Combining GLP-1 receptor agonists and SGLT-2 inhibitors for cardiovascular disease prevention in type 2 diabetes:A systematic review with multiple network meta-regressions

BACKGROUND Glucagon-like peptide-1 receptor agonists(GLP-1RA)and sodium-glucose co-transporter-2 inhibitors(SGLT-2I)are associated with significant cardiovascular benefit in type 2 diabetes(T2D).However,GLP-1RA or SGLT-2I alone may not improve some cardiovascular outcomes in patients with prior cardiovascular co-morbidities.AIM To explore whether combining GLP-1RA and SGLT-2I can achieve additional benefit in preventing cardiovascular diseases in T2D.METHODS The systematic review was conducted according to PRISMA recommendations.The protocol was registered on PROSPERO(ID:42022385007).A total of 107049 participants from eligible cardiovascular outcomes trials of GLP-1RA and SGLT-2I were included in network meta-regressions to estimate cardiovascular benefit of the combination treatment.Effect modification of prior myocardial infarction(MI)and heart failure(HF)was also explored to provide clinical insight as to when the INTRODUCTION The macro-and micro-vascular benefits of glucagon-like peptide-1 receptor agonists(GLP-1RA)and sodium-glucose co-transporter-2 inhibitors(SGLT-2I)are independent of their glucose-lowering effects[1].In patients with type 2 diabetes(T2D),the major cardiovascular outcome trials(CVOT)showed that dipeptidyl peptidase-4 inhibitors(DPP-4I)did not improve cardiovascular outcomes[2],whereas cardiovascular benefit of GLP-1RA or SGLT-2I was significant[3,4].Further subgroup analyses indicated that the background cardiovascular risk should be considered when examining the cardiovascular outcomes of these newer glucose-lowering medications.For instance,prevention of major adverse cardiovascular events(MACE)was only seen in those patients with baseline atherosclerotic cardiovascular disease[3,4].Moreover,a series of CVOT conducted in patients with heart failure(HF)have demonstrated that(compared with placebo)SGLT-2I significantly reduced risk of hospitalization for HF or cardiovascular death,irrespective of their history of T2D[5-8].However,similar cardiovascular benefits were not observed in those with myocardial infarction(MI)[9,10].Cardiovascular co-morbidities are not only approximately twice as common but are also associated with dispropor-tionately worse cardiovascular outcomes in patients with T2D,compared to the general population[11].Therefore,it is of clinical importance to investigate whether the combination treatment of GLP-1RA and SGLT-2I could achieve greater cardiovascular benefit,particularly when considering patients with cardiovascular co-morbidities who may not gain sufficient cardiovascular protection from the monotherapies.This systematic review with multiple network meta-regressions was mainly aimed to explore whether combining GLP-1RA and SGLT-2I can provide additional cardiovascular benefit in T2D.Cardiovascular outcomes of these newer antidiabetic medications were also estimated under effect modification of prior cardiovascular diseases.This was to provide clinical insight as to when the combination treatment might be prioritized.

Impact of baseline hepatitis B virus viral load on the long-term prognosis of advanced hepatocellular carcinoma treated with immunotherapy

BACKGROUND Although the combination of lenvatinib and PD-1 inhibitors has become the standard regimen for the treatment of advanced hepatocellular carcinoma(HCC),real data on the impact of baseline hepatitis B virus(HBV)-DNA levels on the clinical efficacy of this regimen is still limited.AIM To evaluate the effectiveness of camrelizumab combined with lenvatinib in patients with HCC at varying levels of HBV-DNA.METHODS One hundred and twenty patients with HCC who received camrelizumab and lenvatinib treatment were categorized into two cohorts:HBV-DNA≤2000(n=66)and HBV-DNA>2000(n=54).The main outcomes measured were overall survival(OS)and progression-free survival(PFS),while additional outcomes included the rate of objective response rate(ORR),disease control rate(DCR),and any negative events.Cox proportional hazards regression analysis revealed independent predictors of OS,leading to the creation of a nomogram incorporating these variables.RESULTS The median PFS was 8.32 months for the HBV-DNA≤2000 group,which was similar to the 7.80 months observed for the HBV DNA>2000 group(P=0.88).Likewise,there was no notable variation in the median OS between the two groups,with durations of 13.30 and 14.20 months respectively(P=0.14).The ORR and DCR were compared between the two groups,showing ORR of 19.70%vs 33.33%(P=0.09)and DCR of 72.73%vs 74.07%(P=0.87).The nomogram emphasized the importance of antiviral treatment as the main predictor of patient results,with portal vein tumor thrombus and Barcelona Clinic Liver Cancer staging following closely behind.CONCLUSION The clinical outcomes of patients with HBV-associated HCC treated with camrelizumab in combination with lenvatinib are not significantly affected by HBV viral load.

Circular RNAs in early brain development and their influence and clinical significance in neuropsychiatric disorders

Neuropsychiatric disorders represent a set of severe and complex mental illnesses,and the exact etiologies of which are unknown.It has been well documented that impairments in the early development of the brain contribute to the pathogenesis of many neuropsychiatric disorders.Currently,the diagnosis of neuropsychiatric disorders largely relies on subjective cognitive assessment,because there are no widely accepted biochemical or genetic biomarkers for diagnosing mental illness.Circular RNAs (circRNAs) are a novel class of endogenous non-coding RNA (ncRNA) with a closed-loop structure.In recent years,there have been tremendous advances in our understanding of the expression profiles and biological roles of circRNAs.In the brain,circRNAs are particularly enriched and are expressed more abundantly in contrast to linear counterpart transcripts.They are highly active at neuronal synapses.These features make circRNAs uniquely crucial for understanding brain health,disease,and neuropsychiatric disorders.This review focuses on the role of circRNAs in early brain development and other brain-related processes that have been associated with the development of neuropsychiatric disorders.In addition,we discuss the potential for blood or cerebrospinal fluid circRNAs to be used as novel biomarkers in the early diagnosis of neuropsychiatric disorders.The findings reviewed here may provide new insight into the pathological mechanisms underlying the onset and progression of neuropsychiatric disorders.

Synchronous diagnosis and treatment of acute myeloid leukemia and chronic lymphocytic leukemia:Two case reports

BACKGROUND The concurrence of acute myeloid leukemia(AML)and chronic lymphocytic leukemia(CLL)is rare.Previous reports of such cases have focused mainly on clinical diagnosis and characteristics,so the mechanism remains unclear,and therapy options have been poorly explored.CASE SUMMARY Here,we report two cases of synchronous AML and CLL.Flow cytometry revealed two distinct abnormal cell populations(myeloblasts and lymphoid cells)according to scatter characteristics.CD5-positive B cell lymphoma with myeloid leukemia invasion was observed on lymph node biopsy.Chemotherapy regimens indicated for both AML and CLL were used in our patients,and our patients achieved complete response after chemotherapy.Next-generation sequencing of 88 genes was performed.CONCLUSION We conclude that early mutation and dysregulation at the hematopoietic stem cell stage and the accumulation of multiple rearrangements may cause the concurrence of CLL and AML.The treatment of infection and combination therapy aimed at the CLL component are significant in the management of patients with concurrent CLL and AML.

Treatment of vitamin K-dependent coagulation factor deficiency and subarachnoid hemorrhage

BACKGROUND： In adults, vitamin K-dependent coagulation factor deficiency （VKCFD） increases in the recent years. We treated a VKCFD patient with subarachnoid hemorrhage, with favorable outcomes.METHODS： A 19-year-old male student with VKCFD was treated at our hospital. The initial treatment was injection of a large dose of vitamin K and fresh plasma, and then with oral high dose of vitamin K4.RESULTS： At 4 weeks after admission, the focus of hemorrhage subsided, neurological examination was normal, and the patient was discharged.CONCLUSIONS： VKCFD is rare and its diagnosis should be based on the history of the patient and the results of laboratory examinations. A large dose of vitamin K is the fi rst choice of treatment.

A novel micro-straw for cryopreservation of sma number of human spermatozoon

Cryopreservation of few spermatozoa is still a major challenge for male fertility preservation. This study reports use a new micro-straw （LSL straw） for freezing few spermatozoa for intracytoplasmic sperm injection （ICSI）. Semen samples from 22 fertile donors were collected, and each semen sample was diluted and mixed with cryoprotectant in a ratio of 1：1, and then frozen using three different straws such as LSL straw （50-100μl）, traditional 0.25 ml and 0.5 ml straws. For freezing, all straws were fumigated with liquid nitrogen, with temperature directly reducing to -130--140℃. Sperm concentration, progressive motility, morphology, acrosome integrity, and DNA fragmentation index were evaluated before and after freezing. After freezing-thawing, LSL straw group had significantly higher percentage of sperm motility than traditional 0.25 ml and 0.5 ml straw groups （38.5% vs 27.4% and 25.6%, P 〈 0.003）. Sperm motility and acrosomal integrity after freezing-thawing were significantly lower than that of before freezing. However, there was no significant difference in morphology, acrosome, and DNA integrity between the three types of straws （P 〉 0.05）. As LSL straws were thinner and hold very small volume, the freezing rate of LSL straw was obviously faster than 0.25 ml straw and 0.5 ml straws. In conclusion, LSL micro-straws may be useful to store few motile spermatozoa with good recovery of motility for patients undergoing ICSI treatment.

Dynamic recrystallization behavior of Fe–20Cr–30Ni–0.6Nb–2Al–Mo alloy

Single-pass compression tests of an aluminaforming austenite(AFA) alloy(Fe–20Cr–30Ni–0.6Nb–2Al–Mo) were performed using a Gleeble-3500 thermal–mechanical simulator. By combining techniques of electron back-scattered diffraction(EBSD) and transmission electron microscopy(TEM), the dynamic recrystallization(DRX) behavior of the alloy at temperatures of 950–1100 ℃ and strain rates of 0.01–1.00 s^(-1) was investigated. The regression method was adopted to determine the thermal deformation activation energy and apparent stress index and to construct a thermal deformation constitutive model. Results reveal that the flow stress is strongly dependent on temperature and strain rate and it increases with temperature decreasing and strain rate increasing. The DRX phenomenon occurs more easily at comparably higher deformation temperatures and lower strain rates. Based on the method for solving the inflection point via cubic polynomial fitting of strain hardening rate(h) versus strain(e) curves, the ratio of critical strain(ec) to peak strain(ep) during DRX was precisely predicted. The nucleation mechanisms of DRX during thermal deformation mainly include the strain-induced grain boundary(GB)migration, grain fragmentation, and subgrain coalescence.