The KDIGO acute kidney injury guidelines for cardiac surgery patients in critical care: a validation study.

BACKGROUND: The Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury (AKI) guidelines assign the same stage of AKI to patients whether they fulfil urine output criteria, serum creatinine criteria or both criteria for that stage. This study explores the validity of the KDIGO guidelines as a tool to stratify the risk of adverse outcomes in cardiac surgery patients. METHODS: Prospective data from consecutive adult patients admitted to the cardiac intensive care unit (CICU) following cardiac surgery between January 2013 and May 2015 were analysed. Patients were assigned to groups based on the criteria they met for each stage of AKI according to the KDIGO guidelines. Short and mid-term outcomes were compared between these groups. RESULTS: A total of 2267 patients were included with 772 meeting criteria for AKI-1 and 222 meeting criteria for AKI-2. After multivariable adjustment, patients meeting both urine output and creatinine criteria for AKI-1 were more likely to experience prolonged CICU stay (OR 4.9, 95%CI 3.3-7.4, p < 0.01) and more likely to require renal replacement therapy (OR 10.5, 95%CI 5.5-21.9, p < 0.01) than those meeting only the AKI-1 urine output criterion. Patients meeting both urine output and creatinine criteria for AKI-1 were at an increased risk of mid-term mortality compared to those diagnosed with AKI-1 by urine output alone (HR 2.8, 95%CI 1.6-4.8, p < 0.01). Patients meeting both urine output and creatinine criteria for AKI-2 were more likely to experience prolonged CICU stay (OR 16.0, 95%CI 3.2-292.0, p < 0.01) or require RRT (OR 11.0, 95%CI 4.2-30.9, p < 0.01) than those meeting only the urine output criterion. Patients meeting both urine output and creatinine criteria for AKI-2 were at a significantly increased risk of mid-term mortality compared to those diagnosed with AKI-2 by urine output alone (HR 3.6, 95%CI 1.4-9.3, p < 0.01). CONCLUSIONS: Patients diagnosed with the same stage of AKI by different KDIGO criteria following cardiac surgery have significantly different short and mid-term outcomes. The KDIGO criteria need to be revisited before they can be used to stratify reliably the severity of AKI in cardiac surgery patients. The utility of the criteria also needs to be explored in other settings.

Euonymus hamiltonianus Extract Improves Amnesia in APPswe/Tau Transgenic and Scopolamine-Induced Dementia Models.

Dementia is a syndrome exhibiting progressive impairments on cognition and behavior beyond the normal course of aging, and Alzheimer's disease (AD) is one of the neurodegenerative diseases known to cause dementia. We investigated the effect of KGC07EH, the 30% ethanol extract of Euonymus hamiltonianus, against amyloid-ß (Aß) production and cognitive dysfunction in dementia models. KGC07EH was treated on Hela cells expressing the Swedish mutant form of amyloid precursor protein (APP), and the AD triple transgenic (3× TG) mice were given KGC07EH orally during 11-14 months of age (100 and 300 mg/kg/day). SH-SY5Y cell line was used to test KGC07EH on scopolamine-induced elevation of acetylcholinesterase (AChE) activity. ICR mice were intraperitoneally injected with scopolamine, and KGC07EH was administered orally (50, 100, and 200 mg/kg/day) for 4 weeks. KGC07EH treatment decreased Aß, sAPPß-sw, and sAPPß-wt levels and APP protein expressions while sAPPα was increased in Swedish mutant-transfected HeLa cells. KGC07EH treatment also significantly reduced the accumulation of Aß plaques and tau tangles in the brain of 3× TG mice as well as improving the cognitive function. In SH-SY5Y cells cultured with scopolamine, KGC07EH dose-dependently attenuated the increase of AChE activity. KGC07EH also improved scopolamine-induced learning and memory impairment in scopolamine-injected mice, and in their cerebral cortex and hippocampus, the expression levels of p-ERK, p-CREB, p-Akt, and BDNF were attenuated. KGC07EH inhibits APP processing and Aß production both in vitro and in vivo, while enhancing acetylcholine signaling and cognitive dysfunction which are the major symptoms of dementia.

Micro RNA-411 Expression Improves Cardiac Phenotype Following Myocardial Infarction in Mice.

Induction of endogenous regenerative capacity has emerged as one promising approach to repair damaged hearts following myocardial infarction (MI). Re-expression of factors that are exclusively expressed during embryonic development may reactivate the ability of adult cardiomyocytes to regenerate. Here, we identified miR-411 as a potent inducer of cardiomyocyte proliferation. Overexpression of miR-411 in the heart significantly increased cardiomyocyte proliferation and survival in a model MI. We found that miR-411 enhances the activity of YAP, the main downstream effector of the Hippo pathway, in cardiomyocytes. In conclusion, miR-411 induces cardiomyocyte regeneration and improves cardiac function post-MI likely by modulating the Hippo/YAP pathway.

Safety and immunogenicity of the inactivated whole-virus adjuvanted COVID-19 vaccine VLA2001: A randomized, dose escalation, double-blind phase 1/2 clinical trial in healthy adults.

OBJECTIVES: We aimed to evaluate the safety and optimal dose of a novel inactivated whole-virus adjuvanted vaccine against SARS-CoV-2: VLA2001. METHODS: We conducted an open-label, dose-escalation study followed by a double-blind randomized trial using low, medium and high doses of VLA2001 (1:1:1). The primary safety outcome was the frequency and severity of solicited local and systemic reactions within 7 days after vaccination. The primary immunogenicity outcome was the geometric mean titre (GMT) of neutralizing antibodies against SARS-CoV-2 two weeks after the second vaccination. The study is registered as NCT04671017. RESULTS: Between December 16, 2020, and June 3, 2021, 153 healthy adults aged 18-55 years were recruited in the UK. Overall, 81.7% of the participants reported a solicited AE, with injection site tenderness (58.2%) and headache (46.4%) being the most frequent. Only 2 participants reported a severe solicited event. Up to day 106, 131 (85.6%) participants had reported any AE. All observed incidents were transient and non-life threatening in nature. Immunogenicity measured at 2 weeks after completion of the two-dose priming schedule, showed significantly higher GMTs of SARS-CoV-2 neutralizing antibody titres in the highest dose group (GMT 545.6; 95% CI: 428.1, 695.4) which were similar to a panel of convalescent sera (GMT 526.9; 95% CI: 336.5, 825.1). Seroconversion rates of neutralizing antibodies were also significantly higher in the high-dose group (>90%) compared to the other dose groups. In the high dose group, antigen-specific IFN-γ expressing T-cells reactive against the S, M and N proteins were observed in 76, 36 and 49%, respectively. CONCLUSIONS: VLA2001 was well tolerated in all tested dose groups, and no safety signal of concern was identified. The highest dose group showed statistically significantly stronger immunogenicity with similar tolerability and safety, and was selected for phase 3 clinical development.

Inhibitory Effects of Chrysanthemum (Chrysanthemum morifolium Ramat.) Extract and Its Active Compound Isochlorogenic Acid A on Sarcopenia.

Sarcopenia, age-related muscle atrophy, weakening muscle strength, and exercise capacity, generally accompany imbalances in protein metabolism. Chrysanthemum morifolium Ramat. extract (CME) and its active compound, isochlo-rogenic acid A (IcA), have been reported to have anti-oxidative, anti-diabetic, and neuroprotective effects. However, the roles of CME and IcA in the regulation of muscle protein turnover-related signaling pathways to attenuate sarcopenia have not been explored. In this study, we investigated CME and IcA based regulation of protein turnover in synthesizing muscle in vitro and in vivo. At the molecular level, CME and IcA promoted phosphorylation of PI3K/Akt and mTOR pathways, which stimulate synthesis of muscle proteins, and suppressed FoxO3a and E3 ubiquitin ligases during protein degrada-tion. In vivo, CME and IcA increased grip strength, exercise capacity, muscle mass and volume, and cross-sectional area of myofibers in middle-aged C57BL/6J mice. These results suggest that CME and IcA may have roles as functional food supplements for delaying sarcopenia by enhancing muscle mass recovery and function.

Junior doctor-led quality improvement project to improve safety and visibility of an interspecialty referral system.

Interspecialty referrals for increasingly complex hospital inpatients are common and miscommunication often leads to delays in patient care. In a district general hospital, a web-based system generated an email referral, which lacked visibility and tracking/audit of the process, with no record generated automatically in paper inpatient notes or electronic patient records (EPR). We aimed to improve the visibility and safety of the interspecialty referral system.We canvassed stakeholders, informally and via an online satisfaction survey, collecting qualitative and quantitative data about attitudes to the existing system, generating ideas for change. We process mapped the system, identifying points of weakness. We adapted our EPR system, using a work-around solution, to develop a form that could be emailed from the EPR. This generated a permanent record within the EPR and an electronic record of the referral having been sent. We measured the visibility of referrals and responses within the EPR. We generated an online training 'how-to' video and reaudited stakeholder satisfaction.There was a significant increase in the proportion of junior doctors satisfied or very satisfied with the interspecialty referral system (27/31 postintervention; 87.1% vs 26/55 preintervention; 47%; p<0.0001) and more believed that the visibility was adequate or very adequate (24/31 postintervention; 77.4% vs 9/55 preintervention; 16.4%; p<0.0001). Visibility of referrals by project team members on the EPR increased from a baseline of 3.5% to 83.6% and the visibility of responses to these referrals on the EPR increased from 4.6% to 40.7%. Qualitative feedback was excellent, hospital executive approval was gained and our work-around system spread to non-team members.We developed a more visible and reliable interspecialty referral system, adapting existing EPR capabilities, which was popular with users and led to cultural change in interspecialty referral responders. A formal EPR redesign, informed by our project, is in development.

Standardized Kaempferia parviflora Wall. ex Baker (Zingiberaceae) Extract Inhibits Fat Accumulation and Muscle Atrophy in ob/ob Mice.

Obesity, a metabolic disorder caused by an imbalance between energy intake and energy expenditure, is accompanied with fat accumulation and skeletal muscle atrophy. Kaempferia parviflora Wall. ex Baker, also called black ginger, is known to increase physical fitness performance and improve energy metabolism. In this study, we investigated whether Kaempferia parviflora extract (KPE) alleviates both obesity and muscle atrophy using ob/ob mice. Wild-type C57BL/6J and ob/ob mice were provided with a normal diet ad libitum, and ob/ob mice were orally given KPE at a dose of 100 mg/kg/day or 200 mg/kg/day for eight weeks. KPE significantly decreased body weight, fat volume, and fat weight without affecting appetite. It inhibited the expression of adipogenic transcription factors and lipogenic enzymes by upregulating AMP-activated protein kinase (AMPK) in epididymal fat. In contrast, it markedly increased the muscle fiber size, muscle volume, and muscle mass, resulting in the enhancement of muscle function, such as exercise endurance and grip strength. On the molecular level, it activated the phosphatidylinositol 3 kinase (PI3K)/Akt pathway, a key regulator in protein synthesis in skeletal muscle. KPE could be a promising material to alleviate obesity by inhibiting adipogenesis, lipogenesis, and muscle atrophy.