Benchmarking online food delivery applications against menu labelling laws: a cross-sectional observational analysis.

OBJECTIVE: It is unknown how well menu labelling schemes that enforce the display of kilojoule (kJ) labelling at point-of-sale have been implemented on online food delivery (OFD) services in Australia. This study aimed to examine the prevalence of kJ labelling on the online menus of large food outlets with more than twenty locations in the state or fifty locations nationally. A secondary aim was to evaluate the nutritional quality of menu items on OFD from mid-sized outlets that have fewer locations than what is specified in the current scheme. DESIGN: Cross-sectional analysis. Prevalence of kJ labelling by large food outlets on OFD from August to September 2022 was examined. Proportion of discretionary ('junk food') items on menus from mid-sized outlets was assessed. SETTING: Forty-three unique large food outlets on company (e.g. MyMacca's) and third party OFD (Uber Eats, Menulog, Deliveroo) within Sydney, Australia. Ninety-two mid-sized food outlets were analysed. PARTICIPANTS: N/A. RESULTS: On company OFD apps, 35 % (7/23) had complete kJ labelling for each menu item. In comparison, only 4·8 % (2/42), 5·3 % (2/38) and 3·6 % (1/28) of large outlets on Uber Eats, Menulog and Deliveroo had complete kJ labelling at all locations, respectively. Over three-quarters, 76·3 % (345/452) of menu items from mid-sized outlets were classified as discretionary. CONCLUSIONS: Kilojoule labelling was absent or incomplete on a high proportion of online menus. Mid-sized outlets have abundant discretionary choices and yet escape criteria for mandatory menu labelling laws. Our findings show the need to further monitor the implementation of nutrition policies on OFD.

Hippo Kinase MST1-Mediated Cell Metabolism Reprograms the Homeostasis and Differentiation of Granulocyte Progenitor Cells.

The mechanism of the development of granulocyte progenitor cells into neutrophils under steady-state and pathological conditions remains unclear. In this study, our results showed that with the development of neutrophils from hematopoietic stem cells to mature neutrophils, the expression level of the Hippo kinase MST1 gradually increased. Mst1-specific deficiency in myeloid cells caused neutrophilia, with an expanded granulocytic compartment resulting from a cell-autonomous increase in the number of granulocyte-macrophage progenitors under steady-state conditions and during Listeria monocytogenes infection. Mechanistically, mTOR and HIF1α signaling are required for regulating the balance between glycolysis and succinate dehydrogenase-mediated oxidative phosphorylation, which is crucial for Mst1-/--induced proliferation of granulocyte-monocyte progenitors, lineage-decision factor C/EBPα expression, and granulopoiesis. HIF1α directly regulated C/EBPα promoter activities. Blocking mTOR and HIF1α or adjusting the balance between glycolysis and succinate dehydrogenase-mediated oxidative phosphorylation reversed the granulopoiesis induced by Mst1-/- under steady-state conditions or infection in mice. Thus, our findings identify a previously unrecognized interplay between Hippo kinase MST1 signaling and mTOR-HIF1α metabolic reprogramming in granulocyte progenitor cells that underlies granulopoiesis.

Aryl hydrocarbon receptor nuclear translocator limits the recruitment and function of regulatory neutrophils against colorectal cancer by regulating the gut microbiota.

BACKGROUND: Although the role and mechanism of neutrophils in tumors have been widely studied, the precise effects of aryl hydrocarbon receptor nuclear translocator (ARNT) on neutrophils remain unclear. In this study, we investigated the roles of ARNT in the function of CD11b+Gr1+ neutrophils in colitis-associated colorectal cancer. METHODS: Wild-type (WT), ARNT myeloid-specific deficient mice and a colitis-associated colorectal cancer mouse model were used in this study. The level and functions of CD11b+Gr1+ cells were evaluated by flow cytometry and confocal microscopy. RESULTS: We found that ARNT deficiency drives neutrophils recruitment, neutrophil extracellular trap (NET) development, inflammatory cytokine secretion and suppressive activities when cells enter the periphery from bone marrow upon colorectal tumorigenesis. ARNT deficiency displays similar effects to aryl hydrocarbon receptor (AHR) deficiency in neutrophils. CXCR2 is required for NET development, cytokine production and recruitment of neutrophils but not the suppressive activities induced by Arnt-/- in colorectal cancer. The gut microbiota is essential for functional alterations in Arnt-/- neutrophils to promote colorectal cancer growth. The colorectal cancer effects of Arnt-/- neutrophils were significantly restored by mouse cohousing or antibiotic treatment. Intragastric administration of the feces of Arnt-/- mice phenocopied their colorectal cancer effects. CONCLUSION: Our results defined a new role for the transcription factor ARNT in regulating neutrophils recruitment and function and the gut microbiota with implications for the future combination of gut microbiota and immunotherapy approaches in colorectal cancer.

CD8+ T cell exhaustion in anti-tumour immunity: The new insights for cancer immunotherapy.

CD8+ T cells play a crucial role in anti-tumour immunity, but they often undergo exhaustion, which affects the anti-tumour activity of CD8+ T cells. The effect and mechanism of exhausted CD8+ T cells have become the focus of anti-tumour immunity research. Recently, a large number of studies have confirmed that long-term antigen exposure can induce exhaustion. Cytokines previously have identified their effects (such as IL-2 and IL-10) may play a dual role in the exhaustion process of CD8+ T cells, suggesting a new mechanism of inducing exhaustion. This review just focuses our current understanding of the biology of exhausted CD8+ T cells, including differentiation pathways, cellular characteristics and signalling pathways involved in inducing exhaustion, and summarizes how these can be applied to tumour immunotherapy.

Dendritic cell Piezo1 directs the differentiation of TH1 and Treg cells in cancer.

Dendritic cells (DCs) play an important role in anti-tumor immunity by inducing T cell differentiation. Herein, we found that the DC mechanical sensor Piezo1 stimulated by mechanical stiffness or inflammatory signals directs the reciprocal differentiation of TH1 and regulatory T (Treg) cells in cancer. Genetic deletion of Piezo1 in DCs inhibited the generation of TH1 cells while driving the development of Treg cells in promoting cancer growth in mice. Mechanistically, Piezo1-deficient DCs regulated the secretion of the polarizing cytokines TGFß1 and IL-12, leading to increased TGFßR2-p-Smad3 activity and decreased IL-12Rß2-p-STAT4 activity while inducing the reciprocal differentiation of Treg and TH1 cells. In addition, Piezo1 integrated the SIRT1-hypoxia-inducible factor-1 alpha (HIF1α)-dependent metabolic pathway and calcium-calcineurin-NFAT signaling pathway to orchestrate reciprocal TH1 and Treg lineage commitment through DC-derived IL-12 and TGFß1. Our studies provide critical insight for understanding the role of the DC-based mechanical regulation of immunopathology in directing T cell lineage commitment in tumor microenvironments.

Protein Tyrosine Phosphatase PTPRO Signaling Couples Metabolic States to Control the Development of Granulocyte Progenitor Cells.

Protein tyrosine phosphatase (PTPase) is critically involved in the regulation of hematopoietic stem cell development and differentiation. Roles of novel isolated receptor PTPase PTPRO from bone marrow hematopoietic stem cells in granulopoiesis have not been investigated. PTPRO expression is correlated with granulocytic differentiation, and Ptpro -/- mice developed neutrophilia, with an expanded granulocytic compartment resulting from a cell-autonomous increase in the number of granulocyte progenitors under steady-state and potentiated innate immune responses against Listeria monocytogenes infection. Mechanistically, mTOR and HIF1α signaling engaged glucose metabolism and initiated a transcriptional program involving the lineage decision factor C/EBPα, which is critically required for the PTPRO deficiency-directed granulopoiesis. Genetic ablation of mTOR or HIF1α or perturbation of glucose metabolism suppresses progenitor expansion, neutrophilia, and higher glycolytic activities by Ptpro -/- In addition, Ptpro -/- upregulated HIF1α regulates the lineage decision factor C/EBPα promoter activities. Thus, our findings identify a previously unrecognized interplay between receptor PTPase PTPRO signaling and mTOR-HIF1α metabolic reprogramming in progenitor cells of granulocytes that underlies granulopoiesis.

The safety of early administration of oral fluid following general anesthesia in children undergoing tonsillectomy: a prospective randomized controlled trial.

BACKGROUND: The feasibility and safety of administrating a small amount of oral fluid to children in the early recovery period following tonsillectomy under general anesthesia to reduce the thirst and its associated restlessness remain unknown. METHODS: This study was approved by the institutional ethics committee and adhered to the CONSORT guidelines. Pediatric patients undergoing tonsillectomy who met the inclusion and exclusion criteria of our study were randomized into the study and control groups. In the study group, patients were given a small amount of water instantly after recovering from general anesthesia, which included the recovery of the cough and deglutition reflex, and attaining grade V of muscle strength. The control group was given a small amount of water at 4 to 6 h after the operation. The incidence of nausea and vomiting and the degree of thirst relief were measured and compared between the two groups. RESULTS: Three hundred patients were randomized into each group. There was no significant difference in the incidence of nausea and vomiting at 20 min after drinking water between the two groups (P > 0.05). The thirst score of children over 5 years old in the study group was significantly lower than that of the control group (P < 0.05). CONCLUSION: Early administration of a small amount of oral fluid to children following tonsillectomy and recovering from general anesthesia is not only safe but also effective in reducing postoperative thirst. TRIAL REGISTRATION: Current Controlled Trials ChiCTR1800020058 , 12-12-2018.

The crosstalk between gut bacteria and host immunity in intestinal inflammation.

The gut of mammals is considered as a harmonious ecosystem mediated by intestinal microbiota and the host. Both bacteria and mammalian immune cells show region-related distribution characteristics, and the interaction between the two could be demonstrated by synergetic roles in maintaining intestinal homeostasis and dysregulation in intestinal inflammation. The harmonious interplay between bacteria and host requires fine-tuned regulations by environmental and genetic factors. Thus, the disturbed immune response to microbial components or metabolites and dysbiosis related to immunodeficiency are absolute risk factors to intestinal inflammation and cancer. In this review, we discuss the crosstalk between bacteria and host immunity in the gut and highlight the critical roles of bidirectional regulation between bacteria and the mammalian immune system involved in intestinal inflammation.

Functional differentiation and regulation of follicular T helper cells in inflammation and autoimmunity.

Follicular T helper (TFH ) cells are specialized T cells that support B cells, which are essential for humoral immunity. TFH cells express the transcription factor B-cell lymphoma 6 (Bcl-6), chemokine (C-X-C motif) receptor (CXCR) 5, the surface receptors programmed cell death protein 1 (PD-1) and inducible T-cell costimulator (ICOS), the cytokine IL-21 and other molecules. The activation, proliferation and differentiation of TFH cells are closely related to dynamic changes in cellular metabolism. In this review, we summarize the progress made in understanding the development and functional differentiation of TFH cells. Specifically, we focus on the regulatory mechanisms of TFH cell functional differentiation, including regulatory signalling pathways and the metabolic regulatory mechanisms of TFH cells. In addition, TFH cells are closely related to immune-associated diseases, including infections, autoimmune diseases and cancers.

Targeting Myeloid-Derived Suppressor Cells in Cancer Immunotherapy.

Myeloid-derived suppressor cells (MDSCs), which are activated under pathological conditions, are a group of heterogeneous immature myeloid cells. MDSCs have potent capacities to support tumor growth via inhibition of the antitumoral immune response and/or the induction of immunosuppressive cells. In addition, multiple studies have demonstrated that MDSCs provide potential therapeutic targets for the elimination of immunosuppressive functions and the inhibition of tumor growth. The combination of targeting MDSCs and other therapeutic approaches has also demonstrated powerful antitumor effects. In this review, we summarize the characteristics of MDSCs in the tumor microenvironment (TME) and current strategies of cancer treatment by targeting MDSCs.

Early versus delayed postoperative oral hydration in children following general anesthesia: a prospective randomized trial.

BACKGROUND: Oral hydration has typically not been administered for between 4 and 6 h postoperative for children's safety in China. But children are more likely to suffer from apnea, crying and agitation, wound bleeding, and other complications during the post-anesthesia recovery period because of thirsty and fear. This Prospective, randomized study sought to assess the compare the early and late oral hydration (EOH and DOH, respectively) in children following general anesthesia, with the goal of assessing relative safety and tolerability and thereby improving patient comfort. METHODS: A total of 2000 children corresponding to the American Society of Anesthesiology (ASA) I-III were randomized into an EOH group (n = 1000) and a DOH group (n = 1000). For the former group, children were administered a small amount of drinking water following recovery of the swallowing reflex, and children's vital signs were monitored for 20 min in a postanesthesia care unit (PACU). DOH group patients received water at 4 h following general anesthesia). All patients underwent monitoring to assess their thirst, satisfaction, oropharyngeal discomfort, nausea, and vomiting. RESULTS: Complete data were collected from a total of 1770 patients (EOH = 832, DOH = 938) and was compared via chi-squared and t-tests as appropriate. There was no hypoxemia in either group, nor did the incidence of nausea and vomiting differ between the two groups (P > 0.05). The thirst score of the EOH group was significantly decreased relative to the DOH group in the children over 5 years old after drinking for 10 to 20 min (P < 0.05). CONCLUSIONS: For children undergoing general anesthesia, a small amount of drinking water in the early stages of recovery will not increase the incidence of nausea, vomiting, or hypoxemia, but will decrease thirst and improve satisfaction. It is important, however, that medical staff carefully monitor the swallowing reflex and vital signs of all children. TRIAL REGISTRATION: This study was registered on the Chinese Clinical Trial Registry (ChiCTR-IOR-16008197) (http://www.chictr.org.cn/index.aspx. On April 2, 2016 the first patients was enrolled and on March 31, 2016 the trial was registered).

Regulations of Glycolytic Activities on Macrophages Functions in Tumor and Infectious Inflammation.

Macrophages differentiated into a classically activated (M1) or alternatively activated phenotype (M2) in infection and tumor, but the precise effects of glycolysis and oxidative phosphorylation (OXPHOS) metabolic pathway remain unclear. Herein, the effects of glycolysis or OXPHOS on macrophage polarizations were investigated using a pharmacological approach in mice. 2-Deoxy-D-glucose (2-DG) treatments, which blocks the key enzyme hexokinase of glycolysis, efficiently inhibits a specific switch to M1 lineage, decreasing the secretion of pro-inflammatory cytokines and expressions of co-stimulatory molecules associated with relieving infectious inflammation in vitro and in vivo. Glycolytic activation through the hypoxia-inducible factor-1α (HIF-1α) pathway was required for differentiation to the M1 phenotype, which conferred protection against infection. Dimethyl malonate (DMM) treatment, which blocks the key element succinate of OXPHOS, efficiently inhibits a specific switch to M2 lineage when macrophages receiving M2 stimulation, decreasing the secretion of anti-inflammatory cytokine and CD206 expressions. Mitochondrial dynamic alterations including mitochondrial mass, mitochondrial membrane potential (Dym) and ROS productions were critically for differentiation to the M2 phenotype, which conferred protection against anti-tumor immunity. Glycolysis is also required for macrophage M2 differentiation. Thus, these data provide a basis for a comprehensively understanding the role of glycolysis and OXPHOS in macrophage differentiation during anti-infection and anti-tumor inflammation.

Glucocorticoids Promote the Onset of Acute Experimental Colitis and Cancer by Upregulating mTOR Signaling in Intestinal Epithelial Cells.

The therapeutic effects of glucocorticoids on colitis and colitis-associated cancer are unclear. In this study, we investigated the therapeutic roles of glucocorticoids in acute experimental ulcerative colitis and colitis-associated cancer in mice and their immunoregulatory mechanisms. Murine acute ulcerative colitis was induced by dextran sulfate sodium (DSS) and treated with dexamethasone (Dex) at different doses. Dex significantly exacerbated the onset and severity of DSS-induced colitis and potentiated mucosal inflammatory macrophage and neutrophil infiltration, as well as cytokine production. Furthermore, under inflammatory conditions, the expression of the glucocorticoid receptor (GR) did not change significantly, while mammalian target of rapamycin (mTOR) signaling was higher in colonic epithelial cells than in colonic immune cells. The deletion of mTOR in intestinal epithelial cells, but not that in myeloid immune cells, in mice significantly ameliorated the severe course of colitis caused by Dex, including weight loss, clinical score, colon length, pathological damage, inflammatory cell infiltration and pro-inflammatory cytokine production. These data suggest that mTOR signaling in intestinal epithelial cells, mainly mTORC1, plays a critical role in the Dex-induced exacerbation of acute colitis and colitis-associated cancer. Thus, these pieces of evidence indicate that glucocorticoid-induced mTOR signaling in epithelial cells is required in the early stages of acute ulcerative colitis by modulating the dynamics of innate immune cell recruitment and activation.

Metabolic Regulation of Myeloid-Derived Suppressor Cell Function in Cancer.

Myeloid-derived suppressor cells (MDSCs) are a group of immunosuppressive cells that play crucial roles in promoting tumor growth and protecting tumors from immune recognition in tumor-bearing mice and cancer patients. Recently, it has been shown that the metabolic activity of MDSCs plays an important role in the regulation of their inhibitory function, especially in the processes of tumor occurrence and development. The MDSC metabolism, such as glycolysis, fatty acid oxidation and amino acid metabolism, is rewired in the tumor microenvironment (TME), which enhances the immunosuppressive activity, resulting in effector T cell apoptosis and suppressive cell proliferation. Herein, we summarized the recent progress in the metabolic reprogramming and immunosuppressive function of MDSCs during tumorigenesis.

A novel peptide exerts potent immunosuppression by blocking the two-site interaction of NFAT with calcineurin.

The calcineurin/nuclear factor of activated T cell (CN/NFAT) signaling pathway plays a critical role in the immune response. Therefore, inhibition of the CN/NFAT pathway is an important target for inflammatory disease. The conserved PXIXIT and LXVP motifs of CN substrates and targeting proteins have been recognized. Based on the affinity ability and inhibitory effect of these docking sequences on CN, we designed a bioactive peptide (named pep3) against the CN/NFAT interaction, which has two binding sites derived from the RCAN1-PXIXIT motif and the NFATc1-LXVP motif. The shortest linker between the two binding sites in pep3 is derived from A238L, a physiological binding partner of CN. Microscale thermophoresis revealed that pep3 has two docking sites on CN. Pep3 also has the most potent inhibitory effect on CN. It is suggested that pep3 contains an NFATc1-LXVP-substrate recognition motif and RCAN1-PXIXIT-mediated anchoring to CN. Expression of this peptide significantly suppresses CN/NFAT signaling. Cell-permeable 11-arginine-modified pep3 (11R-pep3) blocks the NFAT downstream signaling pathway. Intranasal administration of the 11R-pep3 peptide inhibits airway inflammation in an ovalbumin-induced asthma model. Our results suggest that pep3 is promising as an immunosuppressive agent and can be used in topical remedies.

Hippo Kinases MST1/2 Regulate Immune Cell Functions in Cancer, Infection, and Autoimmune Diseases.

Mammalian STE20-like protein kinases (MST), including MST1, MST2, MST3, and MST4, belong to the germinal center kinase (GCK) family. Kinase MST1/2 is an important component of the Hippo pathway in regulating cell proliferation, tissue homeostasis, and organ development. Recent studies have shown that Hippo kinase MST1/2 plays a crucial role in immune-associated diseases, which has attracted extensive attention of researchers. This review summarizes recent research on Hippo kinases MST1/2 in regulating the function of immune cells in innate and adaptive immune systems, and also includes its regulatory role and significance in cancer, infection, and autoimmune diseases.

Immune effects of glycolysis or oxidative phosphorylation metabolic pathway in protecting against bacterial infection.

The metabolism of immune cells reprograms inflammatory responses to protect against infection by pathogenic microorganisms, but the immune effects of glycolysis and the oxidative phosphorylation (OXPHOS) metabolic pathway remain unclear. Herein, the effects of glycolysis or OXPHOS on the neutrophils and T cells were investigated using a pharmacological approach in mice. 2-Deoxy-d-glucose (2-DG), which blocks the key enzyme hexokinase of glycolysis, and dimethyl malonate (DMM), which blocks the key element succinate of OXPHOS, both efficiently expanded the population of neutrophils, but significantly inhibited tumor necrosis factor a secretion and reactive oxygen species (ROS) production. These compounds also effectively inhibited the differentiation of type 1 T helper cells (Th1) but had no effects on the differentiation of type 2 T helper cells (Th2) and regulatory T cells. A study of the underlying mechanism showed that hypoxia-inducible factor 1-alpha (HIF1α) was an upstream signal in the regulation of glycolysis, but not OXPHOS. In thioglycolate broth-induced neutrophil peritonitis, blockade of glycolysis or OXPHOS efficiently expanded the population of neutrophils, but diminished their abilities to secrete proinflammatory factors, produce ROS, and phagocytose bacteria. In Listeria monocytogenes bacteria-infected mice, 2-DG or DMM treatment consistently inhibited antibacterial activity and Th1 function. Thus, our results provide a basis for comprehensively understanding the role of glycolysis and OXPHOS in anti-infectious immunity.

Safety and Feasibility of Early Oral Hydration in the Postanesthesia Care Unit After Laparoscopic Cholecystectomy: A Prospective, Randomized, and Controlled Study.

PURPOSE: To assess the safety and feasibility of early oral hydration (EOH) in the postanesthesia care unit (PACU) after laparoscopic cholecystectomy. DESIGN: Prospective, randomized, controlled trial. METHODS: Patients were randomly assigned to the EOH group or the conventional oral hydration (COH) group. Outcomes were the incidence of nausea and vomiting, thirst scale, incidence of oropharyngeal discomfort, and patient satisfaction. FINDINGS: Compared with the COH group, the EOH group had lower incidence of nausea before and after the first drink in the ward (P < .05); lower incidence of vomiting before and after the first drink in the ward (P < .05); lower thirst scale when patients were transferred out of the PACU (P < .05) and at 6 hours postoperatively (P < .05); and greater patient satisfaction on postoperative day 1 (P < .05). CONCLUSIONS: Early oral hydration in the PACU following laparoscopic cholecystectomy was safe and well-tolerated.