We read with interest the recent systematic reviewaArtificial intelligence and machine learning for hemorrhagic trauma careoby Peng et al.[1],which evaluated literature on machine learning(ML)in the management of trau...We read with interest the recent systematic reviewaArtificial intelligence and machine learning for hemorrhagic trauma careoby Peng et al.[1],which evaluated literature on machine learning(ML)in the management of traumatic haemorrhage.We thank the authors for their contribution to the role of ML in trauma.展开更多
BACKGROUND Hepatitis C virus(HCV)is a blood-borne virus which globally affects around 79 million people and is associated with high morbidity and mortality.Chronic infection leads to cirrhosis in a large proportion of...BACKGROUND Hepatitis C virus(HCV)is a blood-borne virus which globally affects around 79 million people and is associated with high morbidity and mortality.Chronic infection leads to cirrhosis in a large proportion of patients and often causes hepatocellular carcinoma(HCC)in people with cirrhosis.Of the 6 HCV genotypes(G1-G6),genotype-3 accounts for 17.9%of infections.HCV genotype-3 responds least well to directly-acting antivirals and patients with genotype-3 infection are at increased risk of HCC even if they do not have cirrhosis.AIM To systematically review and critically appraise all risk factors for HCC secondary to HCV-G3 in all settings.Consequently,we studied possible risk factors for HCC due to HCV-G3 in the literature from 1946 to 2023.METHODS This systematic review aimed to synthesise existing and published studies of risk factors for HCC secondary to HCV genotype-3 and evaluate their strengths and limitations.We searched Web of Science,Medline,EMBASE,and CENTRAL for publications reporting risk factors for HCC due to HCV genotype-3 in all settings,1946-2023.RESULTS Four thousand one hundred and forty-four records were identified from the four databases with 260 records removed as duplicates.Three thousand eight hundred and eighty-four records were screened with 3514 excluded.Three hundred and seventy-one full-texts were assessed for eligibility with seven studies included for analysis.Of the seven studies,three studies were retrospective case-control trials,two retrospective cohort studies,one a prospective cohort study and one a cross-sectional study design.All were based in hospital settings with four in Pakistan,two in South Korea and one in the United States.The total number of participants were 9621 of which 167 developed HCC(1.7%).All seven studies found cirrhosis to be a risk factor for HCC secondary to HCV genotype-3 followed by higher age(five-studies),with two studies each showing male sex,high alpha feto-protein,directly-acting antivirals treatment and achievement of sustained virologic response as risk factors for developing HCC.CONCLUSION Although,studies have shown that HCV genotype-3 infection is an independent risk factor for end-stage liver disease,HCC,and liver-related death,there is a lack of evidence for specific risk factors for HCC secondary to HCV genotype-3.Only cirrhosis and age have demonstrated an association;however,the number of studies is very small,and more research is required to investigate risk factors for HCC secondary to HCV genotype-3.展开更多
We comment on the article by Jia et al,in the World Journal of Gastrointestinal Surgery.We focus mainly on the factors that impair gastric motility and cause gastric retention in the pre-operative setting of endoscopi...We comment on the article by Jia et al,in the World Journal of Gastrointestinal Surgery.We focus mainly on the factors that impair gastric motility and cause gastric retention in the pre-operative setting of endoscopic retrograde cholan-giopancreatography(ERCP).ERCP is a complex endoscopic therapeutic proce-dure,which demands great skill from the endoscopist but also has recognized complications.Gastric retention impairs the endoscopist’s visibility but also increases the risk of complications,such as aspiration pneumonia.Therefore,identifying the factors that predispose to gastric retention alerts the endoscopists of the possible risks and enables them to take evasive action.The authors in the current study by Jia et al developed and validated a predictive model,which in-corporates five different factors,i.e.,gender,primary disease,jaundice,opioid use,and gastrointestinal obstruction,which were found to influence gastric retention.This model was shown to have a high predictive value to accurately identify pa-tients at risk for gastric retention before a therapeutic ERCP.展开更多
Currently,there is no cure for traumatic spinal co rd injury but one therapeutic approach showing promise is gene therapy.In this systematic review and meta-analysis,we aim to assess the efficacy of gene therapies in ...Currently,there is no cure for traumatic spinal co rd injury but one therapeutic approach showing promise is gene therapy.In this systematic review and meta-analysis,we aim to assess the efficacy of gene therapies in pre-clinical models of spinal cord injury and the risk of bias.In this metaanalysis,registe red at PROSPERO(Registration ID:CRD42020185008),we identified relevant controlled in vivo studies published in English by searching the PubMed,Web of Science,and Embase databases.No restrictions of the year of publication were applied and the last literature search was conducted on August 3,2020.We then conducted a random-effects meta-analysis using the restricted maximum likelihood estimator.A total of 71 studies met our inclusion crite ria and were included in the systematic review.Our results showed that overall,gene therapies were associated with improvements in locomotor score(standardized mean difference[SMD]:2.07,95%confidence interval[CI]:1.68-2.47,Tau^(2)=2.13,I^(2)=83.6%)and axonal regrowth(SMD:2.78,95%CI:1.92-3.65,Tau^(2)=4.13,I^(2)=85.5%).There was significant asymmetry in the funnel plots of both outcome measures indicating the presence of publication bias.We used a modified CAMARADES(Collaborative Approach to M eta-Analysis and Review of Animal Data in Experimental Studies)checklist to assess the risk of bias,finding that the median score was 4(IQR:3-5).In particula r,reports of allocation concealment and sample size calculations were lacking.In conclusion,gene therapies are showing promise as therapies for spinal co rd injury repair,but there is no consensus on which gene or genes should be targeted.展开更多
MiR-219 and miR-338(miR-219/miR-338)are oligodendrocyte-specific microRNAs.The overexpression of these miRs in oligodendrocyte precursor cells promotes their differentiation and maturation into oligodendrocytes,which ...MiR-219 and miR-338(miR-219/miR-338)are oligodendrocyte-specific microRNAs.The overexpression of these miRs in oligodendrocyte precursor cells promotes their differentiation and maturation into oligodendrocytes,which may enhance axonal remyelination after nerve injuries in the central nervous system(CNS).As such,the delivery of miR-219/miR-338 to the CNS to promote oligodendrocyte precursor cell differentiation,maturation and myelination could be a promising approach for nerve repair.However,nerve injuries in the CNS also involve other cell types,such as microglia and astrocytes.Herein,we investigated the effects of miR-219/miR-338 treatment on microglia and astrocytes in vitro and in vivo.We found that miR-219/miR-338 diminished microglial expression of pro-inflammatory cytokines and suppressed astrocyte activation.In addition,we showed that miR-219/miR-338 enhanced oligodendrocyte precursor cell differentiation and maturation in a scratch assay paradigm that re-created a nerve injury condition in vitro.Collectively,our results suggest miR-219/miR-338 as a promising treatment for axonal remyelination in the CNS following nerve injuries.All experimental procedures were approved by the Institutional Animal Care and Use Committee(IACUC),Nanyang Technological University(approval No.A0309 and A0333)on April 27,2016 and October 8,2016.展开更多
Pancreatic cancer is a highly aggressive tumour that is very resistant to treatments and it is rarely diagnosed early because of absence of specific symptoms. Therefore, the prognosis for this disease is very poor and...Pancreatic cancer is a highly aggressive tumour that is very resistant to treatments and it is rarely diagnosed early because of absence of specific symptoms. Therefore, the prognosis for this disease is very poor and it has the grim supremacy in terms of unfavourable survival rates. There have been great advances in survival rates for many types of cancers over the past few decades but hardly any change for pancreatic cancer. Mutations of the Ras oncogene are the most frequent oncogenic alterations in human cancers. The frequency of KRAS mutations in pancreatic cancer is around 90%. Given the well-established role of KRAS in cancer it is not surprising that it is one of the most attractive targets for cancer therapy. Nevertheless, during the last thirty years all attempts to target directly KRAS protein have failed. Therefore, it is crucial to identify downstream KRAS effectors in order to develop specific drugs able to counteract activation of this pathway. Among the different signalling pathways activated by oncogenic KRAS, the phosphoinositide 3-Kinase(PI3K) pathway is emerging as one of the most critical KRAS effector. In turn, PI3 K activates several parallel pathways making the identification of the precise effectors activated by KRAS/PI3 K more difficult. Recent data identify 3-phosphoinositide-dependent protein kinase 1 as a key tumour-initiating event downstream KRAS interaction with PI3 K in pancreatic cancer.展开更多
BACKGROUND Perianal fistulae are either primary(idiopathic)or secondary[commonly associated with Crohn’s disease,(CD)].It is assumed,although not proven,that the pathophysiology differs.AIM To systematically compare ...BACKGROUND Perianal fistulae are either primary(idiopathic)or secondary[commonly associated with Crohn’s disease,(CD)].It is assumed,although not proven,that the pathophysiology differs.AIM To systematically compare the clinical phenotypes,cytokine and phosphoprotein profiles of idiopathic and CD-related perianal fistulae.METHODS Sixty-one patients undergoing surgery for perianal fistula were prospectively recruited(48 idiopathic,13 CD)into a cohort study.Clinical data,including the Perineal Disease Activity Index(PDAI)and EQ-5D-5L were collected.Biopsies of the fistula tract,granulation tissue,internal opening mucosa and rectal mucosa were obtained at surgery.Concentrations of 30 cytokines and 39 phosphoproteins were measured in each biopsy using a magnetic bead multiplexing instrument and a chemiluminescent antibody array respectively.Over 12000 clinical and 23500 laboratory measurements were made.RESULTS The PDAI was significantly higher(indicating more active disease)in the CD group with a mean difference of 2.40(95%CI:0.52-4.28,P=0.01).Complex pathoanatomy was more prevalent in the CD group,namely more multiple fistulae,supralevator extensions,collections and rectal thickening.The IL-12p70 concentration at the internal opening specimen site was significantly higher(median difference 19.7 pg/mL,99%CI:0.2-40.4,P=0.008)and the IL-1RA/IL-1βratio was significantly lower in the CD group at the internal opening specimen site(median difference 15.0,99%CI=0.4-50.5,P=0.008).However in the remaining 27 cytokines and all 39 of the phosphoproteins across the four biopsy sites,no significant differences were found between the groups.CONCLUSION CD-related perianal fistulae are more clinically severe and anatomically complex than idiopathic perianal fistulae.However,overall there are no major differences in cytokine and phosphoprotein profiles.展开更多
The global prevalence of diabetes mellitus is increasing; arguably as a consequence of changes in diet, lifestyle and the trend towards urbanization. Unsurprisingly, the incidence of both micro and macrovascular compl...The global prevalence of diabetes mellitus is increasing; arguably as a consequence of changes in diet, lifestyle and the trend towards urbanization. Unsurprisingly, the incidence of both micro and macrovascular complications of diabetes mirrors this increasing prevalence. Amongst the complications with the highest symptom burden, yet frequently under-diagnosed and sub-optimally treated, is diabetic autonomic neuropathy, itself potentially resulting in cardiovascular autonomic neuropathy and gastrointestinal(GI) tract dysmotility. The aims of this review are fourfold. Firstly to provide an overview of the pathophysiological processes that cause diabetic autonomic neuropathy. Secondly, to discuss both the established and emerging cardiometric methods for evaluating autonomic nervous system function in vivo. Thirdly, to examine the tools for assessing pan-GI and segmental motility and finally, we will provide the reader with a summary of putative non-invasive biomarkers that provide a pathophysiological link between lowgrade neuro inflammation and diabetes, which may allow earlier diagnosis and intervention, which in future may improve patient outcomes.展开更多
Diabetes mellitus is a common disease and its prevalence is increasing worldwide. In various studies up to 30%-70% of patients present dysfunction and complications related to the gut. To date several clinical studies...Diabetes mellitus is a common disease and its prevalence is increasing worldwide. In various studies up to 30%-70% of patients present dysfunction and complications related to the gut. To date several clinical studies have demonstrated that autonomic nervous system neuropathy and generalized neuropathy of the central nervous system(CNS) may play a major role. This systematic review provides an overview of the neurodegenerative changes that occur as a consequence of diabetes with a focus on the CNS changes and gastrointestinal(GI) dysfunction. Animal models where diabetes was induced experimentally support that the disease induces changes in CNS. Recent investigations with electroencephalography and functional brain imaging in patients with diabetes confirm these structural and functional brain changes. Encephalographic studies demonstrated that altered insular processing of sensory stimuli seems to be a key player in symptom generation. In fact one study indicated that the more GI symptoms the patients experienced, the deeper the insular electrical source was located. The electroencephalography was often used in combination with quantitative sensory testingmainly showing hyposensitivity to stimulation of GI organs. Imaging studies on patients with diabetes and GI symptoms mainly showed microstructural changes,especially in brain areas involved in visceral sensory processing. As the electrophysiological and imaging changes were associated with GI and autonomic symptoms they may represent a future therapeutic target for treating diabetics either pharmacologically or with neuromodulation.展开更多
AIM: To identify risk factors associated with esophageal cancer in Zambia and association between dietary intake and urinary 8-iso prostaglandin F2α(8-iso PGF2α).METHODS: We conducted a prospective, case control stu...AIM: To identify risk factors associated with esophageal cancer in Zambia and association between dietary intake and urinary 8-iso prostaglandin F2α(8-iso PGF2α).METHODS: We conducted a prospective, case control study at the University Teaching Hospital. Subjects included both individuals admitted to the hospital and those presenting for an outpatient upper endoscopy. Esophageal cancer cases were compared to age and sex-matched controls. Cases were defined as patients with biopsy proven esophageal cancer; controls were defined as subjects without endoscopic evidence ofesophageal cancer. Clinical and dietary data were collected using a standard questionnaire, developed a priori. Blood was collected for human immunodeficiency virus(HIV) serology. Urine was collected, and 8-iso PGF2α was measured primarily by enzyme-linked immunosorbent assay and expressed as a ratio to creatinine.RESULTS: Forty five controls(mean age 54.2 ± 15.3, 31 male) and 27 cases(mean age 54.6 ± 16.4, 17 males) were studied. Body mass index was lower in cases(median 16.8) than controls(median 23.2), P = 0.01. Histopathologically, 25/27(93%) were squamous cell carcinoma and 2/27(7%) adenocarcinoma. More cases smoked cigarettes(OR = 11.24, 95%CI: 1.37-92.4, P = 0.02) but alcohol consumption and HIV seropositivity did not differ significantly(P = 0.14 for both). Fruit, vegetables and fish consumption did not differ significantly between groups(P = 0.11, 0.12, and 0.10, respectively). Mean isoprostane level was significantly higher in cases(0.03 ng/mg creatinine) than controls(0.01 ng/mg creatinine)(OR = 2.35, 95%CI: 1.19-4.65, P = 0.014).CONCLUSION: Smoking and isoprostane levels were significantly associated with esophageal cancer in Zambians, but diet, HIV status, and alcohol consumption were not.展开更多
Colony stimulating factor 1 receptor(CSF1R) is a tyrosine kinase receptor primarily expressed on microglia and a small subpopulation of neurons in the central nervous system (CNS),which directly controls the homeostas...Colony stimulating factor 1 receptor(CSF1R) is a tyrosine kinase receptor primarily expressed on microglia and a small subpopulation of neurons in the central nervous system (CNS),which directly controls the homeostasis,activation,and proliferation of microglia.Its ligands include CSF1 and interleukin-34 (IL-34).展开更多
AIM: To ascertain whether caecal pH is different in patients with irritable bowel syndrome (IBS), whose primary symptoms are bloating and distension, to healthy controls.
AIM To characterize antiviral therapy eligibility among hepatitis B virus(HBV)-infected adults at a university hospital in Zambia.METHODS Hepatitis B surface antigen-positive adults(n = 160) who were h IV-negative and...AIM To characterize antiviral therapy eligibility among hepatitis B virus(HBV)-infected adults at a university hospital in Zambia.METHODS Hepatitis B surface antigen-positive adults(n = 160) who were h IV-negative and referred to the hospital after a routine or clinically-driven HBV test were enrolled. Alanine Aminotransferase(ALT),Aspartate Aminotransferase(AST),platelet count,hepatitis B e-antigen,and HBV DNA were measured. Liver fibrosis/cirrhosis was assessed by physical examination,AST-to-platelet ratio index,and transient elastography. In antiviral therapy-na?ve individuals,we described hBV stages and antiviral therapy eligibility per World health Organization(WhO) and by hBV test(routine vs clinical). Elevated ALT was > 19 in women and > 30 U/L in men. Among treatmentexperienced individuals,we described medication side effects,adherence,and viral suppression.RESULTS The median age was 33 years,71.9% were men,and 30.9% were diagnosed with HBV through a clinicallydriven test with the remainder identified via routine testing(at the blood bank,community events,etc.). Among 120 treatment-na?ve individuals,2.5% were categorized as immune tolerant,11.7% were immune active,35.6% were inactive carriers,and 46.7% had an indeterminate phenotype. Per WhO guidelines,13(10.8%) were eligible for immediate antiviral therapy. The odds of eligibility were eight times higher for those diagnosed at clinical vs routine settings(adjusted odds ratio,8.33; 95%CI: 2.26-29.41). Among 40 treatmentexperienced hBV patients,virtually all took tenofovir,and a history of mild side effects was reported in 20%. Though reported adherence was good,12 of 29(41.4%) had HBV DNA > 20 IU/m L. CONCLUSION Approximately one in ten HBV-monoinfected Zambians were eligible for antivirals. Many had indeterminate phenotype and needed clinical follow-up.展开更多
High density lipoproteins (HDL) promote the efflux of excess cholesterol from peripheral tissues to the liver for excretion. This ability is responsible for the most relevant anti-atherogenic effect of HDL. The abilit...High density lipoproteins (HDL) promote the efflux of excess cholesterol from peripheral tissues to the liver for excretion. This ability is responsible for the most relevant anti-atherogenic effect of HDL. The ability of HDL to promote cholesterol efflux results also in the modulation of a series of responses in the immune cells involved in atherosclerosis,includingmonocyte-macrophages, B and T lymphocytes.Furthermore, during inflammation, the composition of this class of lipoproteins varies to a large extent, thus promoting the formation of dysfunctional HDL. The aim of this review is to discuss the emerging role of HDL in modulating the activity of immune cells and immune-inflammatory mediators during atherogenesis.展开更多
Neurons in the central nervous system （CNS） of adult mammals have a weak intrinsic regenerative capacity, which is one contributing factor to the failure of axonal regeneration. Finding the means to elevate the rege...Neurons in the central nervous system （CNS） of adult mammals have a weak intrinsic regenerative capacity, which is one contributing factor to the failure of axonal regeneration. Finding the means to elevate the regenerative capacity of axotomised neurons is one requirement for successful regeneration. Forty-five years ago, it was reported that crushing of the sciatic nerves of adult mice two weeks before cutting the nerves accelerated the regrowth of their axons （McQuarrie and Grafstein, 1973）. The nerve injury two weeks before triggered the regeneration machinery in the injured neurons, leading to faster axonal regrowth after a subsequent lesion. Later it was found that a lesion to a peripheral nerve also strongly enhanced the regeneration of the central branches of the appropriate primary sensory neurons （Richardson and Issa, 1984）. This phenomenon is termed preconditioning lesion （or conditioning lesion if the central branches of the sensory neurons are injured after a concomitant in- jury to their peripheral branches）.展开更多
Both dyskeratosis congenita (DC) and Hoyeraal-Hreidarsson Syndrome (HHS) are rare inherited bone marrow failure conditions. HHS is considered to be a variant of DC in which neurological deficits and immunodeficiencies...Both dyskeratosis congenita (DC) and Hoyeraal-Hreidarsson Syndrome (HHS) are rare inherited bone marrow failure conditions. HHS is considered to be a variant of DC in which neurological deficits and immunodeficiencies are also present. We describe a very interesting familial cluster where an invariant point mutation of DKC1 located in the exon 11 is observed in the carrier mother and in two decedent males. The older child developed the classical phenotype of HHS at a very early age. The second affected child remains poorly symptomatic, with only mild haematological changes. Telomere shortening, with different severity, is also present in both cases. This paper discusses the clinical spectrum of inherited BM failure syndromes from the perspective different clinical presentation within a family with a DKC1 mutation.展开更多
Disease modifying therapies aiming to preserveβ-cell function in patients with adult-onset autoimmune type 1 diabetes are lacking.Here,we conducted a multi-centre,randomized,controlled trial to assess theβ-cell pres...Disease modifying therapies aiming to preserveβ-cell function in patients with adult-onset autoimmune type 1 diabetes are lacking.Here,we conducted a multi-centre,randomized,controlled trial to assess theβ-cell preservation effects of saxagliptin alone and saxagliptin combined with vitamin D as adjunctive therapies in adult-onset autoimmune type 1 diabetes.In this 3-arm trial,301 participants were randomly assigned to a 24-month course of the conventional therapy(metformin with or without insulin)or adjunctive saxagliptin or adjunctive saxagliptin plus vitamin D to the conventional therapy.The primary endpoint was the change from baseline to 24 months in the fasting C-peptide.The secondary endpoints included the area under the concentration-time curve(AUC)for C-peptide level in a 2-h mixed-meal tolerance test,glycemic control,total daily insulin use and safety,respectively.The primary endpoint was not achieved in saxagliptin plus vitamin D group(P=0.18)and saxagliptin group(P=0.26).However,compared with the conventional therapy,2-h C-peptide AUC from 24 months to baseline decreased less with saxagliptin plus vitamin D(-276 pmol/L vs.-419 pmol/L;P=0.01),and not to the same degree with saxagliptin alone(-314 pmol/L;P=0.14).Notably,for participants with higher glutamic acid decarboxylase antibody(GADA)levels,the decline ofβ-cell function was much lower in saxagliptin plus vitamin D group than in the conventional therapy group(P=0.001).Insulin dose was significantly reduced in both active treatment groups than in the conventional therapy group despite all groups having similar glycemic control.In conclusion,the combination of saxagliptin and vitamin D preserves pancreaticβ-cell function in adult-onset autoimmune type 1 diabetes,an effect especially efficacious in individuals with higher GADA levels.Our results provide evidence for a novel adjunct to insulin and metformin as potential initial treatment for adult-onset type 1 diabetes.(ClinicalTrials.gov identifier:NCT02407899).展开更多
Chronic hepatitis B virus （HBV） infection progresses through distinct disease phases that are strongly associated with patient age. The so-called immune tolerant （IT） phase represents the classical early phase of ...Chronic hepatitis B virus （HBV） infection progresses through distinct disease phases that are strongly associated with patient age. The so-called immune tolerant （IT） phase represents the classical early phase of infection; it is associated with high levels of HBV replication and lack of clinical signs of liver Inflammation. Whether this phase of HBV infection is also associated with immunological features of ＂tolerance＇ has recently been challenged. Here, we review the data that dispute this concept of immune tolerance and then propose an alternative interpretation of the immunopathological events that take place during this early phase of CHB infection.展开更多
In multiple sclerosis(MS),human endogenous retrovirus W family(HERV-W)envelope protein,pHERV-W ENV,limits remyelination and induces microglia-mediated neurodegeneration.To better understand its role,we examined the so...In multiple sclerosis(MS),human endogenous retrovirus W family(HERV-W)envelope protein,pHERV-W ENV,limits remyelination and induces microglia-mediated neurodegeneration.To better understand its role,we examined the soluble pHERV-W antigen from MS brain lesions detected by specific antibodies.Physico-chemical and antigenic characteristics confirmed differences between pHERV-W ENV and syncytin-1.pHERV-W ENV monomers and trimers remained associated with membranes,while hexamers self-assembled from monomers into a soluble macrostructure involving sulfatides in MS brain.Extracellular hexamers are stabilized by internal hydrophobic bonds and external hydrophilic moieties.HERV-W studies in MS also suggest that this diffusible antigen may correspond to a previously described highmolecular-weight neurotoxic factor secreted by MS B-cells and thus represents a major agonist in MS pathogenesis.Adapted methods are now needed to identify encoding HERV provirus(es)in affected cells DNA.The properties and origin of MS brain pHERV-W ENV soluble antigen will allow a better understanding of the role of HERVs in MS pathogenesis.The present results anyhow pave the way to an accurate detection of the different forms of pHERV-W ENV antigen with appropriate conditions that remained unseen until now.展开更多
Hydrogel wound dressings can play critical roles in wound healing protecting the wound from trauma or contamination and providing an ideal environment to support the growth of endogenous cells and promote wound closur...Hydrogel wound dressings can play critical roles in wound healing protecting the wound from trauma or contamination and providing an ideal environment to support the growth of endogenous cells and promote wound closure.This work presents a self-assembling hydrogel dressing that can assist the wound repair process mimicking the hierarchical structure of skin extracellular matrix.To this aim,the co-assembly behaviour of a carboxylated variant of xyloglucan(CXG)with a peptide amphiphile(PA-H3)has been investigated to generate hierarchical constructs with tuneable molecular composition,structure,and properties.Transmission electron microscopy and circular dichroism at a low concentration shows that CXG and PA-H3 co-assemble into nanofibres by hydrophobic and electrostatic interactions and further aggregate into nanofibre bundles and networks.At a higher concentration,CXG and PA-H3 yield hydrogels that have been characterized for their morphology by scanning electron microscopy and for the mechanical properties by smallamplitude oscillatory shear rheological measurements and compression tests at different CXG/PAH3 ratios.A preliminary biological evaluation has been carried out both in vitro with HaCat cells and in vivo in a mouse model.展开更多
基金JMW,RSS,EP,EK,WM,ZBP,and NRMT have received research funding from a precision trauma care research award from the Combat Casualty Care Research Program of the US Army Medical Research and Materiel Command(DM180044).
文摘We read with interest the recent systematic reviewaArtificial intelligence and machine learning for hemorrhagic trauma careoby Peng et al.[1],which evaluated literature on machine learning(ML)in the management of traumatic haemorrhage.We thank the authors for their contribution to the role of ML in trauma.
基金Supported by the Clinical Research Fellowship Grant from the Wellcome Trust,United Kingdom,No.227516/Z/23/Z.
文摘BACKGROUND Hepatitis C virus(HCV)is a blood-borne virus which globally affects around 79 million people and is associated with high morbidity and mortality.Chronic infection leads to cirrhosis in a large proportion of patients and often causes hepatocellular carcinoma(HCC)in people with cirrhosis.Of the 6 HCV genotypes(G1-G6),genotype-3 accounts for 17.9%of infections.HCV genotype-3 responds least well to directly-acting antivirals and patients with genotype-3 infection are at increased risk of HCC even if they do not have cirrhosis.AIM To systematically review and critically appraise all risk factors for HCC secondary to HCV-G3 in all settings.Consequently,we studied possible risk factors for HCC due to HCV-G3 in the literature from 1946 to 2023.METHODS This systematic review aimed to synthesise existing and published studies of risk factors for HCC secondary to HCV genotype-3 and evaluate their strengths and limitations.We searched Web of Science,Medline,EMBASE,and CENTRAL for publications reporting risk factors for HCC due to HCV genotype-3 in all settings,1946-2023.RESULTS Four thousand one hundred and forty-four records were identified from the four databases with 260 records removed as duplicates.Three thousand eight hundred and eighty-four records were screened with 3514 excluded.Three hundred and seventy-one full-texts were assessed for eligibility with seven studies included for analysis.Of the seven studies,three studies were retrospective case-control trials,two retrospective cohort studies,one a prospective cohort study and one a cross-sectional study design.All were based in hospital settings with four in Pakistan,two in South Korea and one in the United States.The total number of participants were 9621 of which 167 developed HCC(1.7%).All seven studies found cirrhosis to be a risk factor for HCC secondary to HCV genotype-3 followed by higher age(five-studies),with two studies each showing male sex,high alpha feto-protein,directly-acting antivirals treatment and achievement of sustained virologic response as risk factors for developing HCC.CONCLUSION Although,studies have shown that HCV genotype-3 infection is an independent risk factor for end-stage liver disease,HCC,and liver-related death,there is a lack of evidence for specific risk factors for HCC secondary to HCV genotype-3.Only cirrhosis and age have demonstrated an association;however,the number of studies is very small,and more research is required to investigate risk factors for HCC secondary to HCV genotype-3.
文摘We comment on the article by Jia et al,in the World Journal of Gastrointestinal Surgery.We focus mainly on the factors that impair gastric motility and cause gastric retention in the pre-operative setting of endoscopic retrograde cholan-giopancreatography(ERCP).ERCP is a complex endoscopic therapeutic proce-dure,which demands great skill from the endoscopist but also has recognized complications.Gastric retention impairs the endoscopist’s visibility but also increases the risk of complications,such as aspiration pneumonia.Therefore,identifying the factors that predispose to gastric retention alerts the endoscopists of the possible risks and enables them to take evasive action.The authors in the current study by Jia et al developed and validated a predictive model,which in-corporates five different factors,i.e.,gender,primary disease,jaundice,opioid use,and gastrointestinal obstruction,which were found to influence gastric retention.This model was shown to have a high predictive value to accurately identify pa-tients at risk for gastric retention before a therapeutic ERCP.
基金supported by Scottish Rugby Union,Graham and Pam Dixon,Medical Research Scotland,University of Aberdeen HOTSTART Scholarship Programme(to WH)。
文摘Currently,there is no cure for traumatic spinal co rd injury but one therapeutic approach showing promise is gene therapy.In this systematic review and meta-analysis,we aim to assess the efficacy of gene therapies in pre-clinical models of spinal cord injury and the risk of bias.In this metaanalysis,registe red at PROSPERO(Registration ID:CRD42020185008),we identified relevant controlled in vivo studies published in English by searching the PubMed,Web of Science,and Embase databases.No restrictions of the year of publication were applied and the last literature search was conducted on August 3,2020.We then conducted a random-effects meta-analysis using the restricted maximum likelihood estimator.A total of 71 studies met our inclusion crite ria and were included in the systematic review.Our results showed that overall,gene therapies were associated with improvements in locomotor score(standardized mean difference[SMD]:2.07,95%confidence interval[CI]:1.68-2.47,Tau^(2)=2.13,I^(2)=83.6%)and axonal regrowth(SMD:2.78,95%CI:1.92-3.65,Tau^(2)=4.13,I^(2)=85.5%).There was significant asymmetry in the funnel plots of both outcome measures indicating the presence of publication bias.We used a modified CAMARADES(Collaborative Approach to M eta-Analysis and Review of Animal Data in Experimental Studies)checklist to assess the risk of bias,finding that the median score was 4(IQR:3-5).In particula r,reports of allocation concealment and sample size calculations were lacking.In conclusion,gene therapies are showing promise as therapies for spinal co rd injury repair,but there is no consensus on which gene or genes should be targeted.
基金supported by the Singapore National Research Foundation under its NMRC-CBRG grants(Project award number:NMRC/CBRG/0096/2015) and administered by the Singapore Ministry of Health’s National Medical Research Councilpartially supported by the MOE Academic Research Funding(AcRF) Tier 1 grant(RG148/14) and Tier 2 grant(MOE2015-T2-1-023)
文摘MiR-219 and miR-338(miR-219/miR-338)are oligodendrocyte-specific microRNAs.The overexpression of these miRs in oligodendrocyte precursor cells promotes their differentiation and maturation into oligodendrocytes,which may enhance axonal remyelination after nerve injuries in the central nervous system(CNS).As such,the delivery of miR-219/miR-338 to the CNS to promote oligodendrocyte precursor cell differentiation,maturation and myelination could be a promising approach for nerve repair.However,nerve injuries in the CNS also involve other cell types,such as microglia and astrocytes.Herein,we investigated the effects of miR-219/miR-338 treatment on microglia and astrocytes in vitro and in vivo.We found that miR-219/miR-338 diminished microglial expression of pro-inflammatory cytokines and suppressed astrocyte activation.In addition,we showed that miR-219/miR-338 enhanced oligodendrocyte precursor cell differentiation and maturation in a scratch assay paradigm that re-created a nerve injury condition in vitro.Collectively,our results suggest miR-219/miR-338 as a promising treatment for axonal remyelination in the CNS following nerve injuries.All experimental procedures were approved by the Institutional Animal Care and Use Committee(IACUC),Nanyang Technological University(approval No.A0309 and A0333)on April 27,2016 and October 8,2016.
文摘Pancreatic cancer is a highly aggressive tumour that is very resistant to treatments and it is rarely diagnosed early because of absence of specific symptoms. Therefore, the prognosis for this disease is very poor and it has the grim supremacy in terms of unfavourable survival rates. There have been great advances in survival rates for many types of cancers over the past few decades but hardly any change for pancreatic cancer. Mutations of the Ras oncogene are the most frequent oncogenic alterations in human cancers. The frequency of KRAS mutations in pancreatic cancer is around 90%. Given the well-established role of KRAS in cancer it is not surprising that it is one of the most attractive targets for cancer therapy. Nevertheless, during the last thirty years all attempts to target directly KRAS protein have failed. Therefore, it is crucial to identify downstream KRAS effectors in order to develop specific drugs able to counteract activation of this pathway. Among the different signalling pathways activated by oncogenic KRAS, the phosphoinositide 3-Kinase(PI3K) pathway is emerging as one of the most critical KRAS effector. In turn, PI3 K activates several parallel pathways making the identification of the precise effectors activated by KRAS/PI3 K more difficult. Recent data identify 3-phosphoinositide-dependent protein kinase 1 as a key tumour-initiating event downstream KRAS interaction with PI3 K in pancreatic cancer.
基金Supported by Bowel and Cancer Research charity,No.MMBG1J3R
文摘BACKGROUND Perianal fistulae are either primary(idiopathic)or secondary[commonly associated with Crohn’s disease,(CD)].It is assumed,although not proven,that the pathophysiology differs.AIM To systematically compare the clinical phenotypes,cytokine and phosphoprotein profiles of idiopathic and CD-related perianal fistulae.METHODS Sixty-one patients undergoing surgery for perianal fistula were prospectively recruited(48 idiopathic,13 CD)into a cohort study.Clinical data,including the Perineal Disease Activity Index(PDAI)and EQ-5D-5L were collected.Biopsies of the fistula tract,granulation tissue,internal opening mucosa and rectal mucosa were obtained at surgery.Concentrations of 30 cytokines and 39 phosphoproteins were measured in each biopsy using a magnetic bead multiplexing instrument and a chemiluminescent antibody array respectively.Over 12000 clinical and 23500 laboratory measurements were made.RESULTS The PDAI was significantly higher(indicating more active disease)in the CD group with a mean difference of 2.40(95%CI:0.52-4.28,P=0.01).Complex pathoanatomy was more prevalent in the CD group,namely more multiple fistulae,supralevator extensions,collections and rectal thickening.The IL-12p70 concentration at the internal opening specimen site was significantly higher(median difference 19.7 pg/mL,99%CI:0.2-40.4,P=0.008)and the IL-1RA/IL-1βratio was significantly lower in the CD group at the internal opening specimen site(median difference 15.0,99%CI=0.4-50.5,P=0.008).However in the remaining 27 cytokines and all 39 of the phosphoproteins across the four biopsy sites,no significant differences were found between the groups.CONCLUSION CD-related perianal fistulae are more clinically severe and anatomically complex than idiopathic perianal fistulae.However,overall there are no major differences in cytokine and phosphoprotein profiles.
文摘The global prevalence of diabetes mellitus is increasing; arguably as a consequence of changes in diet, lifestyle and the trend towards urbanization. Unsurprisingly, the incidence of both micro and macrovascular complications of diabetes mirrors this increasing prevalence. Amongst the complications with the highest symptom burden, yet frequently under-diagnosed and sub-optimally treated, is diabetic autonomic neuropathy, itself potentially resulting in cardiovascular autonomic neuropathy and gastrointestinal(GI) tract dysmotility. The aims of this review are fourfold. Firstly to provide an overview of the pathophysiological processes that cause diabetic autonomic neuropathy. Secondly, to discuss both the established and emerging cardiometric methods for evaluating autonomic nervous system function in vivo. Thirdly, to examine the tools for assessing pan-GI and segmental motility and finally, we will provide the reader with a summary of putative non-invasive biomarkers that provide a pathophysiological link between lowgrade neuro inflammation and diabetes, which may allow earlier diagnosis and intervention, which in future may improve patient outcomes.
文摘Diabetes mellitus is a common disease and its prevalence is increasing worldwide. In various studies up to 30%-70% of patients present dysfunction and complications related to the gut. To date several clinical studies have demonstrated that autonomic nervous system neuropathy and generalized neuropathy of the central nervous system(CNS) may play a major role. This systematic review provides an overview of the neurodegenerative changes that occur as a consequence of diabetes with a focus on the CNS changes and gastrointestinal(GI) dysfunction. Animal models where diabetes was induced experimentally support that the disease induces changes in CNS. Recent investigations with electroencephalography and functional brain imaging in patients with diabetes confirm these structural and functional brain changes. Encephalographic studies demonstrated that altered insular processing of sensory stimuli seems to be a key player in symptom generation. In fact one study indicated that the more GI symptoms the patients experienced, the deeper the insular electrical source was located. The electroencephalography was often used in combination with quantitative sensory testingmainly showing hyposensitivity to stimulation of GI organs. Imaging studies on patients with diabetes and GI symptoms mainly showed microstructural changes,especially in brain areas involved in visceral sensory processing. As the electrophysiological and imaging changes were associated with GI and autonomic symptoms they may represent a future therapeutic target for treating diabetics either pharmacologically or with neuromodulation.
基金Supported by NIH grant,No.R24TW007988the American Relief and Recovery Actthe Siteman Comprehensive Cancer Center NCI Cancer Center Support Grant,P30 CA091842
文摘AIM: To identify risk factors associated with esophageal cancer in Zambia and association between dietary intake and urinary 8-iso prostaglandin F2α(8-iso PGF2α).METHODS: We conducted a prospective, case control study at the University Teaching Hospital. Subjects included both individuals admitted to the hospital and those presenting for an outpatient upper endoscopy. Esophageal cancer cases were compared to age and sex-matched controls. Cases were defined as patients with biopsy proven esophageal cancer; controls were defined as subjects without endoscopic evidence ofesophageal cancer. Clinical and dietary data were collected using a standard questionnaire, developed a priori. Blood was collected for human immunodeficiency virus(HIV) serology. Urine was collected, and 8-iso PGF2α was measured primarily by enzyme-linked immunosorbent assay and expressed as a ratio to creatinine.RESULTS: Forty five controls(mean age 54.2 ± 15.3, 31 male) and 27 cases(mean age 54.6 ± 16.4, 17 males) were studied. Body mass index was lower in cases(median 16.8) than controls(median 23.2), P = 0.01. Histopathologically, 25/27(93%) were squamous cell carcinoma and 2/27(7%) adenocarcinoma. More cases smoked cigarettes(OR = 11.24, 95%CI: 1.37-92.4, P = 0.02) but alcohol consumption and HIV seropositivity did not differ significantly(P = 0.14 for both). Fruit, vegetables and fish consumption did not differ significantly between groups(P = 0.11, 0.12, and 0.10, respectively). Mean isoprostane level was significantly higher in cases(0.03 ng/mg creatinine) than controls(0.01 ng/mg creatinine)(OR = 2.35, 95%CI: 1.19-4.65, P = 0.014).CONCLUSION: Smoking and isoprostane levels were significantly associated with esophageal cancer in Zambians, but diet, HIV status, and alcohol consumption were not.
文摘Colony stimulating factor 1 receptor(CSF1R) is a tyrosine kinase receptor primarily expressed on microglia and a small subpopulation of neurons in the central nervous system (CNS),which directly controls the homeostasis,activation,and proliferation of microglia.Its ligands include CSF1 and interleukin-34 (IL-34).
基金Supported by A Grant from the SmartPill Corporation
文摘AIM: To ascertain whether caecal pH is different in patients with irritable bowel syndrome (IBS), whose primary symptoms are bloating and distension, to healthy controls.
基金Supported by School of Medicine at University of Alabama at BirminghamFogarty International Center,No.K01TW009998+1 种基金National Institute of Allergy and Infectious Diseases,U.S.National Institutes of Health,No.U01AI069924Swiss National Science Foundation(to Wandeler G),No.PZ0093_154730
文摘AIM To characterize antiviral therapy eligibility among hepatitis B virus(HBV)-infected adults at a university hospital in Zambia.METHODS Hepatitis B surface antigen-positive adults(n = 160) who were h IV-negative and referred to the hospital after a routine or clinically-driven HBV test were enrolled. Alanine Aminotransferase(ALT),Aspartate Aminotransferase(AST),platelet count,hepatitis B e-antigen,and HBV DNA were measured. Liver fibrosis/cirrhosis was assessed by physical examination,AST-to-platelet ratio index,and transient elastography. In antiviral therapy-na?ve individuals,we described hBV stages and antiviral therapy eligibility per World health Organization(WhO) and by hBV test(routine vs clinical). Elevated ALT was > 19 in women and > 30 U/L in men. Among treatmentexperienced individuals,we described medication side effects,adherence,and viral suppression.RESULTS The median age was 33 years,71.9% were men,and 30.9% were diagnosed with HBV through a clinicallydriven test with the remainder identified via routine testing(at the blood bank,community events,etc.). Among 120 treatment-na?ve individuals,2.5% were categorized as immune tolerant,11.7% were immune active,35.6% were inactive carriers,and 46.7% had an indeterminate phenotype. Per WhO guidelines,13(10.8%) were eligible for immediate antiviral therapy. The odds of eligibility were eight times higher for those diagnosed at clinical vs routine settings(adjusted odds ratio,8.33; 95%CI: 2.26-29.41). Among 40 treatmentexperienced hBV patients,virtually all took tenofovir,and a history of mild side effects was reported in 20%. Though reported adherence was good,12 of 29(41.4%) had HBV DNA > 20 IU/m L. CONCLUSION Approximately one in ten HBV-monoinfected Zambians were eligible for antivirals. Many had indeterminate phenotype and needed clinical follow-up.
文摘High density lipoproteins (HDL) promote the efflux of excess cholesterol from peripheral tissues to the liver for excretion. This ability is responsible for the most relevant anti-atherogenic effect of HDL. The ability of HDL to promote cholesterol efflux results also in the modulation of a series of responses in the immune cells involved in atherosclerosis,includingmonocyte-macrophages, B and T lymphocytes.Furthermore, during inflammation, the composition of this class of lipoproteins varies to a large extent, thus promoting the formation of dysfunctional HDL. The aim of this review is to discuss the emerging role of HDL in modulating the activity of immune cells and immune-inflammatory mediators during atherogenesis.
文摘Neurons in the central nervous system （CNS） of adult mammals have a weak intrinsic regenerative capacity, which is one contributing factor to the failure of axonal regeneration. Finding the means to elevate the regenerative capacity of axotomised neurons is one requirement for successful regeneration. Forty-five years ago, it was reported that crushing of the sciatic nerves of adult mice two weeks before cutting the nerves accelerated the regrowth of their axons （McQuarrie and Grafstein, 1973）. The nerve injury two weeks before triggered the regeneration machinery in the injured neurons, leading to faster axonal regrowth after a subsequent lesion. Later it was found that a lesion to a peripheral nerve also strongly enhanced the regeneration of the central branches of the appropriate primary sensory neurons （Richardson and Issa, 1984）. This phenomenon is termed preconditioning lesion （or conditioning lesion if the central branches of the sensory neurons are injured after a concomitant in- jury to their peripheral branches）.
文摘Both dyskeratosis congenita (DC) and Hoyeraal-Hreidarsson Syndrome (HHS) are rare inherited bone marrow failure conditions. HHS is considered to be a variant of DC in which neurological deficits and immunodeficiencies are also present. We describe a very interesting familial cluster where an invariant point mutation of DKC1 located in the exon 11 is observed in the carrier mother and in two decedent males. The older child developed the classical phenotype of HHS at a very early age. The second affected child remains poorly symptomatic, with only mild haematological changes. Telomere shortening, with different severity, is also present in both cases. This paper discusses the clinical spectrum of inherited BM failure syndromes from the perspective different clinical presentation within a family with a DKC1 mutation.
文摘Disease modifying therapies aiming to preserveβ-cell function in patients with adult-onset autoimmune type 1 diabetes are lacking.Here,we conducted a multi-centre,randomized,controlled trial to assess theβ-cell preservation effects of saxagliptin alone and saxagliptin combined with vitamin D as adjunctive therapies in adult-onset autoimmune type 1 diabetes.In this 3-arm trial,301 participants were randomly assigned to a 24-month course of the conventional therapy(metformin with or without insulin)or adjunctive saxagliptin or adjunctive saxagliptin plus vitamin D to the conventional therapy.The primary endpoint was the change from baseline to 24 months in the fasting C-peptide.The secondary endpoints included the area under the concentration-time curve(AUC)for C-peptide level in a 2-h mixed-meal tolerance test,glycemic control,total daily insulin use and safety,respectively.The primary endpoint was not achieved in saxagliptin plus vitamin D group(P=0.18)and saxagliptin group(P=0.26).However,compared with the conventional therapy,2-h C-peptide AUC from 24 months to baseline decreased less with saxagliptin plus vitamin D(-276 pmol/L vs.-419 pmol/L;P=0.01),and not to the same degree with saxagliptin alone(-314 pmol/L;P=0.14).Notably,for participants with higher glutamic acid decarboxylase antibody(GADA)levels,the decline ofβ-cell function was much lower in saxagliptin plus vitamin D group than in the conventional therapy group(P=0.001).Insulin dose was significantly reduced in both active treatment groups than in the conventional therapy group despite all groups having similar glycemic control.In conclusion,the combination of saxagliptin and vitamin D preserves pancreaticβ-cell function in adult-onset autoimmune type 1 diabetes,an effect especially efficacious in individuals with higher GADA levels.Our results provide evidence for a novel adjunct to insulin and metformin as potential initial treatment for adult-onset type 1 diabetes.(ClinicalTrials.gov identifier:NCT02407899).
文摘Chronic hepatitis B virus （HBV） infection progresses through distinct disease phases that are strongly associated with patient age. The so-called immune tolerant （IT） phase represents the classical early phase of infection; it is associated with high levels of HBV replication and lack of clinical signs of liver Inflammation. Whether this phase of HBV infection is also associated with immunological features of ＂tolerance＇ has recently been challenged. Here, we review the data that dispute this concept of immune tolerance and then propose an alternative interpretation of the immunopathological events that take place during this early phase of CHB infection.
文摘In multiple sclerosis(MS),human endogenous retrovirus W family(HERV-W)envelope protein,pHERV-W ENV,limits remyelination and induces microglia-mediated neurodegeneration.To better understand its role,we examined the soluble pHERV-W antigen from MS brain lesions detected by specific antibodies.Physico-chemical and antigenic characteristics confirmed differences between pHERV-W ENV and syncytin-1.pHERV-W ENV monomers and trimers remained associated with membranes,while hexamers self-assembled from monomers into a soluble macrostructure involving sulfatides in MS brain.Extracellular hexamers are stabilized by internal hydrophobic bonds and external hydrophilic moieties.HERV-W studies in MS also suggest that this diffusible antigen may correspond to a previously described highmolecular-weight neurotoxic factor secreted by MS B-cells and thus represents a major agonist in MS pathogenesis.Adapted methods are now needed to identify encoding HERV provirus(es)in affected cells DNA.The properties and origin of MS brain pHERV-W ENV soluble antigen will allow a better understanding of the role of HERVs in MS pathogenesis.The present results anyhow pave the way to an accurate detection of the different forms of pHERV-W ENV antigen with appropriate conditions that remained unseen until now.
基金support of the ERC Starting Grant(STROFUNSCAFF)the UK Regenerative Medicine Platform(UKRMP2)Acellular/Smart Materials.C.D.acknowledges the support of University of Palermo FFR 2018/2021.
文摘Hydrogel wound dressings can play critical roles in wound healing protecting the wound from trauma or contamination and providing an ideal environment to support the growth of endogenous cells and promote wound closure.This work presents a self-assembling hydrogel dressing that can assist the wound repair process mimicking the hierarchical structure of skin extracellular matrix.To this aim,the co-assembly behaviour of a carboxylated variant of xyloglucan(CXG)with a peptide amphiphile(PA-H3)has been investigated to generate hierarchical constructs with tuneable molecular composition,structure,and properties.Transmission electron microscopy and circular dichroism at a low concentration shows that CXG and PA-H3 co-assemble into nanofibres by hydrophobic and electrostatic interactions and further aggregate into nanofibre bundles and networks.At a higher concentration,CXG and PA-H3 yield hydrogels that have been characterized for their morphology by scanning electron microscopy and for the mechanical properties by smallamplitude oscillatory shear rheological measurements and compression tests at different CXG/PAH3 ratios.A preliminary biological evaluation has been carried out both in vitro with HaCat cells and in vivo in a mouse model.
