Neuroprotection and recovery from early-life adversity: considerations for environmental enrichment

In the laboratory,environmental enrichment（EE）is used as a protocol to understand the functional,behavioral and molecular mechanisms that underlie neural plasticity（van Praag et al.,2000;Sale et al.,2014）.In addition,it is utilized to provide supplementary resources to animals in order to maintain their well-being and to preserve the scientific validity of the study at hand（see http：//www.nap.edu/catalog/12910/guide-for-thecare-and-use-of-laboratory-animals-eighth）.

The Detrimental Effect of Adversity on HIV Outcomes in the Era of Combined Anti-Retroviral Therapy

Socially disadvantaged individuals with HIV experience unacceptably high rates of AIDS and death. The authors developed an adversity index to quantify the impact of demographic and psychosocial factors on HIV care. This retrospective cohort study included 431 participants with HIV on combined antiretroviral therapy between 2000 and 2005. Poor outcome was defined as progression to AIDS, death, virologic failure, or CD4 < 200 cells/μl at six months. The index utilized eight demographic and psychosocial variables independently associated with poor outcome. Exposure to higher numbers of variables in the adversity index significantly increased the rates of poor outcome from 14% (exposure to no variables) to 100% (exposure to seven variables). The odds of poor outcome decreased but remained significant after adjusting for adherence-defining variables, indicating a possible mediating effect of poor adherence. Durably effective therapeutic strategies must include addressing adverse demographic and psychosocial factors affecting people living with HIV.

United Against Adversity Chinese companies join the fight against COVID-19 throughout Africa

Chinese companies join the fight against COVID-19 throughout Africa At a Chinese electricity project deep inside Uganda,Muzinga Hamis and his colleagues put up numerous signs reminding staff and villagers to wear masks,practice social distancing and check their body daily.

Dignity in Adversity

IS there an audience for a Mauritanian director promoting a movie about Mall in China？ It depends on the director and the film French speakers, film students and film lovers packed the China Film Archive auditorium to watch Abderrahmane Sissako＇s famous film Timbuktu with the director himself.

Childhood Adversity Phenotypes and Risky Health Behaviors among Chinese Adolescents: Extending the Concept of Adversity

ObjectiveTo present an approach to phenotyping ACEs and explore the association between ACEs and adolescent health risky behaviors based on the social context of China.Methods Totally,5,726 adolescents aged 12-18 years were investigated about their ACEs in the family,peer,school,and personal domains and the occurrence of six types of risky health behaviors(i.e.,smoking,drinking,sexual intercourse,self-harm,and suicidal ideation and attempts).Latent class analysis(LCA)was used to explore the ACE patterns.Results Six latent classes of ACEs were identified,including low adversity,school adversity,school adversity and peer victimization,peer victimization,maltreatment and peer victimization,and high adversity,and associated with risky health behaviors in adolescents.Being physically punished by a teacher,experiencing sexual abuse,and experiencing family trauma most strongly differentiated from the six AcE classes and were correlated with an increased risk for risky adolescent health behaviors.ConclusionThis study supports a positive association between ACEs and risky adolescent health behaviors.Peer victimization,school adversity and associated contexts need to be considered in future ACEstudies.

DNA Methylation,Behavior and Early Life Adversity

The impact of early physical and social environments on life-long phenotypes is well known. Moreover, we have documented evidence for gene-environment interactions where identical gene variants are associated with different phenotypes that are dependent on early life adversity. What are the mechanisms that embed these early life experiences in the genome？ DNA methylation is an enzymatically- catalyzed modification of DNA that serves as a mechanism by which similar sequences acquire cell type identity during cellular differentiation and embryogenesis in the same individual. The hypothesis that will be discussed here proposes that the same mechanism confers environmental-exposure specific identity upon DNA providing a mechanism for embedding environmental experiences in the genome, thus affecting long-term phenotypes. Particularly important is the environment early in life including both the prenatal and postnatal social environments.

Early life adversity as a risk factor for cognitive impairment and Alzheimer’s disease

Neurological conditions,including cognitive impairment and Alzheimer’s disease(AD),impose a huge burden on society,affecting millions of people globally.In addition to genetic factors,recent studies indicate that environmental and experiential factors may contribute to the pathogenesis of these diseases.Early life adversity(ELA)has a profound impact on brain function and health later in life.In rodent models,exposure to ELA results in specific cognitive deficits and aggravated AD pathology.Extensive concerns have been raised regarding the higher risk of developing cognitive impairments in people with a history of ELA.In this review,we scrutinize findings from human and animal studies focusing on the connection of ELA with cognitive impairment and AD.These discoveries suggest that ELA,especially at early postnatal stages,increases susceptibility to cognitive impairment and AD later in life.In terms of mechanisms,ELA could lead to dysregulation of the hypothalamus-pituitary-adrenal axis,altered gut microbiome,persistent inflammation,oligodendrocyte dysfunction,hypomyelination,and aberrant adult hippocampal neurogenesis.Crosstalks among these events may synergistically contribute to cognitive impairment later in life.Additionally,we discuss several interventions that may alleviate adverse consequences of ELA.Further investigation into this crucial area will help improve ELA management and reduce the burden of related neurological conditions.

The dopaminergic system and Alzheimer's disease

Alzheimer's disease is a common neurodegenerative disorder in older adults.Despite its prevalence,its pathogenesis remains unclea r.In addition to the most widely accepted causes,which in clude excessive amyloid-beta aggregation,tau hyperphosphorylation,and deficiency of the neurotransmitter acetylcholine,numerous studies have shown that the dopaminergic system is also closely associated with the occurrence and development of this condition.Dopamine is a crucial catecholaminergic neurotransmitter in the human body.Dopamine-associated treatments,such as drugs that target dopamine receptor D and dopamine analogs,can improve cognitive function and alleviate psychiatric symptoms as well as ameliorate other clinical manifestations.Howeve r,therapeutics targeting the dopaminergic system are associated with various adverse reactions,such as addiction and exacerbation of cognitive impairment.This review summarizes the role of the dopaminergic system in the pathology of Alzheimer's disease,focusing on currently available dopamine-based therapies for this disorder and the common side effects associated with dopamine-related drugs.The aim of this review is to provide insights into the potential connections between the dopaminergic system and Alzheimer's disease,thus helping to clarify the mechanisms underlying the condition and exploring more effective therapeutic options.

Athenian Adversity

The Greek debt crisis reveals inherent risks in the euro zone The Europeans have seen some fast changes lately-some certainly more welcome than others. The excitement surrounding the celebrations of the Lisbon Treaty’s entry into force had yet

FORTITUDE IN ADVERSITY

China has pulled together to save lives following a major earthquake that ripped through parts of the country’s southwest

关注免疫检查点抑制剂发生irAE后免疫治疗再挑战

免疫检查点抑制剂(immune-checkpoint inhibitors,ICIs)是近年来肿瘤学领域最重要的突破之一,为不同类型的实体瘤治疗提供了新的范式。ICIs通过阻断免疫内在下调因子,如细胞毒性T淋巴细胞抗原4(CTLA-4)和程序性细胞死亡1(PD-1)或其配体程序性细胞死亡配体1(PD-L1),增加抗肿瘤免疫力[1]。然而,由于免疫应答增强和免疫系统失衡,患者可能会发生免疫相关不良事件(immune-related adverse events,irAE)。

Immune checkpoint inhibitor-associated gastritis:Patterns and management

Immune checkpoint inhibitors(ICIs)are widely used due to their effectiveness in treating various tumors.Immune-related adverse events(irAEs)are defined as adverse effects resulting from ICI treatment.Gastrointestinal irAEs are a common type of irAEs characterized by intestinal side effects,such as diarrhea and colitis,which may lead to the cessation of ICIs.Although irAE gastritis is rarely reported,it may lead to serious complications such as gastrorrhagia.Furthermore,irAE gastritis is often difficult to identify early due to its diverse symptoms.Although steroid hormones and immunosuppressants are commonly used to reverse irAEs,the best regimen and dosage for irAE gastritis remains uncertain.In addition,the risk of recurrence of irAE gastritis after the reuse of ICIs should be considered.In this editorial,strategies such as early identification,pathological diagnosis,mana-gement interventions,and immunotherapy rechallenge are discussed to enable clinicians to better manage irAE gastritis and improve the prognosis of these patients.

Excess cardiovascular mortality in men with non-alcoholic fatty liver disease:A cause for concern!

Non-alcoholic fatty liver disease(NAFLD)has emerged as the commonest cause of chronic liver disease worldwide in recent years.With time,our understanding of NAFLD has evolved from an isolated liver condition to a systemic disease with significant manifestations beyond the liver.Amongst them,cardiovascular diseases(CVDs)are the most important and clinically relevant.Recent research supports a strong independent link between NALFD and CVD beyond the shared risk factors and pathophysiology.Female sex hormones are well known to not only protect against CVD in pre-menopausal females,but also contribute to improved adipose tissue function and preventing its systemic deposition.Recent research highlights the increased risk of major adverse cardiovascular-cerebral events(MACCE)amongst male with NAFLD compared to females.Further,racial variation was observed in MACCE outcomes in NAFLD,with excess mortality in the Native Americans and Asian Pacific Islanders compared to the other races.

Prediabetes: An overlooked risk factor for major adverse cardiac and cerebrovascular events in atrial fibrillation patients

BACKGROUND Prediabetes is a well-established risk factor for major adverse cardiac and cerebrovascular events(MACCE).However,the relationship between prediabetes and MACCE in atrial fibrillation(AF)patients has not been extensively studied.Therefore,this study aimed to establish a link between prediabetes and MACCE in AF patients.AIM To investigate a link between prediabetes and MACCE in AF patients.METHODS We used the National Inpatient Sample(2019)and relevant ICD-10 CM codes to identify hospitalizations with AF and categorized them into groups with and without prediabetes,excluding diabetics.The primary outcome was MACCE(all-cause inpatient mortality,cardiac arrest including ventricular fibrillation,and stroke)in AF-related hospitalizations.RESULTS Of the 2965875 AF-related hospitalizations for MACCE,47505(1.6%)were among patients with prediabetes.The prediabetes cohort was relatively younger(median 75 vs 78 years),and often consisted of males(56.3%vs 51.4%),blacks(9.8%vs 7.9%),Hispanics(7.3%vs 4.3%),and Asians(4.7%vs 1.6%)than the non-prediabetic cohort(P<0.001).The prediabetes group had significantly higher rates of hypertension,hyperlipidemia,smoking,obesity,drug abuse,prior myocardial infarction,peripheral vascular disease,and hyperthyroidism(all P<0.05).The prediabetes cohort was often discharged routinely(51.1%vs 41.1%),but more frequently required home health care(23.6%vs 21.0%)and had higher costs.After adjusting for baseline characteristics or comorbidities,the prediabetes cohort with AF admissions showed a higher rate and significantly higher odds of MACCE compared to the non-prediabetic cohort[18.6%vs 14.7%,odds ratio(OR)1.34,95%confidence interval 1.26-1.42,P<0.001].On subgroup analyses,males had a stronger association(aOR 1.43)compared to females(aOR 1.22),whereas on the race-wise comparison,Hispanics(aOR 1.43)and Asians(aOR 1.36)had a stronger association with MACCE with prediabetes vs whites(aOR 1.33)and blacks(aOR 1.21).CONCLUSION This population-based study found a significant association between prediabetes and MACCE in AF patients.Therefore,there is a need for further research to actively screen and manage prediabetes in AF to prevent MACCE.

Safety and efficacy comparison of remimazolam and propofol for intravenous anesthesia during gastroenteroscopic surgery of older patients:A meta-analysis

BACKGROUND Remimazolam is characterized by rapid action and inactive metabolites.It is used as the general anesthetic for many clinical surgeries.In this study,we performed a meta-analysis to evaluate whether remimazolam is superior to propofol for gastroenteroscopy in older patients.AIM To compare the adverse events and efficacy of remimazolam and propofol during gastroenteroscopy in older adults.METHODS The PubMed,Web of Science,the Cochrane Library databases were queried for the relevant key words"remimazolam,""and propofol,""and gastrointestinal endoscopy or gastroscopy."The search scope was"Title and Abstract,"and the search was limited to human studies and publications in English.Seven studies wherein remimazolam and propofol were compared were included for the metaanalysis.RESULTS We selected seven randomized controlled trials involving 1445 cases for the analysis.Remimazolam reduced the hypotension(relative risk,RR=0.44,95%CI:0.29-0.66,P=0.000),respiratory depression(RR=0.46,95%CI:0.30-0.70,P=0.000),injection pain(RR=0.12,95%CI:0.05-0.25,P=0.000),bradycardia(RR=0.37,95%CI:0.24-0.58,P=0.000),and time to discharge[weighted mean difference(WMD)=-0.58,95%CI:-0.97 to-0.18,P=0.005],compared to those after propofol administration.No obvious differences were observed for postoperative nausea and vomiting(RR=1.09,95%CI:0.97-1.24,P=0.151),dizziness(RR=0.77,95%CI:0.43-1.36,P=0.361),successful sedation rate(RR=0.96,95%CI:0.93-1.00,P=0.083),or the time to become fully alert(WMD=0.00,95%CI:-1.08-1.08,P=0.998).CONCLUSION Remimazolam appears to be safer than propofol for gastroenteroscopy in older adults.However,further studies are required to confirm these findings.

Impact of body mass index on adverse kidney events in diabetes mellitus patients: A systematic-review and meta-analysis

BACKGROUND The incidence of chronic kidney disease among patients with diabetes mellitus(DM)remains a global concern.Long-term obesity is known to possibly influence the development of type 2 diabetes mellitus.However,no previous meta-analysis has assessed the effects of body mass index(BMI)on adverse kidney events in patients with DM.AIM To determine the impact of BMI on adverse kidney events in patients with DM.METHODS A systematic literature search was performed on the PubMed,ISI Web of Science,Scopus,Ovid,Google Scholar,EMBASE,and BMJ databases.We included trials with the following characteristics:(1)Type of study:Prospective,retrospective,randomized,and non-randomized in design;(2)participants:Restricted to patients with DM aged≥18 years;(3)intervention:No intervention;and(4)kidney adverse events:Onset of diabetic kidney disease[estimated glomerular filtration rate(eGFR)of<60 mL/min/1.73 m2 and/or microalbuminuria value of≥30 mg/g Cr],serum creatinine increase of more than double the baseline or end-stage renal disease(eGFR<15 mL/min/1.73 m2 or dialysis),or death.RESULTS Overall,11 studies involving 801 patients with DM were included.High BMI(≥25 kg/m2)was significantly associated with higher blood pressure(BP)[systolic BP by 0.20,95%confidence interval(CI):0.15–0.25,P<0.00001;diastolic BP by 0.21 mmHg,95%CI:0.04–0.37,P=0.010],serum albumin,triglycerides[standard mean difference(SMD)=0.35,95%CI:0.29–0.41,P<0.00001],low-density lipoprotein(SMD=0.12,95%CI:0.04–0.20,P=0.030),and lower high-density lipoprotein(SMD=–0.36,95%CI:–0.51 to–0.21,P<0.00001)in patients with DM compared with those with low BMIs(<25 kg/m2).Our analysis showed that high BMI was associated with a higher risk ratio of adverse kidney events than low BMI(RR:1.22,95%CI:1.01–1.43,P=0.036).CONCLUSION The present analysis suggested that high BMI was a risk factor for adverse kidney events in patients with DM.

Efficacy and safety of over-the-scope-clips in the therapy of acute nonvariceal upper gastrointestinal bleeding:Meta-analysis

BACKGROUND Acute nonvariceal upper gastrointestinal bleeding(ANVUGIB)is a frequent lifethreatening acute condition in gastroenterology associated with high morbidity and mortality.Over-the-scope-clip(OTSC)is a new endoscopic hemostasis technique,which is being used in ANVUGIB and is more effective.AIM To summarize and analyze the effects of the OTSC in prevention of recurrent bleeding,clinical success rate,procedure time,hospital stay,and adverse events in the treatment of ANVUGIB,to evaluate whether OTSC can replace standard endoscopic therapy as a new generation of treatment for ANVUGIB.METHODS The literature related to OTSC and standard therapy for ANVUGIB published before January 2023 was searched in PubMed,Web of Science,EMBASE,Cochrane,Google,and CNKI databases.Changes in recurrent bleeding(7 or 30 days),clinical results(clinical success rate,conversion rate to surgery,mortality),therapy time(procedure time,hospital stay),and adverse events in the OTSC intervention group were summarized and analyzed,and the MD or OR of 95%CI is calculated by Review Manager 5.3.RESULTS This meta-analysis involved 11 studies with 1266 patients.Total risk of bias was moderate-to-high.For patients in the OTSC group,7-and 30-days recurrent bleeding rates,as well as procedure time,hospital stay,and intensive care unit stay,were greatly inhibited.OTSC could significantly improve the clinical success rate of ANVUGIB.OTSC therapy did not cause serious adverse and was effective in reducing patient mortality.CONCLUSION OTSC may provide more rapid and sustained hemostasis,and thus,promote recovery and reduce mortality in patients with ANVUGIB.In addition,the safety of OTSC is assured.

Atrial fibrillation and prediabetes:A liaison that merits attention!

Atrial fibrillation(AF)and prediabetes share common pathophysiological mechanisms with endothelial dysfunction and inflammation playing a key role.The resultant vicious cycle which sets in culminates in a higher atherogenicity and thermogenicity of the vascular system resulting in increased major adverse cardiac or cerebrovascular event(MACCE)events.However,the same has not convincingly been verified in real-world settings.In the recent retrospective study by Desai et al amongst AF patients being admitted to hospitals following MACCE,prediabetes emerged as an independent risk factor for MACCE after adjusting for all confounding variables.However,certain questions like the role of metformin,quantifying the risk for MACCE amongst prediabetes compared to diabetes,the positive impact of reversion to normoglycemia remain unanswered.We provide our insights and give future directions for dedicated research in this area to clarify the exact relationship between the two.

Predictive value of bilirubin and serum γ-glutamyltranspeptidase levels in type-2 diabetes mellitus patients with acute coronary syndrome

BACKGROUND Cardiovascular disease is a major complication of diabetes mellitus(DM).Type-2 DM(T2DM)is associated with an increased risk of cardiovascular events and mortality,while serum biomarkers may facilitate the prediction of these outcomes.Early differential diagnosis of T2DM complicated with acute coronary syndrome(ACS)plays an important role in controlling disease progression and improving safety.AIM To investigate the correlation of serum bilirubin andγ-glutamyltranspeptidase(γ-GGT)with major adverse cardiovascular events(MACEs)in T2DM patients with ACS.METHODS The clinical data of inpatients from January 2022 to December 2022 were analyzed retrospectively.According to different conditions,they were divided into the T2DM complicated with ACS group(T2DM+ACS,n=96),simple T2DM group(T2DM,n=85),and simple ACS group(ACS,n=90).The clinical data and laboratory indices were compared among the three groups,and the correlations of serum total bilirubin(TBIL)levels and serumγ-GGT levels with other indices were discussed.T2DM+ACS patients received a 90-day follow-up after discharge and were divided into event(n=15)and nonevent(n=81)groups according to the occurrence of MACEs;Univariate and multivariate analyses were further used to screen the independent influencing factors of MACEs in patients.RESULTS The T2DM+ACS group showed higherγ-GGT,total cholesterol,low-density lipoprotein cholesterol(LDL-C)and glycosylated hemoglobin(HbA1c)and lower TBIL and high-density lipoprotein cholesterol levels than the T2DM and ACS groups(P<0.05).Based on univariate analysis,the event and nonevent groups were significantly different in age(t=3.3612,P=0.0011),TBIL level(t=3.0742,P=0.0028),γ-GGT level(t=2.6887,P=0.0085),LDL-C level(t=2.0816,P=0.0401),HbA1c level(t=2.7862,P=0.0065)and left ventricular ejection fraction(LEVF)levels(t=3.2047,P=0.0018).Multivariate logistic regression analysis further identified that TBIL level and LEVF level were protective factor for MACEs,and age andγ-GGT level were risk factors(P<0.05).CONCLUSION Serum TBIL levels are decreased andγ-GGT levels are increased in T2DM+ACS patients,and the two indices are significantly negatively correlated.TBIL andγ-GGT are independent influencing factors for MACEs in such patients.

Predicting major adverse cardiovascular events after orthotopic liver transplantation using a supervised machine learning model:A cohort study

BACKGROUND Liver transplant(LT)patients have become older and sicker.The rate of post-LT major adverse cardiovascular events(MACE)has increased,and this in turn raises 30-d post-LT mortality.Noninvasive cardiac stress testing loses accuracy when applied to pre-LT cirrhotic patients.AIM To assess the feasibility and accuracy of a machine learning model used to predict post-LT MACE in a regional cohort.METHODS This retrospective cohort study involved 575 LT patients from a Southern Brazilian academic center.We developed a predictive model for post-LT MACE(defined as a composite outcome of stroke,new-onset heart failure,severe arrhythmia,and myocardial infarction)using the extreme gradient boosting(XGBoost)machine learning model.We addressed missing data(below 20%)for relevant variables using the k-nearest neighbor imputation method,calculating the mean from the ten nearest neighbors for each case.The modeling dataset included 83 features,encompassing patient and laboratory data,cirrhosis complications,and pre-LT cardiac assessments.Model performance was assessed using the area under the receiver operating characteristic curve(AUROC).We also employed Shapley additive explanations(SHAP)to interpret feature impacts.The dataset was split into training(75%)and testing(25%)sets.Calibration was evaluated using the Brier score.We followed Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis guidelines for reporting.Scikit-learn and SHAP in Python 3 were used for all analyses.The supplementary material includes code for model development and a user-friendly online MACE prediction calculator.RESULTS Of the 537 included patients,23(4.46%)developed in-hospital MACE,with a mean age at transplantation of 52.9 years.The majority,66.1%,were male.The XGBoost model achieved an impressive AUROC of 0.89 during the training stage.This model exhibited accuracy,precision,recall,and F1-score values of 0.84,0.85,0.80,and 0.79,respectively.Calibration,as assessed by the Brier score,indicated excellent model calibration with a score of 0.07.Furthermore,SHAP values highlighted the significance of certain variables in predicting postoperative MACE,with negative noninvasive cardiac stress testing,use of nonselective beta-blockers,direct bilirubin levels,blood type O,and dynamic alterations on myocardial perfusion scintigraphy being the most influential factors at the cohort-wide level.These results highlight the predictive capability of our XGBoost model in assessing the risk of post-LT MACE,making it a valuable tool for clinical practice.CONCLUSION Our study successfully assessed the feasibility and accuracy of the XGBoost machine learning model in predicting post-LT MACE,using both cardiovascular and hepatic variables.The model demonstrated impressive performance,aligning with literature findings,and exhibited excellent calibration.Notably,our cautious approach to prevent overfitting and data leakage suggests the stability of results when applied to prospective data,reinforcing the model’s value as a reliable tool for predicting post-LT MACE in clinical practice.