ZBTB20 is essential for cochlear maturation and hearing in mice.

The mammalian cochlear epithelium undergoes substantial remodeling and maturation before the onset of hearing. However, very little is known about the transcriptional network governing cochlear late-stage maturation and particularly the differentiation of its lateral nonsensory region. Here, we establish ZBTB20 as an essential transcription factor required for cochlear terminal differentiation and maturation and hearing. ZBTB20 is abundantly expressed in the developing and mature cochlear nonsensory epithelial cells, with transient expression in immature hair cells and spiral ganglion neurons. Otocyst-specific deletion of Zbtb20 causes profound deafness with reduced endolymph potential in mice. The subtypes of cochlear epithelial cells are normally generated, but their postnatal development is arrested in the absence of ZBTB20, as manifested by an immature appearance of the organ of Corti, malformation of tectorial membrane (TM), a flattened spiral prominence (SP), and a lack of identifiable Boettcher cells. Furthermore, these defects are related with a failure in the terminal differentiation of the nonsensory epithelium covering the outer border Claudius cells, outer sulcus root cells, and SP epithelial cells. Transcriptome analysis shows that ZBTB20 regulates genes encoding for TM proteins in the greater epithelial ridge, and those preferentially expressed in root cells and SP epithelium. Our results point to ZBTB20 as an essential regulator for postnatal cochlear maturation and particularly for the terminal differentiation of cochlear lateral nonsensory domain.

Age-stratified risk of suicide in patients with schizophrenia.

OBJECTIVES: Schizophrenia is associated with an increased risk of suicide. Few studies have investigated the risk of suicide across different ages, likely due to limitations around sample size. METHODS: From the National Health Insurance Research Database in Taiwan, this study identified 195,787 patients with schizophrenia from January 1, 2000, to December 31, 2019. During the study period, 3848 patients died from suicide. We calculated the standardized mortality ratio (SMR) for suicide stratified by age. In this age-stratified, nested case-control study, risk set sampling was used to match each case with 4 living controls by age, sex, and the year of the first diagnosis with schizophrenia. Conditional logistic regression was used for estimating age-stratified risk profiles. RESULTS: The SMR was the highest in the <25 years age group (52.8) and inversely correlated with age. Unemployment was associated with an increased risk of suicide in the 25 to 34, 35 to 44, 45 to 54, and 55 to 64 years age groups. Depressive and sleep disorders before suicide were more common among suicide cases with schizophrenia than among controls across all age groups. Drug-induced and alcohol-induced mental disorders were significantly associated with suicide but were observed only in the age group younger than 54. Heart disease, pneumonia, and moderate or severe renal disease were risk factors for suicide in the age groups less than 65. CONCLUSIONS: The risk factors for suicide differ by age. This study's findings can be used to optimize health-care interventions for preventing suicide in patients with schizophrenia.

Phosphorus-doped TiO2mesoporous nanocrystals for anodes in high-current-rate lithium ion batteries.

Limited by the intrinsic low electronic conductivity and inferior electrode kinetics, the use of TiO2as an anode material for lithium ion batteries (LIBs) is hampered. Nanoscale surface-engineering strategies of morphology control and particle size reduction have been devoted to increase the lithium storage performances. It is found that the ultrafine nanocrystal with mesoporous framework plays a crucial role in achieving the excellent electrochemical performances due to the surface area effect. Herein, a promising anode material for LIBs consisting of phosphorus-doped TiO2mesoporous nanocrystals (P-TMC) with ultrafine size of 2-8 nm and high specific surface area (234.164 m2g-1) has been synthesized. It is formed through a hydrothermal process and NaBH4assisted heat treatment for anatase defective TiO2(TiO2-x) formation followed by a simple gas phosphorylation process in a low-cost reactor for P-doping. Due to the merits of the large specific surface area for providing more reaction sites for Li+ions to increase the storage capacity and the presence of oxygen vacancies and P-doping for enhancing material's electronic conductivity and diffusion coefficient of ions, the as-designed P-TMC can display improved electrochemical properties. As a LIB anode, it can deliver a high reversible discharge capacity of 187 mAh g-1at 0.2 C and a good long cycling performance with ∼82.6% capacity retention (101 mAh g-1) after 2500 cycles at 10 C with an average capacity loss of only 0.007% per cycle. Impressively, even the current rate increases to 100 times of the original rate, a satisfactory capacity of 104 mAh g-1can be delivered, displaying good rate capacity. These results suggest the P-TMC a viable choice for application as an anode material in LIB applications. Also, the strategy in this work can be easily extended to the design of other high-performance electrode materials with P-doping for energy storage.

Cluster analysis dissecting cognitive deficits in older adults with major depressive disorder and the association with neurofilament light chain.

BACKGROUND: Cognitive impairment is a growing problem with increasing burden in global aging. Older adults with major depressive disorder (MDD) have higher risk of dementia. Neurofilament light chain (NfL) has been proven as a potential biomarker in neurodegenerative disease, including dementia. We aimed to investigate the association between cognitive deficits and NfL levels in older adults with MDD. METHODS: In this cross-sectional study, we enrolled 39 MDD patients and 15 individuals with mild neurocognitive disorder or major neurocognitive disorder, Alzheimer's type, as controls, from a tertiary psychiatric hospital. Both groups were over age 65 and with matched Mini-Mental State Examination (MMSE) score. Demographic data, clinical variables, and plasma NfL levels were obtained. We used cluster analysis according to their cognitive profile and estimated the correlation between plasma NfL levels and each cognitive domain. RESULTS: In the MDD group, participants had higher rate of family psychiatry history and current alcohol use habit compared with controls. Control group of neurocognitive disorders showed significantly lower score in total MMSE and higher plasma NfL levels. Part of the MDD patients presented cognitive deficits clustered with that of neurocognitive disorders (cluster A). In cluster A, the total MMSE score (r=-0.58277, p=0.0287) and the comprehension domain (r=-0.71717, p=0.0039) were negatively correlated to NfL levels after adjusting for age, while the associations had not been observed in the other cluster. CONCLUSIONS: We noted the negative correlation between NfL levels and cognition in MDD patients clustered with neurodegenerative disorder, Alzheimer's type. NfL could be a promising candidate as a biomarker to predict subtype of patients in MDD to develop cognitive decline. Further longitudinal studies and within MDD cluster analysis are required to validate our findings for clinical implications.

Antipsychotic medications and severe sepsis in schizophrenia: A nested case-control study.

BACKGROUND: Sepsis constitutes a condition that involves life-threatening organ dysfunction induced by severe infection. This nested case-control study investigated risk factors for severe sepsis and whether antipsychotic use is associated with severe sepsis risk in patients with schizophrenia, a topic that has not been comprehensively explored in previous studies. METHODS: We selected 39,432 patients with schizophrenia aged between 15 and 65 years from Taiwan's Psychiatric Inpatient Medical Claims database for the period 2000-2012. The case group comprised patients with severe sepsis after their first psychiatric admission (n = 1382). The case and control groups were randomly matched (1:4) by age, sex and first psychiatric admission (year) and finally comprised 1382 and 5528 individuals, respectively. We employed multivariable conditional logistic regression to identify (1) risk factors (physical illnesses and nonpsychiatric medications) and (2) antipsychotic-severe sepsis associations. RESULTS: Higher numbers of psychiatric admissions and physical illnesses such as delirium, cerebrovascular disease and cancer were significantly associated with a higher risk of severe sepsis. Furthermore, severe sepsis was associated with the use of antithrombotic agents, systemic corticosteroids and agents targeting the renin-angiotensin system. Clozapine (adjusted risk ratio = 1.65) and quetiapine (adjusted risk ratio = 1.59) use were associated with an increased risk of severe sepsis. The use of more than one antipsychotic drug could further increase this risk. CONCLUSION: Several physical illnesses and nonpsychiatric medications increase the risk of severe sepsis in patients with schizophrenia. Specifically, clozapine or quetiapine use significantly increased the risk of severe sepsis in these patients.

Mapping and candidate gene analysis of clustered bud on the main inflorescence in Brassica napus L.

Breeding rapeseed varieties with more main inflorescence siliques is an idea for developing rapeseed varieties that are suitable for light and simplified cultivation. The Brassica napus exhibited cluster bud of the main inflorescence (Bnclib) gene. At the fruiting stage, the main inflorescence had more siliques, higher density, and more main inflorescences. Moreover, the top of the main inflorescence bifurcated. Genetic analysis showed that the separation ratio between Bnclib and the wild type in the F2 generation was 3:1, which indicated that the trait was a single-gene-dominant inheritance. Among the 24 candidate genes, only one gene, BnaA03g53930D, showed differential expression between the groups (False discovery rate, FDR ≤ 0.05, |log2FC|≤ 1). qPCR verification of the BnaA03g53930D gene between Huyou 17 and its Bnclib near-isogenic line showed that BnaA03g53930D was significantly differentially expressed in the stem tissue of Huyou 17 and its Bnclib near-isogenic line (Bnclib NIL). The determination of gibberellin (GA), brassinolide (BR), cytokinin (CTK), jasmonic acid (JA), growth hormone (IAA), and strigolactone (SL) content in the shoot apex of Huyou 17 by Bnclib NIL and wild type showed that all six hormones significantly differed between the Bnclib NIL and Huyou 17. It is necessary to conduct further research on the interactions between JA and the other five hormones and the main inflorescence bud clustering in B. napus.

Effects of Vitamin D Supplementation on Cognitive Outcomes: A Systematic Review and Meta-Analysis.

Clinical studies examining the effects of vitamin D on cognition have reported inconsistent results. To date, no comprehensive study has examined this effect on the basis of sample characteristics or intervention model-related factors. This systematic review and meta-analysis of randomized controlled trials investigated the effects of vitamin D supplementation on global cognitive function and specific cognitive domains. This review was preregistered in the PROSPERO database (CRD42021249908) and comprised 24 trials enrolling 7557 participants (mean age: 65.21 years; 78.54% women). The meta-analysis revealed that vitamin D significantly influenced global cognition (Hedges' g = 0.128, p = .008) but not specific cognitive domains. A subgroup analysis indicated that the effect size of vitamin D was stronger for vulnerable populations (Hedges' g = 0.414) and those with baseline vitamin D deficiency (Hedges' g = 0.480). On the basis of subgroup analyses in studies without biological flaws (Hedges' g = 0.549), we suggest that an intervention model should correct baseline vitamin D deficiency. Our results indicate that vitamin D supplementation has a small but significant positive effect on cognition in adults.

Unfavorable cancer mortality-to-incidence ratios in patients with schizophrenia: A nationwide cohort study in Taiwan, 2000-2019.

OBJECTIVES: Studies on cancer incidence and mortality in patients with schizophrenia have reported inconsistent findings. In this study, we simultaneously investigated cancer incidence and mortality in patients with schizophrenia and evaluated the cancer mortality-to-incidence ratio (MIR), which is rare in the literature. METHODS: From the Taiwan National Health Insurance Database, we collected the data of 107,489 patients who received a diagnosis of schizophrenia between 2000 and 2019. Data regarding cancer incidence and mortality were obtained from the Taiwan Cancer Registry and National Mortality Database, respectively. In total, 3881 incident cancer cases and 2288 cancer mortality cases were identified. Standardized incidence ratios (SIRs), mortality rate ratios (MRRs), and MIRs were compared between patients with schizophrenia and the general population. RESULTS: The overall rate of cancer incidence was slightly lower (SIR: 0.95; 95% confidence interval [CI]: 0.92-0.98; p < 0.001) and that of cancer mortality was higher (MRR: 1.29; 95% CI: 1.23-1.3; p < 0.001) in patients with schizophrenia than in the general population. The MIR for overall cancer was significantly higher in the patients with schizophrenia. The relative MIR (MIR of patients with schizophrenia divided by that of the general population) was 1.36 (95% CI: 1.30-1.42). CONCLUSION: The MIR was significantly higher in the patients with schizophrenia than in the general population, indicating the possible presence of healthcare disparities. Additional studies are required to investigate the potential association between the significantly higher MIR in patients with schizophrenia and healthcare disparities.

Bacterial DNA metabolism analysis by metagenomic next-generation sequencing (mNGS) after treatment of bloodstream infection.

BACKGROUND: With the advent of metagenomic next-generation sequencing (mNGS), the time of DNA metabolism can be explored after bacteria be killed. In this study, we applied mNGS in investigation of the clearance profile of circulating bacteria DNA. METHODS: All of the rabbits were injected with the inactivated Escherichia coli. Using mNGS, we analyzed serial samples of plasma collected from rabbits to detect clearance profile of circulating E. coli DNA. RESULTS: In this study, we found that the of E. coli DNA could still be detected 6 h after injecting killed bacteria. The clearance half-lives associated with the 2 phases are 0.37 and 1.81 h. We also explored there is no correlation between the disease severity with the E. coli DNA reads in circulation. CONCLUSIONS: After the bacteria were completely killed, their DNA could still be detected in the blood circulation. The metabolism of bacterial DNA in the circulation had two phases: fast and slow phases, and there were no correlations between the level of bacteria reads with the severity of patients' disease after the bacteria have been completely killed.

Improving the Thermostability of Thermomyces lanuginosus Lipase by Restricting the Flexibility of N-Terminus and C-Terminus Simultaneously via the 25-Loop Substitutions.

(1) Lipases are catalysts widely applied in industrial fields. To sustain the harsh treatments in industries, optimizing lipase activities and thermal stability is necessary to reduce production loss. (2) The thermostability of Thermomyces lanuginosus lipase (TLL) was evaluated via B-factor analysis and consensus-sequence substitutions. Five single-point variants (K24S, D27N, D27R, P29S, and A30P) with improved thermostability were constructed via site-directed mutagenesis. (3) The optimal reaction temperatures of all the five variants displayed 5 °C improvement compared with TLL. Four variants, except D27N, showed enhanced residual activities at 80 °C. The melting temperatures of three variants (D27R, P29S, and A30P) were significantly increased. The molecular dynamics simulations indicated that the 25-loop (residues 24-30) in the N-terminus of the five variants generated more hydrogen bonds with surrounding amino acids; hydrogen bond pair D254-I255 preserved in the C-terminus of the variants also contributes to the improved thermostability. Furthermore, the newly formed salt-bridge interaction (R27…E56) in D27R was identified as a crucial determinant for thermostability. (4) Our study discovered that substituting residues from the 25-loop will enhance the stability of the N-terminus and C-terminus simultaneously, restrict the most flexible regions of TLL, and result in improved thermostability.

Integrative Proteomics and Phosphoproteomics Analysis of the Rat Adenohypophysis after GnRH Treatment.

The regulation of mammalian reproductive activity is tightly dependent on the HPG axis crosstalk, in which several reproductive hormones play important roles. Among them, the physiological functions of gonadotropins are gradually being uncovered. However, the mechanisms by which GnRH regulates FSH synthesis and secretion still need to be more extensively and deeply explored. With the gradual completion of the human genome project, proteomes have become extremely important in the fields of human disease and biological process research. To explore the changes of protein and protein phosphorylation modifications in the adenohypophysis after GnRH stimulation, proteomics and phosphoproteomics analyses of rat adenohypophysis after GnRH treatment were performed by using TMT markers, HPLC classification, LC/MS, and bioinformatics analysis in this study. A total of 6762 proteins and 15,379 phosphorylation sites contained quantitative information. Twenty-eight upregulated proteins and fifty-three downregulated proteins were obtained in the rat adenohypophysis after GnRH treatment. The 323 upregulated phosphorylation sites and 677 downregulated phosphorylation sites found in the phosphoproteomics implied that a large number of phosphorylation modifications were regulated by GnRH and were involved in FSH synthesis and secretion. These data constitute a protein-protein phosphorylation map in the regulatory mechanism of "GnRH-FSH," which provides a basis for future studies on the complex molecular mechanisms of FSH synthesis and secretion. The results will be helpful for understanding the role of GnRH in the development and reproduction regulated by the pituitary proteome in mammals.

Characteristics and comparisons of the aerobic and anaerobic denitrification of a Klebsiella oxytoca strain: Performance, electron transfer pathway, and mechanism.

The performance and electron (e-) transfer mechanisms of anaerobic and aerobic denitrification by strain Klebsiella were investigated in this study. The RT-PCR results demonstrated that the membrane bound nitrate reductase gene (narG) and Cu-nitrite reductase gene (nirK) were responsible for both aerobic and anerobic denitrification. The extreme low gene relative abundance of nirK might be responsible for the severe accumulation of NO2--N (nitrogen in the form of NO2- ion) under anaerobic condition. Moreover, the nitrite reductase (Nir) activity was 0.31 µg NO2--N min-1 mg-1 protein under anaerobic conditions, which was lower than that under aerobic conditions (0.38 µg NO2--N min-1 mg-1 protein). By using respiration chain inhibitors, the e- transfer pathways of anaerobic and aerobic denitrification of Klebsiella strain were constructed. Fe-S protein and Complex III were the core components under anaerobic conditions, while Coenzyme Q (CoQ), Complexes I and III played a key role in aerobic denitrification. Nitrogen assimilation was found to be the main way to generate NH4+-N (nitrogen in the form of NH4+ ion) during anaerobic denitrification, and also served as the primary nitrogen removal way under aerobic condition. The results of this study may help to improve the understanding of the core components of strain Klebsiella during aerobic and anaerobic denitrifications, and may suggest potential applications of the strain for nitrogen-containing wastewater.

[Chrysin alleviates cerebral ischemia-reperfusion injury by inhibiting ferroptosis in rats].

The purpose of this study is to investigate whether chrysin reduces cerebral ischemia-reperfusion injury(CIRI) by inhi-biting ferroptosis in rats. Male SD rats were randomly divided into a sham group, a model group, high-, medium-, and low-dose chrysin groups(200, 100, and 50 mg·kg~(-1)), and a positive drug group(Ginaton, 21.6 mg·kg~(-1)). The CIRI model was induced in rats by transient middle cerebral artery occlusion(tMCAO). The indexes were evaluated and the samples were taken 24 h after the operation. The neurological deficit score was used to detect neurological function. The 2,3,5-triphenyl tetrazolium chloride(TTC) staining was used to detect the cerebral infarction area. Hematoxylin-eosin(HE) staining and Nissl staining were used to observe the morphological structure of brain tissues. Prussian blue staining was used to observe the iron accumulation in the brain. Total iron, lipid pero-xide, and malondialdehyde in serum and brain tissues were detected by biochemical reagents. Real-time quantitative polymerase chain reaction(RT-qPCR), immunohistochemistry, and Western blot were used to detect mRNA and protein expression of solute carrier fa-mily 7 member 11(SLC7A11), transferrin receptor 1(TFR1), glutathione peroxidase 4(GPX4), acyl-CoA synthetase long chain family member 4(ACSL4), and prostaglandin-endoperoxide synthase 2(PTGS2) in brain tissues. Compared with the model group, the groups with drug intervention showed restored neurological function, decreased cerebral infarction rate, and alleviated pathological changes. The low-dose chrysin group was selected as the optimal dosing group. Compared with the model group, the chrysin groups showed reduced content of total iron, lipid peroxide, and malondialdehyde in brain tissues and serum, increased mRNA and protein expression levels of SLC7A11 and GPX4, and decreased mRNA and protein expression levels of TFR1, PTGS2, and ACSL4. Chrysin may regulate iron metabolism via regulating the related targets of ferroptosis and inhibit neuronal ferroptosis induced by CIRI.

Therapeutic Drug Monitoring of Paliperidone in Patients With Schizophrenia in Taiwan.

BACKGROUND: The blood level of antipsychotics affects clinical responses to the drug; it can be influenced by race and several individual factors. This study analyzed the therapeutic plasma concentrations (Cps) of paliperidone for both oral and long-acting injectable (LAI) formulations in clinical samples from Taiwanese patients. METHODS: Patients diagnosed with schizophrenia and treated with either oral paliperidone for at least 4 weeks or LAI paliperidone for at least 6 months were enrolled. Blood samples were taken before the morning dose of oral paliperidone or the injection of LAI paliperidone to obtain the trough Cps. RESULTS: Among the patients in this study, 51 were taking oral paliperidone, and 26 were receiving LAI paliperidone. In the oral group, the mean Cps were 40.2 ± 19.8 ng/mL in patients taking 9 mg/d and 44.2 ± 15.9 ng/mL in those taking 12 mg/d. In the LAI group, the mean Cps were 32.9 ± 12.7 ng/mL in patients receiving 100 mg per 28 days and 49.9 ± 25.9 ng/mL in those receiving 150 mg per 28 days. The mean Cps per daily dose (Cps/DD) were 4.11 ± 1.99 ng/mL/mg in the oral group and 9.24 ± 3.78 ng/mL/mg in the LAI group. CONCLUSIONS: Under the suggested DD for oral and LAI paliperidone treatment, most Taiwanese patients with schizophrenia can reach the suggested therapeutic Cps range. Wide interindividual differences were observed in the Cps/DD for both the oral (7-fold) and LAI paliperidone (4-fold) groups. Compared with Western reports, no difference was observed in the body weight-adjusted Cps/DD.

Correlations between leaf economics, mechanical resistance and drought tolerance across 41 cycad species.

BACKGROUND AND AIMS: We conducted a comprehensive analysis of the functional traits of leaves (leaflets) of cycads. The aim of this study was to clarify the functional divergence between the earlier origin Cycadaceae and the later differentiated Zamiaceae, and the differences in trait associations between cycads and angiosperms. METHODS: We selected 20 Cycadaceae species and 21 Zamiaceae species from the same cycad garden in South China, and measured their leaf structure, economic traits, mechanical resistance (Fp) and leaf water potential at the turgor loss point (πtlp). In addition, we compiled a dataset of geographical distribution along with climatic variables for these cycad species, and some leaf traits of tropical-sub-tropical angiosperm woody species from the literature for comparison. KEY RESULTS: The results showed significantly contrasting leaf trait syndromes between the two families, with Zamiaceae species exhibiting thicker leaves, higher carbon investments and greater Fp than Cycadaceae species. Leaf thickness (LT) and πtlp were correlated with mean climatic variables in their native distribution ranges, indicating their evolutionary adaptation to environmental conditions. Compared with the leaves of angiosperms, the cycad leaves were thicker and tougher, and more tolerant to desiccation. Greater Fp was associated with a higher structural investment in both angiosperms and cycads; however, cycads showed lower Fp at a given leaf mass per area or LT than angiosperms. Enhancement of Fp led to more negative πtlp in angiosperms, but the opposite trend was observed in cycads. CONCLUSIONS: Our results reveal that variations in leaf traits of cycads are mainly influenced by taxonomy and the environment of their native range. We also demonstrate similar leaf functional associations in terms of economics, but different relationships with regard to mechanics and drought tolerance between cycads and angiosperms. This study expands our understanding of the ecological strategies and likely responses of cycads to future climate change.

Excess mortality and risk factors for mortality among patients with severe mental disorders receiving home care case management.

AIM: Home care case management (CM) is the main intervention for patients with severe mental disorders (SMDs) requiring outreach care. This study investigated the long-term mortality outcome and associated risk factors in patients who received home care CM. METHODS: This nationwide study enrolled patients who received home care CM (n = 10,255) between 1 January 1999 and 31 December 2010. Each patient was followed up from the baseline (when patients underwent home case CM for the first time during the study period) to the censor (i.e. mortality or the end of the study). We calculated the standardized mortality ratio (SMR) and presented by age and diagnosis. Multivariate regression was performed to assess independent risk factors for mortality. RESULTS: Among 10,255 patients who received home care CM, 1409 died during the study period; the overall SMR was 3.13. Specifically, patients with organic mental disorder had the highest SMR (4.98), followed by those with schizophrenia (3.89), major depression (2.98), and bipolar disorder (1.97). In the multivariate analysis, patients with organic mental disorder or dementia had the highest risk, whereas the mortality risk in patients with schizophrenia was comparable to that in patients with bipolar disorder or major depression. Deceased patients had a significantly higher proportion of acute or chronic physical illnesses, including cancer, chronic hepatic disease, pneumonia, diabetes mellitus, cardiovascular disease, and asthma. CONCLUSION: This study presented the gap of mortality in patients with SMDs receiving home care CM in Taiwan. We highlight the need for effective strategies to improve medical care for this specified population.

Chimeric antigen receptor therapy in hematological malignancies: antigenic targets and their clinical research progress.

Chimeric antigen receptor (CAR)-based immunotherapy has achieved dramatic success in the treatment of B cell malignancies, based on the summary of current research data, and has shown good potential in early phase cancer clinical trials. Modified constructs are being optimized to recognize and destroy tumor cells more effectively. By targeting the proper B-lineage-specific antigens such as CD19 and CD20, adoptive immunotherapy has demonstrated promising clinical results and already plays a role in the treatment of several lymphoid malignancies, which highlights the importance of target selection for other CAR therapies. The high efficacy of CAR-T cells has resulted in the approval of anti-CD19-directed CAR-T cells for the treatment of B cell malignancies. In this review, we focus on the basic structure and current clinical application of CAR-T cells, detail the research progress of CAR-T for different antigenic targets in hematological malignancies, and further discuss the current barriers and proposed solutions, investigating the possible mechanisms of recurrence of CAR-T cell therapy. A summary of the paper is also given to overview as the prospects for this therapy.

ADAR1 Alleviates Inflammation in a Murine Sepsis Model via the ADAR1-miR-30a-SOCS3 Axis.

Adenosine deaminase acting on double-stranded RNA 1 (ADAR1) mediates adenosine-to-inosine (A-to-I) RNA editing events. ADAR1 is highly expressed in "septic" macrophages and in small intestinal tissues of mice with sepsis. Overexpression of ADAR1 suppresses inflammation and intestinal damage. However, the specific underlying mechanism is unclear. This study was conducted to explore how microRNA (miRNA) regulates the anti-inflammatory mechanism of macrophages following ADAR1 upregulation. A murine sepsis model was established by cecal ligation and puncture (CLP). Mice were randomly assigned to sham, CLP, and CLP+ADAR1 groups. Hematoxylin and eosin (HE) staining and fluorescence isothiocyanate-dextran were used to evaluate intestinal injury and permeability. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blotting, and Luminex assays were performed to detect changes in the expression of inflammatory cytokines. Adenoviruses were used to express ADAR1 in RAW 264.7 cells. Ribonucleoprotein immunoprecipitation analysis was conducted to detect the binding of ADAR1 and miRNAs. A dual-luciferase reporter assay was used to detect the binding of miRNAs and regulatory factors. We observed that ADAR1 significantly increased the expression of suppressor of cytokine signaling 3 (SOCS3) in macrophages and reduced the expression of interleukin-6 in macrophages and the serum, thereby reducing intestinal permeability and mucosal injury in mice with sepsis. The RNA-ribonucleoprotein immunoprecipitation binding assay and qRT-PCR demonstrated a direct interaction between ADAR1 and pri-miR-30a. The luciferase assay demonstrated that SOCS3 was significantly inhibited by miR-30a-5p, the mature product of miR-30a. Thus, ADAR1 exerts a protective effect against sepsis by reducing inflammation and organ damage via the ADAR1-miR-30a-SOCS3 axis.

Impact of family physician integrated care program on decreasing utilization of emergency department visit and hospital admission: a population-based retrospective cohort study.

BACKGROUND: Hospital admission and emergency department(ED) visits are a massive burden in medical expenditures. In 2003, the Taiwanese government developed Family Physician Integrated Care Program (FPIC) to increase the quality of primary care and decrease medical expenditures. This study's goals were to determine whether FPIC decreased hospital admissions and ED visits and identify the factors influencing the outcomes. METHODS: This nationwide retrospective cohort study was conducted for the period between 2006 and 2013 by using data obtained from the Taiwan National Health Insurance Research Database. A total of 68,218 individuals were divided into those who joined FPIC and those who did not. We used propensity score matching at a ratio of 1:1 and logistic regression with the generalized estimating equation (GEE) model having a difference-in-difference design to investigate the effects of the FPIC policy on hospital admissions and ED visits in 7 years. RESULTS: Using logistic regression with the GEE model with the difference-in-difference design, we found no reduction in ED visits and hospital admissions between the two groups. The participants' risk of hospital admissions increased in the first year after joining FPIC (OR: 1.11, 95% CI: 1.03-1.20, P < .05). However, participants who joined FPIC showed an 8% lower risk of hospital admissions in the sixth and seventh years after joining FPIC, compared with those who did not join FPIC (OR: 0.92, 95% CI: 0.85-1.00, P < .05). CONCLUSIONS: FPIC in Taiwan could not decrease medical utilization initially but might reduce hospital admissions in the long term.

Composition and Associated Factors of Radiological Examination in Major Trauma Patients: A Prospective Observational Study.

The care of major trauma patients continues to be a challenge for emergency physicians and trauma surgeons. We found that the total number of radiological examinations for major trauma patients in this study was high and mainly comprised radiography and computed tomography (CT), with CT being more commonly adopted. The number of CT scans was positively correlated with severity of injury and intensive care unit length of stay. Further study is warranted to optimize radiological examinations involving major trauma patients.