Singapore Paediatric Resuscitation Guidelines 2021

We present the 2021 Singapore Paediatric Resuscitation Guidelines. The International Liaison Committee on Resuscitation’s Pediatric Taskforce Consensus Statements on Science and Treatment Recommendations, which was published in October 2020, and the updated resuscitation guidelines from the American Heart Association and European Resuscitation Council, were reviewed and discussed by the committee. These recommendations were derived after deliberation of peer-reviewed evidence updates on paediatric resuscitation and took into consideration the local setting and clinical practice.     

Amyloid-β disrupts unitary calcium entry through endothelial NMDA receptors in mouse cerebral arteries

Transient increases in intracellular Ca²⁺ activate endothelium-dependent vasodilatory pathways. This process is impaired in cerebral amyloid angiopathy, where amyloid-β_(1-40) accumulates around blood vessels. In neurons, amyloid-β impairs the Ca²⁺-permeable N-methyl-D-aspartate receptor (NMDAR), a mediator of endothelium-dependent dilation in arteries. We hypothesized that amyloid-β_(1-40) reduces NMDAR-elicited Ca²⁺ signals in mouse cerebral artery endothelial cells, blunting dilation. Cerebral arteries isolated from 4-5 months-old, male and female cdh5:Gcamp8 mice were used for imaging of unitary Ca²⁺ influx through NMDAR (NMDAR sparklets) and intracellular Ca²⁺ transients. The NMDAR agonist NMDA (10 µmol/L) increased frequency of NMDAR sparklets and intracellular Ca²⁺ transients in endothelial cells; these effects were prevented by NMDAR antagonists D-AP5 and MK-801. Next, we tested if amyloid-β_(1-40) impairs NMDAR-elicited Ca²⁺ transients. Cerebral arteries incubated with amyloid-β_(1-40) (5 µmol/L) exhibited reduced NMDAR sparklets and intracellular Ca²⁺ transients. Lastly, we observed that NMDA-induced dilation of pial arteries is reduced by acute intraluminal amyloid-β_(1-40), as well as in a mouse model of Alzheimer’s disease, the 5x-FAD, linked to downregulation of Grin1 mRNA compared to wild-type littermates. These data suggest that endothelial NMDAR mediate dilation via Ca²⁺-dependent pathways, a process disrupted by amyloid-β_(1-40) and impaired in 5x-FAD mice.     

Discovery of a dual-action small molecule that improves neuropathological features of Alzheimer’s disease mice

Alzheimer’s disease (AD) is characterized by complex, multifactorial neuropathology, suggesting that small molecules targeting multiple neuropathological factors are likely required to successfully impact clinical progression. Acid sphingomyelinase (ASM) activation has been recognized as an important contributor to these neuropathological features in AD, leading to the concept of using ASM inhibitors for the treatment of this disorder. Here we report the identification of KARI 201, a direct ASM inhibitor evaluated for AD treatment. KARI 201 exhibits highly selective inhibition effects on ASM, with excellent pharmacokinetic properties, especially with regard to brain distribution. Unexpectedly, we found another role of KARI 201 as a ghrelin receptor agonist, which also has therapeutic potential for AD treatment. This dual role of KARI 201 in neurons efficiently rescued neuropathological features in AD mice, including amyloid beta deposition, autophagy dysfunction, neuroinflammation, synaptic loss, and decreased hippocampal neurogenesis and synaptic plasticity, leading to an improvement in memory function. Our data highlight the possibility of potential clinical application of KARI 201 as an innovative and multifaceted drug for AD treatment.

Alzheimer’s disease (AD) is a multifaceted neurodegenerative disease with underlying pathologies that extend well beyond the widely recognized accumulation of amyloid beta (Aβ). Many studies have demonstrated that memory impairment in AD is driven by the interaction of various pathologic processes, such as cell death (1), impaired synapse plasticity (2), neurogenesis loss (3), autophagy dysfunction (4), vascular abnormalities (5), blood–brain barrier (BBB) damage (6), and systemic inflammation (7). Thus, effective drug development for this disorder must focus on therapeutic strategies that target the complex and multiple neuropathological features in AD.We and others have previously reported that the activity of several sphingolipid-metabolizing enzymes, especially acid sphingomyelinase (ASM), which is encoded by the SMPD1 gene, is abnormally expressed in AD patients and mouse models (8–10). The primary role of ASM is to catalyze the conversion of sphingomyelin, a major component of membranes, into ceramide and phosphocholine (11). The increased ASM activity in the blood and brain of AD mice contributes to various pathological features, including cell apoptosis (12), defective autophagy (8), neurogenesis loss (13), BBB leakage (14), and inflammation (15, 16), suggesting that ASM inhibition could be an important therapeutic target that addresses the neuropathological features of AD (17). Although some studies have previously identified direct or indirect functional inhibitors (17–20) of ASM, these inhibitors have lacked specificity, leading to the potential for off-target effects and unclear potential mechanisms of action in AD. Therefore, there is an important need to develop new compounds that block ASM activity by direct interaction with the enzyme.Here, we identify KARI 201 as a direct, selective, and competitive ASM inhibitor with excellent brain distribution and druggability. Interestingly, we also found an unexpected role of KARI 201 as an agonist of growth hormone secretagogue receptor 1α (GHSR1α, also known as the ghrelin receptor) via GPCR (G protein–coupled receptor) screening based on RNA-sequencing (RNA-seq) analysis in KARI 201–treated AD mice. This activity is critical for hippocampal synaptic physiology and may impact neuropathological features in AD as well (21–23). The dual action in neurons of KARI 201 as a direct ASM inhibitor and GHSR1α agonist led to outstanding, synergetic therapeutic effects in AD mouse models on neuropathological features involving learning and memory impairment. Therefore, our data highlight the possibility of clinical application of KARI 201 as an innovative and multifaceted drug for AD treatment.     

Stiffener Design to Maintain Line Heating Efficiency during the Lifting Process Considering Phase Transformation

In the shipbuilding industry, welding is the main technique used to join steel structures. There is a lifting process, post-welding, that can eliminate the correction effect of line heating. Line heating is reperformed after the lifting process. This can significantly delay the ship assembly process. Herein, we present a design method for installing a permanent stiffener to avoid the disappearance of the line heating effect during the lifting process. The change in physical properties due to heating and cooling of the line heating is calculated. The limiting stress, at which the effect of the line heating completely disappears, based on the inherent strain theory, is obtained. The phase fraction by the cooling rate is calculated using the continuous cooling transformation diagram and the Kiustinen–Marburgerm equation. Physical properties affected by the phase transformation are calculated, considering the physical properties and fraction of each phase. The square plate theory and superposition principle are used to construct a local model, with a stiffener, of the ship block. The stress caused by the shape of the stiffener and the distance between the stiffeners were calculated for the local model. The calculated stress and the limiting stress were compared to determine, for the expected line heating efficiency, the most acceptable stiffener design. Finally, to confirm the elimination of the problem, the designed stiffener is analyzed using the finite element method.     

Higher Serum Total Cholesterol to High-Density Lipoprotein Cholesterol Ratio Is Associated with Increased Mortality among Incident Peritoneal Dialysis Patients

This study evaluated the association of the serum total cholesterol to high-density lipoprotein cholesterol ratio (TC/HDL-C) with mortality in incident peritoneal dialysis (PD) patients. We performed a multi-center, prospective cohort study of 630 incident PD patients from 2008 to 2015 in Korea. Participants were stratified into quintiles according to baseline TC, HDL-C, LDL-C and TC/HDL-C. The association between mortality and each lipid profile was evaluated using multivariate Cox regression analysis. During a median follow-up period of 70.3 ± 25.2 months, 185 deaths were recorded. The highest TC/HDL-C group had the highest body mass index, percentage of diabetes and serum albumin level. Multivariate analysis demonstrated that the highest quintile of TC/HDL-C was associated with increased risk of all-cause mortality (hazard ratio 1.69, 95% confidence interval 1.04–2.76; p = 0.036), whereas TC, HDL-C and LDL-C were not associated with mortality. Linear regression analysis showed a positive correlation between TC/HDL-C and body mass index. Increased serum TC/HDL-C was an independent risk factor for mortality in the subgroup of old age, female, cardiovascular disease and low HDL-C. The single lipid marker of TC or HDL-C was not able to predict mortality in PD patients. However, increased serum TC/HDL-C was independently associated with all-cause mortality in PD patients.     

Flat Pattern Peaks of Tacrolimus Absorption and Associated Pharmacogenomic Variants in Kidney Transplantation Recipients

BackgroundTacrolimus is the most commonly used immunosuppressive drug in solid organ transplantation. After administering a conventional twice-daily dose of tacrolimus, peak levels were achieved within the first 1.5 to 2 hours. A group of patients showed different early absorption phase of tacrolimus after kidney transplantation.MethodsTrough(C₀) and 1.5-hour blood levels (C_1.5) of tacrolimus were measured in 95 kidney transplantation recipients. Patients with a C_1.5/C₀ < 1.5 and > 1.5 were defined as those having flat pattern peaks and as controls, respectively. Transplantation outcomes were compared between the groups. Whole exome sequencing was performed to investigate the genetic susceptibility to flat pattern peaks.ResultsTwenty-eight patients showed flat pattern peaks. The mean C_1.5/C₀ values were 1.13 ± 0.22 and 3.78 ± 1.25 in the flat pattern peak and control groups, respectively. In multivariate analysis, flat pattern peak was an independent risk factor for biopsy-proven acute rejection (BPAR) and/or borderline change (P = 0.014). Patients having flat pattern peaks showed significantly lower post-transplant 36-month estimated glomerular filtration rate (P = 0.001). Two single nucleotide variants in ABCB1 genes, rs1922242 and rs2235035, were associated with flat pattern peaks (P = 0.019 and P = 0.027, respectively).ConclusionBoth of C_1.5 and C₀ should be measured to distinguish the patients showing unique initial absorption. A C_1.5/C₀ ratio lower than 1.5 was associated with an increased risk of BPAR and/or borderline change. Single nucleotide variants s in ABCB1 gene might influence the flat pattern peaks of tacrolimus absorption.