the observed sex differences in EtOH responsiveness between male and female animals. METHODS: EtOH was administered i.p. for 7 days to identify the changes in PDE isoforms in response to EtOH treatment. Additionally, EtOH consumption and preference of male and female C57BL/6J mice were assessed using the drinking-in-the-dark and 2-bottle choice tests. Further, pharmacological inhibition of PDE7A heterozygote knockout mice was performed to investigate its effects on EtOH-induced stimulation and sedation in both male and female mice. Finally, Western blotting analysis was performed to evaluate the alterations in cAMP-PKA/Epac2 pathways. RESULTS: EtOH administration resulted in an immediate upregulation in PDE7A expression in female mice, indicating a strong association between PDE7A and EtOH stimulation. Through the pharmacological inhibition of PDE7A KD mice, we have demonstrated for the first time, to our knowledge, that PDE7A selectively attenuates EtOH responsiveness and consumption exclusively in female mice, whichmay be associated with the cAMP-PKA/Epac2 pathway and downstream phosphorylation of CREB and ERK1/2. CONCLUSIONS: Inhibition or knockdown of PDE7A attenuates EtOH responsivenessand consumption exclusively in female mice, which is associated with alterations in the cAMP-PKA/Epac2 signaling pathways, thereby highlighting its potential as a novel therapeutic target for alcohol use disorder.

Upregulation of phosphodiesterase 7A leads to the downregulation of cAMP-PKA-CREB-BDNF signaling and neuroinflammation in the hippocampus and contributes to concurrent chronic pain and depression in two mouse models.

BACKGROUND: Phosphodiesterases (PDEs) are enzymes that catalyze the hydrolysis of cyclic adenosine monophosphate AMP (cAMP) and/or cyclic guanosine monophosphate (cGMP). PDE inhibitors can mitigate chronic pain and depression when these disorders occur individually; however, there is limited understanding of their role in concurrent chronic pain and depression. We aimed to evaluate the mechanisms of action of PDE using two mouse models of concurrent chronic pain and depression. METHODS: C57BL/6J mice were subjected to partial sciatic nerve ligation (PSNL) to induce chronic neuropathic pain or injected with complete Freund's adjuvant (CFA) to induce inflammatory pain, and both animals showed depression-like behavior. First, we determined the change in PDE expression in both animal models. Next, we determined the effect of PDE7 inhibitor BRL50481 or hippocampal PDE7A knockdown on PSNL- or CFA-induced chronic pain and depression-like behavior. We also investigated the role of cAMP-protein kinase A (PKA)-cAMP response element binding protein (CREB)-brain-derived neurotrophic factor (BDNF) signaling and neuroinflammation in the effect of PDE7A inhibition on PSNL- or CFA-induced chronic pain and depression-like behavior. RESULTS: This induction of chronic pain and depression in the two animal models upregulated hippocampal PDE7A. Oral administration of PDE7 inhibitor, BRL50481, or hippocampal PDE7A knockdown significantly reduced mechanical hypersensitivity and depression-like behavior. Hippocampal PDE7 inhibition reversed PSNL- or CFA-induced downregulation of cAMP and BDNF and the phosphorylation of PKA, CREB and p65. cAMP agonist forskolin, reversed these changes and caused milder behavioral symptoms of pain and depression. BRL50481 reversed neuroinflammation in the hippocampus in PSNL mice. CONCLUSIONS: Hippocampal PDE7A mediated concurrent chronic pain and depression in both mouse models by inhibiting cAMP-PKA-CREB-BDNF signaling Inhibiting PDE7A or activating cAMP-PKA-CREB-BDNF signaling are potential strategies to treat concurrent chronic pain and depression.

Phosphodiesterase 8 (PDE8): Distribution and Cellular Expression and Association with Alzheimer's Disease.

Phosphodiesterase 8 (PDE8), as a member of PDE superfamily, specifically promotes the hydrolysis and degradation of intracellular cyclic adenosine monophosphate (cAMP), which may be associated with pathogenesis of Alzheimer's disease (AD). However, little is currently known about potential role in the central nervous system (CNS). Here we investigated the distribution and expression of PDE8 in brain of mouse, which we believe can provide evidence for studying the role of PDE8 in CNS and the relationship between PDE8 and AD. Here, C57BL/6J mice were used to observe the distribution patterns of two subtypes of PDE8, PDE8A and PDE8B, in different sexes in vivo by western blot (WB). Meanwhile, C57BL/6J mice were also used to demonstrate the distribution pattern of PDE8 in selected brain regions and localization in neural cells by WB and multiplex immunofluorescence staining. Furthermore, the triple transgenic (3×Tg-AD) mice and wild type (WT) mice of different ages were used to investigate the changes of PDE8 expression in the hippocampus and cerebral cortex during the progression of AD. PDE8 was found to be widely expressed in multiple tissues and organs including heart, kidney, stomach, brain, and liver, spleen, intestines, and uterus, with differences in expression levels between the two subtypes of PDE8A and PDE8B, as well as two sexes. Meanwhile, PDE8 was widely distributed in the brain, especially in areas closely related to cognitive function such as cerebellum, striatum, amygdala, cerebral cortex, and hippocampus, without differences between sexes. Furthermore, PDE8A was found to be expressed in neuronal cells, microglia and astrocytes, while PDE8B is only expressed in neuronal cells and microglia. PDE8A expression in the hippocampus of both female and male 3×Tg-AD mice was gradually increased with ages and PDE8B expression was upregulated only in cerebral cortex of female 3×Tg-AD mice with ages. However, the expression of PDE8A and PDE8B was apparently increased in both cerebral cortex and hippocampus in both female and male 10-month-old 3×Tg-AD mice compared WT mice. These results suggest that PDE8 may be associated with the progression of AD and is a potential target for its prevention and treatment in the future.

Correction: A poly(thymine)-templated fluorescent copper nanoparticle hydrogel-based visual and portable strategy for an organophosphorus pesticide assay.

Correction for 'A poly(thymine)-templated fluorescent copper nanoparticle hydrogel-based visual and portable strategy for an organophosphorus pesticide assay' by Jihua Chen et al., Analyst, 2019, 144, 2423-2429, https://doi.org/10.1039/C9AN00017H.

Circulating extracellular vesicle-derived miR-1299 disrupts hepatic glucose homeostasis by targeting the STAT3/FAM3A axis in gestational diabetes mellitus.

BACKGROUND: Extracellular vesicles (EVs) are membrane-enclosed structures containing lipids, proteins, and RNAs that play a crucial role in cell-to-cell communication. However, the precise mechanism through which circulating EVs disrupt hepatic glucose homeostasis in gestational diabetes mellitus (GDM) remains unclear. RESULTS: Circulating EVs isolated from human plasma were co-cultured with mammalian liver cells to investigate the potential induction of hepatic insulin resistance by GDM-EVs using glucose output assays, Seahorse assays, metabolomics, fluxomics, qRT-PCR, bioinformatics analyses, and luciferase assays. Our findings demonstrated that hepatocytes exposed to GDM-EVs exhibited increased gluconeogenesis, attenuated energy metabolism, and upregulated oxidative stress. Particularly noteworthy was the discovery of miR-1299 as the predominant miRNA in GDM-EVs, which directly targeting the 3'-untranslated regions (UTR) of STAT3. Our experiments involving loss- and gain-of-function revealed that miR-1299 inhibits the insulin signaling pathway by regulating the STAT3/FAM3A axis, resulting in increased insulin resistance through the modulation of mitochondrial function and oxidative stress in hepatocytes. Moreover, experiments conducted in vivo on mice inoculated with GDM-EVs confirmed the development of glucose intolerance, insulin resistance, and downregulation of STAT3 and FAM3A. CONCLUSIONS: These results provide insights into the role of miR-1299 derived from circulating GDM-EVs in the progression of insulin resistance in hepatic cells via the STAT3/FAM3A axis and downstream metabolic reprogramming.

Facial adult female acne in China: An analysis based on artificial intelligence over one million.

BACKGROUND: To further clarify the acne profile of Chinese adult women, we included 1,156,703 adult women. An artificial intelligence algorithm was used to analyze images taken by high-resolution mobile phones to further explore acne levels in Chinese adult women. METHOD: In this study, we assessed the severity of acne by evaluating patients' selfies through a smartphone application. Furthermore, we gathered basic user information through a questionnaire, including details such as age, gender, skin sensitivity, and dietary habits. RESULTS: This study showed a gradual decrease in acne severity from the age of 25 years. A trough was reached between the ages of 40 and 44, followed by a gradual increase in acne severity. In terms of skin problems and acne severity, we have found that oily skin, hypersensitive skin, frequent makeup application and unhealthy dietary habits can affect the severity of acne. For environment and acne severity, we observed that developed city levels, cold seasons and high altitude and strong radiation affect acne severity in adult women. For the results of the AI analyses, the severity of blackheads, pores, dark circles and skin roughness were positively associated with acne severity in adult women. CONCLUSIONS: AI analysis of high-res phone images in Chinese adult women reveals acne severity trends. Severity decreases after 25, hits a low at 40-44, then gradually rises. Skin type, sensitivity, makeup, diet, urbanization, seasons, altitude, and radiation impact acne. Blackheads, pores, dark circles, and skin roughness are linked to acne severity. These findings inform personalized skincare and public health strategies for adult women.

Physicians' beliefs and perceived importance of traumatic brain injury-associated agitation in critically ill patients: a survey of Canadian intensivists.

PURPOSE: Agitation is a common behavioural problem following traumatic brain injury (TBI). Intensive care unit (ICU) physicians' perspectives regarding TBI-associated agitation are unknown. Our objective was to describe physicians' beliefs and perceived importance of TBI-associated agitation in critically ill patients. METHODS: Following current standard guidance, we built an electronic, self-administrated, 42-item survey, pretested it for reliability and validity, and distributed it to 219 physicians working in 18 ICU level-1 trauma centres in Canada. We report the results using descriptive statistics. RESULTS: The overall response rate was 93/219 (42%), and 76/93 (82%) respondents completed the full survey. Most respondents were men with ten or more years of experience. Respondents believed that pre-existing dementia (90%) and regular recreational drug use (86%) are risk factors for agitation. Concerning management, 91% believed that the use of physical restraints could worsen agitation, 90% believed that having family at the bedside reduces agitation, and 72% believed that alpha-2 adrenergic agonists are efficacious for managing TBI agitation. Variability was observed in beliefs on epidemiology, sex, gender, age, socioeconomic status, and other pharmacologic options. Respondents considered TBI agitation frequent enough to justify the implementation of management protocols (87%), perceived the current level of clinical evidence on TBI agitation management to be insufficient (84%), and expressed concerns about acute and long-term detrimental outcomes and burden to patients, health care professionals, and relatives (85%). CONCLUSION: Traumatic brain injury-associated agitation in critically ill patients was perceived as an important issue for most ICU physicians. Physicians agreed on multiple approaches to manage TBI-associated agitation although agreement on epidemiology and risk factors was variable.

RéSUMé: OBJECTIF: L'agitation est un problème de comportement courant à la suite d'un traumatisme crânien (TC). Le point de vue des médecins des unités de soins intensifs (USI) sur l'agitation associée aux traumatismes crâniens est inconnu. Notre objectif était de décrire les croyances et l'importance perçue par les médecins de l'agitation associée aux traumatismes crâniens chez les patient·es gravement malades. MéTHODE: Conformément aux lignes directrices standard actuelles, nous avons élaboré un sondage électronique auto-administré de 42 questions, l'avons testé au préalable pour en vérifier la fiabilité et la validité, et l'avons distribué à 219 médecins travaillant dans les USI de 18 centres de traumatologie de niveau 1 au Canada. Les résultats sont présentés à l'aide de statistiques descriptives. RéSULTATS: Le taux de réponse global a été de 93 sur 219 (42 %) et 76 sur 93 (82 %) personnes interrogées ont répondu à l'ensemble du sondage. La plupart des répondant·es étaient des hommes comptant dix ans ou plus d'expérience. Les répondant·es sont d'avis que la démence préexistante (90 %) et la consommation régulière de drogues à des fins récréatives (86 %) sont des facteurs de risque d'agitation. En ce qui concerne la prise en charge, 91 % des répondant·es estiment que l'utilisation de contentions physiques peut aggraver l'agitation, 90 % croient que le fait d'avoir de la famille au chevet du patient ou de la patiente réduit l'agitation et 72 % pensent que les agonistes alpha-2 adrénergiques sont efficaces pour gérer l'agitation causée par les traumatismes crâniens. Une variabilité a été observée dans les croyances concernant l'épidémiologie, le sexe, le genre, l'âge, le statut socio-économique et d'autres options pharmacologiques. Les répondant·es considéraient que l'agitation liée aux traumatismes crâniens était suffisamment fréquente pour justifier la mise en œuvre de protocoles de prise en charge (87 %), estimaient que le niveau actuel de données probantes cliniques sur la prise en charge de l'agitation causée par un traumatisme crânien était insuffisant (84 %), et se sont dit·es préoccupé·es par les conséquences préjudiciables aiguës et à long terme et par le fardeau pour les patient·es, les professionnel·les de la santé et les proches (85 %). CONCLUSION: L'agitation associée à un traumatisme crânien chez les patient·es gravement malades était perçue comme un problème important pour la plupart des médecins des soins intensifs. Les médecins s'entendaient sur plusieurs approches pour gérer l'agitation associée aux traumatismes crâniens, bien que l'accord sur l'épidémiologie et les facteurs de risque était variable.

Population pharmacokinetics and pharmacodynamics of efmarodocokin alfa (IL-22Fc).

Efmarodocokin alfa (IL-22Fc) is a fusion protein of human IL-22 linked to the crystallizable fragment (Fc) of human IgG4. It has been tested in multiple indications including inflammatory bowel disease (IBD). The purposes of the present analyses were to describe the population pharmacokinetics (PK) of efmarodocokin alfa and perform pharmacodynamic (PD) analysis on the longitudinal changes of the PD biomarker REG3A after efmarodocokin alfa treatment as well as identify covariates that affect efmarodocokin alfa PK and REG3A PD. The data used for this analysis included 182 subjects treated with efmarodocokin alfa in two clinical studies. The population PK and PD analyses were conducted sequentially. Efmarodocokin alfa concentration-time data were analyzed using a nonlinear mixed-effects modeling approach, and an indirect response model was adopted to describe the REG3A PD data with efmarodocokin alfa serum concentration linked to the increase in REG3A. The analysis software used were NONMEM and R. A 3-compartment model with linear elimination best described the PK of efmarodocokin alfa. The estimated population-typical value for clearance (CL) was 1.12 L/day, and volume of central compartment was 6.15 L. Efmarodocokin alfa CL increased with higher baseline body weight, C-reactive protein, and CL was 27.6% higher in IBD patients compared to healthy subjects. The indirect response PD model adequately described the longitudinal changes of REG3A after efmarodocokin alfa treatment. A popPK and PD model for efmarodocokin alfa and REG3A was developed and covariates affecting the PK and PD were identified.

Suberitolactams A-D and Suberitopyridines A-B: New γ-lactam and Pyridine Alkaloids Isolated from the South China Sea Sponge Pseudospongosorites suberitoides.

Four new γ-lactam alkaloids, suberitolactams A-D (1-4), two new pyridine alkaloids, suberitopyridines A-B (7-8), and two known compounds (5-6) were isolated from the South China Sea sponge Pseudospongosorites suberitoides. The structures were elucidated by detailed 1D and 2D NMR experiments along with HRESIMS analysis and single crystal X-ray diffraction. Compounds 1 and 8 showed moderate to weak antiviral activity against H1 N1 virus with IC50 values of 27.6 and 13.3 µM, respectively.

NMC3D: Non-Overlapping Multi-Camera Calibration Based on Sparse 3D Map.

With the advancement of computer vision and sensor technologies, many multi-camera systems are being developed for the control, planning, and other functionalities of unmanned systems or robots. The calibration of multi-camera systems determines the accuracy of their operation. However, calibration of multi-camera systems without overlapping parts is inaccurate. Furthermore, the potential of feature matching points and their spatial extent in calculating the extrinsic parameters of multi-camera systems has not yet been fully realized. To this end, we propose a multi-camera calibration algorithm to solve the problem of the high-precision calibration of multi-camera systems without overlapping parts. The calibration of multi-camera systems is simplified to the problem of solving the transformation relationship of extrinsic parameters using a map constructed by multiple cameras. Firstly, the calibration environment map is constructed by running the SLAM algorithm separately for each camera in the multi-camera system in closed-loop motion. Secondly, uniformly distributed matching points are selected among the similar feature points between the maps. Then, these matching points are used to solve the transformation relationship between the multi-camera external parameters. Finally, the reprojection error is minimized to optimize the extrinsic parameter transformation relationship. We conduct comprehensive experiments in multiple scenarios and provide results of the extrinsic parameters for multiple cameras. The results demonstrate that the proposed method accurately calibrates the extrinsic parameters for multiple cameras, even under conditions where the main camera and auxiliary cameras rotate 180°.