Apoptosis is executed by caspases, which undergo proteolytic activation in response to cell death stimuli. The apoptotic protease-activating factor 1 (Apaf-1) controls caspase activation downstream ...of mitochondria. During apoptosis, Apaf-1 binds to cytochrome c and in the presence of ATP/dATP forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9 (ref. 2). The mechanisms underlying Apaf-1 function are largely unknown. Here we report the 2.2-Å crystal structure of an ADP-bound, WD40-deleted Apaf-1, which reveals the molecular mechanism by which Apaf-1 exists in an inactive state before ATP binding. The amino-terminal caspase recruitment domain packs against a three-layered α/β fold, a short helical motif and a winged-helix domain, resulting in the burial of the caspase-9-binding interface. The deeply buried ADP molecule serves as an organizing centre to strengthen interactions between these four adjoining domains, thus locking Apaf-1 in an inactive conformation. Apaf-1 binds to and hydrolyses ATP/dATP and their analogues. The binding and hydrolysis of nucleotides seem to drive conformational changes that are essential for the formation of the apoptosome and the activation of caspase-9.
Gender may be related with the outcome of patients with acute traumatic brain injury (TBI). We explored the effect of gender on the outcome of 7145 patients with acute TBI. There was no statistical ...difference between male and female sex in the causes of trauma, age, Glasgow Coma Scale score, computed tomgraphy findings, and surgical management. The mortality of 7145 patients with acute TBI in males and females was 7.48% and 7.22%, respectively, with the corresponding unfavorable outcomes of 16.05% and 17.23%, respectively (
> 0.05 in both cases). The mortality of 1626 patients with severe TBI in males and females was 19.68% and 20.72%, respectively, with the corresponding unfavorable outcomes of 46.96% and 48.85%, respectively (
> 0.05 in both cases). Our data suggest that sex does not play a role in the outcome of patients with acute TBI.
Abstract
Background
Limited real world data show that rivaroxaban following dosage criteria from either ROCKET AF (15mg/day or 10mg/day if creatinine clearance (CrCl)<50ml/min) or J-ROCKET AF ...(15mg/day or 10mg/day if CrCl<50ml/min) are associated with comparable risks of thromboembolism and bleeding with each other in patients with non-valvular atrial fibrillation (NVAF). We aimed to study whether these observations differ between Asian and non-Asian subjects.
Methods
Databases were searched for adjusted observational study that compared relevant clinical outcomes of NVAF patients receiving off-label under-dosing rivaroxaban (10mg/day if CrCl>50ml/min), on-label dose rivaroxaban eligible for ROCKET AF or J-ROCKET AF, and off-label over-dosing rivaroxaban (20mg/day if CrCl<50ml/min).
Results
Eighteen studies were included. Rivaroxaban following J-ROCKET AF criteria (n=19,513) was associated with comparable risks of thromboembolism in the Asian subgroup (n=43,076), whereas rivaroxaban following J-ROCKET AF criteria (n=8555) was associated with higher risks of thromboembolism (hazard ratio (HR):1.27;95% confidential interval (CI):1.05–1.53) and all-cause mortality (HR:1.30;95%CI:1.05–1.60) compared with that of ROCKET AF criteria (n=23,139) in the non-Asian subgroup (n=31,694)(Figure). There was no differences in risks of major bleeding between rivaroxaban following J-ROCKET AF versus ROCKET AF criteria either in the Asian or non-Asian subgroup (Figure). Off-label underdosed rivaroxaban 10mg (n=6305) was associated with a higher risk of thromboembolism (HR:1.64;95%CI:1.28–2.11) but lower risk of major bleeding (HR:0.72;95%CI:0.57–0.90) compared with eligible dosage criteria (n=11,673). Off-label overdosed rivaroxaban 20mg (n=7572) was associated with worse clinical outcomes in the risks of thromboembolism (HR:1.42;95%CI:1.14–1.79), mortality (HR:1.41;95%CI:1.15–1.73) and major bleeding (HR:1.27; 95%CI:1.05–1.54; N=7 with I2=25%) compared with eligible dosage criteria (n=39,097).
Conclusions
Rivaroxaban dosing regimen following J-ROCKET criteria may serve as an alternative to ROCKET-AF criteria for the Asian population with NVAF, whereas the dosing regimen following ROCKET AF criteria was more favorable for the non-Asian population. Off-label underdosed rivaroxaban 10mg was associated with a higher risk of thromboembolism but a lower risk of major bleeding, while off-label overdosed rivaroxaban 20mg was associated with worse outcome in most clinical events.
Abstract
Funding Acknowledgements
Type of funding sources: None.
Background
Non-vitamin K antagonist oral anticoagulants (NOACs) are recommended over warfarin for stroke prevention for patients with ...atrial fibrillation (AF) in 2020 ESC guidelines. However, whether warfarin should be shifted to NOACs for patients who stayed very well with warfarin for years remains unknown.
Methods
From 2007 to 2010, a total of 167,176 newly-diagnosed AF patients aged ≥20 years were identified from the Taiwan National Health Insurance Research Database. Among these patients, 83,604 were alive to June 1st, 2015 and 54,803 of them who did not experience ischemic stroke or intra-cranial hemorrhage (ICH) have constituted the study population. Among the study population, 8,007 patients who continuously received warfarin and survived for at least 90 days after June 1st, 2015 were defined as the "original warfarin cohort". These patients were then categorized into 2 groups according to the stroke prevention strategies they received after June 1st, 2015; that is, staying on warfarin (n = 6,635) and shifting to NOACs (n = 1,372).
Results
Compared to patients staying on warfarin, the risk of ischemic stroke was lower for patients who were shifted NOACs (aHR 0.886; p=0.002). Also, the risk of major bleeding was lower for shifting to NOACs (aHR 0.849; p<0.001)(Figure). Compared to staying on warfarin, NOACs use was associated with a lower composite risk of ischemic stroke or ICH (aHR 0.842; p<0.001) and ischemic stroke or major bleeding (aHR 0.880; p<0.001).
Conclusions
Even for patients staying well on warfarin for years, shifting to NOACs was still associated with better clinical outcomes.
To coordinate research efforts in psychiatric genetics in China, a group of Chinese and foreign investigators have established an annual “Summit on Chinese Psychiatric Genetics” to present their ...latest research and discuss the current state and future directions of this field. To date, two Summits have been held, the first in Changsha in April, 2014, and the second in Kunming in April, 2015. The consensus of roundtable discussions held at these meetings is that psychiatric genetics in China is in need of new policies to promote collaborations aimed at creating a framework for genetic research appropriate for the Chinese population: relying solely on Caucasian population-based studies may result in missed opportunities to diagnose and treat psychiatric disorders. In addition, participants agree on the importance of promoting collaborations and data sharing in areas where China has especially strong resources, such as advanced facilities for non-human primate studies and traditional Chinese medicine: areas that may also provide overseas investigators with unique research opportunities. In this paper, we present an overview of the current state of psychiatric genetics research in China, with emphasis on genome-level studies, and describe challenges and opportunities for future advances, particularly at the dawn of “precision medicine.” Together, we call on administrative bodies, funding agencies, the research community, and the public at large for increased support for research on the genetic basis of psychiatric disorders in the Chinese population. In our opinion, increased public awareness and effective collaborative research hold the keys to the future of psychiatric genetics in China.
Critical ultrasonography is widely used in ICU and has become an indispensable tool for clinicians. However, besides operator-dependency of critical ultrasonography, lack of standardized training ...mainly result in the physicians' heterogenous ultrasonic skill. Therefore, standardized training as well as strict quality control plays the key role in the development of critical ultrasonography. We present this quality control standards to promote better development of critical ultrasonography.
Abstract
Background
Dementia and atrial fibrillation (AF) have many shared risk factors, and the presence of AF is associated with a higher risk of incident dementia. Although patients with dementia ...have higher risk of adverse cardiovascular events, there are limited data on the risks of incident AF, and the associated AF-related clinical outcomes. Patients with dementia are under-represented in randomised trials, and even if AF is present, oral anticoagulants (OAC) are not prescribed frequently. We aimed to report the incidence of newly-diagnosed AF in dementia patients, and the impact on stroke and bleeding outcomes with vitamin K antagonist (VKA, eg warfarin) and non-VKA OAC (NOACs).
Methods
Nationwide cohort study of 544,074 patients with dementia, compared to 554,074 age- and sex-matched patients without dementia.
Results
Rates of newly-diagnosed AF were higher in patients with dementia compared to those without history of dementia (1.89 per 100 person-years vs 1.78 per 100 person-years, respectively); adjusted risk of incident AF was greater in all types of dementia, pre-senile/senile dementia and vascular dementia (Figure 1). When compared to non-OAC users, warfarin use was associated with higher risk of ischaemic stroke (aHR, 1.290; 95% CI, 1.156 - 1.440), intracranial hemorrhage (ICH) risk (aHR, 1.678; 95% CI, 1.346 - 2.09) and major bleeding (aHR, 1.192; 95% CI, 1.073 - 1.323). NOAC use was associated with lower risk of ischaemic stroke (aHR, 0.42; 95% CI, 0.352 - 0.501) and major bleeding (aHR; 0.504, 95% CI, 0.433 - 0.587), when compared to non-OAC use (Figure 2).
Conclusions
In this large nationwide cohort of dementia patients, the incidence rate of newly-diagnosed or incident AF was higher in patients with dementia compared to patients without dementia. Compared to non-OAC users, NOAC use was associated with a lower risk of ischaemic stroke and major bleeding. Patients with dementia require a holistic approach to their care and management, including the use of NOACs to reduce their risks of clinical events.
Information of volatile organic compounds (VOCs) in buildings in Hong Kong is relatively scared compared to other countries. Information of how much VOC accumulation comes from occupants themselves, ...from building materials and other outdoor sources are scarce even on a global basis. This study aimed at collecting information of the levels of individual VOCs using US-EPA Method TO-14. Twenty building premises including offices and public places such as customer service centers, shopping centers, etc. were studied. Samples were taken during the time slots when the mechanical ventilation system was operating. The 43 VOCs were grouped into three categories, i.e. aromatic hydrocarbons, chlorinated hydrocarbons and organohalogen. The most dominant VOCs found in the indoor samples were benzene, toluene, ethylbenzene, xylenes (BETX), chloroform and trichloroethylene as 100% of the samples were found to contain these VOCs. Besides, more than 75% of the samples were found to contain 1,3,5-trimethylbenzene, methylchloride and dichloromethane. The wt% of chlorinated hydrocarbons (48%) and the wt% of aromatic hydrocarbons (38%) only differed by about 10% in the office sector. Organohalogen (14%) contributed to the smallest fraction of the total on all the premises in the office sector on weight basis. A completely different distribution pattern was found in the non-office sector. The most abundant class of VOCs in terms of weight was aromatic hydrocarbons (80%). The second abundant class of VOCs was chlorinated hydrocarbons (14%) and was much less than the level of aromatic hydrocarbons in terms of weight. Organohalogen (6%) contributed to the smallest fraction of the total on all the premises in the non-office sector on weight basis.
The vaccine-mediated elicitation of antibodies (Abs) capable of neutralizing diverse HIV-1 strains has been a long-standing goal. To understand how broadly neutralizing antibodies (bNAbs) can be ...elicited, we identified, characterized, and tracked five neutralizing Ab lineages targeting the HIV-1-fusion peptide (FP) in vaccinated macaques over time. Genetic and structural analyses revealed two of these lineages to belong to a reproducible class capable of neutralizing up to 59% of 208 diverse viral strains. B cell analysis indicated each of the five lineages to have been initiated and expanded by FP-carrier priming, with envelope (Env)-trimer boosts inducing cross-reactive neutralization. These Abs had binding-energy hotspots focused on FP, whereas several FP-directed Abs induced by immunization with Env trimer-only were less FP-focused and less broadly neutralizing. Priming with a conserved subregion, such as FP, can thus induce Abs with binding-energy hotspots coincident with the target subregion and capable of broad neutralization.
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•Vaccine elicitation of FP-directed antibody that neutralizes up to 59% of HIV•Development for five NHP lineages of vaccine-induced broadly neutralizing antibodies•FP-carrier effective at priming and Env-trimer effective at maturing•Priming with a target subregion induces antibodies with target-interaction hotspots
A cross-clade, cross-reactive HIV-1 neutralizing antibody with ∼59% neutralization breadth is elicited in macaques using a fusion-peptide-primed vaccine regimen, which focuses antibody-binding energy on a conserved viral epitope. Further phylogenetic antibody analysis provides insight into the eclipse phase of B cell development.
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