Functional analysis of nuclear receptor genes in molting and metamorphosis of the cigarette beetle, Lasioderma serricorne.

Nuclear receptors (NRs) are ligand-regulated transcription factors that are important for the normal growth and development of insects. However, systematic function analysis of NRs in the molting process of Lasioderma serricorne has not been reported. In this study, we identified and characterized 16 NR genes from L. serricorne. Spatiotemporal expression analysis revealed that six NRs were mainly expressed in 3-d-old 4th-instar larvae; five NRs were primarily expressed in 5-d-old adults and four NRs were predominately expressed in prepupae. All the NRs were highly expressed in epidermis, fat body and foregut. RNA interference (RNAi) experiments revealed that knockdown of 15 NRs disrupted the larva-pupa-adult transitions and caused 64.44-100 % mortality. Hematoxylin-eosin staining showed that depletion of 12 NRs prevented the formation of new cuticle and disrupted apolysis of old cuticle. Silencing of LsHR96, LsSVP and LsE78 led to newly formed cuticle that was thinner than the controls. The 20E titer and chitin content significantly decreased by 17.67-95.12 % after 15 NR dsRNA injection and the gene expression levels of 20E synthesis genes and chitin metabolism genes were significantly reduced. These results demonstrated that 15 NR genes are essential for normal molting and metamorphosis of L. serricorne by regulating 20E synthesis and chitin metabolism.

Disruption of microRNA pathway core genes inhibits molting and reproduction of the cigarette beetle, Lasioderma serricorne.

BACKGROUND: MicroRNA (miRNA) pathway genes have been widely reported to participate in several physiological events in insect lifecycles. The cigarette beetle Lasioderma serricorne is an economically important storage pest worldwide. However, the functions of miRNA pathway genes in L. serricorne remain to be clarified. Herein, we investigated the function of molting and reproduction of the miRNA pathway in L. serricorne. RESULTS: LsDicer-1, LsArgonaute-1, LsLoquacious and LsExportin-5 were universally expressed in adults, whereas LsPasha and LsDrosha were mainly expressed in the pupae. The genes presented different patterns in various tissues. Silencing of LsDicer-1, LsArgonaute-1, LsDrosha and LsExportin-5 resulted in a high proportion of wing deformities and molting defects. Silencing of LsDicer-1, LsArgonaute-1, LsPasha and LsLoquacious affected the development of the ovary and the maturation of oocytes, resulting in a significant decrease in fecundity. Further investigation revealed that the decreases in LsDicer-1 and LsArgonaute-1 expression destroyed follicular epithelia and delayed vitellogenesis and oocyte development. In addition, the expression levels of several miRNAs (let-7, let-7-5p, miR-8-3p, miR-8-5p, miR-9c-5p, miR-71, miR-252-5p, miR-277-3p, miR-263b and Novel-miR-50) were decreased significantly after knockdown of these miRNA pathway core genes, indicating that they played important roles in regulating miRNA-mediated gene expression. CONCLUSION: The results indicate that miRNA pathway genes play important roles in the molting, ovarian development and female fecundity of L. serricorne, and thus are potentially suitable target genes for developing an RNAi strategy against a major pest of stored products. © 2024 Society of Chemical Industry.

First report of leaf blight caused by Nigrospora hainanensis on Euonymus japonicus in China.

Euonymus japonicus Thunb., belonging to the family Celastreace and native to East Asia, is a widely cultivated evergreen ornamental woody plant with important ecological and economic values. In May 2023, serious leaf blight of E. japonicus occurred in the campus green space at Guiyang University, Guizhou Province, China (26°55'85"N, 106°78'04"E). Early symptom appeared as small, circular light brown spots on the edges or tips of the leaves. Then, the spot developed visible necrosis, initially light brown to dark brown halos with clear margins. Subsequently, severely infected leaves appear totally wilt, and significantly decrease their ornamental values. In a 0.07-ha field, the disease incidence reached to 40-55%. To identify the pathogen, ten typical symptomatic E. japonicus leaves were collected. They were initially immersed in 75% ethanol for 3 min, and by sodium hypochlorite (4% NaClO) solution for 45 s, and ultimately rinsed with sterile distilled water (dH2O) five times for not less than 1 min each time, then, placed the leaves on potato dextrose agar (PDA) medium and cultured for 5 days at 25°C in constant temperature incubator. Cultures were purified to yield eight isolates. Early colonies are white and regularly rounded, gradually turning dark brown to black with fluffy mycelium. Conidia were single celled, smooth, black, spherical or ellipsoidal. The conidia size of the representative strain, GY-2 and GY-3, was averagely 12.3-17.3 µm × 10.8-17 µm (n = 50). The conidiogenous cells were monoblastic, hyaline, globose or ampulliform. Morphology-based identification revealed the strain as Nigrospora spp. (Wang et al., 2017). For further confirmation, PCR of GY-2 and GY-3 DNA was performed with the primers ITS1/ITS4 (White et al., 1990), Bt2a-F/Bt2b-R (Glass and Don-aldson 1995), and TEF1-728F/TEF1-986R (Carbone and Kohn 1999). Sequences of the ITS region, TUB and TEF1 genes from the strain GY-2 and GY-3 were deposited in GenBank. (GY-2: OR999377, PP112221 and PP150467; GY-3: PP406871, PP421045 and PP421046, respectively). BLAST analysis showed GY-2 100%, 100%, and 98.36%; GY-3 99.43%, 98.21% and 100% (ITS region, TEF1, and TUB) identity to N. hainanensis sequences (accession numbers. NR_153480.1, KY019415.1, and KY019464.1; KX986094.1, OP611475.1, and KY019597.1). Additionally, tandem sequences of ITS, TUB and TEF1 constructed by MEGA 7.0 confimed the homology through the phylogenetic tree. Pathogenicity tests were conducted on healthy plants grown, each 5 mm diameter of active growing mycelium plug of isolate GY-2 was attached to 15 leaves from five healthy 2-year-old E. japonicu plants. The same number of leaves in the control group were treated with non-inoculated plugs only. All the plants were incubated at 25°C and 75% relative humidity with a 16-h/8-h photoperiod. After 10 days, no symptoms appeared on the leaves of the control group. In contrast, symptomatic blight appeared on all leaves inoculated with GY-2. Pathogenicity tests were performed five times. Pure strains were re-isolated from diseased leaves and, confirmed to be N. hainanensis based on the above methods. Recently, Nigrospora oryzae was reported as causal agent of leaf spots on Euonymus japonicus in China (Xu et al., 2023). To our knowledge, this study is the first report of N. hainanensis causing leaf blight on E. japonicu. Identification of the etiological agent may provide assistance for sustainable management in the future.

The opportunities and challenges of the disease-modifying immunotherapy for type 1 diabetes: A systematic review and meta-analysis.

There are multiple disease-modifying immunotherapies showing the potential of preventing or delaying the progression of type 1 diabetes (T1D). We designed and performed this systematic review and meta-analysis to gain an overview of what a role immunotherapy plays in the treatment of T1D. We searched PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to December 2023. We included clinical trials of immunotherapy conducted in patients with T1D that reported the incidence of hypoglycemia or changes from baseline in at least one of following outcomes: 2 h and 4 h mixed-meal-stimulated C-peptide area under the curve (AUC), fasting C-peptide, daily insulin dosage, glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG). The results were computed as the weighted mean differences (WMDs) or odds ratios (ORs) and 95% confidence intervals (CIs) in random-effect model. In all, 34 clinical trials were included. When compared with control groups, 2 h C-peptide AUC was marginally higher in patient treated with nonantigen-based immunotherapies (WMD, 0.04nmol/L, 95% CI, 0.00-0.09 nmol/L, P=0.05), which was mainly driven by the effects of T cell-targeted therapy. A greater preservation in 4 h C-peptide AUC was observed in patients with nonantigen-based immunotherapies (WMD, 0.10nmol/L, 95% CI, 0.04-0.16 nmol/L, P=0.0007), which was mainly driven by the effects of tumor necrosis factor α (TNF-α) inhibitor and T cell-targeted therapy. After excluding small-sample trials, less daily insulin dosage was observed in patient treated with nonantigen-based immunotherapies when compared with control groups (WMD, -0.07units/kg/day, 95% CI, -0.11 to -0.03units/kg/day, P=0.0004). The use of antigen-based immunotherapies was also associated with a lower daily insulin dosage versus control groups (WMD, -0.11units/kg/day, 95% CI, -0.23 to -0.00units/kg/day, P=0.05). However, changes of HbA1c or FPG were comparable between nonantigen-based immunotherapies or antigen-based immunotherapies and control groups. The risk of hypoglycemia was not increased in patients treated with nonantigen-based immunotherapies or patients treated with antigen-based immunotherapies when compared with control groups. In conclusion, nonantigen-based immunotherapies were associated with a preservation of 2 h and 4 h C-peptide AUC in patients with T1D when compared with the controls, which was mainly driven by the effects of TNF-a inhibitor and T cell-targeted therapy. Both nonantigen-based immunotherapies and antigen-based immunotherapies tended to reduce the daily insulin dosage in patients with T1D when compared with the controls. However, they did not contribute to a substantial improvement in HbA1c or FPG. Both nonantigen-based immunotherapies and antigen-based immunotherapies were well tolerated with not increased risk of hypoglycemia in patients with T1D.

Weight reduction and the risk of gallbladder and biliary disease: A systematic review and meta-analysis of randomized clinical trials.

In this meta-analysis, we aim to evaluate the risk of gallbladder and biliary disease of weight management strategies and investigate the association between weight reduction and risk of gallbladder or biliary disease. Randomized controlled trials (RCTs) with a duration of at least 12 weeks that compare antiobesity medications (AOMs) with placebo or bariatric surgery with less intensive weight management strategy were concluded. Weight management strategy was associated with a significant increased risk of gallbladder or biliary disease (OR 1.361, 95% CI 1.147 to 1.614, P < 0.001, I2 = 3.5%), cholelithiasis, cholecystitis, and cholecystectomy compared with placebo or controls. The increased risk of gallbladder or biliary disease was observed both in pharmacotherapies subgroup and bariatric surgery subgroup. With regards of specific pharmacotherapies, an increased risk of gallbladder or biliary disease was observed in trials with glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatments. In addition, trials with indication of obesity and overweight treatment and trials with higher doses showed significant higher risk of gallbladder or biliary disease compared with placebo or controls. In conclusion, weight management strategy was associated with an increased risk of gallbladder or biliary disease when compared with placebo or control groups.

MicroR-9c-5p and novel-mir50 co-target Akt to regulate Lasioderma serricorne reproduction.

High fecundity is a common characteristic of insect pests which increases the difficulty of population control. Serine/threonine kinase Akt is an indispensable component of the insulin signaling pathway. Silencing of LsAkt severely hinders reproduction in Lasioderma serricorne, a stored product insect pest. However, the post-transcriptional pathway of LsAkt in L. serricorne remains unknown. This study identified 2 binding sites of miR-9c-5p and novel-mir50 in the coding sequences of LsAkt. The expression profiles of 2 microRNAs (miRNAs) and LsAkt displayed an opposite pattern during the adult stages. Luciferase reporter assay showed that novel-mir50 and miR-9c-5p could downregulate the expression of LsAkt. Overexpression of miR-9c-5p and novel-mir50 by injection of mimics inhibited the expression of LsAkt and reduced oviposition, decreased egg hatchability, and blocked ovarian development. It also decreased the expression of genes involved in ovarian development (LsVg and LsVgR) and the nutritional signaling pathway (LsTOR, LsS6K, and Ls4EBP), and reduced the phosphorylation of Akt. Conversely, injection of miR-9c-5p and novel-mir50 inhibitors induced the expressions of LsAkt, LsVg, LsVgR, LsTOR, LsS6K, and Ls4EBP, enhanced Akt phosphorylation level, and accelerated ovarian development. Injection of bovine insulin downregulated the expression of miR-9c-5p and novel-mir50 and upregulated the LsAkt expression. It also rescued the reproductive development defects associated with miR-9c-5p/novel-mir50 overexpression, forming a positive regulatory loop of insulin signaling. These results indicate that miR-9c-5p/novel-mir50 regulates the female reproduction of L. serricorne by targeting Akt in response to insulin signaling. The data also demonstrate the effects of the insulin/miRNA/Akt regulatory axis in insect reproduction.

Dapagliflozin treatment and cardiovascular outcome in RBP4/TTRVal30Met (transthyretin cardiac amyloidosis) mice.

AIMS: Whether sodium-glucose co-transporter 2 inhibitors are effective for heart failure caused by ATTR-CA (transthyretin cardiac amyloidosis) remains uncertain. The aim of this study is to investigate the cardiovascular prognosis in ATTR-CA mice model with dapagliflozin treatment. METHODS AND RESULTS: Humanized RBP4/TTRVal50Met and RBP4/TTR mice models were constructed with clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) techniques and multiple generations breeding. A total of 6 RBP4/TTR mice received placebo treatment, when 12 RBP4/TTRVal50Met received dapagliflozin (1 mg/kg/day, 6 mice) and placebo (6 mice) treatment. Fasting glucose, intraperitoneal glucose tolerance test, and plasma brain natriuretic peptide (BNP) concentration were measured at Day 0, Week 2, and Week 4. BNP, transforming growth factor-beta (TGF-ß), collagen type I alpha 1 (COL1A1) protein levels, and Cola1, TGFß1, TNFα, IL-1ß, BNP relative quantities in cardiac, along with cardiac pathology examination including right ventricular collagen percentage, ventricular septum thickness, left ventricular wall thickness, and left ventricular internal diameter were measured at Week 4 after treatment procedure. All 18 mice completed the experiment. The baseline characteristics were balanced among three treatment groups. In placebo-treated mice, the cardiac BNP relative quantity was significantly higher in RBP4/TTRVal50Met mice than RBP4/TTR mice (RBP4[KI/KI], TTR [KI/KI]: 0.72 ± 0.46, RBP4[KI/KI], TTRVal50Met [KI/KI]: 1.44 ± 0.60, P = 0.043), indicating more significant heart failure progression in ATTR-CA mice than normal mice. In ATTR-CA mice, the cardiovascular prognosis measurements including heart failure (plasma BNP concentration and relative quantities of BNP), cardiac inflammation (relative quantities of Cola1, TGFß1, TNFα, and IL-1ß), and pathological changes (right ventricular collagen percentage, ventricular septum thickness, left ventricular wall thickness, and left ventricular internal diameter) were statistically comparable between those under dapagliflozin and placebo treatment. CONCLUSIONS: Dapagliflozin did not improve cardiovascular prognosis including the progression of heart failure, cardiac inflammation, and pathological changes in ATTR-CA mice compared with placebo. The results of this study were not in support of dapagliflozin's therapeutic effects for ATTR-CA. More pre-clinical and clinical researches to validate these findings and demonstrate the underlying mechanisms are still required.

Primary aldosteronism and obstructive sleep apnea: A meta-analysis of prevalence and metabolic characteristics.

BACKGROUND: Primary aldosteronism (PA) and obstructive sleep apnea (OSA) are both causes for resistant hypertension and contribute to adverse cardiovascular outcome. However, the association of these two disorders remains to be investigated. We conducted this meta-analysis to estimate the prevalence and metabolic characteristics of the coexistence of PA and OSA. METHODS: The databases of MEDLINE, EMBASE and Cochrane Reviews were searched for studies investigating the prevalence or clinical characteristics of PA and OSA until Jan 2023. Single proportions of PA and OSA were meta-analyzed for pooled prevalence and 95% confidence intervals (CIs). Odds ratios (ORs) and 95% CIs were calculated for the comparison of the prevalence. Mean differences (MDs) and 95% CIs were calculated for comparisons of the characteristics between patients with both OSA and PA and control groups. RESULTS: A total of 16 studies were included. The pooled prevalence of PA was 27% (95% CI = 24-29%) in all patients with OSA (n = 3498). The prevalence of PA in patients with OSA was significantly higher than that in the patients without OSA (OR = 2.03, 95% CI = 1.30, 3.16, p = 0.002). The pooled prevalence (95% CI) of OSA was 46% (39-54%) in patients with PA (n = 2335). Compared with the hypertensive patients without PA, the prevalence of OSA in the patients with PA was significantly higher (OR = 2.01, 95% CI = 1.37, 2.95, p < 0.001). Compared with the patients of control groups, the patients with both PA and OSA had higher blood pressure and body mass index (BMI). CONCLUSION: Screening for the coexistence of PA and OSA was warranted.

Indirect comparison of efficacy and safety of chiglitazar and thiazolidinedione in patients with type 2 diabetes: A meta-analysis.

BACKGROUND: Chiglitazar is an emerging pan-agonist of all peroxisome proliferator activated receptors (PPAR)-α, δ and γ, and has therapeutic potential for type 2 diabetes (T2D). However, to date, no clinical studies or meta-analyses have compared the efficacy and safety of chiglitazar and traditional PPAR-γ agonist thiazolidinediones (TZDs). A meta-analysis concerning this topic is therefore required. AIM: To compare the efficacy and safety of chiglitazar and TZD in patients with T2D. METHODS: PubMed, Medline, Embase, the Cochrane Central Register of Controlled Trials, Reference Citation Analysis and Clinicaltrial.gov websites were searched from August 1994 to March 2022. Randomized controlled trials (RCTs) of chiglitazar or TZD vs placebo in patients with T2D were included. Indirect comparisons and sensitivity analyses were implemented to evaluate multiple efficacy and safety endpoints of interest. RESULTS: We included 93 RCTs that compared TZD with placebo and one that compared chiglitazar with placebo. For efficacy endpoints, the augmented dose of chig-litazar resulted in greater reductions in hemoglobin (Hb)A1c [weighted mean difference (WMD) = -0.15%, 95% confidence interval (CI): -0.27 to -0.04%], triglycerides (WMD = -0.17 mmol/L, 95%CI: -0.24 to -0.11 mmol/L) and alanine aminotransferase (WMD = -5.25 U/L, 95%CI: -8.50 to -1.99 U/L), and a greater increase in homeostasis model assessment-ß (HOMA-ß) (WMD = 17.75, 95%CI: 10.73-24.77) when compared with TZD treatment. For safety endpoints, the risks of hypoglycemia, edema, bone fractures, upper respiratory tract infection, urinary tract infection, and weight gain were all comparable between the augmented dose of chiglitazar and TZD. In patients with baseline HbA1c ≥ 8.5%, body mass index ≥ 30 kg/m2 or diabetes duration < 10 years, the HbA1c reduction and HOMA-ß increase were more conspicuous for the augmented dose of chiglitazar compared with TZD. CONCLUSION: Augmented dose of chiglitazar, a pan-activator of PPARs, may serve as an antidiabetic agent with preferable glycemic and lipid control, better ß-cell function preserving capacity, and does not increase the risk of safety concerns when compared with TZD.

Identification and immune analysis of antimicrobial peptides from the cigarette beetle (Lasioderma serricorne).

Antimicrobial peptides (AMPs) in insects are endogenous peptides that are effector components of the innate defense system of the insect. AMPs may serve as antimicrobial agents because of their small molecular weight and broad-spectrum antimicrobial activity. In this study, we performed transcriptome analysis of cigarette beetle (Lasioderma serricorne) larvae, parasitized by the ectoparasitic wasp, Anisopteromalus calandrae. Several AMP genes were significantly upregulated following A. calandrae parasitism, postulating the hypothesis that the parasitization enhanced the host's resistance against pathogenic microorganisms through the regulation of host AMP genes. Specifically, 3 AMP genes (LsDef1, LsDef2, and LsCole) were significantly upregulated and we studied their immune function in L. serricorne. Immune challenge and functional analysis showed that LsCole was responsible for the immune response against Gram-negative and Gram-positive bacteria, while LsDef1 and LsDef2 were involved in insect defense against Gram-positive bacteria. Purified recombinant LsCole exhibited antimicrobial activities against the Gram-negative bacterium Escherichia coli and the Gram-positive bacterium Staphylococcus aureus. LsDef2 showed an antibacterial effect against S. aureus. LsCole and LsDef2 exhibited antibiofilm activity against S. aureus. The 2 AMPs disrupted cell membranes and caused leakage of S. aureus cell contents. The results indicated that the 3 AMPs in L. serricorne are involved in the innate immunity of this pest insect. These AMPs may have potential as antimicrobial agents for bacterial infection chemotherapy. Hence, data are discussed in relation to new control strategies with greater biosafety against pest insects with use of microbial biocontrol agents in combination with RNA interference against the insect's defensive AMP genes.

Strain-tunable magnetism and topological states in layered VBi2Te4.

Similar to the magnetic topological insulator of MnBi2Te4, recent studies have demonstrated that VBi2Te4 is also an ideal candidate to explore many intriguing quantum states. Different from the strong interlayer antiferromagnetic (AFM) coupling in layered MnBi2Te4, based on first-principles calculations, we find that the energy difference between AFM and ferromagnetic (FM) orders in layered VBi2Te4 is much smaller than that of MnBi2Te4. Specifically, it is found that the interlayer FM coupling can be readily achieved by applying strain. Further electronic band structures reveal that the VBi2Te4 bilayer is a time-reversal symmetry broken quantum spin Hall insulator with a spin Chern number of CS = 1, which is essentially different from the QAH state with a Chern number of C = 1 in the MnBi2Te4 bilayer. Most strikingly, the topological states of the magnetic VBi2Te4 bilayer can be well tuned by strain, whose topological phase diagram is mapped out as a function of strain by employing continuum model analyses. All of these results indicate that the layered VBi2Te4 not only enriches the family of magnetic topological materials, but also provides a promising platform to explore more exotic quantum phenomena.

Bi2Te3-intercalated MnBi2Te4: ideal candidate to explore intrinsic Chern insulator and high-temperature quantum anomalous Hall effect.

The recently discovered magnetic topological insulator of MnBi2Te4(MBT), has been demonstrated to realize the quantum anomalous Hall (QAH) effect, while the naturally antiferromagnetic (AFM) interlayer coupling in MBT results in that the QAH effect can only be realized in odd-layered systems and at low temperature. Using first-principles calculations, we find that intercalating Bi2Te3(BT) layers into MBT by forming MBT/(BT)n/MBT (n= 1-6) heterostructures can induce magnetic phase transition from AFM to ferromagnetic (FM) interlayer coupling whenn⩾ 3. Specifically, MBT/(BT)3/MBT and MBT/(BT)4/MBT respectively host Curie temperaturesTcof 14 K and 11 K, which fits well the experimentally measuredTcof 12 K. Detailed band structure calculations and topological identification show that the QAH phases are well preserved for all FM heterostructures. And the topological mechanism of MBT/(BT)n/MBT as a function ofnis revealed by employing continuum model analysis. Most importantly, the FM MBT/(BT)4/MBT has already been experimentally fabricated. Thus, our work provides a practical guideline to explore high-temperature QAH effect in MBT family of materials.

Engineering topological states in a two-dimensional honeycomb lattice.

In this work, we use first-principles calculations to determine the interplay between spin-orbit coupling (SOC) and magnetism which can not only generate a quantum anomalous Hall state but can also result in topologically trivial states although some honeycomb systems host large band gaps. By employing tight-binding model analysis, we have summarized two types of topologically trivial states: one is due to the coexistence of quadratic non-Dirac and linear Dirac bands in the same spin channel that act together destructively in magnetic materials (such as, CrBr3, CrCl3, and VBr3 monolayers); the other one is caused by the destructive coupling effect between two different spin channels due to small magnetic spin splitting in heavy-metal-based materials, such as, BaTe(111)-supported plumbene. Further investigations reveal that topologically nontrivial states can be realized by removing the Dirac band dispersion of the magnetic monolayers for the former case (such as in alkali metal doped CrBr3), while separating the two different spin channels from each other by enhancing the magnetic spin splitting for the latter case (such as in half-iodinated silicene). Thus, our work provides a theoretical guideline to manipulate the topological states in a two-dimensional honeycomb lattice.

Anti-inflammatory therapies were associated with reduced risk of myocardial infarction in patients with established cardiovascular disease or high cardiovascular risks: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: We aimed to evaluate the association between anti-inflammatory therapies and the incidence of cardiovascular events in patients with established cardiovascular disease (CVD) or high cardiovascular risks. METHODS: Literature retrieval was conducted in PubMed, Medline, Embase, the Cochrane Central Register of Controlled Trials and Clinicaltrial.gov website from the inception to December 2022. Randomized controlled trials comparing anti-inflammatory therapies with placebo in patients with established CVD or high cardiovascular risks were included. The results of the meta-analysis were computed as the risk ratio (RR) with 95% confidence interval (CI). RESULTS: Compared with placebo, anti-inflammatory therapies were associated with decreased incidence of myocardial infarction (MI) (RR = 0.93, 95% CI, 0.88 to 0.98), which was mainly driven by therapies targeting central IL-6 signaling pathway (RR = 0.83, 95% CI, 0.74 to 0.93). IL-1 inhibitors treatment was associated with reduced risks of heart failure (RR = 0.38, 95% CI, 0.18 to 0.80) while lower incidence of stroke was observed in patients with colchicine treatment (RR = 0.47, 95% CI, 0.28 to 0.77). MI events were less frequent in patients over 65 years of age (RR = 0.90, 95% CI, 0.83 to 0.98) or with follow-up duration over 1 year (RR = 0.90, 95% CI, 0.85 to 0.96) when comparing anti-inflammatory therapies with placebo. CONCLUSIONS: Anti-inflammatory therapies, especially those targeting the central IL-6 signaling pathway, may serve as promising treating strategies to ameliorate the risk of MI. IL-1 inhibitor and colchicine were associated with decreased risks of heart failure and stroke, respectively. MI risk reduction by anti-inflammatory therapies seemed to be more prominent in older patients with long follow-up duration.

[Bushen Anshen acupuncture for perimenopausal insomnia of kidney-yin deficiency: a randomized controlled trial].

OBJECTIVE: To observe the clinical efficacy of Bushen Anshen acupuncture (acupuncture for tonifying kidney and calming spirit ) in treating perimenopausal insomnia (PMI) of kidney-yin deficiency. METHODS: A total of 72 patients with PMI of kidney-yin deficiency were randomized into an observation group (36 cases, 1 case dropped off) and a control group (36 cases, 1 case dropped off). Acupuncture was applied at Baihui (GV 20) and bilateral Shenshu (BL 23), Taixi (KI 3), Anmian (Extra) in the observation group, while sham acupuncture of shallow needling at non-acupoints was applied in the control group. The treatment was required once every other day, 3 times a week for 10 times in the two groups. Before and after treatment, Pittsburgh sleep quality index (PSQI) was used to evaluate the subjective sleep quality, and polysomnography (PSG) was used to monitor the objective sleep quality in the two groups. RESULTS: After treatment, the scores of sleep quality, sleep latency, sleep duration, sleep efficiency, hypnotic, daytime dysfunction and total score of PSQI were decreased compared with those before treatment in the observation group (P<0.01), the scores of sleep duration, sleep efficiency and total score of PSQI were decreased compared with those before treatment in the control group (P<0.05); the scores of sleep quality, sleep latency, sleep efficiency, hypnotic and total score of PSQI in the observation group were lower than those in the control group (P<0.05). After treatment, the sleep time was prolonged, the sleep efficiency was improved, the sleep latency and the awake time after falling asleep were shortened, the arousal awake index was reduced (P<0.01) when PSG indexes were monitored, and the percentage of non-rapid eye movement sleep period 1 (N1%) was decreased while the percentage of non-rapid eye movement sleep period 3 (N3%) was increased (P<0.05) compared with those before treatment in the observation group; there was no statistical difference in the PSG indexes compared with those before treatment in the control group (P>0.05). After treatment, compared with the control group, the sleep time was prolonged, the sleep efficiency was improved, the sleep latency and the awake time after falling asleep were shortened, the arousal awake index and N1% were decreased in the observation group (P<0.01). CONCLUSION: Bushen Anshen acupuncture can effectively improve the subjective and objective sleep quality in PMI patients of kidney-yin deficiency.

Evaluation of efficacy and safety of glucokinase activators-a systematic review and meta-analysis.

Aims: Glucokinase activators (GKAs) promote the activity of glucokinase (GK) and is under development for the treatment of diabetes. The efficacy and safety of GKAs require evaluation. Methods: This meta-analysis included randomized controlled trials (RCTs) with a duration of at least 12 weeks conducted in patients with diabetes. The primary objective of this meta-analysis was the difference of hemoglobin A1c (HbA1c) change from baseline to study end between GKA groups and placebo groups. Risk of hypoglycemia and laboratory indicators were also evaluated. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated for the continuous outcomes, and odds ratios (ORs) and 95% CI were calculated for the risk of hypoglycemia. Results: Data from 13 RCTs with 2,748 participants treated with GKAs and 2,681 control participants were analyzed. In type 2 diabetes, the level of HbA1c decreased greater in patients with GKA treatment compared with placebo (WMD = -0.339%, 95% CI -0.524 to -0.154%, P < 0.001). The OR comparing GKA versus placebo was 1.448 for risk of hypoglycemia (95% CI 0.808 to 2.596, P = 0.214). The WMD comparing GKA versus placebo was 0.322 mmol/L for triglyceride (TG) levels (95% CI 0.136 to 0.508 mmol/L, P = 0.001). When stratified by drug type, selectivity, and study duration, a significant difference was found between groups. In type 1 diabetes, the result of HbA1c change and lipid indicators showed no significant difference between the TPP399 group and the placebo group. Conclusions: In patients with type 2 diabetes, GKA treatment was associated with a better glycemic control but a significant elevation in TG concentration in general. The efficacy and safety varied with drug type and selectivity. Systematic review registration: International Prospective Register of Systematic Reviews, identifier CRD42022378342.

Improvement of straw decomposition and rice growth through co-application of straw-decomposing inoculants and ammonium nitrogen fertilizer.

BACKGROUND: The growth of rice is reduced by the slow decomposition of accumulated straw, which competes with rice for soil nitrogen nutrient. In recent year, straw-decomposing inoculants (SDIs) that can accelerate straw decomposition and ammonium nitrogen (N) fertilizer that can quickly generate available N is increasingly adopted in China. However, it is still unknown whether the N demand of straw decomposition and crop growth can be simultaneously met through the co-application of SDIs and ammonium N fertilizer. RESULTS: In this study, we investigated the effect of the co-application of SDIs and ammonium bicarbonate on decomposition rate of wheat straw, rice growth and rice yield over two consecutive years in rice-wheat rotation system. Compound fertilizer (A0) was used as control. The ratios of ammonium bicarbonate addition were 20% (A2), 30% (A3) and 40% (A4), respectively, without SDIs or with SDIs (IA2, IA3, IA4). Our results revealed that without SDIs, compared with A0, straw decomposition rate, rice growth and yield were improved under A2; However, under A3, rice yield was decreased due to the slow decomposition rate of straw and limited growth of rice during late growth stage. Combining SDIs and N fertilizer increased straw decomposition rate, rice growth rate and yield more than that of N fertilizer alone, especially under IA3. Compared with A0, straw decomposition rate, tiller number, aboveground biomass, leaf area index, root length, and nitrogen use efficiency were significantly increased by 16%, 8%, 27%, 12%, 17%, and 15% under IA3. Consequently, the average rice yield of IA3 was increased to 10,856 kg/ha, which was 13% and 9% higher, respectively, than of A0 and A2. CONCLUSION: Our results indicated that ammonium bicarbonate application alone carried a risk of nutrient deficiency during late growth stage and yield decline. Therefore, the co-application of SDIs and 30% ammonium N fertilizer substitution can be a favorable practice to simultaneously accelerate straw decomposition and increase rice crop growth.

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors and the Risk of Fracture: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Osteoporosis and hyperlipidemia are closely correlated and statins might be associated with a decreased risk of fracture. We aimed to investigate the association between proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) therapy and the risk of fracture. The PubMed, Cochrane library, and EMBASE databases were systematically searched from the inception dates to October 22, 2022. Randomized clinical trials (RCTs) that addressed to fracture events of participants using alirocumab, evolocumab, bococizumab or inclisiran, with a follow-up of ≥ 24 weeks were included. Meta-analyses were conducted to calculate the odds ratio (OR) with 95% confidence intervals (CIs) for major osteoporotic fracture, hip fracture, osteoporotic non-vertebral fracture, and total fracture. 30 trials assessing PCSK9i among 95, 911 adults were included. There were no significant associations between PCSK9i therapy and the risk of major osteoporotic fracture [OR 1.08 (95% Cl 0.87-1.34), p = 0.49], hip fracture [OR 1.05 (95% Cl 0.73-1.53), p = 0.79], osteoporotic non-vertebral fracture [OR 1.03 (95% Cl 0.80-1.32), p = 0.83], and total fracture [OR 1.03 (95% Cl 0.88-1.19), p = 0.74] over a period of 6-64 months. No significant associations were detected in any of the sensitivity analyses and subgroup analyses stratified by the type of PCSK9i, follow-up duration, age, sex, sample size, and patient profile. Pooled results of our meta-analysis showed that exposure to PCSK9i was not associated with reduced risks of fracture in the short term.

Maternal and Infant Outcomes in GCK-MODY Complicated by Pregnancy.

CONTEXT: Challenges exist in the management of Glucokinase-maturity-onset diabetes of the young (GCK-MODY), especially during pregnancy. OBJECTIVE: This work aimed to evaluate the prevalence of congenital anomaly in newborns from GCK-MODY mothers, and the relationship between fetus genotype and the risk of congenital malformation as well as other adverse pregnancy outcomes. METHODS: Electronic databases including PubMed, EMBASE, and Cochrane database last updated July 16, 2022, were searched. We included observational studies conducted in GCK-MODY complicated by pregnancy, and reporting at least one pregnancy outcome. We extracted data in duplicate, and the risk of bias was evaluated by the Newcastle-Ottawa Quality Assessment Scale (NOS). All statistical analysis was performed by Cochrane Review Manager. RESULTS: Eight studies were selected in the meta-analysis. Five were of high quality and 3 were of medium quality evaluated by NOS. A total of 257 GCK-MODY mothers and 499 offspring were enrolled. Among them, 370 offspring were divided into 2 groups: GCK-affected offspring (GCK+, n = 238) and GCK-unaffected offspring (GCK-, n = 132). The percentage of congenital malformations in GCK pregnant women's offspring was 2.4%. The risk of congenital malformations was similar between the GCK+ and GCK- group (odds ratio = 0.56; 95% CI, 0.07-4.51; I2 = 0%; P = .59). The risk of macrosomia/large for gestational age, neonatal hypoglycemia, and combined adverse neonatal outcome was significantly lower in offspring with the GCK mutation compared with non-GCK mutation carriers. CONCLUSION: The percentage of congenital malformations was 2.4% in GCK-MODY pregnant women's offspring, and newborns with the GCK mutation have lower birth complication than non-GCK mutation carriers.

[Acupuncture for delayed sleep-wake phase disorder: a randomized controlled trial].

OBJECTIVE: To observe the clinical effect of acupuncture for delayed sleep-wake phase disorder (DSWPD). METHODS: A total of 84 patients with DSWPD were randomized into an observation group (42 cases, 2 cases dropped off) and a control group (42 cases, 3 cases dropped off). On the basis of sleep hygiene education, acupuncture was applied at Shenmai (BL 62), Zhaohai (KI 6), Hegu (LI 4), Taichong (LR 3), Zusanli (ST 36) and Sanyinjiao (SP 6) in the observation group, while placebo acupuncture was applied at the same acupoints in the control group. The treatment lasted for 8 weeks, once every other day, 3 times a week in the 1st to 4th weeks; once every 3 days, 2 times a week in the 5th to 8th weeks. Before and after treatment, the actigraphy (ACT) indexes of objective sleep (total time of stay in bed, total sleep time, sleep efficiency, the number of awakenings and the wake time after falling asleep) and plasma cortisol (CORT) level were observed; before and after treatment and in follow-up of 1, 3 months after treatment, the scores of morningness-eveningness questionnaire (MEQ), insomnia severity index (ISI), fatigue severity scale (FSS) and Epworth sleepiness scale (ESS) were observed in the two groups. RESULTS: Compared before treatment, the total sleep time was prolonged, the sleep efficiency was improved, the number of awakenings was reduced, and the wake time after falling asleep was shortened after treatment in the observation group (P<0.01, P<0.05), and those in the observation group after treatment were superior to the control group (P<0.01, P<0.05). Compared before treatment, the MEQ scores after treatment in both groups and in the follow-up of 1, 3 months after treatment in the observation group were increased (P<0.01), and the MEQ score of each time point after treatment in the observation group was higher than the control group (P<0.01). The scores of ISI, FSS and ESS after treatment, and the scores of ISI、ESS in follow-up of 1, 3 months after treatment in the observation group were decreased compared with those before treatment (P<0.01, P<0.05), and in the observation group, the scores of ISI, FSS and ESS of each time point after treatment were lower than those in the control group (P<0.01, P<0.05). After treatment, the plasma CORT level in the observation group was decreased compared with that before treatment and that in the control group (P<0.01, P<0.05). CONCLUSION: Acupuncture can improve the sleep and wake phase of patients with DSWPD, improve sleep quality and daytime function, and its mechanism may be related to the down-regulation of plasma CORT level.