Structural characterization of the Plasmodium falciparum lactate transporter PfFNT alone and in complex with antimalarial compound MMV007839 reveals its inhibition mechanism.

Plasmodium falciparum, the deadliest causal agent of malaria, caused more than half of the 229 million malaria cases worldwide in 2019. The emergence and spreading of frontline drug-resistant Plasmodium strains are challenging to overcome in the battle against malaria and raise urgent demands for novel antimalarial agents. The P. falciparum formate-nitrite transporter (PfFNT) is a potential drug target due to its housekeeping role in lactate efflux during the intraerythrocytic stage. Targeting PfFNT, MMV007839 was identified as a lead compound that kills parasites at submicromolar concentrations. Here, we present 2 cryogenic-electron microscopy (cryo-EM) structures of PfFNT, one with the protein in its apo form and one with it in complex with MMV007839, both at 2.3 Å resolution. Benefiting from the high-resolution structures, our study provides the molecular basis for both the lactate transport of PfFNT and the inhibition mechanism of MMV007839, which facilitates further antimalarial drug design.

Epidemiology of Vancomycin in Combination With Piperacillin/Tazobactam-Associated Acute Kidney Injury in Children: A Systematic Review and Meta-analysis.

BACKGROUND: Several studies have shown that vancomycin combined with piperacillin/tazobactam (VPT) increased the risk of acute kidney injury (AKI) compared with other antibiotics in children. However, the epidemiology of VPT-associated AKI in children is unknown. OBJECTIVE: To evaluate the incidence and risk factors of VPT-associated AKI in children. DATA SOURCES: Literature databases of PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), VIP Database, WanFang Database, and China Biology Medicine Disc were searched from inception to November 2023. References of included studies were also manually checked. STUDY SELECTION AND DATA EXTRACTION: Two independent reviewers selected studies, extracted data, and quality assessment. Meta-analyses were performed to quantify the incidence and risk factors of VPT-associated AKI in children. DATA SYNTHESIS: Sixteen cohort studies were identified. Overall, the incidence of VPT-associated AKI in children was 24.3% (95% CI: 17.9%-30.6%). The incidence of VPT-associated AKI in critically ill children (26.6%) was higher than that in noncritically ill children (10.9%). Moreover, higher serum vancomycin trough concentration (>15 mg/L), use of vasopressors, combination of nephrotoxins and intensive care unit admission were risk factors for VPT-associated AKI in children (P < 0.05). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Identifying high-risk groups and determining safer treatments is critical to reducing the incidence of VPT-associated AKI in children. CONCLUSIONS: The incidence of VPT-associated AKI in children is high, especially in critically ill children. Medication regimens should be personalized based on the presence of individual risk factors. Moreover, renal function was regularly assessed throughout treatment with VPT.

The reference range of lamotrigine in the treatment of epilepsy in children: a systematic review.

PURPOSE: This study intends to assess the reference range of lamotrigine concentration for treating childhood epilepsy. METHODS: PubMed, Ovid-Embase, The Cochrane Library, CNKI, WanFang data and VIP databases were searched from database inception to January 2022. RCT, cohort study, case-control study, cross-sectional study that estimated the reference range of lamotrigine for children epilepsy treatment were included. The data extracted included basic information, statistical methods, data type, and results of reference range. Descriptive analysis was performed for them. RESULTS: 8 studies were included and estimated the reference range, and all of them were calculated based on efficacy data and/or concentration data. Statistical methods including ROC curve, concentration-effect curve, mean ± standard deviation, 95% confidence interval and percentile interval were utilized. For lamotrigine monotherapy, the lower limits ranged from 2.06 mg/L to 3.99 mg/L, and the upper limits ranged from 8.43 mg/L to 9.08 mg/L, showing basic consistency. However, for lamotrigine concomitant with valproate, the lower limits ranged from 2.00 mg/L to 8.00 mg/L, and the upper limit was 11.50 mg/L, for lamotrigine concomitant with other antiepileptics, the lower limits ranged from 1.00 mg/L to 3.09 mg/L, and the upper limits varied from 5.90 mg/L to 16.24 mg/L, indicating inconsistency. CONCLUSION: Several studies have estimated the reference range of lamotrigine for childhood epilepsy, while controversy exist and no studies have determined the upper limit of the range based on safety data. To establish the optimal reference range, further high-quality studies are necessary that consider both efficacy and safety data.

Assessment of Right Ventricular-Arterial Coupling by Echocardiography in Patients with Right Ventricular Pressure and Volume Overload.

Background: Right ventricle-pulmonary arterial (RV-PA) coupling is considered the gold standard for assessing right ventricular (RV) function and can be evaluated noninvasively by echocardiography. The ratios of tricuspid annular plane systolic excursion/pulmonary artery systolic pressure (TAPSE/PASP), RV global longitudinal strain (G-RVLS)/PASP, and stroke volume/end-systolic volume (SV/ESV) have been proposed as surrogates of RV-PA coupling. The relationship of these parameters remains incompletely understood in patients with volume and pressure loading conditions. We aimed to compare these parameters and evaluate their relationship with 3D RV data in patients with RV pressure and volume overload. Methods: This study was performed on 110 individuals who underwent 2D and 3D echocardiography. Fifty-four patients had RV volume overload (atrial septal defect (ASD) group), 34 patients had RV pressure overload (pulmonary hypertension (PH) group), and 22 were controls. TAPSE/PASP, G-RVLS/PASP and SV/ESV ratios were calculated. Correlations between parameters of RV-PA coupling and 3D data were assessed using general linear mixed models. Results: Compared with the ASD group, the PH group had lower TAPSE/PASP and G-RVLS/PASP ratios. The SV/ESV ratio had a strong correlation with right ventricle ejection fraction (RVEF) in both ASD and PH patients (r = 0.8703, p < 0.001 and r = 0.9388, p < 0.001, respectively). The G-RVLS/PASP ratio showed a strong or moderately negative relationship with end-diastolic volume (EDV), ESV and SV (r = -0.7768, p = 0.001; r = -0.7327, p = 0.0005 and r = -0.6816, p = 0.0018, respectively) in PH patients. The TAPSE/PASP ratio showed moderately negative correlations with EDV and ESV (r = -0.5712, p = 0.0012 and r = -0.5594, p = 0.0016, respectively) in PH patients. Conclusions: Non-invasive RV-PA coupling parameters derived from echocardiography appear similar, but not identical to profiles in pressure-overloaded and volume-overloaded patients. The correlations between non-invasive RV-PA coupling parameters and 3D data displayed various degrees of correlation.

Incidence and risk factors of drug-induced kidney injury in children: a systematic review and meta-analysis.

PURPOSE: To comprehensively summarize the incidence and risk factors of drug-induced kidney injury (DIKI) in children. METHODS: We systematically searched seven databases from inception to November 2022. Two independent reviewers selected studies, extracted data, and assessed the risk of bias. Meta-analyses were conducted to quantify the incidence and risk factors of DIKI in children. RESULTS: A total of 69 studies comprising 195,894 pediatric patients were included. Overall, the incidence of DIKI in children was 18.2% (95%CI: 16.4%-20.1%). The incidence of DIKI in critically ill children (19.6%, 95%CI: 15.9%-23.3%) was higher than that in non-critically ill children (16.1%, 95%CI: 12.9%-19.4%). Moreover, the risk factors for DIKI in children were intensive care unit (ICU) admission (OR = 1.59, 95% CI: 1.42-1.78, P = 0.000), treatment days (OR = 1.04, 95% CI: 1.03-1.05, P = 0.000), surgical intervention (OR = 1.43, 95% CI: 1.00-2.02, P = 0.048), infection (OR = 2.30, 95% CI: 1.44-3.66, P = 0.000), patent ductus arteriosus (OR = 4.78, 95% CI: 1.82-12.57, P = 0.002), chronic kidney disease (OR = 2.78, 95% CI: 1.92-4.02, P = 0.000), combination with antibacterial agents (OR = 1.98, 95% CI: 1.54-2.55, P = 0.000), diuretics (OR = 1.97, 95% CI: 1.51-2.56, P = 0.000), combination with antiviral agents (OR = 1.50, 95% CI: 1.11-2.04, P = 0.008), combination with non-steroidal anti-inflammatory drugs (OR = 1.79, 95% CI: 1.40-2.28, P = 0.000), and combination with immunosuppressive agents (OR = 2.84, 95% CI: 1.47-5.47, P = 0.002). CONCLUSION: The incidence of DIKI in children is high, especially in critically ill children. Identifying high-risk groups and determining safer treatments is critical to reducing the incidence of DIKI in children. In clinical practice, clinicians should adjust medication regimens for high-risk pediatric groups, such as ICU admission, some underlying diseases, combination with nephrotoxic drugs, etc., and regularly evaluate kidney function throughout treatment.

Drug-associated kidney injury in children: a disproportionality analysis of the FDA Adverse Event Reporting System.

Drug-associated kidney injury is related to longer hospitalization and increased risk of chronic kidney disease and mortality. However, there is currently a lack of large population studies on drug-associated kidney injury in children. This study aimed to study perform data mining to generate hypotheses on drugs, which may deserve to be assessed as per their potential risk of increasing kidney injury in children. We extracted and analyzed reports on drugs associated with kidney injury in children in the FDA Adverse Event Reporting System (FAERS). We conducted a disproportionality analysis using proportional reporting ratio (PRR) to evaluate the association between drugs and kidney injury in children. Meanwhile, comparisons were performed with drug labels to identify drugs that, despite not having kidney injury currently mentioned in their labels, may potentially be associated with risks of kidney injury in children. A total of 6347 children had drug-associated kidney injury in the FAERS database. The top five drugs with the highest PRR were gentamicin (PRR = 12.28, N = 157 cases, Chi-Squared = 1602.77), piperacillin-tazobactam (PRR = 9.77, N = 129 cases, Chi-Squared = 1003.24), amlodipine (PRR = 8.98, N = 271 cases, Chi-Squared = 1861.46), vancomycin (PRR = 8.91, N = 295 cases, Chi-Squared = 1998.64), and ceftriaxone (PRR = 8.00, N = 251 cases, Chi-Squared = 1494.02). According to drug labels, 9 drugs (9/30) were classified as potential nephrotoxins. CONCLUSIONS: Approximately one-third of drugs associated with kidney injury in children do not list kidney injury as a side effect in their drug labels. Future studies are therefore warranted to evaluate whether these drugs are associated with such a risk. WHAT IS KNOWN: • Nephrotoxic drugs are an increasingly common cause of acute kidney injury in hospitalized children. • Currently, no study has systematically combed drugs associated with kidney injury in children. WHAT IS NEW: • Approximately a third of drugs showing signals for potential kidney injury in children in data mining do not mention this side effect in their drug labels. • This study provides data on drugs needing further study to determine whether they might increase the risk of kidney injury in children.

Global, regional and national availability of essential medicines for children, 2009-2020: a systematic review and meta-analysis.

BACKGROUND: Access to essential medicines is a vital component of universal health coverage. The low availability of essential medicines for children (EMC) has led the World Health Organization (WHO) to issue a number of resolutions calling on member states on its improvement. But its global progress has been unclear. We aimed to systematically evaluate the progress of availability of EMC over the past decade across economic regions and countries. METHODS: We searched eight databases from inception to December 2021 and reference lists to identify included studies. Two reviewers independently conducted literature screening, data extraction and quality evaluation. This study was registered with PROSPERO, CRD42022314003. RESULTS: Overall, 22 cross-sectional studies covering 17 countries, 4 income groups were included. Globally, the average availability rates of EMC were 39.0% (95%CI: 35.5-42.5%) in 2009-2015 and 43.1% (95%CI: 40.1-46.2%) in 2016-2020. Based on the World Bank classification of economic regions, income was not proportional to availability. Nationally, the availability rate of EMC was reasonable and high (> 50%) in only 4 countries, and low or very low for the rest 13 countries. The availability rates of EMC in primary healthcare centers had increased, while that for other levels of hospitals slightly declined. The availability of original medicines decreased while that of generic medicines was stable. All drug categories had not achieved the high availability rate. CONCLUSION: The availability rate of EMC was low globally, with slight increase in the last decade. Continuous monitoring and timely reporting of the availability of EMC are also needed to facilitate targets setting and inform relevant policy making.

Comparison of the effects of ketamine via nebulization versus different pharmacological approaches in pediatric sedation: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Nebulized drug delivery is commonly used in pediatric clinical practice. The growing number of literatures have reported the application of nebulized ketamine in pediatric sedation in recent years. This meta-analysis of randomized controlled trials comparing the efficacy and safety of nebulized ketamine versus different pharmacological approaches was conducted to estimate the effects of this technique in pediatric sedation. METHODS: We searched PubMed, Embase, and Cochrane Library from inception to Feb 2023. All randomized controlled trials used nebulized ketamine as presurgical and pre-procedural sedatives in children were included. Sedative effects and various adverse events were considered as the outcomes. RESULTS: Ten studies with 727 pediatric patients were enrolled. Compared to nebulized dexmedetomidine, using of ketamine via nebulization showed similar sedation satisfaction (54.79% vs. 60.69%, RR = 0.88, with 95%CI [0.61, 1.27]), success rate of parental separation (57.27% vs. 73.64%, RR = 0.81, with 95%CI [0.61, 1.08]), and mask acceptability (37.27% vs. 52.73%, RR = 0.71, with 95%CI [0.45, 1.10]). However, the using of combination of two medications (nebulized ketamine plus nebulized dexmedetomidine) was associated with better sedative satisfaction (33.82% vs. 68.11%, RR = 0.50, with 95%CI [0.27, 0.92]) and more satisfactory mask acceptance (45.59% vs. 71.01%, RR = 0.69, with 95%CI [0.56, 0.86]). Compared with nebulized ketamine, using of nebulized dexmedetomidine was associated with less incidence of emergence agitation (18.18% vs. 3.33%, RR = 4.98, with 95%CI [1.88, 13.16]). CONCLUSIONS: Based on current evidences, compared to nebulized dexmedetomidine, nebulized ketamine provides inconspicuous advantages in pediatric sedation, and it has a relatively high incidence of emergence agitation. Combination of nebulized ketamine and dexmedetomidine might be considered as one preferred option in pediatric sedation as it can provide more satisfactory sedative effects. However, there is insufficient evidence regarding nebulized ketamine versus ketamine administered through other routes and nebulized ketamine versus other sedatives. The overall low or moderate quality of evidence evaluated by the GRADE system also calls for more high-quality studies with larger sample sizes in future. RESEARCH REGISTRATION: The protocol of present study was registered with PROSPERO (CRD42023403226).

Liver injury in children: signal analysis of suspected drugs based on the food and drug administration adverse event reporting system.

BACKGROUND: Evidence of drug-induced liver injury is abundant in adults but is lacking in children. Our aim was to identify suspected drug signals associated with pediatric liver injury. METHODS: Hepatic adverse events (HAEs) among children reported in the Food and Drug Administration Adverse Event Reporting System were analyzed. A descriptive analysis was performed to summarize pediatric HAEs, and a disproportionality analysis was conducted by evaluating reporting odds ratios (RORs) and proportional reporting ratios to detect suspected drugs. RESULTS: Here, 14,143 pediatric cases were reported, specifically 49.6% in males, 45.1% in females, and 5.2% unknown. Most patients (68.8%) were 6-18 years old. Hospitalization ranked first among definite outcomes (7,207 cases, 37.2%). In total, 264 disproportionate drug signals were identified. The top 10 drugs by the number of reports were paracetamol (1,365; ROR, 3.6; 95% confidence interval (CI), 3.4-3.8), methotrexate (878; ROR, 2.5; 95% CI, 2.3-2.7), vincristine (649; ROR, 3.0; 95% CI, 2.8-3.3), valproic acid (511; ROR, 3.2; 95% CI, 2.9-3.6), cyclophosphamide (490; ROR, 2.4; 95% CI, 2.2-2.6), tacrolimus (427; ROR, 2.4; 95% CI, 2.2-2.7), prednisone (416; ROR, 2.1; 95% CI, 1.9-2.3), prednisolone (401; ROR, 2.3; 95% CI, 2.1-2.5), etoposide (378; ROR, 2.3; 95% CI, 2.1-2.6), and cytarabine (344; ROR, 2.8; 95% CI, 2.5-3.2). After excluding validated hepatotoxic drugs, six were newly detected, specifically acetylcysteine, thiopental, temazepam, nefopam, primaquine, and pyrimethamine. CONCLUSIONS: The hepatotoxic risk associated with 264 signals needs to be noted in practice. The causality of hepatotoxicity and mechanism among new signals should be verified with preclinical and clinical studies.

Palladium-Catalyzed Inverse and Normal Dehydrogenative Aza-Morita-Baylis-Hillman Reactions with γ,δ-Unsaturated Compounds.

σ-Lewis base-catalyzed regio- and enantioselective aza-Morita-Baylis-Hillman (MBH) reaction of α,ß,γ,δ-unsaturated systems remains a challenge due to the intrinsic covalent activation mode. Here we demonstrate that a Pd0 complex can mediate the dehydrogenative reaction of γ,δ-unsaturated compounds to give corresponding electron-poor dienes, which further undergo δ-regioselective umpolung Friedel-Crafts-type addition to imines via auto-tandem Pd0 -π-Lewis base catalysis. After ß-H elimination of in situ formed PdII -complexes, unprecedented and chemically inverse aza-MBH-type adducts are finally furnished with fair to outstanding enantioselectivity, and a diversity of functional groups and both ketimine and aldimine acceptors can be well tolerated. Moreover, switchable α-regioselective normal aza-MBH-type reaction also can be realized by tuning catalytic conditions, whereas moderate to good enantioselectivity with low to excellent Z/E-selectivity is attained.

An Enzymatic Platform for Primary Amination of 1-Aryl-2-alkyl Alkynes.

Propargyl amines are versatile synthetic intermediates with numerous applications in the pharmaceutical industry. An attractive strategy for efficient preparation of these compounds is nitrene propargylic C(sp3)-H insertion. However, achieving this reaction with good chemo-, regio-, and enantioselective control has proven to be challenging. Here, we report an enzymatic platform for the enantioselective propargylic amination of alkynes using a hydroxylamine derivative as the nitrene precursor. Cytochrome P450 variant PA-G8 catalyzing this transformation was identified after eight rounds of directed evolution. A variety of 1-aryl-2-alkyl alkynes are accepted by PA-G8, including those bearing heteroaromatic rings. This biocatalytic process is efficient and selective (up to 2610 total turnover number (TTN) and 96% ee) and can be performed on preparative scale.

Combined 18F-FDG and 18F-Alfatide II PET May Predict Luminal B (HER2 Negative) Subtype and Nonluminal Subtype of Invasive Breast Cancer.

Noninvasive PET molecular imaging using radiopharmaceuticals is important to classify breast cancer in the clinic. The aim of this study was to investigate the combination of 18F-FDG and 18F-Alfatide II for predicting molecular subtypes of invasive breast cancer. Forty-four female patients with clinically suspected breast cancer were recruited and underwent 18F-FDG and 18F-Alfatide II PET/CT within a week. Tracer uptake in breast lesions was assessed using the maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), and SUVmax ratio of 18F-FDG to 18F-Alfatide II (FAR). Invasive breast cancer lesions were further classified as luminal A subtype, luminal B subtype, human epidermal growth factor receptor-2 (HER2) overexpressing subtype, and triple negative subtype according to the expression of the estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki-67. Among 44 patients, 35 patients were pathologically diagnosed with invasive breast cancer. The SUVmax and SUVmean of 18F-FDG were significantly higher in the ER-negative group than those in the ER-positive group, as well as in the PR-negative group than those in the PR-positive group. However, the SUVmax and SUVmean of 18F-Alfatide II were higher in the ER-positive group and the PR-positive group. By combining 18F-FDG and 18F-Alfatide II, the FAR was lower in the ER-positive group and the PR-positive group. The HER2 overexpressing subtype showed the highest SUVmax and SUVmean for 18F-FDG while the luminal B (HER2 negative) subtype revealed the lowest values. The luminal B (HER2 negative) subtype showed the highest 18F-Alfatide II SUVmax, while the triple negative subtype showed the lowest 18F-Alfatide II SUVmax. The FAR was the lowest in the luminal B (HER2 negative) subtype and much higher in the HER2 overexpressing and triple negative subtypes. FAR less than 1 predicted the luminal B (HER2 negative) subtype with high specificity (93.1%) and NPV (90%). FAR greater than 3 predicted the HER2 overexpressing subtype and triple negative subtype (namely, the nonluminal subtype) with very high specificity (100%) and PPV (100%). In summary, FAR, the combined PET parameter of 18F-FDG and 18F-Alfatide II, can be used to predict molecular subtypes of invasive breast cancer, especially for the luminal B (HER2 negative) subtype and the nonluminal subtype.

Efficacy and safety of intranasal midazolam versus intranasal ketamine as sedative premedication in pediatric patients: a meta-analysis of randomized controlled trials.

BACKGROUND: Intranasal midazolam and ketamine have been widely used as sedative premedication in children. It is difficult to determine which one yields better sedative effects for clinical practice. We conducted the present meta-analysis by summarizing the evidences to evaluate the efficacy and safety of intranasal midazolam versus intranasal ketamine as sedative premedication in pediatric patients. METHODS: We searched PubMed, Embase, and Cochrane Library from inception to April 2022. All randomized controlled trials (RCTs) used intranasal midazolam and ketamine as sedatives in children were enrolled. The risk of bias in RCTs was assessed by Cochrane risk of bias tool. Condition of parental separation, anesthesia induction or facemask acceptance, sedation level, different hemodynamic parameters and adverse events were considered as the outcomes in our study. RESULTS: A total of 16 studies with 1066 patients were enrolled. Compared with midazolam, administration of intranasal ketamine might be associated with severer changes in hemodynamics parameters including mean blood pressure (SMD = -0.53, with 95% CI [-0.93, -0.13]) and heart rate (HR) (SMD = -1.39, with 95% CI [-2.84, 0.06]). Meanwhile, administration of intranasal midazolam was associated with more satisfactory sedation level (61.76% vs 40.74%, RR = 1.53, with 95%CI [1.28, 1.83]), more rapid onset of sedation (SMD = -0.59, with 95%CI [-0.90, -0.28]) and more rapid recovery (SMD = -1.06, with 95%CI [-1.83, -0.28]). Current evidences also indicated that the differences of various adverse effects between two groups were not significant. CONCLUSIONS: Given that administration of midazolam via intranasal route provides more satisfactory sedative level with less fluctuation of hemodynamics parameters and more rapid onset and recovery, it might be considered as the preferred sedative premedication for pediatric patients compared to ketamine. However, the widespread evidences with low or moderate quality indicated that superiority of intranasal midazolam in pediatric sedation needs to be confirmed by more studies with high quality and large sample size in future. TRIAL REGISTRATION: The protocol of present study was registered with PROSPERO (CRD42022321348).

Efficacy and safety of sugammadex for neuromuscular blockade reversal in pediatric patients: an updated meta-analysis of randomized controlled trials with trial sequential analysis.

BACKGROUND: A recent survey revealed that extensive off-label use of sugammadex in pediatric anesthesia deserved particular attention. The present study with trial sequential analysis (TSA) aimed to evaluate the effects of sugammadex for antagonizing neuromuscular blockade (NMB) in pediatric patients, and to investigate whether the findings achieved the required information size to draw conclusions. METHODS: PubMed, Embase, Cochrane Library and China National Knowledge Infrastructure (CNKI) were searched from inception to April 2021. All randomized controlled trials used sugammadex as reversal agent in pediatric patients were enrolled. Time from NMB reversal to recovery of the train-of-four ratio (TOFr) to 0.9 and extubation time were considered as co-primary outcomes, and incidences of adverse events were considered as secondary outcomes. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used to rate the quality of evidences. RESULTS: Data from 18 studies involving 1,065 pediatric patients were acquired. The results revealed that use of sugammadex was associated with shorter duration from administration of reversal agents to TOFr > 0.9 (MD = -14.42, with 95% CI [-17.08, -11.75]) and shorter interval from reversal from NMB to extubation (MD = -13.98, with 95% CI [-16.70, -11.26]) compared to control groups. TSA also indicated that the current sample sizes were sufficient with unnecessary further trials. Analysis of secondary outcomes indicated that administration of sugammadex was associated with less incidence of postoperative nausea and vomiting (PONV), bradycardia, and dry mouth compared to control groups. CONCLUSION: Considering of satisfactory and rapid neuromuscular blockade reversal with low incidences of adverse events, sugammadex might be considered as the preferred option for children in clinical anesthesia practice compared to acetylcholinesterase inhibitors. However, overall low-quality evidences in present study rated by GRADE system indicated that superiority of sugammadex employed in pediatric patients needs to be confirmed by more studies with high quality and large sample size in future.

Enzymatic Primary Amination of Benzylic and Allylic C(sp3)-H Bonds.

Aliphatic primary amines are prevalent in natural products, pharmaceuticals, and functional materials. While a plethora of processes are reported for their synthesis, methods that directly install a free amine group into C(sp3)-H bonds remain unprecedented. Here, we report a set of new-to-nature enzymes that catalyze the direct primary amination of C(sp3)-H bonds with excellent chemo-, regio-, and enantioselectivity, using a readily available hydroxylamine derivative as the nitrogen source. Directed evolution of genetically encoded cytochrome P411 enzymes (P450s whose Cys axial ligand to the heme iron has been replaced with Ser) generated variants that selectively functionalize benzylic and allylic C-H bonds, affording a broad scope of enantioenriched primary amines. This biocatalytic process is efficient and selective (up to 3930 TTN and 96% ee), and can be performed on preparative scale.

Enantioselective Aminohydroxylation of Styrenyl Olefins Catalyzed by an Engineered Hemoprotein.

Chiral 1,2-amino alcohols are widely represented in biologically active compounds from neurotransmitters to antivirals. While many synthetic methods have been developed for accessing amino alcohols, the direct aminohydroxylation of alkenes to unprotected, enantioenriched amino alcohols remains a challenge. Using directed evolution, we have engineered a hemoprotein biocatalyst based on a thermostable cytochrome c that directly transforms alkenes to amino alcohols with high enantioselectivity (up to 2500 TTN and 90 % ee) under anaerobic conditions with O-pivaloylhydroxylamine as an aminating reagent. The reaction is proposed to proceed via a reactive iron-nitrogen species generated in the enzyme active site, enabling tuning of the catalyst's activity and selectivity by protein engineering.

Catalytic Enantioselective Synthesis of a Pyrrolizidine-Alkaloid-Inspired Compound Collection with Antiplasmodial Activity.

A novel enantioselective approach to the synthesis of a compound collection inspired by natural pyrrolizidine alkaloids was developed, employing an enantioselectively catalyzed 1,3-dipolar cycloaddition as the key step. The cycloadducts were obtained with excellent enantio- and diastereoselectivity. Biological evaluation of the resulting compound collection revealed that the compound class has multiple bioactivities, including activity against Plasmodium falciparum 3D7 and inhibition of Hedgehog signaling.

Enantioselective Synthesis of the Spirotropanyl Oxindole Scaffold through Bimetallic Relay Catalysis.

Spirotropanyl oxindole alkaloids like alstonisine and chitosenine show a wide range of bioactivites. We report the first enantioselective synthesis of the spirotropanyl oxindole scaffold by means of a bimetallic relay catalysis strategy. A new class of E-oximino α-diazo ketones was developed for the intramolecular generation of transient azomethine ylides catalyzed by an achiral RhII complex and a subsequent intermolecular 1,3-dipolar cycloaddition catalyzed by a chiral N,N'-dioxide NdIII Lewis acid complex. The enantioselectively catalyzed transformation has broad scope and yields the desired spirotropanyl oxindole cycloadducts in high yields and with very high enantio- and diastereoselectivity.

Fischer-Tropsch synthesis. Evaluation of an aluminum small channel reactor.

Fischer-Tropsch synthesis was conducted in a small channel compact heat exchange reactor that was constructed of aluminum. While limited to lower temperature-pressure regions of the Fischer-Tropsch synthesis, the reactor could be operated in an isothermal mode with nearly a constant temperature along the length of the channel. The results obtained with the compact heat exchange reactor were similar to those obtained in the isothermal continuous stirred tank reactor, with respect to both activity and selectivity. Following a planned or unplanned shutdown, the reactor could be restarted to produce essentially the same catalytic activity and selectivity as before the shutdown.

Association Between 25-Hydroxyvitamin D and Epicardial Adipose Tissue in Chinese Non-Obese Patients with Type 2 Diabetes.

BACKGROUND Epicardial adipose tissue (EAT) is recognized as a useful indicator for type 2 diabetes mellitus (T2DM) and obesity. However, studies on the association between vitamin D status and EAT thickness in type 2 diabetes (T2D) are limited. In this study, we aimed to evaluate the association of vitamin D (Calcifediol) status and EAT thickness (EATT) in Chinese non-obese patients with T2D. MATERIAL AND METHODS A cross-sectional study was performed among 167 non-obese T2D Chinese patients and 82 non-diabetic patients, who are age- and gender-matched during the winter months. EATT was evaluated by two-dimensional transthoracic echocardiography. Serum 25-hydroxyvitamin D [25(OH)D, Calcifediol] was examined in the diabetic patients and in the control group. RESULTS The concentration of 25(OH)D was 32.00 nmol/l (19.30-53.70 nmol/l) among diabetic patients. Most (93.4%) of the diabetic patients had hypovitaminosis D. We confirmed a clear negative association between 25(OH)D level and EATT in non-obese T2D patients (p=0.01). EATT was significantly correlated with 25(OH)D level (p=0.001) and HOMA-IR (p=0.001). Results of multivariate logistic regression analysis demonstrated increased EATT, which was remarkably associated with 25(OH)D levels (p=0.039), systolic blood pressure (SBP) (p=0.013), HOMA-IR (p=0.030), and waist circumference (p<0.001) in T2D patients after adjusting for the confounding factors. CONCLUSIONS Increased EATT was found in Chinese T2D patients with normal BMI. 25(OH)D and HOMA-IR were independently associated with increased EATT after adjusting for multiple confounders.