Prediction of treatment response to antipsychotic drugs for precision medicine approach to schizophrenia:randomized trials and multiomics analysis

Background:Choosing the appropriate antipsychotic drug(APD)treatment for patients with schizophrenia(SCZ)can be challenging,as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers.Previous studies have indicated the association between treatment response and genetic and epigenetic factors,but no effective biomarkers have been identified.Hence,further research is imperative to enhance precision medicine in SCZ treatment.Methods:Participants with SCZ were recruited from two randomized trials.The discovery cohort was recruited from the CAPOC trial(n=2307)involved 6 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,Quetiapine,Aripiprazole,Ziprasidone,and Haloperidol/Perphenazine(subsequently equally assigned to one or the other)groups.The external validation cohort was recruited from the CAPEC trial(n=1379),which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,and Aripiprazole groups.Additionally,healthy controls(n=275)from the local community were utilized as a genetic/epigenetic reference.The genetic and epigenetic(DNA methylation)risks of SCZ were assessed using the polygenic risk score(PRS)and polymethylation score,respectively.The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis,methylation quantitative trait loci,colocalization,and promoteranchored chromatin interaction.Machine learning was used to develop a prediction model for treatment response,which was evaluated for accuracy and clinical benefit using the area under curve(AUC)for classification,R^(2) for regression,and decision curve analysis.Results:Six risk genes for SCZ(LINC01795,DDHD2,SBNO1,KCNG2,SEMA7A,and RUFY1)involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response.The developed and externally validated prediction model,which incorporated clinical information,PRS,genetic risk score(GRS),and proxy methylation level(proxyDNAm),demonstrated positive benefits for a wide range of patients receiving different APDs,regardless of sex[discovery cohort:AUC=0.874(95%CI 0.867-0.881),R^(2)=0.478;external validation cohort:AUC=0.851(95%CI 0.841-0.861),R^(2)=0.507].Conclusions:This study presents a promising precision medicine approach to evaluate treatment response,which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ.Trial registration Chinese Clinical Trial Registry(https://www.chictr.org.cn/),18 Aug 2009 retrospectively registered:CAPOC-ChiCTR-RNC-09000521(https://www.chictr.org.cn/showproj.aspx?proj=9014),CAPEC-ChiCTRRNC-09000522(https://www.chictr.org.cn/showproj.aspx?proj=9013).

Management of chronic hepatitis B in pregnancy

Pregnancy associated with chronic hepatitis B (CHB) is a common and important problem with unique challenges. Pregnant women infected with CHB are different from the general population, and their special problems need to be considered: such as the effect of hepatitis B virus (HBV) infection on the mother and fetus, the effect of pregnancy on replication of the HBV, whether mothers should take HBV antiviral therapy during pregnancy, the effect of these treatments on the mother and fetus, how to carry out immunization of neonates, whether it can induce hepatitis activity after delivery and other serious issues. At present, there are about 350 million individuals with HBV infection worldwide, of which 50% were infected during the perinatal or neonatal period, especially in HBV-endemic countries. Currently, the rate of HBV infection in thechild-bearing age group is still at a high level, and the infection rate is as high as 8.16%. Effective prevention of mother-to-child transmission is an important means of reducing the global burden of chronic HBV infection. Even after adopting the combined immunization measures, there are still 5%-10% of babies born with HBV infection in hepatitis B e antigen positive pregnant women. As HBV perinatal transmission is the main cause of chronic HBV infection, we must consider how to prevent this transmission to reduce the burden of HBV infection. In this population of chronic HBV infected women of childbearing age, specific detection, intervention and follow-up measures are particularly worthy of attention and discussion.

Transcriptomic analyses of humans and mice provide insights into depression

Accumulating studies have been conducted to identify risk genes and relevant biological mechanisms underlying major depressive disorder(MDD).In particular,transcriptomic analyses in brain regions engaged in cognitive and emotional processes,e.g.,the dorsolateral prefrontal cortex(DLPFC),have provided essential insights.Based on three independent DLPFC RNA-seq datasets of 79 MDD patients and 75 healthy controls,we performed differential expression analyses using two alternative approaches for cross-validation.We also conducted transcriptomic analyses in mice undergoing chronic variable stress(CVS)and chronic social defeat stress(CSDS).We identified 12 differentially expressed genes(DEGs)through both analytical methods in MDD patients,the majority of which were also dysregulated in stressed mice.Notably,the mRNA level of the immediate early gene FOS(Fos proto-oncogene)was significantly decreased in both MDD patients and CVS-exposed mice,and CSDSsusceptible mice exhibited a greater reduction in Fos expression compared to resilient mice.These findings suggest the potential key roles of this gene in the pathogenesis of MDD related to stress exposure.Altered transcriptomes in the DLPFC of MDD patients might be,at least partially,the result of stress exposure,supporting that stress is a primary risk factor for MDD.

Successful Treatment with Triple Therapy of Amphotericin B, Voriconazole and Flucytosine on an AIDS Patients with Severe Cryptococcal Meningitis

A 35-year-old man(body weight=63 kg)with AIDS complaining fever and headache after having commenced anti-retroviral therapy(ART)for a week was admitted to our hospital.Five lumbar punctures performed during38 days could not confirm a cryptococcal meningitis(CM)based on staining or culture methods for cerebrospinal fluid(CSF).The disease quickly progressed with serious hearing/vision impairment and frequent onset of seizure and coma after being treated with corticosteroids for five days,and then CM was confirmed.Subsequent lumbar puncture showed elevated intracranial pressure as high as 870 mm H2O,even though treated with standard antifungal regimens for CM.His disease was finally controlled by a new triple therapy with amphotericin B(0.7mg?kg-1?day-1,intravenously),flucytosine(100 mg/kg perday,orally in four divided doses),and voriconazole(200mg every 12 hours)and ART containing lamivudine(300 mg/day),stavuding(30 mg,twice a day)and efavirenz(300 mg,orally every night).Although it is rare,negative CSF stain or culture for cryptococci in AIDS patients with CM can persist for a long time.Corticosteroids should be used cautiously when an effective anti-fungal therapy is not administered.Triple therapy with amphotericin B,flucytosine and voriconazole may be selectively applied in severe CM.Voriconazole can be co-administered with efavirenz with modified dosing.