Non-benzodiazepine hypnotics (Z-drugs) are advocated to be safer than benzodiazepines (BZDs). This study comprehensively investigated the association of BZD and Z-drug usage with the risk of ...hospitalisation for fall-related injuries in older people.
This study used the Taiwan National Health Insurance Database with a nested matched case-control design. We identified 2238 elderly patients who had been hospitalised for fall-related injuries between 2003 and 2012. They were individually matched (1:4) with a comparison group by age, sex, and index year. Conditional logistic regression was used to determine independent effects of drug characteristics (type of exposure, dosage, half-life, and polypharmacy) on older people.
Older people hospitalisation for fall-related injuries were significantly associated with current use of BZDs (adjusted odds ratio AOR = 1.32, 95% confidential interval CI = 1.17-1.50) and Z-drugs (AOR = 1.24, 95%CI = 1.05-1.48). At all dose levels of BZDs, high dose levels of Z-drugs, long-acting BZD, and short-acting BZD use were all significantly increased the risk of fall-related injuries requiring hospitalisation. Polypharmacy, the use of two or more kinds of BZDs, one kind of BZD plus Z-drugs and two or more kinds of BZDs plus Z-drugs, also significantly increased the risk (AOR = 1.61, 95% CI = 1.38-1.89; AOR = 1.65, 95% CI = 1.08-2.50, and AOR = 1.58, 95% CI = 1.21-2.07).
Different dose levels and half-lives of BZDs, a high dose of Z-drugs, and polypharmacy with BZDs and Z-drugs were associated with an increased risk of fall-related injury requiring hospitalisation in older people. Physicians should balance the risks and benefits when prescribing these drug regimens to older people considering the risk of falls.
Bone metastases occur in 50-70% of patients with late-stage breast cancers and effective therapies are needed. The expression of enhancer of zeste homolog 2 (EZH2) is correlated with breast cancer ...metastasis, but its function in bone metastasis hasn't been well-explored. Here we report that EZH2 promotes osteolytic metastasis of breast cancer through regulating transforming growth factor beta (TGFβ) signaling. EZH2 induces cancer cell proliferation and osteoclast maturation, whereas EZH2 knockdown decreases bone metastasis incidence and outgrowth in vivo. Mechanistically, EZH2 transcriptionally increases ITGB1, which encodes for integrin β1. Integrin β1 activates focal adhesion kinase (FAK), which phosphorylates TGFβ receptor type I (TGFβRI) at tyrosine 182 to enhance its binding to TGFβ receptor type II (TGFβRII), thereby activating TGFβ signaling. Clinically applicable FAK inhibitors but not EZH2 methyltransferase inhibitors effectively inhibit breast cancer bone metastasis in vivo. Overall, we find that the EZH2-integrin β1-FAK axis cooperates with the TGFβ signaling pathway to promote bone metastasis of breast cancer.
International guidelines recommend ivosidenib followed by modified FOLFOX (mFOLFOX) for advanced intrahepatic cholangiocarcinoma (ICC) with isocitrate dehydrogenase 1 (IDH1) mutations. Taiwan ...National Health Insurance covers only fluorouracil/leucovorin (5-FU/LV) chemotherapy for this ICC group, and there has been no prior economic evaluation of ivosidenib. Therefore, we aimed to assess ivosidenib's cost-effectiveness in previously treated, advanced ICC-presenting IDH1 mutations compared with mFOLFOX or 5-FU/LV.
A 3-state partitioned survival model was employed to assess ivosidenib's cost-effectiveness over a 10-year horizon with a 3% discount rate, setting the willingness-to-pay threshold at 3 times the 2022 GDP per capita. Efficacy data for Ivosidenib, mFOLFOX, and 5-FU/LV were sourced from the ClarIDHy, ABC06, and NIFTY trials, respectively. Ivosidenib's cost was assumed to be NT$10,402/500 mg. Primary outcomes included incremental cost-effectiveness ratios (ICERs) and net monetary benefit. Deterministic sensitivity analyses (DSA) and probabilistic sensitivity analyses (PSA) were employed to evaluate uncertainty and explore price reduction scenarios.
Ivosidenib exhibited ICERs of NT$6,268,528 and NT$5,670,555 compared with mFOLFOX and 5-FU/LV, respectively, both exceeding the established threshold. PSA revealed that ivosidenib was unlikely to be cost-effective, except when it was reduced to NT$4,161 and NT$5,201/500 mg when compared with mFOLFOX and 5-FU/LV, respectively. DSA underscored the significant influence of ivosidenib's cost and utility values on estimate uncertainty.
At NT$10,402/500 mg, ivosidenib was not cost-effective for IDH1-mutant ICC patients compared with mFOLFOX or 5-FU/LV, indicating that a 50-60% price reduction is necessary for ivosidenib to be cost-effective in this patient group.
Block Partitioning Structure in the VVC Standard Huang, Yu-Wen; An, Jicheng; Huang, Han ...
IEEE transactions on circuits and systems for video technology,
10/2021, Letnik:
31, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Versatile Video Coding (VVC) is the latest video coding standard jointly developed by ITU-T VCEG and ISO/IEC MPEG. In this paper, technical details and experimental results for the VVC block ...partitioning structure are provided. Among all the new technical aspects of VVC, the block partitioning structure is identified as one of the most substantial changes relative to the previous video coding standards and provides the most significant coding gains. The new partitioning structure is designed using a more flexible scheme. Each coding tree unit (CTU) is either treated as one coding unit or split into multiple coding units by one or more recursive quaternary tree partitions followed by one or more recursive multi-type tree splits. The latter can be horizontal binary tree split, vertical binary tree split, horizontal ternary tree split, or vertical ternary tree split. A CTU dual tree for intra-coded slices is described on top of the new block partitioning structure, allowing separate coding trees for luma and chroma. Also, a new way of handling picture boundaries is presented. Additionally, to reduce hardware decoder complexity, virtual pipeline data unit constraints are introduced, which forbid certain multi-type tree splits. Finally, a local dual tree is described, which reduces the number of small chroma intra blocks.
Proton pump inhibitors, including omeprazole, rabeprazole, lansoprazole, and pantoprazole, achieved simultaneous enantioselective determination in the human plasma by chiral liquid ...chromatography–tandem mass spectrometry. The four corresponding stable isotope‐labeled proton pump inhibitors were adopted as the internal standards. Each enantiomer and the internal standards were extracted with acetonitrile containing 0.1% ammonia, then separated with a Chiralpak IC column (5 µm, 4.6 mm × 150 mm) within 10 min. The mobile phase was composed of acetonitrile–ammonium acetate (10 mM) containing 0.2% acetic acid (50:50, v/v). To quantify all enantiomers, an API 4000 tandem mass spectrometer was used, and multiple reaction monitoring transitions were performed on m/z 360.1→242.1, 384.1→200.1, 370.1→252.1, and 346.1→198.1, respectively. No significant matrix effect was observed for all analytes. The calibration curve for all enantiomers were linear from 1.25 to 2500 ng/mL. The precisions for intra‐ and inter‐run were < 14.2%, and the accuracy fell in the interval of –5.3 to 8.1%. Stability of samples was confirmed under the storage and processing conditions. The developed method was also suitable for separation and determination of ilaprazole enantiomers. The validated method combining the equilibrium dialysis method was applied to the protein binding ratio studies of four pairs proton pump inhibitor enantiomers in human plasma.
Control of translation is a fundamental source of regulation in gene expression. The induction of protein synthesis by brain-derived neurotrophic factor (BDNF) critically contributes to enduring ...modifications of synaptic function, but how BDNF selectively affects only a minority of expressed mRNAs is poorly understood. We report that BDNF rapidly elevates Dicer, increasing mature miRNA levels and inducing RNA processing bodies in neurons. BDNF also rapidly induces Lin28, causing selective loss of Lin28-regulated miRNAs and a corresponding upregulation in translation of their target mRNAs. Binding sites for Lin28-regulated miRNAs are necessary and sufficient to confer BDNF responsiveness to a transcript. Lin28 deficiency, or expression of a Lin28-resistant Let-7 precursor miRNA, inhibits BDNF translation specificity and BDNF-dependent dendrite arborization. Our data establish that specificity in BDNF-regulated translation depends upon a two-part posttranscriptional control of miRNA biogenesis that generally enhances mRNA repression in association with GW182 while selectively derepressing and increasing translation of specific mRNAs.
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► Brain-derived neurotrophic factor (BDNF) increases levels of Dicer and mature miRNAs ► BDNF also induces Lin28 and selective miRNA loss in terminally differentiated neurons ► BDNF-induced dendrite growth requires Lin28-mediated degradation of pre-Let-7 miRNAs ► Regulation of miRNA biogenesis underlies BDNF's target selection in protein synthesis
Brain-derived neurotrophic factor selectively increases the translation of a subset of expressed mRNAs by regulating levels of both Dicer and Lin28 and, in this way, dictating the profile of neuronal miRNAs.
The cumulative effect of multiple pharmaceutics with anticholinergic properties (i.e., anticholinergic burden), can serve as an indicator of suboptimal prescribing in the elderly. Yet, no research is ...available concerning the effect of different compositions of score on adverse outcomes under the same anticholinergic burden. This population‐based cohort study investigated whether different combinations of medications with anticholinergic properties have different impacts on adverse outcomes in the elderly using the Anticholinergic Risk Scale (ARS) and Anticholinergic Cognitive Burden Scale (ACB) scores. We included 116,043 people aged 65 years and older from Taiwan’s Longitudinal Health Insurance Database and measured their monthly anticholinergic burden over a 10‐year follow‐up period (from January 1, 2002, to December 31, 2011). We analyzed the association between different anticholinergic score compositions and adverse outcomes (emergency department visits, all‐cause hospitalizations, fracture‐specific hospitalizations, and incident dementia) via generalized estimating equations. Cumulative effects of multiple medications with low anticholinergic activity were associated with a greater risk for emergency department visits and all‐cause hospitalizations (emergency department visits for 65–74 year olds (y/o): ACB 1 + 1 + 1, adjusted odds ratio (aOR) 2.05 (1.99–2.12); ACB 1 + 2, aOR 2.04 (1.91–2.17); and ACB 3, aOR 1.62 (1.57–1.66)). In contrast, using medications with greater potency had a greater impact on central adverse outcomes (incident dementia for 65–74 y/o: ACB 1 + 1 + 1, aOR 3.30 (2.84–3.84); ACB 1 + 2, aOR 5.84 (4.59–7.41); and ACB 3, aOR 9.15 (8.38–9.99)). The quantity of anticholinergics (even with low score) an older person used matters in risk of emergency department visit and all‐cause hospitalization but the potency of anticholinergics (i.e., those with high score) matters in risk of fracture‐specific hospitalization and incident dementia.
Carbene insertion reactions initiated with diazo compounds have been widely used to develop unnatural enzymatic reactions. However, alternative functionalization of diazo compounds in enzymatic ...processes has been unexploited. Herein, we describe a photoenzymatic strategy for radical‐mediated stereoselective hydroalkylation with diazo compounds. This method generates carbon‐centered radicals through an ene reductase catalyzed photoinduced electron transfer process from diazo compounds, enabling the synthesis of γ‐stereogenic carbonyl compounds in good yields and stereoselectivities. This study further expands the possible reaction patterns in photo‐biocatalysis and offers a new approach to solving the selectivity challenges of radical‐mediated reactions.
A photoenzymatic strategy for radical‐mediated stereoselective hydroalkylation with diazo compounds has been developed. By this method, a series of γ‐chiral carbonyl compounds were synthesized in high yields and stereoselectivities.
A carboxylate‐directed palladium‐catalyzed Mizoroki–Heck alkenylation of γ,δ‐unsaturated carboxylic acids with alkenyl bromides is reported. This carboxylate group is effective for chelation to a Pd ...center, enabling the distal alkenylation of electronically unbiased internal alkenes in the formation of conjugated 1,3‐dienes with high stereoselectivity. In addition, the conjugated 1,3‐diene products can be used for synthetic applications through reduction, epoxidation, methylation, amidation, and cycloaddition.
•Digestibility of fully gelatinized rice starch is independent on amylose content.•Hydrodynamically larger amylopectin molecules have shorter medium chains.•Hydrodynamically larger amylopectin ...molecules have fewer long chains.•Amylopectin with fewer long chains is digested faster at fully gelatinized state.•Gelatinized and retrograded starch have different digestion fractions.
In current study, the effects of starch fine molecular structures on its in vitro digestibility at fully gelatinized stage were investigated. The digestion kinetics of 15 fully gelatinized rice starches were obtained and correlated with starch chain-length distributions and molecular size distributions. Both logarithm of slopes and parallel first-order kinetic model were applied to fit the digestion curves to a few kinetics-based parameters. Result showed there were two simultaneous digestion fractions (fast versus slow) for fully gelatinized rice starches. The rate constants of slowly-digestible fraction significantly correlated with starch molecular sizes, especially with that of amylopectin molecules. Hydrodynamically larger amylopectin molecules tend to contain more shorter branches but less long chains. This slows down the starch hydrolysis by α-amylase while the action of AMG is less antagonistically hindered, increasing overall digestion rate. This study provides important information for rice breeders and manufacturers to develop rice products with reduced starch digestibility.
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