Liquid chromatography tandem mass spectrometry(LC-MS/MS) plays an important role in clinical diagnostics. Although LC-MS/MS is superior in terms of accurately quantifying molecules in complex matrices,instrument footp...Liquid chromatography tandem mass spectrometry(LC-MS/MS) plays an important role in clinical diagnostics. Although LC-MS/MS is superior in terms of accurately quantifying molecules in complex matrices,instrument footprint, operation and maintenance complexity also hinder its expansion as the analytical technique of choice. In this study, a compact LC-MS instrument was developed, in which an assembled liquid chromatograph was coupled with a miniature ion trap mass spectrometer. The overall instrument has a footprint of 69 cm × 31 cm × 31 cm, and it requires no gas supply as well as minimum maintenance. Furthermore, the use of LC-MS is in accord with conventional clinical diagnostic protocols, and the choice of ion trap offers tandem MS performance. The results showed that the use of LC could improve both mixture analysis capability and detection sensitivity of the miniature mass spectrometer. After optimization, feasibility of this instrument in clinical practice was demonstrated by the quantitation of four widely used immunosuppressants in blood samples. Relatively good linearities were obtained, which spanned the reference ranges of effective therapeutic concentrations of each immunosuppressant. Intraday and inter-day accuracy and precision of analytical method were also assessed. This work showed that a compact LC-MS instrument could be used in clinical diagnosis, either to replace conventional lab-scale instruments or to be used in POCT applications.展开更多
AIM: To assess the effectiveness of immunosuppressants in the prophylaxis of corneal allograft rejection after high-risk keratoplasty and normal-risk keratoplasty. METHODS: We searched the Cochrane Central Register of...AIM: To assess the effectiveness of immunosuppressants in the prophylaxis of corneal allograft rejection after high-risk keratoplasty and normal-risk keratoplasty. METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CNKI, VIP and reference lists of articles. Date of most recent search: 18 June, 2011. All randomised controlled trials (RCTs) assessing the use of immunosupressants in the prevention of graft rejection, irrespective of publication language. Two authors assessed trial quality and extracted data independently. Only dichotomous outcomes (clear graft survival, ratio of immune reactions and side effects) were available and were expressed as relative risk (RR) and 95% confidence intervals (CI). RESULTS: Seven studies were included in this review. In the comparing of mycophenolate mofetil (MMF) with placebo, the results showed MMF could significantly reduce immune reactions compared with placebo (RR 1.08 95% Cl 0.95 to 1.21), but no effect on clear graft survival (RR 1.11 95% Cl 0.90 to 1.35). In clear graft survival and immune reactions, MMF and cyclosporine A (CsA) showed similar effect (RR 1.11 95% Cl 0.90 to 1.35, and RR 1.48, 95% Cl 0.56 to 3.93, respectively). Tacrolimus (FK506) and steroid showed similar effects on clear graft survival and immune reactions (RR 0.32, 95% CI 0.02 to 6.21, and RR 1.00, 95%CI 0.88 to 1.14, respectively). No drug relative side effect has been found. CONCLUSION: MMF may reduce immune reactions in both normal-risk and high-risk rejection of penetrating keratoplasty. CsA and FK506 showed similar effects as MMF. However, due to the lack of large clinical trials, the evidence remain weak, the quality of evidences were rated as very low to moderate. Large, properly randomised, placebo-controlled, double masked trials are needed to evaluate the effect of immunosuppressants.展开更多
Prostate cancer is a malignant tumor with a high incidence in elderly men.In recent years,with the improvement of people’s living standards and the advancement of detection technology,the incidence of prostate cancer...Prostate cancer is a malignant tumor with a high incidence in elderly men.In recent years,with the improvement of people’s living standards and the advancement of detection technology,the incidence of prostate cancer has been increasing year by year.Castration-resistant prostate cancer(CRPC)is a highly challenging type of advanced prostate cancer treatment,which clinically shows resistance to hormonal deprivation therapy.The overall treatment efficacy of CRPC is currently poor and further relevant therapeutic studies are needed to improve patient survival and quality of life.Immunosuppressants can play a role in combating the immune system of tumors,and abiraterone has also achieved remarkable results in prostate cancer treatment.This study will investigate the possible clinical effects and safety of immunosuppressants combined with abiraterone in the treatment of metastatic CRPC.The population-based study will provide clinicians with more effective treatment options,as well as enhance the understanding of novel combination therapy strategies to be implemented in the future for such patients.展开更多
IgA nephropathy is the most common primary glomerular disease in China and even in the world, and it is also the most common cause of end-stage renal disease. The pathogenesis of IgA nephropathy is not clear. At prese...IgA nephropathy is the most common primary glomerular disease in China and even in the world, and it is also the most common cause of end-stage renal disease. The pathogenesis of IgA nephropathy is not clear. At present, it is mainly considered that abnormal IgA immune complex deposition in glomerular mesangial area leads to a series of clinical manifestations. Therefore, at present, in addition to supporting treatment, the treatment of IgA nephropathy mainly focuses on glucocorticoids and various immunosuppressants, but the efficacy and safety of the above immunosuppressants on IgA nephropathy are still controversial. This paper reviews the current use of immunosuppressants in the treatment of IgA nephropathy.展开更多
Hepatitis C(HCV)-infected patients have a poorer survival post-liver transplantation compared to patients transplanted for other indications,since HCV recurrence post-transplant is universal and commonly follows an ag...Hepatitis C(HCV)-infected patients have a poorer survival post-liver transplantation compared to patients transplanted for other indications,since HCV recurrence post-transplant is universal and commonly follows an aggressive course.There is increasing evidence that in the non-transplant setting,induction of hepatocyte apoptosis is one of the main mechanisms by which HCV drives liver inflammation and fibrosis,and that HCV proteins directly promote apoptosis.Recent studies have shown that post-liver transplant,there is a link between high levels of HCV replication,enhanced hepatocyte apoptosis and the subsequent development of rapidly progressive liver fibrosis.Although the responsible mechanisms remain unclear,it is likely that immunosuppressive drugs play an important role.It is well known that immunosuppressants impair immune control of HCV,thereby allowing increased viral replication.However there is also evidence that immunosuppressants may directly induce apoptosis and this may be facilitated by the presence of high levels of HCV replication.Thus HCV and immunosuppressants may synergistically interact to further enhance apoptosis and drive more rapid fibrosis.These findings suggest that modulation of apoptosis within the liver either by changing immunosuppressive therapy or the use of apoptosis inhibitors may help prevent fibrosis progression in patients with post-transplant HCV disease.展开更多
Hepatitis B viral(HBV)reactivation in the immunosuppressed is a significant problem even in patients who have achieved serological clearance due to the persistence of HBV as cccDNA.HBV reactivation will continue to po...Hepatitis B viral(HBV)reactivation in the immunosuppressed is a significant problem even in patients who have achieved serological clearance due to the persistence of HBV as cccDNA.HBV reactivation will continue to pose a significant healthcare burden given the high prevalence of HBV and increasing use of immunosuppressants.Screening of hepatitis B surface antigen,antibody to Hepatitis B core antigen antibody and HBV DNA levels should be done routinely in all patients planned for significant immunosuppressant use.We aimed to examine the factors affecting reactivation risk.This depended on HBV disease status,the underlying disease requiring immunosuppression,and the specific immunosuppressive regime.While antiviral prophylaxis can prevent reactivation,it increases cost and still has risk of delayed reactivation after stopping antivirals and close follow-up and on-demand treatment is a good alternative for patients at risk of reactivation.展开更多
AIM To investigate the specific effects of immunosuppressants on the antiviral action of daclatasvir and asunaprevir.METHODS The antiviral activity of daclatasvir(DCV) and asunaprevir(ASV) combined with immunosuppress...AIM To investigate the specific effects of immunosuppressants on the antiviral action of daclatasvir and asunaprevir.METHODS The antiviral activity of daclatasvir(DCV) and asunaprevir(ASV) combined with immunosuppressants was tested using two in vitro models for hepatitis C virus(HCV) infection.RESULTS Tacrolimus, rapamycin and cyclosporine did not negatively affect the antiviral action of DCV or ASV. Mycophenolic acid(MPA) showed additive antiviral effects combined with these direct acting antivirals(DAAs). MPA induces interferon-stimulated genes(ISGs) and is a potent GTP synthesis inhibitor. DCV or ASV did not induce ISGs expression nor affected ISG induction by MPA. Rather, the combined antiviral effect of MPA with DCV and ASV was partly mediated via inhibition of GTP synthesis.CONCLUSION Immunosuppressants do not negatively affect the antiviral activity of DAAs. MPA has additive effect on the antiviral action of DCV and ASV. This combined benefit needs to be confirmed in prospective clinical trials.展开更多
BACKGROUND Chylous ascites is caused by disruption of the lymphatic system,which is characterized by the accumulation of a turbid fluid containing high levels of triglycerides within the abdominal cavity.The two most ...BACKGROUND Chylous ascites is caused by disruption of the lymphatic system,which is characterized by the accumulation of a turbid fluid containing high levels of triglycerides within the abdominal cavity.The two most common causes are cirrhosis and tuberculosis,and colon signer ring cell carcinoma(SRCC)due to the use of immunosuppressants is extremely rare in cirrhotic patients after liver transplantation,making it prone to misdiagnosis and missed diagnosis.CASE SUMMARY A 52-year-old man who underwent liver transplantation and was administered with immunosuppressants for 8 months was admitted with a 3-month history of progressive abdominal distention.Initially,based on lymphoscintigraphy and lymphangiography,lymphatic obstruction was considered,and cystellar chyli decompression with band lysis and external membrane stripping of the lymphatic duct was performed.However,his abdominal distention was persistent without resolution.Abdominal paracentesis revealed allogenic cells in the ascites,and immunohistochemistry analysis revealed adenocarcinoma cells with phenotypic features suggestive of a gastrointestinal origin.Gastrointestinal endoscopy was performed,and biopsy showed atypical signet ring cells in the ileocecal valve.The patient eventually died after a three-month follow-up due to progression of the tumor.CONCLUSION Colon SRCC,caused by immunosuppressants,is an unusual but un-neglected cause of chylous ascites.展开更多
In the pre-biologic era,immunomodulators such as azathioprine,6-mercaptopurine,and methotrexate(MTX)were widely used as first-line maintenance therapies in Crohn’s disease.However,in the current era shaped by biologi...In the pre-biologic era,immunomodulators such as azathioprine,6-mercaptopurine,and methotrexate(MTX)were widely used as first-line maintenance therapies in Crohn’s disease.However,in the current era shaped by biologics,their role has shifted toward adjunctive use,primarily in combination with anti-tumor necrosis factor agents to reduce immunogenicity.Amid growing concerns about thiopurine-associated risks,MTX is receiving renewed attention for its favorable safety profile;however,this agent remains inconsistently utilized in gastroenterology despite its frontline status in rheumatology.This discrepancy was highlighted in a recent nationwide survey by Bonnaud et al published in the World Journal of Gastroenterology,which offers timely insights into MTX prescribing behaviors among French gastroenterologists.Although 71%of respondents reported using MTX,primarily via subcutaneous injection,it is still perceived as a secondary choice after thiopurines.Importantly,this underuse appears to be driven more by clinical inertia and limited guidance rather than by lack of efficacy or safety concerns.Clinicians increasingly recognize the value of MTX,particularly in patients with joint involvement,Epstein-Barr virus negativity,or increased malignancy risk.Notably,even non-prescribers viewed the drug favorably,suggesting that usage barriers may be modifiable.In light of evolving treatment goals that prioritize safety,cost-effectiveness,and individualized care,this editorial argues that MTX should no longer be viewed as a fallback but as a strategic first-line option in well-defined high-risk populations.The survey underscores a persistent gap between guidelines and real-world practice,reinforcing the urgent need for clearer algorithms and education to support the repositioning of MTX in modern Crohn’s disease management.展开更多
Objective:To evaluate the response rate to vaccination in different treatment groups (nonimmunosuppressants and immunosuppressants).Data Sources:We completed an online systematic search using PubMed to identify all ar...Objective:To evaluate the response rate to vaccination in different treatment groups (nonimmunosuppressants and immunosuppressants).Data Sources:We completed an online systematic search using PubMed to identify all articles published in English between January 1990 and December 2013 assessing the effect of the response rate to vaccination in different treatment groups (with and without immunomodulators).The following terms were used:"inflammatory bowel disease (IBD)" OR "Cmhn's disease" OR "ulcerative colitis"AND ("vaccination" OR "vaccine") AND ("corticosteroids" OR "mercaptopurine" OR "azathioprine" OR "methotrexate [MTX]") AND "immunomodulators."Study Selection:The inclusion criteria of articles were that the studies:(1) Randomized controlled trials which included patients with a diagnosis of IBD (established by standard clinical,radiographic,endoscopic,and histologic criteria); (2) exposed patients received immunomodulators for maintenance (weight-appropriate doses of 6-mercaptopurine/azathioprine or within 3 months of stopping,15 mg or more MTX per week or within 3 months of stopping; (3) exposed patients received nonimmunomodulators (no therapy,antibiotics only,mesalazine only,biological agent only such as infliximab,adalimumab,certolizumab or natalizumab or within 3 months of stopping one of these agents).The exclusion criteria of articles were that the studies:(1) History of hepatitis B virus (HBV),influenza or streptococcus pneumoniae infection; (2) patients who had previously been vaccinated against HBV,influenza or streptococcus pneumoniae; (3) any medical condition known to cause immunosuppression (e.g.chronic renal failure and human immunodeficiency virus infection); (4) individuals with positive hepatitis markers or liver cirrhosis; (5) patients with a known allergy to eggs or other components of the vaccines and (6) pregnancy.Results:Patients treated with immunomodulators were associated with lower response rates to vaccination.Conclusions:Immunomodulators may impair the immune response to vaccination in patients with IBD.Vaccination should be made at the time of diagnosis or before starting immunosuppressed therapy.展开更多
Liver transplantation is a life-saving procedure for patients with end-stage liver diseases and acute liver failure.With advances in surgical techniques and immunosuppressive regimens,patient survival rates have signi...Liver transplantation is a life-saving procedure for patients with end-stage liver diseases and acute liver failure.With advances in surgical techniques and immunosuppressive regimens,patient survival rates have significantly improved.While the systemic complications of post-transplantation are well recognized,ophthalmic manifestations remain underreported.Ophthalmic complications can significantly impair visual function and increase morbidity in these patients.Prolonged immunosuppression makes the patients susceptible to the opportunistic pathogens such as Cytomegalovirus,Candida,Aspergillus,etc.Other common findings include dry eye disease,cataracts and retinal vascular complications which further contribute to the long-term morbidity in these patients.Early ophthalmic evaluation and prompt management are essential to prevent irreversible vision loss and improve post-transplant outcomes.High index of suspicion and multidisciplinary approach is essential to facilitate early diagnosis and treatment.This review highlights the range of ophthalmic complications observed in liver transplant recipients and underscores the need for future research focused on understanding the underlying pathophysiological mechanisms and refining the prophylactic protocols to improve outcomes in this unique patient population.展开更多
BACKGROUND The use of induction immunosuppression agents has improved kidney transplant outcomes,but selecting the optimal agent remains a point of debate.AIM To compare the long-term outcomes of kidney transplant rec...BACKGROUND The use of induction immunosuppression agents has improved kidney transplant outcomes,but selecting the optimal agent remains a point of debate.AIM To compare the long-term outcomes of kidney transplant recipients receiving alemtuzumab vs basiliximab induction,focusing on graft function,acute rejection,infection,malignancy,post-transplant glomerulonephritis,and survival,using a propensity score matched cohort design.METHODS Kidney transplant recipients who received alemtuzumab or basiliximab induction from 2014 to 2019 across two nephrology centres in Northwest England were evaluated.Propensity score matching at a 1:1.5 ratio ensured comparability between cohorts.Baseline characteristics,immunosuppression regimens,and outcomes were analyzed.Linear,binary logistic and Cox proportional hazard regression models.RESULTS A total of 436 recipients were included,with a median follow-up of 5.2 years.The matched cohort(n=262)had a mean age of 51.1±13.5 years;39%were female and 92%were white.There was no significant difference in the cumulative incidence of acute rejection[odds ratio(OR)=2.10;95%CI:0.9-4.9;P=0.110].Compared with basiliximab,alemtuzumab was associated with lower estimated glomerular filtration rate at 12 months(-6.6 mL/minute/1.73 m2;95%CI:-10.5 to-2.7;P<0.001)and higher risks of cytomegalovirus viremia(OR=3.2;95%CI:1.6-6.5;P<0.001),BK viremia(OR=2.4;95%CI:1.1-5.5;P=0.02),post-transplant malignancy(OR=6.2;95%CI:1.6-29.9;P=0.013),and death-censored graft loss(hazard ratio=3.6;95%CI:1.2-11.4;P=0.03).No significant differences were observed in post-transplant glomerulonephritis or recipient mortality.CONCLUSION In this propensity score-matched analysis,alemtuzumab induction was associated with lower graft function at 12 months and higher risks of viral infection,post-transplant malignancy,and graft loss compared with basiliximab.These findings highlight the need for further studies to confirm the long-term safety and effectiveness of alemtuzumab in kidney transplantation.展开更多
Background:Immunosuppression compromises the host’s ability to combat pathogens,thereby increasing susceptibility to multisystem disorders.However,safe and effective curative treatments for this condition are current...Background:Immunosuppression compromises the host’s ability to combat pathogens,thereby increasing susceptibility to multisystem disorders.However,safe and effective curative treatments for this condition are currently lacking.Modulating the gut microbiota and their metabolites represents a promising therapeutic strategy.Notably,the Chinese herbal compound Yunzhi Guben Gao(YZG)has demonstrated multi-target immunomodulatory potential.Methods:A mouse model of dexamethasone-induced immunosuppression was employed to evaluate the effects of YZG.Immune organ indices(thymus,spleen),serum cytokine levels(IL-2,TNF-α),mucosal immunity markers(pulmonary/colonic SIgA),gut microbiota structure,and short-chain fatty acids(SCFAs)abundance were evaluated.Key microbial genera and metabolites were identified via Spearman correlation analysis.Pseudo-germ-free model mice established via quadruple antibiotic treatment combined with isovaleric acid intervention were employed to evaluate whether YZG efficacy depends on the intestinal microbiota and its metabolites,and whether its intrinsic mechanisms involve the promotion of isovaleric acid production.Results:YZG intervention ameliorated systemic and mucosal immune function in immunosuppressed mice.Mechanistically,YZG remodeled gut microbiota structure and significantly increased SCFAs levels.Notably,the abundance of the genus Ligilactobacillus exhibited the strongest positive correlation with isovaleric acid levels.Ligilactobacillus abundance was also positively correlated with immune-enhancing parameters and negatively correlated with the proinflammatory cytokine TNF-α,suggesting that Ligilactobacillus plays a pivotal role in the YZG regulatory network.Experiments using pseudo-germ-free mice and isovaleric acid intervention further demonstrated that the immunoprotective effects of YZG are closely related to intestinal microbiota remodeling and increased isovaleric acid production.Conclusion:YZG alleviates immunosuppression through multiple mechanisms,primarily involving the enrichment of the probiotic genus Ligilactobacillus and the consequent increase in isovaleric acid production.This process coordinately modulates mucosal immunity,cytokine networks,and immune organ function.The elucidation of this“microbiota-metabolite-immunity”axis provides both a pharmacological basis for the clinical application of YZG and novel immune-restorative strategies targeting gut microecological regulation.展开更多
In situ tumor vaccines,which leverage the antigenic profile of individual tumors,have demonstrated significant potential in tumor immunotherapy.However,their efficacy is often limited by the immunosuppressive tumor mi...In situ tumor vaccines,which leverage the antigenic profile of individual tumors,have demonstrated significant potential in tumor immunotherapy.However,their efficacy is often limited by the immunosuppressive tumor microenvironment(TME)and insufficient tumor targeting.To address these challenges,we engineered in situ nanovaccines through the self-assembly of the photosensitizer indocyanine green,immune adjuvant aluminum(Al^(3+)),and hydrophilic drug zoledronic acid(ZOL).Intravenous injection of these nanovaccines led to efficient tumor accumulation,enhancing drug bioavailability and enabling the release of tumor-associated antigens via photothermal therapy.Additionally,the built-in ZOL induces polarization of tumor-associated macrophages,reversing the immunosuppressive TME.The potent antitumor immune response triggered by these nanovaccines effectively suppresses tumor growth.This study,which integrates a straightforward assembly method,substantial drug loading capacity,and promising therapeutic outcomes,introduces a novel and effective paradigm for carrier-free in situ nanovaccines in cancer treatment.展开更多
Dear Editor,Lymphocyte activation gene 3(LAG3),the third established target for immune checkpoint blockade therapy,suppresses T cell function by binding to major histocompatibility complex classⅡ(MHCⅡ).Despite its s...Dear Editor,Lymphocyte activation gene 3(LAG3),the third established target for immune checkpoint blockade therapy,suppresses T cell function by binding to major histocompatibility complex classⅡ(MHCⅡ).Despite its significant therapeutic potential in cancer immunotherapy and the substantial attention it has received from academia and industry,the molecular mechanisms of LAG3-mediated immunosuppression remain poorly understood,primarily because of its unique ligand-binding characteristics and intracellular domains[1].展开更多
A clear goal in cold tumor research is to identify strategies for converting them into immunologically‘hot’tumors with enhanced immune cell infiltration and activity,thereby improving their responsiveness to immunot...A clear goal in cold tumor research is to identify strategies for converting them into immunologically‘hot’tumors with enhanced immune cell infiltration and activity,thereby improving their responsiveness to immunotherapy.The genesis of cold tumors is exceedingly intricate.In recent times,as the analysis of this phenomenon has been pursued with greater depth,a suite of advanced diagnostic and therapeutic technologies has surfaced.These novel approaches and tactics are anticipated to modulate the tumor immune microenvironment across various dimensions,thereby facilitating the advancement of personalized and precise treatment modalities for cold tumors.The present article addresses the challenge of diminished therapeutic responsiveness to“cold tumors”within clinical settings.It systematically elucidates the multi-faceted regulatory mechanisms underlying immune evasion in cold tumors and offers a detailed analysis of advanced therapeutic strategies that incorporate nanotechnology,gene editing,and artificial intelligence methodologies.Furthermore,the future development trends of immunotherapy were explored in greater depth.It was posited that the convergence of artificial intelligence,multidimensional genomics,and emerging biotechnologies has presented positive prospects for the treatment of cold tumors,and has offered a theoretical foundation and technical framework for the transformation of cold tumors into“hot tumors”.展开更多
Importance:It remained unclear that the efficacy comparison between low-dose immune tolerance induction(LD-ITI)incorporating immunosuppressants(IS)when severe hemophilia A(SHA)patients had inhibitor-titer≥200 Bethesd...Importance:It remained unclear that the efficacy comparison between low-dose immune tolerance induction(LD-ITI)incorporating immunosuppressants(IS)when severe hemophilia A(SHA)patients had inhibitor-titer≥200 Bethesda Units(BU)/mL(LD-ITI-IS^(200) regimen)and LD-ITI combining with IS when SHA patients had inhibitor-titer≥40 BU/mL(LD-ITI-IS^(40) regimen).Objective:To compare the efficacy of the LD-ITI-IS^(200) regimen with that of the LD-ITI-IS^(40) regimen for SHA patients with high-titer inhibitors.Methods:A prospective cohort study on patients receiving LD-ITI-IS^(200) compared to those receiving LD-ITI-IS^(40) from January 2021 to December 2023.Both received LD-ITI[FVIII 50 IU/kg every other day].IS(rituximab+prednisone)was added when peak inhibitor tier≥200 BU/mL in the LD-ITI-IS^(200) regimen and≥40 BU/mL in the LD-ITI-IS^(40) regimen.Success is defined as a negative inhibitor plus FVIII recovery≥66%of the expected.Results:We enrolled 30 patients on LD-ITI-IS^(200) and 64 patients on LD-ITI-IS^(40),with similar baseline clinical characteristics.A lower IS-use rate was discovered in the LD-ITI-IS^(200) regimen compared to the LD-ITI-IS^(40) regimen(30.0%vs.62.5%).The two regimens(LD-ITI-IS^(200) vs.LD-ITI-IS^(40))had similar success rate(70.0%vs.79.7%),median time to success(9.4 vs.10.6 months),and annualized bleeding rate during ITI(3.7 vs.2.8).The cost to success was lower for LD-ITI-IS^(200) than for LD-ITI-IS^(40)(2107 vs.3256 US Dollar/kg).Among patients with peak inhibitor-titer 40-199 BU/mL,10 non-IS-using(on LD-ITI-IS^(200) regimen)and 28 IS-using(on LD-ITI-IS^(40) regimen)had similar success rates(70.0%vs.78.6%)and time to success(9.0 vs.8.8 months).Interpretation:In LD-ITI,IS are not necessary for inhibitor titer<200 BU/mL.展开更多
Traumatic brain injury is a prevalent disorder of the central nervous system.In addition to primary brain parenchymal damage,the enduring biological consequences of traumatic brain injury pose long-term risks for pati...Traumatic brain injury is a prevalent disorder of the central nervous system.In addition to primary brain parenchymal damage,the enduring biological consequences of traumatic brain injury pose long-term risks for patients with traumatic brain injury;however,the underlying pathogenesis remains unclear,and effective intervention methods are lacking.Intestinal dysfunction is a significant consequence of traumatic brain injury.Being the most densely innervated peripheral tissue in the body,the gut possesses multiple pathways for the establishment of a bidirectional“brain-gut axis”with the central nervous system.The gut harbors a vast microbial community,and alterations of the gut niche contribute to the progression of traumatic brain injury and its unfavorable prognosis through neuronal,hormonal,and immune pathways.A comprehensive understanding of microbiota-mediated peripheral neuroimmunomodulation mechanisms is needed to enhance treatment strategies for traumatic brain injury and its associated complications.We comprehensively reviewed alterations in the gut microecological environment following traumatic brain injury,with a specific focus on the complex biological processes of peripheral nerves,immunity,and microbes triggered by traumatic brain injury,encompassing autonomic dysfunction,neuroendocrine disturbances,peripheral immunosuppression,increased intestinal barrier permeability,compromised responses of sensory nerves to microorganisms,and potential effector nuclei in the central nervous system influenced by gut microbiota.Additionally,we reviewed the mechanisms underlying secondary biological injury and the dynamic pathological responses that occur following injury to enhance our current understanding of how peripheral pathways impact the outcome of patients with traumatic brain injury.This review aimed to propose a conceptual model for future risk assessment of central nervous system-related diseases while elucidating novel insights into the bidirectional effects of the“brain-gut-microbiota axis.”展开更多
BACKGROUND Liver transplant(LT)recipients are susceptible to carbapenem-resistant Klebsiella pneumoniae(CRKP)infections.Comprehensive research addressing the incidence,timing,infection sites,resistance patterns,treatm...BACKGROUND Liver transplant(LT)recipients are susceptible to carbapenem-resistant Klebsiella pneumoniae(CRKP)infections.Comprehensive research addressing the incidence,timing,infection sites,resistance patterns,treatment options,and associated risk factors among LT recipients with CRKP is now lacking.AIM To assess the incidence,resistance,therapy,and risk factors of CRKP infections post-LT,and to evaluate the impact of them on prognosis.METHODS A retrospective study was conducted,including 430 consecutive patients who underwent LT between January 2015 and June 2023.This study aimed to investigate the risk factors for CRKP infections and their influence on outcomes using logistic regression analysis.RESULTS Among the 430 patients who underwent LT,20(4.7%)experienced at least one documented CRKP infection within 3 months post-transplantation.The median time from LT to the onset of CRKP infections was 6.5 days.The lungs and bloodstream were the most common sites of CRKP infections.CRKP isolates were relatively susceptible to ceftazidime/avibactam(93.7%),polymyxin B(90.6%),and tigecycline(75.0%)treatment.However,all isolates were resistant to piperacillin/tazobactam,ceftazidime,cefepime,aztreonam,meropenem,and levofloxacin treatment.Recipients with CRKP infections had a mortality rate of 35%,the rate was 12.5%for those receiving ceftazidime/avibactam therapy.Multivariate analysis identified female sex[odds ratio(OR)=3.306;95%confidence interval(CI):1.239-8.822;P=0.017],intraoperative bleeding≥3000 mL(OR=3.269;95%CI:1.018-10.490;P=0.047),alanine aminotransferase on day 1 post-LT≥1500 U/L(OR=4.370;95%CI:1.686-11.326;P=0.002),and post-LT mechanical ventilation(OR=2.772;95%CI:1.077-7.135;P=0.035)as significant variables associated with CRKP.CRKP infections were related to an intensive care unit length(ICU)of stay≥7 days and 6-month all-cause mortality post-LT.CONCLUSION CRKP infections were frequent complications following LT,with poor associated outcomes.Risk factors for post-LT CRKP infections included female sex,significant intraoperative bleeding,elevated alanine aminotransferase levels,and the need for mechanical ventilation.CRKP infections negatively impacted survival and led to prolonged ICU stays.展开更多
基金supported by the National Key Research and Development Program of China (No. 2020YFF01014502)the National Natural Science of Foundation of China (Nos. 21922401,201827810)。
文摘Liquid chromatography tandem mass spectrometry(LC-MS/MS) plays an important role in clinical diagnostics. Although LC-MS/MS is superior in terms of accurately quantifying molecules in complex matrices,instrument footprint, operation and maintenance complexity also hinder its expansion as the analytical technique of choice. In this study, a compact LC-MS instrument was developed, in which an assembled liquid chromatograph was coupled with a miniature ion trap mass spectrometer. The overall instrument has a footprint of 69 cm × 31 cm × 31 cm, and it requires no gas supply as well as minimum maintenance. Furthermore, the use of LC-MS is in accord with conventional clinical diagnostic protocols, and the choice of ion trap offers tandem MS performance. The results showed that the use of LC could improve both mixture analysis capability and detection sensitivity of the miniature mass spectrometer. After optimization, feasibility of this instrument in clinical practice was demonstrated by the quantitation of four widely used immunosuppressants in blood samples. Relatively good linearities were obtained, which spanned the reference ranges of effective therapeutic concentrations of each immunosuppressant. Intraday and inter-day accuracy and precision of analytical method were also assessed. This work showed that a compact LC-MS instrument could be used in clinical diagnosis, either to replace conventional lab-scale instruments or to be used in POCT applications.
文摘AIM: To assess the effectiveness of immunosuppressants in the prophylaxis of corneal allograft rejection after high-risk keratoplasty and normal-risk keratoplasty. METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CNKI, VIP and reference lists of articles. Date of most recent search: 18 June, 2011. All randomised controlled trials (RCTs) assessing the use of immunosupressants in the prevention of graft rejection, irrespective of publication language. Two authors assessed trial quality and extracted data independently. Only dichotomous outcomes (clear graft survival, ratio of immune reactions and side effects) were available and were expressed as relative risk (RR) and 95% confidence intervals (CI). RESULTS: Seven studies were included in this review. In the comparing of mycophenolate mofetil (MMF) with placebo, the results showed MMF could significantly reduce immune reactions compared with placebo (RR 1.08 95% Cl 0.95 to 1.21), but no effect on clear graft survival (RR 1.11 95% Cl 0.90 to 1.35). In clear graft survival and immune reactions, MMF and cyclosporine A (CsA) showed similar effect (RR 1.11 95% Cl 0.90 to 1.35, and RR 1.48, 95% Cl 0.56 to 3.93, respectively). Tacrolimus (FK506) and steroid showed similar effects on clear graft survival and immune reactions (RR 0.32, 95% CI 0.02 to 6.21, and RR 1.00, 95%CI 0.88 to 1.14, respectively). No drug relative side effect has been found. CONCLUSION: MMF may reduce immune reactions in both normal-risk and high-risk rejection of penetrating keratoplasty. CsA and FK506 showed similar effects as MMF. However, due to the lack of large clinical trials, the evidence remain weak, the quality of evidences were rated as very low to moderate. Large, properly randomised, placebo-controlled, double masked trials are needed to evaluate the effect of immunosuppressants.
文摘Prostate cancer is a malignant tumor with a high incidence in elderly men.In recent years,with the improvement of people’s living standards and the advancement of detection technology,the incidence of prostate cancer has been increasing year by year.Castration-resistant prostate cancer(CRPC)is a highly challenging type of advanced prostate cancer treatment,which clinically shows resistance to hormonal deprivation therapy.The overall treatment efficacy of CRPC is currently poor and further relevant therapeutic studies are needed to improve patient survival and quality of life.Immunosuppressants can play a role in combating the immune system of tumors,and abiraterone has also achieved remarkable results in prostate cancer treatment.This study will investigate the possible clinical effects and safety of immunosuppressants combined with abiraterone in the treatment of metastatic CRPC.The population-based study will provide clinicians with more effective treatment options,as well as enhance the understanding of novel combination therapy strategies to be implemented in the future for such patients.
文摘IgA nephropathy is the most common primary glomerular disease in China and even in the world, and it is also the most common cause of end-stage renal disease. The pathogenesis of IgA nephropathy is not clear. At present, it is mainly considered that abnormal IgA immune complex deposition in glomerular mesangial area leads to a series of clinical manifestations. Therefore, at present, in addition to supporting treatment, the treatment of IgA nephropathy mainly focuses on glucocorticoids and various immunosuppressants, but the efficacy and safety of the above immunosuppressants on IgA nephropathy are still controversial. This paper reviews the current use of immunosuppressants in the treatment of IgA nephropathy.
文摘Hepatitis C(HCV)-infected patients have a poorer survival post-liver transplantation compared to patients transplanted for other indications,since HCV recurrence post-transplant is universal and commonly follows an aggressive course.There is increasing evidence that in the non-transplant setting,induction of hepatocyte apoptosis is one of the main mechanisms by which HCV drives liver inflammation and fibrosis,and that HCV proteins directly promote apoptosis.Recent studies have shown that post-liver transplant,there is a link between high levels of HCV replication,enhanced hepatocyte apoptosis and the subsequent development of rapidly progressive liver fibrosis.Although the responsible mechanisms remain unclear,it is likely that immunosuppressive drugs play an important role.It is well known that immunosuppressants impair immune control of HCV,thereby allowing increased viral replication.However there is also evidence that immunosuppressants may directly induce apoptosis and this may be facilitated by the presence of high levels of HCV replication.Thus HCV and immunosuppressants may synergistically interact to further enhance apoptosis and drive more rapid fibrosis.These findings suggest that modulation of apoptosis within the liver either by changing immunosuppressive therapy or the use of apoptosis inhibitors may help prevent fibrosis progression in patients with post-transplant HCV disease.
文摘Hepatitis B viral(HBV)reactivation in the immunosuppressed is a significant problem even in patients who have achieved serological clearance due to the persistence of HBV as cccDNA.HBV reactivation will continue to pose a significant healthcare burden given the high prevalence of HBV and increasing use of immunosuppressants.Screening of hepatitis B surface antigen,antibody to Hepatitis B core antigen antibody and HBV DNA levels should be done routinely in all patients planned for significant immunosuppressant use.We aimed to examine the factors affecting reactivation risk.This depended on HBV disease status,the underlying disease requiring immunosuppression,and the specific immunosuppressive regime.While antiviral prophylaxis can prevent reactivation,it increases cost and still has risk of delayed reactivation after stopping antivirals and close follow-up and on-demand treatment is a good alternative for patients at risk of reactivation.
文摘AIM To investigate the specific effects of immunosuppressants on the antiviral action of daclatasvir and asunaprevir.METHODS The antiviral activity of daclatasvir(DCV) and asunaprevir(ASV) combined with immunosuppressants was tested using two in vitro models for hepatitis C virus(HCV) infection.RESULTS Tacrolimus, rapamycin and cyclosporine did not negatively affect the antiviral action of DCV or ASV. Mycophenolic acid(MPA) showed additive antiviral effects combined with these direct acting antivirals(DAAs). MPA induces interferon-stimulated genes(ISGs) and is a potent GTP synthesis inhibitor. DCV or ASV did not induce ISGs expression nor affected ISG induction by MPA. Rather, the combined antiviral effect of MPA with DCV and ASV was partly mediated via inhibition of GTP synthesis.CONCLUSION Immunosuppressants do not negatively affect the antiviral activity of DAAs. MPA has additive effect on the antiviral action of DCV and ASV. This combined benefit needs to be confirmed in prospective clinical trials.
基金Supported by National Natural Science Foundation of China,No.82270649.
文摘BACKGROUND Chylous ascites is caused by disruption of the lymphatic system,which is characterized by the accumulation of a turbid fluid containing high levels of triglycerides within the abdominal cavity.The two most common causes are cirrhosis and tuberculosis,and colon signer ring cell carcinoma(SRCC)due to the use of immunosuppressants is extremely rare in cirrhotic patients after liver transplantation,making it prone to misdiagnosis and missed diagnosis.CASE SUMMARY A 52-year-old man who underwent liver transplantation and was administered with immunosuppressants for 8 months was admitted with a 3-month history of progressive abdominal distention.Initially,based on lymphoscintigraphy and lymphangiography,lymphatic obstruction was considered,and cystellar chyli decompression with band lysis and external membrane stripping of the lymphatic duct was performed.However,his abdominal distention was persistent without resolution.Abdominal paracentesis revealed allogenic cells in the ascites,and immunohistochemistry analysis revealed adenocarcinoma cells with phenotypic features suggestive of a gastrointestinal origin.Gastrointestinal endoscopy was performed,and biopsy showed atypical signet ring cells in the ileocecal valve.The patient eventually died after a three-month follow-up due to progression of the tumor.CONCLUSION Colon SRCC,caused by immunosuppressants,is an unusual but un-neglected cause of chylous ascites.
文摘In the pre-biologic era,immunomodulators such as azathioprine,6-mercaptopurine,and methotrexate(MTX)were widely used as first-line maintenance therapies in Crohn’s disease.However,in the current era shaped by biologics,their role has shifted toward adjunctive use,primarily in combination with anti-tumor necrosis factor agents to reduce immunogenicity.Amid growing concerns about thiopurine-associated risks,MTX is receiving renewed attention for its favorable safety profile;however,this agent remains inconsistently utilized in gastroenterology despite its frontline status in rheumatology.This discrepancy was highlighted in a recent nationwide survey by Bonnaud et al published in the World Journal of Gastroenterology,which offers timely insights into MTX prescribing behaviors among French gastroenterologists.Although 71%of respondents reported using MTX,primarily via subcutaneous injection,it is still perceived as a secondary choice after thiopurines.Importantly,this underuse appears to be driven more by clinical inertia and limited guidance rather than by lack of efficacy or safety concerns.Clinicians increasingly recognize the value of MTX,particularly in patients with joint involvement,Epstein-Barr virus negativity,or increased malignancy risk.Notably,even non-prescribers viewed the drug favorably,suggesting that usage barriers may be modifiable.In light of evolving treatment goals that prioritize safety,cost-effectiveness,and individualized care,this editorial argues that MTX should no longer be viewed as a fallback but as a strategic first-line option in well-defined high-risk populations.The survey underscores a persistent gap between guidelines and real-world practice,reinforcing the urgent need for clearer algorithms and education to support the repositioning of MTX in modern Crohn’s disease management.
文摘Objective:To evaluate the response rate to vaccination in different treatment groups (nonimmunosuppressants and immunosuppressants).Data Sources:We completed an online systematic search using PubMed to identify all articles published in English between January 1990 and December 2013 assessing the effect of the response rate to vaccination in different treatment groups (with and without immunomodulators).The following terms were used:"inflammatory bowel disease (IBD)" OR "Cmhn's disease" OR "ulcerative colitis"AND ("vaccination" OR "vaccine") AND ("corticosteroids" OR "mercaptopurine" OR "azathioprine" OR "methotrexate [MTX]") AND "immunomodulators."Study Selection:The inclusion criteria of articles were that the studies:(1) Randomized controlled trials which included patients with a diagnosis of IBD (established by standard clinical,radiographic,endoscopic,and histologic criteria); (2) exposed patients received immunomodulators for maintenance (weight-appropriate doses of 6-mercaptopurine/azathioprine or within 3 months of stopping,15 mg or more MTX per week or within 3 months of stopping; (3) exposed patients received nonimmunomodulators (no therapy,antibiotics only,mesalazine only,biological agent only such as infliximab,adalimumab,certolizumab or natalizumab or within 3 months of stopping one of these agents).The exclusion criteria of articles were that the studies:(1) History of hepatitis B virus (HBV),influenza or streptococcus pneumoniae infection; (2) patients who had previously been vaccinated against HBV,influenza or streptococcus pneumoniae; (3) any medical condition known to cause immunosuppression (e.g.chronic renal failure and human immunodeficiency virus infection); (4) individuals with positive hepatitis markers or liver cirrhosis; (5) patients with a known allergy to eggs or other components of the vaccines and (6) pregnancy.Results:Patients treated with immunomodulators were associated with lower response rates to vaccination.Conclusions:Immunomodulators may impair the immune response to vaccination in patients with IBD.Vaccination should be made at the time of diagnosis or before starting immunosuppressed therapy.
文摘Liver transplantation is a life-saving procedure for patients with end-stage liver diseases and acute liver failure.With advances in surgical techniques and immunosuppressive regimens,patient survival rates have significantly improved.While the systemic complications of post-transplantation are well recognized,ophthalmic manifestations remain underreported.Ophthalmic complications can significantly impair visual function and increase morbidity in these patients.Prolonged immunosuppression makes the patients susceptible to the opportunistic pathogens such as Cytomegalovirus,Candida,Aspergillus,etc.Other common findings include dry eye disease,cataracts and retinal vascular complications which further contribute to the long-term morbidity in these patients.Early ophthalmic evaluation and prompt management are essential to prevent irreversible vision loss and improve post-transplant outcomes.High index of suspicion and multidisciplinary approach is essential to facilitate early diagnosis and treatment.This review highlights the range of ophthalmic complications observed in liver transplant recipients and underscores the need for future research focused on understanding the underlying pathophysiological mechanisms and refining the prophylactic protocols to improve outcomes in this unique patient population.
文摘BACKGROUND The use of induction immunosuppression agents has improved kidney transplant outcomes,but selecting the optimal agent remains a point of debate.AIM To compare the long-term outcomes of kidney transplant recipients receiving alemtuzumab vs basiliximab induction,focusing on graft function,acute rejection,infection,malignancy,post-transplant glomerulonephritis,and survival,using a propensity score matched cohort design.METHODS Kidney transplant recipients who received alemtuzumab or basiliximab induction from 2014 to 2019 across two nephrology centres in Northwest England were evaluated.Propensity score matching at a 1:1.5 ratio ensured comparability between cohorts.Baseline characteristics,immunosuppression regimens,and outcomes were analyzed.Linear,binary logistic and Cox proportional hazard regression models.RESULTS A total of 436 recipients were included,with a median follow-up of 5.2 years.The matched cohort(n=262)had a mean age of 51.1±13.5 years;39%were female and 92%were white.There was no significant difference in the cumulative incidence of acute rejection[odds ratio(OR)=2.10;95%CI:0.9-4.9;P=0.110].Compared with basiliximab,alemtuzumab was associated with lower estimated glomerular filtration rate at 12 months(-6.6 mL/minute/1.73 m2;95%CI:-10.5 to-2.7;P<0.001)and higher risks of cytomegalovirus viremia(OR=3.2;95%CI:1.6-6.5;P<0.001),BK viremia(OR=2.4;95%CI:1.1-5.5;P=0.02),post-transplant malignancy(OR=6.2;95%CI:1.6-29.9;P=0.013),and death-censored graft loss(hazard ratio=3.6;95%CI:1.2-11.4;P=0.03).No significant differences were observed in post-transplant glomerulonephritis or recipient mortality.CONCLUSION In this propensity score-matched analysis,alemtuzumab induction was associated with lower graft function at 12 months and higher risks of viral infection,post-transplant malignancy,and graft loss compared with basiliximab.These findings highlight the need for further studies to confirm the long-term safety and effectiveness of alemtuzumab in kidney transplantation.
基金supported by the Research Fund Project of the Education Department of Yunnan Province(No.2023Y0464)Research Project for Scientific Research Funds of Provincial Research Institutions in Heilongjiang Province(No.CZBZ2025ZR003).
文摘Background:Immunosuppression compromises the host’s ability to combat pathogens,thereby increasing susceptibility to multisystem disorders.However,safe and effective curative treatments for this condition are currently lacking.Modulating the gut microbiota and their metabolites represents a promising therapeutic strategy.Notably,the Chinese herbal compound Yunzhi Guben Gao(YZG)has demonstrated multi-target immunomodulatory potential.Methods:A mouse model of dexamethasone-induced immunosuppression was employed to evaluate the effects of YZG.Immune organ indices(thymus,spleen),serum cytokine levels(IL-2,TNF-α),mucosal immunity markers(pulmonary/colonic SIgA),gut microbiota structure,and short-chain fatty acids(SCFAs)abundance were evaluated.Key microbial genera and metabolites were identified via Spearman correlation analysis.Pseudo-germ-free model mice established via quadruple antibiotic treatment combined with isovaleric acid intervention were employed to evaluate whether YZG efficacy depends on the intestinal microbiota and its metabolites,and whether its intrinsic mechanisms involve the promotion of isovaleric acid production.Results:YZG intervention ameliorated systemic and mucosal immune function in immunosuppressed mice.Mechanistically,YZG remodeled gut microbiota structure and significantly increased SCFAs levels.Notably,the abundance of the genus Ligilactobacillus exhibited the strongest positive correlation with isovaleric acid levels.Ligilactobacillus abundance was also positively correlated with immune-enhancing parameters and negatively correlated with the proinflammatory cytokine TNF-α,suggesting that Ligilactobacillus plays a pivotal role in the YZG regulatory network.Experiments using pseudo-germ-free mice and isovaleric acid intervention further demonstrated that the immunoprotective effects of YZG are closely related to intestinal microbiota remodeling and increased isovaleric acid production.Conclusion:YZG alleviates immunosuppression through multiple mechanisms,primarily involving the enrichment of the probiotic genus Ligilactobacillus and the consequent increase in isovaleric acid production.This process coordinately modulates mucosal immunity,cytokine networks,and immune organ function.The elucidation of this“microbiota-metabolite-immunity”axis provides both a pharmacological basis for the clinical application of YZG and novel immune-restorative strategies targeting gut microecological regulation.
基金supported by Natural Science Foundation of Shandong Province(Nos.ZR2023MB081,ZR2024QB346)Shandong Traditional Chinese Medicine Technology Project(No.Q-2023127).
文摘In situ tumor vaccines,which leverage the antigenic profile of individual tumors,have demonstrated significant potential in tumor immunotherapy.However,their efficacy is often limited by the immunosuppressive tumor microenvironment(TME)and insufficient tumor targeting.To address these challenges,we engineered in situ nanovaccines through the self-assembly of the photosensitizer indocyanine green,immune adjuvant aluminum(Al^(3+)),and hydrophilic drug zoledronic acid(ZOL).Intravenous injection of these nanovaccines led to efficient tumor accumulation,enhancing drug bioavailability and enabling the release of tumor-associated antigens via photothermal therapy.Additionally,the built-in ZOL induces polarization of tumor-associated macrophages,reversing the immunosuppressive TME.The potent antitumor immune response triggered by these nanovaccines effectively suppresses tumor growth.This study,which integrates a straightforward assembly method,substantial drug loading capacity,and promising therapeutic outcomes,introduces a novel and effective paradigm for carrier-free in situ nanovaccines in cancer treatment.
文摘Dear Editor,Lymphocyte activation gene 3(LAG3),the third established target for immune checkpoint blockade therapy,suppresses T cell function by binding to major histocompatibility complex classⅡ(MHCⅡ).Despite its significant therapeutic potential in cancer immunotherapy and the substantial attention it has received from academia and industry,the molecular mechanisms of LAG3-mediated immunosuppression remain poorly understood,primarily because of its unique ligand-binding characteristics and intracellular domains[1].
文摘A clear goal in cold tumor research is to identify strategies for converting them into immunologically‘hot’tumors with enhanced immune cell infiltration and activity,thereby improving their responsiveness to immunotherapy.The genesis of cold tumors is exceedingly intricate.In recent times,as the analysis of this phenomenon has been pursued with greater depth,a suite of advanced diagnostic and therapeutic technologies has surfaced.These novel approaches and tactics are anticipated to modulate the tumor immune microenvironment across various dimensions,thereby facilitating the advancement of personalized and precise treatment modalities for cold tumors.The present article addresses the challenge of diminished therapeutic responsiveness to“cold tumors”within clinical settings.It systematically elucidates the multi-faceted regulatory mechanisms underlying immune evasion in cold tumors and offers a detailed analysis of advanced therapeutic strategies that incorporate nanotechnology,gene editing,and artificial intelligence methodologies.Furthermore,the future development trends of immunotherapy were explored in greater depth.It was posited that the convergence of artificial intelligence,multidimensional genomics,and emerging biotechnologies has presented positive prospects for the treatment of cold tumors,and has offered a theoretical foundation and technical framework for the transformation of cold tumors into“hot tumors”.
基金Capital Health Development Research Project,Grant/Award Number:2022-2-2093Beijing Research Ward Construction Demonstration Unit Project,Grant/Award Number:BCRW202101+1 种基金National Natural Science Foundation of China,Grant/Award Number:82270133Beijing Municipal Scienceand Technology Commission,Grant/Award Number:Z221100007422067。
文摘Importance:It remained unclear that the efficacy comparison between low-dose immune tolerance induction(LD-ITI)incorporating immunosuppressants(IS)when severe hemophilia A(SHA)patients had inhibitor-titer≥200 Bethesda Units(BU)/mL(LD-ITI-IS^(200) regimen)and LD-ITI combining with IS when SHA patients had inhibitor-titer≥40 BU/mL(LD-ITI-IS^(40) regimen).Objective:To compare the efficacy of the LD-ITI-IS^(200) regimen with that of the LD-ITI-IS^(40) regimen for SHA patients with high-titer inhibitors.Methods:A prospective cohort study on patients receiving LD-ITI-IS^(200) compared to those receiving LD-ITI-IS^(40) from January 2021 to December 2023.Both received LD-ITI[FVIII 50 IU/kg every other day].IS(rituximab+prednisone)was added when peak inhibitor tier≥200 BU/mL in the LD-ITI-IS^(200) regimen and≥40 BU/mL in the LD-ITI-IS^(40) regimen.Success is defined as a negative inhibitor plus FVIII recovery≥66%of the expected.Results:We enrolled 30 patients on LD-ITI-IS^(200) and 64 patients on LD-ITI-IS^(40),with similar baseline clinical characteristics.A lower IS-use rate was discovered in the LD-ITI-IS^(200) regimen compared to the LD-ITI-IS^(40) regimen(30.0%vs.62.5%).The two regimens(LD-ITI-IS^(200) vs.LD-ITI-IS^(40))had similar success rate(70.0%vs.79.7%),median time to success(9.4 vs.10.6 months),and annualized bleeding rate during ITI(3.7 vs.2.8).The cost to success was lower for LD-ITI-IS^(200) than for LD-ITI-IS^(40)(2107 vs.3256 US Dollar/kg).Among patients with peak inhibitor-titer 40-199 BU/mL,10 non-IS-using(on LD-ITI-IS^(200) regimen)and 28 IS-using(on LD-ITI-IS^(40) regimen)had similar success rates(70.0%vs.78.6%)and time to success(9.0 vs.8.8 months).Interpretation:In LD-ITI,IS are not necessary for inhibitor titer<200 BU/mL.
基金supported by the National Natural Science Foundation of China,No.82174112(to PZ)Science and Technology Project of Haihe Laboratory of Modern Chinese Medicine,No.22HHZYSS00015(to PZ)State-Sponsored Postdoctoral Researcher Program,No.GZC20231925(to LN)。
文摘Traumatic brain injury is a prevalent disorder of the central nervous system.In addition to primary brain parenchymal damage,the enduring biological consequences of traumatic brain injury pose long-term risks for patients with traumatic brain injury;however,the underlying pathogenesis remains unclear,and effective intervention methods are lacking.Intestinal dysfunction is a significant consequence of traumatic brain injury.Being the most densely innervated peripheral tissue in the body,the gut possesses multiple pathways for the establishment of a bidirectional“brain-gut axis”with the central nervous system.The gut harbors a vast microbial community,and alterations of the gut niche contribute to the progression of traumatic brain injury and its unfavorable prognosis through neuronal,hormonal,and immune pathways.A comprehensive understanding of microbiota-mediated peripheral neuroimmunomodulation mechanisms is needed to enhance treatment strategies for traumatic brain injury and its associated complications.We comprehensively reviewed alterations in the gut microecological environment following traumatic brain injury,with a specific focus on the complex biological processes of peripheral nerves,immunity,and microbes triggered by traumatic brain injury,encompassing autonomic dysfunction,neuroendocrine disturbances,peripheral immunosuppression,increased intestinal barrier permeability,compromised responses of sensory nerves to microorganisms,and potential effector nuclei in the central nervous system influenced by gut microbiota.Additionally,we reviewed the mechanisms underlying secondary biological injury and the dynamic pathological responses that occur following injury to enhance our current understanding of how peripheral pathways impact the outcome of patients with traumatic brain injury.This review aimed to propose a conceptual model for future risk assessment of central nervous system-related diseases while elucidating novel insights into the bidirectional effects of the“brain-gut-microbiota axis.”
文摘BACKGROUND Liver transplant(LT)recipients are susceptible to carbapenem-resistant Klebsiella pneumoniae(CRKP)infections.Comprehensive research addressing the incidence,timing,infection sites,resistance patterns,treatment options,and associated risk factors among LT recipients with CRKP is now lacking.AIM To assess the incidence,resistance,therapy,and risk factors of CRKP infections post-LT,and to evaluate the impact of them on prognosis.METHODS A retrospective study was conducted,including 430 consecutive patients who underwent LT between January 2015 and June 2023.This study aimed to investigate the risk factors for CRKP infections and their influence on outcomes using logistic regression analysis.RESULTS Among the 430 patients who underwent LT,20(4.7%)experienced at least one documented CRKP infection within 3 months post-transplantation.The median time from LT to the onset of CRKP infections was 6.5 days.The lungs and bloodstream were the most common sites of CRKP infections.CRKP isolates were relatively susceptible to ceftazidime/avibactam(93.7%),polymyxin B(90.6%),and tigecycline(75.0%)treatment.However,all isolates were resistant to piperacillin/tazobactam,ceftazidime,cefepime,aztreonam,meropenem,and levofloxacin treatment.Recipients with CRKP infections had a mortality rate of 35%,the rate was 12.5%for those receiving ceftazidime/avibactam therapy.Multivariate analysis identified female sex[odds ratio(OR)=3.306;95%confidence interval(CI):1.239-8.822;P=0.017],intraoperative bleeding≥3000 mL(OR=3.269;95%CI:1.018-10.490;P=0.047),alanine aminotransferase on day 1 post-LT≥1500 U/L(OR=4.370;95%CI:1.686-11.326;P=0.002),and post-LT mechanical ventilation(OR=2.772;95%CI:1.077-7.135;P=0.035)as significant variables associated with CRKP.CRKP infections were related to an intensive care unit length(ICU)of stay≥7 days and 6-month all-cause mortality post-LT.CONCLUSION CRKP infections were frequent complications following LT,with poor associated outcomes.Risk factors for post-LT CRKP infections included female sex,significant intraoperative bleeding,elevated alanine aminotransferase levels,and the need for mechanical ventilation.CRKP infections negatively impacted survival and led to prolonged ICU stays.
