In observational studies, type 2 diabetes is associated with two- to fourfold higher risk of cardiovascular diseases (CVD). Using data from the China Kadoorie Biobank (CKB), we examined associations ...of genetically predicted type 2 diabetes with CVD among ∼160,000 participants to assess whether these relationships are causal. A type 2 diabetes genetic risk score (comprising 48 established risk variants) was associated with the presence of carotid plaque (odds ratio 1.17 95% CI 1.05, 1.29 per 1 unit higher log-odds of type 2 diabetes;
= 6,819) and elevated risk of ischemic stroke (IS) (1.08 1.02, 1.14;
= 17,097), nonlacunar IS (1.09 1.03, 1.16;
= 13,924), and major coronary event (1.12 1.02, 1.23;
= 5,081). There was no significant association with lacunar IS (1.03 0.91, 1.16,
= 3,173) or intracerebral hemorrhage (ICH) (1.01 0.94, 1.10,
= 6,973), although effect estimates were imprecise. These associations were consistent with observational associations of type 2 diabetes with CVD in CKB (
for heterogeneity >0.3) and with the associations of type 2 diabetes with IS, ICH, and coronary heart disease in two-sample Mendelian randomization analyses based on summary statistics from European population genome-wide association studies (
for heterogeneity >0.2). In conclusion, among Chinese adults, genetic predisposition to type 2 diabetes was associated with atherosclerotic CVD, consistent with a causal association.
Polymyxin B, which is a last-line antibiotic for extensively drug-resistant Gram-negative bacterial infections, became available in China in Dec. 2017. As dose adjustments are based solely on ...clinical experience of risk toxicity, treatment failure, and emergence of resistance, there is an urgent clinical need to perform therapeutic drug monitoring (TDM) to optimize the use of polymyxin B. It is thus necessary to standardize operating procedures to ensure the accuracy of TDM and provide evidence for their rational use. We report a consensus on TDM guidelines for polymyxin B, as endorsed by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society. The consensus panel was composed of clinicians, pharmacists, and microbiologists from different provinces in China and Australia who made recommendations regarding target concentrations, sample collection, reporting, and explanation of TDM results. The guidelines provide the first-ever consensus on conducting TDM of polymyxin B, and are intended to guide optimal clinical use.
Apolipoprotein E (apoE) is found in amyloid plaques and neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brains, but its role in their pathogenesis is unclear. Previously, we found ...C-terminal-truncated fragments of apoE in AD brains and showed that such fragments can cause neurodegeneration and can induce NFT-like inclusions in cultured neuronal cells and in transgenic mice. Here, we analyzed apoE fragmentation in brain tissue homogenates from transgenic mice expressing apoE3 or apoE4 in neurons neuron-specific enolase (NSE)-apoE or astrocytes glial fibrillary acidic protein (GFAP)-apoE by Western blotting. The C-terminal-truncated fragments of apoE accumulated, in an age-dependent manner, in the brains of NSE-apoE4 and, to a significantly lesser extent, NSE-apoE3 mice; however, no fragments were detected in GFAP-apoE3 or GFAP-apoE4 mice. In NSE-apoE mice, the pattern of apoE fragmentation resembled that seen in AD brains, and the fragmentation was specific for certain brain regions, occurring in the neocortex and hippocampus, which are vulnerable to AD-related neurodegeneration, but not in the less vulnerable cerebellum. Excitotoxic challenge with kainic acid significantly increased apoE fragmentation in NSE-apoE4 but not NSE-apoE3 mice. Phosphorylated tau (p-tau) also accumulated in an age-dependent manner in NSE-apoE4 mice and, to a much lesser extent, in NSE-apoE3 mice but not in GFAP-apoE3 or GFAP-apoE4 mice. Intraneuronal p-tau inclusions in the hippocampus were prominent in 21-month-old NSE-apoE4 mice but barely detectable in NSE-apoE3 mice. Thus, the accumulation of potentially pathogenic C-terminal-truncated fragments of apoE depends on both the isoform and the cellular source of apoE. Neuron-specific proteolytic cleavage of apoE4 is associated with increased phosphorylation of tau and may play a key role in the development of AD-related neuronal deficits.
Moderate intraoperative hypothermia promotes myocardial injury, surgical site infections, and blood loss. Whether aggressive warming to a truly normothermic temperature near 37°C improves outcomes ...remains unknown. We aimed to test the hypothesis that aggressive intraoperative warming reduces major perioperative complications.
In this multicentre, parallel group, superiority trial, patients at 12 sites in China and at the Cleveland Clinic in the USA were randomly assigned (1:1) to receive either aggressive warming to a target core temperature of 37°C (aggressively warmed group) or routine thermal management to a target of 35·5°C (routine thermal management group) during non-cardiac surgery. Randomisation was stratified by site, with computer-generated, randomly sized blocks. Eligible patients (aged ≥45 years) had at least one cardiovascular risk factor, were scheduled for inpatient non-cardiac surgery expected to last 2–6 h with general anaesthesia, and were expected to have at least half of the anterior skin surface available for warming. Patients requiring dialysis and those with a body-mass index exceeding 30 kg/m2 were excluded. The primary outcome was a composite of myocardial injury (troponin elevation, apparently of ischaemic origin), non-fatal cardiac arrest, and all-cause mortality within 30 days of surgery, as assessed in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03111875.
Between March 27, 2017, and March 16, 2021, 5056 participants were enrolled, of whom 5013 were included in the intention-to-treat population (2507 in the aggressively warmed group and 2506 in the routine thermal management group). Patients assigned to aggressive warming had a mean final intraoperative core temperature of 37·1°C (SD 0·3) whereas the routine thermal management group averaged 35·6°C (SD 0·3). At least one of the primary outcome components (myocardial injury after non-cardiac surgery, cardiac arrest, or mortality) occurred in 246 (9·9%) of 2497 patients in the aggressively warmed group and in 239 (9·6%) of 2490 patients in the routine thermal management group. The common effect relative risk of aggressive versus routine thermal management was an estimated 1·04 (95% CI 0·87–1·24, p=0·69). There were 39 adverse events in patients assigned to aggressive warming (17 of which were serious) and 54 in those assigned to routine thermal management (30 of which were serious). One serious adverse event, in an aggressively warmed patient, was deemed to be possibly related to thermal management.
The incidence of a 30-day composite of major cardiovascular outcomes did not differ significantly in patients randomised to 35·5°C and to 37°C. At least over a 1·5°C range from very mild hypothermia to full normothermia, there was no evidence that any substantive outcome varied. Keeping core temperature at least 35·5°C in surgical patients appears sufficient.
3M and the Health and Medical Research Fund, Food and Health Bureau, Hong Kong.
For the Chinese translation of the abstract see Supplementary Materials section.
Kinase inhibitors against Cyclin Dependent Kinase 4 and 6 (CDK4/6i) are promising cancer therapeutic drugs. However, their effects are limited by primary or acquired resistance in virtually all tumor ...types. Here, we demonstrate that Leucine Rich Pentatricopeptide Repeat Containing (LRPPRC) controls CDK4/6i response in lung cancer by forming a feedback loop with CDK6. LRPPRC binds to CDK6-mRNA, increasing the stability and expression of CDK6. CDK6 and its downstream E2F Transcription Factor 1 (E2F1), bind to the LRPPRC promoter and elevate LRPPRC transcription. The activation of the LRPPRC-CDK6 loop facilitates cell cycle G1/S transition, oxidative phosphorylation, and cancer stem cell generation. Gossypol acetate (GAA), a gynecological medicine that has been repurposed as a degrader of LRPPRC, enhances the CDK4/6i sensitivity in vitro and in vivo. Our study reveals a mechanism responsible for CDK4/6i resistance and provides an enlightening approach to investigating the combinations of CDK4/6 and LRPPRC inhibitors in cancer therapy.
The Lilliput effect following the Permian–Triassic mass extinction and its aftermath has been documented in a variety of marine animal groups, but it is less known in terrestrial and freshwater ...invertebrates. Here we present new investigations of the size variations of terrestrial ostracods of the genus Darwinula based on fossil records from a Permian–Triassic section on the northern limb of the Dalongkou Anticline section in Northwest China. Quantitative analyses reveal that ostracod test sizes decreased sharply through the terrestrial Permian–Triassic mass extinction interval. The Lilliput effect in terrestrial ostracods is characterized by the extinction of large taxa and the rise of small-sized and elongate new forms, coupled with the dramatic loss of conchostracans, charophytes, and the blooming of lycopod spores. The size decrease in terrestrial ostracods, following the biotic crisis through the Permian–Triassic interval, was probably triggered by several interacting events, including global warming, anoxia, and enhanced sediment input following acid rain and wildfire.
•We investigated the freshwater ostracod sizes from a Permian–Triassic section.•Lilliput effect is characterized by large forms extinction and small-sized coming.•Ostracod test sizes decrease coupled with the terrestrial biotic strongest turnover.•Warming, anoxia, and enhanced input were considered for environmental factors.
Post-stroke shoulder-hand syndrome (PS-SHS), a common neurological comorbidity after stroke episodes, poses a grave threat on patients' functional recovery. Preliminary trials have demonstrated that ...the acupuncture and moxibustion treatment, including a dermal acupuncture tapping method known as plum blossom needling (PBN) can improve pain and motor dysfunctions in patients with PS-SHS. However, there are few reports describing simultaneous moxibustion treatment in combination with PBN. Hence, a novel plum blossom needle device with mild moxibustion (PBNMM) was developed to evaluate its potential efficacy and safety in patients with stage 1 PS-SHS.
This multicenter, sham-controlled, randomized controlled trial (RCT) will recruit 102 eligible patients with stage 1 PS-SHS from three clinical centers, randomly allocated in a ratio of 1:1:1 to the PBNMM group, PBNMM with no moxa smoke (PBNMM-NMS) group and sham control group. Patients in each group will receive a 30-minute treatment once per day for 4 weeks, with 5 consecutive sessions per week, for a total of 20 sessions. The primary outcome measure will be defined as the decreased scores from baseline in the visual analog scale (VAS) assessment at week 4. Secondary outcome measures will include scores on the Fugl-Meyer Assessment of the Upper Extremity Scale (FMA-UE), the Modified Barthel Index (MBI), and the somatosensory evoked potential (SEP) records. All outcomes will be evaluated at baseline and weeks 4, 5, 6 and 10, and the intention-to-treat analysis will be applied.
This study aims to provide robust evidence for the efficacy and safety of the PBNMM for PS-SHS treatment, as well as the specific impact of moxibustion smoke itself in dealing with PS-SHS.
Chinese Clinical Trial Registry No. ChiCTR2200062441. Registered on 7 August 2022.
A colistin-resistant
strain isolated from dog feces was characterized in this study.
A multiplex PCR assay was used to detect the presence of colistin-resistant
genes; it was found that
QDFD216 ...co-harbored the
and
genes. Whole-genome sequencing and further bioinformatics analysis revealed that
QDFD216 belonged to serotype O176:H11, fimH1311 type and ST132. The resistance genes
,
, and
were present in the chromosome. The
and
genes were located in two plasmids of different incompatibility groups.
was carried by a IncX4-type plasmid within an typical IS
cassette, while
was encoded by an IncP1-type plasmid with a genetic structure of Tn
-IS
. No additional antibiotic resistance genes were carried by either plasmid.
This is the first report of an
isolate co-harboring a
-carrying IncX4 plasmid and a
-carrying IncP1 plasmid. The evolution and mechanism of
gene co-existence need further study to assess its impact on public health.
Different biomass sources (bamboo, rape straw, lignin, and Yaupon holly) were liquefied using microwave energy to produce biopolyols, which were then used to prepare biofoams without any further ...separation process. The results indicated that the content of hydroxyl groups in biopolyols derived from different biomass sources was sorted in descending order as rape straw, Yaupon holly, bamboo, and lignin. The rheological analysis demonstrated that the biopolyols were pseudoplastic, and the yield stress of biopolyols was remarkably increased with increasing biomass content. The compressive strength of polyurethane (PU) foam was rendered smaller by introducing biomass sources. Nevertheless, the biofoam obtained from biomass sources with higher hydroxyl groups content had better PU performance. In addition, the termite resistance performance of PU foam increased with the introduction of Yaupon holly, rape straw, and bamboo sources. Accordingly, the biofoams derived from the liquefaction of rape straw performed better than those from other biomass sources.
Overcoming immune tolerance of the growth factors associated with tumor growth should be a useful approach to cancer therapy by active immunity. We used vascular endothelial growth factor (VEGF) as a ...model antigen to explore the feasibility of the immunogene tumor therapy with a vaccine based on a single xenogeneic homologous gene, targeting the growth factors associated with angiogenesis. To test this concept, we constructed a plasmid DNA encoding Xenopus homologous VEGF (XVEGF-p) and control vectors. We found that immunogene tumor therapy with a vaccine based on XVEGF was effective at both protective and therapeutic antitumor immunity in several tumor models in mice. VEGF-specific autoantibodies in sera of mice immunized with XVEGF-p could be found in Western blotting analysis and ELISA assay. The purified immunoglobulins were effective at the inhibition of VEGF-mediated endothelial cell proliferation in vitro, and at antitumor activity and the inhibition of angiogenesis by adoptive transfer in vivo. The elevation of VEGF in the sera of the tumor-bearing mice could be abrogated with XVEGF-p immunization. The antitumor activity and production of VEGF-specific autoantibodies, significantly elevated IgG1 and IgG2b, could be abrogated by the depletion of CD4+T lymphocytes. The observations may provide a vaccine strategy for cancer therapy through the induction of autoimmunity against the growth factors associated with tumor growth in a cross reaction with single xenogeneic homologous gene and may be of importance in the further exploration of the applications of other xenogeneic homologous genes identified in human and other animal genome sequence projects in cancer therapy.
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