Dynamics, association, and temporal sequence of cognitive function and frailty: a longitudinal study among Chinese community-dwelling older adults.

BACKGROUND: Little is known about the association of longitudinal dynamics between cognitive function and frailty in Chinese older adults. The temporal sequences between cognitive function and frailty remains unclear. Our study investigates this directionality association using longitudinal data. METHODS: Latent growth and multivariate latent growth models were employed to examine dynamics of cognition and frailty and their association among 2824 older adults in China. Cross-lagged panel analyses were used to assess the temporal sequences between frailty and cognition. The relation between cognitive domains and frailty was also examined using aforementioned methods. RESULTS: Cognitive function was negatively associated with frailty status. Higher initial level of cognition indicated lower baseline level (ß=-0.175, P < 0.001) and change rate (ß=-0.041, P = 0.002) of frailty. We observed a reciprocal association between frailty and cognitive function rather than a unidirectional causal relationship. The initial cognitive performance for all components were negatively associated with baseline (ß ranged between - 0.098 to -0.023) and change rate (ß ranged between - 0.007 to -0.024) of frail status. No consistent associations between change rate of cognitive components and either initial level or change rate of frailty were detected. CONCLUSIONS: Our study detected a reciprocal association between cognition and frailty rather than a unidirectional causal relationship. Our results also revealed different connections between cognitive performance and frailty across diverse cognitive domains.

Integrated metabolic and transcriptomic profiles reveal the germination-associated dynamic changes for the seeds of Cassia obtusifolia L.

INTRODUCTION: The seeds of Cassia obtusifolia L. (Cassiae [C.] semen) have been widely used as both food and traditional Chinese medicine in China. OBJECTIVES: We aimed to analyze the metabolic mechanisms underlying C. semen germination. MATERIALS AND METHODS: Different samples of C. semen at various germination stages were collected. These samples were subjected to 1 H-NMR and UHPLC/Q-Orbitrap-MS-based untargeted metabolomics analysis together with transcriptomics analysis. RESULTS: A total of 50 differential metabolites (mainly amino acids and sugars) and 20 key genes involved in multiple pathways were identified in two comparisons of different groups (36 h vs 12 h and 84 h vs 36 h). The metabolite-gene network for seed germination was depicted. In the germination of C. semen, fructose and mannose metabolism was activated in the testa rupture period, indicating more energy was needed (36 h). In the embryonic axis elongation period (84 h), the pentose and glucuronate interconversions pathway and the phenylpropanoid biosynthesis pathway were activated, which suggested some nutrient sources (nitrogen and sugar) were in demand. Furthermore, oxygen, energy, and nutrition should be supplied throughout the whole germination process. These global views open up an integrated perspective for understanding the complex biological regulatory mechanisms during the germination process of C. semen.

LSTMAtU-Net: A Precipitation Nowcasting Model Based on ECSA Module.

Precipitation nowcasting refers to the use of specific meteorological elements to predict precipitation in the next 0-2 h. Existing methods use radar echo maps and the Z-R relationship to directly predict future rainfall rates through deep learning methods, which are not physically constrained, but suffer from severe loss of predicted image details. This paper proposes a new model framework to effectively solve this problem, namely LSTMAtU-Net. It is based on the U-Net architecture, equipped with a Convolutional LSTM (ConvLSTM) unit with the vertical flow direction and depthwise-separable convolution, and we propose a new component, the Efficient Channel and Space Attention (ECSA) module. The ConvLSTM unit with the vertical flow direction memorizes temporal changes by extracting features from different levels of the convolutional layers, while the ECSA module innovatively integrates different structural information of each layer of U-Net into the channelwise attention mechanism to learn channel and spatial information, thereby enhancing attention to the details of precipitation images. The experimental results showed that the performance of the model on the test dataset was better than other examined models and improved the accuracy of medium- and high-intensity precipitation nowcasting.

Aberrant Function of the C-Terminal Tail of HIST1H1E Accelerates Cellular Senescence and Causes Premature Aging.

Histones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging.

Metabolomic Study on Iohexol-Induced Nephrotoxicity in Rats Based on NMR and LC-MS Analyses.

Iohexol, the raw material of nonionic X-ray computed tomography (X-CT) contrast medium, is usually injected into the vein before CT angiography diagnosis. It is used for angiography, urography, and lymphography. With the advantages of low contrast density and good tolerance, it is currently one of the most popular contrast media. However, the renal toxicity of iohexol seriously affects its safety use. Therefore, it is of great importance to identify new potential diagnostic biomarkers and therapeutic targets in the process of contrast medium-induced acute kidney injury (CI-AKI) in order to safely use iohexol in clinical practice. In this study, in order to understand the metabolic mechanism of CI-AKI, ultra-high-performance liquid chromatography/quadrupole-Orbitrap-mass spectrometry and 1H NMR-based metabolomic techniques were utilized to study the metabolic spectra of kidney, plasma, and urine from CI-AKI rats, and a total of 30 metabolites that were closely related to kidney injury were screened out, which were mainly related to 9 metabolic pathways. The results further indicated that iohexol might intensify kidney dysfunction in vivo by disrupting the metabolic pathways in the body, especially through blocking energy metabolism, amino acid metabolism, and promoting inflammatory reactions.

Iron chelation of hetrombopag in aplastic anemia: a post hoc analysis of a phase II study.

Hetrombopag is the only CFDA-approved thrombopoietin (TPO) receptor agonist for severe aplastic anemia (SAA) in China. Its chemical structure has an iron chelation domain. To explore the iron chelation effect of hetrombopag, we performed a post hoc analysis of the phase II clinical trial (NCT03557099). Thirty-five immunosuppressive therapy (IST)-refractory SAA patients were enrolled in the study, and the longitudinal changes of serum ferritin (SF) were assessed. At 18 weeks post-hetrombopag initiation, 51.4% of patients showed decreased SF levels by a median of 49.0 (18.1-95.5) % from baseline (median ΔSF decrease value, 917.2 ng/ml, range from 104.0 to 7030.0 ng/ml). A decrease in SF was found in 75.0% of hematologic responders and 31.6% of non-responders. Among the 24 patients with iron overload, 12 had decreased SF levels by up to 51% of the baseline. Patients with normal SF levels also showed decreased SF levels, and iron deficiency occurred in two patients. In conclusion, hetrombopag showed a powerful and rapid iron chelation effect.

Sequential acid/reduction response of triblock copolymeric nanomicelles to release camptothecin and toll-like receptor 7/8 agonist for orchestrated chemoimmunotherapy.

BACKGROUND: Immunosuppressive tumor immune microenvironment (TIME) lowers immunotherapy effectiveness. Additionally, low penetration efficiency and unpredictable drug release in tumor areas restrict tumor therapy. METHODS: A triblock copolymeric micelle (NanoPCPT+PIMDQ) was developed to carry the chemotherapeutic drug camptothecin (CPT) and the TLR7/8 agonist 1-(4-(aminomethyl)benzyl)-2-butyl-1H-imidazo[4,5-c] quinoline-4-amine (IMDQ) to achieve deep tumor penetration and on-demand drug release by responding to acid and reduction stimuli sequentially. The synergistic antitumour efficacy of NanoPCPT+PIMDQ was assessed both in vitro and in vivo. RESULTS: NanoPCPT+PIMDQ is composed of a hydrophilic PEG(polyethylene glycol) outer layer, an acid-sensitive EPEMA middle layer, and a drug inner core. Upon intratumoral injection, (i) NanoPCPT+PIMDQ first responds to the acidic tumor microenvironment and disintegrates to PIMDQ and PCPT, penetrating deep regions of the tumor; (ii) tumor cells are killed by the released CPT; (iii) DCs are activated by PIMDQ to increase the infiltration of cytotoxic T lymphocyte (CTL); and (iv) both downregulated Foxp3+ Tregs by CPT and repolarized M2 macrophages by PIMDQ can relieve the TIME. CONCLUSION: This pH/GSH-responsive triblock polymer-drug conjugate reduces immunosuppression and enhances the infiltration of CTLs by codelivering CPT and IMDQ in a controllable manner, providing a promising platform for synergistic tumor chemoimmunotherapy.

The path linking excessive daytime sleepiness and activity of daily living in Parkinson's disease: the longitudinal mediation effect of autonomic dysfunction.

BACKGROUND: Excessive daytime sleepiness (EDS) and autonomic dysfunction have been verified to impair activity of daily living (ADL) in patients with Parkinson's disease (PD). Whether EDS can affect ADL in PD patients through autonomic dysfunction is still unclear. The purpose of this study is to explore the longitudinal mediation effect of autonomic dysfunction between EDS and ADL. METHODS: Data used in this study were from six-follow-up visits of 413 patients with newly diagnosed PD from the Parkinson's Progression Markers Initiative (PPMI). We used latent growth mediation modeling (LGMM) to explore whether the autonomic dysfunction is a longitudinal mediator between EDS and ADL. RESULTS: The results showed that as the disease progresses, EDS (P < 0.001) and autonomic dysfunction (P < 0.001) gradually worsened and ADL (P < 0.001) gradually decreased in PD patients. In addition, the more severe the patients' EDS symptom, the more worsened the symptoms of autonomic dysfunction, which result in a decrease in ADL. Both the intercept (95% CI: 0.142, 0.308) and the slope (95% CI: 0.083, 0.331) of autonomic dysfunction showed a partial mediating effect, and a longitudinal mediation effect was presented. CONCLUSION: Longitudinal changes in EDS affect the ADL of PD patients directly or indirectly by affecting the symptoms of autonomic dysfunction. Controlling the symptoms of autonomic dysfunction may improve the ADL of PD patients with EDS.

Cost-effectiveness of comprehensive preventive measures for coal workers' pneumoconiosis in China.

BACKGROUND: Coal workers' pneumoconiosis (CWP) remains one of the most severe occupational diseases in China. Despite the implementation of CWP comprehensive preventive measures, the unreasonable allocation of investment by coal enterprises limits the effect of preventing CWP, especially when the health resources are inadequate. This study aims to evaluate the cost-effectiveness of comprehensive measures for CWP from the perspective of coal enterprises. METHODS: Comprehensive measures and two primary interventions (engineering controls and individual protective equipment) were selected. A time-dependent Markov model was developed to evaluate cost and quality-adjusted life-years (QALYs). The input data were collected from the survey and literature. A hypothetical null situation, in which the currently implemented interventions were eliminated, was used as a comparator based on the generalised cost-effectiveness analysis (GCEA) recommended by the World Health Organization (WHO). The primary outcomes of the model were reported in terms of incremental cost-effectiveness ratios (ICERs). Uncertainty was verified using one-way and probabilistic sensitivity analyses. RESULTS: The QALYs of the comprehensive measures, engineering controls, and individual protective equipment were 17.60, 17.50, and 16.85 years, respectively. Compared with null, the ICERs of the interventions were 65,044.73, 30,865.15, and 86,952.41 RMB/QALY, respectively. Individual protective equipment was dominated by an ICER of -11,416.02 RMB/QALY compared to engineering controls. Sensitivity analysis suggested the robustness of the results. CONCLUSIONS: The comprehensive preventive measures for CWP that are currently implemented in Chinese state-owned mines are cost-effective. In comprehensive measures, engineering controls are more cost-effective than individual protective equipment. Investment in engineering controls should be increased to improve the cost-effectiveness of preventing CWP.

Metrological properties of neuropsychological tests for measuring cognitive change in individuals with prodromal Alzheimer's disease.

OBJECTIVES: In Alzheimer's Disease (AD) research, choosing appropriate method for measuring change in cognitive function over time can be challenging. The aim for this study was to examine the sensitivity of four neuropsychological tests used to measure cognition during the transition from mild cognitive impairment (MCI) to AD, and the impacts of associated covariates. METHODS: We enrolled 223 patients with MCI who progressed to AD and had completed multiple follow-up assessments in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We constructed nonlinear mixed model for multivariate longitudinal data assuming that multiple neuropsychological tests would exhibit nonlinear transformation of a common factor in the latent cognitive process underlying the progression from MCI to AD. RESULTS: The Clinical Dementia Rating-Sum of the Boxes (CDR-SB) and Alzheimer's Disease Assessment Scale (11 items; ADAS-11) were more sensitive to cognitive changes in individuals with higher cognitive function, the Functional Activities Questionnaire (FAQ) was more sensitive to cognitive changes in individuals with middle cognitive function, and the Mini-Mental State Examination (MMSE) was more sensitive to cognitive changes in individuals with lower cognitive function. Gender (p = 0.0139) and educational level (p = 0.0094) had varying effects on different tests, such that men performed better on the FAQ and CDR-SB, and individuals with higher educational level tended to perform better on the FAQ and MMSE. CONCLUSIONS: When choosing appropriate neuropsychological tests in cognitive measurements, the cognitive functional level of the patient as well as the impacts of covariates should be considered.

Identification of vascular dementia and Alzheimer's disease hub genes expressed in the frontal lobe and temporal cortex by weighted co-expression network analysis and construction of a protein-protein interaction.

Background: It is difficult to distinguish cognitive decline due to AD from that sustained by cerebrovascular disease in view of the great overlap. It is uncertain in the molecular biological pathway behind AD and VaD.Objective: Our study aimed to explore the hub molecules and their associations with each other to identify potential biomarkers and therapeutic targets for the AD and VaD.Methods: We screened the differentially expressed genes of AD and VaD, used weighted gene co-expression network analysis and then constructed a VaD-AD-specific protein-protein interaction network with functional annotation to their related metabolic pathways. Finally, we performed a ROC curve analysis of hub proteins to get an idea about their diagnostic value.Results: In the frontal lobe and temporal cortex, hub genes were identified. With regard to VaD, there were only three hub genes which encoded the neuropeptides, SST, NMU and TAC1. The AUC of these genes were 0.804, 0.768 and 0.779, respectively. One signature was established for these three hub genes with AUC of 0.990. For the identification of AD and VaD, all hub genes were receptors. These genes included SH3GL2, PROK2, TAC3, HTR2A, MET, TF, PTH2R CNR1, CHRM4, PTPN3 and CRH. The AUC of these genes were 0.853, 0.859, 0.796, 0.775, 0.706, 0.677, 0.696, 0.668 and 0.652, respectively. The other signature was built for eleven hub genes with AUC of 0.990.Conclusion: In the frontal lobe and temporal cortex regions, hub genes are used as diagnostic markers, which may provide insight into personalized potential biomarkers and therapeutic targets for patients with VaD and AD.

Longitudinal Mediating Effect of Depression on the Relationship between Excessive Daytime Sleepiness and Activities of Daily Living in Parkinson's Disease.

OBJECTIVES: Whether depression affects activities of daily living (ADLs) in patients with Parkinson's disease (PD) via excessive daytime sleepiness (EDS) remains unclear; moreover, few longitudinal studies have been conducted. METHODS: We recruited 421 patients from the Parkinson's Progression Markers Initiative. We constructed a latent growth mediation model to explore the longitudinal mediating effect of depression on the relationship between EDS and ADLs. RESULTS: EDS (p < .001) and depression scores (p < .001) both increased, and ADL scores (p < .001) decreased. Moreover, EDS was positively correlated with depression, whereas an increase in EDS significantly reduced ADLs. The initial value (95% confidence interval [CI]: 0.026, 0.154) and the rate of change (95% CI: 0.138, 0.514) of self-reported depression measured using the Geriatric Depression Scale(GDS) partially mediated the association between EDS and ADL score. CONCLUSIONS: The indirect effect of the longitudinal changes of depression on the relationship between EDS and ADLs highlights the importance of depression changes in PD patients with EDS. CLINICAL IMPLICATIONS: Depression should be considered a mediator by clinicians; preventing the worsening of depression is essential for improving ADLs in patients with PD, especially those with EDS.

Tumor-Selective Activation of Toll-Like Receptor 7/8 Agonist Nano-Immunomodulator Generates Safe Anti-Tumor Immune Responses upon Systemic Administration.

Agonists of innate pattern recognition receptors such as toll-like receptors (TLRs) prime adaptive anti-tumor immunity and hold promise for cancer immunotherapy. However, small-molecule TLR agonists cause immune-related adverse effects (irAEs) after systemic administration. Herein, we report a polymeric nano-immunomodulator (cN@SS-IMQ) that is inactive until it is selectively metabolized to an active immunostimulant within the tumor. cN@SS-IMQ was obtained via self-assembly of a cyclo(Arg-Gly-Asp-D-Phe-Lys)-modified amphiphilic copolymeric prodrug. Upon systemic administration, cN@SS-IMQ preferentially accumulated at tumor sites and responded to high intracellular glutathione levels to release native imidazoquinolines for dendritic cell maturation, thereby enhancing the infiltration of T lymphocytes. Collectively, cN@SS-IMQ tends to activate the immune system without irAEs, thus suggesting its promising potential for safe systemic targeting delivery.

The path linking disease severity and cognitive function with quality of life in Parkinson's disease: the mediating effect of activities of daily living and depression.

BACKGROUND: Research on quality of life (QOL) with Parkinson's disease (PD) has examined direct influencing factors, not mediators. The study aim was to explore whether PD severity and poor cognitive function may decrease physical and mental QOL by reducing activities of daily living (ADL) and increasing depression in sequence. METHODS: We conducted a cross-sectional questionnaire study of 150 PD hospital patients in China. PD severity, cognitive function, ADL, depression, and QOL were evaluated. We used structural equation modeling to analyze the mediating effects of ADL and depression on the association between PD severity/cognition and the physical health and mental health component summary scores measured by the SF36 quality of life instrument. RESULTS: There was a significant mediating effect of PD severity on physical health via ADL and depression (95% CI: - 0.669, - 0.026), and a significant direct effect (p < 0.001). The mediating effect of PD severity on mental health via ADL and depression was significant (95% CI: - 2.135, - 0.726), but there was no direct effect (p = 0.548). There was a significant mediating effect of cognitive function on physical health via ADL and depression (95% CI: 0.025, 0.219) and a significant direct effect (p < 0.001). The mediating effect of cognitive function on mental health via ADL and depression was significant (95% CI: 0.256, 0.645), but there was no direct effect (p = 0.313). The physical health models showed a partial mediation, and the mental health models showed a complete mediation, of ADL and depression. CONCLUSIONS: PD severity and cognitive function increase depression by reducing ADL, leading to lower QOL, and directly or indirectly affect physical health and mental health through different pathways.

Genotype-phenotype correlations in individuals with pathogenic RERE variants.

Heterozygous variants in the arginine-glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here, we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies, and sensorineural hearing loss when compared with loss-of-function variants that are likely to lead to haploinsufficiency. A high percentage of RERE pathogenic variants affect a histidine-rich region in the Atrophin-1 domain. We have also identified a recurrent two-amino-acid duplication in this region that is associated with the development of a CHARGE syndrome-like phenotype. We conclude that mutations affecting RERE result in a spectrum of clinical phenotypes. Genotype-phenotype correlations exist and can be used to guide medical decision making. Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7.

Prioritizing genes for X-linked diseases using population exome data.

Many new disease genes can be identified through high-throughput sequencing. Yet, variant interpretation for the large amounts of genomic data remains a challenge given variation of uncertain significance and genes that lack disease annotation. As clinically significant disease genes may be subject to negative selection, we developed a prediction method that measures paucity of non-synonymous variation in the human population to infer gene-based pathogenicity. Integrating human exome data of over 6000 individuals from the NHLBI Exome Sequencing Project, we tested the utility of the prediction method based on the ratio of non-synonymous to synonymous substitution rates (dN/dS) on X-chromosome genes. A low dN/dS ratio characterized genes associated with childhood disease and outcome. Furthermore, we identify new candidates for diseases with early mortality and demonstrate intragenic localized patterns of variants that suggest pathogenic hotspots. Our results suggest that intrahuman substitution analysis is a valuable tool to help prioritize novel disease genes in sequence interpretation.

The next generation of population-based spinal muscular atrophy carrier screening: comprehensive pan-ethnic SMN1 copy-number and sequence variant analysis by massively parallel sequencing.

PURPOSE: To investigate pan-ethnic SMN1 copy-number and sequence variation by hybridization-based target enrichment coupled with massively parallel sequencing or next-generation sequencing (NGS). METHODS: NGS reads aligned to SMN1 and SMN2 exon 7 were quantified to determine the total combined copy number of SMN1 and SMN2. The ratio of SMN1 to SMN2 was calculated based on a single-nucleotide difference that distinguishes the two genes. SMN1 copy-number results were compared between the NGS and quantitative polymerase chain reaction and/or multiplex ligation-dependent probe amplification. The NGS data set was also queried for the g.27134T>G single-nucleotide polymorphism (SNP) and other SMN1 sequence pathogenic variants. RESULTS: The sensitivity of the test to detect spinal muscular atrophy (SMA) carriers with one copy of SMN1 was 100% (95% confidence interval (CI): 95.9-100%; n = 90) and specificity was 99.6% (95% CI: 99.4-99.7%; n = 6,648). Detection of the g.27134T>G SNP by NGS was 100% concordant with an restriction fragment-length polymorphism method (n = 493). Ten single-nucleotide variants in SMN1 were detectable by NGS and confirmed by gene-specific amplicon-based sequencing. This comprehensive approach yielded SMA carrier detection rates of 90.3-95.0% in five ethnic groups studied. CONCLUSION: We have developed a novel, comprehensive SMN1 copy-number and sequence variant analysis method by NGS that demonstrated improved SMA carrier detection rates across the entire population examined.Genet Med advance online publication 19 January 2017.

Hecate/Grip2a acts to reorganize the cytoskeleton in the symmetry-breaking event of embryonic axis induction.

Maternal homozygosity for three independent mutant hecate alleles results in embryos with reduced expression of dorsal organizer genes and defects in the formation of dorsoanterior structures. A positional cloning approach identified all hecate mutations as stop codons affecting the same gene, revealing that hecate encodes the Glutamate receptor interacting protein 2a (Grip2a), a protein containing multiple PDZ domains known to interact with membrane-associated factors including components of the Wnt signaling pathway. We find that grip2a mRNA is localized to the vegetal pole of the oocyte and early embryo, and that during egg activation this mRNA shifts to an off-center vegetal position corresponding to the previously proposed teleost cortical rotation. hecate mutants show defects in the alignment and bundling of microtubules at the vegetal cortex, which result in defects in the asymmetric movement of wnt8a mRNA as well as anchoring of the kinesin-associated cargo adaptor Syntabulin. We also find that, although short-range shifts in vegetal signals are affected in hecate mutant embryos, these mutants exhibit normal long-range, animally directed translocation of cortically injected dorsal beads that occurs in lateral regions of the yolk cortex. Furthermore, we show that such animally-directed movement along the lateral cortex is not restricted to a single arc corresponding to the prospective dorsal region, but occur in multiple meridional arcs even in opposite regions of the embryo. Together, our results reveal a role for Grip2a function in the reorganization and bundling of microtubules at the vegetal cortex to mediate a symmetry-breaking short-range shift corresponding to the teleost cortical rotation. The slight asymmetry achieved by this directed process is subsequently amplified by a general cortical animally-directed transport mechanism that is neither dependent on hecate function nor restricted to the prospective dorsal axis.

[The Efficacy and Safety of Venetoclax Combined with Azacitidine in the Treatment of Adult Patients with Acute Myeloid Leukemia Who Are Unfit for Intensive Chemotherapy].

OBJECTIVE: To observe the clinical efficacy and safety of venetoclax (VEN) combined with azacitidine (AZA) in the treatment of adult acute myeloid leukemia (AML) patients who are unfit for intensive chemotherapy. METHODS: The clinical data of 21 adult patients with unfit AML who were treated with VEN combined with AZA in the Second Hospital of Shanxi Medical University from January 2021 to May 2022 were collected, and the efficacy and safety were analyzed retrospectively. RESULTS: After one course of treatment with VEN and AZA, 16 out of 21 unfit AML patients reached complete remission (CR)/CR with incomplete hematologic recovery (CRi), 2 patients reached partial remission (PR), the overall response rate (ORR) was 85.7%. Among the 16 patients with CR/CRi, 13 achieved minimal residual disease (MRD) negativity. Among the 11 patients with adverse prognosis, 8 achieved CR/CRi. By the deadline of follow-up, the median overall suivival (OS) of the entire cohort was not reached, with 1-year OS rate of 61.7%. The main adverse events of VEN combined with AZA were myelosuppression, gastrointestinal reactions and infections. There were 13 cases of leukopenia, 7 cases of neutropenia, 7 cases of anemia, 4 cases of thrombocytopenia, and these hematologic adverse events were all grade 3-4. There were 11 cases with gastrointestinal reactions and 7 cases with infections. The above adverse events were controllable and tolerable. No tumor lysis syndrome or infection related death occurred. CONCLUSION: VEN combined with AZA can quickly achieve deep remission in adult patients with unfit AML, and it shows a good safety profile.

Safety and efficacy of dexmedetomidine vs. midazolam in complex gastrointestinal endoscopy: A systematic review and meta-analysis.

OBJECTIVE: This study aims to perform a meta-analysis to evaluate the safety and efficacy of dexmedetomidine versus midazolam for complex digestive endoscopy procedures, with the goal of offering comprehensive clinical evidence. METHODS: Following predefined inclusion criteria, five databases were systematically searched, with a focus on identifying randomized controlled trials (RCTs) that compared the administration of dexmedetomidine and midazolam during complex digestive endoscopy procedures. The statistical software Stata 15.1 was employed for meticulous data analysis. RESULTS: Sixteen RCTs were encompassed, involving a total of 1218 patients. In comparison to the midazolam group, dexmedetomidine administration was associated with a reduced risk of respiratory depression (RR=0.25, 95 %CI: 0.11-0.56) and hypoxemia (RR=0.22, 95 %CI: 0.12-0.39). Additionally, the dexmedetomidine group exhibited lower incidence rates of choking (RR=0.27, 95 %CI: 0.16-0.47), physical movement (RR=0.16, 95 %CI: 0.09-0.27), and postoperative nausea and vomiting (RR=0.56,95 %CI: 0.34-0.92). Patients and endoscopists in the dexmedetomidine group reported higher levels of satisfaction (patient satisfaction: SMD=0.73, 95 %CI: 0.26-1.21; endoscopist satisfaction: SMD=0.84, 95 %CI: 0.24-1.44). The incidence of hypotension and anesthesia recovery time did not significantly differ between the two groups (hypotension: RR=1.73,95 %CI:0.94-3.20; anesthesia recovery time: SMD=0.02, 95 %Cl: 0.44-0.49). It is noteworthy that the administration of dexmedetomidine was associated with a significant increase in the incidence of bradycardia in patients. CONCLUSION: Compared to midazolam, dexmedetomidine exhibits a favorable safety profile for use in complex gastrointestinal endoscopy by significantly reducing the risk of respiratory depression and hypoxemia. Despite this, dexmedetomidine is associated with a higher incidence of bradycardia. These findings underscore the need for further research through larger, multi-center studies to thoroughly investigate dexmedetomidine's safety and efficacy.